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WO2018156777A1 - Anticorps bispécifiques anti-pd-1/tim -3, compositions de ceux-ci, et procédés de fabrication et d'utilisation de ceux-ci - Google Patents

Anticorps bispécifiques anti-pd-1/tim -3, compositions de ceux-ci, et procédés de fabrication et d'utilisation de ceux-ci Download PDF

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WO2018156777A1
WO2018156777A1 PCT/US2018/019248 US2018019248W WO2018156777A1 WO 2018156777 A1 WO2018156777 A1 WO 2018156777A1 US 2018019248 W US2018019248 W US 2018019248W WO 2018156777 A1 WO2018156777 A1 WO 2018156777A1
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seq
cdr
sequence
region
nos
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PCT/US2018/019248
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Ryan STAFFORD
Alice Yam
Stephanie ARMSTRONG
John Lee
Alexander Steiner
Junhao Yang
Christine Cheng
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Sutro Biopharma, Inc.
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Priority to US16/487,806 priority Critical patent/US20200190192A1/en
Priority to EP18713075.2A priority patent/EP3585813A1/fr
Publication of WO2018156777A1 publication Critical patent/WO2018156777A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • antibodies with dual binding specificity for T cell immunoglobulin domain- and mucin domain-containing molecule 3 (Tim-3) and for programmed cell death protein (PD-1 or PD1) also referred to as PD-l/Tim-3 bi-specific antibodies.
  • antibodies with binding specificity for PD-1 or Tim-3 also referred to as PD-l/Tim-3 bi-specific antibodies.
  • compositions comprising the antibodies, including pharmaceutical compositions, diagnostic compositions, and kits.
  • methods of making the bi-specific antibodies, and methods of using the bi-specific antibodies for example, for therapeutic purposes, diagnostic purposes, and research purposes.
  • Tim-3 is a cell surface protein molecule that belongs to the immunoglobulin superfamily. It is expressed as a transmembrane protein on differentiated type 1 T helper lymphocytes (Thl cells). See Monney et al., Nature 2002, 415:536-541.
  • the Tim-3 protein contains an immunoglobulin variable-like domain and a mucin-like domain. See id.
  • a mouse model of autoimmune disease experimental autoimmune encephalomyelitis, antibodies to Tim-3 were shown to increase the number and activation of macrophages, and to enhance clinical and pathologic severity. See id. From this, it has been proposed that Tim-3 is a regulator of immune function. See id.
  • Tim-3 is constitutively expressed on cells of the innate immune system and can regulate Thl immunity. Anderson et al, 2007, Science 318: 1141-3. Tim-3 has been shown to negatively regulate Thl cells in several studies. See Sabatos et al., Nature Immunol. 4: 1102-110; Sanchez-Fueyo et al., 2003, Nature Immunol. 4: 1093-1101 ; Sakuishi et al, 2010, J. Exp. Med. 207:2187-2194. Galectin-9 and CEACAM1 have been proposed as ligands for Tim-3. Zhu et al., 2005, Nature Immunol. 6: 1245-1252; Huang et al, 2015, Nature 517:386-390.
  • Tim-3 has been proposed as a target for cancer therapeutics. See, e.g., Anderson, 2014, Cancer Immunol. Res. 2:393-397. It has been shown that cancer cells can use immune checkpoint regulators such as Tim-3 to suppress the immune response against themselves. See id. Therapeutics that block other checkpoint regulators such as CTLA-4 have proved successful in treating certain cancers. See id. Indeed, target Tim-3 has shown promise for therapies in models of sarcoma, fibrosarcoma, prostate cancer, colon carcinoma, melanoma, and leukemia.
  • PD-1 Programmed cell death protein 1
  • CD279 Programmed cell death protein 1
  • PD 1 is a cell surface protein molecule that belongs to the immunoglobulin superfamily. It is expressed on T and B lymphocytes and macrophages, and plays a role in cell fate and differentiation. See Ishida et al, EMBO J. , 1992, 1 1 :3887-3895, incorporated by reference in its entirety. Activation of PD-1 is thought to negatively regulate the immune response. See Blank et al, Cancer Immunol. Immunother. , 2007, 56:739-745; and Freeman et al, J. Exp. Med. , 2000, 192: 1027-1034, each of which is incorporated by reference in its entirety.
  • PD-1 has two known ligands, PD-L1 and PD-L2, which are both members of the B7 family. See Freeman et al, supra; and Latchman et al, Nat. Immunol , 2001, 2:261 - 268, each of which is incorporated by reference in its entirety. The interaction between PD-1 and these ligands is thought to play a role in a variety of diseases, including cancer ⁇ see Ribas and Tumeh, Clin. Cancer Res.
  • Tim-3 In view of the role of PD-1 and Tim-3 in multiple disease processes, there is a need for methods of modulating the immune regulation and downstream signaling processes activated by both Tim-3 and PD-1. There is also a need for therapeutics that can specifically target cells and tissues that express Tim-3 and/or PD-1.
  • the antibodies that selectively bind Tim-3.
  • the antibodies bind human Tim-3.
  • the antibodies also bind homologs of human Tim-3.
  • the homologs include a cynomolgus monkey homolog.
  • antibodies that selectively bind PD-1 are also provided herein.
  • the antibodies bind human PD-1.
  • the antibodies also bind homologs of human PD-1.
  • the homologs include a cynomolgus monkey homolog.
  • bi-specific antibodies or bi-specific antibody constructs that comprise a first binding domain that selectively binds Tim-3, including human Tim-3 or a homolog thereof, and a second binding domain that selectively binds PD-1, including human PD-1 or a homolog thereof.
  • the antibodies comprise at least one CDR sequence defined by a consensus sequence provided in this disclosure.
  • the antibodies comprise an illustrative CDR, VH, or VL sequence provided in this disclosure, or a variant thereof.
  • the variant is a variant with one or more conservative amino acid substitutions.
  • compositions and kits comprising the antibodies.
  • the compositions are pharmaceutical compositions. Any suitable pharmaceutical composition may be used.
  • the pharmaceutical composition is a composition for parenteral administration.
  • the method is a method of treatment. In some embodiments, the method is a diagnostic method. In some embodiments, the method is an analytical method. In some embodiments, the method is a method of purifying and/or quantifying Tim-3.
  • the antibodies are used to treat a disease or condition.
  • the disease or condition is selected from a cancer, autoimmune disease, and infection.
  • FIG. 1 provides a comparison of the Kabat and Chothia numbering systems for CDR-H1. Adapted from Martin A.C.R. (2010). Protein Sequence and Structure Analysis of Antibody Variable Domains. In R. Kontermann & S. Diibel (Eds.), Antibody Engineering vol. 2 (pp. 33-51). Springer-Verlag, Berlin Heidelberg.
  • FIG. 2 (A, B) provides alignments of the VH sequences (SEQ ID NOs: 144-
  • VL sequences SEQ ID NOs: 221-227
  • CDRs according to Chothia are boxed, and CDRs according to Kabat are underlined.
  • FIG. 3 (A, B) provides an alignment of the VH sequences (SEQ ID NO:
  • FIG. 4 is a graph that illustrates dose-response activity for IFN- ⁇ in peripheral blood mononuclear cells (PBMCs) isolated from CMV -positive human donors. The activity resulted from exposure of the PBMCs to exemplary bi-specific antibodies disclosed herein.
  • PBMCs peripheral blood mononuclear cells
  • FIG. 5 is a graph that illustrates dose-response activity for IL-6 in peripheral blood mononuclear cells (PBMCs) isolated from CMV -positive human donors. The activity resulted from exposure of the PBMCs to exemplary bi-specific antibodies disclosed herein.
  • PBMCs peripheral blood mononuclear cells
  • FIG. 6 is a graph that illustrates dose-response activity for TNF-a in peripheral blood mononuclear cells (PBMCs) isolated from CMV -positive human donors. The activity resulted from exposure of the PBMCs to exemplary bi-specific antibodies disclosed herein.
  • PBMCs peripheral blood mononuclear cells
  • the term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ⁇ 10%, ⁇ 5%, or ⁇ 1%. In certain embodiments, the term “about” indicates the designated value ⁇ one standard deviation of that value. [0023]
  • the terms “first” and “second” are intended to indicate two separate entities, but does not mean that one is before the other in time or space, unless otherwise noted.
  • a sentence stating that "if 012 is A, then 013 is not D; as is not S; or ⁇ is not S; or combinations thereof includes the following combinations when ai is A: (1) a3 is not D; (2) as is not S; (3) ⁇ is not S; (4) a3 is not D; as is not S; and ⁇ is not S; (5) a3 is not D and as is not S; (6) a3 is not D and ⁇ is not S; and (7)
  • Tim-3 and “Tim-3 antigen” are used interchangeably herein.
  • Tim-3 is also known by synonyms, including HAVCR2, T cell immunoglobulin domain- and mucin domain-containing molecule 3, and T cell immunoglobulin and mucin domains-containing molecule 3, among others. Unless specified otherwise, the terms include any variants, isoforms and species homologs of human Tim-3 that are naturally expressed by cells, or that are expressed by cells transfected with a Tim-3 gene.
  • Tim-3 proteins include, for example, human Tim-3 (GI: 20330552; SEQ ID NO: 1). In some embodiments, Tim-3 proteins include cynomolgus monkey Tim-3 (GI: 355750365; SEQ ID NO: 2). In some embodiments, Tim-3 proteins include murine Tim-3 (GI: 17148681; SEQ ID NO: 3).
  • PD-1 and "PD-1 antigen” are used interchangeably herein. Unless specified otherwise, the terms include any variants, isoforms and species homologs of human PD-1 that are naturally expressed by cells, or that are expressed by cells transfected with a PD-1 gene.
  • PD-1 proteins include full-length PD-1 (e.g., human PD-1 ; GI: 167857792; SEQ ID NO: 292; extracellular domain: Pro21-Glnl67), as well as alternative splice variants of PD-1, such as PD-lAex2, PD-lAex3, PD-lAex2,3, and PD-lAex2,3,4.
  • PD-1 proteins include murine PD-1 (e.g., SEQ ID NO: 293; extracellular domain: Leu25-Glnl67).
  • PD-1 proteins include cynomolgus PD-1 (e.g., SEQ ID NO: 294; extracellular domain: Pro21-Glnl67).
  • immunoglobulin refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an "intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (VH ) and a heavy chain constant region (CH). The heavy chain constant region typically comprises three domains, abbreviated CHI, Cm, and Cro. Each light chain typically comprises a light chain variable region (VL ) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL.
  • antibody describes a type of immunoglobulin molecule and is used herein in its broadest sense.
  • An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), and antibody fragments.
  • Antibodies comprise at least one antigen-binding domain.
  • an antigen-binding domain is an antigen binding domain formed by a VH -VL dimer.
  • a "Tim-3 antibody,” “anti-Tim-3 antibody,” “Tim-3 Ab,” “Tim-3 -specific antibody” or “anti-Tim-3 Ab” is an antibody, as described herein, which binds specifically to the antigen Tim-3. In some embodiments, the antibody binds the extracellular domain of Tim-3.
  • a "PD-1 antibody,” “anti-PD-1 antibody,” “PD-1 Ab,” “PD-1 -specific antibody” or “anti- PD-1 Ab” is an antibody, as described herein, which binds specifically to the antigen PD-1. In some embodiments, the antibody binds the extracellular domain of PD-1.
  • the VH and VL regions may be further subdivided into regions of hypervariability ("hypervariable regions (HVRs);” also called “complementarity determining regions” (CDRs)) interspersed with regions that are more conserved.
  • the more conserved regions are called framework regions (FRs).
  • Each VH and VL generally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4.
  • the CDRs are involved in antigen binding, and influence antigen specificity and binding affinity of the antibody. See Kabat et al, Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, incorporated by reference in its entirety.
  • the light chain from any vertebrate species can be assigned to one of two types, called kappa and lambda, based on the sequence of the constant domain.
  • the heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • the IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.
  • the amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra ("Kabat” numbering scheme); Al-Lazikani et al, 1997, J. Mol. Biol , 273:927-948 ("Chothia” numbering scheme); MacCallum et al., 1996, J. Mol. Biol. 262:732-745 ("Contact” numbering scheme); Lefranc et al, Dev. Comp. Immunol , 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Pluckthun, J. Mol. Biol , 2001, 309:657-70 (“AHo” numbering scheme), each of which is incorporated by reference in its entirety.
  • Kabat numbering scheme
  • Al-Lazikani et al 1997, J. Mol. Biol , 273:927-948
  • Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-Hl,
  • CDR-H2, and CDR-H3 as identified by the Kabat and Chothia schemes.
  • residue numbering is provided using both the Kabat and Chothia numbering schemes.
  • the numbering scheme used for identification of a particular CDR herein is the Kabat/Chothia numbering scheme. Where the residues encompassed by these two numbering schemes diverge (e.g., CDR-Hl and/or CDR-H2), the numbering scheme is specified as either Kabat or Chothia.
  • CDR-H3 is sometimes referred to herein as either Kabat or Chothia. However, this is not intended to imply differences in sequence where they do not exist, and one of skill in the art can readily confirm whether the sequences are the same or different by examining the sequences.
  • CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at http://www.bioinf.org.uk/abs/abnum/, and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, incorporated by reference in its entirety.
  • Abnum available at http://www.bioinf.org.uk/abs/abnum/, and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, incorporated by reference in its entirety.
  • EU numbering scheme is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al, supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.
  • an "antibody fragment” comprises a portion of an intact antibody, such as the antigen binding or variable region of an intact antibody.
  • Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab')2 fragments, Fab' fragments, scFv (sFv) fragments, and scFv-Fc fragments.
  • Fv fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.
  • Fab fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (CHI) of the heavy chain.
  • Fab fragments may be generated, for example, by recombinant methods or by papain digestion of a full-length antibody.
  • F(ab')2 fragments contain two Fab' fragments joined, near the hinge region, by disulfide bonds.
  • F(ab')2 fragments may be generated, for example, by recombinant methods or by pepsin digestion of an intact antibody.
  • the F(ab') fragments can be dissociated, for example, by treatment with ⁇ -mercaptoethanol.
  • Single-chain Fv or “sFv” or “scFv” antibody fragments comprise a VH domain and a VL domain in a single polypeptide chain.
  • the VH and VL are generally linked by a peptide linker.
  • the linker is SEQ ID NO: 168.
  • scFv-Fc fragments comprise an scFv attached to an Fc domain.
  • an Fc domain may be attached to the C-terminus of the scFv.
  • the Fc domain may follow the VH or VL, depending on the orientation of the variable domains in the scFv (i.e., VH -VL or VL -VH ). Any suitable Fc domain known in the art or described herein may be used.
  • the Fc domain comprises an IgGl Fc domain.
  • the IgGl Fc domain comprises SEQ ID NO: 270, or a portion thereof, or SEQ ID NO: 276.
  • SEQ ID NO: 270 provides the sequence of CHI, CH2, and Cm of the human IgGl constant region.
  • SEQ ID NO: 276 provides the sequence of the constant region used in the illustrative scFv-Fc antibodies provided herein.
  • the term "monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies.
  • a population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts.
  • a monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies.
  • the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones.
  • the selected antibody can be further altered, for example, to improve affinity for the target ("affinity maturation"), to humanize the antibody, to improve its production in cell culture, and/or to reduce its immunogenicity in a subject.
  • chimeric antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.
  • Humanized forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody.
  • a humanized antibody is generally a human immunoglobulin (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs of a non-human antibody (donor antibody).
  • the donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biological effect.
  • selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues from the donor antibody.
  • Humanized antibodies may also comprise residues that are not found in either the recipient antibody or the donor antibody.
  • a "human antibody” is one which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.
  • an "isolated antibody” is one that has been separated and/or recovered from a component of its natural environment. Components of the natural environment may include enzymes, hormones, and other proteinaceous or nonproteinaceous materials.
  • an isolated antibody is purified to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, for example by use of a spinning cup sequenator.
  • an isolated antibody is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or nonreducing conditions, with detection by Coomassie blue or silver stain.
  • An isolated antibody includes an antibody in situ within recombinant cells, since at least one component of the antibody's natural environment is not present.
  • an isolated antibody is prepared by at least one purification step.
  • an isolated antibody is purified to at least 80%, 85%,
  • an isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by volume. In some embodiments, an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by weight. In some embodiments, an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by volume.
  • affinity refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen).
  • binding affinity refers to intrinsic binding affinity, which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen).
  • KD dissociation constant
  • Affinity can be measured by common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology, such as a Biacore ® instrument. In some embodiments, the affinity is determined at 25°C.
  • binding means binding that is measurably different from a non-specific or non-selective interaction.
  • Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule.
  • Specific binding can also be determined by competition with a control molecule that mimics the antibody binding site on the target. In that case, specific binding is indicated if the binding of the antibody to the target is competitively inhibited by the control molecule.
  • kd (sec "1 ), as used herein, refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the k 0 ff value.
  • k a (M ⁇ xsec -1 ), as used herein, refers to the association rate constant of a particular antibody-antigen interaction. This value is also referred to as the k on value.
  • KD kd/k a .
