Anti-TL1A antibody treatment methods

Abstract

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

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Application No. 63 / 502,786, filed on May 17, 2023; U.S. Provisional Application No. 63 / 647,481, filed on May 14, 2024; and U.S. Provisional Application No. 63 / 649,269, filed on May 17, 2024. The disclosures of these provisional applications are hereby incorporated by reference in their entirety.

[0002] Sequence Listing This application includes a sequence listing submitted electronically in XML format, which is hereby incorporated by reference in its entirety. The XML copy created on May 17, 2024, is named 50474 - 352WO4_Sequence_Listing_5_17_24 and is 75,503 bytes in size.

[0003] Technical Field of the Invention The present invention relates to the treatment of symptoms and signs of inflammatory bowel disease using anti - tumor necrosis factor - like ligand 1A (TL1A) antibodies.

Background Art

[0004] Background of the Invention Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis (UC), is a chronic inflammatory disorder affecting approximately 1.6 million people in the United States and 2.5 to 3 million people in Europe. To induce remission in patients with moderate to severe active UC, treatment recommendations include appropriate doses of oral corticosteroids, the tumor necrosis factor inhibitor (TNFi) infliximab (monotherapy or in combination with azathioprine), biological therapies such as adalimumab, ustekinumab, golimumab, and the integrin receptor antagonist vedolizumab, and the oral small molecule Janus kinase inhibitor tofacitinib (Rubin et al, 2019 Am J Gastroenterol;114:384-413). However, unresponsiveness and loss of response to treatment have been observed in UC, and 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).

[0005] Various mucosal immune system components, including epithelial cells, innate and adaptive immune cells, cytokines, and chemokines, contribute to the pathogenesis of IBD (Wallace et al, 2014, World J Gastroenterol; 20:6-21). One immune component 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 medically refractory 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 specimens, and its expression level corresponds to the severity of the disease (Bamias et al, 2010, Clin Immunol;137:242-249).

[0006] T cell-mediated signaling and cytokine production, such as interferon-γ-producing T helper (Th)1 cells, interleukin (IL)-6 and IL-17-producing Th17 cells, and IL-4 and IL-13-producing Th2 cells, are co-stimulated by TL1A binding to cell 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). Since increased cytokine production leads to chronic inflammation, inhibition of TL1A may be a therapeutic target for inflammatory diseases, including IBD.

[0007] UC is a chronic inflammatory disease of the large intestine characterized by diffuse mucosal inflammation. The pathophysiology underlying this disease stems from the interaction between genetic susceptibility in immunogenes and changes in the gut microbiota. Current treatments for UC include non-selective agents such as corticosteroids, mesalamines, and thiopurines, as well as selective biological agents (anti-TNFα, anti-α4b7, and anti-IL-12 / 23 agents) and small molecule Janus kinase inhibitors that target immune cell activation. Despite these treatments, many patients have inadequate responses as determined by endoscopy and develop refractory disease. Therefore, there is an urgent need to develop therapeutic agents that promote gastrointestinal healing as determined by endoscopy (referred to as "endoscopic healing"), and to define tissue, blood, and microbiota biomarkers that can help guide therapy.

[0008] In patients with moderate to severe ulcerative colitis, there remains an unmet need for effective, safe, and well-tolerated treatments. Prominent clinical manifestations of UC include bloody diarrhea associated with rectal urgency and tenesmus. The clinical course is characterized by exacerbations and remissions. The diagnosis of UC is suspected on clinical evidence and supported by diagnostic tests and the elimination of infectious causes (Dignass et al., J Crohn's Colitis. 2012;6(10):965-90). The most severe bowel manifestations of UC are toxic megacolon and perforation. Extraintestinal complications include arthritis (peripheral or axial lesions), skin manifestations (erythema nodosum, aphthous stomatitis, and pyoderma gangrenosum), ocular inflammation (uveitis), and liver dysfunction (primary sclerosing cholangitis). Patients with ulcerative colitis (UC) are at increased risk of colon cancer, and this risk increases with the duration of the disease and the extent of colon involvement (Rutter et al, 2004 Gastroenterology;126(2):451-9).

[0009] The goal of medical treatment in UC is to control inflammation and reduce symptoms. Available medical therapies are limited, do not always completely alleviate the inflammatory process, and can have serious adverse effects. Therapies for mild to moderately active UC include 5-aminosalicylic acid derivatives and immunosuppressants.

[0010] Genome-wide association studies have linked more than 200 genes to IBD, many of which are associated with the underlying dysregulated immunomodulatory function (de Lange et al 2017, Nat Genet;49(2):256-610). One of the strongest genetic variants associated with IBD is located at the tumor necrosis factor superfamily member 15 (TNFSF15) locus (Siakavellas et al 2015; Inflamm.Bowel Dis.21(10):2441-52). Variants in TNFSF15 have been linked to the pathogenesis of several autoimmune diseases, including psoriasis, rheumatoid arthritis, and multiple sclerosis, suggesting a broad role of TNFSF15 in human inflammatory diseases. In IBD, the TNFSF15 variant may increase the risk of more invasive, penetrating, fibrostenotic, and perianal disease 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 TNF-like ligand 1A (TL1A), a protein highly expressed in human colon tissue during active colitis (Bamias et al 2013; Curr Opinion Gasteroenterol.29(6):597-602).

[0011] The mechanistic effects of TL1A in preclinical models are multifaceted. Early studies have shown that TL1A overexpression plays a pathogenic role in driving inflammatory Th1, Th17, and group 2 innate lymphoid responses, while more recent reports in mouse models of acute colitis and ileitis have revealed the contrasting protective role of endogenous TL1A in supporting anti-inflammatory regulatory T cell (Treg) and group 3 innate lymphoid function (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, mouse models have revealed the significant impact of TL1A overexpression in intestinal fibrosis. Furthermore, in vitro studies of peripheral blood macrophages revealed the contribution of TNFSF15 risk haplotypes to synergistically regulating NOD2 ligand-induced inflammatory cytokines (Hedl and Abraham, 2014; PNAS 111(37)13451-13456). In summary, these preclinical studies highlight the potential central homeostatic role of TL1A in regulating important selective innate and adaptive immune pathways for IBD, as well as fibrosis, a significant clinical complication. To date, no studies have defined the mechanisms underlying the potential efficacy of anti-TL1A therapy in humans.

[0012] Preclinical studies in rodent colitis models and human cells have shown that anti-TL1A antibodies can reduce histofibrosis, fibroblast count, and clinical disease scores, thereby highlighting their potential as a biological therapy for IBD (Clarke et al 2002, MAbs 10:664-677; Shih et al 2014 Mucosal Immunol;7:1492-1503).

[0013] In the field of the art, there is a need to treat inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, with anti-TNF-like ligand 1A (TL1A) antibody therapy, and a need to identify patients who may be responsive or unresponsive to such therapy. This disclosure addresses these needs. [Overview of the project]

[0014] Summary of the Invention This disclosure provides a method for determining the risk of a patient being unresponsive to a therapeutic dose of anti-TNF-like ligand 1A (TL1A) antibody, the method comprising: performing a genotyping assay on a biological sample from the patient to determine whether the patient is a haplotype B carrier or a non-carrier of TNFSF15, the assay including 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 a therapeutic dose of anti-TL1A antibody, the risk being higher in haplotype B carrier patients than in non-carrier patients. The patient may have inflammatory bowel disease (IBD).

[0015] This disclosure provides a method for treating inflammatory bowel disease (IBD) in a patient, 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 non-carrier of TNFSF15, wherein the assay 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 (b) administering an anti-TNF-like ligand 1A (TL1A) antibody to the patient, provided that the patient is determined to be a non-carrier of haplotype B.

[0016] In some embodiments, the anti-TL1A antibody is administered to the patient in an induction regimen sufficient to improve the signs and symptoms of IBD within at least 12 weeks after the initiation of treatment with the anti-TL1A antibody, the induction regimen comprising several individual induction doses.

[0017] In some embodiments, the anti-TL1A antibody is administered to the patient in a maintenance regimen following the completion of an induction regimen, the maintenance regimen comprising a number of individual maintenance doses administered at intervals of at least two weeks from each other.

[0018] In some aspects, the present disclosure relates to a method for treating IBD in a patient, the method comprising (a) performing a genotyping assay to determine whether the patient is a haplotype B carrier or a non-carrier of TNFSF15, wherein the assay includes 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) using an anti-TL1A antibody The method is characterized by (c) administering an induction regimen to a patient that is sufficient to improve the signs and symptoms of IBD within at least 12 weeks after the commencement of treatment, wherein the induction regimen comprises a plurality of individual induction doses and the patient has been determined to be a non-carrier of haplotype B; and (a) administering a subsequent maintenance regimen to the patient after completion of the induction regimen, wherein the maintenance regimen comprises a plurality of individual maintenance doses administered at intervals of at least two weeks from each other.

[0019] IBD can be ulcerative colitis (UC). UC can be moderate to severe ulcerative colitis. In some aspects, IBD is Crohn's disease (CD).

[0020] In a preferred embodiment, at least two SNPs are SNP rs3810936 and SNP rs7869487.

[0021] In some embodiments, the genotyping assay involves determining the presence of only two SNPs in a biological sample from a patient, namely SNP rs3810936 and SNP rs7869487.

[0022] In some embodiments, a patient is determined to be a non-carrier of haplotype B by any one of the following biomarker conditions in a biological sample from the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (iii) the genotype of the sample is homozygous for the surrogate allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) the genotype of the sample is homozygous for the surrogate allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) the genotype of the sample is homozygous for the surrogate allele at rs3810936 and homozygous for the surrogate allele at rs7869487.

[0023] In some embodiments, (a) a genotyping assay comprises determining the presence of SNPs rs3810936, rs7869487, and rs7848647 in a biological sample from a patient, or (b) a genotyping assay comprises determining the presence of SNPs rs3810936, rs7869487, and rs6478109 in a biological sample from a patient.

[0024] In some embodiments, the genotyping assay includes determining the presence of SNPs rs3810936, rs7869487, rs6478108, and rs6478109 in a biological sample from a patient.

[0025] Genotyping assays can include qPCR. Genotyping assays can include sequencing. Genotyping assays can include long-range sequencing or long-read sequencing. Genotyping assays can be performed on a microarray. In some embodiments, the genotyping assay is a fluorescence-based assay.

[0026] A biological sample can be any sample obtained from a patient. The biological sample can be a cell sample or a tissue sample. The tissue sample can be from an IBD inflammatory site. The biological sample can be an intestinal biopsy sample. The biological sample can be a blood sample. The biological sample can be cells or tissue of the buccal mucosa. Cells or tissue of the buccal mucosa can be obtained by a buccal swab. Preferably, the biological sample is blood or cells or tissue of the buccal mucosa.

[0027] In another aspect, the present disclosure relates to a method for determining the risk of a patient being unresponsive to a therapeutic dose of anti-TL1A antibody, wherein the patient has inflammatory bowel disease (IBD), and the method is (a) performing a genotyping assay on a biological sample from the patient to determine whether the patient is a haplotype B carrier or a non-carrier of TNFSF15, wherein the assay involves SNP rs3810936 and SNP in the biological sample from the patient. Including the determination of the presence of rs7869487, haplotype B noncarrier of TNFSF15 is the following biomarker status in the biological sample from the patient: (i) the sample genotype is homozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (ii) the sample genotype is heterozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (iii) the sample genotype is homozygous for the surrogate allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) the sample genotype is The method is characterized by: (v) the genotype of the sample is identified by one of the following: (v) being homozygous for the alternative allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) being homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487; and (b) identifying that if the patient is a haplotype B carrier, the patient is at high risk of being unresponsive to a therapeutic dose of anti-TL1A antibody; or (c) identifying that if the patient is not a haplotype B carrier, the patient is at low risk of being unresponsive to a therapeutic dose of anti-TL1A antibody. In some embodiments, the patient is determined to be not a haplotype B carrier of TNFSF15, and the method further comprises administering an effective dose of anti-TL1A antibody to the patient.In some embodiments, the anti-TL1A antibody is administered to a patient in a loading dosage regimen sufficient to improve the signs and symptoms of IBD by at least 12 weeks after the start of treatment with the anti-TL1A antibody, said loading dosage regimen comprising a plurality of individual loading doses. In some embodiments, the anti-TL1A antibody is administered to a patient in a maintenance dosage regimen after completion of the loading dosage regimen, said maintenance dosage regimen comprising a plurality of individual maintenance doses administered at intervals of at least 2 weeks from each other.

[0028] In another aspect, the present disclosure relates to a method for treating IBD in a patient, 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 non-carrier of TNFSF15, the assay comprising determining the presence of SNPs rs3810936 and SNPs rs7869487 in the biological sample from the patient, where a non-carrier of TNFSF15 haplotype B is a biomarker state in the biological sample from the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (iii) the genotype of the sample is homozygous for the surrogate allele at rs3810936 and homozygous for rs7869487 The method comprises (b) administering an effective dose of anti-TL1A antibody to a patient, the patient being determined to be a non-carrier of haplotype B. In some embodiments, the anti-TL1A antibody is administered to the patient in an induction regimen sufficient to improve the signs and symptoms of IBD within at least 12 weeks after the initiation of treatment with the anti-TL1A antibody, the induction regimen comprising several individual induction doses. In some embodiments, the anti-TL1A antibody is administered to the patient in a maintenance regimen following the completion of an induction regimen, the maintenance regimen comprising a number of individual maintenance doses administered at intervals of at least two weeks from each other.

[0029] In another aspect, the present disclosure relates to a method for treating IBD in a patient, the method comprising administering an effective amount of anti-TL1A antibody to the patient, the following biomarker statuses in a biological sample from the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (iii) the genotype of the sample is rs381093 The method is characterized by determining that the patient is a non-carrier of haplogroup B of TNFSF15 by any one of the following: (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.

[0030] In some embodiments, the anti-TL1A antibody is administered to the patient in an induction regimen sufficient to improve the signs and symptoms of IBD within at least 12 weeks after the initiation of treatment with the anti-TL1A antibody, and the induction regimen comprises several individual induction doses. In some embodiments, the anti-TL1A antibody is administered to the patient in a maintenance regimen after completion of the induction regimen, and the maintenance regimen comprises several individual maintenance doses administered at intervals of at least two weeks from each other.

[0031] Individual induction doses may be administered at least daily, at least every day, at least every week, at least every two weeks, at least every three weeks, at least every four weeks, at least every five weeks, at least every six weeks, at least every seven weeks, at least every eight weeks, at least every nine weeks, at least every ten weeks, at least every eleven weeks, or at least every twelve weeks. In a preferred embodiment, individual induction doses are administered at one-month intervals. In some embodiments, individual induction doses are administered at four-week intervals.

[0032] Individual induction 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 embodiment, individual induction doses are 50, 150, or 450 mg. In some embodiments, each individual induction dose is administered at a dose of 50 mg. In some embodiments, each individual induction dose is administered at a dose of 150 mg. In some embodiments, each individual induction dose is administered at a dose of 450 mg.

[0033] Each induction dose can be administered by any means. Preferably, each induction dose is administered intravenously or subcutaneously. In some embodiments, each of the individual induction doses is administered subcutaneously.

[0034] In some embodiments, the induction regimen includes four individual induction doses.

[0035] In some embodiments, the induction regimen comprises four individual induction doses administered at 4-week intervals, each of which is administered subcutaneously at a dose of 50, 150, or 450 mg.

[0036] Individual maintenance doses may be administered at least daily, at least every day, at least every week, at least every two weeks, at least every three weeks, at least every month, at least every two months, at least every three months, at least every four months, at least every five months, or at least every six months. In a preferred embodiment, individual maintenance doses are administered at one-month intervals. In some embodiments, individual maintenance doses are administered at four-week intervals.

[0037] 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 preferred embodiments, individual maintenance doses are 50, 150, or 450 mg. In some embodiments, individual maintenance doses are administered in doses of 50 mg. In some embodiments, individual maintenance doses are administered in doses of 150 mg. In some embodiments, individual maintenance doses are administered in doses of 450 mg.

[0038] Individual maintenance doses may be administered by any means. Preferably, individual maintenance doses are administered intravenously or subcutaneously. In some embodiments, individual maintenance doses are administered subcutaneously.

[0039] In some embodiments, the maintenance medication regimen includes at least 10 individual maintenance doses.

[0040] In some embodiments, the induction regimen includes 10 individual maintenance doses administered at 4-week intervals, with each individual maintenance dose being 50, 150, or 450 mg administered subcutaneously. In some embodiments, each individual maintenance dose is 450 mg administered subcutaneously.

[0041] The methods provided herein may further include (a) determining the expression level of one or more candidate genes in a biological sample from a patient, and (b) identifying that the biological sample contains abnormal expression levels of one or more candidate genes. One or more candidate genes may be selected from the group consisting of SOWAHB, COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, PKDREJ, IL-1 B, IL-23A, IFNG, IL-12RB1, IL-21 R, IRF4, BATF, CD80 / 86, HLA-DRB5 / DQB1 / DRB1, HLA-DRA, CD40, ICOS, MMP3, MMP7, MMP10, and CHI3L. In a preferred embodiment, 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 level of one or more candidate genes may be compared to baseline expression levels based on a) the expression levels of one or more candidate genes in healthy individuals not suffering from IBD or UC, or b) the estimated expression levels in individuals unresponsive to anti-TL1A antibody treatment. The abnormal expression level of one or more candidate genes may be at least 50% higher or lower than the baseline level.

[0042] The disclosed method may further include a) determining the expression level of one or more candidate bacterial strains in a stool sample from a patient, and b) identifying whether the sample contains an increased or decreased level of one or more candidate bacterial strains. In one embodiment, the candidate bacterial strain level may be increased, and the candidate strains are selected from the group consisting of Streptococcus salivarius, Streptococcus parasanguinis, and Haemophilus parainfluenzae. In one embodiment, the candidate bacterial strain level may be decreased, and the candidate strains are selected from the group consisting of Ruminococcus albus, Ruminococcus callidus, Ruminococcus bromii, Ruminococcus gnavus, and Bifidobacterium bifidum.

[0043] In another aspect, the present disclosure relates to a method for treating inflammatory bowel disease (IBD) in a patient, the method comprising: (a) performing a genotyping assay to determine whether the patient is a haplotype B carrier or a 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 anti-TL1A antibody to the patient, the patient being determined to be a non-carrier of haplotype B, the anti-TL1A antibody comprising 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, at least two SNPs are SNP rs3810936 and SNP rs7869487. In some embodiments, the assay involves determining the presence of only two SNPs in a biological sample from a patient, where the two SNPs are SNP rs3810936 and SNP rs7869487.

[0044] The antibody may be any anti-TL1A antibody. Examples include, but are not limited to, Afimkibart (also known as PF-06480605 or RVT-3101) from Pfizer / Roivant, PRA023 (also known as Turisokibart) from Prometheus Biosciences, and C03V from Teva Pharmaceuticals. In one embodiment, 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 include HCDR1 having the sequence shown in SEQ ID NO: 3 or 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 (for example, it may include the CDR sequences shown in SEQ ID NOs: 3-8, or the CDR sequences shown in SEQ ID NOs: 4-8 and 68). In some embodiments, the anti-TL1A antibody includes 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 embodiments, the anti-TL1A antibody is afimkivart.

[0045] Anti-TL1A antibodies may contain sequence pairs selected from the group consisting of SEQ ID NOs: 2 and 11; SEQ ID NOs: 2 and 12; SEQ ID NOs: 2 and 13; SEQ ID NOs: 2 and 14; SEQ ID NOs: 2 and 15; SEQ ID NOs: 2 and 16; SEQ ID NOs: 2 and 17; SEQ ID NOs: 2 and 18; SEQ ID NOs: 2 and 19; SEQ ID NOs: 20 and 24; SEQ ID NOs: 21 and 25; SEQ ID NOs: 22 and 26; SEQ ID NOs: 23 and 27; SEQ ID NOs: 28 and 29; SEQ ID NOs: 30 and 31; SEQ ID NOs: 32 and 33; SEQ ID NOs: 35 and 44; SEQ ID NOs: 53 and 54; SEQ ID NOs: 61 and 62; SEQ ID NOs: 63 and 64; SEQ ID NOs: 65 and 64; SEQ ID NOs: 66 and 64; and SEQ ID NOs: 67 and 64.

[0046] In some embodiments, 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 embodiments, 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. In some embodiments, 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 embodiments, 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 embodiments, the anti-TL1A antibody is thrisocibalt.

[0047] In another aspect, the present disclosure relates to a method for treating inflammatory bowel disease (IBD) in a patient, the method comprising (a) performing a genotyping assay to determine whether the patient is a haplotype B carrier or a 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, The method comprises (b) administering an anti-TL1A antibody to a patient, wherein the patient has been determined to be a non-carrier of haplotype B, 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. In some embodiments, 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, the two SNPs being SNP rs3810936 and SNP rs7869487. The disclosed treatment method may further include treatment with an IL-23 antagonist.

[0048] In another embodiment, the present disclosure is a method for treating inflammatory bowel disease (IBD) in a patient, the method comprising administering an effective amount of anti-TNF-like ligand 1A (TL1A) antibody to the patient in a drug regimen comprising an induction regimen and a subsequent maintenance regimen, wherein the induction regimen comprises a plurality of individual induction doses, and the maintenance regimen comprises a plurality of individual maintenance doses, wherein the anti-TL1A antibody is administered subcutaneously during the maintenance phase, 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.

[0049] In some embodiments, individual induction doses are administered at intervals of at least one week, at least two weeks, at least three weeks, or at least four weeks from each other. In some embodiments, individual induction doses are administered at intervals of at least one month from each other. In some embodiments, individual induction doses are administered at four-week intervals.

[0050] In some embodiments, individual induction doses are administered intravenously or subcutaneously. In some embodiments, each of the individual induction doses is administered subcutaneously.

[0051] In some embodiments, individual induction doses are administered in doses of 50, 150, or 450 mg. In some embodiments, each individual induction dose is administered in doses of 50 mg. In some embodiments, each individual induction dose is administered in doses of 150 mg. In some embodiments, each individual induction dose is administered in doses of 450 mg.

[0052] In some embodiments, the induction regimen includes four individual induction doses.

