Methods and systems for selecting and treating patients with inflammatory diseases

Abstract

This document describes methods and systems for identifying subjects suitable for treatment with CD30L activity or expression inhibitors, such as anti-CD30L antibodies. The methods and systems disclosed herein identify subjects suitable for treatment based on the presence or absence of a genotype indicating the disease or condition in which the CD30L inhibitor is appropriate for treatment. Exemplary conditions include Crohn's disease and primary sclerosing cholangitis. Compositions for detecting the genotypes described herein and methods of using them are also provided.

Description

[0001] Cross-referencing

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 664,720, filed April 30, 2018; U.S. Provisional Application No. 62 / 681,557, filed June 6, 2018; and U.S. Provisional Application No. 62 / 784,179, filed December 21, 2018, all of which are incorporated herein by reference in their entirety.

[0003] sequence list

[0004] This application contains a sequence list, which has been electronically submitted in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy created on April 19, 2019, is named 52388-740_601_SL.txt and is 7,862,716 bytes in size. Background Technology

[0005] Inflammatory diseases, fibrotic diseases, and fibrotic diseases constitute a significant health burden worldwide due to the large number of affected individuals, diverse pathogenesis, and varying clinical manifestations. One such disease is inflammatory bowel disease (IBD), which has two common forms: Crohn's disease (CD) and ulcerative colitis (UC). IBD involves chronic, relapsing inflammatory conditions of the gastrointestinal tract. IBD has a high prevalence, affecting nearly 3 million people in the United States alone. Each of these forms has multiple subconditions present in the CD and UC patient subgroups, referred to as subclinical phenotypes. One such condition is obstructive Crohn's disease, which may result from long-term inflammation that can lead to scarring (fibrotic stenosis) or swelling of the intestinal wall. Both outcomes can lead to narrowing or obstruction, referred to as fibrotic stenosis or inflammatory stenosis. Severe stenosis can cause intestinal obstruction, resulting in abdominal pain, bloating, nausea, and inability to pass stool.

[0006] Patients with inflammatory diseases, fibrotic strictures, and fibrotic diseases have few treatment options. Existing anti-inflammatory therapies, such as steroids and tumor necrosis factor (TNF) inhibitors, are typically used as first-line treatments for IBD. Unfortunately, a significant number of patients do not respond to existing anti-inflammatory therapies, especially TNF inhibitors, or lose their response. When patients are treated with ineffective anti-inflammatory therapies, their condition worsens. For patients who do not respond to first-line therapies, surgery in the form of structureplasty (intestinal reconstruction) or resection (intestinal removal) is the only treatment option. Surgical treatment of IBD is invasive, and it is estimated that about one-third of patients undergoing surgery will experience postoperative risks such as anastomotic leakage, infection, and bleeding.

[0007] The pathogenesis of inflammatory diseases, fibrotic stenotic diseases, and fibrotic diseases such as IBD is thought to involve uncontrolled immune responses, which may be triggered by certain environmental factors in genetically susceptible hosts. The heterogeneity of disease pathogenesis and clinical course, coupled with variable responses to treatment and associated side effects, suggests that a personalized medicine approach is the optimal treatment strategy for these diseases. However, personalized therapies available to patients are extremely limited. Therefore, there is a need to identify targeted therapies for treating inflammatory diseases, fibrotic stenotic diseases, and fibrotic diseases and their subclinical phenotypes, and even more importantly, to develop reliable methods for identifying patients who will respond to any given treatment based on their genotype. The desired methods will also identify undiagnosed subjects at risk of developing the disease, allowing for preventative interventions to mitigate the growing health burden. Summary of the Invention

[0008] CD30 ligand (CD30L) is a ligand encoded by the tumor necrosis factor receptor superfamily 8 (TNFSF8) gene. CD30L is a member of the tumor necrosis factor superfamily and is crucial in co-stimulating immune cells to induce cell proliferation and cytokine production. In some cases, CD30L acts on pro-inflammatory cytokines such as interleukin-6 (IL-6). Preliminary studies suggest that the CD30L pathway is a major pathway in the pathogenesis of inflammatory, fibrotic, and fibrotic stenotic diseases such as IBD, particularly in certain subgroups of patients with complex disease forms (e.g., stenotic, penetrating, or obstructive disease phenotypes).

[0009] Various aspects of this application provide methods and systems for treating inflammatory diseases in subjects with CD30L inhibitors. In some cases, CD30L inhibitors inhibit, attenuate, or otherwise interfere with biological responses related to the interaction of CD30L with its homolog CD30. Therefore, in some cases, treatment with CD30L inhibitors can be used to treat conditions associated with the expression or activity of CD30 ligands or CD30.

[0010] This article also describes polymorphisms and their haplotypes at the TNFSF8 gene or genetic locus associated with inflammatory, fibrotic, or fibrotic stenotic diseases. TNFSF8 polymorphisms can be associated with inflammatory bowel disease (IBD) and various subclinical phenotypes of IBD. Additionally, these polymorphisms affect CD30L expression and, in some cases, CD30 expression. Genotypes containing the TNFSF8 polymorphisms described herein can be detected in samples obtained from subjects who may or may not be diagnosed with IBD. Genotyping assays facilitated by existing genotyping tests can be performed when needed or in healthcare settings. Exemplary genotyping tests involve hybridization assays using nucleic acid probes specific to the said polymorphisms.

[0011] This document provides practical applications of the association between the genotypes described herein and the incidence of clinical and subclinical phenotypes in certain individual populations. For example, the genotypes disclosed herein can be used to predict the risk of a subject developing an inflammatory disease, fibrotic stenosis, or fibrotic disease. The genotypes can also be used to predict whether a patient diagnosed with a form of inflammatory, fibrotic, or fibrotic stenosis disease will develop a severe form of that disease, such as its subclinical phenotype. Additionally or alternatively, the genotypes disclosed herein are associated with variations in the expression of CD30 or CD30L, which in some cases means that the genotypes can be used to identify patients who may be suitable for treatment with CD30L-targeted therapies (e.g., patients carrying genotypes associated with elevated CD30L may be suitable for treatment with anti-CD30L or anti-CD30 therapies). Exemplary conditions include Crohn's disease (CD) and primary sclerosing cholangitis. In some cases, a therapeutic agent (e.g., a CD30L inhibitor, a TL1A inhibitor) may be administered to a subject if the genotypes disclosed herein are detected in a sample obtained from the subject. Another example of practical applications disclosed in this article includes laboratory-based methods for detecting this genotype, such as quantitative PCR (qPCR) and sequencing methods.

[0012] The aspects disclosed herein provide a method for inhibiting or reducing CD30 ligand activity or expression in a subject, the method comprising: (a) selecting a subject who has or is suspected of having at least one of an inflammatory disease, a fibrotic stenosis, and a fibrotic disease; (b) identifying the subject as a carrier of a genotype having a polymorphism at at least one of rs911605 and rs1006026; and (c) administering an effective amount of a CD30 ligand inhibitor to the subject to inhibit or reduce CD30 ligand activity or expression in the subject. In some embodiments, the polymorphism at rs911605 comprises an “A” allele at nucleotide 501 within rs911605 (SEQ ID NO:1), and the polymorphism at rs1006026 comprises a “G” allele at nucleotide 501 within rs1006026 (SEQ ID NO:3). In some embodiments, the genotype comprises both the polymorphism at rs911605 and the polymorphism at rs1006026. In some embodiments, the polymorphism at rs911605 includes an “A” allele at nucleotide 501 within rs911605 (SEQ ID NO:1), and the polymorphism at rs1006026 includes a “G” allele at nucleotide 501 within rs1006026 (SEQ ID NO:3). In some embodiments, identifying the subject as a carrier of the genotype includes: (a) contacting a sample containing genetic material obtained from the subject with a nucleic acid sequence capable of hybridizing with at least 10 consecutive nucleobases between nucleobases 400 and 600 of at least one of SEQ ID NO:1 and SEQ ID NO:3 under standard hybridization conditions, wherein the at least 10 consecutive nucleobases include the nucleobase at position 501 of at least one of SEQ ID NO:1 and SEQ ID NO:3; and (b) detecting binding between the nucleic acid sequence and at least 10 consecutive nucleobases between nucleobases 400 and 600 of at least one of SEQ ID NO:1 and SEQ ID NO:2. In some embodiments, the CD30 ligand inhibitor is an antibody or antigen-binding fragment targeting a CD30 ligand or CD30, or a combination thereof. In some embodiments, the method further includes administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is a regulator of gene expression or the expression or activity of a gene expression product, the gene being selected from mitogen-activated protein kinase kinase 4 (MAP4K4), prostaglandin E receptor 4 (PTGER4), and interleukin-18 receptor 1 (IL18R1).The inhibitors include phosphofructosyl-2-kinase / fructose 2,6-bisphosphatase 3 (PFKFB3), interleukin-18 receptor helper protein (IL18RAP), adenylate cyclase 7 (ADCY7), B lymphoid tyrosine kinase (BLK), G protein-coupled receptor 65 (GPR65), protein 2 containing the Sprouty-associated EVH1 domain (SPRED2), Src kinase-associated phosphoprotein 2 (SKAP2), receptor-interacting serine / threonine kinase 2 (RIPK2), and TNF ligand superfamily member 15 (TNFSF15), Janus kinase 1 (JAK1), G protein-coupled receptor 35 (GPR35), and Gasdermin B (GSDMB). In some embodiments, the method further includes administering an effective amount of a tumor necrosis factor ligand superfamily member 15 (TL1A) inhibitor to the subject. In some embodiments, the TL1A inhibitor is an antibody or antigen-binding fragment antagonist targeting TL1A. In some embodiments, antibodies or antigen-binding fragments targeting TL1A are provided in Table 15.

[0013] The aspects disclosed herein provide a method for treating a subject with moderate to severe Crohn's disease, the method comprising: (a) identifying a subject with Crohn's disease (CD) as a carrier of a genotype with a polymorphism at at least one of rs911605 and rs1006026, the genotype being associated with the subject's risk of developing a moderate to severe form of CD, including obstructive CD; and (b) administering to the subject a therapeutically effective amount of an inhibitor of CD30 ligand activity or expression. In some embodiments, the method further comprises determining whether the subject has or will develop at least one of unresponsiveness or loss of response to standard treatment. In some embodiments, the standard treatment is selected from glucocorticoids, anti-TNF therapy, anti-α4-B7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), thalidomide, and cytotoxic agents. In some embodiments, the polymorphism at rs911605 comprises the “A” allele at nucleotide 501 within rs911605 (SEQ ID NO:1), and the polymorphism at rs1006026 comprises the “G” allele at nucleotide 501 within rs1006026 (SEQ ID NO:3). In some embodiments, the genotype comprises both the polymorphism at rs911605 and the polymorphism at rs1006026. In some embodiments, the CD30 ligand activity inhibitor is an antibody or antigen-binding fragment targeting a CD30 ligand or CD30, or a combination thereof. In some embodiments, the method further comprises administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is a regulator of gene expression or the expression or activity of a gene expression product, the gene being selected from mitogen-activated protein kinase kinase kinase 4 (MAP4K4), prostaglandin E receptor 4 (PTGER4), and interleukin-18 receptor 1 (IL18R1). The inhibitors include phosphofructosyl-6-phosphate 2-kinase / fructose 2,6-bisphosphatase 3 (PFKFB3), interleukin-18 receptor cofactor (IL18RAP), adenylate cyclase 7 (ADCY7), B lymphoid tyrosine kinase (BLK), G protein-coupled receptor 65 (GPR65), protein 2 containing the Sprouty-associated EVH1 domain (SPRED2), Src kinase-associated phosphoprotein 2 (SKAP2), receptor-interacting serine / threonine kinase 2 (RIPK2), and TNF ligand superfamily member 15 (TNFSF15), Janus kinase 1 (JAK1), G protein-coupled receptor 35 (GPR35), and Gasdermin B (GSDMB). In some embodiments, the method further includes administering an effective amount of a tumor necrosis factor ligand superfamily member 15 (TL1A) inhibitor to the subject.In some embodiments, the TL1A inhibitor is an antibody or antigen-binding fragment antagonist targeting TL1A. In some embodiments, antibodies or antigen-binding fragments targeting TL1A are provided in Table 15.

[0014] The aspects disclosed herein provide a method for characterizing inflammatory diseases in subjects, the method comprising: (a) determining genetic material in a sample obtained from a subject suffering from an inflammatory disease to detect the presence of a genotype containing at least one of rs911605 and rs1006026; and (b) characterizing the inflammatory disease as Crohn's disease (CD) if the presence of said genotype is detected in step (a). In some embodiments, determining the genetic material in the sample in step (a) comprises: (a) amplifying at least 15 nucleotides from said genetic material within SEQ ID NO:5 or SEQ ID NO:6, said at least 15 nucleotides including nucleotides at the positions indicated by [A / G] in SEQ ID NO:5 or [A / G] in SEQ ID NO:6; and (b) hybridizing said genetic material with a nucleic acid containing a nucleic acid sequence containing at least one of SEQ ID NO:5 and SEQ ID NO:6. In some embodiments, step (a) of determining the genetic material in the sample comprises: (a) amplifying at least 15 nucleotides from the genetic material within SEQ ID NO:7 or SEQ ID NO:8, said at least 15 nucleotides including the nucleotides at the positions indicated by [A / G] in SEQ ID NO:7 or [A / G] in SEQ ID NO:8; and (b) hybridizing a nucleic acid containing a nucleic acid sequence comprising at least one of SEQ ID NO:7 and SEQ ID NO:8 with the genetic material. In some embodiments, the nucleic acid comprises a detectable molecule. In some embodiments, the method further comprises administering an inhibitor of CD30 ligand activity or expression to the subject if the inflammatory disease is characterized as moderate to severe in step (b). In some embodiments, the CD30 ligand activity inhibitor is an antibody or antigen-binding fragment targeting CD30 ligand or CD30, or a combination thereof. In some embodiments, step (b) characterizing the inflammatory disease as CD further includes characterizing the inflammatory disease as refractory to standard treatment selected from glucocorticoids, anti-TNF therapy, anti-α4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), thalidomide, and cytotoxic agents. In some embodiments, the CD is further characterized as obstructive CD. In some embodiments, the method further includes administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is a regulator of gene expression or the expression or activity of a gene expression product selected from mitogen-activated protein kinase kinase kinase 4 (MAP4K4), prostaglandin E receptor 4 (PTGER4), and interleukin-18 receptor 1 (IL18R1).The inhibitors include phosphofructosyl-6-phosphate 2-kinase / fructose 2,6-bisphosphatase 3 (PFKFB3), interleukin-18 receptor helper protein (IL18RAP), adenylate cyclase 7 (ADCY7), B lymphoid tyrosine kinase (BLK), G protein-coupled receptor 65 (GPR65), protein 2 containing the Sprouty-associated EVH1 domain (SPRED2), Src kinase-associated phosphoprotein 2 (SKAP2), receptor-interacting serine / threonine kinase 2 (RIPK2), and TNF ligand superfamily member 15 (TNFSF15), Janus kinase 1 (JAK1), G protein-coupled receptor 35 (GPR35), and Gasdermin B (GSDMB). In some embodiments, the method further includes administering an effective amount of a tumor necrosis factor ligand superfamily member 15 (TL1A) inhibitor to the subject. In some embodiments, the TL1A inhibitor is an antibody or antigen-binding fragment antagonist targeting TL1A. In some embodiments, antibodies or antigen-binding fragments targeting TL1A are provided in Table 15.

[0015] Use of compounds containing CD30 ligand inhibitors in treating subjects identified as carriers of a genotype containing an "A" allele at nucleotide position 501 in SEQ ID NO:2, a "G" allele at nucleotide position 501 in SEQ ID NO:4, or a combination thereof. In some embodiments, the subject is identified as having or being susceptible to developing at least one of unresponsiveness or loss of response to standard treatment selected from glucocorticoids, anti-TNF therapy, anti-α4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), thalidomide, and cytotoxic agents.

[0016] Use of a combination therapy comprising a CD30 ligand inhibitor and a tumor necrosis factor ligand superfamily member 15 (TL1A) inhibitor in treating subjects identified as carriers of a genotype containing an "A" allele at nucleotide position 501 in SEQ ID NO:2, a "G" allele at nucleotide position 501 in SEQ ID NO:4, or a combination thereof. In some embodiments, the CD30 ligand inhibitor and the TL1A inhibitor are administered separately to the subject. In some embodiments, the subject is identified as having or being susceptible to developing at least one of non-response or loss of response to standard therapy selected from glucocorticoids, anti-TNF therapy, anti-α4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), thalidomide, and cytotoxic agents. In some embodiments, the TL1A inhibitor is an antibody or antigen-binding fragment targeting TL1A. In some embodiments, antibodies or antigen-binding fragments targeting TL1A are provided in Table 15. Attached Figure Description

[0017] Figure 1 The results show that using the cis-expression quantitative trait locus (cis-eQTL), compared to individuals without the risk allele (“non-risk, GG”), the risk allele – “A” in rs911605 (P = 4.41 x 10⁻⁶) was significantly higher (P = 4.41 x 10⁻⁶). -4 (rs911605A or rs911605AA) is associated with increased expression of tumor necrosis factor receptor superfamily 8 (TNFSF8) mRNA in the small intestine.