  • an "affinity matured" antibody is one with one or more alterations in one or more CDRs or FRs that result in an improvement in the affinity of the antibody for its antigen, compared to a parent antibody which does not possess the alteration(s).
  • an affinity matured antibody has nanomolar or picomolar affinity for the target antigen.
  • Affinity matured antibodies may be produced using a variety of methods known in the art. For example, Marks et al. ⁇ Bio/Technology, 1992, 10:779-783, incorporated by reference in its entirety) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDR and/or framework residues is described by, for example, Barbas et al. (Pro Nat.
  • Compets with indicates that the two or more antibodies compete for binding to an antigen.
  • an antigen is coated on a plate and allowed to bind a first antibody, after which a second, labeled antibody is added. If the presence of the first antibody reduces binding of the second antibody, then the antibodies compete.
  • a first antibody is coated on a plate and allowed to bind an antigen, and then the second antibody is added.
  • the term "competes with” also includes combinations of antibodies where one antibody reduces binding of another antibody, but where no competition is observed when the antibodies are added in the reverse order. However, in some embodiments, the first and second antibodies inhibit binding of each other, regardless of the order in which they are added.
  • one antibody reduces binding of another antibody to its antigen by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.
  • epitope means a portion of an antigen capable of specific binding to an antibody. Epitopes frequently consist of surface-accessible amino acid residues and/or sugar side chains and may have specific three dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding.
  • the epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to Tim-3 and/or PD-1 variants with different point-mutations, or to chimeric Tim-3 and/or PD-1 variants as described further in the Examples provided herein.
  • Percent "identity" between a polypeptide sequence and a reference sequence is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • a “conservative substitution” or a “conservative amino acid substitution,” refers to the substitution an amino acid with a chemically or functionally similar amino acid. Conservative substitution tables providing similar amino acids are well known in the art. Polypeptide sequences having such substitutions are known as “conservatively modified variants.” By way of example, the groups of amino acids provided in Tables 2-4 are, in some embodiments, considered conservative substitutions for one another.
  • amino acid refers to the twenty common naturally occurring amino acids.
  • Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gin; Q), Glycine (Gly; G); histidine (His; H), isoleucine (He; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).
  • Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic
  • Treating" or “treatment” of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject.
  • “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject.
  • “treating” or “treatment” includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both.
  • “treating” or “treatment” includes delaying or preventing the onset of the disease or disorder.
  • terapéuticaally effective amount refers to an amount of an antibody or composition that when administered to a subject is effective to treat a disease or disorder.
  • the term "subject” means a mammalian subject. Exemplary subjects include, but are not limited to humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, avians, goats, and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has a cancer that can be treated or diagnosed with an antibody provided herein. In some embodiments, the cancer is a cancer of epithelial origin.
  • Tim-3 antibodies that selectively bind human Tim-3.
  • the Tim-3 antibody selectively binds to the extracellular domain of human Tim-3.
  • the Tim-3 antibody binds to a homolog of human
  • Tim-3 binds to a homolog of human Tim-3 from a species selected from monkeys, mice, dogs, cats, rats, cows, horses, goats and sheep.
  • the homolog is a cynomolgus monkey homolog.
  • the Tim-3 antibody has one or more CDRs having particular lengths, in terms of the number of amino acid residues.
  • the Chothia CDR-H1 of the antibody is 6, 7, or 8 residues in length.
  • the Kabat CDR-H1 of the antibody is 4, 5, or 6 residues in length.
  • the Chothia CDR-H2 of the antibody is 5, 6, or 7 residues in length.
  • the Kabat CDR-H2 of the antibody is 16, 17, or 18 residues in length.
  • the Kabat/Chothia CDR-H3 of the antibody is 9, 10, 11, 12, or 13 residues in length.
  • the Kabat/Chothia CDR-L1 of the antibody is 11, 12, 13, 14,
  • the Kabat/Chothia CDR-L2 of the antibody is 6, 7, or 8 residues in length. In some aspects, the Kabat/Chothia CDR-L3 of the antibody is 8, 9, or 10 residues in length.
  • the Tim-3 antibody comprises a light chain. In some aspects, the light chain is a kappa light chain. In some aspects, the light chain is a lambda light chain. [0072] In some embodiments, the Tim-3 antibody comprises a heavy chain. In some aspects, the heavy chain is an IgA. In some aspects, the heavy chain is an IgD. In some aspects, the heavy chain is an IgE. In some aspects, the heavy chain is an IgG. In some aspects, the heavy chain is an IgM. In some aspects, the heavy chain is an IgGl . In some aspects, the heavy chain is an IgG2. In some aspects, the heavy chain is an IgG3. In some aspects, the heavy chain is an IgG4. In some aspects, the heavy chain is an IgAl . In some aspects, the heavy chain is an IgA2.
  • the Tim-3 antibody is an antibody fragment.
  • the antibody fragment is an Fv fragment.
  • the antibody fragment is a Fab fragment.
  • the antibody fragment is a F(ab')2 fragment.
  • the antibody fragment is a Fab' fragment.
  • the antibody fragment is an scFv (sFv) fragment.
  • the antibody fragment is an scFv-Fc fragment.
  • the scFv-Fc fragment comprises a constant region wherein the constant region comprises SEQ ID NO: 276.
  • the constant region in SEQ ID NO: 276 differs from the human IgGl constant region of SEQ ID NO: 270 in several respects.
  • the sequence in SEQ ID NO: 276 comprises the linker AAGSDQEPKSS (SEQ ID NO: 282).
  • SEQ ID NO: 276 also does not comprise the CHI domain of the IgGl constant region.
  • SEQ ID NO: 276 further comprises a C220S (EU numbering system) mutation, which removes an unpaired cysteine reside that is not needed when the light chain constant region is not present (e.g., in an scFv-Fc format).
  • SEQ ID NO: 276 further comprises two, optional, P to S mutations (P230S and P238S by the EU numbering system). Either or both of these serine residues can be reverted to the naturally occurring proline residues.
  • SEQ ID NO: 276 comprises an aspartic acid (D) residue at EU position 356 and a leucine (L) residue at EU position 358.
  • SEQ ID NO: 270 comprises glutamic acid (E) in EU position 356 and methionine (M) in EU position 358.
  • the antibodies provided herein comprise constant regions comprising D356/L358, E356/M358, D356/M358, or E356/L358 (EU numbering).
  • the antibodies provide herein may comprise any suitable constant region and that the constant region sequences provided herein are for illustrative purposes.
  • the Tim-3 antibody is a monoclonal antibody. In some embodiments, the Tim-3 antibody is a polyclonal antibody. [0076] In some embodiments, the Tim-3 antibody is a chimeric antibody. In some embodiments, the Tim-3 antibody is a humanized antibody. In some embodiments, the Tim-3 antibody is a human antibody.
  • the Tim-3 antibody is an affinity matured antibody.
  • the Tim-3 antibody is an affinity matured antibody derived from an illustrative sequence provided in this disclosure.
  • the Tim-3 antibody inhibits the binding of Tim-3 to one or more of its ligands. In some aspects, the Tim-3 antibody inhibits the binding of Tim-3 to a ligand selected from a second Tim-3 molecule, claudin-7, CD44v4-v7, E-cadherin, and CD9.
  • the Tim-3 antibody is provided as a single arm binder.
  • Tim-3 antibody can be provided as part of a bi-specific antibody or bi-specific antibody construct as disclosed here.
  • Tim-3 antibodies provided herein may be useful for the treatment of a variety of diseases and conditions including cancers.
  • the Tim-3 antibodies provided herein may be useful for the treatment of cancers of epithelial origin.
  • the Tim-3 antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of an illustrative antibody or VH sequence provided herein.
  • the CDR-H3 sequence is a CDR-H3 sequence of an scFv-Fc sequence provided in SEQ ID NO: 287.
  • the CDR-H3 sequence is a CDR-H3 sequence of a VH sequence provided in SEQ ID NOs. : 144-180.
  • the Tim-3 antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 111-118. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 111. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 112. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 113.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 114. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 115. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 116. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 117. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 118.
  • the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure.
  • the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure.
  • the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Tim-3 antibody comprises a VH sequence comprising one or more CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-H sequences provided in this disclosure, and variants thereof.
  • the CDR-H sequences comprise, consist of, or consist essentially of one or more CDR-H sequences provided in a VH sequence selected from SEQ ID NOs: 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising one or more Kabat CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Kabat CDR-H sequences provided in this disclosure, and variants thereof.
  • the Tim-3 antibody comprises a VH sequence comprising a CDR-H3 sequence, wherein the CDR-H3 sequence comprises, consists of, or consists essentially of a Kabat CDR-H3 sequence of an illustrative antibody or VH sequence provided herein.
  • the Kabat CDR-H3 sequence is a Kabat CDR-H3 sequence of an scFv-Fc sequence provided in SEQ ID NO: 287.
  • the Kabat CDR-H3 sequence is a Kabat CDR-H3 sequence of a VH sequence provided in SEQ ID NOs.: 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 111-118. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 111. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 112.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 113. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 114. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 115. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 116.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 117. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 118.
  • the Tim-3 antibody comprises a VH sequence comprising a CDR-H2 sequence, wherein the CDR-H2 sequence comprises, consists of, or consists essentially of a Kabat CDR-H2 sequence of an illustrative antibody or VH sequence provided herein.
  • the Kabat CDR-H2 sequence is a Kabat CDR-H2 sequence of an scFv-Fc sequence provided in SEQ ID NO: 287.
  • the Kabat CDR-H2 sequence is a Kabat CDR-H2 sequence of a VH sequence provided in SEQ ID NOs. : 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 82-109. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 82. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 83.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 84. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 85. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 86. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 87.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 88. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 89. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 90. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 91.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 92. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 93. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 94. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 95.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 96. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 97. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 98. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 99.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 100. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 101. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 102. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 103.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 104. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 105. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 106. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 107.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 108. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 109.
  • the Tim-3 antibody comprises a VH sequence comprising a CDR-Hl sequence, wherein the CDR-Hl sequence comprises, consists of, or consists essentially of a Kabat CDR-Hl sequence of an illustrative antibody or VH sequence provided herein.
  • the Kabat CDR-Hl sequence is a Kabat CDR-Hl sequence of an scFv-Fc sequence provided in SEQ ID NO: 287.
  • the Kabat CDR-Hl sequence is a Kabat CDR-Hl sequence of a VH sequence provided in SEQ ID NOs.: 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 39-56. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 39. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 40. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 41.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 42. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 43. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 44. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 45.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 46. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 47. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 48. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 49.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 50. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 51. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 52. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 53.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 54. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 55. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 56.
  • the Tim-3 antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 111-118, and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 82-109.
  • the Kabat CDR-H3 sequence and the Kabat CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure.
  • the Kabat CDR-H3 and Kabat CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOs: 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 111-118, and a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 39-56.
  • the Kabat CDR-H3 sequence and the Kabat CDR-Hl sequence are both from a single illustrative VH sequence provided in this disclosure.
  • the Kabat CDR-H3 and Kabat CDR-Hl are both from a single illustrative VH sequence selected from SEQ ID NOs: 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 39-56 and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 82-109.
  • the Kabat CDR-Hl sequence and the Kabat CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure.
  • the Kabat CDR-Hl and Kabat CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOs: 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 39-56, a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 82-109, and a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 111-118.
  • the Kabat CDR-Hl sequence, Kabat CDR-H2 sequence, and Kabat CDR-H3 sequence are all from a single illustrative VH sequence provided in this disclosure.
  • the Kabat CDR-Hl, Kabat CDR-H2, and Kabat CDR-H3 are all from a single illustrative VH sequence selected from SEQ ID NOs: 144-180.
  • the VH sequences provided herein comprise a variant of an illustrative Kabat CDR-H3, CDR-H2, and/or CDR-Hl sequence provided in this disclosure.
  • the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H3 sequence provided in this disclosure.
  • the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H3 sequences provided in this disclosure.
  • the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H2 sequence provided in this disclosure.
  • the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H2 sequences provided in this disclosure.
  • the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Kabat CDR-Hl sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-Hl sequence provided in this disclosure.
  • the Kabat CDR-Hl sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-Hl sequences provided in this disclosure.
  • the Kabat CDR-Hl sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-Hl sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Tim-3 antibody comprises a VH sequence comprising one or more Chothia CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Chothia CDR-H sequences provided in this disclosure, and variants thereof.
  • the Tim-3 antibody comprises a VH sequence comprising a CDR-H3 sequence, wherein the CDR-H3 sequence comprises, consists of, or consists essentially of a Chothia CDR-H3 sequence of an illustrative antibody or VH sequence provided herein.
  • the Chothia CDR-H3 sequence is a Chothia CDR-H3 sequence of an scFv-Fc sequence provided in SEQ ID NO: 287.
  • the Chothia CDR-H3 sequence is a Chothia CDR-H3 sequence of a VH sequence provided in SEQ ID NOs. : 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 111-118. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 111. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 112.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 113. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 114. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 115. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 116.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 117. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 118.
  • the Tim-3 antibody comprises a VH sequence comprising a CDR-H2 sequence, wherein the CDR-H2 sequence comprises, consists of, or consists essentially of a Chothia CDR-H2 sequence of an illustrative antibody or VH sequence provided herein.
  • the Chothia CDR-H2 sequence is a Chothia CDR-H2 sequence of an scFv-Fc sequence provided in SEQ ID NO: 287.
  • the Chothia CDR-H2 sequence is a Chothia CDR-H2 sequence of a VH sequence provided in SEQ ID NOs. : 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 63-80. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 63. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 64.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 65. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 66. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 67. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 68.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 69. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 70. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 71. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 72.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 73. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 74. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 75. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 76.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 77. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 78. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 79. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 80.
  • the Tim-3 antibody comprises a VH sequence comprising a CDR-H1 sequence, wherein the CDR-H1 sequence comprises, consists of, or consists essentially of a Chothia CDR-H1 sequence of an illustrative antibody or VH sequence provided herein.
  • the Chothia CDR-H1 sequence is a Chothia CDR-H1 sequence of an scFv-Fc sequence provided in SEQ ID NO: 287.
  • the Chothia CDR-H1 sequence is a Chothia CDR-H1 sequence of a VH sequence provided in SEQ ID NOs. : 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 4-23.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 4.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 5.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 6.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 7. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 8. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 9. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 10.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 11. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 12. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 13. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 14.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 15. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 16. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 17. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 18.
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 19. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 20. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 21. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 22. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 23.
  • the Tim-3 antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 111-118, and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 63-80.
  • the Chothia CDR-H3 sequence and the Chothia CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure.
  • the Chothia CDR-H3 and Chothia CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOs: 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 111-118, and a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 4-23.
  • the Chothia CDR-H3 sequence and the Chothia CDR-Hl sequence are both from a single illustrative VH sequence provided in this disclosure.
  • the Chothia CDR-H3 and Chothia CDR-Hl are both from a single illustrative VH sequence selected from SEQ ID NOs: 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 4-23 and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 63-80.
  • the Chothia CDR-H1 sequence and the Chothia CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure.
  • the Chothia CDR-H1 and Chothia CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOs: 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 4-23, a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 63-80, and a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 111-118.
  • the Chothia CDR-H1 sequence, Chothia CDR-H2 sequence, and Chothia CDR-H3 sequence are all from a single illustrative VH sequence provided in this disclosure.
  • the Chothia CDR-H1, Chothia CDR-H2, and Chothia CDR-H3 are all from a single illustrative VH sequence selected from SEQ ID NOs: 144-180.
  • the VH sequences provided herein comprise a variant of an illustrative Chothia CDR-H3, CDR-H2, and/or CDR-H1 sequence provided in this disclosure.
  • the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H3 sequence provided in this disclosure.
  • the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H3 sequences provided in this disclosure.
  • the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H2 sequence provided in this disclosure.
  • the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H2 sequences provided in this disclosure.
  • the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H1 sequence provided in this disclosure.
  • the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H1 sequences provided in this disclosure.
  • the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Tim-3 antibody comprises, consists of, or consists essentially of a VH sequence of an scFv-Fc sequence provided in SEQ ID NO: 287. In some embodiments, the antibody comprises, consists of, or consists essentially of a VH sequence provided in SEQ ID NOs. : 144-180.
  • the Tim-3 antibody comprises a VH sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 144-180. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 144. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 145. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 146. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 147.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 148. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 149. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 150. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 151. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 152.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 153. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 154. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 155. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 156. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 157.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 158. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 159. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 160. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 161. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 162.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 163. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 164. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 165. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 166. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 167.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 168. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 169. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 170. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 171. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 172.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 173. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 174. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 175. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 176. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 177.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 178. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 179. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 180.
  • the VH sequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VH sequence provided in this disclosure.
  • the VH sequence comprises, consists of, or consists essentially of a variant of an illustrative VH sequence provided in this disclosure. In some aspects, the VH sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative VH sequences provided in this disclosure.
  • the VH sequence comprises, consists of, or consists essentially of any of the illustrative VH sequences provided in this disclosure having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Tim-3 antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of an illustrative antibody or VL sequence provided herein.
  • the CDR-L3 sequence is a CDR-L3 sequence of an scFv-Fc sequence provided in SEQ ID NO: 287.
