Anti-tl1a antibody therapeutic methods

Abstract

The present disclosure provides methods and compositions for determining the risk of a patient unresponsive to a therapeutic dose of an anti-TNF-like ligand 1A (TL1A) antibody, and methods and compositions for treating inflammatory bowel disease (IBD) with a therapeutic dose of an anti-TNF-like ligand 1A (TL1A) antibody.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480032663.3 (22) Application Date 2024.05.17 (30) Priority Data 63 / 502,786 2023.05.17 US 63 / 647,481 2024.05.14 US (85) PCT International Application Entering National Phase Date 2025.11.14 (86) PCT International Application Application Data PCT / US2024 / 030118 2024.05.17 (87) PCT International Application Publication Data WO2024 / 239006 EN 2024.11.21 (71) Applicant Genentech, Inc. Address California, USA Applicant Pfizer Inc. (72) Inventors C.R. Banfield D.E. Chandra M. Hassan-Zara X. Hu C.L. Hyde S. Niracontan E. Pipha M.S. Vincent Y. Wu Z. Ye S. Pengoda S. Ramanathan J. Chamberlain K. Hahn M. Sukhatem F. Torti K. Hen S.W. Martin (74) Patent Agency Beijing Kunrui Law Firm 11494 Patent Attorney Feng Xinqin (51) Int.Cl. C12Q 1 / 6886 (2006.01) (54) Invention Title Anti-TL1A Antibody Treatment Method (57) Abstract This disclosure provides methods and compositions for determining the risk of a patient not responding to a therapeutic dose of an anti-TNF-like ligand 1A (TL1A) antibody, and methods and compositions for treating inflammatory bowel disease (IBD) with a therapeutic dose of an anti-TNF-like ligand 1A (TL1A) antibody. Claims (17 pages), Description (64 pages), Sequence Listing (electronic publication), Drawings (10 pages), CN 121532526 A, 2026.02.13, CN 1 21 53 25 26 A. 1. A method for determining the risk of a patient being unresponsive to a therapeutic dose of an anti-TNF-like ligand 1A (TL1A) antibody, the method comprising: genotyping a biological sample from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination comprising determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in the biological sample from the patient; and determining the risk of being unresponsive to the therapeutic dose of the anti-TL1A antibody, wherein the risk is higher for haplotype B carriers than for haplotype B carriers. 2. Non-carrier patients. According to claim 13. A method for treating a patient with inflammatory bowel disease (IBD). The method comprises: (a) performing genotyping to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination comprising determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) administering an effective amount of anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier. 4. The method of claim 3, wherein the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising a plurality of individual induction doses. 5. The method of claim 3, wherein the anti-TL1A antibody is administered to the patient in a maintenance dosing regimen after the induction dosing regimen is completed, the maintenance dosing regimen comprising a plurality of individual maintenance doses spaced at least 2 weeks apart from each other. 6. A method for treating a patient with IBD, the method comprising: (a) performing genotyping to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; (b) administering the anti-TL1A antibody to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising a plurality of individual induction doses, wherein the patient has been identified as a haplotype B non-carrier; and (c) administering a subsequent maintenance dosing regimen to the patient after completion of the induction dosing regimen, the maintenance dosing regimen comprising a plurality of individual maintenance doses spaced at least 2 weeks apart from each other. 7. The method of any one of claims 2 to 6, wherein the IBD is ulcerative colitis (UC). 8. The method of claim 7, wherein the UC is moderate to severe UC. 9. The method of any one of claims 2 to 6, wherein the IBD is Crohn's disease (CD). 10. The method of any one of claims 1 to 9, wherein the at least two SNPs are SNPs.rs3810936 and SNP rs7869487. 11. The method of claim 10, wherein the genotyping assay comprises determining the presence of only two SNPs in the biological sample from the patient, wherein the two SNPs are SNP rs3810936 and SNP rs7869487. 12. The method of claim 10 or 11, wherein the patient is identified as a non-carrier of haplotype B by any of the following biomarker states from the biological sample of the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487. The reference allele at rs3810936 is heterozygous; or (v) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487. 13. The method of claim 10, wherein (a) the genotyping assay comprises determining the presence of SNPs rs3810936, rs7869487, and rs7848647 in the biological sample from the patient; or (b) the genotyping assay comprises determining the presence of SNPs rs3810936, rs7869487, and rs6478109 in the biological sample from the patient. 14. The method of claim 10, wherein the genotyping assay comprises determining the presence of SNPs rs3810936, rs7869487, rs6478108, and rs6478109 in the biological sample from the patient. 15. The method of any one of claims 1 to 14, wherein the genotyping assay comprises qPCR. 16. The method of claims 1 to 15.17. The method of any one of claims 1 to 16, wherein the genotyping assay comprises sequencing. 18. The method of any one of claims 1 to 17, wherein the genotyping assay is performed on a microarray. 19. The method of any one of claims 1 to 18, wherein the genotyping assay is a fluorescence-based assay. 20. The method of any one of claims 1 to 19, wherein the biological sample is blood. 21. The method of any one of claims 1 to 19, wherein the biological sample is oral cells. 22. A method for determining the risk of a patient being unresponsive to a therapeutic dose of an anti-TL1A antibody, wherein the patient has inflammatory bowel disease (IBD), the method comprising: (a) genotyping a biological sample from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, wherein the determination includes determining the presence of SNPs rs3810936 and rs7869487 in the biological sample from the patient, and wherein a haplotype B non-carrier of TNFSF15 is identified by any of the following biomarker states from the biological sample from the patient: (i) the genotype of the sample is homozygous for a reference allele at rs3810936 and homozygous for an alternative allele at rs7869487; (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) the genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487; and (b) if the patient is a haplotype B carrier, the patient is identified as having a high risk of not responding to therapeutic doses of anti-TL1A antibodies; or (c) If the patient is haplotype BFor non-carriers, the patient is identified as having low risk of not responding to therapeutic doses of anti-TL1A antibody. 23. The method of claim 22, wherein the patient has been identified as a haplotype B non-carrier of TNFSF15, and the method further comprises administering an effective amount of anti-TL1A antibody to the patient. 24. The method of claim 23, wherein the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising a plurality of individual induction doses. 25. The method of claim 23, wherein the anti-TL1A antibody is administered to the patient in a maintenance dosing regimen after completion of the induction dosing regimen, the maintenance dosing regimen comprising a plurality of individual maintenance doses spaced at least 2 weeks apart from each other. 26. A method for treating IBD in a patient, the method comprising: (a) genotyping a biological sample from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, wherein the determination includes determining the presence of SNPs rs3810936 and rs7869487 in the biological sample from the patient, and wherein a haplotype B non-carrier of TNFSF15 is identified by any of the following biomarker states from the biological sample from the patient: (i) the genotype of the sample is homozygous for a reference allele at rs3810936 and homozygous for a substitute allele at rs7869487; (ii) the genotype of the sample is heterozygous for a reference allele at rs3810936 and homozygous for a substitute allele at rs7869487; (iii) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) the genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487; and (b) administering an effective amount of anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier. 27. The method of claim 26, wherein the amount is sufficient to initiate the use of the anti-TL1A antibody.Following antibody treatment up to page 3 / 17 of claim 4 CN 121532526 A, an induction dosing regimen is used to administer the anti-TL1A antibody to the patient for at least 12 weeks to improve signs and symptoms of IBD, the induction dosing regimen comprising multiple individual induction doses. 28. The method of claim 26, wherein after completion of the induction dosing regimen, the anti-TL1A antibody is administered to the patient with a subsequent maintenance dosing regimen comprising multiple individual maintenance doses spaced at least 2 weeks apart. 29. A method for treating an IBD patient, the method comprising administering an effective amount of an anti-TL1A antibody to the patient; wherein the patient has been identified as a haplotype B noncarrier of TNFSF15 by any of the following biomarker states from a biological sample of the patient: (i) the genotype of the sample is homozygous for a reference allele at rs3810936 and homozygous for an alternative allele at rs7869487; (ii) the genotype of the sample is heterozygous for a reference allele at rs3810936 and homozygous for an alternative allele at rs7869487; (iii) the genotype of the sample is homozygous for an alternative allele at rs3810936 and homozygous for a reference allele at rs7869487; (iv) the genotype of the sample is homozygous for a reference allele at rs3810936 and homozygous for an alternative allele at rs7869487; The alternative allele at rs7869487 is homozygous and heterozygous for the reference allele at rs7869487; or (v) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487. 30. The method of claim 29, wherein the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising a plurality of individual induction doses. 31. The method of claim 29, wherein the anti-TL1A antibody is administered to the patient in a subsequent maintenance dosing regimen after completion of the induction dosing regimen, the maintenance dosing regimen comprising a plurality of individual maintenance doses spaced at least 2 weeks apart from each other. 32. The method according to any one of claims 4, 6 to 21, 24, 27 and 30, wherein the individual induction doses are spaced at least 1 week, at least 2 weeks, at least 3 weeks or at least 4 weeks apart. 33. The method according to claims 4, 6 to 21, 24, 27, 30 and 32.33. The method of any one of claims 32, wherein the individual induction doses are administered at least one month apart. 34. The method of claim 32, wherein the individual induction doses are administered at four-week intervals. 35. The method of any one of claims 4, 6 to 21, 24, 27, 30 and 32 to 34, wherein the individual induction dose is administered intravenously or subcutaneously. 36. The method of claim 35, wherein each of the individual induction doses is administered subcutaneously. 37. The method of any one of claims 4, 6 to 21, 24, 27, 30 and 32 to 36, wherein the individual induction dose is administered at a dose of 50, 150, or 450 mg. 38. The method of claim 37, wherein each of the individual induction doses is administered at a dose of 50 mg. 39. The method of claim 37, wherein each of the individual induction doses is administered at a dose of 150 mg. Claims 4 / 17, page 5, CN 121532526 A 40. The method of claim 37, wherein each of the individual induction doses is administered at a dose of 450 mg. 41. The method of any one of claims 4 to 21 and 24 to 40, wherein the induction dosing regimen comprises four individual induction doses. 42. The method of any one of claims 4 to 21, 24, 25, 27, 28 and 30 to 41, wherein the induction dosing regimen comprises four individual induction doses administered at 4-week intervals, and wherein each of the individual induction doses is administered subcutaneously at a dose of 50, 150, or 450 mg. 43. The method of any one of claims 5 to 21, 25, 28, 31, 41, and 42, wherein the individual maintenance doses are administered at intervals of at least 2 weeks, at least 3 weeks, or at least 4 weeks. 44. The method of any one of claims 5 to 21, 25, 28, 31, and 41 to 43, wherein the individual maintenance doses are administered at least one month apart. 45. The method of claim 43, wherein the individual maintenance doses are administered at four-week intervals. 46. The method of any one of claims 5 to 21, 25, 28, and 41 to 45, wherein the individual maintenance doses are administered intravenously or subcutaneously. 47. The method of claim 46, wherein each of the individual maintenance doses is administered subcutaneously. 48. The method of any one of claims 5 to 21, 25, 28, and 41 to 47, wherein the individual maintenance doses are in doses of 50, 150, or...49. The method of claim 48, wherein each of the individual maintenance doses is administered at a dose of 50 mg. 50. The method of claim 48, wherein each of the individual maintenance doses is administered at a dose of 150 mg. 51. The method of claim 48, wherein each of the individual maintenance doses is administered at a dose of 450 mg. 52. The method of any one of claims 5 to 21, 25, 28, and 41 to 51, wherein the maintenance dosing regimen comprises at least ten individual maintenance doses. 53. The method of any one of claims 5 to 21, 25, 28, and 41 to 52, wherein the induction dosing regimen comprises ten individual maintenance doses administered at 4-week intervals, and wherein each of the individual maintenance doses is administered subcutaneously at a dose of 50, 150, or 450 mg. 54. The method of claim 53, wherein each of the individual maintenance doses is administered subcutaneously at a dose of 450 mg. 55. The method of any one of claims 3 to 54, further comprising: (a) determining the expression level of one or more candidate genes in a biological sample from the patient, and (b) identifying that the biological sample contains the one or more candidate genes with abnormal expression levels. 56. The method of claim 55, wherein the one or more candidate genes are selected from the group consisting of: SOWAHB, COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, PKDREJ, IL-1B, IL-23A, IFNG, IL-12RB1, IL-21R, IRF4, BATF, CD80 / 86, HLA-DRB5 / DQB1 / DRB1, HLA-DRA, CD40, ICOS, MMP3, MMP7, MMP10, and CHI3L. 57. The method of claim 56, wherein the one or more candidate genes are selected from the group consisting of: SOWAHB, COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, and PKDREJ. Claims 5 / 17, page 6, CN 121532526 A 58. The method of any one of claims 55 to 57, wherein the expression level of the one or more candidate genes is compared with a baseline expression level, the baseline expression level being a) based on the expression level of the one or more candidate genes in a healthy individual without IBD or UC; or b)59. The method of claim 58, wherein the aberrant expression level of the one or more candidate genes is at least 50% higher or lower than baseline. 60. The method of any one of claims 3 to 59, further comprising: a) determining the expression level of one or more candidate bacterial strains in a fecal sample from the patient, and b) identifying whether the sample contains the one or more candidate bacterial strains at increased or decreased levels. 61. The method of claim 60, wherein the candidate bacterial strain level is increased, and the candidate bacterial strain is selected from the group consisting of: *Streptococcus salivarius*, *Streptococcus parasanguinis*, and *Haemophilus parainfluenzae*. 62. The method of claim 61, wherein the level of the candidate bacterial strain is reduced, and the candidate bacterial strain is selected from the group consisting of: *Ruminococcus albus*, *Ruminococcus callidus*, *Ruminococcus bromii*, *Ruminococcus gnavus*, and *Bifidobacterium bifidum*. 63. The method of any one of claims 1 to 62, wherein the anti-TL1A antibody comprises: three CDRs from a variable heavy chain region having the sequence shown in SEQ ID NO: 1; and three CDRs from a variable light chain region having the sequence shown in SEQ ID NO: 2. 64. The method according to any one of claims 1 to 62, wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO: 8. 65. The method according to any one of claims 1 to 64, wherein the anti-TL1A antibody comprises: a variable heavy chain region having SEQ ID NO: 1The method according to any one of claims 1 to 65, wherein the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 9; and a light chain having the sequence shown in SEQ ID NO: 10. 67. The method according to any one of claims 1 to 66, wherein the anti-TL1A antibody is afimzimab. 68. A method for treating a patient with inflammatory bowel disease (IBD), the method comprising: (a) performing genotyping to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination comprising determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) administering an effective amount of an anti-TL1A antibody to the patient, wherein the patient has been determined to be a haplotype B non-carrier; wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; and HCDR3 having the sequence shown in SEQ ID NO: 5. The sequence shown; LCDR1, having the sequence shown in SEQ ID NO: 6; LCDR2, having the sequence shown in SEQ ID NO: 7; and LCDR3, having the sequence shown in SEQ ID NO: 8. 69. The method of claim 68, wherein the at least two SNPs are SNP rs3810936 and SNP rs7869487. 70. The method of claim 69, wherein the determination comprises determining the presence of only two SNPs in the biological sample from the patient, and wherein the two SNPs are SNP rs3810936 and SNP rs7869487. 71. The method according to any one of claims 1 to 62, wherein the anti-TL1A antibody comprises sequence pairs selected from the group consisting of: SEQ ID NO: 2 and 11; SEQ ID NO: 2 and 12; SEQ ID NO: 2 and 13; SEQ ID NO: 2 and 14; SEQ ID NO: 2 and 15; SEQ ID NO: 2 and 15.16; SEQ ID NO: 2 and 17; SEQ ID NO: 2 and 18; SEQ ID NO: 2 and 19; SEQ ID NO: 20 and 24; SEQ ID NO: 21 and 25; SEQ ID NO: 22 and 26; SEQ ID NO: 23 and 27; SEQ ID NO: 28 and 29; SEQ ID NO: 30 and 31; SEQ ID NO: 32 and 33; SEQ ID NO: 35 and 44; SEQ ID NO: 53 and 54; SEQ ID NO: 61 and 62; SEQ ID NO: 63 and 64; SEQ ID NO: 65 and 64; SEQ ID NO: 66 and 64; and SEQ ID NO: 67 and 64. 72. The method of any one of claims 1 to 62, wherein the anti-TL1A antibody comprises: three CDRs from a variable heavy chain region having the sequence shown in SEQ ID NO: 53; and three CDRs from a variable light chain region having the sequence shown in SEQ ID NO: 54. 73. The method of any one of claims 1 to 62, wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 37; HCDR2 having the sequence shown in SEQ ID NO: 39; HCDR3 having the sequence shown in SEQ ID NO: 41; LCDR1 having the sequence shown in SEQ ID NO: 46; LCDR2 having the sequence shown in SEQ ID NO: 48; and LCDR3 having the sequence shown in SEQ ID NO: 50. 74. The method of any one of claims 1 to 62, 72, and 73, wherein the anti-TL1A antibody comprises: a variable heavy chain region having the sequence shown in SEQ ID NO: 53; and a variable light chain region having the sequence shown in SEQ ID NO: 54. 75. The method of any one of claims 1 to 62 and 72 to 74, wherein the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 35; and a light chain having the sequence shown in SEQ ID NO: 44. 76. The method of any one of claims 1 to 62 and 72 to 75, wherein the anti-TL1A antibody is tussockibab. 77. A treatment for patients with inflammatory bowel disease.(IBD) method, the method comprising: (a) performing genotyping to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination comprising determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) administering an anti-TL1A antibody to the patient, wherein the patient has been determined to be a haplotype B non-carrier; wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 37; HCDR2 having the sequence shown in SEQ ID NO: 39; HCDR3 having the sequence shown in SEQ ID NO: 41; LCDR1 having the sequence shown in SEQ ID NO: 41; and LCDR1 having the sequence shown in SEQ ID NO: 41. 46. ​​The sequence shown in SEQ ID NO: 48; LCDR2, having the sequence shown in SEQ ID NO: 50; and LCDR3, having the sequence shown in SEQ ID NO: 50. 78. The method of claim 77, wherein the at least two SNPs are SNP rs3810936 and SNP rs7869487. 79. The method of claim 78, wherein the determination comprises determining the presence of only two SNPs in the biological sample from the patient, wherein the two SNPs are SNP rs3810936 and SNP rs7869487. 80. The method of any one of claims 3 to 79, further comprising treatment with an IL-23 antagonist. 81. The method of any one of claims 22 to 31, 68 to 70, and 77 to 79, wherein the IBD is ulcerative colitis (UC). 82. The method of claim 81, wherein the UC is moderate to severe UC. 83. The method according to any one of claims 22 to 31, 68 to 70, and 77 to 79, wherein the IBD is Crohn's disease (CD). 84. The method according to any one of claims 1 to 83, wherein the patient is human. 85. A method of treating a patient with inflammatory bowel disease (IBD), the method comprising administering an effective amount of an anti-TNF-like ligand 1A (TL1A) antibody to the patient in a dosing regimen including an induction dosing regimen and a subsequent maintenance dosing regimen;The induction dosing regimen includes multiple individual induction doses, and the maintenance dosing regimen includes multiple individual maintenance doses; wherein the anti-TL1A antibody is administered subcutaneously during the maintenance phase, and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO: 8. 86. The method of claim 85, wherein the individual induction doses are spaced at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks apart. 87. The method of claim 85 or 86, wherein the individual induction doses are spaced at least 1 month apart. 88. The method of claim 86, wherein the individual induction doses are administered at 4-week intervals. 89. The method of any one of claims 85 to 88, wherein the individual induction dose is administered intravenously or subcutaneously. 90. The method of claim 89, wherein each of the individual induction doses is administered subcutaneously. 91. The method of any one of claims 85 to 90, wherein the individual induction dose is administered at a dose of 50, 150, or 450 mg. 92. The method of claim 91, wherein each of the individual induction doses is administered at a dose of 50 mg. 93. The method of claim 91, wherein each of the individual induction doses is administered at a dose of 150 mg. 94. The method of claim 91, wherein each of the individual induction doses is administered at a dose of 450 mg. 95. The method of any one of claims 85 to 94, wherein the induction dosing regimen comprises four individual induction doses. 96. The method of any one of claims 85 to 95, wherein the induction dosing regimen comprises four separate induction doses administered at 4-week intervals, and wherein each of the separate induction doses is administered subcutaneously at a dose of 50, 150, or 450 mg. 97. The method of any one of claims 85 to 96, wherein the separate maintenance doses are administered at intervals of at least 2 weeks, at least 3 weeks, or at least 4 weeks. 98. The method of claims 85 to 9799. The method of any one of claims 97, wherein the individual maintenance doses are administered at least one month apart. 100. The method of any one of claims 85 to 99, wherein the individual maintenance doses are administered at a dose of 50, 150, or 450 mg. 101. The method of claim 100, wherein each of the individual maintenance doses is administered at a dose of 50 mg. 102. The method of claim 100, wherein each of the individual maintenance doses is administered at a dose of 150 mg. 103. The method of claim 100, wherein each of the individual maintenance doses is administered at a dose of 450 mg. 104. The method of any one of claims 85 to 103, wherein the maintenance dosing regimen comprises at least ten individual maintenance doses. 105. The method of any one of claims 85 to 104, wherein the induction dosing regimen comprises ten individual maintenance doses administered at 4-week intervals, wherein each of the individual maintenance doses is administered subcutaneously at a dose of 50, 150, or 450 mg. 106. The method of claim 105, wherein each of the individual maintenance doses is administered subcutaneously at a dose of 450 mg. 107. A method of treating a patient with inflammatory bowel disease (IBD), the method comprising administering an effective amount of an anti-TNF-like ligand 1A (TL1A) antibody to the patient in a dosing regimen including an induction dosing regimen and a subsequent maintenance dosing regimen; wherein: (a) the induction dosing regimen comprises subcutaneously administering four separate induction doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg, wherein the separate induction doses are administered at 4-week intervals; and (b) the maintenance dosing regimen comprises subcutaneously administering multiple separate maintenance doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg, wherein the separate maintenance doses are administered at 4-week intervals; and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; and HCDR3 having the sequence shown in SEQ ID NO: 4. The sequence shown in SEQ ID NO: 5; LCDR1, having the sequence shown in SEQ ID NO: 6; LCDR2, having the sequence shown in SEQ ID NO: 7; and LCDR3, having the sequence shown in SEQ ID NO: 6.The sequence shown in NO: 8. 108. A method of treating a patient with inflammatory bowel disease (IBD), the method comprising administering an effective amount of an anti-TNF-like ligand 1A (TL1A) antibody to the patient in a dosing regimen including an induction dosing regimen and a subsequent maintenance dosing regimen; wherein: (a) the induction dosing regimen comprises a plurality of individual induction doses, wherein the individual induction doses are spaced apart from each other for at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks; and (b) the maintenance dosing regimen comprises subcutaneously administering a plurality of individual maintenance doses of the anti-TL1A antibody at a dose of about 450 mg, wherein the individual maintenance doses are administered at 4-week intervals; and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO: 6. 109. The method of claim 108, wherein the induction dosing regimen comprises subcutaneously administering four separate induction doses of the anti-TL1A antibody at a dose of about 450 mg, wherein the separate induction doses are administered at 4-week intervals. 110. The method of any one of claims 85 to 109, wherein the first dose of the maintenance phase is administered about two weeks after the administration of the final dose of the induction phase. 111. The method of any one of claims 85 to 110, wherein the dosing regimen has a duration of about 52 weeks. 112. The method of any one of claims 85 to 111, wherein the anti-TL1A antibody comprises: a variable heavy chain region having the sequence shown in SEQ ID NO: 1; and a variable light chain region having the sequence shown in SEQ ID NO: 2. 113. The method of any one of claims 85 to 112, wherein the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 9; and a light chain having the sequence shown in SEQ ID NO: 10. 114. The method of any one of claims 85 to 113, wherein the anti-TL1A antibody is afimzidimab. 115. The method of any one of claims 85 to 114, wherein the patient has been identified as a haplotype B non-carrier of TNFSF15. 116. According to claim...115. The method of any one of claims 85 to 115, wherein the IBD is ulcerative colitis (UC). 117. The method of claim 116, wherein the UC is moderate to severe UC. 118. The method of any one of claims 85 to 117, wherein the patient is human. 119. The method of any one of claims 85 to 118, wherein, in the patient population treated according to the method, the treatment causes an increase in the proportion of patients who have achieved clinical remission at the end of the induction phase compared to a reference population. 120. The method of claim 119, wherein the induction phase has a duration of about 14 weeks, and the treatment causes an increase in the proportion of patients who have achieved clinical remission at week 14. 121. The method of claim 120, wherein at least about 15% of the patients in the patient population have achieved clinical remission at week 14. 122. The method of claim 121, wherein at least about 40% of the patients in the patient population have achieved clinical remission by week 14. 123. The method of any one of claims 85 to 122, wherein, in the patient population treated according to the method, the treatment results in an increased proportion of patients who have achieved clinical remission at the end of the maintenance phase compared to a reference population. 124. The method of claim 123, wherein the dosing regimen has a duration of about 56 weeks, and the treatment results in an increased proportion of patients who have achieved clinical remission by week 56. 125. The method of claim 124, wherein at least about 20% of the patients in the patient population have achieved clinical remission by week 56. 126. The method of claim 125, wherein at least about 55% of the patients in the patient population have achieved clinical remission by week 56. 127. The method of any one of claims 119 to 126, wherein clinical remission is defined as a total Mayo score ≤ 2 with no individual sub-score > 1. 128. The method according to any one of claims 119 to 126, wherein clinical remission is defined as a modified Mayo Criterion score (mMS) ≤ 2, having a stool frequency subscore (SFS) = 0 or 1, a rectal bleeding subscore (RBS) = 0, and an endoscopy score (ES) = 0 or 1. 129. The method according to any one of claims 85 to 128, wherein, in patients treated according to the method...130. The method of claim 129, wherein the induction phase lasts for about 14 weeks, and the treatment causes an increase in the proportion of patients who have achieved endoscopic improvement by the end of the induction phase compared to the reference group. 131. The method of claim 130, wherein at least about 25% of the patients in the patient population have achieved endoscopic improvement by the end of the 14th week. 132. The method of claim 131, wherein at least about 50% of the patients in the patient population have achieved endoscopic improvement by the end of the 14th week. 133. The method of any one of claims 85 to 132, wherein, in the patient population treated according to the method, the treatment causes an increase in the proportion of patients who have achieved endoscopic improvement by the end of the maintenance phase compared to the reference group. 134. The method of claim 133, wherein the dosing regimen lasts for about 56 weeks, and the treatment causes an increase in the proportion of patients who have achieved endoscopic improvement by the end of the 56th week. 135. The method of claim 134, wherein at least about 20% of the patients in the patient population have achieved endoscopic improvement by week 56. 136. The method of claim 135, wherein at least about 65% of the patients in the patient population have achieved endoscopic improvement by week 56. 137. The method of any one of claims 129 to 136, wherein clinical remission is an endoscopic score of 0 or 1. 138. The method of any one of claims 85 to 137, wherein, in the patient population treated according to the method, the treatment results in an increased proportion of patients who have achieved endoscopic remission, clinical response, symptom relief, or deep remission by the end of the induction phase compared to a reference population. 139. The method of any one of claims 85 to 138, wherein, in the patient population treated according to the method, the treatment results in an increased proportion of patients who have achieved endoscopic remission, clinical response, symptom relief, or deep remission by the end of the maintenance phase compared to a reference population. 140. The method of any one of claims 119 to 139, wherein the reference population is a patient population that has not been treated with an anti-TL1A antibody. 141. The method of claim 140, wherein the reference population is a patient population that has not been treated with a placebo. 142. A kit comprising an anti-TNF-like ligand 1A (TL1A) antibody and a packaging insert, wherein the packaging insert...The product includes instructions for using the antibody to treat patients with inflammatory bowel disease (IBD) in accordance with any one of claims 1 to 141. 143. An anti-TL1A antibody for use in treating a patient with IBD, wherein: (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) an effective amount of the anti-TL1A antibody is administered to the patient, wherein the patient has been determined to be a haplotype B non-carrier. 144. An anti-TL1A antibody for use in treating a patient with IBD, wherein: (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, said assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; (b) the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with said anti-TL1A antibody, said induction dosing regimen comprising multiple individual induction doses, wherein the patient has been identified as a haplotype B non-carrier; and (c) the anti-TL1A antibody is administered to the patient in a subsequent maintenance dosing regimen after completion of said induction dosing regimen, said maintenance dosing regimen comprising at least 2 weeks intervals between each other. Multiple individual maintenance doses per week. 145. An anti-TL1A antibody for use in treating a patient with IBD, wherein: (a) a biological sample from said patient is to be genotyped to determine whether said patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, wherein said determination includes determining the presence of SNP rs3810936 and SNP rs7869487 in the biological sample from said patient, and wherein a haplotype B non-carrier of TNFSF15 is identified by any of the following biomarker states from said biological sample from said patient: (i) the genotype of said sample is homozygous for a reference allele at rs3810936 and for the reference allele at rs3810936 and for the reference allele at rs3810936.(i) The genotype of the sample is homozygous for the alternative allele at rs7869487; (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) The genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487; and (b) An effective amount of the anti-TL1A antibody will be administered to the patient, who has been identified as a haplotype B non-carrier. 146. An anti-TL1A antibody for use in treating a patient with IBD, wherein an effective amount of the anti-TL1A antibody is to be administered to the patient; wherein the patient has been identified as a haplotype B non-carrier of TNFSF15 by any of the following biomarker states from a biological sample of the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) the genotype of the sample is homozygous for the reference allele at rs7869487 and homozygous for the reference allele at rs3810936. The alternative allele at rs7869487 is homozygous and heterozygous for the reference allele at rs3810936; or (v) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487. 147. An anti-TL1A antibody for use in treating a patient with IBD, wherein: (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining at least two selected from biological samples from the patientThe presence of SNPs rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487; and (b) administering an effective amount of the anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier; wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO: 8. 148. An anti-TL1A antibody for use in treating a patient with IBD, wherein: (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, said assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and claim 13 / 17 pages 14 CN 121532526 A (b) the anti-TL1A antibody is administered to the patient, wherein the patient has been determined to be a haplotype B non-carrier; wherein said anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 37; HCDR2 having the sequence shown in SEQ ID NO: 39; HCDR3 having the sequence shown in SEQ ID NO: 41 The sequences shown are: LCDR1, having the sequence shown in SEQ ID NO: 46; LCDR2, having the sequence shown in SEQ ID NO: 48; and LCDR3, having the sequence shown in SEQ ID NO: 50. 149. An anti-TL1A antibody for use in treating a patient with IBD, wherein an effective amount of the anti-TL1A antibody is administered to a subject in a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen; wherein the induction dosing regimen comprises a plurality of individual induction doses, and the maintenance dosing regimen comprises a plurality of individual maintenance doses; wherein the anti-TL1A antibody is administered subcutaneously during the maintenance phase, and wherein the anti-TL1A antibody comprises: HCDR1, having the sequence shown in SEQ ID NO: 3;HCDR2, having the sequence shown in SEQ ID NO: 4; HCDR3, having the sequence shown in SEQ ID NO: 5; LCDR1, having the sequence shown in SEQ ID NO: 6; LCDR2, having the sequence shown in SEQ ID NO: 7; and LCDR3, having the sequence shown in SEQ ID NO: 8. 150. An anti-TL1A antibody for use in treating patients with IBD, wherein an effective amount of the anti-TL1A antibody is administered to a subject via a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen, wherein: (a) the induction dosing regimen comprises subcutaneously administering four separate induction doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg, wherein the separate induction doses are administered at 4-week intervals; and (b) the maintenance dosing regimen comprises subcutaneously administering multiple separate maintenance doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg, wherein the separate maintenance doses are administered at 4-week intervals, and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 6; The sequence shown in NO: 7; and LCDR3, which has the sequence shown in SEQ ID NO: 8. 151. An anti-TL1A antibody for use in treating a patient with inflammatory bowel disease (IBD), wherein an effective amount of the anti-TL1A antibody is administered to a subject in a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen, wherein: (a) the induction dosing regimen comprises a plurality of individual induction doses, wherein the individual induction doses are spaced apart from each other for at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks; and (b) the maintenance dosing regimen comprises subcutaneous administration of a plurality of individual maintenance doses of the anti-TL1A antibody at a dose of about 450 mg, wherein the individual maintenance doses are administered at 4-week intervals, and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; and HCDR3 having the sequence shown in SEQ ID NO: 5.LCDR1, having the sequence shown in SEQ ID NO: 6; LCDR2, having the sequence shown in SEQ ID NO: 7; and LCDR3, having the sequence shown in SEQ ID NO: 8. 152. Use of an anti-TL1A antibody in the manufacture of a medicament for treating a patient with IBD, wherein: (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, said assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) an effective amount of the anti-TL1A antibody is administered to the patient, wherein the patient has been identified as a haplotype B non-carrier. 153. Use of an anti-TL1A antibody in the manufacture of a medicament for treating a patient with IBD, wherein: (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; (b) the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising multiple individual induction doses, wherein the patient has been identified as a haplotype B non-carrier; and (c) the anti-TL1A antibody is administered to the patient in a subsequent maintenance dosing regimen after completion of the induction dosing regimen, the maintenance dosing regimen comprising at least 2 weeks intervals between each other. Multiple individual maintenance doses per week. 154. Use of anti-TL1A antibody in the manufacture of a medicament for treating patients with IBD, wherein: (a) a biological sample from said patient is to be genotyped to determine whether said patient is a haplotype B carrier or haplotype B non-carrier of TNFSF15, wherein said determination includes determining the presence of SNP rs3810936 and SNP rs7869487 in the biological sample from said patient, and wherein haplotype B non-carrier of TNFSF15 is identified by any of the following biomarker statuses from said biological sample from said patient: (i) the genotype of said sample relative to rs3810936(i) The genotype of the sample is homozygous for the reference allele at rs7869487 and homozygous for the alternative allele at rs3810936; (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) The genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487; and (b) An effective amount of the anti-TL1A antibody will be administered to the patient, who has been identified as a haplotype B non-carrier. 155. Use of an anti-TL1A antibody in the manufacture of a medicament for treating a patient with IBD, wherein an effective amount of the anti-TL1A antibody is administered to said patient, and wherein said patient has been identified as a haplotype B noncarrier against TNFSF15 by any of the following biomarker states from a biological sample of said patient: (i) the genotype of said sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) said genotype of said sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) said genotype of said sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487. (iv) The genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487. 156. Use of anti-TL1A antibody in the manufacture of a medicament for treating a patient with IBD, wherein: (a) genotyping is to be performed to determine whether the patient is a haplotype B carrier or a haplotype B carrier of TNFSF15.(b) A non-carrier, wherein the assay comprises determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) administering an effective amount of the anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier, and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO: 8. 157. Use of an anti-TL1A antibody in the manufacture of a medicament for treating a patient with IBD, wherein: (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, said assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) the anti-TL1A antibody is administered to the patient, wherein the patient has been determined to be a haplotype B non-carrier, and wherein said anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 37; HCDR2 having the sequence shown in SEQ ID NO: 39; HCDR3 having the sequence shown in SEQ ID NO: 41; LCDR1 having the sequence shown in SEQ ID NO: 46. The sequence shown; LCDR2, which has the sequence shown in SEQ ID NO: 48; and LCDR3, which has the sequence shown in SEQ ID NO: 50. 158. Use of an anti-TL1A antibody in the manufacture of a medicament for treating a patient with IBD, wherein an effective amount of the anti-TL1A antibody is administered to a subject in a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen; wherein the induction dosing regimen comprises a plurality of individual induction doses, and the maintenance dosing regimen comprises a plurality of individual maintenance doses; wherein the anti-TL1A antibody is administered subcutaneously during the maintenance phase, and wherein the anti-TL1A antibody comprises: HCDR1, which has the sequence shown in SEQ ID NO: 3The sequence shown; Claims 16 / 17, page 17, CN 121532526 A HCDR2, having the sequence shown in SEQ ID NO: 4; HCDR3, having the sequence shown in SEQ ID NO: 5; LCDR1, having the sequence shown in SEQ ID NO: 6; LCDR2, having the sequence shown in SEQ ID NO: 7; and LCDR3, having the sequence shown in SEQ ID NO: 8. 159. Use of an anti-TL1A antibody in the manufacture of a medicament for treating patients with IBD, wherein an effective amount of the anti-TL1A antibody is administered to a subject in a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen, wherein: (a) the induction dosing regimen comprises subcutaneously administering four separate induction doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg, wherein the separate induction doses are administered at 4-week intervals; and (b) the maintenance dosing regimen comprises subcutaneously administering multiple separate maintenance doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg, wherein the separate maintenance doses are administered at 4-week intervals, and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; and LCDR1 having the sequence shown in SEQ ID NO: 6. LCDR2, having the sequence shown in SEQ ID NO: 7; and LCDR3, having the sequence shown in SEQ ID NO: 8. 160. Use of an anti-TL1A antibody in the manufacture of a medicament for treating a patient with inflammatory bowel disease (IBD), wherein an effective amount of the anti-TL1A antibody is administered to a subject in a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen, wherein: (a) the induction dosing regimen comprises a plurality of individual induction doses, wherein the individual induction doses are spaced apart from each other for at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks; and (b) the maintenance dosing regimen comprises subcutaneous administration of a plurality of individual maintenance doses of the anti-TL1A antibody at a dose of about 450 mg, wherein the individual maintenance doses are administered at 4-week intervals, and wherein the anti-TL1A antibody comprises: HCDR1, having the sequence shown in SEQ ID NO: 3; HCDR2, having the sequence shown in SEQ ID NO: 4; HCDR3, having the sequence shown in SEQ ID NO: 5.The sequence shown; LCDR1, having the sequence shown in SEQ ID NO: 6; LCDR2, having the sequence shown in SEQ ID NO: 7; and LCDR3, having the sequence shown in SEQ ID NO: 8. Claims 17 / 17 pages 18 CN 121532526 A Anti-TL1A Antibody Treatment Method

