+

WO1999043713A1 - Amelioration de la demi-vie circulante de proteines hybrides a base d'anticorps - Google Patents

Amelioration de la demi-vie circulante de proteines hybrides a base d'anticorps Download PDF

Info

Publication number
WO1999043713A1
WO1999043713A1 PCT/US1999/003966 US9903966W WO9943713A1 WO 1999043713 A1 WO1999043713 A1 WO 1999043713A1 US 9903966 W US9903966 W US 9903966W WO 9943713 A1 WO9943713 A1 WO 9943713A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibody
fusion protein
protein
based fusion
heavy chain
Prior art date
Application number
PCT/US1999/003966
Other languages
English (en)
Inventor
Stephen D. Gillies
Kin-Ming Lo
Yan Lan
John Wesolowski
Original Assignee
Lexigen Pharmaceuticals Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lexigen Pharmaceuticals Corporation filed Critical Lexigen Pharmaceuticals Corporation
Priority to CA002320403A priority Critical patent/CA2320403A1/fr
Priority to EP99908399A priority patent/EP1060194A1/fr
Priority to PL342497A priority patent/PL199659B1/pl
Priority to AU27842/99A priority patent/AU758240B2/en
Priority to BR9908226-8A priority patent/BR9908226A/pt
Priority to HU0100813A priority patent/HUP0100813A3/hu
Priority to JP2000533463A priority patent/JP2002505086A/ja
Publication of WO1999043713A1 publication Critical patent/WO1999043713A1/fr
Priority to NO20004218A priority patent/NO20004218L/no
Priority to HK01107082A priority patent/HK1036286A1/xx