  • the CDR-L3 sequence is a CDR-L3 sequence of a VL sequence provided in SEQ ID NOs. : 221-235.
  • the Tim-3 antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 140-142 and 356.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 140.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 141.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 142.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 356.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Tim-3 antibody comprises a VL sequence comprising one or more CDR-L sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-L sequences provided in this disclosure, and variants thereof.
  • the Tim-3 antibody comprises a VL sequence comprising a CDR-L3 sequence, wherein the CDR-L3 sequence comprises, consists of, or consists essentially of a CDR-L3 sequence of an illustrative antibody or VL sequence provided herein.
  • the CDR-L3 sequence is a CDR-L3 sequence of an scFv-Fc sequence provided in SEQ ID NO: 287.
  • the CDR-L3 sequence is a CDR-L3 sequence of a VL sequence provided in SEQ ID NOs. : 221-235.
  • the Tim-3 antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 140-142 and 356.
  • the antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 140.
  • the antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 141.
  • the antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 142.
  • the antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 356.
  • the Tim-3 antibody comprises a VL sequence comprising a CDR-L2 sequence, wherein the CDR-L2 sequence comprises, consists of, or consists essentially of a CDR-L2 sequence of an illustrative antibody or VL sequence provided herein.
  • the CDR-L2 sequence is a CDR-L2 sequence of an scFv-Fc sequence provided in SEQ ID NO: 287.
  • the CDR-L2 sequence is a CDR-L2 sequence of a VL sequence provided in SEQ ID NOs.: 221 -235.
  • the Tim-3 antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 125-133 and 355. In some aspects, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 125. In some aspects, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 126. In some aspects, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 127.
  • the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 128. In some aspects, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 129. In some aspects, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 130. In some aspects, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 131.
  • the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 132. In some aspects, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 133. In some aspects, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 355.
  • the Tim-3 antibody comprises a VL sequence comprising a CDR-L1 sequence, wherein the CDR-L1 sequence comprises, consists of, or consists essentially of a CDR-Ll sequence of an illustrative antibody or VL sequence provided herein.
  • the CDR-Ll sequence is a CDR-Ll sequence of an scFv-Fc sequence provided in SEQ ID NO: 287.
  • the CDR-Ll sequence is a CDR-Ll sequence of a VL sequence provided in SEQ ID NOs. : 221-235.
  • the Tim-3 antibody comprises a VL sequence comprising a CDR-Ll sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 120-123 and 354.
  • the antibody comprises a VL sequence comprising a CDR-Ll sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 120.
  • the antibody comprises a VL sequence comprising a CDR-Ll sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 121.
  • the antibody comprises a VL sequence comprising a CDR-Ll sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 122.
  • the antibody comprises a VL sequence comprising a CDR-Ll sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 123. In some aspects, the antibody comprises a VL sequence comprising a CDR-Ll sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 354.
  • the Tim-3 antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 140-142 and 356 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 125-133 and 355.
  • the CDR-L3 sequence and the CDR-L2 sequence are both from a single illustrative VL sequence provided in this disclosure.
  • the CDR-L3 and CDR-L2 are both from a single illustrative VL sequence selected from SEQ ID NOs: 221-235.
  • the Tim-3 antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 140-142 and 356 and a CDR-Ll sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 120-123 and 354.
  • the CDR-L3 sequence and the CDR-Ll sequence are both from a single illustrative VL sequence provided in this disclosure.
  • the CDR-L3 and CDR-Ll are both from a single illustrative VL sequence selected from SEQ ID NOs: 221-235. 2.5.6.
  • the Tim-3 antibody comprises a VL sequence comprising a CDR-Ll sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 120-123 and 354 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 125-133 and 355.
  • the CDR-Ll sequence and the CDR-L2 sequence are both from a single illustrative VL sequence provided in this disclosure.
  • the CDR-Ll and CDR-L2 are both from a single illustrative VL sequence selected from SEQ ID NOs: 221-235.
  • the Tim-3 antibody comprises a VL sequence comprising a CDR-Ll sequence comprising, consisting of, or consisting essentially of a sequence selected from any one of SEQ ID NOs: 120-123 and 354, a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 125-133 and 355, and a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 140-142 and 356.
  • the CDR-Ll sequence, CDR-L2 sequence, and CDR-L3 sequence are all from a single illustrative VL sequence provided in this disclosure.
  • the CDR-Ll, CDR-L2, and CDR-L3 are all from a single illustrative VL sequence selected from SEQ ID NOs: 221-235.
  • the VL sequences provided herein comprise a variant of an illustrative CDR-L3, CDR-L2, and/or CDR-Ll sequence provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-Ll sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-Ll sequence provided in this disclosure.
  • the CDR-Ll sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-Ll sequences provided in this disclosure.
  • the CDR-Ll sequence comprises, consists of, or consists essentially of any of the illustrative CDR-Ll sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Tim-3 antibody comprises, consists of, or consists essentially of a VL sequence of an scFv-Fc sequence provided in SEQ ID NO: 287. In some embodiments, the antibody comprises, consists of, or consists essentially of a VL sequence provided in SEQ ID NOs. : 221-235.
  • the Tim-3 antibody comprises a VL sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 221-235. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 221. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 222. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 223. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 224.
  • the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 225. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 226. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 227. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 228. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 229.
  • the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 230. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 231. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 232. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 233. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 234. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 235.
  • the VL sequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VL sequence provided in this disclosure.
  • the VL sequence comprises, consists of, or consists essentially of a variant of an illustrative VL sequence provided in this disclosure. In some aspects, the VL sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative VL sequences provided in this disclosure.
  • the VL sequence comprises, consists of, or consists essentially of any of the illustrative VL sequences provided in this disclosure having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Tim-3 antibody comprises a CDR-H3 sequence and a CDR-L3 sequence.
  • the CDR-H3 sequence is part of a VH and the CDR-L3 sequence is part of a VL.
  • the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 111-118
  • the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 140-142 and 356.
  • the CDR-H3 - CDR-L3 pairs provided herein comprise a variant of an illustrative CDR-H3 and/or CDR-Ll sequence provided in this disclosure.
  • the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Tim-3 antibody comprises a CDR-H1 sequence and a CDR-Ll sequence.
  • the CDR-H1 sequence is part of a VH and the CDR-Ll sequence is part of a VL.
  • the CDR-H1 sequence is a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 4-23
  • the CDR-Ll sequence is a CDR-Ll sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 120-123 and 354.
  • the CDR-H1 sequence is a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 39-56
  • the CDR-Ll sequence is a CDR-Ll sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 120-123 and 354.
  • the CDR-H1 - CDR-Ll pairs provided herein comprise a variant of an illustrative CDR-H1 and/or CDR-Ll sequence provided in this disclosure.
  • the CDR-Hl sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-Hl sequence provided in this disclosure.
  • the CDR-Hl sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-Hl sequences provided in this disclosure.
  • the CDR-Hl sequence comprises, consists of, or consists essentially of any of the illustrative CDR-Hl sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-L1 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L1 sequence provided in this disclosure.
  • the CDR-L1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L1 sequences provided in this disclosure.
  • the CDR-L1 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Tim-3 antibody comprises a CDR-H2 sequence and a CDR-L2 sequence.
  • the CDR-H2 sequence is part of a VH and the CDR-L2 sequence is part of a VL.
  • the CDR-H2 sequence is a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 63-80
  • the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 125-133 and 355.
  • the CDR-Hl sequence is a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 82-109
  • the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 125-133 and 355.
  • the CDR-H2 - CDR-L2 pairs provided herein comprise a variant of an illustrative CDR-H2 and/or CDR-L2 sequence provided in this disclosure.
  • the CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H2 sequence provided in this disclosure.
  • the CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H2 sequences provided in this disclosure.
  • the CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Tim-3 antibody comprises a VH sequence and a VL sequence.
  • the VH sequence is a VH sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 144-180
  • the VL sequence is a VL sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 221-235.
  • VH - VL pairs are selected from SEQ ID NO: 221 and
  • VH - VL pairs are selected from SEQ ID NO: 222 and
  • VH - VL pairs are selected from SEQ ID NO: 223 and
  • VH - VL pairs are selected from SEQ ID NO: 224 and
  • VH - VL pairs are selected from SEQ ID NO: 225 and
  • VH - VL pairs are selected from SEQ ID NO: 226 and
  • VH - VL pairs are selected from SEQ ID NO: 227 and
  • VH - VL pairs are selected from SEQ ID NO: 228 and
  • VH - VL pairs are selected from SEQ ID NO: 229 and
  • VH - VL pairs are selected from SEQ ID NO: 230 and
  • VH - VL pairs are selected from SEQ ID NO: 231 and
  • VH - VL pairs are selected from SEQ ID NO: 232 and
  • VH - VL pairs are selected from SEQ ID NO: 234 and
  • VH - VL pairs are selected from SEQ ID NO: 235 and
  • the VH - VL pairs provided herein comprise a variant of an illustrative VH and/or VL sequence provided in this disclosure.
  • the VH sequence comprises, consists of, or consists essentially of a variant of an illustrative VH sequence provided in this disclosure. In some aspects, the VH sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative VH sequences provided in this disclosure.
  • the VH sequence comprises, consists of, or consists essentially of any of the illustrative VH sequences provided in this disclosure having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 1 1 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the VL sequence comprises, consists of, or consists essentially of a variant of an illustrative VL sequence provided in this disclosure. In some aspects, the VL sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative VL sequences provided in this disclosure.
  • the VL sequence comprises, consists of, or consists essentially of any of the illustrative VL sequences provided in this disclosure having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Tim-3 antibody comprises a CDR-H1 sequence, a
  • CDR-H2 sequence a CDR-H3 sequence, a CDR-Ll sequence, a CDR-L2 sequence, and a CDR-L3 sequence.
  • the CDR sequences are part of a VH (for CDR-H) or VL (for CDR-L).
  • the CDR-H1 sequence is a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 4-23;
  • the CDR-H2 sequence is a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 63-80;
  • the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 111-118;
  • the CDR-Ll sequence is a CDR-Ll sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 120-123 and 354;
  • the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 125-133 and 355;
  • the CDR-L3 sequence is a
  • the CDR-H1 sequence is a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 39-56;
  • the CDR-H2 sequence is a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 82-109;
  • the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 111-118;
  • the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 120-123 and 354;
  • the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 125-133 and 355;
  • the CDR-L3 sequence is a C
  • the CDR-Hl, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 provided herein comprise a variant of an illustrative CDR-Hl, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and/or CDR-L3 sequence provided in this disclosure.
  • the CDR-Hl sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia or Kabat CDR-Hl sequence provided in this disclosure.
  • the CDR-Hl sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia or Kabat CDR-Hl sequences provided in this disclosure.
  • the CDR-Hl sequence comprises, consists of, or consists essentially of any of the illustrative Chothia or Kabat CDR-Hl sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia or Kabat CDR-H2 sequence provided in this disclosure.
  • the CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia or Kabat CDR-H2 sequences provided in this disclosure.
  • the CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia or Kabat CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure.
  • the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure.
  • the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-Ll sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-Ll sequence provided in this disclosure.
  • the CDR-Ll sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-Ll sequences provided in this disclosure.
  • the CDR-Ll sequence comprises, consists of, or consists essentially of any of the illustrative CDR-Ll sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • anti-Tim-3 antibodies comprising one or more sequences defined by consensus sequences.
  • Each consensus sequence is based, at least in part, on one or more alignments of two or more useful anti-Tim-3 CDR sequences provided in this disclosure. Based on such alignments, a person of skill in the art would recognize that different amino acid residues may useful in certain positions of the CDRs. Accordingly, each consensus sequence encompasses two or more useful anti-Tim-3 CDR sequences.
  • the Tim-3 antibodies comprise one to six of the consensus CDR sequences provided herein. In some embodiments, the antibodies comprise two to six of the consensus CDR sequences provided herein. In some embodiments, the antibodies comprise three to six of the consensus CDR sequences provided herein. In some embodiments, the antibodies comprise four to six of the consensus CDR sequences provided herein. In some embodiments, the antibodies comprise five to six of the consensus CDR sequences provided herein. In some embodiments, the antibodies comprise six of the consensus CDR sequences provided herein. In some embodiments, the antibodies comprise a VL comprising the CDR-L consensus sequence(s). In some embodiments, the antibodies comprise a VH comprising the CDR-H consensus sequence(s). In some embodiments, the antibodies comprise a VH comprising the CDR-H consensus sequence(s) and a VL comprising the CDR-L consensus sequence(s).
  • the Tim-3 antibody comprises a CDR-H3 sequence defined by the consensus sequence ai-a2- 3-Y-R- 6- 7- s- 9- io- n-ai2- i3, where ai is Q, S or G; i is G, F, Y, or H; co is G, F, V, or I; ⁇ is absent or S; a 7 is Y, S, M, or L; as is D, N, or W; co is D; aio is A, W, or S; an is M, Y, F, or L; n is D or V; and ai3 is Y or H.
  • the Tim-3 antibody comprises a CDR-H3 sequence defined by the consensus sequence G-P2- P3-Y-R-P7-W-D-S-Pn-D-Pi3, where P2 is Y or H; P3 is V or I; p 7 is M, or L; Pn is Y, F, or L; and ⁇ 3 is Y or H.
  • the Tim-3 antibody comprises a Chothia CDR-H1 sequence defined by the consensus sequence 0-72-73-7 -75-76-77, where 72 is F or Y; 73 is S, P or N; 74 is L, F, or I; 75 is T, I, S, G, D, K, or R; 76 is S, G, D, R, N, or K; and 77 is N, Y or H.
  • the Tim-3 antibody comprises a Chothia CDR-H1 sequence defined by the consensus sequence G-F- ⁇ - ⁇ - ⁇ 5- ⁇ 6- ⁇ 7, where 85 is T, I , S, G, or R; ⁇ 6 is S, R, N, K, or G; and ⁇ 7 is N, Y or H. 2.9.3. Chothia CDR-H2 Consensus Sequences
  • the Tim-3 antibody comprises a Chothia CDR-H2 sequence defined by the consensus sequence 8i-82-83-84-G-86, where z is W, N, T, V, I , S, A, or M; 82 is S or P; 83 is absent, Y, V, G, D, N, T, or A; 8 is D, G, N, R, Q, A, or V; and ⁇ is Y, I, D, S, or F.
  • the Tim-3 antibody comprises a Chothia CDR-H2 sequence defined by the consensus sequence 8i-P-83-84-G-86, where ⁇ is T, V, I, S, A, or M; S3 is V, G, D, N, T, or A; and ⁇ 4 is G, R, Q, A, or V; and ⁇ 6 is Y, I, D, S, or F.
  • the Tim-3 antibody comprises a Kabat CDR-H1 sequence defined by the consensus sequence ⁇ - ⁇ 2- ⁇ 3- ⁇ 4- ⁇ 5, where ⁇ is D, S, G, R, N, or K; ⁇ is Y, H, or N; ⁇ 3 is G, T, Y, A, or V; ⁇ 4 is V, M, or I; and ⁇ 5 is N or H.
  • the Tim-3 antibody comprises a Kabat CDR-H1 sequence defined by the consensus sequence ⁇ - ⁇ 2- ⁇ 3- ⁇ - ⁇ , where ⁇ is G, R, N, K, or S; x i is Y, H, or N; and ⁇ 3 is Y, A, or V.
  • the Tim-3 antibody comprises a Kabat CDR-H2 sequence defined by the consensus sequence ⁇ 1 - ⁇ - ⁇ 3- ⁇ 4- ⁇ 5 - ⁇ 6- ⁇ 7 - ⁇ 8- ⁇ - ⁇ 1 ⁇ - ⁇ - ⁇ 1 2- ⁇ 1 3- ⁇ 1 4- ⁇ 1 5- ⁇ 1 6- ⁇ 1 7, where ⁇ ! is V, L, G, D, or A; ⁇ 3 is W,
  • the Tim-3 antibody comprises a Kabat CDR-H2 sequence defined by the consensus sequence V-I-W-S-D-G-S-T-T-Y-N-ei3-9i4-9i5-ei6, where ⁇ 13 is P, Q, S, or D; ⁇ 14 is S, K, or A; ⁇ 15 is F, L, or V; ⁇ is Q or K; ⁇ 17 is G or S.
  • the Tim-3 antibody comprises a Kabat CDR-H2 sequence defined by the consensus sequence ⁇ - ⁇ - ⁇ 3- ⁇ - ⁇ 5- ⁇ 6-0- ⁇ 8- ⁇ - ⁇ - ⁇ - ⁇ - ⁇ -8- ⁇ - ⁇ - ⁇ 7, where ⁇ is D, A, or G; ⁇ 3 is T, V, I, S, A, or M; ⁇ 5 is V, G, D, N, T, or A; ⁇ 6 is R, Q, G, A, or V; ⁇ 8 is Y, I , D, S, or F; ⁇ 10 is E, D, or G; and ⁇ 17 is G or D.
