Tl1a antibody compositions and methods of use

Abstract

TL1A is increased in an individual suffering from inflammatory diseases, including Crohn's disease and ulcerative colitis. Provided herein are variant TL1A antibodies and methods for treating inflammatory diseases, including inflammatory bowel disease. These TL1A antibodies also comprise a modified Fc region for extending serum half-life.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480052542.5 (22) Application Date 2024.06.21 (30) Priority Data 63 / 509,463 2023.06.21 US (85) PCT International Application Entering National Phase Date 2026.02.10 (86) PCT International Application Application Data PCT / US2024 / 034949 2024.06.21 (87) PCT International Application Publication Data WO2024 / 263868 EN 2024.12.26 (71) Applicant Paragon Medical Company Address Massachusetts, USA (72) Inventor Eric Franklin Zhu Jiang Bingxia (74) Patent Agency Shenzhen Eagle Wing Intellectual Property Agency Co., Ltd. 44658 Patent Attorney Wang Yijin Ye Huanbiao (51) Int.Cl. C07K 16 / 24 (2006.01) A61K 39 / 395 (2006.01) (54) Invention Title TL1A Antibody Composition and Method of Use (57) Abstract TL1A is elevated in individuals suffering from inflammatory diseases including Crohn's disease and ulcerative colitis. This document provides variant TL1A antibodies and methods for treating inflammatory diseases including inflammatory bowel disease. These TL1A antibodies also contain a modified Fc region for prolonging serum half-life. Claims (5 pages), Description (54 pages), Sequence Listing (electronic publication) CN 121794295 A 2026.04.03 CN 1 21 79 42 95 A 1. A TL1A binding protein comprising: a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 1-18, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 19-36, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 37-54; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 55-72, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 73-90, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 19-36; CDR3 of any one of amino acid sequences 91-108; and c) an Fc domain comprising amino acid modifications of M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS). 2. The TL1A binding protein as claimed in claim 1.The VH comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 1, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 19, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 37; and the VL comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 55, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 73, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 91. 3. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 2, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 20, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 38; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 56, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 74, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 92. 4. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 3, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 21, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 39; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 57, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 75, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 93. 5. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 4, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 22, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 40; and the VL comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 58, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 76, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 94. 6. The TL1A binding protein of claim 1,The VH comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 5, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 23, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 41; and the VL comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 59, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 77, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 95. 7. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 6, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 24, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 42; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 60, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 78, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 96. 8. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having the amino acid sequence according to claim 7, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 25, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 43; and the VL comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 61, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 79, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 97. 9. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 8, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 26, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 44; and the VL comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 62, and (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 80.(i) and (iii) having a CDR3 according to the amino acid sequence of SEQ ID NO: 98. 10. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence of SEQ ID NO: 9, (ii) a CDR2 having an amino acid sequence of SEQ ID NO: 27, and (iii) a CDR3 having an amino acid sequence of SEQ ID NO: 45; and the VL comprises (i) a CDR1 having an amino acid sequence of SEQ ID NO: 63, (ii) a CDR2 having an amino acid sequence of SEQ ID NO: 81, and (iii) a CDR3 having an amino acid sequence of SEQ ID NO: 99. 11. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 10, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 28, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 46; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 64, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 82, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 100. 12. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 11, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 29, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 47; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 65, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 83, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 101. 13. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 12, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 30, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 48; and the VL comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 66.(ii) having a CDR2 having the amino acid sequence according to SEQ ID NO: 84, and (iii) having a CDR3 having the amino acid sequence according to SEQ ID NO: 102. 14. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 13, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 31, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 49; and the VL comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 67, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 85, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 103. 15. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 14, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 32, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 50; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 68, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 86, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 104. Claims 2 / 5, page 3, CN 121794295, A 16. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 15, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 33, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 51; and the VL comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 69, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 87, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 105. 17. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 16, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 34,(i) and (iii) having a CDR3 having an amino acid sequence according to SEQ ID NO: 52; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 70, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 88, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 106. 18. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 17, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 35, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 53; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 71, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 89, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 107. 19. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 18, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 36, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 54; and the VL comprises (i) a CDR1 having the amino acid sequence according to SEQ ID NO: 72, (ii) a CDR2 having the amino acid sequence according to SEQ ID NO: 90, and (iii) a CDR3 having the amino acid sequence according to SEQ ID NO: 108. 20. The TL1A binding protein of any one of claims 1-19, wherein the VH comprises a sequence having at least 80% sequence identity with any one of the amino acid sequences in SEQ ID NO: 325-342, and the VL comprises a sequence having at least 80% sequence identity with any one of the amino acid sequences in SEQ ID NO: 343-360. 21. The TL1A-binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 325, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 343. 22. The TL1A-binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 326.Furthermore, the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 344. 23. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 327, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 345. 24. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 328, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 346. 25. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 329, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 347. 26. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 330, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 348. 27. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 331, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 349. 28. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 332, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 350. 29. The TL1A-binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 333, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 351. 30. The TL1A-binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 334.Furthermore, the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 352. 31. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 335, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 353. 32. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 336, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 354. 33. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 337, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 355. 34. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 338, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 356. 35. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 339, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 357. 36. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 340, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 358. 37. The TL1A-binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 341, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 359. 38. The TL1A-binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 342, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 360. 39. The TL1A-binding protein of any one of claims 1-38.The Fc domain of IgG1, IgG2, or IgG4 immunoglobulin is described in claim 4 / 5 (CN 121794295 A). 40. The TL1A binding protein of claim 39, wherein the Fc domain is an IgG1 immunoglobulin domain. 41. The TL1A binding protein of claim 39, wherein the Fc domain is an IgG2 immunoglobulin domain. 42. The TL1A binding protein of claim 39, wherein the Fc domain is an IgG4 immunoglobulin domain. 43. A TL1A binding protein comprising: a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 1-18, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 19-36, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 37-54; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 55-72, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 73-90, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 91-108; and c) a modified Fc, wherein the modified Fc prolongs the half-life of the TL1A binding protein compared to a TL1A binding protein without said modified Fc. 44. A TL1A binding protein, wherein the TL1A binding protein specifically binds to an epitope of TL1A and comprises an Fc domain containing amino acid modifications of M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS). 45. A method of treating inflammatory bowel disease in a patient in need, the method comprising administering, subcutaneously or intravenously, an effective amount of the TL1A binding protein as described in any one of claims 1-44 to the patient. 46. The method of claim 45, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. 47. The method of claim 46, wherein the inflammatory bowel disease is ulcerative colitis. 48. The method of any one of claims 45-47, wherein the administration of the TL1A binding protein is subcutaneous. 49. The method of any one of claims 45-47,The administration of the TL1A binding protein described herein is intravenous. Claims 5 / 5 Page 6 CN 121794295 A TL1A Antibody Composition and Method of Use Cross-Reference to Related Applications

[0001] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 509,463, filed June 21, 2023, the entire contents of which are incorporated herein by reference. Sequence Listing

[0002] This application contains a sequence listing which has been filed electronically in XML format and is incorporated herein by reference in its entirety. The XML copy was created on June 12, 2024, entitled PRG-006WO_SL.xml, and is 416 kilobytes in size. Background Art

[0003] Tumor necrosis factor (TNF)-like cytokine 1A (TL1A) is part of the TNF superfamily and is a transmembrane protein expressed by myeloid monocytes and endothelial cells. TL1A interacts with its receptor, death receptor 3 (DR3), to initiate signal transduction. TL1A is elevated in individuals with inflammatory diseases, including Crohn's disease and ulcerative colitis, and DR3 expression is upregulated in inflamed tissues. Therefore, TL1A, along with other members of the TNF superfamily, has been investigated as a therapeutic target for treating inflammatory diseases, including inflammatory bowel disease. Currently, biologics targeting TNF are associated with serious side effects, highlighting the need for improved therapies targeting TL1A.

