Monoclonal antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1a (TL1a) and its use

Abstract

FIELD: biotechnology.SUBSTANCE: antibody that specifically binds to TNF-like ligand 1A (TL1A), as well as to variants of a composition containing it, and its use for the treatment of a disease or disorder mediated by TL1A. Also a nucleic acid encoding the above antibody, a host cell and a vector containing it are disclosed, as well as a method for producing said antibody.EFFECT: antibody that specifically binds to TL1A and has high binding affinity parameters for TL1A.24 cl, 14 dwg, 18 tbl, 32 ex

Description

[0001] Field of technology to which the invention relates

[0002] The present invention relates to the field of biotechnology and medicine, namely to a monoclonal antibody or an antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A). The invention also relates to nucleic acids encoding said antibody, expression vectors, host cells and methods for their production, methods for producing antibodies of the invention, pharmaceutical compositions containing the antibody of the invention, pharmaceutical compositions containing the antibody of the invention and other therapeutically active compounds, methods for treating diseases or disorders mediated by TNF-like ligand 1A (TL1A), uses of antibodies or pharmaceutical compositions thereof for treating diseases or disorders mediated by TL1A, and uses of antibodies of the invention and other therapeutically active compounds for treating diseases or disorders mediated by TL1A.

[0003] Technology Level

[0004] Monoclonal antibodies in the form of chimeric, humanized or fully human molecules have proven their value as effective drugs for the treatment of a number of disorders and diseases.

[0005] TL1A (TNF-like ligand 1A, tumor necrosis factor-like ligand 1A), also known as TNFSF15 (TNF superfamily member 15) and VEGI (vascular endothelial growth inhibitor), is a proinflammatory cytokine of the tumor necrosis factor family with a molecular weight of approximately 61.5 kDa in the form of a biologically active soluble trimer.

[0006] TL1A is initially expressed as a transmembrane protein consisting of 251 amino acid residues with a molecular weight of approximately 28.1 kDa (https: / / www.uniprot.org / uniprotkb / O95150 / entry). The overall structure of the TL1A monomer contains three topological domains: an unstructured cytoplasmic domain (35 aa), a helical transmembrane region (21 aa), and an extracellular C-terminal region (195 aa). Under the influence of various factors, TL1A can be cleaved from the membrane by the protease ADAM17 (also known as TACE, from English "TNFα-converting enzyme"); in this case, the cleavage of the polypeptide chain occurs between the 71st alanine residue and the 72nd leucine residue, forming a monomer of 180 amino acid residues (Zhai, Y., Ni, J., Jiang, G.-W., Lu, J., Xing, L., Lincoln, C., Carter, K.C., Janat, F., Kozak, D., Xu, S., Rojas, L., Aggarwal, B.B., Ruben, S., Li, L.-Y., Gentz, R., Yu, G.-L.VEGI, a novel cytokine of the tumor necrosis factor family, is an angiogenesis inhibitor that suppresses the growth of colon carcinomas in vivo. (1999) FASEB J. 13, 181-189, doi: 10.1096 / fasebj.13.1.181).

[0007] The native TL1A monomer has a prominent hydrophobic region on its surface, which leads to the formation of a biologically active trimer (Zhan C., Yan Q., Patskovsky Yu., Li Z., Toro R., Meyer A., ​​Cheng H., Brenowitz M., Nathenson SG, Almo SC, Biochemical and Structural Characterization of the Human TL1A Ectodomain. (2009) Biochemistry: 48(32): 7636-7645, doi: 10.1021 / bi900031w).

[0008] TL1A is expressed by monocytes, macrophages, dendritic cells, synovial fibroblasts, and endothelial cells in response to stimulation by microbial antigens, immune complexes, and other factors (Hsu, H., Viney, J. The tale of TL1A in inflammation. Mucosal Immunol 4, 368-370 (2011). doi.org / 10.1038 / mi.2011.20).

[0009] The main receptor for TL1A is DR3 (death receptor 3), also known as TNFRSF25 (tumor necrosis factor receptor superfamily member 25).

[0010] The DR3 receptor is predominantly expressed on activated lymphocytes such as NK cells and T lymphocytes (Aiba Y, Nakamura M. The role of TL1A and DR3 in autoimmune and inflammatory diseases. Mediators Inflamm. 2013;2013:258164. doi: 10.1155 / 2013 / 258164. Epub 2013 Dec 21. PMID: 24453414; PMCID: PMC3880748).

[0011] TL1A interaction with DR3 can lead to both the development of an inflammatory response and apoptosis—processes that are involved in the regulation of innate and adaptive immunity. The DR3 receptor contains a so-called "death domain" (DD) in its cytoplasmic domain. After binding to TL1A, activated DR3 first interacts with the adaptor protein TRADD in the cell cytoplasm via the DD domain, after which it forms a complex with other proteins such as TRAF2 and RIP1. This receptor-associated signaling complex, also called complex I, can activate MAPK signaling pathways such as ERK, JNK, and p38, as well as the NFκB and PI3K pathways. Activation of these signaling pathways promotes proliferation and increases the inflammatory response through increased expression of anti-apoptotic proteins, cytokines, and chemokines. NFkB activation leads to the induction of the cellular inhibitors of apoptosis proteins cIAP1 / 2.Blocking complex I-mediated activation of anti-apoptotic genes or disrupting the formation and / or function of this complex results in DR3-mediated cytotoxicity. Blocking intracellular protein synthesis with the antibiotic cycloheximide prevents NFκB activation, which in turn leads to the inactivation of apoptosis inhibitor proteins, the dissociation of RIPK1 from complex I, and the interaction of RIPK1 with the adapter protein FADD and caspase 8. Subsequently, the initiator caspase 8 activates a cascade of effector caspases 3 and 7, leading to cell apoptosis. Another variant of cell death involves the proteins FADD, RIP3, RIP1, and the effector protein MLKL, forming an intracellular complex called the necrosome. Caspase 8 activity is blocked in this process. This triggers necroptosis, a form of programmed cell death, accompanied by a strong immune response.In lymphocytes, TL1A interaction with DR3 has been shown to preferentially activate proinflammatory pathways rather than apoptosis (Bittner S, Ehrenschwender M. Multifaceted death receptor 3 signaling-promoting survival and triggering death. FEBS Lett. 2017 Sep;591(17):2543-2555. doi: 10.1002 / 1873-3468.12747. Epub 2017 Jul 20. PMID: 28686297; L. Wen, L. Zhuang, X. Luo, and P. Wei, “TL1A-induced NF-κB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells,” The Journal of Biological Chemistry, vol. 278, no. 40, pp. 39251-39258, 2003; Bamias G, Jia LG, Cominelli F. The tumor necrosis factor-like cytokine 1A / death receptor 3 cytokine system in intestinal inflammation. Curr Opin Gastroenterol. 2013 Nov;29(6):597-602. doi: 10.1097 / MOG.0b013e328365d3a2. PMID: 24100723).

[0012] TL1A is the only known DR3 ligand, but it also binds to the soluble "decoy receptor" DcR3, also known as TNFRSF6B (TNF receptor superfamily member 6B). This interaction does not lead to further biological effects but rather serves to maintain TL1A concentrations in the blood at the required level. DcR3, in turn, is a secreted receptor capable of binding and neutralizing three TNF family ligands: FasL, LIGHT, and TL1A.In studies comparing lamina propria lymphocytes from patients with chronic intestinal inflammation with lymphocytes from healthy volunteers from the control group, DcR3 was shown to be elevated in areas of active intestinal inflammation, as well as in the blood of patients, which is likely a secondary compensatory mechanism in response to increased expression of proinflammatory TL1A (Xu WD, Li R, Huang AF. Role of TL1A in Inflammatory Autoimmune Diseases: A Comprehensive Review. Front Immunol. 2022 Jul 14; 13:891328. doi: 10.3389 / fimmu.2022.891328; Bamias G, Jia LG, Cominelli F. The tumor necrosis factor-like cytokine 1A / death receptor 3 cytokine system in intestinal inflammation. Curr Opin Gastroenterol. 2013 Nov; 29(6):597-602. doi: 10.1097 / MOG.0b013e328365d3a2. PMID: 24100723;Zhan C, Patskovsky Y, Yan Q, Li Z, Ramagopal U, Cheng H, Brenowitz M, Hui X, Nathenson SG, Almo SC. Decoy strategies: the structure of TL1A:DcR3 complex. Structure.2011 Feb 9; 19(2):162-71. doi: 10.1016 / j.str.2010.12.004. PMID: 21300286;Spyros I. Siakavellas, Giorgos Bamias, Tumor Necrosis Factor-like Cytokine TL1A and Its Receptors DR3 and DcR3: Important New Factors in Mucosal Homeostasis and Inflammation, Inflammatory Bowel Diseases, Volume 21, Issue 10, 1 October 2015, Pages 2441-2452, https: / / doi.org / 10.1097 / MIB.0000000000000492).

[0013] In intestinal homeostasis, the TL1A-DR3 signaling pathway plays a protective role, being part of both innate and adaptive immunity. Disruption of the intestinal epithelial mucosal barrier function leads to the penetration of microorganisms into adjacent tissues. Their structural components stimulate antigen-presenting cells (APCs) via Toll-like receptors or Fcγ receptors, thereby increasing TL1A expression, leading to CD4 expansion. + and CD8 +T lymphocytes, their differentiation, and TCR-MHCII-independent production of inflammatory cytokines such as IFNγ, IL-6, TNFα, GM-CSF, IL-5, IL-13, and IL-22. TL1A also co-stimulates NK cells and innate lymphoid cells (ILCs). TL1A interaction with Tregs expressing DR3 constitutively leads to their proliferation, but at the same time inhibits their suppressor function (Valatas V, Kolios G, Bamias G. TL1A (TNFSF15) and DR3 (TNFRSF25): A Co-stimulatory System of Cytokines With Diverse Functions in Gut Mucosal Immunity. Front Immunol. 2019 Mar 27;10:583. doi: 10.3389 / fimmu.2019.00583. PMID: 30972074;Spyros I. Siakavellas, Giorgos Bamias, Tumor Necrosis Factor-like Cytokine TL1A and Its Receptors DR3 and DcR3: Important New Factors in Mucosal Homeostasis and Inflammation, Inflammatory Bowel Diseases, Volume 21, Issue 10, 1 October 2015, Pages 2441–2452, https: / / doi.org / 10.1097 / MIB.0000000000000492;Wallace KL, Zheng LB, Kanazawa Y, Shih DQ. Immunopathology of inflammatory bowel disease.World J Gastroenterol. 2014 Jan 7;20(1):6-21. doi: 10.3748 / wjg.v20.i1.6;Holmkvist P, Roepstorff K, Uronen-Hansson H, Sandén C, Gudjonsson S, Patschan O, Grip O, Marsal J, Schmidtchen A, Hornum L, Erjefält JS, Håkansson K, Agace WW. A major population of mucosal memory CD4+ T cells, coexpressing IL-18Rαand DR3, display innate lymphocyte functionality. Mucosal Immunol. 2015 May;8(3):545-58. doi: 10.1038 / mi.2014.87. Epub 2014 Oct 1. PMID: 25269704; PMCID: PMC4424383).

[0014] The TL1A-DR3 signaling pathway is a mediator of several autoimmune diseases, including chronic inflammatory bowel diseases (IBDs), such as Crohn's disease (CD) and ulcerative colitis (UC). IBD development is thought to be driven by a combination of genetic and environmental factors, leading to an excessive, abnormal immune response against commensal microflora in genetically susceptible individuals. The pathogenesis of chronic intestinal inflammation is partially attributed to TL1A overexpression in APCs in the lamina propria region in response to stimulation by intestinal microflora in patients with Crohn's disease and ulcerative colitis, but not in the intestinal tissues of healthy donors. The level of TL1A expression in patients with Crohn's disease correlated with the intensity of inflammation, especially in areas with severe inflammation (Giorgos Bamias, Charles Martin III, Marco Marini. Expression, Localization, and Functional Activity of TL1A, a Novel Th1-Polarizing Cytokine in Inflammatory Bowel Disease.J Immunol November 1, 2003, 171 (9) 4868-4874; doi.org / 10.4049 / jimmunol.171.9.4868).

[0015] TL1A, through interaction with DR3, activates effector T lymphocytes, primarily Th1, Th2, Th9, Th17, and all ILC groups. This leads to the production of cytokines and chemokines by immune cells, which promote the migration of circulating leukocytes and monocytes from the systemic circulation, as well as the development and maintenance of chronic inflammation in the intestine. TL1A, as a costimulator of IL-12 and IL-18, induces Th1 to produce IFNγ and TNFα, which lead to IFNγ-mediated activation of tissue macrophages and additional expression of TNFα by the latter. These cytokines trigger apoptosis in intestinal epithelial cells and the differentiation of stem cells into myofibroblasts. Activated myofibroblasts are a source of matrix metalloproteinases, enzymes capable of degrading extracellular matrix proteins, causing tissue degradation. Th2 cells produce IL-13, which activates NK cells, increases intestinal permeability, and induces apoptosis in intestinal epithelial cells.Th17 secrete IL-17A, IL-17F, which are responsible for the migration of neutrophils to the site of inflammation and promote the proliferation of myofibroblasts and collagen deposition, which leads to the development of fibrosis (Valatas V, Kolios G, Bamias G. TL1A (TNFSF15) and DR3 (TNFRSF25): A Co-stimulatory System of Cytokines With Diverse Functions in Gut Mucosal Immunity. Front Immunol. 2019 Mar 27; 10:583. doi: 10.3389 / fimmu.2019.00583. PMID: 30972074;Spyros I. Siakavellas, Giorgos Bamias, Tumor Necrosis Factor-like Cytokine TL1A and Its Receptors DR3 and DcR3: Important New Factors in Mucosal Homeostasis and Inflammation, Inflammatory Bowel Diseases, Volume 21, Issue 10, 1 October 2015, Pages 2441-2452, https: / / doi.org / 10.1097 / MIB.0000000000000492;Wallace KL, Zheng LB, Kanazawa Y, Shih DQ. Immunopathology of inflammatory bowel disease. World J Gastroenterol. 2014 Jan 7; 20(1):6-21. doi: 10.3748 / wjg.v20.i1.6;Kokkotis G, Bamias G. TL1A as a therapeutic target in inflammatory bowel disease. Expert Rev Clin Immunol.2022 Jun; 18(6):551-555. doi: 10.1080 / 1744666X.2022.2074401. Epub 2022 May 12. PMID: 35507314;Baumgart DC, Sandborn WJ. Crohn's disease. Lancet. 2012 Nov 3; 380(9853):1590-605. doi: 10.1016 / S0140-6736(12)60026-9. Epub 2012 Aug 20. Erratum in: Lancet. 2013 Jan 19; 381(9862):204. PMID: 22914295;Chen L, Ruan G, Cheng Y, Yi A, Chen D, Wei Y. The role of Th17 cells in inflammatory bowel disease and the research progress. Front Immunol. 2023 Jan 9;13:1055914. doi: 10.3389 / fimmu.2022.1055914. PMID: 36700221; PMCID: PMC9870314;Yamada A, Arakaki R, Saito M, Tsunematsu T, Kudo Y, Ishimaru N. Role of regulatory T cell in the pathogenesis of inflammatory bowel disease. World J Gastroenterol. 2016 Feb 21; 22(7):2195-205. doi: 10.3748 / wjg.v22.i7.2195. PMID: 26900284; PMCID: PMC4734996).

[0016] Thus, it is TL1A, and not TNFα or other proinflammatory cytokine, that is the initial upstream cytokine in the pathogenesis of IBD. TL1A co-stimulates T lymphocytes and leads to the secretion of a wide range of proinflammatory cytokines, including TNFα, but not vice versa, which may explain the relatively low efficacy of anti-TNFα drugs in the treatment of IBD (Holmkvist P, Roepstorff K, Uronen-Hansson H, et al. A major population of mucosal memory CD4+ T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality. Mucosal Immunol. 2015; 8(3):545-558. doi:10.1038 / mi.2014.87;Jin S, Chin J, Seeber S, et al. TL1A / TNFSF15 directly induces proinflammatory cytokines, including TNFα, from CD3+CD161+ T cells to exacerbate gut inflammation. Mucosal Immunol. 2013; 6(5):886-899. doi:10.1038 / mi.2012.124).

[0017] Blockade of the TL1A-DR3 inflammatory signaling pathway can be used to treat a wide range of inflammatory and / or autoimmune diseases, not limited to Crohn's disease and ulcerative colitis. Thus, a similar approach can be used in the treatment of bronchial asthma, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, ankylosing spondylitis, intestinal fibrosis, liver fibrosis, fibrotic lung diseases, including interstitial lung disease associated with systemic sclerosis (Adam W. Clarke, Lynn Poulton, Doris Shim, David Mabon, Danyal Butt, Matthew Pollard, Vanya Pande, Jean Husten, Jacquelyn Lyons, Chen Tian & Anthony G. Doyle (2018) An anti-TL1A antibody for the treatment of asthma and inflammatory bowel disease, mAbs, 10:4, 664-677, DOI: 10.1080 / 19420862.2018.1440164; Rana Herro, Haruka Miki, Gurupreet S. Sethi, David Mills, Amit Kumar Mehta, Xinh-Xinh Nguyen, Carol Feghali-Bostwick, Marina Miller, David H.Broide, Rachel Soloff, Michael Croft; TL1A Promotes Lung Tissue Fibrosis and Airway Remodeling. J Immunol 1 November 2020; 205 (9): 2414-2422. https: / / doi.org / 10.4049 / jimmunol.2000665;Jacob, N., Kumagai, K., Abraham, J.P. et al. Direct signaling of TL1A-DR3 on fibroblasts induces intestinal fibrosis in vivo. Sci Rep 10, 18189 (2020). https: / / doi.org / 10.1038 / s41598-020-75168-5; Hachulla, E., Agard, C., Allanore, Y. et al. French recommendations for the management of systemic sclerosis. Orphanet J Rare Dis 16 (Suppl 2), 322 (2021). https: / / doi.org / 10.1186 / s13023-021-01844-y;Song, YJ., Choi, I.A., Meylan, F. et al. Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF. Arthritis Res Ther 22, 106 (2020). https: / / doi.org / 10.1186 / s13075-020-02198-9;Li L, Fu L, Zhou P, Lu Y, Zhang L, Wang W, Nie J, Zhang D, Liu Y, Wu B, Chen T. Effects of tumor necrosis factor-like ligand 1A (TL1A) on imiquimod-induced psoriasiform skin inflammation in mice.Arch Dermatol Res. 2020 Sep; 312(7):481-490. doi:10.1007 / s00403-019-02030-8. Epub 2020 Jan 18. PMID: 31953572).

[0018] Patent documents WO2015073580, WO2017196663 describe antibodies to TL1A.

[0019] In connection with the above, the creation of antibodies that specifically bind to TL1A is relevant.

[0020] Disclosure of the essence of the invention (detailed description of the invention)

[0021] The authors of this group of inventions developed antibodies that specifically bind to TL1A and exhibit high binding affinity for TL1A. The antibodies according to the invention are effective inhibitors of activity mediated by the DR3 receptor (TNFRSF25). The antibodies according to the invention have a high affinity for the FcRn receptor, increasing the drug's circulation time in patients' blood. Furthermore, the antibodies according to the invention are stable in human serum and resistant to elevated temperatures. The antibodies according to the invention inhibit the release of interferon gamma in the presence of IL-12 and IL-18, and various proinflammatory cytokines in the presence of IL-12, IL-18, and IL-15. The antibodies of the invention do not cause direct and cross-link apoptosis of CHO-tmTL1A cells expressing the membrane-associated form of TL1A and do not lead to the development of cytokine release syndrome.

[0022] Definitions and General Methods

[0023] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those skilled in the art.

[0024] Furthermore, unless the context otherwise requires, singular terms include plural terms, and plural terms include singular terms. The generally used classification and methods of cell culture, molecular biology, immunology, microbiology, genetics, analytical chemistry, organic synthetic chemistry, medicinal and pharmaceutical chemistry, as well as hybridization and protein and nucleic acid chemistry described herein are well known to those skilled in the art and are widely used in this field. Enzymatic reactions and purification methods are carried out in accordance with the manufacturer's instructions, as commonly practiced in the art, or as described herein.

[0025] The term “KD” in this description refers to the affinity constant (or equilibrium dissociation constant), which is obtained from the ratio of Kd to Ka (i.e., Kd / Ka), and is expressed as a molar concentration (M).

[0026] "Binding affinity" typically refers to the strength of the combined non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise specified, "binding affinity" refers to the intrinsic (characteristic, true) binding affinity, which reflects the 1:1 interaction between the members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y can typically be represented by the equilibrium dissociation constant (KD). It is desirable that the KD value is approximately 200 nM, 150 nM, 100 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 8 nM, 6 nM, 4 nM, 2 nM, 1 nM or less. The affinity can be measured by conventional methods known in the art, including the methods described herein.Low-affinity antibodies typically bind to antigen slowly and tend to dissociate easily, whereas high-affinity antibodies typically bind to antigen more quickly and tend to remain bound longer. Various methods for measuring binding affinity are known in the art, and any of these methods can be used for the purposes of the present invention.

[0027] The term "Kd," "koff," or "kdis" refers to the dissociation rate constant of a specific interaction between a binding molecule and an antigen. The dissociation rate constant koff can be measured using biolayer interferometry, such as with the Octet™ system, and surface plasmon resonance, such as with the Biacore™ system.

[0028] The term "Ka", "kon" or "on-rate" refers to the association rate constant.

[0029] The term "R 2 » refers to the coefficient of determination.

[0030] The term “Response” refers to the binding signal of an antibody to an antigen.

[0031] The term "in vitro" refers to a biological object, biological process, or biological reaction outside the body, simulated under artificial conditions. For example, in vitro cell growth should be understood as cell growth in an environment outside the body, such as a test tube, culture flask, or microplate.

[0032] Term ED 50 (EC 50 ) (50% effective dose / concentration, half-maximal effective concentration) refers to the drug concentrations at which 50% of the measurable biological effect is achieved (may include cytotoxicity).

[0033] The terms "anti-TL1A antibody", "antibody to TL1A", "antibody that specifically binds to TL1A" are used interchangeably in the context of the present application and refer to an antibody that specifically binds to TL1A.

[0034] Antigen is a protein with which the antibody(ies) being tested specifically binds.

[0035] Genetic construct (plasmid) is an artificially created circular DNA molecule containing various elements necessary for the expression of target genes and replication within organisms.

[0036] Proliferation is cell division.

[0037] Reporter cell line - a cell line carrying a reporter gene for assessing intracellular signaling.

[0038] Transient production - production of protein from a temporary producer.

[0039] Transfection is a DNA delivery method in which foreign DNA molecules are delivered into a cell using chemical or physical means: as part of liposomal complexes, as a result of electroporation, etc.

[0040] Chromatography is a method for separating and analyzing mixtures of substances, as well as studying the physicochemical properties of substances. It is based on the distribution of substances between two phases: the stationary phase (a solid phase or liquid bound to an inert carrier) and the mobile phase (a gas or liquid phase, the eluent).

[0041] Cytokines are small proteins that regulate the immune response.

[0042] ADCC - antibody-dependent cellular cytotoxicity.

[0043] ADCP - antibody-dependent cellular phagocytosis.

[0044] C1q - protein complex of the complement system C1q (complement component 1q).

[0045] CD16 - cluster of differentiation 16, also FcγRIIIa, has 2 isoforms: V158 (or V176) high-affinity receptor, F158 (or F176) low-affinity receptor.

[0046] CD32 - cluster of differentiation 32 (cluster of differentiation 32), also FcγRIIa, has 2 isoforms: H131 high-affinity receptor, R131 low-affinity receptor

[0047] CD4 - cluster differentiation 4.

[0048] CHO - Chinese hamster ovary cell line.

[0049] DcR3 is a decoy receptor 3 (DR3) and tumor necrosis factor receptor superfamily member 6B (TNFRSF6B).

[0050] DR3 - death receptor 3 (DR3) and tumor necrosis factor receptor superfamily member 25 (TNFRSF25).

[0051] Fc - constant fragment region of the antibody (crystallizable fragment).

[0052] FcRn is a neonatal receptor for the Fc region of human IgG that protects antibodies from destruction in lysosomes / endosomes of cells after uptake.

[0053] FcγRs - receptors for the Fc fragment of immunoglobulin G (receptors for the Fc fragment of IgG).

[0054] HRP - Horseradish peroxidase.

[0055] LIGHT is a protein, member 14 of the tumor necrosis factor-alpha superfamily (TNF superfamily member 14, TNFSF14).

[0056] Luc - luciferase.

[0057] NFAT - nuclear factor of activated T-cells.

[0058] PBMC - peripheral blood mononuclear cells.

[0059] TL1A - TNF-like ligand A1 (TNF-like ligand 1A), also member 15 of the tumor necrosis factor-alpha superfamily (TNF superfamily member 15, TNFSF15), and vascular endothelial growth inhibitor (VEGI-251). The term TL1A refers to any naturally occurring form of TL1A, whether monomeric or multimeric, including dimers, trimers, etc., which can originate from any suitable organism. The term TL1A as used herein refers to TL1A (TNFSF15) from any mammal, such as humans, rats, mice, ferrets, pigs, rabbits, and non-human primates.

[0060] tmTL1A - membrane-associated form of TL1A (membrane-bound or transmembrane form TL1A).

[0061] TNBS - picryl sulfonic acid (2,4,6-trinitrobenzenesulfonic acid).

[0062] Tris-HCl is a buffer solution containing tris(hydroxymethyl)aminomethane and hydrochloric acid (HCl).

[0063] HPLC - high performance liquid chromatography.

[0064] VEF - vertical electrophoresis.

[0065] IL-12 - interleukin 12 (interleukin-12).

[0066] IL-13 - interleukin 13 (interleukin-13).

[0067] IL-15 - interleukin 15 (interleukin-15).

[0068] IL-18 - interleukin 18 (interleukin-18).

[0069] IL-5 - interleukin 5 (interleukin-5).

[0070] IL-6 - interleukin 6 (interleukin-6).

[0071] ELISA - enzyme-linked immunosorbent assay.

[0072] TNFα - tumor necrosis factor alpha.

[0073] In the present description and in the following claims, unless the context otherwise requires, the words "include" and "comprise" or variations thereof such as "includes," "including," "comprises," or "containing" are to be understood as including the stated whole or group of wholes, but not excluding any other whole or group of wholes.

[0074] Antibody

[0075] The present invention relates to a monoclonal antibody or an antigen-binding fragment thereof that specifically binds to TL1A.

[0076] The term “monoclonal antibody” or “mAb” refers to an antibody that is synthesized and secreted by a distinct clonal population of cells.

[0077] The antibody of the invention is a recombinant antibody.

[0078] The term "recombinant antibody" means an antibody that is expressed in a cell or cell line containing a nucleotide sequence(s) that encodes the antibody, wherein said nucleotide sequence(s) is(are) not associated with the cell in nature.

[0079] In one aspect, the present invention relates to a monoclonal antibody or antigen-binding fragment thereof that specifically binds to TL1A, comprising:

[0080] (a) a light chain variable domain comprising:

[0081] (i) CDR1 with the amino acid sequence RASQX1X2SX3X4X5LX6, where

[0082] X1=S or G;

[0083] X2=I or V;

[0084] X3=S or G;

[0085] X4= T, S or 0;

[0086] X5= Y or W;

[0087] X6=N or A;

[0088] (ii) CDR2 with amino acid sequence X7ASX8X9X 10 X 11 , Where

[0089] X7=G, A or K;

[0090] X8=S, T or R;

[0091] X9=L or R;

[0092] X 10 =Q or A;

[0093] X 11 =S, T or A; and

[0094] (iii) CDR3 with amino acid sequence QQX 12 X 13 SX 14 X 15 X 16 X 17 X 18 X 19 , Where

[0095] X 12 = A, Y or 0;

[0096] X 13 = N, G or 0;

[0097] X 14 =Y, F or S;

[0098] X 15 =R, S, P or G;

[0099] X 16 =T, I, L or P;

[0100] X 17 =L, P, T or S;

[0101] X 18 =T, P, I or 0;

[0102] X 19 =D, T or 0;

[0103] and

[0104] (b) a heavy chain variable domain comprising:

[0105] (i) CDR1 with amino acid sequence X 20 YX 21 X 22 S, where

[0106] X 20 =D, S or G;

[0107] X21 =Y, A or D;

[0108] X 22 =W or M;

[0109] (ii) CDR2 with amino acid sequence X 23 IX 24 X 25 X 26 GX 27 X 28 TX 29 YX 30 X 31 SX 32 KX 33 , Where

[0110] X 23 =E, T or A;

[0111] X 24 =N, Q, A, G, I, L, M, S, T, V or R;

[0112] X 25 =H, T or S;

[0113] X 26 =S or G;

[0114] X 27 =N, R or G;

[0115] X 28 =0 or S;

[0116] X 29 =D, T, Y or S;

[0117] X 30 =N or A;

[0118] X 31 =P or D;

[0119] X 32 =L, V or M;

[0120] X 33 =S or G; and

[0121] (iii) CDR3 with amino acid sequence X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X43 YX 44 X 45 X 46 X 47 X 48 , Where

[0122] X 34 = G, S or 0;

[0123] X 35 =G, R or 0;

[0124] X 36 =F, G or 0;

[0125] X 37 =S, T, R or 0;

[0126] X 38 =G, S or L;

[0127] X 39 =S or W;

[0128] X 40 =P, V, W or T;

[0129] X 41 =N, P, G or D;

[0130] X 42 =Y, E, S or F;

[0131] X 43 =Y, I or D;

[0132] X 44 =A, E, R or 0;

[0133] X 45 =M, Y, D or 0;

[0134] X 46 = D or 0;

[0135] X 47 =V, Y, E or 0;

[0136] X 48 = Y or 0.

[0137] In some embodiments of the invention, the monoclonal antibody or antigen-binding fragment thereof comprises:

[0138] (a) a light heavy chain variable domain comprising:

[0139] (i) CDR1 with the amino acid sequence of SEQ ID NO: 1;

[0140] (ii) CDR2 with the amino acid sequence of SEQ ID NO: 6; and

[0141] (iii) CDR3 with the amino acid sequence of SEQ ID NO: 11; and

[0142] (b) a heavy chain variable domain comprising:

[0143] (i) CDR1 with the amino acid sequence of SEQ ID NO: 16;

[0144] (ii) CDR2 with the amino acid sequence EIX1HSGNTDYNPSLKS, where

[0145] X1=N, Q, A, G, I, L, M, S, T or V; And

[0146] (iii) CDR3 with the amino acid sequence of SEQ ID NO: 33.

[0147] In one embodiment of the invention, the antibody of the invention is an isolated antibody.

[0148] The term "isolated" used to describe various antibodies in this specification means an antibody that has been identified and separated and / or recovered from the cell or cell culture in which it is expressed. Contaminants (impurities) from the natural environment are materials that typically interfere with the diagnostic or therapeutic use of the polypeptide and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. Typically, an isolated polypeptide is obtained through at least one purification step.

[0149] The term "antibody" or "immunoglobulin" (Ig), as used herein, includes whole antibodies. The term "antibody" refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant domain can be CK (light chain kappa constant domain) or CL (light chain lambda constant domain). Preferably, the light chain is a light kappa (κ) chain, and the light chain constant domain is preferably CK.

[0150] The antibodies of the invention may be antibodies of any class (e.g., IgA, IgD, IgE, IgG and IgM, preferably IgG) or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2, preferably IgG1).

[0151] The VH and VL regions can be further subdivided into regions of hypervariability, called complementarity-determining regions (CDRs), located between more conserved regions, called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged from N-terminus to C-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains form the binding domain that interacts with the antigen.

[0152] The constant regions of antibodies can mediate the binding of immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system.

[0153] The term "antigen-binding portion" of an antibody or "antigen-binding fragment," as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments included within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) an F(ab')2 fragment, a divalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; (iii) an Fd fragment, consisting of the VH and CH1 domains; (iv) the Fv fragment, which consists of the VL and VH domains in a single arm of the antibody, (v) the dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of the VH / VHH domain.Furthermore, the two regions of the Fv fragment, VL and VH, are encoded by different genes and can be joined recombinantly using a synthetic linker that allows them to be produced as a single protein chain in which the VL and VH regions are paired to form monovalent molecules (known as single-chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423–426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879–5883). Such single-chain molecules are also intended to be included within the term "antigen-binding portion" of an antibody. Such antibody fragments are produced using conventional methods known to those skilled in the art and are screened in the same manner as intact antibodies.