[0018] Figure 2 The study showed that CD30L protein expression on T cells and B cells was upregulated in samples obtained from subjects carrying the rs911605A or rs911605AA risk genotypes compared to non-risk ("NR") individuals who did not express the risk genotype.

[0019] Figure 3 The study showed increased expression of interferon-γ (IFN-γ or IFNg) in samples obtained from subjects compared to non-risk (“NR”) individuals who did not express this risk genotype.

[0020] Figure 4 The study showed increased expression of tumor necrosis factor α (TNFa) in samples obtained from subjects compared to non-risk (“NR”) individuals who did not express this risk genotype.

[0021] Figure 5 The study showed increased expression of interleukin-6 (IL-6) in samples obtained from subjects compared to non-risk (“NR”) individuals who did not express this risk genotype.

[0022] Figures 6A-6C The study showed that CD30L expression was associated with soluble CD30 (sCD30) levels in a patient population carrying various genotypes, including rs911605AA and rs1006026AA / GA / GG genotypes. Figure 6A ), rs911605AA and rs1006026GA / GG genotypes ( Figure 6B ), and rs911605AA and rs1006026GG genotypes ( Figure 6C ).

[0023] Figures 7A-7C The risk genotypes rs911605AA and rs1006026AA / GA / GG were shown. Figure 7A ), rs911605AA and rs1006026GA / GG ( Figure 7B) as well as rs911605AA and rs1006026GG(7C) were correlated with sCD30 levels and the percentage of CD30L in B cells. Detailed Implementation

[0024] This disclosure provides methods and systems for detecting the presence or absence of a specific genotype in a subject, which in some cases can be used to select subjects for specific treatment of certain diseases or conditions, determine the risk of developing a clinical or subclinical phenotype, or a combination thereof. In some embodiments, the genotype includes polymorphisms at rs911605 (SEQ ID NO:1) and optionally rs1006026 (SEQ ID NO:3). For example, the genotype is a haplotype that is polymorphic at both rs911605 and rs1006026. In some cases, the presence of a specific genotype indicates elevated expression of the subject's CD30 ligand (CD30L). In some cases, the presence of a specific genotype indicates elevated levels of soluble CD30 in the subject. In some cases, the presence of a specific genotype indicates elevated expression of the tumor necrosis factor (TNF) family cytokine TL1A (TNFSF15) in the subject. Therefore, subjects who are positive for said genotype may be suitable for treatment with CD30L inhibitors such as anti-CD30L antibodies. Subjects with the aforementioned positive genotype may also be suitable candidates for treatment with TL1A inhibitors. For example, CD30L inhibitors and TL1A inhibitors can be used to treat diseases or conditions associated with CD30L / CD30 or TL1A activity, such as at least one of inflammatory diseases, fibrotic strictures, and fibrotic diseases. Non-limiting examples of inflammatory diseases include diseases of the gastrointestinal tract, liver, and gallbladder; including Crohn's disease (CD). An exemplary fibrotic disease is primary sclerosing cholangitis (PSC).

[0025] In some embodiments, methods and systems are provided for identifying whether a subject has a polymorphism at rs911605 and / or rs1006026. In some cases, the polymorphism is contained in an "A" allele at position 501 of rs911605 (SEQ ID NO:2). In some cases, the polymorphism is contained in a "G" allele at position 501 of rs1006026 (SEQ ID NO:4). Exemplary methods include a hybridization assay comprising contacting genetic material from a subject with a probe containing a nucleic acid sequence capable of hybridizing with at least a portion (e.g., at least about 10 nucleotides) of a nucleic acid sequence containing the polymorphism. As an example, one method includes contacting genetic material with a probe containing at least about 10 consecutive nucleotides of rs911605 (SEQ ID NO:1 or SEQ ID NO:2), wherein the probe contains at least the nucleotide at position 501. As another example, a method includes contacting genetic material with a probe containing at least about 10 consecutive nucleotides of rs1006026 (SEQ ID NO:3 or SEQ ID NO:4), wherein the probe contains at least the nucleotide at position 501. Additional probes include those having a sequence that is reverse complementary to the probes described herein, such as a sequence reverse complementary to any one of SEQ ID NOS:1-4. In some cases, a method includes multiplexing, which involves contacting genetic material with two or more probes, for example, one or more probes specific for the polymorphism at rs911605 and one or more probes specific for the polymorphism at rs1006026. Suitable hybridization assays include quantitative polymerase chain reaction (qPCR). For example, this qPCR is TaqMan. TM Measurement.

[0026] Further provided are compositions and kits for detecting the presence of specific genotypes or haplotypes (e.g., polymorphisms at rs911605 and / or rs1006026). In some cases, the kit contains reagents, such as primers and / or probes, configured to amplify and / or detect genotypes from a genetic sample from a subject. In some cases, the kit includes a sample collection device. Some such devices can be used to obtain samples containing genetic material from a subject. An exemplary collection device is a swab. For the purpose of collecting a sample, one method involves contacting the swab with a surface of the subject to be tested, such as... internal examine Another exemplary collection device is a tube for collecting blood samples from a subject. In some cases, the tube contains additives for preservation and / or facilitating analysis. For example, the tube may contain heparin, potassium oxalate, sodium fluoride, ethylenediaminetetraacetic acid (EDTA), sodium citrate, reagents for activating or reducing coagulation, reagents for separating serum, or combinations thereof.

[0027] Further, CD30L inhibitors and other therapeutic agents are provided, which can be administered to patients with inflammatory diseases, fibrotic stenosis, and / or fibrotic diseases. In some cases, other therapeutic agents may include TL1A inhibitors. A non-limiting example of a CD30L inhibitor is an anti-CD30L antibody, as disclosed elsewhere herein. A non-limiting example of a TL1A inhibitor is an anti-TL1A antibody, as disclosed herein. In some embodiments, the patient contains the genotypes disclosed herein, for example, polymorphisms at rs911605 and / or rs1006026.

[0028] Overview

[0029] The aspects disclosed herein provide the genotypes of subjects. Genotypes can be detected in samples obtained from subjects by analyzing genetic material in the samples. The genotypes disclosed herein may be associated with diseases or conditions or subclinical phenotypes of diseases or conditions. The genotypes disclosed herein may be associated with increased or decreased gene expression or gene expression products expressed by that gene. The genotypes may also be associated with the presence of other biomarkers such as serological markers.

[0030] The presence of the genotypes disclosed herein can be used for the diagnosis, prognosis, monitoring, prevention, and treatment of at least one of the subjects suffering from the stated disease or condition or its subclinical phenotypes or symptoms. The genotypes disclosed herein can also be used to identify subjects who may be unresponsive or have lost a response to standard treatments such as certain first-line therapies (e.g., anti-TNF therapy, steroids, or other immunomodulatory agents). Similarly, the genotypes disclosed herein can be used to identify subjects who may have a positive (e.g., therapeutic) response to the therapeutic agents disclosed herein or other therapeutic agents (e.g., anti-TL1A therapy).

[0031] Subjects

[0032] The subjects disclosed herein may be mammals, such as mice, rats, guinea pigs, rabbits, non-human primates, or farm animals. In some cases, the subject is a human. In some cases, the subject is a patient diagnosed with the disease or condition disclosed herein. In some cases, the subject has not been diagnosed with the disease or condition. In some cases, the subject suffers from symptoms related to the disease or condition disclosed herein (e.g., abdominal pain, cramps, diarrhea, rectal bleeding, fever, weight loss, fatigue, loss of appetite, dehydration and malnutrition, anemia, or ulcers).

[0033] In some implementations, the subject is susceptible to or suffers from thiopurine toxicity or a disease caused by thiopurine toxicity (such as pancreatitis or leukopenia). The subject may have or be suspected of having no response or loss of response to standard treatment (e.g., anti-TNFα therapy, anti-α4-B7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), thalidomide, or cytotoxic agents).

[0034] Disease or condition

[0035] The diseases or conditions disclosed herein are at least one of inflammatory diseases, fibrotic stricture diseases, and fibrotic diseases. Non-limiting examples of inflammatory diseases include diseases of the gastrointestinal (GI) tract, liver, gallbladder, and joints. In some cases, the inflammatory disease includes inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis, systemic lupus erythematosus (SLE), or rheumatoid arthritis. The subject may have isolated or combined fibrotic, fibrotic stricture, or fibrotic disease. In some cases, the CD is obstructive CD. The obstructive CD may be caused by inflammation leading to scarring (fibrotic stricture) and / or swelling of the intestinal wall. In some cases, the CD is characterized by the presence of fibrotic stricture and / or inflammatory stricture. Strictures can be determined by computed tomography colonography (CTE) and magnetic resonance imaging colonography (MRE). In some embodiments, the disease is primary sclerosing cholangitis (PSC). Exemplary methods for diagnosing PSC include magnetic resonance cholangiopancreatography (MRCP), liver function tests, and histological examination. Liver function tests are valuable laboratory tests and may include measurements of serum alkaline phosphatase, serum aminotransferase, gamma-glutamyl transferase levels, and the presence of hypergammaglobulinemia. This disease or condition may include thiopurine toxicity or diseases caused by thiopurine toxicity (such as pancreatitis or leukopenia). In a further embodiment provided, the subject experiences no response to therapy induction or loss of response to therapy following successful induction of the therapy. Non-limiting examples of standard treatments include glucocorticoids, anti-TNF therapy, anti-α4-β7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), thalidomide, and cytotoxic agents.

[0036] genotype

[0037] In some embodiments, this document discloses the detection of genotypes in samples obtained from a subject by analyzing genetic material in the sample. In some cases, the subject may be a human being. In some embodiments, the genetic material is obtained from a subject suffering from a disease or condition disclosed herein. In some cases, the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and other techniques known to those skilled in the art. In some cases, genetic material for biopsy is obtained, for example, from the subject's intestine.

[0038] The genotype disclosed herein contains genetic material as deoxyribonucleic acid (DNA). In some cases, the genotype contains denatured DNA molecules or fragments thereof. In some cases, the genotype contains DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosome DNA. In some cases, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denatured double-stranded DNA, synthetic DNA, and combinations thereof. Circular DNA may be cleaved or fragmented.

[0039] The genotypes disclosed herein contain at least one polymorphism at the gene or locus described herein. In some cases, the gene or locus contains tumor necrosis factor (ligand) superfamily member 8 (TNFSF8). In some cases, the gene or locus contains TNF superfamily member 15 (TNFSF15). In some cases, the polymorphism is located at an intergenic locus spanning both TNFSF8 and TNFSF15. In some cases, the genotypes disclosed herein are haplotypes. In some cases, the genotype contains a specific polymorphism, a polymorphism in its linkage disequilibrium (LD), or a combination thereof. In some cases, the LD is composed of at least or about 0.70, 0.75, 0.80, 0.85, 0.90, or 0.1 r 2 The genotypes disclosed in this article may contain at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more polymorphisms.

[0040] The polymorphism described herein can be a single nucleotide polymorphism or an insertion / deletion. In some cases, the polymorphism is an insertion or deletion of at least one nucleobase (e.g., insertion / deletion). In some cases, the genotype may contain copy number variations (CNVs), which are variations in the number of nucleic acid sequences among individuals in a given population. In some cases, the CNV contains at least two, three, four, five, six, seven, eight, nine, ten, twenty, thirty, forty, or fifty nucleic acid molecules. In some cases, the genotype is heterozygous. In some cases, the genotype is homozygous.

[0041] In some cases, the genotypes provided herein are associated with the presence of serological markers. Serological markers are a type of biomarker, such as an autoantigen, that represents a serological response to a microbial antigen in a subject's body. Non-limiting examples of serological markers include anti-neutrophil cytoplasmic antibodies (ANCA), anti-Saccharomyces cerevisiae antibodies (ASCA), anti-flagellate (CBir1) antibodies, and Escherichia coli outer membrane porin C (OmpC). The serological markers disclosed herein may be used alone or in combination with the genotypes disclosed herein for patient selection for treatment. The serological markers disclosed herein may also be used alone or in combination with the genotypes disclosed herein for the diagnosis, prognosis, prevention, treatment, and / or monitoring of the diseases or conditions disclosed herein.

[0042] In some cases, the genotype contains one or more polymorphisms at genes or loci containing tumor necrosis factor (ligand) superfamily member 8 (TNFSF8) and / or TNF superfamily member 15 (TNFSF15). The genotypes disclosed herein are disclosed in the following embodiments:

[0043] 1. A genotype containing at least one polymorphism at a gene or genetic locus.

[0044] 2. The genotype of implementation scheme 1, which includes the polymorphisms provided in Table 1, or the polymorphisms in linkage disequilibrium (LD).

[0045] 3. The genotypes of implementation schemes 1-2, which include the polymorphisms provided in Table 2, or the polymorphisms in their LDs.

[0046] 4. The genotypes of implementation schemes 1-3, which include the polymorphisms provided in Table 3, or the polymorphisms in their LDs.

[0047] 5. The genotypes of implementation schemes 1-4, which include the polymorphisms provided in Table 4, or the polymorphisms in their LDs.

[0048] 6. The genotypes of implementation schemes 1-5, which include the polymorphisms provided in Table 5, or the polymorphisms in their LDs.

[0049] 7. The genotypes of implementation schemes 1-6, which include the polymorphisms provided in Table 6, or the polymorphisms in their LDs.

[0050] 8. The genotypes of implementation schemes 1-7, which include the polymorphisms provided in Table 7, or the polymorphisms in their LDs.

[0051] 9. The genotypes of implementation schemes 1-8, which include the polymorphisms provided in Table 8, or the polymorphisms in their LDs.

[0052] 10. The genotypes of implementation schemes 1-9, which include the polymorphisms provided in Table 9, or the polymorphisms in their LDs.

[0053] 11. The genotypes of implementation schemes 1-10, which include the polymorphisms provided in Table 10, or the polymorphisms in their LDs.

[0054] 12. The genotypes of implementation schemes 1-11, which include the polymorphisms provided in Table 11, or the polymorphisms in their LDs.

[0055] 13. The genotypes of implementation schemes 1-12, which include the polymorphisms provided in Table 12, or the polymorphisms in their LDs.

[0056] 14. The genotypes of implementation schemes 1-13, which include the polymorphisms provided in Table 13, or the polymorphisms in their LDs.

[0057] 15. The genotypes of implementation schemes 1-14, which include the polymorphisms provided in Table 14, or the polymorphisms in their LDs.

[0058] 16. The genotype of implementation scheme 1-15, which contains a single nucleotide polymorphism (SNP) at rs911605.

[0059] 17. The genotype of implementation scheme 16, wherein the SNP at rs911605 is provided in SEQ ID NO:1.

[0060] 18. The genotype of implementation scheme 16, wherein the SNP at rs911605 contains the “A” allele at position 501 in SEQ ID NO:2.

[0061] 19. The genotypes of implementation schemes 16-18 are heterozygous.

[0062] 20. The genotypes of implementation schemes 16-18 are homozygous.

[0063] 21. The genotype of implementation scheme 1-20 contains an SNP at rs1006026.

[0064] 22. The genotype of implementation scheme 21, wherein the SNP at rs1006026 is provided in SEQ ID NO:3.

[0065] 23. The genotype of implementation scheme 21, wherein the SNP at rs100602 contains the “G” allele at position 501 in SEQ ID NO:4.

[0066] 24. The genotypes of the implementation schemes 21-23 are heterozygous.

[0067] 25. The genotypes of the implementation schemes 21-23 are homozygous.

[0068] The aspects disclosed herein provide genotypes that are associated with and thus indicative of subjects having or being at risk of developing a particular disease or condition or its subclinical phenotype. Table 1 provides exemplary polymorphisms associated with CD. Table 2 provides exemplary polymorphisms associated with UC. Table 3 provides exemplary polymorphisms associated with IBD. Table 4 provides exemplary polymorphisms associated with loss of anti-TNF response. Table 5 provides exemplary polymorphisms associated with primary sclerosing cholangitis (PSC). Table 6 provides exemplary polymorphisms associated with the presence of ASCA. Table 7 provides exemplary polymorphisms associated with the presence of an antigenic response to Cbir1 flagellin.