[0004] In some embodiments, this invention describes a TL1A binding protein comprising: a) a heavy chain variable region (VH) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NO: 1-18, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NO: 19-36, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NO: 37-54; b) a light chain variable region (VL) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NO: 55-72, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NO: 73-90, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NO: 91-108; and c) The Fc domain comprises amino acid modifications of M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS). In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 1, and (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 19.(i) CDR1 having the amino acid sequence according to SEQ ID NO: 55, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 73, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 91. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 2, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 20, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 38; and VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 56, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 74, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 92. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 3, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 21, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 39; and VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 57, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 75, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 93. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 4, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 22, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 40; and VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 58, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 76, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 94. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 5, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 23,(i) CDR1 having the amino acid sequence according to SEQ ID NO: 59, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 77, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 95. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 6, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 24, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 42; and VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 60, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 78, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 96. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 7, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 25, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 43; and VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 61, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 79, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 97. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 8, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 26, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 44; and VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 62, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 80, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 98. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 9, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 27, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 45; and VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 63,(ii) having a CDR2 having the amino acid sequence according to SEQ ID NO: 81, and (iii) having a CDR3 having the amino acid sequence according to SEQ ID NO: 99. In some embodiments, VH comprises (i) having a CDR1 having the amino acid sequence according to SEQ ID NO: 10, (ii) having a CDR2 having the amino acid sequence according to SEQ ID NO: 28, and (iii) having a CDR3 having the amino acid sequence according to SEQ ID NO: 46; and VL comprises (i) having a CDR1 having the amino acid sequence according to SEQ ID NO: 64, (ii) having a CDR2 having the amino acid sequence according to SEQ ID NO: 82, and (iii) having a CDR3 having the amino acid sequence according to SEQ ID NO: 100. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 11, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 29, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 47; and VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 65, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 83, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 101. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 12, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 30, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 48; and VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 66, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 84, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 102. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 13, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 31, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 49; and VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 67, and (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 85.(i) CDR1 having the amino acid sequence according to SEQ ID NO: 14, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 32, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 50; and VL having (i) CDR1 having the amino acid sequence according to SEQ ID NO: 68, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 86, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 104. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 15, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 33, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 51; and VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 69, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 87, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 105. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 16, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 34, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 52; and VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 70, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 88, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 106. In some embodiments, VH comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 17, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 35, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 53; and VL comprises (i) CDR1 having the amino acid sequence according to SEQ ID NO: 71, and (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 89.(i) CDR1 having the amino acid sequence according to SEQ ID NO: 18, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 36, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 54; and VL comprising (i) CDR1 having the amino acid sequence according to SEQ ID NO: 72, (ii) CDR2 having the amino acid sequence according to SEQ ID NO: 90, and (iii) CDR3 having the amino acid sequence according to SEQ ID NO: 108. In some embodiments, VH comprises a sequence having at least 80% sequence identity with any one of the amino acid sequences in SEQ ID NO: 325-342, and VL comprises a sequence having at least 80% sequence identity with any one of the amino acid sequences in SEQ ID NO: 343-360. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 325, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 343. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 326, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 344. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 327, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 345. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 328, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 346. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 329, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 347. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 330, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 348. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 331.Furthermore, VL contains a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 349. In some embodiments, VH contains a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 332, and VL contains a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 350. In some embodiments, VH contains a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 333, and VL contains a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 351. In some embodiments, VH contains a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 334, and VL contains a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 352. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 335, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 353. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 336, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 354. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 337, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 355. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 338, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 356. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 339, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 357. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 340, and VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 358. In some embodiments, VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 341.Furthermore, VL contains a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 359. In some embodiments, VH contains a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 342, and VL contains a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 360. In some embodiments, Fc is the Fc domain of IgG1, IgG2, or IgG4 immunoglobulins. In some embodiments, Fc is the IgG1 immunoglobulin domain. In some embodiments, Fc is the IgG2 immunoglobulin domain. In some embodiments, Fc is the IgG4 immunoglobulin domain.

[0005] In some embodiments, the TL1A binding protein described herein comprises: a) a heavy chain variable region (VH) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NO: 1-18, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NO: 19-36, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NO: 37-54; b) a light chain variable region (VL) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NO: 55-72, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NO: 73-90, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NO: 91-108; and c) The modified Fc, compared to the TL1A binding protein without the modified Fc, prolongs the half-life of the TL1A binding protein.

[0006] In some embodiments, a TL1A binding protein is described herein, wherein the TL1A binding protein specifically binds to an epitope of TL1A and comprises an Fc domain containing amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0007] In some embodiments, a method of treating inflammatory bowel disease in a patient in need is described herein, comprising administering an effective amount of the TL1A binding protein described herein subcutaneously or intravenously to the patient. In some embodiments, the inflammatory bowel disease is Crohn's disease or ulcerative colitis. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the administration of the TL1A binding protein is subcutaneous. In some embodiments, the administration of the TL1A binding protein is intravenous. Detailed Description

[0008] For ease of understanding of this disclosure, a number of terms and phrases are defined below.

[0009] As used herein, unless otherwise stated, the term "antibody" should be understood to mean an intact antibody (e.g.,Intact monoclonal antibodies, or fragments thereof (such as the Fc fragment of an antibody, e.g., the Fc fragment of a monoclonal antibody), or antigen-binding fragments of antibodies (e.g., the antigen-binding fragment of a monoclonal antibody), including modified, engineered, or chemically conjugated intact antibodies, antigen-binding fragments, or Fc fragments. Typically, antibodies are polyproteins containing four polypeptide chains. Two polypeptide chains are called immunoglobulin heavy chains (H chains), and two polypeptide chains are called immunoglobulin light chains (L chains). The immunoglobulin heavy and light chains are linked by interchain disulfide bonds. The immunoglobulin heavy chain is linked by interchain disulfide bonds. The light chain consists of a variable region (VL) and a constant region (CL). The heavy chain consists of a variable region (VH) and at least three constant regions (CH1, CH2, and CH3). The variable region determines the binding specificity of the antibody. Each variable region contains three hypervariable regions (called complementarity-determining regions (CDRs)) flanked by four relatively conserved regions (called frame regions (FRs)). The ranges of FRs and CDRs have been defined (Kabat, E.A. et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242; and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917). The three CDRs (called CDR1, CDR2, and CDR3) contribute to antibody binding specificity. Naturally occurring antibodies have been used as starting materials for engineered antibodies, such as chimeric and humanized antibodies. Examples of antibody-based antigen-binding fragments include Fab, Fab', (Fab')2, Fv, single-chain antibodies (e.g., scFv), microantibodies, and biantibodies. Examples of modified or engineered antibodies include chimeric antibodies, humanized antibodies, and multispecific antibodies (e.g., bispecific antibodies). Examples of chemically conjugated antibodies are antibodies conjugated with a toxic moiety.

[0010] The terms "variable domain" and "variable region" are used interchangeably and refer to portions of an antibody or immunoglobulin domain that exhibit variability in their sequence and are involved in determining the specificity and binding affinity of a particular antibody. The variability is not uniformly distributed throughout the variable domain of the antibody; it is concentrated in subdomains of each heavy and light chain variable region. These subdomains are called "hypervariable regions" or "complementarity-determining regions" (CDRs). More conserved (i.e., non-hypervariable) portions of the variable domain are called "framework" regions (FRMs or FRs).And in three-dimensional space, scaffolds are provided for the six CDRs to form antigen-binding surfaces.

[0011] As used herein, the “Fc polypeptide” of a dimer Fc refers to one of the two polypeptides constituting the Fc domain of the dimer, namely, a polypeptide containing the C-terminal constant region of the immunoglobulin heavy chain that is capable of stable self-association. For example, the Fc polypeptide of a dimer IgG Fc contains the IgG CH2 and IgG CH3 constant domain sequences. Fc may belong to the categories IgA, IgD, IgE, IgG, and IgM. These categories are also designated as α, δ, ε, γ, and µ, respectively. Several of these can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0012] The terms “Fc receptor” and “FcR” are used to describe receptors that bind to the Fc region of an antibody. For example, an FcR may be a naturally occurring human FcR sequence. FcRs are FcRs (γ receptors) that bind to IgG antibodies and include receptors of the FcγRI, FcγRII, and FcγRIIII subclasses (including allelic variants and alternative spliced ​​forms of these receptors). FcγRII receptors include FcγRIIA (“activating receptor”) and FcγRIIB (“inhibitory receptor”), which have similar amino acid sequences.The main difference lies in their cytoplasmic domains. Other isotypes of immunoglobulins can also bind to certain FcRs (see, for example, Janeway et al., *Immuno Biology: the immune system in health and disease*, (Elsevier Science Ltd., New York) (4th ed., 1999)). The activating receptor FcγRIIA contains an activating motif (ITAM) based on the tyrosine residue of the immunoreceptor in its cytoplasmic domain. The repressive receptor FcγRIIB contains an repressive motif (ITIM) based on the tyrosine residue of the immunoreceptor in its cytoplasmic domain (see Daëron, Annu. Rev. Immunol. [Annals of Immunology] 15:203–234 (1997)). FcRs have been reviewed in Ravetch and Kinet, Annu. Rev. Immunol [Annals of Immunology] 9:457–92 (1991); Capel et al., Immunomethods [Journal of Immunology] 4:25–34 (1994); and de Haas et al., J. Lab. Clin. Med. [Journal of Laboratory and Clinical Medicine] 126:330–41 (1995). The term “FcR” as used herein encompasses other FcRs, including those to be identified in the future. The term also includes neonatal receptor FcRn, which is responsible for transferring maternal IgG to the fetus (Guyer et al., J. Immunol. [Journal of Immunology] 117:587 (1976); and Kim et al., J. Immunol. [Journal of Immunology] 24:249 (1994)).

[0013] The terms “recipient,” “individual,” “subject,” “host,” and “patient” are used interchangeably herein and, in some embodiments, refer to any mammalian subject, particularly a human, for whom a diagnosis, treatment, or therapy is desired. For therapeutic purposes, “mammal” means any animal classified as a mammal, including humans, domestic and agricultural animals, and laboratory, zoo, sporting, or pet animals such as dogs, horses, cats, cattle, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys, etc. In some embodiments, the mammal is a human. None of these terms require medical supervision.