[0154] “Kabat nomenclature” or “Kabat nomenclature” is used in this application to refer to a system of numbering amino acid residues that are more variable (i.e., hypervariable) than the rest of the amino acid residues in the variable regions of the heavy and light chains of an antibody (Kabat et al. Ann. NY Acad. Sci., 190:382-93 (1971); Kabat et al. Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242 (1991)).

[0155] The antibody of the present invention, "which specifically binds" to a target antigen, is an antibody that binds the antigen with sufficient affinity such that the antibody can be used as a diagnostic and / or therapeutic agent by targeting a protein or a cell or tissue expressing the antigen.

[0156] The term "specifically binds to" a particular polypeptide or epitope on a particular target polypeptide may be exemplified by a molecule having a KD to the target of at least about 200 nM, or at least about 150 nM, or at least about 100 nM, or at least about 60 nM, or at least about 50 nM, or at least about 40 nM, or at least about 30 nM, or at least about 20 nM, or at least about 10 nM, or at least about 8 nM, or at least about 6 nM, or at least about 4 nM, or at least about 2 nM, or at least about 1 nM, or at least about 100 pM or below.

[0157] In one embodiment of the invention, the term "specific binding" refers to binding in which a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or epitope on the polypeptide.

[0158] In some embodiments of the invention, a monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain that comprises a CDR1 with an amino acid sequence selected from the group: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5.

[0159] In some embodiments of the invention, a monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain that comprises a CDR2 with an amino acid sequence selected from the group: SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 10.

[0160] In some embodiments of the invention, a monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain that comprises a CDR3 with an amino acid sequence selected from the group: SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, or SEQ ID NO: 15.

[0161] In some embodiments of the invention, a monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain that comprises:

[0162] (i) CDR1 with an amino acid sequence selected from the group: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4 or SEQ ID NO: 5;

[0163] (ii) CDR2 with an amino acid sequence selected from the group: SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 10; and

[0164] (iii) CDR3 with an amino acid sequence selected from the group: SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14 or SEQ ID NO: 15.

[0165] In some embodiments of the invention, the monoclonal antibody or antigen-binding fragment thereof comprises:

[0166] (i) a light chain variable domain comprising:

[0167] CDR1 with the amino acid sequence SEQ ID NO: 1,

[0168] CDR2 with the amino acid sequence of SEQ ID NO: 6 and

[0169] CDR3 with the amino acid sequence of SEQ ID NO: 11; or

[0170] (ii) a light chain variable domain comprising:

[0171] CDR1 with the amino acid sequence SEQ ID NO: 2,

[0172] CDR2 with the amino acid sequence of SEQ ID NO: 7 and

[0173] CDR3 with the amino acid sequence of SEQ ID NO: 12; or

[0174] (iii) a light chain variable domain comprising:

[0175] CDR1 with the amino acid sequence SEQ ID NO: 3,

[0176] CDR2 with the amino acid sequence of SEQ ID NO: 8 and

[0177] CDR3 with the amino acid sequence of SEQ ID NO: 13; or

[0178] (iv) a light chain variable domain comprising:

[0179] CDR1 with the amino acid sequence of SEQ ID NO: 4,

[0180] CDR2 with the amino acid sequence of SEQ ID NO: 9 and

[0181] CDR3 with the amino acid sequence of SEQ ID NO: 14 or

[0182] (v) light chain variable domain comprising:

[0183] CDR1 with the amino acid sequence of SEQ ID NO: 5,

[0184] CDR2 with the amino acid sequence of SEQ ID NO: 10 and

[0185] CDR3 with the amino acid sequence SEQ ID NO: 15.

[0186] In some embodiments of the invention, a monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain that comprises a CDR1 with an amino acid sequence selected from the group: SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18 or SEQ ID NO: 19.

[0187] In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain that comprises a CDR2 with an amino acid sequence selected from the group of: SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, or SEQ ID NO: 32.

[0188] In some embodiments of the invention, a monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain that comprises a CDR3 with an amino acid sequence selected from the group: SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, or SEQ ID NO: 36.

[0189] In some embodiments of the invention, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain that comprises:

[0190] (i) CDR1 with an amino acid sequence selected from the group: SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18 or SEQ ID NO: 19;

[0191] (ii) CDR2 having an amino acid sequence selected from the group: SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, or SEQ ID NO: 32; and

[0192] (iii) CDR3 with an amino acid sequence selected from the group: SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35 or SEQ ID NO: 36.

[0193] In some embodiments of the invention, the monoclonal antibody or antigen-binding fragment thereof comprises:

[0194] (i) a heavy chain variable domain comprising:

[0195] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0196] CDR2 with the amino acid sequence of SEQ ID NO: 20 and

[0197] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0198] (ii) a heavy chain variable domain comprising:

[0199] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0200] CDR2 with the amino acid sequence of SEQ ID NO: 21 and

[0201] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0202] (iii) a heavy chain variable domain comprising:

[0203] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0204] CDR2 with the amino acid sequence of SEQ ID NO: 22 and

[0205] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0206] (iv) a heavy chain variable domain comprising:

[0207] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0208] CDR2 with the amino acid sequence of SEQ ID NO: 23 and

[0209] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0210] (v) heavy chain variable domain comprising:

[0211] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0212] CDR2 with the amino acid sequence of SEQ ID NO: 24 and

[0213] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0214] (vi) a heavy chain variable domain comprising:

[0215] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0216] CDR2 with the amino acid sequence of SEQ ID NO: 25 and

[0217] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0218] (vii) a heavy chain variable domain comprising:

[0219] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0220] CDR2 with the amino acid sequence of SEQ ID NO: 26 and

[0221] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0222] (viii) a heavy chain variable domain comprising:

[0223] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0224] CDR2 with the amino acid sequence of SEQ ID NO: 27 and

[0225] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0226] (ix) a heavy chain variable domain comprising:

[0227] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0228] CDR2 with the amino acid sequence of SEQ ID NO: 28 and

[0229] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0230] (x) heavy chain variable domain comprising:

[0231] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0232] CDR2 with the amino acid sequence of SEQ ID NO: 29 and

[0233] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0234] (xi) heavy chain variable domain comprising:

[0235] CDR1 with the amino acid sequence of SEQ ID NO: 17,

[0236] CDR2 with the amino acid sequence of SEQ ID NO: 30 and

[0237] CDR3 with the amino acid sequence of SEQ ID NO: 34; or

[0238] (xii) a heavy chain variable domain comprising:

[0239] CDR1 with the amino acid sequence of SEQ ID NO: 18,

[0240] CDR2 with the amino acid sequence of SEQ ID NO: 31 and

[0241] CDR3 with the amino acid sequence of SEQ ID NO: 35; or

[0242] (xiii) a heavy chain variable domain comprising:

[0243] CDR1 with the amino acid sequence of SEQ ID NO: 19,

[0244] CDR2 with the amino acid sequence of SEQ ID NO: 32 and

[0245] CDR3 with the amino acid sequence SEQ ID NO: 36.

[0246] In some embodiments of the invention, the monoclonal antibody or antigen-binding fragment thereof comprises:

[0247] (a) a light chain variable domain comprising:

[0248] (i) CDR1 with an amino acid sequence selected from the group: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4 or SEQ ID NO: 5;

[0249] (ii) CDR2 with an amino acid sequence selected from the group: SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 10; and

[0250] (iii) CDR3 with an amino acid sequence selected from the group: SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14 or SEQ ID NO: 15; and

[0251] (b) a heavy chain variable domain comprising:

[0252] (i) CDR1 with an amino acid sequence selected from the group: SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18 or SEQ ID NO: 19;

[0253] (ii) CDR2 with an amino acid sequence selected from the group: SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, or SEQ ID NO: 32; and

[0254] (iii) CDR3 with an amino acid sequence selected from the group: SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35 or SEQ ID NO: 36.

[0255] In some embodiments of the invention, the monoclonal antibody or antigen-binding fragment thereof comprises:

[0256] (i) (a) a light chain variable domain comprising:

[0257] CDR1 with the amino acid sequence SEQ ID NO: 1,

[0258] CDR2 with the amino acid sequence of SEQ ID NO: 6 and

[0259] CDR3 with the amino acid sequence of SEQ ID NO: 11; and

[0260] (b) a heavy chain variable domain comprising:

[0261] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0262] CDR2 with the amino acid sequence of SEQ ID NO: 20 and

[0263] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0264] (ii) (a) a light chain variable domain comprising:

[0265] CDR1 with the amino acid sequence SEQ ID NO: 1,

[0266] CDR2 with the amino acid sequence of SEQ ID NO: 6 and

[0267] CDR3 with the amino acid sequence of SEQ ID NO: 11; and

[0268] (b) a heavy chain variable domain comprising:

[0269] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0270] CDR2 with the amino acid sequence of SEQ ID NO: 21 and

[0271] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0272] (iii) (a) a light chain variable domain comprising:

[0273] CDR1 with the amino acid sequence SEQ ID NO: 1,

[0274] CDR2 with the amino acid sequence of SEQ ID NO: 6 and

[0275] CDR3 with the amino acid sequence of SEQ ID NO: 11; and

[0276] (b) a heavy chain variable domain comprising:

[0277] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0278] CDR2 with the amino acid sequence of SEQ ID NO: 22 and

[0279] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0280] (iv) (a) a light chain variable domain comprising:

[0281] CDR1 with the amino acid sequence SEQ ID NO: 1,

[0282] CDR2 with the amino acid sequence of SEQ ID NO: 6 and

[0283] CDR3 with the amino acid sequence of SEQ ID NO: 11; and

[0284] (b) a heavy chain variable domain comprising:

[0285] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0286] CDR2 with the amino acid sequence of SEQ ID NO: 23 and

[0287] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0288] (v) (a) a light chain variable domain comprising:

[0289] CDR1 with the amino acid sequence of SEQ ID NO: 1,

[0290] CDR2 with the amino acid sequence of SEQ ID NO: 6 and

[0291] CDR3 with the amino acid sequence of SEQ ID NO: 11; and

[0292] (b) a heavy chain variable domain comprising:

[0293] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0294] CDR2 with the amino acid sequence of SEQ ID NO: 24 and

[0295] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0296] (vi) (a) a light chain variable domain comprising:

[0297] CDR1 with the amino acid sequence SEQ ID NO: 1,

[0298] CDR2 with the amino acid sequence of SEQ ID NO: 6 and

[0299] CDR3 with the amino acid sequence of SEQ ID NO: 11; and

[0300] (b) a heavy chain variable domain comprising:

[0301] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0302] CDR2 with the amino acid sequence of SEQ ID NO: 25 and

[0303] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0304] (vii) (a) a light chain variable domain comprising:

[0305] CDR1 with the amino acid sequence SEQ ID NO: 1,

[0306] CDR2 with the amino acid sequence of SEQ ID NO: 6 and

[0307] CDR3 with the amino acid sequence of SEQ ID NO: 11; and

[0308] (b) a heavy chain variable domain comprising:

[0309] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0310] CDR2 with the amino acid sequence of SEQ ID NO: 26 and

[0311] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0312] (viii) (a) a light chain variable domain comprising:

[0313] CDR1 with the amino acid sequence SEQ ID NO: 1,

[0314] CDR2 with the amino acid sequence of SEQ ID NO: 6 and

[0315] CDR3 with the amino acid sequence of SEQ ID NO: 11; and

[0316] (b) a heavy chain variable domain comprising:

[0317] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0318] CDR2 with the amino acid sequence of SEQ ID NO: 27 and

[0319] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0320] (ix) (a) a light chain variable domain comprising:

[0321] CDR1 with the amino acid sequence SEQ ID NO: 1,

[0322] CDR2 with the amino acid sequence of SEQ ID NO: 6 and

[0323] CDR3 with the amino acid sequence of SEQ ID NO: 11; and

[0324] (b) a heavy chain variable domain comprising:

[0325] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0326] CDR2 with the amino acid sequence of SEQ ID NO: 28 and

[0327] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0328] (x) (a) a light chain variable domain comprising:

[0329] CDR1 with the amino acid sequence of SEQ ID NO: 1,

[0330] CDR2 with the amino acid sequence of SEQ ID NO: 6 and

[0331] CDR3 with the amino acid sequence of SEQ ID NO: 11; and

[0332] (b) a heavy chain variable domain comprising:

[0333] CDR1 with the amino acid sequence of SEQ ID NO: 16,

[0334] CDR2 with the amino acid sequence of SEQ ID NO: 29 and

[0335] CDR3 with the amino acid sequence of SEQ ID NO: 33; or

[0336] (xi) (a) a light chain variable domain comprising:

[0337] CDR1 with the amino acid sequence SEQ ID NO: 2,

[0338] CDR2 with the amino acid sequence of SEQ ID NO: 7 and

[0339] CDR3 with the amino acid sequence of SEQ ID NO: 12; and

[0340] (b) a heavy chain variable domain comprising:

[0341] CDR1 with the amino acid sequence of SEQ ID NO: 17,

[0342] CDR2 with the amino acid sequence of SEQ ID NO: 30 and

[0343] CDR3 with the amino acid sequence of SEQ ID NO: 34; or

[0344] (xii) (a) a light chain variable domain comprising:

[0345] CDR1 with the amino acid sequence SEQ ID NO: 3,

[0346] CDR2 with the amino acid sequence of SEQ ID NO: 8 and

[0347] CDR3 with the amino acid sequence of SEQ ID NO: 13; and

[0348] (b) a heavy chain variable domain comprising:

[0349] CDR1 with the amino acid sequence of SEQ ID NO: 17,

[0350] CDR2 with the amino acid sequence of SEQ ID NO: 30 and

[0351] CDR3 with the amino acid sequence of SEQ ID NO: 34; or

[0352] (xiii) (a) a light chain variable domain comprising:

[0353] CDR1 with the amino acid sequence SEQ ID NO: 4,

[0354] CDR2 with the amino acid sequence of SEQ ID NO: 9 and

[0355] CDR3 with the amino acid sequence of SEQ ID NO: 14; and

[0356] (b) a heavy chain variable domain comprising:

[0357] CDR1 with the amino acid sequence of SEQ ID NO: 18,

[0358] CDR2 with the amino acid sequence of SEQ ID NO: 31 and

[0359] CDR3 with the amino acid sequence of SEQ ID NO: 35; or

[0360] (xiv) (a) a light chain variable domain comprising:

[0361] CDR1 with the amino acid sequence of SEQ ID NO: 5,

[0362] CDR2 with the amino acid sequence of SEQ ID NO: 10 and

[0363] CDR3 with the amino acid sequence of SEQ ID NO: 15; and

[0364] (b) a heavy chain variable domain comprising:

[0365] CDR1 with the amino acid sequence of SEQ ID NO: 19,

[0366] CDR2 with the amino acid sequence of SEQ ID NO: 32 and

[0367] CDR3 with the amino acid sequence SEQ ID NO: 36.

[0368] In some embodiments of the invention, a monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain that comprises an amino acid sequence selected from the group: SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, or SEQ ID NO: 41.

[0369] In some embodiments, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain that comprises an amino acid sequence selected from the group of: SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, or SEQ ID NO: 55.

[0370] In some embodiments of the invention, the monoclonal antibody or antigen-binding fragment thereof comprises:

[0371] (a) a light chain variable domain that comprises an amino acid sequence selected from the group: SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40 or SEQ ID NO: 41; and

[0372] (b) a heavy chain variable domain that comprises an amino acid sequence selected from the group: SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54 or SEQ ID NO: 55.

[0373] In some embodiments of the invention, the monoclonal antibody or antigen-binding fragment thereof comprises:

[0374] (i) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and

[0375] (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 42; or

[0376] (ii) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and

[0377] (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 43; or

[0378] (iii) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and

[0379] (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 44; or

[0380] (iv) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and

[0381] (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 45; or

[0382] (v) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and

[0383] (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 46; or

[0384] (vi) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and

[0385] (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 47; or

[0386] (vii) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and

[0387] (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 48; or

[0388] (viii) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and

[0389] (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 49; or

[0390] (ix) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and

[0391] (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 50; or

[0392] (x) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and

[0393] (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 51; or

[0394] (xi) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 38 and

[0395] (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 52; or

[0396] (xii) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 39 and

[0397] (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 53; or

[0398] (xiii) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 40 and

[0399] (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 54; or

[0400] (xiv) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 41 and

[0401] (b) The heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 55.

[0402] In some embodiments, the monoclonal antibody that specifically binds to TL1A is a full-length IgG antibody.

[0403] In some embodiments of the invention, a monoclonal antibody that specifically binds to TL1A is a full-length IgG antibody that is of the human IgG1, IgG2, IgG3, or IgG4 isotype.

[0404] In some embodiments of the invention, a monoclonal antibody that specifically binds to TL1A is a full-length IgG antibody that is of the human IgG1 isotype.

[0405] In some embodiments of the invention, the monoclonal antibody comprises mutations M252Y, S254T, T256E in the Fc region according to the amino acid numbering of EU antibodies in the CH2 region (Edelman GM et al., Proc. Natl. Acad. Sci. USA 63, 1969, pp. 78-85; Kabat EA et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, 1991).

[0406] In some embodiments of the invention, the monoclonal antibody comprises mutations L234A and L235A according to the amino acid numbering of EU antibodies in the CH2 region.

[0407] In some embodiments, the monoclonal antibody comprises a deletion of 446G and 447K according to the amino acid numbering of EU antibodies in the CH3 region.

[0408] In some embodiments, the monoclonal antibody comprises a light chain comprising an amino acid sequence selected from the group: SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, or SEQ ID NO: 60.

[0409] In some embodiments, the monoclonal antibody comprises a heavy chain comprising an amino acid sequence selected from the group: SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, or SEQ ID NO: 74.

[0410] In some embodiments, the monoclonal antibody comprises:

[0411] (i) (a) a light chain comprising an amino acid sequence selected from the group: SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59 or SEQ ID NO: 60, and

[0412] (b) a heavy chain comprising an amino acid sequence selected from the group: SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73 or SEQ ID NO: 74.

[0413] In some embodiments, the monoclonal antibody comprises:

[0414] (i) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and

[0415] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 61; or

[0416] (ii) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and

[0417] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 62; or

[0418] (iii) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and

[0419] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 63; or

[0420] (iv) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and

[0421] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 64; or

[0422] (v) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and

[0423] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 65; or

[0424] (vi) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and

[0425] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 66; or

[0426] (vii) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and

[0427] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 67; or

[0428] (viii) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and

[0429] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 68; or

[0430] (ix) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and

[0431] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 69; or

[0432] (x) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and

[0433] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 70; or

[0434] (xi) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 57, and

[0435] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 71; or

[0436] (xii) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 58, and

[0437] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 72; or

[0438] (xiii) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 59, and

[0439] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 73; or

[0440] (xiv) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 60, and

[0441] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 74.

[0442] In some embodiments, a monoclonal antibody that specifically binds to TL1A is an antibody selected from the group: 01-001, 05-001, 05-002, 05-006, 05-008, 05-010, 05-011, 05-013, 05-014, 05-015, 03-001, 03-002, 04-001 or 04-002.

[0443] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 01-001.

[0444] Antibody 01-001 includes:

[0445] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56; and

[0446] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 61.

[0447] Antibody 01-001 includes:

[0448] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 37;

[0449] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 42.

[0450] Antibody 01-001 includes:

[0451] (a) a light chain variable domain comprising:

[0452] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 1,

[0453] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 6,

[0454] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 11, and

[0455] (b) a heavy chain variable domain comprising:

[0456] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 16,

[0457] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 20,

[0458] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 33.

[0459] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 05-001.

[0460] Antibody 05-001 includes:

[0461] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56; and

[0462] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 62.

[0463] Antibody 05-001 includes:

[0464] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 37;

[0465] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 43.

[0466] Antibody 05-001 includes:

[0467] (a) a light chain variable domain comprising:

[0468] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 1,

[0469] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 6,

[0470] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 11, and

[0471] (b) a heavy chain variable domain comprising:

[0472] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 16,

[0473] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 21,

[0474] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 33.

[0475] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 05-002.

[0476] Antibody 05-002 includes:

[0477] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56; and

[0478] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 63.

[0479] Antibody 05-002 includes:

[0480] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 37;

[0481] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 44.

[0482] Antibody 05-002 includes:

[0483] (a) a light chain variable domain comprising:

[0484] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 1,

[0485] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 6,

[0486] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 11, and

[0487] (b) a heavy chain variable domain comprising:

[0488] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 16,

[0489] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 22,

[0490] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 33.

[0491] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 05-006.

[0492] Antibody 05-006 includes:

[0493] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56; and

[0494] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 64.

[0495] Antibody 05-006 includes:

[0496] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 37;

[0497] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 45.

[0498] Antibody 05-006 includes:

[0499] (a) a light chain variable domain comprising:

[0500] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 1,

[0501] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 6,

[0502] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 11, and

[0503] (b) a heavy chain variable domain comprising:

[0504] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 16,

[0505] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 23,

[0506] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 33.

[0507] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 05-008.

[0508] Antibody 05-008 includes:

[0509] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56; and

[0510] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 65.

[0511] Antibody 05-008 includes:

[0512] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 37;

[0513] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 46.

[0514] Antibody 05-008 includes:

[0515] (a) a light chain variable domain comprising:

[0516] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 1,

[0517] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 6,

[0518] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 11, and

[0519] (b) a heavy chain variable domain comprising:

[0520] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 16,

[0521] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 24,

[0522] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 33.

[0523] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 05-010.

[0524] Antibody 05-010 includes:

[0525] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56; and

[0526] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 66.

[0527] Antibody 05-010 includes:

[0528] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 37;

[0529] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 47.

[0530] Antibody 05-010 includes:

[0531] (a) a light chain variable domain comprising:

[0532] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 1,

[0533] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 6,

[0534] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 11, and

[0535] (b) a heavy chain variable domain comprising:

[0536] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 16,

[0537] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 25,

[0538] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 33.

[0539] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 05-011.

[0540] Antibody 05-011 includes:

[0541] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56; and

[0542] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 67.

[0543] Antibody 05-011 includes:

[0544] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 37;

[0545] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 48.

[0546] Antibody 05-011 includes:

[0547] (a) a light chain variable domain comprising:

[0548] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 1,

[0549] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 6,

[0550] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 11, and

[0551] (b) a heavy chain variable domain comprising:

[0552] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 16,

[0553] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 26,

[0554] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 33.

[0555] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 05-013.

[0556] Antibody 05-013 includes:

[0557] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56; and

[0558] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 68.

[0559] Antibody 05-013 includes:

[0560] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 37;

[0561] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 49.

[0562] Antibody 05-013 includes:

[0563] (a) a light chain variable domain comprising:

[0564] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 1,

[0565] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 6,

[0566] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 11, and

[0567] (b) a heavy chain variable domain comprising:

[0568] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 16,

[0569] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 27,

[0570] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 33.

[0571] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 05-014.

[0572] Antibody 05-014 includes:

[0573] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56; and

[0574] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 69.

[0575] Antibody 05-014 includes:

[0576] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 37;

[0577] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 50.

[0578] Antibody 05-014 includes:

[0579] (a) a light chain variable domain comprising:

[0580] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 1,

[0581] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 6,

[0582] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 11, and

[0583] (b) a heavy chain variable domain comprising:

[0584] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 16,

[0585] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 28,

[0586] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 33.

[0587] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 05-015.

[0588] Antibody 05-015 includes:

[0589] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56; and

[0590] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 70.

[0591] Antibody 05-015 includes:

[0592] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 37;

[0593] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 51.

[0594] Antibody 05-015 includes:

[0595] (a) a light chain variable domain comprising:

[0596] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 1,

[0597] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 6,

[0598] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 11, and

[0599] (b) a heavy chain variable domain comprising:

[0600] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 16,

[0601] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 29,

[0602] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 33.

[0603] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 03-001.

[0604] Antibody 03-001 includes:

[0605] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 57; and

[0606] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 71.

[0607] Antibody 03-001 includes:

[0608] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 38;

[0609] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 52.

[0610] Antibody 03-001 includes:

[0611] (a) a light chain variable domain comprising:

[0612] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 2,

[0613] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 7,

[0614] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 12, and

[0615] (b) a heavy chain variable domain comprising:

[0616] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 17,

[0617] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 30,

[0618] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 34.

[0619] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 03-002.

[0620] Antibody 03-002 includes:

[0621] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 58; and

[0622] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 72.

[0623] Antibody 03-002 includes:

[0624] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 39;

[0625] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 53.

[0626] Antibody 03-002 includes:

[0627] (a) a light chain variable domain comprising:

[0628] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 3,

[0629] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 8,

[0630] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 13, and

[0631] (b) a heavy chain variable domain comprising:

[0632] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 17,

[0633] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 30,

[0634] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 34.

[0635] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 04-001.

[0636] Antibody 04-001 includes:

[0637] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 59; and

[0638] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 73.

[0639] Antibody 04-001 includes:

[0640] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 40;

[0641] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 54.

[0642] Antibody 04-001 includes:

[0643] (a) a light chain variable domain comprising:

[0644] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 4,

[0645] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 9,

[0646] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 14, and

[0647] (b) a heavy chain variable domain comprising:

[0648] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 18,

[0649] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 31,

[0650] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 35.

[0651] In some embodiments, the monoclonal antibody that specifically binds to TL1A is antibody 04-002.

[0652] Antibody 04-002 includes:

[0653] (a) a light chain comprising the amino acid sequence of SEQ ID NO: 60; and

[0654] (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 74.

[0655] Antibody 04-002 includes:

[0656] (a) a light chain variable domain that comprises the amino acid sequence of SEQ ID NO: 41;

[0657] (b) a heavy chain variable domain that comprises the amino acid sequence of SEQ ID NO: 55.

[0658] Antibody 04-002 includes:

[0659] (a) a light chain variable domain comprising:

[0660] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 5,

[0661] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 10,

[0662] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 15, and

[0663] (b) a heavy chain variable domain comprising:

[0664] (i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 19,

[0665] (ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 32,

[0666] (iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 36.

[0667] The hypervariable regions of the variable domains of the light and heavy chains (LCDR1, 2, 3 and HCDR1, 2, 3) of all the above-mentioned antibodies are indicated in accordance with the Kabat nomenclature. It is obvious to one skilled in the art that the hypervariable regions of the variable domains of the light and heavy chains (LCDR1, 2, 3 and HCDR1, 2, 3) can also be represented in accordance with other well-known nomenclature, for example, IMGT, Chothia or AbM. Thus, all the above-mentioned antibodies, which are characterized through the hypervariable regions of the variable domains of the light and heavy chains (LCDR1, 2, 3 and HCDR1, 2, 3) in accordance with the IMGT, Chothia or AbM nomenclature, are also the subject of the present invention.

[0668] The antibodies of the invention, which specifically bind to TL1A, exhibit high binding affinity parameters for TL1A. The antibodies of the invention are effective inhibitors of the activity mediated by the DR3 receptor (TNFRSF25). The antibodies of the invention have a high affinity for the FcRn receptor to increase the circulation time of the drug in the blood of patients. In addition, the antibodies of the invention are stable in human serum and resistant to elevated temperatures. The antibodies of the invention inhibit the release of interferon gamma in the presence of IL-12 and IL-18 and various proinflammatory cytokines in the presence of IL-12, IL-18, and IL-15. The antibodies of the invention do not cause direct and cross-linked apoptosis of CHO-tmTL1A cells expressing the membrane-associated form of TL1A and do not lead to the development of cytokine release syndrome.

[0669] Nucleic acid molecule

[0670] In one aspect, the present invention relates to a nucleic acid that encodes any of the above-mentioned antibodies or antigen-binding fragments thereof that specifically binds to TL1A.

[0671] In any of the embodiments of the invention, the nucleic acid molecules may be isolated.

[0672] The terms "nucleic acid," "nucleic sequence" or "nucleic acid sequence," "polynucleotide," "oligonucleotide," "polynucleotide sequence," and "nucleotide sequence," which are used interchangeably in this specification, mean a distinct sequence of nucleotides, whether modified or not modified, defining a fragment or section of nucleic acid, whether or not containing non-natural nucleotides, and being either double-stranded DNA or RNA, or single-stranded DNA or RNA, or transcription products of said DNA, or reverse transcription products of said RNA.

[0673] The term "nucleotide sequence" encompasses its complement unless otherwise specified. Thus, a nucleic acid having a certain sequence should be understood to encompass its complementary strand with its complementary sequence.

[0674] An "isolated" nucleic acid molecule is a nucleic acid molecule that has been identified and separated from at least one contaminating nucleic acid molecule. An isolated nucleic acid molecule is distinct from the form or composition in which it is naturally found. Thus, an isolated nucleic acid molecule is distinct from a nucleic acid molecule naturally occurring in cells.

[0675] In one aspect, the present invention relates to a nucleic acid molecule comprising a nucleotide sequence that encodes an amino acid sequence selected from SEQ ID NO: 75-112. The nucleic acid molecule may also comprise any combination of said nucleotide sequences.

[0676] It will be apparent to those skilled in the art that the amino acid sequence of the light or heavy chain of the antibody of the invention or fragments thereof (VH, VL, CDR, etc.) can be encoded by a wide range of different DNA sequences, given the degeneracy of the genetic code. Those skilled in the art are well-versed in obtaining such alternative DNA sequences encoding the same amino acid sequences. Such variant DNA sequences are within the scope of the present invention.

[0677] In some embodiments of the invention, the nucleic acid is DNA.

[0678] The nucleic acid molecule of the present invention can be isolated from any source that produces a monoclonal antibody or antigen-binding fragment thereof that specifically binds to TL1A. In certain embodiments, the nucleic acid molecule of the present invention can be synthesized by chemical synthesis rather than isolated.

[0679] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain variable domain of antibodies 01-001, 05-001, 05-002, 05-006, 05-008, 05-010, 05-011, 05-013, 05-014, 05-015, and includes the nucleotide sequence of SEQ ID NO: 75.

[0680] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain variable domain of antibody 03-001, and includes the nucleotide sequence of SEQ ID NO: 76.

[0681] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain variable domain of antibody 03-002, and includes the nucleotide sequence of SEQ ID NO: 77.

[0682] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain variable domain of antibody 04-001, and includes the nucleotide sequence of SEQ ID NO: 78.

[0683] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain variable domain of antibody 04-002, and includes the nucleotide sequence of SEQ ID NO: 79.

[0684] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 01-001 and comprises the nucleotide sequence of SEQ ID NO: 80.

[0685] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 05-001, and includes the nucleotide sequence of SEQ ID NO: 81.

[0686] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 05-002, and includes the nucleotide sequence of SEQ ID NO: 82.

[0687] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 05-006, and includes the nucleotide sequence of SEQ ID NO: 83.

[0688] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 05-008, and includes the nucleotide sequence of SEQ ID NO: 84.

[0689] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 05-010, and includes the nucleotide sequence of SEQ ID NO: 85.

[0690] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 05-011, and includes the nucleotide sequence of SEQ ID NO: 86.

[0691] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 05-013, and includes the nucleotide sequence of SEQ ID NO: 87.

[0692] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 05-014, and includes the nucleotide sequence of SEQ ID NO: 88.

[0693] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 05-015, and includes the nucleotide sequence of SEQ ID NO: 89.

[0694] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 03-001 and comprises the nucleotide sequence of SEQ ID NO: 90.

[0695] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 03-002, and includes the nucleotide sequence of SEQ ID NO: 91.

[0696] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 04-001, and includes the nucleotide sequence of SEQ ID NO: 92.

[0697] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain variable domain of antibody 04-002, and includes the nucleotide sequence of SEQ ID NO: 93.

[0698] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibodies 01-001, 05-001, 05-002, 05-006, 05-008, 05-010, 05-011, 05-013, 05-014, 05-015, and includes the nucleotide sequence of SEQ ID NO: 94.

[0699] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 03-001 and includes the nucleotide sequence of SEQ ID NO: 95.

[0700] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 03-002 and includes the nucleotide sequence of SEQ ID NO: 96.

[0701] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 04-001 and includes the nucleotide sequence of SEQ ID NO: 97.

[0702] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 04-002 and includes the nucleotide sequence of SEQ ID NO: 98.

[0703] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 01-001 and includes the nucleotide sequence of SEQ ID NO: 99.

