ANTIBODIES FOR USE IN CANCER TREATMENT

Abstract

The present invention provides antibodies that bind to human Anx-A1 for use in the treatment of cancer, including drug-resistant cancer. Kits and products for this use are also provided.

Description

CANCER TREATMENT WITH AN ANTIBODY The present invention provides a specific binding molecule for use in the treatment of cancer in a subject. The specific binding molecule binds to human annexin-A1 (Anx-A1) and, in particular embodiments, is an antibody or antibody fragment. Cancer is a group of diseases characterized by abnormal cell growth. Characteristically, the abnormal cell growth associated with cancer results in the formation of a tumor (a solid mass of cells formed due to abnormal cell growth), although this is not always the case (particularly in blood cancers). In 2010 (the most recent year for which detailed statistics are available), more people worldwide (approximately 8 million) died from cancer than from any other cause (Lozano et al., Lancet 380: 2095-2128, 2012). Furthermore, as populations worldwide age, cancer rates are expected to rise. Therefore, there is an urgent need for new and improved cancer therapies. Furthermore, many cancer deaths result from cancer becoming resistant to chemotherapy drugs. The methods by which cancers become drug-resistant are reviewed in Housman et al. (Cancers 6: 1769–1792, 2014). As detailed therein, cancers can become drug-resistant through a variety of different mechanisms, including drug inactivation or metabolism (or prevention of their metabolic activation), mutation or alteration of the drug target, and drug efflux through ABC transporters. Such mechanisms can lead to cancers becoming multidrug-resistant (MDR). As discussed below, drug resistance is a particular problem for therapy with platinum-based chemotherapy agents. Platinum-based chemotherapy agents are a common first-line treatment option for several different cancers, including testicular cancer, ovarian cancer, colorectal cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, lymphoma, brain tumors, and neuroblastoma. Platinum-based chemotherapy agents include cisplatin, oxaloplatin, and carboplatin. All platinum-based chemotherapy agents essentially work in the same way, by reacting with the N-7 position on guanine residues to form interstrand and intrastrand DNA crosslinks and DNA-protein crosslinks. These crosslinks inhibit DNA synthesis and / or repair and trigger the initiation of apoptosis (Shen et al., Pharmacol. Rev. 64: 706-721, 2012).However, while patients generally respond well initially to platinum-based chemotherapy, the vast majority subsequently relapse due to the development of treatment resistance (particularly to cisplatin), resulting in treatment failure (Shen et al., supra). Therefore, the development of resistance to platinum-based therapies is a major challenge in current oncology. Cancers develop resistance to platinum-based therapies through a number of mechanisms, including reduced accumulation of platinum-based chemotherapeutic agents in target cells (due to reduced influx and / or increased efflux) and (re)activation of DNA repair pathways. A / C / ZUZ l / U IZOOZ Therefore, the development of resistance to platinum-based therapies is a major challenge in current oncology. New treatment options are urgently needed for cancers that are or have become resistant to traditional chemotherapeutics (particularly platinum-based chemotherapeutics). The present inventors discovered that specific binding molecules (e.g., antibodies) against Anx-A1 are effective in cancer treatment. These molecules were found to be particularly effective in treating drug-resistant cancer, including cancer resistant to platinum-based chemotherapy. Therefore, the present invention provides a novel treatment option for cancer patients, particularly those with cancer resistant to chemotherapy agents. This treatment option addresses an urgent need for new therapies for individuals whose disease does not respond to traditional chemotherapy. The specific binding molecules of the invention were found to be effective in the treatment of a wide variety of cancers, including breast cancer, colorectal cancer, ovarian cancer, lung cancer, and pancreatic cancer. Breast cancer is the most common cancer among women and causes more deaths in women worldwide than any other cancer (Becker, Int J Gynaecol Obstet 131 (2015), S36-S39). More than 55,000 cases of breast cancer are diagnosed each year in the UK (and more than 300 cases in men). Although the mortality rate for breast cancer is lower than that of many other cancers, breast cancer causes more than 11,000 deaths annually in the UK. Breast cancer that lacks expression of the estrogen receptor, the progesterone receptor, and the HER2 hormone receptor (known as triple-negative breast cancer) is particularly difficult to treat, as many modern breast cancer drugs target these receptors.The specific binding molecules of the invention were found to be effective in the treatment of breast cancer, including triple-negative breast cancer, providing an important new treatment option for this disease. Ovarian cancer is another common cancer in women, which is difficult to treat. In the UK alone, there are over 7,500 cases of ovarian cancer each year, resulting in more than 4,000 deaths (ovarian cancer is frequently diagnosed at a late stage, resulting in this relatively low survival rate). Pancreatic cancer is also relatively common, with over 9,000 cases each year in the UK alone, but it is known to be one of the least treatable cancers, with a survival rate of less than 1% (again, this is mainly because the disease is diagnosed at a late stage). The invention's specific binding molecules were found to be effective in treating both of these cancers, thus providing a much-needed new therapy for cancers that are difficult to treat. Colorectal (or bowel) cancer is also a common cancer, with 42,000 cases diagnosed in the UK each year.Despite being only the fourth most common cancer in the UK, it is the second most common cancer resulting in death. Similarly, lung cancer is diagnosed in over 47,000 people each year in the UK, and only 5% survive for ten years or more after diagnosis. The invention's targeted binding molecules offer promising new therapies for these cancers. A / C / ZUZ l / U IZOOZ The full-length human Anx-A1 has the amino acid sequence established in SEQ ID NO: 17. Anx-A1 is a member of the annexin protein family. Most proteins in this family, including Anx-A1, are characterized by the presence of a core region comprising four homologous repeat domains, each of which contains at least one Ca2+ binding site. Each member of the family is distinguished by a unique N-terminal region. Anx-A1 is a monomeric amphipathic protein, located predominantly in the cytoplasm of the cells in which it is expressed. However, Anx-A1 can also be exported, resulting in its localization to the cell surface (DAcquisto et al., Br. J. Pharmacol. 155: 152-169, 2008). Anx-A1 is known to play a role in regulating the immune system by participating in the homeostasis of various cell types in both the innate and adaptive immune systems. For example, Anx-A1 has been shown to exert homeostatic control over innate immune cells such as neutrophils and macrophages, and it also plays a role in T cells by modulating the strength of T cell receptor (TCR) signaling (DAcquisto et al., Blood 109: 1095-1102, 2007). The use of a neutralizing antibody against Anx-A1 to inhibit its function in the adaptive immune system has been shown to be effective in treating various T cell-mediated diseases, including autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (Document No. WO 2010 / 064012; Document No. WO 2011 / 154705). Antibodies against Anx-A1 have also been shown to be useful in the treatment of certain psychiatric conditions, particularly anxiety, obsessive-compulsive disorder (OCD) and related illnesses (document no. WO 2013 / 088111), although the mechanism by which this occurs is unknown. Document No. WO 2005 / 027965 demonstrates that Anx-A1 is localized on the surface of apoptotic cells and that anti-Anx-A1 antibodies can be used to monitor apoptosis. The document states that, based on this, such antibodies can be used to monitor and diagnose cancer. The document also states that the expression of Anx-A1 on the surface of apoptotic cells inhibits an immune response against the cells. Based on this, the document speculates that an antibody that binds to Anx-A1 can be used to treat cancer by blocking the immunosuppressive effect of Anx-A1 on cells that have begun apoptosis, thereby stimulating an immune response against the cancer. Oh et al. (Nature 429: 629-635, 2004) show that Anx-A1 is expressed in some solid tumors and can be used as a target for directing radioimmunotherapy to these cancers, and demonstrate that such therapy improves survival in an animal model of the disease. Document no. US 2015 / 0086553 suggests that anti-Anx-A1 antibodies can be used in the treatment and diagnosis of cancer, but does not explain how such treatment could be carried out. The binding of an anti-Anx-A1 scFv to the SNU-1 gastric cancer cell line is demonstrated. Wang et al. (Biochem. BioPhys. Fies. Common. 314: 565-570, 2004) demonstrate a correlation between Anx-A1 expression and multidrug resistance in cancer. Thus, several diseases, including cancer, have been shown to be associated with Anx-A1 expression.However, prior to the present invention, it had not been demonstrated that an anti-Anx-A1 antibody, particularly when used without any co-treatment, could be used to treat cancer. A / C / ZUZ l / U IZOOZ In fact, the present invention demonstrates that efficacy in cancer treatment does not extend to all specific binding molecules that bind to human Anx-A1. The present invention provides particular specific binding molecules that bind to human Anx-A1 and can be used advantageously to treat cancer, particularly cancer that is resistant to chemotherapy drugs and / or breast cancer, colorectal cancer, ovarian cancer, lung cancer, and pancreatic cancer. It is unknown why the specific binding molecules of the invention are effective in cancer treatment, while other specific binding molecules that also bind to human Anx-A1 are not. Without intending to impose any theory, it is speculated that the activity of the specific binding molecules that bind to human Anx-A1 may depend on the recognized epitope. Several monoclonal antibodies that recognize human Anx-A1 are described in patent no. WO 2018 / 146230. The antibodies described in patent no. WO 2018 / 146230 have particularly advantageous properties, as they can bind to human Anx-A1 with very high affinity. The inventors have now discovered that the antibodies described in patent no. WO 2018 / 146230 are useful in the treatment of cancer, as described below. Therefore, in a first aspect, the invention provides a specific binding molecule that binds to human Anx-A1 for use in the treatment of cancer in a subject, wherein: (i) said specific binding molecule comprises the complementarity-determining regions (CDRs) VLCDR1, VLCDR2, VLCDR3, VHCDR1, VHCDR2 and VHCDR3, each of said CDRs having an amino acid sequence as follows: VLCDR1 has the sequence indicated in the SEQ ID NO: 1,7 or 8; V LCDR2 has the sequence indicated in SEQ ID NO: 2; V LCDR3 has the sequence indicated in SEQ ID NO: 3; V HCDR1 has the sequence indicated in the SEQ ID NO: 4; V HCDR2 has the sequence indicated in SEQ ID NO: 5; and VHCDR3 has the sequence indicated in SEQ ID NO: 6; or, for each sequence, an amino acid sequence with at least 85% sequence identity with the same; and / or (ii) said specific binding molecule binds to Anx-A1 at a discontinuous epitope consisting of amino acids 197-206, 220-224 and 227-237 of SEQ ID NO: 17. Similarly, the invention provides a method for treating cancer in a subject, comprising administering to said subject a specific binding molecule as defined above. The use of a specific binding molecule as defined above in the manufacture of a medicament for the treatment of cancer in a subject is also provided. In a second aspect, the invention provides a kit comprising a specific binding molecule as defined above and a chemotherapeutic agent. In a third aspect, the invention provides a product comprising a specific binding molecule as defined above and a second therapeutic agent for separate, simultaneous or sequential use in the treatment of cancer in a subject. As mentioned above, the invention provides a specific binding molecule that binds to human Anx-A1 for use in the treatment of cancer in a subject. A “binding molecule A “specific binding molecule” as defined herein is a molecule that binds specifically to a particular molecular pair, in this case, human Anx-A1. A molecule that binds specifically to human Anx-A1 is a molecule that binds to human Anx-A1 with a higher affinity than it has for other molecules, or at least for most other molecules. Therefore, for example, if a specific binding molecule that binds to human Anx-A1 were to come into contact with a human cell lysate, the specific binding molecule would bind primarily to Anx-A1. In particular, the specific binding molecule binds to a sequence or configuration present on that human Anx-A1. When the specific binding molecule is an antibody, the sequence or configuration is the epitope to which the specific binding molecule binds.The Anx-A1 epitope bound by the specific binding molecules for use according to the invention is described below. The binding molecule specific for use in the present description does not necessarily bind only to human Anx-A1: the binding molecule may cross-react with other undefined target molecules, or it may exhibit a non-specific binding level when in contact with a mixture of a large number of molecules (such as a cell lysate or the like). For example, the binding molecule may exhibit cross-reactivity with other members of the human annexin family and / or with Anx-A1 proteins from other animals. Regardless, a binding molecule specific for use according to the invention exhibits specificity for Anx-A1. A person skilled in the art can readily identify whether a binding molecule exhibits specificity for Anx-A1 by using standard techniques, such as ELISA, Western blot, surface plasmon resonance (SPR), etc.The molecule for use in the present description binds to human Anx-A1 with a Kd (dissociation constant) of less than 20 nM, 15 nM, or 10 nM. In a preferred embodiment, the specific binding molecule for use in the present description binds to human Anx-A1 with a Kd of less than 5 nM. The Kd of the binding of the specific binding molecule to Anx-A1 is preferably measured under binding conditions in which Ca2+ ions are present at a concentration of at least 1 mM and, optionally, HEPES is present at a concentration of 10–20 mM, and the pH is between 7 and 8, preferably at a physiological level between 7.2 and 7.5 inclusive. NaCl may be present, for example, at a concentration of 100–250 mM, and a low concentration of a detergent, such as polysorbate 20, may also be present. Such a low concentration may be, for example, 0.01 to 0.5% v / v. Several methods for calculating the Kd of an interaction between a specific binding molecule and its ligand are well known in the art. Known techniques include SPR (e.g., Biacore) and polarization-modulated oblique incidence reflectivity difference (OI-RD). As described above, a molecule that “binds to human Anx-A1” exhibits specificity for a human Anx-A1 molecule. There are three human isoforms of human Anx-A1, derived from the translation of four alternately spliced ​​Anx-A1 mRNAs. The full-length human Anx-A1 protein is derived from the translation of either the ANXA1-002 or ANXA1-003 transcript and, as previously stated, has the amino acid sequence indicated in SEQ ID NO: 17. The ANXA1-004 and ANXA1-006 transcripts encode fragments of the full-length human Anx-A1 protein, which have the amino acid sequences listed in SEQ ID NO: 18 and 19, respectively. a / c / zuz ι / u izoor The specific binding molecule for use according to the invention binds to full-length human Anx-A1 (i.e., Anx-A1 of SEQ ID NO: 17, encoded by transcript ANXA1-002 or ANXA1-003, which is a 346-amino-acid protein). The specific binding molecule can also bind to particular fragments, parts, or variants of full-length Anx-A1, such as the fragments encoded by transcripts ANXA1-004 and ANXA1-006. As discussed below, antibodies (and CDR-containing molecules) form