[0001] Cross-Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 502,786, filed May 17, 2023, U.S. Provisional Application No. 63 / 647,481, filed May 14, 2024, and U.S. Provisional Application No. 63 / 649,269, filed May 17, 2024, the disclosures of which are incorporated herein by reference in their entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing, which has been submitted electronically in XML format and incorporated herein by reference in its entirety. The XML copy was created on May 17, 2024, named 50474-352WO4_Sequence_Listing_5_17_24, and is 75,503 bytes in size. Technical Field

[0005] The present invention relates to the treatment of signs and symptoms of inflammatory bowel disease with anti-tumor necrosis factor-like ligand 1A (TL1A) antibodies. Background Art

[0006] Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis (UC), is a chronic inflammatory disease affecting approximately 1.6 million people in the United States and approximately 2.5 million to 3 million people in Europe. To induce remission in patients with moderate to severe active UC, treatment recommendations include: oral corticosteroids at appropriate doses; biologics such as tumor necrosis factor inhibitors (TNFi) infliximab (as a monotherapy or in combination with azathioprine), adalimumab, ustekinumab, golimumab; integrin receptor antagonists vedozizumab; and oral small molecule Janus kinase inhibitor tofacitinib (Rubin et al., 2019 Am J Gastroenterol; 114:384-413). However, no response and loss of response to treatment have been observed in UC, therefore, the development of novel treatments for UC and IBD remains an unmet clinical need (Lichtenstein et al., 2018 Am J Gastroenterol; 113:481-517).

[0007] A range of mucosal immune system components, including epithelial cells, innate and adaptive immune cells, cytokines, and chemokines, promote IBD.The pathogenesis of IBD (Wallace et al., 2014, World J Gastroenterol; 20:6-21). One of the immune components involved in the pathogenesis of IBD is TNF-like ligand 1A (TL1A, or tissue necrosis factor superfamily member 15 (TNFSF15)). Genome-wide association studies have linked TNFSF15 single nucleotide polymorphisms to disease severity; for example, an association was observed between the rs11554257 single nucleotide polymorphism and drug-resistant UC compared to healthy controls (Haritunians et al., 2010, Inflammatory bowel diseases; 16: 1830-1840). TL1A has been found to be upregulated in IBD tissue samples, with expression levels corresponding to disease severity (Bamias et al., 2010, Clin Immunol; 137:242-249).

[0008] T cell-mediated signal transduction and cytokine production, for example, T helper (Th)1 cells that produce interferon-γ, Th17 cells that produce interleukin (IL)-6 and IL-17, and Th2 cells that produce IL-4 and IL-13 are co-stimulated by TL1A that binds to death receptor 3 (Migone et al., 2002, Immunity 16; 16:479-492; Takedatsu et al., 2008, Gastroenterology 135; 552-567; Meylan et al., 2011; Mucosal Immunity 4; 172-185; Meylan et al., 2008; Immunity 29; 79-89). Because increased cellular factor production leads to chronic inflammation, inhibition of TL1A may be a therapeutic target for inflammatory diseases, including IBD.

[0009] UC is a chronic inflammatory disease of the large intestine characterized by diffuse mucosal inflammation. The underlying pathophysiology of this disease is caused by the interaction of genetic susceptibility to immune genes and changes in the gut microbiome. Current treatments targeting the activation of immune cells in UC include non-selective drugs (such as corticosteroids, mesalazine, thiopurine) and selective biologics (anti-TNFα, anti-α4b7, and anti-IL-12 / 23 agents) and small molecule Janus kinase inhibitors. Despite these treatments, many patients show inadequate response on endoscopy and develop refractory disease. Therefore,There is an urgent need to develop therapeutic agents that drive gastrointestinal healing as determined by, for example, endoscopy (referred to as “endoscopic healing”) and to identify tissue, blood, and microbiome biomarkers to help guide therapy.

[0010] There remains an unmet need for effective, safe, and well-tolerated treatment in subjects with moderate to severe ulcerative colitis. The hallmark clinical symptoms of UC include bloody diarrhea with rectal urgency and tenesmus. The clinical course is marked by exacerbations and remissions. The diagnosis of UC is questionable on clinical grounds and is supported by diagnostic testing and elimination of infectious causes (Dignass et al., J Crohn's Colitis. 2012; 6(10):965-90). The most severe intestinal manifestations of UC are toxic megacolon and perforation. Extraintestinal complications include arthritis (peripheral or axial involvement), skin conditions (erythema nodosum, aphthous stomatitis, and pyoderma gangrenosa), ocular inflammation (uveitis), and liver dysfunction (primary sclerosing cholangitis). Subjects with UC have an increased risk of colon cancer, and the risk increases with the duration of the disease and the extent to which the colon is affected by the disease (Rutter et al., 2004 Gastroenterology; 126(2):451–9).

[0011] The goal of medical treatment for UC is to control inflammation and alleviate symptoms. The available drug therapies are limited, are not always able to completely eliminate the inflammatory process, and may have significant side effects. Therapies for mild to moderate active UC include 5-aminosalicylic acid derivatives and immunosuppressants.

[0012] Genome-wide association studies have linked more than 200 genes to IBD, many of which are associated with this underlying immune dysregulation (de Lange et al., 2017, Nat Genet.; 49(2): 256–610). One of the strongest genetic variants associated with IBD resides at the tumor necrosis factor superfamily member 15 (TNFSF15) locus (Siakavellas et al. 2015; Inflamm. Bowel Dis. 21 (10): 2441–52). Variants of TNFSF15 have been associated with the pathogenesis of a variety of autoimmune diseases, including psoriasis, rheumatoid arthritis, and multiple sclerosis, suggesting that TNFSF15 plays a broad role in human inflammatory diseases. In IBD, TNFSF15 variants may contribute to a higher risk of more aggressive, penetrating, fibrotic stenosis, and perianal complications (Yang et al. 2014 J Crohns Colitis; 8(10): 1315–26; Tung et al. 2014 J Gasteroenterl).Hepatol; 29(4):273-9). TNFSF15 encodes the protein TNF-like ligand 1A (TL1A), which is highly expressed in human colon tissue during active colitis (Bamias et al. 2013; Curr Opinion Gasteroenterol. 29(6): 597-602).

[0013] The mechanistic effects of TL1A in preclinical models are pleiotropic. While earlier studies have shown that TL1A overexpression plays a pathogenic role in driving inflammatory Th1, Th17, and group 2 innate lymphocyte responses, recent reports in mouse models of acute colitis and ileitis have revealed the opposite protective effect of endogenous TL1A in supporting the function of anti-inflammatory regulatory T cells (Tregs) and group 3 innate lymphocytes (Prehn et al., 2004, Clin Immunol 112(1):66–77; Castellanos et al., 2019; Mucosal Immunol .11(5): 1466–1476). In addition to its effects on lymphocytes, the mouse models have also revealed the crucial role of TL1A overexpression in intestinal fibrosis. Furthermore, in vitro studies using peripheral blood macrophages have revealed the contribution of the TNFSF15 risk haplotype in the co-regulation of NOD2 ligand-induced inflammatory cytokines (Hedl and Abraham, 2014; PNAS 111(37) 13451- 2 / 64 pages, CN 121532526 A 13456). In summary, these preclinical studies highlight the potential central homeostatic role of TL1A in regulating selective innate and adaptive immune pathways crucial for IBD and in key clinical complications of fibrosis. To date, no studies have clarified the mechanism of the potential effectiveness of anti-TL1A therapy in humans.

[0014] Preclinical studies using rodent colitis models and human cells have shown that anti-TL1A antibodies can reduce tissue fibrosis, fibroblast number, and clinical disease scores, thus highlighting their potential as a biotherapy for IBD (Clarke et al. 2002, MAbs 10:664-677; Shih et al. 2014 Mucosal Immunol; 7:1492-1503).

[0015] There is a need in the art for the use of anti-TNF-like ligand 1A (TL1A) antibody therapy to treat inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), and there is a need to identify patients who may or may not respond to such therapies. This disclosure addresses these needs. Summary of the Invention

[0016] This disclosure provides a method for determining the risk of a patient being unresponsive to a therapeutic dose of an anti-TNF-like ligand 1A (TL1A) antibody. The method includes genotyping a biological sample from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15. This genotyping includes determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in the biological sample from the patient, and determining the risk of unresponsiveness to the therapeutic dose of the anti-TL1A antibody, wherein the risk is higher in haplotype B carriers than in haplotype B non-carriers. The patient may have inflammatory bowel disease (IBD).

[0017] This disclosure provides a method for treating a patient with inflammatory bowel disease (IBD), the method comprising: (a) performing genotyping on a biological sample from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier against TNFSF15, the determination comprising determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in the biological sample from the patient; and (b) administering an anti-TNF-like ligand 1A (TL1A) antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier.

[0018] In some aspects, the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising multiple individual induction doses.

[0019] In some aspects, the anti-TL1A antibody is administered to the patient in a maintenance dosing regimen after completion of the induction dosing regimen, the maintenance dosing regimen comprising multiple individual maintenance doses spaced at least 2 weeks apart from each other.

[0020] In some aspects, this disclosure is characterized by a method for treating a patient with IBD, the method comprising: (a) performing a genotyping assay to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) administering the anti-TL1A antibody to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD at least 12 weeks after initiation of treatment with the anti-TL1A antibody.TL1A antibody, the induction dosing regimen comprising multiple individual induction doses, wherein the patient has been identified as a haplotype B non-carrier; and (c) administering a subsequent maintenance dosing regimen to the patient after completion of the induction dosing regimen, the maintenance dosing regimen comprising multiple individual maintenance doses spaced at least 2 weeks apart from each other.

[0021] IBD may be ulcerative colitis (UC). UC may be moderate to severe ulcerative colitis. In some aspects, specification 3 / 64 page 21 CN 121532526 A IBD is Crohn's disease (CD).

[0022] In a preferred aspect, the at least two SNPs are SNP rs3810936 and SNP rs7869487.

[0023] In some aspects, genotyping includes determining the presence of only two SNPs in a biological sample from the patient, wherein the two SNPs are SNP rs3810936 and SNP rs7869487.

[0024] In some aspects, a patient is identified as a non-carrier of haplotype B by any of the following biomarker states from a biological sample of that patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) the genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487.

[0025] In some aspects, (a) genotyping includes determining the presence of SNPs rs3810936, rs7869487, and rs7848647 in a biological sample from a patient; or (b) genotyping includes determining the presence of SNPs rs3810936, rs7869487, and rs6478109 in a biological sample from a patient.

[0026] In some aspects, genotyping includes determining the presence of SNPs rs3810936, rs7869487, and rs6478109 in a biological sample from a patient.The presence of rs7869487, SNP rs6478108, and SNP rs6478109.

[0027] Genotyping may include qPCR. Genotyping may include sequencing. Genotyping may include long-range sequencing or long-read sequencing. Genotyping may be performed on a microarray. In some aspects, genotyping is a fluorescence-based assay.

[0028] The biological sample may be any sample obtained from the patient. The biological sample may be a cell sample or a tissue sample. The tissue sample may be from the site of IBD inflammation. The biological sample may be an intestinal biopsy sample. The biological sample may be a blood sample. The biological sample may be oral cells or tissue. Oral cells or tissue may be obtained by oral swabs. Preferably, the biological sample is blood or oral cells or tissue.

[0029] In another aspect, this disclosure is characterized by a method for determining the risk of a patient being unresponsive to a therapeutic dose of an anti-TL1A antibody, wherein the patient has inflammatory bowel disease (IBD), the method comprising: (a) performing genotyping on a biological sample from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, wherein the determination comprises determining the presence of SNPs rs3810936 and rs7869487 in the biological sample from the patient, and wherein a haplotype B non-carrier of TNFSF15 is identified by any of the following biomarker states from the biological sample from the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) The sample's genotype is homozygous for the alternative allele at rs7869487 and homozygous for the alternative allele at rs3810936; (iv) The sample's genotype is homozygous for the alternative allele at rs3810936 and heterozygous for the alternative allele at rs7869487; or (v) The sample's genotype is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487; and (b) If the patient is a carrier of haplotype B, the patient is identified as having a high risk of not responding to therapeutic doses of anti-TL1A antibodies; or (c) If the patient is haplotype BFor non-carriers, the patient is identified as having low risk of not responding to therapeutic doses of anti-TL1A antibody. In some aspects, the patient has been identified as a haplotype B non-carrier of TNFSF15, and the method further includes administering an effective amount of anti-TL1A antibody to the patient. In some aspects, the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of anti-TL1A antibody treatment, the induction dosing regimen comprising multiple individual induction doses. In some aspects, the anti-TL1A antibody is administered to the patient in a maintenance dosing regimen after completion of the induction dosing regimen, the maintenance dosing regimen comprising multiple individual maintenance doses spaced at least 2 weeks apart from each other.

[0030] In another aspect, this disclosure features a method for treating a patient with IBD, the method comprising: (a) performing genotyping on a biological sample from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, wherein the determination comprises determining the presence of SNP rs3810936 and SNP rs7869487 in the biological sample from the patient, and wherein a haplotype B non-carrier of TNFSF15 is identified by any of the following biomarker states from the biological sample from the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and heterozygous for the alternative allele at rs7869487. (iii) The sample genotype is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) The sample genotype is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The sample genotype is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487; and (b) The patient is given an effective amount of anti-TL1A antibody, wherein the patient has been identified as a haplotype B non-carrier. In some respects, the anti-TL1A antibody was administered to the patient using an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of anti-TL1A antibody treatment, the induction dosing regimen comprising multiple individual induction doses. In some respects,After the induction dosing regimen is completed, the anti-TL1A antibody is administered to the patient in a maintenance dosing regimen consisting of multiple individual maintenance doses spaced at least 2 weeks apart.

[0031] In another aspect, this disclosure is characterized by a method for treating a patient with IBD, the method comprising administering an effective amount of anti-TL1A antibody to the patient; wherein the patient has been identified as a haplotype B non-carrier of TNFSF15 by any of the following biomarker states from a biological sample of the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) the genotype of the sample is homozygous for the reference ...3810936 and homozygous for the reference allele at rs7869487; (iv) the genotype of the sample is homozygous for the reference allele at rs7869487; (iii) the genotype of the sample is homozygous for the reference allele at rs7869487; (iv) the genotype of the sample is homozygous for the reference allele at rs7869487; (iv) the genotype of the reference allele at rs7869487 and homozygous for the reference allele at rs7869 The alternative allele at rs7869487 is homozygous and heterozygous for the reference allele at rs7869487; or (v) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487. In some aspects, the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising multiple individual induction doses. In some aspects, the anti-TL1A antibody is administered to the patient in a maintenance dosing regimen after completion of the induction dosing regimen, the maintenance dosing regimen comprising multiple individual maintenance doses spaced at least 2 weeks apart from each other. Instructions for Use, page 5 / 64, CN 121532526 A

[0032] The induction dose alone may be administered at least daily, at least one day apart, at least one week apart, at least two weeks apart, at least three weeks apart, at least four weeks apart, at least five weeks apart, at least six weeks apart, at least seven weeks apart, at least eight weeks apart, at least nine weeks apart, at least ten weeks apart, at least eleven weeks apart, or at least twelve weeks apart. In a preferred aspect, the induction dose alone is administered one month apart. In some aspects, the induction dose alone is administered four weeks apart.

[0033] The induction dose alone may be 1, 5, 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500,550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg. In a preferred aspect, the individual induction dose is 50, 150, or 450 mg. In some aspects, each of the individual induction doses is administered at a dose of 50 mg. In some aspects, each of the individual induction doses is administered at a dose of 150 mg. In some aspects, each of the individual induction doses is administered at a dose of 450 mg.

[0034] The individual induction doses may be administered by any means. Preferably, the individual induction doses are administered intravenously or subcutaneously. In some aspects, each of the individual induction doses is administered subcutaneously.

[0035] In some aspects, the induction dosing regimen comprises four individual induction doses.

[0036] In some aspects, the induction dosing regimen comprises four individual induction doses administered at 4-week intervals, wherein each of the individual induction doses is administered subcutaneously at a dose of 50, 150, or 450 mg.

[0037] The maintenance dose alone may be administered at least daily, at least one day apart, at least one week apart, at least two weeks apart, at least three weeks apart, at least one month apart, at least two months apart, at least three months apart, at least four months apart, at least five months apart, or at least six months apart. In a preferred aspect, the maintenance dose alone is administered at one-month intervals. In some aspects, the maintenance dose alone is administered at four-week intervals.

[0038] The maintenance dose alone may be 1, 5, 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg. In a preferred aspect, the maintenance dose alone is 50, 150, or 450 mg. In some aspects, each of the individual maintenance doses is administered at a dose of 50 mg. In some aspects, each of the individual maintenance doses is administered at a dose of 150 mg. In some aspects, each of the individual maintenance doses is administered at a dose of 450 mg.

[0039] The individual maintenance doses may be administered by any means. Preferably, the individual maintenance doses are administered intravenously or subcutaneously. In some aspects, each of the individual maintenance doses is administered subcutaneously.

[0040] In some aspects, the maintenance dosing regimen comprises at least ten individual maintenance doses.

[0041] In some aspects, the induction dosing regimen comprises ten individual maintenance doses administered at 4-week intervals, wherein each of these individual maintenance doses is administered subcutaneously at a dose of 50, 150, or 450 mg. In some aspects, each of the individual maintenance doses is administered subcutaneously at a dose of 450 mg.

[0042] The method provided herein may further include: (a) determining the expression levels of one or more candidate genes in a biological sample from a patient, and (b) identifying one or more candidate genes with aberrant expression levels in the biological sample. The one or more candidate genes are selected from the group consisting of: SOWAHB, COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, PKDREJ, IL-1B, IL-23A, IFNG, IL-12RB1, IL-21R, IRF4, BATF, CD80 / 86, HLA-DRB5 / DQB1 / DRB1, HLA-DRA, CD40, ICOS, MMP3, MMP7, MMP10, and CHI3L. In a preferred aspect, the one or more candidate genes are selected from the group consisting of: SOWAHB, COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, and PKDREJ. The expression levels of one or more candidate genes can be compared to baseline expression levels, which are a) based on the expression levels of one or more candidate genes in healthy individuals who have not developed IBD or UC; or b) based on estimated expression levels in individuals who are unresponsive to anti-TL1A antibody treatment. The aberrant expression levels of one or more candidate genes can be at least 50% higher or lower than baseline levels.

[0043] The disclosed method may further include: (a) determining the expression levels of one or more candidate bacterial strains in a fecal sample from a patient; and (b) identifying whether the sample contains one or more candidate bacterial strains at increased or decreased levels. In one aspect, the candidate bacterial strain level may be increased, and the candidate bacterial strain is selected from the group consisting of: *Streptococcus salivarius*, *Streptococcus parasanguinis*, and *Haemophilus parainfluenzae*. In one respect, the level of candidate bacterial strains may be reduced, and the candidate bacterial strains are selected from the group consisting of: *Ruminococcus albus*, *Ruminococcus callidus*, *Ruminococcus bromii*, *Ruminococcus gnavus*, and *Bifidobacterium bifidum*.

[0044] On the other hand, this disclosure features a method for treating a patient with inflammatory bowel disease (IBD), the method comprising: (a) performing a genotyping assay to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) administering an effective amount of an anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier; wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; and LCDR1 having the sequence shown in SEQ ID NO: 6. The sequence shown; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3, which has the sequence shown in SEQ ID NO: 8. In some aspects, the at least two SNPs are SNP rs3810936 and SNP rs7869487. In some aspects, the assay includes determining the presence of only two SNPs in a biological sample from a patient, wherein the two SNPs are SNP rs3810936 and SNP rs7869487.

[0045] The antibody may be any anti-TL1A antibody. Examples include, but are not limited to, afimizumab from Pfizer / Roivant (also known as PF-06480605 or RVT-3101), PRA023 from Prometheus Biosciences (also known as tusozibazumab), and CO3V from Teva Pharmaceuticals. In one aspect, the anti-TL1A antibody comprises: a variable heavy chain region having the sequence shown in SEQ ID NO: 1; and a variable light chain region having the sequence shown in SEQ ID NO: 2. The anti-TL1A antibody may comprise three CDRs from the variable heavy chain region having the sequence shown in SEQ ID NO: 1; and three CDRs from the variable light chain region having the sequence shown in SEQ ID NO: 2. The anti-TL1A antibody may comprise: HCDR1 having the sequence shown in SEQ ID NO: 3 or SEQ ID NO: 68; HCDR2 having the sequence shown in SEQ ID NO: 3; and HCDR2 having the sequence shown in SEQ ID NO: 68.The anti-TL1A antibody comprises: the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO: 8 (e.g., may include CDR sequences according to SEQ ID NO: 3 to 8, or may include CDR sequences according to SEQ ID NO: 4 to 8 and 68). In some aspects, the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 9; and a light chain having the sequence shown in SEQ ID NO: 10. In some aspects, the anti-TL1A antibody is afimizumab.

[0046] The anti-TL1A antibody may comprise sequence pairs selected from the group consisting of: SEQ ID NO: 2 and 11; SEQ ID NO: 2 and 12; SEQ ID NO: 2 and 13; SEQ ID NO: 2 and 14; SEQ ID NO: 2 and 15; SEQ ID NO: 2 and 16; SEQ ID NO: 2 and 17; SEQ ID NO: 2 and 18; SEQ ID NO: 2 and 19; SEQ ID NO: 20 and 24; SEQ ID NO: 21 and 25; SEQ ID NO: 22 and 26; SEQ ID NO: 23 and 27; SEQ ID NO: 28 and 29; SEQ ID NO: 30 and 31; SEQ ID NO: 32 and 33; SEQ ID NO: 35 and 44; SEQ ID NO: 53 and 54; SEQ ID NO: 61 and 62; SEQ ID NO: 63 and 64; SEQ ID NO: 65, page 7 / 64, CN 121532526 A and 64; SEQ ID NO: 66 and 64; and SEQ ID NO: 67 and 64.

[0047] In some aspects, the anti-TL1A antibody comprises three CDRs from a variable heavy chain region having the sequence shown in SEQ ID NO: 53; and three CDRs from a variable light chain region having the sequence shown in SEQ ID NO: 54. In some aspects, the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 37; HCDR2 having the sequence shown in SEQ ID NO: 39.The sequence shown is: HCDR3, having the sequence shown in SEQ ID NO: 41; LCDR1, having the sequence shown in SEQ ID NO: 46; LCDR2, having the sequence shown in SEQ ID NO: 48; and LCDR3, having the sequence shown in SEQ ID NO: 50. In some aspects, the anti-TL1A antibody comprises: a variable heavy chain region having the sequence shown in SEQ ID NO: 53; and a variable light chain region having the sequence shown in SEQ ID NO: 54. In some aspects, the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 35; and a light chain having the sequence shown in SEQ ID NO: 44. In some aspects, the anti-TL1A antibody is tusozymeab.

[0048] In another aspect, this disclosure is characterized by a method for treating a patient with inflammatory bowel disease (IBD), the method comprising: (a) performing a genotyping assay to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier against TNFSF15, the assay comprising determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) administering an anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier; wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 37; HCDR2 having the sequence shown in SEQ ID NO: 39; HCDR3 having the sequence shown in SEQ ID NO: 41; LCDR1 having the sequence shown in SEQ ID NO: 41; and LCDR1 having the sequence shown in SEQ ID NO: 41. The sequence shown in SEQ ID NO: 46; LCDR2, having the sequence shown in SEQ ID NO: 48; and LCDR3, having the sequence shown in SEQ ID NO: 50. In some aspects, the at least two SNPs are SNP rs3810936 and SNP rs7869487. In some aspects, the assay includes determining the presence of only two SNPs in the biological sample from the patient, wherein the two SNPs are SNP rs3810936 and SNP rs7869487. The disclosed treatment method may further include treatment with an IL-23 antagonist.

[0049] In another aspect, this disclosure is characterized by a method for treating a patient with inflammatory bowel disease (IBD), which...The method includes administering an effective amount of anti-TNF-like ligand 1A (TL1A) antibody to the patient using a dosing regimen that includes an induction dosing regimen and a subsequent maintenance dosing regimen; wherein the induction dosing regimen includes multiple individual induction doses, and the maintenance dosing regimen includes multiple individual maintenance doses; wherein the anti-TL1A antibody is administered subcutaneously during the maintenance phase, and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO: 8.

[0050] In some aspects, the individual induction doses are spaced at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks apart. In some aspects, the individual induction doses are spaced at least 1 month apart. In some aspects, the individual induction doses are administered at 4-week intervals.