[0704] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 05-001 and includes the nucleotide sequence of SEQ ID NO: 100.

[0705] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 05-002 and includes the nucleotide sequence of SEQ ID NO: 101.

[0706] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 05-006, and includes the nucleotide sequence of SEQ ID NO: 102.

[0707] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 05-008 and includes the nucleotide sequence of SEQ ID NO: 103.

[0708] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 05-010, and includes the nucleotide sequence of SEQ ID NO: 104.

[0709] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 05-011 and includes the nucleotide sequence of SEQ ID NO: 105.

[0710] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 05-013, and includes the nucleotide sequence of SEQ ID NO: 106.

[0711] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 05-014, and includes the nucleotide sequence of SEQ ID NO: 107.

[0712] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 05-015, and includes the nucleotide sequence of SEQ ID NO: 108.

[0713] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 03-001 and includes the nucleotide sequence of SEQ ID NO: 109.

[0714] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 03-002 and includes the nucleotide sequence of SEQ ID NO: 110.

[0715] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 04-001 and includes the nucleotide sequence of SEQ ID NO: 111.

[0716] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 04-002 and includes the nucleotide sequence of SEQ ID NO: 112.

[0717] Nucleic acid molecules can be used to express a recombinant monoclonal antibody or antigen-binding fragment thereof that specifically binds to TL1A.

[0718] Vector

[0719] In one aspect, the present invention relates to an expression vector comprising any of the above nucleic acid molecules that encode the corresponding amino acid sequences of an antibody that specifically binds to TL1A, or a portion thereof (e.g., heavy chain and / or light chain binding domain sequences). The present invention relates to a vector suitable for expressing any of the nucleotide sequences described herein.

[0720] The term "vector" as used herein means a nucleic acid molecule capable of transporting another nucleic acid to which it is linked.

[0721] As used herein, the term "expression" is defined as the transcription and / or translation of a particular nucleotide sequence.

[0722] In some embodiments of the invention, the vector is a plasmid, i.e., a circular double-stranded piece of DNA into which additional DNA segments can be inserted.

[0723] In some embodiments of the invention, the vector is a viral (expression) vector in which additional DNA segments can be inserted into the viral genome.

[0724] In some embodiments, vectors are capable of autonomous replication in the host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal vectors). In other embodiments, vectors (e.g., non-episomal vectors) can be integrated into the host cell genome upon introduction into the host cell and thus replicate along with the host genome. Moreover, some vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply "expression vectors" ("expression vector" or "expression vector")).

[0725] In some embodiments, expression vectors include plasmids, retroviruses, adenoviruses, adeno-associated viruses (AAV), plant viruses such as cauliflower mosaic virus, tobacco mosaic viruses, cosmids, YACs, and the like. DNA molecules can be inserted into the vector such that transcription and translation control sequences in the vector perform the intended function of regulating DNA transcription and translation. The expression vector and expression control sequences can be selected to be compatible with the expression host cell used.

[0726] In one embodiment of the invention, DNA molecules encoding part or all of the heavy and light chain sequences may be introduced into separate vectors.

[0727] In one embodiment of the invention, any combination of the above DNA molecules is introduced into the same expression vector.

[0728] In one embodiment of the invention, DNA molecules can be introduced into an expression vector by standard methods (e.g., by ligating complementary restriction sites on the antibody gene fragment and the vector, or by blunt-end ligation if restriction sites are absent).

[0729] In some embodiments, a suitable vector is one that includes restriction sites such that any VH or VL sequence can be readily incorporated and expressed as described above. The recombinant expression vector can also encode a signal peptide that facilitates production of the antibody chain by the host cell. The antibody chain sequence can be cloned into the vector such that the signal peptide is linked in-frame to the N-terminus of the immunoglobulin chain. The signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide of a non-immunoglobulin protein).

[0730] In some embodiments, the vector may include an expression control sequence. The term "expression control sequence," as used herein, refers to polynucleotide sequences that are necessary to influence the expression and processing of the coding sequences into which they are inserted. Those skilled in the art will appreciate that the design of an expression vector, including the choice of expression control sequences, may depend on factors such as the choice of host cell type for transformation, the desired level of antibody expression, etc.Expression control sequences include appropriate transcription initiation and termination sequences; a promoter, enhancer, and / or insulator; efficient RNA processing signals such as splice sites and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (e.g., a Kozak consensus sequence); sequences that enhance protein stability; and, optionally, sequences that enhance protein secretion. The nature of such expression control sequences varies depending on the host organism; in prokaryotes, such expression control sequences typically include a promoter, a ribosome binding site, and transcription termination sequences; in eukaryotes, such expression control sequences typically include promoters and transcription termination sequences.Preferred expression control sequences for the mammalian expression host cell include viral elements that provide high-level protein expression in mammalian cells, such as promoters and / or enhancers derived from the retroviral long terminal repeat (LTR), cytomegalovirus (CMV) (e.g., the CMV enhancer / promoter), simian virus 40 (SV40) (e.g., the SV40 promoter / enhancer), adenovirus (e.g., the adenovirus large late promoter (AdMLP)), polyoma virus, and strong mammalian promoters such as the TTR promoter, the native immunoglobulin promoter, or the actin promoter. The expression control sequences include, at a minimum, all components whose presence is essential for expression and processing.

[0731] In some embodiments, in addition to antibody chain genes and expression control sequences, the recombinant expression vectors of the invention may carry additional sequences, such as sequences that regulate vector replication in host cells (e.g., origins of replication) and selectable marker genes. A selectable marker gene facilitates selection of host cells into which the vector has been introduced.

[0732] Host cell

[0733] In one aspect, the present invention relates to a method for producing a host cell for producing any of the above-mentioned antibody or antigen-binding fragment thereof that specifically binds to TL1A, and comprises transforming the cell with the above-mentioned vector.

[0734] In one aspect, the present invention relates to a host cell for producing any of the above-mentioned antibodies or antigen-binding fragments thereof that specifically binds to TL1A, which comprises any of the above-mentioned nucleic acids.

[0735] The term "host cell," as used herein, refers to a cell into which a recombinant expression vector has been introduced. The present invention relates to host cells that may comprise, for example, a vector according to the present invention described above. The present invention also relates to host cells that comprise, for example, a nucleotide sequence encoding a heavy chain or its antigen-binding portions, a nucleotide sequence encoding a light chain or its antigen-binding portions, or both. It should be understood that "host cell" refers not only to the specific cell claimed, but also to the progeny of such a cell. Because modifications may occur in subsequent generations due to mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but such cells are still included within the scope of the term "host cell" as used herein.

[0736] Nucleic acid molecules encoding a monoclonal antibody or an antigen-binding fragment thereof that specifically binds to TL1A, according to the invention, and vectors containing these nucleic acid molecules can be used to transfect a mammalian cell, a plant cell, a bacterial cell, or a yeast cell. Transfection can occur by any known method for introducing polynucleotides into a host cell. Methods for introducing heterologous polynucleotides into mammalian cells are well known in the art and include dextran-mediated transfection, transfection with a complex of a nucleic acid and a positively charged polymer, transfection by electroporation, transfection with a nucleic acid-calcium phosphate precipitate, polybrene-mediated transfection, protoplast fusion, transfection with liposome-encapsulated polynucleotides, and direct microinjection of DNA into nuclei.In addition, nucleic acid molecules can be introduced into mammalian cells by viral (expression) vectors.

[0737] Mammalian cell lines used as transformation hosts are well known in the art and include many immortalized cell lines. These include, for example, Chinese hamster ovary (CHO) cells, NS0 cells, SP2 cells, HEK-293T cells, 293 Freestyle cells (Invitrogen), NIH-3T3 cells, HeLa cells, hamster kidney (BHK) cells, African green monkey kidney (COS) cells, human hepatocellular carcinoma cells (e.g., Hep G2), A549, SK-HEP1, HUH7, Hep-RG cells, and a number of other cell lines. Cell lines are selected by determining which cell lines have high expression levels and provide the desired characteristics of the produced protein. Other cell lines that can be used are insect cell lines such as Sf9 or Sf21 cells.When recombinant expression vectors encoding a monoclonal antibody or antigen-binding fragment thereof that specifically binds to TL1A are introduced into mammalian host cells, the antibodies or fragments thereof are produced by culturing the host cells for a time sufficient to express the antibodies or fragments thereof in the host cells or, preferably, by isolating the antibodies or fragments thereof into the nutrient medium in which the host cells are grown. The monoclonal antibody or antigen-binding fragment thereof that specifically binds to TL1A can be isolated from the nutrient medium using standard protein purification methods. Plant host cells, for example, include Nicotiana, Arabidopsis, duckweed, corn, wheat, potato, etc. Bacterial host cells include, for example, genera such as Escherichia and Streptomyces. Yeast host cells include Schizosaccharomyces pombe, Saccharomyces cerevisiae, and Pichia pastoris.

[0738] Furthermore, the production level of a monoclonal antibody or its antigen-binding fragment that specifically binds to TL1A can be enhanced from the producing cell line using a number of known methods. For example, the glutamine synthetase gene expression system (GS system) is widely used for enhancing expression under certain conditions.

[0739] It is likely that a monoclonal antibody or antigen-binding fragment thereof that specifically binds to TL1A from different cell lines will differ from one another in their glycosylation profile. However, a monoclonal antibody or antigen-binding fragment thereof that specifically binds to TL1A, encoded by the nucleic acid molecules described herein or comprising the amino acid sequences provided herein, is part of the present invention, regardless of the glycosylation state of the binding molecules and, in general, regardless of the presence or absence of post-translational modifications.

[0740] The above host cell does not refer to the host cell obtained using human embryos.

[0741] The above host cell does not refer to a host cell obtained by modifying the genetic integrity of human germline cells.

[0742] Method for producing antibodies

[0743] In one aspect, the present invention relates to a method for producing an antibody or an antigen-binding fragment thereof that specifically binds to TL1A, comprising culturing the above-described host cell in a culture medium under conditions sufficient to produce said antibody or fragment thereof, followed by isolating and purifying the obtained antibody or fragment thereof.

[0744] Pharmaceutical compositions

[0745] Another aspect of the invention is a pharmaceutical composition comprising as an active ingredient (or as the only active ingredient) a monoclonal antibody of the present invention or an antigen-binding fragment thereof that specifically binds to TL1A.

[0746] In one aspect, the present invention relates to a pharmaceutical composition that comprises any of the above-mentioned antibodies or antigen-binding fragments thereof in combination with one or more pharmaceutically acceptable excipients.

[0747] In one aspect, the present invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by TL1A, which comprises any of the above-mentioned antibodies or antigen-binding fragments thereof in combination with one or more pharmaceutically acceptable excipients.

[0748] In one aspect, the present invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by TL1A, which comprises any of the above-mentioned antibodies or antigen-binding fragments thereof in a therapeutically effective amount in combination with one or more pharmaceutically acceptable excipients.

[0749] “Pharmaceutical composition” means a composition comprising an antibody according to the invention and at least one component selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, auxiliary, distributing and receiving means, delivery means.

[0750] The term "pharmaceutically acceptable" means one or more compatible liquid or solid components that are suitable for administration to a mammal, preferably a human.

[0751] The term "excipient" or "auxiliary substance" is used herein to describe any component other than the antibody of the invention. These are substances of inorganic or organic origin used in the manufacturing process of medicinal products to impart the necessary physicochemical properties.

[0752] In some embodiments, the compositions are for ameliorating or treating diseases or disorders that may be mediated by TL1A.

[0753] The term “TL1A-mediated disease or disorder” refers to all diseases or disorders that are either directly or indirectly associated with TL1A, including the pathogenesis, progression, recurrence, or chronicity of the disease or disorder.

[0754] “Treat,” “treatment,” and “therapy” refer to a method of alleviating or eliminating a biological disorder and / or at least one of its associated symptoms.

[0755] The term "disorder" means any condition that can be improved by treatment according to the present invention. This term is defined to include chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to developing the disorder.

[0756] A "therapeutically effective amount" is defined as the amount of a therapeutic agent administered during treatment that will relieve, to a specified degree, one or more symptoms of the disease being treated. A therapeutically effective amount may vary depending on factors such as the specific condition being treated, the patient's age, gender, and weight, and whether the administration of a monoclonal antibody or antigen-binding fragment thereof that specifically binds to TL1A is a stand-alone treatment or is administered in combination with one or more additional drugs or therapies.

[0757] In one aspect, the treatment subject or patient is a human subject. The said subject may be male or female of any age.

[0758] The pharmaceutical compositions of the present invention and the methods for their manufacture will be readily apparent to those skilled in the art. The manufacture of the pharmaceutical compositions should preferably comply with GMP (good manufacturing practice) requirements.

[0759] In some embodiments of the pharmaceutical composition, it may include a buffer composition, tonic agents (osmolytic or osmotic agent), stabilizers and / or solubilizers.

[0760] The pharmaceutical composition according to the invention is stable.

[0761] A pharmaceutical composition is considered "stable" if the active ingredient retains its physical stability and / or chemical stability and / or biological activity throughout the stated shelf life at a storage temperature of, for example, 2-8°C. Preferably, the active ingredient retains both physical and chemical stability, as well as biological activity. The shelf life is determined based on the results of stability studies under accelerated and natural storage.

[0762] In some embodiments, the pharmaceutical composition is an injectable dosage form.

[0763] In some embodiments, the injectable dosage form is an infusion solution.

[0764] In some embodiments, the injectable dosage form is a solution for subcutaneous administration.

[0765] Injectable dosage forms can be manufactured in unit dosage form such as, but not limited to, ampoules, vials, polymer containers, pre-filled syringes, autoinjector devices.

[0766] In some embodiments, the pharmaceutical composition is a pharmaceutical composition provided in dry form, i.e., a powder or granules for reconstitution in a suitable solvent (e.g., sterile, pyrogen-free water) prior to administration. Such a drug can be obtained, for example, by lyophilization, i.e., a process known in the art as freeze-drying, which involves freezing the drug and then removing the solvent from the frozen contents.

[0767] In some embodiments, the pharmaceutical composition is a lyophilisate for the preparation of an infusion solution.

[0768] In some embodiments, the pharmaceutical composition is a lyophilisate for the preparation of a solution for subcutaneous administration.

[0769] In some embodiments, the pharmaceutical composition is a concentrate for the preparation of an infusion solution.

[0770] In some embodiments, the pharmaceutical composition is a concentrate for the preparation of a solution for subcutaneous administration.

[0771] In one aspect, the present invention relates to a pharmaceutical composition that comprises a monoclonal antibody of the present invention or an antigen-binding fragment thereof that specifically binds to TL1A and at least one other therapeutically active compound.

[0772] In one aspect, the present invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by TL1A, which comprises any of the above-mentioned antibodies or antigen-binding fragments thereof and at least one other therapeutically active compound.

[0773] In one aspect, the present invention relates to a pharmaceutical composition that comprises any of the above-mentioned antibodies or antigen-binding fragments thereof and, additionally, at least one other therapeutically active compound.

[0774] In one aspect, the present invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by TL1A, which comprises any of the above-mentioned antibodies or antigen-binding fragments thereof and, additionally, at least one other therapeutically active compound.

[0775] In one aspect, the present invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by TL1A, which comprises any of the above-mentioned antibodies or antigen-binding fragments thereof and at least one other therapeutically active compound, which is an antibody, a small molecule, a hormonal therapy agent, or any combination thereof.

[0776] In some embodiments of the pharmaceutical composition, the other therapeutically active compound is selected from the group consisting of: azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate, glucocorticosteroids (GCS), long-acting β2-agonists (LABA), long-acting anticholinergics (LAACH), hydroxychloroquine, prednisolone, methylprednisolone, belimumab, anifrolumab, acitretin, apremilast, tacrolimus, mycophenolate mofetil, or any combination thereof.

[0777] In some embodiments of the pharmaceutical composition, the disease or disorder mediated by TL1A is selected from the group: Crohn's disease, ulcerative colitis, bronchial asthma, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, ankylosing spondylitis, interstitial lung disease associated with systemic sclerosis (SSc-ILD), intestinal fibrosis, liver fibrosis or fibrotic pulmonary diseases.

[0778] Therapeutic use of a monoclonal antibody or antigen-binding fragment thereof that specifically binds to TL1A

[0779] In one aspect, an antibody or antigen-binding fragment thereof that specifically binds to TL1A is used in the treatment of diseases or disorders mediated by TL1A.

[0780] In one aspect, the treatment subject or patient is a human subject. The said subject may be male or female and of any age.

[0781] In one aspect, the present invention relates to a method of treating a disease or disorder mediated by TL1A, which comprises administering to a subject in need of such treatment any of the above-mentioned antibody or antigen-binding fragment thereof or the above-mentioned pharmaceutical composition in a therapeutically effective amount.

[0782] In one aspect, the present invention relates to a method of treating a disease or disorder mediated by TL1A, which comprises administering to a subject in need of such treatment any of the above-mentioned antibodies or antigen-binding fragments thereof and at least one other therapeutically active compound in a therapeutically effective amount.

[0783] In some embodiments of the method of treatment, the disease or disorder mediated by TL1A is selected from the group: Crohn's disease, ulcerative colitis, bronchial asthma, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, ankylosing spondylitis, interstitial lung disease associated with systemic sclerosis (SSc-ILD), intestinal fibrosis, liver fibrosis or fibrotic pulmonary diseases.

[0784] In some embodiments of the method of treatment, the other therapeutically active compound is an antibody, a small molecule, a hormonal therapy agent, or any combination thereof.

[0785] In one aspect, the present invention relates to the use of the above antibody or antigen-binding fragment thereof or the above pharmaceutical composition for treating a disease or disorder mediated by TL1A in a subject in need of such treatment.

[0786] In one aspect, the present invention relates to the use of the above-mentioned antibody or antigen-binding fragment thereof and at least one other therapeutically active compound for the treatment of a disease or disorder mediated by TL1A in a subject in need of such treatment.

[0787] In some embodiments of the use, the disease or disorder mediated by TL1A is selected from the group: Crohn's disease, ulcerative colitis, bronchial asthma, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, ankylosing spondylitis, interstitial lung disease associated with systemic sclerosis (SSc-ILD), intestinal fibrosis, liver fibrosis, or fibrotic pulmonary diseases.

[0788] In some embodiments of the use, the other therapeutically active compound is an antibody, a small molecule, a hormonal therapy agent, or any combination thereof.

[0789] As used herein, uses or methods relating to an antibody or antigen-binding fragment thereof that specifically binds to TL1A, with one or more other therapeutic agents are intended to mean, refer to, or include:

[0790] 1) the simultaneous administration of such a combination of an antibody or antigen-binding fragment thereof that specifically binds to TL1A and a therapeutic agent to a patient in need of treatment, when such components are formulated together in a single dosage form from which said components are released substantially simultaneously to said patient,

[0791] 2) the simultaneous administration of such a combination of an antibody or antigen-binding fragment thereof that specifically binds to TL1A and a therapeutic agent to a patient in need of treatment, wherein such components are formulated separately in different dosage forms, the administration of which occurs at substantially the same time to said patient, whereupon said components are released substantially simultaneously to said patient,

[0792] 3) sequentially administering such a combination of an antibody or antigen-binding fragment thereof that specifically binds to TL1A and a therapeutic agent to a patient in need of treatment, wherein such components are formulated separately from each other in separate dosage forms that are administered sequentially in time to said patient with a significant time interval between each administration, whereupon said components are released at substantially different times to said patient; and

[0793] 4) sequential administration of such a combination of an antibody or antigen-binding fragment thereof that specifically binds to TL1A and a therapeutic agent to a patient in need of treatment, when such components are formulated together in a single dosage form from which the release of said components occurs in a controlled manner, after which they are simultaneously, sequentially or jointly released at the same time and / or different times to said patient, where each part can be administered by the same or different routes.

[0794] An antibody or its antigen-binding fragment that specifically binds to TL1A can be administered without additional therapeutic treatment, i.e., as a stand-alone therapy.

[0795] In some embodiments of the method of treating or using an antibody or antigen-binding fragment thereof that specifically binds to TL1A, it may be administered in combination with another therapeutically active compound that is selected from the group: azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate, glucocorticosteroids (GCS), long-acting β2-agonists (LABA), long-acting anticholinergics (LAC), hydroxychloroquine, prednisolone, methylprednisolone, belimumab, anifrolumab, acitretin, apremilast, tacrolimus, mycophenolate mofetil, or any combination thereof.

[0796] In some embodiments of the method of treating or using an antibody or antigen-binding fragment thereof that specifically binds to TL1A, it may be administered in combination with another therapeutically active compound that is selected from the group: azathioprine, 6-mercaptopurine, methotrexate, or any combination thereof.

[0797] In some embodiments of the method of treatment or use, an antibody or antigen-binding fragment thereof that specifically binds to TL1A may be administered in combination with another therapeutically active compound that is selected from the group: glucocorticosteroids, long-acting β2-agonists, long-acting anticholinergics, or any combination thereof.

[0798] In some embodiments of the method of treating or using an antibody or antigen-binding fragment thereof that specifically binds to TL1A, it may be administered in combination with methotrexate.

[0799] In some embodiments of the method of treating or using an antibody or antigen-binding fragment thereof that specifically binds to TL1A, it may be administered in combination with another therapeutically active compound that is selected from the group: hydroxychloroquine, prednisolone, methylprednisolone, azathioprine, belimumab, anifrolumab, or any combination thereof.

[0800] In some embodiments of the method of treatment or use, an antibody or antigen-binding fragment thereof that specifically binds to TL1A may be administered in combination with another therapeutically active compound selected from the group: acitretin, apremilast, methotrexate, or any combination thereof. Furthermore, the subject may receive topical therapy concurrently.

[0801] In some embodiments of the method of treatment or use, an antibody or antigen-binding fragment thereof that specifically binds to TL1A may be administered in combination with another therapeutically active compound that is selected from the group: methotrexate, tacrolimus, mycophenolate mofetil, azathioprine, or any combination thereof.

[0802] The antibody or antigen-binding fragment thereof that specifically binds to TL1A and the pharmaceutical composition of the present invention are suitable for parenteral administration in the form of sterile drugs intended for administration into the body of a subject with damage to the integrity of the skin or mucous membranes, bypassing the gastrointestinal tract by injection or infusion. In particular, it is contemplated that parenteral administration includes, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, ​​intracranial, intra-articular, transdermal injection or infusion; and renal dialysis infusion techniques.

[0803] In some embodiments of the method of treatment or use, the antibody or antigen-binding fragment thereof that specifically binds to TL1A, or the pharmaceutical composition is administered intravenously.

[0804] In some embodiments, intravenous administration is carried out by infusion, prolonged infusion, or long-term continuous infusion.

[0805] In some embodiments of the method of treatment or use, the antibody or antigen-binding fragment thereof that specifically binds to TL1A, or the pharmaceutical composition is administered subcutaneously.

[0806] In some embodiments, subcutaneous administration is performed by subcutaneous injection.

[0807] In some embodiments of the method of treatment or use, a suitable dose of the monoclonal antibody or antigen-binding fragment thereof that specifically binds to TL1A according to the present invention will be in the range of 0.1-200 mg / kg.

[0808] Brief description of drawings

[0809] Figure 1 is a map of an expression vector for transient protein production in eukaryotic cells carrying the genetic sequence of human TL1A (TNFSF15) antigen.

[0810] Figure 2 is a map of an expression vector for transient protein production in eukaryotic cells carrying the genetic sequence of the heavy chain of the TL1A antibody of the invention.

[0811] Figure 3 is a map of a vector for transient protein production in eukaryotic cells carrying the genetic sequence of the light chain of the anti-TL1A antibody of the invention.

[0812] Comments for figures 1-3.

[0813] Name Transcript eCMV pCMV A regulatory element consisting of an enhancer (eCMV) and a promoter (pCMV) of cytomegalovirus CMV, required for the initiation of transcription of mRNA of the target transgene (TL1A antigen or antibodies of the invention). AV MLP The adenovirus major late promoter (ADEN) is required to enhance mRNA transcription of the target transgene (TL1A antigen or antibodies of the invention) via a cap-independent mechanism, without the involvement of eIF-4F (eukaryotic initiation factor). The chimeric intron stabilizes the target mRNA and increases the likelihood of its nuclear transport. Cossack The Kozak consensus sequence surrounding the start codon and required to enhance translation initiation of the target transgene (TL1A antigen or antibodies of the invention). SP Signal peptide is an N-terminal amino acid sequence that ensures co- or post-translational transport of the target transgene (TL1A antigen or antibodies according to the invention) to the secretion pathway from the cell into the culture fluid. PM Peptide tag to facilitate purification of TL1A antigen. Linker A flexible glycine-serine linker separating the TL1A target antigen from the peptide tag. TL1A (TNFSF15) TL1A (TNFSF15) antigen sequence. VH The variable domain of the heavy chain of the antibodies of the invention. HC IgG1 The sequence of the constant domains of the human IgG1 heavy chain (CH1, CH2, and CH3), as well as its hinge region. This sequence may be wild-type or include the following amino acid substitutions, which are selected from the group: 1) deletion of 446G and 447K, or 2) mutations L234A and L235A, or 3) mutations M252Y, S254T, T256E, or any combination thereof. According to the amino acid numbering of EU antibodies. VL Light chain variable domain of antibodies of the invention CK Sequence of the constant domain of the light chain of human immunoglobulin IgG1 of the kappa family. Stop Stop codon(s) for termination of translation of the target transgene (antibodies of the invention). poly(A) Polyadenylation signal for transcription termination and mRNA polyadenylation. EBNA1 website The Epstein-Barr virus regulatory element is a 20-fold repeat of the EBNA1 protein binding site, which directs the plasmid to transcriptionally active regions of the cell nucleus. It functions as a "eukaryotic origin of replication." pAmpR A weak constitutive promoter of the beta-lactamase gene. Activates beta-lactamase gene expression in response to changes in peptide glycan (PG) metabolite levels that occur during exposure to β-lactams (antibiotics). AmpR A sequence encoding a beta-lactamase that hydrolyzes the beta-lactam ring of a corresponding group of antibiotics. It provides prokaryotic cells (e.g., E. coli) with resistance to ampicillin. ori A high-copy origin of replication that functions in prokaryotic cells (e.g., E. coli).

[0814] Figure 4 is a map of a vector for continuous protein production in eukaryotic cells carrying the genetic sequence of the heavy chain of the TL1A antibody of the invention.

[0815] Figure 5 is a map of a vector for continuous protein production in eukaryotic cells carrying the genetic sequence of the light chain of the anti-TL1A antibody of the invention.

[0816] Comments for figures 4-5.

[0817] Name Transcript HS4 Hypersensitive open chromatin site 4; an insulator used to enhance the efficiency of transgene transcription by unwinding nearby chromatin. eCMV pEF-1α A hybrid regulatory element consisting of a cytomegalovirus CMV enhancer and a promoter of the eukaryotic translation elongation factor EF-1α, which are necessary for the initiation of transcription of the mRNA of the target transgene (encoding the antibodies of the invention); as well as an EF-1α intron, which increases the stability of this mRNA. Cossack The Kozak consensus sequence surrounding the start codon and required to enhance translation initiation of the target transgene (TL1A antigen or antibodies of the invention). SP Signal peptide - an N-terminal amino acid sequence that ensures co- or post-translational transport of antibodies according to the invention to the secretion pathway from the cell to the culture fluid. VH The variable domain of the heavy chain of the antibodies of the invention. HC IgG1 The sequence of the constant domains of the human IgG1 heavy chain (CH1, CH2, and CH3), as well as its hinge region. This sequence may be wild-type or include the following amino acid substitutions, which are selected from the group: 1) deletion of 446G and 447K, or 2) mutations L234A and L235A, or 3) mutations M252Y, S254T, T256E, or any combination thereof. According to the amino acid numbering of EU antibodies. VL The variable domain of the light chain of the antibodies of the invention. CK Sequence of the constant domain of the light chain of human immunoglobulin IgG1 of the kappa family. Stop Stop codon for termination of translation of the target transgene (antibodies according to the invention). poly(A) Polyadenylation signal for transcription termination and mRNA polyadenylation. MAR The MAR (matrix attachment region) region of the human β-globin gene is used to maintain the copy number of the episome in eukaryotic cells by binding to the nuclear matrix during interphase, as well as to enhance the efficiency of expression of the target transgene (antibodies according to the invention) due to partial insulator properties for unwinding nearby chromatin. ori A high-copy origin of replication that functions in prokaryotic cells (e.g., E. coli). AmpR A sequence encoding a beta-lactamase that provides prokaryotic cells (e.g., E. coli) with resistance to ampicillin. pAmpR Constitutive promoter of the beta-lactamase gene. pSV40 Eukaryotic promoter of simian virus SV-40 required for constitutive expression of the selectable marker resistance gene in mammalian cells. PurR Puromycin resistance gene. Allows selection of transfected mammalian cell cultures. BsR Blasticidin resistance gene. Allows selection of transfected mammalian cell cultures.

[0818] Figure 6 is a graph showing the interaction evaluation of antibody 01-001 with CHO-tmTL1A cells expressing the membrane-associated form of human TL1A.

[0819] Figure 7 is a graph of the inhibition of interferon gamma (IFNγ) release by antibody 01-001 in response to TL1A on primary cells activated by IL-12 and IL-18.

[0820] Figure 8 is a graph of the inhibition of tumor necrosis factor alpha (TNFα) release by antibody 01-001 in response to TL1A on primary cells activated by IL-12, IL-18, and IL-15.

[0821] Figure 9 is a graph showing the inhibition of IL-13 release by antibody 01-001 in response to TL1A on primary cells activated by IL-12, IL-18, and IL-15.

[0822] Figure 10 is a graph showing the inhibition of IL-6 release by antibody 01-001 in response to TL1A on primary cells activated by IL-12, IL-18, and IL-15.

[0823] Figure 11 is a graph showing the inhibition of IL-17 release by antibody 01-001 in response to TL1A on primary cells activated by IL-12, IL-18, and IL-15.

[0824] Figure 12 is a graph showing the inhibition of IL-5 release by antibody 01-001 in response to TL1A on primary cells activated by IL-12, IL-18, and IL-15.

[0825] Figure 13 is a graph showing the inhibition of GM-CSF release by antibody 01-001 in response to TL1A on primary cells activated by IL-12, IL-18, and IL-15.

[0826] Figure 14 is a graph showing the results of the comparison of the efficacy of antibody 01-001 with the placebo control in the TNBS-induced ulcerative colitis rat model.

[0827] Examples

[0828] For a better understanding of the invention, the following examples are provided. These examples are provided for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0829] Materials and General Methods

[0830] General information concerning the nucleotide sequences of the light and heavy chains of human immunoglobulin is given in: Kabat EA et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, 1991. The amino acids of the antibody chains are numbered according to the EU numbering (Edelman GM et al., Proc. Natl. Acad. Sci. USA 63, 1969, ee. 78-85; Kabat EA et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, 1991).

[0831] Recombinant DNA methods

[0832] DNA manipulations were performed using standard methods described in Sambrook J. et al., Molecular cloning: A laboratory manual; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989. Molecular biology reagents were used according to the manufacturers' instructions.

[0833] Gene synthesis

[0834] The desired gene segments were obtained from oligonucleotides created by chemical synthesis. Gene segments ranging from 300 to 1400 bp in length, flanked by unique restriction sites, were assembled by annealing and ligation of the oligonucleotides, including PCR amplification and subsequent cloning via restriction sites. The DNA sequences of the cloned gene fragments were confirmed by DNA sequencing.

[0835] DNA Sequencing

[0836] DNA sequences were determined by Sanger sequencing.

[0837] DNA and protein sequence analysis and sequence data processing

[0838] Unipro UGENE version 1.29 and SnapGene version 6.1 software packages were used to generate, map, analyze, annotate, and illustrate sequences.

[0839] Expression vectors

[0840] To produce the antibodies described in the application materials, genetic constructs designed for transgene expression in eukaryotic cells (e.g., Chinese hamster ovary (CHO) cells) and for maintaining plasmid copy number in prokaryotic cells (e.g., E. coli) were used. In addition to the transgene encoding the antibody sequence, the vectors contained all the necessary elements for protein expression in eukaryotic cells, as well as all the necessary elements for maintaining plasmid copy number in prokaryotic cells.

[0841] Fusions of genes containing the described antibody chains, as described below, were achieved by PCR and / or gene synthesis and assembly using known recombination methods and procedures by joining corresponding nucleic acid segments, for example, by using unique restriction sites in the corresponding vectors. The resulting nucleotide sequences were confirmed by DNA sequencing. For transfection of eukaryotic cells, large quantities of plasmids were generated by obtaining them from transformed E. coli cultures.