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70514—CD4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • the present invention relates generally to fusion proteins. More specifically, the present invention relates to methods of enhancing the circulating half-life of antibody-based fusion proteins.
  • antibodies for treatment human disease is well established and has become more sophisticated with the introduction of genetic engineering.
  • Several techniques have been developed to improve the utility of antibodies. These include: (1) the generation of monoclonal antibodies by cell fusion to create "hyridomas", or by molecular cloning of antibody heavy (H) and light (L) chains from antibody-producing cells; (2) the conjugation of other molecules to antibodies to deliver them to preferred sites in vivo, e.g., radioisotopes, toxic drugs, protein toxins, and cytokines; (3) the manipulation of antibody effector functions to enhance or diminish biological activity; (4) the joining of other protein such as toxins and cytokines with antibodies at the genetic level to produce antibody-based fusion proteins; and (5) the joining of one or more sets of antibody combining regions at the genetic level to produce bi-specific antibodies.
  • the present invention provides methods for the production of fusion proteins between an immunoglobulin with a reduced binding affinity for an Fc receptor, and a second non-immunoglobulin protein.
  • Antibody-based fusion proteins with reduced binding affinity for Fc receptors have a significantly longer in vivo circulating half-life than the unlinked second non-immunoglobulin protein.
  • the immunoglobulin (Ig) component of the fusion protein has at least a portion of the constant region of an IgG that has a reduced binding affinity for at least one of Fc ⁇ RI, Fc ⁇ RII or Fc ⁇ RIII.
  • the binding affinity of fusion proteins for Fc receptors is reduced by using heavy chain isotypes as fusion partners that have reduced binding affinity for Fc receptors on cells.
  • heavy chain isotypes as fusion partners that have reduced binding affinity for Fc receptors on cells.
  • both human IgGl and IgG3 have been reported to bind to FcR ⁇ l with high affinity, while IgG4 binds 10-fold less well, and IgG2 does not bind at all.
  • the important sequences for the binding of IgG to the Fc receptors have been reported to be located in the CH2 domain.
  • an antibody-based fusion protein with enhanced in vivo circulating half-life is obtained by linking at least the CH2 domain of IgG2 or IgG4 to a second non-immunoglobulin protein.
  • the binding affinity of fusion proteins for Fc receptors is reduced by introducing a genetic modification of one or more amino acid in the constant - 3 - region of the IgGl or IgG3 heavy chains that reduces the binding affinity of these isotypes for Fc receptors.
  • modifications include alterations of residues necessary for contacting Fc receptors or altering others that affect the contacts between other heavy chain residues and Fc receptors through induced conformational changes.
  • an antibody-based fusion protein with enhanced in vivo circulating half-life is obtained by first introducing a mutation, deletion, or insertion in the IgGl constant region at one or more amino acid selected from Leu 234 , Leu 235 , Gly 236 , Gly 237 , Asn 297 , and Pro 331 , and then linking the resulting immunoglobulin, or portion thereof, to a second non-immunoglobulin protein.
  • the mutation, deletion, or insertion is introduced in the IgG3 constant region at one or more amino acid selected from Leu 28) , Leu 282 , Gly 283 , Gly 284 , Asn 344 , and Pro 378 , and the resulting immunoglobulin, or portion thereof, is linked to a second non-immunoglobulin protein.
  • the resulting antibody-based fusion proteins have a longer in vivo circulating half-life than the unlinked second non-immunoglobulin protein.
  • the second non-immunoglobulin component of the fusion protein is a cytokine.
  • cytokine is used herein to describe proteins, analogs thereof, and fragments thereof which are produced and excreted by a cell, and which elicit a specific response in a cell which has a receptor for that cytokine.
  • cytokines include interleukins such as interleukin-2 (IL-2), hematopoietic factors such as granulocyte-macrophage colony stimulating factor (GM-CSF), tumor necrosis factor (TNF) such as TNF ⁇ , and lymphokines such as lymphotoxin.
  • IL-2 interleukin-2
  • GM-CSF granulocyte-macrophage colony stimulating factor
  • TNF tumor necrosis factor
  • lymphokines such as lymphotoxin.
  • the antibody-cytokine fusion protein of the present invention displays cytokine biological activity.
  • the second non-immunoglobulin component of the fusion protein is a ligand-binding protein with biological activity.
  • ligand-binding proteins may, for example, (1) block receptor-ligand interactions at the cell surface; or (2) neutralize the biological activity of a molecule (e.g., a cytokine) in the fluid phase of the blood, thereby preventing it from reaching its cellular target.
  • ligand-binding proteins include CD4, CTLA-4, TNF receptors, or interleukin receptors such as the IL-1 and IL-4 receptors.
  • the antibody-receptor fusion protein of the present invention displays the biological activity of the ligand-binding protein.
  • the second non-immunoglobulin component of the fusion protein is a protein toxin.
  • the antibody-toxin fusion protein of the present invention displays the toxicity activity of the protein toxin.
  • the antibody-based fusion protein comprises a variable region specific for a target antigen and a constant region linked through a peptide bond to a second non- immunoglobulin protein.
  • the constant region may be the constant region normally associated with the variable region, or a different one, e.g., variable and constant regions from different species.
  • the heavy chain can include a CHI, CH2, and/or CH3 domains.
  • fusion protein also embraced within the term "fusion protein” are constructs having a binding domain comprising framework regions and variable regions (i.e., complementarity determining regions) from different species, such as are disclosed by Winter, et al., GB 2,188, 638.
  • Antibody-based fusion proteins comprising a variable region preferably display antigen-binding specificity.
  • the antibody-based fusion protein further comprises a light chain.
  • the invention thus provides fusion proteins in which the antigen-binding specificity and activity of an antibody are combined with the potent biological activity of a second non-immunoglobulin protein, such as a cytokine.
  • a fusion protein of the present invention can be used to deliver selectively the second non-immunoglobulin protein to a target cell in vivo so that the second non- immunoglobulin protein can exert a localized biological effect.
  • the antibody-based fusion protein comprises a heavy chain constant region linked through a peptide bond to a second non-immunoglobulin protein, but does not comprise a heavy chain variable region.
  • the invention thus further provides fusion proteins which retain the potent biological activity of a second non- immunoglobulin protein, but which lack the antigen-binding specificity and activity of an antibody.
  • the antibody -based fusion proteins of the present invention further comprise sequences necessary for binding to Fc protection receptors (FcRp), such as beta-2 microglobulin-containing neonatal intestinal transport receptor (FcRn).
  • the fusion protein comprises two chimeric chains comprising at least a portion of a heavy chain and a second, non-Ig protein are linked by a disulfide bond.
  • - 5 The invention also features DNA constructs encoding the above-described fusion proteins, and cell lines, e.g., myelomas, transfected with these constructs.
  • FIG. 1 is a homology alignment of the amino acid sequences of the constant region of C ⁇ l and C ⁇ 3, aligned to maximize amino acid identity, and wherein non-conserved amino acids are identified by boxes;
  • FIG. 2 is a homology alignment of the amino acid sequences of constant region of C ⁇ l, C ⁇ 2, and C ⁇ 4, aligned to maximize amino acid identity, and wherein non-conserved amino acids are identified by boxes;
  • FIG. 3 is a diagrammatic representation of a map of the genetic construct encoding an antibody-based fusion protein showing the relevant restriction sites;
  • FIG. 4 is a bar graph depicting the binding of antibody hu-KS-1/4 and antibody-based fusion proteins, hu-KS ⁇ l-IL2 and hu-KS ⁇ 4-IL2, to Fc receptors on mouse J774 cells in the presence (solid bars) or absence (stippled bars) of an excess of mouse IgG;
  • FIG. 5 is a line graph depicting the in vivo plasma concentration of total antibody (free antibody and fusion protein) of hu-KS ⁇ l-IL2 (closed diamond) and hu-KS ⁇ 4-IL2 (closed triangle) and of intact fusion protein of hu-KS ⁇ l-IL2 (open diamond) and hu-KS ⁇ 4-IL2 (open triangle) as a function of time;
  • FIG. 6 is a diagrammatic representation of protocol for constructing an antibody-based fusion protein with a mutation that reduces the binding affinity to Fc receptors;
  • FIG. 7 is a line graph depicting the in vivo plasma concentration of intact fusion protein of hu-KS ⁇ l-IL2 (0); mutated hu-KS ⁇ l-IL2 (ffl) and hu-KS ⁇ 4-IL2 ( ⁇ ) as a function of time. - 6 - Detailed Description of the Invention
  • the present invention describes antibody-based fusion proteins with enhanced in vivo circulating half-lives and involves producing, through recombinant DNA technology, antibody-based fusion proteins with reduced binding affinity for one or more Fc receptor.
  • an antibody-based fusion protein with an enhanced in vivo circulating half-life can be obtained by constructing a fusion protein with isotypes having reduced binding affinity for a Fc receptor, and avoiding the use of sequences from antibody isotypes that bind to Fc receptors.
  • IgGl C ⁇ l
  • IgG3 C ⁇ 3
  • IgG4 C ⁇ 4
  • IgG2 C ⁇ 2
  • an antibody-based fusion protein with reduced binding affinity for a Fc receptor could be obtained by constructing a fusion protein with a C ⁇ 2 constant region (Fc region) or a C ⁇ 4 Fc region, and avoiding constructs with a C ⁇ l Fc region or a C ⁇ 3 Fc region.
  • an antibody-based fusion protein with an enhanced in vivo circulating half-life can be obtained by modifying sequences necessary for binding to Fc receptors in isotypes that have binding affinity for an Fc receptor, in order to reduce or eliminate binding.
  • IgG molecules interact with three classes of Fc receptors (FcR), namely Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII.
  • FcR Fc receptors
  • C ⁇ l and C ⁇ 3 bind FcR ⁇ l with high affinity
  • C ⁇ 4 and C ⁇ 2 have reduced or no binding affinity for FcR ⁇ l.
  • a comparison of the C ⁇ l and C ⁇ 3 indicates that, with the exception of an extended hinge segment in C ⁇ 3, the amino acid sequence homology between these two isotypes is very high.
  • FIG. 1 provides a alignment of the amino acid sequences of C ⁇ l and C ⁇ 3.
  • the other two isotypes of human IgG (C ⁇ 2 and C ⁇ 4) have sequence differences which have been associated with FcR binding.
  • FIG. 2 provides a alignment of the amino acid sequences of C ⁇ l, C ⁇ 2, and C ⁇ 4.
  • the important - 7 - sequences for Fc ⁇ R binding are Leu-Leu-Gly-Gly (residues 234 through 237 in C ⁇ l), located in the CH2 domain adjacent to the hinge.
  • Brumbell et al. postulated the existence of a protection receptor (FcRp) that would slow the rate of catabolism of circulating antibodies by binding to the Fc portion of antibodies and, following their pinocytosis into cells, would redirect them back into the circulation.
  • FcRp protection receptor
  • Brumbell et al. NATURE 203: 1352-1355 (1964).
  • the beta-2 microglobulin-containing neonatal intestinal transport receptor (FcRn) has recently been identified as a FcRp. See, Junghans et al., PROC NATL. ACAD. SCI. USA 93: 5512-5516 (1996).
  • the sequences necessary for binding to this receptor are conserved in all four classes of human IgG and are located at the interface between the CH2 and CH3 domains.
  • the preferred gene construct encoding a chimeric chain includes, in 5' to 3' orientation, a DNA segment which encodes at least a portion of an immunoglobulin and DNA which encodes a second, non-immunoglobulin protein.
  • An alternative preferred gene construct includes, in 5' to 3' orientation, a DNA segment which encodes a second, non-immunoglobulin protein and DNA which encodes at least a portion of an immunoglobulin.
  • the fused gene is assembled in or inserted into an expression vector for transfection of the appropriate recipient cells where it is expressed. - 8 -
  • the invention is illustrated further by the following non-limiting examples:
  • Example 1 Improving the in vivo circulating half-life of an antibody-IL2 fusion protein by class switching from C ⁇ l to C ⁇ 4 IgG constant regions.
  • antibody-based fusion proteins with enhanced in vivo circulating half-lives can be obtained by constructing antibody-based fusion proteins using sequences from antibody isotypes that have reduced or no binding affinity for Fc receptors.
  • an antibody-IL2 fusion protein with a human C ⁇ l constant region was compared to an antibody-IL2 fusion protein with a human C ⁇ 4 Fc region.
  • a plasmid vector capable of expressing a humanized antibody-IL2 fusion protein with variable (V) regions specific for a human pancarcinoma antigen (KSA) and the human C ⁇ l heavy chain fused to human IL-2, was modified by removing the C ⁇ l gene fragment and replacing it with the corresponding sequence from the human C ⁇ 4 gene.
  • V variable
  • KSA pancarcinoma antigen
  • These plasmid constructs contain the cytomegalovirus (CMV) early promoter for transcription of the mRNA encoding the light (L) and heavy (H) chain variable (V) regions derived from the mouse antibody KS-1/4.
  • the mouse V regions were humanized by standard methods and their encoding DNA sequences were chemically synthesized.
  • a functional splice donor site was added at the end of each V region so that it could be used in vectors containing H and L chain constant region genes.
  • the human CK light chain gene was inserted downstream of the cloning site for the VL gene and was followed by its endogenous 3' untranslated region and poly adenylation site. This transcription unit was followed by a second independent transcription unit for the heavy chain-IL2 fusion protein.
  • the VH encoding sequence was inserted upstream of the DNA encoding the C ⁇ heavy chain gene of choice, fused to human IL-2 encoding sequences.
  • Such C ⁇ genes contain splice acceptor sites for the first heavy chain exon (CHI), just downstream from a unique Hind III common to all human C ⁇ genes.
  • CHI first heavy chain exon
  • a 3' untranslated and polyadenylation site from SV40 virus was inserted at the end of the IL-2 encoding sequence.
  • the remainder of the vector contained bacterial plasmid DNA necessary for propagation in E. coli and a selectable marker gene (dihydrofolate reductase - dhfr) for selection of transfectants of mammalian cells.
  • the swapping of the C ⁇ l and C ⁇ 4 fragments was accomplished by digesting the original C ⁇ l -containing plasmid DNA with Hind III and Xho I and purifying the large 7.8 kb fragment by agarose gel electrophoresis.
  • a second plasmid DNA containing the C ⁇ 4 gene was digested with Hind III and Nsi I and the 1.75 kb fragment was purified.
  • mouse and human cell lines express one or more Fc receptor.
  • the mouse J774 macrophage-like cell line expresses FcR ⁇ l that is capable of binding mouse or human IgG of the appropriate subclasses.
  • the human K562 erythroleukemic cell line - 10 - expresses FcR ⁇ ll but not FcR ⁇ l.
  • the binding affinities of an antibody, a C ⁇ l-IL2 fusion protein, and a C ⁇ 4-IL2 fusion protein for FcR ⁇ l were compared in the mouse J774 cell line.
  • FACS fluorescence-activated cell sorter
  • Cell lines expressing Fc receptors are useful for testing the binding affinities of candidate fusion proteins to Fc receptors in order to identify antibody-based fusion proteins with enhanced in vivo half lives.
  • Candidate antibody-based fusion proteins can be tested by the above-described methods.
  • Candidate antibody-based fusion proteins with substantially reduced binding affinity - 11 - for an Fc receptor will be identified as antibody-based fusion proteins with enhanced in vivo half lives.
  • fusion proteins containing the C ⁇ l isotype heavy chain i.e., hu-KS ⁇ l-IL2
  • fusion proteins containing the C ⁇ 4 isotype heavy chain were compared to fusion proteins containing the C ⁇ 4 isotype heavy chain (i.e., hu-KS ⁇ 4-IL2).
  • KS-1/4-IL2 fusion proteins containing either the C ⁇ l or C ⁇ 4 isotype heavy chain were buffer-exchanged by diafiltration into phosphate buffered saline (PBS) and diluted further to a concentration of -100 ⁇ g/ml.
  • PBS phosphate buffered saline
  • small blood samples were taken by retro-orbital bleeding from anaesthetized animals and collected in tubes containing citrate buffer to prevent clotting. Cells were removed by centrifugation in an Eppendorf high-speed tabletop centrifuge for 5 min.
  • the plasma was removed with a micropipettor and frozen at -70°C.
  • the concentration of human antibody determinants in the mouse blood was measured by ELISA.
  • a capture antibody specific for human H and L antibody chains was used for capture of the fusion proteins from the diluted plasma samples. After a two hour incubation in antibody-coated 96-well plates, the unbound material was removed by three washes with
  • ELISA buffer 0.01% Tween 80 in PBS.
  • a second incubation step used either an anti-human Fc antibody (for detection of both antibody and intact fusion protein), or an anti-human IL-2 antibody (for detection of only the intact fusion protein). Both antibodies were conjugated to horse radish peroxidase (HRP). After a one hour incubation, the unbound detecting antibody was removed by washing with ELISA buffer and the amount of bound HPR was determined by incubation with substrate and measuring in a spectrophotometer.
  • HRP horse radish peroxidase
  • the ⁇ phase half-life of the hu-KS ⁇ 4-IL2 fusion protein was significantly longer than the ⁇ phase half-life of the hu-KS ⁇ l-IL2 fusion protein.
  • the increased half-life is best exemplified by the significantly higher concentrations of the hu-KS ⁇ 4-IL2 fusion - 12 - protein (3.3 ⁇ g/ml) compared to the hu-KS ⁇ l-IL2 fusion protein (60 ng/ml) found in mice after 24 hours.
  • the hu-KS ⁇ l-IL2 protein had a rapid distribution ( ⁇ ) phase followed by a slower catabolic ( ⁇ ) phase, as reported earlier for the chimeric 14.18-IL2 fusion protein.
  • ⁇ rapid distribution
  • ⁇ catabolic
  • samples were assayed using both (1) an antibody-specific ELISA, and (2) a fusion protein- specific ELISA (i.e., an ELISA that requires that both the antibody and IL-2 components be physically linked).
  • a fusion protein-specific ELISA i.e., an ELISA that requires that both the antibody and IL-2 components be physically linked.
  • C ⁇ l and C ⁇ 3 have binding affinity for Fc receptors, whereas while C ⁇ 4 has reduced binding affinity and C ⁇ 2 has no binding affinity for Fc receptors.
  • the present Example described methods for producing antibody-based fusion proteins using the C ⁇ 4 Fc region, an IgG isotype having reduced affinity for Fc receptors, and established that such antibody-based fusion proteins have enhanced in vivo circulating half-life. Accordingly, a skilled artisan can use these methods to produce antibody-based fusion proteins with the C ⁇ 2 Fc region, instead of the C ⁇ 4 Fc region, in order to enhance the circulating half-life of fusion proteins.
  • a Hu-KS-IL2 fusion protein utilizing the human C ⁇ 2 region can be constructed using the same restriction fragment replacement and the above-described methods for C ⁇ 4-IL2 fusion protein, and tested using the methods described herein to demonstrate increased circulating half-life.
  • Antibody-based fusion proteins with the C ⁇ 2 Fc region, or any other Fc region having reduced binding affinity or lacking binding affinity for a Fc receptor will have enhanced in vivo - 13 - circulating half-life compared to antibody-based fusion proteins having binding affinity for a Fc receptor.
  • Example 2 Mutating the human C ⁇ l or C ⁇ 3 gene in antibody-based fusion protein constructs to improve their in vivo circulating half-life.
  • IgG molecules interact with several molecules in the circulation, including members of the complement system of proteins (e.g., Clq fragment), as well as the three classes of FcR.
  • the important residues for Clq binding are residues Glu 318 , Lys 320 , and Lys 322 which are located in the CH2 domains of human heavy chains.
  • the mutation was achieved by cloning and adapting the small region between the hinge and the beginning of the CH2 exon of the germ line C ⁇ l gene using overlapping polymerase chain reactions (PCR).
  • the PCR primers were designed to substitute the new sequence at the junction of two adjacent PCR fragments spanning a Pst I to Drd I fragment (see FIG. 6).
  • two separate PCR reactions with primers 1 and 2 (SEQ ID NOS: 5 and 6, respectively), or primers 3 and 4 (SEQ ID NOS: 7 and 8, respectively), were prepared using the C ⁇ l gene as the template.
  • the cycle conditions for the primary PCR were 35 cycles of: 94°C for 45 sec, annealing at 48°C for 45 seconds, and primer extension at 72°C for 45 sec.
  • each PCR reaction was used as template for the second, joining reaction step.
  • One tenth of each primary reaction was mixed together and combined with primers 1 and 4 to amplify only the combined product of the two initial PCR products.
  • the conditions for the secondary PCR were: 94°C for 1 min, annealing at 51°C for 1 min, and primer extension at 72°C for 1 min.
  • Joining occurs as a result of the overlapping between the two individual fragments which pairs with the end of the other, following denaturation and annealing.
  • the fragments that form hybrids get extended by the Taq polymerase, and the complete, mutated product was selectively amplified by the priming of the outer primers, as shown in FIG. 6.
  • the final PCR product was cloned in a plasmid vector and its sequence verified by DNA sequence analysis.
  • the assembly of the mutated gene was done in multiple steps.
  • a cloning vector containing the human C ⁇ l gene was digested with Pst I and Xho I to remove the - 14 - non-mutated hinge-CH2-CH3 coding sequences.
  • CH2 all of CH3 and the fused human IL-2 coding sequences was prepared from the C ⁇ l-IL2 vector, described above.
  • a third fragment was prepared from the subcloned PCR product by digestion with Pst I and Drd I. All three fragments were purified by agarose gel electrophoresis and ligated together in a single reaction mixture. The ligation product was used to transform competent E coli and colonies were selected by growth on plates containing ampicillin. Correctly assembled recombinant plasmids were identified by restriction analyses of plasmid DNA preparations from isolated transformants and mutated genes were confirmed by DNA sequence analysis. The Hind III to Xho I fragment from the mutated C ⁇ l-IL2 gene was used to reassemble the complete hu-KS antibody-IL2 fusion protein expression vector.
  • the in vivo plasma concentration of the mutated hu-KS ⁇ l-IL2 was compared to the plasma concentration of hu-KS ⁇ l-IL2 at various specified times. As illustrated in FIG. 7, the in vivo clearance rates of the mutated hu-KS ⁇ l-IL2 and hu- S ⁇ 4-IL2 were significantly lower than the clearance rate of hu-KS ⁇ l-IL2.
  • mutations to the C ⁇ l or C ⁇ 3 genes can be introduced in order to reduce binding to FcR and enhance the in vivo circulating half-life of an antibody-based fusion protein.
  • mutations can also be introduced into the C ⁇ 4 gene in order to further reduce the binding of C ⁇ 4 fusion proteins to FcR.
  • additional possible mutations include mutations in the hinge proximal amino acid residues, mutating Pro 331 , or by mutating the single N-linked glycosylation site in all IgG Fc regions.
  • the latter is located at Asn 297 as part of the canonical sequence: Asn-X-Thr/Ser, where the second position can be any amino acid (with the possible exception of Pro), and the third position is either Thr or Ser.
  • a conservative mutation to the amino acid Gin would have little effect on the protein but would prevent the - 15 - attachment of any carbohydrate side chain.
  • a strategy for mutating this residue might follow the general procedure, just described, for the hinge proximal region. Methods for generating point mutations in cloned DNA sequences are well established in the art and commercial kits are available from several vendors for this purpose.
  • Example 3 Increasing the circulating half-life of receptor-antibody-based fusion proteins.
  • Fc portion of human IgG can serve as a useful carrier for many ligand-binding proteins, or receptors, with biological activity. Some of these ligand-binding proteins have been fused to the N-terminal of the Fc portion of an Ig, such as CD4, CTLA-4, and TNF receptors. See, for example, Capon et al, NATURE 337: 525-531
  • ligand-binding protein partner i.e., the second non-Ig protein
  • the ligand-binding protein partner i.e., the second non-Ig protein
  • the biological activity of a molecule e.g., a cytokine
  • receptor-antibody-based fusion proteins with human C ⁇ l Fc regions are compared to antibody- based fusion proteins with human C ⁇ 4 Fc regions.
  • CD4-antibody-based fusion proteins the ectodomain of the human CD4 cell surface receptor is cloned using PCR from human peripheral blood monocytic cells (PBMC).
  • PBMC peripheral blood monocytic cells
  • the expression vector contains a unique Xba I cloning site downstream of the CMV early promoter, and the human C ⁇ l or C ⁇ 4 gene downstream of their endogenous Hind III site.
  • the remainder of the plasmid contains bacterial genetic information for propagation in E. coli, as well as a dhfr selectable marker gene.
  • Ligated DNAs are used to transform competent bacteria and recombinant plasmids are identified from restriction analyses from individual bacterial colonies. Two plasmid DNA constructs are obtained: CD4-C ⁇ l and CD4-C ⁇ 4.
  • the expression plasmids are used to transfect mouse myeloma cells by electroporation and transfectants are selected by growth in culture medium containing methotrexate (0.1 ⁇ M).
  • - 16 - Transfectants expressing the fusion proteins are identified by ELISA analyses and are expanded in culture in order to generate fusion protein for purification by binding to and elution from protein A Sepharose.
  • Purified proteins in chromatography elution buffer are diafiltered into PBS and diluted to a final concentration of 100 ⁇ g/ml.
  • Balb/c mice are injected with 0.2 ml (20 ⁇ g) of either the CD4-C ⁇ l or CD4-C ⁇ 4 fusion protein and the pharmacokinetics are tested as described in Example 1.3.
  • the CD4-C ⁇ 4 fusion protein has a significantly greater half-life than the CD4-C ⁇ l fusion protein.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Immunology (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Cell Biology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