[0051] In some aspects, the individual induction doses are administered intravenously or subcutaneously. In some aspects, each of the individual induction doses is administered subcutaneously.

[0052] In some aspects, the individual induction doses are administered at 50, 150, or 450 mg. In some aspects, each of the individual induction doses is administered at a dose of 50 mg. In some aspects, each of the individual induction doses is administered at a dose of 150 mg. In some aspects, each of the individual induction doses is administered at a dose of 450 mg. Specification 8 / 64 pages 26 CN 121532526 A

[0053] In some aspects, the induction dosing regimen includes four individual induction doses.

[0054] In some aspects, the induction dosing regimen includes four individual induction doses administered at 4-week intervals, wherein each of the individual induction doses is administered subcutaneously at a dose of 50, 150, or 450 mg.

[0055] In some aspects, the maintenance doses are administered at intervals of at least 2 weeks, at least 3 weeks, or at least 4 weeks. In some aspects, the maintenance doses are administered at intervals of at least 1 month. In some aspects, the maintenance doses are administered at intervals of 4 weeks.

[0056] In some aspects, the maintenance doses are administered at 50, 150, or 450 mg. In some aspects, each of the maintenance doses is administered at a dose of 50 mg. In some aspects, each of the maintenance doses is administered at a dose of 150 mg. In some aspects, each of the maintenance doses is administered at a dose of 450 mg.

[0057] In some aspects, the maintenance dosing regimen includes at least ten individual maintenance doses. In some aspects, the induction dosing regimen includes ten individual maintenance doses administered at 4-week intervals, wherein each of these individual maintenance doses is administered subcutaneously at a dose of 50, 150, or 450 mg. In some aspects, each of the individual maintenance doses is administered subcutaneously at a dose of 450 mg.

[0058] In another aspect, this disclosure is characterized by a method of treating a patient with inflammatory bowel disease (IBD), the method comprising administering an effective amount of an anti-TNF-like ligand 1A (TL1A) antibody to the patient in a dosing regimen including an induction dosing regimen and a subsequent maintenance dosing regimen; wherein (a) the induction dosing regimen comprises subcutaneously administering four separate induction doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg, wherein these separate induction doses are administered at 4-week intervals; and (b) the maintenance dosing regimen comprises subcutaneously administering multiple separate maintenance doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg, wherein these separate maintenance doses are administered at 4-week intervals; and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 5; The sequence shown in SEQ ID NO: 6; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3, which has the sequence shown in SEQ ID NO: 8.

[0059] In another aspect, this disclosure is characterized by a method of treating a patient with inflammatory bowel disease (IBD), the method comprising administering an effective amount of an anti-TNF-like ligand 1A (TL1A) antibody to the patient in a dosing regimen including an induction dosing regimen and a subsequent maintenance dosing regimen; wherein (a) the induction dosing regimen includes a plurality of individual induction doses, wherein these individual induction doses are spaced apart from each other for at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks; and (b) the maintenance dosing regimen includes subcutaneous administration of a plurality of individual maintenance doses of the anti-TL1A antibody at a dose of about 450 mg, wherein these individual maintenance doses are administered at 4-week intervals; and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; and LCDR1 having the sequence shown in SEQ ID NO: 6.The sequence shown is: LCDR2, having the sequence shown in SEQ ID NO: 7; and LCDR3, having the sequence shown in SEQ ID NO: 8. In some aspects, the induction dosing regimen comprises subcutaneous administration of four separate induction doses of the anti-TL1A antibody at a dose of about 450 mg, wherein these separate induction doses are administered at 4-week intervals.

[0060] In some aspects, the first dose of the maintenance phase is administered about two weeks after the administration of the final dose of the induction phase.

[0061] In some aspects, the dosing regimen has a duration of about 52 weeks.

[0062] In some aspects, the anti-TL1A antibody comprises: a variable heavy chain region having the sequence shown in SEQ ID NO: 1; and a variable light chain region having the sequence shown in SEQ ID NO: 2. In some aspects, the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 9; and a light chain having the sequence shown in SEQ ID NO: 10. In some aspects, the anti-TL1A antibody is afimizumab. Instructions for Use, Page 9 / 64, 27 CN 121532526 A

[0063] In some aspects, the patient has been identified as a haplotype B non-carrier of TNFSF15.

[0064] In some aspects, IBD is ulcerative colitis (UC). In some aspects, UC is moderate to severe UC.

[0065] In some aspects, in the patient population treated according to the method, the treatment results in an increased proportion of patients who have achieved clinical remission at the end of the induction phase compared to the reference population. In some aspects, the induction phase has a duration of about 14 weeks, and the treatment results in an increased proportion of patients who have achieved clinical remission at week 14. In some aspects, at least about 15% of the patients in the patient population have achieved clinical remission at week 14. In some aspects, at least about 40% of the patients in the patient population have achieved clinical remission at week 14.

[0066] In some aspects, in the patient population treated according to the method, the treatment results in an increased proportion of patients who have achieved clinical remission at the end of the maintenance phase compared to the reference population. In some aspects, the dosing regimen has a duration of approximately 56 weeks, and the treatment results in an increased proportion of patients who have achieved clinical remission by week 56. In some aspects, at least approximately 20% of the patient population has achieved clinical remission by week 56. In some aspects, at least approximately 55% of the patient population has achieved clinical remission by week 56.

[0067] In some aspects, clinical remission is defined as a total Mayo score ≤ 2 with no individual sub-score > 1. In some aspects, IBD is UC, and clinical remission is modified.Mayo score (mMS) ≤ 2, with stool frequency subscore (SFS) = 0 or 1, rectal bleeding subscore (RBS) = 0, and endoscopy score (ES) = 0 or 1.

[0068] In some aspects, in the patient population treated according to the method, the treatment resulted in an increased proportion of patients who had achieved endoscopic improvement at the end of the induction phase compared to the reference population. In some aspects, the induction phase lasted for about 14 weeks, and the treatment resulted in an increased proportion of patients who had achieved endoscopic improvement at week 14. In some aspects, at least about 25% of the patients in the patient population achieved endoscopic improvement at week 14. In some aspects, at least about 50% of the patients in the patient population achieved endoscopic improvement at week 14.

[0069] In some aspects, in the patient population treated according to the method, the treatment resulted in an increased proportion of patients who had achieved endoscopic improvement at the end of the maintenance phase compared to the reference population. In some aspects, the dosing regimen has a duration of approximately 56 weeks, and the treatment results in an increased proportion of patients who have achieved endoscopic improvement at week 56. In some aspects, at least approximately 20% of the patients in the patient population have achieved endoscopic improvement at week 56. In some aspects, at least approximately 65% ​​of the patients in the patient population have achieved endoscopic improvement at week 56.

[0070] In some aspects, clinical remission is defined as an endoscopic score of 0 or 1.

[0071] In some aspects, in the patient population treated according to the method, compared to the reference population, the treatment results in an increased proportion of patients who have achieved endoscopic remission, clinical response, symptom relief, or deep remission at the end of the induction phase.

[0072] In some aspects, in the patient population treated according to the method, compared to the reference population, the treatment results in an increased proportion of patients who have achieved endoscopic remission, clinical response, symptom relief, or deep remission at the end of the maintenance phase.

[0073] In some aspects, the reference population is a patient population that has not been treated with anti-TL1A antibodies. In some aspects, the reference population is a patient population that has not been treated with placebo.

[0074] In another aspect, this disclosure features a kit comprising an anti-TNF-like ligand 1A (TL1A) antibody and a packaging insert containing instructions for using the antibody to treat a patient with inflammatory bowel disease (IBD) according to any of the methods provided herein.

[0075] In another aspect, this disclosure features an anti-TL1A antibody for use in treating a patient with IBD, wherein (a) genotyping is to be performed to determine whether the patient is a haplotype B carrier or haplotype B against TNFSF15.(a) Non-carrier, the assay includes determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647 and rs7869487 in a biological sample from the patient; and (b) administering an effective amount of the anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier.

[0076] In another aspect, this disclosure features an anti-TL1A antibody for use in treating a patient with IBD, wherein (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; (b) the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising multiple individual induction doses, wherein the patient has been identified as a haplotype B non-carrier; and (c) the anti-TL1A antibody is administered to the patient in a subsequent maintenance dosing regimen after completion of the induction dosing regimen. The antibody, and the maintenance dosing regimen consists of multiple individual maintenance doses spaced at least 2 weeks apart from each other.

[0077] In another aspect, this disclosure features an anti-TL1A antibody for use in treating a patient with IBD, wherein (a) a biological sample from the patient is to be genotyped to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, wherein the determination includes determining the presence of SNP rs3810936 and SNP rs7869487 in the biological sample from the patient, and wherein a haplotype B non-carrier of TNFSF15 is identified by either of the following biomarker states from the biological sample from the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and heterozygous for the alternative allele at rs7869487. (iii) The sample genotype is homozygous for the alternative allele at rs3810936 and for the alternative allele at rs3810936.(iv) The genotype of the sample is homozygous for the alternative allele at rs7869487 and heterozygous for the reference allele at rs3810936; or (v) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487; and (b) An effective amount of the anti-TL1A antibody is to be administered to the patient, who has been identified as a haplotype B non-carrier.

[0078] In another aspect, this disclosure features an anti-TL1A antibody for use in treating a patient with IBD, wherein an effective amount of the anti-TL1A antibody is to be administered to the patient; wherein the patient has been identified as a haplotype B non-carrier of TNFSF15 by any of the following biomarker states from a biological sample of the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) The sample genotype is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) the sample genotype is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487.

[0079] In another aspect, this disclosure is characterized by an anti-TL1A antibody for use in treating a patient with IBD, wherein: (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) an effective amount of the anti-TL1A antibody is administered to the patient, wherein the patient has been identified as a haplotype B non-carrier; wherein the anti-TL1A antibody comprises: HCDR1, which has SEQ ID NOW 10 ...The sequence shown in SEQ ID NO: 3; HCDR2, which has the sequence shown in SEQ ID NO: 4; HCDR3, which has the sequence shown in SEQ ID NO: 5; LCDR1, which has the sequence shown in SEQ ID NO: 6; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3, which has the sequence shown in SEQ ID NO: 8.

[0080] In another aspect, this disclosure features an anti-TL1A antibody for use in treating a patient with IBD, wherein (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) the anti-TL1A antibody is administered to the patient, wherein the patient has been identified as a haplotype B non-carrier; wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 37; HCDR2 having the sequence shown in SEQ ID NO: 39; HCDR3 having the sequence shown in SEQ ID NO: 41; LCDR1 having the sequence shown in SEQ ID NO: 46. The sequence shown is: LCDR1, having the sequence shown in SEQ ID NO: 48; and LCDR3, having the sequence shown in SEQ ID NO: 50.

[0081] In another aspect, the present disclosure is characterized by an anti-TL1A antibody for use in treating a patient with IBD, wherein an effective amount of the anti-TL1A antibody is administered to a subject in a dosing regimen including an induction dosing regimen and a subsequent maintenance dosing regimen; wherein the induction dosing regimen includes a plurality of individual induction doses, and the maintenance dosing regimen includes a plurality of individual maintenance doses; wherein the anti-TL1A antibody is administered subcutaneously during the maintenance phase, and wherein the anti-TL1A antibody comprises: HCDR1, having the sequence shown in SEQ ID NO: 3; HCDR2, having the sequence shown in SEQ ID NO: 4; HCDR3, having the sequence shown in SEQ ID NO: 5; LCDR1, having the sequence shown in SEQ ID NO: 6; LCDR2, having the sequence shown in SEQ ID NO: 7; and LCDR3, having the sequence shown in SEQ ID NO: 8.

[0082] On the other hand, this disclosure features an anti-TL1A antibody for use in the treatment of patients with IBD, wherein an effective amount of the anti-TL1A antibody is administered to a subject via a dosing regimen including an induction dosing regimen and a subsequent maintenance dosing regimen, wherein (a) the induction dosing regimen comprises subcutaneous administration of four separate induction doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg, wherein these separate induction doses are administered at 4-week intervals; and (b) the maintenance dosing regimen comprises subcutaneous administration of multiple separate maintenance doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg, wherein these separate maintenance doses are administered at 4-week intervals, and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 6; and LCDR3 having the sequence shown in SEQ ID NO: 4. The sequence shown in NO: 7; and LCDR3, which has the sequence shown in SEQ ID NO: 8.

[0083] In another aspect, this disclosure features an anti-TL1A antibody for use in the treatment of patients with inflammatory bowel disease (IBD), wherein an effective amount of the anti-TL1A antibody is administered to a subject in a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen, wherein: (a) the induction dosing regimen comprises a plurality of individual induction doses, wherein these individual induction doses are spaced apart from each other for at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks; and (b) the maintenance dosing regimen comprises the subcutaneous administration of a plurality of individual maintenance doses of the anti-TL1A antibody at a dose of about 450 mg, wherein these individual maintenance doses are administered at 4-week intervals, and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3 (page 12 / 64 of specification, 30 CN 121532526 A NO: 3); HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6. The sequence shown; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3, which has the sequence shown in SEQ ID NO: 8.

[0084] In another aspect, the present disclosure is characterized in that the anti-TL1A antibody is used in the manufacture of a drug for treating patients with IBD.The use of the substance, wherein: (a) a genotyping assay is to be performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647 and rs7869487 in a biological sample from the patient; and (b) an effective amount of the anti-TL1A antibody is to be administered to the patient, wherein the patient has been identified as a haplotype B non-carrier.

[0085] In another aspect, this disclosure is characterized by the use of an anti-TL1A antibody in the manufacture of a medicament for treating a patient with IBD, wherein (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; (b) the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising multiple individual induction doses, wherein the patient has been identified as a haplotype B non-carrier; and (c) the anti-TL1A antibody is administered to the patient in a subsequent maintenance dosing regimen after completion of the induction dosing regimen. The antibody, and the maintenance dosing regimen consists of multiple individual maintenance doses spaced at least 2 weeks apart from each other.

[0086] In another aspect, this disclosure is characterized by the use of the anti-TL1A antibody in the manufacture of a medicament for treating a patient with IBD, wherein: (a) a biological sample from the patient is to be genotyped to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, wherein the determination includes determining the presence of SNPs rs3810936 and rs7869487 in the biological sample from the patient, and wherein a haplotype B non-carrier of TNFSF15 is identified by any of the following biomarker states from the biological sample from the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and heterozygous for the alternative allele at rs7869487. (iii) The alternative allele at the location is homozygous;(iv) The sample’s genotype is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; or (v) The sample’s genotype is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; and (b) An effective amount of the anti-TL1A antibody is to be administered to the patient, who has been identified as a haplotype B noncarrier.

[0087] In another aspect, this disclosure is characterized by the use of the anti-TL1A antibody in the manufacture of a medicament for treating a patient with IBD, wherein an effective amount of the anti-TL1A antibody is to be administered to the patient, and wherein the patient has been identified as a haplotype B non-carrier of TNFSF15 by any of the following biomarker states from a biological sample of the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487. (See page 13 / 64 of the specification, 31 CN) 121532526 A The reference allele is homozygous; (iv) The sample genotype is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The sample genotype is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487.

[0088] In another aspect, this disclosure is characterized by the use of the anti-TL1A antibody in the manufacture of a medicament for treating a patient with IBD, wherein: (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) an effective amount of the anti-TL1A antibody is administered to the patient.The antibody, wherein the patient has been identified as a haplotype B non-carrier, and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO: 8.

[0089] In another aspect, this disclosure is characterized by the use of an anti-TL1A antibody in the manufacture of a medicament for treating a patient with IBD, wherein (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; and (b) the anti-TL1A antibody is administered to the patient, wherein the patient has been identified as a haplotype B non-carrier, and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 37; HCDR2 having the sequence shown in SEQ ID NO: 39; HCDR3 having the sequence shown in SEQ ID NO: 41; LCDR1 having the sequence shown in SEQ ID NO: 41; and LCDR1 having the sequence shown in SEQ ID NO: 41. The sequence shown in SEQ ID NO: 46; LCDR2, having the sequence shown in SEQ ID NO: 48; and LCDR3, having the sequence shown in SEQ ID NO: 50.

[0090] In another aspect, the present disclosure is characterized by the use of the anti-TL1A antibody in the manufacture of a medicament for treating patients with IBD, wherein an effective amount of the anti-TL1A antibody is administered to a subject in a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen; wherein the induction dosing regimen comprises a plurality of individual induction doses, and the maintenance dosing regimen comprises a plurality of individual maintenance doses; wherein the anti-TL1A antibody is administered subcutaneously during the maintenance phase, and wherein the anti-TL1A antibody comprises: HCDR1, having the sequence shown in SEQ ID NO: 3; HCDR2, having the sequence shown in SEQ ID NO: 4; HCDR3, having the sequence shown in SEQ ID NO: 5; LCDR1, having the sequence shown in SEQ ID NO: 6; and LCDR2, having the sequence shown in SEQ ID NO: 7.The sequence shown; and LCDR3, which has the sequence shown in SEQ ID NO: 8.

[0091] In another aspect, this disclosure is characterized by the use of an anti-TL1A antibody in the manufacture of a medicament for treating patients with IBD, wherein an effective amount of the anti-TL1A antibody is administered to a subject in a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen, wherein (a) the induction dosing regimen comprises subcutaneously administering four separate induction doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg, wherein these separate induction doses are administered at 4-week intervals; and (b) the maintenance dosing regimen comprises subcutaneously administering multiple separate maintenance doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg, wherein these separate maintenance doses are administered at 4-week intervals, and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; and LCDR1 having the sequence shown in SEQ ID NO: 6. The sequence shown; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3, which has the sequence shown in SEQ ID NO: 8. (See page 14 / 64 of the specification, CN 121532526 A).

[0092] In another aspect, this disclosure is characterized by the use of an anti-TL1A antibody in the manufacture of a medicament for treating a patient with inflammatory bowel disease (IBD), wherein an effective amount of the anti-TL1A antibody is administered to a subject in a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen, wherein (a) the induction dosing regimen comprises a plurality of individual induction doses, wherein these individual induction doses are spaced apart from each other for at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks; and (b) the maintenance dosing regimen comprises the subcutaneous administration of a plurality of individual maintenance doses of the anti-TL1A antibody at a dose of about 450 mg, wherein these individual maintenance doses are administered at 4-week intervals, and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7. The sequence shown; and LCDR3, which has the sequence shown in SEQ ID NO: 8.

[0093] In some respects, the patient is a person.

[0094] Any of the foregoing aspects or any other aspect described herein may be combined with any other aspect.

[0095] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In this specification, the singular form also includes the plural unless the context clearly requires otherwise; for example, the terms “a,” “an,” and “the” should be understood as singular or plural, and the term “or” should be understood as inclusive. By way of example, “an element” means one or more elements.

[0096] Although similar or equivalent methods and materials to those described herein may be used in practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. References cited herein are not considered prior art to the claimed invention. In case of conflict, this specification (including definitions) shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be limiting. Other features and advantages of this disclosure will become apparent from the following detailed description and claims.

[0097] Figure 1 is a diagram showing the locations of the five single nucleotide polymorphisms (SNPs) at the TNFSF15 locus.

[0098] Figure 2 is a schematic diagram showing the workflow of the TL1A 2-SNP test. qPCR = quantitative PCR.

[0099] Figure 3 is a schematic diagram showing the design of the TUSCANY-2 study. After the screening period, subjects received four monthly doses of afimizumab (50 mg, 150 mg, or 450 mg) during the 12-week induction period, followed by monthly doses of afimizumab (50 mg, 150 mg, or 450 mg) during the maintenance period. SC = subcutaneous. The endpoints assessed at weeks 14 and 56 were clinical remission and endoscopic improvement.

[0100] Figure 4A is a histogram showing the percentage of patients who received at least one dose of afimizumab or placebo during the induction phase of the TUSCANY-2 study and experienced clinical remission at week 14 (defined as modified Mayo score (mMS) ≤ 2, with stool frequency subscore (SFS) = 0 or 1, rectal bleeding subscore (RBS) = 0, and endoscopy score (ES) = 0 or 1). Unadjusted outcome rates with 90% confidence intervals are shown.

[0101] Figure 4B is a histogram showing the percentage of patients who received at least one dose of afimizumab or placebo during the induction phase of the TUSCANY-2 study and experienced endoscopic improvement at week 14.

[0101] Unadjusted outcome rates with 90% confidence intervals.

[0102] Figure 5 is a histogram showing the percentage of patients who received at least one dose of afimizumab or placebo during the maintenance phase of the TUSCANY-2 study and experienced clinical remission at week 14 or week 56 (defined as Mayo score (mMS) ≤ 2, stool frequency subscore (SFS) = 0 or 1, rectal bleeding subscore (RBS) = 0, and endoscopy score (ES) = 0 or 1). Unadjusted outcome rates with 90% confidence intervals are shown.

[0103] Figure 6 is a histogram showing the percentage of patients who received at least one dose of afimizumab or placebo during the maintenance phase of the TUSCANY-2 study and experienced endoscopic improvement at week 14 or week 56. The unadjusted outcome rates with 90% confidence intervals are shown.

[0104] Figure 7A is a set of histograms showing the percentage of patients who experienced clinical remission (based on modified Mayo score (mMS)) at week 14 during the induction phase of the TUSCANY-2 study treated with afimaziximab or placebo. Pbo: placebo. Biomarker positive: TNFSF15 haplotype B non-carrier.

[0105] Figure 7B is a set of histograms showing the percentage of patients who experienced endoscopic improvement at week 14 during the induction phase of the TUSCANY-2 study treated with afimaziximab or placebo. Pbo: placebo. Biomarker positive: TNFSF15 haplotype B non-carrier.

[0106] Figure 8A is a set of histograms showing the percentage of patients who experienced clinical remission at week 14 during the induction phase of the TUSCANY-2 study treated with afimaziximab or placebo. IR: Intolerance, inadequate response, or loss of response to prior advanced therapy (anti-tumor necrosis factor (TNF) agents, anti-integrin agents, anti-IL-12 / 23 agents, and / or Janus kinase (JAK) inhibitors). Non-IR: No failure of advanced therapy.

[0107] Figure 8B is a set of histograms showing the percentage of patients treated with afimazib or placebo during the induction phase of the TUSCANY-2 study who experienced endoscopic improvement at week 14. IR: Intolerance, inadequate response, or loss of response to prior advanced therapy (anti-tumor necrosis factor (TNF) agents, anti-integrin agents, anti-IL-12 / 23 agents, and / or Janus kinase (JAK) inhibitors). Non-IR: No failure of advanced therapy.

[0108] Figure 9AFigure 9B is a set of histograms showing the percentage of patients who experienced clinical remission at week 14 during the induction phase of the TUSCANY-2 study, treated with afimizumab or placebo. IR: Intolerance, inadequate response, or loss of response to previously administered anti-TNF therapy. Non-IR: No failure of anti-TNF therapy.

[0109] Figure 9B is a set of histograms showing the percentage of patients who experienced endoscopic improvement at week 14 during the induction phase of the TUSCANY-2 study, treated with afimizumab or placebo. IR: Intolerance, inadequate response, or loss of response to previously administered anti-TNF therapy. Non-IR: No failure of anti-TNF therapy.

[0110] Figure 10 is a set of histograms showing the percentage of biomarker-evaluable, biomarker-positive, and biomarker-negative patients who experienced clinical remission (left) or endoscopic improvement (right) at week 14 during the induction phase of the TUSCANY-2 study, treated with afimazibium or placebo. Biomarker-positive: TNFSF15 haplotype B non-carrier. Biomarker-negative: TNFSF15 haplotype B carrier. Unadjusted outcome rates with 90% confidence intervals are shown. Detailed Description

[0111] I. Clinical Management and Treatment Methods

[0112] A primary goal of emerging therapies is to leverage participants’ genomics and transcriptomics at baseline, which may help stratify and maximize treatment efficacy while minimizing risk. This disclosure provides methods for optimizing clinical management using anti-TL1A therapy. In some embodiments, the methods provided herein utilize anti-TL1A to optimize clinical management for the treatment of inflammatory bowel diseases, such as Crohn's disease (CD) or ulcerative colitis (UC), including any of the treatments described in Section II below and / or known in the art, such as U.S. Patent Nos. 10822422, 10138296, CN 121532526 A, US11292848, 9068003, 10590201, 9896511, 8642741, 9290576, and 8728482. The contents of each of the following patents, namely US8263743, US9416185, US10322174, US10689439, US11440954, US11220549, US11767364; US Patent Publication No. 2023 / 0235070 and US Patent Publication No. US20240059799A1, are incorporated herein by reference in their entirety. Any of the methods described in this section (i.e., Section I) may be used in conjunction with Section IV below.Treatment with any of the anti-TL1A antibodies described in Section IV.

[0113] A. TNFSF15 Haplotype and Risk of Non-Reactivity

[0114] In some aspects, any of the methods, uses, or compositions provided herein comprise determining a patient’s TNFSF15 haplotype (e.g., comprising determining whether the patient is (a) a TL1A haplotype B carrier or (b) a TL1A haplotype B non-carrier). These methods, uses, or compositions may further comprise making treatment decisions based on the patient’s TNFSF15 haplotype (e.g., deciding to administer an anti-TL1A antibody (e.g., the anti-TL1A antibody provided in Section IV herein, such as afimazibazumab, tusozibazumab, or TEV-48574) or an anti-DR3 antibody).

[0115] TNFSF15 haplotype B is defined as a TCATC on the positive strand at five single nucleotide polymorphism (SNP) sites rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 at the TL1A locus on chromosome 9, spanning a 28 kb region surrounding the TNFSF15 gene encoding TL1A (Figure 1). TNFSF15 haplotype B and other TNFSF15 haplotypes are shown in Table 1.

[0116] In Japanese and European cohorts, TNFSF15 haplotype B has been associated with disease susceptibility and / or TL1A expression. Data suggest that Jewish Crohn's disease (CD) patients who are haplotype B carriers have more severe disease. Phase 2a and 2b studies showed differential effects between haplotype B carrier and non-carrier subgroups. Data from internal UC studies support the specificity of haplotype B status in predicting responses to TL1A therapy.

[0117] TNFSF15 haplotype B noncarriers are any subjects who do not carry TCATC on the positive strand of chromosome 9 in their mother or father. Haplotype B noncarriers exhibit moderate TL1A tissue expression and an increased response to TL1A therapy.

[0118] TL1A haplotype determination can be accomplished using a 2-SNP assay. The two SNPs can be any two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 to distinguish haplotype B from non-haplotype B (carriers vs. noncarriers). In one instance, the two SNPs are rs3810936 and rs7869487. In a preferred aspect, SNPs rs3810936 and rs7869487It can distinguish between haplotype B and non-haplotype B (carriers and non-carriers). The determination can be made as follows: Step 1: Evaluate SNP rs7869487 in the biological sample from the patient. If (T / T), the patient is identified as a non-haplotype B carrier. If (C / C) or (C / T), proceed to Step 2. Step 2: Evaluate SNP rs3810936. If (C / C), the patient is identified as a non-haplotype B carrier. If (T / T) or (C / T), the patient is identified as a haplotype B carrier (probability >99%).

[0119] Table 1. TNFSF15 Haplotype B Single Nucleotide Polymorphism

[0120]

[0121] The average misclassification rate of the above 2-SNP analysis is extremely low and it is easy to use for clinical analysis. 41% of the US participants (with multiple ancestry) and those of European descent (total) were haplotype B carriers, with an average misclassification rate of approximately 0.5%. Participants of European descent had a higher frequency of haplotype B carriers compared to US participants (with multiple ancestry). 49.2% of participants of East and South Asian descent (total) were haplotype B carriers, with an average misclassification rate of approximately 1.6%. Participants of East Asian descent constituted the largest group of haplotype B carriers (approximately 66%). 8.32% of participants of African descent were haplotype B carriers, and no misclassifications were identified in this group. In the 2-SNP analysis assessment of the phase 2 study, 62 / 192 samples were heterozygous or homozygous for minor allele frequencies (MAF) at rs7869487 or rs3810936. All 62 subjects were considered haplotype B positive – 0% misclassification.

[0122] Method for determining the risk of non-responsiveness

[0123] This disclosure provides a method for determining the risk of a patient being unresponsive to a therapeutic dose of an anti-TNF-like ligand 1A (TL1A) antibody (e.g., an anti-TL1A antibody provided in Section IV herein, such as afimizumab, tusotiazumab, or TEV-48574) or an anti-DR3 antibody, the method comprising: (a) performing a genotyping assay on a biological sample from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient.The presence of at least two SNPs is determined, and (b) the risk of non-response to therapeutic doses of anti-TL1A or anti-DR3 antibodies is determined, wherein: (i) the risk is higher in haplotype B carriers than in haplotype B non-carriers; (ii) the risk of non-response is lower in haplotype B non-carriers than in haplotype B carriers; and / or (iii) the likelihood of response is higher in haplotype B non-carriers than in haplotype B carriers. The presence of at least two SNPs is determined to identify the patient as a haplotype B carrier. The patient may have inflammatory bowel disease (IBD). In a preferred aspect, the at least two SNPs are SNP rs3810936 and SNP rs7869487.

[0124] In another aspect, this disclosure provides a method for determining the risk of a patient being unresponsive to a therapeutic dose of an anti-TL1A antibody (e.g., an anti-TL1A antibody provided in Section IV herein, such as afimazibazumab, tusozibazumab, or TEV-48574) or an anti-DR3 antibody, the method comprising: (a) performing a genotyping assay on a biological sample from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two single nucleotide polymorphisms (SNPs) comprising r3810936 and rs7869487 in the biological sample from the patient, and (b) determining the risk of being unresponsive to a therapeutic dose of an anti-TL1A antibody or an anti-DR3 antibody, wherein: (i) the risk is higher in haplotype B carrier patients than in haplotype B non-carrier patients; and (ii) the risk of being unresponsive is lower in haplotype B non-carrier patients than in haplotype B patients. The likelihood of a patient responding to a therapeutic dose of an anti-TL1A antibody (e.g., an anti-TL1A antibody provided in Section IV herein, such as afimazibumab, tusoazibumab, or TEV-48574) or an anti-DR3 antibody is higher than that of a haplotype B carrier; and / or (iii) a haplotype B non-carrier patient is more likely to respond than a haplotype B carrier patient.