[0053] In some embodiments, the induction regimen comprises four individual induction doses administered at 4-week intervals, each of which is administered subcutaneously at a dose of 50, 150, or 450 mg.

[0054] In some embodiments, individual maintenance doses are administered at intervals of at least two weeks, at least three weeks, or at least four weeks. In some embodiments, individual maintenance doses are administered at intervals of at least one month. In some embodiments, individual maintenance doses are administered at intervals of four weeks.

[0055] In some embodiments, the individual maintenance dose is administered in doses of 50, 150, or 450 mg. In some embodiments, the individual maintenance dose is administered in doses of 50 mg. In some embodiments, the individual maintenance dose is administered in doses of 150 mg. In some embodiments, the individual maintenance dose is administered in doses of 450 mg.

[0056] In some embodiments, the maintenance regimen includes at least 10 individual maintenance doses. In some embodiments, the induction regimen includes 10 individual maintenance doses administered at 4-week intervals, with each individual maintenance dose being 50, 150, or 450 mg administered subcutaneously. In some embodiments, each individual maintenance dose is 450 mg administered subcutaneously.

[0057] In another aspect, the Disclosure relates to a method for treating inflammatory bowel disease (IBD) in a patient, the method comprising administering an effective amount of anti-TNF-like ligand 1A (TL1A) antibody to the patient in a dosage regimen comprising an induction regimen and a subsequent maintenance regimen, (a) the induction regimen comprising subcutaneous administration of four individual induction doses of anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg, with the individual induction doses administered at 4-week intervals, and (b) the maintenance regimen comprising anti-TL1A The treatment involves subcutaneous administration of multiple individual maintenance doses of the antibody at doses of approximately 50 mg, 150 mg, or 450 mg, with each individual maintenance dose administered at 4-week intervals, 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.

[0058] In another embodiment, the present disclosure is a method for treating inflammatory bowel disease (IBD) in a patient, the method comprising administering an effective amount of anti-TNF-like ligand 1A (TL1A) antibody to the patient in a dosing regimen comprising an induction regimen and a subsequent maintenance regimen, wherein (a) the induction regimen comprises a plurality of individual induction doses, the individual induction doses administered at intervals of at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks from each other, and (b) the maintenance regimen comprises subcutaneous administration of a plurality of individual maintenance doses of anti-TL1A antibody at doses of approximately 450 mg, the individual maintenance doses administered at intervals of 4 weeks, 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. In some embodiments, the induction regimen comprises subcutaneous administration of four individual induction doses of anti-TL1A antibody at doses of approximately 450 mg, with each induction dose administered at 4-week intervals.

[0059] In some embodiments, the initial maintenance dose is administered approximately two weeks after the final induction dose.

[0060] In some embodiments, the medication regimen has a duration of approximately 52 weeks.

[0061] In some embodiments, 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 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. In some embodiments, the anti-TL1A antibody is afimquivart.

[0062] In some cases, patients are determined to be non-carriers of haplotype B of TNFSF15.

[0063] In some aspects, IBD is ulcerative colitis (UC). In some aspects, UC is moderate to severe UC.

[0064] In some embodiments, in patient populations treated according to this method, the treatment results in an increased proportion of patients achieving clinical remission at the end of the induction phase compared to the reference population. In some embodiments, the induction phase has a duration of approximately 14 weeks, and the treatment results in an increased proportion of patients achieving clinical remission at week 14. In some embodiments, at least approximately 15% of patients in the patient population achieve clinical remission at week 14. In some embodiments, at least approximately 40% of patients in the patient population achieve clinical remission at week 14.

[0065] In some embodiments, in patient populations treated according to this method, the treatment results in an increased proportion of patients achieving clinical remission at the end of the maintenance phase compared to the reference population. In some embodiments, the medication regimen has a duration of approximately 56 weeks, and the treatment results in an increased proportion of patients achieving clinical remission at week 56. In some embodiments, at least approximately 20% of patients in the patient population achieve clinical remission at week 56. In some embodiments, at least approximately 55% of patients in the patient population achieve clinical remission at week 56.

[0066] In some embodiments, clinical remission is defined as a sum of Mayo scores ≤ 2, with no individual subscores > 1. In some embodiments, IBD is UC, and clinical remission is defined as a modified Mayo score (mMS) ≤ 2, with a bowel movement frequency subscore (SFS) = 0 or 1, a rectal bleeding subscore (RBS) = 0, and an endoscopy subscore (ES) = 0 or 1.

[0067] In some embodiments, the treatment in the patient population treated according to this method results in an increased proportion of patients achieving endoscopic improvement at the end of the induction phase compared to the reference population. In some embodiments, the induction phase has a duration of approximately 14 weeks, and the treatment results in an increased proportion of patients achieving endoscopic improvement at week 14. In some embodiments, at least approximately 25% of patients in the patient population achieve endoscopic improvement at week 14. In some embodiments, at least approximately 50% of patients in the patient population achieve endoscopic improvement at week 14.

[0068] In some embodiments, in patient populations treated according to this method, the treatment results in an increased proportion of patients achieving endoscopic improvement at the end of the maintenance phase compared to the reference population. In some embodiments, the medication regimen has a duration of approximately 56 weeks, and the treatment results in an increased proportion of patients achieving endoscopic improvement at week 56. In some embodiments, at least about 20% of patients in the patient population achieve endoscopic improvement at week 56. In some embodiments, at least about 65% of patients in the patient population achieve endoscopic improvement at week 56.

[0069] In some aspects, clinical remission is defined as an endoscopic subscore of 0 or 1.

[0070] In some embodiments, in patient populations treated according to this method, the treatment results in an increased proportion of patients achieving endoscopic remission, clinical response, symptomatic remission, or deep remission at the end of the induction phase, compared to the reference population.

[0071] In some embodiments, in patient populations treated according to this method, the treatment results in an increased proportion of patients achieving endoscopic remission, clinical response, symptomatic remission, or deep remission at the end of the maintenance phase compared to the reference population.

[0072] In some embodiments, the reference population is a group of patients who have never been treated with an anti-TL1A antibody. In some embodiments, the reference population is a group of patients treated with a placebo.

[0073] In another embodiment, the present disclosure features a kit comprising an anti-TNF-like ligand 1A (TL1A) antibody and a package insert containing instructions for using the antibody to treat inflammatory bowel disease (IBD) in a patient requiring treatment of IBD, according to one of the methods provided herein.

[0074] In another aspect, the Disclosure relates to an anti-TL1A antibody for use in the treatment of IBD in a patient, characterized in that (a) a genotyping assay is to be performed to determine whether the patient is a haplotype B carrier or a 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 to be administered to the patient, and the patient is determined to be a non-carrier of haplotype B.

[0075] In another aspect, the disclosure relates to an anti-TL1A antibody for use in the treatment of IBD in a patient, wherein (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a 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 anti-TL (c) The patient is to be administered an induction regimen sufficient to improve the signs and symptoms of IBD within at least 12 weeks after the initiation of treatment with the 1A antibody, wherein the induction regimen comprises several individual induction doses, the patient is determined to be a non-carrier of haplotype B, and (c) the anti-TL1A antibody is to be administered to the patient in subsequent maintenance regimens after the completion of the induction regimen, wherein the maintenance regimens comprise several individual maintenance doses administered at intervals of at least two weeks from each other.

[0076] In another aspect, the Disclosure relates to an anti-TL1A antibody for use in the treatment of IBD in a patient, wherein (a) a genotyping assay is performed on a biological sample from the patient to determine whether the patient is a haplotype B carrier or a non-carrier of TNFSF15, the assay comprising determining the presence of SNPs rs3810936 and SNPs rs7869487 in the biological sample from the patient, and a non-carrier of TNFSF15 haplotype B is a biomarker state in the biological sample from the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (iii) the genotype of the sample is homozygous for the surrogate allele at rs3810936 and rs786 (iv) The genotype of the sample is identified by one of the following: (iv) homozygous for the reference allele at 9487; (v) homozygous for the surrogate allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) homozygous for the surrogate allele at rs3810936 and homozygous for the surrogate allele at rs7869487; and (b) an effective dose of anti-TL1A antibody is to be administered to the patient, and the patient has been determined to be a non-carrier of haplotype B.

[0077] In another aspect, the disclosure relates to an anti-TL1A antibody for use in the treatment of IBD in a patient, wherein an effective amount of the anti-TL1A antibody is to be administered to the patient, and the patient is determined to be a non-carrier of haplotype B of TNFSF15 by one of the following biomarker states in a biological sample from the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and rs78694 (iii) The genotype of the sample is homozygous for the surrogate allele at rs3810936 and homozygous for the reference allele at rs7869487; (iv) The genotype of the sample is homozygous for the surrogate allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) The genotype of the sample is homozygous for the surrogate allele at rs3810936 and homozygous for the surrogate allele at rs7869487, characterized by an anti-TL1A antibody.

[0078] In another embodiment, the Disclosure relates to an anti-TL1A antibody for use in the treatment of IBD in a patient, wherein (a) a genotyping assay is to be performed to determine whether the patient is a haplotype B carrier or a 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, the patient is determined to be a non-carrier of haplotype B, 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.

[0079] In another embodiment, the Disclosure relates to an anti-TL1A antibody for use in the treatment of IBD in a patient, wherein (a) a genotyping assay is to be performed to determine whether the patient is a haplotype B carrier or a 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 to be administered to the patient, the patient is determined to be a non-carrier of haplotype B, 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.

[0080] In another embodiment, the present disclosure is an anti-TL1A antibody for use in the treatment of IBD in a patient, wherein an effective amount of the anti-TL1A antibody is administered to the subject in a drug regimen comprising an induction regimen and a subsequent maintenance regimen, the induction regimen comprising a plurality of individual induction doses, the maintenance regimen comprising a plurality of individual maintenance doses, the anti-TL1A antibody is administered subcutaneously during the maintenance phase, 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.

[0081] In another embodiment, the Disclosure relates to an anti-TL1A antibody for use in the treatment of IBD in a patient, wherein an effective amount of the anti-TL1A antibody is administered to the target in a dosing regimen comprising an induction regimen and a subsequent maintenance regimen, (a) the induction regimen comprising subcutaneous administration of four individual induction doses of the anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg, with each induction dose administered at 4-week intervals, and (b) the maintenance regimen comprising several individual maintenance doses of the anti-TL1A antibody The treatment involves subcutaneous administration of doses of approximately 50 mg, 150 mg, or 450 mg, with each maintenance dose administered at 4-week intervals, and the anti-TL1A antibody is characterized by comprising 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] In another embodiment, the Disclosure relates to an anti-TL1A antibody for use in the treatment of inflammatory bowel disease (IBD) in a patient, wherein an effective amount of the anti-TL1A antibody is administered to the subject in a dosage regimen comprising an induction regimen and a subsequent maintenance regimen, (a) the induction regimen comprising a plurality of individual induction doses, each administered at intervals of at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks from each other, and (b) the maintenance regimen comprising the subcutaneous administration of a plurality of individual maintenance doses of the anti-TL1A antibody at doses of approximately 450 mg, each administered at intervals of 4 weeks, 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.

[0083] In another aspect, the Disclosure relates to the use of an anti-TL1A antibody in the manufacture of a pharmaceutical product for the treatment of IBD in a patient, characterized in that (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a 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 anti-TL1A antibody is administered to the patient, and the patient is determined to be a non-carrier of haplotype B.

[0084] In another aspect, the disclosure relates to the use of an anti-TL1A antibody in the manufacture of a pharmaceutical for the treatment of IBD in a patient, wherein (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a 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 anti-TL1A The antibody is to be administered to the patient in an induction regimen sufficient to improve the signs and symptoms of IBD within at least 12 weeks after the initiation of treatment with the anti-TL1A antibody, wherein the induction regimen comprises several individual induction doses, the patient has been determined to be a non-carrier of haplotype B, and (c) the anti-TL1A antibody is to be administered to the patient in a subsequent maintenance regimen after the completion of the induction regimen, wherein the maintenance regimen comprises several individual maintenance doses administered at intervals of at least two weeks from each other.

[0085] In another aspect, the disclosure relates to the use of an anti-TL1A antibody in the manufacture of a pharmaceutical for the treatment of IBD in a patient, wherein (a) a genotyping assay is performed on a biological sample from the patient to determine whether the patient is a haplotype B carrier or a non-carrier of TNFSF15, the assay comprising determining the presence of SNPs rs3810936 and SNPs rs7869487 in the biological sample from the patient, and a non-carrier of TNFSF15 haplotype B is a biomarker state in the biological sample from the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (iii) the genotype of the sample is homozygous for the surrogate allele at rs3810936 and rs The use is characterized by: (iv) the sample genotype is identified by either (iv) being homozygous for the reference allele at rs3810936 and heterozygous for the reference allele at rs7869487; or (v) the sample genotype is identified by either being homozygous for the surrogate allele at rs3810936 and homozygous for the surrogate allele at rs7869487, and (b) an effective dose of anti-TL1A antibody is to be administered to the patient, and the patient has been determined to be a non-carrier of haplotype B.

[0086] In another aspect, the disclosure relates to the use of an anti-TL1A antibody in the manufacture of a pharmaceutical for the treatment of IBD in a patient, wherein an effective amount of the anti-TL1A antibody is administered to the patient, and the following biomarker statuses are present in a biological sample from the patient: (i) the genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (ii) the genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the surrogate allele at rs7869487; (iii) the genotype of the sample is The use is characterized by the determination that the patient is a non-carrier of haplogroup B of TNFSF15 by any one of the following: (iv) the genotype of the sample is homozygous for the surrogate allele at rs3810936 and homozygous for the reference allele at rs7869487; or (v) the genotype of the sample is homozygous for the surrogate allele at rs3810936 and homozygous for the surrogate allele at rs7869487.

[0087] In another aspect, the Disclosure relates to the use of an anti-TL1A antibody in the manufacture of a pharmaceutical product for the treatment of IBD in a patient, characterized in that (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a 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 anti-TL1A antibody is administered to the patient, the patient is determined to be a non-carrier of haplotype B, 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.

[0088] In another aspect, the Disclosure relates to the use of an anti-TL1A antibody in the manufacture of a pharmaceutical product for the treatment of IBD in a patient, characterized in that (a) a genotyping assay is performed to determine whether the patient is a haplotype B carrier or a 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, the patient is determined to be a non-carrier of haplotype B, 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.

[0089] In another embodiment, the Disclosure relates to the use of an anti-TL1A antibody in the manufacture of a pharmaceutical product for the treatment of IBD in a patient, wherein an effective amount of the anti-TL1A antibody is administered to the subject in a dosing regimen comprising an induction dosing regimen and a subsequent maintenance dosing regimen, the induction dosing regimen comprising a plurality of individual induction doses, the maintenance dosing regimen comprising a plurality of individual maintenance doses, the anti-TL1A antibody is administered subcutaneously during the maintenance phase, and the use of 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.

[0090] In another aspect, the disclosure relates to the use of an anti-TL1A antibody in the manufacture of a pharmaceutical product for the treatment of IBD in a patient, wherein an effective amount of anti-TL1A antibody is administered to the subject 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 individual induction doses of anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg, with each induction dose administered at 4-week intervals, and (b) the maintenance dosing regimen comprises multiple doses of anti-TL1A antibody The use is characterized by the subcutaneous administration of individual maintenance doses of approximately 50 mg, 150 mg, or 450 mg, with each maintenance dose administered at 4-week intervals, and the anti-TL1A antibody comprising 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.

[0091] In another embodiment, the Disclosure relates to the use of an anti-TL1A antibody in the manufacture of a pharmaceutical product for the treatment of inflammatory bowel disease (IBD) in a patient, wherein an effective amount of the anti-TL1A antibody is administered to the subject in a dosing regimen comprising an induction regimen and a subsequent maintenance regimen, wherein (a) the induction regimen comprises several individual induction doses, each administered at intervals of at least one week, at least two weeks, at least three weeks, or at least four weeks from each other, and (b) the maintenance regimen comprises the subcutaneous administration of several individual maintenance doses of the anti-TL1A antibody at doses of approximately 450 mg, each administered at four-week intervals, 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.

[0092] In some cases, the patient is a human being.

[0093] Any of the above embodiments, or any other embodiments described herein, may be combined with any other embodiments.

[0094] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art in which this disclosure pertains. Herein, unless the context explicitly indicates otherwise, singular forms include plural forms; for example, the terms “a,” “an,” and “the” are singular or plural, and the term “or” is understood to be inclusive. For example, “an element” means one or more elements.

[0095] Methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, but preferred methods and materials are described below. All publications, patent applications, patents, and other references referenced herein are incorporated by reference in their entirety. No reference cited herein is considered prior art to the claimed disclosure. In case of any conflict, this specification, including definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative and not intended to be limiting. Other features and advantages of this disclosure will become apparent from the detailed description and claims below. [Brief explanation of the drawing]

[0096] Brief explanation of the drawing [Figure 1] Figure 1 shows the locations of five single nucleotide polymorphisms (SNPs) at the TNFSF15 gene locus. [Figure 2] Figure 2 is a schematic diagram showing the TL1A 2-SNP test workflow. qPCR = quantitative PCR. [Figure 3] Figure 3 is a schematic diagram illustrating the design of the TUSCANY-2 trial. After the screening period, subjects received afimquivar once a month for a total of four times during a 12-week induction period (50 mg, 150 mg, or 450 mg), followed by afimquivar once a month during the maintenance period (50 mg, 150 mg, or 450 mg). SC = subcutaneous. Endpoints assessed at weeks 14 and 56 were clinical remission and endoscopic improvement. [Figure 4A] Figure 4A is a bar graph showing the percentage of patients who received at least one indicated dose of afimkivart or placebo during the induction phase of the TUSCANY-2 trial and experienced clinical remission at week 14 (defined as a modified Mayo score (mMS) ≤ 2, with a bowel movement frequency subscore (SFS) = 0 or 1, rectal bleeding subscore (RBS) = 0, and endoscopic subscore (ES) = 0 or 1). Unadjusted outcome rates with 90% confidence intervals are shown. [Figure 4B]Figure 4B is a bar graph showing the percentage of patients who received at least one dose of the indicated dose of afimquivar or placebo during the introductory phase of the TUSCANY-2 trial and experienced endoscopic improvement at week 14. Unadjusted outcome rates with a 90% confidence interval are shown. [Figure 5] Figure 5 is a bar graph showing the percentage of patients in the TUSCANY-2 trial who received at least one indicated dose of afimkivart or placebo during the maintenance phase and experienced clinical remission (defined as a modified Mayo score (mMS) ≤ 2, with a bowel movement frequency subscore (SFS) = 0 or 1, rectal bleeding subscore (RBS) = 0, and endoscopic subscore (ES) = 0 or 1). Unadjusted outcome rates with 90% confidence intervals are shown. [Figure 6] Figure 6 is a bar graph showing the percentage of patients in the TUSCANY-2 trial who received at least one dose of the indicated dose of afimquivar or placebo during the maintenance phase and experienced endoscopic improvement at week 14 or week 56. Unadjusted outcome rates with a 90% confidence interval are shown. [Figure 7A] Figure 7A is a set of bar graphs showing the percentage of patients treated with afimkivart or placebo during the induction phase of the TUSCANY-2 trial who experienced clinical remission (by modified Mayo score (mMS)) at week 14. Pbo: Placebo. Biomarker positive: TNFSF15 haplotype B non-carrier. [Figure 7B] Figure 7B is a set of bar graphs showing the percentage of patients treated with afimkivart or placebo during the induction phase of the TUSCANY-2 trial who experienced endoscopic improvement at week 14. Pbo: Placebo. Biomarker positive: TNFSF15 haplotype B non-carrier. [Figure 8A]Figure 8A is a set of bar graphs showing the percentage of patients treated with afimkivart or placebo during the induction phase of the TUSCANY-2 trial who experienced clinical remission at week 14. IR: Intolerance, inadequate response, or loss of response to previous high-intensity therapy (antitumor necrosis factor (TNF) agents, antiintegrin agents, anti-IL-12 / 23 agents, and / or Janus kinase (JAK) inhibitors). Not IR: Naive to high-intensity therapy failure. [Figure 8B] Figure 8B is a set of bar graphs showing the percentage of patients treated with afimkivart or placebo during the induction phase of the TUSCANY-2 trial who experienced endoscopic improvement at week 14. IR: Intolerance, inadequate response, or loss of response to previous high-intensity therapy (antitumor necrosis factor (TNF) agents, antiintegrin agents, anti-IL-12 / 23 agents, and / or Janus kinase (JAK) inhibitors). Not IR: Naive to high-intensity therapy failure. [Figure 9A] Figure 9A is a set of bar graphs showing the percentage of patients treated with afimkivart or placebo during the induction phase of the TUSCANY-2 trial who experienced clinical remission at week 14. IR: Intolerance, inadequate response, or loss of response to previously administered anti-TNF-containing therapy. Not IR: Naive to failure of anti-TNF-containing therapy. [Figure 9B] Figure 9B is a set of bar graphs showing the percentage of patients treated with afimkivart or placebo during the induction phase of the TUSCANY-2 trial who experienced endoscopic improvement at week 14. IR: Intolerance, inadequate response, or loss of response to previously administered anti-TNF-containing therapy. Not IR: Naive to failure of anti-TNF-containing therapy. [Figure 10]Figure 10 is a set of bar graphs showing the proportion of biomarker-evaluable, biomarker-positive, and biomarker-negative patients treated with afimkivart or placebo during the induction phase of the TUSCANY-2 trial who experienced clinical remission (left) or endoscopic improvement (right) at week 14. Biomarker-positive: TNFSF15 haplotype B non-carrier. Biomarker-negative: TNFSF15 haplotype B carrier. Unadjusted outcome rates with 90% confidence intervals are shown. [Modes for carrying out the invention]

[0097] Detailed description of the invention I. Clinical Management and Treatment Methods The primary goal of the new therapy is to leverage the genomics and transcriptomics of participants at baseline, which can help stratify and maximize therapeutic effects while minimizing risk. This disclosure provides methods for optimizing clinical management using anti-TL1A treatment. In some embodiments, the methods provided herein optimize clinical management using anti-TL1A to treat inflammatory bowel disease (such as Crohn's disease (CD) or ulcerative colitis (UC)) and / or treatment methods described in Section II below and / or known in the art (e.g., U.S. Patent Nos. 1,0822422, 1,0138296, 1,1292848, 9068003, 10590201, 9896511, 86427) This includes any one of the following: Nos. 41, 9290576, 8728482, 8263743, 9416185, 10322174, 10689439, 11440954, 11220549, 11767364, U.S. Patent Application Publication 2023 / 0235070, and U.S. Patent Application Publication 20240059799A1 (each of which is incorporated herein by reference in its entirety). Any method described in this section (i.e., Section I) may be used for treatment using any of the anti-TL1A antibodies described in Section IV below.