On décrit des procédés de construction génétique et d'expression de protéines hybrides à base d'anticorps ayant une demi-vie circulante améliorée. Les protéines hybrides de l'invention sont incapables de se lier aux récepteurs pour le fragment Fc des immunoglobulines, soit en conséquence de l'utilisation de l'isotype des anticorps pour construire la protéine hybride, soit par mutagenèse dirigée des isotypes des anticorps qui se lient normalement aux récepteurs pour le fragment Fc. Les protéines hybrides de l'invention peuvent également contenir un domaine fonctionnel capable de lier un récepteur de protection des immunoglobulines.
PCT/US1999/003966 1998-02-25 1999-02-24 Amelioration de la demi-vie circulante de proteines hybrides a base d'anticorps WO1999043713A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
CA002320403A CA2320403A1 (fr) 1998-02-25 1999-02-24 Amelioration de la demi-vie circulante de proteines hybrides a base d'anticorps
EP99908399A EP1060194A1 (fr) 1998-02-25 1999-02-24 Amelioration de la demi-vie circulante de proteines hybrides a base d'anticorps
PL342497A PL199659B1 (pl) 1998-02-25 1999-02-24 Białko fuzyjne przeciwciała hu-KS IL2, cząsteczka DNA kodująca białko fuzyjne przeciwciała hu-KS IL2 i sposób wytwarzania białka fuzyjnego przeciwciała hu-KS IL2
AU27842/99A AU758240B2 (en) 1998-02-25 1999-02-24 Enhancing the circulating half-life of antibody-based fusion proteins
BR9908226-8A BR9908226A (pt) 1998-02-25 1999-02-24 Melhoramento da meia vida de circulação de proteìnas de fusão com base em anticorpo
HU0100813A HUP0100813A3 (en) 1998-02-25 1999-02-24 Enhancing the circulating half-life of antibody-based fusion proteins
JP2000533463A JP2002505086A (ja) 1998-02-25 1999-02-24 抗体ベースの融合タンパク質の循環半減期の増強
NO20004218A NO20004218L (no) 1998-02-25 2000-08-23 Íkning av den sirkulerende halveringstiden til et antistoff- basert fusjonsprotein
HK01107082A HK1036286A1 (en) 1998-02-25 2001-10-09 Enhancing the circulating half-life of antibody-based fusion proteins

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7588798P 1998-02-25 1998-02-25
US60/075,887 1998-02-25

Publications (1)

Publication Number Publication Date
WO1999043713A1 true WO1999043713A1 (fr) 1999-09-02

Family

ID=22128576

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/003966 WO1999043713A1 (fr) 1998-02-25 1999-02-24 Amelioration de la demi-vie circulante de proteines hybrides a base d'anticorps

Country Status (12)

Country Link
EP (1) EP1060194A1 (fr)
JP (1) JP2002505086A (fr)
CN (1) CN1204147C (fr)
AU (1) AU758240B2 (fr)
BR (1) BR9908226A (fr)
CA (1) CA2320403A1 (fr)
CZ (1) CZ20003099A3 (fr)
HK (1) HK1036286A1 (fr)
HU (1) HUP0100813A3 (fr)
NO (1) NO20004218L (fr)
PL (1) PL199659B1 (fr)
WO (1) WO1999043713A1 (fr)