[0069] Table 1. Exemplary polymorphisms associated with Crohn's disease

[0070]

[0071]

[0072]

[0073] Table 2. Exemplary polymorphisms associated with ulcerative colitis

[0074]

[0075]

[0076]

[0077] Table 3. Exemplary polymorphisms associated with inflammatory bowel disease

[0078]

[0079]

[0080] Table 4. Exemplary polymorphisms associated with loss of anti-TNF response

[0081]

[0082]

[0083] Table 5. Exemplary polymorphisms associated with primary sclerosing cholangitis (PSC)

[0084]

[0085] Table 6. Exemplary polymorphisms associated with the existence of ASCA

[0086]

[0087] Table 7. Exemplary polymorphisms associated with the presence of Cbir1 antigen response

[0088]

[0089] In one aspect, this article provides genotypes that are associated with and thus indicative of a subject having or developing a specific subclinical phenotype of a disease or condition. A subclinical phenotype can be a specific phenotype associated with a disease or condition, or an indicator of disease progression specific to a severe or unusual form of disease. In some cases, a subclinical phenotype is diagnosable. In some cases, a subclinical phenotype is not diagnosable. Non-limiting examples of IBD subclinical phenotypes include, but are not limited to, non-strictive disease, strictive and penetrating disease, perianal Crohn's disease (pCD), defects in Panette cells, PSC, and blood clot formation (e.g., thrombosis). The time to first surgery and the time to second surgery are used to identify a subject at risk for a severe form of disease based on their subclinical phenotype. In the case of inflammatory bowel disease, the time to first surgery can be the time from the onset of symptoms of inflammatory bowel disease to surgery. The time to first surgery can be the time from the initial diagnosis of IBD to the first surgery. The time to second surgery can be the time from the first surgery to the second surgery. The first and / or second surgery may include surgery on at least a portion of the subject's gastrointestinal tract. Non-restrictive surgeries include bowel resection, colectomy, perianal surgery, and stricture repair. Symptoms can be those described herein. Gastrointestinal tract portions may include the anus, colon, large intestine, small intestine, stomach, and esophagus. Table 8 provides exemplary polymorphisms associated with the time of the first surgery. Table 9 provides exemplary polymorphisms associated with the time of the second surgery. Table 10 provides exemplary polymorphisms associated with various Panette cell phenotypes. Table 11 provides exemplary SNPs associated with thrombosis development. Table 12 provides exemplary polymorphisms associated with non-stenotic and non-penetrating diseases or stenotic and penetrating diseases of various parts of the small intestine.

[0090] Table 8. Exemplary polymorphisms related to time to first surgery

[0091]

[0092] Table 9. Exemplary polymorphisms related to second surgery time

[0093]

[0094]

[0095] Table 10. Exemplary polymorphisms associated with various Panette cell defects

[0096]

[0097] Table 11. Exemplary polymorphisms associated with thrombosis development

[0098]

[0099] Table 12. Exemplary polymorphisms associated with stenotic and / or penetrating diseases at various disease locations

[0100]

[0101] CD30 and the nucleic acid encoding CD30 (TNFSF8) are characterized by NCBI Entrez gene ID 944. CD30 is the transmembrane receptor for its ligand CD30L, both belonging to the tumor necrosis factor (TNF) family. In some embodiments, the presence of a genotype containing one or more polymorphisms in Table 13 is associated with decreased CD30 levels compared to CD30 levels in individuals without this genotype. In some embodiments, the presence of a genotype containing one or more polymorphisms in Table 14 is associated with increased CD30 levels compared to CD30 levels in individuals without this genotype. In some cases, a genotype indicating a decrease in CD30 detected in a sample obtained from a subject indicates that the subject has decreased CD30 levels compared to individuals without this genotype. In some cases, a genotype indicating an increase in CD30 detected in a sample obtained from a subject indicates that the subject has increased CD30 levels compared to individuals without this genotype. An increase or decrease in CD30 may indicate a corresponding increase or decrease in its ligand CD30L.

[0102] In some cases, an increase or decrease in CD30 or CD30L is expressed as a fold change. As used herein, a "fold change" refers to a change in the amount or level of gene expression or its gene expression product from an initial value to a final value. The fold change can be measured over a period of time, at a single time point, or a combination thereof. The fold change can be an increase or a decrease compared to an initial value. In some embodiments, the gene comprises deoxyribonucleic acid (DNA). In some embodiments, the gene expression product comprises ribonucleic acid (RNA) or a protein, or both. In some embodiments, the RNA comprises messenger RNA (mRNA). In some implementations, the fold change in CD30 or CD30L increase or decrease includes an increase of 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.0, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 or more times between the expression of CD30 or CD30L in samples obtained from subjects and in individuals without genotypes associated with the fold change.

[0103] In some implementations, an increase or decrease in CD30 or CD30L in a subject indicates that the subject has or will develop a specific disease or condition. In some cases, subjects with a specific disease or condition associated with a genotype related to elevated CD30 or CD30L levels are suitable for treatment with CD30L inhibitors such as anti-CD30L antibodies. In some cases, subjects with a specific disease or condition associated with a genotype related to decreased CD30 or CD30L levels are suitable for treatment with CD30L or CD30 agonists.

[0104] Table 13. Exemplary polymorphisms associated with decreased CD30 expression

[0105]

[0106]

[0107] Table 14. Exemplary polymorphisms associated with increased CD30 expression

[0108]

[0109]

[0110]

[0111]

[0112] In some embodiments, the genotype is homozygous, meaning that two copies of the same allele exist at the same SNP. In some embodiments, the genotype is heterozygous, meaning that one copy of the allele exists at the same SNP. In some embodiments, the genotype includes a polymorphism at rs911605 (SEQ ID NO:1). For example, the genotype includes the "A" allele at position 501 within rs911605 shown in SEQ ID NO:2. In some cases, a subject with this genotype is homozygous for the "A" allele (rs911605AA). In some cases, a subject with this genotype is heterozygous (rs911605A). In some embodiments, the genotype includes a polymorphism at rs1006026 (SEQ ID NO:3). For example, the genotype includes the "G" allele at position 501 within rs1006026 shown in SEQ ID NO:4. In some cases, subjects with this genotype are homozygous for the "G" allele (rs1006026GG). In other cases, subjects with this genotype are heterozygous (rs1006026G).

[0113] A haplotype is further provided, which includes polymorphisms at rs911605 (SEQ ID NO:1) and rs1006026 (SEQ ID NO:3). In some cases, as used herein, "haplotype" refers to a set of polymorphisms that are often inherited together. In some cases, the polymorphism at rs911605 includes the "A" allele at position 501 within rs911605 as shown in SEQ ID NO:2. In some cases, the polymorphism at rs1006026 includes the "G" allele at position 501 within rs1006026 as shown in SEQ ID NO:4. In some cases, the haplotype includes rs911605AA and rs1006026GG.

[0114] method

[0115] Methods for detecting genotype

[0116] The method disclosed herein for detecting genotypes in samples from subjects includes analyzing the genetic material in the sample to detect at least one of the presence, absence, and amount of a nucleic acid sequence containing a target genotype. In some cases, the nucleic acid sequence contains DNA. In some cases, the nucleic acid sequence contains denatured DNA molecules or fragments thereof. In some cases, the nucleic acid sequence contains DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosome DNA. In some cases, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denatured double-stranded DNA, synthetic DNA, and combinations thereof. Circular DNA may be cleaved or fragmented. In some cases, the nucleic acid sequence contains RNA. In some cases, the nucleic acid sequence contains fragmented RNA. In some cases, the nucleic acid sequence contains partially degraded RNA. In some cases, the nucleic acid sequence contains microRNA or portions thereof. In some cases, the nucleic acid sequence contains RNA molecules or fragmented RNA molecules (RNA fragments) selected from the following: microRNA (miRNA), pre-miRNA, pri-miRNA, mRNA, pre-mRNA, viral RNA, viroid RNA, viral RNA, circular RNA (circRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), pre-tRNA, long noncoding RNA (lncRNA), small nuclear RNA (snRNA), circulating RNA, cell-free RNA, exogenous RNA, vector-expressed RNA, RNA transcripts, synthetic RNA, and combinations thereof.

[0117] Nucleic acid-based detection techniques that can be used with the method described in this paper include quantitative polymerase chain reaction (qPCR), gel electrophoresis, immunochemistry, in situ hybridization such as fluorescence in situ hybridization (FISH), cytochemistry, and next-generation sequencing. In some implementations, the method involves TaqMan. TM qPCR, which involves a nucleic acid amplification reaction using specific primer pairs and the hybridization of the amplified nucleic acid with a hydrolyzable probe specific to the target nucleic acid, provides exemplary probes that can hybridize with target nucleic acid sequences within rs911605. Exemplary probes that can hybridize with target nucleic acid sequences within rs1006026 are also provided in this disclosure.

[0118] In some cases, the methods involve hybridization and / or amplification assays, including but not limited to Southern or Northern blotting, polymerase chain reaction (PCR) assays, and probe arrays. Non-restriction amplification reactions include, but are not limited to, qPCR, automated sequence replication, transcription amplification systems, Q-Beta replicase, rolling circle replication, or any other nucleic acid amplification known in the art. As discussed herein, references to qPCR include the use of TaqMan. TM Methods. Another exemplary hybridization assay includes the use of nucleic acid probes conjugated or otherwise immobilized on beads, multi-well plates, or other substrates, wherein the nucleic acid probes are configured to hybridize with target nucleic acid sequences of the genotypes provided herein. Non-limiting methods are those used in Anal Chem. 2013 Feb 5; 85(3):1932-9.

[0119] In some implementations, detecting the presence or absence of a genotype involves sequencing genetic material from the subject. Sequencing can be performed using any suitable sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, polymerase cloning (Polony) sequencing, ligation sequencing, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or synthetic sequencing. Sequencing methods also include next-generation sequencing, such as modern sequencing technologies like Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion Torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Other sequencing methods available to those skilled in the art may also be employed.

[0120] In some cases, the number of nucleotides sequenced is at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400, 500, 2000, 4000, 6000, 8000, 10000, 20000, 50000, 100000 or more than 100000 nucleotides. In some cases, the number of nucleotides sequenced ranges from approximately 1 to 100,000 nucleotides, approximately 1 to 10,000 nucleotides, approximately 1 to 1,000 nucleotides, approximately 1 to 500 nucleotides, approximately 1 to 300 nucleotides, approximately 1 to 200 nucleotides, approximately 1 to 100 nucleotides, approximately 5 to 100,000 nucleotides, approximately 5 to 10,000 nucleotides, approximately 5 to 1,000 nucleotides, approximately 5 to 500 nucleotides, approximately 5 to 300 nucleotides, approximately 5 to 200 nucleotides, approximately 5 to 100 nucleotides, approximately 10 to 100,000 nucleotides, approximately 10 to 10,000 nucleotides, approximately 10 to 1,000 nucleotides, approximately 10 to 500 nucleotides, approximately 10 to 300 nucleotides, approximately 10 to 200 nucleotides, approximately 10 to 100 nucleotides. The range of approximately 20 to approximately 100,000 nucleotides, approximately 20 to approximately 10,000 nucleotides, approximately 20 to approximately 1,000 nucleotides, approximately 20 to approximately 500 nucleotides, approximately 20 to approximately 300 nucleotides, approximately 20 to approximately 200 nucleotides, approximately 20 to approximately 100 nucleotides, approximately 30 to approximately 100,000 nucleotides, approximately 30 to approximately 1,000 nucleotides, approximately 30 to approximately 1,000 nucleotides, approximately 30 to approximately 500 nucleotides, approximately 30 to approximately 300 nucleotides, approximately 30 to approximately 200 nucleotides, approximately 30 to approximately 100 nucleotides, approximately 50 to approximately 100,000 nucleotides, approximately 50 to approximately 10,000 nucleotides, approximately 50 to approximately 1,000 nucleotides, approximately 50 to approximately 500 nucleotides, approximately 50 to approximately 300 nucleotides, approximately 50 to approximately 200 nucleotides, or approximately 50 to approximately 100 nucleotides.

[0121] In some cases, the methods provided herein include determining the presence, absence, and / or quantity of a nucleic acid sequence from a specific genotype. In some embodiments, a method for detecting a genotype is provided, which includes detecting the presence, absence, and / or quantity of a nucleic acid sequence selected from SEQ ID NO: 5-8 or a portion thereof, or a combination thereof. In some cases, the portion of the nucleic acid sequence provided herein contains at least about 10, 15, 20, 25, 30, 35, 40, 45, or 50 consecutive nucleotides. In some cases, the portion of the nucleic acid sequence provided herein contains about 10 to about 50 consecutive nucleotides, about 10 to about 40 consecutive nucleotides, about 15 to about 50 consecutive nucleotides, about 15 to about 40 consecutive nucleotides, about 20 to about 50 consecutive nucleotides, and about 20 to about 40 consecutive nucleotides. In some cases, the nucleic acid sequence portions provided herein contain approximately 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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, or 50 consecutive nucleobases. In some cases, the nucleic acid sequence portion containing SEQ ID NO:5 contains the "A" allele at the position in parentheses. In some cases, the nucleic acid sequence portion containing SEQ ID NO:5 contains the "G" allele at the position in parentheses. In some cases, the nucleic acid sequence portion containing SEQ ID NO:6 contains the "A" allele at the position in parentheses. In some cases, the portion of the nucleic acid sequence containing SEQ ID NO:6 contains the "G" allele at the position in parentheses. In some cases, the portion of the nucleic acid sequence containing SEQ ID NO:7 contains the "A" allele at the position in parentheses. In some cases, the portion of the nucleic acid sequence containing SEQ ID NO:7 contains the "G" allele at the position in parentheses. In some cases, the portion of the nucleic acid sequence containing SEQ ID NO:8 contains the "A" allele at the position in parentheses. In some cases, the portion of the nucleic acid sequence containing SEQ ID NO:8 contains the "G" allele at the position in parentheses.

[0122] In some embodiments, the method includes determining the presence or absence of the rs911605A genotype in a sample of genetic material from a subject, such as by detecting the presence or absence of SEQ ID NO:5, SEQ ID NO:6, a portion of SEQ ID NO:5, a portion of SEQ ID NO:6, or a combination thereof in the genetic material. In some cases, if the subject contains the rs911605A genotype, an inhibitor of CD30L is administered to the subject. In some cases, if the subject is homozygous for rs911605A, an inhibitor of CD30L is administered to the subject.

[0123] In some embodiments, the method includes determining the presence or absence of the rs911605A genotype in a sample of genetic material from a subject, such as by detecting the presence or absence of a nucleic acid sequence that is at least or about 90% identical to SEQ ID NO:5, at least or about 90% identical to SEQ ID NO:6, at least or about 90% identical to a portion of SEQ ID NO:5, at least or about 90% identical to a portion of SEQ ID NO:6, or a combination thereof. In some cases, if the subject contains the rs911605A genotype, an inhibitor of CD30L is administered to the subject. In some cases, if the subject is homozygous for rs911605A, an inhibitor of CD30L is administered to the subject.

[0124] In some embodiments, the method includes determining the presence or absence of the rs911605A genotype in a sample of genetic material from a subject, such as by detecting the presence or absence of a nucleic acid sequence that is at least or about 95% identical to SEQ ID NO:5, at least or about 95% identical to SEQ ID NO:6, at least or about 95% identical to a portion of SEQ ID NO:5, at least or about 95% identical to a portion of SEQ ID NO:6, or a combination thereof. In some cases, if the subject contains the rs911605A genotype, an inhibitor of CD30L is administered to the subject. In some cases, if the subject is homozygous for rs911605A, an inhibitor of CD30L is administered to the subject.

[0125] In some embodiments, the method includes determining the presence or absence of the rs1006026G genotype in a sample of genetic material from a subject, such as by detecting the presence or absence of SEQ ID NO:7, SEQ ID NO:8, a portion of SEQ ID NO:7, a portion of SEQ ID NO:8, or a combination thereof in the genetic material. In some cases, if the subject contains the rs1006026G genotype, an inhibitor of CD30L is administered to the subject. In some cases, if the subject is homozygous for rs1006026G, an inhibitor of CD30L is administered to the subject.

[0126] In some embodiments, the method includes determining the presence or absence of the rs1006026G genotype in a sample of genetic material from a subject, such as by detecting the presence or absence of a nucleic acid sequence in the genetic material that is at least or about 90% identical to SEQ ID NO:7, at least or about 90% identical to SEQ ID NO:8, at least or about 90% identical to a portion of SEQ ID NO:7, at least or about 90% identical to a portion of SEQ ID NO:8, or a combination thereof. In some cases, if the subject contains the rs1006026G genotype, an inhibitor of CD30L is administered to the subject. In some cases, if the subject is homozygous for rs1006026G, an inhibitor of CD30L is administered to the subject.