[0014] As used herein, the term “effective amount” refers to an amount of compound (e.g., the compound disclosed herein) sufficient to achieve a beneficial or desired result. An effective amount may be administered in one or more doses, by application, or by dosage.And it is not intended to be limited to a particular formulation or route of administration. As used herein, the term “treatment” includes any effect, such as relief, reduction, modulation, improvement, or elimination of a symptom, disease, or disorder (resulting in improvement of the symptom, disease, or disorder), or improvement of its symptoms.

[0015] As used herein, the term “pharmaceutical composition” refers to a combination of an active pharmaceutical agent with an inert or active carrier, such that the composition is particularly suitable for in vivo or in vitro diagnostic or therapeutic use.

[0016] As used herein, the term “pharmaceuticalally acceptable carrier” refers to any standard pharmaceutical carrier, such as phosphate-buffered saline solution, water, emulsion (e.g., oil / water or water / oil emulsion), and various types of wetting agents. These compositions may also include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th edition, Mack Publ. Co., Easton, Pennsylvania (1975).

[0017] Unless the context is inappropriate, as used herein, the term "a / an" means "one or more" and includes plurals.

[0018] As used herein, unless the context clearly indicates otherwise, all numerical values ​​or ranges of values ​​are included as integers that are within or cover such ranges, and as fractions of values ​​or integers that are within or cover such ranges. Thus, for example, references to the range of 90%–100% include 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, etc., and 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so on. In another example, mentioning a range of 1-5,000 times includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, etc., and 1.1, 1.2, 1.3, 1.4, 1.5 times, etc., 2.1, 2.2, 2.3, 2.4, 2.5 times, etc., and so on.

[0019] As used herein, “about” a value means a range that includes that value, and the range is from 10% below that value to 10% above that value. “About” a range means 10% below the lower limit of the range, spanning to 10% above the upper limit of the range.

[0020] “Percentage (%) identity” refers to the degree to which two sequences (nucleotides or amino acids) have the same residues at the same position in the alignment. For example, "the amino acid sequence is X% identical to SEQ ID NO: Y" means that the amino acid sequence is % identical to SEQ ID NO: Y.It is further stated that X% of the residues in the amino acid sequence are identical to the residues in the sequence disclosed in SEQ ID NO: Y. Typically, such calculations are performed using computer programs. Exemplary programs for comparing and aligning sequence pairs include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990), and vacancy BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984).

[0021] Throughout this specification, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, the existence of compositions of this disclosure substantially consisting of or composed of the listed components is also contemplated, as are processes and methods of this disclosure substantially consisting of or composed of the listed processing steps.

[0022] Generally, unless otherwise stated, the specified percentages of the composition are by weight. Additionally, if a variable is not defined, its previously defined meaning shall prevail. TL1A Binding Protein

[0023] This document provides for TL1A binding proteins comprising a modified Fc region. In some embodiments, this document describes a TL1A binding protein comprising: a) a heavy chain variable region (VH) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NO: 1-18, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NO: 19-36, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NO: 37-54; b) a light chain variable region (VL) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NO: 55-72, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NO: 73-90, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NO: 91-108; and c) comprising amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L. and the Fc domain of N434S (LS).

[0024] In some embodiments, the TL1A binding protein is further described herein, comprising: a) a heavy chain variable region (VH), comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NO: 1-18, and (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NO: 19-36,(i) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 37-54; (ii) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 55-72, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 73-90, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 91-108; and (c) a modified Fc that prolongs the half-life of the TL1A binding protein compared to a TL1A binding protein without the modified Fc.

[0025] In some embodiments, the TL1A binding protein is further described herein, wherein the TL1A binding protein specifically binds to an epitope of TL1A and comprises an Fc domain containing amino acid modifications of M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0026] The amino acid sequences of exemplary CDRs of the TL1A binding protein are provided in Table 1. Specification 7 / 54 pages 13 CN 121794295 A Specification 8 / 54 pages 14 CN 121794295 A Specification 9 / 54 pages 15 CN 121794295 A

[0027] In some embodiments, the TL1A binding protein comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 as listed in Table 1. In some embodiments, the TL1A binding protein includes a heavy chain variable region comprising, as specified in the specification (page 10 / 54, CN 121794295 A), (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 1-18, (b) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 19-36, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 37-54.

[0028] In some embodiments, the TL1A binding protein includes a light chain variable region comprising CDR1, CDR2, and CDR3 as listed in Table 1. In some embodiments, the TL1A binding protein includes a light chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 55-72, (b) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 73-90, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 91-108.

[0029] In some embodiments, the TL1A binding protein includes: a heavy chain variable region,It comprises (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 1-18, (b) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 19-36, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 37-54; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 55-72, (b) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 73-90, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 91-108.

[0030] In some embodiments, the TL1A binding protein includes a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 109-126, (b) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 127-144, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 145-162.

[0031] In some embodiments, the TL1A binding protein includes a light chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 163-180, (b) a CDR2 having an amino acid sequence according to DAS, ATS, GAS, GYY, WAS, AAS, KIS, KAS or KVS or SEQ ID NO: 198, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 199-216.

[0032] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 109-126, (b) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 127-144, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 145-162; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 163-180, (b) a CDR2 having an amino acid sequence according to any one of DAS, ATS, GAS, GYY, WAS, AAS, KIS, KAS, or KVS or SEQ ID NO: 198, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 199-216.

[0033] In some embodiments,The TL1A binding protein includes a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 217-234, (b) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 235-252, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 253-270.

[0034] In some embodiments, the TL1A binding protein includes a light chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 271-288, (b) a CDR2 having an amino acid sequence according to any one of DAS, ATS, GAS, GYY, WAS, AAS, KIS, KAS, KVS, or DA, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 307-324.

[0035] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 217-234, (b) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 235-252, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 253-270; and a light chain variable region comprising (a) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 271-288, (b) a CDR2 having an amino acid sequence according to any one of DAS, ATS, GAS, GYY, WAS, AAS, KIS, KAS, KVS, or DA, and (c) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 307-324.

[0036] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 1, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 19, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 37; and a light chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 55, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 73, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 91.

[0037] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region,It comprises (a) a CDR1 having the amino acid sequence of SEQ ID NO: 2, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 20, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 38; and a light chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 56, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 74, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 92.

[0038] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 3, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 21, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 39; and a light chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 57, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 75, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 93.

[0039] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 4, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 22, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 40; and a light chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 58, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 76, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 94.

[0040] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 5, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 23, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 41; and a light chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 59, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 77, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 95.

[0041] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 6,(b) CDR2 having the amino acid sequence of SEQ ID NO: 24, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 42; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 60, (b) CDR2 having the amino acid sequence of SEQ ID NO: 78, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 96.

[0042] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 7, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 25, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 43; and a light chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 61, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 79, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 97. Specification 12 / 54 pages 18 CN 121794295 A

[0043] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 8, (b) CDR2 having the amino acid sequence of SEQ ID NO: 26, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 44; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 62, (b) CDR2 having the amino acid sequence of SEQ ID NO: 80, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 98.

[0044] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 9, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 27, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 45; and a light chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 63, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 81, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 99.

[0045] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 10,(b) CDR2 having the amino acid sequence of SEQ ID NO: 28, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 46; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 64, (b) CDR2 having the amino acid sequence of SEQ ID NO: 82, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 100.

[0046] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 11, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 29, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 47; and a light chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 65, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 83, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 101.

[0047] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 12, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 30, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 48; and a light chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 66, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 84, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 102.

[0048] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 13, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 31, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 49; and a light chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 67, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 85, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 103.

[0049] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 14, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 32,(c) CDR3 having the amino acid sequence of SEQ ID NO: 50; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 68, (b) CDR2 having the amino acid sequence of SEQ ID NO: 86, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 104.

[0050] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 15, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 33, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 51; and a light chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 69, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 87, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 105.

[0051] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 16, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 34, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 52; and a light chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 70, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 88, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 106.

[0052] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 17, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 35, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 53; and a light chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 71, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 89, and (c) a CDR3 having the amino acid sequence of SEQ ID NO: 107.

[0053] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising (a) a CDR1 having the amino acid sequence of SEQ ID NO: 18, (b) a CDR2 having the amino acid sequence of SEQ ID NO: 36,(a) CDR3 having the amino acid sequence of SEQ ID NO: 54; and a light chain variable region comprising (a) CDR1 having the amino acid sequence of SEQ ID NO: 72, (b) CDR2 having the amino acid sequence of SEQ ID NO: 90, and (c) CDR3 having the amino acid sequence of SEQ ID NO: 108.

[0054] Exemplary heavy chain variable region (VH) and light chain variable region (VL) amino acid sequences of TL1A binding proteins are provided in Table 2. Table 2. Sequences of the heavy chain variable region (VH) and light chain variable region (VL) of the TL1A binding protein. Specification page 14 / 54, 20 CN 121794295 A. Specification page 15 / 54, 21 CN 121794295 A.