[0842] Example 1. Production of recombinant TL1A antigens.

[0843] Soluble recombinant TL1A (TNFSF15) protein from humans (Homo sapiens), rhesus macaques (Macaca mulatta), cynomolgus monkeys (Macaca fascicularis), rats (Rattus norvegicus), and mice (Mus musculus) was produced in the CHO-K1 suspension cell line using transient transfection. Antigens for immunization, selection, kinetic, and cellular assays included the secreted form of the human TL1A (TNFSF15) antigen (https: / / www.uniprot.org / uniprotkb / O95150) fused to various peptide tags. By analogy, we also used the secreted form of TNFSF15 from rhesus macaque (https: / / www.uniprot.org / uniprotkb / F6S8F9), cynomolgus macaque (https: / / www.uniprot.org / uniprotkb / G7PRK8), rat (https: / / www.uniprot.org / uniprotkb / Q8K3Y7) and mouse (https: / / www.uniprot.org / uniprotkb / Q5UBV8).

[0844] To produce the described antigens, plasmid variants were used, designed both for short-term transgene expression in eukaryotic cells (e.g., Chinese hamster ovary (CHO) cells) and for maintaining copy number in prokaryotic cells (e.g., E. coli). The nucleotide sequences of the genes encoding the above-described antigens were obtained by de novo synthesis. The sequences were codon-optimized for expression in CHO cells. The resulting sequences were then cloned into a plasmid vector either at SalI / NotI restriction sites or using ligase-free molecular cloning methods. Assembly accuracy was determined using Sanger sequencing. The resulting genetic constructs contained all the necessary elements for protein expression in eukaryotic cells, as well as all the necessary elements for maintaining plasmid copy number in prokaryotic cells. As an example, Figure 1 shows a map of a vector encoding human TL1A as a transgene.

[0845] Antigens were produced in a constant cell line derived from Chinese hamster ovary cells (CHO-K1 line) according to published protocols [Biotechnol Bioeng. 2005 Sep 20; 91(6):670–677, Liao Metal., 2004; Biotechnol Lett. 2006 Jun;28(11):843–848; Biotechnol Bioeng. 2003 Nov 5;84(3):332–342]. The day before transient transfection, the cell culture was subcultured into a separate flask. After reaching the optimal concentration, the cell culture was subcultured into bioreactors for further manipulations. Suspension cultivation was performed in flasks on an orbital shaker using serum-free media. For transient expression, cells were transfected using linear polyethyleneimine (PEI) mixed with plasmid DNA in RPMI medium B in separate tubes. Transfection efficiency was then assessed using a flow cytometer and a technique well known in the art.Forty-eight hours after transient transfection, cell culture supplements were added to the cells and they were cultured for 5-6 days. At the end of the culture period, the culture fluid was clarified using a filtration system.

[0846] Purification of the obtained antigens was carried out in two stages. The first stage used metal chelate affinity chromatography. The second stage was performed by size-exclusion chromatography.

[0847] Example 2. Obtaining variable domain sequences of anti-TL1A antibodies by selection in a naive human antibody Fab library.

[0848] Human TL1A (TNFSF15) antigen was immobilized on the surface of specifically treated tubes for three rounds of selection using phage display. For the third round of selection, rat TNFSF15 antigen was immobilized using the same method. For the fourth round of selection, human TL1A (TNFSF15) antigen was used. The fifth and sixth rounds of selection (if necessary) were performed with both human TL1A antigen and rat and mouse TNFSF15 (for different libraries).

[0849] All of the above antigens were immobilized on the surface of specifically treated tubes. The tubes were then washed with phosphate-buffered saline containing 0.1% Tween 20 and blocked with a solution of skim milk or bovine serum albumin in the same phosphate-buffered saline. A naive library of human antibodies was used as a selection library. For this, it was diluted in phosphate-buffered saline with the addition of skim milk and an additional neutral protein with the peptide tags used in the above-mentioned TL1A antigens (to filter out non-specifically binding phage particles). Immunotubes with immobilized antigen were then incubated with the libraries.

[0850] Unbound phage particles were removed by several washes with phosphate-buffered saline containing 0.1% Tween 20. Antigen-bound phage particles were eluted with glycine-HCl buffer (pH 2.2), after which the solution was neutralized with 1 M Tris-HCl (pH 7.6). E. coli cells were infected with phages, cultured, and used in the next round of selection. Enrichment of libraries for target antigens and assessment of the presence of nonspecifically binding phage particles were performed using enzyme-linked immunosorbent assay (ELISA) of the polyclonal phage preparation.

[0851] For ELISA, target antigens of TL1A (TNFSF15) from humans, rhesus macaques, cynomolgus monkeys, mice, and rats, as well as non-target neutral proteins with peptide tags used in the target TL1A antigens, were immobilized on high-sorption plates. The analysis was performed according to the standard ELISA protocol.

[0852] After the fifth and sixth rounds of selection on the target antigens TL1A (TNFSF15), ELISA of the polyclonal phage preparation revealed sufficient library enrichment. Libraries with a signal to the target antigens TL1A (TNFSF15) greater than 5-fold higher than that of non-homologous control proteins were selected for monoclonal sequencing. Based on the polyclonal phage ELISA results, nine libraries were selected for extraction of phagemid DNA from E. coli cultures using the manufacturer's standard protocol (Qiagen). This DNA was then used to transform electrocompetent E. coli cells, followed by cell dissemination to produce monoclones and determination of the unambiguous sequence of the genetic constructs using Sanger sequencing (according to the standard protocol). As a result of sequencing, 115 clones were analyzed, which contained 21 unique combinations of Fab fragments of heavy and light chains of antibodies.Of these, one sequence was selected for further work based on non-obvious structural features, the degree of correspondence to the human sequence, and other criteria.

[0853] In this way, the sequences of the variable domains of the antibody 01-001, which specifically binds to TL1A (TNFSF15), were obtained.

[0854] Example 3. Obtaining variable domain sequences of anti-TL1A antibodies by selection in immune libraries.

[0855] Recombinant soluble human TL1A antigens with different peptide tags were used to immunize several guanaco (Lama guanicoe) individuals. Each individual received alternating antigens with different peptide tags to minimize off-target immune responses.

[0856] In some cases, guanacos were injected weekly with human TL1A antigen in Freund's adjuvant for 6 weeks. Before each new antigen injection, 25 ml of blood was collected for subsequent isolation of the peripheral blood mononuclear cell (PBMC) fraction.

[0857] In some cases, guanacos were injected with human TL1A antigen in Freund's adjuvant for 16 weeks. Before each new antigen injection, 25 ml of blood was collected for subsequent PBMC isolation.

[0858] The obtained blood sera were analyzed by ELISA according to a standard protocol to determine antibody titers to the human TL1A antigens used. Blood samples with antibody titers that met the accepted internal criteria were used as the starting material for PBMC isolation.

[0859] The PBMC fraction was isolated from the blood of immunized animals. Total RNA was then isolated. The isolated RNA served as a template for cDNA synthesis using reverse transcriptase and random hexamer and oligo(dT) oligonucleotides as primers.

[0860] Two phage libraries in Fab format were constructed from the isolated cDNA, containing combinations of sequences of the variable domains of the heavy chain of immunized guanacos and the light chains of humans (both kappa and lambda).

[0861] Human TL1A antigen was immobilized on the surface of specifically treated tubes for four rounds of phage display selection. The fifth round was conducted on the mouse TNFSF15 antigen. Selection was performed using the phage display method described above.

[0862] As a result of sequencing, four unique Fab fragment sequences of the heavy and light chains of antibodies were identified. All of these were submitted for screening by Koff.

[0863] Thus, the sequences of variable domains of the following antibodies of the invention were obtained: 03-001, 03-002, 04-001, 04-002.

[0864] Example 4. Obtaining sequences of variable domains of anti-TL1A antibodies that do not contain glycosylation sites in the CDR regions.

[0865] To eliminate a potential glycosylation site in CDR2 of the heavy chain variable domain of antibody 01-001, genetic constructs encoding the heavy chain variable domain of 01-001 with substitutions in CDR2 were synthesized (the sequences are presented in Table 1). In this way, the sequences of the variable domains of the following antibodies of the invention were obtained: 05-001, 05-002, 05-006, 05-008, 05-010, 05-011, 05-013, 05-014, 05-015. The sequence of the light chain variable domain of antibody 01-001 was used as the light chain variable domain of all the listed antibodies of the invention.

[0866] Table 1. Sequences of the CDR2 regions of the variable domains of the heavy chains of the antibodies of the invention (numbering according to Kabat E.A. et al., 1991). Antibody Heavy chain CDR2 sequence Replacement for 01-001 01-001 EINHSGNTDYNPSLKS - 05-001 EIQHSGNTDYNPSLKS N52Q 05-002 EIAHSGNTDYNPSLKS N52A 05-006 EIGHSGNTDYNPSLKS N52G 05-008 EIIHSGNTDYNPSLKS N52I 05-010 EILHSGNTDYNPSLKS N52L 05-011 EIMHSGNTDYNPSLKS N52M 05-013 EISHSGNTDYNPSLKS N52S 05-014 EITHSGNTDYNPSLKS N52T 05-015 EIVHSGNTDYNPSLKS N52V

[0867] Example 5. Obtaining genetic constructs encoding sequences of full-length antibodies against TL1A for production in eukaryotic cells.

[0868] The nucleotide sequences of the variable domains of antibodies were synthesized de novo. The sequences were codon-optimized for expression in CHO. Cloning of the selected variable domain sequences into expression vectors containing the constant domain sequences of human IgG1 immunoglobulin was performed using standard methods. For this purpose, PCR products containing the genes for the variable domains of the heavy and light chains of antibodies were generated. During PCR, the necessary overlaps (sequence regions identical for both the insert and the vector) of 20-30 nucleotides were added to the 5' and 3' ends of the molecule for subsequent molecular cloning using ligation-free methods.

[0869] The heavy chain variable domain was cloned into a vector containing the sequence encoding the constant domains of the human IgG1 immunoglobulin heavy chain.

[0870] In some cases, the resulting vector contained all the necessary elements for transient protein production in eukaryotic cells (for example, in Chinese hamster ovary (CHO) cells). A schematic map of such a vector is shown in Figure 2.

[0871] In some cases, the resulting vector contained all the necessary elements for continuous protein production in eukaryotic cells (for example, in Chinese hamster ovary (CHO) cells). A schematic map of such a vector is shown in Figure 4.

[0872] The light chain variable domain was cloned into a vector containing the sequence of the light chain constant domain of the kappa family immunoglobulin IgG1.

[0873] In some cases, the resulting vector contained all the necessary elements for transient protein production in eukaryotic cells (for example, in Chinese hamster ovary (CHO) cells). A schematic map of such a vector is shown in Figure 3.

[0874] In some cases, the resulting vector contained all the necessary elements for continuous protein production in eukaryotic cells (for example, in Chinese hamster ovary (CHO) cells). A schematic map of such a vector is shown in Figure 5.

[0875] Assembly accuracy was determined using Sanger sequencing. The resulting genetic constructs contained all the necessary elements for protein expression in eukaryotic cells.

[0876] Example 6. Production and purification of antibodies against TL1A.

[0877] In some cases, full-length antibodies were produced in Chinese hamster ovary cell culture (CHO-K1 line) using the genetic constructs described above for transient protein production in eukaryotic cells. Cell culture preparation and cultivation are described in Example 1.

[0878] In some cases, full-length antibodies were produced in Chinese hamster ovary cell culture (CHO-S line) using the genetic constructs described above for continuous protein production in eukaryotic cells.

[0879] Full-length antibodies were purified in two stages. The first stage involved affinity chromatography using a protein A ligand chromatographic sorbent. Viral inactivation was then performed, and the solution was filtered using a 0.22 µm filter. The second stage of chromatographic purification was performed using a multimodal anion exchange sorbent.

[0880] The purity of the obtained molecules was assessed by polyacrylamide gel electrophoresis (PAGE) using a technique well known in the art (Table 2).

[0881] The purity of the obtained molecules was further assessed using high-performance liquid chromatography (HPLC) technique, which is well known in the art (Table 2).

[0882] Table 2. Monomer content according to HEF and HPLC results.

[0883] Antibody Monomer content (VEF), % Monomer content (HPLC), % 01-001 95,8 87,1 03-001 84,0 98,7 03-002 82,3 99,4 04-001 86,5 97,6 04-002 91,2 96,9 05-001 88,2 83,1 05-002 87,0 87,1 05-006 88,0 83,3 05-008 85,9 80,5 05-010 88,1 76,4 05-011 84,4 76,7 05-013 88,4 83,4 05-014 86,5 80,1 05-015 85,6 79,0

[0884] Example 7. Determination of the dissociation constant of antibodies according to the invention with TL1A (TNFSF15) of humans and animals by the method of biolayer interferometry.

[0885] The interaction of the obtained antibodies with TL1A antigens was assessed using biolayer interferometry on a ForteBio Octet RED 384 instrument using specialized AR2G sensors (ForteBio). The protein was immobilized on the surface of activated sensors, followed by quenching of unreacted groups, recording of the baseline, recording of analyte association, and recording of analyte dissociation. Recording of the baseline, like all other stages of the analysis, was carried out in a kinetic buffer solution (based on Na2HPO4 and KH2PO4, with the addition of NaCl, KCl, 0.1% Tween 20, 0.1% bovine serum albumin). The obtained data were processed using Octet Data Analysis software (version 9.0) using the 1:1 interaction model. The processing results are presented in Tables 3-5.

[0886] Table 3. Equilibrium dissociation constants (KD) of antibodies and human TL1A based on kinetic tests using ForteBio. Antibody KD, mol / l kon, 1 / (Mc) kdis, 1 / c 01-001 The sensitivity limit of the device has been exceeded (<1*10-12) 3,83*105 The sensitivity limit of the device has been exceeded (<1*10-7) 03-001 4,84*10-10 5,80*105 2,81*10-4 03-002 2,73*10-10 6,15*105 1,68*10-4 04-001 9,29*10-12 2,93*105 2,72*10-6 04-002 The sensitivity limit of the device has been exceeded (<1*10-12) 2,81*105 The sensitivity limit of the device has been exceeded (<1*10-7) 05-001 4,43*10-8 2,92*105 1,29*10-4 05-002 1,98*10-10 4,29*105 2,35*10-4 05-006 5,87*10-10 3,88*105 2,28*10-4 05-008 1,81*10-10 3,82*105 2,34*10-4 05-010 1,81*10-10 4,24*105 2,07*10-4 05-011 6,40*10-10 3,69*105 2,36*10-4 05-013 6,39*10-10 3,02*105 1,93*10-4 05-014 7,11*10-10 3,38*105 2,40*10-4 05-015 2,58*10-10 4,71*105 2,88*10-4

[0887] Thus, all the antibodies studied according to the invention have a high degree of interaction with human TL1A.

[0888] Table 4. Equilibrium dissociation constants (KD) of antibodies and TL1A (TNFSF15) from rhesus macaque and cynomolgus macaque (with identical sequence) as measured by kinetic assays using ForteBio.

[0889] Antibody KD, mol / l kon, 1 / (Mc) kdis, 1 / c 01-001 4,93*10-12 2,16*105 1,06*10-6 03-001 1,64*10-9 2,46*105 4,03*10-4 03-002 8,63*10-10 2,23*105 1,93*10-4

[0890] Thus, all of the above antibodies of the invention have a high degree of interaction with TL1A (TNFSF15) of rhesus macaque and cynomolgus macaque (the sequences are identical).

[0891] Table 5. Equilibrium dissociation constants (KD) of antibodies and rat TL1A (TNFSF15) based on kinetic tests using ForteBio. Antibody KD, mol / l kon, 1 / (Mc) kdis, 1 / c 01-001 1,44*10-11 2,34*105 3,38*10-6 03-002 4,08*10-9 4,63*106 1,89*10-2

[0892] Thus, all of the above antibodies of the invention have a high degree of interaction with rat TL1A (TNFSF15).

[0893] Example 8. Evaluation of the affinity of antibodies of the invention to TL1A (TNFSF15) in humans and animals by surface plasmon resonance (SPR).

[0894] The interaction of 01-001 with human and animal TL1A (TNFSF15) antigens was assessed by surface plasmon resonance (SPR) on a Biacore 8K analyzer. The antigens were immobilized via amine binding on the surface of a sensor chip based on carboxymethylated dextran (CM5). TL1A (TNFSF15) antigens of human, rhesus macaque, cynomolgus macaque, green monkey, ferret, pig, rabbit, and rat were diluted in kinetic sodium phosphate buffer (PBS) supplemented with KCl, NaCl, and Tween 20; and passed over the plate surface using an immobilizing buffer solution based on C2H3NaO2 (pH 4.0 ± 0.1). Next, the plate surface was activated by introducing a mixture of activators, after which the antibody solution was introduced. The level of immobilization was monitored by changes in surface plasmon resonance.To correct for possible signal distortion, one of the detection channels was used as a reference; that is, the antibody solution was not injected through this channel at the corresponding stage. Deactivation of active carboxyl groups was performed using a kinetic solution.

[0895] The calculated values ​​of equilibrium dissociation constants (KD) are presented in Table 6.

[0896] Table 6. Equilibrium dissociation constants (KD) of 01-001 and TL1A (TNFSF15) of humans and animals (with assessment of the identity of the amino acid sequences of the secreted portion of animal TNFSF15 relative to human TNFSF15).

[0897] View Identity of TL1A with Homo sapiens, % TL1A encoding in the UniProt database KD with TL1A antigen, mol / l Human 100 O95150 7,96×10-11 Green monkey 99 A0A0D9RKK8 6,84×10-9 Javan macaque 98 G7PRK8 7,60×10-10 Rhesus macaque 98 F6S8F9 7,60×10-10 Ferret 88 M3XRG1 5,88×10-10 Pig 87 I3LL00 7,54×10-10 Rabbit 83 G1T1T1 9,19×10-9 Rat 76 Q8K3Y7 6,74×10-11

[0898] Thus, the antibody 01-001 interacts with human TL1A antigen with high affinity, the obtained KD value was 7.96×10 -11M. Furthermore, 01-001 exhibits high affinity for TL1A (TNFSF15) in rhesus macaque, cynomolgus macaque, green monkey, ferret, pig, rabbit, and rat. Based on these data, rat, cynomolgus macaque, rhesus macaque, minipig, ferret, green monkey, and rabbit are relevant species for preclinical testing.

[0899] Example 9. Binding specificity of antibodies of the invention to human TL1A (TNFSF15) homologues.

[0900] To evaluate the off-target binding of antibody 01-001 to the closest homologues of human TL1A, the affinity of 01-001 was assessed with the proteins TRAIL (TNFSF10), FASL (TNFSF6), LIGHT (TNFSF14), EDA-A1 and EDA-A2, the extracellular portions of which are identical to the extracellular portion of human TL1A by 39%, 35%, 34%, 36% and 36%, respectively. The binding strength was assessed by biolayer interferometry on a ForteBio Octet RED 384 instrument using specialized AR2G sensors (ForteBio), according to the method described above. The study analyzed antigens with various peptide tags. Human TL1A, the preparation of which was described above, was used as a positive control.

[0901] The calculated values ​​of equilibrium dissociation constants (KD) are presented in Table 7.

[0902] Table 7. Equilibrium dissociation constants (KD) of 01-001 and human TL1A (TNFSF15) homologues based on kinetic assays using ForteBio Human antigen KD, mol / l kon, 1 / (Mc) kdis, 1 / c TL1A (TNFSF15) The sensitivity limit of the device has been exceeded (<1*10-12) 3,83*105 The sensitivity limit of the device has been exceeded (<1*10-7) TRAIL (TNFSF10) -- No binding detected -- FASL (TNFSF6) -- No binding detected -- LIGHT (TNFSF14) -- No binding detected -- EDA-A1 -- No binding detected -- EDA-A2 -- No binding detected --

[0903] Thus, the applied method demonstrated no interaction between antibody 01-001 and any of the tested tumor necrosis factor (TNF) family proteins, but did demonstrate binding to human TL1A on the same plate on which the homologous proteins were tested. Thus, antibody 01-001 is highly selective for binding to human TL1A, but not to its closest homologous proteins in the TNF family.

[0904] Example 10. Determination of thermal stability of antibodies of the invention.

[0905] Thermal stability of the antibody was assessed by thermal stress at 50°C for 48 hours in three buffer solutions of different compositions: buffer solution 1 with pH 5.0, buffer solution 2 with pH 6.0, and buffer solution 3 with pH 7.0. Homogeneity control was performed using SEC HPLC, a well-known method in this field. The results of the study are presented in Tables 7–9.

[0906] Table 7. Results of the study of intact and thermostatted samples of antibody 01-001 in buffer solution 1 with pH 5.0 by HPLC.

[0907] Thermostating time, h Monomer content, % High molecular weight impurities, % Low molecular weight impurities, % 0 87,0 12,7 0,3 24 86,8 11,0 2,2 36 85,1 12,3 2,6 48 85,0 12,1 2,9

[0908] Table 8. Results of the study of intact and thermostatted samples of antibody 01-001 in 20 mM buffer solution 2 with pH 6.0 by HPLC.

[0909] Thermostating time, h Monomer content, % High molecular weight impurities, % Low molecular weight impurities, % 0 87,2 12,4 0,4 24 86,0 12,0 2,0 36 85,8 12,1 2,1 48 85,5 12,0 2,5 Table 9. Results of the study of intact and thermostatted samples of antibody 01-001 in buffer solution 3 with pH 7.0 by HPLC. Thermostating time, h Monomer content, % High molecular weight impurities, % Low molecular weight impurities, % 0 86,3 13,3 0,4 24 84,5 13,6 1,9 36 83,7 14,0 2,3 48 82,0 15,4 2,6

[0910] Thus, the change in the area of ​​the main peak (monomer 01-001) in the three studied buffer solutions upon heating for 48 hours was 2.0-4.3%, indicating high thermal stability of the antibody 01-001.

[0911] Example 11. Determination of the aggregation temperature of antibodies according to the invention.

[0912] Next, the aggregation temperature of antibody 01-001 was determined using a dynamic light scattering (DLS) method, which is well known in the art.

[0913] The aggregation temperature determination consisted of the following steps: determination of the antibody aggregation temperature by DLS, incubation of the antibody at 50°C for 48 hours, analysis of the incubation samples by HPLC, and particle size analysis of the samples by DLS. Intact samples were used as a control—the test antibody in the above-mentioned buffer solutions, which were not incubated at 50°C for 48 hours but stored at 2-8°C. The study results are presented in Table 10.

[0914] Table 10. Results of the study of intact and thermostatted samples of antibody 01-001 by the DLS method using HPLC.

[0915] Buffer solution Before thermal stress After thermostress Radius of the target fraction, Rh, nm PD of the target fraction, % Intensity of target fraction Average particle radius, Rh, nm Radius of the target fraction, Rh, nm PD of the target fraction, % Intensity of target fraction Average particle radius, Rh, nm No. 1 (pH 5.0) 5,7 11,5 94,8 6,0 6,0 18,7 94,1 6,0 No. 2 (pH 6.0) 6,3 29,2 100 5,6 But But But But No. 3 (pH 7.0) 6,1 9,9 100 5,8 7,0 23,4 98,9 6,2

[0916] Note: PD - polydispersity; n / a - not determined.

[0917] The aggregation temperatures of antibody 01-001 obtained during the analysis were: 65.92°C for buffer solution 1 (pH 5.0); 66.03°C for buffer solution 2 (pH 6.0), and 63.99°C for buffer solution 3 (pH 7.0).

[0918] Example 12. Determination of the melting temperature of the antibodies of the invention.

[0919] The melting point of antibody 01-001 was determined using differential scanning fluorometry (DSF). According to this method, sample stability is directly proportional to the difference between the temperatures of the blank solution (the solution containing the antibody) and the sample. The results are presented in Table 11.

[0920] Table 11. Melting temperatures of samples 01-001 Sample Group of peaks on the melting curve, °C Bin A Bin B Bin C Bin D Bin E Bin F Bin G Bin H Buffer solution 1 (pH 5.0) n / a n / a 55,0 n / a n / a n / a n / a n / a Antibody 01-001 in buffer solution 1 (pH 5.0) 47,4 51,2 54,8 60,9 65,2 71,5 75,4 n / a Buffer solution 2 (pH 6.0) 55,2 n / a n / a n / a n / a n / a n / a n / a Antibody 01-001 in buffer solution 2 (pH 6.0) 55,3 63,0 70,3 73,4 75,7 n / a n / a n / a Buffer solution 3 (pH 7.0) 55,2 n / a n / a n / a n / a n / a n / a n / a Antibody 01-001 in buffer solution 3 (pH 7.0) 55,0 64,8 67,3 70,3 77,5 n / a n / a n / a

[0921] Note: n / a - value not detected.

[0922] The melting points of antibody 01-001 obtained during the analysis were: 47.4-60.9°C for buffer solution 1 (pH 5.0); 64.8°C for buffer solution 2 (pH 6.0), and 63.0°C for buffer solution 3 (pH 7.0).

[0923] Example 13. Determination of changes in the kinetic properties of antibodies according to the invention upon prolonged heating.

[0924] To further evaluate the stability of antibody 01-001, we determined changes in its kinetic properties after the previously described incubation at 50°C for 48 hours in three different buffer solutions. The affinity of 01-001 samples to human TL1A was assessed using biolayer interferometry on a ForteBio Octet RED 384 instrument and specialized AR2G sensors (ForteBio), as described previously. The study results are presented in Table 12.

[0925] Table 12. Equilibrium dissociation constants (KD) of intact and thermostatted samples of antibody 01-001 with human TL1A in different buffer solutions

[0926] Buffer solution Time of exposure to temperature 50°C, h KD, mol / l kon, 1 / (Mc) kdis, 1 / c Buffer solution 1 (pH 5.0) 0 3,85*10-11 4,53*105 1,74*10-5 24 1,36*10-11 3,95*105 5,38*10-6 36 1,04*10-11 3,98*105 4,12*10-6 48 1,87*10-11 3,89*105 7,27*10-6 Buffer solution 2 (pH 6.0) 0 <1*10-12 4,55*105 3,77*10-7 24 3,35*10-11 5,01*105 1,68*10-5 36 4,11*10-11 4,57*105 1,88*10-5 48 5,12*10-11 4,36*105 2,23*10-5 Buffer solution 3 (pH 7.0) 0 1,25*10-11 3,65*105 4,55*10-6 24 2,88*10-11 3,70*105 1,06*10-5 36 2,54*10-11 3,68*105 9,32*10-6 48 3,29*10-11 3,58*105 1,18*10-5

[0927] Based on the experimental results, antibody 01-001 has significant heat stability over a long period of time while maintaining high affinity for human TL1A.

[0928] Example 14. Determination of post-translational modifications of antibodies of the invention.

[0929] To determine post-translational modifications of antibody 01-001, the presence and profile of glycosylation of the molecule, the presence of calculated disulfide bonds, the content and position of trisulfides, thioesters and free cysteines were checked; as well as their changes after the previously described incubation of 01-001 in three buffer solutions at 50°C for 48 hours.

[0930] In this analytical experiment, post-translational modifications of samples 01-001 were determined using ultra-high-pressure high-performance chromatography with mass spectrometric detection. The post-translational modification library, which served as the basis for analyzing and processing all submitted samples, was assembled using standard samples (N-terminal form of glutamic acid, succinimide form of asparagine and glutamine, etc.) and antibody 01-001 in three buffer solutions described previously. Data obtained during the analytical experiment were processed using Protein Metrics software.

[0931] The study confirmed the native molecular weight of antibody 01-001. It was shown that antibody 01-001 occupies two standard N-glycosylation sites of IgG1 immunoglobulins (at residue Asn297 in the CH2 constant domain of the heavy chain). Glycosylation of the Fab domain was not detected. These results indicate that the theoretical N-glycosylation site in CDR2 of the variable domain of the heavy chain of antibody 01-001 is unoccupied.

[0932] No oxidized forms of methionine or tryptophan were detected in samples 01-001, nor was the N-terminal pyroform of glutamic acid detected. An analytical experiment confirmed the location of disulfide bonds in 01-001. No miscrosslinked disulfide bonds, trisulfides, or thioesters were detected.

[0933] No significant changes in post-translational modifications were detected after incubation of 01-001 at 50°C for 48 hours.

[0934] Example 15. Determination of the stability of antibodies according to the invention in human blood serum.

[0935] The stability of 01-001 in normal human serum was assessed for 14 and 28 days at 37°C. The ability of the 01-001 antibody to bind human TL1A was assessed after incubation under the specified conditions using ELISA according to a standard procedure. Briefly, recombinant TL1A was added to pretreated wells of a high-capacity plate, after which human serum samples containing a known amount of the 01-001 antibody (before incubation at 37°C) were added. After a series of washes, the reaction was developed using a horseradish peroxidase-conjugated polyclonal antibody to the Fc fragment of human IgG, and the optical density of the solution was determined using a spectrophotometer at a wavelength of 450 nm. Next, the content of 01-001 in the blood serum sample was determined based on the correlation of the obtained data and the calibration curve reflecting the dependence of the optical density of the solution on the concentration of the antibody.

[0936] The study showed that after 14 days of incubation in human serum at 37°C, 70% of the initially introduced 01-001 molecules were retained, and after 28 days, 63%. The average stability of IgG1 monoclonal antibodies in human serum is considered to be the retention of 60% of functional molecules for a month (28 days) at +37°C. Thus, the stability of the 01-001 antibody is above average.

[0937] Example 16. Interaction of antibodies of the invention with the membrane-associated form of human TL1A on the surface of cells.

[0938] The interaction of 01-001 with human TL1A on the surface of eukaryotic cells was assessed using CHO-tmTL1A cells, which stably express the membrane-associated form of human TL1A, by flow cytometry with commercial antibodies specific to the Fc fragment of human IgG labeled with phycoerythrin (PE). The CHO-K1-S cell line, which does not express the membrane-associated form of human TL1A, was used as a negative control.

[0939] Cell suspensions were incubated with serial dilutions of 01-001 on ice in the dark, then washed to remove unbound 01-001. The cell pellets were then incubated with secondary staining antibodies to the human IgG Fc fragment on ice in the dark. The cells were then washed to remove unbound secondary antibodies, resuspended in staining buffer, and fluorescence intensity was measured on a flow cytometer. The dependence of median fluorescence intensity on drug concentration was assessed. The results are presented in Figure 6.

[0940] Thus, 01-001 interacts with the membrane-associated form of human TL1A on the surface of eukaryotic cells. The magnitude of the observed effect is directly dependent on the concentration of 01-001, the EC value 50 are in the nanogram range (163.8 ng / ml).

[0941] Based on the obtained results, CHO-tmTL1A cells stably expressing the membrane-associated form of human TL1A were selected for further in vitro testing to investigate the potential mechanism of action of 01-001 and to evaluate the Fc-mediated functions of the antibody.

[0942] Example 17. Inhibition by antibodies of the invention of the interaction of soluble human TL1A with the human DR3 receptor on the surface of a cell line.

[0943] The effect of antibody 01-001 on the interaction of soluble TL1A with DR3 on the surface of the TF-1 NF-kB Luc cl.4 cell line was analyzed by flow cytometry using commercial human TL1A conjugated with a biotin label. For this, the cell suspension was incubated with serial dilutions of 01-001 and a solution of biotinylated TL1A, washed to remove unbound 01-001 and TL1A, after which the cell pellets were incubated with a solution of phycoerythrin-streptavidin conjugate on ice in the dark. The cells were washed to remove unbound conjugate, resuspended in staining buffer, and the fluorescence intensity was measured on a flow cytometer. The dependence of the median fluorescence intensity on the concentration of the drug was assessed. The EC value 50 amounted to 1113 ng / ml.

[0944] Thus, 01-001 inhibits the interaction of soluble human TL1A (TNFSF15) with the human DR3 receptor (TNFRSF25) on the surface of the TF-1 NF-kB Luc cl.4 cell line. The severity of the observed effect is directly dependent on the concentration of 01-001, the EC value 50 are in the microgram range (1113 ng / ml). This feature of 01-001 indicates its effectiveness in preventing the activation of the proinflammatory signaling cascade mediated by the interaction of TL1A with DR3.

