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WO2013034933A1 - Anticorps anti ddr1, utilisations de ceux-ci, et procédés d'identification correspondants - Google Patents

Anticorps anti ddr1, utilisations de ceux-ci, et procédés d'identification correspondants Download PDF

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Publication number
WO2013034933A1
WO2013034933A1 PCT/GB2012/052219 GB2012052219W WO2013034933A1 WO 2013034933 A1 WO2013034933 A1 WO 2013034933A1 GB 2012052219 W GB2012052219 W GB 2012052219W WO 2013034933 A1 WO2013034933 A1 WO 2013034933A1
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Prior art keywords
antibody
ddr1
cancer
tumour
amino acid
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PCT/GB2012/052219
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English (en)
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Birgit LEITINGER
Erhard Hohenester
Federico CARAFOLI
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Imperial Innovations Limited
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Publication of WO2013034933A1 publication Critical patent/WO2013034933A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2851—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2299/00—Coordinates from 3D structures of peptides, e.g. proteins or enzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention generally relates to agents that target discoidin domain receptor 1 , and more particularly to agents that bind to the DS-like domain of discoidin domain receptor 1.
  • the invention also relates to methods, uses, kits, compounds and compositions comprising such agents.
  • Receptor tyrosine kinases are the targets of many anti-cancer therapies. Small-molecule drugs are used to target their intracellular portion, and more recently, monoclonal antibodies against their extracellular regions have been developed for clinical use. Since monoclonal antibodies selectively target tumour cells, their use minimises the cytotoxic side effects caused by traditional chemotherapeutics. Monoclonal antibodies are often non-mutagenic and are associated with few long-term adverse events, making them attractive therapeutic agents. Monoclonal antibodies against receptor tyrosine kinases have become critical components of clinical treatments for a variety of disorders, especially in oncology. Established monoclonal antibody-based therapies are routinely used for breast cancer treatment and haematological malignancies, and are in development for other cancers, such as colorectal, lung and ovarian cancers, for which new molecular targets are being sought.
  • DDR1 Discoidin domain receptor 1
  • tumour formation In particular, fast growing, invasive tumours often show enhanced DDR1 expression and there is good evidence that cancer invasion and metastasis are mediated by DDR1.
  • High level of DDR1 expression was correlated with advanced tumour stage and significantly poorer survival in several cohorts of patients with brain, breast, lung and ovarian cancer.
  • DDR1 was found to be among the top 10 activated kinases, both in patient samples and in cell lines.
  • DDR1 is mutated in certain lung cancers and leukaemia.
  • DDR1 In addition to cancer cell invasion and metastasis, DDR1 contributes to cancer cell survival. Several studies have shown that depletion of DDR1 blocked cancer cell invasion, in both in vitro and in vivo models, indicating that DDR1 is a valid clinical target in cancer therapy.
  • DDR1 is a collagen receptor that plays a key role in cell attachment, migration, survival and proliferation. DDR1 mediates disease progression, particularly tumorigenesis, but also certain inflammatory and fibrotic disorders and atherosclerosis. Collagen binding to DDR1 results in enhanced DDR1 kinase activity, which is manifested as increased autophosphorylation.
  • the extracellular domain of DDR1 consists of two protein modules, the discoidin domain and the discoidin-like (DS-like) domain.
  • the discoidin domain fully contains the DDR1 ligand-binding site, which is located at the "top" of the domain.
  • US patent publication no. 2009/0142345 describes DDR1 neutralising antibodies, and their use in treating cancer.
  • WO 2010/019702 describes the use of neutralising antibodies against DDR1 , and more specifically antibodies that bind to the ligand binding site of DDR1 and which prevent or inhibit collagen binding to DDR1.
  • the entire disclosure of WO 2010/019702 relating to the use of anti-DDR1 antibodies is incorporated herein in its entirety by reference.
  • a first aspect of the invention provides an antibody that specifically binds to the extracellular domain of human discoidin domain receptor 1 (DDR1) outside the discoidin domain, and which reduces or blocks collagen-induced autophosphorylation of DDR1 without preventing collagen binding to DDR1.
  • DDR1 discoidin domain receptor 1
  • Such antibodies will bind their target with a greater affinity than for an irrelevant polypeptide, such as human serum albumin (HSA).
  • an irrelevant polypeptide such as human serum albumin (HSA).
  • the antibody binds the DDR1 with at least 5, or at least 10 or at least 50 times greater affinity than for the irrelevant polypeptide. More preferably, the antibody molecule binds the DDR1 with at least 100, or at least 1 ,000, or at least 10,000 times greater affinity than for the irrelevant polypeptide.
  • Such binding may be determined by methods well known in the art, such as one of the Biacore ® systems.
  • the antibodies have an affinity for DDR1 of at least 10 "7 M and more preferably 10 "8 M, although antibodies with higher affinities, e.g. 10 "9 M, or higher, may be even more preferred.
  • the antibody when the antibody is administered to an individual, the antibody binds to DDR1 or to the specified portion thereof, with a greater affinity than for DDR2.
  • the antibody binds to (the specified portion of) DDR1 with at least 2, or at least 5, or at least 0 or at least 50 times greater affinity than for DDR2 in the individual.
  • the agent binds the DDR1 (at the specified domain) with at least 100, or at least 1 ,000, or at least 10,000 times greater affinity than for DDR2 in the individual.
  • the antibody molecule selectively binds the DDR1 without significantly binding DDR2, or only binds to DDR2 at undetectable levels.
  • the antibody when the antibody is administered to an individual, the antibody binds to DDR1 or to the specified portion thereof, with a greater affinity than for any other molecule in the individual.
  • the antibody binds to the specified portion of DDR1 with at least 2, or at least 5, or at least 10 or at least 50 times greater affinity than for any other molecule in the individual.
  • the agent binds the DDR1 at the specified domain with at least 100, or at least 1,000, or at least 10,000 times greater affinity than any other molecule in the individual.
  • the antibody molecule 5 selectively binds the DDR1 without significantly binding other polypeptides in the body, such as for example other RTKs, although in practice there may be some cross reactivity that does not affect the intended use of the antibody.
  • antibody we include substantially intact antibody molecules, as well as antigenic) binding fragments of antibodies, chimaeric antibodies, humanised antibodies, human antibodies (wherein at least one amino acid is mutated relative to the naturally occurring human antibodies), single chain antibodies, bispecific antibodies, antibody heavy chains, antibody light chains, homodimers and heterodimers of antibody heavy and/or light chains, and antigen binding fragments and derivatives of the same.
  • the antibody or antigen-binding fragment, or fusion or derivative thereof may comprise, consist or consist essentially of an intact antibody.
  • consist essentially of we mean that the antibody or antigen-binding fragment, fusion or derivative thereof consists of a portion of an intact antibody sufficient to retain binding specificity for the specified region or epitope of DDR1.
  • the term 'antibody' also includes all classes of antibodies, including IgG, IgA, IgM, IgD and IgE.
  • the antibody may be an IgG molecule, such as an lgG1 , lgG2, lgG3, or lgG4 molecule.
  • the antibody is an IgG antibody, for example, an lgG2 or lgG4 antibody.