[0055] In some embodiments, the TL1A binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 325-342. In some embodiments, the TL1A binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence of any one of the amino acids in SEQ ID NO: 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NO: 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence of any one of SEQ ID NO: 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence of any one of SEQ ID NO: 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH) comprising an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 325-342. In some embodiments, the TL1A-binding protein includes a heavy chain variable region (VH).The heavy chain variable region comprises an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 325-342. In some embodiments, the TL1A binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence according to any one of SEQ ID NO: 325-342.

[0056] In some embodiments, the TL1A binding protein comprises a light chain variable region (VL) comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 343-360. In some embodiments, the TL1A binding protein comprises a light chain variable region (VL) comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 343-360. In some embodiments, the TL1A binding protein antibody comprises a light chain variable region (VL) containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 343-360. In some embodiments, the TL1A binding protein comprises a light chain variable region (VL) containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 343-360. In some embodiments, the TL1A binding protein comprises a light chain variable region (VL) containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 343-360. In some embodiments, the TL1A binding protein comprises a light chain variable region (VL) containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 343-360. In some embodiments, the TL1A binding protein includes a light chain variable region (VL) comprising an amino acid sequence having at least 98% sequence identity with an amino acid sequence according to any one of SEQ ID NO: 343-360. In some embodiments, the TL1A binding protein includes a light chain variable region (VL) comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NO: 343-360. In some embodiments, the TL1A binding protein includes a light chain variable region (VL) comprising an amino acid sequence according to any one of SEQ ID NO: 343-360.

[0057] In some embodiments, the TL1A binding protein includes a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region comprising at least 60% (e.g., the heavy chain variable region of the TL1A binding protein disclosed in Table 2) of the heavy chain variable region (VH).The light chain variable region contains at least 60% (e.g., at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) of the same amino acid sequence as the light chain variable region (VL) of the same TL1A binding protein disclosed in Table 2.

[0058] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to any one of SEQ ID NO: 325-342; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to any one of SEQ ID NO: 343-360. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NO: 325-342; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with an amino acid sequence according to any one of SEQ ID NO: 343-360. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with the amino acid sequence of any one of SEQ ID NO: 325-342; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with the amino acid sequence of any one of SEQ ID NO: 343-360. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NO: 325-342; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NO: 343-360. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NO: 325-342; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with an amino acid sequence according to any one of SEQ ID NO: 343-360. In some embodiments,The TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 325-342; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 343-360. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 325-342; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 343-360. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NO: 325-342; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with an amino acid sequence according to any one of SEQ ID NO: 343-360. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence according to any one of SEQ ID NO: 325-342; and a light chain variable region comprising an amino acid sequence according to any one of SEQ ID NO: 343-360.

[0059] In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 325; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with an amino acid sequence according to SEQ ID NO: 343. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 325; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 343. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 325; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 343. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 325; and a light chain variable region...It comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 343. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 325; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 343. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 325; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 343. In some embodiments described on pages 18 / 54 of CN 121794295 A, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 325; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 343. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 325; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 343. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing the amino acid sequence according to SEQ ID NO: 325; and a light chain variable region containing the amino acid sequence according to SEQ ID NO: 343.

[0060] In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 326; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 344. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 326; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 344. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region,It comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 326; and a light chain variable region having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 344. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 326; and a light chain variable region having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 344. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 326; and a light chain variable region having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 344. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 326; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 344. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 326; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 344. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 326; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 344. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising the amino acid sequence according to SEQ ID NO: 326; and a light chain variable region comprising the amino acid sequence according to SEQ ID NO: 344.

[0061] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 327; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 345. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region,It comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 327; and a light chain variable region having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 345. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 327; and a light chain variable region having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 345. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 327; and a light chain variable region having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 345. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 327; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 345. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 327; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 345. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 327; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 345. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 327; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 345. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising the amino acid sequence according to SEQ ID NO: 327; and a light chain variable region comprising the amino acid sequence according to SEQ ID NO: 345.

[0062] In some embodiments,The TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 328; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 346. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 328; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 346. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 328; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 346. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 328; and a light chain variable region comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 346. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 328; and a light chain variable region comprising an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 346. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 328; and a light chain variable region comprising an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 346. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 328; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 346. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 328; and a light chain variable region,It comprises an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 346. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 328; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 346.

[0063] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 329; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 347. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 329; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 347. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 329; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 347. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 329; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 347. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 329; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 347. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 329; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 347. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region,It comprises an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 329; and a light chain variable region having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 347. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 329; and a light chain variable region having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 347. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having the amino acid sequence according to SEQ ID NO: 329; and a light chain variable region having the amino acid sequence according to SEQ ID NO: 347.

[0064] In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 330; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 348. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 330; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 348. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 330; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 348. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 330; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 348. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 330; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 348. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region,It comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 330; and a light chain variable region having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 348. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 330; and a light chain variable region having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 348. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 330; and a light chain variable region having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 348. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising the amino acid sequence according to SEQ ID NO: 330; and a light chain variable region comprising the amino acid sequence according to SEQ ID NO: 348.

[0065] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 331; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 349. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 331; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 349. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 331; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 349. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 331; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 349. In some embodiments,The TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 331; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 349. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 331; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 349. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 331; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 349. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 331; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 349. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 331; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 349.

[0066] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 332; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 350. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 332; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 350. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 332; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 350. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region,It comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 332; and a light chain variable region having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 350. In some embodiments, the TL1A binding protein specification (page 22 / 54, CN 121794295 A) comprises: a heavy chain variable region having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 332; and a light chain variable region having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 350. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 332; and a light chain variable region having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 350. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 332; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 350. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 332; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 350. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising the amino acid sequence according to SEQ ID NO: 332; and a light chain variable region comprising the amino acid sequence according to SEQ ID NO: 350.

[0067] In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 333; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 351. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 333; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 351. In some embodiments,The TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 351. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 351. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 351. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 351. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 351. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 333; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 351. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising the amino acid sequence according to SEQ ID NO: 333; and a light chain variable region comprising the amino acid sequence according to SEQ ID NO: 351.

[0068] In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 334; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 352. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region,It comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 334 (page 23 / 54, CN 121794295 A); and a light chain variable region having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 352. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 334; and a light chain variable region having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 352. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 334; and a light chain variable region having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 352. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 334; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 352. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 334; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 352. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 334; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 352. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 334; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 352. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising the amino acid sequence according to SEQ ID NO: 334; and a light chain variable region comprising the amino acid sequence according to SEQ ID NO: 352.

[0069] In some embodiments,The TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 353. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 353. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 353. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 353. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 353. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 353. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 335; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 353. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 335; and a light chain variable region.It comprises an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 353. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 335; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 353.

[0070] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 336; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 354. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 336; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 354. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 336; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 354. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 336; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 354. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 336; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 354. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 336; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 354. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 336; and a light chain variable region,It comprises an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 354. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 336; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 354. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 336; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 354.

[0071] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 337; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 355. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 337; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 355. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 337; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 355. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 337; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 355. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 337; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 355. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region,It comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 337; and a light chain variable region having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 355. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 337; and a light chain variable region having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 355. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 337; and a light chain variable region having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 355. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising the amino acid sequence according to SEQ ID NO: 337; and a light chain variable region comprising the amino acid sequence according to SEQ ID NO: 355.

[0072] In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 338; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 356. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 338; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 356. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 338; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 356. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 338; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 356. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region,It comprises an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 338; and a light chain variable region having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 356. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 338; and a light chain variable region having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 356. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 338; and a light chain variable region having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 356. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 338; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 356. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence according to SEQ ID NO: 338; and a light chain variable region comprising an amino acid sequence according to SEQ ID NO: 356.

[0073] In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 339; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 357. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 339; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 357. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 339; and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 357. In some embodiments,The TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 339; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 357. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 339; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 357. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 339; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 357. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 339; and a light chain variable region comprising an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 357. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 339; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 357. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising the amino acid sequence according to SEQ ID NO: 339; and a light chain variable region comprising the amino acid sequence according to SEQ ID NO: 357.

[0074] In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 340; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 358. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 340; and a light chain variable region comprising an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 358. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region,It comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 340; and a light chain variable region having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 358. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 340; and a light chain variable region having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 358. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 340; and a light chain variable region having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 358. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 340; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 358. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 340; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 358. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 340; and a light chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 358. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 340 (page 27 / 54, CN 121794295 A); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 358.

[0075] In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 341; and a light chain variable region comprising an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 359. In some embodiments,The TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 359. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 359. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 359. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 359. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 359. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 341; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 359. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 341; and a light chain variable region comprising an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 359. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region comprising the amino acid sequence according to SEQ ID NO: 341; and a light chain variable region comprising the amino acid sequence according to SEQ ID NO: 359.