[0945] Example 18. Comparison of the inhibition of the interaction of soluble human TL1A with the DR3 receptor and the DcR3 decoy receptor by the antibodies of the invention.

[0946] The ability of 01-001 to inhibit the interaction of TL1A with the DcR3 and DR3 receptors was assessed using ELISA according to the standard method. Briefly, soluble human DR3 (TNFRSF25) and human DcR3 (TNFRSF6B) proteins were immobilized on the surface of plate wells, after which serial dilutions of 01-001 were incubated with biotinylated human TL1A. Then, solutions of 01-001 with biotinylated TL1A were added to the immobilized receptors. Detection was carried out using a streptavidin-HRP conjugate, and the optical density (OD) signal was measured on a microplate reader. The percentage of inhibition of the interaction of TL1A with DR3 and TL1A with DcR3 by 01-001 was calculated. EC values 50 were 1.5 ng / ml for the interaction of TL1A with the cellular receptor DR3, and 67.7 ng / ml for the interaction of TL1A with the soluble decoy receptor DcR3.

[0947] The experimental results show that antibody 01-001 selectively inhibits the interaction of human TL1A with the target cellular receptor DR3, while inhibiting the interaction of TL1A with the decoy receptor DcR3, a natural antagonist of TL1A, much weaker (45 times).

[0948] Example 19. Inhibition of caspase-dependent apoptosis mediated by the interaction of TL1A and DR3 by antibodies of the invention.

[0949] T1A binding to the natural DR3 receptor, when cycloheximide disrupts the synthesis of the inhibitor of apoptosis protein 2 (cIAP2), which is part of the NFkB signaling pathway, leads to the activation of caspases and the induction of apoptosis. The ability of the antibodies of the invention to inhibit TL1A-mediated apoptosis in the presence of cycloheximide was assessed in a cell assay using the TF-1 cell line expressing the DR3 receptor. For this purpose, a cell suspension was incubated with serial dilutions of the antibodies of the invention and a solution of human TL1A in the presence of cycloheximide. A solution of a reagent for detecting caspase-3 / 7 by luminescence intensity was then added, and after additional incubation, the luminescence signal was measured on a plate reader. The study results are presented in Table 13.

[0950] Table 13. EC 50 values ​​for inhibition of caspase signaling in the TF-1 cell line by antibodies of the invention. Antibody EC50, ng / ml Antibody EC50, ng / ml 01-001 218 05-006 566 03-001 9585 05-008 450 03-002 1914 05-010 334 04-001 943 05-011 508 04-002 421 05-013 >15000 05-001 508 05-014 >15000 05-002 377 05-015 >15000

[0951] Thus, the above-mentioned antibodies of the invention inhibit the initiation of apoptosis mediated by the interaction of TL1A and DR3 in the presence of cycloheximide. The severity of the observed effect is directly dependent on the concentration of 01-001, the EC value 50 are in the nanogram range (218-287 ng / ml).

[0952] Example 20. Determination of the change in the inhibitory properties of antibodies according to the invention upon prolonged heating.

[0953] To further evaluate the stability of antibody 01-001, we determined changes in its functional properties for inhibiting TL1A-mediated apoptosis after the previously described incubation at 50°C for 48 hours in three different buffer solutions. Inhibitory activity was assessed using the previously described caspase-3 / 7 luminescence intensity detection assay. The study results are presented in Table 14.

[0954] Table 14. EC values 50 and the EU 90inhibition of caspase signaling of the TF-1 cell line by intact and thermostatted samples of antibody 01-001 in different buffer solutions

[0955] Buffer solution Time of exposure to temperature 50°C, h EC50, ng / ml EC90, ng / ml Buffer solution 3 (pH 7.0) 0 208,96 716 24 282,27 1234 36 308,19 1052 48 417,34 1350 Buffer solution 2 (pH 6.0) 0 316,82 993 24 540,21 1182 36 418,44 894 48 536,11 1300 Buffer solution 1 (pH 5.0) 0 517,71 1016 24 474,94 1217 36 339,41 985 48 433,32 1148

[0956] Based on the experimental results, the antibody 01-001 has significant heat stability over a long period of time while maintaining its biological properties of inhibiting caspase signaling mediated by the interaction of TL1A and DR3.

[0957] Example 21. Inhibition of NFkB signaling pathway activation mediated by TL1A and DR3 interaction by antibodies of the invention.

[0958] To further confirm the effect of the antibodies of the invention on TL1A-mediated DR3 activation, the efficiency of inhibition of the NFkB signaling pathway was assessed. A cell suspension of the TF-1 NF-kB reporter cell line Luc cl.4, which expresses the DR3 receptor and carries the luciferase gene under the control of an NFkB-responsive element, was incubated with serial dilutions of the antibodies of the invention and a solution of human TL1A at the same concentration. The presence of the luciferase enzyme was detected by measuring the luminescence signal on a microplate reader. The study results are presented in Table 15.

[0959] Table 15. EC values 50 inhibition of the NFkB signaling pathway of the TF-1 NF-kB Luc cl.4 cell line by antibodies of the invention.

[0960] Antibody EC50, μg / ml 01-001 0,72 03-001 9,67 03-002 6,36

[0961] Thus, the antibodies of the invention effectively inhibit the activation of the NFkB signaling pathway mediated by the interaction of TL1A and DR3. The observed effect is directly dependent on the concentration of the drugs; the EC value 50 are in the nano- and microgram concentration range.

[0962] Example 22. Inhibition of interferon gamma release in response to TL1A in the presence of IL-12 and IL-18 by antibodies of the invention.

[0963] IL-12 and IL-18 have been shown to induce TCR (T cell receptor)-independent interferon gamma (IFNγ) production in CD4+ T lymphocytes, and increasing the concentration of soluble TL1A or IL-15 (for example, during the development of inflammatory bowel diseases) can enhance this effect.

[0964] The ability of 01-001 to inhibit IFNγ release in response to TL1A was assessed in PBMCs isolated from healthy volunteer whole blood activated by IL-12 and IL-18 using enzyme-linked immunosorbent assay (ELISA). Briefly, PBMCs were incubated with solutions of human cytokines TL1A, IL-12, IL-18, and serial dilutions of 01-001 for 20-24 hours. PBMCs activated by IL-12 and IL-18 (without TL1A) were used as a control for TL1A-independent IFNγ release, and non-activated PBMCs (cell control) were used as a negative control for IFNγ release. After the incubation period, the amount of IFNγ in the supernatants was determined using ELISA, and the optical density signal was measured using a microplate reader. The results are presented in Figure 7.

[0965] Thus, 01-001 inhibits the release of IFNγ in response to TL1A on primary blood cells activated by IL-12 and IL-18. The observed effect is directly dependent on the concentration of 01-001; the EC value 50 are in the nanogram concentration range (496.5 ng / ml).

[0966] Example 23. Inhibition of cytokine release in response to TL1A in the presence of IL-12, IL-18 and IL-15 by antibodies of the invention.

[0967] The presence of soluble TL1A together with IL-12, IL-18 and IL-15 was shown to lead to a significant increase in the production of a wide range of pro-inflammatory cytokines such as IFNγ, IL-6, GM-CSF, IL-5, IL-13, TNFα and IL-22 in CD45RO+CD4+ T lymphocytes.

[0968] The ability of 01-001 to inhibit the release of cytokines TNFα, IL-13, IL-6, IL-17, IL-5, and GM-CSF in response to TL1A was assessed in T lymphocytes isolated from healthy volunteer PBMCs activated by IL-12, IL-18, and IL-15 using a multiplex assay. T lymphocytes activated by IL-12, IL-18, and IL-15 without TL1A were used as a control for TL1A-independent cytokine release, and non-activated T lymphocytes were used as a negative control for cytokine release.

[0969] T lymphocytes were incubated with solutions of human cytokines TL1A, IL-12, IL-18, and IL-15, along with serial dilutions of 01-001, for 96 hours. After incubation, the amounts of cytokines TNFα, IL-13, IL-6, IL-17, IL-5, and GM-CSF in the supernatants were determined using multiplex analysis, and the fluorescence signal was measured. The results are presented in Figures 8-13.

[0970] Thus, the antibody 01-001 inhibits the release of proinflammatory cytokines TNFα, IL-13, IL-6, IL-17, IL-5, GM-CSF by blood cells in response to TL1A along with IL-12, IL-18 and IL-15. The observed effect is directly dependent on the concentration of the drug 01-001; the EC value 50 are in the nanogram concentration range (12.07-126.6 ng / ml). According to the obtained results, the use of 01-001 will lead to a reduction in the severity of symptoms of diseases or disorders mediated by TL1A.

[0971] Example 24. Affinity of antibodies of the invention to Fcγ receptors

[0972] The affinity of 01-001 to Fcγ receptors (FcγRIIa-131H, FcγRIIa-131R, FcγRIIIa-158V, FcγRIIIa-158F, FcγRIIb, FcγRIIIb) was assessed by analyzing changes in surface plasmon resonance (SPR). The affinity of 01-001 to FcγRIa was assessed by biolayer interferometry (BLI). The calculated equilibrium dissociation constants (KD) are presented in Table 16.

[0973] Table 16. Equilibrium dissociation constants (KD) of 01-001 to Fcγ receptors

[0974] Sample Receptor affinity FcγRIIa-131H, KD (M) FcγRIIa-131R, KD (M) FcγRIIIa-158V, KD (M) FcγRIIIa-158F, KD (M) FcγRIIb, KD (M) Fc?RIa, KD (M) FcγRIIIb, cKD (M) 01-001 5,41×10-4 3,30×10-4 5,50×10-5 4.19x10-4 3,60×10-4 3,00×10-6 -*

[0975] * KD values ​​were not determined due to low affinity binding

[0976] Thus, 01-001 has low affinity for all Fcγ receptors.

[0977] Example 25. Affinity of antibodies of the invention to FcRn.

[0978] Evaluation of the affinity of a drug to the FcRn receptor is important, since the degree of binding to this receptor affects the circulation time of the drug in the bloodstream and its half-life in the body.

[0979] A comparative analysis of the affinity of 01-001 for the FcRn receptor was performed on a ForteBio Octet RED 384 instrument using the previously described method and specialized SA streptavidin biosensors (ForteBio). The assay was controlled by the PF-06480605 anti-TL1A antibody (Pfizer Inc., patent WO2021260577) and the adalimumab anti-TNF-alpha (tumor necrosis factor alpha) antibody. The calculated equilibrium dissociation constants (KD) are presented in Table 17.

[0980] Table 17. Affinity of antibody for FcRn receptor based on kinetic tests using ForteBio. Antibody KD, mol / l kon, 1 / (Mc) kdis, 1 / c 01-001 1,20*10-9 1,27*106 1,53*10-3 PF-06480605 1,04*10-8 2,14*106 2,23*10-2 Adalimumab 1,17*10-8 1,78*106 2,09*10-2

[0981] Conclusion: The test antibody of the invention has a high affinity for FcRn, exceeding that of the control antibodies.

[0982] Example 26. Affinity of antibodies of the invention to C1q.

[0983] The affinity of 01-001 for C1q was assessed using surface plasmon resonance (SPR) analysis. KD values ​​were not determined due to the low affinity binding of 01-001 to C1q.

[0984] Example 27. Evaluation of the induction of antibody-dependent cellular cytotoxicity (ADCC) by the antibodies of the invention.

[0985] The ability of 01-001 to induce antibody-dependent cellular cytotoxicity against cells expressing the membrane-associated form of TL1A was assessed in a reporter cell assay. CHO-tmTL1A cells were used as target cells, while Jurkat-based reporter cell lines carrying the gene encoding luciferase under the control of NFAT-responsive elements and expressing the high-affinity or low-affinity CD16 receptor served as effector cells. Suspensions of the target and effector cell lines were incubated with serial dilutions of 01-001, and the luminescence signal was measured using a microplate reader.

[0986] The experimental data showed that 01-001 did not induce antibody-dependent cellular cytotoxicity mediated by high-affinity and low-affinity CD16 receptor against CHO-tmTL1A cells expressing the membrane-associated form of TL1A.

[0987] Example 28. Evaluation of the induction of antibody-dependent cellular phagocytosis (ADCP) by the antibodies of the invention.

[0988] The ability of 01-001 to induce antibody-dependent cellular phagocytosis against cells expressing the membrane-associated form of TL1A was assessed in a reporter cell assay. CHO-tmTL1A cells were used as target cells, and Jurkat-based reporter cell lines carrying the gene encoding luciferase under the control of NFAT-responsive elements and expressing either the high-affinity CD32 receptor or the low-affinity CD32 receptor served as effector cells. Suspensions of target and effector cell lines were incubated with serial dilutions of 01-001, and the luminescence signal was measured using a microplate reader.

[0989] The experimental data showed that 01-001 did not induce antibody-dependent cellular phagocytosis against CHO-tmTL1A cells expressing the membrane-associated form of TL1A.

[0990] Example 29. Evaluation of induction of complement-dependent cytotoxicity (CDC) by antibodies of the invention.

[0991] The ability of 01-001 to induce complement-dependent cytotoxicity was assessed using a cell-based assay in which CDC is determined by a decrease in cell viability and their ability to metabolize the vital dye resazurin, which in turn leads to a decrease in fluorescence signal.

[0992] CHO-tmTL1A cells expressing the membrane-associated form of TL1A were used as target cells.

[0993] The experimental data showed that 01-001 did not induce complement-dependent cytotoxicity against CHO-tmTL1A cells expressing the membrane-associated form of TL1A.

[0994] Example 30. Evaluation of the induction of direct and cross-link apoptosis by antibodies of the invention.

[0995] The ability of 01-001 to induce direct and cross-linked apoptosis in CHO-tmTL1A cells expressing the membrane-associated form of TL1A was assessed by flow cytometry using annexin V to detect apoptotic cells.

[0996] To ​​assess direct apoptosis, serial dilutions of 01-001 were added to a CHO-tmTL1A cell suspension and incubated for 24 hours. To assess cross-link apoptosis, Fc-specific cross-link antibodies were added to the system, followed by incubation with a mixture of annexin V labeled with PE (phycoerythrin) and 7-aminoactinomycin D in the dark at room temperature. A 1% hydrogen peroxide solution was used as a positive control. The percentage of the annexin V-positive population was measured using a flow cytometer.

[0997] According to the results obtained, 01-001 does not induce direct and cross-link apoptosis of CHO-tmTL1A cells expressing the membrane-associated form of TL1A.

[0998] Example 31. Evaluation of the change in the level of cytokine release by PBMC in response to exposure to antibodies of the invention.

[0999] Evaluation of cytokine release in response to exposure to 01-001 allows us to draw a conclusion about the potential risk of developing cytokine release syndrome, thus having prognostic value for confirming the safety of the invention.

[1000] The ability of 01-001 to induce the release of 23 cytokines: eotaxin, GM-CSF, IFNα2, IFNγ, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17A, IL1RA, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-7, MIP-1α, MIP-1β, TNFα, TNFβ, VEGF was evaluated using PBMCs of 10 healthy volunteers. A monolayer of HUVEC cells was incubated with PBMC and 01-001 for 24 hours, after which the amount of cytokines in the supernatants was determined using multiplex analysis.

[1001] According to the results obtained, the use of 01-001 does not lead to the development of cytokine release syndrome.

[1002] Example 32. Efficacy of antibodies of the invention in the treatment of inflammatory bowel diseases in mammals.

[1003] The in vivo efficacy of antibody 01-001 was evaluated in a TNBS-induced ulcerative colitis model. Rats received a fourfold dose of trinitrobenzenesulfonic acid (TNBS) in 40% ethanol via intrarectal administration on days 23, 35, 48, and 59 of life. Control animals received an equivalent volume of ethanol without TNBS. All animals developed focal colitis, characterized by colonic ulceration with inflammatory infiltrate and varying degrees of fibrosis. Antibody treatment was initiated several days after the onset of colitis stimulation (on days 26–57 of life).

[1004] The treatment effect was determined by changes in body weight, stool consistency, and bleeding. Histological analysis of colon sections was also performed to determine the degree of inflammation. A semiquantitative scoring scale for general intestinal inflammation was used to assess the effectiveness of antibody 01-001:

[1005] 1) Inflammation severity: none = 0, mild = 1, moderate = 2, severe = 3.

[1006] 2) Depth of inflammation: absent = 0, mucosa only = 1, mucosa and submucosa = 2, transmural = 3.

[1007] 3) Crypt damage: one-third damaged = 1, two-thirds damaged = 2, crypts absent but surface epithelium present = 3, crypts and surface epithelium absent = 4.

[1008] 4) Proportion of visual field affected by inflammation: absent = 0, 1-25% = 1, 26-50% = 2, 51-75% = 3, 76-100% = 4.

[1009] Six independent visual fields were assessed, the scores for which were summed, and a total score was assigned to each individual. The assessment results are presented in Table 18.

[1010] Table 18. Summary score of intestinal inflammation of an individual.

[1011] Preparation Animal number Total score 01-001 1 7 2 3 3 3 4 10 5 4 6 7 7 3 8 0 9 3 10 0 Without drug (control group) 11 13 12 23 13 7 14 4 15 15 16 25 17 9 18 21 19 7 20 15

[1012] Thus, administration of antibody 01-001 significantly reduced multiple symptoms of the disease (p < 0.002 by the Mann-Whitney test, Figure 14).

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[1034] <insdfeature>

[1035] <INSDFeature_key>source< / INSDFeature_key>

[1036] <INSDFeature_location>1..11< / INSDFeature_location>

[1037] <INSDFeature_quals>

[1038] <insdqualifier>

[1039] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1040] <INSDQualifier_value>protein< / INSDQualifier_value>

[1041] < / insdqualifier>

[1042] <insdqualifier id="q2">

[1043] <INSDQualifier_name>organism< / INSDQualifier_name>

[1044] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1045] < / insdqualifier>

[1046] < / INSDFeature_quals>

[1047] < / insdfeature>

[1048] < / INSDSeq_feature-table>

[1049] <INSDSeq_sequence> RASQSISSYLN< / INSDSeq_sequence>

[1050] < / insdseq>

[1051] < / sequencedata>

[1052] <sequencedata sequenceidnumber="2">

[1053] <insdseq>

[1054] <INSDSeq_length> 11< / INSDSeq_length>

[1055] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1056] <INSDSeq_division> PAT< / INSDSeq_division>

[1057] <INSDSeq_feature-table>

[1058] <insdfeature>

[1059] <INSDFeature_key>source< / INSDFeature_key>

[1060] <INSDFeature_location>1..11< / INSDFeature_location>

[1061] <INSDFeature_quals>

[1062] <insdqualifier>

[1063] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1064] <INSDQualifier_value>protein< / INSDQualifier_value>

[1065] < / insdqualifier>

[1066] <insdqualifier id="q4">

[1067] <INSDQualifier_name>organism< / INSDQualifier_name>

[1068] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1069] < / insdqualifier>

[1070] < / INSDFeature_quals>

[1071] < / insdfeature>

[1072] < / INSDSeq_feature-table>

[1073] <INSDSeq_sequence> RASQGISSWLA< / INSDSeq_sequence>

[1074] < / insdseq>

[1075] < / sequencedata>

[1076] <sequencedata sequenceidnumber="3">

[1077] <insdseq>

[1078] <INSDSeq_length> 11< / INSDSeq_length>

[1079] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1080] <INSDSeq_division> PAT< / INSDSeq_division>

[1081] <INSDSeq_feature-table>

[1082] <insdfeature>

[1083] <INSDFeature_key>source< / INSDFeature_key>

[1084] <INSDFeature_location>1..11< / INSDFeature_location>

[1085] <INSDFeature_quals>

[1086] <insdqualifier>

[1087] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1088] <INSDQualifier_value>protein< / INSDQualifier_value>

[1089] < / insdqualifier>

[1090] <insdqualifier id="q6">

[1091] <INSDQualifier_name>organism< / INSDQualifier_name>

[1092] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1093] < / insdqualifier>

[1094] < / INSDFeature_quals>

[1095] < / insdfeature>

[1096] < / INSDSeq_feature-table>

[1097] <INSDSeq_sequence> RASQSISSWLA< / INSDSeq_sequence>

[1098] < / insdseq>

[1099] < / sequencedata>

[1100] <sequencedata sequenceidnumber="4">

[1101] <insdseq>

[1102] <INSDSeq_length> 12< / INSDSeq_length>

[1103] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1104] <INSDSeq_division> PAT< / INSDSeq_division>

[1105] <INSDSeq_feature-table>

[1106] <insdfeature>

[1107] <INSDFeature_key>source< / INSDFeature_key>

[1108] <INSDFeature_location>1..12< / INSDFeature_location>

[1109] <INSDFeature_quals>

[1110] <insdqualifier>

[1111] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1112] <INSDQualifier_value>protein< / INSDQualifier_value>

[1113] < / insdqualifier>

[1114] <insdqualifier id="q8">

[1115] <INSDQualifier_name>organism< / INSDQualifier_name>

[1116] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1117] < / insdqualifier>

[1118] < / INSDFeature_quals>

[1119] < / insdfeature>

[1120] < / INSDSeq_feature-table>

[1121] <INSDSeq_sequence> RASQSVSGTYLA< / INSDSeq_sequence>

[1122] < / insdseq>

[1123] < / sequencedata>

[1124] <sequencedata sequenceidnumber="5">

[1125] <insdseq>

[1126] <INSDSeq_length> 12< / INSDSeq_length>

[1127] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1128] <INSDSeq_division> PAT< / INSDSeq_division>

[1129] <INSDSeq_feature-table>

[1130] <insdfeature>

[1131] <INSDFeature_key>source< / INSDFeature_key>

[1132] <INSDFeature_location>1..12< / INSDFeature_location>

[1133] <INSDFeature_quals>

[1134] <insdqualifier>

[1135] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1136] <INSDQualifier_value>protein< / INSDQualifier_value>

[1137] < / insdqualifier>

[1138] <insdqualifier id="q10">

[1139] <INSDQualifier_name>organism< / INSDQualifier_name>

[1140] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1141] < / insdqualifier>

[1142] < / INSDFeature_quals>

[1143] < / insdfeature>

[1144] < / INSDSeq_feature-table>

[1145] <INSDSeq_sequence> RASQSVSSSYLA< / INSDSeq_sequence>

[1146] < / insdseq>

[1147] < / sequencedata>

[1148] <sequencedata sequenceidnumber="6">

[1149] <insdseq>

[1150] <INSDSeq_length> 7< / INSDSeq_length>

[1151] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1152] <INSDSeq_division> PAT< / INSDSeq_division>

[1153] <INSDSeq_feature-table>

[1154] <insdfeature>

[1155] <INSDFeature_key>source< / INSDFeature_key>

[1156] <INSDFeature_location>1..7< / INSDFeature_location>

[1157] <INSDFeature_quals>

[1158] <insdqualifier>

[1159] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1160] <INSDQualifier_value>protein< / INSDQualifier_value>

[1161] < / insdqualifier>

[1162] <insdqualifier id="q12">

[1163] <INSDQualifier_name>organism< / INSDQualifier_name>

[1164] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1165] < / insdqualifier>

[1166] < / INSDFeature_quals>

[1167] < / insdfeature>

[1168] < / INSDSeq_feature-table>

[1169] <INSDSeq_sequence> GASSLQS< / INSDSeq_sequence>

[1170] < / insdseq>

[1171] < / sequencedata>

[1172] <sequencedata sequenceidnumber="7">

[1173] <insdseq>

[1174] <INSDSeq_length> 7< / INSDSeq_length>

[1175] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1176] <INSDSeq_division> PAT< / INSDSeq_division>

[1177] <INSDSeq_feature-table>

[1178] <insdfeature>

[1179] <INSDFeature_key>source< / INSDFeature_key>

[1180] <INSDFeature_location>1..7< / INSDFeature_location>

[1181] <INSDFeature_quals>

[1182] <insdqualifier>

[1183] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1184] <INSDQualifier_value>protein< / INSDQualifier_value>

[1185] < / insdqualifier>

[1186] <insdqualifier id="q14">

[1187] <INSDQualifier_name>organism< / INSDQualifier_name>

[1188] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1189] < / insdqualifier>

[1190] < / INSDFeature_quals>

[1191] < / insdfeature>

[1192] < / INSDSeq_feature-table>

[1193] <INSDSeq_sequence> AASSLQS< / INSDSeq_sequence>

[1194] < / insdseq>

[1195] < / sequencedata>

[1196] <sequencedata sequenceidnumber="8">

[1197] <insdseq>

[1198] <INSDSeq_length> 7< / INSDSeq_length>

[1199] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1200] <INSDSeq_division> PAT< / INSDSeq_division>

[1201] <INSDSeq_feature-table>

[1202] <insdfeature>

[1203] <INSDFeature_key>source< / INSDFeature_key>

[1204] <INSDFeature_location>1..7< / INSDFeature_location>

[1205] <INSDFeature_quals>

[1206] <insdqualifier>

[1207] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1208] <INSDQualifier_value>protein< / INSDQualifier_value>

[1209] < / insdqualifier>

[1210] <insdqualifier id="q16">

[1211] <INSDQualifier_name>organism< / INSDQualifier_name>

[1212] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1213] < / insdqualifier>

[1214] < / INSDFeature_quals>

[1215] < / insdfeature>

[1216] < / INSDSeq_feature-table>

[1217] <INSDSeq_sequence> KASTLQT< / INSDSeq_sequence>

[1218] < / insdseq>

[1219] < / sequencedata>

[1220] <sequencedata sequenceidnumber="9">

[1221] <insdseq>

[1222] <INSDSeq_length> 7< / INSDSeq_length>

[1223] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1224] <INSDSeq_division> PAT< / INSDSeq_division>

[1225] <INSDSeq_feature-table>

[1226] <insdfeature>

[1227] <INSDFeature_key>source< / INSDFeature_key>

[1228] <INSDFeature_location>1..7< / INSDFeature_location>

[1229] <INSDFeature_quals>

[1230] <insdqualifier>

[1231] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1232] <INSDQualifier_value>protein< / INSDQualifier_value>

[1233] < / insdqualifier>

[1234] <insdqualifier id="q18">

[1235] <INSDQualifier_name>organism< / INSDQualifier_name>

[1236] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1237] < / insdqualifier>

[1238] < / INSDFeature_quals>

[1239] < / insdfeature>

[1240] < / INSDSeq_feature-table>

[1241] <INSDSeq_sequence> GASRRAA< / INSDSeq_sequence>

[1242] < / insdseq>

[1243] < / sequencedata>

[1244] <sequencedata sequenceidnumber="10">

[1245] <insdseq>

[1246] <INSDSeq_length> 7< / INSDSeq_length>

[1247] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1248] <INSDSeq_division> PAT< / INSDSeq_division>

[1249] <INSDSeq_feature-table>

[1250] <insdfeature>

[1251] <INSDFeature_key>source< / INSDFeature_key>

[1252] <INSDFeature_location>1..7< / INSDFeature_location>

[1253] <INSDFeature_quals>

[1254] <insdqualifier>

[1255] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1256] <INSDQualifier_value>protein< / INSDQualifier_value>

[1257] < / insdqualifier>

[1258] <insdqualifier id="q20">

[1259] <INSDQualifier_name>organism< / INSDQualifier_name>

[1260] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1261] < / insdqualifier>

[1262] < / INSDFeature_quals>

[1263] < / insdfeature>

[1264] < / INSDSeq_feature-table>

[1265] <INSDSeq_sequence> GASSRAT< / INSDSeq_sequence>

[1266] < / insdseq>

[1267] < / sequencedata>

[1268] <sequencedata sequenceidnumber="11">

[1269] <insdseq>

[1270] <INSDSeq_length> 8< / INSDSeq_length>

[1271] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1272] <INSDSeq_division> PAT< / INSDSeq_division>

[1273] <INSDSeq_feature-table>

[1274] <insdfeature>

[1275] <INSDFeature_key>source< / INSDFeature_key>

[1276] <INSDFeature_location>1..8< / INSDFeature_location>

[1277] <INSDFeature_quals>

[1278] <insdqualifier>

[1279] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1280] <INSDQualifier_value>protein< / INSDQualifier_value>

[1281] < / insdqualifier>

[1282] <insdqualifier id="q22">

[1283] <INSDQualifier_name>organism< / INSDQualifier_name>

[1284] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1285] < / insdqualifier>

[1286] < / INSDFeature_quals>

[1287] < / insdfeature>

[1288] < / INSDSeq_feature-table>

[1289] <INSDSeq_sequence> QQSYRTLT< / INSDSeq_sequence>

[1290] < / insdseq>

[1291] < / sequencedata>

[1292] <sequencedata sequenceidnumber="12">

[1293] <insdseq>

[1294] <INSDSeq_length> 9< / INSDSeq_length>

[1295] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1296] <INSDSeq_division> PAT< / INSDSeq_division>

[1297] <INSDSeq_feature-table>

[1298] <insdfeature>

[1299] <INSDFeature_key>source< / INSDFeature_key>

[1300] <INSDFeature_location>1..9< / INSDFeature_location>

[1301] <INSDFeature_quals>

[1302] <insdqualifier>

[1303] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1304] <INSDQualifier_value>protein< / INSDQualifier_value>

[1305] < / insdqualifier>

[1306] <insdqualifier id="q24">

[1307] <INSDQualifier_name>organism< / INSDQualifier_name>

[1308] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1309] < / insdqualifier>

[1310] < / INSDFeature_quals>

[1311] < / insdfeature>

[1312] < / INSDSeq_feature-table>

[1313] <INSDSeq_sequence> QQSYSTPPD< / INSDSeq_sequence>

[1314] < / insdseq>

[1315] < / sequencedata>

[1316] <sequencedata sequenceidnumber="13">

[1317] <insdseq>

[1318] <INSDSeq_length> 9< / INSDSeq_length>

[1319] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1320] <INSDSeq_division> PAT< / INSDSeq_division>

[1321] <INSDSeq_feature-table>

[1322] <insdfeature>

[1323] <INSDFeature_key>source< / INSDFeature_key>

[1324] <INSDFeature_location>1..9< / INSDFeature_location>

[1325] <INSDFeature_quals>

[1326] <insdqualifier>

[1327] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1328] <INSDQualifier_value>protein< / INSDQualifier_value>

[1329] < / insdqualifier>

[1330] <insdqualifier id="q26">

[1331] <INSDQualifier_name>organism< / INSDQualifier_name>

[1332] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1333] < / insdqualifier>

[1334] < / INSDFeature_quals>

[1335] < / insdfeature>

[1336] < / INSDSeq_feature-table>

[1337] <INSDSeq_sequence> QQANSFIT< / INSDSeq_sequence>

[1338] < / insdseq>

[1339] < / sequencedata>

[1340] <sequencedata sequenceidnumber="14">

[1341] <insdseq>

[1342] <INSDSeq_length> 9< / INSDSeq_length>

[1343] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1344] <INSDSeq_division> PAT< / INSDSeq_division>

[1345] <INSDSeq_feature-table>

[1346] <insdfeature>

[1347] <INSDFeature_key>source< / INSDFeature_key>

[1348] <INSDFeature_location>1..9< / INSDFeature_location>

[1349] <INSDFeature_quals>

[1350] <insdqualifier>

[1351] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1352] <INSDQualifier_value>protein< / INSDQualifier_value>

[1353] < / insdqualifier>

[1354] <insdqualifier id="q28">

[1355] <INSDQualifier_name>organism< / INSDQualifier_name>

[1356] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1357] < / insdqualifier>

[1358] < / INSDFeature_quals>

[1359] < / insdfeature>

[1360] < / INSDSeq_feature-table>

[1361] <INSDSeq_sequence> QQYGSSGLT< / INSDSeq_sequence>

[1362] < / insdseq>

[1363] < / sequencedata>

[1364] <sequencedata sequenceidnumber="15">

[1365] <insdseq>

[1366] <INSDSeq_length>11< / INSDSeq_length>

[1367] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[1368] <INSDSeq_division>PAT< / INSDSeq_division>

[1369] <INSDSeq_feature-table>

[1370] <insdfeature>

[1371] <INSDFeature_key>source< / INSDFeature_key>

[1372] <INSDFeature_location>1..11< / INSDFeature_location>

[1373] <INSDFeature_quals>

[1374] <insdqualifier>

[1375] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1376] <INSDQualifier_value>protein< / INSDQualifier_value>

[1377] < / insdqualifier>

[1378] <insdqualifier id="q30">

[1379] <INSDQualifier_name>organism< / INSDQualifier_name>

[1380] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1381] < / insdqualifier>