[0127] In some embodiments, the method includes determining the presence or absence of the rs1006026G genotype in a sample of genetic material from a subject, such as by detecting the presence or absence of a nucleic acid sequence in the genetic material that is at least or about 95% identical to SEQ ID NO:7, at least or about 95% identical to SEQ ID NO:8, at least or about 95% identical to a portion of SEQ ID NO:7, at least or about 95% identical to a portion of SEQ ID NO:8, or a combination thereof. In some cases, if the subject contains the rs1006026G genotype, an inhibitor of CD30L is administered to the subject. In some cases, if the subject is homozygous for rs1006026G, an inhibitor of CD30L is administered to the subject.

[0128] In some embodiments, the method includes determining the presence or absence of haplotypes rs911605A and rs1006026G in a genetic material sample from a subject, such as by detecting the presence or absence of the following sequences in the genetic material: (a) SEQ ID NO:5, SEQ ID NO:6, a portion of SEQ ID NO:5, a portion of SEQ ID NO:6, or a combination thereof; and (b) SEQ ID NO:7, SEQ ID NO:8, a portion of SEQ ID NO:7, a portion of SEQ ID NO:8, or a combination thereof. In some cases, if the subject contains rs911605A and rs1006026G, an inhibitor of CD30L is administered to the subject. In some cases, if the subject is homozygous for both rs911605A and rs1006026G, an inhibitor of CD30L is administered to the subject.

[0129] In some embodiments, the method includes determining the presence or absence of haplotypes rs911605A and rs1006026G in a genetic material sample from a subject, such as by detecting the presence or absence of the following sequences in the genetic material: (a) a nucleic acid sequence at least or about 90% identical to SEQ ID NO:5, at least or about 90% identical to SEQ ID NO:6, at least or about 90% identical to a portion of SEQ ID NO:5, at least or about 90% identical to a portion of SEQ ID NO:6, or a combination thereof; and (b) a nucleic acid sequence at least or about 90% identical to SEQ ID NO:7, at least or about 90% identical to SEQ ID NO:8, at least or about 90% identical to a portion of SEQ ID NO:7, at least or about 90% identical to a portion of SEQ ID NO:8, or a combination thereof. In some cases, if the subject contains rs911605A and rs1006026G, an inhibitor of CD30L is administered to the subject. In some cases, if a subject is homozygous for both rs911605A and rs1006026G, an inhibitor of CD30L is administered to that subject.

[0130] In some embodiments, the method includes determining the presence or absence of haplotypes rs911605A and rs1006026G in a genetic material sample from a subject, such as by detecting the presence or absence of the following sequences in the genetic material: (a) a nucleic acid sequence at least or about 95% identical to SEQ ID NO:5, at least or about 95% identical to SEQ ID NO:6, at least or about 95% identical to a portion of SEQ ID NO:5, at least or about 95% identical to a portion of SEQ ID NO:6, or a combination thereof; and (b) a nucleic acid sequence at least or about 95% identical to SEQ ID NO:7, at least or about 95% identical to SEQ ID NO:8, at least or about 95% identical to a portion of SEQ ID NO:7, at least or about 95% identical to a portion of SEQ ID NO:8, or a combination thereof. In some cases, if the subject contains rs911605A and rs1006026G, an inhibitor of CD30L is administered to the subject. In some cases, if a subject is homozygous for both rs911605A and rs1006026G, an inhibitor of CD30L is administered to that subject.

[0131] In some cases, methods for detecting genotype include contacting a nucleic acid from a subject sample with a nucleic acid polymer that hybridizes with a region of a target nucleic acid sequence. In some cases, the target nucleic acid sequence is at least about 30, 40, 50, 60, 70, 80, 90, 100, or all of the sequence of SEQ ID NO:1, wherein the target nucleic acid sequence contains the nucleobase at position 501. In some cases, the region of the target nucleic acid sequence contains the nucleobase at position 501 of SEQ ID NO:1. In some cases, the target nucleic acid sequence is at least about 30, 40, 50, 60, 70, 80, 90, 100, or all of the sequence of SEQ ID NO:2, wherein the target nucleic acid sequence contains the nucleobase at position 501. In some cases, the region of the target nucleic acid sequence contains the nucleobase at position 501 of SEQ ID NO:2. In some cases, the target nucleic acid sequence is at least about 30, 40, 50, 60, 70, 80, 90, 100, or all of the sequence of SEQ ID NO:3, wherein the target nucleic acid sequence contains the nucleobase at position 501. In some cases, the region of the target nucleic acid sequence contains the nucleobase at position 501 of SEQ ID NO:3. In some cases, the target nucleic acid sequence is at least about 30, 40, 50, 60, 70, 80, 90, 100, or all of the sequence of SEQ ID NO:4, wherein the target nucleic acid sequence contains the nucleobase at position 501. In some cases, the region of the target nucleic acid sequence contains the nucleobase at position 501 of SEQ ID NO:4. In some cases, the method is a multiplex assay in which two or more target nucleic acid sequences are detected. As an example, the method includes detecting a target nucleic acid sequence containing the nucleobase at position 501 of SEQ ID NO:1 and a target nucleic acid sequence containing the nucleobase at position 501 of SEQ ID NO:3. As another example, the method includes detecting a target nucleic acid sequence containing nucleosides at position 501 of SEQ ID NO:2 and a target nucleic acid sequence containing nucleosides at position 501 of SEQ ID NO:4.

[0132] The nucleic acid polymer may comprise oligonucleotides of at least or about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100 or more nucleotides, sufficient to specifically hybridize with the target nucleic acid described herein. In some cases, the nucleic acid polymer comprises about 10 to about 100 nucleotides, about 10 to about 75 nucleotides, about 10 to about 50 nucleotides, about 15 to about 100 nucleotides, about 15 to about 75 nucleotides, about 15 to about 50 nucleotides, about 20 to about 100 nucleotides, about 20 to about 75 nucleotides, about 20 to about 50 nucleotides, about 25 to about 100 nucleotides, about 25 to about 75 nucleotides, or about 25 to about 50 nucleotides. In some cases, the nucleic acid polymer hybridizes with a region of the target nucleic acid sequence of at least one of SEQ ID NO: 1-8. In some cases, the nucleic acid polymer hybridizes with the target nucleic acid sequence containing SEQ ID NO:1. In some cases, the nucleic acid polymer hybridizes with the target nucleic acid sequence containing SEQ ID NO:2. In some cases, the nucleic acid polymer hybridizes with the target nucleic acid sequence containing SEQ ID NO:3. In some cases, the nucleic acid polymer hybridizes with the target nucleic acid sequence containing SEQ ID NO:4. In some cases, the nucleic acid polymer hybridizes with the target nucleic acid sequence containing SEQ ID NO:5. In some cases, the nucleic acid polymer hybridizes with the target nucleic acid sequence containing SEQ ID NO:6. In some cases, the nucleic acid polymer hybridizes with the target nucleic acid sequence containing SEQ ID NO:7. In some cases, the nucleic acid polymer hybridizes with the target nucleic acid sequence containing SEQ ID NO:8. Hybridization can be performed in standard PCR buffer at standard hybridization temperatures, for example, from about 35°C to about 65°C.

[0133] Further, primers for amplifying the target nucleic acids described herein are provided. For example, for amplification assays such as qPCR. In some cases, the primers hybridize with at least a portion of one of SEQ ID NO:1-8. In some cases, a forward primer hybridizing with at least about 10 consecutive bases of SEQ ID NO:1 and a reverse primer hybridizing with at least 10 consecutive bases of SEQ ID NO:1 are provided, such that the forward and reverse primers are located flanking nucleotide position 501 in SEQ ID NO:1. In some cases, a forward primer hybridizing with at least about 10 consecutive bases of SEQ ID NO:2 and a reverse primer hybridizing with at least 10 consecutive bases of SEQ ID NO:2 are provided, such that the forward and reverse primers are located flanking nucleotide position 501 in SEQ ID NO:2. In some cases, a forward primer for hybridizing with at least about 10 consecutive bases of SEQ ID NO:3 and a reverse primer for hybridizing with at least 10 consecutive bases of SEQ ID NO:3 are provided, such that the forward and reverse primers are located flanking position 501 of SEQ ID NO:3. In some cases, a forward primer for hybridizing with at least about 10 consecutive bases of SEQ ID NO:4 and a reverse primer for hybridizing with at least 10 consecutive bases of SEQ ID NO:4 are provided, such that the forward and reverse primers are located flanking position 501 of SEQ ID NO:4.

[0134] In some cases, a forward primer comprising SEQ ID NO:9 is provided. In some cases, a forward primer having at least about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:9 is provided. In some cases, a reverse primer comprising SEQ ID NO:10 is provided. In some cases, a reverse primer having at least about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:10 is provided. In some cases, a primer pair comprising a forward primer comprising SEQ ID NO:9 and a reverse primer comprising SEQ ID NO:10 is provided. In some cases, a primer pair is provided comprising a forward primer having at least about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:9, and a reverse primer having at least about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:10.

[0135] In some cases, a forward primer comprising SEQ ID NO:11 is provided. In some cases, a forward primer having at least about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:11 is provided. In some cases, a reverse primer comprising SEQ ID NO:12 is provided. In some cases, a reverse primer having at least about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:12 is provided. In some cases, a primer pair comprising a forward primer comprising SEQ ID NO:11 and a reverse primer comprising SEQ ID NO:12 is provided. In some cases, a primer pair is provided comprising a forward primer having at least about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:11, and a reverse primer having at least about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:12.

[0136] Further, probe or reporter sequences that hybridize with the target nucleic acids described herein are provided. Target nucleic acids rs911605 and / or rs1006026 are provided as non-limiting examples. In some cases, the probe is a reporter molecule comprising a dye label at one end and a quencher at the other. When the probe hybridizes with the target nucleic acid, an added DNA polymerase cleaves those hybridized probes, separating the reporter dye from the quencher, thereby increasing the fluorescence emitted by the reporter molecule. In some cases, probes comprising the nucleic acid polymer sequences described above are provided. These probes can be used to detect and / or quantify the presence of the target nucleic acid in a given sample.

[0137] In some cases, a probe comprising SEQ ID NO:13 is provided. In some cases, a probe having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:13 is provided. In some cases, a probe comprising SEQ ID NO:14 is provided. In some cases, a probe having at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:14 is provided. In some cases, a probe comprising SEQ ID NO:15 is provided. In some cases, a probe is provided that has at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:15. In some cases, a probe comprising SEQ ID NO:16 is provided. In some cases, a probe is provided that has at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:16.

[0138] Examples of molecules used as probes include, but are not limited to, RNA and DNA. In some embodiments, the term "probe" in relation to nucleic acids refers to any molecule capable of selectively binding to a specific target nucleic acid sequence. In some cases, probes are specifically designed to be labeled, for example, with radioactive labels, fluorescent labels, enzymes, chemiluminescent labels, colorimetric labels, or other labels or tags known in the art. In some cases, the fluorescent label contains a fluorophore. In some cases, the fluorophore is an aromatic or heteroaromatic compound. In some cases, the fluorophore is pyrene, anthracene, naphthalene, acridine, zirconia, benzoxazole, indole, benzoindole, oxazole, thiazole, benzothiazole, canine, carbonyl cyanine, salicylates, anthranilates, xanthan dyes, and coumarin. Exemplary xanthan dyes include, for example, fluorescein and rhodamine dyes. Fluorescein and rhodamine dyes include, but are not limited to, 6-carboxyfluorescein (FAM), 2′7′-dimethoxy-4′5′-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N;N′-tetramethyl-6-carboxyrhodamine (TAMRA), and 6-carboxy-X-rhodamine (ROX). Suitable fluorescent probes also include naphthylamine dyes having an amino group at the α or β position. For example, naphthylamine compounds include 1-dimethylaminonaphthyl-5-sulfonate, 1-anilino-8-naphthalenesulfonate, and 2-p-toluidine-6-naphthalenesulfonate, and 5-(2'-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS). Exemplary coumarins include, for example, 3-phenyl-7-isocyanate coumarin; acridines, such as 9-isothiocyanate acridine and acridine orange; N-(p-(2-benzoxazolyl)phenyl)maleimide; anthocyanins, such as indole dicarbonyl cyanine 3 (Cy3), indole dicarbonyl cyanine 5 (Cy5), indole dicarbonyl cyanine 5.5 (Cy5.5), and 3-(-carboxy-pentyl)-3'-ethyl-5,5'-dimethyloxacarbonyl cyanine (CyA); 1H,5H,11H,15H-oxanthro[2,3,4-ij:5,6,7-i'j']diquinazine-18-onium,9-[2(or 4)-[[[6-[2,5-dioxo-1-pyrrolyl)oxy]-6-oxohexyl]amino]sulfonyl]-4(or 2)-sulfophenyl]-2,3,6,7,12,13,16,17-octahydro-inner salt (TR or Texas Red); or BODIPY™ dye. In some cases, the probe contains FAM as a dye label.

[0139] In some cases, the primers and / or probes described herein for detecting the target nucleic acid are used in the amplification reaction. In some cases, this amplification reaction is qPCR. An exemplary qPCR is performed using TaqMan. TM The method of measurement.

[0140] In some cases, qPCR involves the use of intercalation dyes. Examples of intercalation dyes include SYBR Green I, SYBR Green II, SYBR Gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View, or phycoerythrin. In some cases, the intercalation dye is SYBR.

[0141] In some cases, the number of amplification cycles used to detect the target nucleic acid in the amplification assay is approximately 5 to approximately 30 cycles. In some cases, the number of amplification cycles used to detect the target nucleic acid is at least approximately 5 cycles. In some cases, the number of amplification cycles used to detect the target nucleic acid is at most approximately 30 cycles. In some cases, the number of amplification cycles used to detect the target nucleic acid is approximately 5 to approximately 10, approximately 5 to approximately 15, approximately 5 to approximately 20, approximately 5 to approximately 25, approximately 5 to approximately 30, approximately 10 to approximately 15, approximately 10 to approximately 20, approximately 10 to approximately 25, approximately 10 to approximately 30, approximately 15 to approximately 20, approximately 15 to approximately 25, approximately 15 to approximately 30, approximately 20 to approximately 25, approximately 20 to approximately 30, or approximately 25 to approximately 30 cycles.

[0142] In one aspect, the methods provided herein for determining the presence, absence, and / or quantity of nucleic acid sequences from a specific genotype include amplification reactions such as qPCR. In exemplary methods, genetic material is obtained from a sample of a subject, such as a blood or serum sample. In some embodiments of nucleic acid extraction, nucleic acids are extracted using any technique that does not interfere with subsequent analysis. In some embodiments, the technique employs alcohol precipitation using ethanol, methanol, or isopropanol. In some embodiments, the technique uses phenol, chloroform, or any combination thereof. In some embodiments, the technique uses cesium chloride. In some embodiments, the technique uses sodium acetate, potassium acetate, or ammonium acetate, or any other salt commonly used to precipitate DNA. In some embodiments, the technique utilizes a column- or resin-based nucleic acid purification protocol, such as those commonly commercially available; a non-limiting example is the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In some embodiments, after extraction and before subsequent analysis, the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer. In exemplary embodiments, the nucleic acid material is extracted in water. In some cases, extraction does not include nucleic acid purification.

[0143] In an exemplary qPCR assay, a nucleic acid sample is combined with primers and probes specific to target nucleic acids that may or may not be present in the sample, along with DNA polymerase. The amplification reaction is performed using a thermal cycler that heats and cools the sample to amplify the nucleic acid, and the sample is irradiated at a specific wavelength to excite fluorophores on the probes and detect the emitted fluorescence. For TaqMan... TMThe method involves a probe that is a hydrolyzable probe containing a fluorophore and a quencher, which is hydrolyzed by DNA polymerase upon hybridization with a target nucleic acid. In some cases, the presence of the target nucleic acid is determined when the number of amplification cycles required to reach a threshold is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles. In some cases, the target nucleic acid contains SEQ ID NO:5, and its presence indicates the rs911605A genotype. In some cases, the target nucleic acid contains SEQ ID NO:6, and its presence indicates the rs911605A genotype. In some cases, the target nucleic acid contains SEQ ID NO:7, and its presence indicates the rs1006026G genotype. In some cases, the target nucleic acid contains SEQ ID NO:8, and its presence indicates the rs1006026G genotype. The primers and probes used in this assay may include any combination of primers and probes described herein. This allows for multiple determinations, in which the rs911605A and rs1006026G unit types are detectable.