[0125] In another aspect, this disclosure provides a method for determining the risk of a patient not responding to a therapeutic dose of an anti-TL1A antibody (e.g., an anti-TL1A antibody provided in Section IV herein, such as afimazibumab, tusoazibumab, or TEV-48574) or an anti-DR3 antibody, the method comprising: (a) performing a genotyping assay on a biological sample from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of two single nucleotide polymorphisms (SNPs) r3810936 and rs7869487 in the biological sample from the patient, and (b) determining the risk of not responding to a therapeutic dose of an anti-TL1A antibody or an anti-DR3 antibody, wherein: (i) a haplotype B carrier patient is more likely to respond to a therapeutic dose of an anti-TL1A antibody or an anti-DR3 antibody; and / or (iii) a haplotype B non-carrier patient is more likely to respond to a therapeutic dose of an anti-TL1A antibody or an anti-DR3 antibody.(ii) The risk of non-response in haplotype B patients is higher than that in haplotype B non-carrier patients; and / or (iii) the likelihood of response in haplotype B non-carrier patients is higher than that in haplotype B carrier patients. Instructions for Use, Page 18 / 64, 36 CN 121532526 A

[0126] In one aspect, this disclosure provides a method for determining the risk of a patient being unresponsive to a therapeutic dose of an anti-TL1A antibody or an anti-DR3 antibody, the method comprising: (a) performing a genotyping assay on a biological sample from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, wherein the assay comprises determining the presence of SNP rs3810936 and SNP rs7869487 in the biological sample from the patient, and wherein a haplotype B non-carrier of TNFSF15 is identified by any of the following biomarker states from the biological sample from the patient:

[0127] (i) the genotype of the sample is homozygous for a reference allele at rs3810936 (i.e., the sample is T / T at rs3810936), and for rs7869487... The alternative allele at rs7869487 is homozygous (i.e., the sample is T / T at rs7869487);

[0128] (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 (e.g., the sample is C / T at rs3810936) and homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487);

[0129] (iii) The genotype of the sample is homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936) and homozygous for the reference allele at rs7869487 (i.e., the sample is C / C at rs7869487);

[0130] (iv) The genotype of the sample is heterozygous for the reference allele at rs3810936 (i.e., the sample is C / C at rs3810936); The alternative allele at rs3810936 is homozygous (i.e., the sample is C / C at rs3810936) and heterozygous for the reference allele at rs7869487 (e.g., the sample is T / C at rs7869487); or

[0131] (v) the genotype of the sample is homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936) and heterozygous for the reference allele at rs7869487 (i.e., the sample is T / C at rs7869487);(rs7869487 is T / T); and

[0132] (b) if the patient is a haplotype B carrier, the patient is identified as having a high risk of not responding to therapeutic doses of antiTL1A antibody or antiDR3 antibody; or (c) if the patient is a haplotype B non-carrier, the patient is identified as having a low risk of not responding to therapeutic doses of antiTL1A antibody or antiDR3 antibody.

[0133] Method for treating IBD based on TNFSF15 haplotype

[0134] In another aspect, this disclosure provides a method for treating a patient with inflammatory bowel disease (IBD), the method comprising: (a) performing a genotyping assay to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647 and rs7869487 in a biological sample from the patient; and (b) administering an effective amount of an anti-TL1A antibody (e.g., an anti-TL1A antibody provided in Section IV herein, such as afimazibazumab, tusoazibazumab or TEV-48574) or an anti-DR3 antibody to the patient, wherein the patient has been determined to be a haplotype B non-carrier.

[0135] In some embodiments, the anti-TL1A antibody is administered to the patient in an induction dosing regimen (e.g., administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising multiple individual induction doses).

[0136] In some embodiments, the anti-TL1A antibody is administered to the patient in a maintenance dosing regimen following the induction dosing regimen (e.g., administered to the patient in a maintenance dosing regimen after completion of the induction dosing regimen, the maintenance dosing regimen comprising multiple individual maintenance doses spaced at least 2 weeks apart from each other). Exemplary induction and maintenance dosing regimens are provided below in Section II.

[0137] Therefore, in some aspects, this disclosure provides a method for treating a patient with IBD, the method comprising: (a) performing a genotyping assay to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the assay comprising determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient; (b) to the extent sufficient to initiate the use of anti-An induction dosing regimen that improves signs and symptoms of IBD for at least 12 weeks after TL1A antibody treatment administers the anti-TL1A antibody to the patient, the induction dosing regimen comprising multiple individual induction doses, wherein the patient has been identified as a haplotype B non-carrier; and (c) administering a subsequent maintenance dosing regimen to the patient after completion of the induction dosing regimen, the maintenance dosing regimen comprising multiple individual maintenance doses spaced at least 2 weeks apart from each other.

[0138] In some embodiments, the at least two SNPs are SNP rs3810936 and SNP rs7869487. In some embodiments, the assay comprises determining the presence of only two SNPs in a biological sample from the patient, wherein the two SNPs are SNP rs3810936 and SNP rs7869487. At the position of SNP rs3810936, the wild-type nucleotide (“reference allele”) is “T”, and the alternative allele is “C”. At the position of SNP rs7869487, the wild-type nucleotide (“reference allele”) is “C”, and the alternative allele is “T”.

[0139] In some embodiments, haplotype B noncarriers of TNFSF15 are identified by any of the following biomarker states from a biological sample from a patient:

[0140] (i) the sample genotype is homozygous for the reference allele at rs3810936 (i.e., the sample is T / T at rs3810936) and homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487);

[0141] (ii) the sample genotype is heterozygous for the reference allele at rs3810936 (e.g., the sample is C / T at rs3810936) and homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487);

[0142] (iii) The sample genotype is homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936) and homozygous for the reference allele at rs7869487 (i.e., the sample is C / C at rs7869487);

[0143] (iv) The sample genotype is homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936) and heterozygous for the reference allele at rs7869487 (e.g., the sample is T / C at rs7869487); or

[0144] (v)The sample's genotype is homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936) and homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487).

[0145] In some embodiments, the at least two SNPs comprise SNP rs3810936, SNP rs7869487, and SNP rs7848647. In some embodiments, the assay comprises determining the presence of only three SNPs in a biological sample from a patient, wherein these three SNPs are SNP rs3810936, SNP rs7869487, and SNP rs7848647. In some embodiments, the determination includes determining the presence of only three SNPs in a biological sample from a patient, wherein the three SNPs are SNP rs3810936, SNP rs7869487, and SNP rs6478109.

[0146] In some embodiments, the at least two SNPs include SNP rs3810936, SNP rs7869487, SNP rs6478108, and SNP rs6478109. In some embodiments, the determination includes determining the presence of only four SNPs in a biological sample from a patient, wherein the four SNPs are SNP rs3810936, SNP rs7869487, SNP rs6478108, and SNP rs6478109.

[0147] Therefore, in some aspects, this disclosure provides a method for treating a patient with IBD, the method comprising: (a) Genotyping a biological sample from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, wherein the determination comprises determining the presence of SNP rs3810936 and SNP rs7869487 in the biological sample from the patient, and wherein a haplotype B non-carrier of TNFSF15 is identified by any of the following biomarker states from the biological sample from the patient:

[0148] (i) The genotype of the sample is homozygous for a reference allele at rs3810936 (i.e., the sample is T / T at rs3810936), and for rs7869487... The alternative allele at rs7869487 is homozygous (i.e., the sample is T / T at rs7869487);

[0149] (ii) The genotype of the sample for the substitution allele at rs7869487 is homozygous (i.e., the sample is T / T at rs7869487);The reference allele at rs3810936 is heterozygous (e.g., the sample is C / T at rs3810936) and homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487);

[0150] (iii) The genotype of the sample is homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936) and homozygous for the reference allele at rs7869487 (i.e., the sample is C / C at rs7869487);

[0151] (iv) The genotype of the sample is homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936) and homozygous for the reference allele at rs7869487 (i.e., the sample is T / T at rs7869487). The reference allele at rs7869487 is heterozygous (e.g., the sample is T / C at rs7869487); or

[0152] (v) the genotype of the sample is homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936) and homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487); and

[0153] (b) administering an anti-TL1A antibody or an anti-DR3 antibody to a patient who has been identified as a haplotype B non-carrier. In some embodiments, the anti-TL1A antibody is administered to the patient in an induction dosing regimen (e.g., an induction dosing regimen sufficient to improve signs and symptoms of IBD at least 12 weeks after initiation of treatment with the anti-TL1A antibody or anti-DR3 antibody, the induction dosing regimen comprising multiple individual induction doses). In some embodiments, the anti-TL1A antibody is further administered to the patient in a maintenance dosing regimen following an induction dosing regimen (e.g., administered to the patient in a subsequent maintenance dosing regimen after completion of the induction dosing regimen, the maintenance dosing regimen comprising a plurality of individual maintenance doses spaced at least 2 weeks apart from each other).

[0154] In another aspect, this disclosure provides a method for treating a patient with IBD, the method comprising: (a) administering an effective amount of anti-TL1A antibody to the patient in an induction dosing regimen (e.g., an induction dosing regimen sufficient to improve signs and symptoms of IBD at least 12 weeks after initiation of treatment with anti-TL1A antibody, the induction dosing regimen comprising a plurality of individual induction doses); and (b) administering an effective amount of anti-TL1A antibody to the patient in a subsequent maintenance dosing regimen after completion of the induction dosing regimen, e.g., the maintenance dosing regimen comprising a plurality of individual maintenance doses spaced at least 2 weeks apart from each other; wherein the patient has been identified as haplotype B against TNFSF15.Non-carriers, wherein haplotype B non-carriers of TNFSF15 are identified by any of the following biomarker states from biological samples from the patient:

[0155] (i) the sample genotype is homozygous for the reference allele at rs3810936 (i.e., the sample is T / T at rs3810936) and homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487);

[0156] (ii) the sample genotype is heterozygous for the reference allele at rs3810936 (e.g., the sample is C / T at rs3810936) and homozygous for the alternative allele at rs7869487 (i.e., the sample is C / T at rs7869487).

[0157] (iii) The sample genotype is homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936) and homozygous for the reference allele at rs7869487 (i.e., the sample is C / C at rs7869487);

[0158] (iv) The sample genotype is homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936) and heterozygous for the reference allele at rs7869487 (e.g., the sample is T / C at rs7869487); or

[0159] The sample genotype is homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936); The sample is C / C at rs7869487 and is homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487).

[0160] In some embodiments of any of the above aspects, the anti-TL1A antibody comprises: HCDR1 (CDR H1) having the sequence shown in SEQ ID NO: 3; HCDR2 (CDR H2) having the sequence shown in SEQ ID NO: 4; HCDR3 (CDR H3) having the sequence shown in SEQ ID NO: 5; LCDR1 (CDR L1) having the sequence shown in SEQ ID NO: 6; LCDR2 (CDR L2) having the sequence shown in SEQ ID NO: 7; and LCDR3 (CDR L3) having the sequence shown in SEQ ID NO: 8. In some embodiments of any of the above aspects, the anti-TL1A antibody comprises: HCDR1 (CDR H1) having the sequence shown in SEQ ID NO: 6; LCDR2 (CDR L2) having the sequence shown in SEQ ID NO: 7; and LCDR3 (CDR L3) having the sequence shown in SEQ ID NO: 8. In some embodiments of any of the above aspects, the anti-TL1A antibody comprises: HCDR1 (CDR H1) having the sequence shown in SEQ ID NO: 3; HCDR2 (CDR H2) having the sequence shown in SEQ ID NO: 7; and LCDR3 (CDR L3) having the sequence shown in SEQ ID NO: 8.The TL1A antibody comprises: HCDR1 (CDR H1) having the sequence shown in SEQ ID NO: 68; HCDR2 (CDR H2) having the sequence shown in SEQ ID NO: 4; HCDR3 (CDR H3) having the sequence shown in SEQ ID NO: 5; LCDR1 (CDR L1) having the sequence shown in SEQ ID NO: 6; LCDR2 (CDR L2) having the sequence shown in SEQ ID NO: 7; and LCDR3 (CDR L3) having the sequence shown in SEQ ID NO: 8. In some embodiments, the anti-TL1A antibody is afimizumab.

[0161] In some embodiments of any of the foregoing aspects, the anti-TL1A antibody comprises: CDR-H1 having the sequence shown in SEQ ID NO: 37; CDR-H2 having the sequence shown in SEQ ID NO: 39; CDR-H3 having the sequence shown in SEQ ID NO: 41; CDR-L1 having the sequence shown in SEQ ID NO: 46; CDR-L2 having the sequence shown in SEQ ID NO: 48; and CDR-L3 having the sequence shown in SEQ ID NO: 50. In some embodiments, the anti-TL1A antibody is tusozymeab.

[0162] In some embodiments of any of the foregoing aspects, the anti-TL1A antibody has the HVR sequence of TEV-48574. In some embodiments, the anti-TL1A antibody is TEV-48574.

[0163] In some embodiments of any of the foregoing aspects, IBD is ulcerative colitis. In some embodiments, UC is moderate to severe UC.

[0164] Determination of TNFSF15 haplotype

[0165] Any suitable method can be used to determine whether a patient is a carrier of haplotype B against TNFSF15 or a non-carrier of haplotype B. For example, any suitable method can be used to determine the genotype of a patient in a biological sample from the patient at one or more locations of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487. Exemplary methods for determining a patient's TNFSF15 haplotype are provided herein.

[0166] In some embodiments, the genotyping assay used in any of the methods provided herein includes the use of quantitative PCR (qPCR).

[0167] In some embodiments, the genotyping assay includes sequencing (e.g., containing DNA)Sequencing). In some embodiments, genotyping assays include long-read sequencing.

[0168] In some embodiments, genotyping assays are fluorescence-based assays. In some embodiments, genotyping assays are defined as fluorescence-based qPCR assays, such as Taqman™ qPCR assays.

[0169] The biological sample may be any suitable sample containing genomic DNA. In some embodiments, the biological sample is blood. In some embodiments, the biological sample is or contains oral cells.

[0170] B. Expression Levels of Candidate Genes

[0171] In some aspects, any of the methods, uses, or compositions provided herein comprises determining the expression of one or more candidate genes (described below) in a sample from a patient. These methods, uses, or compositions may further comprise making treatment decisions based on the patient's gene expression.

[0172] In some aspects of this disclosure, the method further includes the steps of: a) determining the expression level of one or more candidate genes in a sample from a patient, b) identifying that the sample contains an aberrant expression level of one or more candidate genes, and c) administering an induction dosing regimen or an induction dose of anti-TL1A antibody to the patient.

[0173] Whether a patient has an aberrant expression level of one or more candidate genes can be determined by obtaining or having obtained a sample from the patient. The sample may be a tissue sample. The sample may be a tissue sample from a site of IBD inflammation. The sample may be a peripheral blood sample. The sample may be an intestinal biopsy sample.

[0174] The method may further include performing or having performed a assay on the sample to determine whether the patient exhibits an aberrant level of one or more candidate genes.

[0175] In some aspects, if the sample contains an aberrant level of one or more candidate genes, the method provides the further step of administering an induction dosing regimen or an induction dose of anti-TL1A antibody to the patient.

[0176] In some aspects, in patients with an aberrant level of one or more candidate genes, the risk of the patient not responding to an induction dosing regimen or an induction dose of anti-TL1A antibody is low.

[0177] In some aspects, this disclosure provides a method for treating a patient with inflammatory bowel disease (IBD), the method comprising the steps of: a) determining the expression levels of one or more candidate genes in a sample from the patient; b) identifying abnormal expression levels of one or more candidate genes in the sample; and c) administering to the patient an induction dosing regimen or an induction dose of an anti-TNF-like ligand 1A (TL1A) antibody alone.

[0178] The one or more candidate genes may be selected from the group consisting of: IL-1B, IL-23A, IFNG, IL-12RB1,IL-21R, IRF4, BATF, CD80 / 86, HLA-DRB5 / DQB1 / DRB1, HLA-DRA, CD40, ICOS, MMP3, MMP7, MMP10, and CHI3L. One or more candidate genes can be selected from the group consisting of: IL-1B, IL-23A, IFNG, IL-12RB1, IL-21R, IRF4, and BATF. One or more candidate genes can be selected from the group consisting of: CD80 / 86, HLA-DRB5 / DQB1 / DRB1, HLA-DRA, CD40, and ICOS. One or more candidate genes can be selected from the group consisting of: MMP3, MMP7, MMP10, and CHI3L.

[0179] One or more candidate genes may be selected from the group consisting of: SOWAHB, COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, PKDREJ, IL-1B, IL-23A, IFNG, IL-12RB1, IL-21R, IRF4, BATF, CD80 / 86, HLA-DRB5 / DQB1 / DRB1, HLA-DRA, CD40, ICOS, MMP3, MMP7, MMP10, and CHI3L.

[0180] One or more candidate genes may be selected from the group consisting of: SOWAHB, COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, and PKDREJ. One or more candidate genes may include SOWAHB. One or more candidate genes may include SOWAHB and at least one or more candidate genes selected from the group consisting of: COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, and PKDREJ. One or more candidate genes may include SOWAHB and COLCA2 and at least one or more candidate genes selected from the group consisting of: SOWAHB, COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, and PKDREJ. One or more candidate genes may include SOWAHB, COLCA2, and TBX20 and at least one or more candidate genes selected from the group consisting of: SOWAHB, COLCA2, and TBX20. (See page 23 / 64 of CN 121532526 A for details.) Candidate genes: FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, and PKDREJ.

[0181] In some aspects, the method provides for determining 2, 3, 4, 5, 6, or 7The expression levels of one, eight, nine, or ten candidate genes selected from a group consisting of the following: SOWAHB, COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, and PKDREJ.

[0182] The aberrant expression levels of one or more candidate genes may be based on the levels of the mRNA or expressed protein of one or more candidate genes.

[0183] The aberrant expression levels of one or more candidate genes may be based on the mRNA levels of one or more candidate genes.

[0184] The expression levels of one or more candidate genes may be compared to baseline expression levels based on the expression levels of one or more candidate genes in healthy subjects who have not developed IBD or UC.

[0185] The expression levels of one or more candidate genes may be compared to baseline expression levels based on estimated expression levels in subjects who are unresponsive to anti-TL1A antibody treatment.

[0186] The aberrant expression levels of one or more candidate genes may be at least 50% higher or lower than baseline levels. The aberrant expression level of one or more candidate genes may be at least 2, 5, 10, 50, 100, 500, or 1000 times higher or lower than the baseline level.

[0187] In some aspects, when one or more candidate genes are selected from the group consisting of SOWAHB, COLCA2, FRZB, HOXB5, NET1, FOXD2, PARK2, and PKDREJ, the aberrant expression level may be elevated. In some aspects, when one or more candidate genes are selected from the group consisting of TBX20 and DESI1, the aberrant expression level may be decreased.

[0188] C. Bacterial strain level

[0189] In some aspects, any of the methods, uses, or compositions provided herein includes determining the level of one or more bacterial strains (described below) in a fecal sample from a patient. These methods, uses, or compositions may further include making treatment decisions based on the level of bacterial strains in the sample.

[0190] In some aspects, this disclosure includes the steps of: a) determining the level of one or more candidate bacterial strains in a fecal sample from a patient, b) identifying an elevated level of one or more candidate bacterial strains in the fecal sample, and c) administering an induction dose of anti-TL1A antibody to the patient.

[0191] In some aspects, the candidate bacterial strains are selected from the group consisting of: *Streptococcus salivarius*, *Streptococcus parasanguinis*, and *Haemophilus parainfluenzae*.

[0192] In some aspects, this disclosure includes the steps of: a) determining the level of one or more candidate bacterial strains in a stool sample from a patient, b) identifying a reduced level of one or more candidate bacterial strains in the stool sample, and c) administering an induction dose of anti-TL1A antibody to the patient.

[0193] In some aspects, the candidate bacterial strains are selected from the group consisting of: Ruminococcus albus, Ruminococcus callidus, Ruminococcus bromii, Ruminococcus gnavus, and Bifidobacterium bifidum.

[0194] In some aspects, the level of one or more candidate bacterial strains is compared to a baseline bacterial level, which is based on the level of one or more candidate bacterial strains in a healthy subject who has not suffered from IBD or UC. In some aspects, the levels of one or more candidate bacterial strains are compared to baseline bacterial levels, which are estimated levels of those candidate bacterial strains based on subjects unresponsive to anti-TL1A antibody treatment.

[0195] In some aspects, the levels of one or more candidate bacterial strains are at least 50%, 2, 5, 10, 20, 50, 100, 500, or 1000 times higher or lower than baseline bacterial levels.

[0196] In some aspects, this disclosure further includes treatment with an IL-23 antagonist.

[0197] D. Method for identifying patients who may benefit from treatment based on abnormal gene expression

[0198] This disclosure provides a method for identifying a patient with inflammatory bowel disease who may benefit from initial or continued treatment with an anti-TL1A antibody and optionally treating the patient, wherein the method comprises: (a) identifying the patient as having abnormal levels of one or more candidate genes selected from the group consisting of: SOWAHB, COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, PKDREJ, IL-1B, IL-23A, IFNG, IL-12RB1, IL-21R, IRF4, BATF, CD80 / 86, HLA-DRB5 / DQB1 / DRB1, HLA-DRA, CD40, ICOS, MMP3, MMP7, MMP10, and CHI3L; and optionally further comprising (b)The patient was given or has been given anti-TL1A antibody under certain conditions, wherein one or more of the following groups were reduced after the administration: inflammatory macrophages, TH17, ILC3, OX40, OX40L, IFNy, ILC2, IL-13, MMP, tissue remodeling, fibrosis, enteric streptococcus salivarius population, enteric streptococcus parasanguinis population, and enteric Haemophilus parainfluenzae population.

[0199] II. Method of treating inflammatory bowel disease with anti-TL1A antibody

[0200] In some aspects, this disclosure provides a method of treating a patient (e.g., a human) with inflammatory bowel disease (IBD) (e.g., ulcerative colitis (UC) or Crohn's disease (CD)), the method comprising administering to the patient an effective amount of an anti-TNF-like ligand 1A (TL1A) antibody (e.g., the anti-TL1A antibody provided in Section IV herein) in a dosing regimen comprising an induction phase (induction dosing regimen) and a subsequent maintenance phase (maintenance dosing regimen), wherein the induction dosing regimen comprises a plurality of individual induction doses and the maintenance dosing regimen comprises a plurality of individual maintenance doses, and wherein the anti-TL1A antibody is administered subcutaneously during the maintenance phase. In some embodiments, the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO: 8. In some embodiments, the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 68; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO: 8. In some embodiments, the anti-TL1A antibody is afimzimab.

[0201] As a general principle, the use of anti-TL1A antibodies to treat IBD is described in PCT Publication No. WO 2021 / 260577 and U.S. Patent Application Publication No. 2023 / 0235070.

[0202] In some aspects of any of the treatments provided herein, IBD is ulcerative colitis (e.g., moderate to severe ulcerative colitis).

[0203] In some aspects of any of the treatments provided herein, the patient has been identified as having a relatively low risk of non-responsiveness to a therapeutic dose of anti-TL1A antibody. In some aspects, the patient has been identified as a haplotype B non-carrier of TNFSF15. For example, methods for determining a patient's risk of non-responsiveness and for determining whether a patient is a haplotype B carrier of TNFSF15 are provided in Section I of this document.

[0204] A. Induction Phase

[0205] Any of the methods provided herein may include administration of anti-TL1A antibody in an induction phase. The induction phase may include administration of one or more doses of anti-TL1A antibody.

[0206] In some aspects, the induction phase includes administering at least two doses of anti-TL1A antibody, with the time interval between each individual induction dose being the same. Individual induction doses may be administered at least daily, at least one day apart, at least one week apart, at least two weeks apart, at least three weeks apart, at least four weeks apart, at least five weeks apart, at least six weeks apart, at least seven weeks apart, at least eight weeks apart, at least nine weeks apart, at least ten weeks apart, at least eleven weeks apart, or at least twelve weeks apart. In a preferred aspect, individual induction doses are administered one month apart. In a preferred aspect, individual induction doses are administered four weeks apart (Q4W).

[0207] In some aspects, the induction phase includes administering four doses of anti-TL1A antibody. In some aspects, the doses of anti-TL1A antibody are administered approximately four weeks apart (e.g., administered four weeks apart). In some aspects, the induction phase has a duration of approximately 14 weeks, and (a) the first dose of anti-TL1A antibody is administered on day 1 of week 0; (b) the second dose of anti-TL1A antibody is administered on day 1 of week 4; (c) the third dose of anti-TL1A antibody is administered on day 1 of week 8; and (d) the fourth dose of anti-TL1A antibody is administered on day 1 of week 12.

[0208] The individual induction dose may be 1, 5, 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg of anti-TL1A antibody. In a preferred aspect, the individual induction dose is 50, 150 or450 mg anti-TL1A antibody. In one aspect, the single induction dose is 450 mg anti-TL1A antibody (e.g., each single induction dose is administered at a dose of 450 mg). In another aspect, the single induction dose is 150 mg anti-TL1A antibody (e.g., each single induction dose is administered at a dose of 150 mg). In another aspect, the single induction dose is 50 mg anti-TL1A antibody (e.g., each single induction dose is administered at a dose of 50 mg). The single induction dose can be administered by any means. Preferably, the single induction dose is administered subcutaneously. In one aspect, the single induction dose is 50, 150, or 450 mg administered subcutaneously. In one aspect, the single induction dose is 50, 150, or 450 mg administered subcutaneously monthly. In one aspect, the single induction dose is 50, 150, or 450 mg administered subcutaneously every four weeks (Q4W).

[0209] In some aspects, during the induction phase, the anti-TL1A antibody is administered subcutaneously (SC) at a dose of about 450 mg (e.g., 450 mg dose). (e.g., each dose in the induction phase comprises the administration of about 450 mg (e.g., 450 mg) of the anti-TL1A antibody via SC).

[0210] B. Maintenance Phase

[0211] Any of the methods provided herein may include the subcutaneous administration of the anti-TL1A antibody in a maintenance phase following the administration of the anti-TL1A antibody in the induction phase. The maintenance phase may include the administration of one or more doses of the anti-TL1A antibody.

[0212] The maintenance phase may begin at any appropriate time after the induction phase. In some aspects, the first dose of the maintenance phase is administered about two weeks (e.g., two weeks) after the administration of the last dose of the induction phase. For example, in an aspect where the induction phase includes the administration of four doses of the anti-TL1A antibody, the first dose of the maintenance phase may be administered about two weeks (e.g., two weeks) after the administration of the last dose of the induction phase.

[0213] The maintenance phase includes some aspects of administering at least two doses of anti-TL1A antibody, with the time interval between each individual maintenance dose being the same. Individual maintenance doses may be administered at least daily, at least one day apart, at least one week apart, at least two weeks apart, at least three weeks apart, at least one month apart, at least two months apart, at least three months apart, at least four months apart, at least five months apart, or at least six months apart. In a preferred aspect, individual maintenance doses are administered one month apart. In a preferred aspect, individual maintenance doses are administered four weeks apart.

[0214] In some aspects, the maintenance phase includes administering anti-TL1A antibody every four weeks (Q4W).

[0215] Individual maintenance doses may be...1, 5, 10, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg. In a preferred aspect, the maintenance dose alone is 50, 150, or 450 mg. In another aspect, the maintenance dose alone is about 450 mg (e.g., 450 mg). The maintenance dose can be administered by any means. Preferably, the maintenance dose alone is administered subcutaneously. In one aspect, the maintenance dose alone is 50, 150, or 450 mg administered subcutaneously. In another aspect, the maintenance dose alone is 450 mg of anti-TL1A antibody (e.g., each maintenance dose is administered subcutaneously at a dose of 450 mg). In another aspect, the maintenance dose alone is 150 mg of anti-TL1A antibody (e.g., each individual maintenance dose is administered subcutaneously at a dose of 150 mg). In another aspect, the maintenance dose alone is 50 mg of anti-TL1A antibody (e.g., each individual maintenance dose is administered subcutaneously at a dose of 50 mg). In one aspect, the maintenance dose alone is 50, 150, or 450 mg administered subcutaneously monthly.

[0216] In some aspects, the maintenance phase includes administration of at least 10 doses of anti-TL1A antibody (e.g., including 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more than 20 doses of anti-TL1A antibody administered in a Q4W dosing regimen). In some aspects, the maintenance phase includes administration of 10 doses of anti-TL1A antibody (e.g., including ten doses of anti-TL1A antibody administered in a Q4W dosing regimen).

[0217] Accordingly, in some aspects, this disclosure provides a method of treating a patient with IBD, the method comprising administering an effective amount of an anti-TL1A antibody to the patient in a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen; wherein (a) the induction dosing regimen comprises subcutaneously administering four separate induction doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg (e.g., a dose of 50 mg, 150 mg, or 450 mg), wherein these separate induction doses are administered at 4-week intervals; and (b) the maintenance dosing regimen comprises subcutaneously administering multiple separate maintenance doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg, or 450 mg (e.g., a dose of 50 mg, 150 mg, or 450 mg), wherein these separate maintenance doses are administered at 4-week intervals.The anti-TL1A antibody is administered weekly; and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO: 8. In some aspects, the anti-TL1A antibody is afimizumab.

[0218] In some aspects, this disclosure provides a method of treating a patient with IBD, the method comprising administering an effective amount of an anti-TL1A antibody to the patient in a dosing regimen including an induction dosing regimen and a subsequent maintenance dosing regimen; wherein (a) the induction dosing regimen comprises subcutaneously administering four separate induction doses of the anti-TL1A antibody at a dose of about 450 mg (e.g., a dose of 450 mg), wherein these separate induction doses are administered at 4-week intervals; and (b) the maintenance dosing regimen comprises subcutaneously administering multiple separate maintenance doses of the anti-TL1A antibody at a dose of about 450 mg (e.g., a dose of 450 mg), wherein these separate maintenance doses are administered at 4-week intervals; and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 6; and LCDR3 having the sequence shown in SEQ ID NO: 6. The sequence shown in NO: 7; and LCDR3, which has the sequence shown in SEQ ID NO: 8.

[0219] In some aspects, this disclosure provides a method of treating a patient with IBD, the method comprising administering an effective amount of an anti-TL1A antibody to the patient in a dosing regimen including an induction dosing regimen and a subsequent maintenance dosing regimen; wherein (a) the induction dosing regimen comprises subcutaneously administering four separate induction doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg or 450 mg (e.g., a dose of 50 mg, 150 mg or 450 mg), wherein these separate induction doses are administered at 4-week intervals; and (b) the maintenance dosing regimen comprises subcutaneously administering multiple separate maintenance doses of the anti-TL1A antibody at a dose of about 50 mg, 150 mg or 450 mg (e.g., a dose of 50 mg, 150 mg or 450 mg), wherein these separate maintenance doses are administered at 4-week intervals.The anti-TL1A antibody is administered weekly; and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 68; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7 (page 27 / 64, CN 121532526 A); and LCDR3 having the sequence shown in SEQ ID NO: 8. In some aspects, the anti-TL1A antibody is afimizumab.

[0220] In some aspects, this disclosure provides a method of treating a patient with IBD, the method comprising administering an effective amount of an anti-TL1A antibody to the patient in a dosing regimen including an induction dosing regimen and a subsequent maintenance dosing regimen; wherein (a) the induction dosing regimen comprises subcutaneously administering four separate induction doses of the anti-TL1A antibody at a dose of about 450 mg (e.g., a dose of 450 mg), wherein these separate induction doses are administered at 4-week intervals; and (b) the maintenance dosing regimen comprises subcutaneously administering multiple separate maintenance doses of the anti-TL1A antibody at a dose of about 450 mg (e.g., a dose of 450 mg), wherein these separate maintenance doses are administered at 4-week intervals; and wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 68; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 68; and LCDR3 having the sequence shown in SEQ ID NO: 5. The sequence shown in ID NO: 7; and LCDR3, which has the sequence shown in SEQ ID NO: 8.

[0221] In some aspects, the dosing regimen, including the induction phase and the maintenance phase, has a duration of approximately 52 weeks (e.g., a duration of 52 weeks).