[0098] A. TNFSF15 haplotypes and non-responsiveness risks In some embodiments, any of the methods, uses, or compositions for use provided herein include determining a patient's TNFSF15 haplotype (e.g., determining whether the patient is (a) a TL1A haplotype B carrier or (b) a TL1A haplotype B non-carrier). The methods, uses, or compositions for use may further include making a treatment decision based on the patient's TNFSF15 haplotype (e.g., a decision to administer an anti-TL1A antibody (e.g., an anti-TL1A antibody provided in Section IV of this specification, e.g., Afimkivart, Turisokivart, or TEV-48574) or an anti-DR3 antibody to the patient).

[0099] TNFSF15 haplotype B is defined as a positive-strand TCATC at five single nucleotide polymorphism (SNP) sites—rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487—at the TL1A locus on chromosome 9, encompassing a 28kb region surrounding the TNFSF15 gene encoding TL1A (Figure 1). Table 1 shows TNFSF15 haplotype B and other TNFSF15 haplotypes.

[0100] TNFSF15 haplogroup B is associated with disease susceptibility and / or TL1A expression in Japanese and European cohorts. Data suggest that Jewish Crohn's disease (CD) patients who are haplogroup B carriers have more severe disease. Phase 2a and 2b studies demonstrate difference effects between haplogroup B carrier and non-carrier subpopulations. Data from internal UC studies support the specificity of haplogroup B status in predicting response to anti-TL1A therapy.

[0101] TNFSF15 haplogroup B noncarriers are any individuals that do not possess TCATC on either the positive strand of chromosome 9 in their maternal or paternal lineage. Haplogroup B noncarriers exhibit moderate TL1A tissue expression and increased response to anti-TL1A therapy.

[0102] TL1A haplotype determination can be achieved 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 nonhaplotype B (carrier vs. noncarrier). In one embodiment, the two SNPs are rs3810936 and rs7869487. In a preferred embodiment, the SNPs rs3810936 and rs7869487 can distinguish haplotype B from nonhaplotype B (carrier vs. noncarrier). The determination can proceed as follows: Step 1: Evaluate the SNP rs7869487 in the biological sample from the patient. If (T / T), the patient is identified as a nonhaplotype 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%). [Table 1]

[0103] The average misclassification rate from the 2-SNP analysis described above is very low, making it easy to use in clinical assays. 41% of American subjects (multiple ancestral backgrounds) and subjects with European ancestry (total) were haplotype B carriers with an average misclassification rate of approximately 0.5%. Subjects with European ancestry had a higher frequency of haplotype B carriers compared to American subjects (multiple ancestral backgrounds). 49.2% of subjects with East Asian and South Asian ancestry (total) were haplotype B carriers with an average misclassification rate of approximately 1.6%. Subjects with East Asian ancestry constituted the largest population of haplotype B carriers (approximately 66%). 8.32% of subjects with African ancestry were haplotype B carriers, and no misclassification was identified in this population. In the evaluation of 2-SNP analysis in the Phase 2 trial, 62 / 192 samples were heterozygous or homozygous for minor allele frequencies (MAF) at rs7869487 or rs3810936. All 62 subjects were considered positive for haplotype B - misclassification rate 0%.

[0104] Methods for determining non-responsiveness risk This disclosure relates to a method for determining the risk of a patient being unresponsive to a therapeutic dose of anti-TNF-like ligand 1A (TL1A) antibody (e.g., anti-TL1A antibodies provided in Section IV of this Spec, e.g., Afimkivart, Turisokivart, or TEV-48574) or 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 non-carrier of TNFSF15, the assay comprising rs3810936, rs6478108, rs64781 The present invention provides a method comprising: (b) determining the presence of at least two single nucleotide polymorphisms (SNPs) selected from rs7848647 and rs7869487; and (c) determining the risk of non-responsiveness to a therapeutic dose of anti-TL1A antibody or anti-DR3 antibody, wherein (i) haplotype B carrier patients are at higher risk than non-haplotype B carrier patients; (ii) non-haplotype B carrier patients are at lower risk of non-responsiveness than haplotype B carrier patients; and / or (iii) non-haplotype B carrier patients are more likely to be responsive than haplotype B carrier patients. By determining the presence of at least two SNPs, the patient is determined to be a haplotype B carrier. The patient may have inflammatory bowel disease (IBD). In a preferred embodiment, the at least two SNPs are SNP rs3810936 and SNP rs7869487.

[0105] In another aspect, the present disclosure provides a method for determining the risk of a patient being unresponsive to a therapeutic dose of an anti-TL1A antibody (e.g., anti-TL1A antibodies provided in Section IV of this Spec, e.g., Afimkivart, Turisokivart, 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 non-carrier of TNFSF15, the assay comprising r3810936 and r in the biological sample from the patient. The method provides a way to perform (b) determine the presence of at least two single nucleotide polymorphisms (SNPs), including s7869487, and (b) determine the risk of non-responsiveness to a therapeutic dose of anti-TL1A antibody or anti-DR3 antibody, wherein (i) haplotype B carriers are at higher risk than non-haplotype B carriers, (ii) non-haplotype B carriers are at lower risk of non-responsiveness than haplotype B carriers, and / or (iii) non-haplotype B carriers are more likely to be responsive than haplotype B carriers.

[0106] In another aspect, the present disclosure provides a method for determining the risk of a patient being unresponsive to a therapeutic dose of an anti-TL1A antibody (e.g., anti-TL1A antibodies provided in Section IV of this Spec, e.g., Afimkivart, Turisokivart, 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 non-carrier of TNFSF15, the assay comprising two single nucleotide polymorphisms in the biological sample from the patient The method provides a way in which (b) a person performs the following actions, including determining the presence of (SNPs)r3810936 and rs7869487, and (c) determining the risk of being unresponsive to a therapeutic dose of anti-TL1A antibody or anti-DR3 antibody, wherein (i) haplotype B carriers are at higher risk than non-haplotype B carriers, (ii) non-haplotype B carriers are at lower risk of being unresponsive than haplotype B carriers, and / or (iii) non-haplotype B carriers are more likely to be responsive than haplotype B carriers.

[0107] In one embodiment, the present disclosure relates to 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 being: (a) Performing a genotyping assay on a biological sample from the patient to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, the assay comprising determining the presence of SNPs rs3810936 and rs7869487 in the biological sample from the patient, wherein a TNFSF15 haplotype B non-carrier indicates the following biomarker status in the biological sample from the patient: (i) The genotype of the sample 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); (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 (for example, the sample is C / T at rs3810936) and homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487); (iii) The genotype of the sample is homozygous for the substitute 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); (iv) 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 (e.g., the sample is T / C at rs7869487); or (v) The genotype of the sample is identified by either being homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936) or being homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487), and The present invention provides a method comprising (b) identifying that the patient is at high risk of being unresponsive to a therapeutic dose of anti-TL1A antibody or anti-DR3 antibody if the patient is a haplotype B carrier, or (c) identifying that the patient is at low risk of being unresponsive to a therapeutic dose of anti-TL1A antibody or anti-DR3 antibody if the patient is not a haplotype B carrier.

[0108] Treatment methods for IBD based on the TNFSF15 haplotype In another aspect, the present disclosure provides a method for treating inflammatory bowel disease (IBD) in a patient, the method comprising: (a) performing a genotyping assay to determine whether the patient is a haplotype B carrier or a non-carrier of TNFSF15, wherein 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 an anti-TL1A antibody (e.g., an anti-TL1A antibody provided in Section IV of this Spec, e.g., Afimkivart, Turisokivart or TEV-48574) or an anti-DR3 antibody to the patient, wherein the patient has been determined to be a non-carrier of haplotype B.

[0109] In some embodiments, the anti-TL1A antibody is administered to the patient in an induction regimen (for example, an induction regimen sufficient to improve the signs and symptoms of IBD within at least 12 weeks after the initiation of treatment with the anti-TL1A antibody, the induction regimen comprising several individual induction doses).

[0110] In some embodiments, the anti-TL1A antibody is administered to the patient in a maintenance regimen following an induction regimen (for example, administered to the patient in a maintenance regimen after completion of the induction regimen, the maintenance regimen comprising several individual maintenance doses administered at intervals of at least two weeks from each other). Exemplary induction and maintenance regimens are provided in Section II below.

[0111] Accordingly, in some embodiments, the present disclosure is a method for treating IBD in a patient, the method comprising (a) performing a genotyping assay to determine whether the patient is a haplotype B carrier or a non-carrier of TNFSF15, wherein the assay includes 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) anti-TL1A anti The present invention provides a method comprising: (a) administering an induction regimen to a patient sufficient to improve the signs and symptoms of IBD within at least 12 weeks after the initiation of physical treatment, wherein the induction regimen comprises a plurality of individual induction doses, and the patient has been determined to be a haplotype B noncarrier; and (c) administering a subsequent maintenance regimen to the patient after completion of the induction regimen, wherein the maintenance regimen comprises a plurality of individual maintenance doses administered at intervals of at least two weeks from each other.

[0112] In some embodiments, at least two SNPs are SNP rs3810936 and SNP rs7869487. In some embodiments, the assay involves determining the presence of only two SNPs in a biological sample from a patient, where the two SNPs are SNP rs3810936 and SNP rs7869487. At the location of SNP rs3810936, the wild-type nucleotide ("reference allele") is "T" and the surrogate allele is "C". At the location of SNP rs7869487, the wild-type nucleotide ("reference allele") is "C" and the surrogate allele is "T".

[0113] In some embodiments, TNFSF15 haplotype B non-carrier exhibits the following biomarker states in biological samples from patients: (i) The genotype of the sample 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); (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 (for example, the sample is C / T at rs3810936) and homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487); (iii) The genotype of the sample is homozygous for the substitute 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); (iv) 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 (e.g., the sample is T / C at rs7869487); or (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). It is identified by one of the following:

[0114] In some embodiments, at least two SNPs include SNP rs3810936, SNP rs7869487, and SNP rs7848647. In some embodiments, the assay includes determining the presence of only three SNPs in a biological sample from a patient, the three SNPs being SNP rs3810936, SNP rs7869487, and SNP rs7848647. In some embodiments, the assay includes determining the presence of only three SNPs in a biological sample from a patient, the three SNPs being SNP rs3810936, SNP rs7869487, and SNP rs6478109.

[0115] In some embodiments, at least two SNPs include SNP rs3810936, SNP rs7869487, SNP rs6478108, and SNP rs6478109. In some embodiments, the assay involves determining the presence of only four SNPs in a biological sample from a patient, where the four SNPs are SNP rs3810936, SNP rs7869487, SNP rs6478108, and SNP rs6478109.

[0116] Accordingly, in some embodiments, the present disclosure relates to a method for treating IBD in a patient, 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 non-carrier of TNFSF15, the assay comprising determining the presence of SNP rs3810936 and SNP rs7869487 in the biological sample from the patient, the non-carrier of TNFSF15 haplotype B being a biomarker state in the biological sample from the patient: (i) The genotype of the sample 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); (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 (for example, the sample is C / T at rs3810936) and homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487); (iii) The genotype of the sample is homozygous for the substitute 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); (iv) 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 (e.g., the sample is T / C at rs7869487); or (v) The genotype of the sample is identified by either homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936) or homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487), and the procedure is carried out accordingly. (b) A method is provided comprising administering an anti-TL1A antibody or an anti-DR3 antibody to a patient who has been determined to be a non-carrier of haplotype B. In some embodiments, the anti-TL1A antibody is administered to the patient in an induction regimen (e.g., an induction regimen sufficient to improve the signs and symptoms of IBD within at least 12 weeks after the initiation of treatment with the anti-TL1A antibody or anti-DR3 antibody, wherein the induction regimen comprises several individual induction doses). In some embodiments, the anti-TL1A antibody is administered to the patient in a maintenance regimen following the induction regimen (e.g., an induction regimen following the completion of the induction regimen, wherein the maintenance regimen comprises several individual maintenance doses administered at intervals of at least two weeks from each other).

[0117] In another aspect, the present disclosure relates to a method for treating IBD in a patient, the method comprising (a) administering to the patient an effective amount of anti-TL1A antibody in an induction regimen (e.g., an induction regimen sufficient to improve the signs and symptoms of IBD by at least 12 weeks after the initiation of treatment with anti-TL1A antibody, the induction regimen comprising a plurality of individual induction doses), and (b) administering to the patient an effective amount of anti-TL1A antibody in a subsequent maintenance regimen after the completion of the induction regimen (e.g., a maintenance regimen comprising a plurality of individual maintenance doses administered at intervals of at least 2 weeks from each other), wherein the patient has been determined to be a non-carrier of haplotype B of TNFSF15, and non-carrier of haplotype B of TNFSF15 is a biomarker state in a biological sample from the patient: (i) The genotype of the sample 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); (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 (for example, the sample is C / T at rs3810936) and homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487); (iii) The genotype of the sample is homozygous for the substitute 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); (iv) 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 (e.g., the sample is T / C at rs7869487); or The present invention provides a method for identifying the genotype of a sample by either being homozygous for the alternative allele at rs3810936 (i.e., the sample is C / C at rs3810936) or being homozygous for the alternative allele at rs7869487 (i.e., the sample is T / T at rs7869487).

[0118] In some embodiments of any of the above, the anti-TL1A antibody includes 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, the anti-TL1A antibody includes 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 afimquivart.

[0119] In some embodiments of any of the above, the anti-TL1A antibody includes 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 thrisocibalt.

[0120] In some embodiments of any of the above, the anti-TL1A antibody has the HVR sequence TEV-48574. In some embodiments, the anti-TL1A antibody is TEV-48574.

[0121] In some embodiments of any of the above, IBD is ulcerative colitis. In some embodiments, UC is moderate to severe ulcerative colitis.

[0122] Assay for determining the TNFSF15 haplotype Any suitable method may be used to determine whether a patient is a TNFSF15 haplotype B carrier or not. For example, any suitable method may be used to determine the patient's genotype at the position of one or more of at least two SNPs selected from rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487 in a biological sample from the patient. Exemplary methods for determining a patient's TNFSF15 haplotype are provided herein.

[0123] In some embodiments, the genotyping assay used in any one of the methods provided herein involves the use of quantitative PCR (qPCR).

[0124] In some embodiments, the genotyping assay includes sequencing (e.g., DNA sequencing). In some embodiments, the genotyping assay includes long-read sequencing.

[0125] In some embodiments, the genotyping assay is a fluorescence-based assay. In some embodiments, the genotyping assay is a Taqman assay. (商標) This is a fluorescence-based qPCR assay, such as a qPCR assay.

[0126] The biological sample can be any suitable sample containing genomic DNA. In some embodiments, the biological sample is blood. In some embodiments, the biological sample is or contains buccal mucosal cells.

[0127] B. Expression level of candidate gene In some embodiments, any of the methods, uses, or compositions for use provided herein include determining the expression of one or more candidate genes (as described below) in a sample from a patient. The methods, uses, or compositions for use may further include making a treatment decision based on the patient's gene expression.

[0128] In some aspects of the present disclosure, the method further includes a) determining the expression level of one or more candidate genes in a sample from a patient; b) identifying that the sample contains an abnormal expression level of one or more candidate genes; and c) administering an induction regimen or individual induction doses of an anti-TL1A antibody to the patient.

[0129] Determining whether a patient has abnormal expression levels of one or more candidate genes may be done by obtaining a sample from the patient or by obtaining a sample from the patient. The sample may be a tissue sample. The sample may be a tissue sample from an IBD inflammation site. The sample may be a peripheral blood sample. The sample may be a bowel biopsy sample.

[0130] This method may further include performing, or having performed, an assay on a sample to determine whether the patient expresses abnormal levels of one or more candidate genes.

[0131] In some embodiments, if the sample contains one or more candidate genes at abnormal levels, the method provides a further step of administering an anti-TL1A antibody induction regimen or induction dose to the patient.

[0132] In some embodiments, the risk of patients being unresponsive to an anti-TL1A antibody induction regimen or individual induction doses is lower in patients with abnormal levels of one or more candidate genes.

[0133] In some embodiments, the present disclosure provides a method for treating inflammatory bowel disease (IBD) in a patient, the method comprising: a) determining the expression level of one or more candidate genes in a sample from the patient; b) identifying that the sample contains an abnormal expression level of one or more candidate genes; and c) administering an induction regimen or individual induction doses of an anti-TNF-like ligand 1A (TL1A) antibody to the patient.

[0134] 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 may be selected from the group consisting of IL-1B, IL-23A, IFNG, IL-12RB1, IL-21R, IRF4, and BATF. One or more candidate genes may be selected from the group consisting of CD80 / 86, HLA-DRB5 / DQB1 / DRB1, HLA-DRA, CD40, and ICOS. One or more candidate genes may be selected from the group consisting of MMP3, MMP7, MMP10, and CHI3L.

[0135] 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.

[0136] 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 candidate gene selected from the group consisting of COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, and PKDREJ. One or more candidate genes may include SOWHAB and COLCA2 and at least one candidate gene 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 candidate gene selected from the group consisting of FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, and PKDREJ.

[0137] In some embodiments, the method provides for determining the expression levels of 2, 3, 4, 5, 6, 7, 8, 9, or 10 candidate genes selected from the group consisting of SOWAHB, COLCA2, TBX20, FRZB, HOXB5, NET1, FOXD2, DESI1, PARK2, and PKDREJ.

[0138] The abnormal expression levels of one or more candidate genes can be determined based on the levels of mRNA or expressed proteins of one or more candidate genes.

[0139] The abnormal expression levels of one or more candidate genes can be determined based on the mRNA levels of one or more candidate genes.

[0140] The expression levels of one or more candidate genes can be compared to baseline expression levels based on the expression levels of one or more candidate genes in healthy individuals who do not have IBD or UC.

[0141] The expression levels of one or more candidate genes can be compared to baseline expression levels based on estimated expression levels for individuals that are unresponsive to anti-TL1A antibody treatment.

[0142] The abnormal expression levels of one or more candidate genes may be at least 50% higher or lower than baseline levels. The abnormal expression levels of one or more candidate genes may be at least 2 times, 5 times, 10 times, 50 times, 100 times, 500 times, or 1000 times higher or lower than baseline levels.

[0143] In some embodiments, when one or more candidate genes are selected from the group consisting of SOWAHB, COLCA2, FRZB, HOXB5, NET1, FOXD2, PARK2, and PKDREJ, the level of abnormal expression may be elevated. In some embodiments, when one or more candidate genes are selected from the group consisting of TBX20 and DESI1, the level of abnormal expression is reduced.

[0144] C. Level of bacterial strain In some embodiments, any of the methods, uses, or compositions for use provided herein include determining the level of one or more bacterial strains (as described below) in a stool sample from a patient. The methods, uses, or compositions for use may further include making a treatment decision based on the level of bacterial strains in the sample.

[0145] In some embodiments, the disclosure includes a) determining the level of one or more candidate bacterial strains in a stool sample from a patient; b) identifying that the stool sample contains one or more candidate bacterial strains at elevated levels; and c) administering an induction dose of anti-TL1A antibody to the patient.

[0146] In some embodiments, candidate bacterial strains are selected from the group consisting of Streptococcus salivarius, Streptococcus parasanguinis, and Haemophilus parainfluenzae.

[0147] In some embodiments, the disclosure includes a) determining the level of one or more candidate bacterial strains in a stool sample from a patient; b) identifying that the stool sample contains reduced levels of one or more candidate bacterial strains; and c) administering an induction dose of an anti-TL1A antibody to the patient.

[0148] In some embodiments, candidate bacterial strains are selected from the group consisting of Ruminococcus albus, Ruminococcus callidus, Ruminococcus bromii, Ruminococcus gnavus, and Bifidobacterium bifidum.

[0149] In some embodiments, the level of one or more candidate bacterial strains is compared to a baseline bacterial level based on the level of one or more candidate bacterial strains in healthy individuals not suffering from IBD or UC. In some embodiments, the level of one or more candidate bacterial strains is compared to a baseline bacterial level based on the estimated level of those candidate bacterial strains in individuals unresponsive to anti-TL1A antibody treatment.

[0150] In some embodiments, the level of one or more candidate bacterial strains is at least 50%, 2, 5, 10, 20, 50, 100, 500, or 1000 times greater or less than the baseline bacterial level.

[0151] In some embodiments, the disclosure further includes treatment with an IL-23 antagonist.

[0152] D. Methods for identifying patients who are likely to benefit from treatment based on abnormal gene expression. This disclosure relates to a method for identifying patients with inflammatory bowel disease who are likely to benefit from initial or continuous treatment with anti-TL1A antibody therapy, and optionally treating such patients, wherein the method comprises (a) 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 The present invention provides a method comprising identifying a patient as having abnormal levels of one or more candidate genes selected from the group, and optionally (b) administering an anti-TL1A antibody to the patient under the condition that one or more selected from the group consisting of inflammatory macrophages, TH17, ILC3, 0X40, OX40L, IFNy, ILC2, IL-13, MMP, tissue remodeling, fibrosis, the intestinal population of S. salivarius, the intestinal population of S. parasanguinis, and the intestinal population of H. parainfluenzae decreases after the administration.

[0153] II. Treatment of inflammatory bowel disease using anti-TL1A antibodies In some embodiments, the Disclosure provides a method for treating inflammatory bowel disease (IBD) (e.g., ulcerative colitis (UC) or Crohn's disease (CD)) in a patient (e.g., a human), the method comprising administering an effective amount of anti-TNF-like ligand 1A (TL1A) antibody (e.g., the anti-TL1A antibody provided in Section IV of this Spec) to the patient in a dosing regimen comprising an induction phase (induction regimen) and a subsequent maintenance phase (maintenance regimen), wherein the induction regimen comprises a plurality of individual induction doses, the maintenance regimen comprises a plurality of individual maintenance doses, and 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 afimquivart.