[0144] Methods for detecting and quantifying soluble CD30

[0145] The aspects provided herein include methods for analyzing CD30 protein levels in a subject by detecting and quantifying CD30 protein levels from samples taken from the subject. Non-limiting examples of sample materials include serum, plasma, and / or whole blood. CD30 can be detected using antibody-based assays, wherein anti-CD30 antibodies are used. For antibody-based detection methods, anti-CD30 antibodies can bind to any region of CD30. In some cases, anti-CD30 antibodies bind to a CD30 protein region having the sequence of SEQ ID NO:17 or SEQ ID NO:18, or any isotype encoding the CD30 protein (e.g., P28908). In some cases, anti-CD30 antibodies bind to a CD30 protein region having a sequence that is at least or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of SEQ ID NO:17. Exemplary analytical methods include performing an enzyme-linked immunosorbent assay (ELISA). The ELISA assay can be a sandwich ELISA or a direct ELISA. Other exemplary assays include immunohistochemistry and lateral flow analysis.

[0146] In some cases, CD30 protein can be detected by detecting the binding between CD30 and CD30L. Analytical methods for the binding between CD30 and CD30L include in vivo, in vitro, or ex vivo assays. In some cases, this assay may include co-immunoprecipitation (co-IP), pull-down assays, cross-linked protein-protein interaction assays, labeled transfer protein-protein interaction assays, or Far-Western blot analysis, FRET-based assays including, for example, FRET-FLIM, yeast two-hybrid assays, BiFC, or luciferase resolving assays.

[0147] Methods for characterizing a disease or condition or its subtype

[0148] This document discloses methods for characterizing a disease or condition, or a subtype or symptom of a disease or condition, in a subject. In some cases, the disease or condition is at least one of an inflammatory disease, a fibrotic stricture disease, and a fibrotic disease. In some cases, the inflammatory disease is Crohn's disease (CD). In some cases, the inflammatory disease is ulcerative colitis (UC). In some cases, the inflammatory disease is systemic lupus erythematosus (SLE). In some cases, the inflammatory disease is rheumatoid arthritis (RA). In some cases, the fibrotic disease is primary sclerosing cholangitis (PSC). The subject may be diagnosed with a disease or condition, and the embodiments disclosed herein provide methods for characterizing the disease or condition as a severe form of the disease or condition (e.g., a refractory disease). In some cases, the severe form of the disease is characterized by the presence or predisposition to develop a subclinical phenotype of the disease or condition, such as perianal disease (e.g., pCD), stricture disease, penetrating disease, stricture and penetrating disease, ileal disease, and ileocolonic disease.

[0149] The aspects disclosed herein provide a method for characterizing a disease or condition or a subtype of such disease or condition, comprising: (a) performing a assay on a sample obtained from a subject, configured to detect the presence, absence, or level of a genotype; and (b) characterizing the disease as a severe form of the disease or condition if the presence or level of the genotype is detected in the sample obtained from the subject. In some cases, the genotype comprises at least one polymorphism selected from Tables 1-14. In some cases, the genotype comprises the rs911605A genotype (e.g., containing an “A” allele at position 501 of rs911605). In some cases, the genotype is a haplotype comprising the rs911605A genotype (e.g., containing an “A” allele at position 501 of rs911605) and the rs1006026G genotype (e.g., containing a “G” allele at position 501 of rs10060026), which is detected in a sample obtained from a subject. In some cases, the genotype includes the rs1006026G genotype (e.g., containing a “G” allele at position 501 of rs1006026). In some cases, the subtype of the disease or condition includes subclinical phenotypes selected from non-stenotic diseases, stenotic diseases, stenotic and penetrating diseases, perianal Crohn's disease (pCD), defects in Panette cells, PSC, and blood clot formation (e.g., thrombosis). In some cases, a therapeutic agent is administered to the subject if the presence of the genotype is detected in a sample obtained from the subject. In some cases, the therapeutic agent is an inhibitor of CD30 ligand, TL1A, or a combination thereof. In some cases, the genotype is detected in a sample obtained from the subject using methods described herein, such as genotyping devices (e.g., qPCR, sequencers, microarrays, etc.).

[0150] Diagnostic and prognostic methods

[0151] This document discloses methods for diagnosing or determining a subject's susceptibility to developing a disease or condition, or a subtype or symptom of such a disease or condition (e.g., providing its prognosis). In some cases, the disease or condition is at least one of an inflammatory disease, a fibrotic stenotic disease, and a fibrotic disease. In some cases, the inflammatory disease is Crohn's disease (CD). In some cases, the inflammatory disease is ulcerative colitis (UC). In some cases, the inflammatory disease is systemic lupus erythematosus (SLE). In some cases, the inflammatory disease is rheumatoid arthritis (RA). In some cases, the fibrotic disease is primary sclerosing cholangitis (PSC). Subjects may be diagnosed with a disease or condition, and the embodiments disclosed herein provide methods for characterizing the disease or condition as a severe form of the disease or condition (e.g., a refractory disease). In some cases, a severe form of the disease is characterized by the presence or predisposition to develop a subclinical phenotype of the disease or condition, such as perianal diseases (e.g., pCD), stenotic diseases, penetrating diseases, both stenotic and penetrating diseases, ileal diseases, and ileocolonic diseases.

[0152] The aspects disclosed herein provide a method for diagnosing a disease or condition, or a subtype of such disease or condition, in a subject, comprising: (a) performing a determination on a sample obtained from the subject configured to detect the presence, absence, or level of a genotype; and (b) diagnosing the disease as a severe form of the disease or condition if the presence or level of the genotype is detected in a sample obtained from the subject.

[0153] This article also provides a method for determining a subject’s susceptibility to developing a disease or condition or a subtype of such disease or condition, the method comprising: (a) performing a assay on a sample obtained from the subject configured to detect the presence, absence or level of a genotype; and (b) if the presence or level of the genotype is detected in a sample obtained from the subject, determining that the subject is at risk of developing the disease or condition or a subtype of such disease or condition.

[0154] In some cases, the genotype contains at least one polymorphism selected from Tables 1-14. In some cases, the genotype includes the rs911605A genotype (e.g., containing an "A" allele at position 501 of rs911605). In some cases, the genotype is a haplotype containing both the rs911605A genotype (e.g., containing an "A" allele at position 501 of rs911605) and the rs1006026G genotype (e.g., containing a "G" allele at position 501 of rs10060026), which was detected in samples obtained from the subject. In some cases, the genotype includes the rs1006026G genotype (e.g., containing a "G" allele at position 501 of rs1006026). In some cases, the subtype of the disease or condition includes subclinical phenotypes selected from non-stenotic diseases, stenotic diseases, stenotic and penetrating diseases, perianal Crohn's disease (pCD), defects in Panette cells, PSC, and blood clot formation (e.g., thrombosis). In some cases, the presence of the genotype indicates an increased level of CD30 ligand in the subject compared to individuals who do not carry the genotype. In some cases, if the presence of the genotype is detected in a sample obtained from the subject, a therapeutic agent is administered to the subject. In some cases, the therapeutic agent is an inhibitor of CD30 ligand, TL1A, or a combination thereof. In some cases, the genotype is detected in a sample obtained from the subject using methods described herein, such as genotyping devices (e.g., qPCR, sequencers, microarrays, etc.).

[0155] Treatment

[0156] This article further provides methods for treating the subject's disease or condition. In some cases, the disease or condition is at least one of an inflammatory disease, a fibrotic stricture disease, and a fibrotic disease. In some cases, the inflammatory disease is Crohn's disease (CD). In some cases, the inflammatory disease is ulcerative colitis (UC). In some cases, the inflammatory disease is systemic lupus erythematosus (SLE). In some cases, the inflammatory disease is rheumatoid arthritis (RA). In some cases, the fibrotic disease is primary sclerosing cholangitis (PSC).

[0157] This document discloses a method for treating a subject with the disease or condition disclosed herein by administering a CD30L inhibitor if a genotype disclosed herein is detected in a sample obtained from a subject. The genotype can be any of the genotypes described in the embodiments provided in this disclosure, including but not limited to any one or combination of polymorphisms from Tables 1-14. In some cases, the genotype includes the rs911605A genotype (e.g., containing an “A” allele at position 501 of rs911605). In some cases, this document discloses a method for treating a subject with the disease or condition disclosed herein by administering a CD30L inhibitor if a haplotype containing both the rs911605A genotype (e.g., containing an “A” allele at position 501 of rs911605) and the rs1006026G genotype (e.g., containing a “G” allele at position 501 of rs10060026) is detected in a sample obtained from a subject. In some cases, the detection methods disclosed herein are used to detect genotypes in samples obtained from subjects.

[0158] This document discloses methods for monitoring the progression of treatment in subjects with CD30L inhibitors. In some cases, monitoring includes quantifying the levels of soluble CD30 or CD30L in samples from the subject before and after administration of the CD30L inhibitor. This document also discloses methods for optimizing subject treatment, which include determining the amount of CD30 and / or CD30L in samples from treated subjects and modifying, discontinuing, or continuing treatment based on that amount.

[0159] CD30L inhibitors

[0160] In some cases, the treatment comprises administering to an individual a therapeutic agent containing a CD30L inhibitor. In some embodiments, the CD30L inhibitor specifically binds directly or indirectly to CD30L, CD30, or molecules that directly or indirectly interfere with the binding between CD30L and CD30. In some embodiments, as used herein, the CD30L inhibitor comprises an agent that modulates at least one functional activity of CD30L (e.g., binding to CD30). Non-limiting examples of CD30L inhibitors include agents that specifically bind to CD30L, including peptides such as anti-CD30L antibodies or antigen-binding fragments thereof, and nucleic acids such as antisense constructs, siRNA, and ribozymes. Antisense constructs include expression plasmids that, when transcribed in cells, produce RNA complementary to a portion of the mRNA encoding CD30L, and oligonucleotides that inhibit protein expression by hybridizing with CD30L mRNA. In some embodiments, the CD30L inhibitor comprises a non-peptide or non-nucleic acid moiety as an active agent that binds to and inhibits CD30L activity.

[0161] In some embodiments, the inhibitor of CD30L is a polypeptide that binds to CD30L and / or CD30. In some cases, the polypeptide is a CD30 polypeptide or a portion thereof, wherein the portion retains the ability to bind to CD30L. The portion of the CD30 polypeptide contains at least about 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids having at least about 85%, 90%, or 95% identity with human CD30 having SEQ ID NO:17 or SEQ ID NO:18. For example, the inhibitor of CD30L contains a CD30 polypeptide containing all or part of the extracellular region of human CD30. In some embodiments, the CD30 polypeptide contains amino acids 19-390 of SEQ ID NO:18 or a binding fragment thereof, which has at least about 85%, 90%, or 95% sequence identity with CD30. In some embodiments, the CD30 polypeptide is a homolog of mammalian CD30; for example, the CD30 polypeptide inhibitor of CD30L is a viral CD30 polypeptide or a fragment thereof. As a non-limiting example, the viral CD30 peptide contains viral CD30 derived from poxviruses such as mousepoxvirus or cowpoxvirus.

[0162] In a non-limiting example, the inhibitor is an anti-CD30L antibody or an anti-CD30 antibody. As used herein, the antibody comprises an antigen-binding fragment of a full-length antibody, such as Fab or scFv. In some embodiments, the antibody binds to the extracellular domain of CD30L. In some embodiments, the anti-CD30L antibody comprises a heavy chain containing the three complementarity-determining regions HCDR1, HCDR2, and HCDR3; and a light chain containing the three complementarity-determining regions LCDR1, LCDR2, and LCDR3. In some embodiments, the anti-CD30L antibody comprises HCDR1 containing SEQ ID NO:100, HCDR2 containing SEQ ID NO:101, HCDR3 containing SEQ ID NO:102, LCDR1 containing SEQ ID NO:103, LCDR2 containing SEQ ID NO:104, and LCDR3 containing SEQ ID NO:105.

[0163] In some embodiments, the anti-CD30L antibody comprises HCDR1 containing SEQ ID NO:106, HCDR2 containing SEQ ID NO:107, HCDR3 containing SEQ ID NO:108, LCDR1 containing SEQ ID NO:109, LCDR2 containing SEQ ID NO:110, and LCDR3 containing SEQ ID NO:111.

[0164] In some embodiments, the anti-CD30L antibody comprises HCDR1 containing SEQ ID NO:112, HCDR2 containing SEQ ID NO:113, HCDR3 containing SEQ ID NO:114, LCDR1 containing SEQ ID NO:115, LCDR2 containing SEQ ID NO:116, and LCDR3 containing SEQ ID NO:117.

[0165] In some embodiments, the anti-CD30L antibody comprises HCDR1 containing SEQ ID NO:118, HCDR2 containing SEQ ID NO:119, HCDR3 containing SEQ ID NO:120, LCDR1 containing SEQ ID NO:121, LCDR2 containing SEQ ID NO:122, and LCDR3 containing SEQ ID NO:123.

[0166] In some embodiments, the anti-CD30L antibody comprises HCDR1 containing SEQ ID NO:124, HCDR2 containing SEQ ID NO:125, HCDR3 containing SEQ ID NO:126, LCDR1 containing SEQ ID NO:127, LCDR2 containing SEQ ID NO:128, and LCDR3 containing SEQ ID NO:129.

[0167] In some embodiments, the anti-CD30L antibody comprises HCDR1 containing SEQ ID NO:130, HCDR2 containing SEQ ID NO:131, HCDR3 containing SEQ ID NO:132, LCDR1 containing SEQ ID NO:133, LCDR2 containing SEQ ID NO:134, and LCDR3 containing SEQ ID NO:135.

[0168] In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:136 and a light chain (LC) variable domain containing SEQ ID NO:137. In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:138 and a light chain (LC) variable domain containing SEQ ID NO:139. In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:140 and a light chain (LC) variable domain containing SEQ ID NO:141. In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:142 and a light chain (LC) variable domain containing SEQ ID NO:143. In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:144 and a light chain (LC) variable domain containing SEQ ID NO:145. In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:146 and a light chain (LC) variable domain containing SEQ ID NO:154. In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:147 and a light chain (LC) variable domain containing SEQ ID NO:154. In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:148 and a light chain (LC) variable domain containing SEQ ID NO:154. In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:149 and a light chain (LC) variable domain containing SEQ ID NO:154. In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:150 and a light chain (LC) variable domain containing SEQ ID NO:154. In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain of SEQ ID NO:151 and a light chain (LC) variable domain of SEQ ID NO:154. In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain of SEQ ID NO:152 and a light chain (LC) variable domain of SEQ ID NO:154. In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain of SEQ ID NO:153 and a light chain (LC) variable domain of SEQ ID NO:154.

[0169] In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region containing SEQ ID NO:19 and a light chain variable region containing SEQ ID NO:20. Non-limiting examples of anti-CD30 antibodies include MDX-60, Ber-H2, SGN-30(cAC10), Ki-4.dgA, HRS-3 / A9, AFM13, and H22xKi-4.

[0170] In some embodiments, the CD30L conjugate comprises an anti-CD30L antibody containing at least one amino acid and a conjugate moiety binding to said at least one amino acid. In some embodiments, said at least one amino acid is located proximal to the N-terminus (e.g., proximal to an N-terminal residue). For example, said at least one amino acid is optionally located within 10, 20, 30, 40, or 50 residues from the N-terminus. In some cases, said at least one amino acid is located at the N-terminus (i.e., said at least one amino acid is an N-terminal residue of the CD30L polypeptide). In other embodiments, said at least one amino acid is located proximal to the C-terminus (e.g., proximal to a C-terminal residue). For example, said at least one amino acid is optionally located within 10, 20, 30, 40, or 50 residues from the C-terminus. In some cases, said at least one amino acid is located at the C-terminus (i.e., said at least one amino acid is a C-terminal residue of the CD30L polypeptide). In some cases, the CD30L conjugate has an enhanced plasma half-life, such as the half-life described herein. In some embodiments, the CD30L conjugate has functional activity (e.g., retained activity). In some embodiments, the CD30L conjugate is non-functional (e.g., lacks activity). In some embodiments, the conjugate moiety comprises a polymer containing polyethylene glycol (PEG). In some embodiments, the conjugate moiety is a pharmaceutical agent, such as other therapeutic agents disclosed herein. In some embodiments, the anti-CD30 antibody comprises an antibody-pharmaceutical conjugate. As a non-limiting example, the antibody-pharmaceutical conjugate is brentuximab, an anti-CD30 antibody conjugated to monomethylaurestatin E.

[0171] Other treatments

[0172] Treatments that can be used with the methods described herein include therapeutic agents that can be used alone or in combination with a CD30L inhibitor. In some embodiments, treatment includes administration of a first therapeutic agent followed by administration of a CD30L inhibitor. In some embodiments, treatment includes administration of both a first therapeutic agent and a CD30L inhibitor together. In some embodiments, treatment includes administration of a CD30L inhibitor followed by administration of a first therapeutic agent. Combination therapies can be administered on the same day, or can be administered one or more days, weeks, months, or years apart. In some cases, a CD30L inhibitor is administered if it is determined that the subject is unresponsive to first-line therapy such as a TNF inhibitor and / or steroids. Such determination can be made by treating with first-line therapy and monitoring the disease status and / or diagnosis to determine that the subject will be unresponsive to the first-line therapy.