  • the Tim-3 antibody comprises a CDR-L3 sequence defined by the consensus sequence 11-Q-13-14-15-I6-P-I8-T, where u is Q or F; 13 S or G; 14 is N or S 15 is E or H; i6 is D or V; and is is Y or W. [00206] In some embodiments, the Tim-3 antibody comprises a CDR-L3 sequence defined by the consensus sequence Q-Q-H-Y-T-T-P-P-T.
  • the Tim-3 antibody comprises a CDR-L2 sequence defined by the consensus sequence i- i-S-N- s-ta-S, where ⁇ is A or K; ⁇ is A or V; s is
  • the Tim-3 antibody comprises a CDR-L2 sequence defined by the consensus sequence ⁇ - m- ⁇ 3- nt-L- ⁇ - ⁇ 7 , where ⁇ is S or D; m is A or D; 3 is S or D; m is F or D; ⁇ is Y or D; and m is D or S.
  • the Tim-3 antibody comprises a CDR-L1 sequence defined by the consensus sequence ⁇ - ⁇ 2-8-(5-8- ⁇ 6- ⁇ 7 - ⁇ 8- ⁇ 9- ⁇ - ⁇ - ⁇ 2- ⁇ 3- ⁇ 4- ⁇ 5- ⁇ 6, where ⁇ is K or R; ⁇ 2 is A or S; ⁇ is V or I; ⁇ 7 is D or V; ⁇ 8 is Y or H; ⁇ 9 is D or T; ⁇ is absent or N; ⁇ is G; ⁇ 2 is N; ⁇ « is S or T; ⁇ is Y; ⁇ 5 is V or L; and ⁇ is N, A, or E.
  • the Tim-3 antibody comprises a CDR-L1 sequence defined by the consensus sequence K-A-S-S-Q-V-D-Y-D-G-N-S-Y-V- ⁇ , where ⁇ is N or A.
  • the Tim-3 antibody comprises a CDR-L1 sequence defined by the consensus sequence R-A-S-Q-D-V-N-T-A-V-A.
  • PD-1 antibodies that selectively bind human PD-1.
  • the antibody selectively binds to the extracellular domain of human PD-1.
  • the antibody selectively binds to one or more of full-length human PD-1, PD-lAex2, PD-lAex3, PD-lAex2,3, and PD-lAex2,3,4. See Nielsen et al, Cellular Immunology, 2005, 235: 109-116, incorporated by reference in its entirety.
  • the PD-1 antibody binds to a homolog of human PD-1.
  • the antibody binds to a homolog of human Tim-3 from a species selected from monkeys, mice, dogs, cats, rats, cows, horses, goats and sheep.
  • the homolog is a cynomolgus monkey homolog.
  • the homolog is a murine homolog.
  • the PD-1 antibody comprises a light chain.
  • the light chain is a kappa light chain.
  • the light chain is a lambda light chain.
  • the PD-1 antibody comprises a heavy chain.
  • the heavy chain is an IgA.
  • the heavy chain is an IgD.
  • the heavy chain is an IgE.
  • the heavy chain is an IgG.
  • the heavy chain is an IgM.
  • the heavy chain is an IgGl .
  • the heavy chain is an IgG2.
  • the heavy chain is an IgG3.
  • the heavy chain is an IgG4.
  • the heavy chain is an IgAl .
  • the heavy chain is an IgA2.
  • the PD-1 antibody is an antibody fragment.
  • the antibody fragment is an Fv fragment.
  • the antibody fragment is a Fab fragment.
  • the antibody fragment is a F(ab')2 fragment.
  • the antibody fragment is a Fab' fragment.
  • the antibody fragment is an scFv (sFv) fragment.
  • the antibody fragment is an scFv-Fc fragment.
  • the PD-1 antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody.
  • the PD-1 antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody.
  • the PD-1 antibody is an affinity matured antibody.
  • the antibody is an affinity matured antibody derived from an illustrative sequence provided in this disclosure or in, e.g., WO 2016/077397, which is incorporated herein by reference in its entirety.
  • the PD-1 antibody inhibits the binding of PD-1 to its ligands. In some aspects, the antibody inhibits the binding of PD-1 to PD-L1. In some aspects, the antibody inhibits the binding of PD-1 to PD-L2. In some aspects, the antibody inhibits the binding of PD-1 to PD-L1 and PD-L2.
  • the PD-1 antibody is provided as a single arm binder.
  • the PD-1 antibody can be provided as part of a bi-specific antibody or bi- specific antibody construct as disclosed here.
  • the PD-1 antibodies provided herein may be useful for the treatment of a variety of diseases and conditions, including cancers, autoimmune diseases, and infections.
  • the PD-1 antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of an illustrative antibody or VH sequence provided herein.
  • the CDR-H3 sequence is a CDR-H3 sequence of a VH sequence provided in SEQ ID NOs.: 181-220.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 119.
  • the PD-1 antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence selected from SEQ ID NOs.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 182. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 183. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 184.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 185. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 186. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 187.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 188. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 189. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 190.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 191. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 192. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 193.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 194. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 195. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 196.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 197. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 198. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 199.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 200. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 201. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 202.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 203. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 204. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 205.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 206. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 207. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 208.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 209. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 210. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 211.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 212. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 213. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 214.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 215. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 216. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 217.
  • the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 218. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 219. In some aspects, the antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of a VH sequence of SEQ ID NO: 220. In some embodiments, the PD-1 antibody comprises a CDR-H3 sequence comprising, consisting of, or consisting essentially of a CDR-H3 sequence of an illustrative antibody or VH sequence provided in WO 2016/077397.
  • the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. 3.2 PD-1 VH Sequences Comprising Illustrative CDRs
  • the PD-1 antibody comprises a VH sequence comprising one or more CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-H sequences provided in this disclosure, and variants thereof.
  • the CDR-H sequences comprise, consist of, or consist essentially of one or more CDR-H sequences provided in a VH sequence selected from SEQ ID NOs: 181-220.
  • the PD-1 antibody comprises a VH sequence comprising one or more CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-H sequences provided in WO 2016/077397.
  • the PD-1 antibody comprises a VH sequence comprising one or more Kabat CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Kabat CDR-H sequences provided in this disclosure, and variants thereof.
  • the CDR-H sequences comprise, consist of, or consist essentially of one or more CDR-H sequences provided in a VH sequence selected from SEQ ID NOs: 181-220.
  • the PD-1 antibody comprises a VH sequence comprising a CDR-H3 sequence, wherein the CDR-H3 sequence comprises, consists of, or consists essentially of a Kabat CDR-H3 sequence of an illustrative antibody or VH sequence provided herein.
  • the Kabat CDR-H3 sequence is a Kabat CDR-H3 sequence of a VH sequence provided in SEQ ID NOs. : 181-220.
  • the PD-1 antibody comprises a VH sequence comprising a CDR-H3 sequence, wherein the CDR-H3 sequence comprises, consists of, or consists essentially of a Kabat CDR-H3 sequence of an illustrative antibody or VH sequence provided in WO 2016/077397.
  • the antibody comprises a VH sequence comprising a
  • Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 119.
  • the PD-1 antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence selected from SEQ ID NOs. : 182-220. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 182.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 183. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 184. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 185.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 186. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 187. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 188.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 189. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 190. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 191.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 192. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 193. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 194.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 195. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 196. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 197.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 198. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 199.
  • the antibody comprises a VH sequence comprising a Kabat
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 200.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 201.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 202.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 203. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 204. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 205.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 206. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 207. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 208.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 209. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 210. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 211.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 212. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 213. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 214.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 215. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 216. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 217.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 218. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 219. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H3 sequence of a VH sequence of SEQ ID NO: 220.
  • the PD-1 antibody comprises a VH sequence comprising a CDR-H2 sequence, wherein the CDR-H2 sequence comprises, consists of, or consists essentially of a Kabat CDR-H2 sequence of an illustrative antibody or VH sequence provided herein.
  • the Kabat CDR-H2 sequence is a Kabat CDR-H2 sequence of a VH sequence provided in SEQ ID NOs. : 181-220.
  • the PD-1 antibody comprises a VH sequence comprising a CDR-H2 sequence, wherein the CDR-H2 sequence comprises, consists of, or consists essentially of a Kabat CDR-H2 sequence of an illustrative antibody or VH sequence provided in WO 2016/077397.
  • the antibody comprises a VH sequence comprising a
  • Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 110.
  • the PD-1 antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence selected from SEQ ID NOs. : 182-220. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 182.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 183. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 184. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 185.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 186. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 187. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 188.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 189. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 190. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 191.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 192. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 193. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 194.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 195. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 196. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 197.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 198. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 199.
  • the antibody comprises a VH sequence comprising a Kabat
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 200.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 201.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 202.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 203. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 204. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 205.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 206. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 207. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 208.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 209. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 210. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 211.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 212. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 213. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 214.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 215. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 216. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 217.
  • the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 218. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 219. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a Kabat CDR-H2 sequence of a VH sequence of SEQ ID NO: 220. 3.2.2.3 Kabat CDR-Hl
  • the PD-1 antibody comprises a VH sequence comprising a CDR-Hl sequence, wherein the CDR-Hl sequence comprises, consists of, or consists essentially of a Kabat CDR-Hl sequence of an illustrative antibody or VH sequence provided herein.
  • the Kabat CDR-Hl sequence is a Kabat CDR-Hl sequence of a VH sequence provided in SEQ ID NOs. : 181-220.
  • the PD-1 antibody comprises a VH sequence comprising a CDR-Hl sequence, wherein the CDR-Hl sequence comprises, consists of, or consists essentially of a Kabat CDR-Hl sequence of an illustrative antibody or VH sequence provided in WO 2016/077397.
  • the PD-1 antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 57-62. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 57. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 58.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 59. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 60. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 61. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 62.
  • the PD-1 antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence selected from SEQ ID NOs. : 182-220. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 182.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 183. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 184. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 185.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 186. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 187. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 188.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 189. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 190. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 191.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 192. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 193. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 194.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 195. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 196. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 197.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 198. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 199.
  • the antibody comprises a VH sequence comprising a Kabat
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 200.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 201.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 202.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 203. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 204. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 205.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 206. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 207. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 208.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 209. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 210. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 211.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 212. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 213. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 214.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 215. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 216. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 217.
  • the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 218. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 219. In some aspects, the antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a Kabat CDR-Hl sequence of a VH sequence of SEQ ID NO: 220.
  • the PD-1 antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 119, and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 110.
  • the PD-1 antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from a Kabat CDR-H3 sequence of a VH sequence selected from SEQ ID NOs.: 181-220, and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from a Kabat CDR-H2 sequence of a VH sequence selected from SEQ ID NOs. : 181-220.
  • the Kabat CDR-H3 sequence and the Kabat CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure.
  • the Kabat CDR-H3 and Kabat CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOs: 181- 220. 3.2.2.5 Kabat CDR-H3 + Kabat CDR-Hl
  • the PD-1 antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 119, and a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 57-62.
  • the PD-1 antibody comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from a Kabat CDR-H3 sequence of a VH sequence provided in any one of SEQ ID NOs.: 181-220, and a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from a Kabat CDR-Hl sequence of a VH sequence provided in any one of SEQ ID NOs. : 181- 220.
  • the Kabat CDR-H3 sequence and the Kabat CDR-Hl sequence are both from a single illustrative VH sequence provided in this disclosure.
  • the Kabat CDR-H3 and Kabat CDR-Hl are both from a single illustrative VH sequence selected from SEQ ID NOs: 181-220.
  • the PD-1 antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 57-62, and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 110.
  • the PD-1 antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from a Kabat CDR-Hl sequence of a VH sequence provided in any one of SEQ ID NOs.: 181-220, and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from a Kabat CDR-H2 sequence of a VH sequence provided in any one of SEQ ID NOs. : 181- 220.
  • the Kabat CDR-Hl sequence and the Kabat CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure.
  • the Kabat CDR-Hl and Kabat CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOs: 181-220.
  • the PD-1 antibody comprises a VH sequence comprising a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 57-62, a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 110, and a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 119.
  • the PD-1 antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from a Kabat CDR-H1 sequence of a VH sequence selected from SEQ ID NOs.: 181-220, a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from a Kabat CDR-H2 sequence of a VH sequence selected from SEQ ID NOs.: 181-220, and a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from a Kabat CDR-H3 sequence of a VH sequence selected from SEQ ID NOs.
  • the Kabat CDR-H1 sequence, Kabat CDR-H2 sequence, and Kabat CDR-H3 are all from a single illustrative VH sequence provided in this disclosure.
  • the Kabat CDR-H1, Kabat CDR-H2, and Kabat CDR-H3 are all from a single illustrative VH sequence selected from SEQ ID NOs: 181-220.
  • the VH sequences provided herein comprise a variant of an illustrative Kabat CDR-H3, CDR-H2, and/or CDR-H1 sequence provided in this disclosure. In some embodiments, the VH sequences provided herein comprise a variant of an illustrative Kabat CDR-H3, CDR-H2, and/or CDR-H1 sequence provided in WO 2016/077397.
  • the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H3 sequence provided in this disclosure.
  • the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H3 sequences provided in this disclosure.
  • the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H2 sequence provided in this disclosure.
  • the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H2 sequences provided in this disclosure.
  • the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Kabat CDR-Hl sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-Hl sequence provided in this disclosure.
  • the Kabat CDR-Hl sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-Hl sequences provided in this disclosure.
  • the Kabat CDR-Hl sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-Hl sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the PD-1 antibody comprises a VH sequence comprising one or more Chothia CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Chothia CDR-H sequences provided in this disclosure, and variants thereof.
  • the PD-1 antibody comprises a VH sequence comprising one or more Chothia CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Chothia CDR-H sequences provided in WO 2016/077397.
  • the PD-1 antibody comprises a VH sequence comprising a CDR-H3 sequence, wherein the CDR-H3 sequence comprises, consists of, or consists essentially of a Chothia CDR-H3 sequence of an illustrative antibody or VH sequence provided herein.
  • the Chothia CDR-H3 sequence is a Chothia CDR-H3 sequence of a VH sequence provided in SEQ ID NOs. : 181-220.
  • the PD-1 antibody comprises a VH sequence comprising a CDR-H3 sequence, wherein the CDR-H3 sequence comprises, consists of, or consists essentially of a Chothia CDR-H3 sequence of an illustrative antibody or VH sequence provided in WO 2016/077397.
  • the antibody comprises a VH sequence comprising a
  • Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 119.
  • the PD-1 antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence selected from SEQ ID NOs. : 182-220.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 182.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 183. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 184. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 185.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 186. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 187. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 188.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 189. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 190. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 191.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 192. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 193. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 194.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 195. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 196. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 197.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 198. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 199.
  • the antibody comprises a VH sequence comprising a Chothia
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 200.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 201.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 202.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 203. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 204. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 205.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 206. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 207. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 208.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 209. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 210. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 211.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 212. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 213. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 214.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 215. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 216. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 217.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 218. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 219. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H3 sequence of a VH sequence of SEQ ID NO: 220.
  • the PD-1 antibody comprises a VH sequence comprising a CDR-H2 sequence, wherein the CDR-H2 sequence comprises, consists of, or consists essentially of a Chothia CDR-H2 sequence of an illustrative antibody or VH sequence provided herein.
  • the Chothia CDR-H2 sequence is a Chothia CDR-H2 sequence of a VH sequence provided in SEQ ID NOs. : 181-220.
  • the PD-1 antibody comprises a VH sequence comprising a CDR-H2 sequence, wherein the CDR-H2 sequence comprises, consists of, or consists essentially of a Chothia CDR-H2 sequence of an illustrative antibody or VH sequence provided in WO 2016/077397.
  • the antibody comprises a VH sequence comprising a
  • Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 81.
  • the PD-1 antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence selected from SEQ ID NOs. : 182-220.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 182.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 183. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 184. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 185.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 186. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 187. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 188.
  • the antibody comprises a VH sequence comprising a Chothia CDR- H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 189. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 190. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 191.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 192. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 193. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 194.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 195. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 196. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 197.
  • the antibody comprises a VH sequence comprising a Chothia CDR- H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 198. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 199.
  • the antibody comprises a VH sequence comprising a Chothia
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 200.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 201.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 202.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 203. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 204. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 205.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 206. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 207. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 208.
  • the antibody comprises a VH sequence comprising a Chothia CDR- H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 209. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 210. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 211.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 212. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 213. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 214.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 215. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 216. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 217.
  • the antibody comprises a VH sequence comprising a Chothia CDR- H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 218. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 219. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a Chothia CDR-H2 sequence of a VH sequence of SEQ ID NO: 220.
  • the PD-1 antibody comprises a VH sequence comprising a CDR-H1 sequence, wherein the CDR-H1 sequence comprises, consists of, or consists essentially of a Chothia CDR-H1 sequence of an illustrative antibody or VH sequence provided herein.
  • the Chothia CDR-H1 sequence is a Chothia CDR-H1 sequence of a VH sequence provided in SEQ ID NOs. : 181-220.
  • the PD-1 antibody comprises a VH sequence comprising a CDR-H1 sequence, wherein the CDR-H1 sequence comprises, consists of, or consists essentially of a Chothia CDR-H1 sequence of an illustrative antibody or VH sequence provided in WO 2016/077397.
  • the PD-1 antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 24-38. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 24. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 25.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 26. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 27. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 28. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 29.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 30. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 31. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 32. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 33.