[0222] C. Response to Treatment

[0223] Clinical Response

[0224] Following the induction and / or maintenance dosing regimens, patients may experience improvement in IBD signs and symptoms characterized by a clinical response. The term “clinical response” may be defined as a decrease of at least 3 points in the total Mayo score from baseline, a change of at least 30%, accompanied by a decrease of at least one point in the rectal bleeding sub-score or an absolute score of 0 or 1.

[0225] The abbreviation “Mayo” refers to the Mayo scoring system used to assess ulcerative colitis activity. “Adaptive Mayo score” refers to the adaptive Mayo score.The scoring system has three Mayo score sub-scores ranging from 0 to 9, without a Physician Overall Assessment (PGA) sub-score.

[0226] In some aspects, in patient populations treated according to any of the methods provided herein, the treatment resulted in an increased proportion of patients who had achieved a clinical response at the end of the induction phase compared to a reference population. For example, in some aspects, the induction phase has a duration of approximately 14 weeks, and the treatment resulted in an increased proportion of patients who had achieved a clinical response at week 14. For example, in some aspects, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100%) achieved a clinical response by week 14. In some aspects, the proportion of patients in the patient population who achieved a clinical response at week 14 was at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% higher than the proportion of patients in the reference population who achieved a clinical response at week 14.

[0227] In some aspects, in patient populations treated according to any of the methods provided herein that include a maintenance phase, the treatment resulted in an increased proportion of patients who achieved a clinical response at the end of the maintenance phase compared to the reference population. For example, in some aspects, the dosing regimen has a duration of about 56 weeks, and the treatment resulted in an increased proportion of patients who achieved a clinical response at week 56. For example, in some respects, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients in the patient population (e.g., 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100% of patients) achieved a clinical response at week 56. In some respects, the proportion of patients in the patient population who achieved a clinical response at week 56 was higher than that in the reference population who achieved a clinical response at week 56. (Instructions for Use, page 28 / 64, 46)CN 121532526 A The proportion of patients with clinical response is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99%.

[0228] In any of the methods provided herein, the reference population may be any population used as a suitable control. For example, in some aspects, the reference population is a group of subjects with IBD (e.g., UC, e.g., moderate or severe active UC) who have not been treated with anti-TL1A antibodies (e.g., have been treated with placebo).

[0229] Endoscopic Response

[0230] Following induction and / or maintenance dosing regimens, patients may experience improvement in IBD signs and symptoms characterized by endoscopic response. The term “endoscopic response” refers to a Mayo endoscopy score of 0 or 1.

[0231] Clinical Remission

[0232] Following the induction and / or maintenance dosing regimens, patients may experience improvement in IBD signs and symptoms characterized by clinical remission.

[0233] In some aspects, in a patient population treated according to any of the methods provided herein, the treatment results in an increased proportion of patients who have achieved clinical remission at the end of the induction phase compared to a reference population. For example, in some aspects, the induction phase has a duration of approximately 14 weeks, and the treatment results in an increased proportion of patients who have achieved clinical remission at week 14. In some respects, at least 1%, 5%, 10%, 15%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100% of patients) achieved clinical remission at week 14. In some areas, at least approximately 15% of patients in the patient population achieved clinical remission by week 14. In some areas, at least approximately 40% of patients in the patient population achieved clinical remission by week 14. In some areas, between 15% and 45.2% of patients in the patient population achieved clinical remission by week 14. In some areas, in the patient population...23.3%, 23.9%, 25.5%, 29.8%, 31.8%, or 35% of patients achieved clinical remission by week 14.

[0234] In some aspects, the proportion of patients in the patient population who achieved clinical remission by week 14 was at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% greater than the proportion of patients in the reference population who achieved clinical remission by week 14.

[0235] In some aspects, in patient populations treated according to any of the methods provided herein that include a maintenance phase, the treatment resulted in an increased proportion of patients who achieved clinical remission at the end of the maintenance phase compared to the reference population. For example, in some aspects, the dosing regimen has a duration of about 56 weeks, and the treatment resulted in an increased proportion of patients who achieved clinical remission by week 56. In some respects, at least 1%, 5%, 10%, 15%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100% of patients) achieved clinical remission at week 56. In some aspects, at least approximately 20% of the patients in the patient population achieved clinical remission at week 56. In some aspects, at least approximately 55% of the patients in the patient population achieved clinical remission at week 56. In some aspects, between 19.4% and 56.5% of the patients in the patient population achieved clinical remission at week 56. In some aspects, 31.0%, 34.6%, 35.7%, 38.5%, or 39.3% of the patients in the patient population achieved clinical remission at week 56.

[0236] In some aspects, the proportion of patients in the patient population who achieved clinical remission at week 56 was at least greater than the proportion of patients in the reference population who achieved clinical remission at week 56.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99%.

[0237] In some aspects, in patient populations treated according to any of the methods provided herein that include a maintenance phase, the treatment results in an increased proportion of patients experiencing remission maintenance throughout the maintenance phase compared to a reference population. For example, in some aspects, the induction phase has a duration of approximately 14 weeks, the entire dosing regimen has a duration of approximately 56 weeks, and the treatment results in an increased proportion of patients experiencing clinical remission at weeks 14 and 56.

[0238] In some aspects, clinical remission is defined as a modified Mayo score (mMS) ≤ 2, with a stool frequency subscore (SFS) = 0 or 1, a rectal bleeding subscore (RBS) = 0, and an endoscopy score (ES) = 0 or 1.

[0239] In other respects, the term “clinical remission” is based on a total Mayo score of 12: a total Mayo score ≤ 2, with no individual sub-score > 1. In some respects, the modified (altered) Mayo score is defined as an endoscopy score = 0 or 1, a decrease of >= 1 point from baseline to achieve a bowel frequency sub-score = 0 or 1, and a rectal bleeding sub-score = 0. In some respects, the modified (altered) Mayo score is defined as an endoscopy score = 0 or 1, a bowel frequency sub-score = 0 or 1 and no increase from baseline, and a rectal bleeding sub-score = 0.

[0240] Endoscopy Remission

[0241] Following induction and / or maintenance dosing regimens, patients may experience improvement in IBD signs and symptoms characterized by endoscopic remission. The term “endoscopic remission” refers to a Mayo endoscopy score of 0. In some respects, patients experience endoscopic remission at or before the end of the induction phase (e.g., at or before week 14 of treatment). In some respects, in a patient population treated according to any of the methods provided herein, treatment resulted in an increased proportion of patients achieving endoscopic remission at the end of the induction phase compared to a reference population. In some respects, patients experience endoscopic remission at or before the end of the maintenance phase (e.g., at or before week 56 of treatment). In some respects, in a patient population treated according to any of the methods provided herein, treatment resulted in an increased proportion of patients achieving endoscopic remission at the end of the maintenance phase compared to a reference population.

[0242] Deep Remission

[0243] Following the induction and / or maintenance dosing regimens, patients may experience improvement in IBD signs and symptoms characterized by deep remission. “Deep remission” is defined as a total Mayo score of 2.

[0244] In some aspects, in the patient population treated according to any of the methods provided herein, the treatment resulted in an increased proportion of patients who had achieved deep remission at the end of the induction phase compared to the reference population. In some aspects, patients experienced deep remission at or before the end of the maintenance phase (e.g., at or before week 56 of treatment). In some aspects, in the patient population treated according to any of the methods provided herein, the treatment resulted in an increased proportion of patients who had achieved deep remission at the end of the maintenance phase compared to the reference population.

[0245] Symptom Relief

[0246] Following the induction and / or maintenance dosing regimens, patients may experience improvement in IBD signs and symptoms characterized by symptom relief. “Symptom relief” is defined as a total Mayo score of 2 or lower, with no individual sub-score exceeding 1, and both rectal bleeding and bowel frequency sub-scores being 0.

[0247] In some aspects, in a patient population treated according to any of the methods provided herein, the treatment resulted in an increased proportion of patients who had achieved symptom remission at the end of the induction phase compared to a reference population. In some aspects, patients experienced symptom remission at or before the end of the maintenance phase (e.g., at or before week 56 of treatment). In some aspects, in a patient population treated according to any of the methods provided herein, as described on pages 30 / 64 of the specification 48 CN 121532526 A, the treatment resulted in an increased proportion of patients who had achieved symptom remission at the end of the maintenance phase compared to a reference population.

[0248] Endoscopic Improvement

[0249] Following the induction and / or maintenance dosing regimens, patients may experience improvement in IBD signs and symptoms characterized by endoscopic improvement. The term “endoscopic improvement” (“E1”) means a Mayo endoscopy score reduction of ≥1 point or an absolute endoscopy score ≤1. In some aspects, endoscopic improvement is defined as an endoscopy score = 0 or 1.

[0250] In some aspects, patients experience endoscopic improvement at or before the end of the induction phase (e.g., at or before week 14 of treatment). In some aspects, in a patient population treated according to any of the methods provided herein, the treatment results in an increased proportion of patients who have achieved endoscopic improvement at the end of the induction phase compared to a reference population. For example, in some aspects, the induction phase has a duration of approximately 14 weeks, and the treatment results in an increased proportion of patients who have achieved endoscopic improvement at week 14. In some aspects, at least 1%, 5%, 10%, 15%, 20%, 21%, 22%, 23%, and 24% of the patient population...25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100% of patients) achieved endoscopic improvement at week 14. In some respects, at least approximately 25% of patients in the patient population achieved endoscopic improvement at week 14. In some aspects, at least approximately 50% of patients in the patient population achieved endoscopic improvement by week 14. In some aspects, between 9.6% and 53.5% of patients in the patient population achieved endoscopic improvement by week 14. In some aspects, 38.3%, 40.4%, or 40.9% of patients in the patient population achieved endoscopic improvement by week 14.

[0251] In some aspects, the proportion of patients in the patient population who achieved endoscopic improvement by week 14 was at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% greater than the proportion of patients in the reference population who achieved endoscopic improvement by week 14.

[0252] In some aspects, patients experienced endoscopic improvement at or before the end of the maintenance phase (e.g., at or before week 56 of treatment). In some respects, in patient populations treated according to any of the methods provided herein, treatment resulted in an increased proportion of patients achieving endoscopic improvement at the end of the maintenance phase, compared to a reference population. In some respects, at least 1%, 5%, 10%, 15%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60%) in the patient population...70%, 70% to 80%, 80% to 90%, or 90% to 100% of patients achieved endoscopic improvement by week 56. In some cases, at least 20% of patients in the population achieved endoscopic improvement by week 56. In some cases, at least 65% of patients in the population achieved endoscopic improvement by week 56. In some cases, between 23.8% and 66.7% of patients in the population achieved endoscopic improvement by week 56. In some cases, 38.1%, 39.3%, or 50.0% of patients in the population achieved endoscopic improvement by week 56.

[0253] In some aspects, the proportion of patients in the patient population who achieved endoscopic improvement at week 56 was at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% higher than the proportion of patients in the reference population who achieved endoscopic improvement at week 56.

[0254] Improvement of signs and symptoms of IBD

[0255] Following induction and / or maintenance dosing regimens, patients may experience improvements in signs and symptoms of IBD that were maintained when the patient received maintenance dosing regimen (page 31 / 64 of CN 121532526 A).

[0256] In some aspects of this disclosure, induction and / or maintenance dosing regimens using anti-TL1A antibodies effectively improve signs and symptoms of IBD for at least 14 weeks after initiation of treatment with anti-TL1A antibodies. These improvements in the signs and symptoms of IBD can be characterized by an improvement in the Mayo Cognitive Index (MCI) score. The patient's MCI score can be reduced by an integer of at least 1, 2, or 3.

[0257] Improvements in the signs and symptoms of IBD can be characterized by a Mayo CCI score of 0, 1, 2, or 3. Improvements in the signs and symptoms of IBD can be characterized by a total Mayo CCI score of 0, 1, 2, or 3. Improvements in the signs and symptoms of IBD can be characterized by a Robarts Histopathological Index (RHI) of less than 5. Improvements in the signs and symptoms of IBD can be characterized by a Geboes Index of less than 3.2.

[0258] Improvements in the signs and symptoms of IBD can be maintained for at least 2, 3, 4, 6, or 12 months during the maintenance dosing regimen.

[0259] D. Prior Treatment

[0260] In some respects, the patient was treated with corticosteroids before administration of anti-TL1A antibodies. In some respects,The patient was initially treated with one or more treatments selected from the group consisting of: tumor necrosis factor inhibitors, anti-integrin, azathioprine, 6-mercaptopurine, and methotrexate.

[0261] In some aspects, the patient had previously been treated with a therapy for IBD (e.g., a therapy for UC) and had experienced inadequate response, loss of response, and / or intolerance to the therapy. In some aspects, the therapy was a routine therapy for UC, for example, including the administration of steroids or immunosuppressants (e.g., the patient had experienced inadequate response, loss of response, and / or intolerance to steroids or immunosuppressants).

[0262] In some aspects, the therapy is an advanced therapy for UC, for example, including administration of an anti-tumor necrosis factor (TNF) agent, an anti-integrin agent, an anti-IL12 / IL23 agent, and / or a Janus kinase (JAK) inhibitor (e.g., the patient has experienced inadequate response, loss of response, and / or intolerance to the anti-TNF agent, anti-integrin agent, anti-IL12 / IL23 agent, and / or JAK inhibitor). Thus, in some aspects, the patient had received prior advanced therapy at baseline (e.g., prior to administration of the first dose in the induction phase). In other aspects, the patient had not received prior advanced therapy at baseline.

[0263] E. Fecal calprotectin and hsCRP

[0264] In some aspects, during the course of treatment (e.g., from week 2 to week 26 of treatment), the patient showed a reduction of at least 50% in fecal calprotectin from baseline. In some aspects, from week 2 to week 26 of treatment, the patient showed a reduction of at least 60% in fecal calprotectin from baseline. In some respects, from week 2 to week 26 of treatment, patients showed a decrease in high-sensitivity C-reactive protein (hsCRP) from baseline.

[0265] F. Inflammatory Bowel Disease

[0266] In some respects, IBD is ulcerative colitis (UC). In some respects, patients have moderate to severe ulcerative colitis. The term “moderate to severe ulcerative colitis” is defined as a modified Mayo score of 5 to 9, an endoscopy score of 2 or 3, and / or is defined as a total Mayo score of at least 6 and an endoscopy score of at least 2.

[0267] In some respects, IBD is Crohn's disease (CD). In some respects, patients have moderate to severe CD. The term “moderate to severe CD” is defined as the Crohn's Disease Activity Index (CDAI) and the CD Mini-Endoscopic Score (SES-CD).

[0268] In some respects, the patient was diagnosed with ulcerative colitis, undifferentiated colitis, microscopic colitis, ischemic colitis, infectious colitis, radiation colitis, or active diverticulosis.

[0269] III. Kit

[0270] This disclosure also provides kits that include any or all of the anti-TL1A antibodies described herein. The kits disclosed in this disclosure (pages 32 / 64, CN 121532526 A) include one or more containers containing the anti-TL1A antibody described herein and instructions regarding any of the methods disclosed herein. Generally, these instructions contain a description of administering the anti-TL1A antibody for the aforementioned therapeutic treatment. In some aspects, kits for generating a single-dose administration unit are provided. In some aspects, the kit may contain both a first container having a dried protein and a second container having an aqueous formulation. In some aspects, kits include kits containing single-compartment and multi-compartment pre-filled syringes (e.g., liquid syringes and lyosyringes).

[0271] Instructions for use related to the use of anti-TL1A antibodies generally include information regarding the dosage, dosing schedule, and route of administration for the intended treatment. Containers may be unit doses, bulk packages (e.g., multi-dose packages), or subunit doses. The instructions provided in the kits of this disclosure are typically written instructions on a label or packaging insert (e.g., paper included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.

[0272] The kits of this disclosure are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, wide-mouth bottles, flexible packaging (e.g., sealed Mylar or plastic bags), etc. Packaging for use in conjunction with specific devices (such as inhalers, nasal delivery devices (e.g., nebulizers), or infusion devices (such as micropumps)) is also contemplated. The kit may have a sterile inlet (e.g., the container may be an intravenous solution bag or a vial with a stopper that can be punctured by a hypodermic needle). The container may also have a sterile inlet (e.g., the container may be an intravenous solution bag or a vial with a stopper that can be punctured by a hypodermic needle). At least one active agent in the composition is an anti-TL1A antibody. The container may further contain a second pharmaceutical active agent.

[0273] The kit may optionally provide additional components, such as buffers and explanatory information. Typically, a kit includes a container and a label or packaging insert on or associated with that container.

[0274] IV. Anti-TL1A and Anti-DR3 Antibodies

[0275] The methods of this disclosure include administering an anti-TL1A antibody. Exemplary anti-TL1A antibodies of this disclosure are shown in Table 2 and below. Exemplary anti-DR3 antibodies of this disclosure are also provided below.

[0276] Table 2. Sequences of Exemplary Antibodies of this Disclosure 33 / 64 pages 51 CN 121532526 A

[0277] 34 / 64 pages 52 CN 121532526 A 35 / 64Page 53 CN 121532526 A Specification 36 / 64 Page 54 CN 121532526 A Specification 37 / 64 Page 55 CN 121532526 A

[0278] In some aspects of this disclosure, the anti-TL1A antibody comprises three CDRs from a variable heavy chain region having the sequence shown in SEQ ID NO: 1; and three CDRs from a variable light chain region having the sequence shown in SEQ ID NO: 2.

[0279] In some aspects of this disclosure, the anti-TL1A antibody comprises: HCDR1 (CDR H1) having the sequence shown in SEQ ID NO: 3; HCDR2 (CDR H2) having the sequence shown in SEQ ID NO: 4; HCDR3 (CDR H3) having the sequence shown in SEQ ID NO: 5; LCDR1 (CDR L1) having the sequence shown in SEQ ID NO: 6; LCDR2 (CDR L2) having the sequence shown in SEQ ID NO: 7; and LCDR3 (CDR L3) having the sequence shown in SEQ ID NO: 8. In some aspects, the anti-TL1A antibody comprises one, two, three, four, five, six, seven, or all eight of the frame regions shown in SEQ ID NO: 69 to 76.

[0280] In some aspects of this disclosure, the anti-TL1A antibody comprises: HCDR1 (CDR H1) having the sequence shown in SEQ ID NO: 68; HCDR2 (CDR H2) having the sequence shown in SEQ ID NO: 4; HCDR3 (CDR H3) having the sequence shown in SEQ ID NO: 5; LCDR1 (CDR L1) having the sequence shown in SEQ ID NO: 6; LCDR2 (CDR L2) having the sequence shown in SEQ ID NO: 7; and LCDR3 (CDR L3) having the sequence shown in SEQ ID NO: 8. In some aspects, the anti-TL1A antibody comprises one, two, three, four, five, six, seven, or all eight of the frame regions shown in SEQ ID NO: 70 to 77.

[0281] In some aspects of this disclosure, the anti-TL1A antibody comprises: a variable heavy chain region having the sequence shown in SEQ ID NO: 1; and a variable light chain region having the sequence shown in SEQ ID NO: 2.

[0282] In some aspects of this disclosure, the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 34. In some embodiments, the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 34; and a light chain having the sequence shown in SEQ ID NO: 10, wherein the C-terminal lysine (K) of the amino acid sequence of the heavy chain in SEQ ID NO: 34 is optional. In some embodiments, the heavy chain does not have a C-terminal lysine (K). In some embodiments, the heavy chain has the sequence shown in SEQ ID NO: 9. In some embodiments, the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 9; and a light chain having the sequence shown in SEQ ID NO: 10.

[0283] In some aspects of this disclosure, the anti-TL1A antibody is afimzibazanol (also known as RO7790121, RVT-3101, or PF-06480605).

[0284] In some aspects of this disclosure, the anti-TL1A antibody comprises a VH encoded by a nucleic acid sequence of an insert of a vector having ATCC accession number PTA-120639 deposited at 1 D1 1.31 VH and a VL encoded by a nucleic acid sequence of an insert of a vector having ATCC accession number PTA-120640 deposited at 1 D1 1.31 VL.

[0285] In some aspects of this disclosure, the anti-TL1A antibody competitively binds to an anti-TL1A antibody comprising: a variable heavy chain region having the sequence shown in SEQ ID NO: 1; and a variable light chain region having the sequence shown in SEQ ID NO: 2.

[0286] In some aspects of this disclosure, the anti-TL1A antibody competitively binds to an antibody comprising a VH encoded by a nucleic acid sequence of an insert of a vector having ATCC accession number PTA-120639 with accession number 1D1 1.31 VH and a VL encoded by a nucleic acid sequence of an insert of a vector having ATCC accession number PTA-120640 with accession number 1D1 1.31 VL.

[0287] In some aspects of this disclosure, the anti-TL1A antibody comprises sequence pairs selected from the group consisting of: SEQ ID NO: 2 and 11; SEQ ID NO: 2 and 12; SEQ ID NO: 2 and 13; SEQ ID NO: 2 and 14; SEQ ID NO: 2 and 15; SEQ ID NO: 2 and 16; SEQ ID NO: 2 and 17; SEQ ID NO: 2 and 18; SEQ ID NO: 2 and 19; SEQ ID NO: 2 and 10; SEQ ID NO: 2 and 11; SEQ ID NO: 2 and 12; SEQ ID NO: 2 and 13; SEQ ID NO: 2 and 14; SEQ ID NO: 2 and 15; SEQ ID NO: 2 and 16; SEQ ID NO: 2 and 17; SEQ ID NO: 2 and 19 ...18; SEQ ID NO: 2 and 19; SEQ ID NO: 20 and 24; SEQ ID NO: 21 and 25; SEQ ID NO: 22 and 26; SEQ ID NO: 23 and 27; SEQ ID NO: 28 and 29; SEQ ID NO: 30 and 31; SEQ ID NO: 32 and 33; SEQ ID NO: 35 and 44; SEQ ID NO: 53 and 54; SEQ ID NO: 61 and 62; SEQ ID NO: 63 and 64; SEQ ID NO: 65 and 64; SEQ ID NO: 66 and 64; and SEQ ID NO: 67 and 64.

[0288] In some aspects of this disclosure, the anti-TL1A antibody comprises: CDR-H1 having the sequence shown in SEQ ID NO: 37; CDR-H2 having the sequence shown in SEQ ID NO: 39; CDR-H3 having the sequence shown in SEQ ID NO: 41; CDR-L1 having the sequence shown in SEQ ID NO: 46; CDR-L2 having the sequence shown in SEQ ID NO: 48; and CDR-L3 having the sequence shown in SEQ ID NO: 50.

[0289] In some aspects of this disclosure, the anti-TL1A antibody comprises a heavy chain backbone region as shown in SEQ ID NO: 36, 38, 40 and 42, and / or a light chain backbone region as shown in SEQ ID NO: 45, 47, 49 and 51.

[0290] In some aspects of this disclosure, the anti-TL1A antibody comprises: a heavy chain variable region having the sequence shown in SEQ ID NO: 53; and a light chain variable region having the sequence shown in SEQ ID NO: 54.

[0291] In some aspects of this disclosure, the anti-TL1A antibody comprises the heavy chain tail sequence as provided in SEQ ID NO: 43, page 39 / 64, CN 121532526 A. In some aspects of this disclosure, the anti-TL1A antibody comprises the light chain tail sequence as provided in SEQ ID NO: 52.

[0292] In some aspects of this disclosure, the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 35; and / or a light chain having the sequence shown in SEQ ID NO: 44. In some aspects of this disclosure, the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 35; and a light chain having the sequence shown in SEQ ID NO: 44.The sequence shown in NO: 44.

[0293] In some aspects of this disclosure, the anti-TL1A antibody is tulisokibart.

[0294] In some aspects, the antibody used in any of the methods, compositions, uses, and compositions provided herein is the anti-TL1A antibody provided in Table 2A of U.S. Patent No. 11,136,386, which is incorporated herein by reference in its entirety.

[0295] In some aspects, the antibody used in any of the methods, compositions, uses, and compositions provided herein is the anti-DR3 antibody provided in Table 2A of U.S. Patent No. 11,136,386, which is incorporated herein by reference in its entirety.

[0296] In some aspects of the methods, compositions, uses, and compositions provided herein, the anti-TL1A antibody is the anti-TL1A antibody provided in U.S. Patent Nos. 10,322,174, 10,689,439, 11,292,848, 10,138,296, 10,822,422, and 11,220,549, which are incorporated herein by reference in their entirety. In some embodiments, the anti-TL1A antibody comprises the CDR sequence of clone 320-179 provided in U.S. Patent No. 10,689,439. In some embodiments, the anti-TL1A antibody is clone 320-179 provided in U.S. Patent No. 10,689,439.

[0297] In some aspects of this disclosure, the anti-TL1A antibody comprises: CDR-H1 having the sequence shown in SEQ ID NO: 55; CDR-H2 having the sequence shown in SEQ ID NO: 56; CDR-H3 having the sequence shown in SEQ ID NO: 57; CDR-L1 having the sequence shown in SEQ ID NO: 58; CDR-L2 having the sequence shown in SEQ ID NO: 59; and CDR-L3 having the sequence shown in SEQ ID NO: 60.

[0298] In some aspects of this disclosure, the anti-TL1A antibody comprises: a heavy chain variable region having the sequence shown in SEQ ID NO: 61; and a light chain variable region having the sequence shown in SEQ ID NO: 62.

[0299] In some aspects of this disclosure, the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 63, 65, 66 or 67; and / or a light chain having the sequence shown in SEQ ID NO: 64. In some aspects of this disclosure, the anti-TL1A antibody...The antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 63, 65, 66 or 67; and a light chain having the sequence shown in SEQ ID NO: 64. In some aspects of this disclosure, the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 63; and a light chain having the sequence shown in SEQ ID NO: 64. In some aspects of this disclosure, the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 65; and a light chain having the sequence shown in SEQ ID NO: 64. In some aspects of this disclosure, the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 66; and a light chain having the sequence shown in SEQ ID NO: 64. In some aspects of this disclosure, the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 67; and a light chain having the sequence shown in SEQ ID NO: 64.

[0300] In some aspects of this disclosure, the anti-TL1A antibody is TEV-48574.

[0301] In some aspects of this disclosure, the anti-TL1A antibody is CO3V.

[0302] In some aspects of this disclosure, the anti-TL1A antibody is SPY002.

[0303] The antibodies described herein can be prepared by any method known in the art. For the generation of hybridoma cell lines, the immunization pathway and program of the host animal are generally consistent with established and conventional techniques for antibody stimulation and generation—see specification 40 / 64 pages 58 CN 121532526 A, as further described herein. General techniques for generating antibodies in humans and mice are those known in the art and / or described herein.

[0304] It is contemplated that any mammalian subject (including humans) or antibody-generating cells derived therefrom can be manipulated to serve as the basis for the generation of mammalian (including human) and hybridoma cell lines. Typically, host animals are inoculated with a certain amount of immunogen (including immunogens as described herein) via intraperitoneal, intramuscular, oral, subcutaneous, plantar, and / or intradermal administration.

[0305] Hybridomas can be prepared from lymphocytes and immortalized myeloma cells using the universal somatic cell hybridization technique described in Kohler, B. and Milstein, C., Nature 256:495-497, 1975, or the modified somatic cell hybridization technique described in Buck, DW et al., In Vitro, 18:377-381, 1982. Available myeloma lines include, but are not limited to, X63-Ag8.653 and those from the Salk Institute, Cell Distribution.Those from the Center (San Diego, California, USA) can be used for hybridization. Generally, this technique involves fusing myeloma cells and lymphocytes using a fusion agent such as polyethylene glycol or by electrofusion methods well known to those skilled in the art. After fusion, the cells are separated from the fusion medium and grown in a selective growth medium (such as hypoxanthine-aminopterin-thymidine (HAT) medium) to eliminate unhybridized parental cells. Any of the media described herein (with or without serum supplementation) can be used to culture hybridomas that secrete monoclonal antibodies. As an alternative to cell fusion techniques, EBV immortalized B cells can be used to generate the monoclonal antibodies of this disclosure. If desired, the hybridoma is amplified and subcloned, and the antiimmunogen activity in the supernatant is determined by conventional immunoassay procedures (e.g., radioimmunoassay, enzyme immunoassay, or fluorescence immunoassay).

[0306] Hybridomas that can be used as antibody sources encompass all derivatives and progeny cells of parental hybridomas that produce monoclonal antibodies.

[0307] Hybridomas producing antibodies for use in this disclosure can be grown in vitro or in vivo using known procedures. If desired, monoclonal antibodies can be isolated from culture media or body fluids using conventional immunoglobulin purification procedures such as ammonium sulfate precipitation, gel electrophoresis, dialysis, chromatography, and ultrafiltration. Undesirable activity (if present) can be removed, for example, by running the formulation on an adsorbent made by attaching an immunogen to a solid phase and eluting or releasing the desired antibody from the immunogen. Using bifunctional or derivatizing agents (e.g., maleimide benzoyl sulfosuccinimide (conjugated via cysteine ​​residues), N-hydroxysuccinimide (conjugated via lysine residues), glutaraldehyde, succinic anhydride, SOC, or R1N=C=NR (where R and R1 are different alkyl groups)) to immunize host animals with cells expressing antibody targets (e.g., PD-1), human target proteins (e.g., PD-1), or fragments containing target amino acid sequences conjugated with proteins that are immunogenic in the species to be immunized (e.g., keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, or soybean trypsin inhibitors), a population of antibodies (e.g., monoclonal antibodies) can be generated.

[0308] If desired, the antibody of interest (monoclonal or polyclonal) can be sequenced, and the polynucleotide sequence can then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest can be maintained in a vector within the host cell, and the host cell can then be amplified and frozen for future use. The generation of recombinant monoclonal antibodies in cell cultures can be performed using methods known in the art via cloning antibody genes from B cells. See, for example, Tiller et al., J. Immunol. Methods 329.112, 2008; U.S. Patent No. 7,314,622.

[0309] In some aspects, hybridoma technology can be used to prepare antibodies. It is envisioned that any mammalian subject (including humans) or antibody-producing cells derived therefrom can be manipulated to serve as the basis for generating mammalian (including human) hybridoma cell lines. The immunization route and program for the host animal are generally consistent with established and conventional techniques for antibody stimulation and production, as further described herein. Typically, the host animal is inoculated with an amount of immunogen (including immunogens as described herein) via intraperitoneal, intramuscular, oral, subcutaneous, plantar, and / or intradermal administration. Instructions for use, pages 41 / 64, 59 CN 121532526 A

[0310] In some aspects, the antibodies described herein are glycosylated at conserved sites in their constant regions (Jefferis and Lund, 1997, Chem. Immunol. 65:111-128; Wright and Morrison, 1997, TibTECH 15:26-32). Oligosaccharide side chains of immunoglobulins affect protein function (Boyd et al., 1996, Mol. Immunol. 32: 1311-1318; Wittwe and Howard, 1990, Biochem. 29: 4175-4180) and intramolecular interactions between glycoprotein moieties, which can influence glycoprotein conformation and the three-dimensional surface it presents (Jefferis and Lund, ibid.; Wyss and Wagner, 1996, Current Opin. Biotech. 7: 409-416). Oligosaccharides can also be used to target given glycoproteins to certain molecules based on specific recognition structures. Antibody glycosylation has been reported to affect antibody-dependent cytotoxicity (ADCC). Specifically, antibodies produced by CHO cells expressing tetracycline-regulated β(1,4)-N-acetylglucosamine transferase III (GnTIII), a glycosyltransferase that catalyzes the formation of bimeric GlcNAc, have been reported to have improved ADCC activity (Umana et al., 1999, Nature Biotech. 17: 176-180).