[0154] As a general principle, the treatment of IBD with anti-TL1A antibodies is described in PCT Publication No. WO2021 / 260577 and U.S. Patent Application Publication No. 2023 / 0235070, which are incorporated herein by reference for all purposes.

[0155] In some aspects of any treatment method provided herein, IBD is ulcerative colitis (e.g., moderate to severe ulcerative colitis).

[0156] In some embodiments of any treatment method provided herein, the patient is determined to have a relatively low risk of being unresponsive to a therapeutic dose of anti-TL1A antibody. In some embodiments, the patient is determined to be a non-carrier of TNFSF15 haplotype B. Methods for determining the patient's risk of unresponsiveness and for determining whether the patient is a TNFSF15 haplotype B carrier are provided (for example, in Section I of this specification).

[0157] A. Introduction Phase Any method provided herein may include administration of an anti-TL1A antibody during the induction phase. The induction phase may include one or more administrations of the anti-TL1A antibody.

[0158] In some embodiments, the induction phase includes at least two doses of anti-TL1A antibody, and the time interval between each individual induction dose may be the same. Individual induction doses may be administered at least daily, at least every day, at least every week, at least every two weeks, at least every three weeks, at least every four weeks, at least every five weeks, at least every six weeks, at least every seven weeks, at least every eight weeks, or at least every nine weeks, at least every ten weeks, at least every eleven weeks, or at least every twelve weeks. In one preferred embodiment, individual induction doses are administered at one-month intervals. In one preferred embodiment, individual induction doses are administered at four-week intervals (Q4W).

[0159] In some embodiments, the induction phase includes four doses of anti-TL1A antibody. In some embodiments, doses of anti-TL1A antibody are administered at approximately 4-week intervals (e.g., every 4 weeks). In some embodiments, the induction phase has a duration of approximately 14 weeks, with (a) the first dose of anti-TL1A antibody administered on day 1 of week 0, (b) the second dose of anti-TL1A antibody administered on day 1 of week 4, (c) the third dose of anti-TL1A antibody administered on day 1 of week 8, and (d) the fourth dose of anti-TL1A antibody administered on day 1 of week 12.

[0160] 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 one preferred embodiment, the individual induction dose is 50, 150, or 450 mg of anti-TL1A antibody. In one embodiment, the individual induction dose is 450 mg of anti-TL1A antibody (for example, each individual induction dose is administered in a 450 mg dose). In another embodiment, the individual induction dose is 150 mg of anti-TL1A antibody (for example, each individual induction dose is administered in a 150 mg dose). In another embodiment, the individual induction dose is 50 mg of anti-TL1A antibody (for example, each individual induction dose is administered in a dose of 50 mg). Individual induction doses may be administered by any means. Preferably, individual induction doses are administered subcutaneously. In one embodiment, individual induction doses are administered subcutaneously at 50, 150, or 450 mg. In one embodiment, individual induction doses are administered subcutaneously monthly at 50, 150, or 450 mg. In one embodiment, individual induction doses are administered subcutaneously every four weeks (Q4W) at 50, 150, or 450 mg.

[0161] In some embodiments, during the induction phase, the anti-TL1A antibody is administered subcutaneously (SC) in doses of approximately 450 mg (e.g., 450 mg doses) (for example, each dose during the induction phase includes SC administration of approximately 450 mg (e.g., 450 mg) of anti-TL1A antibody).

[0162] B. Maintenance phase Any method provided herein may include subcutaneous administration of an anti-TL1A antibody in a maintenance phase, following administration of an anti-TL1A antibody in an induction phase. The maintenance phase may include one or more administrations of the anti-TL1A antibody.

[0163] The maintenance phase may be initiated at any appropriate point after the induction phase. In some embodiments, the first dose of the maintenance phase is administered approximately two weeks (e.g., two weeks) after the final dose of the induction phase. For example, in an embodiment where the induction phase involves four doses of anti-TL1A antibody, the first dose of the maintenance phase may be administered approximately two weeks (e.g., two weeks) after the final dose of the induction phase.

[0164] In some embodiments, the maintenance phase includes at least two doses of anti-TL1A antibody, and the time interval between each individual maintenance dose may be the same. Individual maintenance doses may be administered at least daily, at least every day, at least every week, at least every two weeks, at least every three weeks, at least every month, at least every two months, at least every three months, at least every four months, at least every five months, or at least every six months. In one preferred embodiment, individual maintenance doses are administered at one-month intervals. In one preferred embodiment, individual maintenance doses are administered at four-week intervals.

[0165] In some embodiments, the maintenance phase includes administration of anti-TL1A antibodies every four weeks (Q4W).

[0166] 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 embodiment, individual maintenance doses are 50, 150, or 450 mg. In one embodiment, individual maintenance doses are approximately 450 mg (e.g., 450 mg). Individual maintenance doses may be administered by any means. Preferably, individual maintenance doses are administered subcutaneously. In one embodiment, individual maintenance doses are administered subcutaneously at doses of 50, 150, or 450 mg. In one embodiment, individual maintenance doses are 450 mg of anti-TL1A antibody (e.g., each individual maintenance dose is administered subcutaneously at a dose of 450 mg). In another embodiment, the individual maintenance dose is 150 mg of anti-TL1A antibody (for example, each individual maintenance dose is administered subcutaneously at a dose of 150 mg). In another embodiment, the individual maintenance dose is 50 mg of anti-TL1A antibody (for example, each individual maintenance dose is administered subcutaneously at a dose of 50 mg). In one embodiment, the individual maintenance dose is administered subcutaneously monthly at doses of 50, 150, or 450 mg.

[0167] In some embodiments, the maintenance phase includes at least 10 doses of anti-TL1A antibody (e.g., 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 embodiments, the maintenance phase includes 10 doses of anti-TL1A antibody (e.g., 10 doses of anti-TL1A antibody administered in a Q4W dosing regimen).

[0168] Accordingly, in some embodiments, the present disclosure is a method for treating IBD in a patient, comprising administering an effective amount of anti-TL1A antibody to the patient in a drug regimen comprising an induction regimen and a subsequent maintenance regimen, (a) the induction regimen comprising subcutaneous administration of four individual induction doses of anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg (e.g., 50 mg, 150 mg, or 450 mg), with the individual induction doses administered at 4-week intervals, and (b) the maintenance regimen comprising multiple individual doses of anti-TL1A antibody The present invention provides a method comprising subcutaneous administration of a maintenance dose of approximately 50 mg, 150 mg, or 450 mg (for example, 50 mg, 150 mg, or 450 mg), wherein each maintenance dose is administered at 4-week intervals, 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. In some embodiments, the anti-TL1A antibody is afimquivart.

[0169] In some embodiments, the Disclosure provides a method for treating IBD in a patient, comprising administering an effective amount of anti-TL1A antibody to the patient in a drug regimen comprising an induction regimen and a subsequent maintenance regimen, wherein (a) the induction regimen comprises subcutaneous administration of four individual induction doses of anti-TL1A antibody at doses of approximately 450 mg (e.g., 450 mg), with each induction dose administered at 4-week intervals, and (b) the maintenance regimen comprises subcutaneous administration of a plurality of individual maintenance doses of anti-TL1A antibody at doses of approximately 450 mg (e.g., 450 mg), with each maintenance dose administered at 4-week intervals, 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.

[0170] In some embodiments, the Disclosure relates to a method for treating IBD in a patient, comprising administering an effective amount of anti-TL1A antibody to the patient in a dosage regimen comprising an induction dosage regimen and a subsequent maintenance dosage regimen, wherein (a) the induction dosage regimen comprises subcutaneous administration of four individual induction doses of anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg (e.g., 50 mg, 150 mg, or 450 mg), with each induction dose administered at 4-week intervals, and (b) the maintenance dosage regimen comprises several individual doses of anti-TL1A antibody The treatment involves subcutaneous administration of a maintenance dose of approximately 50 mg, 150 mg, or 450 mg (for example, 50 mg, 150 mg, or 450 mg), with each maintenance dose administered at 4-week intervals, and 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 afimquivart.

[0171] In some embodiments, the Disclosure provides a method for treating IBD in a patient, comprising administering an effective amount of anti-TL1A antibody to the patient in a drug regimen comprising an induction regimen and a subsequent maintenance regimen, wherein (a) the induction regimen comprises subcutaneous administration of four individual induction doses of anti-TL1A antibody at doses of approximately 450 mg (e.g., 450 mg), with each induction dose administered at 4-week intervals, and (b) the maintenance regimen comprises subcutaneous administration of a plurality of individual maintenance doses of anti-TL1A antibody at doses of approximately 450 mg (e.g., 450 mg), with each maintenance dose administered at 4-week intervals, 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, and LCDR3 having the sequence shown in SEQ ID NO: 8.

[0172] In some embodiments, a medication regimen including induction and maintenance phases has a duration of approximately 52 weeks (for example, a duration of 52 weeks).

[0173] C. Response to the treatment Clinical response Following an induction and / or maintenance regimen, patients may experience improvement in the signs and symptoms of IBD, characterized by a clinical response. The term “clinical response” can be defined as a decrease of at least 3 points from baseline in the total Mayo score, a decrease of at least 1 point in the rectal bleeding subscore, or a decrease with an absolute score of 0 or 1.

[0174] The abbreviation "Mayo" refers to the Mayo Scoring System for evaluating ulcerative colitis activity. The "adaptive Mayo score" refers to the adaptive Mayo scoring system, which has three subscores ranging from 0 to 9, without a physician's overall assessment (PGA) subscore.

[0175] In some embodiments, in a patient population treated according to any one of the methods provided herein, the treatment results in an increased proportion of patients achieving a clinical response at the end of the induction phase compared to a reference population. For example, in some embodiments, the induction phase has a duration of approximately 14 weeks, and the treatment results in an increased proportion of patients achieving a clinical response at week 14. For example, in some embodiments, 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., 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) achieve a clinical response by week 14. In some aspects, the proportion of patients in the patient population achieving a clinical response at week 14 is 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 achieving a clinical response at week 14.

[0176] In some embodiments, in a patient population treated according to any one of the methods provided herein, including a maintenance phase, the treatment results in an increased proportion of patients achieving a clinical response at the end of the maintenance phase compared to a reference population. For example, in some embodiments, the medication regimen has a duration of approximately 56 weeks, and the treatment results in an increased proportion of patients achieving a clinical response at week 56. For example, in some embodiments, 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., 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) achieve a clinical response by week 56. In some aspects, the proportion of patients in the patient population achieving a clinical response at week 56 is 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 achieving a clinical response at week 56.

[0177] In any of the methods provided herein, the reference population may be any population that serves as a suitable control. For example, in some embodiments, the reference population is a control population having IBD (e.g., UC (e.g., moderate or severe active UC)) that has never been treated with an anti-TL1A antibody (e.g., treated with a placebo).

[0178] Endoscopic response Following induction and / or maintenance medication regimens, patients may experience improvement in the signs and symptoms of IBD characterized by an endoscopic response. The term “endoscopic response” refers to a Mayo endoscopy subscore of 0 or 1.

[0179] Clinical remission Following induction and / or maintenance regimens, patients may experience improvement in the signs and symptoms of IBD, characterized by clinical remission.

[0180] In some embodiments, in a patient population treated according to any one of the methods provided herein, the treatment results in an increased proportion of patients achieving clinical remission at the end of the induction phase compared to a reference population. For example, in some embodiments, the induction phase has a duration of approximately 14 weeks, and the treatment results in an increased proportion of patients achieving clinical remission at week 14. In some embodiments, the proportion of patients in the patient population is 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., 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) achieve clinical remission at week 14. In some embodiments, at least about 15% of patients in the patient population achieve clinical remission at week 14. In some embodiments, at least about 40% of patients in the patient population achieve clinical remission at week 14. In some embodiments, 15% to 45.2% of patients in the patient population achieve clinical remission at week 14. In some cases, 23.3%, 23.9%, 25.5%, 29.8%, 31.8%, or 35% of patients in the patient population achieved clinical remission at week 14.

[0181] In some aspects, the proportion of patients in the patient population achieving clinical remission at week 14 is 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 achieving clinical remission at week 14 in the reference population.

[0182] In some embodiments, in a patient population treated according to any one of the methods provided herein, including a maintenance phase, the treatment results in an increased proportion of patients achieving clinical remission at the end of the maintenance phase compared to a reference population. For example, in some embodiments, the medication regimen has a duration of approximately 56 weeks, and the treatment results in an increased proportion of patients achieving clinical remission at week 56. In some embodiments, the proportion of patients in the patient population is 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., 1–10%, 10–20%, 20–30%, 30–40%, 40–50%, 50–60%, 60–70%, 70–80%, 80–90%, or 90–100%) achieve clinical remission at week 56. In some embodiments, at least about 20% of patients in the patient population achieve clinical remission at week 56. In some embodiments, at least about 55% of patients in the patient population achieve clinical remission at week 56. In some embodiments, 19.4%–56.5% of patients in the patient population achieve clinical remission at week 56. In some aspects, 31.0%, 34.6%, 35.7%, 38.5%, or 39.3% of patients in the patient population achieved clinical remission at week 56.

[0183] In some aspects, the proportion of patients in the patient population achieving clinical remission at week 56 is 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 achieving clinical remission at week 56 in the reference population.

[0184] In some embodiments, in patient populations treated according to any one of the methods provided herein, including a maintenance phase, the treatment results in an increased proportion of patients experiencing maintained remission throughout the maintenance phase compared to a reference population. For example, in some embodiments, the induction phase has a duration of approximately 14 weeks, the entire medication 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.

[0185] In some embodiments, clinical remission is defined as a modified Mayo score (mMS) ≤ 2, with a bowel movement frequency subscore (SFS) = 0 or 1, a rectal bleeding subscore (RBS) = 0, and an endoscopy subscore (ES) = 0 or 1.

[0186] In other embodiments, the term “clinical remission” is based on a total Mayo score of 12 points, where no individual subscore > 1: total Mayo score ≤ 2. In some embodiments, the Per Adapted Mayo score is defined as an endoscopic subscore = 0 or 1, a decrease of 1 or more points from baseline to achieve a bowel movement frequency subscore = 0 or 1, and a rectal bleeding subscore = 0. In some embodiments, the Per Adapted Mayo score is defined as an endoscopic subscore = 0 or 1, a bowel movement frequency subscore = 0 or 1 (no increase from baseline), and a rectal bleeding subscore = 0.

[0187] Endoscopic remission Following induction and / or maintenance regimens, patients may experience improvement in the signs and symptoms of IBD, characterized by endoscopic remission. The term “endoscopic remission” refers to a Mayo endoscopy subscore of 0. In some embodiments, patients experience endoscopic remission at or before the end of the induction phase, for example, at or before week 14 of the treatment. In some embodiments, in a patient population treated according to any one of the methods provided herein, the treatment results in an increased proportion of patients achieving endoscopic remission at the end of the induction phase compared to a reference population. In some embodiments, patients experience endoscopic remission at or before the end of the maintenance phase, for example, at or before week 56 of the treatment. In some embodiments, in a patient population treated according to any one of the methods provided herein, the treatment results in an increased proportion of patients achieving endoscopic remission at the end of the maintenance phase compared to a reference population.

[0188] Deep remission Following induction and / or maintenance regimens, patients may experience improvement in the signs and symptoms of IBD, characterized by deep remission. The term “deep remission” refers to a total Mayo score of 2 or less, with no individual subscores exceeding 1, and both the endoscopic and rectal bleeding subscores being 0.

[0189] In some embodiments, in a patient population treated according to any one of the methods provided herein, the treatment results in an increased proportion of patients achieving deep remission at the end of the induction phase compared to a reference population. In some embodiments, patients experience deep remission at or before the end of the maintenance phase, for example, at week 56 of treatment or earlier. In some embodiments, in a patient population treated according to any one of the methods provided herein, the treatment results in an increased proportion of patients achieving deep remission at the end of the maintenance phase compared to a reference population.

[0190] Symptomatic remission Following induction and / or maintenance regimens, patients may experience improvement in the signs and symptoms of IBD, characterized by symptomatic remission. The term “symptomatic remission” refers to a total Mayo score of 2 or less, with no individual subscores exceeding 1, and both the rectal bleeding subscore and the bowel movement frequency subscore being 0.

[0191] In some embodiments, in a patient population treated according to any one of the methods provided herein, the treatment results in an increased proportion of patients achieving symptomatic remission at the end of the induction phase compared to a reference population. In some embodiments, patients experience symptomatic remission at or before the end of the maintenance phase, for example, at week 56 of treatment or earlier. In some embodiments, in a patient population treated according to any one of the methods provided herein, the treatment results in an increased proportion of patients achieving symptomatic remission at the end of the maintenance phase compared to a reference population.

[0192] Endoscopic improvement Following induction and / or maintenance medication regimens, patients may experience improvement in the signs and symptoms of IBD, characterized by endoscopic improvement. The term “endoscopic improvement” (“El”) refers to a decrease of one or more points in the Mayo endoscopic subscore or an absolute endoscopic score of 1 or less. In some embodiments, endoscopic improvement is defined as an endoscopic subscore of 0 or 1.

[0193] In some embodiments, patients experience endoscopic improvement at or before the end of the induction phase, for example, at or before week 14 of the procedure. In some embodiments, in a patient population treated according to any one of the methods provided herein, the procedure results in an increased proportion of patients achieving endoscopic improvement at the end of the induction phase compared to a reference population. For example, in some embodiments, the induction phase has a duration of approximately 14 weeks, and the procedure results in an increased proportion of patients achieving endoscopic improvement at week 14. In some embodiments, 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%, in the patient population. 49%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 80%, 95%, or 99% of patients (e.g., 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) achieve endoscopic improvement at week 14. In some embodiments, at least approximately 25% of patients in the patient population achieve endoscopic improvement at week 14. In some embodiments, at least approximately 50% of patients in the patient population achieve endoscopic improvement at week 14. In some embodiments, 9.6% to 53.5% of patients in the patient population achieve endoscopic improvement at week 14. In some aspects, 38.3%, 40.4%, or 40.9% of patients in the patient population achieved endoscopic improvement at week 14.

[0194] In some aspects, the proportion of patients in the patient population achieving endoscopic improvement at week 14 is 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 achieving endoscopic improvement at week 14 in the reference population.

[0195] In some embodiments, patients experience endoscopic improvement at or before the end of the maintenance phase, for example, at week 56 of the procedure or earlier. In some embodiments, in a patient population treated according to any one of the methods provided herein, the procedure results in an increased proportion of patients achieving endoscopic improvement at the end of the maintenance phase compared to a reference population. In some embodiments, 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., 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%) achieve endoscopic improvement at week 56. In some embodiments, at least 20% of patients in the patient population achieve endoscopic improvement at week 56. In some embodiments, at least 65% of patients in the patient population achieve endoscopic improvement at week 56. In some embodiments, 23.8% to 66.7% of patients in the patient population achieve endoscopic improvement at week 56. In some aspects, 38.1%, 39.3%, or 50.0% of patients in the patient population achieved endoscopic improvement at week 56.

[0196] In some aspects, the proportion of patients in the patient population achieving endoscopic improvement at week 56 is 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 achieving endoscopic improvement at week 56 in the reference population.

[0197] Improvement of IBD signs and symptoms Following an induction and / or maintenance regimen, patients may experience improvement in the signs and symptoms of IBD that are maintained while the patient is receiving the maintenance regimen.

[0198] In some aspects of this disclosure, induction and / or maintenance regimens using anti-TL1A antibodies effectively improve the signs and symptoms of IBD within at least 14 weeks after initiation of treatment with anti-TL1A antibodies. These improvements in the signs and symptoms of IBD may be characterized by improvements in the Mayo endoscopic subscore. The reduction in the patient's Mayo endoscopic subscore may be at least 1, 2, or 3, or a greater integer.

[0199] Improvement in the signs and symptoms of IBD may be characterized in patients with a Mayo endoscopic subscore of 0 or 1, 2, or 3. Improvement in the signs and symptoms of IBD may be characterized in patients with a total Mayo score of 0, 1, 2, or 3. Improvement in the signs and symptoms of IBD may be characterized in patients with a Roberts histopathology index (RHI) of less than 5. Improvement in the signs and symptoms of IBD may be characterized in patients with a Geboes index of less than 3.2.

[0200] Improvement in the signs and symptoms of IBD may be maintained for at least 2, 3, 4, 6, or 12 months during the maintenance medication regimen.

[0201] D. Pre-treatment In some embodiments, the patient had been previously treated with corticosteroids prior to administration of the anti-TL1A antibody. In some embodiments, the patient had been previously treated with one or more treatments selected from the group consisting of tumor necrosis factor inhibitors, anti-integrins, azathioprine, 6-mercaptopurine, and methotrexate.

[0202] In some embodiments, the patient has been previously treated with IBD therapy (e.g., UC therapy) and has experienced an inadequate response to therapy, loss of response to therapy, and / or intolerance to therapy. In some embodiments, the therapy is a conventional therapy for UC and includes, for example, the administration of steroids or immunosuppressants (e.g., the patient has experienced an inadequate response to steroids or immunosuppressants, loss of response, and / or intolerance to steroids or immunosuppressants).

[0203] In some embodiments, the therapy was an advanced therapy for UC, and included, for example, the administration of antitumor necrosis factor (TNF) agents, antiintegrin agents, anti-IL12 / IL23 agents, and / or Janus kinase (JAK) inhibitors (e.g., the patient had experienced an inadequate response, loss of response, and / or intolerance to anti-TNF agents, antiintegrin agents, anti-IL12 / IL23 agents, and / or JAK inhibitors). Thus, in some embodiments, the patient had received prior advanced therapy at baseline (e.g., before the first dose in the induction phase). In other embodiments, the patient had not received prior advanced therapy at baseline.

[0204] E. Fecal calprotectin and hsCRP In some embodiments, patients show a reduction of at least 50% from baseline in fecal calprotectin during the course of treatment (e.g., from week 2 to week 26 of treatment). In some embodiments, patients show a reduction of at least 60% from baseline in fecal calprotectin between week 2 and week 26 of treatment. In some embodiments, patients show a reduction from baseline in highly sensitive C-reactive protein (hsCRP) between week 2 and week 26 of treatment.