  • the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 34. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 35. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 36. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 37. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 38.
  • the PD-1 antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence selected from SEQ ID NOs. : 182-220.
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 182.
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 183. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 184. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 185.
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 186. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 187. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 188.
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 189. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 190. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 191.
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 192. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 193. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 194.
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 195. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 196. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 197.
  • the antibody comprises a VH sequence comprising a Chothia CDR- Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 198. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 199.
  • the antibody comprises a VH sequence comprising a Chothia
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 200.
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 201.
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 202.
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 203. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 204. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 205.
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 206. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 207. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 208.
  • the antibody comprises a VH sequence comprising a Chothia CDR- Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 209. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 210. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 211.
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 212. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 213. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 214.
  • the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 215. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 216. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 217.
  • the antibody comprises a VH sequence comprising a Chothia CDR- Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 218. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 219. In some aspects, the antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a Chothia CDR-Hl sequence of a VH sequence of SEQ ID NO: 220.
  • the PD-1 antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 119, and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 81.
  • the PD-1 antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from a Chothia CDR-H3 sequence of a VH sequence selected from SEQ ID NOs.: 181-220, and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from a Chothia CDR-H2 sequence of a VH sequence selected from SEQ ID NOs.: 181-220.
  • the Chothia CDR-H3 sequence and the Chothia CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure.
  • the Chothia CDR-H3 and Chothia CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOs: 181-220.
  • the PD-1 antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 119, and a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 24-38.
  • the PD-1 antibody comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from a Chothia CDR-H3 sequence of a VH sequence provided in any one of SEQ ID NOs.: 181-220, and a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from a Chothia CDR-Hl sequence of a VH sequence provided in any one of SEQ ID NOs.: 181-220.
  • the Chothia CDR-H3 sequence and the Chothia CDR-Hl sequence are both from a single illustrative VH sequence provided in this disclosure.
  • the Chothia CDR-H3 and Chothia CDR-Hl are both from a single illustrative VH sequence selected from SEQ ID NOs: 181-220. 3.2.2.6 Chothia CDR-Hl + Chothia CDR-H2
  • the PD-1 antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 24-38 and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 81.
  • the PD-1 antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from a Chothia CDR-Hl sequence of a VH sequence provided in any one of SEQ ID NOs.: 181-220, and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from a Chothia CDR-H2 sequence of a VH sequence provided in any one of SEQ ID NOs. : 181-220.
  • the Chothia CDR-Hl sequence and the Chothia CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure.
  • the Chothia CDR-Hl and Chothia CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOs: 181-220.
  • the PD-1 antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs:24-38, a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 81, and a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 119.
  • the PD-1 antibody comprises a VH sequence comprising a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from a Chothia CDR-Hl sequence of a VH sequence provided in any one of SEQ ID NOs.
  • a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from a Chothia CDR-H2 sequence of a VH sequence provided in any one of SEQ ID NOs.: 181-220
  • a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from a Chothia CDR-H3 sequence of a VH sequence provided in any one of SEQ ID NOs. : 181-220.
  • the Chothia CDR-Hl sequence, Chothia CDR-H2 sequence, and Chothia CDR-H3 sequence are all from a single illustrative VH sequence provided in this disclosure.
  • the Chothia CDR-Hl, Chothia CDR-H2, and Chothia CDR-H3 are all from a single illustrative VH sequence selected from SEQ ID NOs: 181-220. 3.2.2.8 Variants of V H Sequences Comprising Illustrative Chothia CDRs
  • the VH sequences provided herein comprise a variant of an illustrative Chothia CDR-H3, CDR-H2, and/or CDR-Hl sequence provided in this disclosure.
  • the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H3 sequence provided in this disclosure.
  • the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H3 sequences provided in this disclosure.
  • the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H2 sequence provided in this disclosure.
  • the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H2 sequences provided in this disclosure.
  • the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the Chothia CDR-Hl sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-Hl sequence provided in this disclosure.
  • the Chothia CDR-Hl sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-Hl sequences provided in this disclosure.
  • the Chothia CDR-Hl sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-Hl sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the PD-1 antibody comprises, consists of, or consists essentially of a VH sequence provided in SEQ ID NOs. : 181-220.
  • the PD-1 antibody comprises a VH sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 181-220. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 181. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 182. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 183. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 184.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 185. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 186. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 187. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 188. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 189.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 190. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 191. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 192. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 193. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 194.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 195. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 196. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 197. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 198. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 199.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 200. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 201. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 202. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 203. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 204.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 205. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 206. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 207. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 208. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 209.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 210. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 211. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 212. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 213. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 214.
  • the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 215. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 216. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 217. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 218. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 219. In some aspects, the antibody comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 220.
  • the VH sequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VH sequence provided in this disclosure. In some embodiments, the VH sequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VH sequence provided in WO 2016/077397. [00273] In some aspects, the VH sequence comprises, consists of, or consists essentially of a variant of an illustrative VH sequence provided in this disclosure.
  • the VH sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative VH sequences provided in this disclosure.
  • the VH sequence comprises, consists of, or consists essentially of any of the illustrative VH sequences provided in this disclosure having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the PD-1 antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of an illustrative antibody or VL sequence provided herein.
  • the CDR-L3 sequence is a CDR-L3 sequence of a VL sequence provided in SEQ ID NOs. : 236-269.
  • the PD-1 antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of an illustrative antibody or VL sequence provided in WO 2016/077397.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 143.
  • the PD-1 antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence selected from SEQ ID NOs. : 237-269. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 237. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 238.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 239. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 240. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 241.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 242. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 243. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 244.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 245. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 246. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 247.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 248. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 249.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 250. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 251. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 252.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 253. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 254. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 255.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 256. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 257. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 258.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 259. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 260. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 261.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 262. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 263. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 264.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 265. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 266. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 267.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 268. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 269.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.
  • the PD-1 antibody comprises a VL sequence comprising one or more CDR-L sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-L sequences provided in this disclosure, and variants thereof.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-L3 sequence, wherein the CDR-L3 sequence comprises, consists of, or consists essentially of a CDR-L3 sequence of an illustrative antibody or VL sequence provided herein.
  • the CDR-L3 sequence is a CDR-L3 sequence of a VL sequence provided in SEQ ID NOs. : 236-269.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-L3 sequence, wherein the CDR-L3 sequence comprises, consists of, or consists essentially of a CDR-L3 sequence of an illustrative antibody or VL sequence provided in WO 2016/077397.
  • the antibody comprises a VL sequence comprising a
  • CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 143.
  • the PD-1 antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence selected from SEQ ID NOs. : 237-269. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 237. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 238.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 239. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 240. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 241.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 242. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 243. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 244.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 245. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 246. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 247.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 248. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 249.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 250. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 251. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 252.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 253. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 254. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 255.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 256. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 257. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 258.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 259. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 260. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 261.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 262. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 263. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 264.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 265. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 266. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 267.
  • the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 268. In some aspects, the antibody comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a CDR-L3 sequence of a VL sequence of SEQ ID NO: 269.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-L2 sequence, wherein the CDR-L2 sequence comprises, consists of, or consists essentially of a CDR-L2 sequence of an illustrative antibody or VL sequence provided herein.
  • the CDR-L2 sequence is a CDR-L2 sequence of a VL sequence provided in SEQ ID NOs. : 236-269.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-L2 sequence, wherein the CDR-L2 sequence comprises, consists of, or consists essentially of a CDR-L2 sequence of an illustrative antibody or VL sequence provided in WO 2016/077397.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 134-139. In some aspects, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 134. In some aspects, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 135. In some aspects, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 136.
  • the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 137. In some aspects, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 138. In some aspects, the antibody comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 139.
  • the PD-1 antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence selected from SEQ ID NOs. : 237-269. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 237. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 238.
  • the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 239. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 240. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 241.
  • the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 242. In some aspects, the antibody comprises a CDR L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 243. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 244.
  • the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 245. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 246. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 247.
  • the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 248. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 249.
  • the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 250. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 251. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 252.
  • the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 253. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 254. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 255.
  • the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 256. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 257. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 258.
  • the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 259. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 260. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 261.
  • the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 262. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 263. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 264.
  • the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 265. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 266. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 267.
  • the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 268. In some aspects, the antibody comprises a CDR-L2 sequence comprising, consisting of, or consisting essentially of a CDR-L2 sequence of a VL sequence of SEQ ID NO: 269.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-Ll sequence, wherein the CDR-Ll sequence comprises, consists of, or consists essentially of a CDR-Ll sequence of an illustrative antibody or VL sequence provided herein.
  • the CDR-Ll sequence is a CDR-Ll sequence of a VL sequence provided in SEQ ID NOs. : 236-269.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-Ll sequence, wherein the CDR-Ll sequence comprises, consists of, or consists essentially of a CDR-Ll sequence of an illustrative antibody or VL sequence provided in WO 2016/077397.
  • the antibody comprises a VL sequence comprising a
  • CDR-Ll sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 124.
  • the PD-1 antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence selected from SEQ ID NOs. : 237-269. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 237. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 238.
  • the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 239. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 240. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 241.
  • the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 242. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 243. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 244.
  • the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 245. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 246. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 247.
  • the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 248. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 249.
  • the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 250. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 251. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 252.
  • the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 253. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 254. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 255.
  • the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 256. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 257. In some aspects, the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-Ll sequence of a VL sequence of SEQ ID NO: 258.
  • the antibody comprises a CDR-Ll sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence of a VL sequence of SEQ ID NO: 259. In some aspects, the antibody comprises a CDR-L1 sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence of a VL sequence of SEQ ID NO: 260. In some aspects, the antibody comprises a CDR-L1 sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence of a VL sequence of SEQ ID NO: 261.
  • the antibody comprises a CDR-L1 sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence of a VL sequence of SEQ ID NO: 262. In some aspects, the antibody comprises a CDR-L1 sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence of a VL sequence of SEQ ID NO: 263. In some aspects, the antibody comprises a CDR-L1 sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence of a VL sequence of SEQ ID NO: 264.
  • the antibody comprises a CDR-L1 sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence of a VL sequence of SEQ ID NO: 265. In some aspects, the antibody comprises a CDR-L1 sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence of a VL sequence of SEQ ID NO: 266. In some aspects, the antibody comprises a CDR-L1 sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence of a VL sequence of SEQ ID NO: 267.
  • the antibody comprises a CDR-L1 sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence of a VL sequence of SEQ ID NO: 268. In some aspects, the antibody comprises a CDR-L1 sequence comprising, consisting of, or consisting essentially of a CDR-L1 sequence of a VL sequence of SEQ ID NO: 269.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 143 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 134-139.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from a CDR-L3 sequence of a VL sequence selected from SEQ ID NOs.
  • the CDR-L3 sequence and the CDR-L2 sequence are both from a single illustrative VL sequence provided in this disclosure.
  • the CDR-L3 and CDR-L2 are both from a single illustrative VL sequence selected from SEQ ID NOs: 236-269.
  • the CDR-L3 sequence and the CDR-L2 sequence are both from a single illustrative VL sequence provided in WO 2016/077397.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 143 and a CDR-Ll sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 124.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from a CDR-L3 sequence of a VL sequence selected from SEQ ID NOs.: 236-269, and a CDR-Ll sequence comprising, consisting of, or consisting essentially of a sequence selected from a CDR-Ll sequence of a VL sequence selected from SEQ ID NOs.: 236-269.
  • the CDR-L3 sequence and the CDR-Ll sequence are both from a single illustrative VL sequence provided in this disclosure.
  • the CDR-L3 and CDR-Ll are both from a single illustrative VL sequence selected from SEQ ID NOs: 236-269.
  • the CDR-L3 sequence and the CDR-Ll sequence are both from a single illustrative VL sequence provided in WO 2016/077397.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-Ll sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 124 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 134-139.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-Ll sequence comprising, consisting of, or consisting essentially of a sequence selected from a CDR-Ll sequence of a VL sequence selected from SEQ ID NOs.: 236-269, and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from a CDR-L2 sequence of a VL sequence selected from SEQ ID NOs.: 236-269.
  • the CDR-Ll sequence and the CDR-L2 sequence are both from a single illustrative VL sequence provided in this disclosure.
  • the CDR-Ll and CDR-L2 are both from a single illustrative VL sequence selected from SEQ ID NOs: 236-269.
  • the CDR-Ll sequence and the CDR-L2 sequence are both from a single illustrative VL sequence provided in WO 2016/077397. 3.5.7 CDR-L1 + CDR-L2 + CDR-L3
  • the PD-1 antibody comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 124, a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 134-139, and a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 143.
  • the PD-1 antibody comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from a CDR-L1 sequence of a VL sequence selected from SEQ ID NOs.
  • a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from a CDR-L2 sequence of a VL sequence selected from SEQ ID NOs. : 236-269
  • a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from a CDR-L3 sequence of a VL sequence selected from SEQ ID NOs. : 236-269.
  • the CDR-L1 sequence, CDR-L2 sequence, and CDR-L3 sequence are all from a single illustrative VL sequence provided in this disclosure.
  • the CDR-L1, CDR-L2, and CDR-L3 are all from a single illustrative VL sequence selected from SEQ ID NOs: 236-269.
  • the CDR-L1 sequence, CDR-L2 sequence, and CDR-L3 sequence are all from a single illustrative VL sequence provided in WO 2016/077397.
  • the VL sequences provided herein comprise a variant of an illustrative CDR-L3, CDR-L2, and/or CDR-L1 sequence provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-Ll sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-Ll sequence provided in this disclosure.
  • the CDR-Ll sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-Ll sequences provided in this disclosure.
  • the CDR-Ll sequence comprises, consists of, or consists essentially of any of the illustrative CDR-Ll sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the PD-1 antibody comprises, consists of, or consists essentially of a VL sequence provided in SEQ ID NOs. : 236-269.
  • the PD-1 antibody comprises a VL sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 236-269. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 236. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 237. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 238. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 239.
  • the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 240. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 241. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 242. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 243. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 244.
  • the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 245. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 246. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 247. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 248. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 249.
  • the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 250. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 251. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 252. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 253. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 254.
  • the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 255. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 256. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 257. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 258. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 259.
  • the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 260. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 261. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 262. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 263. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 264.
  • the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 265. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 266. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 267. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 268. In some aspects, the antibody comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 269. 3.6.1 Variants of V L Sequences
  • the VL sequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VL sequence provided in this disclosure. In some embodiments, the VL sequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VL sequence provided in WO 2016/077397.
  • the VL sequence comprises, consists of, or consists essentially of a variant of an illustrative VL sequence provided in this disclosure. In some aspects, the VL sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative VL sequences provided in this disclosure.
  • the VL sequence comprises, consists of, or consists essentially of any of the illustrative VL sequences provided in this disclosure having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the PD-1 antibody comprises a CDR-H3 sequence and a CDR-L3 sequence.
  • the CDR-H3 sequence is part of a VH and the CDR-L3 sequence is part of a VL.
  • the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NO: 119 and a CDR-H3 sequence of a a VH sequence selected from SEQ ID NOs.: 182-220
  • the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NO: 143 and a CDR-L3 sequence of a a VL sequence selected from SEQ ID NOs. : 237-269.
  • the CDR-H3 - CDR-L3 pairs provided herein comprise a variant of an illustrative CDR-H3 and/or CDR-L1 sequence provided in this disclosure.
  • the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some aspects, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some aspects, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.
  • the PD-1 antibody comprises a CDR-Hl sequence and a CDR-L1 sequence.
  • the CDR-Hl sequence is part of a VH and the CDR-L1 sequence is part of a VL.
  • the CDR-Hl sequence is a Chothia CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 24-38 and a Chothia CDR-Hl sequence of a a VH sequence selected from SEQ ID NOs. : 182-220
  • the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NO: 124 and a CDR-L1 sequence of a a VL sequence selected from SEQ ID NOs. : 237-269.
  • the CDR-Hl sequence is a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 57-62 and a Kabat CDR-Hl sequence of a a VH sequence selected from SEQ ID NOs. : 182-220
  • the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NO: 124 and a CDR-L1 sequence of a a VL sequence selected from SEQ ID NOs. : 237-269.
  • the CDR-Hl - CDR-Ll pairs provided herein comprise a variant of an illustrative CDR-Hl and/or CDR-Ll sequence provided in this disclosure.
  • the CDR-Hl sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-Hl sequence provided in this disclosure. In some aspects, the CDR-Hl sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-Hl sequences provided in this disclosure. In some aspects, the CDR-Hl sequence comprises, consists of, or consists essentially of any of the illustrative CDR-Hl sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-Ll sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-Ll sequence provided in this disclosure.
  • the CDR-Ll sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-Ll sequences provided in this disclosure.
  • the CDR-Ll sequence comprises, consists of, or consists essentially of any of the illustrative CDR-Ll sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the PD-1 antibody comprises a CDR-H2 sequence and a CDR-L2 sequence.
  • the CDR-H2 sequence is part of a VH and the CDR-L2 sequence is part of a VL.