Cited By (137)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
WO2001032714A1 (fr) * 1999-11-03 2001-05-10 King's College London Molécules hybrides de recombinaison
US6242195B1 (en) 1998-04-02 2001-06-05 Genentech, Inc. Methods for determining binding of an analyte to a receptor
WO2001058957A3 (fr) * 2000-02-11 2002-05-02 Lexigen Pharm Corp Amelioration de la demi-vie circulante de proteines de fusion a base d'anticorps
WO2002022680A3 (fr) * 2000-09-15 2002-09-12 Klaus Pfizenmaier Activation localement specifique, par l'intermediaire d'anticorps, d'une zytokine pro-apoptose : amaize (antibody-mediated apoptosis inducing zytokine)
WO2002072605A3 (fr) * 2001-03-07 2002-11-14 Lexigen Pharm Corp Technique d'expression pour des proteines contenant un fragment d'anticorps isotype chimerique
US6528624B1 (en) 1998-04-02 2003-03-04 Genentech, Inc. Polypeptide variants
WO2002060919A3 (fr) * 2000-12-12 2003-09-04 Medimmune Inc Molecules a demi-vies longues, compositions et utilisations de celles-ci
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
EP1446157A2 (fr) * 2001-10-29 2004-08-18 Sunol Molecular Corporation Anticorps permettant d'inhiber la coagulation sanguine et procedes d'utilisation associes
US6838260B2 (en) 1997-12-08 2005-01-04 Emd Lexigen Research Center Corp. Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation
EP1495055A2 (fr) * 2002-04-18 2005-01-12 Genencor International, Inc. Production d'anticorps fonctionnels dans des champignons filamenteux
US6969517B2 (en) 2001-05-03 2005-11-29 Emd Lexigen Research Center Corp. Recombinant tumor specific antibody and use thereof
US6992174B2 (en) 2001-03-30 2006-01-31 Emd Lexigen Research Center Corp. Reducing the immunogenicity of fusion proteins
US7067110B1 (en) 1999-07-21 2006-06-27 Emd Lexigen Research Center Corp. Fc fusion proteins for enhancing the immunogenicity of protein and peptide antigens
US7132100B2 (en) 2002-06-14 2006-11-07 Medimmune, Inc. Stabilized liquid anti-RSV antibody formulations
US7141651B2 (en) 1999-08-09 2006-11-28 Emd Lexigen Research Center Corp. Multiple cytokine protein complexes
US7169904B2 (en) 2002-12-17 2007-01-30 Emd Lexigen Research Center Corp. Immunocytokine sequences and uses thereof
US7183387B1 (en) 1999-01-15 2007-02-27 Genentech, Inc. Polypeptide variants with altered effector function
US7186804B2 (en) 2001-12-04 2007-03-06 Emd Lexigen Research Center Corp. IL-2 fusion proteins with modulated selectivity
US7211253B1 (en) 1999-11-12 2007-05-01 Merck Patentgesellschaft Mit Beschrankter Haftung Erythropoietin forms with improved properties
US7323549B2 (en) 2003-12-30 2008-01-29 Emd Lexigen Research Center Corp. IL-7 fusion proteins
US7355008B2 (en) 2003-01-09 2008-04-08 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US7371826B2 (en) 1999-01-15 2008-05-13 Genentech, Inc. Polypeptide variants with altered effector function
US7416726B2 (en) 2000-04-13 2008-08-26 The Rockefeller University Enhancement of antibody-mediated immune responses
WO2008118093A1 (fr) * 2007-03-28 2008-10-02 Astrazeneca Ab Protéine de fusion pouvant dégrader le peptide bêta-amyloïde
US7465447B2 (en) 2003-12-31 2008-12-16 Merck Patent Gmbh Fc-erythropoietin fusion protein with improved pharmacokinetics
US7517526B2 (en) 2000-06-29 2009-04-14 Merck Patent Gmbh Enhancement of antibody-cytokine fusion protein mediated immune responses by combined treatment with immunocytokine uptake enhancing agents
WO2009092011A1 (fr) 2008-01-18 2009-07-23 Medimmune, Llc Anticorps obtenus par la cystéine pour conjugaison spécifique d'un site
US7589179B2 (en) 2004-12-09 2009-09-15 Merck Patent Gmbh IL-7 variants with reduced immunogenicity
AU2003286467B2 (en) * 2002-10-15 2009-10-01 Abbvie Biotherapeutics Inc. Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis
US7632497B2 (en) 2004-11-10 2009-12-15 Macrogenics, Inc. Engineering Fc Antibody regions to confer effector function
US7658921B2 (en) 2000-12-12 2010-02-09 Medimmune, Llc Molecules with extended half-lives, compositions and uses thereof
US7749498B2 (en) 1997-03-10 2010-07-06 Genentech, Inc. Antibodies for inhibiting blood coagulation and methods of use thereof
WO2010106180A2 (fr) 2009-03-20 2010-09-23 Lfb Biotechnologies Variants fc optimisés
EP2241577A1 (fr) 2007-08-09 2010-10-20 Boehringer Ingelheim International GmbH Anticorps anti-CD37
US7824677B2 (en) 1997-03-10 2010-11-02 Genentech, Inc. Method for using antibodies for inhibiting blood coagulation
WO2010141329A1 (fr) 2009-06-01 2010-12-09 Medimmune, Llc Molecules a demi-vie prolongee et utilisations associees
AU2004231078B2 (en) * 2003-04-10 2011-06-09 Abbvie Biotherapeutics Inc. Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis
US7968094B2 (en) 1997-03-10 2011-06-28 Genentech, Inc. Use of anti-tissue factor antibodies for treating thromboses
US8007795B2 (en) 2001-10-29 2011-08-30 Genentech, Inc. Anti-tissue factor antibodies and methods of use thereof
US8106161B2 (en) 2001-01-17 2012-01-31 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
US8147835B2 (en) 2001-01-17 2012-04-03 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
WO2012045752A1 (fr) 2010-10-04 2012-04-12 Boehringer Ingelheim International Gmbh Agents se liant aux cd33
WO2012069557A1 (fr) 2010-11-24 2012-05-31 Glaxo Group Limited Protéines multispécifique se liant à un antigène et ciblant hgf
WO2012069433A2 (fr) 2010-11-23 2012-05-31 Glaxo Group Limited Protéines de liaison à l'antigène
WO2012083370A1 (fr) 2010-12-22 2012-06-28 Cephalon Australia Pty Ltd Anticorps modifié présentant une demi-vie améliorée
US8329182B2 (en) 2003-05-06 2012-12-11 Syntonix Pharmaceuticals, Inc. Immunoglobulin chimeric monomer-dimer hybrids
US8333966B2 (en) 2008-04-11 2012-12-18 Emergent Product Development Seattle, Llc CD37 immunotherapeutics and uses thereof
WO2013014208A2 (fr) 2011-07-27 2013-01-31 Glaxo Group Limited Constructions de liaison à un antigène
US8409577B2 (en) 2006-06-12 2013-04-02 Emergent Product Development Seattle, Llc Single chain multivalent binding proteins with effector function
US8420087B2 (en) 2004-01-05 2013-04-16 Antisoma Research Limited Interleukin-12 targeted to oncofoetal fibronectin
WO2013055745A2 (fr) 2011-10-11 2013-04-18 Medimmune, Llc Échafaudages dérivés de la ténascine-3 et spécifiques du cd40l et leurs méthodes d'utilisation
US8449884B2 (en) 2003-05-06 2013-05-28 Syntonix Pharmaceuticals, Inc. Clotting factor-fc chimeric proteins to treat hemophilia
WO2013093809A1 (fr) 2011-12-23 2013-06-27 Pfizer Inc. Régions constantes d'anticorps modifiés pour conjugaison spécifique à un site, et leurs procédés et utilisations
EP2614837A1 (fr) 2007-11-09 2013-07-17 Affitech Research AS Compositions d'anticorps anti-VEGF et procédés
US8562991B2 (en) 2008-09-26 2013-10-22 Chugai Seiyaku Kabushiki Kaisha Antibody molecules that bind to IL-6 receptor
US8624007B2 (en) 2002-10-15 2014-01-07 Abbvie Biotherapeutics Inc. Alteration of Fc-fusion protein serum half-lives by mutagenesis
WO2014023752A1 (fr) * 2012-08-10 2014-02-13 Roche Glycart Ag Protéines de fusion d'interleukine-2 et leurs utilisations
AU2014200579A1 (en) * 2000-12-12 2014-02-20 Board Of Regents, The University Of Texas System Molecules with extended half-lives, compositions and uses thereof
WO2014029752A1 (fr) 2012-08-22 2014-02-27 Glaxo Group Limited Anticorps anti-lrp6
EP2711018A1 (fr) 2009-06-22 2014-03-26 MedImmune, LLC Régions Fc modifiées pour conjugaison spécifique d'un site
US8697071B2 (en) 2005-08-10 2014-04-15 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US8722615B2 (en) 2009-12-02 2014-05-13 Acceleron Pharma, Inc. Compositions and methods for increasing serum half-life
US8775090B2 (en) 2008-12-12 2014-07-08 Medimmune, Llc Crystals and structure of a human IgG Fc variant with enhanced FcRn binding
US8795667B2 (en) 2007-12-19 2014-08-05 Macrogenics, Inc. Compositions for the prevention and treatment of smallpox
WO2014140180A1 (fr) 2013-03-15 2014-09-18 Glaxosmithkline Intellectual Property Development Limited Protéines de liaison anti-lag-3
US8883982B2 (en) 2011-06-08 2014-11-11 Acceleron Pharma, Inc. Compositions and methods for increasing serum half-life
US8907066B2 (en) 2009-04-22 2014-12-09 Merck Patent Gmbh Antibody fusion proteins with a modified FcRn binding site
US8946387B2 (en) 2002-08-14 2015-02-03 Macrogenics, Inc. FcγRIIB specific antibodies and methods of use thereof
US8951517B2 (en) 2003-01-09 2015-02-10 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US8969526B2 (en) 2011-03-29 2015-03-03 Roche Glycart Ag Antibody Fc variants
US8968730B2 (en) 2002-08-14 2015-03-03 Macrogenics Inc. FcγRIIB specific antibodies and methods of use thereof
US8993730B2 (en) 2008-04-02 2015-03-31 Macrogenics, Inc. BCR-complex-specific antibodies and methods of using same
US9096877B2 (en) 2009-10-07 2015-08-04 Macrogenics, Inc. Fc region-containing polypeptides that exhibit improved effector function due to alterations of the extent of fucosylation, and methods for their use
US9150656B2 (en) 2010-03-04 2015-10-06 Macrogenics, Inc. Antibodies reactive with B7-H3, immunologically active fragments thereof and uses thereof
WO2015175874A2 (fr) 2014-05-16 2015-11-19 Medimmune, Llc Molécules présentant une altération de liaison de récepteur fc néonatal ayant des propriétés thérapeutiques et diagnostiques améliorées
US9243069B2 (en) 2008-04-02 2016-01-26 Macrogenics, Inc. HER2/neu-specific antibodies and methods of using the same
US9284375B2 (en) 2005-04-15 2016-03-15 Macrogenics, Inc. Covalent diabodies and uses thereof
US9296816B2 (en) 2005-04-15 2016-03-29 Macrogenics, Inc. Covalent diabodies and uses thereof
US9359437B2 (en) 2013-02-01 2016-06-07 Regeneron Pharmaceuticals, Inc. Antibodies comprising chimeric constant domains
US9376495B2 (en) 2011-05-21 2016-06-28 Macrogenics, Inc. Deimmunized serum-binding domains and their use in extending serum half-life
US9441049B2 (en) 2010-03-04 2016-09-13 Macrogenics, Inc. Antibodies reactive with B7-H3 and uses thereof
US9487587B2 (en) 2013-03-05 2016-11-08 Macrogenics, Inc. Bispecific molecules that are immunoreactive with immune effector cells of a companion animal that express an activating receptor and cells that express B7-H3 and uses thereof
WO2017049009A1 (fr) 2015-09-15 2017-03-23 Genentech, Inc. Plate-forme d'échafaudage à noeud de cystine
US9695233B2 (en) 2012-07-13 2017-07-04 Roche Glycart Ag Bispecific anti-VEGF/anti-ANG-2 antibodies and their use in the treatment of ocular vascular diseases
US9708408B2 (en) 2006-12-08 2017-07-18 Macrogenics, Inc. Methods for the treatment of disease using immunoglobulins having Fc Regions with altered affinities for FcγRactivating and FcγRinhibiting
US9737599B2 (en) 2006-06-26 2017-08-22 Macrogenics, Inc. Combination of FcγRIIB-specific antibodies and CD20-specific antibodies and methods of use thereof
US9822181B2 (en) 2013-08-23 2017-11-21 Macrogenics, Inc. Bi-specific monovalent diabodies that are capable of binding CD123 and CD3, and uses thereof
US20170342128A1 (en) * 2012-08-02 2017-11-30 Hoffmann-La Roche Inc. Method for producing monomeric and multimeric molecules and uses thereof
US9889197B2 (en) 2005-04-15 2018-02-13 Macrogenics, Inc. Covalently-associated diabody complexes that possess charged coil domains and that are capable of enhanced binding to serum albumin
US9908938B2 (en) 2013-03-14 2018-03-06 Macrogenics, Inc. Bispecific molecules that are immunoreactive with immune effector cells that express an activating receptor and an antigen expressed by a cell infected by a virus and uses thereof
WO2018049275A1 (fr) 2016-09-09 2018-03-15 Genentech, Inc. Inhibiteurs peptidiques sélectifs de frizzled
US9932400B2 (en) 2013-08-23 2018-04-03 Macrogenics, Inc. Bi-specific monovalent diabodies that are capable of binding to gpA33 and CD3, and uses thereof
US9963510B2 (en) 2005-04-15 2018-05-08 Macrogenics, Inc. Covalent diabodies and uses thereof
US10022319B2 (en) 2010-01-20 2018-07-17 Chugai Seiyaku Kabushiki Kaisha Stabilized antibody-containing liquid formulations
US10035836B1 (en) 2014-08-11 2018-07-31 Delinia, Inc. Modified IL-2 variants that selectively activate regulatory T cells
US10100116B2 (en) 2006-06-26 2018-10-16 Macrogenics, Inc. FcγRIIB-specific antibodies and methods of use thereof
US10144768B2 (en) 2015-12-04 2018-12-04 Novartis Ag Antibody cytokine engrafted compositions and methods of use for immunoregulation
US10143748B2 (en) 2005-07-25 2018-12-04 Aptevo Research And Development Llc B-cell reduction using CD37-specific and CD20-specific binding molecules
US10202464B2 (en) 2011-04-29 2019-02-12 Roche Glycart Ag Immunoconjugates
US10294287B2 (en) 2016-01-20 2019-05-21 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US10344092B2 (en) 2013-08-09 2019-07-09 Macrogenics, Inc. Bi-specific monovalent Fc diabodies that are capable of binding CD32B and CD79b and uses thereof
US20190359945A1 (en) * 2016-10-19 2019-11-28 Hoffmann-La Roche Inc. Method for producing an immunoconjugate
US10550193B2 (en) 2014-03-19 2020-02-04 Regeneron Pharmaceuticals, Inc. Methods and antibody compositions for tumor treatment
US10556952B2 (en) 2015-03-30 2020-02-11 Regeneron Pharmaceuticals, Inc. Heavy chain constant regions with reduced binding to Fc gamma receptors
US10562946B2 (en) 2014-06-20 2020-02-18 Genentech, Inc. Chagasin-based scaffold compositions, methods, and uses
US10604576B2 (en) 2016-06-20 2020-03-31 Kymab Limited Antibodies and immunocytokines
US10662244B2 (en) 2014-11-17 2020-05-26 Regeneron Pharmaceuticals, Inc. Methods for tumor treatment using CD3XCD20 bispecific antibody
US10717778B2 (en) 2014-09-29 2020-07-21 Duke University Bispecific molecules comprising an HIV-1 envelope targeting arm
US10774148B2 (en) 2015-02-27 2020-09-15 Chugai Seiyaku Kabushiki Kaisha Composition for treating IL-6-related diseases
WO2021024133A2 (fr) 2019-08-06 2021-02-11 Glaxosmithkline Intellectual Property Development Limited Compositions biopharmaceutiques et procédés associés
US10961311B2 (en) 2016-04-15 2021-03-30 Macrogenics, Inc. B7-H3 binding molecules, antibody drug conjugates thereof and methods of use thereof
US11077172B2 (en) 2016-11-08 2021-08-03 Delinia, Inc. IL-2 variants for the treatment of psoriasis
US11098099B2 (en) 2014-02-06 2021-08-24 Hoffmann-La Roche Inc. Interleukin-2 fusion proteins and uses thereof
US11254748B2 (en) 2005-04-15 2022-02-22 Macrogenics, Inc. Covalent diabodies and uses thereof
US11319355B2 (en) 2017-12-19 2022-05-03 Xencor, Inc. Engineered IL-2 Fc fusion proteins
US11352426B2 (en) 2015-09-21 2022-06-07 Aptevo Research And Development Llc CD3 binding polypeptides
US11384149B2 (en) 2013-08-09 2022-07-12 Macrogenics, Inc. Bi-specific monovalent Fc diabodies that are capable of binding CD32B and CD79b and uses thereof
US11466093B2 (en) 2015-07-27 2022-10-11 The General Hospital Corporation Antibody derivatives with conditionally enabled effector function
US11472889B2 (en) 2017-10-14 2022-10-18 Cytomx Therapeutics, Inc. Antibodies, activatable antibodies, bispecific antibodies, and bispecific activatable antibodies and methods of use thereof
WO2022248870A1 (fr) 2021-05-28 2022-12-01 Glaxosmithkline Intellectual Property Development Limited Polythérapies pour traiter le cancer
WO2023012669A2 (fr) 2021-08-03 2023-02-09 Glaxosmithkline Intellectual Property Development Limited Compositions biopharmaceutiques et procédé de cartographie peptidique de marquage isotopique stable
US11590223B2 (en) 2018-08-31 2023-02-28 Regeneron Pharmaceuticals, Inc. Dosing strategy that mitigates cytokine release syndrome for therapeutic antibodies
WO2023057893A1 (fr) 2021-10-05 2023-04-13 Glaxosmithkline Intellectual Property Development Limited Polythérapies pour le traitement du cancer
US11680104B2 (en) 2015-09-02 2023-06-20 Immutep S.A.S. Anti-LAG-3 antibodies
WO2023114951A1 (fr) 2021-12-17 2023-06-22 Viiv Healthcare Company Polythérapies pour infections par vih et utilisations associées
US11753479B2 (en) 2014-03-04 2023-09-12 Kymab Limited Nucleic acids encoding anti-OX40L antibodies
US11779604B2 (en) 2016-11-03 2023-10-10 Kymab Limited Antibodies, combinations comprising antibodies, biomarkers, uses and methods
WO2023212304A1 (fr) 2022-04-29 2023-11-02 23Andme, Inc. Protéines de liaison à un antigène
US11851486B2 (en) 2017-05-02 2023-12-26 National Center Of Neurology And Psychiatry Method for predicting and evaluating therapeutic effect in diseases related to IL-6 and neutrophils
WO2024042112A1 (fr) 2022-08-25 2024-02-29 Glaxosmithkline Intellectual Property Development Limited Protéines de liaison à l'antigène et leurs utilisations
US11930837B2 (en) 2017-05-24 2024-03-19 Novartis Ag Antibody-cytokine engrafted proteins and methods of use for immune related disorders
WO2024083945A1 (fr) 2022-10-20 2024-04-25 Glaxosmithkline Intellectual Property (No.3) Limited Protéines de liaison à un antigène
WO2024094690A1 (fr) 2022-11-02 2024-05-10 VIIV Healthcare UK (No.5) Limited Protéines de liaison à un antigène
US12006354B2 (en) 2017-05-24 2024-06-11 Novartis Ag Antibody-IL2 engrafted proteins and methods of use in the treatment of cancer
US12209128B2 (en) 2016-06-20 2025-01-28 Kymab Limited Anti-PD-L1 antibodies