[0205] F. Inflammatory bowel disease In some embodiments, IBD is ulcerative colitis (UC). In some embodiments, the patient has moderate to severe ulcerative colitis. The term “moderate to severe ulcerative colitis” is defined as a modified Mayo score of 5–9 with an endoscopic subscore of 2 or 3, and / or a total Mayo score of at least 6 and an endoscopic subscore of at least 2.

[0206] In some embodiments, IBD is Crohn's disease (CD). In some embodiments, patients have moderate to severe CD. The term “moderate to severe CD” is defined by the Crohn's Disease Activity Index (CDAI) and the Simple Endoscopic Score of CD (SES-CD).

[0207] In some embodiments, the patient has a diagnosis of ulcerative colitis, uncertain colitis, microscopic colitis, ischemic colitis, infectious colitis, radiation colitis, or active diverticular disease.

[0208] III. Kit This disclosure also provides kits comprising any or all of the anti-TL1A antibodies described herein. The kits of this disclosure comprise one or more containers comprising the anti-TL1A antibodies described herein, and instructions for use according to any of the methods of this disclosure described herein. Generally, these instructions comprise instructions for the administration of the anti-TL1A antibodies for the therapeutic treatment described herein. In some embodiments, kits are provided for preparing single-dose dosing units. In certain embodiments, the kit may comprise both a first container containing a dry protein and a second container containing an aqueous formulation. In certain embodiments, the kit comprises single and multi-chamber prefilled syringes (e.g., liquid syringes and rio-syringes).

[0209] Instructions for the use of anti-TL1A antibodies generally include information regarding the dosage, dosage schedule, and route of administration for the intended treatment. Containers may be unit doses, bulk packages (e.g., multi-dose packages), or sub-unit doses. Instructions supplied within the kits of this disclosure are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions delivered on a magnetic or optical storage disk) are also acceptable.

[0210] The kits of this disclosure are in appropriate packaging. Appropriate packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), etc. Packaging is also intended for use in combination with specific devices such as inhalers, nasal administration devices (e.g., nebulizers), or infusion devices such as minipumps. The kits may have a sterile access port (e.g., the container may be an intravenous solution bag or vial with a stopper that can be punctured by a subcutaneous needle). The container may have a sterile access port (e.g., the container may be an intravenous solution bag or vial with a stopper that can be punctured by a subcutaneous needle). At least one active agent in the composition is an anti-TL1A antibody. The container may further contain a second pharmaceutically active agent.

[0211] The kit may optionally provide additional components such as buffers and interpretation information. Typically, the kit includes a container and labels or accompanying documents on or attached to the container.

[0212] IV. Anti-TL1A antibodies and anti-DR3 antibodies The method disclosed herein involves the administration of 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. [Table 2] TIFF2026518039000004.tif255170TIFF2026518039000005.tif253170TIFF20265180390 00006.tif255170TIFF2026518039000007.tif255170TIFF2026518039000008.tif136170

[0213] 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.

[0214] 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 eight of the framework region sequences shown in SEQ ID NOs: 69-76.

[0215] 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 1, 2, 3, 4, 5, 6, 7, or all 8 of the framework region sequences shown in SEQ ID NOs: 70-77.

[0216] 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.

[0217] In some embodiments 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 heavy chain amino acid sequence of 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.

[0218] In some aspects of this disclosure, the anti-TL1A antibody is Afimquivart (also known as RO7790121, RVT-3101, or PF-06480605).

[0219] In some aspects of this disclosure, the anti-TL1A antibody comprises VH, encoded by the nucleic acid sequence of an insert in a vector deposited as 1 D1 1.31 VH having ATCC accession number PTA-120639, and VL, encoded by the nucleic acid sequence of an insert in a vector deposited as 1 D1 1.31 VL having ATCC accession number PTA-120640.

[0220] In some aspects of this disclosure, an anti-TL1A antibody competes for binding 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.

[0221] In some aspects of this disclosure, an anti-TL1A antibody competes for binding to an antibody comprising VH encoded by the nucleic acid sequence of an insert in a vector deposited as 1D1 1.31 VH having ATCC accession number PTA-120639, and VL encoded by the nucleic acid sequence of an insert in a vector deposited as 1D1 1.31 VL having ATCC accession number PTA-120640.

[0222] In some aspects of the present disclosure, the anti-TL1A antibody comprises a sequence pair selected from the group consisting of SEQ ID NOs: 2 and 11; SEQ ID NOs: 2 and 12; SEQ ID NOs: 2 and 13; SEQ ID NOs: 2 and 14; SEQ ID NOs: 2 and 15; SEQ ID NOs: 2 and 16; SEQ ID NOs: 2 and 17; SEQ ID NOs: 2 and 18; SEQ ID NOs: 2 and 19; SEQ ID NOs: 20 and 24; SEQ ID NOs: 21 and 25; SEQ ID NOs: 22 and 26; SEQ ID NOs: 23 and 27; SEQ ID NOs: 28 and 29; SEQ ID NOs: 30 and 31; SEQ ID NOs: 32 and 33; SEQ ID NOs: 35 and 44; SEQ ID NOs: 53 and 54; SEQ ID NOs: 61 and 62; SEQ ID NOs: 63 and 64; SEQ ID NOs: 65 and 64; SEQ ID NOs: 66 and 64; and SEQ ID NOs: 67 and 64.

[0223] 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.

[0224] In some aspects of this disclosure, the anti-TL1A antibody comprises a heavy chain framework region as shown in SEQ ID NOs. 36, 38, 40, and 42, and / or a light chain framework region as shown in SEQ ID NOs. 45, 47, 49, and 51.

[0225] 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.

[0226] In some aspects of this disclosure, the anti-TL1A antibody comprises a heavy chain tail sequence provided in SEQ ID NO: 43. In some aspects of this disclosure, the anti-TL1A antibody comprises a light chain tail sequence provided in SEQ ID NO: 52.

[0227] 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.

[0228] In some aspects of this disclosure, the anti-TL1A antibody is thurisocibalt.

[0229] In some embodiments, the antibody used in any of the methods, compositions, uses, and compositions for use provided herein is the anti-TL1A antibody provided in Table 2A of U.S. Patent No. 11,136,386, which is incorporated herein in whole by reference.

[0230] In some embodiments, the antibody used in any of the methods, compositions, uses, and compositions for use provided herein is the anti-DR3 antibody provided in Table 2A of U.S. Patent No. 11,136,386, which is incorporated herein in whole by reference.

[0231] In some embodiments of any of the methods, compositions, uses, and compositions for use provided herein, the anti-TL1A antibody is the anti-TL1A antibody provided in U.S. Patent No. 10,322,174, U.S. Patent No. 10,689,439, U.S. Patent No. 11,292,848, U.S. Patent No. 10,138,296, U.S. Patent No. 10,822,422 and U.S. Patent No. 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.

[0232] In some aspects of this disclosure, the anti-TL1A antibody includes 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.

[0233] 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.

[0234] 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 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.

[0235] In some aspects of this disclosure, the anti-TL1A antibody is TEV-48574.

[0236] In some aspects of this disclosure, the anti-TL1A antibody is C03V.

[0237] In some aspects of this disclosure, the anti-TL1A antibody is SPY002.

[0238] The antibodies described herein may be produced by any method known in the art. For the production of hybridoma cell lines, the immunization pathways and schedules of host animals generally follow established conventional techniques for antibody stimulation and production, as further described herein. General techniques for producing human and mouse antibodies are known in the art and / or described herein.

[0239] Any mammalian subject, including human or human antibody-producing cells, is intended to be manipulated to serve as a basis for mammalian antibody production, including human and hybridoma cell lines. Typically, a host animal is inoculated with an immunogen containing the amounts described herein, intraperitoneally, intramuscularly, orally, subcutaneously, in the sole of the foot, and / or intradermally.

[0240] Hybridomas can be prepared from lymphocytes and immortalized myeloma cells using the general somatic cell hybridization technique described in Kohler, B. and Milstein, C., Nature 256:495-497, 1975, or as modified by Buck, DW, et al., In Vitro, 18:377-381, 1982. Available myeloma strains include, but are not limited to, X63-Ag8.653 and those from Salk Institute, Cell Distribution Center, San Diego, Calif., USA, and can be used for hybridization. Generally, this technique involves fusing myeloma cells and lymphocytes using a fusion agent such as polyethylene glycol, or by electrical means 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 parent cells. Any of the media described herein, with or without serum, can be used to culture hybridomas that secrete monoclonal antibodies. As an alternative to cell fusion techniques, EBV immortalized B cells may be used to produce the monoclonal antibodies of interest of this disclosure. Hybridomas are grown, subcloned as needed, and the supernatant is assayed for anti-immunogen activity by conventional immunoassay procedures (e.g., radioimmunoassay, enzyme immunoassay, or fluorescence immunoassay).

[0241] Hybridomas that can be used as antibody sources include all derivatives and progeny cells of parent hybridomas that produce monoclonal antibodies.

[0242] Hybridomas producing the antibodies used in this disclosure can be grown in vitro or in vivo using known procedures. Monoclonal antibodies can be isolated from culture media or body fluids by conventional immunoglobulin purification procedures such as ammonium sulfate precipitation, gel electrophoresis, dialysis, chromatography, and ultrafiltration, if necessary. Undesirable activity, if present, can be removed, for example, by passing the preparation through an adsorbent consisting of an immunogen bound to a solid phase and eluting or releasing the desired antibody from the immunogen. An antibody population (e.g., monoclonal antibodies) can be obtained by immunizing a host animal with a fragment containing a target amino acid sequence conjugated using a bifunctional or derivatizing agent (e.g., maleimidobenzoylsulfosuccinimide ester (cysteine ​​residue-mediated conjugation), N-hydroxysuccinimide (lysine residue-mediated conjugation), glutaraldehyde, succinic anhydride, SOC, or R1N=C=NR (where R and R1 are different alkyl groups)) to cells expressing an antibody target (e.g., PD-1), a human target protein (e.g., PD-1), or a protein that is immunogenic in the immunized species (e.g., keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor).

[0243] If necessary, the antibody of interest (monoclonal or polyclonal) may be sequenced, and the polynucleotide sequence may then be cloned into a vector for expression or proliferation. The sequence encoding the antibody of interest may be maintained in the vector in host cells, which may then be expanded and frozen for future use. Production of recombinant monoclonal antibodies in cell culture may be carried out by cloning the antibody gene from B cells by means known in the art. See, for example, Tiller et al., J.Immunol.Methods 329,112,2008; U.S. Patent No. 7,314,622.

[0244] In some embodiments, antibodies may be produced using hybridoma technology. Any mammalian subject, including human or human antibody-producing cells, is intended to be engineered to serve as a basis for production in mammals, including human and hybridoma cell lines. The immunization pathways and schedules of host animals generally follow established conventional techniques for antibody stimulation and production, as further described herein. Typically, host animals are inoculated intraperitoneally, intramuscularly, orally, subcutaneously, plantarly, and / or intradermally with immunogens in amounts described herein.

[0245] In some embodiments, the antibodies described herein are glycosylated at conserved locations within their constant regions (Jefferis and Lund, 1997, Chem.Immunol. 65:111-128; Wright and Morrison, 1997, TibTECH 15:26-32). The 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 segments, which can affect the three-dimensional structure and the three-dimensional surface presented by the glycoprotein (Jefferis and Lund, supra; Wyss and Wagner, 1996, Current Opin. Biotech. 7:409-416). Oligosaccharides may also help target a given glycoprotein to a specific molecule based on its specific recognition structure. Antibody glycosylation has also been reported to affect antibody-dependent cell-mediated cytotoxicity (ADCC). In particular, antibodies produced by CHO cells with tetracycline-regulated expression of b(1,4)-N-acetylglucosaminyltransferase III (GnTIII), a glycosyltransferase that catalyzes the formation of bibranched GlcNAc, have been reported to improve ADCC activity (Umana et al., 1999, Nature Biotech. 17:176-180).

[0246] Antibody glycosylation is typically either N-linked or O-linked. N-linked glycosylation refers to the binding of an asparagine residue in the carbohydrate moiety to the 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 enzymatic binding of the carbohydrate moiety to the asparagine side chain. Therefore, the presence of any of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the binding of one of the sugars, such as N-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.

[0247] The addition of a glycosylation site to this antibody is conveniently achieved by modifying the amino acid sequence, thereby causing it to contain one or more of the aforementioned tripeptide sequences (in the case of an N-linked glycosylation site). This modification can be carried out by adding or substituting one or more serine or threonine residues into the original antibody sequence (in the case of an O-linked glycosylation site).

[0248] The glycosylation pattern of antibodies can also be altered without modifying the underlying nucleotide sequence. Glycosylation is highly dependent on the host cells used to express the antibody. Since the cell types used to express recombinant glycoproteins (e.g., antibodies) as 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).

[0249] In addition to host cell selection, factors influencing glycosylation during antibody recombinant production include growth mode, culture medium formulation, culture density, oxygenation, pH, and purification scheme. Various methods have been proposed to alter the glycosylation pattern achieved in specific host organisms, including the expression or overexpression of specific enzymes involved in oligosaccharide production (U.S. Patents 5,047,335; 5,510,261 and 5,278,299). Glycosylation, or specific types of glycosylation, can be enzymatically removed from glycoproteins using, for example, endoglycosidase H (Endo H), N-glycosidase F, endoglycosidase F1, endoglycosidase F2, and endoglycosidase F3. Furthermore, recombinant host cells can be genetically engineered to have defects in the processing of specific types of polysaccharides. These and similar techniques are well known in the art.

[0250] Other modification methods include, but are not limited to, the use of coupling techniques known in the art, including enzymatic means, oxidative substitution, and chelation. Modifications may be used, for example, for the conjugation of labels in immunoassays. Modified polypeptides may be prepared using procedures established in the art and screened using standard assays known in the art.

[0251] V. Polynucleotides, vectors, and host cells This disclosure also provides polynucleotides encoding any of the anti-TL1A antibodies described herein. These polynucleotides can be prepared and expressed by procedures known in the art.

[0252] In another aspect, the Disclosure provides a composition (such as a pharmaceutical composition) comprising any of the polynucleotides of the Disclosure for use in one or more of the methods of the Disclosure. In some aspects, the composition comprises an expression vector comprising a polynucleotide encoding any of the anti-TL1A antibodies described herein for use in one or more of the methods of the Disclosure.

[0253] In another embodiment, an isolated cell line producing the anti-TL1A antibody described herein is provided for use in one or more of the methods of this disclosure.

[0254] Polynucleotides complementary to any such sequence are also included 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 may include HnRNA molecules containing introns and corresponding one-to-one with DNA molecules, and mRNA molecules without introns. Additional coding or non-coding sequences may, but are not required, be present within the polynucleotides of this disclosure, and polynucleotides may, but are not required, be ligated to other molecules and / or support materials.

[0255] The polynucleotide may contain a native sequence (i.e., an endogenous sequence encoding an antibody or a fragment thereof) or a variant of such a sequence. The polynucleotide variant includes one or more substitutions, additions, deletions, and / or insertions such that the immunoreactivity of the encoded polypeptide is not reduced compared to the native immunoreactive molecule. The effect of the encoded polypeptide on immunoreactivity can generally be evaluated as described herein. The variant preferably exhibits 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 to the polynucleotide sequence encoding the native antibody or its fragment.

[0256] VI. Compositions and Formulations A. Composition This disclosure also provides pharmaceutical compositions comprising an effective amount of the anti-TL1A antibodies described herein, and such pharmaceutical compositions for use in the treatment methods described herein. Examples of such compositions, as well as methods of formulation, are also described herein. It is understood that the compositions may comprise two or more anti-TL1A antibodies.

[0257] The compositions used in this disclosure may, in the form of lyophilized formulations or aqueous solutions, further comprise pharmaceutically acceptable carriers, excipients, or stabilizers (Remington: The Science and Practice of Pharmacy 20th Ed., 2000, Lippincott Williams and Wlkins, Ed. KE. Hoover).

[0258] Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at dosage and concentration and include buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol, etc.); low molecular weight (less than approximately 10 residues) polypeptides; serum This may include proteins such as 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., Zn-protein complexes); and / or nonionic surfactants such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG). Pharmaceutically acceptable excipients are further described herein.

[0259] Anti-TL1A antibodies and their compositions may also be used in combination with other drugs that help enhance and / or complement the efficacy of the drug, or they may be administered separately, simultaneously, or sequentially.

[0260] B. Formulations Therapeutic formulations of anti-TL1A antibodies used in accordance with this disclosure are prepared for storage in the form of lyophilized formulations or aqueous solutions by mixing the protein of the desired purity with any pharmaceutically acceptable carrier, excipient, or stabilizer (Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000). Acceptable carriers, excipients, or stabilizers are nontoxic to the recipient at the dosage and concentration used and include buffers such as phosphates, citrates, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol, etc.); and 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 dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG).

[0261] Liposomes that may contain anti-TL1A antibodies can be 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. Patent Nos. 4,485,045 and 4,544,545. Liposomes with improved circulation times are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be made by the reverse-phase evaporation method using a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes having a desired diameter are obtained by extruding the liposomes through a filter with a defined pore size.

[0262] The active ingredient may also be encapsulated, for example, in microcapsules prepared by coacervation techniques or by interfacial polymerization (e.g., hydroxyethylmethylcellulose or gelatin microcapsules and poly(methylmethacrylate) microcapsules, respectively), or in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing (2000).

[0263] Sustained release preparations may be prepared. Suitable examples of sustained release preparations include a semipermeable matrix of a solid hydrophobic polymer containing an antibody, and this matrix is in the form of a molded article, for example, a film or a microcapsule. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. 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, LUPRON DEPOT (trademark) (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0264] Formulations used for in vivo administration must be sterilized. This can be easily achieved, for example, by filtering through a sterile filtration membrane. Therapeutic anti-TL1A antibody compositions are generally placed in a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper that can be punctured by a subcutaneous injection needle.

[0265] The compositions according to the present 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 administration by inhalation or insufflation.

[0266] To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutically acceptable compound (e.g., conventional tableting components such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum) and other pharmaceutical diluents (e.g., water) to form a solid pre-formulation composition containing a homogeneous mixture of the compound of the Disclosure or a non-toxic, pharmaceutically acceptable salt thereof. When these pre-formulation compositions are referred to as homogeneous, 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. This solid pre-formulation composition is then subdivided into the above-mentioned unit dosage forms containing about 0.1 to about 500 mg of the active ingredient of the Disclosure. Tablets or pills of novel compositions can be coated or otherwise formulated to provide dosage forms that offer the advantage of longer action. For example, a tablet or pill may contain internal and external dosage components, the latter in the form of an envelope covering the former. Two components can be separated by a single enteric-coated layer, which acts to withstand disintegration in the stomach, allowing the internal components to pass through the duodenum intact or to have their release delayed. Various materials can be used for such enteric-coated layers or coatings, including numerous polymer acids and mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0267] Suitable surfactants include nonionic agents such as polyoxyethylene sorbitan (e.g., Tween® 20, 40, 60, 80, or 85) and other sorbitans (e.g., Span® 20, 40, 60, 80, or 85). A composition containing a surfactant may conveniently contain between 0.05 and 5% of the surfactant, and may be between 0.1 and 2.5%. It will be understood that other components, such as mannitol or other pharmaceutically acceptable vehicles, may be added as needed.

[0268] Suitable emulsions can be prepared using commercially available lipid emulsions such as INTRALIPID®, LIPOSYN®, INFONUTROL®, LIPOFUNDIN®, and LIPIPHYSAN®. The active ingredient may be dissolved in a pre-mixed emulsion composition, or it may be dissolved in an emulsion formed by mixing oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and phospholipids (e.g., egg phospholipid, soybean phospholipid, or soybean lecithin) with water. It will be understood that other components, such as glycerol or glucose, may be added to adjust the tonicity of the emulsion.

[0269] A suitable emulsion typically contains up to 20% oil, for example, 5–20%. Fatty emulsions can contain fatty droplets of 0.1–1.0 pm, especially 0.1–0.5 pm, and have a pH in the range of 5.5–8.0.

[0270] The emulsion composition may be prepared by mixing an anti-TL1A antibody with Intralipid® or its components (soybean oil, egg phospholipid, glycerol, and water).

[0271] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain the above-mentioned suitable pharmaceutically acceptable excipients. In some embodiments, compositions are administered orally or via nasal respiration for topical or systemic effects. Compositions in preferably sterile, pharmaceutically acceptable solvents may be sprayed using gas. Sprayed solutions may be inhaled directly from a spraying device, or the spraying device may be attached to a face mask, tent, or intermittent positive airway pressure (CPAP) respirator. Solutions, suspensions, or powder compositions may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0272] In embodiments of the methods for treating IBD described herein, such embodiments also include further embodiments of anti-TL1A antibodies for use in such treatment, or further embodiments of the use of anti-TL1A antibodies in the manufacture of pharmaceuticals for use in such treatment.

[0273] VII. General Techniques Unless otherwise stated, the implementation of this disclosure will utilize prior arts in molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the scope of the art of those skilled in the art. Such techniques are described in the literature, for example, Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al., 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Culture(RlFreshney,ed.,1987);Introduction to Cell and Tissue Culture(JPMather and PERoberts,1998)Plenum Press;Cell and Tissue Culture:Laboratory Procedures(A.Doyle,JBGriffiths,and DGNewell,eds.,1993-1998)J.Wiley and Sons;Methods in Enzymology(Academic Press, Inc.);Handbook of Experimental Immunology(DMWeir and CCBlackwell, eds.); Gene Transfer Vectors for Mammalian Cells (JMMiller and MP Calos, eds., 1987); Current Protocols in Molecular Biology (FMAusubel et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (JEColigan et al., eds.Detailed explanations can be found in works such as: *Short Protocols in Molecular Biology* (Wley and Sons, 1999); *Immunobiology* (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); and *The Antibodies* (M. Zanetti and JDCapra, eds., Harwood Academic Publishers, 1995).

[0274] VIII.Definitions Unless otherwise specified, the following terms should be understood to have the following meanings:

[0275] As used herein, "Afimkivart" (also known as RO7790121, RVT-3101, or PF-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.