  • the CDR-H2 sequence is a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NO: 81 and a Chothia CDR-H2 sequence of a a VH sequence selected from SEQ ID NOs. : 182-220
  • the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 134-139 and a CDR-L2 sequence of a a VL sequence selected from SEQ ID NOs. : 237-269.
  • the CDR-Hl sequence is a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NO: 110 and a Kabat CDR-H2 sequence of a a VH sequence selected from SEQ ID NOs. : 182-220
  • the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOs: 134-139 and a CDR-L2 sequence of a a VL sequence selected from SEQ ID NOs. : 237-269.
  • the CDR-H2 - CDR-L2 pairs provided herein comprise a variant of an illustrative CDR-H2 and/or CDR-L2 sequence provided in this disclosure.
  • the CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H2 sequence provided in this disclosure.
  • the CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H2 sequences provided in this disclosure.
  • the CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H2 sequences provided in this disclosure, with 1 , 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1 , 2, or 3 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions.
  • the PD-1 antibody comprises a VH sequence and a VL sequence.
  • the VH sequence is a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 181-220
  • the VL sequence is a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 236-269.
  • VH - VL pairs are selected from SEQ ID NO: 181 and
  • SEQ ID NO: 236 SEQ ID NO: 181 and SEQ ID NO: 325; SEQ ID NO: 181 and SEQ ID NO: 237; SEQ ID NO: 181 and SEQ ID NO: 238; SEQ ID NO: 181 and SEQ ID NO: 239; SEQ ID NO: 181 and SEQ ID NO: 240; SEQ ID NO: 181 and SEQ ID NO: 241 ; SEQ ID NO: 181 and SEQ ID NO: 242; SEQ ID NO: 181 and SEQ ID NO: 243; SEQ ID NO: 181 and SEQ ID NO: 244; SEQ ID NO: 181 and SEQ ID NO: 245; SEQ ID NO: 181 and SEQ ID NO: 246; SEQ ID NO: 181 and SEQ ID NO: 247; SEQ ID NO: 181 and SEQ ID NO: 248; SEQ ID NO: 181 and SEQ ID NO: 249; SEQ ID NO: 181 and SEQ ID NO: 250; SEQ ID NO: 181
  • VH - VL pairs are selected from SEQ ID NO: 182 and
  • VH - VL pairs are selected from SEQ ID NO: 183 and
  • VH - VL pairs are selected from SEQ ID NO: 184 and
  • VH - VL pairs are selected from SEQ ID NO: 185 and
  • VH - VL pairs are selected from SEQ ID NO: 186 and
  • VH - VL pairs are selected from SEQ ID NO: 187 and
  • VH - VL pairs are selected from SEQ ID NO: 188 and
  • VH - VL pairs are selected from SEQ ID NO: 189 and
  • VH - VL pairs are selected from SEQ ID NO: 190 and
  • SEQ ID NO: 236 SEQ ID NO: 191 and SEQ ID NO: 325; SEQ ID NO: 191 and SEQ ID NO: 237; SEQ ID NO: 191 and SEQ ID NO: 238; SEQ ID NO: 191 and SEQ ID NO: 239; SEQ ID NO: 191 and SEQ ID NO: 240; SEQ ID NO: 191 and SEQ ID NO: 241 ; SEQ ID NO: 191 and SEQ ID NO: 242; SEQ ID NO: 191 and SEQ ID NO: 243; SEQ ID NO: 191 and SEQ ID NO: 244; SEQ ID NO: 191 and SEQ ID NO: 245; SEQ ID NO: 191 and SEQ ID NO: 246; SEQ ID NO: 191 and SEQ ID NO: 247; SEQ ID NO: 191 and SEQ ID NO: 248; SEQ ID NO: 191 and SEQ ID NO: 249; SEQ ID NO: 191 and SEQ ID NO: 250; SEQ ID NO: 191
  • VH - VL pairs are selected from SEQ ID NO: 192 and
  • VH - VL pairs are selected from SEQ ID NO: 194 and
  • VH - VL pairs are selected from SEQ ID NO: 195 and
  • VH - VL pairs are selected from SEQ ID NO: 196 and
  • VH - VL pairs are selected from SEQ ID NO: 197 and
  • SEQ ID NO: 236 SEQ ID NO: 199 and SEQ ID NO: 325; SEQ ID NO: 199 and SEQ ID NO: 237; SEQ ID NO: 199 and SEQ ID NO: 238; SEQ ID NO: 199 and SEQ ID NO: 239; SEQ ID NO: 199 and SEQ ID NO: 240; SEQ ID NO: 199 and SEQ ID NO: 241 ; SEQ ID NO: 199 and SEQ ID NO: 242; SEQ ID NO: 199 and SEQ ID NO: 243; SEQ ID NO: 199 and SEQ ID NO: 244; SEQ ID NO: 199 and SEQ ID NO: 245; SEQ ID NO: 199 and SEQ ID NO: 246; SEQ ID NO: 199 and SEQ ID NO: 247; SEQ ID NO: 199 and SEQ ID NO: 248; SEQ ID NO: 199 and SEQ ID NO: 249; SEQ ID NO: 199 and SEQ ID NO: 250; SEQ ID NO: 199
  • VH - VL pairs are selected from SEQ ID NO: 200 and
  • VH - VL pairs are selected from SEQ ID NO: 201 and
  • VH - VL pairs are selected from SEQ ID NO: 205 and
  • VH - VL pairs are selected from SEQ ID NO: 206 and
  • VH - VL pairs are selected from SEQ ID NO: 209 and
  • SEQ ID NO: 236 SEQ ID NO: 209 and SEQ ID NO: 325; SEQ ID NO: 209 and SEQ ID NO: 237; SEQ ID NO: 209 and SEQ ID NO: 238; SEQ ID NO: 209 and SEQ ID NO: 239; SEQ ID NO: 209 and SEQ ID NO: 240; SEQ ID NO: 209 and SEQ ID NO: 241 ; SEQ ID NO: 209 and SEQ ID NO: 242; SEQ ID NO: 209 and SEQ ID NO: 243; SEQ ID NO: 209 and SEQ ID NO: 244; SEQ ID NO: 209 and SEQ ID NO: 245; SEQ ID NO: 209 and SEQ ID NO: 246; SEQ ID NO: 209 and SEQ ID NO: 247; SEQ ID NO: 209 and SEQ ID NO: 248; SEQ ID NO: 209 and SEQ ID NO: 249; SEQ ID NO: 209 and SEQ ID NO: 250; SEQ ID NO: 209
  • VH - VL pairs are selected from SEQ ID NO: 210 and
  • VH - VL pairs are selected from SEQ ID NO: 21 1 and
  • VH - VL pairs are selected from SEQ ID NO: 212 and
  • VH - VL pairs are selected from SEQ ID NO: 213 and
  • SEQ ID NO: 236 SEQ ID NO: 213 and SEQ ID NO: 325; SEQ ID NO: 213 and SEQ ID NO: 237; SEQ ID NO: 213 and SEQ ID NO: 238; SEQ ID NO: 213 and SEQ ID NO: 239; SEQ ID NO: 213 and SEQ ID NO: 240; SEQ ID NO: 213 and SEQ ID NO: 241 ; SEQ ID NO: 213 and SEQ ID NO: 242; SEQ ID NO: 213 and SEQ ID NO: 243; SEQ ID NO: 213 and SEQ ID NO: 244; SEQ ID NO: 213 and SEQ ID NO: 245; SEQ ID NO: 213 and SEQ ID NO: 246; SEQ ID NO: 213 and SEQ ID NO: 247; SEQ ID NO: 213 and SEQ ID NO: 248; SEQ ID NO: 213 and SEQ ID NO: 249; SEQ ID NO: 213 and SEQ ID NO: 250; SEQ ID NO: 213
  • VH - VL pairs are selected from SEQ ID NO: 215 and
  • VH - VL pairs are selected from SEQ ID NO: 216 and
  • SEQ ID NO: 236 SEQ ID NO: 217 and SEQ ID NO: 325; SEQ ID NO: 217 and SEQ ID NO: 237; SEQ ID NO: 217 and SEQ ID NO: 238; SEQ ID NO: 217 and SEQ ID NO: 239; SEQ ID NO: 217 and SEQ ID NO: 240; SEQ ID NO: 217 and SEQ ID NO: 241 ; SEQ ID NO: 217 and SEQ ID NO: 242; SEQ ID NO: 217 and SEQ ID NO: 243; SEQ ID NO: 217 and SEQ ID NO: 244; SEQ ID NO: 217 and SEQ ID NO: 245; SEQ ID NO: 217 and SEQ ID NO: 246; SEQ ID NO: 217 and SEQ ID NO: 247; SEQ ID NO: 217 and SEQ ID NO: 248; SEQ ID NO: 217 and SEQ ID NO: 249; SEQ ID NO: 217 and SEQ ID NO: 250; SEQ ID NO: 217
  • VH - VL pairs are selected from SEQ ID NO: 218 and
  • VH - VL pairs are selected from SEQ ID NO: 219 and
  • SEQ ID NO: 236 SEQ ID NO: 219 and SEQ ID NO: 325; SEQ ID NO: 219 and SEQ ID NO: 237; SEQ ID NO: 219 and SEQ ID NO: 238; SEQ ID NO: 219 and SEQ ID NO: 239; SEQ ID NO: 219 and SEQ ID NO: 240; SEQ ID NO: 219 and SEQ ID NO: 241 ; SEQ ID NO: 219 and SEQ ID NO: 242; SEQ ID NO: 219 and SEQ ID NO: 243; SEQ ID NO: 219 and SEQ ID NO: 244; SEQ ID NO: 219 and SEQ ID NO: 245; SEQ ID NO: 219 and SEQ ID NO: 246; SEQ ID NO: 219 and SEQ ID NO: 247; SEQ ID NO: 219 and SEQ ID NO: 248; SEQ ID NO: 219 and SEQ ID NO: 249; SEQ ID NO: 219 and SEQ ID NO: 250; SEQ ID NO: 219
  • VH - VL pairs are selected from SEQ ID NO: 220 and
  • the VH - VL pairs provided herein comprise a variant of an illustrative VH and/or VL sequence provided in this disclosure.
  • the VH sequence comprises, consists of, or consists essentially of any of the illustrative VH sequences provided in this disclosure having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the VL sequence comprises, consists of, or consists essentially of a variant of an illustrative VL sequence provided in this disclosure. In some aspects, the VL sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative VL sequences provided in this disclosure.
  • the VL sequence comprises, consists of, or consists essentially of any of the illustrative VL sequences provided in this disclosure having 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the PD-1 antibody comprises a CDR-H1 sequence, a
  • CDR-H2 sequence a CDR-H3 sequence, a CDR-Ll sequence, a CDR-L2 sequence, and a CDR-L3 sequence.
  • the CDR sequences are part of a VH (for CDR-H) or VL (for CDR-L).
  • the CDR-H1 sequence is a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 24-38 or a Chothia CDR- Hl sequence of a VH sequence provided in any one of SEQ ID NOs.
  • the CDR-Hl sequence is a Kabat CDR-Hl sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 57-62 or a Kabat CDR- Hl sequence of a VH sequence selected from SEQ ID NOs.: 181-220;
  • the CDR-H2 sequence is a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 110 or a Kabat CDR-H2 sequence of a VH sequence selected from SEQ ID NOs.
  • the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 119 or a Kabat CDR-H3 sequence of a VH sequence selected from SEQ ID NOs. : 181-220;
  • the CDR-L1 sequence is a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 124 or a CDR-L1 sequence of a VL sequence selected from SEQ ID NOs.
  • the CDR-L2 sequence is a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 134-139 or a CDR-L2 sequence of a VL sequence selected from SEQ ID NOs. : 236-269
  • the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 143 or or a CDR-L3 sequence of a VL sequence selected from SEQ ID NOs. : 236-269.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia or Kabat CDR-H2 sequence provided in this disclosure.
  • the CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia or Kabat CDR-H2 sequences provided in this disclosure.
  • the CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia or Kabat CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure.
  • the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure.
  • the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-L1 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L1 sequence provided in this disclosure.
  • the CDR-L1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L1 sequences provided in this disclosure.
  • the CDR-L1 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure.
  • the CDR-L2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure.
  • the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1 , 2, or 3 amino acid substitutions.
  • the amino acid substitutions are conservative amino acid substitutions.
  • bi-specific antigen-binding constructs e.g. , antibodies, that bind Tim-3 and PD-1.
  • the bi-specific antigen-binding construct includes two antigen- binding polypeptide constructs, e.g. , antigen binding domains, that specifically binding to Tim-3 and/or PD-1.
  • the antigen-binding construct is derived from known antibodies or antigen-binding constructs.
  • the antigen-binding polypeptide constructs comprise two antigen binding domains that comprise antibody fragments.
  • the first antigen binding domain and second antigen binding domain each independently comprises an antibody fragment selected from the group of: an scFv, a Fab, and an Fc domain.
  • the first and second antigen-binding polypeptide constructs independently comprise different light chains.
  • the first antigen-binding polypeptide construct comprises a VL sequence selected from any one of SEQ ID NOs: 221-235
  • the second antigen-binding polypeptide construct comprises a VL sequence selected from any one of SEQ ID NOs: 236-269.
  • the first antigen-binding polypeptide construct comprises a VL sequence selected from any one of SEQ ID NOs: 236-269
  • the second antigen-binding polypeptide construct comprises a VL sequence selected from any one of SEQ ID NOs: 221-235.
  • the first and second antigen-binding polypeptide constructs comprise the same light chain.
  • the first and second antigen-binding polypeptide constructs comprise a same VL sequence selected from any one of SEQ ID NOs: 221-269.
  • the first and second antigen-binding polypeptide constructs further comprise a CL sequence selected from any one of SEQ ID NOs: 327-338 and 346-347.
  • the first and second antigen- binding polypeptide constructs comprise the same CL sequence.
  • the first and second antigen-binding polypeptide constructs comprise different CL sequences.
  • an antigen-binding construct refers to any agent, e.g. , polypeptide or polypeptide complex capable of binding to an antigen.
  • an antigen-binding construct is a polypeptide that specifically binds to an antigen of interest.
  • An antigen-binding construct can be a monomer, dimer, multimer, a protein, a peptide, or a protein or peptide complex; an antibody, an antibody fragment, or an antigen-binding fragment thereof; an scFv and the like.
  • An antigen-binding construct can be a polypeptide construct that is monospecific, bi-specific, or multispecific.
  • an antigen-binding construct can include, e.g. , one or more antigen-binding components (e.g., Fabs or scFvs) linked to one or more Fc. Further examples of antigen-binding constructs are described below and provided in the Examples.
  • bi-specific includes any agent, e.g., an antigen-binding construct, which has two antigen-binding moieties (e.g. antigen-binding polypeptide constructs), each with a unique binding specificity.
  • an antigen-binding construct which has two antigen-binding moieties (e.g. antigen-binding polypeptide constructs), each with a unique binding specificity.
  • a first antigen-binding moiety binds to an epitope on a first antigen
  • a second antigen-binding moiety binds to an epitope on a second antigen, where the first antigen is different from the second antigen.
  • a bi-specific agent can bind to, or interact with, (a) a cell surface target molecule and (b) an Fc receptor on the surface of an effector cell.
  • the agent can bind to, or interact with (a) a first cell surface target molecule and (b) a second cell surface target molecule that is different from the first cell surface target molecule.
  • the agent can bind to and bridge two cells, i.e. interact with (a) a first cell surface target molecule on a first call and (b) a second cell surface target molecule on a second cell that is different from the first cells surface target molecule on the first cell.
  • a monospecific antigen-binding construct refers to an antigen- binding construct with a single binding specificity.
  • both antigen-binding moieties bind to the same epitope on the same antigen.
  • monospecific antigen- binding constructs include the anti-CD19 antibody HD37 and the anti-CD3 antibody OKT3 for example.
  • An antigen-binding construct can be an antibody or antigen-binding portion thereof as disclosed herein.
  • the bi-specific antigen-binding construct comprises at least two antigen- binding polypeptide constructs, e.g. , antigen binding domains.
  • the format of the antigen- binding polypeptide construct determines certain functional characteristics of the bi-specific antigen-binding construct.
  • the bi-specific antigen-binding construct has an scFv-scFv format, i.e. both antigen-binding polypeptide constructs are scFvs.
  • the bi-specific antigen-binding construct has a Fab-Fab format, i.e. both antigen-binding polypeptide constructs are Fabs.
  • the bi-specific antigen-binding construct has an scFv-Fab format, i.e. a first antigen-binding polypeptide construct is an scFv, and a second antigen-binding polypeptide construct is an Fab.
  • the bi- specific antibody or antigen-binding construct can have any form suitable for the antibody or antigen-binding construct, so long as it comprises a first antigen binding domain and a second antigen binding domain that bind to distinct targets.
  • the bi-specific antibody or antigen-binding construct comprising a first antigen binding domain that specifically binds Tim-3 and a second antigen binding domain that specifically binds PD-1.
  • a bi- specific antigen construct comprising a first scFv that specifically binds Tim-3 and a second scFv that specifically binds PD-1.
  • a bi-specific antigen construct comprising a first Fab that specifically binds Tim-3 and a second Fab that specifically binds PD-1.