[0311] Antibody glycosylation is typically N-linked or O-linked. “N-linked” refers to the carbohydrate moiety being linked to the asparagine residue side chain. The tripeptide sequences asparagine-X-serine, asparagine-X-threonine, and asparagine-X-cysteine ​​(where X is any amino acid other than proline) are recognition sequences for the enzymatic linking of the carbohydrate moiety to the asparagine side chain. Therefore, the presence of any of these tripeptide sequences in the polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the glycosylation of the carbohydrate moiety being linked to the asparagine side chain.One of N-acetylgalactosamine, galactose, or xylose is linked to a hydroxy amino acid, most commonly serine or threonine, but 5-hydroxyproline or 5-hydroxylysine may also be used.

[0312] Glycosylation sites can be conveniently added to antibodies by altering the amino acid sequence to include one or more of the aforementioned tripeptide sequences (for N-linked glycosylation sites). This alteration can also be achieved by adding or substituting one or more serine or threonine residues in the sequence of the original antibody (for O-linked glycosylation sites).

[0313] The glycosylation pattern of an antibody can also be altered without changing the basic nucleotide sequence. Glycosylation is largely dependent on the host cell used to express the antibody. Due to the cell type used to express recombinant glycoproteins, such as antibodies, since potential therapeutic agents are rarely native cells, variations in the glycosylation pattern of antibodies can be expected (see, for example, Hse et al., 1997, J. Biol. Chem. 272:9062-9070).

[0314] Besides the choice of host cells, factors affecting glycosylation during recombinant antibody production include growth pattern, culture medium formulation, culture density, oxygenation, pH, purification protocol, etc. Various methods have been proposed to modify the glycosylation pattern achieved in a particular host organism, including the introduction or overexpression of certain enzymes involved in oligosaccharide production (US Patent Nos. 5,047,335; 5,510,261 and 5,278,299). Glycosylation, or certain types of glycosylation, can be removed from glycoproteins enzymatically, for example using endoglycosidase H (endo-H), N-glycosidase F, endoglycosidase F1, endoglycosidase F2, and endoglycosidase F3. In addition, recombinant host cells can be genetically engineered to be defective in processing certain types of polysaccharides. These and similar techniques are well known in the art.

[0315] Other modification methods include the use of coupling techniques known in the art, including but not limited to enzymatic methods, oxidative substitution, and chelation. Modifications can be used, for example, to attach markers for immunoassays. The modified peptides are prepared using procedures established in the art and can be screened using standard assays known in the art.

[0316] V. Polynucleotides, Vectors, and Host Cells

[0317] This disclosure also provides polynucleotides encoding any of the anti-TL1A antibodies described herein. Polynucleotides can be prepared and expressed using procedures known in the art.

[0318] In another aspect, this disclosure provides compositions (e.g., pharmaceutical compositions) for use in one or more methods of this disclosure, comprising any of the polynucleotides of this disclosure. In some aspects, the compositions comprise expression vectors for use in one or more methods of this disclosure, the expression vectors comprising encoding any of the anti-TL1A antibodies described herein. (42 / 64 pages, 60 CN)121532526 A TL1A antibody polynucleotide.

[0319] In another aspect, isolated cell lines for use in one or more methods of this disclosure, the isolated cell lines producing anti-TL1A antibodies as described herein.

[0320] Polynucleotides complementary to any such sequences are also covered in this disclosure. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNA, or synthetic) or RNA molecules. RNA molecules include HnRNA molecules containing introns and corresponding to DNA molecules in a one-to-one manner; and mRNA molecules that do not contain introns. Other coding or non-coding sequences may, but not necessarily, be present in the polynucleotides of this disclosure, and polynucleotides may, but not necessarily, be linked to other molecules and / or carrier materials.

[0321] Polynucleotides may contain native sequences (i.e., endogenous sequences encoding antibodies or fragments thereof) or may contain variants of such sequences. Polynucleotide variants contain one or more substitutions, additions, deletions, and / or insertions such that the immunoreactivity of the encoded polypeptide is not reduced relative to native immunoreactive molecules. The effect on the immunoreactivity of the encoded polypeptide can generally be assessed as described herein. Variants preferably exhibit at least about 70% identity, more preferably at least about 80% identity, even more preferably at least about 90% identity, and most preferably at least about 95% identity with a polynucleotide sequence encoding a natural antibody or a fragment thereof.

[0322] VI. Compositions and Formulations

[0323] A. Compositions

[0324] This disclosure also provides pharmaceutical compositions comprising an effective amount of an anti-TL1A antibody as described herein, and such pharmaceutical compositions for use in treatments as described herein. Examples of such compositions and methods of formulation are also described herein. It should be understood that a composition may comprise more than one anti-TL1A antibody.

[0325] The compositions used in this disclosure, in the form of lyophilized formulations or aqueous solutions, may further comprise pharmaceutically acceptable carriers, excipients, or stabilizers (Remington: The Science and Practice of Pharmacy, 20th Edition, 2000, edited by Lippincott Williams and Wlkins, KE Hoover).

[0326] Acceptable carriers, excipients, and stabilizers are non-toxic to recipients at doses and concentrations and may include: phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethyl diammonium chloride; benzalkonium chloride; benzyl chloride; phenol, butanol, or benzyl alcohol; p-hydroxybenzoic acid).Alkyl esters, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextran; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc protein complexes); and / or nonionic surfactants, such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG). Pharmaceutical excipients are further described herein.

[0327] Anti-TL1A antibodies and their compositions may also be used in combination with other pharmaceutical agents for enhancing and / or supplementing the effectiveness of the agent, or administered alone, simultaneously or sequentially.

[0328] B. Formulations

[0329] The therapeutic formulations of anti-TL1A antibodies used according to this disclosure are prepared for storage by mixing a protein of desired purity with optional pharmaceutical carriers, excipients or stabilizers (Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing, 2000). Acceptable carriers, excipients, and stabilizers are non-toxic to recipients at the doses and concentrations used and may include: phosphates, citrates, and other organic acids; salts, such as sodium chloride; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethyl diammonium chloride; benzalkonium chloride; benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10). (1 residue) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc protein complexes); and / or nonionic surfactants, such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG).

[0330] May contain anti-TL1AThe liposomes of the antibody are prepared by methods known in the art, such as those described in Epstein et al., Proc. Natl. Acad. Sci. USA 82:3688 (1985); Hwang et al., Proc. Natl. Acad. Sci. USA 77:4030 (1980); and U.S. Patents 4,485,045 and 4,544,545. U.S. Patent No. 5,013,556 discloses liposomes with enhanced cycle times. Particularly useful liposomes can be produced by a reverse-phase evaporation method using a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derived phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter with defined pore sizes to obtain liposomes with the desired diameter.

[0331] The active ingredient can be encapsulated in microcapsules (e.g., hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively) prepared by, for example, cohesive techniques or interfacial polymerization, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in coarse drop emulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing (2000).

[0332] Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semi-permeable matrices containing solid hydrophobic polymers of antibodies, which are in the form of molded articles such as membranes or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (US Patent No. 3,773,919), copolymers of L-glutamic acid and 7-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate)), sucrose isobutyrate acetate, and poly-D-(-)-3-hydroxybutyrate.

[0333] The formulation intended for in vivo administration must be sterile. This is readily achieved, for example, by filtration through a sterile filter membrane. Therapeutic anti-TL1A antibody compositions are typically placed in containers with sterile access ports, such as intravenous solution bags or vials with stoppers that can be punctured by a hypodermic needle.

[0334] The compositions according to this disclosure can be in unit dosage forms, such as tablets, pills, capsules, powders, granules, solutions or suspensions or suppositories, for oral, parenteral or rectal administration, or by inhalation or blowing.

[0335] To prepare solid compositions such as tablets, the main active ingredient is combined with a pharmaceutical carrier (e.g., conventional tableting ingredients).A solid preformulation composition is formed by mixing ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum, with other pharmaceutical diluents (e.g., water) to form a homogeneous mixture containing the compounds of this disclosure or their non-toxic pharmaceutical salts. When these preformulation compositions are referred to as homogeneous compositions, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The preformulation composition is then subdivided into unit dosage forms of the aforementioned type, containing about 0.1 to about 500 mg of the active ingredient of this disclosure. The novel composition can be coated or otherwise compounded into tablets or pills to provide a dosage form with a prolonged effect. For example, tablets or pills may comprise an inner dosage form and an outer dosage form component, the latter being an encapsulation of the former. The two components can be separated by an enteric coating that resists disintegration in the stomach and allows the internal components to enter the duodenum intact or with delayed release. Various materials can be used for such enteric coatings or coatings, including a variety of polymeric acids and mixtures of polymeric acids with shellac, cetyl alcohol, and cellulose acetate.

[0336] Suitable surfactants specifically include nonionic agents such as polyoxyethylene sorbitol (e.g., Tween™ 20, 40, 60, 80, or 85) and other sorbitols (e.g., Span™ 20, 40, 60, 80, or 85). Compositions containing surfactants will conveniently contain between 0.05% and 5% surfactant, and may be between 0.1% and 2.5%. It should be understood that other ingredients, such as mannitol or other pharmaceutical mediators, may be added if necessary.

[0337] Suitable emulsions can be prepared using commercially available fat emulsions such as INTRALIPID™, LIPOSYN™, INFONUTROL™, LIPOFUNDIN™, and LIPIPHYSAN™. The active ingredient is soluble in the pre-mixed emulsion composition, or alternatively soluble in oils (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and forms an emulsion when mixed with phospholipids (e.g., lecithin, soybean lecithin, or soybean lecithin) and water. It should be understood that other ingredients, such as glycerol or glucose, may be added to adjust the emulsion tension.

[0338] Suitable emulsions will typically contain up to 20% (e.g., between 5% and 20%) of oil. Fat emulsions may contain fat droplets between 0.1 pm and 1.0 pm, particularly between 0.1 pm and 0.5 pm, and have a pH in the range of 5.5 to 8.0.

[0339] The emulsion composition may be formed by mixing anti-TL1AThose prepared with Intralipid™ or its components (soybean oil, lecithin, glycerol, and water).

[0340] Compositions for inhalation or inhalation include solutions and suspensions or mixtures thereof in aqueous or organic solvents, as well as powders. Liquid or solid compositions may contain suitable pharmaceutical excipients as set forth above. In some aspects, the composition is administered via the oral or nasal route to obtain local or systemic effects. Compositions in preferably sterile pharmaceutical solvents may be nebulized using a gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be attached to a face mask, oxygen tent, or intermittent positive pressure ventilation machine. Solution, suspension, or powder compositions may be administered from a device that delivers the formulation in a suitable manner, preferably orally or nasally.

[0341] Such aspects are also a further aspect of the use of anti-TL1A antibodies in the treatment as described herein, or alternatively, a further aspect of the use of anti-TL1A antibodies in the manufacture of medicaments for use in the treatment.

[0342] VII. General Techniques

[0343] Unless otherwise stated, the practice of this disclosure will employ conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the scope of the art. The following references provide a comprehensive explanation of these techniques: *Molecular Cloning: A Laboratory Manual, 2nd Edition* (Sambrook et al., 1989), Cold Spring Harbor Press; *Oligonucleotide Synthesis* (edited by M.J. Gait, 1984); *Methods in Molecular Biology*, Humana Press; *Cell Biology: A Laboratory Notebook* (edited by J.E.C. Lis, 1998), Academic Press; *Animal Cell Culture* (edited by R.L. Freshney, 1987); *Introduction to Cell and Tissue Culture* (JP. Mather and PE. Roberts, 1998), Plenum Press; *Cell and Tissue Culture: Laboratory Procedures* (edited by A. Doyle, J.B. Griffiths, and D.G. Newell, 1993–1998), J. Wiley and...Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (edited by D.M. Weir and C.C. Blackwell); Gene Transfer Vectors for Mammalian Cells (edited by J.M. Miller and MP Calos, 1987); Current Protocols in Molecular Biology, manual 45 / 64 pages, 63 CN 121532526 A (edited by F.M. Usubel et al., 1987); PCR: The Polymerase Chain Reaction (edited by Mullis et al., 1994); Current Protocols in Immunology (edited by J.E. Coligan et al., 1991); Short Protocols in Molecular Biology (Wley and Sons, 1999); Immunobiology (edited by CA. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a practical approach (D. Catty, ed., IRL Press, 1988–1989); Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995).

[0344] VIII. Definitions

[0345] Unless otherwise stated, the following terms shall be understood to have the following meanings:

[0346] As used herein, “afimzibayumab” (also known as RO7790121, RVT-3101, orPF-06480605) is an antibody that binds to the tumor necrosis factor (TNF) superfamily protein TNF-like 1A (TL1A) and contains the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10.

[0347] An “antibody” is an immunoglobulin molecule capable of specifically binding to a target (such as carbohydrates, polynucleotides, lipids, polypeptides, etc.) via at least one antigen recognition site located in the variable region of an immunoglobulin molecule. As used herein, the term covers not only complete polyclonal or monoclonal antibodies, but also, unless otherwise stated, any antigen-binding portion that competes for specific binding with a complete antibody, fusion proteins containing antigen-binding portions, and any other modified conformation of an immunoglobulin molecule containing an antigen recognition site. Antigen-binding portions include, for example, Fab, Fab', F(ab')2, Fd, Fv, domain antibodies (dAb, e.g., shark and camel antibodies), fragments including complementarity-determining regions (CDRs), single-chain variable fragment antibodies (scFv), giant antibodies, microantibodies, intracellular antibodies, dimeric antibodies, trimeric antibodies, tetrameric antibodies, v-NARs, and bi-scFvs, as well as polypeptides containing at least a portion of an immunoglobulin sufficient to bind to a polypeptide-specific antigen. Antibodies include any class of antibodies, such as IgG, IgA, or IgM (or their subclasses), and antibodies do not need to belong to any particular class. Immunoglobulins can be classified into different classes based on the amino acid sequence of their heavy chain constant regions. Immunoglobulins are mainly divided into five classes: IgA, IgD, IgE, IgG, and IgM, and several of these classes can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The constant regions of the heavy chain corresponding to different classes of immunoglobulins are referred to as α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of different types of immunoglobulins are well known.

[0348] The “variable region” of an antibody refers to the variable region of the antibody light chain alone or in combination or the variable region of the antibody heavy chain. As is known in the art, the variable regions of the heavy and light chains each consist of four backbone regions (FRs) connected by three complementary determinant regions (CDRs) (also known as hypervariable regions) and contribute to the formation of the antigen-binding site of the antibody. If a variant of the subject variable region is desired, particularly having substitutions in amino acid residues outside the CDR region (i.e., in the backbone region), appropriate amino acid substitutions can be identified by comparing the subject variable region with the variable regions of other antibodies containing CDR1 and CDR2 sequences in the same classical class as the subject variable region, preferably conserved amino acid substitutions (Chothia and Lesk, J Mol Biol 196(4):901-917, 1987).

[0349] In some aspects, a clear description of the CDR and the identification of residues containing antibody binding sites are achieved by resolving the antibody structure and / or resolving the structure of the antibody-ligand complex. In some aspects, this can be achieved by any of a variety of techniques known to those skilled in the art (such as X-ray crystallography). In some aspects, various analytical methods can be used to identify or approximate the CDR region. In some aspects, various analytical methods can be used to identify or approximate the CDR region (pages 46 / 64, CN 121532526 A). Examples of such methods include, but are not limited to, Kabat definitions, Chothia definitions, AbM definitions, contact definitions, and conformational definitions.

[0350] Kabat definitions are a standard for numbering residues in antibodies and are commonly used to identify CDR regions. See, for example, a continuation of Johnson & Wu, 2000, Nucleic Acids Res., 28: 214-8. The Chothia definition is similar to the Kabat definition, but the Chothia definition takes into account the location of certain structural loop regions. See, for example, Chothia et al., 1986, J. Mol. Biol., 196: 901-17; Chothia et al., 1989, Nature, 342: 877-83. The AbM definition uses an integrated suite of computer programs for modeling antibody structures produced by the Oxford Molecular Group. See, for example, Martin et al., 1989, Proc Natl Acad Sci (USA), 86: 9268-9272; “AbM™, A Computer Program for Modeling Variable Regions of Antibodies,” Oxford, UK;

[0351] Oxford Molecular, Ltd. AbM defines the modeling of the tertiary structure of an antibody derived from a primary sequence using a combination of knowledge databases and de novo methods (such as those described by Samudrala et al., 1999, “Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach,” PROTEINS, Structure, Function and Genetics Suppl., 3:194–198).The definition of a contact is based on the analytical results of available complex crystal structures. See, for example, MacCallum et al., 1996, J. Mol. Biol., 5:732-45. In another approach (referred to herein as the “conformational definition” of a CDR), the position of a CDR can be identified as a residue that contributes enthalpy to antigen binding. See, for example, Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166. Other CDR boundary definitions may not strictly follow one of the above methods, but will overlap at least partially with the Kabat CDR, although they may be shortened or lengthened based on predictions or experimental findings that a particular residue or group of residues does not significantly affect antigen binding. As used herein, a CDR may refer to a CDR defined by any method known in the art, including combinations thereof. The methods used herein may utilize CDRs defined according to any of these methods. For any given embodiment containing more than one CDR, the CDR may be defined according to any of the definitions of Kabat, Chothia, extension, AbM, contact, and / or conformation.

[0352] As is known in the art, the “constant region” of an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, either alone or in combination.

[0353] As used herein, a “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous group of antibodies, for example, the individual antibodies contained in the group are identical except for a small number of naturally occurring mutations that may be present. Monoclonal antibodies have high specificity for a single antigenic site. Furthermore, unlike polyclonal antibody formulations, which typically comprise different antibodies targeting different determinants (epitopes), each monoclonal antibody targets a single determinant on the antigen. The modifier “monoclonal” indicates that the antibody is characterized by being obtained from a substantially homogeneous group of antibodies and should not be construed as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies used according to this disclosure can be prepared by the hybridoma method first described by Kohler and Milstein, 1975, Nature 256:495, or by recombinant DNA methods (such as those described in U.S. Patent 4,816,567). For example, monoclonal antibodies can also be isolated from phage libraries generated using the techniques described by McCafferty et al., 1990, Nature 348:552-554.

[0354] As is known in the art, “polynucleotide” or “nucleic acid” as used interchangeably herein refers to a chain of nucleotides of any length and includes DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases and / or analogs thereof, or can be prepared by DNA orRNA polymerase incorporates any substrate into the chain. Polynucleotides may contain modified nucleotides, such as methylated nucleotides and their analogues. If present, the nucleotide structure can be modified before or after chain assembly. The sequence of nucleotides can be interrupted by non-nucleotide components. Polynucleotides may be further modified after polymerization, such as by conjugation with labeled components. (See specification 47 / 64, page 65, CN 121532526 A) Other types of modifications include, for example, "terminal capping," with similar internucleotide modifications, such as those with uncharged bonds (e.g., methyl phosphate, triphosphate, amino phosphate, carbamate) and charged bonds (e.g., thiophosphate, dithiophosphate, etc.), those containing side groups, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine, etc.), those containing intercalating agents (e.g., acridine, psoralen, etc.), those containing chelating agents (e.g., metals, radioactive metals, boron, oxidizing metals, etc.), those containing alkylating agents, those with modified bonds (e.g., α-anomeric nucleic acids, etc.), and unmodified polynucleotides to replace one or more naturally occurring nucleotides. Furthermore, any hydroxyl groups typically present in sugars can be replaced (e.g., phosphate groups, phosphate groups), protected by standard protecting groups, or activated to prepare additional linkages with other nucleotides, or can be conjugated to a solid support. The OH groups at the 5' and 3' ends may be phosphorylated or partially substituted with amine or organic end-capping groups of 1 to 20 carbon atoms. Other hydroxyl groups may also be derived as standard protecting groups. Polynucleotides may also contain similar forms of ribose or deoxyribose known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro-, or 2'-azido-ribose, carbocyclic sugar analogs, α- or β-anomeric sugars, epimeric sugars (such as arabinose, xylose, or lythose, pyranose, furanose, heptacaphesose), acyclic analogs, and non-basic nucleoside analogs such as methylriboside. One or more phosphodiester bonds may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, wherein the phosphate ester is replaced by P(O)S (“thioester”), P(S)S (“dithioester”), (O)NR2 (“amic acid ester”), P(O)R, P(O)OR', CO or CH2 (“methylal”), wherein each R or R' is independently H or a substituted or unsubstituted alkyl group (1-20 C) optionally comprising an ether (-O-) bond, aryl, alkenyl, cycloalkyl, cycloalkenyl or aryl substituted aspect. Not all links in a polynucleotide need to be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.

[0355] Antibodies that “preferentially bind” or “specifically bind” to epitopes (these terms are used interchangeably herein) are well-known terms in the art, and methods for determining such specificity or preferential binding are also well-known in the art. A molecule is said to “specifically bind” or “preferentially bind” if it reacts or associates with a particular cell or substance more frequently, more rapidly, for a longer duration, and / or with a greater affinity than with alternative cells or substances. An antibody is said to “specifically bind” or “preferentially bind” to a target if it binds to the target with greater affinity, affinity, ease, and / or for a longer duration than it binds to other substances. For example, an antibody that specifically or preferentially binds to a target (e.g., TL1A) epitope is an antibody that binds to that epitope with greater affinity, affinity, ease, and / or for a longer duration than it binds to other target or non-target epitopes. It should also be understood from reading this definition that, for example, an antibody (or part or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Therefore, “specific binding” or “preferential binding” does not necessarily require (but may include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding.

[0356] As used herein, “substantially pure” means material that is at least 50% pure (i.e., free of impurities), more preferably at least 90% pure, more preferably at least 95% pure, even more preferably at least 98% pure, and most preferably at least 99% pure.

[0357] “Host cell” includes a single cell or cell culture that may be or has been a recipient for a vector incorporating a polynucleotide insert. Host cell includes progeny of a single host cell, and the progeny may not necessarily be completely identical to the original parent cell (in terms of morphology or genomic DNA complementarity) due to natural mutation, accidental mutation, or intentional mutation. Host cell includes cells transfected in vivo with the polynucleotides of this disclosure.

[0358] As is known in the art, the term “Fc region” is used to define the C-terminal region of the immunoglobulin heavy chain. “Fc region” can be a native sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of the immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is generally defined as extending from the amino acid residue at position Cys226 or from Pro230 to the carboxyl terminus of the heavy chain. The residue numbering in the Fc region is based on the EU index, such as Kabat et al., Sequences, 48 / 64 pages, 66 CN 121532526 A of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health.As described in Bethesda, Md., 1991. The Fc region of an immunoglobulin typically contains two constant domains: CH2 and CH3. As is known in the art, the Fc region can exist in dimer or monomeric form.

[0359] As used in the art, “Fc receptor” and “FcR” describe receptors for Fc regions that bind to antibodies. Preferred FcRs are native human FcRs. Furthermore, preferred FcRs are FcRs that bind to IgG antibodies (a type of γ receptor) and include receptors of the FcyRI, FcyRII, and FcyRIII subclasses, which include allelic variants or spliced ​​forms of these receptors. FcyRII receptors include FcyRIIA (“activating receptor”) and FcyRIIB (“inhibitory receptor”), which have similar amino acid sequences and differ primarily in their cytoplasmic domains. FcR is reviewed in Ravetch and Kinet, 1991, Ann. Rev. Immunol., 9:457–92; Capel et al., 1994, Immunomethods, 4:25–34; and de Haas et al., 1995, J. Lab. Clin. Med., 126:330–41. “FcR” also includes the neonatal receptor FcRn, which is responsible for transferring maternal IgG to the fetus (Guyer et al., 1976, J. Immunol., 117:587; and Kim et al., 1994, J. Immunol., 24:249).

[0360] As used herein with respect to antibodies, the term "competitive" means that the binding of a first antibody or its antigen-binding portion to an epitope is sufficiently similar to the binding of a second antibody or its antigen-binding portion to an epitope, such that the binding of the first antibody to its homologous epitope in the presence of the second antibody is detectably reduced compared to the binding of the first antibody to its homologous epitope in the absence of the second antibody. Alternative expressions (wherein the binding of the second antibody to its epitope is also detectably reduced in the presence of the first antibody) may, but are not necessary. That is, the first antibody may inhibit the binding of the second antibody to its epitope, while the second antibody does not inhibit the binding of the first antibody to its corresponding epitope. However, when antibodies detectably inhibit the binding of another antibody to its homologous epitope or ligand to the same, greater, or lesser extent, these antibodies are said to "cross-compete" with each other for binding to their respective epitopes. This disclosure covers both competitive and cross-competitive antibodies. Regardless of the mechanism by which such competition or cross-competition occurs (e.g., steric hindrance, conformational change, or binding to a common epitope or its portion), those skilled in the art will understand, based on the teachings provided herein, that such competitive and / or cross-competitive antibodies encompassAnd can be used in the methods disclosed herein.

[0361] As used herein, “treatment” is a method for obtaining a beneficial or desired clinical outcome. For the purposes of this disclosure, a beneficial or desired clinical outcome includes, for example, a reduction or improvement in signs and symptoms of inflammatory bowel disease (IBD) (e.g., ulcerative colitis (UC) or Crohn's disease (CD)) compared to, for example, before administration of an anti-TL1A antibody.

[0362] “Improvement” means, for example, a reduction or improvement in one or more signs or symptoms of IBD (e.g., UC or CD) compared to, for example, without administration of the anti-TL1A antibody described herein. “Improvement” also includes a reduction or decrease in the duration of symptoms.

[0363] As used herein, an “effective dose” or “effective amount” of a drug, compound, or pharmaceutical composition is an amount sufficient to affect any one or more beneficial or desired outcomes. In a more specific sense, an effective amount prevents, alleviates, or improves signs or symptoms of IBD, and / or prolongs the survival of the treated subject. For prophylactic use, beneficial or desired outcomes include eliminating or reducing risk, lessening severity, or delaying disease onset, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that occur during disease development. For therapeutic use, beneficial or desired outcomes include clinical outcomes such as reducing one or more signs or symptoms of IBD, reducing the dosage of other agents required to treat the disease, enhancing the effect of another drug, and / or delaying disease progression in patients. An effective dose may be administered in one or more administrations. For the purposes of this disclosure, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve prevention or treatment. As understood in a clinical context, an effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Therefore, an "effective dose" may be considered in the context of administration of one or more therapeutic agents, and an effective amount of a single agent may be considered if combined with one or more other agents to obtain or achieve the desired outcome.

[0364] Treatment is “effectively improved” or “effectively reduced” when the assessment of signs or symptoms of IBD is quantified via clinical measurements relative to baseline and during and / or after treatment. The difference between clinical measurements at baseline and those during / after treatment is compared and used to determine whether signs or symptoms have improved and whether treatment is effective. This comparison may include a comparison with placebo or with one or more of prior therapies.

[0365] The term “mucosal healing” refers to a Mayo endoscopy score of 0 or 1 and a Geboes histological score of 0 or 1. Aranzazu, J-E. et al. Journal ofCrohn's and Colitis, Vol. 11(3), 2017, 305-313. In one respect, mucosal healing was defined as endoscopic improvement + histological improvement (Mayo endoscopy score ≤ 1 and Geboes ≤ 3.1). Histological improvement was defined as neutrophil crypt involvement in the epithelium < 5% (Geboes ≤ 3.1). Histological remission was defined as no crypt involvement in the epithelium (Geboes < 2).

[0366] In this document, “effective amount” refers to the level of a therapeutic agent (e.g., an anti-TL1A antibody (e.g., RO7790121) or a combination of therapeutic agents (e.g., an anti-TL1A antibody with one or more additional therapeutic agents) that achieves the therapeutic outcome. In some instances, an effective amount of a therapeutic agent or combination of therapeutic agents is the level at which a clinical endpoint is achieved, such as clinical remission, clinical response (e.g., improved modified Mayo score (mMS) or partially modified Mayo score (pmMS)), endoscopic improvement, endoscopic remission, histological-endoscopic mucosal improvement, histological-endoscopic remission, and / or no corticosteroid remission. Improvement (e.g., in terms of clinical remission) can be relative to a suitable reference treatment (e.g., treatment excluding anti-TL1A antibody).

[0367] As used herein, the term “induction phase” refers to a series of one or more doses or dosing cycles (e.g., about 2 to 6 doses or dosing cycles) of one or more therapeutic agents (e.g., anti-TL1A antibody (e.g., RO7790121)) administered to a subject, wherein the one or more doses or dosing cycles optionally follow a maintenance phase.

[0368] As used herein, the term “maintenance phase” refers to a series of one or more doses or cycles of administration of one or more therapeutic agents (e.g., an anti-TL1A antibody (e.g., RO7790121)) to a subject after the induction phase, in the absence of associated interventional procedures (i.e., no interventional procedures related to a disease or symptom expected to be treated by one or more therapeutic agents). In some cases, the maintenance phase is initiated only if the subject does not experience disease progression or unacceptable toxicity during the induction phase. The induction phase and the maintenance phase may or may not include the use of the same therapeutic agent.

[0369] The terms “patient,” “individual,” or “subject” used interchangeably herein refer to mammals, more preferably humans. Mammals also include, but are not limited to, farm animals (e.g., cattle, pigs, horses, chickens, etc.), locomotives, pets, primates, horses, dogs, cats, mice, and rats.

[0370] As used herein, a “medicinal carrier” or “medicinal excipient” includes any material that, when combined with an active ingredient, enables that ingredient to retain its biological activity and not react with the subject’s immune system. Examples include, but are not limited to, any standard pharmaceutical...Carriers, such as phosphate-buffered saline solutions, water, emulsions (such as oil / water emulsions), and various types of wetting agents. Preferred diluents for aerosol or parenteral administration are phosphate-buffered saline (PBS) or physiological (0.9%) saline. Compositions containing such carriers are formulated using well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990; and Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing, 2000).

[0371] References to “about” values ​​or parameters herein include (and describe) aspects relating to that value or parameter itself. For example, a description relating to “about X” includes a description of “X”, and a range of numbers includes numbers that define a range. Generally, the term “about” refers to the specified value of a variable and all values ​​of the variable within the experimental error of that specified value (e.g., within the 95% confidence interval of the mean) or within 10% of that specified value, whichever is greater. When the term “about” is used in the context of a time period (year, month, week, day, etc.), the term “about” means a subsequent secondary time period after the time period plus or minus one amount (e.g., about 1 year means 11 to 13 months; about 6 months means 6 months plus or minus 1 week; about 1 week means 6 to 8 days, etc.), or within 10% of the specified value, whichever is greater.

[0372] The term “subcutaneous application” means the application of a substance into the subcutaneous layer.

[0373] The term “preventing / prevent” means (a) preventing the occurrence of a disease or (b) delaying the onset of a disease or the onset of disease symptoms.

[0374] It should be understood that whenever an aspect is described herein with the language “comprising,” other similar aspects described with “consisting of” and / or “substantially consisting of” are also provided.