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005073528A (ja) * 2003-08-28 2005-03-24 Genetics Inst Llc 生物学的系における生物学的組織への血球の接着を阻害する方法、ならびにその方法に使用するための組成物
SI1873166T1 (sl) * 2006-06-30 2011-01-31 Conaris Res Inst Ag IZBOLJĹ ANI sgp 130Fc DIMERJI
TWI440470B (zh) * 2009-03-19 2014-06-11 Chugai Pharmaceutical Co Ltd 含改良抗體分子之醫藥配方
GB201506389D0 (en) * 2015-04-15 2015-05-27 Berkel Patricius H C Van And Howard Philip W Site-specific antibody-drug conjugates
GB201506393D0 (en) * 2015-04-15 2015-05-27 Berkel Patricius H C Van And Howard Philip W Site-specific antibody-drug conjugates
EP3929212A4 (fr) * 2019-02-22 2022-11-23 Wuhan Yzy Biopharma Co., Ltd. Fragment fc modifié, anticorps le comprenant et son application

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997000319A2 (fr) * 1995-06-13 1997-01-03 Smithkline Beecham Plc Leptine chimirasee par fusion avec un domaine d'immunoglobuline et utilisation correspondante
WO1997033617A1 (fr) * 1996-03-13 1997-09-18 Protein Design Labs, Inc. Proteines hybrides de ligand fas et leurs utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997000319A2 (fr) * 1995-06-13 1997-01-03 Smithkline Beecham Plc Leptine chimirasee par fusion avec un domaine d'immunoglobuline et utilisation correspondante
WO1997033617A1 (fr) * 1996-03-13 1997-09-18 Protein Design Labs, Inc. Proteines hybrides de ligand fas et leurs utilisations

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
GILLIES S D ET AL: "Biological activity and in vivo clearance of antitumor antibody/cytokine fusion proteins.", BIOCONJUGATE CHEMISTRY, (1993 MAY-JUN) 4 (3) 230-5. JOURNAL CODE: A1T. ISSN: 1043-1802., United States, XP002107032 *
GILLIES S D ET AL: "Improving the efficacy of antibody-interleukin 2 fusion proteins by reducing their interaction with Fc receptors.", CANCER RESEARCH, (1999 MAY 1) 59 (9) 2159-66. JOURNAL CODE: CNF. ISSN: 0008-5472., United States, XP002107035 *
HARVILL E T ET AL: "In vivo properties of an IgG3-IL-2 fusion protein. A general strategy for immune potentiation.", JOURNAL OF IMMUNOLOGY, (1996 OCT 1) 157 (7) 3165-70. JOURNAL CODE: IFB. ISSN: 0022-1767., United States, XP002107033 *
REISFELD R A ET AL: "Recombinant antibody fusion proteins for cancer immunotherapy.", CURRENT TOPICS IN MICROBIOLOGY AND IMMUNOLOGY, (1996) 213 ( PT 3) 27-53. REF: 67 JOURNAL CODE: DWQ. ISSN: 0070-217X., GERMANY: Germany, Federal Republic of, XP002107034 *
ZHENG, XIN XIAO ET AL: "Administration of noncytolytic IL-10/Fc in murine models of lipopolysaccharide-induced septic shock and allogeneic islet transplantation", J. IMMUNOL. (1995), 154(10), 5590-600 CODEN: JOIMA3;ISSN: 0022-1767, XP002082460 *