[1382] < / INSDFeature_quals>

[1383] < / insdfeature>

[1384] < / INSDSeq_feature-table>

[1385] <INSDSeq_sequence>QQYGSSPPSIT< / INSDSeq_sequence>

[1386] < / insdseq>

[1387] < / sequencedata>

[1388] <sequencedata sequenceidnumber="16">

[1389] <insdseq>

[1390] <INSDSeq_length> 5< / INSDSeq_length>

[1391] <INSDSeq_moltype> ARE< / INSDSeq_moltype>

[1392] <INSDSeq_division> PAT< / INSDSeq_division>

[1393] <INSDSeq_feature-table>

[1394] <insdfeature>

[1395] <INSDFeature_key>source< / INSDFeature_key>

[1396] <INSDFeature_location>1..5< / INSDFeature_location>

[1397] <INSDFeature_quals>

[1398] <insdqualifier>

[1399] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1400] <INSDQualifier_value>protein< / INSDQualifier_value>

[1401] < / insdqualifier>

[1402] <insdqualifier id="q32">

[1403] <INSDQualifier_name>organism< / INSDQualifier_name>

[1404] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1405] < / insdqualifier>

[1406] < / INSDFeature_quals>

[1407] < / insdfeature>

[1408] < / INSDSeq_feature-table>

[1409] <INSDSeq_sequence> GOD< / INSDSeq_sequence>

[1410] < / insdseq>

[1411] < / sequencedata>

[1412] <sequencedata sequenceidnumber="17">

[1413] <insdseq>

[1414] <INSDSeq_length> 5< / INSDSeq_length>

[1415] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1416] <INSDSeq_division> PAT< / INSDSeq_division>

[1417] <INSDSeq_feature-table>

[1418] <insdfeature>

[1419] <INSDFeature_key>source< / INSDFeature_key>

[1420] <INSDFeature_location>1..5< / INSDFeature_location>

[1421] <INSDFeature_quals>

[1422] <insdqualifier>

[1423] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1424] <INSDQualifier_value>protein< / INSDQualifier_value>

[1425] < / insdqualifier>

[1426] <insdqualifier id="q34">

[1427] <INSDQualifier_name>organism< / INSDQualifier_name>

[1428] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1429] < / insdqualifier>

[1430] < / INSDFeature_quals>

[1431] < / insdfeature>

[1432] < / INSDSeq_feature-table>

[1433] <INSDSeq_sequence> SYAMS< / INSDSeq_sequence>

[1434] < / insdseq>

[1435] < / sequencedata>

[1436] <sequencedata sequenceidnumber="18">

[1437] <insdseq>

[1438] <INSDSeq_length>5< / INSDSeq_length>

[1439] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[1440] <INSDSeq_division>PAT< / INSDSeq_division>

[1441] <INSDSeq_feature-table>

[1442] <insdfeature>

[1443] <INSDFeature_key>source< / INSDFeature_key>

[1444] <INSDFeature_location>1..5< / INSDFeature_location>

[1445] <INSDFeature_quals>

[1446] <insdqualifier>

[1447] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1448] <INSDQualifier_value>protein< / INSDQualifier_value>

[1449] < / insdqualifier>

[1450] <insdqualifier id="q36">

[1451] <INSDQualifier_name>organism< / INSDQualifier_name>

[1452] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1453] < / insdqualifier>

[1454] < / INSDFeature_quals>

[1455] < / insdfeature>

[1456] < / INSDSeq_feature-table>

[1457] <INSDSeq_sequence>SYDMS< / INSDSeq_sequence>

[1458] < / insdseq>

[1459] < / sequencedata>

[1460] <sequencedata sequenceidnumber="19">

[1461] <insdseq>

[1462] <INSDSeq_length> 5< / INSDSeq_length>

[1463] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1464] <INSDSeq_division> PAT< / INSDSeq_division>

[1465] <INSDSeq_feature-table>

[1466] <insdfeature>

[1467] <INSDFeature_key>source< / INSDFeature_key>

[1468] <INSDFeature_location>1..5< / INSDFeature_location>

[1469] <INSDFeature_quals>

[1470] <insdqualifier>

[1471] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1472] <INSDQualifier_value>protein< / INSDQualifier_value>

[1473] < / insdqualifier>

[1474] <insdqualifier id="q38">

[1475] <INSDQualifier_name>organism< / INSDQualifier_name>

[1476] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1477] < / insdqualifier>

[1478] < / INSDFeature_quals>

[1479] < / insdfeature>

[1480] < / INSDSeq_feature-table>

[1481] <INSDSeq_sequence> GYAMS< / INSDSeq_sequence>

[1482] < / insdseq>

[1483] < / sequencedata>

[1484] <sequencedata sequenceidnumber="20">

[1485] <insdseq>

[1486] <INSDSeq_length> 16< / INSDSeq_length>

[1487] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1488] <INSDSeq_division> PAT< / INSDSeq_division>

[1489] <INSDSeq_feature-table>

[1490] <insdfeature>

[1491] <INSDFeature_key>source< / INSDFeature_key>

[1492] <INSDFeature_location>1..16< / INSDFeature_location>

[1493] <INSDFeature_quals>

[1494] <insdqualifier>

[1495] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1496] <INSDQualifier_value>protein< / INSDQualifier_value>

[1497] < / insdqualifier>

[1498] <insdqualifier id="q40">

[1499] <INSDQualifier_name>organism< / INSDQualifier_name>

[1500] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1501] < / insdqualifier>

[1502] < / INSDFeature_quals>

[1503] < / insdfeature>

[1504] < / INSDSeq_feature-table>

[1505] <INSDSeq_sequence> UNIHGNTDYNSPLKS< / INSDSeq_sequence>

[1506] < / insdseq>

[1507] < / sequencedata>

[1508] <sequencedata sequenceidnumber="21">

[1509] <insdseq>

[1510] <INSDSeq_length> 16< / INSDSeq_length>

[1511] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1512] <INSDSeq_division> PAT< / INSDSeq_division>

[1513] <INSDSeq_feature-table>

[1514] <insdfeature>

[1515] <INSDFeature_key>source< / INSDFeature_key>

[1516] <INSDFeature_location>1..16< / INSDFeature_location>

[1517] <INSDFeature_quals>

[1518] <insdqualifier>

[1519] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1520] <INSDQualifier_value>protein< / INSDQualifier_value>

[1521] < / insdqualifier>

[1522] <insdqualifier id="q42">

[1523] <INSDQualifier_name>organism< / INSDQualifier_name>

[1524] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1525] < / insdqualifier>

[1526] < / INSDFeature_quals>

[1527] < / insdfeature>

[1528] < / INSDSeq_feature-table>

[1529] <INSDSeq_sequence> EIQHSGNTDYNPSLKS< / INSDSeq_sequence>

[1530] < / insdseq>

[1531] < / sequencedata>

[1532] <sequencedata sequenceidnumber="22">

[1533] <insdseq>

[1534] <INSDSeq_length> 16< / INSDSeq_length>

[1535] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1536] <INSDSeq_division> PAT< / INSDSeq_division>

[1537] <INSDSeq_feature-table>

[1538] <insdfeature>

[1539] <INSDFeature_key>source< / INSDFeature_key>

[1540] <INSDFeature_location>1..16< / INSDFeature_location>

[1541] <INSDFeature_quals>

[1542] <insdqualifier>

[1543] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1544] <INSDQualifier_value>protein< / INSDQualifier_value>

[1545] < / insdqualifier>

[1546] <insdqualifier id="q44">

[1547] <INSDQualifier_name>organism< / INSDQualifier_name>

[1548] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1549] < / insdqualifier>

[1550] < / INSDFeature_quals>

[1551] < / insdfeature>

[1552] < / INSDSeq_feature-table>

[1553] <INSDSeq_sequence> EIAHSGNTDYNPSLKS< / INSDSeq_sequence>

[1554] < / insdseq>

[1555] < / sequencedata>

[1556] <sequencedata sequenceidnumber="23">

[1557] <insdseq>

[1558] <INSDSeq_length> 16< / INSDSeq_length>

[1559] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1560] <INSDSeq_division> PAT< / INSDSeq_division>

[1561] <INSDSeq_feature-table>

[1562] <insdfeature>

[1563] <INSDFeature_key>source< / INSDFeature_key>

[1564] <INSDFeature_location>1..16< / INSDFeature_location>

[1565] <INSDFeature_quals>

[1566] <insdqualifier>

[1567] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1568] <INSDQualifier_value>protein< / INSDQualifier_value>

[1569] < / insdqualifier>

[1570] <insdqualifier id="q46">

[1571] <INSDQualifier_name>organism< / INSDQualifier_name>

[1572] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1573] < / insdqualifier>

[1574] < / INSDFeature_quals>

[1575] < / insdfeature>

[1576] < / INSDSeq_feature-table>

[1577] <INSDSeq_sequence> OWNERSGNTDYNPLSKS< / INSDSeq_sequence>

[1578] < / insdseq>

[1579] < / sequencedata>

[1580] <sequencedata sequenceidnumber="24">

[1581] <insdseq>

[1582] <INSDSeq_length>16< / INSDSeq_length>

[1583] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[1584] <INSDSeq_division>PAT< / INSDSeq_division>

[1585] <INSDSeq_feature-table>

[1586] <insdfeature>

[1587] <INSDFeature_key>source< / INSDFeature_key>

[1588] <INSDFeature_location>1..16< / INSDFeature_location>

[1589] <INSDFeature_quals>

[1590] <insdqualifier>

[1591] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1592] <INSDQualifier_value>protein< / INSDQualifier_value>

[1593] < / insdqualifier>

[1594] <insdqualifier id="q48">

[1595] <INSDQualifier_name>organism< / INSDQualifier_name>

[1596] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1597] < / insdqualifier>

[1598] < / INSDFeature_quals>

[1599] < / insdfeature>

[1600] < / INSDSeq_feature-table>

[1601] <INSDSeq_sequence>EIIHSGNTDYNPSLKS< / INSDSeq_sequence>

[1602] < / insdseq>

[1603] < / sequencedata>

[1604] <sequencedata sequenceidnumber="25">

[1605] <insdseq>

[1606] <INSDSeq_length> 16< / INSDSeq_length>

[1607] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1608] <INSDSeq_division> PAT< / INSDSeq_division>

[1609] <INSDSeq_feature-table>

[1610] <insdfeature>

[1611] <INSDFeature_key>source< / INSDFeature_key>

[1612] <INSDFeature_location>1..16< / INSDFeature_location>

[1613] <INSDFeature_quals>

[1614] <insdqualifier>

[1615] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1616] <INSDQualifier_value>protein< / INSDQualifier_value>

[1617] < / insdqualifier>

[1618] <insdqualifier id="q50">

[1619] <INSDQualifier_name>organism< / INSDQualifier_name>

[1620] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1621] < / insdqualifier>

[1622] < / INSDFeature_quals>

[1623] < / insdfeature>

[1624] < / INSDSeq_feature-table>

[1625] <INSDSeq_sequence> EILHSGNTDYNPSLKS< / INSDSeq_sequence>

[1626] < / insdseq>

[1627] < / sequencedata>

[1628] <sequencedata sequenceidnumber="26">

[1629] <insdseq>

[1630] <INSDSeq_length>16< / INSDSeq_length>

[1631] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[1632] <INSDSeq_division>PAT< / INSDSeq_division>

[1633] <INSDSeq_feature-table>

[1634] <insdfeature>

[1635] <INSDFeature_key>source< / INSDFeature_key>

[1636] <INSDFeature_location>1..16< / INSDFeature_location>

[1637] <INSDFeature_quals>

[1638] <insdqualifier>

[1639] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1640] <INSDQualifier_value>protein< / INSDQualifier_value>

[1641] < / insdqualifier>

[1642] <insdqualifier id="q52">

[1643] <INSDQualifier_name>organism< / INSDQualifier_name>

[1644] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1645] < / insdqualifier>

[1646] < / INSDFeature_quals>

[1647] < / insdfeature>

[1648] < / INSDSeq_feature-table>

[1649] <INSDSeq_sequence>EIMHSGNTDYNPSLKS< / INSDSeq_sequence>

[1650] < / insdseq>

[1651] < / sequencedata>

[1652] <sequencedata sequenceidnumber="27">

[1653] <insdseq>

[1654] <INSDSeq_length> 16< / INSDSeq_length>

[1655] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1656] <INSDSeq_division> PAT< / INSDSeq_division>

[1657] <INSDSeq_feature-table>

[1658] <insdfeature>

[1659] <INSDFeature_key>source< / INSDFeature_key>

[1660] <INSDFeature_location>1..16< / INSDFeature_location>

[1661] <INSDFeature_quals>

[1662] <insdqualifier>

[1663] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1664] <INSDQualifier_value>protein< / INSDQualifier_value>

[1665] < / insdqualifier>

[1666] <insdqualifier id="q54">

[1667] <INSDQualifier_name>organism< / INSDQualifier_name>

[1668] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1669] < / insdqualifier>

[1670] < / INSDFeature_quals>

[1671] < / insdfeature>

[1672] < / INSDSeq_feature-table>

[1673] <INSDSeq_sequence> EISHSGNTNDYNPSLKS< / INSDSeq_sequence>

[1674] < / insdseq>

[1675] < / sequencedata>

[1676] <sequencedata sequenceidnumber="28">

[1677] <insdseq>

[1678] <INSDSeq_length>16< / INSDSeq_length>

[1679] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[1680] <INSDSeq_division>PAT< / INSDSeq_division>

[1681] <INSDSeq_feature-table>

[1682] <insdfeature>

[1683] <INSDFeature_key>source< / INSDFeature_key>

[1684] <INSDFeature_location>1..16< / INSDFeature_location>

[1685] <INSDFeature_quals>

[1686] <insdqualifier>

[1687] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1688] <INSDQualifier_value>protein< / INSDQualifier_value>

[1689] < / insdqualifier>

[1690] <insdqualifier id="q56">

[1691] <INSDQualifier_name>organism< / INSDQualifier_name>

[1692] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1693] < / insdqualifier>

[1694] < / INSDFeature_quals>

[1695] < / insdfeature>

[1696] < / INSDSeq_feature-table>

[1697] <INSDSeq_sequence>EITHSGNTDYNPSLKS< / INSDSeq_sequence>

[1698] < / insdseq>

[1699] < / sequencedata>

[1700] <sequencedata sequenceidnumber="29">

[1701] <insdseq>

[1702] <INSDSeq_length> 16< / INSDSeq_length>

[1703] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1704] <INSDSeq_division> PAT< / INSDSeq_division>

[1705] <INSDSeq_feature-table>

[1706] <insdfeature>

[1707] <INSDFeature_key>source< / INSDFeature_key>

[1708] <INSDFeature_location>1..16< / INSDFeature_location>

[1709] <INSDFeature_quals>

[1710] <insdqualifier>

[1711] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1712] <INSDQualifier_value>protein< / INSDQualifier_value>

[1713] < / insdqualifier>

[1714] <insdqualifier id="q58">

[1715] <INSDQualifier_name>organism< / INSDQualifier_name>

[1716] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1717] < / insdqualifier>

[1718] < / INSDFeature_quals>

[1719] < / insdfeature>

[1720] < / INSDSeq_feature-table>

[1721] <INSDSeq_sequence> EIVHSGNTDYNPSLKS< / INSDSeq_sequence>

[1722] < / insdseq>

[1723] < / sequencedata>

[1724] <sequencedata sequenceidnumber="30">

[1725] <insdseq>

[1726] <INSDSeq_length>16< / INSDSeq_length>

[1727] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[1728] <INSDSeq_division>PAT< / INSDSeq_division>

[1729] <INSDSeq_feature-table>

[1730] <insdfeature>

[1731] <INSDFeature_key>source< / INSDFeature_key>

[1732] <INSDFeature_location>1..16< / INSDFeature_location>

[1733] <INSDFeature_quals>

[1734] <insdqualifier>

[1735] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1736] <INSDQualifier_value>protein< / INSDQualifier_value>

[1737] < / insdqualifier>

[1738] <insdqualifier id="q60">

[1739] <INSDQualifier_name>organism< / INSDQualifier_name>

[1740] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1741] < / insdqualifier>

[1742] < / INSDFeature_quals>

[1743] < / insdfeature>

[1744] < / INSDSeq_feature-table>

[1745] <INSDSeq_sequence>TIRTGGRTTYADSVKG< / INSDSeq_sequence>

[1746] < / insdseq>

[1747] < / sequencedata>

[1748] <sequencedata sequenceidnumber="31">

[1749] <insdseq>

[1750] <INSDSeq_length> 17< / INSDSeq_length>

[1751] <INSDSeq_moltype> A A< / INSDSeq_moltype>

[1752] <INSDSeq_division> PAT< / INSDSeq_division>

[1753] <INSDSeq_feature-table>

[1754] <insdfeature>

[1755] <INSDFeature_key>source< / INSDFeature_key>

[1756] <INSDFeature_location>1..17< / INSDFeature_location>

[1757] <INSDFeature_quals>

[1758] <insdqualifier>

[1759] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1760] <INSDQualifier_value>protein< / INSDQualifier_value>

[1761] < / insdqualifier>

[1762] <insdqualifier id="q62">

[1763] <INSDQualifier_name>organism< / INSDQualifier_name>

[1764] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1765] < / insdqualifier>

[1766] < / INSDFeature_quals>

[1767] < / insdfeature>

[1768] < / INSDSeq_feature-table>

[1769] <INSDSeq_sequence> AINSGGGSTYYADSMKG< / INSDSeq_sequence>

[1770] < / insdseq>

[1771] < / sequencedata>

[1772] <sequencedata sequenceidnumber="32">

[1773] <insdseq>

[1774] <INSDSeq_length> 17< / INSDSeq_length>

[1775] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1776] <INSDSeq_division> PAT< / INSDSeq_division>

[1777] <INSDSeq_feature-table>

[1778] <insdfeature>

[1779] <INSDFeature_key>source< / INSDFeature_key>

[1780] <INSDFeature_location>1..17< / INSDFeature_location>

[1781] <INSDFeature_quals>

[1782] <insdqualifier>

[1783] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1784] <INSDQualifier_value>protein< / INSDQualifier_value>

[1785] < / insdqualifier>

[1786] <insdqualifier id="q64">

[1787] <INSDQualifier_name>organism< / INSDQualifier_name>

[1788] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1789] < / insdqualifier>

[1790] < / INSDFeature_quals>

[1791] < / insdfeature>

[1792] < / INSDSeq_feature-table>

[1793] <INSDSeq_sequence> TINSGGGSTSYADSVKG< / INSDSeq_sequence>

[1794] < / insdseq>

[1795] < / sequencedata>

[1796] <sequencedata sequenceidnumber="33">

[1797] <insdseq>

[1798] <INSDSeq_length> 15< / INSDSeq_length>

[1799] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1800] <INSDSeq_division> PAT< / INSDSeq_division>

[1801] <INSDSeq_feature-table>

[1802] <insdfeature>

[1803] <INSDFeature_key>source< / INSDFeature_key>

[1804] <INSDFeature_location>1..15< / INSDFeature_location>

[1805] <INSDFeature_quals>

[1806] <insdqualifier>

[1807] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1808] <INSDQualifier_value>protein< / INSDQualifier_value>

[1809] < / insdqualifier>

[1810] <insdqualifier id="q66">

[1811] <INSDQualifier_name>organism< / INSDQualifier_name>

[1812] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1813] < / insdqualifier>

[1814] < / INSDFeature_quals>

[1815] < / insdfeature>

[1816] < / INSDSeq_feature-table>

[1817] <INSDSeq_sequence> GGFSGSPNYYYAMDV< / INSDSeq_sequence>

[1818] < / insdseq>

[1819] < / sequencedata>

[1820] <sequencedata sequenceidnumber="34">

[1821] <insdseq>

[1822] <INSDSeq_length> 15< / INSDSeq_length>

[1823] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1824] <INSDSeq_division> PAT< / INSDSeq_division>

[1825] <INSDSeq_feature-table>

[1826] <insdfeature>

[1827] <INSDFeature_key>source< / INSDFeature_key>

[1828] <INSDFeature_location>1..15< / INSDFeature_location>

[1829] <INSDFeature_quals>

[1830] <insdqualifier>

[1831] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1832] <INSDQualifier_value>protein< / INSDQualifier_value>

[1833] < / insdqualifier>

[1834] <insdqualifier id="q68">

[1835] <INSDQualifier_name>organism< / INSDQualifier_name>

[1836] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1837] < / insdqualifier>

[1838] < / INSDFeature_quals>

[1839] < / insdfeature>

[1840] < / INSDSeq_feature-table>

[1841] <INSDSeq_sequence> SRGTSWVPEIYEYDY< / INSDSeq_sequence>

[1842] < / insdseq>

[1843] < / sequencedata>

[1844] <sequencedata sequenceidnumber="35">

[1845] <insdseq>

[1846] <INSDSeq_length> 13< / INSDSeq_length>

[1847] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[1848] <INSDSeq_division> PAT< / INSDSeq_division>

[1849] <INSDSeq_feature-table>

[1850] <insdfeature>

[1851] <INSDFeature_key>source< / INSDFeature_key>

[1852] <INSDFeature_location>1..13< / INSDFeature_location>

[1853] <INSDFeature_quals>

[1854] <insdqualifier>

[1855] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1856] <INSDQualifier_value>protein< / INSDQualifier_value>

[1857] < / insdqualifier>

[1858] <insdqualifier id="q70">

[1859] <INSDQualifier_name>organism< / INSDQualifier_name>

[1860] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1861] < / insdqualifier>

[1862] < / INSDFeature_quals>

[1863] < / insdfeature>

[1864] < / INSDSeq_feature-table>

[1865] <INSDSeq_sequence> RLSWGSYYRDDEY< / INSDSeq_sequence>

[1866] < / insdseq>

[1867] < / sequencedata>

[1868] <sequencedata sequenceidnumber="36">

[1869] <insdseq>

[1870] <INSDSeq_length>7< / INSDSeq_length>

[1871] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[1872] <INSDSeq_division>PAT< / INSDSeq_division>

[1873] <INSDSeq_feature-table>

[1874] <insdfeature>

[1875] <INSDFeature_key>source< / INSDFeature_key>

[1876] <INSDFeature_location>1..7< / INSDFeature_location>

[1877] <INSDFeature_quals>

[1878] <insdqualifier>

[1879] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1880] <INSDQualifier_value>protein< / INSDQualifier_value>

[1881] < / insdqualifier>

[1882] <insdqualifier id="q72">

[1883] <INSDQualifier_name>organism< / INSDQualifier_name>

[1884] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1885] < / insdqualifier>

[1886] < / INSDFeature_quals>

[1887] < / insdfeature>

[1888] < / INSDSeq_feature-table>

[1889] <INSDSeq_sequence>GWTDFDY< / INSDSeq_sequence>

[1890] < / insdseq>

[1891] < / sequencedata>

[1892] <sequencedata sequenceidnumber="37">

[1893] <insdseq>

[1894] <INSDSeq_length>106< / INSDSeq_length>

[1895] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[1896] <INSDSeq_division>PAT< / INSDSeq_division>

[1897] <INSDSeq_feature-table>

[1898] <insdfeature>

[1899] <INSDFeature_key>source< / INSDFeature_key>

[1900] <INSDFeature_location>1..106< / INSDFeature_location>

[1901] <INSDFeature_quals>

[1902] <insdqualifier>

[1903] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1904] <INSDQualifier_value>protein< / INSDQualifier_value>

[1905] < / insdqualifier>

[1906] <insdqualifier id="q74">

[1907] <INSDQualifier_name>organism< / INSDQualifier_name>

[1908] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1909] < / insdqualifier>

[1910] < / INSDFeature_quals>

[1911] < / insdfeature>

[1912] < / INSDSeq_feature-table>

[1913] <INSDSeq_sequence>NIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIY

[1914] GASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYHCQQSYRTLTFGGGTKVEIK< / INSDSeq_seq

[1915] uence>

[1916] < / insdseq>

[1917] < / sequencedata>

[1918] <sequencedata sequenceidnumber="38">

[1919] <insdseq>

[1920] <INSDSeq_length>107< / INSDSeq_length>

[1921] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[1922] <INSDSeq_division>PAT< / INSDSeq_division>

[1923] <INSDSeq_feature-table>

[1924] <insdfeature>

[1925] <INSDFeature_key>source< / INSDFeature_key>

[1926] <INSDFeature_location>1..107< / INSDFeature_location>

[1927] <INSDFeature_quals>

[1928] <insdqualifier>

[1929] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1930] <INSDQualifier_value>protein< / INSDQualifier_value>

[1931] < / insdqualifier>

[1932] <insdqualifier id="q76">

[1933] <INSDQualifier_name>organism< / INSDQualifier_name>

[1934] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1935] < / insdqualifier>

[1936] < / INSDFeature_quals>

[1937] < / insdfeature>

[1938] < / INSDSeq_feature-table>

[1939] <INSDSeq_sequence>DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIY

[1940] AASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPDFGQGTRLEIK< / INSDSeq_se

[1941] quence>

[1942] < / insdseq>

[1943] < / sequencedata>

[1944] <sequencedata sequenceidnumber="39">

[1945] <insdseq>

[1946] <INSDSeq_length>107< / INSDSeq_length>

[1947] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[1948] <INSDSeq_division>PAT< / INSDSeq_division>

[1949] <INSDSeq_feature-table>

[1950] <insdfeature>

[1951] <INSDFeature_key>source< / INSDFeature_key>

[1952] <INSDFeature_location>1..107< / INSDFeature_location>

[1953] <INSDFeature_quals>

[1954] <insdqualifier>

[1955] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1956] <INSDQualifier_value>protein< / INSDQualifier_value>

[1957] < / insdqualifier>

[1958] <insdqualifier id="q78">

[1959] <INSDQualifier_name>organism< / INSDQualifier_name>

[1960] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1961] < / insdqualifier>

[1962] < / INSDFeature_quals>

[1963] < / insdfeature>

[1964] < / INSDSeq_feature-table>

[1965] <INSDSeq_sequence>ETTLTQSPSSLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIY

[1966] KASTLQTGVPSRFSGSGSGTEFTLIISSLQPEDSATYYCQQANSFPITFGQGTRLEIK< / INSDSeq_se

[1967] quence>

[1968] < / insdseq>

[1969] < / sequencedata>

[1970] <sequencedata sequenceidnumber="40">

[1971] <insdseq>

[1972] <INSDSeq_length>108< / INSDSeq_length>

[1973] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[1974] <INSDSeq_division>PAT< / INSDSeq_division>

[1975] <INSDSeq_feature-table>

[1976] <insdfeature>

[1977] <INSDFeature_key>source< / INSDFeature_key>

[1978] <INSDFeature_location>1..108< / INSDFeature_location>

[1979] <INSDFeature_quals>

[1980] <insdqualifier>

[1981] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[1982] <INSDQualifier_value>protein< / INSDQualifier_value>

[1983] < / insdqualifier>

[1984] <insdqualifier id="q80">

[1985] <INSDQualifier_name>organism< / INSDQualifier_name>

[1986] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[1987] < / insdqualifier>

[1988] < / INSDFeature_quals>

[1989] < / insdfeature>

[1990] < / INSDSeq_feature-table>

[1991] <INSDSeq_sequence>EIVLTQSPGTLSLSPGERATLSCRASQSVSGTYLAWYKQKPGQAPRLLI

[1992] FGASRRAAGIPDRFSGSRSGTDFTLTISRLEPEDFAVYYCQQYGSSGLTFGGGTKLEIK< / INSDSeq_s

[1993] equence>

[1994] < / insdseq>

[1995] < / sequencedata>

[1996] <sequencedata sequenceidnumber="41">

[1997] <insdseq>

[1998] <INSDSeq_length>110< / INSDSeq_length>

[1999] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2000] <INSDSeq_division>PAT< / INSDSeq_division>

[2001] <INSDSeq_feature-table>

[2002] <insdfeature>

[2003] <INSDFeature_key>source< / INSDFeature_key>

[2004] <INSDFeature_location>1..110< / INSDFeature_location>

[2005] <INSDFeature_quals>

[2006] <insdqualifier>

[2007] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2008] <INSDQualifier_value>protein< / INSDQualifier_value>

[2009] < / insdqualifier>

[2010] <insdqualifier id="q82">

[2011] <INSDQualifier_name>organism< / INSDQualifier_name>

[2012] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2013] < / insdqualifier>

[2014] < / INSDFeature_quals>

[2015] < / insdfeature>

[2016] < / INSDSeq_feature-table>

[2017] <INSDSeq_sequence>EIVMTQSPATLSVSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLI

[2018] YGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPPSITFGQGTRLEIK< / INSDSeq

[2019] _sequence>

[2020] < / insdseq>

[2021] < / sequencedata>

[2022] <sequencedata sequenceidnumber="42">

[2023] <insdseq>

[2024] <INSDSeq_length>123< / INSDSeq_length>

[2025] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2026] <INSDSeq_division>PAT< / INSDSeq_division>

[2027] <INSDSeq_feature-table>

[2028] <insdfeature>

[2029] <INSDFeature_key>source< / INSDFeature_key>

[2030] <INSDFeature_location>1..123< / INSDFeature_location>

[2031] <INSDFeature_quals>

[2032] <insdqualifier>

[2033] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2034] <INSDQualifier_value>protein< / INSDQualifier_value>

[2035] < / insdqualifier>

[2036] <insdqualifier id="q84">

[2037] <INSDQualifier_name>organism< / INSDQualifier_name>

[2038] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2039] < / insdqualifier>

[2040] < / INSDFeature_quals>

[2041] < / insdfeature>

[2042] < / INSDSeq_feature-table>

[2043] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2044] EINHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2045] TVSS< / INSDSeq_sequence>

[2046] < / insdseq>

[2047] < / sequencedata>

[2048] <sequencedata sequenceidnumber="43">

[2049] <insdseq>

[2050] <INSDSeq_length>123< / INSDSeq_length>

[2051] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2052] <INSDSeq_division>PAT< / INSDSeq_division>

[2053] <INSDSeq_feature-table>

[2054] <insdfeature>

[2055] <INSDFeature_key>source< / INSDFeature_key>

[2056] <INSDFeature_location>1..123< / INSDFeature_location>

[2057] <INSDFeature_quals>

[2058] <insdqualifier>

[2059] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2060] <INSDQualifier_value>protein< / INSDQualifier_value>

[2061] < / insdqualifier>

[2062] <insdqualifier id="q86">

[2063] <INSDQualifier_name>organism< / INSDQualifier_name>

[2064] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2065] < / insdqualifier>

[2066] < / INSDFeature_quals>

[2067] < / insdfeature>

[2068] < / INSDSeq_feature-table>

[2069] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2070] EIQHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2071] TVSS< / INSDSeq_sequence>

[2072] < / insdseq>

[2073] < / sequencedata>

[2074] <sequencedata sequenceidnumber="44">

[2075] <insdseq>

[2076] <INSDSeq_length>123< / INSDSeq_length>

[2077] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2078] <INSDSeq_division>PAT< / INSDSeq_division>

[2079] <INSDSeq_feature-table>

[2080] <insdfeature>

[2081] <INSDFeature_key>source< / INSDFeature_key>

[2082] <INSDFeature_location>1..123< / INSDFeature_location>

[2083] <INSDFeature_quals>

[2084] <insdqualifier>

[2085] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2086] <INSDQualifier_value>protein< / INSDQualifier_value>

[2087] < / insdqualifier>

[2088] <insdqualifier id="q88">

[2089] <INSDQualifier_name>organism< / INSDQualifier_name>

[2090] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2091] < / insdqualifier>

[2092] < / INSDFeature_quals>

[2093] < / insdfeature>

[2094] < / INSDSeq_feature-table>

[2095] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2096] EIAHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2097] TVSS< / INSDSeq_sequence>

[2098] < / insdseq>

[2099] < / sequencedata>

[2100] <sequencedata sequenceidnumber="45">

[2101] <insdseq>

[2102] <INSDSeq_length>123< / INSDSeq_length>

[2103] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2104] <INSDSeq_division>PAT< / INSDSeq_division>

[2105] <INSDSeq_feature-table>

[2106] <insdfeature>

[2107] <INSDFeature_key>source< / INSDFeature_key>

[2108] <INSDFeature_location>1..123< / INSDFeature_location>

[2109] <INSDFeature_quals>

[2110] <insdqualifier>

[2111] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2112] <INSDQualifier_value>protein< / INSDQualifier_value>