  • the antibody is an lgG4 antibody in which the Serine amino acid at position 241 has been substituted with a Proline residue (i.e.
  • CDRs Complementarity Determining Regions
  • variable heavy (V H ) and variable light (V L ) domains of the antibody are involved in antigen recognition, a fact first recognised by early protease digestion experiments. Further confirmation was found by "humanisation" of rodent antibodies. Variable domains of rodent origin may be fused to constant domains of human origin such that the resultant antibody retains the antigenic specificity of the rodent-parented antibody (Morrison ef al (1984) Proc. Natl. Acad. Sci. USA 81 , 6851-6855).
  • variable domains Antigenic specificity is conferred by variable domains and is independent of the constant domains, as known from experiments involving the bacterial expression of antibody fragments, all containing one or more variable domains.
  • variable domains include Fab-like molecules (Better et al (1988) Science 240, 1041); Fv molecules (Skerra et al (1988) Science 240, 1038); single-chain Fv (ScFv) molecules where the V H and V L partner domains are linked via a flexible oligopeptide (Bird et al (1988) Science 242, 423; Huston et al (1988) Proc. Natl. Acad. Sci.
  • antigen-binding fragment we mean a functional fragment of an antibody that is capable of binding to the specified region or epitope of DDR1.
  • exemplary antigen-binding fragments of the invention may be selected from the group consisting of Fv fragments (e.g. single chain Fv and disulphide-bonded Fv), and Fab-like fragments (e.g. Fab fragments, Fab' fragments and F(ab) 2 fragments).
  • the antigen-binding fragment is an scFv.
  • antibody fragments rather than whole antibodies
  • the smaller size of the fragments may lead to improved pharmacological properties, such as better penetration of solid tissue.
  • antigen-binding fragments such as Fab, Fv, ScFv and dAb antibody fragments can be expressed in and secreted from E. coli or yeast, thus allowing the facile production of large amounts of the said fragments.
  • modified versions of antibodies and antigen-binding fragments thereof e.g. modified by the covalent attachment of polyethylene glycol or other suitable polymer.
  • antibodies may be generated via any one of several methods which employ induction of in vivo production of antibody molecules, screening of immunoglobulin libraries (Orlandi. ef a/, 1989. Proc. Natl. Acad. Sci. U.S.A. 86:3833-3837; Winter ef a/., 1991 , Nature 349:293-299) or generation of monoclonal antibody molecules by cell lines in culture.
  • these include, but are not limited to, the hybridoma technique, the human B- cell hybridoma technique, and the Epstein-Barr virus (EBV)-hybridoma technique (Kohler et a/., 1975.
  • EBV Epstein-Barr virus
  • the antibody or antigen-binding fragment or derivative thereof may be produced by recombinant means.
  • the antibody is a monoclonal antibody.
  • Suitable monoclonal antibodies to selected antigens may be prepared by known techniques, for example those disclosed in “Monoclonal Antibodies: A manual of techniques", H Zola (CRC Press, 1988) and in “Monoclonal Hybridoma Antibodies: Techniques and Applications", J G R Hurrell (CRC Press, 1982) , which are incorporated herein by reference.
  • Antibody fragments can also be obtained using methods well known in the art (see, for example, Harlow & Lane, 1988, "Antibodies: A Laboratory Manual', Cold Spring Harbor Laboratory, New York, which is incorporated herein by reference).
  • antibody fragments according to the present invention can be prepared by proteolytic hydrolysis of the antibody or by expression in E. coli or mammalian cells (e.g. Chinese hamster ovary cell culture or other protein expression systems) of DNA encoding the fragment.
  • antibody fragments can be obtained by pepsin or papain digestion of whole antibodies by conventional methods.
  • antibody fragments can be obtained by cell-free in vitro expression, as is known in the art.
  • the antibody may be a single-domain antibody, such as a Nanobody.
  • a Nanobody Such antibodies are known to exist in camelids (Curr. Opin. Pharmacol., 8, (2008), 600-608) and sharks (e.g. IgNAR; Curr. Opin. Pharmacol., 8, (2008), 600-608).
  • Nanobodies ® are antibody-derived therapeutic proteins that contain the structural and functional properties of naturally-occurring heavy-chain antibodies.
  • the Nanobody ® technology was developed following the discovery that camelidae (camels and llamas) possess fully functional antibodies that lack light chains. These heavy-chain antibodies contain a single variable domain (VHH) and two constant domains (C H 2 and C H 3).
  • VHH domain is a perfectly stable polypeptide harbouring the full antigen-binding capacity of the original heavy-chain antibody.
  • These VHH domains with their unique structural and functional properties form the basis of Nanobodies ® . They combine the advantages of conventional antibodies (high target specificity, high target affinity and low inherent toxicity) with important features of small molecule drugs (the ability to inhibit enzymes and access receptor clefts). Furthermore, they are stable, have the potential to be administered by means other than injection, are easier to manufacture, and can be humanised.
  • DDR1 DS-like domain of DDR1
  • residues 187 to 367 of DDR1 isoform 1 whose sequence, taken from Q08345, is listed above.
  • epitope we mean a site of a molecule to which an antibody binds, i.e. a molecular region of an antigen.
  • An epitope may be a linear epitope, which is determined by e.g. the amino acid sequence, i.e. the primary structure, or a three-dimensional epitope, defined by the secondary structure, e.g. folding of a peptide chain into beta sheet or alpha helical, or by the tertiary structure, e.g. way which helices or sheets are folded or arranged to give a three-dimensional structure, of an antigen.
  • an antibody that specifically binds to the DDR1 epitope encompassed by amino acid residues Tyr203 to Tyr209 we mean that the antibody binds to DDR1 through at least one of the seven amino acid residues encompassed by Tyr203 to Tyr209.
  • the antibody binds to the DDR1 through at least 2, at least 3, at least 4, at least 5, or at least 6 of the seven amino acid residues encompassed by Tyr203 to Tyr209.
  • the antibody binds to DDR1 through all seven of the residues encompassed by Tyr203 to Tyr209.
  • This antibody may further comprise:
  • a light chain CDR1 comprising the amino acid sequence SSSVTF
  • the invention provides an antibody that specifically binds to the discoidin-like domain of human DDR1 , wherein the antibody comprises:
  • a light chain CDR2 comprising the amino acid sequence YLTSN, and
  • a light chain CDR3 comprising the amino acid sequence QWSSNPYT, or a variant of any of these sequences comprising 1 or 2 amino acid substitutions.
  • the invention provides an antibody that specifically binds to the discoidin-like domain of human DDR1 , wherein the antibody comprises:
  • the amino acid substitutions are conservative amino acid substitutions.
  • Conservative substitutions providing functionally similar amino acids are well known in the art, and described for example in Table 1 of WO 2010/019702, which is incorporated herein by reference.
  • Guidance concerning which amino acid changes are likely to be phenotypically silent can also be found in Bowie et a/., 1990, Science 247: 1306-1310.
  • Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologues, and alleles.
  • Typical conservative substitution groups include: (1) Alanine (A), Glycine (G); (2) Aspartic acid (D), Glutamic acid (E); (3) Asparagine (N), Glutamine (Q); (4) Arginine (R), Lysine (K); (5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); (6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); (7) Serine (S), Threonine (T); and (8) Cysteine (C), Methionine (M) (see, e.g., Creighton, Proteins (1984)). As indicated, changes are typically of a minor nature that do not significantly affect the folding, binding or activity of the protein.