[0173] In some embodiments, the therapeutic agent includes an anti-TNF therapy, such as anti-TNFα therapy. In some embodiments, the therapeutic agent includes second-line treatment with an anti-TNF therapy. In some embodiments, the therapeutic agent includes an immunosuppressant or a class of drugs that suppress or reduce the strength of the immune system. In some embodiments, the immunosuppressant is an antibody. Non-limiting examples of immunosuppressive therapeutic agents include... (ustekinumab), azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate, cyclosporine A (CsA).

[0174] In some embodiments, the therapeutic agent comprises a selective anti-inflammatory drug or a class of drugs that specifically target pro-inflammatory molecules in the body. In some embodiments, the anti-inflammatory drug comprises an antibody. In some embodiments, the anti-inflammatory drug comprises a small molecule. Non-limiting examples of anti-inflammatory drugs include ENTYVIO (vedolizumab), corticosteroids, aminosalicylates, mesalazine, balsalazine (Colazal), and olsalazine (Dipentum).

[0175] In some embodiments, the therapeutic agent includes stem cell therapy. This stem cell therapy can be embryonic stem cells or somatic stem cells. The stem cells can be isolated from a donor (allogeneic) or from a subject (autologous). The stem cells can be expanded adipose-derived stem cells (eASC), hematopoietic stem cells (HSC), mesenchymal stem (stromal) cells (MSC), or induced pluripotent stem cells (iPSC) derived from the subject's cells. In some embodiments, the therapeutic agent includes... (darvadstrocel).

[0176] In some embodiments, the therapeutic agent comprises a small molecule. This small molecule can be used to treat inflammatory diseases or conditions, or fibrotic or stenotic diseases. Non-limiting examples of small molecules include... (apremilast), alicaforsen, or ozanimod (RPC-1063).

[0177] In some embodiments, the therapeutic agents include agonists of mitogen-activated protein kinase kinase 4 (MAP4K4), prostaglandin E receptor 4 (PTGER4), and interleukin-18 receptor 1 (IL18R1); gene expression products of genes associated with the pathogenesis of inflammatory, fibrotic, or fibrous stenosis diseases; phosphofructosyl-6-phosphate 2-kinase / fructose 2,6-bisphosphatase 3 (PFKFB3); interleukin-18 receptor accessory protein (IL18RAP); adenylate cyclase 7 (ADCY7); B lymphoid tyrosine kinase (BLK); G protein-coupled receptor 65 (GPR65); protein 2 containing the Sprouty-associated EVH1 domain (SPRED2); Src kinase-associated phosphoprotein 2 (SKAP2); receptor-interacting serine / threonine kinase 2 (RIPK2); TNF ligand superfamily member 15 (TL1A); Janus kinase 1 (JAK1); G protein-coupled receptor 35 (GPR35); Gasdermin B (GSDMB); and gene expression products of genes associated with the pathogenesis of inflammatory, fibrotic, or fibrotic stenotic diseases. The therapeutic agent may be an allosteric modulator of MAP4K4, PTGER4, IL18R1, PFKFB3, IL18RAP, ADCY7, GPR65, SPRED2, SKAP2, RIPK2, TL1A, JAK1, GPR35, and GSDMB, as well as the gene expression products of genes involved in the pathogenesis of inflammatory, fibrotic, or fibrotic stenotic diseases.

[0178] In some implementations, the therapeutic agent includes an antagonist. The antagonist may include inhibitors of the activity or expression of MAP4K4, PTGER4, IL18R1, PFKFB3, IL18RAP, ADCY7, GPR65, SPRED2, SKAP2, RIPK2, TL1A, JAK1, GPR35, and GSDMB, as well as gene expression products of genes associated with the pathogenesis of inflammatory, fibrotic, or fibrotic stenotic diseases. Non-limiting examples of JAK1 inhibitors include ruxolitinib (INCB018424), S-ruxolitinib (INCB018424), baricitinib (FY3009104, INCB028050), filgotinib (GFPG0634), momotelotin (CYT387), cerdulatinib (PRT062070, PRT2070), LY2784544, NVP-BSK805, 2HC1, tofacitinib (CP-690550, Tasocitinib), XF019, Pacntimb (SB1518), or ZM 39923HC1.

[0179] In some embodiments, additional therapeutic agents include inhibitors of TL1A expression or activity. In some cases, inhibitors of TL1A expression or activity effectively inhibit TL1A-DR3 binding. In some embodiments, inhibitors of TL1A expression or activity include allosteric modulators of TL1A. Allosteric modulators of TL1A can indirectly affect the effect of TL1A on DR3, or the effect of TR6 / DcR3 on TL1A or DR3. Inhibitors of TL1A expression or activity can be direct or indirect inhibitors. Non-limiting examples of TL1A expression inhibitors include TL1A translation inhibitors from RNA to protein, antisense oligonucleotides (such as miRNA or siRNA) targeting TNFSF15 mRNA, and epigenetic editing (such as targeting the DNA-binding domain of TNFSF15, or histone tails and / or post-translational modifications of DNA molecules). Non-limiting examples of TL1A activity inhibitors include TL1A receptor (DR3 and TR6 / DcR3) antagonists, TL1A antigen antagonists, and antagonists of gene expression products associated with TL1A-mediated diseases. The antagonists disclosed herein may include, but are not limited to, anti-TL1A antibodies, anti-TL1A binding antibody fragments, or small molecules. The small molecule may be a small molecule that binds to TL1A or DR3. The anti-TL1A antibody may be monoclonal or polyclonal. The anti-TL1A antibody may be humanized or chimeric. The anti-TL1A antibody may be a fusion protein. The anti-TL1A antibody may be a blocking anti-TL1A antibody. Blocking antibodies block the binding between two proteins, such as a ligand and its receptor. Therefore, TL1A blocking antibodies include antibodies that prevent TL1A from binding to DR3 or TR6 / DcR3 receptors. In a non-limiting example, the TL1A blocking antibody binds to DR3. In another example, the TL1A blocking antibody binds to DcR3. In some cases, the TL1A antibody is an anti-TL1A antibody that specifically binds to TL1A.

[0180] The anti-TL1A antibody may comprise one or more antibody sequences from Tables 16 and / or 17. The anti-DR3 antibody may comprise an amino acid sequence that is at least 85% identical to any one of SEQ ID NO:200258-200270 and at least 85% identical to any one of SEQ ID NO:200271-200275. The anti-DR3 antibody may comprise amino acid sequences constituting the HCDR1, HCDR2, and HCDR3 domains of any one of SEQ ID NO:200258-200270 and the LCDR1, LCDR2, and LCDR3 domains of any one of SEQ ID NO:200271-200275.

[0181] In some embodiments, the anti-TL1A antibody comprises a heavy chain containing the three complementarity-determining regions HCDR1, HCDR2, and HCDR3; and a light chain containing the three complementarity-determining regions LCDR1, LCDR2, and LCDR3. In some embodiments, the anti-TL1A antibody comprises HCDR1 (SEQ ID NO: 200109), HCDR2 (SEQ ID NO: 200110), HCDR3 (SEQ ID NO: 200111), LCDR1 (SEQ ID NO: 200112), LCDR2 (SEQ ID NO: 200113), and LCDR3 (SEQ ID NO: 200114). In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain (SEQ ID NO: 200115) and a light chain (LC) variable domain (SEQ ID NO: 200116).

[0182] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200117, HCDR2 containing SEQ ID NO:200118, HCDR3 containing SEQ ID NO:200119, LCDR1 containing SEQ ID NO:200120, LCDR2 containing SEQ ID NO:200121, and LCDR3 containing SEQ ID NO:200122. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200123 and a light chain (LC) variable domain containing SEQ ID NO:200124.

[0183] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200125, HCDR2 containing SEQ ID NO:200126, HCDR3 containing SEQ ID NO:200127, LCDR1 containing SEQ ID NO:200128, LCDR2 containing SEQ ID NO:200129, and LCDR3 containing SEQ ID NO:200130. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200131 and a light chain (LC) variable domain containing SEQ ID NO:200132.

[0184] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200133, HCDR2 containing SEQ ID NO:200134, HCDR3 containing SEQ ID NO:200135, LCDR1 containing SEQ ID NO:200139, LCDR2 containing SEQ ID NO:200140, and LCDR3 containing SEQ ID NO:200141. In some cases, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200136, HCDR2 containing SEQ ID NO:200137, HCDR3 containing SEQ ID NO:200138, LCDR1 containing SEQ ID NO:200139, LCDR2 containing SEQ ID NO:200140, and LCDR3 containing SEQ ID NO:200141. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200142 and a light chain (LC) variable domain containing SEQ ID NO:200143. In some cases, the anti-TL1A antibody contains a heavy chain containing SEQ ID NO:200144. In some cases, the anti-TL1A antibody contains a light chain containing SEQ ID NO:200145.

[0185] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200146, HCDR2 containing SEQ ID NO:200147, HCDR3 containing SEQ ID NO:200148, LCDR1 containing SEQ ID NO:200149, LCDR2 containing SEQ ID NO:200150, and LCDR3 containing SEQ ID NO:200151. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200152 and a light chain (LC) variable domain containing SEQ ID NO:200153.

[0186] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200154, HCDR2 containing SEQ ID NO:200155, HCDR3 containing SEQ ID NO:200156, LCDR1 containing SEQ ID NO:200157, LCDR2 containing SEQ ID NO:200158, and LCDR3 containing SEQ ID NO:200159. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200160 and a light chain (LC) variable domain containing SEQ ID NO:200161.

[0187] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200162, HCDR2 containing SEQ ID NO:200164, HCDR3 containing SEQ ID NO:200165, LCDR1 containing SEQ ID NO:200167, LCDR2 containing SEQ ID NO:200169, and LCDR3 containing SEQ ID NO:200170. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200171 and a light chain (LC) variable domain containing SEQ ID NO:200175. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200171 and a light chain (LC) variable domain containing SEQ ID NO:200176. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200171 and a light chain (LC) variable domain containing SEQ ID NO:200177. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200171 and a light chain (LC) variable domain containing SEQ ID NO:200178.

[0188] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200162, HCDR2 containing SEQ ID NO:200164, HCDR3 containing SEQ ID NO:200165, LCDR1 containing SEQ ID NO:200168, LCDR2 containing SEQ ID NO:200169, and LCDR3 containing SEQ ID NO:200170. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200171 and a light chain (LC) variable domain containing SEQ ID NO:200179. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200171 and a light chain (LC) variable domain containing SEQ ID NO:200180. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200171 and a light chain (LC) variable domain containing SEQ ID NO:200181. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200171 and a light chain (LC) variable domain containing SEQ ID NO:200182.

[0189] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200162, HCDR2 containing SEQ ID NO:200164, HCDR3 containing SEQ ID NO:200165, LCDR1 containing SEQ ID NO:200167, LCDR2 containing SEQ ID NO:200169, and LCDR3 containing SEQ ID NO:200170. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200172 and a light chain (LC) variable domain containing SEQ ID NO:200175. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200172 and a light chain (LC) variable domain containing SEQ ID NO:200176. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200172 and a light chain (LC) variable domain containing SEQ ID NO:200177. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200172 and a light chain (LC) variable domain containing SEQ ID NO:200178.

[0190] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200162, HCDR2 containing SEQ ID NO:200164, HCDR3 containing SEQ ID NO:200165, LCDR1 containing SEQ ID NO:200168, LCDR2 containing SEQ ID NO:200169, and LCDR3 containing SEQ ID NO:200170. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200172 and a light chain (LC) variable domain containing SEQ ID NO:200179. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200172 and a light chain (LC) variable domain containing SEQ ID NO:200180. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200172 and a light chain (LC) variable domain containing SEQ ID NO:200181.

[0191] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200163, HCDR2 containing SEQ ID NO:200164, HCDR3 containing SEQ ID NO:200166, LCDR1 containing SEQ ID NO:200167, LCDR2 containing SEQ ID NO:200169, and LCDR3 containing SEQ ID NO:200170. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200173 and a light chain (LC) variable domain containing SEQ ID NO:200175. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200173 and a light chain (LC) variable domain containing SEQ ID NO:200176. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200173 and a light chain (LC) variable domain of SEQ ID NO:200177. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200173 and a light chain (LC) variable domain of SEQ ID NO:200178. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200173 and a light chain (LC) variable domain of SEQ ID NO:200179. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200173 and a light chain (LC) variable domain of SEQ ID NO:200180. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200173 and a light chain (LC) variable domain containing SEQ ID NO:200181. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200173 and a light chain (LC) variable domain containing SEQ ID NO:200182.

[0192] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200163, HCDR2 containing SEQ ID NO:200164, HCDR3 containing SEQ ID NO:200166, LCDR1 containing SEQ ID NO:200168, LCDR2 containing SEQ ID NO:200169, and LCDR3 containing SEQ ID NO:200170. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200174 and a light chain (LC) variable domain containing SEQ ID NO:200179. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200174 and a light chain (LC) variable domain containing SEQ ID NO:200180. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200174 and a light chain (LC) variable domain of SEQ ID NO:200181. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200174 and a light chain (LC) variable domain of SEQ ID NO:200182. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200174 and a light chain (LC) variable domain of SEQ ID NO:200175. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200174 and a light chain (LC) variable domain of SEQ ID NO:200176. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200174 and a light chain (LC) variable domain containing SEQ ID NO:200177. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200174 and a light chain (LC) variable domain containing SEQ ID NO:200178.

[0193] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200183, HCDR2 containing SEQ ID NO:200184, HCDR3 containing SEQ ID NO:200185, LCDR1 containing SEQ ID NO:200186, LCDR2 containing SEQ ID NO:200187, and LCDR3 containing SEQ ID NO:200188. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200189 and a light chain (LC) variable domain containing SEQ ID NO:200194. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200189 and a light chain (LC) variable domain containing SEQ ID NO:200195. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200189 and a light chain (LC) variable domain of SEQ ID NO:200196. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200189 and a light chain (LC) variable domain of SEQ ID NO:200197. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200190 and a light chain (LC) variable domain of SEQ ID NO:200194. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200190 and a light chain (LC) variable domain of SEQ ID NO:200195. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200190 and a light chain (LC) variable domain of SEQ ID NO:200196. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200190 and a light chain (LC) variable domain of SEQ ID NO:200197. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200191 and a light chain (LC) variable domain of SEQ ID NO:200194. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200191 and a light chain (LC) variable domain of SEQ ID NO:200195. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200191 and a light chain (LC) variable domain containing SEQ ID NO:200196.In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200191 and a light chain (LC) variable domain of SEQ ID NO:200197. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200192 and a light chain (LC) variable domain of SEQ ID NO:200194. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200192 and a light chain (LC) variable domain of SEQ ID NO:200195. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200192 and a light chain (LC) variable domain of SEQ ID NO:200196. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200192 and a light chain (LC) variable domain of SEQ ID NO:200197. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200193 and a light chain (LC) variable domain of SEQ ID NO:200194. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200193 and a light chain (LC) variable domain of SEQ ID NO:200195. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200193 and a light chain (LC) variable domain of SEQ ID NO:200196. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200193 and a light chain (LC) variable domain containing SEQ ID NO:200197.

[0194] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200198, HCDR2 containing SEQ ID NO:200199, HCDR3 containing SEQ ID NO:200200, LCDR1 containing SEQ ID NO:200201, LCDR2 containing SEQ ID NO:200202, and LCDR3 containing SEQ ID NO:200203. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200204 and a light chain (LC) variable domain containing SEQ ID NO:200205. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200206 and a light chain (LC) variable domain containing SEQ ID NO:200207. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200208 and a light chain (LC) variable domain of SEQ ID NO:200209. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200210 and a light chain (LC) variable domain of SEQ ID NO:200211. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200212 and a light chain (LC) variable domain of SEQ ID NO:200213. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200214 and a light chain (LC) variable domain of SEQ ID NO:200215. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200216 and a light chain (LC) variable domain of SEQ ID NO:200217. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200218 and a light chain (LC) variable domain of SEQ ID NO:200219. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200220 and a light chain (LC) variable domain of SEQ ID NO:200221. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain of SEQ ID NO:200222 and a light chain (LC) variable domain of SEQ ID NO:200223. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200224 and a light chain (LC) variable domain containing SEQ ID NO:200225.In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200226 and a light chain (LC) variable domain containing SEQ ID NO:200227.

[0195] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200228, HCDR2 containing SEQ ID NO:200229, HCDR3 containing SEQ ID NO:200230, LCDR1 containing SEQ ID NO:200231, LCDR2 containing SEQ ID NO:200232, and LCDR3 containing SEQ ID NO:200233. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200234 and a light chain (LC) variable domain containing SEQ ID NO:200235.