preferred specific binding molecules for use according to the invention. As mentioned previously, several monoclonal antibodies that recognize human Anx-A1 are described in document no. WO 2018 / 146230. As is known to experts, antibodies are proteins comprising four polypeptide chains: two heavy chains and two light chains. Typically, the heavy chains are identical to each other, and the light chains are also identical to each other. Light chains are shorter (and therefore lighter) than heavy chains. Heavy chains comprise four or five domains: a variable domain (Vh) is located at the N-terminus, followed by three or four constant domains (from the N-terminus to the C-terminus: Ch1, Ch2, Ch3, and, when present, Ch4, respectively). Light chains comprise two domains: a variable domain (Vl) is located at the N-terminus, and a constant domain (Cl) is located at the C-terminus. In the heavy chain, an unstructured hinge region is located between the Ch1 and Ch2 domains.The two heavy chains of an antibody are joined by disulfide bonds formed between cistern residues present in the hinge region, and each heavy chain is joined to a light chain by a disulfide bond between cysteine ​​residues present in the Ch1 and Cl domains, respectively. In mammals, two types of light chains are produced, known as lambda (λ) and kappa (k). For kappa light chains, the variable and constant domains can be called Vk and Ck domains, respectively. Whether a light chain is a λ or κ light chain is determined by its constant region: the constant regions of λ and κ light chains differ, but are the same in all light chains of the same type in any given species. The constant regions of heavy chains are the same in all antibodies of any given isotype in a species, but they differ between isotypes (examples of antibody isotypes are the IgG, IgE, IgM, IgA, and IgD classes; there are also a number of antibody subtypes, for example, there are four IgG antibody subtypes: IgG1, IgG2, IgG3, and IgG4). The specificity of an antibody is determined by the sequence of its variable region. The sequence of variable regions varies among antibodies of the same type in any given individual. In particular, both the light and heavy chains of an antibody comprise three hypervariable complementarity-determining regions (CDRs). In a light-heavy-chain pair, the CDRs of the two chains form the antigen-binding site. The CDR sequences determine the specificity of an antibody. The three CDRs of a heavy chain are known as VHCDR1, VHCDR2 and VHCDR3, from the N end to the C end, and the three CDRs of a light chain are known as VLCDR1, VLCDR2 and VLCDR3, from the N end to the C end. An antibody described in document no. WO 2018 / 146230 has the following sequences of A / C / ZUZ l / U IZOOZ CDR: VLCDR1: RSSQSLENSNAKTYLN (SEQ ID NO: 1); VLCDR2: GVSNRFS (SEQ ID NO: 2); VLCDR3: LQVTHVPYT (SEQ ID NO: 3); V HCDR1: GYTFTNYWIG (SEQ ID NO: 4); VHCDR2: DIYPGGDYTNYNEKFKG (SEQ ID NO: 5); and VHCDR3: ARWGLGYYFDY (SEQ ID NO: 6). Another antibody described in document no. WO 2018 / 146230 has the following CDR sequences: V LCDR1: RSSQSLENSNGKTYLN (SEQ ID NO: 7); V LCDR2: GVSNRFS (SEQ ID NO: 2); V LCDR3: LQVTHVPYT (SEQ ID NO: 3); V HCDR1: GYTFTNYWIG (SEQ ID NO: 4); VHCDR2: DIYPGGDYTNYNEKFKG (SEQ ID NO: 5); and VHCDR3: ARWGLGYYFDY (SEQ ID NO: 6). Another antibody described in document no. WO 2018 / 146230 has the following CDR sequences: V LCDR1: RSSQSLENTNGKTYLN (SEQ ID NO: 8); V LCDR2: GVSNRFS (SEQ ID NO: 2); V LCDR3: LQVTHVPYT (SEQ ID NO: 3); V HCDR1: GYTFTNYWIG (SEQ ID NO: 4); VHCDR2: DIYPGGDYTNYNEKFKG (SEQ ID NO: 5); and VHCDR3: ARWGLGYYFDY (SEQ ID NO: 6). Therefore, the antibodies described in document no. WO 2018 / 146230 have identical CDR sequences, except for the VLCDR1 sequences. The VLCDR1 sequence in SEQ ID NO: 7 is a wild-type VLCDR1 sequence found in the murine antibody Mdx001, which was constructed from a minor mRNA sequence obtained from the hybridoma deposited with the ECACC, accession number 10060301. Humanized versions of Mdx001 were generated, and surprisingly, modification of the VLCDR1 sequence in these humanized antibodies was found to produce enhanced antibodies. Substitution of the glycine residue at position 11 of SEQ ID NO: 7 improves the stability and function of the antibody. Without committing to any specific theory, it is believed that this is achieved by eliminating a site for post-translational modification of the CDR. Specifically, it is believed that replacing this glycine residue removes a deamidation site from the protein.The VLCDR1 sequence indicated in SEQ ID NO: 7 comprises the Ser-Asn-Gly sequence motif. This sequence motif is associated with the deamidation of the Asn residue, which leads to the conversion of the asparagine residue to aspartic acid or isoaspartic acid, potentially affecting antibody stability and target binding. It is believed that substitution of any of the residues within the Ser-Asn-Gly motif eliminates the deamidation site. The inventors identified antibodies in which the glycine residue at position 11 of SEQ ID NO: 7 (which is the glycine residue located within the deamidation site described above) is A / C / ZUZ l / U IZOOZ substitutes alanine and show improved binding to their target (Anx-A1) compared to the native antibody, Mdx001. The VLCDR1 comprising the alanine-glycine substitution at position 11 has the amino acid sequence RSSQSLENSNAKTYLN (the residue in bold is the alanine introduced by the aforementioned substitution), which is indicated in SEQ ID NO: 1. In addition, humanized antibodies comprising a VLCDR1 modified at position 9, by the threonine-serine substitution, were also found to exhibit improved binding to Anx-A1 compared to Mdx001. The VLCDR1 comprising the substitution of threonine for serine at position 9 has the amino acid sequence RSSQSLENTNGKTYLN (the residue in bold is the threonine introduced by the aforementioned substitution), which is indicated in SEQ ID NO: 8. As mentioned above, the inventors discovered that the antibodies described in document no.WO 2018 / 146230 are suitable for use in cancer therapy. The antibodies described in document no. WO 2018 / 146230 were generated by genetically immunizing a mouse with human Anx-A1, meaning that the mouse's immune system was exposed to the complete and intact human Anx-A1 in its native conformation. As detailed in the examples, hydrogen-deuterium exchange (HDX) analysis of the antibodies in document no. WO 2018 / 146230 showed that they bind to human Anx-A1 at a discontinuous epitope consisting of amino acids 197-206, 220-224, and 227-237 of human Anx-A1 (i.e., amino acids 197-206, 220-224, and 227-237 of SEQ ID NO: 17). In particular, the antibodies in patent no. WO 2018 / 146230 bind Anx-A1 only in the presence of physiological concentrations of Ca2+. Without being linked to any specific theory, this is believed to be a result of the location of its epitope on the Anx-A1 molecule. In the absence of Ca2+, its N-terminus is located in a pocket adjacent to this discontinuous epitope. The binding of Ca2+ to Anx-A1 (which occurs at physiological concentrations of Ca2+) results in a conformational change of Anx-A1 that leads to the expulsion of the N-terminus from its pocket in the core domain, which is believed to expose the epitope, allowing the antibody to bind. Any antibody (or similar specific-binding molecule) that binds to this epitope of Anx-A1 may be used in the methods and uses described herein. The specific binding molecule for use according to the present invention may comprise the CDR sequences of any of the three antibodies described in WO 2018 / 146230, or variants thereof. Alternatively or additionally, the specific binding molecule for use according to the invention may bind to Anx-A1 at the same epitope as the antibodies of WO 2018 / 146230. Accordingly, the specific binding molecule for use according to the present invention: (i) comprises the complementarity-determining regions (CDRs) VLCDR1, VLCDR2, VLCDR3, VHCDR1, VHCDR2 and VHCDR3, each of said CDRs having an amino acid sequence as follows: VLCDR1 has the sequence indicated in the SEQ ID NO: 1,7 or 8; VLCDR2 has the sequence indicated in SEQ ID NO:2; VLCDR3 has the sequence indicated in SEQ ID NO:3; VHCDR1 has the sequence indicated in SEQ ID NO:4; A / C / ZUZ l / U IZOOZ VHCDR2 has the sequence indicated in SEQ ID NO: 5; and VHCDR3 has the sequence indicated in SEQ ID NO: 6; or, for each sequence, an amino acid sequence with at least 85%, 90% or 95% sequence identity with the same; and / or (ii) binds to human Anx-A1 at a discontinuous epitope consisting of amino acids 197-206, 220-224 and 227-237 of SEQ ID NO: 17. In a preferred aspect, the specific binding molecules of (i) bind to the epitope as described in (i). The phrase “or, for each sequence, an amino acid sequence with at least 85%, 90%, or 95% sequence identity with the same” means that each of these CDRs may have either the amino acid sequence specified in the non-relevant SEQ ID, or an amino acid sequence with at least 85%, 90%, or 95% sequence identity with it. Therefore, VLCDR1 has the sequence indicated in SEQ ID NO: 1, 7, or 8, or an amino acid sequence with at least 85%, 90%, or 95% sequence identity with SEQ ID NO: 1, 7, or 8; VLCDR2 has the sequence indicated in SEQ ID NO: 2, or an amino acid sequence with at least 85%, 90%, or 95% sequence identity with SEQ ID NO: 2;VLCDR3 has the sequence indicated in SEQ ID NO: 3, or an amino acid sequence with at least 85%, 90% or 95% sequence identity with SEQ ID NO: 3; VHCDR1 has the sequence indicated in SEQ ID NO: 4, or an amino acid sequence with at least 85%, 90% or 95% sequence identity with SEQ ID NO: 4; VHCDR2 has the sequence indicated in SEQ ID NO: 5, or an amino acid sequence with at least 85%, 90% or 95% sequence identity with SEQ ID NO: 5;and VHCDR3 has the sequence indicated in SEQ ID NO: 6, or an amino acid sequence with at least 85%, 90%, or 95% sequence identity with SEQ ID NO: 6. An amino acid sequence with at least 85, 90, or 95% sequence identity (but less than 100% sequence identity) with a particular SEQ ID NO is referred to herein as a variant of that SEQ ID NO; for example, an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 1, but less than 100% sequence identity with SEQ ID NO: 1, is a variant of SEQ ID NO: 1. In one particular embodiment, the specific binding molecule for use according to the invention comprises CDRs having the following amino acid sequences: V LCDR1 has the sequence indicated in the SEQ ID NO: 1; V LCDR2 has the sequence indicated in SEQ ID NO: 2; V LCDR3 has the sequence indicated in SEQ ID NO: 3; V HCDR1 has the sequence indicated in the SEQ ID NO: 4; V HCDR2 has the sequence indicated in SEQ ID NO: 5; and V HCDR3 has the sequence indicated in the SEQ ID NO: 6. As indicated, the specific binding molecule for use according to the invention may comprise six CDRs consisting of polypeptide sequences. As used herein, “protein” and “polypeptide” are interchangeable, each referring to a sequence of two or more amino acids linked by one or more peptide bonds. Therefore, the specific binding molecule may be a polypeptide. Alternatively, the specific binding molecule may comprise one or more A / C / ZUZ l / U IZOO / polypeptides comprising the CDR sequences. Preferably, the specific binding molecule for use according to the invention is an antibody or an antibody fragment. The specific binding molecule for use according to the invention can be synthesized by any method known in the art. In particular, the specific binding molecule can be synthesized using a protein expression system, such as a cell expression system using prokaryotic cells (e.g., bacterial) or eukaryotic cells (e.g., yeast, fungal, insect, or mammalian). An alternative protein expression system is a cell-free in vitro expression system, in which a nucleotide sequence encoding the specific binding molecule is transcribed into mRNA, and the mRNA is translated into a protein in vitro. Cell-free expression system kits are widely available and can be purchased, for example, from Thermo Fisher Scientific (USA). Alternatively, the specific binding molecules can be chemically synthesized in a non-biological system.Liquid-phase or solid-phase synthesis may be used to generate polypeptides that can be formed or incorporated within the specific binding molecule for use according to the invention. The skilled worker can readily produce specific binding molecules using appropriate methods common in the art. In particular, the specific binding molecule can be recombinantly expressed in mammalian cells, such as CHO cells. A specific binding molecule that binds to human Anx-A1 at an epitope as defined above (i.e., consisting of amino acids 197–206, 220–224, and 227–237 of SEQ ID NO: 17) can be generated using standard methods in the art (e.g., genetic immunization for antibodies), and an antibody with the required epitope can be identified by standard epitope mapping methods known in the art. Examples of such methods include HDX, epitope cleavage, peptide panning, X-ray cocrystallography, NMR, etc. (Clementi et al., Methods Mol. Bioi. 1131: 427–446, 2014; Abbott et al., Immunology 142(4): 526–535, 2014).Specific binding molecules can also be generated by modifying existing specific binding molecules known to bind to the relevant epitope (e.g., by expressing modified sequences) and molecules that bind to the relevant epitope identified by the methods described herein. Specific binding molecules that bind to the relevant epitope can also be identified by competition with antibodies known to bind to the epitope (e.g., as described herein) or by comparing their binding to the epitope as described herein with epitope variants thereof (where failure to bind to an epitope variant is indicative of specific binding to the epitope of interest). The specific binding molecule for use according to the invention can, if necessary, be isolated (i.e., purified). “Isolated,” as used herein, means that the specific binding molecule is the main component (i.e., the major component) of any solution or the like in which it is provided. In particular, if the specific binding molecule is initially produced in a mixture or mixed solution, isolation of the specific binding molecule means that it has been separated or purified from it. Thus, for example, if the specific binding molecule is a polypeptide, and that polypeptide is produced by using a protein expression system as discussed above, the specific binding molecule is isolated such that it is the most abundant polypeptide in A / C / ZUZ l / U IZOOZ, the solution or composition in which it is present, such that it preferably constitutes the majority of the polypeptides in the solution or composition and is enriched with respect to other polypeptides and biomolecules present in the native production medium. In particular, the specific binding molecule for use according to the invention is isolated such that it is the predominant (majority) specific binding molecule in the solution or composition. In a preferred embodiment, the specific binding molecule is present in the solution or composition with a purity of at least 60, 70, 80, 90, 95, or 99% w / w when evaluated against the presence of other components, particularly other polypeptide components, in the solution or composition. If the specific binding molecule is a protein, for example, produced in a protein expression system, a solution of the specific binding molecule can be analyzed by quantitative proteomics to identify whether the specific binding molecule for use according to the invention is predominant and therefore isolated. For example, 2D gel electrophoresis and / or mass spectrometry can be used. Such isolated molecules may be present in preparations or compositions as described below. The specific binding molecule of the present invention can be isolated using any technique known in the art. For example, the specific binding molecule can be produced with an affinity tag such as a polyhistidine tag, a strep tag, a FLAG tag, an HA tag, or the like, to allow isolation of the molecule by affinity chromatography using an appropriate binding partner. For example, a molecule bearing a polyhistidine tag can be purified using Ni2+ ions. In embodiments where the specific binding molecule is an antibody, the specific binding molecule can be isolated by affinity chromatography using one or more antibody-binding proteins, such as protein G, protein A, protein A / G, or protein L.The specific binding molecule can be isolated, for example, by size