  • the antibody comprises:
  • the antibody is capable of inhibiting or otherwise interfering, at least in part, with the binding of an antibody molecule having these variable region sequences to the DS-like domain of DDR1.
  • the antibody may be capable of inhibiting the binding of an antibody molecule having these variable region sequences by at least 10%, for example at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 35% or even by 100%.
  • Competitive binding may be determined by methods well known to those skilled in the art, such as ELISA and/or SPR as is very well known in the art.
  • the antibody is capable of binding to the same epitope as an antibody having the sequence shown in Figure 11.
  • Another aspect of the invention provides a binding moiety that specifically binds to:
  • a binding moiety that specifically binds to a specified DDR1 epitope we mean an agent, e.g, a molecule or compound, capable of reversibly and/or irreversibly associating with and binding to at least one of the specified amino acid residues by covalent and/or apolar and/or ionic interaction.
  • the binding moiety that specifically binds to the human DDR1 epitope defined by the amino acid residues Met318, Asn321 and Asn32 binds to or associates with at least two of these residues, for example Met318 and Asn321 , Met318 and Asn325, or Asn321 and Asn325.
  • the binding moiety binds to or associates with DDR1 through all three of Met318, Asn321 and Asn325.
  • the binding moiety is an antibody mimic (such as a non- antibody scaffold).
  • antibody mimics for example, non-antibody scaffold structures that have a high degree of stability yet allow variability to be introduced at certain positions
  • Such molecules may be used as a binding moiety in the agent of the present invention. Exemplary antibody mimics are discussed in Skerra et al. (2007, Curr. Opin.
  • the antibody mimic is selected from the group comprising or consisting of affibodies, tetranectins (CTLDs), adnectins (monobodies), anticalins, DARPins (ankyrins), avimers, iMabs, microbodies, peptide aptamers, Kunitz domains and affilins.
  • RNA aptamers represent a unique emerging class of therapeutic agents (Que-Gewirth et al, Gene Ther. 74:283 (2007); Ireson et al, Mol. Cancer Ther. 5:2957 (2006)).
  • RNA aptamers have been demonstrated to target the Ku DNA repair proteins with resulting sensitization of breast cancer cells to etoposide (Zhang et al, Int. J. Mol. Med. 74: 153 (2004)).
  • small molecule we mean a low molecular weight organic compound of 900 Daltons or less.
  • large biopolymers such as nucleic acids, proteins, and polysaccharides (such as starch or cellulose) are not included as “small molecules", their constituent monomers (ribo- or deoxyribonucleotides, amino acids, and monosaccharides, respectively) and oligomers (i.e. short polymers such as dinucleotides, peptides such as the antioxidant glutathione, and disaccharides such as sucrose) are included.
  • oligomers i.e. short polymers such as dinucleotides, peptides such as the antioxidant glutathione, and disaccharides such as sucrose
  • CovX-Bodies are created by covalently joining a pharmacophore via a linker to the binding site of a specially-designed antibody, effectively reprogramming the antibody (Tryder et al., 2007, Bioorg. Med. Chem. Lett., 17:501-6).
  • the result is a new class of chemical entities that is formed where each component contributes desirable traits to the intact CovX-Body - in particular, the entity has the biologic actions of the peptide and the extended half-life of the antibody.
  • Another aspect of the invention provides a polynucleotide encoding an antibody or a binding moiety of the invention - provided that the binding moiety is a polypeptide.
  • the invention also includes an expression vector comprising the polynucleotide, and a host cell comprising the polynucleotide or the expression vector.
  • the host cell is capable of expressing producing the antibody or the polypeptide binding moiety , such that it can readily be obtained and purified, as is well known in the art.
  • Another aspect of the invention provides a compound comprising an antibody or a binding moiety as defined above, and a detectable moiety.
  • a “detectable moiety” we include the meaning that the moiety is one which, when located at the target site following administration of an agent of the invention to a patient, may be detected, typically non-invasively from outside the body and the site of the target located.
  • the detectable moiety may be a single atom or molecule which is either directly or indirectly involved in the production of a detectable species.
  • the agents of this embodiment of the invention are useful in imaging and diagnosis, especially of cells and tissues that express DDR1. Detectable compounds also aid in research and development.
  • detectable moieties are well known in medicinal chemistry and the linking of these moieties to polypeptides and proteins is well known in the art.
  • detectable moieties include, but are not limited to, the following: radioisotopes (e.g. 3 H, 14 C, 35 S, 123 l, 125 l, 131 l, "Tc, 1 ln, 90 Y, 88 Re), radionuclides (e.g. 1 C, 18 F, 64 Cu), fluorescent labels (e.g. FITC, rhodamine, lanthanide phosphors, carbocyanine), enzymatic labels (e.g.
  • labels are attached by spacer arms of various lengths to reduce potential steric hindrance.
  • the detectable moiety comprises a radioactive atom, such as a radioactive atom selected from the group consisting of: technetium-99; technitium-99m; iodine-123; iodine-124; iodine-131 ; indium-111 ; fluorine-18; fluorine-19; carbon-11 ; carbon-13; copper-64; nitrogen-13; nitrogen-15; oxygen-15; oxygen-17; arsenic-72; gadolinium; manganese; iron; deuterium; tritium; yttrium-86; zirconium-89.
  • a radioactive atom such as a radioactive atom selected from the group consisting of: technetium-99; technitium-99m; iodine-123; iodine-124; iodine-131 ; indium-111 ; fluorine-18; fluorine-19; carbon-11 ; carbon-13; copper-64; nitrogen-13; nitrogen-15; oxygen-15; oxygen-17; arsenic
  • the radio- or other labels may be incorporated into the agents of the invention in known ways.
  • the binding moiety is a polypeptide it may be biosynthesised or may be synthesised by chemical amino acid synthesis using suitable amino acid precursors involving, for example, fluorine-19 in place of hydrogen.
  • Labels such as 99m Tc, 23 l, 186 Rh, 88 Rh and 111 ln can, for example, be attached via cysteine residues in the binding moiety.
  • Yttrium-90 can be attached via a lysine residue.
  • the IODOGEN method (Fraker et al (1978) Biochem. Biophys. Res. Comm.
  • Another aspect of the invention provides a compound comprising an antibody or a binding moiety as defined above, and a cytotoxic moiety. Such a compound may be used in the treatment and medical use aspects of the invention described below.
  • cytotoxic moiety we include the meaning that the moiety is one which is capable of inducing cell death in vivo or in vitro, for example when administered to a patient.
  • the cytotoxic moiety may be a single atom or molecule which is either directly or indirectly involved in inducing cell death.
  • the agents of this embodiment of the invention are useful in therapy (for example, where it is desired to remove or destroy one or more cell in an individual).
  • Suitable cytotoxic moieties are well known in medicinal chemistry and the linking of these moieties to polypeptides and proteins is well known in the art.
  • the two portions may be linked together by any of the conventional ways of cross-linking polypeptides, such as those generally described in O'Sullivan e? al (1979) Anal. Biochem. 100, 100-108.