[0076] In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region,It comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 342; and a light chain variable region having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 360. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 342; and a light chain variable region having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 360. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 342; and a light chain variable region having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 360. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 342; and a light chain variable region containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 360. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 342; and a light chain variable region containing an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 360. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 342; and a light chain variable region, as described on page 28 / 54 of the specification (CN 121794295 A), containing an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 360. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 342; and a light chain variable region containing an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 360. In some embodiments, the TL1A-binding protein comprises: a heavy chain variable region containing an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 342; and a light chain variable region,It comprises an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 360. In some embodiments, the TL1A binding protein comprises: a heavy chain variable region comprising the amino acid sequence according to SEQ ID NO: 342; and a light chain variable region comprising the amino acid sequence according to SEQ ID NO: 360. Fc Modification

[0077] This document describes TL1A binding proteins comprising modified Fc regions. Unless otherwise stated herein, the amino acid residues in the Fc region or constant region are numbered according to the EU numbering system (also known as the EU index), as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0078] In some embodiments, the TL1A binding protein comprises a modified Fc that comprises one or more modifications. In some embodiments, one or more modifications are located in the Fc region from IgG1 (e.g., human IgG1 (hIgG1)). In some embodiments, one or more modifications are located in the Fc region from IgG4 (e.g., human IgG4 (hIgG4)). In some embodiments, one or more modifications are located in the Fc region from IgG2. In some embodiments,One or more modifications promote selective binding to the Fc-γ receptor.

[0079] The amino acid sequences of exemplary Fc sequences are provided in Table 3. Table 3. Fc Sequence Specification Pages 29 / 54 35 CN 121794295 A Specification Pages 30 / 54 36 CN 121794295 A Specification Pages 31 / 54 37 CN 121794295 A Specification Pages 32 / 54 38 CN 121794295 A Specification Pages 33 / 54 39 CN 121794295 A Specification Pages 34 / 54 40 CN 121794295 A Specification Pages 35 / 54 41 CN 121794295 A Specification Pages 36 / 54 42 CN 121794295 A Specification Pages 37 / 54 43 CN 121794295 A Specification Pages 38 / 54 44 CN 121794295 A Specification Pages 39 / 54 45 CN 121794295 A Specification 40 / 54 Pages 46 CN 121794295 A Specification 41 / 54 Pages 47 CN 121794295 A Specification 42 / 54 Pages 48 CN 121794295 A Specification 43 / 54 Pages 49 CN 121794295 A Specification 44 / 54 Pages 50 CN 121794295 A Specification 45 / 54 Pages 51 CN 121794295 A

[0080] In some embodiments, the TL1A binding protein includes one or more modified Fcs as specified in SEQ ID NO: 361. In some embodiments, the TL1A binding protein includes one or more modified Fcs as specified in SEQ ID NO: 362. In some embodiments, the TL1A binding protein includes one or more modified Fcs as specified in SEQ ID NO: 363. In some embodiments, Fc comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence of any one of SEQ ID NO: 361-363. In some embodiments, Fc comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence of any one of SEQ ID NO: 361-363. In some embodiments, Fc comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of any one of SEQ ID NO: 361-363. In some embodiments,Fc comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 361-363. In some embodiments, Fc comprises an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 361-363. In some embodiments, Fc comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 361-363. In some embodiments, Fc comprises an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 361-363. In some embodiments, Fc comprises an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 361-363. In some embodiments, Fc comprises an amino acid sequence according to any one of SEQ ID NO: 361-363.

[0081] In some embodiments, one or more modifications in the modified Fc are selected from the group consisting of: S298A, E333A, K334A, K326A, F243L, R292P, Y300L, V305I, P396L, F243L, R292P, Y300L, L235V, P396L, F243L, S239D, I332E, A330L, S267E, L328F, D265S, S239E, K326A, A327H, G237F, Specification 46 / 54 pages 52 CN 121794295 A K326E, G236A, D270L, H268D, S324T, L234F, N325L, V266L, and S267D. In some embodiments, one or more modifications of the modified Fc are selected from the group consisting of: S228P, M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W.

[0082] In some embodiments,The modified Fc contains specific combinations of amino acid substitutions selected from the following groups: L234A / L235A; V234A / G237A; L235A / G237A / E318A; S228P / L236E; H268Q / V309L / A330S / A331S; C220S / C226S / C229S / P238S; C226S / C229S / E3233P / L235V / L235A; L234F / L235E / P331S; C226S / P230S; L234A / G237A; L234A / L235A / G237A; Q311R / M428L; and L234A / L235A / P329G.

[0083] In some embodiments,The modified Fc comprises a specific combination of amino acid substitutions selected from the group consisting of: M428L / N434S (LS); M252Y / S254T / T256E (YTE); T250Q / M428L; T307A / E380A / N434A; T256D / T307Q (DQ); T256D / T307W (DW); M252Y / T256D (YD); T307Q / Q311V / A378V (QVV); T256D / H285D / T307R / Q311V / A378V (DDRVV); L309D / Q311H / N434S (DHS); S228P / L235E (SPLE); L234A / L235A (LALA); M428L / N434A (LA); L234A / G237A (LAGA); L234A / L235A / G237A (LALAGA); L234A / L235A / P329G (LALAPG); N297A / YTE; D265A / YTE; LALA / YTE; LAGA / YTE; LALAGA / YTE; LALAPG / YTE; N297A / LS; D265A / LS; LALA / LS; LAGA / LS; LALAGA / LS; LALAPG / LS; N297A / DHS; D265A / DHS; LALA / DHS; LAGA / DHS; LALAGA / DHS; LALAPG / DHS; SP / YTE; SPLE / YTE; SP / LS; SPLE / LS; SP / DHS; SPLE / DHS; N297A / LA; D265A / LA; LALA / LA; LAGA / LA; LALAGA / LA; LALAPG / LA; N297A / N434A; D265A / N434A; LALA / N434A; LAGA / N434A; LALAGA / N434A; LALAPG / N434A; N297A / N434W; D265A / N434W; LALA / N434W; LAGA / N434W; LALAGA / N434W; LALAPG / N434W; N297A / DQ; D265A / DQ; LALA / DQ; LAGA / DQ; LALAGA / DQ; LALAPG / DQ; N297A / DW; D265A / DW; LALA / DW; LAGA / DW; LALAGA / DW; LALAPG / DW; N297A / YD; D265A / YD; LALA / YD; LAGA / YD; LALAGA / YD; LALAPG / YD; N297A / QVV; D265A / QVV; LALA / QVV; LAGA / QVVLALAGA / QVV; LALAPG / QVV; N297A / DDRVV; D265A / DDRVV; LALA / DDRVV; LAGA / DDRVV; LALAGA / DDRVV; LALAPG / DDRVV; SP / Q311R / M428L; SPLE / Q311R / M428L; N297A / Q311R / M428L; D265A / Q311R / M428L; LALA / Q311R / M428L; LAGA / Q311R / M428L; LALAGA / Q311R / M428L; and LALAPG / Q311R / M428L. In some embodiments, the modified Fc comprises a specific combination of amino acid substitutions selected from the group consisting of M428L / N434S (LS) and M252Y / S254T / T256E (YTE). In some embodiments, the modified Fc comprises M428L / N434S (LS) (e.g., SEQ ID NO: 379, SEQ ID NO: 396, SEQ ID NO: 403). In some embodiments, the modified Fc comprises M252Y / S254T / T256E (YTE) (e.g., SEQ ID NO: 372, SEQ ID NO: 393, SEQ ID NO: 402).

[0084] In some embodiments, the TL1A binding protein described herein comprises modifications that enhance its ability to mediate effector function. Such modifications are known in the art and include defucosylation or engineering of Fc affinity for activating receptors (primarily FCGR3a, for antibody-dependent cytotoxicity (ADCC)) and for C1q (for complement-dependent cytotoxicity (CDC)).

[0085] In some aspects, the antibodies provided herein comprise an Fc domain (e.g., IgG1) having a reduced fucose content at position Asn 297 (EU number) compared to a naturally occurring Fc domain. Such Fc domains are known to have improved ADCC. In some aspects, such antibodies do not contain any fucose at position Asn 297.

[0086] In some embodiments, the TL1A binding protein described herein comprises an Fc region having one or more amino acid substitutions that improve ADCC, such as substitutions at one or more positions 298, 333, and 334 of the Fc region. In some implementation specifications, pages 47 / 54, document number 53 CN 121794295 A, the antibody provided herein comprises an Fc region having one or more amino acid substitutions at positions 239, 332, and 330.

[0087] In some embodiments,Fc comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence of any one of SEQ ID NO: 364-472. In some embodiments, Fc comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence of any one of SEQ ID NO: 364-472. In some embodiments, Fc comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of any one of SEQ ID NO: 364-472. In some embodiments, Fc comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NO: 364-472. In some embodiments, Fc comprises an amino acid sequence having at least 96% sequence identity with the amino acid sequence of any one of SEQ ID NO: 364-472. In some embodiments, Fc comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence of any one of SEQ ID NO: 364-472. In some embodiments, Fc comprises an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 364-472. In some embodiments, Fc comprises an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to any one of SEQ ID NO: 364-472. In some embodiments, Fc comprises an amino acid sequence according to any one of SEQ ID NO: 364-472.