[0276] An “antibody” is an immunoglobulin molecule capable of specifically binding to a target such as a carbohydrate, polynucleotide, lipid, or polypeptide via at least one antigen-recognition site located in the variable region of the immunoglobulin molecule. As used herein, this term encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen-binding moiety of an intact antibody that competes with it for specific binding, fusion proteins containing the antigen-binding moiety, and any other modified structures of an immunoglobulin molecule containing the antigen-recognition site. Antigen-binding moieties include, for example, Fab, Fab', F(ab')2, Fd, Fv, domain antibodies (dAb, e.g., shark antibodies and camel antibodies), fragments containing complementarity-determining regions (CDRs), single-chain variable fragment antibodies (scFv), maxi-bodies, mini-bodies, intra-bodies, dia-bodies, tria-bodies, tetra-bodies, v-NARs, and bis-scFvs, as well as polypeptides containing at least a portion of immunoglobulin sufficient to confer specific antigen binding to the polypeptide. Antibodies can be any class of antibody, such as IgG, IgA, or IgM (or their subclasses), and an antibody does not have to be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chain, immunoglobulins can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), such as IgGi, IgG2, IgG3, IgG4, IgAi, and IgGA2. The heavy chain constant regions corresponding to different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional structures of different classes of immunoglobulins are well known.

[0277] The “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. As is known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FRs) linked by three complementarity-determining regions (CDRs), also known as hypervariable regions, and contribute to the formation of the antibody's antigen-binding site. When a variant of the target variable region is desired, particularly involving substitutions of amino acid residues outside the CDR region (i.e., within the framework region), appropriate amino acid substitutions, preferably conservative amino acid substitutions, can be identified by comparing the target variable region with the variable regions of other antibodies containing the same canonical class CDR1 and CDR2 sequences as the target variable region (Chothia and Lesk, J Mol Biol 196(4):901-917, 1987).

[0278] In certain embodiments, a clear depiction of the CDR and identification of residues containing the antibody binding site are achieved by elucidating the structure of the antibody and / or the structure of the antibody-ligand complex. In certain embodiments, this can be achieved by any of the various techniques known to those skilled in the art, such as X-ray crystallography. In certain embodiments, various analytical methods can be used to identify or approximate the CDR region. Examples of such methods include, but are not limited to, Kabat definitions, Chothia definitions, AbM definitions, contact definitions, and conformational definitions.

[0279] Kabat's definition is a standard for numbering residues in antibodies and is typically used to identify CDR regions. See, for example, Johnson & Wu, 2000, Nucleic Acids Res., 28:214-8. Chothia's definition is similar to Kabat's, but takes into account the location of specific structural loop regions. See, for example, Chothia et al., 1986, J.Mol.Biol., 196:901-17; Chothia et al., 1989, Nature, 342:877-83. AbM's definition uses a suite of integrated computer programs developed by the Oxford Molecular Group to model antibody structures. See, for example, Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272; "AbM (trademark), A Computer Program for Modeling Variable Regions of Antibodies," Oxford, UK;

[0280] See Oxford Molecular, Ltd. The definition of AbM involves modeling the tertiary structure of an antibody from its primary sequence using a combination of knowledge databases and the ab initio method, as described in Samudrala et al., 1999, “Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach,” in PROTEINS, Structure, Function and Genetics Suppl., 3:194-198. The definition of contact is based on the analysis 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 “Defining the Three-Dimensional Structure” of CDRs, the position of a CDR can be identified as a residue that makes an enthalpy contribution to antigen binding. See, for example, Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166. Still, other definitions of CDR boundaries may not strictly adhere to one of the approaches described above. Boundaries may be shortened or extended in light of predictions or experimental findings that certain residues or groups of residues do not significantly affect antigen binding, but nevertheless overlap with at least a portion of Kabat CDRs. As used herein, CDR may refer to a CDR defined by any approach known in the art, including combinations of approaches. Methods used herein may utilize CDRs defined according to any of these approaches. For any given embodiment containing two or more CDRs, a CDR may be defined according to any of the definitions of Kabat, Chothia, extended, AbM, contact, and / or conformation.

[0281] 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.

[0282] As used herein, “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies, that is, the individual antibodies in that population are identical except for any spontaneous mutations that may be present in trace amounts. Monoclonal antibodies are highly specific and target a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which typically contain different antibodies targeting different determinants (epitopes), each monoclonal antibody targets a single determinant on an antigen. The modifier “monoclonal” indicates that the antibody is obtained from a substantially homogeneous population of antibodies and should not be interpreted as requiring antibody production by any particular method. For example, monoclonal antibodies used in accordance with this disclosure may be produced by the hybridoma method first described by Kohler and Milstein, 1975, Nature 256:495, or by the recombinant DNA method as described in U.S. Patent No. 4,816,567. Monoclonal antibodies can also be isolated from phage libraries generated using techniques such as those described in McCafferty et al., 1990, Nature 348:552-554.

[0283] As is known in the art, the terms “polynucleotide” or “nucleic acid” as used interchangeably herein refer to a chain of nucleotides of any length, including DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or analogs thereof, or any substrate that can be incorporated into the chain by DNA or RNA polymerase. Polynucleotides may include modified nucleotides, such as methylated nucleotides and their analogs. Where present, modifications to the nucleotide structure may be conjugated before or after the assembly of the chain. The sequence of nucleotides may be interrupted by non-nucleotide components. Polynucleotides may be further modified after polymerization, such as by conjugation with labeling components. Other types of modifications include, for example, "caps," substitution with one or more analogues of naturally occurring nucleotides, internucleotide modifications, such as those by uncharged bonds (e.g., methyl phosphonate, phosphotryester, phosphoamidate, carbamate, etc.) and charged bonds (e.g., phosphorothioates, phosphorodithioates, etc.), pendant portions, such as those containing proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), intercalators (e.g., those containing acridine, psoralens, etc.), those containing chelating agents (e.g., metals, radioactive metals, boron, metal oxides, etc.), those containing alkylating agents, those having modified bonds (e.g., alpha-anomeric nucleic acids, etc.), and unmodified forms of polynucleotides. Furthermore, any of the hydroxyl groups normally present in the sugar may be replaced by, for example, a phosphonic acid group or a phosphate group, protected by a standard protecting group, or activated to prepare for additional binding to additional nucleotides, or conjugated to a solid support. The 5' and 3' terminal OH groups can be phosphorylated or substituted with amines or organic capping groups of 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups.Polynucleotides may also include analogues of ribose or deoxyribose sugars known in the art, which include, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro-, or 2'-azid-ribose, carbocyclic sugar analogues, α- or β-anomeric sugars, epimeric sugars (e.g., arabinose, xylose, or lyxose), pyranose sugars, furanose sugars, sedoheptulose, acyclic analogues, and nonbasic nucleoside analogues (e.g., methylriboside). One or more phosphodiester bonds may be replaced by alternative bonding groups. These alternative binding groups include, but are not limited to, embodiments in which the phosphate is replaced by P(0)S ("thioate"), P(S)S ("dithioate"), (0)NR2 ("amidate"), P(0)R, P(0)OR', CO, or CH2 ("formacetal"), where each R or R' is independently H or a substituted or unsubstituted alkyl (1 to 20 Cs) optionally containing an ether (-0-) bond, aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl. Not all bonds in the polynucleotide need to be identical. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.

[0284] Antibodies that "preferentially bind" or "specifically bind" (used interchangeably herein) to an epitope are terms well understood in the art, and methods for determining such specific or preferential binding are also known in the art. A molecule is said to exhibit "specific binding" or "preferential binding" if it reacts or associates more frequently, more rapidly, for a longer duration, and / or with a higher affinity with a particular cell or substance than with an alternative cell or substance. An antibody "specifically binds" or "preferentially binds" to a target if it binds to the target with a higher affinity, binding activity, more readily, 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 this epitope with a higher affinity, binding activity, more readily, and / or for a longer duration than it binds to other target epitopes or non-target epitopes. By reading this definition, it is understood, for example, that an antibody (or portion or epitope) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Thus, "specific binding" or "preferential binding" does not necessarily require (although it can include) exclusive binding. Generally, although not always, reference to binding means preferential binding.

[0285] As used herein, "substantially pure" refers to a material that is at least 50% pure (i.e., free of contaminants), 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.

[0286] "Host cells" include individual cells or cell cultures that may or may have been recipients of a vector for incorporating a polynucleotide insert. Host cells include offspring of a single host cell, which may not necessarily be completely identical (morphologically or in genomic DNA complement) to the original parent cell due to natural, accidental, or intentional mutations. Host cells include cells transfected in vivo with the polynucleotides of this disclosure.

[0287] As is known in the art, the term “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain. The “Fc region” can be a native sequence Fc region or a variant Fc region. While the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is typically defined as extending from the amino acid residue at position Cys226 or from Pro230 to its carboxyl terminus. The numbering of residues in the Fc region is the EU index numbering in Kabat. (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, Md., 1991). The Fc region of an immunoglobulin generally contains two constant domains, CH2 and CH3. As is known in the art, the Fc region can exist in dimeric or monomeric form.

[0288] In the context of this art, “Fc receptor” and “FcR” refer to receptors that bind to the Fc region of an antibody. The preferred FcR is the native human FcR sequence. Furthermore, preferred FcRs are those that bind to IgG antibodies (gamma receptors) and include the FcyRI, FcyRII, and FcyRIII subclass receptors, including allele variants and alternatively spliced ​​forms of these receptors. The FcyRII receptor includes FcyRIIA ("activating receptor") and FcyRIIB ("inhibiting receptor"), which have similar amino acid sequences, primarily differing in their cytoplasmic domains. FcRs are outlined 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 the transfer of maternal IgG to the fetus (Guyer et al., 1976, J.Immunol., 117:587; and Kim et al., 1994, J.Immunol., 24:249).

[0289] As used herein with respect to antibodies, the term “competing” means that the binding of a first antibody or its antigen-binding moiety to an epitope is sufficiently similar to the binding of a second antibody or its antigen-binding moiety, and as a result, the binding of the first antibody to its congener epitope is detectedly reduced in the presence of the second antibody compared to the binding of the first antibody in the absence of the second antibody. Alternatively, the binding of the second antibody to its epitope may also be detectedly reduced in the presence of the first antibody, but is not necessarily so. That is, the first antibody can inhibit the binding of the second antibody to its respective epitope without the second antibody inhibiting the binding of the first antibody to its respective epitope. However, if each antibody detectably inhibits the binding of other antibodies to their congener epitopes or ligands, to the same, greater, or lesser extent, those antibodies are said to “cross-cornpete” with respect to their respective epitope binding. Both competing and mutually competing antibodies are included in this disclosure. Regardless of the mechanism by which such competition or mutual competition occurs (e.g., steric hindrance, conformational changes, or binding to a common epitope, or part thereof), those skilled in the art will understand, based on the teachings provided herein, that such competing and / or mutually competing antibodies are included and may be useful in the methods disclosed herein.

[0290] As used herein, “treatment” is an approach to obtain a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical outcomes include, for example, a reduction or improvement in the signs and symptoms of inflammatory bowel disease (IBD) (e.g., ulcerative colitis (UC) or Crohn's disease (CD)) compared to before administration of an anti-TL1A antibody.

[0291] "Recovery" means, for example, a reduction or improvement in one or more signs or symptoms of IBD (e.g., UC or CD) compared to no administration of the anti-TL1A antibody described herein. "Recovery" also includes a reduction or shortening of the duration of symptoms.

[0292] As used herein, “effective dose” or “effective amount” of a drug, compound, or pharmaceutical composition is an amount sufficient to produce any one or more beneficial or desired outcome. In more specific embodiments, an effective dose prevents, alleviates or reverses the signs or symptoms of IBD and / or extends the survival of the subject being treated. Beneficial or desired outcomes for prophylactic use include the elimination or reduction of risk, reduction of severity, or delay of the onset of the disease, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the onset of the disease. For therapeutic use, beneficial or desired outcomes include clinical outcomes such as the reduction of one or more signs or symptoms of IBD, a reduction in the dose of other medications required to treat the disease, an enhancement of the effect of another medication, and / or delay of disease progression in the patient. An effective dose may be administered in one or more doses. 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 a prophylactic or therapeutic action. As understood in the clinical field, the effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with other drugs, compounds, or pharmaceutical compositions. Therefore, the “effective dose” may be considered in relation to the administration of one or more therapeutic agents, and a monotherapy agent may be considered effective if, in combination with one or more other agents, the desired outcome can or would be achieved.

[0293] A treatment is considered "effectively improved" or "effectively reduced" when the assessment of IBD signs or symptoms is quantified by clinical measures relative to baseline, and during and / or after the treatment period. The difference between baseline and clinical measurements during / after the treatment is compared and used to determine whether signs or symptoms have improved and whether the treatment is effective. This comparison may include comparison with placebo or one or more prior therapies.

[0294] The term "mucosal healing" refers to a Mayo endoscopic subscore of 0 or 1 and a Geboes histological score of 0 or 1. (Aranzazu, JE., et al. Journal of Crohn's and Colitis, Volume 11(3), 2017, 305-313). In one embodiment, mucosal healing was defined as endoscopic improvement + histological improvement (Mayo endoscopic subscore <= 1 and Geboes <= 3.1). Histological improvement was defined as crypt infiltration of less than 5% of neutrophils in the epithelium (Geboes ≤ 3.1). Histological remission was defined as the absence of crypt infiltration in the epithelium (Geboes < 2).

[0295] In this specification, “effective dose” refers to the amount of a therapeutic agent (e.g., anti-TL1A antibody (e.g., RO7790121)) or combination of therapeutic agents (e.g., anti-TL1A antibody and one or more additional therapeutic agents)) that achieves a therapeutic outcome. In some examples, an effective dose of a therapeutic agent or combination of therapeutic agents is the amount of an agent or combination of agents that achieves the clinical endpoint of 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 remission without corticosteroids. Improvement (e.g., with respect to clinical remission) may be relative to an appropriate reference treatment, e.g., treatment without anti-TL1A antibody.

[0296] As used herein, the term “induction phase” refers to a series of one or more administrations or dosing cycles (e.g., approximately 2 to 6 administrations or dosing cycles) of one or more therapeutic agents (e.g., anti-TL1A antibody (e.g., RO7790121)) administered to a subject, optionally followed by a maintenance phase.

[0297] As used herein, the term “maintenance phase” refers to a series of one or more administrations or dosing cycles of one or more therapeutic agents (e.g., an anti-TL1A antibody (e.g., RO7790121)) administered to a subject after the induction phase without the intervention of any related surgery (i.e., without any surgical intervention related to the disease or condition that is intended to be treated by one or more therapeutic agents). In some cases, the maintenance phase is initiated only if the subject has not experienced disease progression or unacceptable toxicity during the induction phase. The induction phase and the maintenance phase may or may not involve the use of the same therapeutic agent.

[0298] As used interchangeably herein, “patient,” “individual,” or “subject” refers to a mammal, more preferably a human. Mammals include, but are not limited to, livestock (e.g., cattle, pigs, horses, chickens), sporting animals, pets, primates, horses, dogs, cats, mice, and rats.

[0299] Where used in the specification, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” include any substance that, when combined with an active ingredient, enables that ingredient to retain its biological activity and does not react with the target immune system. Examples include, but are not limited to, any standard pharmaceutical carriers such as phosphate-buffered saline, water, emulsions such as oil / water emulsions, and various types of wetting agents. Preferably, the diluent for aerosol or parenteral administration is phosphate-buffered saline (PBS) or ordinary (0.9%) saline. Compositions containing such carriers are formulated by well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990; and Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing, 2000).

[0300] In this specification, any “approximately” reference to a value or parameter includes (and describes) a manner directed toward the value or parameter itself. For example, a statement referring to “approximately X” includes a statement of “X.” A numerical range includes the numerical value that defines that range. Generally speaking, the term “approximately” refers to all values ​​of a variable that are wider than the given value and the experimental error of the given value (e.g., within the 95% confidence interval of the mean) or within 10% of the given value. When the term “approximately” is used in the context of a period (year, month, week, day, etc.), the term “approximately” means the period plus or minus one unit of the next subperiod (e.g., approximately one year means 11 to 13 months, approximately six months means 6 months ± one week, approximately one week means 6 to 8 days, etc.), or within 10% of the given value, whichever is wider.

[0301] The term "subcutaneous administration" refers to the administration of a substance into the subcutaneous layer.

[0302] The terms “prevention” or “to prevent” refer to (a) preventing the occurrence of a disability, or (b) delaying the onset of a disability or the onset of its symptoms.

[0303] Where an aspect is described using the expression “including,” it is understood that other similar aspects are also provided, which are described using the terms “consisting of” and / or “essentially consisting of.”

[0304] Where any aspect of the disclosure describes a Markush group or any other alternative grouping, the disclosure includes not only the entire enumerated group as a whole, but also each individual member of the group, and all possible subgroups of the principal group, as well as the principal group from which one or more group members have been excluded. The disclosure also assumes the express exclusion of one or more group members in the claimed disclosure.

[0305] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art in which this disclosure pertains. In case of any conflict, this specification, including the definitions, shall prevail. Throughout this specification and the claims, it will be understood that the word “comprise,” or variations such as “comprises,” or “comprising,” means the inclusion of the integer or group of integers described, but not the exclusion of any other integer or group of integers. Unless otherwise specified in the context, singular terms shall include the plural, and plural terms shall include the singular. Any example following the term “eg” or “for example” shall not be exclusive or limiting.

[0306] While exemplary methods and materials are described herein, similar or equivalent methods and materials may also be used in the practice or testing of this disclosure. Materials, methods, and examples are illustrative and not intended to limit the scope of this disclosure. [Examples]

[0307] IX. Examples Example 1. TNFSF15 haplotype SNP combination In this experiment, we developed a computational algorithm to determine whether a subject is a carrier of the TNFSF15 haplotype (i.e., whether the subject is a haplotype B carrier) based on a selected number of single nucleotide polymorphisms (SNPs) from DNA sequencing data (e.g., genome sequencing data).

[0308] As shown in Figure 1, haplotype B is defined as the TNFSF15 gene region having nucleotides T / C / A / T / C at positions 15,524; 9,706; -358; -638; and -12,506, respectively, based on the reference sequence GenBank NM_005118.2, with the first nucleotide of the exon 1 start site designated as position 1 in the TNFSF15 gene region encoding the TL1A gene (haplotype positions 26 / 31 / 35 / 36 / 41, respectively (provided in Yamazaki et al., Human Molecular Genetics, 14(22):3499-3506, 2005)) (Table 3). A subject is identified as haplotype B if it is heterozygous or homozygous for haplotype B, i.e., if one or both copies of the gene region are haplotype B (i.e., if one or both copies of the TNFSF15 gene region have nucleotides T / C / A / T / C (26 / 31 / 35 / 36 / 41) at haplotype positions 15,524;9,706;-358;-638; and-12,506).

[0309] Haplotype locations 15,524;9,706;-358;-638; and -12,506 (26, 31, 35, 36, and 41) correspond to the sites of SNPs rs3810936, rs6478108, rs6478109, rs7848647, and rs7869487, respectively, identified in the NIH NCBI 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 the wild-type allele at each of these sites).

[0310] Haplotype B non-carrier subjects are defined as subjects that do not possess 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) (for example, they may have nucleotides C / T / G / C / T at haplotype positions 26 / 31 / 35 / 36 / 41). [Table 3]

[0311] In developing the algorithm, we used different combinations of five SNP sites, rs3810936 (SNP 1), rs6478108 (SNP 2), rs6478109 (SNP 3), rs7848647 (SNP 4), and rs7869487 (SNP 5) (including all viable combinations of 2, 3, and 4 SNPs selected from SNP 1, SNP 2, SNP 3, SNP 4, and SNP 5) to determine whether a subject was a haplotype B carrier or a non-carrier. A subject was defined as a non-carrier of haplotype B if both copies of the gene region corresponding to any one of the five SNP sites did not contain the nucleotide corresponding to the haplotype B nucleotide of the SNP site, e.g., CC / TT / GG / CC / TT for SNP1-SNP5. For each SNP combination, if the first SNP site from the tested combination was of a haplotype other than haplotype B in both copies of the gene region (i.e., hereinafter referred to as "non-haplotype B homozygous"), the subject was determined to be a non-haplotype B carrier. If the first SNP site from the tested combination was haplotype B homozygous or heterozygous (i.e., if either or both copies of the gene region corresponding to the SNP site contained nucleotides corresponding to the haplotype B nucleotide at the SNP site), the next SNP site in the combination was tested until one of the SNP sites was determined to be non-haplotype B homozygous (in which case the subject was determined to be a non-haplotype B carrier), or until all SNP sites in the combination had been tested. If the SNP site was not determined to be non-haplotype B homozygous, the subject was determined to be a haplotype B carrier. The final step of this algorithm was where misclassification could occur. Therefore, by testing all SNP combinations, it was possible to determine which SNP combination resulted in the fewest misclassifications.