  • the binding moiety may be enriched with thiol groups and the further moiety reacted with a bifunctional agent capable of reacting with those thiol groups, for example the N-hydroxysuccinimide ester of iodoacetic acid (NHIA) or N-succinimidyl-3-(2- pyridyldithio)propionate (SPDP).
  • a bifunctional agent capable of reacting with those thiol groups
  • a bifunctional agent capable of reacting with those thiol groups
  • a bifunctional agent capable of reacting with those thiol groups
  • a bifunctional agent capable of reacting with those thiol groups
  • a bifunctional agent capable of reacting with those thiol groups
  • a bifunctional agent capable of reacting with those thiol groups
  • a bifunctional agent capable of reacting with those thiol groups
  • tumour endothelial markers are specific for tumour endothelial markers. Due to their accessibility and to the therapeutic options that they allow (for example, intraluminal blood coagulation or recruitment of immune cells), markers selectively expressed on tumour cells are ideally suited for ligand-based tumour-targeting strategies, allowing for the targeting cytotoxic agents directly to the tumour. Thus these compounds may be useful in targeting a cytotoxic agent to tumour/cells expressing DDR1 in the body of an individual.
  • the cytotoxic moiety is selected from a directly cytotoxic chemotherapeutic agent, a directly cytotoxic polypeptide, a moiety which is able to convert a prodrug into a cytotoxic drug, a radiosensitizer, a directly cytotoxic nucleic acid, a nucleic acid molecule that encodes a directly or indirectly cytotoxic polypeptide or a radioactive atom.
  • cytotoxic moieties as well as methods of making the conjugates comprising the antibody and the cytotoxic moiety, are provided in WO 02/36771 , incorporated herein by reference.
  • the cytotoxic moiety may be directly or indirectly toxic to cells expressing DDR1.
  • directly cytotoxic we include the meaning that the moiety is one which on its own is cytotoxic.
  • indirectly cytotoxic we include the meaning that the moiety is one which, although is not itself cytotoxic, can induce cytotoxicity, for example by its action on a further molecule or by further action on it.
  • the cytotoxic moiety is a cytotoxic chemotherapeutic agent. Cytotoxic chemotherapeutic agents are well known in the art. Cytotoxic chemotherapeutic agents, such as anticancer agents, include those listed herein.
  • cytotoxic moieties such as cytotoxic chemotherapeutic agents
  • cytotoxic chemotherapeutic agents have previously been attached to antibodies and other targeting agents, and so compounds of the invention comprising these agents may readily be made by the person skilled in the art.
  • carbodiimide conjugation (Bauminger & Wilchek (1980) Methods Enzymol. 70, 151-159) may be used to conjugate a variety of agents, including doxorubicin, to antibodies.
  • Other methods for conjugating a cytotoxic moiety to an antibody can also be used. For example, sodium periodate oxidation followed by reductive alkylation of appropriate reactants can be used, as can glutaraldehyde cross- linking.
  • the cytotoxic moiety may be a cytotoxic peptide or polypeptide moiety by which we include any moiety which leads to cell death.
  • Cytotoxic peptide and polypeptide moieties are well known in the art and include, for example, ricin, abrin, Pseudomonas exotoxin, tissue factor and the like. Methods for linking them to targeting moieties such as antibodies are also known in the art.
  • ricin as a cytotoxic agent is described in Burrows & Thorpe (1993) Proc. Natl, Acad. Sci. USA 90, 8996-9000, and the use of tissue factor, which leads to localised blood clotting and infarction of a tumour, has been described by Ran et al (1998) Cancer Res. 58, 4646-4653 and Huang et al (1997) Science 275, 547-550. Tsai et al (1995) Dis. Colon Rectum 38, 1067-1074 describes the abrin A chain conjugated to a monoclonal antibody. Other ribosome inactivating proteins are described as cytotoxic agents in WO 96/06641.
  • Pseudomonas exotoxin may also be used as the cytotoxic polypeptide moiety (Aiello et al (1995) Proc. Natl. Acad. Sci. USA 92, 10457-10461 ). Certain cytokines, such as TNFa, INFv and IL-2, may also be useful as cytotoxic agents.
  • radioactive atoms may also be cytotoxic if delivered in sufficient doses.
  • the cytotoxic moiety may comprise a radioactive atom which, in use, delivers a sufficient quantity of radioactivity to the target site so as to be cytotoxic.
  • Suitable radioactive atoms include phosphorus-32, iodine-125, iodine-131 , indium-1 11 , rhenium-186, rhenium-188 or yttrium-90, or any other isotope which emits enough energy to destroy neighbouring cells, organelles or nucleic acid.
  • the isotopes and density of radioactive atoms in the compound of the invention are such that a dose of more than 4000 cGy (preferably at least 6000, 8000 or 10000 cGy) is delivered to the target site and, preferably, to the cells at the target site and their organelles, particularly the nucleus.
  • the radioactive atom may be attached to the antibody in known ways.
  • EDTA or another chelating agent may be attached to the antibody and used to attach 11 ln or 0 Y.
  • Tyrosine residues may be labelled with 125 l or 131 1.
  • the cytotoxic moiety may be a radiosensitizer.
  • Radiosensitizers include fluoropyrimidines, thymidine analogues, hydroxyurea, gemcitabine, fludarabine, nicotinamide, halogenated pyrimidines, 3-aminobenzamide, 3-aminobenzodiamide, etanixadole, pimonidazole and misonidazole (see, for example, McGinn et al (1996) J. Natl. Cancer Inst. 88, 1193-11203; Shewach & Lawrence (1996) Invest. New Drugs 14, 257-263; Horsman (1995) Acta Oncol.
  • the cytotoxic moiety may be a procoagulant factor, such as the extracellular domain of tissue factor (Rippmann ef a/ (2000) "Fusion of the tissue factor extracellular domain to a tumour stroma specific single-chain fragment variable antibody results in an antigen- specific coagulation-promoting molecule.” Biochem J. 349: 805-12; Huang ef a/ (1997) "Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature.” Science. 275(5299): 547-550.
  • the cytotoxic moiety may be an indirectly cytotoxic polypeptide.
  • the indirectly cytotoxic polypeptide is a polypeptide which has enzymatic activity and can convert a relatively non-toxic prodrug into a cytotoxic drug.
  • ADEPT Antibody-Directed Enzyme Prodrug Therapy
  • the system requires that the targeting moiety locates the enzymatic portion to the desired site in the body of the patient (e.g.
  • the object of the approach is to maximise the concentration of drug at the desired site and to minimise the concentration of drug in normal tissues (Senter ef al (1988) "Anti-tumor effects of antibody-alkaline phosphatase conjugates in combination with etoposide phosphate" Proc. Natl. Acad. Sci. USA 85, 4842-4846; Bagshawe (1987) Br. J.
  • the prodrug is relatively non-toxic compared to the cytotoxic drug. Typically, it has less than 10% of the toxicity, preferably less than 1% of the toxicity as measured in a suitable in vitro cytotoxicity test.
  • the moiety which is able to convert a prodrug to a cytotoxic drug will be active in isolation from the rest of the compound but it is necessary only for it to be active when (a) it is in combination with the rest of the compound and (b) the compound is attached to, adjacent to or internalised in target cells.