[0196] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200236, HCDR2 containing SEQ ID NO:200237, HCDR3 containing SEQ ID NO:200238, LCDR1 containing SEQ ID NO:200239, LCDR2 containing SEQ ID NO:200240, and LCDR3 containing SEQ ID NO:200241. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200242 and a light chain (LC) variable domain containing SEQ ID NO:200243.

[0197] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200246, HCDR2 containing SEQ ID NO:200247, HCDR3 containing SEQ ID NO:200248, LCDR1 containing SEQ ID NO:200249, LCDR2 containing SEQ ID NO:200250, and LCDR3 containing SEQ ID NO:200251. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200244 and a light chain (LC) variable domain containing SEQ ID NO:200245. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200252 and a light chain (LC) variable domain containing SEQ ID NO:200253. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200254 and a light chain (LC) variable domain containing SEQ ID NO:200255. In some cases, anti-TL1A antibodies contain a heavy chain (HC) variable domain containing SEQ ID NO:200256 and a light chain (LC) variable domain containing SEQ ID NO:200257.

[0198] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200276, HCDR2 containing SEQ ID NO:200277, HCDR3 containing SEQ ID NO:200278, LCDR1 containing SEQ ID NO:200279, LCDR2 containing SEQ ID NO:200280, and LCDR3 containing SEQ ID NO:200281. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200282 and a light chain (LC) variable domain containing SEQ ID NO:200283.

[0199] In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200284, HCDR2 containing SEQ ID NO:200285, HCDR3 containing SEQ ID NO:200286, LCDR1 containing SEQ ID NO:200287, LCDR2 containing SEQ ID NO:200288, and LCDR3 containing SEQ ID NO:200299. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200290 and a light chain (LC) variable domain containing SEQ ID NO:200291.

[0200] In some embodiments, the anti-TL1A antibody comprises one or more of A101-A177 in Table 15. In some embodiments, the anti-TL1A antibody is A100. In some embodiments, the anti-TL1A antibody is A101. In some embodiments, the anti-TL1A antibody is A102. In some embodiments, the anti-TL1A antibody is A103. In some embodiments, the anti-TL1A antibody is A104. In some embodiments, the anti-TL1A antibody is A105. In some embodiments, the anti-TL1A antibody is A106. In some embodiments, the anti-TL1A antibody is A107. In some embodiments, the anti-TL1A antibody is A108. In some embodiments, the anti-TL1A antibody is A109. In some embodiments, the anti-TL1A antibody is A110. In some embodiments, the anti-TL1A antibody is A111. In some embodiments, the anti-TL1A antibody is A112. In some embodiments, the anti-TL1A antibody is A113. In some embodiments, the anti-TL1A antibody is A114. In some embodiments, the anti-TL1A antibody is A115. In some embodiments, the anti-TL1A antibody is A116. In some embodiments, the anti-TL1A antibody is A117. In some embodiments, the anti-TL1A antibody is A118. In some embodiments, the anti-TL1A antibody is A119. In some embodiments, the anti-TL1A antibody is A120. In some embodiments, the anti-TL1A antibody is A121. In some embodiments, the anti-TL1A antibody is A122. In some embodiments, the anti-TL1A antibody is A123. In some embodiments, the anti-TL1A antibody is A124. In some embodiments, the anti-TL1A antibody is A125. In some embodiments, the anti-TL1A antibody is A126. In some embodiments, the anti-TL1A antibody is A127. In some embodiments, the anti-TL1A antibody is A128. In some embodiments, the anti-TL1A antibody is A129. In some embodiments, the anti-TL1A antibody is A130. In some embodiments, the anti-TL1A antibody is A131. In some embodiments, the anti-TL1A antibody is A132. In some embodiments, the anti-TL1A antibody is A133. In some embodiments, the anti-TL1A antibody is A134. In some embodiments, the anti-TL1A antibody is A135. In some embodiments, the anti-TL1A antibody is A136. In some embodiments, the anti-TL1A antibody is A137. In some embodiments, the anti-TL1A antibody is A138. In some embodiments, the anti-TL1A antibody is A139.In some embodiments, the anti-TL1A antibody is A140. In some embodiments, the anti-TL1A antibody is A141. In some embodiments, the anti-TL1A antibody is A142. In some embodiments, the anti-TL1A antibody is A143. In some embodiments, the anti-TL1A antibody is A144. In some embodiments, the anti-TL1A antibody is A145. In some embodiments, the anti-TL1A antibody is A146. In some embodiments, the anti-TL1A antibody is A147. In some embodiments, the anti-TL1A antibody is A148. In some embodiments, the anti-TL1A antibody is A149. In some embodiments, the anti-TL1A antibody is A150. In some embodiments, the anti-TL1A antibody is A151. In some embodiments, the anti-TL1A antibody is A152. In some embodiments, the anti-TL1A antibody is A153. In some embodiments, the anti-TL1A antibody is A154. In some embodiments, the anti-TL1A antibody is A155. In some embodiments, the anti-TL1A antibody is A156. In some embodiments, the anti-TL1A antibody is A157. In some embodiments, the anti-TL1A antibody is A158. In some embodiments, the anti-TL1A antibody is A159. In some embodiments, the anti-TL1A antibody is A160. In some embodiments, the anti-TL1A antibody is A161. In some embodiments, the anti-TL1A antibody is A162. In some embodiments, the anti-TL1A antibody is A163. In some embodiments, the anti-TL1A antibody is A164. In some embodiments, the anti-TL1A antibody is A165. In some embodiments, the anti-TL1A antibody is A166. In some embodiments, the anti-TL1A antibody is A167. In some embodiments, the anti-TL1A antibody is A168. In some embodiments, the anti-TL1A antibody is A169. In some embodiments, the anti-TL1A antibody is A170. In some embodiments, the anti-TL1A antibody is A171. In some embodiments, the anti-TL1A antibody is A172. In some embodiments, the anti-TL1A antibody is A173. In some embodiments, the anti-TL1A antibody is A174. In some embodiments, the anti-TL1A antibody is A175. In some embodiments, the anti-TL1A antibody is A176. In some embodiments, the anti-TL1A antibody is A177.

[0201] In some embodiments, the anti-DR3 is A178. In some embodiments, the anti-DR3 is A179. In some embodiments, the anti-DR3 is A180. In some embodiments, the anti-DR3 is A181. In some embodiments, the anti-DR3 is A182. In some embodiments, the anti-DR3 is A183. In some embodiments, the anti-DR3 is A184. In some embodiments, the anti-DR3 is A185. In some embodiments, the anti-DR3 is A186. In some embodiments, the anti-DR3 is A187. In some embodiments, the anti-DR3 is A188. In some embodiments, the anti-DR3 is A189. In some embodiments, the anti-DR3 is A190. In some embodiments, the anti-DR3 is A191. In some embodiments, the anti-DR3 is A192. In some embodiments, the anti-DR3 is A193. In some embodiments, the anti-DR3 is A194. In some embodiments, the anti-DR3 is A195. In some embodiments, the anti-DR3 is A196. In some embodiments, the anti-DR3 is A197. In some embodiments, the anti-DR3 is A198. In some embodiments, the anti-DR3 is A199. In some embodiments, the anti-DR3 is A200. In some embodiments, the anti-DR3 is A201. In some embodiments, the anti-DR3 is A202. In some embodiments, the anti-DR3 is A203. In some embodiments, the anti-DR3 is A204. In some embodiments, the anti-DR3 is A205. In some embodiments, the anti-DR3 is A206. In some embodiments, the anti-DR3 is A207. In some embodiments, the anti-DR3 is A208. In some embodiments, the anti-DR3 is A209. In some embodiments, the anti-DR3 is A210. In some embodiments, the anti-DR3 is A211. In some embodiments, the anti-DR3 is A212. In some embodiments, the anti-DR3 is A213. In some embodiments, the anti-DR3 is A214. In some embodiments, the anti-DR3 is A215. In some embodiments, the anti-DR3 is A216. In some embodiments, the anti-DR3 is A217. In some embodiments, the anti-DR3 is A218. In some embodiments, the anti-DR3 is A219. In some embodiments, the anti-DR3 is A220. In some embodiments, the anti-DR3 is A221. In some embodiments, the anti-DR3 is A222. In some embodiments, the anti-DR3 is A223. In some embodiments, the anti-DR3 is A224.In some embodiments, the anti-DR3 is A225. In some embodiments, the anti-DR3 is A226. In some embodiments, the anti-DR3 is A227. In some embodiments, the anti-DR3 is A228. In some embodiments, the anti-DR3 is A229. In some embodiments, the anti-DR3 is A230. In some embodiments, the anti-DR3 is A231. In some embodiments, the anti-DR3 is A232. In some embodiments, the anti-DR3 is A233. In some embodiments, the anti-DR3 is A234. In some embodiments, the anti-DR3 is A235. In some embodiments, the anti-DR3 is A236. In some embodiments, the anti-DR3 is A237. In some embodiments, the anti-DR3 is A238. In some embodiments, the anti-DR3 is A239. In some embodiments, the anti-DR3 is A240. In some embodiments, the anti-DR3 is A241. In some implementations, the anti-DR3 is A242.

[0202] Table 15. Non-limiting examples of anti-TL1A and anti-DR3 antibodies

[0203]

[0204]

[0205]

[0206]

[0207] In some cases, anti-TL1A antibodies bind to at least one or more identical residues of human TL1A with antibodies selected from A100-A177 in Table 17. In some cases, anti-TL1A antibodies bind to the same epitopes of human TL1A with antibodies selected from A100-A177. In some cases, anti-TL1A antibodies bind to the same regions of human TL1A with antibodies selected from A100-A177.

[0208] In some embodiments, the anti-TL1A antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% of the same amino acid sequence as any one of SEQ ID NO: 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, or 541; and (b) a light chain variable region comprising the same amino acid sequence as ... NO: Any one of 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538 or 540 has at least about 85%, 90%, 95%, 97%, 98%, 99% or 100% identical amino acid sequences.

[0209] In some embodiments, the anti-TL1A antibody comprises any one of the following embodiments 1-547.

[0210] 1. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0211] The heavy chain variable region comprises four heavy chain framework regions (HFR1, HFR2, HFR3, and HFR4) and three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3). This heavy chain variable region includes:

[0212] (a) HFR1, selected from: (i) HFR1 containing SEQ ID NO: 100100, (ii) HFR1 containing SEQ ID NO: 100108, and (iii) HFR1 containing an amino acid sequence that differs from the sequence selected from SEQ ID NO: 100100 and 100108 by a maximum of five, four, three, or two amino acids.

[0213] (b) HFR2, selected from: (i) HFR2 containing SEQ ID NO:100101, and (ii) HFR2 containing an amino acid sequence that differs from SEQ ID NO:100101 by a maximum of five, four, three, or two amino acids.

[0214] (c) HFR3, selected from: (i) HFR3 comprising SEQ ID NO:100102, (ii) HFR3 comprising SEQ ID NO:100109, and (iii) HFR3 comprising an amino acid sequence differing from the sequence selected from SEQ ID NO:100102 and 100109 by a maximum of five, four, three, or two amino acids.

[0215] (d) HFR4, selected from: (i) HFR4 containing SEQ ID NO:100103, and (ii) HFR4 containing an amino acid sequence that differs from SEQ ID NO:100103 by a maximum of five, four, three, or two amino acids.

[0216] (e) HCDR1, selected from: (i) HCDR1 containing SEQ ID NO:1009, (ii) HCDR1 containing SEQ ID NO:100150, wherein X1 is selected from D and E, X2 is selected from I, P and V, X3 is selected from G, Q, S and V, X4 is selected from F and Y, and X5 is selected from I and M, (iii) HCDR1 selected from SEQ ID NO:100200-100295, and (iv) HCDR1 containing an amino acid sequence that differs from the sequence selected from SEQ ID NO:1009, 100150 and 100200-295 by a maximum of five, four, three or two amino acids.

[0217] (f) HCDR2, selected from: (i) HCDR2 comprising SEQ ID NO:10012, and (ii) HCDR2 comprising an amino acid sequence differing from SEQ ID NO:10012 by a maximum of five, four, three, or two amino acids, and

[0218] (g) HCDR3, selected from (i) HCDR3 comprising SEQ ID NO: 10015, (ii) HCDR3 comprising SEQ ID NO: 100152, wherein X1 is selected from L and M, and X2 is selected from E, I, K, L, M, Q, T, V, W, and Y, (iii) HCDR3 comprising SEQ ID NO: 100296-100314, and (iv) HCDR3 comprising an amino acid sequence differing from the sequence selected from SEQ ID NO: 10015, 100152, and 100296-100314 by a maximum of five, four, three, or two amino acids, and

[0219] The light chain variable region comprises four light chain framework regions (LFR1, LFR2, LFR3, and LFR4) and three light chain complementarity determination regions (LCDR1, LCDR2, and LCDR3). This light chain variable region includes:

[0220] (a) LFR1, selected from: (i) LFR1 containing SEQ ID NO:100104, and (ii) LFR1 containing an amino acid sequence that differs from SEQ ID NO:100104 by a maximum of five, four, three, or two amino acids.

[0221] (b) LFR2, selected from: (i) LFR2 comprising SEQ ID NO:100105, and (ii) LFR2 comprising an amino acid sequence differing from SEQ ID NO:100105 by a maximum of five, four, three, or two amino acids.

[0222] (c) LFR3, selected from: (i) LFR3 comprising SEQ ID NO:100106, (ii) LFR3 comprising SEQ ID NO:100110, and (iii) LFR3 comprising an amino acid sequence differing from the sequence selected from SEQ ID NO:100106 and 100110 by a maximum of five, four, three, or two amino acids.

[0223] (d) LFR4, selected from: (i) LFR4 containing SEQ ID NO:100107, and (ii) LFR4 containing an amino acid sequence that differs from SEQ ID NO:100107 by a maximum of five, four, three, or two amino acids.

[0224] (e) LCDR1, selected from: (i) LCDR1 containing SEQ ID NO:10018, and (ii) LCDR1 containing an amino acid sequence that differs from SEQ ID NO:10018 by a maximum of five, four, three, or two amino acids.

[0225] (f) LCDR2, selected from: (i) LCDR2 comprising SEQ ID NO:10021, and (ii) LCDR2 comprising an amino acid sequence differing from SEQ ID NO:10021 by a maximum of five, four, three, or two amino acids, and

[0226] (g) LCDR3, selected from (i) LCDR3 containing SEQ ID NO:10024, (ii) LCDR3 containing SEQ ID NO:100155, wherein X1 is selected from Q and N, X2 is selected from D, E, H, N, Q and S, X3 is selected from A and G, and X4 is selected from D, F, K, N, R, S and T, (iii) LCDR3 selected from SEQ ID NO:100315-100482, and (iv) LCDR3 containing an amino acid sequence that differs from the sequence selected from SEQ ID NO:10024, 100155 and 100315-100482 by a maximum of five, four, three or two amino acids.

[0227] 2. The antibody or antigen-binding fragment of embodiment 1, wherein the HFR1 contains SEQ ID NO:100100.

[0228] 3. The antibody or antigen-binding fragment of embodiment 1, wherein the HFR1 contains SEQ ID NO:100108.

[0229] 4. The antibody or antigen-binding fragment of embodiment 1, wherein the HFR1 contains an amino acid sequence that differs from SEQ ID NO:100100 by a maximum of five, four, three, or two amino acids.

[0230] 5. The antibody or antigen-binding fragment of embodiment 1, wherein the HFR1 contains an amino acid sequence that differs from SEQ ID NO:100108 by a maximum of five, four, three, or two amino acids.

[0231] 6. An antibody or antigen-binding fragment of any one of embodiments 1-5, wherein the HFR2 contains SEQ ID NO:100101.

[0232] 7. An antibody or antigen-binding fragment of any one of embodiments 1-5, wherein the HFR2 contains an amino acid sequence that differs from SEQ ID NO:100101 by a maximum of five, four, three, or two amino acids.

[0233] 8. An antibody or antigen-binding fragment of any one of embodiments 1-7, provided that the HFR3 contains SEQ ID NO:100102.

[0234] 9. An antibody or antigen-binding fragment of any one of embodiments 1-7, wherein the HFR3 contains SEQ ID NO:100109.

[0235] 10. An antibody or antigen-binding fragment of any one of embodiments 1-7, wherein the HFR3 contains an amino acid sequence that differs from SEQ ID NO:100102 by a maximum of five, four, three, or two amino acids.

[0236] 11. An antibody or antigen-binding fragment of any one of embodiments 1-7, wherein the HFR3 contains an amino acid sequence that differs from SEQ ID NO:100109 by a maximum of five, four, three, or two amino acids.

[0237] 12. An antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the HFR4 contains SEQ ID NO: 100103.