exclusion chromatography or ion-exchange chromatography. Conversely, a specific binding molecule produced by chemical synthesis (i.e., by a non-biological method) is likely to be produced in an isolated form. Therefore, a specific purification or isolation step is not required for a specific binding molecule to be considered isolated if it is synthesized in a manner that produces an isolated molecule for use according to the invention. In embodiments of the invention where the specific binding molecule comprises a CDR sequence that is a variant of SEQ ID NO: 1 (or 7 or 8) or 2-6, that variant can be altered with respect to its reference CDR sequence (i.e., the CDR sequence with which it has at least 85%, but less than 100% sequence identity) by substitution, addition and / or deletion of amino acid residues. When a CDR sequence is modified by substituting a particular amino acid residue, the substitution may be a conservative amino acid substitution. The term “conservative amino acid substitution,” as used herein, refers to an amino acid substitution in which one amino acid residue is replaced with another amino acid residue that has a similar side chain. Amino acids with similar side chains tend to have similar properties, and therefore, a conservative substitution of a major amino acid can be expected. A / C / ZUZ l / U IZOO / for the structure or function of a polypeptide affects the structure / function of the polypeptide less than a non-conservative substitution of amino acids at the same position. Families of amino acid residues that have similar side chains are defined in the art, and include basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), polar uncharged side chains (e.g., asparagine, glutamine, serine, threonine, tyrosine), nonpolar side chains (e.g., glycine, cysteine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Therefore, a conservative amino acid substitution can be considered to be a substitution in which a particular amino acid residue is replaced by a different amino acid from the same family.However, a substitution of a CDR residue can equally be a non-conservative substitution, in which one amino acid is replaced by another with a side chain that belongs to a different family. The substitutions or additions of amino acids within the scope of the invention may be made using a proteinogenic amino acid encoded by the genetic code, a proteinogenic amino acid not encoded by the genetic code, or a non-proteinogenic amino acid. Preferably, any substitution or addition of amino acids is made using a proteinogenic amino acid. The amino acids forming the CDR sequence may include amino acids that are not naturally occurring but are modifications of naturally occurring amino acids. Provided that these non-naturally occurring amino acids do not alter the sequence and do not affect the specificity, they may be used to generate the CDRs described herein without reducing the sequence identity; that is, they are considered to provide an amino acid of the CDR. For example, amino acid derivatives such as methylated amino acids may be used.In one embodiment, the specific bonding molecule for use according to the invention is not a natural molecule, i.e., it is not a molecule found in nature. Modifications to the amino acid sequences of the CDRs established in SEQ ID NO: 1 8 can be made using any suitable technique, such as site-directed mutagenesis of the coding DNA sequence or solid-state synthesis. The specific binding molecules for use according to the invention may comprise the CDRs described above. Additionally, such molecules may contain linker residues or framework sequences to enable the appropriate presentation of the CDRs. Additional sequences may also be present that conveniently confer additional properties, for example, peptide sequences that allow the isolation or identification of the CDR-containing molecules, as described above. In such cases, a fusion protein may be generated. As stated above, the specific binding molecule for use according to the invention may comprise CDRs having at least 85% sequence identity with SEQ IDs 1 (or 7 or 8) and 2-6, as previously established. In another embodiment of the invention, each of the CDR sequences may be modified by substitution, addition, or deletion of up to two amino acids with respect to SEQ IDs 1 (or 7 or 8) and 2-6, provided that the resulting CDR sequences have at least 85% or 90% sequence identity with SEQ IDs 1 (or 7 or 8) and 2-6, as A / C / ZUZ l / U IZOOZ was previously established. “Substitution, addition, or deletion” includes combinations of substitutions, additions, and deletions. Therefore, in particular, VLCDR1 may have the sequence of SEQ ID NO: 1 (or 7 or 8) with 1 or 2 amino acid substitutions, additions, or deletions; VLCDR2 may have the sequence of SEQ ID NO: 2 with 1 amino acid substitution, addition, or deletion; VLCDR3 may have the sequence of SEQ ID NO: 3 with 1 amino acid substitution, addition, or deletion; VHCDR1 may have the sequence of SEQ ID NO: 4 with 1 amino acid substitution, addition, or deletion; VHCDR2 may have the sequence of SEQ ID NO: 5 with 1 or 2 amino acid substitutions, additions, or deletions; and VHCDR3 may have the sequence of SEQ ID NO: 6 with 1 amino acid substitution, addition or deletion. Preferably, such 1 or 2 amino acid substitutions of SEQ ID NO: 1,7 or 8 are at position 9 and / or 11 in that sequence. Sequence identity can be assessed using any convenient method. However, to determine the degree of sequence identity between sequences, software programs that perform pairwise or multiple sequence alignments are useful. For example, EMBOSS Needle or EMBOSS Stretcher (both Rice, P. et al., Trends Genet. 16, (6) pp. 276-277, 2000) can be used for pairwise sequence alignments, while Clustal Omega (Sievers F et al., Mol. Syst. Biol. 7: 539, 2011) or MUSCLE (Edgar, RC, Nucleic Acids Res. 32(5): 1792-1797, 2004) can be used for multiple sequence alignments, although any other appropriate program may be used. Whether the alignment is pairwise or multiple, it should be performed globally (i.e., on the entire reference sequence) rather than locally. Sequence alignments and % identity calculations can be determined using, for example, standard Clustal Omega parameters: Gonnet array, interrupt opening penalty 6, interrupt extension penalty 1. Alternatively, standard EMBOSS Needle parameters can be used: BLOSUM62 array, interrupt opening penalty 10, interrupt extension penalty 0.5. Alternatively, any other suitable parameters can be used. For the purposes of this application, when there is a dispute between the sequence identity values ​​obtained by different methods, the value obtained by global pairwise alignment using EMBOSS Needle with the default parameters will be considered valid. As indicated above, the specific binding molecule to be used according to the invention is preferably an antibody or an antibody fragment. An “antibody” is an immunoglobulin having the characteristics described above. The invention also contemplates variants of naturally occurring antibodies that retain the CDRs but are presented in a different framework, as discussed below, and that function in the same manner, i.e., retain specificity for the antigen. Therefore, the antibodies include functional equivalents or homologs in which the naturally occurring domains have been partially or completely replaced with natural or non-natural equivalents or homologs that function in the same manner. When the specific binding molecule for use according to the invention is an antibody, preferably a monoclonal antibody. A “monoclonal antibody” is understood to be an antibody preparation consisting of a single antibody species, i.e., all the antibodies in the preparation have the same amino acid sequences, including the same CDRs, and are therefore A / C / ZUZ l / U IZOO / bind to the same epitope on their target antigen (the “target antigen” being the antigen containing the epitope bound by a particular antibody, i.e., the target antigen of an anti-Anx-A1 antibody is Anx-A1) with the same effect. In other words, the antibody for use according to the invention, preferably, is not part of a polyclonal mixture of antibodies. In an antibody, as described above, the CDR sequences are located in the variable domains of the heavy and light chains. The CDR sequences are embedded within a polypeptide frame, which positions the CDRs appropriately for antigen binding. Therefore, the remaining variable domains (i.e., the portions of the variable domain sequences that are not part of any of the CDRs) constitute frame regions. The N-terminus of a mature variable domain forms frame region 1 (FR1); the polypeptide sequence between CDR1 and CDR2 forms FR2; the polypeptide sequence between CDR2 and CDR3 forms FR3; and the polypeptide sequence linking CDR3 to the constant domain forms FR4. In an antibody for use according to the invention, the frame regions of the variable region can have any appropriate amino acid sequence such that the antibody binds to human Anx-A1 via its CDRs.The constant regions can be the constant regions of any mammalian antibody isotype (preferably human). In certain embodiments of the invention, the specific binding molecule can be multispecific, for example, a bispecific monoclonal antibody. A multispecific binding molecule contains regions or domains (antigen-binding regions) that bind to at least two different molecular binding partners, for example, two or more different antigens or epitopes. In the case of a bispecific antibody, the antibody comprises two heavy and two light chains, in the configuration described above, except that the variable domains of the two heavy chains and the two light chains, respectively, are different and thus form two different antigen-binding regions.In a multispecific (e.g., bispecific) binding molecule, e.g., a monoclonal antibody, for use according to the invention, one of the antigen-binding regions has the CDR sequences of a specific binding molecule for use according to the invention as defined herein and, therefore, binds to Anx-A1. The other antigen-binding regions of the multispecific binding molecule for use according to the invention are different from the antigen-binding regions formed by CDRs for use according to the invention; for example, they have CDRs with sequences different from those defined herein for the specific binding molecule for use according to the invention.The additional antigen-binding region(s) (e.g., second) of the specific binding molecule, for example, in the bispecific antibody, may also bind to AnxA1, but at a different epitope than the first antigen-binding region that binds to Anx-A1 (which has the CDRs of the specific binding molecule for use according to the invention). Alternatively, the additional antigen-binding region(s) (e.g., second) may bind to different additional antigen(s) (e.g., a second) that is / are not Anx-A1. In an alternative embodiment, the two or more antigen-binding regions in the specific binding molecule, for example, in an antibody, may each bind to the same antigen, i.e., provide a multivalent (e.g., bivalent) molecule. A / C / ZUZ l / U IZOOZ The specific binding molecule may be an antibody fragment or a synthetic construct capable of binding to human Anx-A1. Therefore, an antibody fragment for use according to the invention comprises an antigen-binding domain (i.e., the antigen-binding domain of the antibody from which it is derived). Antibody fragments are discussed in Rodrigo et al., Antibodies, vol. 4(3), pp. 259-277, 2015. The antibody fragments for use according to the invention are preferably monoclonal (i.e., they are not part of a polyclonal mixture of antibody fragments). Antibody fragments include, for example, Fab, F(abj2), Fab', and Fv fragments. Fab fragments are described in Roitt et al., Immunology, second edition (1989), Churchill Livingstone, London.A Fab fragment consists of the antigen-binding domain of an antibody. A single antibody contains two Fab fragments, each consisting of a light chain and its attached N-terminal portion of the heavy chain. Therefore, a Fab fragment contains a complete light chain and the Vh and Ch1 domains of the heavy chain to which it binds. Fab fragments can be obtained by digesting an antibody with papain. F(abj2) fragments consist of the two Fab fragments of an antibody, plus the hinge regions of the heavy domains, which include the disulfide bonds linking the two heavy chains. In other words, an F(abj2) fragment can be viewed as two covalently linked Fab fragments. F(abj2) fragments can be obtained by digesting an antibody with pepsin. Reduction of the F(abj2) fragments yields two Fab' fragments, which can be viewed as Fab fragments containing an additional sulfhydryl group that can be useful for conjugating the fragment with other molecules. Fv fragments consist only of the variable domains of the light and heavy chains. These are not covalently linked and are held together only weakly by non-covalent interactions. Fv fragments can be modified to produce a synthetic construct known as a single-stranded Fv molecule (scFv). This modification is typically performed recombinantly, by recombination of the antibody gene to produce a fusion protein in which a single polypeptide comprises both the Vh and Vl domains. scFv fragments generally include a peptide linker that covalently links the Vh and Vl regions, contributing to the molecule's stability. The linker can comprise 1 to 20 amino acids, such as 1, 2, 3, or 4 amino acids, 5, 10, or 15 amino acids, or other intermediate numbers in the range of 1 to 20 as required.The peptide linker can be formed from any generally convenient amino acid residue, such as glycine and / or serine. An example of a suitable linker is Gly4Ser. Multimers of such linkers can be used, such as a dimer, trimer, tetramer, or pentamer, for example (Gly4Ser)2, (Gly4Ser)3, (Gly4Ser)4, or (Gly4Ser)s. However, the presence of a linker is not essential, and the Vl domain can be linked to the Vh domain by a peptide bond. An scFv is defined herein as an antibody fragment. The specific binding molecule can be an analog of a scFv. For example, an scFv can bind to other specific binding molecules (e.g., other scFvs, Fab antibody fragments, and chimeric IgG antibodies (e.g., with human frames)). An scFv can bind to other scFvs to form a multimer, which is a multispecific binding protein, such as a dimer, trimer, or tetramer. Bispecific scFvs are sometimes called diabodies, trispecific scFvs are sometimes called tribodies, and so on. A / C / ZUZ l / U IZOO / tetraspecific scFv as tetrabodies. In other embodiments, the scFv for use according to the invention can be joined to other identical scFv molecules, thus forming a multimer that is monospecific but multivalent, for example, a bivalent dimer or a trivalent trimer can be formed. Synthetic constructs that can be used include CDR peptides. These are synthetic peptides that comprise antigen-binding determinants. Peptide mimetics can also be used. These molecules are usually conformationally constrained organic rings that mimic the structure of a CDR loop and include antigen-interacting side chains. As indicated above, in particular embodiments, the specific binding molecule for use according to the present invention comprises CDRs having the amino acid sequences indicated in SEQ ID NO: 1, 7 or 8 and 2-6. As detailed, these are derived from or modified from the murine antibody Mdx001. However, an antibody or fragment thereof for use according to the present invention is preferably human or humanized. The antibody or antibody fragment for use according to the invention may be a chimeric human / mouse antibody or, preferably, may be humanized. This is particularly the case for monoclonal antibodies and antibody fragments. Humanized or chimeric antibodies or antibody fragments are desirable when the molecule is to be used for human therapeutics.Therapeutic treatment of humans with non-human (e.g., murine) antibodies may be ineffective for several reasons, e.g., a short in vivo half-life of the antibody; weak effector functions mediated by the foreign heavy chain constant region, due to poor recognition of non-human heavy chain constant regions by Fe receptors on human immune effector cells; sensitization of the patient to the antibody and (in the context of murine antibodies) generation of a human anti-mouse antibody response (RAMA); and neutralization of the mouse antibody by HAMA leading to loss of therapeutic efficacy. A chimeric antibody is an antibody