[0312] Algorithm iterations including different SNP combinations were applied to genome sequence data (total of 2504 subjects) from the 1000 Genomes Project (Sudmant et al., Nature 526, 75-81 (2015)). True positive rate, true negative rate, false positive rate, and false negative rate were determined for each SNP combination to determine the optimal SNP combination that can effectively identify haplotype B carriers and non-carriers. As shown in Table 4, the combination of SNP 1 (rs3810936) and SNP 5 (rs7869487) provided the highest accuracy among various combinations of two SNP sites, and the accuracy rate was comparable to the best-performing combinations of three and four SNP sites. [Table 4]

[0313] The algorithm was further applied to genome sequence data from the Human Genome Diversity Project (Bergstrom et al., Science 367(6484), eaay5012(2020)) (a total of 4151 samples, 2501 of which overlap with the 1000 Genome Project). Unlike the 1000 Genomes data, the data from the Human Genome Diversity Project was not phased, and misclassified subjects within the overlapping datasets have different true values ​​due to phasing. Table 5 shows the analysis results for the Human Genome Diversity Project. In particular, the combination of three SNP sites, SNP 1 (rs3810936), SNP 3 (rs6478109), and SNP 5 (rs7869487), resulted in 0 misclassifications. Table 6 shows the accuracy rates for specific SNP site combinations evaluated using the Human Genome Diversity Project. [Table 5] [Table 6]

[0314] Example 2.2 - SNP Multiplex qPCR Assay The TL1A SNP Test is a multiplexed qPCR-based assay that detects the presence of two specific germline SNPs, rs3810936 (SNP 1) and rs7869487 (SNP 5), in biological samples from patients to identify TNFSF15 haplotype B non-carrier patients who may benefit further from afimkivart therapy (see Example 1). This assay exponentially amplifies a short DNA target (amplicon) over multiple cycles. Fluorescently labeled probes designed to bind to the amplicon allow for appropriate identification of the presence of the SNP (mutant / MUT, also called "alternate" or "Alt") or the absence of the SNP (wild-type / WT, "Ref"). Samples with mixed amplicons have a mixture of WT and MUT probes that bind to the amplicon, thus enabling identification of heterozygous (HET) samples. The probes are constructed using reporter dyes (FAM, SUN, TAMRA, and Cy5) at the 5' end and quencher dyes (BHQ-1 and BHQ-2) at the 3' end. While the probe remains intact, the proximity of the quencher dyes significantly reduces the fluorescence emitted from the reporter dyes by fluorescence resonance energy transfer (FRET). If a target sequence is present, the probe anneals to its specific complementary region in the amplicon, and as this primer extends, it is cleaved by the 5' nuclease activity of Taq DNA polymerase. This cleavage separates the reporter dye from the quencher dye, resulting in an increase in the reporter dye signal. Additional reporter dyes are cleaved from their probes in each cycle, resulting in an increase in fluorescence intensity proportional to the amount of amplicon produced. The fluorescence signal is monitored after each cycle, and genotyping is determined by the unique automated determination function of QuantStudio® 5 Dx software.

[0315] Once the genotypes of the two target SNP sites are 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), the reference ("Ref") allele is C and the alternative ("Alt") allele is T.

[0316] Patients identified as haplotype B carriers are classified as having a negative biomarker status. Patients identified as non-carriers of haplotype B are classified as having a positive biomarker status (i.e., identified as patients who may further benefit from afimkivar therapy). [Table 7]

[0317] Example 3. Efficacy and safety of RO7790121, a fully human monoclonal antibody that blocks TL1A in moderate to severe active ulcerative colitis: Results of the randomized, double-blind, placebo-controlled, dose-setting Phase 2b TUSCANY-2 study. Introduction 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 Afimkivart (RO7790121) (a fully human neutralizing monoclonal antibody against TL1A) demonstrated significant endoscopic improvement and adequate safety in the Phase 2a TUSCANY-1 trial (Danese et al., Clin Gastroenterol Hepatol, 19:2324-32.e6, 2021).

[0318] This example provides data from the international, randomized, double-blind, placebo-controlled, dose-finding Phase 2b Tuscany-2 (NCT04090411) trial, which evaluated the efficacy and safety of various subcutaneous (SC) doses of afimkivart administered every four weeks (Q4W) to male or female patients aged 18–75 years with moderate to severe active UC (total Mayo score ≥6, endoscopic subscore ≥2) who had previously failed or been intolerant to one or more lines of conventional or advanced treatment (selected from the following classes: steroids, immunosuppressants, anti-TNF, anti-integrin inhibitors, anti-IL-12 / 23 inhibitors, and JAK inhibitors).

[0319] Objectives and Methods Patients were randomized to receive either Afimkivart SC 50 mg, 150 mg, 450 mg, or matched placebo (PBO) monthly during a 12-week induction period, and Afimkivart SC 50, 150, or 450 mg monthly during a maintenance period from treatment to 40 weeks (Figure 3). Efficacy endpoints were assessed at weeks 14 and 56 in induction and maintenance intention-of-treatment analysis sets, respectively. The primary endpoints were clinical remission at week 14 by total Mayo score (MS) and safety at weeks 14 and 56. Pre-specified key secondary endpoints for clinical remission using modified Mayo score (mMS) are consistent with updated FDA guidance. Other secondary endpoints include clinical remission at week 56 (by total MS and mMS) and endoscopic improvement at weeks 14 and 56. Efficacy analyses were also performed by designated biomarker subgroups.

[0320] Table 8 provides definitions of the efficacy endpoints for the TUSCANY-2 study. [Table 8]

[0321] The term "Mayo score" refers to the Mayo score obtained using the Mayo Scoring System to evaluate ulcerative colitis activity.

[0322] research design TUSCANY-2 was a phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy, safety, and pharmacokinetics of PF-06480605 in participants with moderate to severe active UC. Approximately 240 participants were planned to be randomized, of which 216 were expected to complete the induction period with a 10% dropout rate. 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). [Table 9]

[0323] This study was conducted over four periods: a screening period, an induction period, a chronic therapy period, and a follow-up period. The screening period lasted up to six 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 via subcutaneous administration every four weeks. During the 40-week chronic therapy period, all participants received the active drug: 50 mg, 150 mg, or 450 mg via subcutaneous administration every four weeks. A final safety and efficacy assessment was planned during the 12-week follow-up period. Overall, each participant's participation in the study was up to 70 weeks. Participants who discontinued at any point during the study proceeded to a follow-up period with an early withdrawal visit. Participants who withdrew prematurely from the treatment period (after randomization and during active study intervention) were followed for a total of 12 weeks from the final dose of the intervention product, with three study visits (one of which was an early withdrawal visit).

[0324] Two interim analyses were conducted for the study. The first analysis was conducted when 100% of participants had completed or had the opportunity to complete the 14-week visit. The second interim analysis was conducted when all participants had completed or had the opportunity to complete the induction period, and when approximately 100% of them had completed or had the opportunity to complete at least 6 months of chronic therapy.

[0325] result A total of 246 participants were enrolled at 114 sites in 23 countries. Overall, 245 patients participated in the induction phase (receiving at least one induction dose), 228 patients completed the induction phase, and 224 patients entered the maintenance phase of the study (receiving at least one maintenance dose).

[0326] During the induction period, all 245 participants who received treatment (45 in the placebo group, 47 in the PF-06480605 50 mg group, 150 mg group, and 91 in the 450 mg group, respectively) were included in the safety and intention-to-treatment (ITT) analysis population. 240 participants (40 in the four groups, 47 in the four groups, 62 in the four groups, and 91 in the four groups) were included in the biomarker analysis population. 239 participants (40 in the four groups, 47 in the four groups, 62 in the four groups, and 90 in the four groups) were included in the immunogenicity analysis population.

[0327] During the chronic therapy 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 intention-to-treat (mITT) analysis.

[0328] A. Demographic and baseline characteristics Table 10 shows the demographic and baseline characteristics of patients treated in the TUSCANY-2 study. Demographic characteristics were generally similar between the placebo group and the PF-06480605 group. [Table 10]

[0329] 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 group and the three PF-06480605 groups.

[0330] Among participants treated during the induction period, the most common disease area was left-sided colitis (43.3%), followed by pancolitis (diagnosed in 39.2% of participants). Disease area was generally balanced between the placebo group and the three PF-06480605 groups.

[0331] Among participants treated during the induction period, a total of 95.5%, 41.2%, 38.8%, and 23.7% had received prior steroid, biological, anti-TNF, and / or anti-integrin treatments, respectively. Prior medical experience (i.e., steroids, biological, anti-TNF, anti-integrin, azathioprine, 6-MP, methotrexate, anti-IL-12 / 23 inhibitors, and JAK inhibitors) was generally balanced between the placebo group and the three PF-06480605 groups.

[0332] Among participants treated during the chronic therapy period, a total of 96.0%, 41.5%, 39.3%, and 24.1% had received prior steroid, biological, anti-TNF, and / or anti-integrin treatments, respectively. Prior medical experience was generally balanced across all treatment sequences.

[0333] Among participants treated during the induction period, 97.1% received common concomitant medications. A total of 73.1% of participants received mesalazine (ranging from 67.7% to 80.2% between the placebo group and the three PF-06480605 groups).

[0334] Among participants treated during the chronic therapy period, 76.8% received common concomitant medications.

[0335] Of the 245 participants treated during the induction period, 90 used steroids at baseline. Of those 90 participants, 89 (98.9%) did not change their steroid dosage.

[0336] Among the 224 participants treated during the chronic therapy period, 86 used steroids at baseline. Of those 86 participants, 43 (50.0%) did not change their steroid dosage. B. Effectiveness

[0337] At week 14, 25.5%, 23.3%, and 23.9% of patients in the Afimquivert 50mg, 150mg, and 450mg groups, respectively, experienced clinical remission based on the total Mayo score, compared to 11.6% in the placebo group (p > 0.05 (Table 11)).

[0338] At week 14, the proportion of patients achieving clinical remission by modified Mayo score (mMS) was 29.8%, 35.0%, and 31.8% in the afimkivart 50 mg, 150 mg, and 450 mg groups, respectively, compared to 11.6% in the placebo group (p<0.05) (Table 11 and Figure 4A). Consistently, statistically significant effects were observed at week 14 across endpoints and patient populations. As shown in Figures 7A and 7B, afimkivart achieved higher clinical remission (by mMS) and endoscopic improvement than placebo in both the overall subject population and the TNFSF15 biomarker-positive (haplotype B non-carrier, i.e., "biomarker-positive") patient population.

[0339] The improvement in clinical remission was sustained through maintenance (Table 11 and Figure 5).

[0340] Furthermore, a larger proportion of patients showed endoscopic improvement over the entire dose of afimkivar compared to placebo at weeks 14 and 56 (Table 11 and Figures 4B and 6). Compared to all subjects, biomarker-positive patients showed a tendency toward numerically higher treatment efficacy. [Table 11]

[0341] Statistically significant and clinically meaningful efficacy results were observed at all doses tested in both the overall population and the biomarker-positive patient population. Results at the 450 mg dose at week 14 are shown in Table 12 below. “Having biological experience” is defined as prior experience with anti-TNF agents, anti-integrin agents, and / or anti-IL-12 / 23 agents. [Table 12]

[0342] The efficacy results in subjects who were intolerant to, had an inadequate response to, or experienced a loss of response to previously administered therapies are shown in Figures 8A, 8B, 8B, and 9B. Figures 8A and 8B show the clinical remission and endoscopic improvement rates in patients who were intolerant to, had an inadequate response to, or experienced a loss of response to previous intensive therapies (antitumor necrosis factor (TNF) agents, anti-integrin agents, anti-IL-12 / 23 agents and / or Janus kinase (JAK) inhibitors). Figures 8A and 8B show the clinical remission and endoscopic improvement rates in patients who were intolerant to, had an inadequate response to, or experienced a loss of response to previous therapies including anti-TNF agents.

[0343] C. Safety Afimquivar was well-tolerated, and no safety signals were identified. No dose-related trends were observed in adverse events.

[0344] During the induction period, 47.8% (117 / 245) of patients reported a first adverse event (TEAE) occurring with one or more treatments (Tables 13 and 14). The most common TEAEs, using preferred terminology (occurring in ≥5% of patients), were anemia (5.3%) and headache (5.3%) (Table 15). As shown in Table 14, the adverse events occurring with treatment—"infection," "anemia," and "injection site reaction"—were balanced across treatment groups. In total, 10 patients experienced serious TEAEs up to week 14 (placebo = 4 patients, 50 mg = 3 patients, 450 mg = 3 patients). Severe and serious adverse events were sporadic and generally considered unrelated to the study drug. No patients discontinued the study due to TEAEs. A similar safety profile was observed during the maintenance period. [Table 13] [Table 14] [Table 15]

[0345] No immunogenic effects on clinical efficacy or safety outcomes were observed. At week 14 with a 450 mg dose, the anti-drug antibody (ADA) rate was 46% and the neutralizing antibody (NAb) rate was 8%. These immunogenic results are consistent with approved biologics. Humira showed ADA rates of 32–46% and neutralizing antibody rates of 11–23% at week 24 (Hanauer et al., 2021; Weinblatt et al., 2017; Cohen et al., 2019), while Skyrizi showed ADA rates of 19% and neutralizing antibody rates of 8% at week 16 (Skyrizi (risankizumab) FDA Summary Basis of Approval). As shown in Table 16, higher levels of ADA were associated with lower doses of subcutaneous (SC) administration. The median time to first detection of ADA and NAb was 30–57 days and 58–85 days, respectively, during induction with the SC regimen. [Table 16]

[0346] C. Exposure response to introduction and maintenance As shown in Table 17, higher exposure to afimkivat during the induction phase (C at week 14) ave (By ternary) was associated with a higher outcome rate at week 14. ave This represents the predicted mean concentration of afimkivat up to week 14. [Table 17]

[0347] As shown in Table 18, higher exposure to Afimkivat (C at 56 weeks) ave (By tertile) was associated with a higher 56-week outcome rate in induction responders who continued the same dose during the maintenance phase. ave This represents the predicted mean concentration of afimkivat up to week 56. [Table 18]

[0348] As shown in Table 19, almost all patients who received the 450 mg dose (approximately 74% in the induction phase and approximately 96% in the maintenance phase) had the highest tertile of exposure, indicating that this dose was necessary to achieve systemic exposure equivalent to maximum and sustained efficacy. [Table 19]

[0349] D.450mg dose The 450 mg SC Q4W dosing regimen was the only dose group that showed a tendency for efficacy to increase over time.

[0350] At a 450 mg dose, superior efficacy was observed at week 52 compared to week 14 (36% vs. 29% of all subjects; 43% vs. 33% of biomarker-positive patients).

[0351] The percentage of patients with a sustained clinical response (when the same dose was administered during the induction and maintenance phases) was highest at the 450 mg dose (75%). (i.e., higher efficacy was observed in participants who maintained the same 450 mg dose during the induction and maintenance phases compared to participants who received lower doses (50 mg or 150 mg)).

[0352] Compared to patients who received lower doses (e.g., 50 mg or 150 mg), participants who maintained the same 450 mg dose during the maintenance phase showed higher efficacy.

[0353] As shown above, exposure response analysis using individual exposures suggested that participants with the highest tertile of mean PK concentration over 56 weeks had numerically higher corrected remission (mMS remission), endoscopic improvement, sustained corrected remission, and sustained endoscopic improvement responses than those in the two lower tertiles. Almost all patients (approximately 96%) who received a 450 mg dose during the maintenance phase had the highest tertile of exposure, indicating that this dose was necessary to achieve systemic exposure equivalent to the maximum and sustained efficacy over the long term.

[0354] Furthermore, during the maintenance phase of the study, the sustained response rates of anti-drug antibodies (ADA) and neutralizing antibodies (NAb) in the 450 mg → 450 mg treatment sequence group (450 mg dose administered during the induction and maintenance phases) were the lowest compared to other treatment sequence sequences (see Table 16). In the 450 mg → 450 mg sequence, the effect of ADA status on serum afimquivat was minimal or nonexistent.

[0355] E. Conclusion Data from the Phase 2b Tuscany-2 dose-finding study demonstrate that afimkivar has a favorable benefit / risk profile with clinically meaningful improvement in patients with moderate to severe active UC.

Claims

1. A method for determining the risk of a patient being unresponsive to a therapeutic dose of anti-TNF-like ligand 1A (TL1A) antibody, wherein the method is: Performing a genotyping assay on a biological sample from the patient to determine whether the patient is a TNFSF15 haplotype B carrier or not, wherein the assay 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. Determining the risk of non-responsiveness to the aforementioned therapeutic dose of anti-TL1A antibody, and determining that the risk is higher in haplotype B carrier patients than in haplotype B non-carrier patients. Methods that include...

2. The method according to claim 1, wherein the patient has inflammatory bowel disease (IBD).

3. A method for treating inflammatory bowel disease (IBD) in a patient, wherein the method is (a) Performing a genotyping assay to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, wherein 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, (b) Administering an effective amount of anti-TL1A antibody to the patient, provided that the patient is determined to be a non-carrier of haplotype B. Methods that include...

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

5. The method according to claim 3, wherein the anti-TL1A antibody is administered to the patient in a maintenance regimen after completion of an induction regimen, and the maintenance regimen comprises a plurality of individual maintenance doses administered at intervals of at least two weeks from each other.

6. A method for treating IBD in a patient, wherein the method is (a) Performing a genotyping assay to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, wherein the assay includes 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 anti-TL1A antibody to the patient in an induction regimen sufficient to improve the signs and symptoms of IBD within at least 12 weeks after the initiation of treatment with anti-TL1A antibody, wherein the induction regimen comprises a plurality of individual induction doses, and the patient has been determined to be a non-carrier of haplotype B. (c) After the completion of the induction regimen, administer a subsequent maintenance regimen to the patient, wherein the maintenance regimen comprises a number of individual maintenance doses administered at intervals of at least two weeks from each other. Methods that include...

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

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

12. The patient exhibited the following biomarker conditions in the biological sample from the patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (iii) The genotype of the sample is homozygous for the substitute allele at rs3810936 and homozygous for the reference allele at rs7869487. (iv) The genotype of the sample is homozygous for the surrogate 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. The method according to claim 10 or 11, wherein the carrier is determined to be a non-carrier of haplotype B by any one of the following.

13. The method according to 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 according to 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 includes 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 buccal mucosa cells.

22. A method for determining the risk of a patient being unresponsive to a therapeutic dose of anti-TL1A antibody, wherein the patient has inflammatory bowel disease (IBD), and the method is (a) Performing a genotyping assay on a biological sample from the patient to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, wherein the assay determines the presence of SNPs rs3810936 and rs7869487 in the biological sample from the patient, and a TNFSF15 haplotype B non-carrier indicates the following biomarker status in the biological sample from the patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (iii) The genotype of the sample is homozygous for the substitute allele at rs3810936 and homozygous for the reference allele at rs7869487. (iv) The genotype of the sample is homozygous for the surrogate allele at rs3810936 and heterozygous for the reference allele at rs7869487, or (v) The genotype of the sample is identified by either being homozygous for the alternative allele at rs3810936 or being homozygous for the alternative allele at rs7869487, and the procedure is carried out accordingly. (b) If the patient is a haplotype B carrier, identify that the patient is at high risk of being unresponsive to a therapeutic dose of anti-TL1A antibody, or (c) If the patient is not a haplotype B carrier, identify that the patient has a low risk of being unresponsive to a therapeutic dose of anti-TL1A antibody. Methods that include...

23. The method according to claim 22, wherein the patient is determined to be a non-carrier of haplotype B of TNFSF15, and the method further comprises administering an effective amount of anti-TL1A antibody to the patient.

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

25. The method according to claim 23, wherein the anti-TL1A antibody is administered to the patient in a maintenance regimen after completion of an induction regimen, and the maintenance regimen comprises a plurality of individual maintenance doses administered at intervals of at least two weeks from each other.

26. A method for treating IBD in a patient, wherein the method is (a) Performing a genotyping assay on a biological sample from the patient to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, wherein the assay determines the presence of SNPs rs3810936 and rs7869487 in the biological sample from the patient, and a TNFSF15 haplotype B non-carrier indicates the following biomarker status in the biological sample from the patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (iii) The genotype of the sample is homozygous for the substitute allele at rs3810936 and homozygous for the reference allele at rs7869487. (iv) The genotype of the sample is homozygous for the surrogate allele at rs3810936 and heterozygous for the reference allele at rs7869487, or (v) The genotype of the sample is identified by either being homozygous for the alternative allele at rs3810936 or being homozygous for the alternative allele at rs7869487, (b) A method comprising administering an effective amount of anti-TL1A antibody to the patient, wherein the patient has been determined to be a non-carrier of haplotype B.

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

28. The method according to claim 26, wherein the anti-TL1A antibody is administered to the patient in a subsequent maintenance regimen following the completion of an induction regimen, and the maintenance regimen comprises a plurality of individual maintenance doses administered at intervals of at least two weeks from each other.

29. A method for treating IBD in a patient, the method comprising administering an effective amount of anti-TL1A antibody to the patient, The following biomarkers were present in the biological samples from the aforementioned patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (iii) The genotype of the sample is homozygous for the substitute allele at rs3810936 and homozygous for the reference allele at rs7869487. (iv) The genotype of the sample is homozygous for the surrogate allele at rs3810936 and heterozygous for the reference allele at rs7869487, or (v) A method by which the patient is determined to be a non-carrier of haplotype B of TNFSF15 by either the genotype of the sample being homozygous for the surrogate allele at rs3810936 or homozygous for the surrogate allele at rs7869487.

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

31. The method according to claim 29, wherein the anti-TL1A antibody is administered to the patient in a subsequent maintenance regimen following the completion of an induction regimen, and the maintenance regimen comprises a plurality of individual maintenance doses administered at intervals of at least two weeks 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 administered at intervals of at least one week, at least two weeks, at least three weeks, or at least four weeks 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 administered at intervals of at least one month from each other.

34. The method according to 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 doses are administered intravenously or subcutaneously.

36. The method according to 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 doses are administered in amounts of 50, 150, or 450 mg.

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

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

40. The method according to 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 drug regimen comprises four individual 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 regimen comprises four individual induction doses administered at four-week intervals, each of which is administered subcutaneously in 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 two weeks, at least three weeks, or at least four 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 intervals of at least one month.

45. The method according to claim 43, wherein the individual maintenance doses are 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 doses are administered intravenously or subcutaneously.

47. The method according to claim 46, wherein each of the 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 doses are administered in amounts of 50, 150, or 450 mg.

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

50. The method according to claim 48, wherein each of the aforementioned maintenance doses is administered in a dose of 150 mg.

51. The method according to claim 48, wherein each of the aforementioned maintenance doses is administered in 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 drug regimen comprises at least 10 individual maintenance doses.

53. The method according to any one of claims 5 to 21, 25, 28, and 41 to 52, wherein the induction regimen comprises 10 individual maintenance doses administered at 4-week intervals, and each individual maintenance dose is administered subcutaneously in doses of 50, 150, or 450 mg.

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

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

56. The method according to claim 55, wherein 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 according to claim 56, wherein 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 according to any one of claims 55 to 57, wherein the expression level of the one or more candidate genes is compared to a) a baseline expression level based on the expression level of the one or more candidate genes in healthy individuals not suffering from IBD or UC, or b) a baseline expression level based on the estimated expression level for individuals unresponsive to anti-TL1A antibody treatment.