Cited By (264)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7749498B2 (en) 1997-03-10 2010-07-06 Genentech, Inc. Antibodies for inhibiting blood coagulation and methods of use thereof
US7968094B2 (en) 1997-03-10 2011-06-28 Genentech, Inc. Use of anti-tissue factor antibodies for treating thromboses
US7824677B2 (en) 1997-03-10 2010-11-02 Genentech, Inc. Method for using antibodies for inhibiting blood coagulation
US6838260B2 (en) 1997-12-08 2005-01-04 Emd Lexigen Research Center Corp. Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation
US7226998B2 (en) 1997-12-08 2007-06-05 Emd Lexigen Research Center Corp. Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation
US7576193B2 (en) 1997-12-08 2009-08-18 Merck Patent Gmbh Heterodimeric fusion proteins useful for targeted immune therapy and general immune stimulation
US7297775B2 (en) 1998-04-02 2007-11-20 Genentech, Inc. Polypeptide variants
US6538124B1 (en) 1998-04-02 2003-03-25 Genentech, Inc. Polypeptide variants
US7741072B2 (en) 1998-04-02 2010-06-22 Genentech, Inc. Polypeptide variants
US6528624B1 (en) 1998-04-02 2003-03-04 Genentech, Inc. Polypeptide variants
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
US6242195B1 (en) 1998-04-02 2001-06-05 Genentech, Inc. Methods for determining binding of an analyte to a receptor
US7364731B2 (en) 1998-04-02 2008-04-29 Genentech, Inc. Polypeptide variants
US8163882B2 (en) 1999-01-15 2012-04-24 Genentech, Inc. Polypeptide variants with altered effector function
US6737056B1 (en) 1999-01-15 2004-05-18 Genentech, Inc. Polypeptide variants with altered effector function
US7790858B2 (en) 1999-01-15 2010-09-07 Genentech, Inc. Polypeptide variants with altered effector function
US7785791B2 (en) 1999-01-15 2010-08-31 Genentech, Inc. Polypeptide variants with altered effector function
US7416727B2 (en) 1999-01-15 2008-08-26 Genentech, Inc. Polypeptide variants with altered effector function
US7332581B2 (en) 1999-01-15 2008-02-19 Genentech, Inc. Polypeptide variants with altered effector function
US7335742B2 (en) 1999-01-15 2008-02-26 Genentech, Inc. Polypeptide variants with altered effector function
US7122637B2 (en) 1999-01-15 2006-10-17 Genentech, Inc. Polypeptide variants with altered effector function
US7183387B1 (en) 1999-01-15 2007-02-27 Genentech, Inc. Polypeptide variants with altered effector function
US7371826B2 (en) 1999-01-15 2008-05-13 Genentech, Inc. Polypeptide variants with altered effector function
US7067110B1 (en) 1999-07-21 2006-06-27 Emd Lexigen Research Center Corp. Fc fusion proteins for enhancing the immunogenicity of protein and peptide antigens
US7582288B2 (en) 1999-08-09 2009-09-01 Merck Patent Gmbh Methods of targeting multiple cytokines
US7141651B2 (en) 1999-08-09 2006-11-28 Emd Lexigen Research Center Corp. Multiple cytokine protein complexes
WO2001032714A1 (fr) * 1999-11-03 2001-05-10 King's College London Molécules hybrides de recombinaison
US7211253B1 (en) 1999-11-12 2007-05-01 Merck Patentgesellschaft Mit Beschrankter Haftung Erythropoietin forms with improved properties
JP2012176969A (ja) * 2000-02-11 2012-09-13 Merck Patent Gmbh 抗体ベース融合タンパク質の循環系内半減期の増強
US7507406B2 (en) 2000-02-11 2009-03-24 Emd Serono Research Center, Inc. Enhancing the circulating half-life of antibody-based fusion proteins
WO2001058957A3 (fr) * 2000-02-11 2002-05-02 Lexigen Pharm Corp Amelioration de la demi-vie circulante de proteines de fusion a base d'anticorps
JP2003522200A (ja) * 2000-02-11 2003-07-22 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング 抗体ベース融合タンパク質の循環系内半減期の増強
US7091321B2 (en) 2000-02-11 2006-08-15 Emd Lexigen Research Center Corp. Enhancing the circulating half-life of antibody-based fusion proteins
US7416726B2 (en) 2000-04-13 2008-08-26 The Rockefeller University Enhancement of antibody-mediated immune responses
US7517526B2 (en) 2000-06-29 2009-04-14 Merck Patent Gmbh Enhancement of antibody-cytokine fusion protein mediated immune responses by combined treatment with immunocytokine uptake enhancing agents
WO2002022680A3 (fr) * 2000-09-15 2002-09-12 Klaus Pfizenmaier Activation localement specifique, par l'intermediaire d'anticorps, d'une zytokine pro-apoptose : amaize (antibody-mediated apoptosis inducing zytokine)
EP2354149A1 (fr) 2000-12-12 2011-08-10 MedImmune, LLC Molécules à demi-vies longues, compositions et utilisations de celles-ci
US7704497B2 (en) 2000-12-12 2010-04-27 Medimmune, Llc Molecules with extended half-lives, compositions and uses thereof
US8475792B2 (en) 2000-12-12 2013-07-02 Medimmune, Llc Molecules with extended half-lives, compositions and uses thereof
AU2002248184B2 (en) * 2000-12-12 2008-01-10 Board Of Regents, The University Of Texas System Molecules with extended half-lives, compositions and uses thereof
AU2014200579A1 (en) * 2000-12-12 2014-02-20 Board Of Regents, The University Of Texas System Molecules with extended half-lives, compositions and uses thereof
JP2016020344A (ja) * 2000-12-12 2016-02-04 メディミューン，エルエルシー 延長した半減期を有する分子ならびにその組成物および用途
JP2014050385A (ja) * 2000-12-12 2014-03-20 Medimmune Llc 延長した半減期を有する分子ならびにその組成物および用途
AU2014200579C1 (en) * 2000-12-12 2018-01-18 Board Of Regents, The University Of Texas System Molecules with extended half-lives, compositions and uses thereof
WO2002060919A3 (fr) * 2000-12-12 2003-09-04 Medimmune Inc Molecules a demi-vies longues, compositions et utilisations de celles-ci
JP2010154855A (ja) * 2000-12-12 2010-07-15 Medimmune Llc 延長した半減期を有する分子ならびにその組成物および用途
US7083784B2 (en) 2000-12-12 2006-08-01 Medimmune, Inc. Molecules with extended half-lives, compositions and uses thereof
US8012476B2 (en) 2000-12-12 2011-09-06 Medimmune, Llc Molecules with extended half-lives, compositions and uses thereof
AU2002248184C1 (en) * 2000-12-12 2018-01-04 Board Of Regents, The University Of Texas System Molecules with extended half-lives, compositions and uses thereof
US9562100B2 (en) 2000-12-12 2017-02-07 Medimmune Llc Molecules with extended half-lives, compositions and uses thereof
EP2357187A1 (fr) 2000-12-12 2011-08-17 MedImmune, LLC Molécules à demi-vies longues, compositions et utilisations de celles-ci
EP2341060A1 (fr) 2000-12-12 2011-07-06 MedImmune, LLC Molecules a demi-vies longues, compositions et utilisations de celles-ci
AU2016202471C1 (en) * 2000-12-12 2017-11-09 Board Of Regents, The University Of Texas System Molecules with extended half-lives, compositions and uses thereof
EP3569610A2 (fr) 2000-12-12 2019-11-20 Medlmmune, LLC Molécules à demi-vies longues, compositions et utilisations associées
US8323962B2 (en) 2000-12-12 2012-12-04 Medimmune, Llc Molecules with extended half-lives, compositions and uses thereof
US8795661B2 (en) 2000-12-12 2014-08-05 Medimmune, Llc Molecules with extended half-lives, compositions and uses thereof
US7658921B2 (en) 2000-12-12 2010-02-09 Medimmune, Llc Molecules with extended half-lives, compositions and uses thereof
US7670600B2 (en) 2000-12-12 2010-03-02 MedImmine, LLC Molecules with extended half-lives, compositions and uses thereof
AU2016202471B2 (en) * 2000-12-12 2017-05-25 Board Of Regents, The University Of Texas System Molecules with extended half-lives, compositions and uses thereof
US8197810B2 (en) 2001-01-17 2012-06-12 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
US9005612B2 (en) 2001-01-17 2015-04-14 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
US8106161B2 (en) 2001-01-17 2012-01-31 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
US8853366B2 (en) 2001-01-17 2014-10-07 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
US8147835B2 (en) 2001-01-17 2012-04-03 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
US8188237B2 (en) 2001-01-17 2012-05-29 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
WO2002072605A3 (fr) * 2001-03-07 2002-11-14 Lexigen Pharm Corp Technique d'expression pour des proteines contenant un fragment d'anticorps isotype chimerique
US7148321B2 (en) 2001-03-07 2006-12-12 Emd Lexigen Research Center Corp. Expression technology for proteins containing a hybrid isotype antibody moiety
CN1330664C (zh) * 2001-03-07 2007-08-08 默克专利有限公司 用于含杂合同种型抗体部分的蛋白质的表达技术
US8066994B2 (en) 2001-03-07 2011-11-29 Merck Patent Gmbh Proteins comprising an IgG2 domain
AU2002248571B2 (en) * 2001-03-07 2007-01-18 Merck Patent Gmbh Expression technology for proteins containing a hybrid isotype antibody moiety
US8926973B2 (en) 2001-03-30 2015-01-06 Merck Patent Gmbh Reducing the immunogenicity of fusion proteins
US7601814B2 (en) 2001-03-30 2009-10-13 Merck Patent Gmbh Reducing the immunogenicity of fusion proteins
US6992174B2 (en) 2001-03-30 2006-01-31 Emd Lexigen Research Center Corp. Reducing the immunogenicity of fusion proteins
US6969517B2 (en) 2001-05-03 2005-11-29 Emd Lexigen Research Center Corp. Recombinant tumor specific antibody and use thereof
US7459538B2 (en) 2001-05-03 2008-12-02 Merck Patent Gmbh Recombinant tumor specific antibody and use thereof
EP1446157A2 (fr) * 2001-10-29 2004-08-18 Sunol Molecular Corporation Anticorps permettant d'inhiber la coagulation sanguine et procedes d'utilisation associes
US8007795B2 (en) 2001-10-29 2011-08-30 Genentech, Inc. Anti-tissue factor antibodies and methods of use thereof
EP1446157A4 (fr) * 2001-10-29 2005-12-28 Sunol Molecular Corp Anticorps permettant d'inhiber la coagulation sanguine et procedes d'utilisation associes
US7186804B2 (en) 2001-12-04 2007-03-06 Emd Lexigen Research Center Corp. IL-2 fusion proteins with modulated selectivity
US7462350B2 (en) 2001-12-04 2008-12-09 Emd Serono Research Center, Inc. Cancer treatments including administering IL-2 fusion proteins with modulated selectivity
EP1495055A2 (fr) * 2002-04-18 2005-01-12 Genencor International, Inc. Production d'anticorps fonctionnels dans des champignons filamenteux
EP1495055A4 (fr) * 2002-04-18 2007-08-01 Genencor Int Production d'anticorps fonctionnels dans des champignons filamenteux
US7132100B2 (en) 2002-06-14 2006-11-07 Medimmune, Inc. Stabilized liquid anti-RSV antibody formulations
US7294336B2 (en) 2002-06-14 2007-11-13 Medimmune, Inc. Stabilized liquid anti-RSV antibody formulations
US11180542B2 (en) 2002-06-14 2021-11-23 Arexis Ab Stabilized liquid anti-RSV antibody formulations
US9272032B2 (en) 2002-06-14 2016-03-01 Medimmune, Llc Stabilized liquid anti-RSV antibody formulations
US9879067B2 (en) 2002-06-14 2018-01-30 Medimmune, Llc Stabilized liquid anti-RSV antibody formulations
US10604560B2 (en) 2002-06-14 2020-03-31 Arexis Ab Stabilized liquid anti-RSV antibody formulations
US8986686B2 (en) 2002-06-14 2015-03-24 Medimmune, Llc Stabilized liquid anti-RSV antibody formulations
US8968730B2 (en) 2002-08-14 2015-03-03 Macrogenics Inc. FcγRIIB specific antibodies and methods of use thereof
US8946387B2 (en) 2002-08-14 2015-02-03 Macrogenics, Inc. FcγRIIB specific antibodies and methods of use thereof
US8624007B2 (en) 2002-10-15 2014-01-07 Abbvie Biotherapeutics Inc. Alteration of Fc-fusion protein serum half-lives by mutagenesis
AU2003286467B2 (en) * 2002-10-15 2009-10-01 Abbvie Biotherapeutics Inc. Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis
US7169904B2 (en) 2002-12-17 2007-01-30 Emd Lexigen Research Center Corp. Immunocytokine sequences and uses thereof
US8951517B2 (en) 2003-01-09 2015-02-10 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US9028815B2 (en) 2003-01-09 2015-05-12 Macrogenics, Inc. Identification and engineering of antibodies with variant FC regions and methods of using same
US7355008B2 (en) 2003-01-09 2008-04-08 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
AU2004231078B2 (en) * 2003-04-10 2011-06-09 Abbvie Biotherapeutics Inc. Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis
US11401322B2 (en) 2003-05-06 2022-08-02 Bioverativ Therapeutics Inc. Immunoglobulin chimeric monomer-dimer hybrids
US9725496B1 (en) 2003-05-06 2017-08-08 Bioverative Therapeutics Inc. Immunoglobulin chimeric monomer-dimer hybrids
US11168125B2 (en) 2003-05-06 2021-11-09 Bioverativ Therapeutics Inc. Immunoglobulin chimeric monomer-dimer hybrids
US8932830B2 (en) 2003-05-06 2015-01-13 Biogen Idec Hemophilia, Inc. Immunoglobulin chimeric monomer-dimer hybrids
US9636416B2 (en) 2003-05-06 2017-05-02 Bioverativ Therapeutics Inc. Immunoglobulin chimeric monomer-dimer hybrids
US8815250B2 (en) 2003-05-06 2014-08-26 Biogen Idec Hemophilia Inc. Clotting factor-Fc chimeric proteins to treat hemophilia
US8449884B2 (en) 2003-05-06 2013-05-28 Syntonix Pharmaceuticals, Inc. Clotting factor-fc chimeric proteins to treat hemophilia
US8329182B2 (en) 2003-05-06 2012-12-11 Syntonix Pharmaceuticals, Inc. Immunoglobulin chimeric monomer-dimer hybrids
US7323549B2 (en) 2003-12-30 2008-01-29 Emd Lexigen Research Center Corp. IL-7 fusion proteins
US7465447B2 (en) 2003-12-31 2008-12-16 Merck Patent Gmbh Fc-erythropoietin fusion protein with improved pharmacokinetics
US8420087B2 (en) 2004-01-05 2013-04-16 Antisoma Research Limited Interleukin-12 targeted to oncofoetal fibronectin
US7632497B2 (en) 2004-11-10 2009-12-15 Macrogenics, Inc. Engineering Fc Antibody regions to confer effector function
US7589179B2 (en) 2004-12-09 2009-09-15 Merck Patent Gmbh IL-7 variants with reduced immunogenicity
US9296816B2 (en) 2005-04-15 2016-03-29 Macrogenics, Inc. Covalent diabodies and uses thereof
US10093738B2 (en) 2005-04-15 2018-10-09 Macrogenics, Inc. Covalent diabodies and uses thereof
US9889197B2 (en) 2005-04-15 2018-02-13 Macrogenics, Inc. Covalently-associated diabody complexes that possess charged coil domains and that are capable of enhanced binding to serum albumin
US9284375B2 (en) 2005-04-15 2016-03-15 Macrogenics, Inc. Covalent diabodies and uses thereof
US9963510B2 (en) 2005-04-15 2018-05-08 Macrogenics, Inc. Covalent diabodies and uses thereof
US10093739B2 (en) 2005-04-15 2018-10-09 Macrogenics, Inc. Covalent diabodies and uses thereof
US11254747B2 (en) 2005-04-15 2022-02-22 Macrogenics, Inc. Covalent diabodies and uses thereof
US11254748B2 (en) 2005-04-15 2022-02-22 Macrogenics, Inc. Covalent diabodies and uses thereof
US10143748B2 (en) 2005-07-25 2018-12-04 Aptevo Research And Development Llc B-cell reduction using CD37-specific and CD20-specific binding molecules
US10307481B2 (en) 2005-07-25 2019-06-04 Aptevo Research And Development Llc CD37 immunotherapeutics and uses thereof
US8697071B2 (en) 2005-08-10 2014-04-15 Macrogenics, Inc. Identification and engineering of antibodies with variant Fc regions and methods of using same
US8409577B2 (en) 2006-06-12 2013-04-02 Emergent Product Development Seattle, Llc Single chain multivalent binding proteins with effector function
US11098125B2 (en) 2006-06-26 2021-08-24 Macrogenics, Inc. FcγRIIB-specific antibodies and methods of use thereof
US9737599B2 (en) 2006-06-26 2017-08-22 Macrogenics, Inc. Combination of FcγRIIB-specific antibodies and CD20-specific antibodies and methods of use thereof
US10100116B2 (en) 2006-06-26 2018-10-16 Macrogenics, Inc. FcγRIIB-specific antibodies and methods of use thereof
US9708408B2 (en) 2006-12-08 2017-07-18 Macrogenics, Inc. Methods for the treatment of disease using immunoglobulins having Fc Regions with altered affinities for FcγRactivating and FcγRinhibiting
US11787871B2 (en) 2006-12-08 2023-10-17 Macrogenics, Inc. Methods for the treatment of disease using immunoglobulins having fc regions with altered affinities for FcgammaRactivating and FegammaRinhibiting
US10711069B2 (en) 2006-12-08 2020-07-14 Macrogenics, Inc. Methods for the treatment of disease using immunoglobulins having Fc regions with altered affinities for FcγRactivating and FcγRinhibiting
WO2008118093A1 (fr) * 2007-03-28 2008-10-02 Astrazeneca Ab Protéine de fusion pouvant dégrader le peptide bêta-amyloïde
EP2241577A1 (fr) 2007-08-09 2010-10-20 Boehringer Ingelheim International GmbH Anticorps anti-CD37
EP2562187A1 (fr) 2007-08-09 2013-02-27 Boehringer Ingelheim International GmbH Anticorps anti-CD37
EP2614837A1 (fr) 2007-11-09 2013-07-17 Affitech Research AS Compositions d'anticorps anti-VEGF et procédés
US8795667B2 (en) 2007-12-19 2014-08-05 Macrogenics, Inc. Compositions for the prevention and treatment of smallpox
WO2009092011A1 (fr) 2008-01-18 2009-07-23 Medimmune, Llc Anticorps obtenus par la cystéine pour conjugaison spécifique d'un site
US11028183B2 (en) 2008-04-02 2021-06-08 Macrogenics, Inc. HER2/neu-specific antibodies and methods of using same