  • the further moiety may be one which becomes cytotoxic, or releases a cytotoxic moiety, upon irradiation.
  • the boron-10 isotope when appropriately irradiated, releases a particles which are cytotoxic (US 4,348,376; Primus et al (1996) Bioconjug. Chem. 7: 532-535).
  • the cytotoxic moiety may be one which is useful in photodynamic therapy such as photofrin (see, for example, Dougherty er a/ (1998) J. Natl. Cancer Inst. 90, 889-905).
  • the invention provides a compound comprising an antibody or binding moiety as described above, and a drug to be delivered to a cell having a DDR1 receptor localised on its surface, for example a cancer or tumour cell, including tumour stem cells.
  • the therapeutically effective amount of the drug has a therapeutic effect and as such can reduce the number of cancer cells; decrease tumorigenicity, tumorigenic frequency or tumorigenic capacity; reduce the number or frequency of cancer stem cells; reduce the tumor size; inhibit or stop cancer cell infiltration into peripheral organs including, for example, the spread of cancer into soft tissue and bone; inhibit and stop tumor metastasis; inhibit and stop tumor growth; relieve to some extent one or more of the symptoms associated with the cancer; reduce morbidity and mortality; improve quality of life; or a combination of such effects.
  • Still a yet further aspect of the invention provides method of inhibiting growth of a tumour in a human patient, the method comprising administering to the patient a therapeutically effective amount of an antibody, binding moiety, compound or pharmaceutical composition of the invention, and, optionally, at least one additional anti-cancer agent.
  • Another aspect of the invention provides a method of treating an inflammatory disorder, a fibrotic disorder or atherosclerosis in a human patient, the method comprising administering to the patient a therapeutically effective amount of an antibody, binding moiety or pharmaceutical composition of the invention, and, optionally, at least one additional agent suitable for treating the said inflammatory disorder, a fibrotic disorder or atherosclerosis.
  • the invention includes an antibody, binding moiety or pharmaceutical composition of the invention for use in for use in treating an inflammatory disorder, a fibrotic disorder or atherosclerosis in a human patient, optionally, together with at least one additional agent suitable for treating the inflammatory disorder, fibrotic disorder or atherosclerosis.
  • the invention also includes the use of an antibody or binding moiety of the invention in the preparation of a medicament for treating an inflammatory disorder, a fibrotic disorder or atherosclerosis in a human patient, wherein, optionally, the patient is one who is administered at least one additional agent suitable for treating the inflammatory disorder, fibrotic disorder or atherosclerosis.
  • a further aspect of the invention provides a method of identifying an agent that inhibits activity of human DDR1 , or a lead compound for identifying an agent that inhibits activity of human DDR1 , the method comprising:
  • test agent or candidate compound to bind to or interact with the human DDR1 epitope defined by the amino acid residues Ala279, Gln281 , Ala282, Ser335, Pro337, Gly340, Arg341 , Val342, Ile365 and Asp367 may also be determined via competitive binding assays with antibody 3E3, i.e. an antibody having the heavy and light chain sequences listed in Figure 11.
  • screening assays which are capable of high throughput operation are particularly preferred.
  • Examples may include cell based assays and protein-protein binding assays.
  • An SPA-based (Scintillation Proximity Assay; Amersham International) system may be used.
  • an assay for identifying a compound capable of modulating the activity of a protein kinase may be performed as follows. Beads comprising scintillant and a substrate polypeptide that may be phosphorylated may be prepared. The beads may be mixed with a sample comprising the protein kinase and 32 P-ATP or 33 P-ATP and with the test compound. Conveniently this is done in a multi- well (e.g., 96 or 384) format.
  • the identification of a candidate compound that binds to the DDR1 epitope may be an initial step in the drug screening pathway, and the identified compound(s) may be further selected e.g. for the ability to inhibit DDR1 activity.
  • the method further comprises the step determining whether the test agent reduces collagen-induced autophosphorylation of DDR1 , for example using the methods described herein and known in the art.
  • a drug-like compound may be a molecule that may be synthesised by the techniques of organic chemistry, less preferably by techniques of molecular biology or biochemistry, and is preferably a small molecule, which may be of less than 5000 Daltons and which may be water-soluble.
  • a drug-like compound may additionally exhibit features of selective interaction with a particular protein or proteins and be bioavailable and/or able to penetrate target cellular membranes or the blood:brain barrier, but it will be appreciated that these features are not essential.
  • Suitable animal models of cancer are known in the art and include Lewis lung carcinoma subcutaneous implants in mice (homograft in Black 57 mice) or HT29 xenografts subcutaneous implants in nude mice.
  • a suitable animal model to study fibrosis is bleomycin induced lung fibrosis, as used in a DDR1 study by Avivi-Green et al (2006) Am J Respir Crit Care Med, 174, 420.
  • a suitable in vitro fibrosis model is described by Xu ei al (2007) Am J Physiol Renal Physiol, 293, F631.
  • Suitable atherosclerosis models include LDL-receptor-deficient (Ldlf 1' ) mouse model, which was also used to study effect of DDR1 on atherosclerosis (e.g., Franco et al (2008) Circ Res, 102, 1202; Franco ei al (2009), Circ Res, 105: 1141). Other atherosclerosis models can be found in Singh er al (2009) Curr Vase Pharm, 7, 75. Suitable in vitro models for atherosclerosis include co-culture of arterial wall cells and macrophages, and the in vitro model described by Dorweller ei al (2006) Thromb Haemost, 95, 182.
  • the anti-DDR1 mAbs block collagen-induced DDR1 phosphorylation.
  • the ⁇ -strands of the jelly roll in the DS and DS-like domains are numbered 1-8 and the extra ⁇ -strands in the DS-like domain are labelled a- e.
  • B Superposition of the DS domain (cyan) and the DS-like domain (green) of DDR1.
  • C Detailed structure of the interface between the DS domain (cyan) and the DS-like domain (green) in DDR1. Selected residues are shown in atomic detail and labelled. Hydrogen bonds are indicated by dashed lines. Figure 5.
  • DDR1 and DDR2 sequences Homo sapiens DDR1 , Q08345; Mus musculus DDR1 , Q03146; Danio rerio DDR1 , XP_001345829; Xenopus tropicalis DDR1 , XP_002939505; Homo sapiens DDR2, Q16832; Mus musculus DDR2, Q62371 ; Danio rerio DDR2, XP_684261 ; Xenopus tropicalis DDR2, XP_002933824).
  • the numbers above the alignment refer to the human DDR1 sequence. conserveed residues are in bold and cysteines are in orange.
  • Predicted /V-linked glycosylation sites are underlined.
  • the secondary structure elements of the DDR1 structure are indicated above the alignment.
  • Red inverted triangles indicate key collagen-binding residues in DDR2 (Carafoli et al., 2009).
  • Magenta filled circles indicate calcium ligands in DDR1.
  • Pink diamonds indicate residues contributing to the conserved surface patch in the DS domain.
  • the seven linear and non-conservative human-to-mouse substitutions in the DS-like domain are boxed in blue and labelled epi1-7.
  • FIG. 6 Superposition of DDR1 (cyan, DS domain; green DS-like domain) and the DS domain pair of neuropilin-1 (Nrp1 , magenta) (Vander Kooi et al., 2007).