with variable regions derived from one species and constant regions derived from another. Therefore, an antibody or antibody fragment for use according to the invention may be a chimeric antibody or a chimeric antibody fragment comprising murine variable domains and human constant domains. As detailed above, the isotype of an antibody is defined by the sequence of its heavy chain constant regions. The chimeric antibody for use according to the invention may have the constant regions of any human antibody isotype and any subclass within each isotype. For example, the chimeric antibody may have the Fe regions of an IgA, IgD, IgE, IgG, or IgM antibody (i.e., the chimeric antibody may comprise the constant domains of the α, δ, ε, and μ heavy chains, respectively), although, preferably, the antibody for use according to the invention is of the IgG isotype. Therefore, the chimeric antibody may be of any isotype. The light chain of the chimeric antibody may be a κ or λ light chain; that is, it may comprise the constant region of a human λ light chain or a human κ light chain.A chimeric antibody fragment is, correspondingly, an antibody fragment comprising constant domains (e.g., a Fab, Fab', or Fjabjz fragment). The constant domains of an antibody fragment. A / C / ZUZ l / U IZOOZ chimeric for use according to the invention may be as described above for a chimeric monoclonal antibody. Chimeric antibodies can be generated using any suitable technique, for example, recombinant DNA technology in which the DNA sequence of the murine variable domain is fused with the DNA sequence of the human constant domain(s) to encode a chimeric antibody. A chimeric antibody fragment can be obtained by using recombinant DNA technology to produce a DNA sequence encoding such a polypeptide, or by processing a chimeric antibody for use according to the invention to produce the desired fragments, as described above. Chimeric antibodies can be expected to overcome the problems of short in vivo half-life and weak effector functions associated with the use of a foreign, e.g., murine antibody in human therapy, and may reduce the likelihood of patient sensitization and HAMA (human antibody-associated immunosorbent reaction).However, patient sensitization and HAMA can still occur when a chimeric antibody is administered to a human patient, due to the presence of murine sequences in the variable domains. Preferably, the antibody or antibody fragment for use according to the invention is therefore fully humanized. A humanized antibody is an antibody derived from another species, for example, a mouse, in which the constant domains of the antibody chains are replaced with human constant domains, and the amino acid sequences of the variable regions are modified to replace foreign (for example, murine) frame sequences with human frame sequences, so that, preferably, the only non-human sequences in the antibody are the CDR sequences. A humanized antibody can overcome all the problems associated with the therapeutic use of a non-human antibody in a human, including avoiding or minimizing the likelihood of patient sensitization and HAMA. Antibody humanization is generally performed using a process known as CDR grafting, although any other technique can be used. Antibody grafting is well described in Williams, D.G., et al., Antibody Engineering, vol. 1, edited by R. Kontermann and S. Dübel, chapter 21, pp. 319–339. In this process, a chimeric antibody is first generated as described above. Thus, in the context of antibody humanization, the non-human constant domain is first replaced with a human constant domain, resulting in a chimeric antibody comprising a human constant domain and a non-human variable domain. Subsequent humanization of foreign variable domains, such as murine variable domains, involves inserting the murine CDRs of each immunoglobulin chain within the FRs of the most appropriate human variable region. This is done by aligning the murine variable domains with databases of known human variable domains (e.g., IMGT or Kabat). Appropriate human structural regions are identified from the best-aligned variable domains, for example, domains with high sequence identity between the human and murine framework regions, domains containing CDRs of the same length, domains with the most similar structures (based on homology models), and so on. The murine CDR sequences are then grafted onto the main human structural sequences at the appropriate locations using recombinant DNA technology, and antibodies are then produced. Humanized A / C / ZUZ l / U IZOOZ are produced and analyzed to determine binding to the target antigen. The antibody humanization process is known and understood by the expert, who can perform the technique without further instructions. Several commercial companies also offer antibody humanization services, for example, GenScript (USA / China) or MRC Technology (UK). Humanized antibody fragments can be easily obtained from humanized antibodies, as described above. Alternatively, fully human monoclonal antibodies can be obtained in vitro without immunization by using phage presentation technology, as described in Frenzel et al. (Transfus. Medicina. Hemother. 44(5): 312-318, 2017). Therefore, the antibody or antibody fragment for use according to the invention may be derived from any species; for example, it may be a murine antibody or antibody fragment. However, it is preferred that the antibody or antibody fragment be a chimeric antibody or antibody fragment, i.e., that only the variable domains of the antibody or antibody fragment are non-human and the constant domains are all human. Optimally, the antibody or antibody fragment for use according to the invention is a human or humanized antibody or antibody fragment. The inventors developed humanized versions of Mdx001, as detailed in document no. WO 2018 / 146230. Humanized light chain variable domains were developed with the amino acid sequences established in SEQ ID NO: 9 (known as variable region L1M2) and SEO ID NO: 10 (known as variable region L2M2), containing the CDRs as described above. In one particular embodiment, the antibody or fragment thereof for use according to the invention comprises a light chain variable region comprising or consisting of the amino acid sequence indicated in SEQ ID NO: 9 or SEQ ID NO: 10, or an amino acid sequence having at least 70% (preferably at least 80, 90, 95, 96, 97, 98 or 99%) sequence identity to the same, and wherein the CDR VLCDR1-3 sequences have at least 85% sequence identity with SEQ ID NO: 1, 7 or 8 and 2-3 respectively. Humanized heavy chain variable domains were developed with the amino acid sequences indicated in SEQ ID NO: 11 (known as variable region H4) and SEQ ID NO: 12 (known as variable region H2). In one particular embodiment, the antibody or fragment thereof for use according to the invention comprises a heavy chain variable region comprising or consisting of the amino acid sequence set out in SEQ ID NO: 11 or SEQ ID NO: 12, or an amino acid sequence having at least 70% (preferably at least 80, 90, 95, 96, 97, 98, or 99%) sequence identity with the same, and wherein the CDR VHCDR1-3 sequences have at least 85% sequence identity with SEQ ID NO: 4-6, respectively. In one particular embodiment, the binding molecule specific for use according to the invention is a monoclonal antibody of the IgG1 type and comprises light chains of the kappa subtype. The L1M2 light chain is of the kappa subtype and has the amino acid sequence indicated in SEQ ID NO: 13. The H4 heavy chain has the amino acid sequence indicated in SEQ ID NO: 14. In one particular embodiment, the binding molecule specific for use according to the invention is the L1M2H4 antibody comprising the L1M2 light chain and the H4 heavy chain. Therefore, the binding molecule specific for use according to the invention may be a monoclonal antibody comprising or consisting of: (i) a light chain comprising or consisting of the amino acid sequence set out in SEQ ID NO: 13, or an amino acid sequence having at least 70% (preferably at least 80, 90, 95, 96, 97, 98 or 99%) sequence identity with the same, and wherein the CDR sequences VLCDR1-3 have at least 85% sequence identity with SEQ ID NO: 1, 7 or 8 and 2-3 respectively; and i) a heavy chain comprising or consisting of the amino acid sequence indicated in SEQ ID NO: 14, or an amino acid sequence having at least 70% (preferably at least 80, 90, 95, 96, 97, 98 or 99%) sequence identity with the same, and wherein the CDR VHCDR1-3 sequences have at least 85% sequence identity with SEQ ID NO: 4-6 respectively. Similarly, the L2M2 light chain is of subtype κ and has the amino acid sequence specified in SEQ ID NO: 15. The H2 heavy chain has the amino acid sequence specified in SEQ ID NO: 16. In one particular embodiment, the specific binding molecule for use according to the invention is the L2M2H2 antibody comprising the L2M2 light chain and the H2 heavy chain. Therefore, the specific binding molecule for use according to the invention may be a monoclonal antibody comprising: (i) a light chain comprising or consisting of the amino acid sequence indicated in SEQ ID NO: 15, or an amino acid sequence having at least 70% (preferably at least 80, 90, 95, 96, 97, 98 or 99%) sequence identity with the same, and wherein the CDR VLCDR1-3 sequences have at least 85% sequence identity with SEQ ID NO: 1, 7 or 8 and 2-3 respectively; and i) a heavy chain comprising or consisting of the amino acid sequence set out in SEQ ID NO: 16, or an amino acid sequence having at least 70% (preferably at least 80, 90, 95, 96, 97, 98 or 99%) sequence identity with the same, and wherein the CDR VHCDR1-3 sequences have at least 85% sequence identity with SEQ ID NO: 4-6 respectively. In an alternative configuration, the L1M2 light chain can be paired with the H2 heavy chain and the L2M2 light chain can be paired with the H4 heavy chain. As is known to experts, antibody chains occur naturally with signal sequences. Antibody signal sequences are amino acid sequences located at the N-terminus of the light and heavy chains, N-terminal to variable regions. Signal sequences direct antibody chains for export from the cell in which they are produced. If produced in a cell expression system, the light and heavy chains with the amino acid sequences in SEQ ID NO: 13-16 can be encoded with a signal sequence. The signal sequences for the light chains L1M2 and L2M2 are indicated in SEQ ID NO: 20; the signal sequences for the heavy chains H2 and H4 are indicated in SEQ ID NO: 21.If synthesized with a signal sequence, the L1M2 chain can therefore be synthesized with the amino acid sequence indicated in SEQ ID NO: 22; the H4 chain can be synthesized with the amino acid sequence indicated in SEQ ID NO: 23; the L2M2 chain can be synthesized with the amino acid sequence indicated in SEQ ID NO: 24 and the H2 chain can be synthesized with the amino acid sequence indicated in SEQ ID NO: 25. The nucleotide sequences encoding such sequences can be easily derived by someone skilled in the art, but the examples... A / C / ZUZ l / U IZOOZ of suitable nucleotide sequences encoding the antibody chains of SEQ ID NO: 2225, and which can be used for their synthesis, are indicated in SEQ ID NO: 26-29, respectively. As detailed above, the invention provides a specific binding molecule (as described above) for use in the treatment of cancer in a subject. Use is covered in the treatment of any type of cancer, including testicular cancer, ovarian cancer, colorectal cancer, cervical cancer, breast cancer, bladder cancer, biliary tract cancer, stomach cancer, head and neck cancer, esophageal cancer, lung cancer, pancreatic cancer, mesothelioma, lymphoma, brain tumors, and neuroblastoma. In a preferred embodiment, ovarian cancer is treated. In another preferred embodiment, breast cancer is treated. In a preferred embodiment, the breast cancer expresses one or more of an estrogen receptor (ER), a progesterone receptor (PR), and the human epidermal growth factor receptor HER2. In another embodiment, the breast cancer is triple-negative (i.e., ER- / PR- / HER2-).In another preferred embodiment, colorectal cancer is treated. In another preferred embodiment, pancreatic cancer is treated. In another preferred embodiment, lung cancer is treated. Any type of cancer can be treated according to the present invention, including carcinoma (including adenocarcinoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, etc.), sarcoma, leukemia, and lymphoma. According to the invention, cancer of any stage (or grade) can be treated, including stage I, stage II, stage III, and stage IV cancer. Both metastatic and localized (i.e., non-metastatic) cancer can be treated. In one particular embodiment of the invention, the cancer expresses Anx-A1 (it being understood that the cancer cells express Anx-A1, for example, on the cell surface). It is straightforward for a person skilled in the art to determine whether a cancer expresses Anx-A1. Anx-A1 expression can be analyzed in a cancer biopsy sample, for example, at the protein level by immunohistochemical analysis. A sample can be immunostained using an anti-Anx-A1 antibody (such as the antibodies described above that can be used according to the invention) to detect Anx-A1 expression, following standard procedures in the art. By permeabilizing a sample (for example, using a detergent, as is standard in the art), both intracellular and extracellular Anx-A1 can be detected. Alternatively, Anx-A1 expression can be analyzed at the nucleic acid level, for example, by quantitative PCR (qPCR). mRNA can be extracted from a tissue sample and reverse transcribed into DNA using standard procedures. Anx-A1 expression levels can then be determined by quantitative amplification of a target Anx-A1 sequence. Suitable qPCR techniques, such as TaqMan, are well known. In one particular modality, cancer overexpresses Anx-A1. “Overexpresses Anx-A1” means that the cancer expresses Anx-A1 at a higher level than healthy tissue from the same source. That is, cancer cells express Anx-A1 at a higher level than healthy (i.e., non-cancerous) cells from the same source. The same source is understood to be the same tissue. For example, an ovarian epithelial cell carcinoma may be considered to overexpress Anx-A1 if it expresses Anx-A1 at a higher level than healthy ovarian epithelial tissue. If cancerous tissue overexpresses Anx-A1, therefore, a quantitative comparison of Anx-A1 expression in at least two different tissues (the cancerous tissue and a healthy control tissue) is required. Any appropriate technique can be used to perform this comparison, although qPCR may be the most suitable. It would be easy for the expert to determine if a cancer overexpresses Anx-A1.In one particular modality, the difference between the Anx-A1 expression level in overexpressing cancer and healthy tissue is statistically significant. In other modalities, Anx-A1 expression increases by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% or more in cancerous tissue compared to the corresponding healthy tissue. In another embodiment of the invention, the cancer expresses Anx-A1 on its surface (i.e., Anx-A1 is expressed on the surface of the cancer cells). Expression of Anx-A1 on the surface of cancer cells means that the cells express Anx-A1, and the expressed Anx-A1 is exported and localized on the cell surface. Cell surface expression of Anx-A1 can be identified by immunohistochemistry, as described above. In particular, to analyze cell surface expression of Anx-A1, the immunohistochemical analysis is performed without cell permeabilization. This means that the antibody used to detect Anx-A1 in the tissue cannot enter the cells, and only extracellular proteins (e.g., located on the surface) can be detected.Exported AnxA1 generally adheres to cell surfaces (rather than being released into the plasma or any other extracellular space), and therefore any AnxA1 detected by immunohistochemistry of non-permeabilized cells can be considered surface AnxA1. However, by following standard protocols, tissue can be washed prior to staining to remove loose extracellular material, including proteins. The cancer treated by the present invention may be a drug-resistant cancer. That is, the cancer may be resistant to one or more chemotherapeutic agents (chemotherapeutic drugs). Drug resistance in cancer is reviewed in Housman et al. (supra). A cancer may be considered resistant to a chemotherapy drug if it is able to tolerate it, that is, if the drug is (or becomes) ineffective against the cancer. As detailed in Housman et al. (supra), cancers may become resistant to drugs through a variety of different mechanisms, including inactivation or metabolism of the drugs (or prevention of their metabolic activation), mutation or alteration of the drug target, and efflux of the drug through ABC transporters.Methods for identifying whether a cancer is drug-resistant are known in the art; see, for example, the teachings of Wang et al. (Genes & Diseases 2: 219-221, 2015) and Volm & Efferth (Front. Oncol. 