[0088] In some embodiments, the Fc of the TL1A binding protein comprises an amino acid sequence according to any one of SEQ ID NO: 364-472, the amino acid sequence having one or more amino acid modifications (e.g., substitution, addition, deletion, e.g., relative to the amino acid sequence shown in any one of SEQ ID NO: 364-472). In some embodiments, one or more amino acid modifications comprise the deletion of a C-terminal lysine. In some embodiments, one or more amino acid modifications comprise the addition of a C-terminal lysine. As just one example, the Fc of the TL1A binding protein provided herein may contain the amino acid sequence according to SEQ ID NO: 376, but with the addition of a C-terminal lysine so that the amino acid sequence ends with "K" instead of "G".

[0089] In some embodiments, any of SEQ ID NO: 346-472 containing a C-terminal lysine may have that C-terminal lysine deleted or substituted. In some embodiments, any of SEQ ID NO: 346-472 not containing a C-terminal lysine may have a C-terminal lysine added. In some embodiments, any of SEQ ID NO: 346-472 that does not inherently contain a C-terminal lysine may also have its C-terminal amino acid substituted with lysine (e.g.,

[0090] In some embodiments, the TL1A binding protein described herein comprises an Fc region, wherein at least one galactose residue is present in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function.

[0091] In some embodiments, the TL1A binding protein described herein comprises one or more alterations that improve or weaken C1q binding and / or CDC.

[0092] In some embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared to an Fc without the one or more substitutions. In some embodiments, the one or more amino acid substitutions result in an increase in antibody half-life at pH 6.0 compared to antibodies comprising a wild-type Fc region. In some embodiments, the antibody has an increased half-life compared to antibodies containing the wild-type Fc region, specifically approximately 10,000, 1,000, 500, 100, 50, 20, 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.95, 1.9, 1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.50, 1.45, 1.4, 1.35, 1.3, 1.25, 1.2, 1.15, 1.1, or 1.05 times that of antibodies containing the wild-type Fc region.

[0093] In some embodiments, the Fc region contains one or more amino acid substitutions, wherein the one or more substitutions result in a reduction of one or more of ADCC activity, ADCP activity, or CDC activity compared to an Fc without such substitutions. Specification 48 / 54 pages 54 CN 121794295 A

[0094] In some embodiments, the Fc region binds to an Fc γ receptor selected from the group consisting of: Fc γ RI, Fc γ RIIa, Fc γ RIIb, Fc γ RIIc, Fc γ RIIIa, and Fc γ RIIIb. In some embodiments, the Fc region binds to the Fc γ receptor with a higher affinity at pH 6.0 compared to an antibody containing a wild-type Fc region.

[0095] In some embodiments, the TL1A binding protein described herein comprises an extended half-life (i.e., serum half-life). In some embodiments, the TL1A-binding protein described herein has a half-life of at least about 14, 28, 42, 56, 70, 84, 96, or more than 96 weeks. In some embodiments,The TL1A-binding protein described herein has a half-life in the following ranges: about 14 days to about 96 days, about 14 days to about 84 days, about 14 days to about 70 days, about 14 days to about 56 days, about 14 days to about 42 days, about 14 days to about 28 days, about 28 days to about 96 days, about 28 days to about 84 days, about 28 days to about 70 days, about 28 days to about 56 days, about 28 days to about 42 days, about 42 days to about 96 days, about 42 days to about 84 days, about 42 days to about 70 days, or about 42 days to about 56 days. In some embodiments, the TL1A-binding protein described herein has a half-life in the range of about 42 days to about 56 days. In some embodiments, the TL1A-binding protein described herein has a half-life of at least about 50 days. In some embodiments, the TL1A-binding protein described herein has a half-life of about 50 days. Methods for measuring the half-life are known in the art. In some embodiments, the half-life is measured in non-human primates. In some embodiments, the half-life is measured in humans. In some embodiments, the half-life is measured after intravenous administration. In some embodiments, the half-life is measured after subcutaneous administration.

[0096] In some embodiments, the TL1A binding protein described herein has a half-life at least 20% longer than that of the comparative antibody. In some embodiments, the comparative antibody comprises the same complementarity-determining region and variable region but different Fc region. In some embodiments, the half-life of the TL1A binding protein described herein is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% longer than that of the comparative antibody. In some embodiments, the half-life of the TL1A binding protein described herein is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 times that of the comparative antibody. Treatment Methods

[0097] In some embodiments, methods for treating inflammatory bowel disease in patients in need are described herein, comprising administering an effective amount of a TL1A binding protein comprising a modified Fc region subcutaneously or intravenously to the patient. In some embodiments, this document describes a method of treating inflammatory bowel disease in a patient in need, the method comprising administering, subcutaneously or intravenously, an effective amount of a TL1A-binding protein comprising a) a heavy chain variable region (VH) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 1-18, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 19-36, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 37-54; b) a light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 55-72,(ii) CDR2 having an amino acid sequence according to any one of SEQ ID NO: 73-90, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NO: 91-108; and (c) an Fc domain comprising amino acid modifications of M252Y, S254T and T256E (YTE) and / or M428L and N434S (LS).

[0098] In some embodiments, this document further describes a method of treating inflammatory bowel disease in a patient in need, the method comprising administering, subcutaneously or intravenously, an effective amount of TL1A-binding protein to the patient, the TL1A-binding protein comprising: a) a heavy chain variable region (VH) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NO: 1-18, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NO: 19-36, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NO: 37-54; b) a light chain variable region (VL) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NO: 55-72, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NO: 73-90, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NO: 91-108; and c) The modified Fc, compared to the TL1A binding protein without the modified Fc, prolongs the half-life of the TL1A binding protein described on pages 49 / 54 of this specification, CN 121794295 A.

[0099] In some embodiments, a method of treating inflammatory bowel disease in a patient in need is further described herein, the method comprising administering an effective amount of TL1A binding protein subcutaneously or intravenously to the patient, wherein the TL1A binding protein specifically binds to an epitope of TL1A and comprises an Fc domain containing amino acid modifications M252Y, S254T, and T256E (YTE) and / or M428L and N434S (LS).

[0100] In some embodiments, the inflammatory bowel disease is Crohn's disease or ulcerative colitis. In some embodiments, the inflammatory bowel disease is ulcerative colitis.

[0101] In some embodiments, the TL1A binding protein is administered at a dose of about 75 mg to about 150 mg. In some embodiments, TL1A-binding protein is administered at a dose of about 250 mg to about 750 mg. In some embodiments, TL1A-binding protein is administered at a dose of about 300 mg to about 700 mg. In some embodiments, TL1A-binding protein is administered at a dose of about 300 mg to about 600 mg. In some embodiments,TL1A binding protein is administered at a dose of about 300 mg to about 500 mg. In some embodiments, TL1A binding protein is administered at a dose of about 300 mg to about 400 mg. In some embodiments, TL1A binding protein is administered at a dose of about 400 mg to about 700 mg. In some embodiments, TL1A binding protein is administered at a dose of about 400 mg to about 600 mg. In some embodiments, TL1A binding protein is administered at a dose of about 300 mg to about 500 mg. In some embodiments, TL1A binding protein is administered at a dose of about 500 mg to about 700 mg. In some embodiments, TL1A binding protein is administered at a dose of about 500 mg to about 600 mg. In some embodiments, TL1A binding protein is administered at a dose of about 600 mg to about 700 mg. In some embodiments, TL1A binding protein is administered at doses of about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg.

[0102] In some embodiments, TL1A binding protein is administered intravenously, intratumorally, intramuscularly, subcutaneously, intralesionally, intraintestinally, intracolonally, intrarectally, intraperitoneally, or intra-peritoneally. In some embodiments, TL1A binding protein is administered via a parenteral route, such as intravenously, intramuscularly, subcutaneously, intra-arterially, or intraperitoneally. In some embodiments, TL1A binding protein is administered intravenously or subcutaneously. In some embodiments, TL1A binding protein is administered intravenously. In some embodiments, the TL1A binding protein is administered subcutaneously.

[0103] The TL1A binding protein may be administered at different intervals. In some embodiments, the TL1A binding protein is administered to the patient at least once at intervals of more than 8 weeks. In some embodiments, the interval is about 12 to about 26 weeks. In some embodiments, the interval for the TL1A binding protein is about 12 to about 22 weeks. In some embodiments, the interval is about 12 to about 18 weeks. In some embodiments, the interval is about 12 to about 14 weeks. In some embodiments, the interval is about 16 to about 26 weeks. In some embodiments, the interval is about 16 to about 22 weeks. In some embodiments, the interval is about 16 to about 18 weeks. In some embodiments, the interval is about 20 to about 26 weeks. In some embodiments, the interval is about 20 to about 22 weeks. In some embodiments, the interval is about 12 weeks. In some embodiments, the interval is about 16 weeks. In some embodiments,The interval is approximately 26 weeks. Pharmaceutical Composition

[0104] This disclosure is further characterized by a pharmaceutical composition containing a therapeutically effective amount of the TL1A binding protein described herein. The composition can be formulated for use in a variety of drug delivery systems. One or more physiologically acceptable excipients or carriers may also be included in the composition for use in a suitable formulation. Suitable formulations for use in this disclosure are available in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pennsylvania, 17th edition, 1985. For a brief overview of drug delivery methods, see, for example, Langer (Science 249:1527-1533, 1990).