  • a bi-specific antigen construct comprising an scFv that specifically binds Tim-3 and a Fab that specifically binds PD-1.
  • a bi-specific antigen construct comprising a Fab that specifically binds Tim-3 and an scFv that specifically binds PD-1.
  • the bi-specific antibody or bi-specific antigen-binding construct can be generated as a dual-variable domain antibody.
  • a "dual -variable domain antibody” also referred to as a DVD-Ig refers to fusion of an additional VH domain and VL domain of a second specificity to a given IgG heavy chain and light chain. Generation of dual-variable domain antibody formats are described, for example, in Wu et al. 2007. Nature Biotechnology 25: 1290-1297 and U.S. 2007/0071675, each of which is incorporated herein by reference in its entirety.
  • the bi-specific antibody or bi-specific antigen-binding construct is generated as a cross-over dual-variable domain antibody.
  • a "cross-over dual-variable domain antibody” (also referred to as a CODV-Ig) refers to a format related to the dual-variable domain antibody format wherein the two VH domains and two VL domains are linked to allow cross-over pairing of the variable VH-VL domains. Generation of cross-over dual- variable domain antibody formats are described, for example, in Steinmetz et al. 2016. mAbs 8:867-878, which is incorporated herein by reference in its entirety.
  • the "Single domain antibodies” or “sdAb” format is an individual immunoglobulin domain. SdAbs are fairly stable and easy to express as fusion partner with the Fc chain of an antibody (see Harmsen M M, De Haard H J (2007). “Properties, production, and applications of camelid single-domain antibody fragments.” Appl. Microbiol Biotechnol. 77(1): 13-22). 4.1.1 Format scFv
  • the scFv is optimized by changing the order of the variable domains VL and VH in the scFv.
  • the C-terminus of the light chain variable region can be linked to the N-terminus of the heavy chain variable region.
  • the C-terminus of the heavy chain variable region can be linked to the N-terminus of the light chain variable region.
  • n is a number between 4 and 8. In some embodiments, n is a number between 3 and 6. In some embodiments, n is a number between 2 and 4.
  • Other linkers are described, for example, in Bird et al. 1988. Science 242:423-426; Huston et al. 1988. PNAS 85:5879- 5883; and McCafferty et al. 1990. Nature 348:552-554.
  • the scFv molecule can be optimized for protein expression and yield by including stabilizing disulfide bridges between the heavy and light chain variable domains, for example as described in Reiter et al. (Nat Biotechnol 14, 1239-1245 (1996)). Accordingly, in some embodiments, the bi-specific antigen-binding molecule disclosed herein can comprise an scFv molecule wherein an amino acid in the heavy chain variable domain and an amino acid in the light chain variable domain have been replaced by cysteine so that a disulfide bridge can be formed between the heavy and light chain variable domain. [00400] ScFvs can also be stabilized by mutation of CDR sequences, as described in the art (Miller et al, Protein Eng Des Sel.
  • the antigen-binding constructs described herein comprise an Fc domain, e.g., a dimeric Fc.
  • the Fc domain is a heterodimeric Fc comprising first and second Fc polypeptides each comprising a modified CH3 sequence, wherein each modified CH3 sequence comprises asymmetric amino acid modifications that promote the formation of a heterodimeric Fc and the dimerized CH3 domains have a melting temperature (Tm) of about 68°C or higher, and wherein the first Fc polypeptide is linked to the first antigen-binding polypeptide construct, with a first hinge linker, and the second Fc polypeptide is linked to the second antigen-binding polypeptide construct with a second hinge linker.
  • Tm melting temperature
  • Fc domain or "Fc region” herein refers to a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region.
  • the term includes native sequence Fc regions and variant Fc regions and is used interchangeably with "Fc.”
  • numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991.
  • an "Fc polypeptide" of a dimeric Fc as used herein refers to one of the two polypeptides forming the dimeric Fc domain, i.e. a polypeptide comprising C-terminal constant regions of an immunoglobulin heavy chain, capable of stable self-association.
  • an Fc polypeptide of a dimeric IgG Fc comprises an IgG CH2 and an IgG CH3 constant domain sequence.
  • the CH3 domain comprises two CH3 sequences, one from each of the two Fc polypeptides of the dimeric Fc.
  • the CH2 domain comprises two CH2 sequences, one from each of the two Fc polypeptides of the dimeric Fc.
  • the Fc comprises one or more modifications in at least one of the CH3 sequences. In some embodiments, the Fc comprises one or more modifications in at least one of the CH2 sequences.
  • the Fc can include one or modifications selected from the group consisting of: V262E, V262D, V262K, V262R, V262S, V264S, V303R, and V305R.
  • an Fc is a single polypeptide. In some embodiments, an Fc is multiple peptides, e.g., two polypeptides.
  • This heterodimerization can be a result of modification of one of the two amino acids at the same respective amino acid position on each sequence; or modification of both amino acids on each sequence at the same respective position on each of the first and second CH3 sequences.
  • the first and second CH3 sequence of a heterodimeric Fc can comprise one or more than one asymmetric amino acid modification.
  • one or both sequences of an Fc include one or more mutations or modifications at the following locations: L351, L368, F405, Y407, T366, K392, T394, T350, S400, and/or N390, using EU numbering.
  • an Fc includes the mutations as disclosed in the art (see Von Kreudenstein et al. 2013. mAbs 5(5):646-654; Von Kreudenstein et al. 2014. Methods 65:77-94; U.S. 2013/0195849; Ridgway et al. 1996. Protein Eng 9(7):617-621; and Brinkmann, U., and R. E. Kontermann. 2017. mAbs 9(2): 182- 212, each of which is incorporated herein by reference in its entirety.)
  • the first and second CH3 sequences can comprise amino acid mutations as described herein.
  • the heterodimeric Fc comprises a modified CH3 domain with a first CH3 sequence having one or more amino acid modifications selected from L351Y, F405A, and Y407V, and the second CH3 sequence having one or more amino acid modifications selected from T366L, T366I, K392L, K392M, and T394W.
  • the bi-specific antibodies or bi-specific antigen-binding constructs disclosed herein comprise one or more light chains. In some embodiments, the bi-specific antibody or bi-specific antigen-binding construct comprises two light chains. In some embodiments, the two light chains are different. In some embodiments, the two light chains are the same.
  • the modification involves mutating residues to modify electrostatic interactions between the VH-VL pairs and/or the CH1-CL pairs.
  • the result of modification to the VH-VL and/or the CH1-CL interactions can result in improved accuracy (or improved "steering") in pairing of cognate heavy and light chains.
  • Exemplary modifications in these domains are described, for example, in Lewis et al. 2014. Nature Biotechnology 32: 191-198 and WO 2014/082179, each of which is incorporated herein by reference in its entirety.
  • the first Fc polypeptide is linked to the first antigen-binding polypeptide construct with a first hinge linker
  • the second Fc polypeptide is linked to the second antigen- binding polypeptide construct with a second hinge linker.
  • hinge linker sequences are well-known to one of skill in the art and can be used in the antigen-binding constructs described herein. Alternatively, modified versions of known hinge linkers can be used.
  • the hinge linker polypeptides are selected such that they maintain or optimize the functional activity of the antigen-binding construct.
  • Suitable linker polypeptides include IgG hinge regions such as, for example those from IgGi, IgG2, or IgG4, including the upper hinge sequences and core hinge sequences.
  • the amino acid residues corresponding to the upper and core hinge sequences vary depending on the IgG type, as is known in the art and one of skill in the art would readily be able to identify such sequences for a given IgG type. Modified versions of these exemplary linkers can also be used. For example, modifications to improve the stability of the IgG4 hinge are known in the art (see for example, Labrijn et al. (2009) Nature Biotechnology 27, 767-771). Examples of hinge linker sequences are found, for example, in U.S. 2016/0326249.
  • the bi-specific antigen-binding construct can have a variety of different arrangements.
  • the bi-specific antigen-binding construct can comprise a 2-chain scFvFc, a 3-chain Fab x scFvFc, or a 4-chain IgG-like bispecific construct as described below.
  • the scFv is arranged in a VH -VL arrangement.
  • the scFv comprises a VH sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 181-197; a linker selected from SEQ ID NOs: 278- 281 ; and a VL sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 236-245.
  • the scFv comprises a VH sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 144-180; a linker selected from SEQ ID NOs: 278-281; and a VL sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 221-235.
  • the scFv is arranged in a VL -VH arrangement.
  • the scFv comprises a VL sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 236-245; a linker selected from SEQ ID NOs: 278- 281 ; and a VH sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 181-197.
  • the scFv comprises a VL sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 221-235; a linker selected from SEQ ID NOs: 278-281 ; and a VH sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 144-180.
  • a PD-l/Tim-3 bi-specific antigen-binding construct comprising a two-chain scFvFc arrangement, wherein the scFvFc pairing comprises knob-in- hole mutations.
  • a PD-l/Tim-3 bi-specific antigen-binding construct comprising an anti-PD-1 scFvFc knob paired with an anti-Tim-3 scFvFc hole.
  • a PD-l/Tim-3 bi-specific antigen-binding construct comprising an anti-PD-1 scFvFc hole paired with an anti-Tim-3 scFvFc knob.
  • the scFvFcs include scFvs generated in accordance with Section 4.1.6.1.
  • a PD-l/Tim-3 bi-specific antigen-binding construct comprising a two-chain scFvFc arrangement is prepared using the following arrangement: an anti-PD-1 scFvFc knob (Table 12, design (a)) paired with an anti-Tim-3 scFvFc hole (Table 12, design (d)).
  • a PD-l/Tim-3 bi-specific antigen-binding construct comprising a two-chain scFvFc arrangement is prepared using the following arrangement: an anti-PD-1 scFvFc hole (Table 12, design (c)) paired with an anti-Tim-3 scFvFc knob (Table 12, design (b)).
  • the anti-PD-1 scFvFc knob is constructed from: (1) an anti-PD-1 scFv; (2) a linker-hinge; and (3) a CH2-CH3 region.
  • the anti-PD-1 scFv comprises a VH-VL arrangement and comprises a VH sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 181-197; a linker selected from SEQ ID NOs: 278-281 ; and a VL sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 236-245.
  • the anti-PD-1 scFv comprises a VL-VH arrangement and comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 236-245; a linker selected from SEQ ID NOs: 278- 281; and a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 181-197.
  • the linker-hinge comprises, consists of, or consists essentially of SEQ ID NO:285.
  • the CH2-CH3 region comprises, consists of, or consists essentially of any one of SEQ ID NOs. : 295-299.
  • the anti-PD-1 scFv comprises a VL-VH arrangement and comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 236-245; a linker selected from SEQ ID NOs: 278- 281; and a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 181-197.
  • the linker-hinge comprises, consists of, or consists essentially of SEQ ID NO:285.
  • the CH2-CH3 region comprises, consists of, or consists essentially of any one of SEQ ID NOs. : 300-304.
  • the anti-Tim-3 scFvFc knob is constructed from: (1) an anti-Tim-3 scFv; (2) a linker-hinge; and (3) a CH2-CH3 region.
  • the anti-Tim-3 scFv comprises a VH-VL arrangement and comprises a VH sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 144-180; a linker selected from SEQ ID NOs: 278-281 ; and a VL sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 221-235.
  • the anti-Tim-3 scFv comprises a VL-VH arrangement and comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 221-235; a linker selected from SEQ ID NOs: 278- 281; and a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 144-180.
  • the linker-hinge comprises, consists of, or consists essentially of SEQ ID NO: 285.
  • the CH2-CH3 region comprises, consists of, or consists essentially of any one of SEQ ID NOs. : 295-299.
  • the anti-Tim-3 scFvFc hole is constructed from: (1) an anti-Tim-3 scFv; (2) a linker-hinge; and (3) a CH2-CH3 region.
  • the anti-Tim-3 scFv comprises a VH-VL arrangement and comprises a VH sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 144-180; a linker selected from SEQ ID NOs: 278-281 ; and a VL sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 221 -235.
  • the bi-specific antigen-binding construct comprises a
  • the asymmetry of the scaffold facilitates correct HC/LC pairing as there is only one HC/LC pairing that can correctly form the Fab domain; the other arm is an scFv.
  • a PD-l/Tim-3 bi-specific antigen-binding construct comprising a three-chain Fab x scFvFc structure
  • a PD-l/Tim-3 bi-specific antigen-binding construct comprising a three-chain Fab x scFvFc structure
  • an anti-PD-1 scFvFc knob paired with an anti-Tim-3 half IgG (HC + LC) hole
  • an anti-PD-1 scFvFc hole paired with an anti-Tim-3 half IgG (HC + LC) knob
  • an anti-PD-1 half IgG (HC + LC) knob paired with an anti-Tim-3 scFvFc hole
  • an anti-PD-1 half IgG (HC + LC) hole paired with an anti-Tim-3 scFvFc knob.
  • the scFvs included within such scFvFc arrangements can be generated in accordance with Section 4.1.6.1.
  • Tim 3 half IgGs (HC + LC, knob or hole) for use in a PD-l/Tim-3 bi-specific antigen-binding construct comprising a three-chain Fab x scFv arrangement with knob-in-hole mutations is provided below in Tables 8 and 9.
  • Table 8 Exemplary HCs of anti-PD-1 and anti-Tim-3 Half IgGs
  • the anti-PD-1 half IgG knob comprises a heavy chain and a light chain, wherein the heavy chain comprises: a VH comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 181-197; a CHi region comprising, consisting of, or consisting essentially of SEQ ID NO: 345; a linker comprising, consisting of, or consisting essentially of SEQ ID NO: 286; and a CH2-CH3 region comprising, consisting of, or consisting essentially of any one of SEQ ID NOs.
  • the light chain comprises: a VL comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 236-245 and a CL comprising, consisting of, or consisting essentially of any one of SEQ ID NOs:346-347.
  • the anti-PD-1 half IgG hole comprises a heavy chain and a light chain, wherein the heavy chain comprises: a VH comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 181 -197; a CHi region comprising, consisting of, or consisting essentially of SEQ ID NO: 345; a linker comprising, consisting of, or consisting essentially of SEQ ID NO: 286; and a CH2-CH3 region comprising, consisting of, or consisting essentially of any one of SEQ ID NOs.
  • the light chain comprises: a VL comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 236-245 and a CL comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 346-347.
  • the light chain comprises: a VL comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 221-235 and a CL comprising, consisting of, or consisting essentially of SEQ ID NO: 346.
  • the anti-Tim-3 half IgG hole comprises a heavy chain and a light chain, wherein the heavy chain comprises: a VH comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 144-180; a CHi region comprising, consisting of, or consisting essentially of SEQ ID NO: 345; a linker comprising, consisting of, or consisting essentially of SEQ ID NO: 286; and a CH2-CH3 region comprising, consisting of, or consisting essentially of any one of SEQ ID NOs.
  • the light chain comprises: a VL comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 221-235 and a CL comprising, consisting of, or consisting essentially of SEQ ID NO: 346.
  • the anti-Tim-3 scFvFc hole is constructed from: (1) an anti-Tim-3 scFv; (2) a linker-hinge; and (3) a CH2-CH3 region.
  • the anti-Tim-3 scFv comprises a VH-VL arrangement and comprises a VH sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 144-180; a linker selected from SEQ ID NOs: 278-281 ; and a VL sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 221 -235.
  • the anti-Tim-3 scFv comprises a VL-VH arrangement and comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 221 -235; a linker selected from SEQ ID NOs: 278- 281 ; and a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 144-180.
  • the linker-hinge comprises, consists of, or consists essentially of SEQ ID NO: 285.
  • the CH2-CH3 region comprises, consists of, or consists essentially of any one of SEQ ID NOs. : 300-304.
  • the bi-specific antigen-binding construct comprises a three-chain Fab x scFvFc scaffold, wherein the Fab and scFvFc structures comprise knob-in- hole mutations.
  • the asymmetry of the scaffold facilitates correct HC/LC pairing as there is only one HC/LC pairing that can correctly form the Fab domain; the other arm is an scFv.
  • a PD-l/Tim-3 bi-specific antigen-binding construct comprising a three-chain Fab x scFvFc structure comprising an anti-PD-1 half IgG (HC + LC) with zwA mutations paired with an anti-Tim-3 scFvFc with zwB mutations.
  • a PD-l/Tim-3 bi-specific antigen-binding construct comprising a three-chain Fab x scFvFc structure comprising an anti-PD-1 half IgG (HC + LC) with zwB mutations paired with an anti-Tim-3 scFvFc with zwA mutations.
  • the mutations encompassed by "zwA” mutations include T350V/L351Y/F405A/Y407V in the CH3 domain.
  • the mutations encompassed by “zwB” mutations include T350V/T366L/K392L/T394W in the CH3 domain.
  • HC + LC anti-Tim-3 half IgGs
  • HC + LC anti-Tim-3 bi-specific antigen-binding construct comprising a three-chain Fab x scFv arrangement
  • Exemplary LC embodiments for the half IgGs correspond to those in Table 9 above.
  • the anti-PD-1 scFvFc zwA is constructed from: (1) an anti-PD-1 scFv; (2) a linker-hinge; and (3) a CH2-CH3 region.