  • the DDR1 DS domain was fitted to the first DS domain (b1) of Nrp1.
  • the DDR1 DS-like domain and the second DS domain (b2) of Nrp1 are related by a ⁇ 60° rotation about a vertical axis.
  • Figure 7. (A) The lattice contact resulting in a 2-fold symmetric DDR1 dimer (see text).
  • the DDR1 molecule on the left is in cyan (DS domain) and green (DS-like domain); the DDR1 molecule on the right is in grey with the collagen-binding loops (Carafoli et al., 2009) in red.
  • the 2-fold symmetry axis is vertical. Selected residues are shown in atomic detail (pink, conserved surface patch in the DS domain).
  • Wild-type DDRI b or the indicated mutants were transiently expressed in HEK293 cells. The cells were stimulated for 90 min at 37° C with collagen I at the indicated concentrations (in pg/ml). Aliquots of cell lysates were analysed by SDS-PAGE and Western blotting.
  • the blots were probed with anti-phosphotyrosine (anti-PY) mAb 4G10 (upper blot) and re-probed with anti- DDR1 Abs (lower blot). The experiment was performed three times with very similar results.
  • FIG. 8 Detailed structure of the DDR1-3E3 Fab interface.
  • the 3E3 Fab fragment is shown as a semitransparent surface (tan, light chain; grey, heavy chain) and the DDR1 region interacting with the Fab is shown as a green cartoon. Selected interface residues are shown in atomic detail and labelled. Hydrogen bonds are indicated by dashed lines.
  • FIG. 9 (A) Epitope mapping of anti-DDR1 mAbs.
  • A Wild-type DDRIb or the indicated mutants were transiently expressed in HEK293 cells. The cells were stained on ice with 10 pg/ml of the indicated anti-DDR1 mAbs or mouse lgG1 isotype control Ab followed by FITC-conjugated goat-anti mouse IgG and analysis by flow cytometry. Binding of isotype control Ab is shown by the filled grey histograms. Shown are representative data of at least three experiments for each DDR1 mutant.
  • the DS and DS-like domains are in cyan and green, respectively.
  • the collagen binding site is in red.
  • the conserved surface patch (Arg32, Leu99, Leu 152, Tyr183) is in pink.
  • Figure 10 Mean fluorescence values of the flow cytometry data shown in Figure 9.
  • DDR b wild-type or the indicated DDR1 mutants were transiently expressed in HEK293 cells. The cells were stained on ice with 10 g/ml of the indicated anti-DDR1 mAbs or mouse lgG1 isotype control Ab followed by FITC-conjugated goat-anti mouse IgG and analysis by flow cytometry.
  • Figure 11 Anti DDR1 mAb 3E3 sequence: V regions amplified as in Orlandi ef al, (1989). PNAS USA 86:3833-7. Residues encoded by the PCR primers are underlined.
  • Constant regions are from PDB entry 12E8 (mouse lgG1) with one change (W) Figure 12.
  • mAb 1F10 blocks collagen-induced DDR1 phosphorylation in cancer cell lines.
  • the cell lines are DLD-1 (colon carcinoma cell line) and the breast cancer cell lines SKBr-3, MCF-7 and T47D. Cells were stimulated, or not, with 10 9 ⁇ collagen (rat tail collagen I, Coll I,) for 90 minutes at 37°C in the presence or absence of 10 pg/ml anti- DDR1 mAb 1 F10, as indicated.
  • DDR1 was immunoprecipitated with rabbit anti-DDR1 antibodies and the immunoprecipiates were analysed by SDS-PAGE and Western blotting. The blots were probed with anti-phosphotyrosine (anti-PY) mAb 4G10 (upper blots) and reprobed with anti-DDR1 Abs (lower blots).
  • Example 1 Structure of the extracellular region of discoidin domain receptor 1 bound to an inhibitory Fab fragment reveals features important for signalling
  • the DDRs are also implicated in cancer, fibrotic diseases, atherosclerosis and arthritis (Vogel et al., 2006).
  • the DDRs have several features that distinguish them from other RTKs. Compared with the rapid response of typical RTKs to their soluble ligands (e.g. growth factors), collagen- induced DDR autophosphorylation is slow and sustained (Shrivastava et al., 1997; Vogel et al., 1997).
  • Src kinase plays an essential role in DDR activation (Ikeda et al., 2002).
  • Both DDRs are composed of an N-terminal discoidin (DS) domain (Baumgartner et al., 1998), followed by a unique sequence of just over 200 amino acids, a transmembrane domain, a large cytosolic juxtamembrane domain and a C-terminal tyrosine kinase domain.
  • Collagen binds to the DS domain and the structural determinants of the DDR- collagen interaction have been extensively studied (Carafoli et al., 2009; lchikawa et al., 2007; Konitsiotis et al., 2008; Leitinger, 2003; Xu et al., 2011). The remainder of the extracellular region has not been characterised structurally.
  • DNAs coding for full-length DDR1 mutants were generated by strand overlap extension PCR using a cDNA of human DDR1 as a template (Leitinger, 2003).
  • the PCR primers used to generate these constructs are available on request.
  • the amplified DNAs were cloned into the mammalian expression vectors pcDNA3.1/Zeo (Invitrogen) or pRK5 (BD Pharmingen).
  • DNA coding for the DDR1 construct used for crystallography was generated by PCR and cloned into a modified pCEP-Pu vector adding a C-terminal His- tag (Kohfeldt et al., 1997). All PCR-derived DNA constructs were verified by sequencing.
  • His-DDR1 contains the entire extracellular region of human DDR1 (residues 19-416 of UniProt entry Q08345).
  • His-DDR2 contains the entire extracellular region of human DDR2 (residues 22-398 of UniProt entry Q16832).
  • His-DS-DDR1 and His-ADS-DDR1 are deletion constructs based on His-DDR1 : His-DS-DDR1 lacks the DS-like domain ( ⁇ 201-369) and His-ADS-DDR1 lacks the DS domain ( ⁇ 31-185).
  • DDR1-Fc contains the entire DDR1 extracellular region fused to a C-terminal human lgG1 Fc sequence (Leitinger, 2003; Xu et al., 2011).
  • the DDR1 construct for crystallography contains the DS and DS-like domains of human DDR1 (residues 30-367) fused to a C-terminal His-tag (AAAHHHHHH).
  • a vector-derived APLA sequence is present at the N-terminus of the mature protein.
  • the protein was produced in human embryonic kidney HEK293 c18 cells (ATCC). The cells were grown at 37° C with 5% C0 2 in Dulbecco's modified Eagle's medium/F12 (Invitrogen) containing 10% fetal bovine serum, 2 mM glutamine, 10 U/ml penicillin, 100 pg/ml streptomycin and 250 pg/ml geneticin.
  • the cells were transfected with the pCEP-Pu expression plasmid using Fugene (Roche Diagnostics) and selected with 1 pg/ml puromycin (Sigma). Confluent cells in a HYPERFIask (Corning) were washed twice with PBS and incubated with serum-free medium for 3-4 weeks, with weekly medium exchanges. The pooled serum-free conditioned medium was loaded onto a 5-ml HisTrap column (GE Healthcare) using an Akta Purifier (GE Healthcare).