[0105] In some embodiments, the pharmaceutical composition may contain formulation materials for altering, maintaining, or preserving, for example, the pH, permeability, viscosity, transparency, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption, or permeation of the composition. In such an embodiment,Suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (such as ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (such as borates, bicarbonates, Tris-HCl, citrates, phosphates, or other organic acids); fillers (such as mannitol or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, β-cyclodextrin, or hydroxypropyl-β-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose, or dextrin); proteins (serum albumin, gelatin, or immunoglobulins); colorants, flavorings, and diluents; emulsifiers; and hydrophilic polymers (such as...). Polyvinylpyrrolidone; low molecular weight peptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (such as glycerol, propylene glycol, or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, dehydrated sorbitol esters, polysorbates (such as polysorbate 20, polysorbate esters), triton, tromethamine, lecithin, cholesterol, tyloxapal)); Stability enhancers (such as sucrose or sorbitol); tension enhancers (such as alkali metal halides (preferably sodium chloride or potassium chloride), mannitol, sorbitol); delivery media; diluents; excipients and / or adjuvants (see Remington's Pharmaceutical Sciences, 18th edition (Mack Publishing Company, 1990)).

[0106] In some embodiments, the pharmaceutical composition is citrate-free.

[0107] In some embodiments, the pharmaceutical composition may contain nanoparticles (e.g., polymer nanoparticles), liposomes, or micelles.

[0108] In some embodiments, the pharmaceutical composition may contain a sustained or controlled delivery formulation. Techniques for formulating sustained or controlled delivery methods (such as liposome carriers, bio-erectible microparticles, or porous beads and reservoir-type injections) are also known to those skilled in the art. Sustained-release formulations may include, for example, porous polymer microparticles or in the form of molded articles (e.g.,A semi-permeable polymer matrix (membrane or microcapsule). Sustained-release matrices may include polyesters, hydrogels, polylactide, copolymers of L-glutamic acid and L-glutamic acid-γ-ethyl ester, poly(2-hydroxyethyl-methacrylate), ethylene vinyl acetate, or poly-D(-)-3-hydroxybutyric acid. Sustained-release compositions may also include liposomes prepared by any of several methods known in the art.

[0109] Pharmaceutical compositions containing the TL1A binding protein disclosed herein may be provided in unit dosage forms and may be prepared by any suitable method. The pharmaceutical composition shall be formulated to be compatible with its intended route of administration. Examples of routes of administration are intravenous (IV), intradermal, inhalation, transdermal, topical, transmucosal, intrathecal, and rectal administration. In some embodiments, the TL1A binding protein disclosed herein is administered intravenously or subcutaneously. In some embodiments, the TL1A binding protein disclosed herein is administered intravenously. In some embodiments, the TL1A binding protein disclosed herein is administered subcutaneously.

[0110] Useful formulations may be prepared by methods known in the pharmaceutical industry. For example, see Remington's Pharmaceutical Sciences, 18th edition (Mack Publishing Company, 1990). Suitable formulation components for parenteral administration include sterile diluents such as water for injection, saline solution, fixative oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetate, citrate, or phosphate; and agents for tonication such as sodium chloride or dextran. In some embodiments, formulations for parenteral administration do not contain citrate.

[0111] For intravenous or subcutaneous administration, suitable carriers include physiological saline, antimicrobial water, Cremophor ELTM (BASF, Parsipponyck, NJ), or phosphate-buffered saline (PBS). The carrier should be stable under manufacturing and storage conditions and should be resistant to microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.

[0112] Intravenous or subcutaneous drug delivery formulations may be contained in syringes, pens, or pouches. In some embodiments, the pouch is connected to a channel containing a tube and / or needle. In some embodiments, the formulation is a lyophilized formulation or a liquid formulation.

[0113] These compositions can be sterilized using conventional sterilization techniques or can be sterile filtered. The resulting aqueous solution can be packaged for use as is or lyophilized.The lyophilized formulation is combined with a sterile aqueous carrier prior to application.

[0114] Polyols (which act as tonicators and can stabilize TL1A-binding proteins) may also be included in the formulation. The amount of polyol added to the formulation may vary depending on the desired isotonicity of the formulation. In some embodiments, the aqueous formulation is isotonic. The amount of polyol added may also vary depending on the molecular weight of the polyol. For example, a lower amount of monosaccharide (e.g., mannitol) may be added compared to a disaccharide (e.g., trehalose). In some embodiments, the polyol used as a tonicator in the formulation is mannitol.

[0115] Detergents or surfactants may also be added to the formulation. Exemplary detergents include nonionic detergents such as polysorbates (e.g., polysorbate 20, polysorbate 80, etc.) or poloxamer (e.g., poloxamer 188). The amount of detergent added reduces the aggregation of the formulated antibody and / or minimizes particle formation and / or reduces adsorption in the formulation. In some embodiments, the formulation may include a surfactant (i.e., polysorbate). In some embodiments, the formulation may contain detergent polysorbate 80 or Tween 80. Tween 80 is a term used to describe polyoxyethylene (20) dehydrated sorbitol monooleate (see Fiedler, Lexikon der Hifsstoffe [Dictionary of Pharmaceutical Excipients], Editio Cantor Verlag Aulendorf [Cantor Verlag Aulendorf, Germany], 4th edition, 1996).

[0116] In embodiments, the protein product disclosed herein is formulated as a liquid formulation. In some embodiments, the liquid formulation is prepared in combination with a sugar at a stabilization level. In some embodiments, the liquid formulation is prepared in an aqueous carrier. In some embodiments, the amount of stabilizer added is not greater than an amount that would result in an undesirable or inappropriate viscosity for intravenous administration. In some embodiments, the sugar is a disaccharide, such as sucrose. In some embodiments, the liquid formulation may also include one or more of a buffer, surfactant, and preservative.

[0117] In some embodiments, the pH of the liquid formulation is set by adding a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the base is sodium hydroxide.

[0118] The aqueous carriers of interest herein are pharmaceutically acceptable (safe and non-toxic to humans) and can be used to prepare liquid formulations. Exemplary carriers include sterile water for injection (SWFI), antibacterial water for injection (BWFI), pH buffer solutions (e.g.,Phosphate-buffered saline, sterile saline solution, Ringer's solution, or dextrose solution.

[0119] Preservatives may optionally be added to the formulations herein to reduce bacterial activity. The addition of preservatives may, for example, facilitate the production of multi-use (multi-dose) formulations.

[0120] TL1A can be combined with protein lyophilization to produce a lyophilized formulation comprising protein and a lyophilization protectant. The lyophilization protectant may be a sugar, such as a disaccharide. In some embodiments, the lyophilization protectant is sucrose or maltose. The lyophilized formulation may also include one or more of buffers, surfactants, fillers, and / or preservatives.

[0121] The amount of sucrose or maltose that can be used to stabilize the lyophilized pharmaceutical product may be at least a protein to sucrose or maltose weight ratio of 1:2. In some embodiments, the protein to sucrose or maltose weight ratio is 1:2 to 1:5. In some embodiments, the pH of the formulation prior to lyophilization is set by adding a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, a pharmaceutically acceptable base is sodium hydroxide.

[0122] In some embodiments, TL1A binding protein is administered at a dose of about 75 mg to about 150 mg. In some embodiments, on pages 52 / 54 of CN 121794295 A, TL1A binding protein is administered at a dose of about 250 mg to about 750 mg. In some embodiments, TL1A binding protein is administered at a dose of about 300 mg to about 700 mg. In some embodiments, TL1A binding protein is administered at a dose of about 300 mg to about 600 mg. In some embodiments, TL1A binding protein is administered at a dose of about 300 mg to about 500 mg. In some embodiments, TL1A binding protein is administered at a dose of about 300 mg to about 400 mg. In some embodiments, TL1A binding protein is administered at a dose of about 400 mg to about 700 mg. In some embodiments, TL1A binding protein is administered at a dose of about 400 mg to about 600 mg. In some embodiments, TL1A binding protein is administered at a dose of about 300 mg to about 500 mg. In some embodiments, TL1A-binding protein is administered at a dose of about 500 mg to about 700 mg. In some embodiments, TL1A-binding protein is administered at a dose of about 500 mg to about 600 mg. In some embodiments, TL1A-binding protein is administered at a dose of about 600 mg to about 700 mg. In some embodiments,TL1A-binding protein is administered at doses of about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg. In some embodiments, TL1A-binding protein is administered at a dose of about 300 mg. The actual dose level of the active ingredient in the pharmaceutical compositions disclosed herein may be about 250 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, or 700 mg to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and administration mode without toxicity to the patient.