5: 282, 2015), both incorporated in this description by reference. Such methods include testing the effect of a drug on a cell population ex vivo and genetic screening of cancer cells for susceptibility / resistance markers. In one particular embodiment, the cancer treated by the present invention is multidrug-resistant (MDR). MDR cancer is understood to be cancer that is resistant to more than one chemotherapy drug, in particular to more than one family of chemotherapy drugs. MDR cancer may be resistant to 2, 3, 4, or 5 or more different chemotherapy drugs, or families (or classes) of chemotherapy drugs. The term “MDR cancer” is well known in the art and is used in the present context according to its meaning in the art. MDR cancer may be resistant to all known chemotherapy drugs. Multidrug resistance (A / C / ZUZ l / U IZOOZ) can be mediated by the expression of one or more of the ABC transporters, multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP). All three have broad substrate specificity and can expel chemotherapy agents from multiple different classes of cells that express them. The examples show that the specific binding molecules for use according to the present invention are particularly effective in inhibiting the proliferation of cancer cells that are resistant to platinum-based chemotherapy. In one particular embodiment, the cancer treated according to the present invention is resistant to platinum-based chemotherapeutic agents. (Preferably, in this case, the cancer is breast cancer, colorectal cancer, ovarian cancer, lung cancer, or pancreatic cancer.) Platinum-based chemotherapy agents include cisplatin, oxaliplatin, carboplatin, and nedaplatin, all of which are approved for human use. Other known platinum-based chemotherapeutic agents include satraplatin, picoplatin, phenantriplatin, and triplatin tetranitrate. The cancer treated according to the present invention may be resistant to any or all of these agents.In one particular form, the cancer is resistant to cisplatin. Cancer cells may also or alternatively be resistant to other bifunctional alkylating agents that include nitrogen mustards (e.g., bendamustine, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, and melphalan). In an alternative or additional embodiment, the cancer treated according to the present invention may be resistant to chemotherapeutic agents such as taxanes (such as paclitaxel and docetaxel), topoisomerase inhibitors (such as topotecan), anthracyclines (such as doxorubicin and epirubicin), and nucleoside analogues (such as gemcitabine). Preferably, the chemotherapeutic agent in this embodiment is an anthracycline, for example, doxorubicin (also known as doxorubicin). In another embodiment, the cancer treated according to the present invention is resistant to hormonal therapies (for example, antiestrogen hormonal therapies, such as tamoxifen). Breast cancer, in particular, may be resistant to hormonal therapies such as tamoxifen. The cancer treated according to the present invention may be resistant to any or all of these agents.(Preferably, in this case, the cancer is breast cancer, colorectal cancer, ovarian cancer, lung cancer, or pancreatic cancer.) In one particular modality, the cancer is resistant to doxorubicin (optionally in addition to resistance to a platinum-based chemotherapeutic agent). Cancer cells can acquire resistance to platinum-based chemotherapy agents through several mechanisms, as discussed previously. For example, the production of metallothioneins and / or glutathione by the cancer can lead to the inactivation of platinum-based agents, while DNA damage induced by such agents can be repaired by active pathways of nucleotide excision repair and homologous recombination, thus reversing the action of the platinum-based agent. Other mechanisms may also play a role, and multiple non-redundant mechanisms may be necessary to make a cell resistant to platinum-based therapy. Patients identified as platinum-resistant exhibit tumor progression within 6 months of their last platinum chemotherapy treatment. The cells can be identified IZOOS are classified as platinum-resistant using the clonogenic assay to test the survival of reproductive cells after drug exposure. This identifies whether cancer cells can form tumors or colonies after drug exposure. The specific binding molecule can be administered to the subject in the form of a pharmaceutical composition. Such a composition may contain one or more pharmaceutically acceptable diluents, vehicles, or excipients. “Pharmaceutically acceptable,” as used herein, refers to ingredients that are compatible with other ingredients in the composition and physiologically acceptable to the recipient. The nature of the composition and vehicles or excipients, dosage, etc., can be routinely selected according to the choice and desired route of administration, etc. Dosages can also be routinely determined and may depend on the nature of the molecule, the patient's age, the mode of administration, etc. The pharmaceutical composition may be prepared for administration to a subject by any suitable means. Such administration may be, for example, oral, rectal, nasal, topical, vaginal, or parenteral. Oral administration, as used in this description, includes buccal and sublingual administration. Topical administration, as used in this description, includes transdermal administration. Parenteral administration, as defined in this description, includes subcutaneous, intramuscular, intravenous, intraperitoneal, and intradermal administration. Pharmaceutical compositions as described herein include liquid solutions or syrups, solid compositions such as powders, granules, tablets, or capsules, creams, ointments, and any other style of composition commonly used in the art. Pharmaceutically acceptable diluents, vehicles, and excipients suitable for use in such compositions are well known in the art. For example, suitable excipients include lactose, corn starch or derivatives thereof, stearic acid or salts thereof, vegetable oils, waxes, fats, and polyols.Suitable carriers or diluents include carboxymethylcellulose (CMC), methylcellulose, hydroxypropyl methylcellulose (HPMC), dextrose, trehalose, liposomes, polyvinyl alcohol, pharmaceutical-grade starch, mannitol, lactose, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose (and other sugars), magnesium carbonate, gelatin, oil, alcohol, detergents, and emulsifiers such as polysorbates. Stabilizing agents, wetting agents, emulsifiers, sweeteners, etc., may also be used. Liquid pharmaceutical compositions, whether solutions, suspensions, or other similar forms, may include one or more of the following: sterile diluents such as water for injection, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono- or diglycerides that may serve as solvents or suspension media, polyethylene glycols, glycerin, propylene glycol, or other solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; flakes such as acetates, citrates, or phosphates; and tonicity-adjusting agents such as dextrose. A parenteral preparation may be contained in ampoules, disposable syringes, or multidose vials made of glass or plastic. An injectable pharmaceutical composition is preferably sterile. A / C / ZUZ l / U IZOOZ Pharmaceutical compositions for use according to the present invention may be administered in any appropriate manner. The amount and frequency of administration will be determined by factors such as the patient's condition and the type and severity of the patient's disease, although appropriate doses may be determined by clinical trials. Conveniently, a subject may be provided with a specific binding molecule for use according to the invention at a daily, weekly, or monthly dose, or at an intermediate frequency, for example, a dose may be provided every 2, 3, 4, 5, or 6 days, every 2, 3, 4, 5, or 6 weeks, every 2, 3, 4, 5, or 6 months, annually, or biannually. The dose may be provided in an amount from 10 ng / kg to 100 mg / kg, for example, from 1 pg / kg to 10 mg / kg of body weight, or from 10 pg / kg to 1 mg / kg.The expert physician will be able to calculate an appropriate dose for a patient based on all relevant factors, for example, age, height, weight and the condition being treated. Preferably, the specific binding molecule or pharmaceutical composition for use according to the invention is administered to the subject in need in a therapeutically effective amount. "Therapeutically effective amount" means an amount sufficient to produce a benefit for the subject's condition. The physician / veterinarian can determine whether an amount is sufficient to produce a benefit for the subject's condition. The treatment may also include the administration of a second therapeutic agent to the subject. However, conveniently, in the uses according to the invention, the specific binding molecule is the only therapeutic molecule used in the treatment; for example, the treatment is not carried out in conjunction with other cytotoxic or immunotherapeutic agents. Cytotoxic agents are as described below. Immunotherapeutic agents are administered agents that act to induce, enhance, or suppress an immune response. In one particular embodiment, the specific binding molecule for use according to the present invention is not used to deliver a second therapeutic molecule to a target cancer. For example, in one particular embodiment, the specific binding molecule is not conjugated with (and does not provide a binding partner for) a second therapeutic molecule, such as a cytotoxic molecule or a radionuclide. When used, the second therapeutic agent may be administered within the same pharmaceutical composition as the specific binding molecule that binds to Anx-A1, or within a separate pharmaceutical composition, which may be as described above. (Therefore, in uses where a drug is manufactured, the drug may contain the specific binding molecule (or a second therapeutic agent), and such treatment may comprise the separate, sequential, or simultaneous administration of the second therapeutic agent (or specific binding molecule) with the drug.) The specific binding molecule that binds to Anx-A1 and the second therapeutic agent may be administered to the subject separately, simultaneously, or sequentially.“Separate” administration, as used herein, means that the specific binding molecule and the second therapeutic agent are administered to the subject at the same time, or at least substantially at the same time, but by different routes of administration. “Simultaneous” administration, as used herein, means that the specific binding molecule and the second therapeutic agent are administered to the subject at the same time, or at least substantially at the same time, by the same route of administration. A / C / ZUZ l / U IZOOZ “sequential,” as used herein, means that the specific binding molecule and the second therapeutic agent are administered to the subject at different times. In particular, administration of the first therapeutic agent is completed before administration of the second therapeutic agent begins. Sequential administration may be performed in which the first and second therapeutic agents are administered at intervals of 10 minutes to 30 days, for example, 1 hour to 96 hours (or 2 weeks). When administered sequentially to a subject, the first and second therapeutic agents may be administered by the same or different routes of administration. The second therapeutic agent may be a second anticancer agent, although in other modalities it may have a different activity; for example, it may be an antibacterial or antifungal agent, or any other agent useful in the patient's treatment. In one particular modality, the second therapeutic agent is a chemotherapeutic agent, specifically a cytotoxic agent. As defined herein, a chemotherapeutic agent is an administered drug that is destructive to malignant cells and tissues. A cytotoxic agent is a substance that destroys cells or prevents their multiplication.Any chemotherapy agent of any class may be used, for example, taxanes (such as paclitaxel and docetaxel), topoisomerase inhibitors (such as topotecan), anthracyclines (such as doxorubicin and epirubicin), nucleoside analogues (such as gemcitabine), platinum-based agents (such as cisplatin and carboplatin), alkylating agents (such as cyclophosphamide) and kinase inhibitors (such as imatinib) or other chemotherapeutic agents or drugs as described above. Such agents may be used in combination with the specific binding molecule for use according to the invention. In one respect, the chemotherapeutic agent may be an agent to which the cancer is resistant (when treated without the specific binding molecule for use in the invention). Alternatively, the chemotherapeutic agent may not be an agent to which the cancer is resistant (when treated without the specific binding molecule for use in the invention). The specific binding molecule for use according to the invention can also be administered to the subject in combination with radiotherapy and / or surgery. As detailed above, the present invention relates to the treatment of cancer in a subject. The treatment may be (or may be expected to be) curative, but alternatively it may be palliative (i.e., designed merely to limit, relieve, or improve the symptoms of cancer, or to prolong survival). Preferably, the size of the tumor is reduced by the treatment, or its growth rate is stabilized or slowed. A reduction of at least 10%, and preferably at least 20%, 30%, or 50% (e.g., up to 30%, 50%, 75%, or 100%) in tumor size is preferred, and similar levels of growth reduction are preferred. The subject of the invention can be any mammal, for example, a farm animal such as a cow, horse, sheep, pig, or goat; a pet such as a rabbit, cat, or dog; or a primate such as a monkey, chimpanzee, gorilla, or human. Preferably, the subject is a human. The subject can be any animal (preferably a human) that has cancer or is suspected of having cancer. Therefore, the subject is an individual in need of cancer treatment. A / C / ZUZ l / U IZOO / Therefore, the present invention may be considered to provide a method for treating cancer in a subject, comprising administering to said subject a specific binding molecule that binds to human Anx-A1. The treatment, cancer, subject, and / or specific binding molecule may be as defined above. Similarly, the present invention provides for the use of a specific binding molecule that binds to human Anx-A1 in the manufacture of a medicament for the treatment of cancer in a subject. The treatment, cancer, subject, and / or specific binding molecule may be as defined above. In another aspect, the invention provides a kit comprising a specific binding molecule that binds to human Anx-A1, as defined above, and a chemotherapeutic agent. Suitable chemotherapeutic agents are described above. The specific binding molecule and the chemotherapeutic agent may be provided in separate containers, i.e., in separate compositions, or in a single composition in a single container. Each therapeutic agent may be provided in any appropriate form, for example, in an aqueous solution or as a lyophilized powder. In another aspect, the invention provides a product comprising a specific binding molecule that binds to human Anx-A1, as defined above, and a second therapeutic agent for separate, concurrent, or sequential use in the treatment of cancer in a subject. The second therapeutic agent, cancer, and / or subject may be as defined above. In one particular embodiment, the second therapeutic agent is a chemotherapeutic agent. The specific binding molecule and the second therapeutic agent may be provided in separate containers, i.e., in separate compositions, or in a single composition in a single container. Each therapeutic agent may be provided in any appropriate form, for example, in an aqueous solution or as a lyophilized powder. All documents cited in this application are incorporated in full into this description by reference. The invention can be better