[2113] < / insdqualifier>

[2114] <insdqualifier id="q90">

[2115] <INSDQualifier_name>organism< / INSDQualifier_name>

[2116] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2117] < / insdqualifier>

[2118] < / INSDFeature_quals>

[2119] < / insdfeature>

[2120] < / INSDSeq_feature-table>

[2121] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2122] EIGHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2123] TVSS< / INSDSeq_sequence>

[2124] < / insdseq>

[2125] < / sequencedata>

[2126] <sequencedata sequenceidnumber="46">

[2127] <insdseq>

[2128] <INSDSeq_length>123< / INSDSeq_length>

[2129] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2130] <INSDSeq_division>PAT< / INSDSeq_division>

[2131] <INSDSeq_feature-table>

[2132] <insdfeature>

[2133] <INSDFeature_key>source< / INSDFeature_key>

[2134] <INSDFeature_location>1..123< / INSDFeature_location>

[2135] <INSDFeature_quals>

[2136] <insdqualifier>

[2137] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2138] <INSDQualifier_value>protein< / INSDQualifier_value>

[2139] < / insdqualifier>

[2140] <insdqualifier id="q92">

[2141] <INSDQualifier_name>organism< / INSDQualifier_name>

[2142] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2143] < / insdqualifier>

[2144] < / INSDFeature_quals>

[2145] < / insdfeature>

[2146] < / INSDSeq_feature-table>

[2147] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2148] EIIHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2149] TVSS< / INSDSeq_sequence>

[2150] < / insdseq>

[2151] < / sequencedata>

[2152] <sequencedata sequenceidnumber="47">

[2153] <insdseq>

[2154] <INSDSeq_length>123< / INSDSeq_length>

[2155] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2156] <INSDSeq_division>PAT< / INSDSeq_division>

[2157] <INSDSeq_feature-table>

[2158] <insdfeature>

[2159] <INSDFeature_key>source< / INSDFeature_key>

[2160] <INSDFeature_location>1..123< / INSDFeature_location>

[2161] <INSDFeature_quals>

[2162] <insdqualifier>

[2163] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2164] <INSDQualifier_value>protein< / INSDQualifier_value>

[2165] < / insdqualifier>

[2166] <insdqualifier id="q94">

[2167] <INSDQualifier_name>organism< / INSDQualifier_name>

[2168] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2169] < / insdqualifier>

[2170] < / INSDFeature_quals>

[2171] < / insdfeature>

[2172] < / INSDSeq_feature-table>

[2173] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2174] EILHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2175] TVSS< / INSDSeq_sequence>

[2176] < / insdseq>

[2177] < / sequencedata>

[2178] <sequencedata sequenceidnumber="48">

[2179] <insdseq>

[2180] <INSDSeq_length>123< / INSDSeq_length>

[2181] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2182] <INSDSeq_division>PAT< / INSDSeq_division>

[2183] <INSDSeq_feature-table>

[2184] <insdfeature>

[2185] <INSDFeature_key>source< / INSDFeature_key>

[2186] <INSDFeature_location>1..123< / INSDFeature_location>

[2187] <INSDFeature_quals>

[2188] <insdqualifier>

[2189] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2190] <INSDQualifier_value>protein< / INSDQualifier_value>

[2191] < / insdqualifier>

[2192] <insdqualifier id="q96">

[2193] <INSDQualifier_name>organism< / INSDQualifier_name>

[2194] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2195] < / insdqualifier>

[2196] < / INSDFeature_quals>

[2197] < / insdfeature>

[2198] < / INSDSeq_feature-table>

[2199] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2200] EIMHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2201] TVSS< / INSDSeq_sequence>

[2202] < / insdseq>

[2203] < / sequencedata>

[2204] <sequencedata sequenceidnumber="49">

[2205] <insdseq>

[2206] <INSDSeq_length>123< / INSDSeq_length>

[2207] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2208] <INSDSeq_division>PAT< / INSDSeq_division>

[2209] <INSDSeq_feature-table>

[2210] <insdfeature>

[2211] <INSDFeature_key>source< / INSDFeature_key>

[2212] <INSDFeature_location>1..123< / INSDFeature_location>

[2213] <INSDFeature_quals>

[2214] <insdqualifier>

[2215] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2216] <INSDQualifier_value>protein< / INSDQualifier_value>

[2217] < / insdqualifier>

[2218] <insdqualifier id="q98">

[2219] <INSDQualifier_name>organism< / INSDQualifier_name>

[2220] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2221] < / insdqualifier>

[2222] < / INSDFeature_quals>

[2223] < / insdfeature>

[2224] < / INSDSeq_feature-table>

[2225] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2226] EISHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2227] TVSS< / INSDSeq_sequence>

[2228] < / insdseq>

[2229] < / sequencedata>

[2230] <sequencedata sequenceidnumber="50">

[2231] <insdseq>

[2232] <INSDSeq_length>123< / INSDSeq_length>

[2233] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2234] <INSDSeq_division>PAT< / INSDSeq_division>

[2235] <INSDSeq_feature-table>

[2236] <insdfeature>

[2237] <INSDFeature_key>source< / INSDFeature_key>

[2238] <INSDFeature_location>1..123< / INSDFeature_location>

[2239] <INSDFeature_quals>

[2240] <insdqualifier>

[2241] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2242] <INSDQualifier_value>protein< / INSDQualifier_value>

[2243] < / insdqualifier>

[2244] <insdqualifier id="q100">

[2245] <INSDQualifier_name>organism< / INSDQualifier_name>

[2246] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2247] < / insdqualifier>

[2248] < / INSDFeature_quals>

[2249] < / insdfeature>

[2250] < / INSDSeq_feature-table>

[2251] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2252] EITHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2253] TVSS< / INSDSeq_sequence>

[2254] < / insdseq>

[2255] < / sequencedata>

[2256] <sequencedata sequenceidnumber="51">

[2257] <insdseq>

[2258] <INSDSeq_length>123< / INSDSeq_length>

[2259] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2260] <INSDSeq_division>PAT< / INSDSeq_division>

[2261] <INSDSeq_feature-table>

[2262] <insdfeature>

[2263] <INSDFeature_key>source< / INSDFeature_key>

[2264] <INSDFeature_location>1..123< / INSDFeature_location>

[2265] <INSDFeature_quals>

[2266] <insdqualifier>

[2267] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2268] <INSDQualifier_value>protein< / INSDQualifier_value>

[2269] < / insdqualifier>

[2270] <insdqualifier id="q102">

[2271] <INSDQualifier_name>organism< / INSDQualifier_name>

[2272] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2273] < / insdqualifier>

[2274] < / INSDFeature_quals>

[2275] < / insdfeature>

[2276] < / INSDSeq_feature-table>

[2277] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2278] EIVHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2279] TVSS< / INSDSeq_sequence>

[2280] < / insdseq>

[2281] < / sequencedata>

[2282] <sequencedata sequenceidnumber="52">

[2283] <insdseq>

[2284] <INSDSeq_length> 123< / INSDSeq_length>

[2285] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[2286] <INSDSeq_division> PAT< / INSDSeq_division>

[2287] <INSDSeq_feature-table>

[2288] <insdfeature>

[2289] <INSDFeature_key>source< / INSDFeature_key>

[2290] <INSDFeature_location>1..123< / INSDFeature_location>

[2291] <INSDFeature_quals>

[2292] <insdqualifier>

[2293] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2294] <INSDQualifier_value>protein< / INSDQualifier_value>

[2295] < / insdqualifier>

[2296] <insdqualifier id="q104">

[2297] <INSDQualifier_name>organism< / INSDQualifier_name>

[2298] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2299] < / insdqualifier>

[2300] < / INSDFeature_quals>

[2301] < / insdfeature>

[2302] < / INSDSeq_feature-table>

[2303] <INSDSeq_sequence> ELQLQESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGPDWVS

[2304] TIRTGGRTTYADSVKGRFTISRDNAKNTLYLQMNSLKSDDTAVYYCAKSRGTSWVPEIYEYDYWGQGTLV

[2305] TVSS< / INSDSeq_sequence>

[2306] < / insdseq>

[2307] < / sequencedata>

[2308] <sequencedata sequenceidnumber="53">

[2309] <insdseq>

[2310] <INSDSeq_length> 123< / INSDSeq_length>

[2311] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[2312] <INSDSeq_division> PAT< / INSDSeq_division>

[2313] <INSDSeq_feature-table>

[2314] <insdfeature>

[2315] <INSDFeature_key>source< / INSDFeature_key>

[2316] <INSDFeature_location>1..123< / INSDFeature_location>

[2317] <INSDFeature_quals>

[2318] <insdqualifier>

[2319] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2320] <INSDQualifier_value>protein< / INSDQualifier_value>

[2321] < / insdqualifier>

[2322] <insdqualifier id="q106">

[2323] <INSDQualifier_name>organism< / INSDQualifier_name>

[2324] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2325] < / insdqualifier>

[2326] < / INSDFeature_quals>

[2327] < / insdfeature>

[2328] < / INSDSeq_feature-table>

[2329] <INSDSeq_sequence> EVQLQQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGPDWVS

[2330] TIRTGGRTTYADSVKGRFTISRDNAKNTLYLQMNSLKSDDTAVYYCAKSRGTSWVPEIYEYDYWGQGTMV

[2331] TVSS< / INSDSeq_sequence>

[2332] < / insdseq>

[2333] < / sequencedata>

[2334] <sequencedata sequenceidnumber="54">

[2335] <insdseq>

[2336] <INSDSeq_length>122< / INSDSeq_length>

[2337] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2338] <INSDSeq_division>PAT< / INSDSeq_division>

[2339] <INSDSeq_feature-table>

[2340] <insdfeature>

[2341] <INSDFeature_key>source< / INSDFeature_key>

[2342] <INSDFeature_location>1..122< / INSDFeature_location>

[2343] <INSDFeature_quals>

[2344] <insdqualifier>

[2345] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2346] <INSDQualifier_value>protein< / INSDQualifier_value>

[2347] < / insdqualifier>

[2348] <insdqualifier id="q108">

[2349] <INSDQualifier_name>organism< / INSDQualifier_name>

[2350] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2351] < / insdqualifier>

[2352] < / INSDFeature_quals>

[2353] < / insdfeature>

[2354] < / INSDSeq_feature-table>

[2355] <INSDSeq_sequence>ELQLVQSGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLEWVS

[2356] AINSGGGSTYYADSMKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCNARLSWGSYYRDDEYWGQGTQVT

[2357] VSS< / INSDSeq_sequence>

[2358] < / insdseq>

[2359] < / sequencedata>

[2360] <sequencedata sequenceidnumber="55">

[2361] <insdseq>

[2362] <INSDSeq_length>116< / INSDSeq_length>

[2363] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2364] <INSDSeq_division>PAT< / INSDSeq_division>

[2365] <INSDSeq_feature-table>

[2366] <insdfeature>

[2367] <INSDFeature_key>source< / INSDFeature_key>

[2368] <INSDFeature_location>1..116< / INSDFeature_location>

[2369] <INSDFeature_quals>

[2370] <insdqualifier>

[2371] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2372] <INSDQualifier_value>protein< / INSDQualifier_value>

[2373] < / insdqualifier>

[2374] <insdqualifier id="q110">

[2375] <INSDQualifier_name>organism< / INSDQualifier_name>

[2376] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2377] < / insdqualifier>

[2378] < / INSDFeature_quals>

[2379] < / insdfeature>

[2380] < / INSDSeq_feature-table>

[2381] <INSDSeq_sequence>EVTLKESGGGLVQPGGSLRLSCAASGFTFSGYAMSWVRQAPGKGPEWVS

[2382] TINSGGGSTSYADSVKGRFTISRDNAKSTLYLQMNSLKPEDTAVYYCAEGWTDFDYWGQGTQVTVSS

[2383] NSDSeq_sequence>

[2384] < / insdseq>

[2385] < / sequencedata>

[2386] <sequencedata sequenceidnumber="56">

[2387] <insdseq>

[2388] <INSDSeq_length>213< / INSDSeq_length>

[2389] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2390] <INSDSeq_division>PAT< / INSDSeq_division>

[2391] <INSDSeq_feature-table>

[2392] <insdfeature>

[2393] <INSDFeature_key>source< / INSDFeature_key>

[2394] <INSDFeature_location>1..213< / INSDFeature_location>

[2395] <INSDFeature_quals>

[2396] <insdqualifier>

[2397] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2398] <INSDQualifier_value>protein< / INSDQualifier_value>

[2399] < / insdqualifier>

[2400] <insdqualifier id="q112">

[2401] <INSDQualifier_name>organism< / INSDQualifier_name>

[2402] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2403] < / insdqualifier>

[2404] < / INSDFeature_quals>

[2405] < / insdfeature>

[2406] < / INSDSeq_feature-table>

[2407] <INSDSeq_sequence>NIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIY

[2408] GASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYHCQQSYRTLTFGGGTKVEIKRTVAAPSVFIFPP

[2409] SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK

[2410] VYACEVTHQGLSSPVTKSFNRGEC< / INSDSeq_sequence>

[2411] < / insdseq>

[2412] < / sequencedata>

[2413] <sequencedata sequenceidnumber="57">

[2414] <insdseq>

[2415] <INSDSeq_length>214< / INSDSeq_length>

[2416] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2417] <INSDSeq_division>PAT< / INSDSeq_division>

[2418] <INSDSeq_feature-table>

[2419] <insdfeature>

[2420] <INSDFeature_key>source< / INSDFeature_key>

[2421] <INSDFeature_location>1..214< / INSDFeature_location>

[2422] <INSDFeature_quals>

[2423] <insdqualifier>

[2424] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2425] <INSDQualifier_value>protein< / INSDQualifier_value>

[2426] < / insdqualifier>

[2427] <insdqualifier id="q114">

[2428] <INSDQualifier_name>organism< / INSDQualifier_name>

[2429] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2430] < / insdqualifier>

[2431] < / INSDFeature_quals>

[2432] < / insdfeature>

[2433] < / INSDSeq_feature-table>

[2434] <INSDSeq_sequence>DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIY

[2435] AASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPDFGQGTRLEIKRTVAAPSVFIFP

[2436] PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH

[2437] KVYACEVTHQGLSSPVTKSFNRGEC< / INSDSeq_sequence>

[2438] < / insdseq>

[2439] < / sequencedata>

[2440] <sequencedata sequenceidnumber="58">

[2441] <insdseq>

[2442] <INSDSeq_length>214< / INSDSeq_length>

[2443] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2444] <INSDSeq_division>PAT< / INSDSeq_division>

[2445] <INSDSeq_feature-table>

[2446] <insdfeature>

[2447] <INSDFeature_key>source< / INSDFeature_key>

[2448] <INSDFeature_location>1..214< / INSDFeature_location>

[2449] <INSDFeature_quals>

[2450] <insdqualifier>

[2451] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2452] <INSDQualifier_value>protein< / INSDQualifier_value>

[2453] < / insdqualifier>

[2454] <insdqualifier id="q116">

[2455] <INSDQualifier_name>organism< / INSDQualifier_name>

[2456] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2457] < / insdqualifier>

[2458] < / INSDFeature_quals>

[2459] < / insdfeature>

[2460] < / INSDSeq_feature-table>

[2461] <INSDSeq_sequence>ETTLTQSPSSLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIY

[2462] KASTLQTGVPSRFSGSGSGTEFTLIISSLQPEDSATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIFP

[2463] PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH

[2464] KVYACEVTHQGLSSPVTKSFNRGEC< / INSDSeq_sequence>

[2465] < / insdseq>

[2466] < / sequencedata>

[2467] <sequencedata sequenceidnumber="59">

[2468] <insdseq>

[2469] <INSDSeq_length>215< / INSDSeq_length>

[2470] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2471] <INSDSeq_division>PAT< / INSDSeq_division>

[2472] <INSDSeq_feature-table>

[2473] <insdfeature>

[2474] <INSDFeature_key>source< / INSDFeature_key>

[2475] <INSDFeature_location>1..215< / INSDFeature_location>

[2476] <INSDFeature_quals>

[2477] <insdqualifier>

[2478] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2479] <INSDQualifier_value>protein< / INSDQualifier_value>

[2480] < / insdqualifier>

[2481] <insdqualifier id="q118">

[2482] <INSDQualifier_name>organism< / INSDQualifier_name>

[2483] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2484] < / insdqualifier>

[2485] < / INSDFeature_quals>

[2486] < / insdfeature>

[2487] < / INSDSeq_feature-table>

[2488] <INSDSeq_sequence>EIVLTQSPGTLSLSPGERATLSCRASQSVSGTYLAWYKQKPGQAPRLLI

[2489] FGASRRAAGIPDRFSGSRSGTDFTLTISRLEPEDFAVYYCQQYGSSGLTFGGGTKLEIKRTVAAPSVFIF

[2490] PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK

[2491] HKVYACEVTHQGLSSPVTKSFNRGEC< / INSDSeq_sequence>

[2492] < / insdseq>

[2493] < / sequencedata>

[2494] <sequencedata sequenceidnumber="60">

[2495] <insdseq>

[2496] <INSDSeq_length>217< / INSDSeq_length>

[2497] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2498] <INSDSeq_division>PAT< / INSDSeq_division>

[2499] <INSDSeq_feature-table>

[2500] <insdfeature>

[2501] <INSDFeature_key>source< / INSDFeature_key>

[2502] <INSDFeature_location>1..217< / INSDFeature_location>

[2503] <INSDFeature_quals>

[2504] <insdqualifier>

[2505] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2506] <INSDQualifier_value>protein< / INSDQualifier_value>

[2507] < / insdqualifier>

[2508] <insdqualifier id="q120">

[2509] <INSDQualifier_name>organism< / INSDQualifier_name>

[2510] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2511] < / insdqualifier>

[2512] < / INSDFeature_quals>

[2513] < / insdfeature>

[2514] < / INSDSeq_feature-table>

[2515] <INSDSeq_sequence>EIVMTQSPATLSVSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLI

[2516] YGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPPSITFGQGTRLEIKRTVAAPSVF

[2517] IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY

[2518] EKHKVYACEVTHQGLSSPVTKSFNRGEC< / INSDSeq_sequence>

[2519] < / insdseq>

[2520] < / sequencedata>

[2521] <sequencedata sequenceidnumber="61">

[2522] <insdseq>

[2523] <INSDSeq_length>451< / INSDSeq_length>

[2524] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2525] <INSDSeq_division>PAT< / INSDSeq_division>

[2526] <INSDSeq_feature-table>

[2527] <insdfeature>

[2528] <INSDFeature_key>source< / INSDFeature_key>

[2529] <INSDFeature_location>1..451< / INSDFeature_location>

[2530] <INSDFeature_quals>

[2531] <insdqualifier>

[2532] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2533] <INSDQualifier_value>protein< / INSDQualifier_value>

[2534] < / insdqualifier>

[2535] <insdqualifier id="q122">

[2536] <INSDQualifier_name>organism< / INSDQualifier_name>

[2537] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2538] < / insdqualifier>

[2539] < / INSDFeature_quals>

[2540] < / insdfeature>

[2541] < / INSDSeq_feature-table>

[2542] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2543] EINHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2544] TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

[2545] SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYI

[2546] TREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[2547] SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

[2548] TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence

[2549] >

[2550] < / insdseq>

[2551] < / sequencedata>

[2552] <sequencedata sequenceidnumber="62">

[2553] <insdseq>

[2554] <INSDSeq_length>451< / INSDSeq_length>

[2555] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2556] <INSDSeq_division>PAT< / INSDSeq_division>

[2557] <INSDSeq_feature-table>

[2558] <insdfeature>

[2559] <INSDFeature_key>source< / INSDFeature_key>

[2560] <INSDFeature_location>1..451< / INSDFeature_location>

[2561] <INSDFeature_quals>

[2562] <insdqualifier>

[2563] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2564] <INSDQualifier_value>protein< / INSDQualifier_value>

[2565] < / insdqualifier>

[2566] <insdqualifier id="q124">

[2567] <INSDQualifier_name>organism< / INSDQualifier_name>

[2568] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2569] < / insdqualifier>

[2570] < / INSDFeature_quals>

[2571] < / insdfeature>

[2572] < / INSDSeq_feature-table>

[2573] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2574] EIQHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2575] TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

[2576] SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYI

[2577] TREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[2578] SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

[2579] TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence

[2580] >

[2581] < / insdseq>

[2582] < / sequencedata>

[2583] <sequencedata sequenceidnumber="63">

[2584] <insdseq>

[2585] <INSDSeq_length>451< / INSDSeq_length>

[2586] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2587] <INSDSeq_division>PAT< / INSDSeq_division>

[2588] <INSDSeq_feature-table>

[2589] <insdfeature>

[2590] <INSDFeature_key>source< / INSDFeature_key>

[2591] <INSDFeature_location>1..451< / INSDFeature_location>

[2592] <INSDFeature_quals>

[2593] <insdqualifier>

[2594] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2595] <INSDQualifier_value>protein< / INSDQualifier_value>

[2596] < / insdqualifier>

[2597] <insdqualifier id="q126">

[2598] <INSDQualifier_name>organism< / INSDQualifier_name>

[2599] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2600] < / insdqualifier>

[2601] < / INSDFeature_quals>

[2602] < / insdfeature>

[2603] < / INSDSeq_feature-table>

[2604] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2605] EIAHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2606] TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

[2607] SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYI

[2608] TREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[2609] SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

[2610] TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence

[2611] >

[2612] < / insdseq>

[2613] < / sequencedata>

[2614] <sequencedata sequenceidnumber="64">

[2615] <insdseq>

[2616] <INSDSeq_length>451< / INSDSeq_length>

[2617] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2618] <INSDSeq_division>PAT< / INSDSeq_division>

[2619] <INSDSeq_feature-table>

[2620] <insdfeature>

[2621] <INSDFeature_key>source< / INSDFeature_key>

[2622] <INSDFeature_location>1..451< / INSDFeature_location>

[2623] <INSDFeature_quals>

[2624] <insdqualifier>

[2625] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2626] <INSDQualifier_value>protein< / INSDQualifier_value>

[2627] < / insdqualifier>

[2628] <insdqualifier id="q128">

[2629] <INSDQualifier_name>organism< / INSDQualifier_name>

[2630] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2631] < / insdqualifier>

[2632] < / INSDFeature_quals>

[2633] < / insdfeature>

[2634] < / INSDSeq_feature-table>

[2635] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2636] EIGHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2637] TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

[2638] SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYI

[2639] TREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[2640] SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

[2641] TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence

[2642] >

[2643] < / insdseq>

[2644] < / sequencedata>

[2645] <sequencedata sequenceidnumber="65">

[2646] <insdseq>

[2647] <INSDSeq_length>451< / INSDSeq_length>

[2648] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2649] <INSDSeq_division>PAT< / INSDSeq_division>

[2650] <INSDSeq_feature-table>

[2651] <insdfeature>

[2652] <INSDFeature_key>source< / INSDFeature_key>

[2653] <INSDFeature_location>1..451< / INSDFeature_location>

[2654] <INSDFeature_quals>

[2655] <insdqualifier>

[2656] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2657] <INSDQualifier_value>protein< / INSDQualifier_value>

[2658] < / insdqualifier>

[2659] <insdqualifier id="q130">

[2660] <INSDQualifier_name>organism< / INSDQualifier_name>

[2661] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2662] < / insdqualifier>

[2663] < / INSDFeature_quals>

[2664] < / insdfeature>

[2665] < / INSDSeq_feature-table>

[2666] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2667] EIIHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2668] TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

[2669] SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYI

[2670] TREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[2671] SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

[2672] TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence

[2673] >

[2674] < / insdseq>

[2675] < / sequencedata>

[2676] <sequencedata sequenceidnumber="66">

[2677] <insdseq>

[2678] <INSDSeq_length>451< / INSDSeq_length>

[2679] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2680] <INSDSeq_division>PAT< / INSDSeq_division>

[2681] <INSDSeq_feature-table>

[2682] <insdfeature>

[2683] <INSDFeature_key>source< / INSDFeature_key>

[2684] <INSDFeature_location>1..451< / INSDFeature_location>

[2685] <INSDFeature_quals>

[2686] <insdqualifier>

[2687] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2688] <INSDQualifier_value>protein< / INSDQualifier_value>

[2689] < / insdqualifier>

[2690] <insdqualifier id="q132">

[2691] <INSDQualifier_name>organism< / INSDQualifier_name>

[2692] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2693] < / insdqualifier>

[2694] < / INSDFeature_quals>

[2695] < / insdfeature>

[2696] < / INSDSeq_feature-table>

[2697] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2698] EILHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2699] TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

[2700] SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYI

[2701] TREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[2702] SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

[2703] TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence

[2704] >

[2705] < / insdseq>

[2706] < / sequencedata>

[2707] <sequencedata sequenceidnumber="67">

[2708] <insdseq>

[2709] <INSDSeq_length>451< / INSDSeq_length>

[2710] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2711] <INSDSeq_division>PAT< / INSDSeq_division>

[2712] <INSDSeq_feature-table>

[2713] <insdfeature>

[2714] <INSDFeature_key>source< / INSDFeature_key>

[2715] <INSDFeature_location>1..451< / INSDFeature_location>

[2716] <INSDFeature_quals>

[2717] <insdqualifier>

[2718] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2719] <INSDQualifier_value>protein< / INSDQualifier_value>

[2720] < / insdqualifier>

[2721] <insdqualifier id="q134">

[2722] <INSDQualifier_name>organism< / INSDQualifier_name>

[2723] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2724] < / insdqualifier>

[2725] < / INSDFeature_quals>

[2726] < / insdfeature>

[2727] < / INSDSeq_feature-table>

[2728] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2729] EIMHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2730] TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

[2731] SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYI

[2732] TREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[2733] SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

[2734] TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence

[2735] >

[2736] < / insdseq>

[2737] < / sequencedata>

[2738] <sequencedata sequenceidnumber="68">

[2739] <insdseq>

[2740] <INSDSeq_length>451< / INSDSeq_length>

[2741] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2742] <INSDSeq_division>PAT< / INSDSeq_division>

[2743] <INSDSeq_feature-table>

[2744] <insdfeature>

[2745] <INSDFeature_key>source< / INSDFeature_key>

[2746] <INSDFeature_location>1..451< / INSDFeature_location>

[2747] <INSDFeature_quals>

[2748] <insdqualifier>

[2749] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2750] <INSDQualifier_value>protein< / INSDQualifier_value>

[2751] < / insdqualifier>

[2752] <insdqualifier id="q136">

[2753] <INSDQualifier_name>organism< / INSDQualifier_name>

[2754] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2755] < / insdqualifier>

[2756] < / INSDFeature_quals>

[2757] < / insdfeature>

[2758] < / INSDSeq_feature-table>

[2759] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2760] EISHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2761] TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

[2762] SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYI

[2763] TREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[2764] SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

[2765] TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence

[2766] >

[2767] < / insdseq>

[2768] < / sequencedata>

[2769] <sequencedata sequenceidnumber="69">

[2770] <insdseq>

[2771] <INSDSeq_length>451< / INSDSeq_length>

[2772] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2773] <INSDSeq_division>PAT< / INSDSeq_division>

[2774] <INSDSeq_feature-table>

[2775] <insdfeature>

[2776] <INSDFeature_key>source< / INSDFeature_key>

[2777] <INSDFeature_location>1..451< / INSDFeature_location>

[2778] <INSDFeature_quals>

[2779] <insdqualifier>

[2780] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2781] <INSDQualifier_value>protein< / INSDQualifier_value>

[2782] < / insdqualifier>

[2783] <insdqualifier id="q138">

[2784] <INSDQualifier_name>organism< / INSDQualifier_name>

[2785] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2786] < / insdqualifier>

[2787] < / INSDFeature_quals>

[2788] < / insdfeature>

[2789] < / INSDSeq_feature-table>

[2790] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2791] EITHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2792] TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

[2793] SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYI

[2794] TREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[2795] SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

[2796] TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence

[2797] >

[2798] < / insdseq>

[2799] < / sequencedata>

[2800] <sequencedata sequenceidnumber="70">

[2801] <insdseq>

[2802] <INSDSeq_length>451< / INSDSeq_length>

[2803] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2804] <INSDSeq_division>PAT< / INSDSeq_division>

[2805] <INSDSeq_feature-table>

[2806] <insdfeature>

[2807] <INSDFeature_key>source< / INSDFeature_key>

[2808] <INSDFeature_location>1..451< / INSDFeature_location>

[2809] <INSDFeature_quals>

[2810] <insdqualifier>

[2811] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2812] <INSDQualifier_value>protein< / INSDQualifier_value>

[2813] < / insdqualifier>

[2814] <insdqualifier id="q140">

[2815] <INSDQualifier_name>organism< / INSDQualifier_name>

[2816] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2817] < / insdqualifier>

[2818] < / INSDFeature_quals>

[2819] < / insdfeature>

[2820] < / INSDSeq_feature-table>

[2821] <INSDSeq_sequence>EVQLQQWGAGVLKPSETLSLTCAVYGGSLSDYYWSWIRQPPGKGLEWIG

[2822] EIVHSGNTDYNPSLKSRVTISVDTSKNQFSLRVSSVTAEDTAFYFCARGGFSGSPNYYYAMDVWGQGTTV

[2823] TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

[2824] SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYI

[2825] TREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[2826] SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

[2827] TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence

[2828] >

[2829] < / insdseq>

[2830] < / sequencedata>

[2831] <sequencedata sequenceidnumber="71">

[2832] <insdseq>

[2833] <INSDSeq_length>451< / INSDSeq_length>

[2834] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2835] <INSDSeq_division>PAT< / INSDSeq_division>

[2836] <INSDSeq_feature-table>

[2837] <insdfeature>

[2838] <INSDFeature_key>source< / INSDFeature_key>

[2839] <INSDFeature_location>1..451< / INSDFeature_location>

[2840] <INSDFeature_quals>

[2841] <insdqualifier>

[2842] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2843] <INSDQualifier_value>protein< / INSDQualifier_value>

[2844] < / insdqualifier>

[2845] <insdqualifier id="q142">

[2846] <INSDQualifier_name>organism< / INSDQualifier_name>

[2847] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2848] < / insdqualifier>

[2849] < / INSDFeature_quals>

[2850] < / insdfeature>

[2851] < / INSDSeq_feature-table>

[2852] <INSDSeq_sequence>ELQLQESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGPDWVS

[2853] TIRTGGRTTYADSVKGRFTISRDNAKNTLYLQMNSLKSDDTAVYYCAKSRGTSWVPEIYEYDYWGQGTLV

[2854] TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

[2855] SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYI

[2856] TREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[2857] SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

[2858] TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence

[2859] >

[2860] < / insdseq>

[2861] < / sequencedata>

[2862] <sequencedata sequenceidnumber="72">

[2863] <insdseq>

[2864] <INSDSeq_length>451< / INSDSeq_length>

[2865] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2866] <INSDSeq_division>PAT< / INSDSeq_division>

[2867] <INSDSeq_feature-table>

[2868] <insdfeature>

[2869] <INSDFeature_key>source< / INSDFeature_key>

[2870] <INSDFeature_location>1..451< / INSDFeature_location>

[2871] <INSDFeature_quals>

[2872] <insdqualifier>

[2873] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2874] <INSDQualifier_value>protein< / INSDQualifier_value>

[2875] < / insdqualifier>

[2876] <insdqualifier id="q144">

[2877] <INSDQualifier_name>organism< / INSDQualifier_name>

[2878] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2879] < / insdqualifier>

[2880] < / INSDFeature_quals>

[2881] < / insdfeature>

[2882] < / INSDSeq_feature-table>

[2883] <INSDSeq_sequence>EVQLQQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGPDWVS

[2884] TIRTGGRTTYADSVKGRFTISRDNAKNTLYLQMNSLKSDDTAVYYCAKSRGTSWVPEIYEYDYWGQGTMV

[2885] TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS

[2886] SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYI

[2887] TREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV

[2888] SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT

[2889] TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence

[2890] >

[2891] < / insdseq>

[2892] < / sequencedata>

[2893] <sequencedata sequenceidnumber="73">

[2894] <insdseq>

[2895] <INSDSeq_length>450< / INSDSeq_length>

[2896] <INSDSeq_moltype>AA< / INSDSeq_moltype>

[2897] <INSDSeq_division>PAT< / INSDSeq_division>

[2898] <INSDSeq_feature-table>

[2899] <insdfeature>

[2900] <INSDFeature_key>source< / INSDFeature_key>

[2901] <INSDFeature_location>1..450< / INSDFeature_location>

[2902] <INSDFeature_quals>

[2903] <insdqualifier>

[2904] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2905] <INSDQualifier_value>protein< / INSDQualifier_value>