[0123] A specific dose may be a uniform dose of approximately 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of protein per patient. Alternatively, the dose may be tailored to the patient’s approximate weight or body surface area. Other factors in determining an appropriate dose may include the disease or condition to be treated or prevented, the severity of the disease, the route of administration, and the patient’s age, sex, and medical condition. Further refinement of the estimates required to determine an appropriate therapeutic dose is routinely performed by those skilled in the art, particularly based on the dosage information and assays disclosed herein. The dose may also be determined by using known assays for determining the dosage used in conjunction with appropriate dose-response data. The dose for an individual patient may be adjusted as the disease progresses. Blood levels of the target construct or complex may be measured in the patient to see if dose adjustments are needed to achieve or maintain an effective concentration. Pharmacogenomics can be used to determine which targetable constructs and / or complexes and their dosages are most likely to be effective for a given individual (Schmitz et al., Clinica Chimica Acta [Journal of Clinical Chemistry] 308: 43-53, 2001; Steimer et al., Clinica Chimica Acta [Journal of Clinical Chemistry] 308: 33-41, 2001). Preparation Method

[0124] The above-mentioned TL1A binding protein can be prepared using recombinant DNA techniques well known to those skilled in the art. For example, one or more isolated polynucleotides encoding the TL1A binding protein can be linked with other suitable nucleotide sequences, including, for example, constant region coding sequences and expression control sequences.To produce a conventional gene expression construct (i.e., an expression vector) encoding the desired TL1A binding protein. The generation of the defined gene construct is within the conventional techniques of the art.

[0125] Nucleic acids encoding the desired TL1A binding protein can be introduced (ligated) into expression vectors, which can be introduced into host cells by conventional transfection or transformation techniques. Exemplary host cells are E. coli cells that do not normally produce IgG proteins, Chinese hamster ovary (CHO) cells, human embryonic kidney 293 (HEK 293) cells, HeLa cells, young hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and myeloma cells. Transformed host cells can be grown under conditions that allow host cells to express the gene encoding the TL1A binding protein.

[0126] Specific expression and purification conditions will vary depending on the expression system used. For example, if the gene is expressed in *E. coli*, the engineered gene is first cloned into an expression vector by positioning the engineered gene downstream of a suitable bacterial promoter (e.g., Trp or Tac) and a prokaryotic signal sequence. The expressed protein can be secreted. The expressed protein can accumulate in a refractive body or inclusion body, which can be harvested after the cells have been destroyed by Freund's crusher or sonication. The refractive body is then dissolved, and the protein can be refolded and / or cleaved using methods known in the art.

[0127] If the engineered gene is expressed in a eukaryotic host cell (e.g., CHO cells), it is first inserted into an expression vector containing a suitable eukaryotic promoter, secretion signal, poly-A sequence, and stop codon. Optionally, the vector or gene construct may contain enhancers and introns. In embodiments involving fusion proteins comprising TL1A-binding protein or a portion thereof, the expression vector optionally contains a sequence encoding all or part of a constant region, thereby enabling all or part of the heavy or light chain to be expressed. Gene constructs can be introduced into eukaryotic host cells using conventional techniques.

[0128] In some embodiments, an N-terminal signal sequence is included in the protein construct for expressing TL1A-binding protein. Exemplary N-terminal signal sequences include signal sequences from interleukin-2, CD-5, IgG κ light chain, trypsinogen, serum albumin, and prolactin.

[0129] Following transfection, individual clones can be isolated for cell bank generation using methods known in the art, such as limiting dilution, ELISA, FACS, microscopy, or Clonepix. Clones can be cultured under conditions suitable for bioreactor scale-up and maintenance of TL1A-binding protein expression.

[0130] TL1A-binding protein can be isolated and purified using methods known in the art.These methods include centrifugation, deep filtration, cell lysis, homogenization, freeze-thaw cycles, affinity purification, gel filtration, ion exchange chromatography, hydrophobic interaction exchange chromatography, and mixed-mode chromatography. All publications and patents (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.) cited throughout this specification are hereby incorporated in their entirety for all purposes, both above and below. If any material incorporated by reference contradicts or is inconsistent with this specification, this specification shall prevail over any such material. Equivalents

[0132] This disclosure may be practiced in other specific forms without departing from its spirit or essential characteristics. Therefore, the foregoing embodiments should be considered illustrative in all respects and not as limiting of the disclosure described herein. Therefore, the scope of this disclosure is indicated by the appended claims rather than the foregoing description, and all variations falling within the meaning and scope of the equivalents of the claims are intended to be included within said scope. Specification 54 / 54 pages 60 CN 121794295 A,

Claims

1. A TL1A-binding protein comprising: a) Heavy chain variable region (VH) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NO: 1-18, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NO: 19-36, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NO: 37-54; b) A light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 55-72, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 73-90, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 91-108; and c) Fc domains containing amino acid modifications of M252Y, S254T and T256E (YTE) and / or M428L and N434S (LS).

2. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 1, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 19, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 37; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 55, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 73, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

91.

3. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 2, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 20, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 38; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 56, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 74, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

92.

4. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 3, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 21, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 39; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 57, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 75, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

93.

5. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 4, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 22, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 40; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 58, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 76, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

94.

6. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 5, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 23, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 41; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 59, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 77, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

95.

7. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 6, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 24, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 42; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 60, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 78, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

96.

8. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 7, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 25, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 43; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 61, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 79, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

97.

9. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 8, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 26, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 44; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 62, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 80, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

98.

10. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 9, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 27, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 45; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 63, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 81, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

99.

11. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 10, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 28, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 46; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 64, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 82, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

100.

12. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 11, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 29, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 47; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 65, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 83, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

101.

13. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 12, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 30, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 48; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 66, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 84, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

102.

14. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 13, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 31, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 49; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 67, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 85, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

103.

15. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 14, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 32, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 50; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 68, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 86, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

104.

16. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 15, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 33, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 51; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 69, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 87, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

105.

17. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 16, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 34, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 52; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 70, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 88, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

106.

18. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 17, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 35, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 53; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 71, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 89, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

107.

19. The TL1A binding protein of claim 1, wherein the VH comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 18, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 36, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO: 54; and the VL comprises (i) a CDR1 having an amino acid sequence according to SEQ ID NO: 72, (ii) a CDR2 having an amino acid sequence according to SEQ ID NO: 90, and (iii) a CDR3 having an amino acid sequence according to SEQ ID NO:

108.

20. The TL1A binding protein according to any one of claims 1-19, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of any one of SEQ ID NO: 325-342, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of any one of SEQ ID NO: 343-360.

21. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 325, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

343.

22. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 326, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

344.

23. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 327, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

345.

24. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 328, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

346.

25. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 329, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

347.

26. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 330, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

348.

27. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 331, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

349.

28. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 332, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

350.

29. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 333, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

351.

30. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 334, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

352.

31. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 335, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

353.

32. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 336, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

354.

33. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 337, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

355.

34. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 338, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

356.

35. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 339, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

357.

36. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 340, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

358.

37. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 341, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

359.

38. The TL1A binding protein of claim 20, wherein the VH comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 342, and the VL comprises a sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:

360.

39. The TL1A binding protein according to any one of claims 1-38, wherein the Fc is the Fc domain of IgG1, IgG2 or IgG4 immunoglobulin.

40. The TL1A binding protein of claim 39, wherein the Fc is an IgG1 immunoglobulin domain.

41. The TL1A binding protein of claim 39, wherein the Fc is an IgG2 immunoglobulin domain.

42. The TL1A binding protein of claim 39, wherein the Fc is an IgG4 immunoglobulin domain.

43. A TL1A-binding protein comprising: a) Heavy chain variable region (VH) comprising (i) CDR1 having an amino acid sequence according to any one of SEQ ID NO: 1-18, (ii) CDR2 having an amino acid sequence according to any one of SEQ ID NO: 19-36, and (iii) CDR3 having an amino acid sequence according to any one of SEQ ID NO: 37-54; b) A light chain variable region (VL) comprising (i) a CDR1 having an amino acid sequence according to any one of SEQ ID NO: 55-72, (ii) a CDR2 having an amino acid sequence according to any one of SEQ ID NO: 73-90, and (iii) a CDR3 having an amino acid sequence according to any one of SEQ ID NO: 91-108; and c) The modified Fc, compared with the TL1A binding protein without the modified Fc, prolongs the half-life of the TL1A binding protein.

44. A TL1A binding protein, wherein the TL1A binding protein specifically binds to an epitope of TL1A and comprises an Fc domain containing amino acid modifications of M252Y, S254T and T256E (YTE) and / or M428L and N434S (LS).

45. A method of treating inflammatory bowel disease in a patient in need, the method comprising administering, subcutaneously or intravenously, an effective amount of TL1A-binding protein as described in any one of claims 1-44 to the patient.

46. ​​The method of claim 45, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

47. The method of claim 46, wherein the inflammatory bowel disease is ulcerative colitis.

48. The method of any one of claims 45-47, wherein the TL1A binding protein is administered subcutaneously.

49. The method of any one of claims 45-47, wherein the administration of the TL1A binding protein is intravenous.