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

60. a) Determining the expression level of one or more candidate bacterial strains in the stool sample from the patient, b) Identifying that the sample includes an increase or decrease in the level of one or more candidate bacterial strains. The method according to any one of claims 3 to 59, further comprising:

61. The method according to claim 60, wherein the number of candidate bacterial strains increases, and the candidate bacterial strains are selected from the group consisting of Streptococcus salivarius, Streptococcus parasanguinis, and Haemophilus parainfluenzae.

62. The method according to claim 61, wherein the candidate bacterial strain level decreases and the candidate bacterial strain is selected from the group consisting of Ruminococcus albus, Ruminococcus callidus, Ruminococcus bromii, Ruminococcus gnavas, 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 afimkivart.

68. A method for treating inflammatory bowel disease (IBD) in a patient, wherein the method is (a) Performing a genotyping assay to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, wherein 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, (b) Administering an effective amount of anti-TL1A antibody to the patient, provided that the patient is determined to be a non-carrier of haplotype B. The anti-TL1A antibody is administered by comprising 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. Methods that include...

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

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

71. The method according to any one of claims 1 to 62, wherein the anti-TL1A antibody comprises a sequence pair selected from the group consisting of SEQ ID NOs: 2 and 11; SEQ ID NOs: 2 and 12; SEQ ID NOs: 2 and 13; SEQ ID NOs: 2 and 14; SEQ ID NOs: 2 and 15; SEQ ID NOs: 2 and 16; SEQ ID NOs: 2 and 17; SEQ ID NOs: 2 and 18; SEQ ID NOs: 2 and 19; SEQ ID NOs: 20 and 24; SEQ ID NOs: 21 and 25; SEQ ID NOs: 22 and 26; SEQ ID NOs: 23 and 27; SEQ ID NOs: 28 and 29; SEQ ID NOs: 30 and 31; SEQ ID NOs: 32 and 33; SEQ ID NOs: 35 and 44; SEQ ID NOs: 53 and 54; SEQ ID NOs: 61 and 62; SEQ ID NOs: 63 and 64; SEQ ID NOs: 65 and 64; SEQ ID NOs: 66 and 64; and SEQ ID NOs: 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 thurisocibalt.

77. A method for treating inflammatory bowel disease (IBD) in a patient, wherein the method is (a) Performing a genotyping assay to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, wherein 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, (b) Administering an anti-TL1A antibody to the patient, provided that the patient is determined to be a non-carrier of haplotype B. 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, and is administered accordingly. Methods that include...

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

79. The method according to claim 78, wherein the assay comprises determining the presence of only two SNPs in the biological sample from the patient, the two SNPs being 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 according to 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 human.

85. A method for treating inflammatory bowel disease (IBD) in a patient, the method comprising administering an effective amount of anti-TNF-like ligand 1A (TL1A) antibody to the patient in a drug regimen comprising an induction regimen and a subsequent maintenance regimen, The induction regimen comprises a plurality of individual induction doses, and the maintenance regimen comprises a plurality of individual maintenance doses. The anti-TL1A antibody is administered subcutaneously during the maintenance phase, and the anti-TL1A antibody HCDR1 having the sequence shown in Sequence ID No. 3, HCDR2 having the sequence shown in Sequence ID No. 4, HCDR3 having the sequence shown in Sequence ID No. 5, LCDR1 having the sequence shown in Sequence ID No. 6, LCDR2 having the sequence shown in Sequence ID 7, and LCDR3 having the sequence shown in Sequence ID No. 8 Methods that include...

86. The method according to claim 85, wherein the individual induction doses are administered at intervals of at least one week, at least two weeks, at least three weeks, or at least four weeks from each other.

87. The method according to claim 85 or 86, wherein the individual induction doses are administered at intervals of at least one month from each other.

88. The method according to 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 doses are administered intravenously or subcutaneously.

90. The method according to 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 doses are administered in amounts of 50, 150, or 450 mg.

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

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

94. The method according to 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 drug regimen comprises four individual induction doses.

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

97. The method according to any one of claims 85 to 96, wherein the individual maintenance doses are administered at intervals of at least two weeks, at least three weeks, or at least four weeks.

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

99. The method according to claim 97, wherein the individual maintenance doses are administered at 4-week intervals.

100. The method according to any one of claims 85 to 99, wherein the individual maintenance doses are administered in amounts of 50, 150, or 450 mg.

101. The method according to claim 100, wherein each of the aforementioned maintenance doses is administered in a dose of 50 mg.

102. The method according to claim 100, wherein each of the aforementioned maintenance doses is administered in a dose of 150 mg.

103. The method according to claim 100, wherein each of the aforementioned maintenance doses is administered in a dose of 450 mg.

104. The method according to any one of claims 85 to 103, wherein the maintenance medication regimen comprises at least 10 individual maintenance doses.

105. The method according to any one of claims 85 to 104, wherein the induction regimen comprises 10 individual maintenance doses administered at 4-week intervals, and each individual maintenance dose is administered subcutaneously in doses of 50, 150, or 450 mg.

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

107. A method for treating inflammatory bowel disease (IBD) in a patient, the method comprising administering an effective amount of anti-TNF-like ligand 1A (TL1A) antibody to the patient in a drug regimen comprising an induction regimen and a subsequent maintenance regimen, (a) The induction regimen comprises subcutaneous administration of four individual induction doses of the anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg, with each induction dose administered at 4-week intervals, and (b) The maintenance regimen comprises subcutaneous administration of a plurality of 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 aforementioned anti-TL1A antibody HCDR1 having the sequence shown in Sequence ID No. 3, HCDR2 having the sequence shown in Sequence ID No. 4, HCDR3 having the sequence shown in Sequence ID No. 5, LCDR1 having the sequence shown in Sequence ID No. 6, LCDR2 having the sequence shown in Sequence ID 7, and LCDR3 having the sequence shown in Sequence ID No. 8 Methods that include...

108. A method for treating inflammatory bowel disease (IBD) in a patient, the method comprising administering an effective amount of anti-TNF-like ligand 1A (TL1A) antibody to the patient in a drug regimen comprising an induction regimen and a subsequent maintenance regimen, (a) The induction regimen comprises a plurality of individual induction doses, and the individual induction doses are administered at intervals of at least one week, at least two weeks, at least three weeks, or at least four weeks from each other, (b) The maintenance regimen comprises subcutaneous administration of a plurality of individual maintenance doses of the anti-TL1A antibody at doses of approximately 450 mg, wherein the individual maintenance doses are administered at 4-week intervals, and The aforementioned anti-TL1A antibody HCDR1 having the sequence shown in Sequence ID No. 3, HCDR2 having the sequence shown in Sequence ID No. 4, HCDR3 having the sequence shown in Sequence ID No. 5, LCDR1 having the sequence shown in Sequence ID No. 6, LCDR2 having the sequence shown in Sequence ID 7, and LCDR3 having the sequence shown in Sequence ID No. 8 Methods that include...

109. The method according to claim 108, wherein the induction regimen comprises subcutaneous administration of four individual induction doses of the anti-TL1A antibody at doses of approximately 450 mg, and the individual induction doses are administered at intervals of four weeks.

110. The method according to any one of claims 85 to 109, wherein the initial 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 drug regimen has a duration of approximately 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 afimkivart.

115. The method according to any one of claims 85 to 114, wherein the patient is determined to be a non-carrier of haplotype B of TNFSF15.

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

117. The method according to 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 human being.

119. The method according to any one of claims 85 to 118, wherein in a patient population treated according to the method, the treatment results in an increase in the proportion of patients who achieve clinical remission at the end of the induction period compared to a reference population.

120. The method according to claim 119, wherein the induction period has a duration of approximately 14 weeks, and the treatment results in an increase in the percentage of patients who achieve clinical remission at 14 weeks.

121. The method according to claim 120, wherein at least about 15% of the patients in the patient population achieve clinical remission at 14 weeks.

122. The method according to claim 121, wherein at least about 40% of the patients in the patient population achieve clinical remission at 14 weeks.

123. The method according to any one of claims 85 to 122, wherein in a patient population treated according to the method, the treatment results in an increase in the proportion of patients achieving clinical remission at the end of the maintenance period compared to a reference population.

124. The method according to claim 123, wherein the drug regimen has a duration of approximately 56 weeks, and the treatment results in an increased percentage of patients achieving clinical remission at 56 weeks.

125. The method according to claim 124, wherein at least about 20% of the patients in the patient population achieve clinical remission at 56 weeks.

126. The method according to claim 125, wherein at least about 55% of the patients in the patient population achieve clinical remission at 56 weeks.

127. The method according to any one of claims 119 to 126, wherein clinical remission is achieved by a total Mayo score ≤ 2 and no individual subscores exceed 1.

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

129. The method according to any one of claims 85 to 128, wherein in a patient population treated according to the method, the treatment results in an increase in the proportion of patients who achieve endoscopic improvement at the end of the introductory period compared to a reference population.

130. The method according to claim 129, wherein the introductory period has a duration of approximately 14 weeks, and the procedure results in an increase in the percentage of patients who achieve endoscopic improvement at the 14th week.

131. The method according to claim 130, wherein at least about 25% of the patients in the patient population achieve endoscopic improvement at 14 weeks.

132. The method according to claim 131, wherein at least about 50% of the patients in the patient population achieve endoscopic improvement at 14 weeks.

133. The method according to any one of claims 85 to 132, wherein in a patient population treated according to the method, the treatment results in an increase in the proportion of patients who achieve endoscopic improvement at the end of the maintenance period compared to a reference population.

134. The method according to claim 133, wherein the drug regimen has a duration of approximately 56 weeks, and the treatment results in an increased percentage of patients achieving endoscopic improvement at 56 weeks.

135. The method according to claim 134, wherein at least about 20% of the patients in the patient population achieve endoscopic improvement at 56 weeks.

136. The method according to claim 135, wherein at least about 65% of the patients in the patient population achieve endoscopic improvement at 56 weeks.

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

138. The method according to any one of claims 85 to 137, wherein in a patient population treated according to the method, the treatment results in an increase in the proportion of patients achieving endoscopic remission, clinical response, symptomatic remission, or deep remission at the end of the induction period, compared to a reference population.

139. The method according to any one of claims 85 to 138, wherein in a patient population treated according to the method, the treatment results in an increase in the proportion of patients achieving endoscopic remission, clinical response, symptomatic remission or deep remission at the end of the maintenance phase compared to a reference population.

140. The method according to any one of claims 119 to 139, wherein the reference population is a population of patients who have not been treated with an anti-TL1A antibody.

141. The method according to claim 140, wherein the reference population is a population of patients treated with a placebo.

142. A kit comprising an anti-TNF-like ligand 1A (TL1A) antibody and a package insert containing instructions for using the antibody for the treatment of inflammatory bowel disease (IBD) in patients requiring treatment of IBD according to any one of claims 1 to 141.

143. An anti-TL1A antibody for use in the treatment of IBD in patients, (a) A genotyping assay is to be performed to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, 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 antibody in which an effective amount of the anti-TL1A antibody is to be administered to the patient, and the patient has been determined to be a non-carrier of haplotype B.

144. An anti-TL1A antibody for use in the treatment of IBD in patients, (a) A genotyping assay is to be performed to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, 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 to be administered to the patient in an induction regimen sufficient to improve the signs and symptoms of IBD within at least 12 weeks after the initiation of treatment with the anti-TL1A antibody, the induction regimen comprises a number of individual induction doses, the patient has been determined to be a non-carrier of haplotype B, and (c) The anti-TL1A antibody is to be administered to the patient in a subsequent maintenance regimen after the completion of the induction regimen, wherein the maintenance regimen comprises a plurality of individual maintenance doses administered at intervals of at least two weeks from each other.

145. An anti-TL1A antibody for use in the treatment of IBD in patients, (a) A genotyping assay is performed on a biological sample from the patient to determine whether the patient is a TNFSF15 haplotype B carrier or a non-carrier, the assay comprising determining the presence of SNPs rs3810936 and rs7869487 in the biological sample from the patient, wherein a non-carrier of TNFSF15 haplotype B is indicated by the following biomarker status in the biological sample from the patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (iii) The genotype of the sample is homozygous for the substitute allele at rs3810936 and homozygous for the reference allele at rs7869487. (iv) The genotype of the sample is homozygous for the surrogate allele at rs3810936 and heterozygous for the reference allele at rs7869487, or (v) The genotype of the sample is identified by either being homozygous for the alternative allele at rs3810936 or being homozygous for the alternative allele at rs7869487, and (b) An antibody in which an effective amount of the anti-TL1A antibody is to be administered to the patient, and the patient has been determined to be a non-carrier of haplotype B.

146. An anti-TL1A antibody for use in the treatment of IBD in a patient, wherein an effective amount of the anti-TL1A antibody is to be administered to the patient. The following biomarkers were present in the biological samples from the aforementioned patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (iii) The genotype of the sample is homozygous for the substitute allele at rs3810936 and homozygous for the reference allele at rs7869487. (iv) The genotype of the sample is homozygous for the surrogate allele at rs3810936 and heterozygous for the reference allele at rs7869487, or (v) An antibody in which the genotype of the sample is homozygous for the alternative allele at rs3810936 and homozygous for the alternative allele at rs7869487, thereby determining that the patient is a non-carrier of haplotype B of TNFSF15.

147. An anti-TL1A antibody for use in the treatment of IBD in patients, (a) A genotyping assay is to be performed to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, 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, and the patient has been determined to be a non-carrier of haplotype B, 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 the treatment of IBD in patients, (a) A genotyping assay is to be performed to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, 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 to be administered to the patient, and the patient has been determined to be a non-carrier of haplotype B, 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 the treatment of IBD in patients, wherein an effective amount of the anti-TL1A antibody is administered to the subject in a drug regimen that includes an induction regimen and a subsequent maintenance regimen. The induction regimen comprises a plurality of individual induction doses, and the maintenance regimen comprises a plurality of individual maintenance doses. The anti-TL1A antibody is administered subcutaneously during the maintenance phase, and the anti-TL1A antibody HCDR1 having the sequence shown in Sequence ID No. 3, HCDR2 having the sequence shown in Sequence ID No. 4, HCDR3 having the sequence shown in Sequence ID No. 5, LCDR1 having the sequence shown in Sequence ID No. 6, LCDR2 having the sequence shown in Sequence ID 7, and LCDR3 having the sequence shown in Sequence ID No. 8 Anti-TL1A antibody, including

150. An anti-TL1A antibody for use in the treatment of IBD in patients, wherein an effective amount of the anti-TL1A antibody is administered to the subject in a drug regimen that includes an induction regimen and a subsequent maintenance regimen. (a) The induction regimen comprises subcutaneous administration of four individual induction doses of the anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg, with each induction dose administered at 4-week intervals, and (b) The maintenance regimen comprises subcutaneous administration of a plurality of 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 aforementioned anti-TL1A antibody HCDR1 having the sequence shown in Sequence ID No. 3, HCDR2 having the sequence shown in Sequence ID No. 4, HCDR3 having the sequence shown in Sequence ID No. 5, LCDR1 having the sequence shown in Sequence ID No. 6, LCDR2 having the sequence shown in Sequence ID 7, and LCDR3 having the sequence shown in Sequence ID No. 8 Anti-TL1A antibody, including

151. An anti-TL1A antibody for use in the treatment of inflammatory bowel disease (IBD) in patients, wherein an effective amount of the anti-TL1A antibody is administered to the subject in a drug regimen that includes an induction regimen and a subsequent maintenance regimen. (a) The induction regimen comprises a plurality of individual induction doses, and the individual induction doses are administered at intervals of at least one week, at least two weeks, at least three weeks, or at least four weeks from each other, (b) The maintenance regimen comprises subcutaneous administration of a plurality of individual maintenance doses of the anti-TL1A antibody at doses of approximately 450 mg, wherein the individual maintenance doses are administered at 4-week intervals, and The aforementioned anti-TL1A antibody HCDR1 having the sequence shown in Sequence ID No. 3, HCDR2 having the sequence shown in Sequence ID No. 4, HCDR3 having the sequence shown in Sequence ID No. 5, LCDR1 having the sequence shown in Sequence ID No. 6, LCDR2 having the sequence shown in Sequence ID 7, and LCDR3 having the sequence shown in Sequence ID No. 8 Anti-TL1A antibody, including

152. The use of anti-TL1A antibodies in the manufacture of pharmaceuticals for the treatment of IBD in patients, (a) A genotyping assay is to be performed to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, 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) Use in which an effective amount of the anti-TL1A antibody is to be administered to the patient, and the patient is determined to be a non-carrier of haplotype B.

153. The use of anti-TL1A antibodies in the manufacture of pharmaceuticals for the treatment of IBD in patients, (a) A genotyping assay is to be performed to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, 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 to be administered to the patient in an induction regimen sufficient to improve the signs and symptoms of IBD within at least 12 weeks after the initiation of treatment with the anti-TL1A antibody, the induction regimen comprises a number of individual induction doses, the patient has been determined to be a non-carrier of haplotype B, and (c) Use wherein the anti-TL1A antibody is administered to the patient in a subsequent maintenance regimen after the completion of the induction regimen, and the maintenance regimen comprises a number of individual maintenance doses administered at intervals of at least two weeks from each other.

154. The use of anti-TL1A antibodies in the manufacture of pharmaceuticals for the treatment of IBD in patients, (a) A genotyping assay is performed on a biological sample from the patient to determine whether the patient is a TNFSF15 haplotype B carrier or a non-carrier, the assay comprising determining the presence of SNPs rs3810936 and rs7869487 in the biological sample from the patient, wherein a non-carrier of TNFSF15 haplotype B is indicated by the following biomarker status in the biological sample from the patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (iii) The genotype of the sample is homozygous for the substitute allele at rs3810936 and homozygous for the reference allele at rs7869487. (iv) The genotype of the sample is homozygous for the surrogate allele at rs3810936 and heterozygous for the reference allele at rs7869487, or (v) The genotype of the sample is identified by either being homozygous for the alternative allele at rs3810936 or being homozygous for the alternative allele at rs7869487, and (b) Use in which an effective amount of the anti-TL1A antibody is to be administered to the patient, and the patient is determined to be a non-carrier of haplotype B.

155. The use of an anti-TL1A antibody in the manufacture of a pharmaceutical product for the treatment of IBD in a patient, wherein an effective amount of the anti-TL1A antibody is administered to the patient. The following biomarkers were present in the biological samples from the aforementioned patient: (i) The genotype of the sample is homozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (ii) The genotype of the sample is heterozygous for the reference allele at rs3810936 and homozygous for the substitute allele at rs7869487. (iii) The genotype of the sample is homozygous for the substitute allele at rs3810936 and homozygous for the reference allele at rs7869487. (iv) The genotype of the sample is homozygous for the surrogate allele at rs3810936 and heterozygous for the reference allele at rs7869487, or (v) The patient is determined to be a non-carrier of haplotype B of TNFSF15 by either the genotype of the sample being homozygous for the alternative allele at rs3810936 or homozygous for the alternative allele at rs7869487.

156. The use of anti-TL1A antibodies in the manufacture of pharmaceuticals for the treatment of IBD in patients, (a) A genotyping assay is to be performed to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, 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, and the patient has been determined to be a non-carrier of haplotype B, 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. The use of anti-TL1A antibodies in the manufacture of pharmaceuticals for the treatment of IBD in patients, (a) A genotyping assay is to be performed to determine whether the patient is a TNFSF15 haplotype B carrier or a haplotype B non-carrier, 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 to be administered to the patient, and the patient has been determined to be a non-carrier of haplotype B, 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. The use of an anti-TL1A antibody in the manufacture of a pharmaceutical product for the treatment of IBD in a patient, wherein an effective amount of the anti-TL1A antibody is administered to the subject in a drug regimen comprising an induction regimen and a subsequent maintenance regimen. The induction regimen comprises a plurality of individual induction doses, and the maintenance regimen comprises a plurality of individual maintenance doses. The anti-TL1A antibody is administered subcutaneously during the maintenance phase, and the anti-TL1A antibody HCDR1 having the sequence shown in Sequence ID No. 3, HCDR2 having the sequence shown in Sequence ID No. 4, HCDR3 having the sequence shown in Sequence ID No. 5, LCDR1 having the sequence shown in Sequence ID No. 6, LCDR2 having the sequence shown in Sequence ID 7, and LCDR3 having the sequence shown in Sequence ID No. 8 Includes, use.

159. The use of an anti-TL1A antibody in the manufacture of a pharmaceutical product for the treatment of IBD in a patient, wherein an effective amount of the anti-TL1A antibody is administered to the subject in a drug regimen comprising an induction regimen and a subsequent maintenance regimen. (a) The induction regimen comprises subcutaneous administration of four individual induction doses of the anti-TL1A antibody at doses of approximately 50 mg, 150 mg, or 450 mg, with each induction dose administered at 4-week intervals, and (b) The maintenance regimen comprises subcutaneous administration of a plurality of 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 aforementioned anti-TL1A antibody HCDR1 having the sequence shown in Sequence ID No. 3, HCDR2 having the sequence shown in Sequence ID No. 4, HCDR3 having the sequence shown in Sequence ID No. 5, LCDR1 having the sequence shown in Sequence ID No. 6, LCDR2 having the sequence shown in Sequence ID 7, and LCDR3 having the sequence shown in Sequence ID No. 8 Includes, use.

160. The use of an anti-TL1A antibody in the manufacture of a pharmaceutical product for treating inflammatory bowel disease (IBD) in a patient, wherein an effective amount of the anti-TL1A antibody is administered to the subject in a drug regimen comprising an induction regimen and a subsequent maintenance regimen. (a) The induction regimen comprises a plurality of individual induction doses, and the individual induction doses are administered at intervals of at least one week, at least two weeks, at least three weeks, or at least four weeks from each other, (b) The maintenance regimen comprises subcutaneous administration of a plurality of individual maintenance doses of the anti-TL1A antibody at doses of approximately 450 mg, wherein the individual maintenance doses are administered at 4-week intervals, and The aforementioned anti-TL1A antibody HCDR1 having the sequence shown in Sequence ID No. 3, HCDR2 having the sequence shown in Sequence ID No. 4, HCDR3 having the sequence shown in Sequence ID No. 5, LCDR1 having the sequence shown in Sequence ID No. 6, LCDR2 having the sequence shown in Sequence ID 7, and LCDR3 having the sequence shown in Sequence ID No. 8 Includes, use.

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