understood with reference to the non-limiting figures and examples below. Figure 1 shows the effect of anti-Anx-A1 antibodies L1M2H4 and L2M2H2 on the proliferation of the MCF7 breast cancer cell line. Error bars indicate the standard error of the mean. Figure 2 shows the effect of anti-Anx-A1 antibodies L1M2H4 and L2M2H2 on the proliferation of the HCC1806 breast cancer cell line. Error bars indicate the standard error of the mean. Figure 3 shows the effect of anti-Anx-A1 antibodies L1M2H4 and L2M2H2 on the proliferation of the A2780 ovarian cancer cell line. Error bars indicate the standard error of the mean. Figure 4 shows the effect of anti-Anx-A1 antibodies L1M2H4 and L2M2H2 on the proliferation of the A2780cis ovarian cancer cell line. Error bars indicate the standard error of the mean. Figure 5 shows the effect of the anti-Anx-A1 L2M2H2 antibody on the proliferation of the A2780ADR ovarian cancer cell line. Error bars indicate the standard error of the mean. A / C / ZUZ l / U IZOOZ Figure 6 shows the effect of anti-Anx-A1 antibodies L1M2H4 and L2M2H2 on the proliferation of the MIA PaCa-2 pancreatic cancer cell line. Error bars indicate the standard error of the mean. Figure 7 shows the effect of anti-Anx-A1 antibodies L1M2H4 and L2M2H2 on the proliferation of the BxPC-3 pancreatic cancer cell line. Error bars indicate the standard error of the mean. Figure 8 shows the effect of the anti-Anx-A1 antibodies MDX-124 and ab65844 on the proliferation of the HCC1806 breast cancer cell line. The impact of a non-specific control IgG is also shown. Error bars indicate the standard error of the mean. Figure 9 shows the effect of the anti-Anx-A1 antibody MDX-124 and a nonspecific control IgG on the proliferation of the MCF7 breast cancer cell line. Error bars indicate the standard error of the mean. Figure 10 shows the effect of the anti-Anx-A1 antibody MDX-124 and a nonspecific control IgG on the proliferation of the tamoxifen-resistant breast cancer MCF-7 / TAMR7 cell line. Error bars indicate the standard error of the mean. Figure 11 shows the effect of the anti-Anx-A1 antibodies MDX-124 and ab65844 on the proliferation of the A2780 ovarian cancer cell line. The impact of a non-specific control IgG is also shown. Error bars indicate the standard error of the mean. Figure 12 shows the effect of the anti-Anx-A1 antibodies MDX-124 and ab65844 on the proliferation of the HCT116 colorectal cancer cell line. The impact of a nonspecific control IgG is also shown. Error bars indicate the standard error of the mean. Figure 13 shows the effect of the anti-Anx-A1 antibody MDX-124 and a non-specific control IgG on the proliferation of the Caco-2 colorectal cancer cell line. Error bars indicate the standard error of the mean. Figure 14 shows the effect of the anti-Anx-A1 antibody MDX-124 and a non-specific control IgG on the proliferation of the SW480 colorectal cancer cell line. Error bars indicate the standard error of the mean. Figure 15 shows the effect of the anti-Anx-A1 antibodies MDX-124 and ab65844 on the proliferation of the BxPC-3 pancreatic cancer cell line. The impact of a nonspecific control IgG is also shown. Error bars indicate the standard error of the mean. Figure 16 shows the effect of the anti-Anx-A1 antibody MDX-124 and a non-specific control IgG on the proliferation of the MIA PaCa-2 pancreatic cancer cell line. Error bars indicate the standard error of the mean. Figure 17 shows the effect of the anti-Anx-A1 antibody MDX-124 and a non-specific control IgG on the proliferation of the PANC-1 pancreatic cancer cell line. Error bars indicate the standard error of the mean. Figure 18 shows the effect of the anti-Anx-A1 antibodies MDX-124 and ab65844 on the proliferation of the COR-L23 lung cancer cell line. The impact of a non-specific control IgG is also shown. Error bars indicate the standard error of the mean. A / C / ZUZ l / U IZOO / Figure 19 shows the effect of the anti-Anx-A1 antibody MDX-124 and a non-specific control IgG on the proliferation of the adriamycin-resistant lung cancer cell line COR-L23.5010. Error bars indicate the standard error of the mean. Figure 20 shows the results of MDX-124 treatment in a mouse model of breast cancer. The figure shows the mean tumor volumes for the four treatment groups. Group 1 is the control group, which received only vehicle doses (PBS). Group 2 received 1 mg / kg of MDX-124, group 3 received 10 mg / kg of MDX-124, and group 4 received 25 mg / kg of MDX-124. The error bars indicate the standard error of the mean. Figure 21 shows the results of MDX-124 treatment in a mouse model of breast cancer. The figure shows the mean relative tumor volumes for the four treatment groups. Group 1 is the control group, which received only vehicle doses (PBS). Group 2 received 1 mg / kg of MDX-124, group 3 received 10 mg / kg of MDX-124, and group 4 received 25 mg / kg of MDX-124. The tumor volume on day 12, the day of the first treatment dose, is defined as the baseline tumor volume, i.e., a relative tumor volume of 100%. Therefore, the relative tumor volumes presented represent the volume of each tumor as a percentage of its total volume on day 12. EXAMPLES Example 1: Effect of antibodies on cell proliferation Materials The cell lines MCF7, MCF-7 / TAMR7, A2780, A2780cis, A2780ADR, HCT116, Caco-2, SW480, COR-L23, COR-L23.5010, MIA-PaCa-2, PANC-1, and BxPC-3 were obtained from the Public Health England Culture Collections. The HCC1806 cell line was obtained from the ATCC. MCF7 is a human breast adenocarcinoma cell line positive for both estrogen and progesterone receptors; MCF-7 / TAMR7 is a tamoxifen-resistant MCF7 derivative; HCC1806 is a human triple-negative breast cancer cell line; A2780 is a human ovarian carcinoma cell line; A2780cis is a cisplatin-resistant human ovarian carcinoma cell line (derived from A2780). A2780ADR is an adriamycin-resistant human ovarian carcinoma cell line (derived from A2780); MIA PaCa-2 is a human pancreatic carcinoma cell line; BxPC-3 is a human pancreatic adenocarcinoma cell line; PANC-1 is a human pancreatic epithelioid carcinoma cell line;Caco-2 is a human colorectal adenocarcinoma cell line; HCT116 is a human colorectal carcinoma cell line; SW480 is a human colorectal adenocarcinoma cell line; COR-L23 is a human large cell lung carcinoma cell line; COR-L23.5010 is an adriamycin-resistant COR-L23 derivative. The anti-Anx-A1 antibodies L1M2H4 and L2M2H2 are described in document no. WO 2018 / 146230 with sequences as described herein. The L1M2H4 antibody has a light chain with the amino acid sequence indicated in SEQ ID NO: 13 and a heavy chain with the amino acid sequence indicated in SEQ ID NO: 14; the L2M2H2 antibody has a light chain A / C / ZUZ l / U IZOO / with the amino acid sequence indicated in SEQ ID NO: 15 and a heavy chain with the amino acid sequence indicated in SEQ ID NO: 16. The anti-Anx-A1 antibody ab65844 was obtained from Abcam (UK). The antibody is a rabbit polyclonal antibody that binds to amino acids 3-24 of human Anx-A1 (SEQ ID NO: 30). This epitope sequence is part of the N-terminal region of Anx-A1, which, in the absence of Ca2+, binds within a pocket in the Anx-A1 core, as discussed previously. Methods Cell culture In the initial proliferation assays, cells were cultured in the following media: DMEM + Glutamax, 10% FBS + pen / strep (MCF7, MIA PaCa-2, HCC1806), RPMI 1640 + 2 mM L-glu, 10% FBS + pen / strep (BxPc-3, A2780). A2780cis and A2780ADR were cultured in the same growth medium as A2780 but included the respective drug at various culture stages to maintain drug resistance (i.e., cisplatin for A2780cis and doxorubicin for A2780ADR). In the additional proliferation assays, the cells were cultured in the following media under the following conditions: MCF7, HCC1806, MIA PaCa-2 and PANC-1 in DMEM containing 10% FBS, 1% pen / strep and 1% L-glutamine; MCF7 / TAMR7 in DMEM / F12 without phenol red containing 1% FBS, 1% pen / strep, 1% L-glutamine and 1% insulin; A2780, COR-L23, COR-L23.5010 and BxPC-3 in RPMI containing 10% FBS, 1% pen / estrep and 1% L-glutamine; HCT116 in McCoy 5A containing 10% FBS, 1% pen / strep and 1% L-glutamine; SW480 in L-15 containing 10% FBS, 1% pen / strep and 1% L-glutamine; Caco-2 in MEM containing 10% FBS, 1% pen / strep, 1% L-glutamine and 1% non-essential amino acid solution. Additionally, COR-L23.5010 was cultured in the presence of doxorubicin to maintain drug resistance. All cell lines were cultured at 37 °C in an atmosphere containing 5% CO2. Cell proliferation assay Cell proliferation was measured using the MTT colorimetric assay to assess cellular metabolic activity. In this assay, NADPH-dependent cellular oxidoreductase enzymes reduce the yellow tetrazolium dye, MTT, to an insoluble purple formazan product, quantified by measuring absorbance at 500–600 nm using a spectrophotometer. The amount of formazan is proportional to the level of cell proliferation, with rapidly dividing cells reducing a higher level of MTT. Assays were performed in triplicate. Cells were seeded in a final volume of 100 µL. In the initial proliferation assays, the cells were seeded at the following densities: 1 x105 / mL (MCF7, MIA PaCa-2 yn=2 of A2780cis), 2 x105 / mL (A2780, A2780ADR yn=1 of A2780cis), 5 x104 / mL (HCC1806) and 2.5 x104 / mL (BxPC-3). A / C / ZUZ l / U IZOO / In the additional proliferation assays, the cells were seeded at the following densities: MCF7, HCC1806, A2780, A2780ADR, A2780cis, COR-L23 and HCT116 at 5 x 103 cells per well; MCF7 / TAMR7, COR-L23.5010, SW480, Caco-2, MIA PaCa-2, BxPC-3 and PANC-1 at 1 x 104 per well. The cells were then cultured for 24 hours before the assay, after which cell proliferation was measured. Cell proliferation was measured following one of the following protocols: (a) 48 h culture in the absence of antibody (as a control), with 1 μM antibody (either L1M2H4 or L2M2H2) or 10 μM antibody (either L1M2H4 or L2M2H2). MTT assays were performed in the various cancer cell lines up to three separate times (initial proliferation assays); or (b) 72 h culture in the absence of antibody, or in the presence of antibody at a concentration of 2.5, 5, 7.5, or 10 pM. The antibodies used in this protocol were L1M2H4 (also referred to herein as MDX-124), the commercially available anti-Anx-A1 antibody ab65844, and a non-specific IgG for Anx-A1 as an isotype control (Thermo Fisher Scientific, USA, catalog number 31154) (additional proliferation assays). The number of cells in the control culture was defined as the baseline count for the proliferation assay. Cell counts for cultures containing an antibody were normalized to the baseline and presented as a percentage of the baseline value (referred to as “viability”). Statistical analysis of the cell proliferation assay results was performed using the Mann-Whitney U test. ELISA The ELISA was performed by The Antibody Company (UK) using standard ELISA techniques. ELISA plates were coated with 25 pg / ml of Anx-A1 N-terminal peptide or full-length Anx-A1 (corresponding to amino acids 2-26 of Anx-A1, SEQ ID NO: 31) and coating buffer (45 mM Na2CO3, pH 9.6 supplemented with 1 mM CaCE) for 17 hours at 4 °C. The plates were then blocked for 1.5 hours at room temperature with blocking buffer (1 mM CaCl2, 10 mM HEPES, 2% w / v BSA). The primary antibody (ab65844) was then applied to the plates. The antibody was applied in duplicate in quadruple dilutions made across the plate, starting at a concentration of 1 pg / ml and ending at a concentration of 2.38 x 10⁷ pg / ml. The antibody was diluted in wash buffer (10 mM HEPES, 150 mM NaCl, 0.05% (v / v) Tween-20, and 1 mM CaCE) supplemented with 0.1 g BSA. The primary antibody was applied to the plate for 1 hour at room temperature, and then the plate was washed with wash buffer. The detection antibody was then applied. A horseradish peroxidase-conjugated goat-rabbit anti-anti-rabies antibody (HRP) (Merck KGaA, Germany; catalog number AP156P) was used for detection at a dilution of 1:3000. This was applied to the ELISA plate for 1 hour at room temperature. The ELISA plate was then washed again with wash buffer. The OPD colorimetric substrate (o-phenylenediamine dihydrochloride, SigmaAldrich P4664) was then applied to the plate. The OPD solution was prepared according to the manufacturer's instructions to produce a 0.4 mg / ml OPD solution in phosphate-citrate buffer, pH 5. 40 ml of 30% H2O2 were added. A / C / ZUZ l / U IZOO / 100 ml of OPD solution was prepared immediately before use. Then, 100 ml of the resulting OPD solution was added to each well of the plate. The plate was incubated for 20 minutes in the dark at room temperature, after which 50 μL of 3 M H₂SO₄ were added to stop the reaction. Immediately after the addition of H₂SO₄, the absorbances of the plate were read at 492 nm. Results The commercially available anti-Anx-A1 antibody ab65844 was assayed by ELISA to confirm binding to its reported epitope. The assay demonstrated that antibody ab65844 binds to both full-length Anx-A1 and an N-terminal Anx-A1 peptide (data not shown), indicating that the reported epitope of amino acids 3-24 of human Anx-A1 (SEQ ID NO: 30) is correct. Initial proliferation assays The first proliferation assays carried out measured proliferation for 48 hours and compared the effect of the two antibodies L1M2H4 and L2M2H2 on the cell lines of interest, relative to incubation without any antibody (i.e., by using protocol (a) described above). The results of these proliferation assays with the breast cancer cell lines are shown in Figures 1 and 2. As shown, the antibody L1M2H4 had a statistically significant effect (p<0.001) at 10 μM, reducing the proliferation of MCF7 cells, although this was only n=1. In the HCC1806 cell line, the antibody L2M2H2 also showed a statistically significant decrease in proliferation (p<0.05) at 10 μM (n=2). The results of the proliferation assay with the ovarian cancer cell line, A2780, are shown in Figure 3. As shown, a statistically significant reduction in proliferation was observed after incubation with the L1M2H4 antibody at 10 μM (p<0.01) (n=2). In the cisplatin-resistant ovarian cancer cell line, A2780cis (Figure 4), a statistically significant reduction in proliferation was observed after incubation with the L1M2H4 antibody at 1 μM (p<0.001) and 10 μM (p<0.01) (n=2), with a statistically significant decrease in proliferation observed with the L2M2H2 antibody at 10 μM (p<0.05) (n=3). The results of proliferation assays with the adriamycin-resistant ovarian cancer cell line, A2780ADR, are shown in Figure 5. The antibody L2M2H2 had a significant effect on the proliferation of these cells. The results of the proliferation assays with the pancreatic cancer cell lines are shown in Figures 6 and 7. Additional proliferation assays The proliferation assays were repeated, and proliferation was measured for 72 hours. These assays compared the effect of an antibody of the invention (L1M2H4, also known as MDX-124) with the effect on proliferation of a non-specific IgG control and, where indicated, the commercially available anti-Anx-A1 antibody ab65844. A comparison was also made with proliferation in the absence of any antibody, and this was used as a baseline. All experiments were performed in triplicate (for MDX-124 and the IgG control, and where ab65844 was also tested, the experiments with this antibody were performed in duplicate). A / C / ¿U¿ l / U IZOO / MDX-124 was found to have a significant effect on the proliferation of the HCC1806 breast cancer cell line, causing a nearly two-thirds (63%) reduction in viability relative to baseline (Figure 8). The nonspecific IgG control had no effect on viability. Compared to the nonspecific IgG control, MDX-124 was found to cause a statistically significant reduction in HCC1806 cell viability at all concentrations tested, with a P-value of <0.001 (at an antibody concentration of 2.5 μM) or <0.0001 (at all other antibody concentrations). Notably, the polyclonal anti-Anx-A1 antibody ab65844 actually caused an increase in cell viability (and thus proliferation).In fact, at all antibody concentrations, MDX-124 was found to cause a statistically significant reduction in HCC1806 cell viability compared to ab65844, with a P-value of <0.01 (at an antibody concentration of 2.5 μM) or <0.001 (at all other antibody concentrations). This result demonstrates that MDX-124 inhibits HCC1806 cell proliferation (leading to a significant reduction in viability). However, this effect is not observed for all anti-Anx-A1 antibodies, as ab65844 has the opposite effect on cell viability. MDX-124 