US9469692B2 (en) 2008-04-02 2016-10-18 Macrogenics, Inc. HER2/neu-specific antibodies and methods of using same
US10479831B2 (en) 2008-04-02 2019-11-19 Macrogenics, Inc BCR-complex-specific antibodies and methods of using same
US10131713B2 (en) 2008-04-02 2018-11-20 Macrogenics, Inc. HER2/neu-specific antibodies and methods of using same
US9243069B2 (en) 2008-04-02 2016-01-26 Macrogenics, Inc. HER2/neu-specific antibodies and methods of using the same
US8993730B2 (en) 2008-04-02 2015-03-31 Macrogenics, Inc. BCR-complex-specific antibodies and methods of using same
US12024569B2 (en) 2008-04-02 2024-07-02 Macrogenics, Inc. HER2/neu-specific antibodies and methods of using same
US9695236B2 (en) 2008-04-02 2017-07-04 Macrogenics, Inc. BCR-complex-specific antibodies and methods of using same
US9101609B2 (en) 2008-04-11 2015-08-11 Emergent Product Development Seattle, Llc CD37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof
US8333966B2 (en) 2008-04-11 2012-12-18 Emergent Product Development Seattle, Llc CD37 immunotherapeutics and uses thereof
US10662245B2 (en) 2008-09-26 2020-05-26 Chugai Seiyaku Kabushiki Kaisha Methods of reducing IL-6 activity for disease treatment
US8562991B2 (en) 2008-09-26 2013-10-22 Chugai Seiyaku Kabushiki Kaisha Antibody molecules that bind to IL-6 receptor
US8775090B2 (en) 2008-12-12 2014-07-08 Medimmune, Llc Crystals and structure of a human IgG Fc variant with enhanced FcRn binding
EP3395831A1 (fr) 2009-03-20 2018-10-31 Laboratoire Français du Fractionnement et des Biotechnologies Variantes optimisées de fc
EP2233500A1 (fr) 2009-03-20 2010-09-29 LFB Biotechnologies Variantes Fc optimisées
EP4491226A2 (fr) 2009-03-20 2025-01-15 Laboratoire Français du Fractionnement et des Biotechnologies Variants fc optimisés
WO2010106180A2 (fr) 2009-03-20 2010-09-23 Lfb Biotechnologies Variants fc optimisés
EP3674318A1 (fr) 2009-03-20 2020-07-01 Laboratoire Français du Fractionnement et des Biotechnologies Variantes optimisées de fc
US8907066B2 (en) 2009-04-22 2014-12-09 Merck Patent Gmbh Antibody fusion proteins with a modified FcRn binding site
WO2010141329A1 (fr) 2009-06-01 2010-12-09 Medimmune, Llc Molecules a demi-vie prolongee et utilisations associees
EP2711018A1 (fr) 2009-06-22 2014-03-26 MedImmune, LLC Régions Fc modifiées pour conjugaison spécifique d'un site
US9096877B2 (en) 2009-10-07 2015-08-04 Macrogenics, Inc. Fc region-containing polypeptides that exhibit improved effector function due to alterations of the extent of fucosylation, and methods for their use
US8722615B2 (en) 2009-12-02 2014-05-13 Acceleron Pharma, Inc. Compositions and methods for increasing serum half-life
US11612562B2 (en) 2010-01-20 2023-03-28 Chugai Seiyaku Kabushiki Kaisha Solution preparation containing stabilized antibody
US10022319B2 (en) 2010-01-20 2018-07-17 Chugai Seiyaku Kabushiki Kaisha Stabilized antibody-containing liquid formulations
US9714296B2 (en) 2010-03-04 2017-07-25 Macrogenics, Inc. Antibodies reactive with B7-H3, immunologically active fragments thereof and uses thereof
US10683364B2 (en) 2010-03-04 2020-06-16 Macrogenics, Inc. Antibodies reactive with B7-H3, immunologically active fragments thereof and uses thereof
US9441049B2 (en) 2010-03-04 2016-09-13 Macrogenics, Inc. Antibodies reactive with B7-H3 and uses thereof
US9896508B2 (en) 2010-03-04 2018-02-20 Macrogenics, Inc. Antibodies reactive with B7-H3 and uses thereof
US10730945B2 (en) 2010-03-04 2020-08-04 Macrogenics, Inc. Antibodies reactive with B7-H3 and users thereof
US9714295B2 (en) 2010-03-04 2017-07-25 Macrogenics, Inc. Antibodies reactive with B7-H3, immunologically active fragments thereof and uses thereof
US9150656B2 (en) 2010-03-04 2015-10-06 Macrogenics, Inc. Antibodies reactive with B7-H3, immunologically active fragments thereof and uses thereof
EP3133088A1 (fr) 2010-10-04 2017-02-22 Boehringer Ingelheim International GmbH Agents se liant aux cd33
WO2012045752A1 (fr) 2010-10-04 2012-04-12 Boehringer Ingelheim International Gmbh Agents se liant aux cd33
WO2012069433A2 (fr) 2010-11-23 2012-05-31 Glaxo Group Limited Protéines de liaison à l'antigène
WO2012069557A1 (fr) 2010-11-24 2012-05-31 Glaxo Group Limited Protéines multispécifique se liant à un antigène et ciblant hgf
EP2853542A1 (fr) 2010-11-24 2015-04-01 Glaxo Group Limited Protéines multispécifique se liant à un antigène et ciblant HGF
WO2012083370A1 (fr) 2010-12-22 2012-06-28 Cephalon Australia Pty Ltd Anticorps modifié présentant une demi-vie améliorée
US8969526B2 (en) 2011-03-29 2015-03-03 Roche Glycart Ag Antibody Fc variants
US10202464B2 (en) 2011-04-29 2019-02-12 Roche Glycart Ag Immunoconjugates
US9376495B2 (en) 2011-05-21 2016-06-28 Macrogenics, Inc. Deimmunized serum-binding domains and their use in extending serum half-life
US8883982B2 (en) 2011-06-08 2014-11-11 Acceleron Pharma, Inc. Compositions and methods for increasing serum half-life
WO2013014208A2 (fr) 2011-07-27 2013-01-31 Glaxo Group Limited Constructions de liaison à un antigène
US11104720B2 (en) 2011-10-11 2021-08-31 Viela Bio, Inc. Nucleic acids encoding a Tn3 scaffold comprising a CD40L-specific monomer subunit
WO2013055745A2 (fr) 2011-10-11 2013-04-18 Medimmune, Llc Échafaudages dérivés de la ténascine-3 et spécifiques du cd40l et leurs méthodes d'utilisation
US11555062B2 (en) 2011-10-11 2023-01-17 Viela Bio, Inc. Methods of administering a composition comprising a Tn3 scaffold and a CD40L-specific monomer
EP3753567A1 (fr) 2011-10-11 2020-12-23 Viela Bio, Inc. Échafaudages dérivés de la ténascine-3 et spécifiques du cd40l et leurs méthodes d'utilisation
WO2013093809A1 (fr) 2011-12-23 2013-06-27 Pfizer Inc. Régions constantes d'anticorps modifiés pour conjugaison spécifique à un site, et leurs procédés et utilisations
US9695233B2 (en) 2012-07-13 2017-07-04 Roche Glycart Ag Bispecific anti-VEGF/anti-ANG-2 antibodies and their use in the treatment of ocular vascular diseases
US10683345B2 (en) 2012-07-13 2020-06-16 Roche Glycart Ag Bispecific anti-VEGF/anti-ANG-2 antibodies and their use in the treatment of ocular vascular diseases
US20170342128A1 (en) * 2012-08-02 2017-11-30 Hoffmann-La Roche Inc. Method for producing monomeric and multimeric molecules and uses thereof
US10570188B2 (en) * 2012-08-02 2020-02-25 Hoffmann-La Roche Inc. Method for producing monomeric and multimeric molecules and uses thereof
WO2014023752A1 (fr) * 2012-08-10 2014-02-13 Roche Glycart Ag Protéines de fusion d'interleukine-2 et leurs utilisations
US11365232B2 (en) 2012-08-10 2022-06-21 Roche Glycart Ag Interleukin-2 fusion proteins and uses thereof
US10562949B2 (en) 2012-08-10 2020-02-18 Roche Glycart Ag Interleukin-2 fusion proteins and uses thereof
WO2014029752A1 (fr) 2012-08-22 2014-02-27 Glaxo Group Limited Anticorps anti-lrp6
US10988537B2 (en) 2013-02-01 2021-04-27 Regeneren Pharmaceuticals, Inc. Antibodies comprising chimeric constant domains
US9359437B2 (en) 2013-02-01 2016-06-07 Regeneron Pharmaceuticals, Inc. Antibodies comprising chimeric constant domains
US10106610B2 (en) 2013-02-01 2018-10-23 Regeneron Pharmaceuticals, Inc. Antibodies comprising chimeric constant domains
US9487587B2 (en) 2013-03-05 2016-11-08 Macrogenics, Inc. Bispecific molecules that are immunoreactive with immune effector cells of a companion animal that express an activating receptor and cells that express B7-H3 and uses thereof
US11421031B2 (en) 2013-03-14 2022-08-23 Macrogenics, Inc. Bispecific molecules that are immunoreactive with immune effector cells that express an activating receptor and an antigen expressed by a cell infected by a virus and uses thereof
US9908938B2 (en) 2013-03-14 2018-03-06 Macrogenics, Inc. Bispecific molecules that are immunoreactive with immune effector cells that express an activating receptor and an antigen expressed by a cell infected by a virus and uses thereof
US10730947B2 (en) 2013-03-14 2020-08-04 Macrogenics, Inc. Bispecific molecules that are immunoreactive with immune effector cells that express an activating receptor and an antigen expressed by a cell infected by a virus and uses thereof
WO2014140180A1 (fr) 2013-03-15 2014-09-18 Glaxosmithkline Intellectual Property Development Limited Protéines de liaison anti-lag-3
US10344088B2 (en) 2013-03-15 2019-07-09 Glaxosmithkline Intellectual Property Development Limited Antigen binding proteins
US10280221B2 (en) 2013-03-15 2019-05-07 Glaxosmithkline Intellectual Property Development Limited Anti-LAG-3 binding proteins
EP3712177A1 (fr) 2013-03-15 2020-09-23 GlaxoSmithKline Intellectual Property Development Limited Protéines de liaison anti-lag-3
US10344092B2 (en) 2013-08-09 2019-07-09 Macrogenics, Inc. Bi-specific monovalent Fc diabodies that are capable of binding CD32B and CD79b and uses thereof
US11384149B2 (en) 2013-08-09 2022-07-12 Macrogenics, Inc. Bi-specific monovalent Fc diabodies that are capable of binding CD32B and CD79b and uses thereof
US9822181B2 (en) 2013-08-23 2017-11-21 Macrogenics, Inc. Bi-specific monovalent diabodies that are capable of binding CD123 and CD3, and uses thereof
US10787521B2 (en) 2013-08-23 2020-09-29 Macrogenics, Inc. Bi-specific monovalent diabodies that are capable of binding CD123 and CD3, and uses thereof
US10858430B2 (en) 2013-08-23 2020-12-08 Macrogenics, Inc. Bi-specific monovalent diabodies that are capable of binding to gpA33 and CD3, and uses thereof
US9932400B2 (en) 2013-08-23 2018-04-03 Macrogenics, Inc. Bi-specific monovalent diabodies that are capable of binding to gpA33 and CD3, and uses thereof
US11098099B2 (en) 2014-02-06 2021-08-24 Hoffmann-La Roche Inc. Interleukin-2 fusion proteins and uses thereof
US11773175B2 (en) 2014-03-04 2023-10-03 Kymab Limited Antibodies, uses and methods
US11753479B2 (en) 2014-03-04 2023-09-12 Kymab Limited Nucleic acids encoding anti-OX40L antibodies
US10550193B2 (en) 2014-03-19 2020-02-04 Regeneron Pharmaceuticals, Inc. Methods and antibody compositions for tumor treatment
US11434300B2 (en) 2014-03-19 2022-09-06 Regeneron Pharmaceuticals, Inc. Methods and antibody compositions for tumor treatment
WO2015175874A2 (fr) 2014-05-16 2015-11-19 Medimmune, Llc Molécules présentant une altération de liaison de récepteur fc néonatal ayant des propriétés thérapeutiques et diagnostiques améliorées
EP3888690A2 (fr) 2014-05-16 2021-10-06 MedImmune, LLC Molécules présentant une altération de liaison de récepteur fc néonatal ayant des propriétés thérapeutiques et diagnostiques améliorées
US10562946B2 (en) 2014-06-20 2020-02-18 Genentech, Inc. Chagasin-based scaffold compositions, methods, and uses
US10035836B1 (en) 2014-08-11 2018-07-31 Delinia, Inc. Modified IL-2 variants that selectively activate regulatory T cells
US12173051B2 (en) 2014-09-29 2024-12-24 Duke University Bispecific molecules comprising an HIV-1 envelope targeting arm
US10717778B2 (en) 2014-09-29 2020-07-21 Duke University Bispecific molecules comprising an HIV-1 envelope targeting arm
US10662244B2 (en) 2014-11-17 2020-05-26 Regeneron Pharmaceuticals, Inc. Methods for tumor treatment using CD3XCD20 bispecific antibody
US10774148B2 (en) 2015-02-27 2020-09-15 Chugai Seiyaku Kabushiki Kaisha Composition for treating IL-6-related diseases
US10556952B2 (en) 2015-03-30 2020-02-11 Regeneron Pharmaceuticals, Inc. Heavy chain constant regions with reduced binding to Fc gamma receptors
US11518807B2 (en) 2015-03-30 2022-12-06 Regeneron Pharmaceuticals, Inc. Heavy chain constant regions with reduced binding to Fc gamma receptors
US11466093B2 (en) 2015-07-27 2022-10-11 The General Hospital Corporation Antibody derivatives with conditionally enabled effector function
US11680104B2 (en) 2015-09-02 2023-06-20 Immutep S.A.S. Anti-LAG-3 antibodies
US11078243B2 (en) 2015-09-15 2021-08-03 Genentech, Inc. Cystine knot scaffold platform
US11155586B2 (en) 2015-09-15 2021-10-26 Genentech, Inc. Cystine knot scaffold platform
US10696721B2 (en) 2015-09-15 2020-06-30 Genentech, Inc. Cystine knot scaffold platform
WO2017049009A1 (fr) 2015-09-15 2017-03-23 Genentech, Inc. Plate-forme d'échafaudage à noeud de cystine
US10428125B2 (en) 2015-09-15 2019-10-01 Genentech, Inc. Cystine knot scaffold platform
US11407794B2 (en) 2015-09-15 2022-08-09 Genetech, Inc. Cystine knot scaffold platform
US11352426B2 (en) 2015-09-21 2022-06-07 Aptevo Research And Development Llc CD3 binding polypeptides
US11136366B2 (en) 2015-12-04 2021-10-05 Novartis Ag Methods of treating immune related disorders using antibody-cytokine engrafted compositions
US10144768B2 (en) 2015-12-04 2018-12-04 Novartis Ag Antibody cytokine engrafted compositions and methods of use for immunoregulation
US10766938B2 (en) 2016-01-20 2020-09-08 Delinia, Inc. Nucleic acid encoding human IL-2 variant
US10294287B2 (en) 2016-01-20 2019-05-21 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US10774126B2 (en) 2016-01-20 2020-09-15 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US10875901B2 (en) 2016-01-20 2020-12-29 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US11535657B2 (en) 2016-01-20 2022-12-27 Delinia, Inc. Molecules that selectively activate regulatory T cells for the treatment of autoimmune diseases
US10961311B2 (en) 2016-04-15 2021-03-30 Macrogenics, Inc. B7-H3 binding molecules, antibody drug conjugates thereof and methods of use thereof
US11591400B2 (en) 2016-04-15 2023-02-28 Macrogenics, Inc. B7-H3 directed antibody drug conjugates
US12209128B2 (en) 2016-06-20 2025-01-28 Kymab Limited Anti-PD-L1 antibodies
US10604576B2 (en) 2016-06-20 2020-03-31 Kymab Limited Antibodies and immunocytokines
WO2018049275A1 (fr) 2016-09-09 2018-03-15 Genentech, Inc. Inhibiteurs peptidiques sélectifs de frizzled
US20190359945A1 (en) * 2016-10-19 2019-11-28 Hoffmann-La Roche Inc. Method for producing an immunoconjugate
US11779604B2 (en) 2016-11-03 2023-10-10 Kymab Limited Antibodies, combinations comprising antibodies, biomarkers, uses and methods
US11077172B2 (en) 2016-11-08 2021-08-03 Delinia, Inc. IL-2 variants for the treatment of psoriasis
US11851486B2 (en) 2017-05-02 2023-12-26 National Center Of Neurology And Psychiatry Method for predicting and evaluating therapeutic effect in diseases related to IL-6 and neutrophils
US11930837B2 (en) 2017-05-24 2024-03-19 Novartis Ag Antibody-cytokine engrafted proteins and methods of use for immune related disorders
US12006354B2 (en) 2017-05-24 2024-06-11 Novartis Ag Antibody-IL2 engrafted proteins and methods of use in the treatment of cancer
US11472889B2 (en) 2017-10-14 2022-10-18 Cytomx Therapeutics, Inc. Antibodies, activatable antibodies, bispecific antibodies, and bispecific activatable antibodies and methods of use thereof
US11859010B2 (en) 2017-10-14 2024-01-02 Cytomx Therapeutics, Inc. Antibodies, activatable antibodies, bispecific antibodies, and bispecific activatable antibodies and methods of use thereof
US11319355B2 (en) 2017-12-19 2022-05-03 Xencor, Inc. Engineered IL-2 Fc fusion proteins
US11981717B2 (en) 2017-12-19 2024-05-14 Xencor, Inc. Engineered IL-2 Fc fusion proteins
US11590223B2 (en) 2018-08-31 2023-02-28 Regeneron Pharmaceuticals, Inc. Dosing strategy that mitigates cytokine release syndrome for therapeutic antibodies
WO2021024133A2 (fr) 2019-08-06 2021-02-11 Glaxosmithkline Intellectual Property Development Limited Compositions biopharmaceutiques et procédés associés
WO2022248870A1 (fr) 2021-05-28 2022-12-01 Glaxosmithkline Intellectual Property Development Limited Polythérapies pour traiter le cancer
WO2023012669A2 (fr) 2021-08-03 2023-02-09 Glaxosmithkline Intellectual Property Development Limited Compositions biopharmaceutiques et procédé de cartographie peptidique de marquage isotopique stable
WO2023057893A1 (fr) 2021-10-05 2023-04-13 Glaxosmithkline Intellectual Property Development Limited Polythérapies pour le traitement du cancer
WO2023114951A1 (fr) 2021-12-17 2023-06-22 Viiv Healthcare Company Polythérapies pour infections par vih et utilisations associées
WO2023212304A1 (fr) 2022-04-29 2023-11-02 23Andme, Inc. Protéines de liaison à un antigène
WO2024042112A1 (fr) 2022-08-25 2024-02-29 Glaxosmithkline Intellectual Property Development Limited Protéines de liaison à l'antigène et leurs utilisations
WO2024083945A1 (fr) 2022-10-20 2024-04-25 Glaxosmithkline Intellectual Property (No.3) Limited Protéines de liaison à un antigène
WO2024094690A1 (fr) 2022-11-02 2024-05-10 VIIV Healthcare UK (No.5) Limited Protéines de liaison à un antigène