[0375] When an aspect or aspect of this disclosure is described according to the Markush Group or other alternative groupings, this disclosure covers not only the entire group listed as a whole, but also each member of that group individually and all possible subgroups of the main group, and also the main group lacking one or more of its members. This disclosure also contemplates the express exclusion of one or more members of any group in the claimed disclosure.

[0376] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those in this disclosure.The meanings are the same as those commonly understood by one of ordinary skill in the art. In case of conflict, this specification (including the definitions) shall prevail. Throughout the specification and claims, the word “comprising” or variations such as “comprises” should be understood to imply inclusion of the stated integers or groups of integers, but not to exclude any other integers or groups of integers. Unless the context requires otherwise, singular terms shall include plural terms, and plural terms shall include singular terms. Any instance following the term “e.g., for example” is not intended to be exhaustive or limiting.

[0377] Exemplary methods and materials are described herein, although methods and materials similar to or equivalent to those described herein may also be used in practice or testing of this disclosure. These materials, methods, and embodiments are illustrative only and are not intended to be limiting.

[0378] IX. Examples

[0379] Example 1. TNFSF15 Haplotype SNP Combinations

[0380] In this experiment, a computational algorithm was developed to determine whether a subject is a haplotype B carrier of the TNFSF15 haplotype (i.e., whether the subject is a haplotype B carrier) based on DNA sequencing data (e.g., genome sequencing data) based on a selected number of single nucleotide polymorphisms (SNPs).

[0381] As shown in Figure 1, based on the reference sequence GenBank NM_005118.2, haplotype B is defined as the TNFSF15 gene region, which has nucleotide T / C / A / T / C at positions 15,524; 9,706; -358; -638; and -12,506, respectively. The first nucleotide of the exon 1 start site is designated as position 1 (haplotype positions are 26 / 31 / 35 / 36 / 41, as provided in Yamazaki et al., Human Molecular Genetics, 14(22): 3499-3506, 2005), which is in the TNFSF15 gene region encoding the TL1A gene (Table 3). If a subject is heterozygous or homozygous for haplotype B, meaning one or both copies of the gene region are haplotype B (i.e., one or both copies of the TNFSF15 gene region have nucleotide T / C / A / T / C at haplotype positions 15,524; 9,706; -358; -638; and -12,506 (26 / 31 / 35 / 36 / 41)), then the subject is identified as haplotype B.

[0382] Haplotype positions 15,524; 9,706; -358; -638; and -12,506 (26, 31, 35, 36, and 41) correspond to, respectively, as per NIH NCBI.The SNPs rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 identified in the dbSNP database (see Table 3). Haplotype B contains a reference nucleotide at each of these locations: therefore, the haplotype B TNFSF15 gene region can be identified by the absence of each of the SNPs rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 (i.e., the presence of a wild-type allele at each of these locations).

[0383] Haplotype B non-carrier subjects are defined as subjects who do not carry the haplotype B TNFSF15 gene region. For example, haplotype B non-carrier subjects may be homozygous for non-haplotype B alleles, such as haplotype A as shown in Figure 1 (Michelsen et al., PLoS One, 4(3): e4719, 2009) (e.g., may have nucleotide C / T / G / C / T at haplotype positions 26 / 31 / 35 / 36 / 41).

[0384] Table 3. SNPs in the TNFSF15 gene region of interest

[0385]

[0386] In the development of the algorithm, different combinations of five SNP sites rs3810936 (SNP 1), rs6478108 (SNP 2), rs6478109 (SNP 3), rs7848647 (SNP 4) and rs7869487 (SNP 5) were used, including all feasible combinations of 2, 3 and 4 SNPs selected from SNP 1, SNP 2, SNP 3, SNP 4 and SNP 5, to determine whether the subject was a haplotype B carrier or a haplotype B non-carrier. If neither copy of the gene region corresponding to any of the five SNP sites contains the nucleotide corresponding to haplotype B at the SNP site (e.g., CC / TT / GG / CC / TT at SNP1–SNP5), the subject is defined as a haplotype B non-carrier. For each SNP combination, if the first SNP site from the test combination belongs to a haplotype other than haplotype B in either of the two copies of the gene region (i.e., referred to below as "non-haplotype B homozygous"), the subject is defined as a haplotype B non-carrier. If the first SNP site from the test combination is haplotype B homozygous or heterozygous (i.e., if one or both copies of the gene region corresponding to the SNP site contain the nucleotide corresponding to haplotype B at the SNP site), the subject is defined as a haplotype B non-carrier.If the SNP is not homozygous for haplotype B, the next SNP site in the combination is tested until a SNP site is determined to be non-haplotype B homozygous. In this case, the subject is identified as a haplotype B non-carrier, or all SNP sites in the combination are tested. If no SNP site is determined to be non-haplotype B homozygous, the subject is identified as a haplotype B carrier. The last step of the algorithm is the stage where misclassification may occur. Therefore, testing all SNP combinations can determine which SNP combination produces the fewest misclassifications.

[0387] The algorithm containing different SNP combinations was iterated and applied to genomic sequence data from the 1000 Genomes Project (a total of 2504 subjects) (Sudmant et al., Nature 526, 75-81 (2015)), and the true positive rate, false positive rate, and false negative rate of each SNP combination were determined to determine the optimal SNP combination that can effectively identify haplotype B carriers and haplotype B non-carriers. As shown in Table 4, the combination of SNP 1 (rs3810936) and SNP 5 (rs7869487) provided the highest accuracy among various two-SNP combinations, and the accuracy was comparable to the best-performing three-SNP and four-SNP combinations.

[0388] Table 4. Accuracy of SNP combination in determining whether a subject is a carrier of TNFSF15 haplotype B (1000 Genomes Project data) Specification 52 / 64 pages 70 CN 121532526 A

[0389]

[0390] The algorithm was further applied to the genome sequence data of the Human Genome Diversity Project (Bergstrom et al., Science 367 (6484), eaay5012 (2020)) (a total of 4151 samples, of which 2501 samples overlapped with the 1000 Genomes Project). Unlike the 1000-person genome data, the Human Genome Diversity Project (HGDP) data is not phased, and due to the phased nature, misclassified subjects in overlapping datasets have different true values. Table 5 shows the analysis results from the HGDP. Notably, the three-SNP combination of SNP1 (rs3810936), SNP3 (rs6478109), and SNP5 (rs7869487) yielded 0 misclassifications. Table 6 shows the accuracy of certain SNP combinations assessed using the HGDP.

[0391] Table 5. Accuracy of SNP combinations in determining whether a subject is a carrier of TNFSF15 haplotype B (HGDP data)Instructions for Use, Pages 53 / 64, 71 CN 121532526 A

[0392]

[0393] Table 6. Accuracy of SNP Combinations in Determining Whether a Subject is a TNFSF15 Haplotype B Carrier (Human Genome Diversity Project Data) Instructions for Use, Pages 54 / 64, 72 CN 121532526 A

[0394]

[0395] Example 2. 2-SNP Multiplex qPCR Assay

[0396] The TL1A SNP assay is a multiplex qPCR-based assay that detects the presence of two specific lineage SNPs, rs3810936 (SNP 1) and rs7869487 (SNP 5), in biological samples from patients, identifying non-carrier patients with TNFSF15 haplotype B who may receive additional benefit from afimazibium therapy (see Example 1). In this assay, short DNA targets (amplifiers) are exponentially amplified in multiple cycles. Fluorescently labeled probes designed to bind to amplicon allow for proper differentiation of the presence of a SNP (mutant / MUT; also known as "alternative" or "Alt") or the absence of a SNP (wild-type / WT; "Ref"). Samples with mixed amplicons will have a mixture of WT and MUT probes that bind to the amplicon, thus enabling differentiation of heterozygous (HET) samples. The probes are constructed with reporter dyes (FAM, SUN, TAMRA, and Cy5) at the 5' end and quencher dyes (BHQ-1 and BHQ-2) at the 3' end. Although the probes are intact, the proximity of the quencher dyes significantly reduces the fluorescence emitted by the reporter dyes via fluorescence resonance energy transfer (FRET). If a target sequence is present, the probe will anneal to its specific complementary region in the amplicon and cleave upon primer extension by the 5' nuclease activity of Taq DNA polymerase. Cleavage separates the reporter dye from the quencher dye, resulting in an increased signal from the reporter dye. Additional report dye cleaved from the probe during each cycle, resulting in an increase in fluorescence intensity proportional to the amount of amplicon produced. Fluorescence signals were monitored after each cycle, and the proprietary automated identification function of the QuantStudio™ 5 Dx software determined the genotype interpretation.

[0397] Once the genotypes of the two target SNP sites have been identified, the patient's haplotype B carrier / non-carrier status can be determined by comparing the SNP alleles to the reference table provided below (see Table 7 and Figure 2). For rs3810936 (SNP 1), the reference (“Ref”) allele is T, and the alternative (“Alt”) allele is C. For 7869487...(SNP 5), with the reference (“Ref”) allele being C and the alternative (“Alt”) allele being T.

[0398] Patients identified as haplotype B carriers were classified as having a negative biomarker status. Patients identified as haplotype B non-carriers were classified as having a positive biomarker status (i.e., identified as patients who may receive additional benefit from afimizumab therapy).

[0399] Table 7. Reference Table of TNFSF15 Biomarker Status

[0400]

[0401] 1 According to the 1000 Genomes Project database, 97.3% of the subjects in these categories were haplotype B carriers (see Example 1).

[0402] 2 Based on the overall misclassification rate of approximately 1% in the 1000 Genomes Project database, the subjects were presumed to be biomarker negative (see Example 1).

[0403] Example 3. Efficacy and safety of the fully human monoclonal antibody RO7790121 blocking TL1A in moderate to severe active ulcerative colitis: Results of the randomized, double-blind, placebo-controlled dose-range phase 2b TUSCANY-2 study

[0404] Introduction

[0405] Tumor necrosis factor-like ligand 1A (TL1A) is a novel therapeutic target for inflammatory bowel disease. Patients with moderate to severe active ulcerative colitis (UC) treated with the anti-TL1A antibody afimzibazumab (RO7790121) (a fully human neutralizing monoclonal antibody against TL1A) showed significant endoscopic improvements and adequate safety in the phase 2a TUSCANY-1 trial (Danese et al., Clin Gastroenterol Hepatol, 19:2324–32.e6, 2021).

[0406] This example provides data from the global, randomized, double-blind, placebo-controlled, dose-range Phase 2b TUSCANY-2 instruction manual, pages 56 / 64, CN 121532526 A (NCT04090411), which evaluated the efficacy and safety of afimkibart at various subcutaneous (SC) doses every four weeks (Q4W) in men or women aged 18 to 75 years with moderate to severe active UC (total Mayo score ≥ 6, endoscopic score ≥ 2) who had previously failed or were intolerant to ≥ 1 line of conventional or advanced therapy (selected from the following categories: steroids, immunosuppressants, anti-TNF, anti-integrin inhibitors, anti-IL-12 / 23 inhibitors, and JAK inhibitors).

[0407] Objectives and Methods

[0408] Patients were randomized to receive afimkibart SC monthly during a 12-week induction period.Afimzidimab SC 50, 150, 450 mg or matched placebo (PBO) was administered monthly during the 40-week maintenance period (Figure 3). Efficacy endpoints were assessed in the induction and maintenance intention-to-treat analysis groups at weeks 14 and 56, respectively. The primary endpoint was clinical response at week 14 (based on total Mayo score (MS)) and safety at weeks 14 and 56. Pre-specified key secondary endpoints of clinical response using modified Mayo score (mMS) were consistent with updated FDA guidance. Other secondary endpoints included clinical response at week 56 (based on total MS and mMS) and endoscopic improvement at weeks 14 and 56. Efficacy analyses of predefined biomarker subgroups were also performed.

[0409] Table 8 provides the definitions of efficacy endpoints for the TUSCANY-2 study.

[0410] Table 8. Definition of Efficacy Endpoints

[0411]

[0412] “Mayo score” refers to the Mayo score according to the Mayo scoring system used to assess the activity of ulcerative colitis.

[0413] Study Design

[0414] TUSCANY-2 is a phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy, safety, and pharmacokinetics (PK) of PF-06480605 in participants with moderate to severe active UC. Approximately 240 participants were planned to be randomized, and assuming a dropout rate of 10%, 216 of them were expected to complete the induction phase. Participants were randomly assigned to one of nine treatment sequences using an allocation ratio of 2:2:2:2:2:3:1:1:1 (Table 9).

[0415] Table 9. Treatment Sequence Instructions 57 / 64 pages 75 CN 121532526 A

[0416]

[0417] SC = subcutaneous; Q4W = every 4 weeks.

[0418] The study was conducted in 4 phases: screening, induction, long-term treatment, and follow-up. The screening period lasted up to 6 weeks to assess eligibility. During the 12-week induction period, participants were randomized to receive 50 mg, 150 mg, 450 mg, or a matched placebo every 4 weeks via subcutaneous administration. During the 40-week long-term treatment period, all participants received the active drug: 50 mg, 150 mg, or 450 mg every 4 weeks via subcutaneous administration. During the 12-week follow-up period, a final safety and efficacy assessment was planned. Overall, each participant participated in the study for up to 70 weeks. Participants who discontinued the study at any time during the study period...Participants will enter the follow-up period and receive an early withdrawal visit. Any participant who withdraws early from treatment (after randomization and during the active study intervention) will receive three study visits (one of which will be an early withdrawal visit) within a total of 12 weeks from the last dose of the intervention product.

[0419] Two interim analyses were performed in this study. The first analysis was performed when 100% of participants had completed or had the opportunity to complete the week 14 visit. The second interim analysis was performed when all participants had completed or had the opportunity to complete the induction phase and approximately 100% of them had completed or had the opportunity to complete at least 6 months of long-term treatment.

[0420] Results

[0421] A total of 246 participants were enrolled at 114 centers in 23 countries. Overall, 245 patients entered the induction phase (receiving at least one induction dose); 228 patients completed the induction phase, and 224 patients entered the study maintenance phase (receiving at least one maintenance dose).

[0422] During the induction period, all 245 treated participants (45, 47, 62, and 91 in the placebo, PF-06480605 50 mg, 150 mg, and 450 mg groups, respectively) were included in the safety and intention-to-treat (ITT) analysis cohort; 240 participants (40, 47, 62, and 91 in the four groups, respectively) were included in the biomarker analysis cohort; and 239 participants (40, 47, 62, and 90 in the four groups, respectively) were included in the immunogenicity analysis cohort.

[0423] During the long-term treatment period, a total of 224 participants (12 participants [placebo → 50 mg], 14 participants [placebo → 150 mg], 14 participants [placebo → 450 mg], 46 participants [50 mg → 50 mg], 27 participants [150 mg → 50 mg], 30 participants [150 mg → 150 mg], 26 participants [450 mg → 50 mg], 26 participants [450 mg → 150 mg], and 29 participants [450 mg → 450 mg]) were included in the maintenance intention-to-treat (mITT) analysis.

[0424] A. Demographic and Baseline Characteristics

[0425] The demographic and baseline characteristics of the patients treated in the TUSCANY-2 study are shown in Table 10. The demographic characteristics of the placebo and PF-06480605 groups were largely similar.

[0426] Table 10. Demographic and baseline characteristics description 58 / 64 pages 76 CN 121532526 A

[0427]

[0428] Among participants treated during the induction period, the median duration of disease was 4.70 years, ranging from 0.25 to 36.2 years. Baseline disease characteristics were balanced between the placebo and the three PF-06480605 groups.

[0429] Among participants treated during the induction period, the majority had left-sided colitis (43.3%), followed by pancolitis (diagnosed in 39.2% of participants). Disease severity was generally balanced between the placebo and the three PF-06480605 groups.

[0430] Among participants treated during the induction period, a total of 95.5%, 41.2%, 38.8%, and 23.7% of participants had received prior steroid, biologic, anti-TNF, and / or anti-integrin therapy, respectively. Prior medical experience (i.e., steroids, biologics, anti-TNF, anti-integrin, azathioprine, 6-MP, methotrexate, anti-IL-12 / 23 inhibitors, and JAK inhibitors) was generally balanced between the placebo and the three PF-06480605 groups.

[0431] Among participants treated during the long-term treatment period, a total of 96.0%, 41.5%, 39.3%, and 24.1% of participants had received prior steroid, biologic, anti-TNF, and / or anti-integrin treatments, respectively. Prior medical experience was generally balanced across all treatment sequences.

[0432] Among participants treated during the induction period, 97.1% of participants received conventional concomitant medication. A total of 73.1% of participants received mesalazine (ranging from 67.7% to 80.2% in the placebo and three PF-06480605 groups).

[0433] Among participants treated during the long-term treatment period, 76.8% received routine concomitant medication.

[0434] Among participants treated during the induction period, 90 out of 245 participants were using steroids at baseline (see 59 / 64 pages, CN 121532526, Retinol). Of those 90 participants, 89 (98.9%) did not change their steroid dose.

[0435] Among participants treated during the long-term treatment period, 86 out of 224 participants were using steroids at baseline. Of those 86 participants, 43 (50.0%) did not change their steroid dose.

[0436] B. Efficacy

[0437] At week 14, based on total Mayo Criteria, 25.5%, 23.3%, and 23.9% of patients in the afimizumab 50 mg, 150 mg, and 450 mg arms, respectively, experienced clinical remission, compared to 11.6% in the placebo group.Patients experienced clinical remission (p > 0.05) (Table 11).

[0438] At week 14, the proportions of patients achieving clinical remission in the afimzimab 50 mg, 150 mg, and 450 mg arms, based on modified Mayo score (mMS), were 29.8%, 35.0%, and 31.8%, respectively, compared to 11.6% in the placebo arm (p < 0.05) (Table 11 and Figure 4A). Consistent, statistically significant effects were observed at week 14 across the endpoint and patient cohort. As shown in Figures 7A and 7B, afimzimab achieved a higher rate of clinical remission (based on mMS) and endoscopic improvement than placebo in all participants and in the TNFSF15 biomarker-positive (haplotype B non-carrier; "biomarker-positive") patient cohort.

[0439] Improvements in clinical remission were sustained with maintenance therapy (Table 11 and Figure 5).

[0440] Furthermore, at weeks 14 and 56, a larger proportion of patients showed endoscopic improvement with all doses of afimizumab compared to placebo (Table 11 and Figures 4B and 6). A trend toward higher numerical values ​​of treatment efficacy was observed in patients with positive biomarkers compared to all participants.

[0441] Table 11. Summary of efficacy results at weeks 14 and 56

[0442]

[0443] n = number of participants with observational data or non-responder imputation (NRI) in the analysis set, excluding a total of seven participants whose data were missing due to medical or procedural complications caused by COVID-19.

[0444] *Primary endpoint: defined as total Mayo score ≤ 2 with no individual sub-score > 1.

[0445] † Secondary endpoints: defined according to the mMS definition of the U.S. Food and Drug Administration (FDA) (endoscopy score = 0 or 1, a reduction of ≥ 1 point from baseline to achieve a bowel frequency sub-score = 0 or 1, and a rectal bleeding sub-score = 0).

[0446] ‡ Defined as an endoscopy score = 0 or 1.

[0447] § All dose groups were analyzed; however, maintenance efficacy results are only available for patients who received the same dose during the induction and maintenance periods.

[0448] ¶ Data for week 56 are not shown because no placebo was administered during the maintenance period.

[0449] ** Data for the endoscopic improvement endpoint at week 56 with a 150 mg dose, n = 28 patients, are available. 60 / 64 pages, 78 CN 121532526 A

[0450] Statistically significant results were observed at each test dose in both the overall population and the biomarker-positive patient population.Efficacy results with both medical and clinical significance. Table 12 below provides the results for the 450 mg dose at week 14. “Experience with biologics” was defined as prior experience with anti-TNF agents, anti-integrin agents, and / or anti-IL-12 / 23 agents.

[0451] Table 12. Summary of efficacy results for the 450 mg dose at week 14

[0452]

[0453] Efficacy results for subjects who were intolerant to, had an inadequate response to, or experienced loss of response to prior therapy are shown in Figures 8A, 8B, 8B, and 9B. Figures 8A and 8B show the rates of clinical remission and endoscopic improvement in patients who were intolerant to, had an inadequate response to, or experienced loss of response to prior advanced therapy (anti-tumor necrosis factor (TNF) agents, anti-integrin agents, anti-IL-12 / 23 agents, and / or Janus kinase (JAK) inhibitors). Figures 8A and 8B show the rates of clinical remission and endoscopic improvement in patients who were intolerant to, had an inadequate response to, or experienced loss of response to prior therapy containing anti-TNF agents.

[0454] C. Safety

[0455] Afimzimab was well tolerated, and no safety signals were identified. No dose-related trends in adverse events were observed.

[0456] During the induction period, 47.8% (117 / 245) of patients reported ≥1 treatment-induced adverse event (TEAE) (Tables 13 and 14). According to preferred terminology, the most common TEAEs (occurring in ≥5% of patients) were anemia (5.3%) and headache (5.3%) (Table 15). As shown in Table 14, the treatment-induced adverse events “infection,” “anemia,” and “injection site reaction” were balanced across treatment arms. As of week 14, a total of 10 patients experienced serious TEAEs (placebo = 4 patients; 50 mg = 3 patients; 450 mg = 3 patients). Severe and serious adverse events were incidental and generally considered unrelated to the study drug. No patients discontinued the study due to TEAEs. Similar safety profiles were observed during the maintenance period.

[0457] Table 13. Treatment-related adverse events observed in the TUSCANY-2 set of the induction phase safety analysis

[0458]

[0459] † Participants with records of AEs that indicated that the participant discontinued the study. ‡ Participants with records of AEs that indicated that the action taken in response to the study treatment was to withdraw the drug but did not lead to the participant discontinuing the study.

[0460] Adverse events were categorized based on MedDRA version 25.1.

[0461] Abbreviation: mg = milligram. Instruction manual, pages 61 / 64, 79 CN 121532526 A

[0462] Table 14. Safety analysis set during induction periodTreatment-related adverse events observed in TUSCANY-2 (summary data)

[0463]

[0464] Table 15. Treatment-related adverse events observed in ≥5% of participants during the induction phase safety analysis

[0465]

[0466] All values ​​are n (%).

[0467] Adverse events were categorized based on MedDRA version 25.1.

[0468] No effect of immunogenicity on clinical efficacy or safety outcomes was observed. At week 14, the anti-drug antibody (ADA) rate was 46% and the neutralizing antibody (NAb) rate was 8% at a dose of 450 mg. These immunogenicity results are consistent with those of approved biologics: Humira showed ADA rates of 32% to 46% and neutralizing antibody rates of 11% to 23% at week 24 (Hanauer et al., 2021; Weinblatt et al., 2017; Cohen et al., 2019), and Skyrizi showed ADA rates of 19% and neutralizing antibody rates of 8% at week 16 (Skyrizi Prescription 62 / 64 pages 80 CN 121532526 A (risankizumab) FDA Summary Basis of Approval). As shown in Table 16, higher levels of ADA were associated with lower doses of subcutaneous (SC) administration. During induction using the SC regimen, the median times for first detection of ADA and NAb were 30 to 57 days and 58 to 85 days, respectively.

[0469] Table 16. Immunogenicity as shown by dose

[0470]

[0471] C. Induction and maintenance exposure-response

[0472] As shown in Table 17, higher afimizumab exposure (Cave tertiary up to week 14) during the induction phase was associated with a higher week 14 outcome rate. Week 14 Cave is the predicted mean concentration of afimizumab up to week 14.

[0473] Table 17. Exposure response at the Cave tertiary up to week 14

[0474]

[0475] As shown in Table 18, higher afimizumab exposure (Cave tertiary up to week 56) was associated with a higher week 56 outcome rate among inducing responders who continued to use the same dose during the maintenance phase. Week 56 Cave is the predicted mean concentration of afimizumab up to week 56.

[0476] Table 18. Exposure response of Cave tertiaries up to week 56

[0477]

[0478] As shown in Table 19, almost all recipientsPatients receiving the 450 mg dose (approximately 74% in the induction phase and approximately 96% in the maintenance phase) had exposures in the top tertiary, indicating that this dose is necessary to achieve systemic exposure corresponding to the maximum specification page 63 / 64 81 CN 121532526 A and sustained efficacy.

[0479] Table 19. Pharmacokinetic exposure during induction and maintenance

[0480]

[0481] D. 450 mg dose

[0482] The 450 mg SC Q4W dosing regimen is the only dose arm where efficacy tends to increase over time.

[0483] At the 450 mg dose, excellent efficacy was observed at both week 52 and week 14 (36% and 29% of all participants; 43% and 33% of biomarker-positive patients, respectively).

[0484] The percentage of patients with sustained clinical response (when receiving the same dose in both the induction and maintenance phases) was highest (75%) at the 450 mg dose compared to participants receiving lower doses (50 mg or 150 mg) (i.e., higher efficacy was observed in participants maintaining the same 450 mg dose during both the induction and maintenance phases).

[0485] Higher efficacy was observed in participants maintaining the same 450 mg dose during the maintenance phase compared to patients receiving lower doses (e.g., 50 mg or 150 mg).

[0486] As shown above, exposure-response analysis of subject exposures indicated that participants with the highest tertiary mean PK concentration over 56 weeks had significantly higher modified response (mMS response), endoscopic improvement, sustained modified response, and sustained endoscopic improvement response in the two lower tertiaries. Almost all patients receiving the 450 mg dose in the maintenance phase (approximately 96%) had exposures in the highest tertiary, indicating that this dose was necessary to achieve systemic exposure corresponding to maximum and sustained long-term efficacy.

[0487] Furthermore, during the maintenance phase of the study, the sustained response rates of antidrug antibodies (ADA) and neutralizing antibodies (NAb) in the 450 mg → 450 mg treatment sequence arm (administered at a dose of 450 mg during both the induction and maintenance phases) were the lowest compared to other treatment sequences (see Table 16). ADA status was observed to have minimal or no effect on serum afimizumab in the 450 mg → 450 mg sequence.

[0488] E. Conclusion

[0489] Data from the Phase 2b TUSCANY-2 dose-range study demonstrate that afimizumab has a positive benefit / risk profile, providing clinically meaningful improvement in patients with moderate to severe active UC. (Instructions for Use, pages 64 / 64)82 CN 121532526 A Instruction Manual Illustration 1 / 10 page 83 CN 121532526 A Instruction Manual Illustration 2 / 10 page 84 CN 121532526 A Instruction Manual Illustration 3 / 10 page 85 CN 121532526 A Instruction Manual Illustration 4 / 10 page 86 CN 121532526 A Instruction Manual Illustration 5 / 10 page 87 CN 121532526 A Instruction Manual Illustration 6 / 10 page 88 CN 121532526 A Instruction Manual Illustration 7 / 10 page 89 CN 121532526 A Instruction Manual Illustration 8 / 10 page 90 CN 121532526 A Instruction Manual Illustration 9 / 10 page 91 CN 121532526 A Instruction Manual Illustration 10 / 10 page 92 CN 121532526 A

Claims

1. A method for determining the risk of a patient not responding to a therapeutic dose of an anti-TNF-like ligand 1A (TL1A) antibody, the method comprising: Genotyping was performed on biological samples from the patient to determine whether the patient was a haplotype B carrier or a haplotype B non-carrier of TNFSF15. The determination included identifying the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in the biological samples from the patient; and The risk of non-response to the therapeutic dose of anti-TL1A antibody was determined, with haplotype B carriers at higher risk than haplotype B non-carriers.

2. The method of claim 1, wherein the patient suffers from inflammatory bowel disease (IBD).

3. A method for treating a patient with inflammatory bowel disease (IBD), the method comprising: (a) Genotyping was performed to determine whether the patient was a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination including determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in biological samples from the patient; and (b) Administer an effective amount of anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier.

4. The method of claim 3, wherein the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising a plurality of individual induction doses.

5. The method of claim 3, wherein the anti-TL1A antibody is administered to the patient in a maintenance dosing regimen after the induction dosing regimen is completed, the maintenance dosing regimen comprising a plurality of individual maintenance doses spaced at least 2 weeks apart from each other.

6. A method for treating a patient with IBD, the method comprising: (a) Genotyping is performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination including determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647 and rs7869487 in biological samples from the patient; (b) The anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising multiple individual induction doses, wherein the patient has been identified as a haplotype B non-carrier; and (c) After the induction dosing regimen is completed, the patient is given a subsequent maintenance dosing regimen, which consists of multiple individual maintenance doses spaced at least 2 weeks apart from each other.

7. The method according to any one of claims 2 to 6, wherein the IBD is ulcerative colitis (UC).

8. The method of claim 7, wherein the UC is moderate to severe UC.

9. The method according to any one of claims 2 to 6, wherein the IBD is Crohn's disease (CD).

10. The method according to any one of claims 1 to 9, wherein the at least two SNPs are SNP rs3810936 and SNP rs7869487.

11. The method of claim 10, wherein the genotyping assay comprises determining the presence of only two SNPs in the biological sample from the patient, wherein the two SNPs are SNP rs3810936 and SNP rs7869487.

12. The method of claim 10 or 11, wherein the patient is identified as a haplotype B non-carrier by any of the following biomarker states from the biological sample of the patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) The genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487.

13. The method of claim 10, wherein (a) the genotyping assay comprises determining the presence of SNP rs3810936, SNP rs7869487 and SNP rs7848647 in the biological sample from the patient; or (b) the genotyping assay comprises determining the presence of SNP rs3810936, SNP rs7869487 and SNP rs6478109 in the biological sample from the patient.

14. The method of claim 10, wherein the genotyping assay comprises determining the presence of SNPs rs3810936, rs7869487, rs6478108, and rs6478109 in the biological sample from the patient.

15. The method according to any one of claims 1 to 14, wherein the genotyping assay comprises qPCR.

16. The method according to any one of claims 1 to 15, wherein the genotyping assay includes sequencing.

17. The method according to any one of claims 1 to 16, wherein the genotyping assay comprises long sequencing.

18. The method according to any one of claims 1 to 17, wherein the genotyping assay is performed on a microarray.

19. The method according to any one of claims 1 to 18, wherein the genotyping assay is a fluorescence-based assay.

20. The method according to any one of claims 1 to 19, wherein the biological sample is blood.

21. The method according to any one of claims 1 to 19, wherein the biological sample is oral cells.

22. A method for determining the risk of a patient not responding to a therapeutic dose of an anti-TL1A antibody, wherein the patient has inflammatory bowel disease (IBD), the method comprising: (a) Genotyping of biological samples from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, wherein the determination includes determining the presence of SNPs rs3810936 and rs7869487 in the biological samples from the patient, and wherein a haplotype B non-carrier of TNFSF15 is identified by any of the following biomarker statuses from the biological samples from the patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) The genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487; as well as (b) If the patient is a haplotype B carrier, the patient is identified as being at high risk of not responding to therapeutic doses of anti-TL1A antibodies; or (c) If the patient is a haplotype B noncarrier, the patient is identified as having low risk of not responding to therapeutic doses of anti-TL1A antibody.

23. The method of claim 22, wherein the patient has been identified as a haplotype B non-carrier of TNFSF15, and the method further comprises administering an effective amount of anti-TL1A antibody to the patient.

24. The method of claim 23, wherein the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising a plurality of individual induction doses.

25. The method of claim 23, wherein the anti-TL1A antibody is administered to the patient in a maintenance dosing regimen after the induction dosing regimen is completed, the maintenance dosing regimen comprising a plurality of individual maintenance doses spaced at least 2 weeks apart from each other.