was also found to have significant effects on the proliferation of the MCF7 breast cancer cell line and its tamoxifen-resistant derivative (Figures 9 and 10, respectively). In both cases, the nonspecific IgG control reduced proliferation by up to 26%. At its maximum concentration, MDX-124 caused a significant 76% reduction in MCF7 cell viability, and also a significant (albeit smaller) 47% reduction in the viability of tamoxifen-resistant MCF7 cells. Compared to the nonspecific IgG control, MDX-124 was found to cause a statistically significant reduction in MCF7 cell viability at all concentrations tested, with a P-value <0.0001. MDX-124 was also found to cause statistically significant reductions in MCD7 / TAMR7 cell viability, relative to nonspecific IgG control, at concentrations of 5 and 7.5 μM (P<0.01) and 10 μM (P<0.05).These results show that MDX-124 is highly effective at inhibiting the proliferation of breast cancer cells, both triple-negative and hormone receptor-positive cell lines. The antibody is also effective against drug-resistant breast cancer. This effect is specific to MDX-124 and is not observed with all anti-Anx-A1 antibodies. Similarly, MDX-124 was found to have a significant effect on the proliferation of the A2780 ovarian cancer cell line (Figure 11). While nonspecific IgG reduces proliferation by up to 30% (at the maximum concentration), MDX-124 has more than twice the effect on proliferation (causing a 61% reduction in proliferation at the maximum concentration). Compared to the nonspecific IgG control, MDX-124 was found to cause a statistically significant reduction in A2780 cell viability at concentrations of 5 and 7.5 μM (P<0.05) and 10 μM (P<0.01). Again, this was not observed for the polyclonal anti-Anx-A1 antibody ab65844, which did not have a significant impact on proliferation. For this antibody, a slightly increased proliferation was observed at low concentrations of this antibody (up to 5 μM), while at the maximum concentration a modest reduction in proliferation of 5% was observed.In fact, at antibody concentrations of 5, 7.5 and 10 pM, MDX-124 was found to cause a statistically significant reduction in the viability of A2780 cells relative to ab65844, with a P value<0.001. MDX-124 was also found to have a substantial impact on colorectal cancer cell proliferation (Figures 12-14). Results on HCT116 cell line proliferation are shown in Figure 12. MDX-124 halves the proliferation of these cells (reducing proliferation by up to 54% at the maximum concentration). The non-specific IgG control had no real impact on proliferation, and the polyclonal anti-Anx-A1 antibody ab65844 had variable impacts at different concentrations. Compared to the non-specific IgG control, MDX-124 was found to cause a statistically significant reduction in HCT116 cell viability at all concentrations tested, with a p-value of <0.001 (at antibody concentrations of 2.5 and 7.5 μM) or <0.0001 (at antibody concentrations of 5 and 10 pM).While the data for ab65844 are slightly inconsistent, there is a clear overall trend that the antibody again promotes greater proliferation of cancer cells, and in relation to ab65844, MDX-124 was found to cause statistically significant reductions in HCT116 cell viability at antibody concentrations of 2.5 pM (P<0.01) and 5 and 10 pM (both P<0.001). No data point suggests that ab65844 causes a reduction in proliferation. The results using the Caco-2 (Figure 13) and SW480 (Figure 14) cell lines tell a similar story, in that MDX-124 causes a significant reduction in proliferation, while the nonspecific IgG control has at most a minimal impact. Compared to the nonspecific IgG control, MDX-124 was found to cause a statistically significant reduction in Caco-2 cell viability at all concentrations tested, with a P-value of <0.05 (at antibody concentrations of 2.5 and 5 pM) or <0.001 (at antibody concentrations of 7.5 and 10 pM). In relation to the non-specific IgG control, MDX-124 was found to cause a statistically significant reduction in SW480 cell viability at all concentrations tested, with a P value of <0.01 (at an antibody concentration of 2.5 pM) or <0.0001 (at all other antibody concentrations tested).These results demonstrate that MDX-124 is highly effective at inhibiting the proliferation of colorectal cancer cells. Again, this effect is specific to MDX-124 and is not observed with all anti-Anx-A1 antibodies. The impact of MDX-124 on pancreatic cancer cell lines is shown in Figures 15 and 17. The impact of MDX-124 on the BxPC-3 cell line is shown in Figure 15. Again, MDX-124 has a significant impact on cell proliferation, reducing it by half at the maximum concentration. The nonspecific IgG control had minimal impact on proliferation, while the polyclonal anti-Anx-A1 antibody ab65844 again resulted in a significant increase in proliferation. Compared to the nonspecific IgG control, MDX-124 was found to cause a statistically significant reduction in BxPC-3 cell viability at all concentrations tested, with a P-value of <0.001 (at an antibody concentration of 2.5 pM) or <0.0001 (at all other antibody concentrations tested).Regarding ab65844, MDX-124 was found to cause a statistically significant reduction in the viability of BxPC-3 cells with a P value of <0.001 at all antibody concentrations tested. A / C / ZUZ l / U IZOO / The impact of MDX-124 on the MIA PaCa-2 and PANC-1 cell lines is shown in Figures 16 and 17, respectively. In both cases, MDX-124 caused a significant reduction in proliferation of almost half, while nonspecific IgG caused much smaller reductions in viability. Compared to the nonspecific IgG control, MDX-124 was found to cause a statistically significant reduction in the viability of MIA PaCa-2 cells at antibody concentrations of 5 and 10 μM, with a P-value <0.05. Compared to the nonspecific IgG control, MDX-124 was found to cause a statistically significant reduction in the viability of PANC-1 cells at all antibody concentrations, with a P-value <0.05 (at an antibody concentration of 2.5 μM) or <0.001 (at all other antibody concentrations tested). The impact of MDX-124 on the COR-L23 and COR-L23.5010 lung cancer cell lines is shown in Figures 18 and 19, respectively. These results show that the MDX-124 antibody has a modest but negative effect on proliferation, whereas the nonspecific IgG control and the polyclonal anti-Anx-A1 antibody ab65844 showed very little effect on proliferation. Similar results were obtained with other lung cancer cell lines (data not shown). Conclusions Exposure to MDX-124 causes a significant reduction in the proliferation of breast cancer cell lines (including triple-negative, hormone receptor-positive, and drug-resistant cell lines), colorectal cancer, ovarian cancer, lung cancer, and pancreatic cancer. The impact of MDX-124 on cancer cell proliferation is antibody-specific; that is, not all antibodies against the same target (Anx-A1) have the same effect. This is demonstrated by the fact that ab65844 failed to significantly reduce proliferation in any of the cell lines tested and, in fact, increased proliferation in most cases. The non-specific IgG control also failed to produce the significant reduction in proliferation observed with MDX-124. Example 2 - Epitope Determination The HDX analysis was performed at the Natural and Medical Sciences Institute (NMI), University of Tübingen, Germany, using the L1M2H4 antibody. Sample preparation and analysis Formation of the antibody-antigen complex and hydrogen-deuterium exchange Five aliquots of antigen-antibody samples and five aliquots of antigen without antibody were prepared as follows: 0.8 pL of Anx-A1 (41 μM), 1.8 pL of antibody (38.7 pM) or HEPES buffer (HEPES 10 mM, CaCh 1 mM, 150 mM NaCl pH 7.4), respectively, 1 pL of HEPES buffer, and 0.5 pL of CaCl2 (8 mM) were mixed and incubated for 10 minutes at 20 °C. 8.5 pL of HEPES buffer was added to adjust the salt content. The antibody-antigen complex was lyophilized overnight at 0 °C and subsequently at 15 °C for 2 h to remove as much water as possible. The ten lyophilized aliquots were frozen at -20 °C until HDX exchange and LC-MS analysis. One aliquot each of the antibody-antigen complex and the antigen without antibody was solubilized in 12.5 pl of HzO, the others A / C / ZUZ l / U IZOOZ in 12.5 μI of D2O. Aliquots were incubated for the following times, so each aliquot was prepared separately just before analysis: minutes (reference H2O samples); 5, 70, 360 minutes and 24 hours (samples of deuterium exchange kinetics D2O). The exchange was inactivated by the addition of 12.5 pL of freshly prepared inactivation solution (0.8 M guanidine hydrochloride with 0.4 M TCEP in 100 mM ammonium formate buffer, pH 2.5). Peptic digestion Immediately after the addition of the quenching solution, 0.35 pL of pepsin (100 μM) was added and digestion was carried out for 2 minutes at 20 °C. Aliquots were immediately placed into autosampler vials pre-cooled to -20 °C and injected using a pre-cooled injection syringe into the LC-MS. LC-MS The resulting peptide mixture was injected and separated without pretreatment by reversed-phase HPLC (RSLC3000 LC, Thermo Scientific Dionex, Idstein, Germany). An LC column (ACQUITY UPLC BEH300 C18 1.7 pm 1x50 mm Thermo Scientific Dionex, Idstein, Germany) was used for sample separation. Blank and column wash analyses were performed within consecutive sample analyses. Chromatographic separation was achieved using a near-isocratic gradient for 31 minutes. Eluent A was water with 0.1% formic acid, and eluent B was acetonitrile with 0.1% formic acid. An optimized linear gradient of 20 minutes with varying slopes at ~0 °C was applied as follows (minute / %B): 0 / 8, 3 / 8, 11.9 / 20, 31.9 / 20, 33 / 99, 34 / 99, 35 / 8. Manual injection was performed. The injection volume was 25.35 pL using a 20 pL sample loop. The flow rate was 40 pL / min. The HPLC eluate was infused directly into a QTOF mass spectrometer (MaXis HD, Bruker). The mass spectrometer operated in positive ion mode, the spray voltage was 1.9 kV, the capillary temperature was 275 °C, and the S-Lens RF voltage was 55 V. Data analysis The data were analyzed using HDExaminer 2.40 beta 1 64-bit software (Sierra Analytics, Modest, CA, USA). Briefly, a raw dataset containing different exchange time points was examined, and for each time point, Anx-A1 was analyzed with and without the antibody. Using Anx-A1 sequence information and a list of peptide sequences with their corresponding retention and loading times, the software identified peptides with and without deuterium exchange and calculated deuterium uptake per peptide as the difference between the centroid mass of the deuterated versus the non-deuterated peptide. Using overlapping peptide information (mass shift of individual overlapping peptides), the epitope region was further narrowed manually. Results After initial data evaluation using HDExaminer, individual peptides were manually checked for statistically significant deuterium uptake. In cases of multiple overlapping peptides, the epitope region was further narrowed down using [methods not specified in the original text]. Λ / C / ZUZ l / U IZOOZ HDX data without deuterium uptake covering the N- and C-terminal portions of the peptide with deuterium uptake. The entire experiment was repeated twice. In the first experiment, a potential epitope region was identified, but statistically significant deuterium uptake was also observed in a very long peptide containing the N-terminus, which is structurally quite flexible. In the second experiment, the epitope region was confirmed, while the N-terminus showed no deuterium uptake. The underlined regions in the sequence indicate the epitope bound by the antibody: MAMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDVAALHKAIMVKGVDEATIIDILTKRN NAQRQQIKAAYLQETGKPLDETLKKALTGHLEEVVLALLKTPAQFDADELRAAMKGLGTDEDTLIEILASRTNK EIRDINRVYREELKRDLAKDITSDTSGDFRNALLSLAKGDRSEDFGVNEDLADSDARALYEAGERRKGTDVNV FNTILTTRSYPQLRRVFQKYTKYSKHDMNKVLDLELKGDIEKCLTAIVKCATSKPAFFAEKLHQAMKGVGTRH KALIRIMVSRSEIDMNDIKAFYQKMYGISLCQAILDETKGDYEKILVALCGGN The identified epitope regions are not in the Anx-A1 self-interacting region, but the peptides in the self-interacting region show a slight tendency to higher deuterium uptake in the antigen-antibody complex samples, which could be due to slight differences in local Anx-A1 concentration when two Anx-A1 molecules bind to the two antibody arms. Example 3 - In vivo anticancer activity of MDX-124 Methods Tolerability study The tolerability study was conducted by Crown Bioscience (USA). Mice were administered a dose of MDX-124 once a week for 2 weeks at 1 mg / kg, 10 mg / kg, or 29 mg / kg. The body weight of each mouse was measured daily throughout the study. A reduction in body weight was considered an indication of antibody toxicity in the mice. Murine model of breast cancer The mouse work was performed by Crown Bioscience. The mice used were 8- to 9-week-old female BALB / c mice. The breast cancer model used employed the luciferase-expressing murine breast cancer cell line 4T1-Luc. The cell line was obtained from ATCC and cultured in RPMI medium containing 10% FBS, 2 mM L-glutamine, and 2 pg / ml puromycin. The mice were shaved, and 72 hours later a transponder chip was implanted to identify individual mice. Bepanthen cream was applied immediately after shaving and then daily until tumor inoculation. Each mouse was first inoculated with 5 x 10⁴⁴ T1-Luc cells, suspended in 100 µL of PBS. Inoculation was performed on day 0 in a mammary fat pad (lower left side, second pad from the bottom) while the mice were under gas anesthesia. The skin at the inoculation site was cleaned with 70% ethanol prior to inoculation. Tumor size was measured three times per week starting on day 5, using an IVIS Spectrum In Vivo Imaging System (PerkinElmer, USA). Bioluminescent imaging was used to measure each tumor in two dimensions, using electronic calipers. Tumor volumes were estimated using the formula 0.5 (LxW2), where L = tumor length and W = tumor width. Treatment began when the mean tumor volume reached 50–60 mm3. After the first tumor measurement, Bepanthen cream was reapplied to the area around the tumor. Subsequently, Bepanthen cream was applied daily. The mice were divided into four groups of 12 mice each, with a uniform mean tumor volume across groups. Treatment was administered weekly. Of the four mouse groups, one control group received vehicle only (PBS). The three experimental groups received doses of 1, 10, or 25 mg / kg of MDX-124 in PBS. Each dose was administered intravenously in a volume of 10 mL / kg. Treatment was to be continued for a maximum of three weeks. Tumor measurements continued three times per week after the start of treatment. Mice were weighed three times per week before the start of treatment and daily thereafter. Results To verify that MDX-124 was not inherently toxic to mice, a tolerability study was conducted. Mice were administered the antibody, and their body weight was monitored. No weight loss was evident in the mice (data not shown), indicating that the antibody was not toxic to them at any of the doses tested. The anticancer effect of MDX-124 was then tested in a murine model of breast cancer. The average tumor volumes for each group of mice tested are shown in Figure 20. After inoculation of tumor cells on day 0, the first treatment dose was administered to all groups on day 12. As shown, by day 17 of the study, the mice treated with MDX-124 had significantly lower tumor volumes than the vehicle-treated control mice. The pattern of increased tumor growth in the control group continued until day 19. The lower tumor volumes observed in the MDX-124-treated groups also corresponded to the lower relative tumor volumes in these groups (see Figure 21). The tumor volume on day 12 was defined as the baseline tumor volume (i.e., 100% of the total tumor volume). By day 19, tumors in mice treated with MDX-124 had increased in size approximately 2.5-fold. Tumors in control mice had increased in size approximately 3.3-fold. This means that treatment with MDX-124 resulted in approximately a one-third reduction in tumor growth relative to the control on day 19, demonstrating the anticancer effect of the antibody. Although the antibody was administered to mice at three different concentrations (1 mg / kg, 10 mg / kg, and 25 mg / kg), each of these treatment regimens had a similar effect on tumor growth (i.e., increasing the amount of antibody administered did not appear to increase the treatment effect). A / C / ZUZ l / U IZOOZ