  • the protein was eluted with 500 mM imidazole in PBS, concentrated using a Vivaspin centrifugal device (Sartorius), and further purified on a Superdex 200 HR10/30 size exclusion chromatography column (GE Healthcare) with Tris-buffered saline (TBS) (25 mM Tris, 150 mM NaCI, 2 mM KCI, pH 7.4) as the running buffer.
  • TBS Tris-buffered saline
  • Hybridoma cell supernatants were screened against DDR1-Fc and His-DDR1 proteins by enzyme-linked immunosorbent assay (ELISA). Reactive hybridoma supernatants were further screened for recognition of native DDR1 by cell-based ELISA, using HEK293 cells expressing full-length DDR1. Positive hybridoma cells were subcloned by limited dilution and screened as above. The isotype of each mAb was determined by standard methods. All mAbs are of the lgG1 isotype, with the exception of mAb 1 F10, which is lgG2b.
  • Hybridoma cells were grown at 37° C with 5% C0 2 in RPMI-1640 medium (Invitrogen) containing 10% fetal bovine serum, 1 mM sodium pyruvate, 10 U/ml penicillin, 100 g/ml streptomycin and 1 pg/ml fungizone (Invitrogen). The serum concentration was gradually reduced to 5% in a final culture volume of 1 litre.
  • the hybridoma cell culture supernatant was loaded onto a 2 x 1-ml HiTrap rProtein A column (GE Healthcare). The mAbs were eluted with Immunopure gentle elution buffer (Pierce) and dialysed against TBS.
  • Fab fragments were generated with a Fab Preparation Kit (Pierce) according to the manufacturer's protocol. Briefly, 8 mg of mAb were incubated overnight at 37° C with activated papain immobilised on agarose resin. The Fc fragment and undigested mAb were removed using a 1-ml HiTrap rProtein A column (GE Healthcare), yielding ⁇ 3 mg of Fab fragment. The Fab fragments used in co-crystallisation experiments were further purified by size exclusion chromatography on a Superdex 200 HR10/30 column (GE Healthcare) with TBS as the running buffer. mAb cDNA Synthesis and Sequencing
  • RNA was prepared from ⁇ 10 7 3E3 hybridoma cells using the RNeasy Mini Kit (Qiagen). The RNA was reverse-transcribed and cDNA fragments encoding the heavy- and light-chain variable regions of the mAb were amplified using the Superscript III One- Step RT-PCR system (Invitrogen) and suitable universal primers (Orlandi et al., 1989). The PCR products were gel-purified and sequenced using the same primers. The mAb residues are numbered according to (Al-Lazikani et al., 1997). DDR1 Activation Assay
  • HEK293 cells were grown in 12-well tissue culture plates and transfected with 2 pg/well of DDR1 wild-type or mutant plasmid DNA using calcium phosphate precipitation. 24 h after transfection the cells were incubated with serum-free medium for 16 h. Cells were then stimulated with 10-50 pg/ml acid-soluble rat tail collagen I (Sigma) for 90 min at 37° C before being lysed. In the inhibition experiments, anti-DDR1 mAbs or their Fab fragments were added together with collagen I, without prior incubation. Aliquots of the cell lysates were subjected to SDS-PAGE and blotted onto nitrocellulose membranes.
  • the blots were first probed with an mouse anti-phosphotyrosine mAb (clone 4G10, Upstate Biotechnology) followed by a horseradish peroxidase-conjugated sheep anti-mouse Ig (Amersham Biosciences). Detection was done by Enhanced Chemiluminescence Plus (Amersham Biosciences) using an Ettan DIGE Imager (GE Healthcare). To reprobe the blots, the membranes were treated with Ab stripping solution (Alpha Diagnostic International), followed by incubation with rabbit anti-DDR1 Ab (SC-532, Santa Cruz Biotechnology) and finally goat horseradish peroxidase-conjugated anti-rabbit Ig (P0448, DAKO).
  • Ab stripping solution Alpha Diagnostic International
  • rabbit anti-DDR1 Ab SC-532, Santa Cruz Biotechnology
  • goat horseradish peroxidase-conjugated anti-rabbit Ig P0448, DAKO.
  • Recombinant DDR proteins diluted to 10 pg/ml in 50 mM Tris, 100 mM NaCI, pH 8.5, were coated in 50 ⁇ aliquots onto Maxisorp 96-well plates (Nalgene NUNC) overnight at room temperature. The wells were blocked with 150 ⁇ of incubation buffer (PBS containing 40 ⁇ g/ml bovine milk -casein (Sigma) and 0.05% Tween-20) for 1 h at room temperature. Anti-DDR1 mAbs were added at 30 ⁇ g ml in 50 ⁇ aliquots and incubated for 1.5 h at room temperature.
  • HEK293 cells were grown in 6-well plates and transfected with 5 g/well of DDR1 wild- type or mutant plasmid DNA using calcium phosphate precipitation. 48 h after transfection, the cells were dissociated with non-enzymatic cell dissociation solution (Sigma) and resuspended in PBS containing 1 % BSA. The cells were incubated with primary mAb or mouse lgG1 isotype control Ab (Cambridge Bioscience) at 10 g/ml in 100 ⁇ PBS/BSA for 30 minutes on ice, followed by three washes with PBS/BSA and incubation with FITC-conjugated goat anti-mouse IgG (F-9006, Sigma) for 30 min on ice. After three washes as above, the cells were resuspended in 2% formaldehyde in PBS and analysed on a FACS Calibur flow cytometer using Cell Quest Pro software (Becton Dickinson Biosciences).
  • the purified DDR1 protein for crystallography and the 3E3 Fab fragment were mixed in an equimolar ratio and incubated on ice for 30 minutes.
  • the solution was subjected to size exclusion chromatography on a Superdex 200 HR10/30 column (GE Healthcare) with TBS as the running buffer.
  • the DDR1-3E3 Fab complex eluted as a single peak and was concentrated to 6 mg/ml.
  • Sitting drop vapour diffusion crystallisation screens were set up using a Mosquito nanolitre robot (TTP LabTech). Crystals were obtained after 1-2 days at room temperature using 2% Tacsimate pH 5.0 (Hampton Research), 100 mM sodium citrate tribasic dihydrate pH 5.6, 20% PEG 3350 as precipitant.
  • the DDR1 DS domain is very similar (r.m.s. deviation of 0.61 A for 156 Ca atoms) to the DDR2 DS domain, which was previously crystallised in complex with a collagen-like peptide (Carafoli et al., 2009).
  • the collagen binding loops of the DDR1 DS domain which are opposite the DS-like domain, have weak electron density and high temperature factors, suggesting that they are quite mobile in the absence of the collagen ligand.
  • the 3E3 Fab fragment is bound near the C-terminus of the DS-like domain, distant from the collagen binding site (for a description of the epitope, see below).
  • the DS-like domain of DDR1 belongs to the F5/8 type C superfamily.
  • a search with the program SSM showed that the DS-like domain is most closely related to family 32 carbohydrate binding modules (CBMs) (Boraston et al., 2004), but a pairwise alignment of the DS and DS-like domains of DDR1 gave only a marginally lower Z-score and a r.m.s. deviation of 3.0 A for 120 aligned Ca atoms ( Figure 4B).