26. A method for treating a patient with IBD, the method comprising: (a) Genotyping of biological samples from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, wherein the determination includes determining the presence of SNPs rs3810936 and rs7869487 in the biological samples from the patient, and wherein a haplotype B non-carrier of TNFSF15 is identified by any of the following biomarker statuses from the biological samples from the patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) The genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487; as well as (b) Administer an effective amount of anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier.

27. The method of claim 26, wherein the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising a plurality of individual induction doses.

28. The method of claim 26, wherein the anti-TL1A antibody is administered to the patient following an induction dosing regimen, the maintenance dosing regimen comprising a plurality of individual maintenance doses spaced at least 2 weeks apart from each other.

29. A method for treating a patient with IBD, the method comprising administering an effective amount of anti-TL1A antibody to the patient; The patient has been identified as a haplotype B noncarrier of TNFSF15 by any of the following biomarker statuses from biological samples of the patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) The genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487.

30. The method of claim 29, wherein the anti-TL1A antibody is administered to the patient in an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising a plurality of individual induction doses.

31. The method of claim 29, wherein the anti-TL1A antibody is administered to the patient following an induction dosing regimen, the maintenance dosing regimen comprising a plurality of individual maintenance doses spaced at least 2 weeks apart from each other.

32. The method according to any one of claims 4, 6 to 21, 24, 27 and 30, wherein the individual induction doses are spaced at least 1 week, at least 2 weeks, at least 3 weeks or at least 4 weeks apart from each other.

33. The method according to any one of claims 4, 6 to 21, 24, 27, 30 and 32, wherein the individual induction doses are spaced at least one month apart from each other.

34. The method of claim 32, wherein the individual induction doses are administered at 4-week intervals.

35. The method according to any one of claims 4, 6 to 21, 24, 27, 30 and 32 to 34, wherein the individual induction dose is administered intravenously or subcutaneously.

36. The method of claim 35, wherein each of the individual induction doses is administered subcutaneously.

37. The method according to any one of claims 4, 6 to 21, 24, 27, 30 and 32 to 36, wherein the individual induction dose is administered at 50, 150 or 450 mg.

38. The method of claim 37, wherein each of the individual induction doses is administered at a dose of 50 mg.

39. The method of claim 37, wherein each of the individual induction doses is administered at a dose of 150 mg.

40. The method of claim 37, wherein each of the individual induction doses is administered at a dose of 450 mg.

41. The method according to any one of claims 4 to 21 and 24 to 40, wherein the induction dosing regimen comprises four separate induction doses.

42. The method according to any one of claims 4 to 21, 24, 25, 27, 28 and 30 to 41, wherein the induction dosing regimen comprises four separate induction doses administered at 4-week intervals, and wherein each of the separate induction doses is administered subcutaneously at a dose of 50, 150 or 450 mg.

43. The method according to any one of claims 5 to 21, 25, 28, 31, 41 and 42, wherein the individual maintenance doses are administered at intervals of at least 2 weeks, at least 3 weeks or at least 4 weeks.

44. The method according to any one of claims 5 to 21, 25, 28, 31 and 41 to 43, wherein the individual maintenance doses are administered at least one month apart.

45. The method of claim 43, wherein the individual maintenance dose is administered at 4-week intervals.

46. ​​The method according to any one of claims 5 to 21, 25, 28 and 41 to 45, wherein the individual maintenance dose is administered intravenously or subcutaneously.

47. The method of claim 46, wherein each of the individual maintenance doses is administered subcutaneously.

48. The method according to any one of claims 5 to 21, 25, 28 and 41 to 47, wherein the individual maintenance dose is administered at 50, 150 or 450 mg.

49. The method of claim 48, wherein each of the individual maintenance doses is administered at a dose of 50 mg.

50. The method of claim 48, wherein each of the individual maintenance doses is administered at a dose of 150 mg.

51. The method of claim 48, wherein each of the individual maintenance doses is administered at a dose of 450 mg.

52. The method according to any one of claims 5 to 21, 25, 28 and 41 to 51, wherein the maintenance dosing regimen comprises at least ten individual maintenance doses.

53. The method according to any one of claims 5 to 21, 25, 28 and 41 to 52, wherein the induction dosing regimen comprises ten separate maintenance doses administered at 4-week intervals, and wherein each of the separate maintenance doses is administered subcutaneously at a dose of 50, 150 or 450 mg.

54. The method of claim 53, wherein each of the individual maintenance doses is administered subcutaneously at a dose of 450 mg.

55. The method according to any one of claims 3 to 54, further comprising: (a) Determine the expression levels of one or more candidate genes in biological samples from the patient, and (b) Identify that the biological sample contains one or more candidate genes with abnormal expression levels.

56. The method of claim 55, wherein the one or more candidate genes are selected from the group consisting of: SOWAHB, COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, PKDREJ, IL-1B, IL-23A, IFNG, IL-12RB1, IL-21R, IRF4, BATF, CD80 / 86, HLA-DRB5 / DQB1 / DRB1, HLA-DRA, CD40, ICOS, MMP3, MMP7, MMP10, and CHI3L.

57. The method of claim 56, wherein the one or more candidate genes are selected from the group consisting of: SOWAHB, COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, and PKDREJ.

58. The method of any one of claims 55 to 57, wherein the expression level of the one or more candidate genes is compared with a baseline expression level, the baseline expression level being a) based on the expression level of the one or more candidate genes in a healthy individual who has not developed IBD or UC; or b) based on an estimated expression level in an individual who is unresponsive to anti-TL1A antibody treatment.

59. The method of claim 58, wherein the abnormal expression level of the one or more candidate genes is at least 50% higher or lower than the baseline level.

60. The method according to any one of claims 3 to 59, further comprising: a) Determine the expression levels of one or more candidate bacterial strains in fecal samples from the patient, and b) Identify whether the sample contains an increased or decreased level of one or more candidate bacterial strains.

61. The method of claim 60, wherein the level of candidate bacterial strains is increased, and the candidate bacterial strains are selected from the group consisting of: Streptococcus salivarius, Streptococcus parasanguinis, and Haemophilus parainfluenzae.

62. The method of claim 61, wherein the level of the candidate bacterial strain is reduced, and the candidate bacterial strain is selected from the group consisting of: Ruminococcus albus, Ruminococcus callidus, Ruminococcus bromii, Ruminococcus gnavus, and Bifidobacterium bifidum.

63. The method according to any one of claims 1 to 62, wherein the anti-TL1A antibody comprises: three CDRs from a variable heavy chain region having the sequence shown in SEQ ID NO: 1; and three CDRs from a variable light chain region having the sequence shown in SEQ ID NO:

2.

64. The method according to any one of claims 1 to 62, wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO:

8.

65. The method according to any one of claims 1 to 64, wherein the anti-TL1A antibody comprises: a variable heavy chain region having the sequence shown in SEQ ID NO: 1; and a variable light chain region having the sequence shown in SEQ ID NO:

2.

66. The method according to any one of claims 1 to 65, wherein the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 9; and a light chain having the sequence shown in SEQ ID NO:

10.

67. The method according to any one of claims 1 to 66, wherein the anti-TL1A antibody is afimzimab.

68. A method for treating a patient with inflammatory bowel disease (IBD), the method comprising: (a) Genotyping was performed to determine whether the patient was a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination including determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in biological samples from the patient; and (b) Administer an effective amount of anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier; The anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO:

8.

69. The method of claim 68, wherein the at least two SNPs are SNP rs3810936 and SNP rs7869487.

70. The method of claim 69, wherein the determination comprises determining the presence of only two SNPs in the biological sample from the patient, and wherein the two SNPs are SNP rs3810936 and SNP rs7869487.

71. The method according to any one of claims 1 to 62, wherein the anti-TL1A antibody comprises sequence pairs selected from the group consisting of: SEQ ID NO: 2 and 11; SEQ ID NO: 2 and 12; SEQ ID NO: 2 and 13; SEQ ID NO: 2 and 14; SEQ ID NO: 2 and 15; SEQ ID NO: 2 and 16; SEQ ID NO: 2 and 17; SEQ ID NO: 2 and 18; SEQ ID NO: 2 and 19; SEQ ID NO: 20 and 24; SEQ ID NO: 21 and 25; SEQ ID NO: 22 and 26; SEQ ID NO: 23 and 27; SEQ ID NO: 28 and 29; SEQ ID NO: 30 and 31; SEQ ID NO: 32 and 33; SEQ ID NO: 35 and 44; SEQ ID NO: 53 and 54; SEQ ID NO: 61 SEQ ID NO: 62; SEQ ID NO: 63 and 64; SEQ ID NO: 65 and 64; SEQ ID NO: 66 and 64; and SEQ ID NO: 67 and 64.

72. The method according to any one of claims 1 to 62, wherein the anti-TL1A antibody comprises: three CDRs from a variable heavy chain region having the sequence shown in SEQ ID NO: 53; and three CDRs from a variable light chain region having the sequence shown in SEQ ID NO:

54.

73. The method according to any one of claims 1 to 62, wherein the anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 37; HCDR2 having the sequence shown in SEQ ID NO: 39; HCDR3 having the sequence shown in SEQ ID NO: 41; LCDR1 having the sequence shown in SEQ ID NO: 46; LCDR2 having the sequence shown in SEQ ID NO: 48; and LCDR3 having the sequence shown in SEQ ID NO:

50.

74. The method according to any one of claims 1 to 62, 72 and 73, wherein the anti-TL1A antibody comprises: a variable heavy chain region having the sequence shown in SEQ ID NO: 53; and a variable light chain region having the sequence shown in SEQ ID NO:

54.

75. The method according to any one of claims 1 to 62 and 72 to 74, wherein the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 35; and a light chain having the sequence shown in SEQ ID NO:

44.

76. The method according to any one of claims 1 to 62 and 72 to 75, wherein the anti-TL1A antibody is tusocitabine.

77. A method for treating a patient with inflammatory bowel disease (IBD), the method comprising: (a) Genotyping was performed to determine whether the patient was a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination including determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in biological samples from the patient; and (b) Administer anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier; The anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 37; HCDR2 having the sequence shown in SEQ ID NO: 39; HCDR3 having the sequence shown in SEQ ID NO: 41; LCDR1 having the sequence shown in SEQ ID NO: 46; LCDR2 having the sequence shown in SEQ ID NO: 48; and LCDR3 having the sequence shown in SEQ ID NO:

50.

78. The method of claim 77, wherein the at least two SNPs are SNP rs3810936 and SNP rs7869487.

79. The method of claim 78, wherein the determination comprises determining the presence of only two SNPs in the biological sample from the patient, wherein the two SNPs are SNP rs3810936 and SNP rs7869487.

80. The method according to any one of claims 3 to 79, further comprising treatment with an IL-23 antagonist.

81. The method according to any one of claims 22 to 31, 68 to 70 and 77 to 79, wherein the IBD is ulcerative colitis (UC).

82. The method of claim 81, wherein the UC is moderate to severe UC.

83. The method according to any one of claims 22 to 31, 68 to 70 and 77 to 79, wherein the IBD is Crohn's disease (CD).

84. The method according to any one of claims 1 to 83, wherein the patient is a person.

85. A method of treating a patient with inflammatory bowel disease (IBD), the method comprising administering an effective amount of anti-TNF-like ligand 1A (TL1A) antibody to the patient in a dosing regimen that includes an induction dosing regimen and a subsequent maintenance dosing regimen; The induction dosing regimen includes multiple individual induction doses, and the maintenance dosing regimen includes multiple individual maintenance doses; The anti-TL1A antibody is administered subcutaneously during the maintenance phase, and the anti-TL1A antibody comprises: HCDR1, which has the sequence shown in SEQ ID NO: 3; HCDR2, which has the sequence shown in SEQ ID NO: 4; HCDR3, which has the sequence shown in SEQ ID NO: 5; LCDR1, which has the sequence shown in SEQ ID NO: 6; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3 has the sequence shown in SEQ ID NO:

8.

86. The method of claim 85, wherein the individual induction doses are spaced at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks apart from each other.

87. The method of claim 85 or 86, wherein the individual induction doses are spaced at least one month apart from each other.

88. The method of claim 86, wherein the individual induction doses are administered at 4-week intervals.

89. The method according to any one of claims 85 to 88, wherein the individual induction dose is administered intravenously or subcutaneously.

90. The method of claim 89, wherein each of the individual induction doses is administered subcutaneously.

91. The method according to any one of claims 85 to 90, wherein the individual induction dose is administered at 50, 150, or 450 mg.

92. The method of claim 91, wherein each of the individual induction doses is administered at a dose of 50 mg.

93. The method of claim 91, wherein each of the individual induction doses is administered at a dose of 150 mg.

94. The method of claim 91, wherein each of the individual induction doses is administered at a dose of 450 mg.

95. The method according to any one of claims 85 to 94, wherein the induction dosing regimen comprises four separate induction doses.

96. The method according to any one of claims 85 to 95, wherein the induction administration regimen comprises four separate induction doses administered at 4-week intervals, and wherein each of the separate induction doses is administered subcutaneously at a dose of 50, 150, or 450 mg.

97. The method according to any one of claims 85 to 96, wherein the individual maintenance dose is administered at intervals of at least 2 weeks, at least 3 weeks, or at least 4 weeks.

98. The method according to any one of claims 85 to 97, wherein the individual maintenance doses are administered at least one month apart.

99. The method of claim 97, wherein the individual maintenance dose is administered at 4-week intervals.

100. The method according to any one of claims 85 to 99, wherein the individual maintenance dose is administered at 50, 150, or 450 mg.

101. The method of claim 100, wherein each of the individual maintenance doses is administered at a dose of 50 mg.

102. The method of claim 100, wherein each of the individual maintenance doses is administered at a dose of 150 mg.

103. The method of claim 100, wherein each of the individual maintenance doses is administered at a dose of 450 mg.

104. The method according to any one of claims 85 to 103, wherein the maintenance dosing regimen comprises at least ten individual maintenance doses.

105. The method according to any one of claims 85 to 104, wherein the induction dosing regimen comprises ten separate maintenance doses administered at 4-week intervals, wherein each of the separate maintenance doses is administered subcutaneously at a dose of 50, 150, or 450 mg.

106. The method of claim 105, wherein each of the individual maintenance doses is administered subcutaneously at a dose of 450 mg.

107. A method of treating a patient with inflammatory bowel disease (IBD), the method comprising administering an effective amount of an anti-TNF-like ligand 1A (TL1A) antibody to the patient in a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen; wherein: (a) The induction dosing regimen comprises subcutaneous administration of four separate induction doses of the anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg, wherein the separate induction doses are administered at 4-week intervals; and (b) The maintenance dosing regimen comprises subcutaneous administration of multiple individual maintenance doses of the anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg, wherein the individual maintenance doses are administered at 4-week intervals; and The anti-TL1A antibody comprises: HCDR1, which has the sequence shown in SEQ ID NO: 3; HCDR2, which has the sequence shown in SEQ ID NO: 4; HCDR3, which has the sequence shown in SEQ ID NO: 5; LCDR1, which has the sequence shown in SEQ ID NO: 6; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3 has the sequence shown in SEQ ID NO:

8.

108. A method of treating a patient with inflammatory bowel disease (IBD), the method comprising administering an effective amount of an anti-TNF-like ligand 1A (TL1A) antibody to the patient in a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen; wherein: (a) The induction dosing regimen comprises multiple individual induction doses, wherein the individual induction doses are spaced at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks apart; and (b) The maintenance dosing regimen comprises subcutaneous administration of multiple individual maintenance doses of the anti-TL1A antibody at a dose of approximately 450 mg, wherein the individual maintenance doses are administered at 4-week intervals; and The anti-TL1A antibody comprises: HCDR1, which has the sequence shown in SEQ ID NO: 3; HCDR2, which has the sequence shown in SEQ ID NO: 4; HCDR3, which has the sequence shown in SEQ ID NO: 5; LCDR1, which has the sequence shown in SEQ ID NO: 6; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3 has the sequence shown in SEQ ID NO:

8.

109. The method of claim 108, wherein the induction dosing regimen comprises subcutaneously administering four separate induction doses of the anti-TL1A antibody at a dose of about 450 mg, wherein the separate induction doses are administered at 4-week intervals.

110. The method according to any one of claims 85 to 109, wherein the first dose of the maintenance phase is administered approximately two weeks after the final dose of the induction phase.

111. The method according to any one of claims 85 to 110, wherein the dosing regimen has a duration of about 52 weeks.

112. The method according to any one of claims 85 to 111, wherein the anti-TL1A antibody comprises: a variable heavy chain region having the sequence shown in SEQ ID NO: 1; and a variable light chain region having the sequence shown in SEQ ID NO:

2.

113. The method according to any one of claims 85 to 112, wherein the anti-TL1A antibody comprises: a heavy chain having the sequence shown in SEQ ID NO: 9; and a light chain having the sequence shown in SEQ ID NO:

10.

114. The method according to any one of claims 85 to 113, wherein the anti-TL1A antibody is afimzimab.

115. The method according to any one of claims 85 to 114, wherein the patient has been identified as a haplotype B non-carrier of TNFSF15.

116. The method according to any one of claims 85 to 115, wherein the IBD is ulcerative colitis (UC).

117. The method of claim 116, wherein the UC is moderate to severe UC.

118. The method according to any one of claims 85 to 117, wherein the patient is a person.

119. The method according to any one of claims 85 to 118, wherein, In the patient population treated according to the method, compared with the reference population, the treatment resulted in an increased proportion of patients who had achieved clinical remission by the end of the induction phase.

120. The method of claim 119, wherein the induction phase lasts for about 14 weeks, and the treatment causes an increase in the proportion of patients who have achieved clinical remission by week 14.

121. The method of claim 120, wherein at least about 15% of the patients in the patient population have achieved clinical remission by week 14.

122. The method of claim 121, wherein at least about 40% of the patients in the patient population have achieved clinical remission by week 14.

123. The method according to any one of claims 85 to 122, wherein, In the patient population treated according to the method, the treatment resulted in an increased proportion of patients who had achieved clinical remission by the end of the maintenance phase, compared to the reference population.

124. The method of claim 123, wherein the dosing regimen has a duration of approximately 56 weeks, and the treatment results in an increased proportion of patients who have achieved clinical remission at week 56.

125. The method of claim 124, wherein at least about 20% of the patients in the patient population have achieved clinical remission by week 56.

126. The method of claim 125, wherein at least about 55% of the patients in the patient population have achieved clinical remission by week 56.

127. The method according to any one of claims 119 to 126, wherein clinical remission is defined as a total Mayo score ≤ 2 with no individual sub-score > 1.

128. The method according to any one of claims 119 to 126, wherein clinical remission is a modified Mayo score (mMS) ≤ 2, having a stool frequency subscore (SFS) = 0 or 1, a rectal bleeding subscore (RBS) = 0, and an endoscopy score (ES) = 0 or 1.

129. The method according to any one of claims 85 to 128, wherein, In the patient population treated according to the method, compared with the reference population, the treatment resulted in an increased proportion of patients who achieved endoscopic improvement by the end of the induction phase.

130. The method of claim 129, wherein the induction phase lasts for approximately 14 weeks, and the treatment results in an increased proportion of patients who have achieved endoscopic improvement by week 14.

131. The method of claim 130, wherein at least about 25% of the patients in the patient population have achieved endoscopic improvement by week 14.

132. The method of claim 131, wherein at least about 50% of the patients in the patient population have achieved endoscopic improvement by week 14.

133. The method according to any one of claims 85 to 132, wherein, In the patient population treated according to the method, compared with the reference population, the treatment resulted in an increased proportion of patients who had achieved endoscopic improvement by the end of the maintenance phase.

134. The method of claim 133, wherein the dosing regimen has a duration of approximately 56 weeks, and the treatment results in an increased proportion of patients who have achieved endoscopic improvement by week 56.

135. The method of claim 134, wherein at least about 20% of the patients in the patient population have achieved endoscopic improvement by week 56.

136. The method of claim 135, wherein at least about 65% of the patients in the patient population have achieved endoscopic improvement by week 56.

137. The method according to any one of claims 129 to 136, wherein the clinical remission is an endoscopic score of 0 or 1.

138. The method according to any one of claims 85 to 137, wherein, In the patient population treated according to the method, compared with the reference population, the treatment resulted in an increased proportion of patients who achieved endoscopic remission, clinical response, symptom relief, or deep remission by the end of the induction phase.

139. The method according to any one of claims 85 to 138, wherein, In the patient population treated according to the method, compared with the reference population, the treatment resulted in an increased proportion of patients who achieved endoscopic remission, clinical response, symptom relief, or deep remission at the end of the maintenance phase.

140. The method according to any one of claims 119 to 139, wherein the reference population is a patient population that has not been treated with anti-TL1A antibodies.

141. The method of claim 140, wherein the reference population is a patient population that has not been treated with a placebo.

142. A kit comprising an anti-TNF-like ligand 1A (TL1A) antibody and a packaging insert containing instructions for using the antibody to treat inflammatory bowel disease (IBD) in a patient in need using any one of claims 1 to 141.

143. An anti-TL1A antibody for use in treating patients with IBD, wherein: (a) Genotyping will be performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination including determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in biological samples from the patient; and (b) To administer an effective amount of the anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier.

144. An anti-TL1A antibody for use in treating patients with IBD, wherein: (a) Genotyping will be performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination including determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647 and rs7869487 in biological samples from the patient; (b) The anti-TL1A antibody shall be administered to the patient using an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising multiple individual induction doses, wherein the patient has been identified as a haplotype B non-carrier; and (c) After the induction dosing regimen is completed, the patient is given the anti-TL1A antibody in a subsequent maintenance dosing regimen, which includes multiple individual maintenance doses spaced at least 2 weeks apart from each other.

145. An anti-TL1A antibody for use in treating patients with IBD, wherein: (a) Genotyping is performed on biological samples from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, wherein the determination includes determining the presence of SNPs rs3810936 and rs7869487 in the biological samples from the patient, and wherein a haplotype B non-carrier of TNFSF15 is identified by any of the following biomarker statuses from the biological samples from the patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) The genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487; and (b) To administer an effective amount of the anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier.

146. An anti-TL1A antibody for use in treating a patient with IBD, wherein an effective amount of the anti-TL1A antibody is to be administered to the patient; The patient has been identified as a haplotype B noncarrier of TNFSF15 by any of the following biomarker statuses from biological samples of the patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) The genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487.

147. An anti-TL1A antibody for use in treating patients with IBD, wherein: (a) Genotyping will be performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination including determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in biological samples from the patient; and (b) To administer an effective amount of the anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier; The anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO:

8.

148. An anti-TL1A antibody for use in treating patients with IBD, wherein: (a) Genotyping will be performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination including determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in biological samples from the patient; and (b) The anti-TL1A antibody is to be administered to the patient, wherein the patient has been identified as a haplotype B non-carrier; The anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 37; HCDR2 having the sequence shown in SEQ ID NO: 39; HCDR3 having the sequence shown in SEQ ID NO: 41; LCDR1 having the sequence shown in SEQ ID NO: 46; LCDR2 having the sequence shown in SEQ ID NO: 48; and LCDR3 having the sequence shown in SEQ ID NO:

50.

149. An anti-TL1A antibody for use in treating patients with IBD, wherein an effective amount of the anti-TL1A antibody is administered to the subject via a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen; The induction dosing regimen includes multiple individual induction doses, and the maintenance dosing regimen includes multiple individual maintenance doses; The anti-TL1A antibody is administered subcutaneously during the maintenance phase, and the anti-TL1A antibody comprises: HCDR1, which has the sequence shown in SEQ ID NO: 3; HCDR2, which has the sequence shown in SEQ ID NO: 4; HCDR3, which has the sequence shown in SEQ ID NO: 5; LCDR1, which has the sequence shown in SEQ ID NO: 6; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3 has the sequence shown in SEQ ID NO:

8.

150. An anti-TL1A antibody for use in treating patients with IBD, wherein an effective amount of the anti-TL1A antibody is administered to a subject via a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen, wherein: (a) The induction dosing regimen comprises subcutaneous administration of four separate induction doses of the anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg, wherein the separate induction doses are administered at 4-week intervals; and (b) The maintenance dosing regimen comprises subcutaneous administration of multiple individual maintenance doses of the anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg, wherein the individual maintenance doses are administered at 4-week intervals, and The anti-TL1A antibody comprises: HCDR1, which has the sequence shown in SEQ ID NO: 3; HCDR2, which has the sequence shown in SEQ ID NO: 4; HCDR3, which has the sequence shown in SEQ ID NO: 5; LCDR1, which has the sequence shown in SEQ ID NO: 6; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3 has the sequence shown in SEQ ID NO:

8.

151. An anti-TL1A antibody for use in the treatment of patients with inflammatory bowel disease (IBD), wherein an effective amount of the anti-TL1A antibody is administered to a subject via a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen, wherein: (a) The induction dosing regimen comprises multiple individual induction doses, wherein the individual induction doses are spaced at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks apart; and (b) The maintenance dosing regimen comprises subcutaneous administration of multiple individual maintenance doses of the anti-TL1A antibody at a dose of approximately 450 mg, wherein the individual maintenance doses are administered at 4-week intervals, and The anti-TL1A antibody comprises: HCDR1, which has the sequence shown in SEQ ID NO: 3; HCDR2, which has the sequence shown in SEQ ID NO: 4; HCDR3, which has the sequence shown in SEQ ID NO: 5; LCDR1, which has the sequence shown in SEQ ID NO: 6; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3 has the sequence shown in SEQ ID NO:

8.

152. Use of anti-TL1A antibodies in the manufacture of medicaments for treating patients with IBD, wherein: (a) Genotyping will be performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination including determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in biological samples from the patient; and (b) To administer an effective amount of the anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier.

153. Use of anti-TL1A antibodies in the manufacture of medicaments for treating patients with IBD, wherein: (a) Genotyping will be performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination including determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647 and rs7869487 in biological samples from the patient; (b) The anti-TL1A antibody shall be administered to the patient using an induction dosing regimen sufficient to improve signs and symptoms of IBD for at least 12 weeks after initiation of treatment with the anti-TL1A antibody, the induction dosing regimen comprising multiple individual induction doses, wherein the patient has been identified as a haplotype B non-carrier; and (c) After the induction dosing regimen is completed, the patient is given the anti-TL1A antibody in a subsequent maintenance dosing regimen, which includes multiple individual maintenance doses spaced at least 2 weeks apart from each other.

154. Use of anti-TL1A antibodies in the manufacture of medicaments for treating patients with IBD, wherein: (a) Genotyping is performed on biological samples from the patient to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, wherein the determination includes determining the presence of SNPs rs3810936 and rs7869487 in the biological samples from the patient, and wherein a haplotype B non-carrier of TNFSF15 is identified by any of the following biomarker statuses from the biological samples from the patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) The genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487; and (b) To administer an effective amount of the anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier.

155. Use of anti-TL1A antibody in the manufacture of a medicament for treating a patient with IBD, wherein an effective amount of the anti-TL1A antibody is to be administered to said patient, and The patient has been identified as a haplotype B noncarrier of TNFSF15 by any of the following biomarker statuses from biological samples of the patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the alternative allele at rs7869487; (iii) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) The genotype of the sample is homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487.

156. Use of anti-TL1A antibodies in the manufacture of medicaments for treating patients with IBD, wherein: (a) Genotyping will be performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination including determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in biological samples from the patient; and (b) To administer an effective amount of the anti-TL1A antibody to the patient, wherein the patient has been identified as a haplotype B non-carrier, and The anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 3; HCDR2 having the sequence shown in SEQ ID NO: 4; HCDR3 having the sequence shown in SEQ ID NO: 5; LCDR1 having the sequence shown in SEQ ID NO: 6; LCDR2 having the sequence shown in SEQ ID NO: 7; and LCDR3 having the sequence shown in SEQ ID NO:

8.

157. Use of anti-TL1A antibodies in the manufacture of medicaments for treating patients with IBD, wherein: (a) Genotyping will be performed to determine whether the patient is a haplotype B carrier or a haplotype B non-carrier of TNFSF15, the determination including determining the presence of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in biological samples from the patient; and (b) The anti-TL1A antibody is to be administered to the patient, wherein the patient has been identified as a haplotype B non-carrier, and The anti-TL1A antibody comprises: HCDR1 having the sequence shown in SEQ ID NO: 37; HCDR2 having the sequence shown in SEQ ID NO: 39; HCDR3 having the sequence shown in SEQ ID NO: 41; LCDR1 having the sequence shown in SEQ ID NO: 46; LCDR2 having the sequence shown in SEQ ID NO: 48; and LCDR3 having the sequence shown in SEQ ID NO:

50.

158. Use of anti-TL1A antibody in the manufacture of a medicament for treating patients with IBD, wherein an effective amount of the anti-TL1A antibody is administered to a subject by a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen; The induction dosing regimen includes multiple individual induction doses, and the maintenance dosing regimen includes multiple individual maintenance doses; The anti-TL1A antibody is administered subcutaneously during the maintenance phase, and the anti-TL1A antibody comprises: HCDR1, which has the sequence shown in SEQ ID NO: 3; HCDR2, which has the sequence shown in SEQ ID NO: 4; HCDR3, which has the sequence shown in SEQ ID NO: 5; LCDR1, which has the sequence shown in SEQ ID NO: 6; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3 has the sequence shown in SEQ ID NO:

8.

159. Use of anti-TL1A antibody in the manufacture of a medicament for treating patients with IBD, wherein an effective amount of the anti-TL1A antibody is administered to a subject via a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen, wherein: (a) The induction dosing regimen comprises subcutaneous administration of four separate induction doses of the anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg, wherein the separate induction doses are administered at 4-week intervals; and (b) The maintenance dosing regimen comprises subcutaneous administration of multiple individual maintenance doses of the anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg, wherein the individual maintenance doses are administered at 4-week intervals, and The anti-TL1A antibody comprises: HCDR1, which has the sequence shown in SEQ ID NO: 3; HCDR2, which has the sequence shown in SEQ ID NO: 4; HCDR3, which has the sequence shown in SEQ ID NO: 5; LCDR1, which has the sequence shown in SEQ ID NO: 6; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3 has the sequence shown in SEQ ID NO:

8.

160. Use of anti-TL1A antibody in the manufacture of a medicament for treating patients with inflammatory bowel disease (IBD), wherein an effective amount of the anti-TL1A antibody is administered to a subject via a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen, wherein: (a) The induction dosing regimen comprises multiple individual induction doses, wherein the individual induction doses are spaced at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks apart; and (b) The maintenance dosing regimen comprises subcutaneous administration of multiple individual maintenance doses of the anti-TL1A antibody at a dose of approximately 450 mg, wherein the individual maintenance doses are administered at 4-week intervals, and The anti-TL1A antibody comprises: HCDR1, which has the sequence shown in SEQ ID NO: 3; HCDR2, which has the sequence shown in SEQ ID NO: 4; HCDR3, which has the sequence shown in SEQ ID NO: 5; LCDR1, which has the sequence shown in SEQ ID NO: 6; LCDR2, which has the sequence shown in SEQ ID NO: 7; and LCDR3 has the sequence shown in SEQ ID NO: 8.

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