Claims

1. A specific binding molecule that binds to human Anx-A1 for use in the treatment of cancer in a subject, wherein: (i) said specific binding molecule comprises the complementarity-determining regions (CDRs) VLCDR1, VLCDR2, VLCDR3, VHCDR1, VHCDR2, and VHCDR3, each of said CDRs having an amino acid sequence as follows: VLCDR1 having the sequence indicated in SEQ ID NO: 1, 7, or 8; VLCDR2 having the sequence indicated in SEQ ID NO: 2; VLCDR3 having the sequence indicated in SEQ ID NO: 3; VHCDR1 having the sequence indicated in SEQ ID NO: 4; VHCDR2 having the sequence indicated in SEQ ID NO: 5; and VHCDR3 having the sequence indicated in SEQ ID NO: 6; or, for each sequence, an amino acid sequence with at least 85% sequence identity with the same; and / or (i) said specific binding molecule binds to Anx-A1 at a discontinuous epitope consisting of amino acids 197-206, 220-224 and 227-237 of SEQ ID NO:

17.

2. The specific binding molecule for use according to claim 1, wherein: V LCDR1 has the sequence indicated in SEQ ID NO: 1; V LCDR2 has the sequence indicated in SEQ ID NO: 2; V LCDR3 has the sequence indicated in SEQ ID NO: 3; V HCDR1 has the sequence indicated in SEQ ID NO: 4; V HCDR2 has the sequence indicated in SEQ ID NO: 5; and V HCDR3 has the sequence indicated in SEQ ID NO:

6.

3. The specific binding molecule for use according to claim 1 or 2, wherein said specific binding molecule is an antibody or a fragment thereof.

4. The specific binding molecule for use according to claim 3, wherein said antibody or fragment thereof is humanized.

5. The specific binding molecule for use according to claim 3 or 4, wherein said antibody is a monoclonal antibody, or said antibody fragment is a Fab, Fab' or F (abja) antibody fragment or an scFv molecule.

6. The specific binding molecule for use according to claim 5, wherein said antibody or fragment thereof comprises: i) a light chain variable region comprising the amino acid sequence indicated in SEQ ID NO: 9 or 10, or an amino acid sequence having at least 70% sequence identity with the same; and i) a heavy chain variable region comprising the amino acid sequence indicated in SEQ ID NO: 11 or 12, or an amino acid sequence having at least 70% sequence identity with the same.

7. The specific binding molecule for use according to claim 6, wherein said specific binding molecule is a monoclonal antibody comprising: i) a light chain comprising the amino acid sequence indicated in SEQ ID NO: 13, or an amino acid sequence having at least 70% sequence identity with the same; and ii) a heavy chain comprising the amino acid sequence indicated in SEQ ID NO: 14, or an amino acid sequence having at least 70% sequence identity with the same.

8. The specific binding molecule for use according to claim 6, wherein said specific binding molecule is a monoclonal antibody comprising: i) a light chain comprising the amino acid sequence indicated in SEQ ID NO: 15, or an amino acid sequence having at least 70% sequence identity with the same; and ii) a heavy chain comprising the amino acid sequence indicated in SEQ ID NO: 16, or an amino acid sequence having at least 70% sequence identity with the same.

9. The specific binding molecule for use according to any of claims 1 to 8, wherein said cancer expresses Anx-A1.

10. The specific binding molecule for use according to claim 9, wherein Anx-A1 is expressed on the surface of said cancer cells.

11. The specific binding molecule for use according to any of claims 1 to 10, wherein said cancer is resistant to one or more chemotherapeutic agents.

12. The specific binding molecule for use according to claim 11, wherein said cancer is resistant to multiple drugs.

13. The specific binding molecule for use according to claim 11 or 12, wherein said cancer is resistant to platinum-based chemotherapeutic agents.

14. The specific binding molecule for use according to any of claims 11 to 13, wherein said cancer is resistant to cisplatin, doxorubicin, and / or tamoxifen.

15. The specific binding molecule for use according to any of claims 1 to 14, wherein said treatment further comprises the administration of a second therapeutic agent to said subject. A / C / ZUZ l / U IZOOZ 16. The specific binding molecule for use according to claim 15, wherein said second therapeutic agent is a chemotherapeutic agent.

17. The specific binding molecule for use according to claim 16, wherein said chemotherapeutic agent is a cytotoxic agent.

18. The specific bonding molecule for use according to any of claims 1 to 17, wherein said subject is a human being.

19. The specific binding molecule for use according to any of claims 1 to 18, wherein said cancer is selected from breast cancer, colorectal cancer, ovarian cancer, lung cancer, and pancreatic cancer.

20. A method for treating cancer in a subject, comprising administering to said subject a specific binding molecule as defined in any of claims 1 to 8.

21. The method of claim 20, wherein said cancer, treatment and / or subject is as defined in any of claims 9 to 19.

22. The use of a specific binding molecule in the manufacture of a drug for the treatment of cancer in a subject, wherein said specific binding molecule is as defined in any of claims 1 to 8.

23. The use of claim 22, wherein said cancer, treatment and / or subject is as defined in any of claims 9 to 19.

24. A kit comprising a specific binding molecule as defined in any of claims 1 to 8 and a chemotherapeutic agent.

25. A product comprising a specific binding molecule as defined in any of claims 1 to 8 and a second therapeutic agent for separate, simultaneous or sequential use in the treatment of cancer in a subject.

26. The product for use according to claim 25, wherein said cancer, second therapeutic agent and / or subject is as defined in any of claims 9 to 14 or 16 to 19.