  • CBMs carbohydrate binding modules
  • Figure 4B To facilitate the comparison of the DS and DS- like domains, the eight ⁇ -strands that are common to both domains have been labelled ⁇ 1- ⁇ 8.
  • the DS-like domain contains five additional strands, labelled ⁇ - ⁇ , in a long insertion between ⁇ 1 and ⁇ 2.
  • Both domains are characterised by two antiparallel ⁇ - sheets with jellyroll topology ( ⁇ 1- ⁇ 2- ⁇ 7- ⁇ 4 sheet and ⁇ 5- ⁇ 6- ⁇ 3- ⁇ 8 sheet).
  • ⁇ -barrel the “bottom”
  • the ⁇ 2- ⁇ 3 and ⁇ 6- ⁇ 7 loops cross over between the sheets and create a relatively flat surface.
  • the other end the “top”
  • several long and irregular loops protrude from the barrel.
  • these loops constitute the collagen binding site (Carafoli et al., 2009; lchikawa et al., 2007; Leitinger, 2003).
  • these loops contribute the extra strands ⁇ - ⁇ , two A/-linked glycosylation sites (Asn211 and Asn260) and a calcium binding site.
  • the calcium ion is coordinated by the side chains of Asp233 and Glu361 , as well as by three main chain carbonyl groups; an analogous calcium coordination is seen in many family 32 CBMs (Boraston et al., 2004). It is noteworthy that the glycosylation site at Asn211 and the calcium ligands are strictly conserved in all vertebrate DDRs (Figure 5).
  • the DS-like domain of DDR1 contains three cysteines: Cys303 and Cys343, which form a deeply buried disulphide bridge linking the adjacent ⁇ 4 and ⁇ 7 strands, and Cys287, which is unpaired and also buried.
  • Cys303 and Cys343 may be involved in the covalent dimerisation of DDR1 (Abdulhussein et al., 2008).
  • the DS-like domain would have to unfold for these two residues to become available for intermolecular disulphide bridges. The disulphide-linked dinners seen in that study therefore are more likely to have resulted from oxidation following denaturation.
  • the interface between the DS and DS-like domains of DDR1 is formed between the bottom of the DS domain, in particular the ⁇ 4- ⁇ 5 and ⁇ 6- ⁇ 7 loops, and the long convoluted insertion between strands ⁇ 1 and ⁇ 2 of the DS-like domain ( Figure 4C).
  • a key interface residue is Trp187, which is located in the short linker between the two domains and which interacts with residues of both the DS domain (Leu94 and Val160) and the DS-like domain (Leu191 , Leu192, Leu228, Ala232). With the exception of Leu192 and Ala232, these residues are strictly conserved in all vertebrate DDRs (Figure 5).
  • the DDRs are believed to be constitutive dimers at the cell surface (Mihai et al., 2009; Noordeen et al., 2006).
  • the soluble extracellular region of DDR1 is monomeric (Leitinger, 2003), but because the high protein concentration in the crystallisation buffer might favour a weak dimer association, we inspected the crystal lattice for DDR1 dimers. There was only one plausible dimer.
  • the interface between the two DDR1 molecules in this dimer which has a total area of 791 A 2 , is dominated by two identical, symmetry- related, contacts.
  • the 3E3 epitope is formed from three regions of the DDR1 DS-like domain, which are discontinuous in sequence, but contiguous in space: the start of ⁇ 3 (Ala279, Gln281 , Ala282), the ⁇ 6- ⁇ 7 loop (Ser 335, Pro337, Gly340, Arg341 , Val342) and the very end of the DS-like domain (Ile365, Asp367) ( Figure 8).
  • the 3E3 Fab uses predominantly aromatic residues to recognise this epitope: Thr30, Phe32, Tyr34, Tyr49 and Leu50 of the light chain; and Ile31, Trp33, Tyr52, Tyr56 and Tyr96 of the heavy chain.
  • the DDR1-3E3 interface measures 696 A 2 , of which ⁇ 60% are accounted for by contacts involving the heavy chain.
  • the finding that mAb 3E3 binds close to the C-terminus of the DS-like domain suggests that it may inhibit DDR1 function by preventing the association of the DS-like domains and/or juxtamembrane regions in the signalling DDR1 dimer.
  • the epil mutation (203-YLSEAVY to QLSEVMVH) abolished binding of mAbs 3G10, 3H10 and 7A9.
  • the epi5 mutation (A279T/A282T) reduced binding of mAb 3E3, consistent with the crystal structure, which shows that Ala279 and Ala282 make close contacts with the 3E3 Fab fragment ( Figure 8).
  • the epi6 mutation (M318V/N321A/N325S) abolished binding of mAbs 1 F7 and 1 F10.
  • the N-terminal domain of DDRs has long been recognised as a member of the DS superfamily (e.g., Johnson et al., 1993; Karn et al., 1993) and its role in collagen binding is understood in atomic detail (Carafoli et al., 2009; lchikawa et al., 2007).
  • Our new crystal structure shows that the second DDR domain is a distant relative of the DS domain, termed the DS-like domain. Tandem repeats of DS domains occur in a number of secreted and cell surface proteins (Baumgartner et al., 1998; Kiedzierska et al., 2007).
  • the two DS domains are arranged side-by- side with limited contacts between them, so that their top loops can both interact with the same cell membrane (Adams et al., 2004; Ngo et al., 2008; Shen et al., 2008).
  • the two DS domains are related by a -90° rotation and form a compact structure, as in DDR1 (Appleton et al., 2007; Vander Kooi et al., 2007). This angled arrangement in DDR1 results in the C-terminus of the DS-like domain emerging near the interdomain linker.
  • the presumably unstructured juxtamembrane region of DDR1 linking the DS-like domain to the transmembrane helix contains 12 prolines and a number of predicted N- and O-linked glycosylation sites. If fully extended, it would project the DS and DS-like domains of DDR1 ⁇ 150 A from the cell surface.
  • the juxtamembrane regions of other DDRs are similarly long, ranging from 32 to 74 residues. mAbs directed against RTKs are invaluable tools for research and have been developed into successful therapeutics (Adams and Weiner, 2005).
  • Discoidin domain receptor 2 interacts with Src and She following its activation by type I collagen. J. Biol. Chem. 277, 19206-19212.
  • a receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin l-like domain. Proc. Natl.
  • TKT from man and mouse a new subclass of receptor tyrosine kinases with a factor Vlll-like domain.
  • SSM Secondary-structure matching
  • Discoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development. Mol. Cell.
  • antibody 1 F10 which binds the discoidin-like domain of human DDR1 , blocks collagen-induced autophosphorylation in cancer cell lines.

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Abstract

La présente invention concerne un anticorps qui se lie spécifiquement au domaine extracellulaire du récepteur à domaine discoïdine humain 1 ou "DDR1" (Discoidin Domain Receptor 1) à l'extérieur du domaine discoïdine, et qui réduit ou bloque l'autophosphorylation induite par le collagène du DDR1, et ce, sans empêcher le collagène de se lier au DDR1. De préférence, l'anticorps se lie au domaine semblable au DS du DDR1 humain.
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