  • the anti-PD-1 scFv comprises a VH-VL arrangement and comprises a VH sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 181-197; a linker selected from SEQ ID NOs: 278-281 ; and a VL sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 236-245.
  • the anti-PD-1 scFv comprises a VL-VH arrangement and comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 236-245; a linker selected from SEQ ID NOs:278- 281; and a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 181-197.
  • the linker-hinge comprises, consists of, or consists essentially of SEQ ID NO: 285.
  • the CH2-CH3 region comprises, consists of, or consists essentially of any one of SEQ ID NOs. : 305-307.
  • the anti-PD-1 scFvFc zwB is constructed from: (1) an anti-PD-1 scFv; (2) a linker-hinge; and (3) a CH2-CH3 region.
  • the anti-PD-1 scFv comprises a VH-VL arrangement and comprises a VH sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 181-197; a linker selected from SEQ ID NOs: 278-281; and a VL sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 236-245.
  • the anti-PD-1 scFv comprises a VL-VH arrangement and comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 236-245; a linker selected from SEQ ID NOs: 278- 281; and a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 181-197.
  • the linker-hinge comprises, consists of, or consists essentially of SEQ ID NO: 285.
  • the CH2-CH3 region comprises, consists of, or consists essentially of any one of SEQ ID NOs. : 308-310.
  • the anti-Tim-3 scFv comprises a VL-VH arrangement and comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 221-235; a linker selected from SEQ ID NOs: 278- 281; and a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 144-180.
  • the linker-hinge comprises, consists of, or consists essentially of SEQ ID NO: 285.
  • the CH2-CH3 region comprises, consists of, or consists essentially of any one of SEQ ID NOs.: 305-307.
  • the anti-Tim-3 scFvFc zwB is constructed from: (1) an anti-Tim-3 scFv; (2) a linker-hinge; and (3) a CH2-CH3 region.
  • the anti-Tim-3 scFv comprises a VH-VL arrangement and comprises a VH sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 144-180; a linker selected from SEQ ID NOs: 278-281; and a VL sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 221-235.
  • the anti-Tim-3 scFv comprises a VL-VH arrangement and comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 221-235; a linker selected from SEQ ID NOs: 278- 281; and a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NOs: 144-180.
  • the linker-hinge comprises, consists of, or consists essentially of SEQ ID NO: 285.
  • the CH2-CH3 region comprises, consists of, or consists essentially of any one of SEQ ID NOs.: 308-310.
  • the anti-PD-1 half IgG with zwA mutations comprises a heavy chain and a light chain, wherein the heavy chain comprises: a VH comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 181-197; a CHi region comprising, consisting of, or consisting essentially of SEQ ID NO: 345; a linker comprising, consisting of, or consisting essentially of SEQ ID NO: 286; and a CH2-CH3 region comprising, consisting of, or consisting essentially of any one of SEQ ID NOs.
  • the light chain comprises: a VL comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 236-245 and a CL comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 346-347.
  • the anti-PD-1 half IgG with zwB mutations comprises a heavy chain and a light chain, wherein the heavy chain comprises: a VH comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 181-197; a CHi region comprising, consisting of, or consisting essentially of SEQ ID NO: 345; a linker comprising, consisting of, or consisting essentially of SEQ ID NO: 286; and a CH2-CH3 region comprising, consisting of, or consisting essentially of any one of SEQ ID NOs.
  • the light chain comprises: a VL comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 221-235 and a CL comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 346-347.
  • the anti-Tim-3 half IgG with zwB mutations comprises a heavy chain and a light chain, wherein the heavy chain comprises: a VH comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 144-180; a CHi region comprising, consisting of, or consisting essentially of SEQ ID NO: 345; a linker comprising, consisting of, or consisting essentially of SEQ ID NO: 286; and a CH2-CH3 region comprising, consisting of, or consisting essentially of any one of SEQ ID NOs.
  • the light chain comprises: a VL comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 221-235 and a CL comprising, consisting of, or consisting essentially of any one of SEQ ID NOs: 346-347. 4.1.6.5. Generation of a PD-l/Tim-3 Bi-Specific Antigen-binding
  • the bi-specific antigen-binding construct comprises a four-chain IgG-like scaffold comprising a Fab domain fused to the N-termini of a heterodimeric Fc.
  • this bispecific format comprises four chains: heavy chain 1 (HC1), light chain 1 (LCI), heavy chain 2 (HC2), and light chain 2 (LC2).
  • the HC and LC sequences are mutated as described herein in sections 4.1.2 - 4.1.4 to facilitate correct pairing between HCs and LCs.
  • the HC/LC pairing designs listed in Tables 12-14 can be incorporated into the construct to facilitate correct HC/LC pairing.
  • HC1 is designed such that it pairs specifically with LCI rather than LC2.
  • HC2 is designed such this it pairs specifically with LC2 rather than LCI.
  • Six designs are shown below in Tables 12 and 13 that enforce correct light-chain pairing: (a), (b) (c), (d), (e), and (f).
  • Designs (a) and (b) in Table 12 can be incorporated for an embodiment in which one light chain is a kappa chain (LCI) and the second light chain is a lambda chain (LC2).
  • Designs (c), (d), (e) and (f) in Table 13 can be incorporated for embodiments in which the first and second light chains (LCI, LC2) are kappa chains.
  • Table 14 Exemplary embodiments of a four-chain bi-specific antibody arrangement (kappa x kappa)
  • HCl and HC2 incorporate complementary Zymeworks mutations A (T350V/L351Y/F405A/Y407V; "zwA”) and B (T350V/T366L/K392L/T394W; “zwB”) to enforce heterodimerization of HCl with HC2 (see, e.g. , Von Kreudenstein et al. 2013. mAbs 5(5):646-654; Von Kreudenstein et al. 2014. Methods 65:77-94; U.S. 2013/0195849, each of which is incorporated herein by reference in its entirety).
  • CH3 pairing mutations e.g. , knobs-in-holes mutations
  • the CH2 domains can either be wild-type or have stability/solubility/assembly/yield enhancing mutations V262E or V264S.
  • a full-length antibody Tim-3 heavy chain typically includes a VH domain, a
  • the VH domain comprises, consists, or consists essentially of any one of SEQ ID NOs: 144-180.
  • the CHT domain is selected from SEQ ID NOs: 317-326.
  • the linker comprises, consists of, or consists essentially of SEQ ID NO: 286.
  • the CH2-CH3 region comprises, consists of, or consists essentially of any one of SEQ ID NOs: 305-310.
  • an anti-Tim-3 heavy chain with design (a)
  • HCl(a) can be constructed from: (1) a VH sequence of 1649-AOl (SEQ ID NO: 151); (2) CHl-(a)l ; (3) a linker comprising, consisting of, or consisting essentially of SEQ ID NO: 286, and (4) a CH2-CH3 region comprising, consisting of, or consisting essentially of Fc-zwA.
  • Table 15 provides various exemplary components for the VH domain, CHI domain, linker, and CH2-CH3 region that are contemplated for generation of a Tim-3 heavy chain sequence.
  • the VH sequence can be selected from the group consisting of: the VH sequence of 1649-AOl (SEQ ID NO: 151), the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), the VH sequence of 1649-AOl S30D/R31D (SEQ ID NO: 167), the VH sequence of 1649-AOl S30D/Y56D (SEQ ID NO: 166), and the VH sequence of 1649-AOl S30D/R31D/Y56D (SEQ ID NO: 165).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(a)l (SEQ ID NO: 317), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO:305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(a)l (SEQ ID NO: 317), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(a)l (SEQ ID NO: 317), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CHl-(a)l (SEQ ID NO: 317), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(a)l (SEQ ID NO: 317), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(a)l (SEQ ID NO: 317), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(a)2 (SEQ ID NO: 322), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(a)2 (SEQ ID NO: 322), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(a)2 (SEQ ID NO: 322), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CHl-(a)2 (SEQ ID NO: 322), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(a)2 (SEQ ID NO: 322), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CHl-(a)2 (SEQ ID NO: 322), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(b)l (SEQ ID NO: 318), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CHI -(b) 1 (SEQ ID NO: 318), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of Cu ⁇ -(b) ⁇ (SEQ ID NO: 318), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CHl-(b)l (SEQ ID NO: 318), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(b)l (SEQ ID NO: 318), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CHI -(b) 1 (SEQ ID NO: 318), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(b)2 (SEQ ID NO: 323), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(b)2 (SEQ ID NO: 323), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(b)2 (SEQ ID NO: 323), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CHl-(b)2 (SEQ ID NO: 323), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(b)2 (SEQ ID NO: 323), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(b)2 (SEQ ID NO: 323), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CH1 -(C)1 (SEQ ID NO: 319), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CH1 -(C)1 (SEQ ID NO: 319), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CH1-(C)1 (SEQ ID NO: 319), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CH1-(C)1 (SEQ ID NO: 319), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CH1 -(C)1 (SEQ ID NO: 319), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CH1 -(C)1 (SEQ ID NO: 319), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CH1 -(C)2 (SEQ ID NO: 324), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CH1 -(C)2 (SEQ ID NO: 324), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CH1-(C)2 (SEQ ID NO: 324), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CH1-(C)2 (SEQ ID NO: 324), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CH1 -(C)2 (SEQ ID NO: 324), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CH1 -(C)2 (SEQ ID NO: 324), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(d)l (SEQ ID NO: 320), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(d)l (SEQ ID NO: 320), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(d)l (SEQ ID NO: 320), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of CHl-(d)l (SEQ ID NO: 320), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(d)l (SEQ ID NO: 320), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(d)l (SEQ ID NO: 320), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(d)2 (SEQ ID NO: 325), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(d)2 (SEQ ID NO: 325), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(d)2 (SEQ ID NO: 325), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(d)2 (SEQ ID NO: 325), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(d)2 (SEQ ID NO: 325), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(e)(f)l (SEQ ID NO: 321), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(e)(f)l (SEQ ID NO: 321), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(e)(f)l (SEQ ID NO: 321), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l-(e)(f)l (SEQ ID NO: 321), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of Cul-(e)(i)l (SEQ ID NO: 321), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of Cul -(e)(f)l (SEQ ID NO: 321), a linker of hinge- wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l -(e)(f)2 (SEQ ID NO: 326), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l -(e)(f)2 (SEQ ID NO: 326), a linker of hinge-wt (SEQ ID NO : 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO : 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l -(e)(f)2 (SEQ ID NO: 326), a linker of hinge-wt (SEQ ID NO : 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l -(e)(f)2 (SEQ ID NO: 326), a linker of hinge-wt (SEQ ID NO : 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO : 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of C H l -(e)(f)2 (SEQ ID NO : 326), a linker of hinge-wt (SEQ ID NO : 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl (SEQ ID NO: 151), a CHI sequence comprising the sequence of Cul -(e)(f)2 (SEQ ID NO: 326), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO : 179), a CHI sequence comprising the sequence of CHl -(a)l (SEQ ID NO : 317), a linker of hinge-wt (SEQ ID NO : 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO:305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(a)l (SEQ ID NO: 317), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHI -(a) 1 (SEQ ID NO: 317), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(a)l (SEQ ID NO: 317), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(a)l (SEQ ID NO: 317), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(a)l (SEQ ID NO: 317), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(a)2 (SEQ ID NO: 322), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(a)2 (SEQ ID NO: 322), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(a)2 (SEQ ID NO: 322), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(a)2 (SEQ ID NO: 322), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(a)2 (SEQ ID NO: 322), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(a)2 (SEQ ID NO: 322), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(b)l (SEQ ID NO: 318), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(b)l (SEQ ID NO: 318), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(b)l (SEQ ID NO: 318), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(b)l (SEQ ID NO: 318), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(b)l (SEQ ID NO: 318), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(b)l (SEQ ID NO: 318), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(b)2 (SEQ ID NO: 323), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(b)2 (SEQ ID NO: 323), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(b)2 (SEQ ID NO: 323), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(b)2 (SEQ ID NO: 323), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(b)2 (SEQ ID NO: 323), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(b)2 (SEQ ID NO: 323), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHI -(c) 1 (SEQ ID NO: 319), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CH1-(C)1 (SEQ ID NO: 319), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CH1-(C)1 (SEQ ID NO: 319), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CH1-(C)1 (SEQ ID NO: 319), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CH1-(C)1 (SEQ ID NO: 319), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHI -(c) 1 (SEQ ID NO: 319), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CH1-(C)2 (SEQ ID NO: 324), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CH1-(C)2 (SEQ ID NO: 324), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CH1-(C)2 (SEQ ID NO: 324), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CH1-(C)2 (SEQ ID NO: 324), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CH1-(C)2 (SEQ ID NO: 324), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CH1-(C)2 (SEQ ID NO: 324), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(d)l (SEQ ID NO: 320), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(d)l (SEQ ID NO: 320), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(d)l (SEQ ID NO: 320), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V264S (SEQ ID NO: 307).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(d)l (SEQ ID NO: 320), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB (SEQ ID NO: 308).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of CHl-(d)l (SEQ ID NO: 320), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V262E (SEQ ID NO: 309).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(d)l (SEQ ID NO: 320), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwB V264S (SEQ ID NO: 310).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(d)2 (SEQ ID NO: 325), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA (SEQ ID NO: 305).
  • the anti-Tim-3 heavy chain comprises a VH sequence comprising the VH sequence of 1649-AOl S30D (SEQ ID NO: 179), a CHI sequence comprising the sequence of C H l-(d)2 (SEQ ID NO: 325), a linker of hinge-wt (SEQ ID NO: 286), and a CH2-CH3 region comprising the sequence of Fc-zwA V262E (SEQ ID NO: 306).

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Abstract

La présente invention concerne des anticorps qui se lient sélectivement à TIM-3 et ses isoformes et homologues, ainsi que des compositions comprenant les anticorps. La présente invention concerne également des anticorps qui se lient sélectivement à PD-1 et ses isoformes et homologues, ainsi que des compositions comprenant les anticorps. Par ailleurs, l'invention concerne des anticorps bispécifiques et des constructions de liaison aux antigènes qui se lient sélectivement à Tim-3 et/ou PD -1, et à leurs isoformes et homologues, et des compositions comprenant les anticorps et les constructions de liaison aux antigènes. L'invention concerne également des méthodes d'utilisation des anticorps, telles que des méthodes diagnostiques et thérapeutiques.
PCT/US2018/019248 2017-02-22 2018-02-22 Anticorps bispécifiques anti-pd-1/tim -3, compositions de ceux-ci, et procédés de fabrication et d'utilisation de ceux-ci WO2018156777A1 (fr)

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US16/487,806 US20200190192A1 (en) 2017-03-07 2018-02-22 Pd-1/tim-3 bi-specific antibodies, compositions thereof, and methods of making and using the same
EP18713075.2A EP3585813A1 (fr) 2017-02-22 2018-02-22 Anticorps bispécifiques anti-pd-1/tim -3, compositions de ceux-ci, et procédés de fabrication et d'utilisation de ceux-ci

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PCT/US2018/019248 WO2018156777A1 (fr) 2017-02-22 2018-02-22 Anticorps bispécifiques anti-pd-1/tim -3, compositions de ceux-ci, et procédés de fabrication et d'utilisation de ceux-ci

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Cited By (10)

* Cited by examiner, † Cited by third party
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WO2019055931A1 (fr) 2017-09-18 2019-03-21 Sutro Biopharma, Inc. Conjugués anticorps-récepteur alpha anti-folate et leurs utilisations
WO2020060944A1 (fr) 2018-09-17 2020-03-26 Sutro Biopharma, Inc. Polythérapies avec des conjugués d'anticorps anti-récepteur du folate
WO2020227110A1 (fr) 2019-05-03 2020-11-12 Sutro Biopharma, Inc. Conjugué d'anticorps anti-bcma, compositions les comprenant, et procédés de fabrication et d'utilisation de ceux-ci
WO2020227105A1 (fr) 2019-05-03 2020-11-12 Sutro Biopharma, Inc. Conjugués d'anticorps anti-bcma
WO2020252043A1 (fr) 2019-06-10 2020-12-17 Sutro Biopharma, Inc. Composés 5h-pyrrolo[3,2-d]pyrimidine-2,4-diamino et conjugués d'anticorps associés
WO2020257235A1 (fr) 2019-06-17 2020-12-24 Sutro Biopharma, Inc. Dérivés de 1-(4-(aminométhyl)benzyl)-2-butyl-2h-pyrazolo[3,4-c]quinoléin-4-amine et composés apparentés en tant qu'agonistes du récepteur 7/8 de type toll (tlr), ainsi que des conjugués anticorps-médicament de ceux-ci destinés à être utilisés dans la thérapie et le diagnostic du cancer
CN113785057A (zh) * 2019-02-26 2021-12-10 特韦斯特生物科学公司 用于抗体优化的变异核酸文库
WO2022217123A2 (fr) 2021-04-08 2022-10-13 Nurix Therapeutics, Inc. Polythérapies comprenant des composés inhibiteurs de cbl-b
WO2022232488A1 (fr) 2021-04-30 2022-11-03 Celgene Corporation Polythérapies utilisant un conjugué anticorps-médicament (adc) anti-bcma en combinaison avec un inhibiteur de gamma-sécrétase (gsi)
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