Also Published As

Publication number Publication date
HUP0100813A2 (hu) 2001-06-28
AU2784299A (en) 1999-09-15
CZ20003099A3 (cs) 2002-04-17
EP1060194A1 (fr) 2000-12-20
CA2320403A1 (fr) 1999-09-02
JP2002505086A (ja) 2002-02-19
PL342497A1 (en) 2001-06-04
CN1204147C (zh) 2005-06-01
NO20004218L (no) 2000-10-24
PL199659B1 (pl) 2008-10-31
CN1291995A (zh) 2001-04-18
BR9908226A (pt) 2000-10-24
HK1036286A1 (en) 2001-12-28
AU758240B2 (en) 2003-03-20
NO20004218D0 (no) 2000-08-23
HUP0100813A3 (en) 2003-08-28

Similar Documents

Publication Publication Date Title
AU758240B2 (en) Enhancing the circulating half-life of antibody-based fusion proteins
US20060194952A1 (en) Enhancing the circulating half-life of antibody-based fusion proteins
JP4234438B2 (ja) ハイブリッド・イソタイプ抗体部分を含有する蛋白質の発現技術
US5892019A (en) Production of a single-gene-encoded immunoglobulin
US7053202B2 (en) Immunoglobulin DNA cassette molecules, monobody constructs, methods of production, and methods of use therefor
EP1997894B1 (fr) Protéine de liaison biosynthétique pour un marqueur du cancer
JP5572665B2 (ja) 抗体ベース融合タンパク質の循環系内半減期の増強
JP3081641B2 (ja) 抗体の調製
CA1341351C (fr) Production d'anticorps chimeres souris-homme, specifiques pour les antigenes tumoraux chez l'homme
AU2002248571A1 (en) Expression technology for proteins containing a hybrid isotype antibody moiety
TW201932142A (zh) 自單特異性抗體產生多特異性抗體之方法
CA2328606A1 (fr) Anticorps diriges contre la cd23, derives de ces derniers et utilisations therapeutiques
CA2582157A1 (fr) Procedes et compositions permettant d'ameliorer la production de proteines recombinees
CN112243444A (zh) 具有减少的翻译后修饰的肽接头
Shin et al. Hybrid antibodies
EP0730649A1 (fr) Fragments d'hig-e ayant subi une mutation et leur derive
US20210253741A1 (en) Bispecific antibodies
CA2131355C (fr) Production d'une immunoglobuline codee par un gene unique
MXPA00008312A (es) Metodos para mejorar la vida media en circulacion de proteinas de fusion a base de anticuerpo
AU2001243148B2 (en) Enhancing the circulating half-life of antibody-based fusion proteins
AU2001243148A1 (en) Enhancing the circulating half-life of antibody-based fusion proteins

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 99803277.8

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 27842/99

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2320403

Country of ref document: CA

Ref document number: 2320403

Country of ref document: CA

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2000 533463

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/2000/008312

Country of ref document: MX

Ref document number: PV2000-3099

Country of ref document: CZ

NENP Non-entry into the national phase

Ref country code: KR

WWE Wipo information: entry into national phase

Ref document number: 1999908399

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1999908399

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV2000-3099

Country of ref document: CZ

WWG Wipo information: grant in national office

Ref document number: 27842/99

Country of ref document: AU

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载