[2906] < / insdqualifier>

[2907] <insdqualifier id="q146">

[2908] <INSDQualifier_name>organism< / INSDQualifier_name>

[2909] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2910] < / insdqualifier>

[2911] < / INSDFeature_quals>

[2912] < / insdfeature>

[2913] < / INSDSeq_feature-table>

[2914] <INSDSeq_sequence>ELQLVQSGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLEWVS

[2915] AINSGGGSTYYADSMKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCNARLSWGSYYRDDEYWGQGTQVT

[2916] VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS

[2917] VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYIT

[2918] REPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS

[2919] NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT

[2920] PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence>

[2921] < / insdseq>

[2922] < / sequencedata>

[2923] <sequencedata sequenceidnumber="74">

[2924] <insdseq>

[2925] <INSDSeq_length> 444< / INSDSeq_length>

[2926] <INSDSeq_moltype> AA< / INSDSeq_moltype>

[2927] <INSDSeq_division> PAT< / INSDSeq_division>

[2928] <INSDSeq_feature-table>

[2929] <insdfeature>

[2930] <INSDFeature_key>source< / INSDFeature_key>

[2931] <INSDFeature_location>1..444< / INSDFeature_location>

[2932] <INSDFeature_quals>

[2933] <insdqualifier>

[2934] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2935] <INSDQualifier_value>protein< / INSDQualifier_value>

[2936] < / insdqualifier>

[2937] <insdqualifier id="q148">

[2938] <INSDQualifier_name>organism< / INSDQualifier_name>

[2939] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2940] < / insdqualifier>

[2941] < / INSDFeature_quals>

[2942] < / insdfeature>

[2943] < / INSDSeq_feature-table>

[2944] <INSDSeq_sequence> EVTLKESGGGLVQPGGSLRLSCAASGFTFSGYAMSWVRQAPGKGPEWVS

[2945] TINSGGGSTSYADSVKGRFTISRDNAKSTLYLQMNSLKPEDTAVYCAEGWTDFDYWGQGTQVTVSSAST

[2946] KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS

[2947] SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPPKPKDTLYITREPEVT

[2948] CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA

[2949] FRIDAYKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS

[2950] DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP< / INSDSeq_sequence>

[2951] < / insdseq>

[2952] < / sequencedata>

[2953] <sequencedata sequenceidnumber="75">

[2954] <insdseq>

[2955] <INSDSeq_length>318< / INSDSeq_length>

[2956] <INSDSeq_moltype>DNA< / INSDSeq_moltype>

[2957] <INSDSeq_division>PAT< / INSDSeq_division>

[2958] <INSDSeq_feature-table>

[2959] <insdfeature>

[2960] <INSDFeature_key>source< / INSDFeature_key>

[2961] <INSDFeature_location>1..318< / INSDFeature_location>

[2962] <INSDFeature_quals>

[2963] <insdqualifier>

[2964] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2965] <INSDQualifier_value>other DNA< / INSDQualifier_value>

[2966] < / insdqualifier>

[2967] <insdqualifier id="q150">

[2968] <INSDQualifier_name>organism< / INSDQualifier_name>

[2969] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2970] < / insdqualifier>

[2971] < / INSDFeature_quals>

[2972] < / insdfeature>

[2973] < / INSDSeq_feature-table>

[2974] <INSDSeq_sequence>aacatccagatgacccagtctccatcctccctgtctgcatctgtaggag

[2975] acagagtcaccatcacttgccgggcaagtcagagcattagcagctatttaaattggtatcagcagaaacc

[2976] agggaaagcccctaagctcctgatctatggtgcatccagtttgcaaagtggggtcccatcaaggttcagt

[2977] ggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacctgaagattttgcaacttatc

[2978] actgtcagcagagttacagaaccctcactttcggcggagggaccaaggtggagatcaaa< / INSDSeq_s

[2979] equence>

[2980] < / insdseq>

[2981] < / sequencedata>

[2982] <sequencedata sequenceidnumber="76">

[2983] <insdseq>

[2984] <INSDSeq_length>321< / INSDSeq_length>

[2985] <INSDSeq_moltype>DNA< / INSDSeq_moltype>

[2986] <INSDSeq_division>PAT< / INSDSeq_division>

[2987] <INSDSeq_feature-table>

[2988] <insdfeature>

[2989] <INSDFeature_key>source< / INSDFeature_key>

[2990] <INSDFeature_location>1..321< / INSDFeature_location>

[2991] <INSDFeature_quals>

[2992] <insdqualifier>

[2993] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[2994] <INSDQualifier_value>other DNA< / INSDQualifier_value>

[2995] < / insdqualifier>

[2996] <insdqualifier id="q152">

[2997] <INSDQualifier_name>organism< / INSDQualifier_name>

[2998] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[2999] < / insdqualifier>

[3000] < / INSDFeature_quals>

[3001] < / insdfeature>

[3002] < / INSDSeq_feature-table>

[3003] <INSDSeq_sequence>gacatccagatgacccagtctccatcttccgtgtctgcatctgtaggag

[3004] acagagtcaccatcacttgtcgggcgagtcagggtattagcagctggttagcctggtatcagcagaaacc

[3005] agggaaagcccctaagctcctgatctatgctgcatccagtttgcaaagtggggtcccatcaaggttcagt

[3006] ggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacctgaagattttgcaacttact

[3007] actgtcaacagagttacagtacccctccggacttcggccaagggacacgactggagattaaa< / INSDSe

[3008] q_sequence>

[3009] < / insdseq>

[3010] < / sequencedata>

[3011] <sequencedata sequenceidnumber="77">

[3012] <insdseq>

[3013] <INSDSeq_length>321< / INSDSeq_length>

[3014] <INSDSeq_moltype>DNA< / INSDSeq_moltype>

[3015] <INSDSeq_division>PAT< / INSDSeq_division>

[3016] <INSDSeq_feature-table>

[3017] <insdfeature>

[3018] <INSDFeature_key>source< / INSDFeature_key>

[3019] <INSDFeature_location>1..321< / INSDFeature_location>

[3020] <INSDFeature_quals>

[3021] <insdqualifier>

[3022] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[3023] <INSDQualifier_value>other DNA< / INSDQualifier_value>

[3024] < / insdqualifier>

[3025] <insdqualifier id="q154">

[3026] <INSDQualifier_name>organism< / INSDQualifier_name>

[3027] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[3028] < / insdqualifier>

[3029] < / INSDFeature_quals>

[3030] < / insdfeature>

[3031] < / INSDSeq_feature-table>

[3032] <INSDSeq_sequence>gaaacgacactcacgcagtctccatcctccctgtctgcatctgtagggg

[3033] acagggtcaccatcacttgccgggccagtcagagtattagtagttggttggcctggtatcagcagaaacc

[3034] agggaaagccccaaagctcctgatctataaggcgtctactttacaaactggggtcccatcaaggttcagc

[3035] ggcagtggatctgggacagaattcactctcatcatcagcagcctgcagcctgaagattctgcaacttact

[3036] attgtcaacaggctaacagtttcccgatcactttcggccaagggacacgactggagattaaa< / INSDSe

[3037] q_sequence>

[3038] < / insdseq>

[3039] < / sequencedata>

[3040] <sequencedata sequenceidnumber="78">

[3041] <insdseq>

[3042] <INSDSeq_length>324< / INSDSeq_length>

[3043] <INSDSeq_moltype>DNA< / INSDSeq_moltype>

[3044] <INSDSeq_division>PAT< / INSDSeq_division>

[3045] <INSDSeq_feature-table>

[3046] <insdfeature>

[3047] <INSDFeature_key>source< / INSDFeature_key>

[3048] <INSDFeature_location>1..324< / INSDFeature_location>

[3049] <INSDFeature_quals>

[3050] <insdqualifier>

[3051] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[3052] <INSDQualifier_value>other DNA< / INSDQualifier_value>

[3053] < / insdqualifier>

[3054] <insdqualifier id="q156">

[3055] <INSDQualifier_name>organism< / INSDQualifier_name>

[3056] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[3057] < / insdqualifier>

[3058] < / INSDFeature_quals>

[3059] < / insdfeature>

[3060] < / INSDSeq_feature-table>

[3061] <INSDSeq_sequence>gaaattgtgctgactcagtctccaggcaccctgtctttgtctccaggag

[3062] aaagagccaccctctcctgcagggccagtcagagtgttagcggcacctacttagcctggtataagcagaa

[3063] gcctggccaggctcccaggctcctcatctttggtgcatcccgcagggccgctggcatcccagacaggttc

[3064] agtggcagtaggtctgggacagacttcactctcaccatcagcagactggagcctgaagattttgcagtgt

[3065] attactgtcagcaatatggtagctcaggtctcactttcggcggagggaccaagctggagatcaaa< / INS

[3066] DSeq_sequence>

[3067] < / insdseq>

[3068] < / sequencedata>

[3069] <sequencedata sequenceidnumber="79">

[3070] <insdseq>

[3071] <INSDSeq_length>330< / INSDSeq_length>

[3072] <INSDSeq_moltype>DNA< / INSDSeq_moltype>

[3073] <INSDSeq_division>PAT< / INSDSeq_division>

[3074] <INSDSeq_feature-table>

[3075] <insdfeature>

[3076] <INSDFeature_key>source< / INSDFeature_key>

[3077] <INSDFeature_location>1..330< / INSDFeature_location>

[3078] <INSDFeature_quals>

[3079] <insdqualifier>

[3080] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[3081] <INSDQualifier_value>other DNA< / INSDQualifier_value>

[3082] < / insdqualifier>

[3083] <insdqualifier id="q158">

[3084] <INSDQualifier_name>organism< / INSDQualifier_name>

[3085] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[3086] < / insdqualifier>

[3087] < / INSDFeature_quals>

[3088] < / insdfeature>

[3089] < / INSDSeq_feature-table>

[3090] <INSDSeq_sequence>gaaattgtgatgacgcagtctccagccaccctgtctgtgtctccagggg

[3091] aaagagccaccctctcctgcagggccagtcagagtgttagcagcagctacttagcctggtaccagcagaa

[3092] acctggccaggctcccaggctcctcatctatggtgcatccagcagggccactggcatcccagacaggttc

[3093] agtggcagtgggtctgggacagacttcactctcaccatcagtagactggagcctgaagattttgcagtgt

[3094] attactgtcagcagtatggtagctcacctccctcgatcaccttcggccaagggacacgactggagattaa

[3095] a< / INSDSeq_sequence>

[3096] < / insdseq>

[3097] < / sequencedata>

[3098] <sequencedata sequenceidnumber="80">

[3099] <insdseq>

[3100] <INSDSeq_length>369< / INSDSeq_length>

[3101] <INSDSeq_moltype>DNA< / INSDSeq_moltype>

[3102] <INSDSeq_division>PAT< / INSDSeq_division>

[3103] <INSDSeq_feature-table>

[3104] <insdfeature>

[3105] <INSDFeature_key>source< / INSDFeature_key>

[3106] <INSDFeature_location>1..369< / INSDFeature_location>

[3107] <INSDFeature_quals>

[3108] <insdqualifier>

[3109] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[3110] <INSDQualifier_value>other DNA< / INSDQualifier_value>

[3111] < / insdqualifier>

[3112] <insdqualifier id="q160">

[3113] <INSDQualifier_name>organism< / INSDQualifier_name>

[3114] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[3115] < / insdqualifier>

[3116] < / INSDFeature_quals>

[3117] < / insdfeature>

[3118] < / INSDSeq_feature-table>

[3119] <INSDSeq_sequence>gaggtgcagctacaacagtggggcgcaggagtgttgaagccttcggaga

[3120] ccctgtccctcacctgcgctgtgtatggtgggtcccttagtgattattactggagctggatccgccagcc

[3121] cccagggaagggactggagtggattggagagatcaatcatagtggaaacaccgactacaacccgtccctc

[3122] aagagtcgagtcaccatatcagtagacacgtccaagaaccagttctccctgagggtgagctctgtgaccg

[3123] ccgaggacacggccttctatttctgtgcgagaggaggatttagtgggagccccaactactactacgcaat

[3124] ggacgtctggggccaagggaccacggtcaccgtctcgagt< / INSDSeq_sequence>

[3125] < / insdseq>

[3126] < / sequencedata>

[3127] <sequencedata sequenceidnumber="81">

[3128] <insdseq>

[3129] <INSDSeq_length>369< / INSDSeq_length>

[3130] <INSDSeq_moltype>DNA< / INSDSeq_moltype>

[3131] <INSDSeq_division>PAT< / INSDSeq_division>

[3132] <INSDSeq_feature-table>

[3133] <insdfeature>

[3134] <INSDFeature_key>source< / INSDFeature_key>

[3135] <INSDFeature_location>1..369< / INSDFeature_location>

[3136] <INSDFeature_quals>

[3137] <insdqualifier>

[3138] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[3139] <INSDQualifier_value>other DNA< / INSDQualifier_value>

[3140] < / insdqualifier>

[3141] <insdqualifier id="q162">

[3142] <INSDQualifier_name>organism< / INSDQualifier_name>

[3143] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[3144] < / insdqualifier>

[3145] < / INSDFeature_quals>

[3146] < / insdfeature>

[3147] < / INSDSeq_feature-table>

[3148] <INSDSeq_sequence>gaggtccagctacaacagtggggagcaggagtgctgaagccctcagaga

[3149] ccctttccctcacctgtgccgtgtatggcggtagcctgagcgactactactggtcctggattcggcagcc

[3150] tcccggcaagggactggagtggattggcgagatccagcacagtgggaacaccgactacaacccaagcctc

[3151] aagtcccgggtgacgatctccgtggacacgagcaagaaccaattcagcctgcgggtgagcagcgtgaccg

[3152] ccgaagacacagccttctacttttgcgccaggggtgggtttagtggctcccctaactactactacgcgat

[3153] ggacgtgtggggtcagggcactacggtgacagtgagcagc< / INSDSeq_sequence>

[3154] < / insdseq>

[3155] < / sequencedata>

[3156] <sequencedata sequenceidnumber="82">

[3157] <insdseq>

[3158] <INSDSeq_length>369< / INSDSeq_length>

[3159] <INSDSeq_moltype>DNA< / INSDSeq_moltype>

[3160] <INSDSeq_division>PAT< / INSDSeq_division>

[3161] <INSDSeq_feature-table>

[3162] <insdfeature>

[3163] <INSDFeature_key>source< / INSDFeature_key>

[3164] <INSDFeature_location>1..369< / INSDFeature_location>

[3165] <INSDFeature_quals>

[3166] <insdqualifier>

[3167] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[3168] <INSDQualifier_value>other DNA< / INSDQualifier_value>

[3169] < / insdqualifier>

[3170] <insdqualifier id="q164">

[3171] <INSDQualifier_name>organism< / INSDQualifier_name>

[3172] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[3173] < / insdqualifier>

[3174] < / INSDFeature_quals>

[3175] < / insdfeature>

[3176] < / INSDSeq_feature-table>

[3177] <INSDSeq_sequence>gaggtccagctacaacagtggggagcaggagtgctgaagccctcagaga

[3178] ccctttccctcacctgtgccgtgtatggcggtagcctgagcgactactactggtcctggattcggcagcc

[3179] tcccggcaagggactggagtggattggcgagatcgcccacagtgggaacaccgactacaacccaagcctc

[3180] aagtcccgggtgacgatctccgtggacacgagcaagaaccaattcagcctgcgggtgagcagcgtgaccg

[3181] ccgaagacacagccttctacttttgcgccaggggtgggtttagtggctcccctaactactactacgcgat

[3182] ggacgtgtggggtcagggcactacggtgacagtgagcagc< / INSDSeq_sequence>

[3183] < / insdseq>

[3184] < / sequencedata>

[3185] <sequencedata sequenceidnumber="83">

[3186] <insdseq>

[3187] <INSDSeq_length>369< / INSDSeq_length>

[3188] <INSDSeq_moltype>DNA< / INSDSeq_moltype>

[3189] <INSDSeq_division>PAT< / INSDSeq_division>

[3190] <INSDSeq_feature-table>

[3191] <insdfeature>

[3192] <INSDFeature_key>source< / INSDFeature_key>

[3193] <INSDFeature_location>1..369< / INSDFeature_location>

[3194] <INSDFeature_quals>

[3195] <insdqualifier>

[3196] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[3197] <INSDQualifier_value>other DNA< / INSDQualifier_value>

[3198] < / insdqualifier>

[3199] <insdqualifier id="q166">

[3200] <INSDQualifier_name>organism< / INSDQualifier_name>

[3201] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[3202] < / insdqualifier>

[3203] < / INSDFeature_quals>

[3204] < / insdfeature>

[3205] < / INSDSeq_feature-table>

[3206] <INSDSeq_sequence>gaggtccagctacaacagtggggagcaggagtgctgaagccctcagaga

[3207] ccctttccctcacctgtgccgtgtatggcggtagcctgagcgactactactggtcctggattcggcagcc

[3208] tcccggcaagggactggagtggattggcgagatcggccacagtgggaacaccgactacaacccaagcctc

[3209] aagtcccgggtgacgatctccgtggacacgagcaagaaccaattcagcctgcgggtgagcagcgtgaccg

[3210] ccgaagacacagccttctacttttgcgccaggggtgggtttagtggctcccctaactactactacgcgat

[3211] ggacgtgtggggtcagggcactacggtgacagtgagcagc< / INSDSeq_sequence>

[3212] < / insdseq>

[3213] < / sequencedata>

[3214] <sequencedata sequenceidnumber="84">

[3215] <insdseq>

[3216] <INSDSeq_length>369< / INSDSeq_length>

[3217] <INSDSeq_moltype>DNA< / INSDSeq_moltype>

[3218] <INSDSeq_division>PAT< / INSDSeq_division>

[3219] <INSDSeq_feature-table>

[3220] <insdfeature>

[3221] <INSDFeature_key>source< / INSDFeature_key>

[3222] <INSDFeature_location>1..369< / INSDFeature_location>

[3223] <INSDFeature_quals>

[3224] <insdqualifier>

[3225] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[3226] <INSDQualifier_value>other DNA< / INSDQualifier_value>

[3227] < / insdqualifier>

[3228] <insdqualifier id="q168">

[3229] <INSDQualifier_name>organism< / INSDQualifier_name>

[3230] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[3231] < / insdqualifier>

[3232] < / INSDFeature_quals>

[3233] < / insdfeature>

[3234] < / INSDSeq_feature-table>

[3235] <INSDSeq_sequence>gaggtccagctacaacagtggggagcaggagtgctgaagccctcagaga

[3236] ccctttccctcacctgtgccgtgtatggcggtagcctgagcgactactactggtcctggattcggcagcc

[3237] tcccggcaagggactggagtggattggcgagatcatccacagtgggaacaccgactacaacccaagcctc

[3238] aagtcccgggtgacgatctccgtggacacgagcaagaaccaattcagcctgcgggtgagcagcgtgaccg

[3239] ccgaagacacagccttctacttttgcgccaggggtgggtttagtggctcccctaactactactacgcgat

[3240] ggacgtgtggggtcagggcactacggtgacagtgagcagc< / INSDSeq_sequence>

[3241] < / insdseq>

[3242] < / sequencedata>

[3243] <sequencedata sequenceidnumber="85">

[3244] <insdseq>

[3245] <INSDSeq_length>369< / INSDSeq_length>

[3246] <INSDSeq_moltype>DNA< / INSDSeq_moltype>

[3247] <INSDSeq_division>PAT< / INSDSeq_division>

[3248] <INSDSeq_feature-table>

[3249] <insdfeature>

[3250] <INSDFeature_key>source< / INSDFeature_key>

[3251] <INSDFeature_location>1..369< / INSDFeature_location>

[3252] <INSDFeature_quals>

[3253] <insdqualifier>

[3254] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[3255] <INSDQualifier_value>other DNA< / INSDQualifier_value>

[3256] < / insdqualifier>

[3257] <insdqualifier id="q170">

[3258] <INSDQualifier_name>organism< / INSDQualifier_name>

[3259] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[3260] < / insdqualifier>

[3261] < / INSDFeature_quals>

[3262] < / insdfeature>

[3263] < / INSDSeq_feature-table>

[3264] <INSDSeq_sequence>gaggtccagctacaacagtggggagcaggagtgctgaagccctcagaga

[3265] ccctttccctcacctgtgccgtgtatggcggtagcctgagcgactactactggtcctggattcggcagcc

[3266] tcccggcaagggactggagtggattggcgagatcctgcacagtgggaacaccgactacaacccaagcctc

[3267] aagtcccgggtgacgatctccgtggacacgagcaagaaccaattcagcctgcgggtgagcagcgtgaccg

[3268] ccgaagacacagccttctacttttgcgccaggggtgggtttagtggctcccctaactactactacgcgat

[3269] ggacgtgtggggtcagggcactacggtgacagtgagcagc< / INSDSeq_sequence>

[3270] < / insdseq>

[3271] < / sequencedata>

[3272] <sequencedata sequenceidnumber="86">

[3273] <insdseq>

[3274] <INSDSeq_length>369< / INSDSeq_length>

[3275] <INSDSeq_moltype>DNA< / INSDSeq_moltype>

[3276] <INSDSeq_division>PAT< / INSDSeq_division>

[3277] <INSDSeq_feature-table>

[3278] <insdfeature>

[3279] <INSDFeature_key>source< / INSDFeature_key>

[3280] <INSDFeature_location>1..369< / INSDFeature_location>

[3281] <INSDFeature_quals>

[3282] <insdqualifier>

[3283] <INSDQualifier_name>mol_type< / INSDQualifier_name>

[3284] <INSDQualifier_value>other DNA< / INSDQualifier_value>

[3285] < / insdqualifier>

[3286] <insdqualifier id="q172">

[3287] <INSDQualifier_name>organism< / INSDQualifier_name>

[3288] <INSDQualifier_value>synthetic construct< / INSDQualifier_value>

[3289] < / insdqualifier>

[3290] < / INSDFeature_quals>

[3291] < / insdfeature>

[3292] < / INSDSeq_feature-table>

[3293] <INSDSeq_sequence>gaggtccagctacaacagtggggagcaggagtgctgaagccctcagaga

[3294] ccctttccctcacctgtgccgtgtatggcggtagcctgagcgactactactggtcctggattcggcagcc

[3295] tcccggcaagggactggagtggattggcgagatcatgcacagtgggaacaccgactacaacccaagcctc

[3296] aagtcccgggtgacgatctccgtggacacgagcaagaaccaattcagcctgcgggtgagcagcgtgaccg

[3297] ccgaagacacagccttctacttttgcgccaggggtgggtttagtggctcccctaactactactacgcgat

[3298] ggacgtgtggggtcagggcactacggtgacagtgagcagc< / INSDSeq_sequence>

[3299] < / insdseq>

[3300] < / seque...

Claims

1. A monoclonal antibody or antigen-binding fragment thereof that specifically binds to TNF-like ligand 1A (TL1A), comprising: (i) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 1, CDR2 with the amino acid sequence of SEQ ID NO: 6 and CDR3 with the amino acid sequence of SEQ ID NO: 11; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 16, CDR2 with the amino acid sequence of SEQ ID NO: 20 and CDR3 with the amino acid sequence of SEQ ID NO: 33; or (ii) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 1, CDR2 with the amino acid sequence of SEQ ID NO: 6 and CDR3 with the amino acid sequence of SEQ ID NO: 11; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 16, CDR2 with the amino acid sequence of SEQ ID NO: 21 and CDR3 with the amino acid sequence of SEQ ID NO: 33; or (iii) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 1, CDR2 with the amino acid sequence of SEQ ID NO: 6 and CDR3 with the amino acid sequence of SEQ ID NO: 11; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 16, CDR2 with the amino acid sequence of SEQ ID NO: 22 and CDR3 with the amino acid sequence of SEQ ID NO: 33; or (iv) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 1, CDR2 with the amino acid sequence of SEQ ID NO: 6 and CDR3 with the amino acid sequence of SEQ ID NO: 11; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 16, CDR2 with the amino acid sequence of SEQ ID NO: 23 and CDR3 with the amino acid sequence of SEQ ID NO: 33; or (v) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 1, CDR2 with the amino acid sequence of SEQ ID NO: 6 and CDR3 with the amino acid sequence of SEQ ID NO: 11; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 16, CDR2 with the amino acid sequence of SEQ ID NO: 24 and CDR3 with the amino acid sequence of SEQ ID NO: 33; or (vi) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 1, CDR2 with the amino acid sequence of SEQ ID NO: 6 and CDR3 with the amino acid sequence of SEQ ID NO: 11; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 16, CDR2 with the amino acid sequence of SEQ ID NO: 25 and CDR3 with the amino acid sequence of SEQ ID NO: 33; or (vii) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 1, CDR2 with the amino acid sequence of SEQ ID NO: 6 and CDR3 with the amino acid sequence of SEQ ID NO: 11; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 16, CDR2 with the amino acid sequence of SEQ ID NO: 26 and CDR3 with the amino acid sequence of SEQ ID NO: 33; or (viii) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 1, CDR2 with the amino acid sequence of SEQ ID NO: 6 and CDR3 with the amino acid sequence of SEQ ID NO: 11; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 16, CDR2 with the amino acid sequence of SEQ ID NO: 27 and CDR3 with the amino acid sequence of SEQ ID NO: 33; or (ix) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 1, CDR2 with the amino acid sequence of SEQ ID NO: 6 and CDR3 with the amino acid sequence of SEQ ID NO: 11; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 16, CDR2 with the amino acid sequence of SEQ ID NO: 28 and CDR3 with the amino acid sequence of SEQ ID NO: 33; or (x) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 1, CDR2 with the amino acid sequence of SEQ ID NO: 6 and CDR3 with the amino acid sequence of SEQ ID NO: 11; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 16, CDR2 with the amino acid sequence of SEQ ID NO: 29 and CDR3 with the amino acid sequence of SEQ ID NO: 33; or (xi) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 2, CDR2 with the amino acid sequence of SEQ ID NO: 7 and CDR3 with the amino acid sequence of SEQ ID NO: 12; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 17, CDR2 with the amino acid sequence of SEQ ID NO: 30 and CDR3 with the amino acid sequence of SEQ ID NO: 34; or (xii) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 3, CDR2 with the amino acid sequence of SEQ ID NO: 8 and CDR3 with the amino acid sequence of SEQ ID NO: 13; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 17, CDR2 with the amino acid sequence of SEQ ID NO: 30 and CDR3 with the amino acid sequence of SEQ ID NO: 34; or (xiii) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 4, CDR2 with the amino acid sequence of SEQ ID NO: 9 and CDR3 with the amino acid sequence of SEQ ID NO: 14; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 18, CDR2 with the amino acid sequence of SEQ ID NO: 31 and CDR3 with the amino acid sequence of SEQ ID NO: 35; or (xiv) (a) a light chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 5, CDR2 with the amino acid sequence of SEQ ID NO: 10 and CDR3 with the amino acid sequence of SEQ ID NO: 15; and (b) a heavy chain variable domain comprising: CDR1 with the amino acid sequence SEQ ID NO: 19, CDR2 with the amino acid sequence of SEQ ID NO: 32 and CDR3 with the amino acid sequence SEQ ID NO:

36.

2. A monoclonal antibody or antigen-binding fragment thereof according to claim 1, where: (i) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 42; or (ii) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 43; or (iii) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 44; or (iv) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 45; or (v) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 46; or (vi) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 47; or (vii) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 48; or (viii) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 49; or (ix) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 50; or (x) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 37 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 51; or (xi) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 38 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 52; or (xii) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 39 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 53; or (xiii) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 40 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 54; or (xiv) (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 41 and (b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:

55.

3. A monoclonal antibody according to any one of claims 1, 2, wherein the antibody that specifically binds to TL1A is a full-length IgG antibody.

4. The monoclonal antibody of claim 3, wherein the full-length IgG antibody is of the human IgG1, IgG2, IgG3 or IgG4 isotype.

5. The monoclonal antibody of claim 4, wherein the full-length IgG antibody is of the human IgG1 isotype.

6. A monoclonal antibody according to claim 5, wherein the antibody comprises a deletion of 446G and 447K according to the amino acid numbering of EU antibodies in the CH3 region.

7. A monoclonal antibody according to claim 5, wherein the antibody comprises the mutations L234A and L235A according to the amino acid numbering of EU antibodies.

8. A monoclonal antibody according to claim 5, wherein the antibody contains the mutations M252Y, S254T, T256E according to the amino acid numbering of EU antibodies.

9. A monoclonal antibody according to claim 1, comprising: (i) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 61; or (ii) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 62; or (iii) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 63; or (iv) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 64; or (v) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 65; or (vi) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 66; or (vii) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 67; or (viii) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 68; or (ix) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 69; or (x) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 56, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 70; or (xi) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 57, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 71; or (xii) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 58, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 72; or (xiii) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 59, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 73; or (xiv) (a) a light chain comprising the amino acid sequence of SEQ ID NO: 60, and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO:

74.

10. A nucleic acid that encodes an antibody or antigen-binding fragment thereof according to any one of claims 1-9.

11. The nucleic acid of claim 10, wherein the nucleic acid is DNA.

12. An expression vector containing a nucleic acid according to any one of claims 10, 11.

13. A host cell for producing an antibody or an antigen-binding fragment thereof according to any one of claims 1-9, containing a nucleic acid according to any one of claims 10, 11.

14. A method for producing an antibody or an antigen-binding fragment thereof according to any one of claims 1-9, comprising culturing the host cell according to claim 13 in a culture medium under conditions sufficient to produce said antibody, followed by isolating and purifying the resulting antibody.

15. A pharmaceutical composition for the treatment of a disease or disorder mediated by TL1A, comprising an antibody or antigen-binding fragment thereof according to any one of claims 1-9 in a therapeutically effective amount in combination with one or more pharmaceutically acceptable excipients.

16. The pharmaceutical composition of claim 15, wherein the disease or disorder mediated by TL1A is selected from the group: Crohn's disease, ulcerative colitis, bronchial asthma, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, ankylosing spondylitis, interstitial lung disease associated with systemic sclerosis (SSc-ILD), intestinal fibrosis, liver fibrosis or fibrotic lung diseases.

17. A pharmaceutical composition for the treatment of a disease or disorder mediated by TL1A, comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 9 and at least one other therapeutically active compound.

18. The pharmaceutical composition of claim 17, wherein the disease or disorder mediated by TL1A is selected from the group: Crohn's disease, ulcerative colitis, bronchial asthma, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, ankylosing spondylitis, interstitial lung disease associated with systemic sclerosis (SSc-ILD), intestinal fibrosis, liver fibrosis or fibrotic lung diseases.

19. A pharmaceutical composition according to any one of claims 17, 18, wherein the other therapeutically active compound is an antibody, a small molecule, a hormonal therapy agent, or any combination thereof.

20. The use of an antibody or antigen-binding fragment thereof according to any one of claims 1-9 or a pharmaceutical composition according to any one of claims 15-19 for the treatment of a disease or disorder mediated by TL1A in a subject in need of such treatment.

21. The use according to claim 20, wherein the disease or disorder mediated by TL1A is selected from the group: Crohn's disease, ulcerative colitis, bronchial asthma, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, ankylosing spondylitis, interstitial lung disease associated with systemic sclerosis (SSc-ILD), intestinal fibrosis, liver fibrosis or fibrotic lung diseases.

22. The use of an antibody or antigen-binding fragment thereof according to any one of claims 1-9 or a pharmaceutical composition according to any one of claims 15-19 and at least one other therapeutically active compound for the treatment of a disease or disorder mediated by TL1A in a subject in need of such treatment.

23. The use according to claim 22, wherein the disease or disorder mediated by TL1A is selected from the group: Crohn's disease, ulcerative colitis, bronchial asthma, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, ankylosing spondylitis, interstitial lung disease associated with systemic sclerosis (SSc-ILD), intestinal fibrosis, liver fibrosis or fibrotic lung diseases.

24. The use according to any one of claims 22, 23, wherein the other therapeutically active compound is an antibody, a small molecule, a hormonal therapy agent, or any combination thereof.

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