[0238] 13. An antibody or antigen-binding fragment of any one of embodiments 1-11, wherein the HFR4 contains an amino acid sequence that differs from SEQ ID NO:100103 by a maximum of five, four, three, or two amino acids.

[0239] 14. An antibody or antigen-binding fragment of any one of embodiments 1-13, wherein the HCDR1 contains SEQ ID NO: 1009.

[0240] 15. An antibody or antigen-binding fragment of any one of embodiments 1-13, wherein the HCDR1 contains SEQ ID NO: 100150.

[0241] 16. The antibody or antigen-binding fragment of implementation scheme 15, provided that X1 is E.

[0242] 17. An antibody or antigen-binding fragment of implementation scheme 15 or implementation scheme 16, wherein X2 is selected from P and V.

[0243] 18. An antibody or antigen-binding fragment of any one of the implementation schemes 15-17, provided that X3 is selected from G, S, and V.

[0244] 19. An antibody or antigen-binding fragment of any one of the implementation schemes 15-18, provided that X4 is F.

[0245] 20. An antibody or antigen-binding fragment of any one of the implementation schemes 15-19, provided that X5 is I.

[0246] 21. An antibody or antigen-binding fragment of any one of embodiments 1-13, wherein the HCDR1 comprises an amino acid sequence selected from SEQ ID NO:100200-100295.

[0247] 22. An antibody or antigen-binding fragment of any one of embodiments 1-21, wherein the HCDR2 comprises SEQ ID NO:10012.

[0248] 23. An antibody or antigen-binding fragment of any one of embodiments 1-21, wherein the HCDR2 contains an amino acid sequence that differs from SEQ ID NO:10012 by a maximum of five, four, three, or two amino acids.

[0249] 24. An antibody or antigen-binding fragment of any one of embodiments 1-23, wherein the HCDR3 contains SEQ ID NO:10015.

[0250] 25. An antibody or antigen-binding fragment of any one of embodiments 1-23, wherein the HCDR3 contains SEQ ID NO:100152.

[0251] 26. Implement the antibody or antigen-binding fragment of scheme 25, provided that X1 is M.

[0252] 27. An antibody or antigen-binding fragment of implementation scheme 25 or implementation scheme 26, wherein X2 is selected from E, I, K, L, M, Q, T, W and Y.

[0253] 28. An antibody or antigen-binding fragment of any one of embodiments 1-23, wherein the HCDR3 comprises a sequence selected from SEQ ID NO:100296-100314.

[0254] 29. An antibody or antigen-binding fragment of any one of embodiments 1-28, wherein the LFR1 contains SEQ ID NO:100104.

[0255] 30. An antibody or antigen-binding fragment of any one of embodiments 1-28, wherein the LFR1 contains an amino acid sequence that differs from SEQ ID NO:100104 by a maximum of five, four, three, or two amino acids.

[0256] 31. An antibody or antigen-binding fragment of any one of embodiments 1-30, wherein the LFR2 comprises SEQ ID NO:100105.

[0257] 32. An antibody or antigen-binding fragment of any one of embodiments 1-30, wherein the LFR2 comprises an amino acid sequence that differs from SEQ ID NO:100105 by a maximum of five, four, three, or two amino acids.

[0258] 33. An antibody or antigen-binding fragment of any one of embodiments 1-32, wherein the LFR3 contains SEQ ID NO:100106.

[0259] 34. An antibody or antigen-binding fragment of any one of embodiments 1-32, wherein the LFR3 contains SEQ ID NO: 100110.

[0260] 35. An antibody or antigen-binding fragment of any one of embodiments 1-32, wherein the LFR3 contains an amino acid sequence that differs from SEQ ID NO:100106 by a maximum of five, four, three, or two amino acids.

[0261] 36. An antibody or antigen-binding fragment of any one of embodiments 1-32, wherein the LFR3 contains an amino acid sequence that differs from SEQ ID NO:100110 by a maximum of five, four, three, or two amino acids.

[0262] 37. An antibody or antigen-binding fragment of any one of embodiments 1-36, wherein the LFR4 contains SEQ ID NO: 100107.

[0263] 38. An antibody or antigen-binding fragment of any one of embodiments 1-36, wherein the LFR4 comprises an amino acid sequence that differs from SEQ ID NO:100107 by a maximum of five, four, three, or two amino acids.

[0264] 39. An antibody or antigen-binding fragment of any one of embodiments 1-38, wherein the LCDR1 contains SEQ ID NO:10018.

[0265] 40. An antibody or antigen-binding fragment of any one of embodiments 1-38, wherein the LCDR1 contains an amino acid sequence that differs from SEQ ID NO:10018 by a maximum of five, four, three, or two amino acids.

[0266] 41. An antibody or antigen-binding fragment of any one of embodiments 1-40, wherein the LCDR2 contains SEQ ID NO:10021.

[0267] 42. An antibody or antigen-binding fragment of any one of embodiments 1-40, wherein the LCDR2 contains an amino acid sequence that differs from SEQ ID NO:10021 by a maximum of five, four, three, or two amino acids.

[0268] 43. An antibody or antigen-binding fragment of any one of embodiments 1-42, wherein the LCDR3 contains SEQ ID NO:10024.

[0269] 44. An antibody or antigen-binding fragment of any one of embodiments 1-42, wherein the LCDR3 contains SEQ ID NO:100155.

[0270] 45. Implement the antibody or antigen-binding fragment of scheme 44, provided that X1 is N.

[0271] 46. ​​An antibody or antigen-binding fragment of implementation scheme 44 or implementation scheme 45, wherein X2 is selected from D, E, H, N and Q.

[0272] 47. An antibody or antigen-binding fragment of any one of the implementation schemes 44-46, provided that X3 is A.

[0273] 48. An antibody or antigen-binding fragment of any one of the implementation schemes 44-47, wherein X4 is selected from D, F, K, R, S and T.

[0274] 49. An antibody or antigen-binding fragment of any one of embodiments 1-42, wherein the LCDR3 comprises an amino acid sequence selected from SEQ ID NO:100315-100482.

[0275] 50. The antibody or antigen-binding fragment of Embodiment 1, wherein the HFR1 contains SEQ ID NO: 100100, the HFR2 contains SEQ ID NO: 100101, the HFR3 contains SEQ ID NO: 100102, the HFR4 contains SEQ ID NO: 100103, the LFR1 contains SEQ ID NO: 100104, the LFR2 contains SEQ ID NO: 100105, the LFR3 contains SEQ ID NO: 100106, and the LFR4 contains SEQ ID NO: 100107.

[0276] 51. The antibody or antigen-binding fragment of Embodiment 1, wherein the HFR1 contains SEQ ID NO:100108, the HFR2 contains SEQ ID NO:100101, the HFR3 contains SEQ ID NO:100109, the HFR4 contains SEQ ID NO:100103, the LFR1 contains SEQ ID NO:100104, the LFR2 contains SEQ ID NO:100105, the LFR3 contains SEQ ID NO:100110, and the LFR4 contains SEQ ID NO:100107.

[0277] 52. The antibody or antigen-binding fragment of Embodiment 1, wherein the HFR1 contains SEQ ID NO:100108, the HFR2 contains SEQ ID NO:100101, the HFR3 contains SEQ ID NO:100109, the HFR4 contains SEQ ID NO:100103, the LFR1 contains SEQ ID NO:100104, the LFR2 contains SEQ ID NO:100105, the LFR3 contains SEQ ID NO:100106, and the LFR4 contains SEQ ID NO:100107.

[0278] 53. An antibody or antigen-binding fragment of any one of embodiments 1 and 50-52, wherein the HCDR1 contains SEQ ID NO:1009, the HCDR2 contains SEQ ID NO:10012, the HCDR3 contains SEQ ID NO:10015, the LCDR1 contains SEQ ID NO:10018, the LCDR2 contains SEQ ID NO:10021, and the LCDR3 contains SEQ ID NO:10024.

[0279] 54. An antibody or antigen-binding fragment of any one of embodiments 1 and 50-52, wherein the HCDR1 contains SEQ ID NO:100150, the HCDR2 contains SEQ ID NO:10012, the HCDR3 contains SEQ ID NO:100152, the LCDR1 contains SEQ ID NO:10018, the LCDR2 contains SEQ ID NO:10021, and the LCDR3 contains SEQ ID NO:100155.

[0280] 55. The antibody or antigen-binding fragment of Embodiment 1, wherein the HFR1 contains SEQ ID NO: 100100, the HFR2 contains SEQ ID NO: 100101, the HFR3 contains SEQ ID NO: 100102, the HFR4 contains SEQ ID NO: 100103, the LFR1 contains SEQ ID NO: 100104, the LFR2 contains SEQ ID NO: 100105, the LFR3 contains SEQ ID NO: 100106, the LFR4 contains SEQ ID NO: 100107, the HCDR1 contains SEQ ID NO: 1009, the HCDR2 contains SEQ ID NO: 10012, the HCDR3 contains SEQ ID NO: 10015, the LCDR1 contains SEQ ID NO: 10018, the LCDR2 contains SEQ ID NO: 10021, and the LCDR3 contains SEQ ID NO: 10024.

[0281] 56. The antibody or antigen-binding fragment of Embodiment 1, wherein the HFR1 contains SEQ ID NO: 100100, the HFR2 contains SEQ ID NO: 100101, the HFR3 contains SEQ ID NO: 100102, the HFR4 contains SEQ ID NO: 100103, the LFR1 contains SEQ ID NO: 100104, the LFR2 contains SEQ ID NO: 100105, the LFR3 contains SEQ ID NO: 100106, the LFR4 contains SEQ ID NO: 100107, the HCDR1 contains SEQ ID NO: 100150, the HCDR2 contains SEQ ID NO: 10012, the HCDR3 contains SEQ ID NO: 100152, the LCDR1 contains SEQ ID NO: 10018, the LCDR2 contains SEQ ID NO: 10021, and the LCDR3 contains SEQ ID NO: 100155.

[0282] 57. The antibody or antigen-binding fragment of Embodiment 1, wherein the HFR1 contains SEQ ID NO: 100108, the HFR2 contains SEQ ID NO: 100101, the HFR3 contains SEQ ID NO: 100109, the HFR4 contains SEQ ID NO: 100103, the LFR1 contains SEQ ID NO: 100104, the LFR2 contains SEQ ID NO: 100105, the LFR3 contains SEQ ID NO: 100110, the LFR4 contains SEQ ID NO: 100107, the HCDR1 contains SEQ ID NO: 1009, the HCDR2 contains SEQ ID NO: 10012, the HCDR3 contains SEQ ID NO: 10015, the LCDR1 contains SEQ ID NO: 10018, the LCDR2 contains SEQ ID NO: 10021, and the LCDR3 contains SEQ ID NO: 10024.

[0283] 58. The antibody or antigen-binding fragment of Embodiment 1, wherein the HFR1 contains SEQ ID NO: 100108, the HFR2 contains SEQ ID NO: 100101, the HFR3 contains SEQ ID NO: 100109, the HFR4 contains SEQ ID NO: 100103, the LFR1 contains SEQ ID NO: 100104, the LFR2 contains SEQ ID NO: 100105, the LFR3 contains SEQ ID NO: 100110, the LFR4 contains SEQ ID NO: 100107, the HCDR1 contains SEQ ID NO: 100150, the HCDR2 contains SEQ ID NO: 10012, the HCDR3 contains SEQ ID NO: 100152, the LCDR1 contains SEQ ID NO: 10018, the LCDR2 contains SEQ ID NO: 10021, and the LCDR3 contains SEQ ID NO: 100155.

[0284] 59. The antibody or antigen-binding fragment of Embodiment 1, wherein the HFR1 contains SEQ ID NO: 100108, the HFR2 contains SEQ ID NO: 100101, the HFR3 contains SEQ ID NO: 100109, the HFR4 contains SEQ ID NO: 100103, the LFR1 contains SEQ ID NO: 100104, the LFR2 contains SEQ ID NO: 100105, the LFR3 contains SEQ ID NO: 100106, the LFR4 contains SEQ ID NO: 100107, the HCDR1 contains SEQ ID NO: 1009, the HCDR2 contains SEQ ID NO: 10012, the HCDR3 contains SEQ ID NO: 10015, the LCDR1 contains SEQ ID NO: 10018, the LCDR2 contains SEQ ID NO: 10021, and the LCDR3 contains SEQ ID NO: 10024.

[0285] 60. The antibody or antigen-binding fragment of Embodiment 1, wherein the HFR1 contains SEQ ID NO: 100108, the HFR2 contains SEQ ID NO: 100101, the HFR3 contains SEQ ID NO: 100109, the HFR4 contains SEQ ID NO: 100103, the LFR1 contains SEQ ID NO: 100104, the LFR2 contains SEQ ID NO: 100105, the LFR3 contains SEQ ID NO: 100106, the LFR4 contains SEQ ID NO: 100107, the HCDR1 contains SEQ ID NO: 100150, the HCDR2 contains SEQ ID NO: 10012, the HCDR3 contains SEQ ID NO: 100152, the LCDR1 contains SEQ ID NO: 10018, the LCDR2 contains SEQ ID NO: 10021, and the LCDR3 contains SEQ ID NO: 100155.

[0286] 61. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60, provided that X1 of SEQ ID NO: 100150 is D.

[0287] 62. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60, provided that X1 of SEQ ID NO: 100150 is E.

[0288] 63. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-62, provided that X2 of SEQ ID NO: 100150 is I.

[0289] 64. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-62, provided that X2 of SEQ ID NO: 100150 is P.

[0290] 65. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-62, provided that X2 of SEQ ID NO: 100150 is V.

[0291] 66. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-65, provided that X3 of SEQ ID NO: 100150 is G.

[0292] 67. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-65, provided that X3 of SEQ ID NO: 100150 is Q.

[0293] 68. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-65, provided that X3 of SEQ ID NO: 100150 is S.

[0294] 69. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-65, provided that X3 of SEQ ID NO: 100150 is V.

[0295] 70. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-69, provided that X4 of SEQ ID NO: 100150 is F.

[0296] 71. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-69, provided that X4 of SEQ ID NO: 100150 is Y.

[0297] 72. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-71, provided that X5 of SEQ ID NO:100150 is I.

[0298] 73. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-71, provided that X5 of SEQ ID NO:100150 is M.

[0299] 74. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-73, provided that X1 of SEQ ID NO:100152 is L.

[0300] 75. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-73, provided that X1 of SEQ ID NO:100152 is M.

[0301] 76. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-75, provided that X2 of SEQ ID NO: 100152 is E.

[0302] 77. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-75, provided that X2 of SEQ ID NO:100152 is I.

[0303] 78. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-75, provided that X2 of SEQ ID NO: 100152 is K.

[0304] 79. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-75, provided that X2 of SEQ ID NO:100152 is L.

[0305] 80. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-75, provided that X2 of SEQ ID NO:100152 is M.

[0306] 81. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-75, provided that X2 of SEQ ID NO:100152 is Q.

[0307] 82. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-75, provided that X2 of SEQ ID NO:100152 is T.

[0308] 83. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-75, provided that X2 of SEQ ID NO:100152 is V.

[0309] 84. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-75, provided that X2 of SEQ ID NO:100152 is W.

[0310] 85. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-75, provided that X2 of SEQ ID NO: 100152 is Y.

[0311] 86. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-85, provided that X1 of SEQ ID NO: 100155 is Q.

[0312] 87. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-85, provided that X1 of SEQ ID NO:100155 is N.

[0313] 88. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-87, provided that X2 of SEQ ID NO: 100155 is D.

[0314] 89. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-87, provided that X2 of SEQ ID NO: 100155 is E.

[0315] 90. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-87, provided that X2 of SEQ ID NO: 100155 is H.

[0316] 91. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-87, provided that X2 of SEQ ID NO: 100155 is N.

[0317] 92. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-87, provided that X2 of SEQ ID NO: 100155 is Q.

[0318] 93. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-87, provided that X2 of SEQ ID NO: 100155 is S.

[0319] 94. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-93, provided that X3 of SEQ ID NO: 100155 is A.

[0320] 95. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-93, provided that X3 of SEQ ID NO: 100155 is G.

[0321] 96. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-95, provided that X4 of SEQ ID NO: 100155 is D.

[0322] 97. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-95, provided that X4 of SEQ ID NO: 100155 is F.

[0323] 98. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-95, provided that X4 of SEQ ID NO: 100155 is K.

[0324] 99. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-95, provided that X4 of SEQ ID NO: 100155 is N.

[0325] 100. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-95, provided that X4 of SEQ ID NO:100155 is R.

[0326] 101. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-95, provided that X4 of SEQ ID NO:100155 is S.

[0327] 102. An antibody or antigen-binding fragment of any one of embodiments 1, 54, 56, 58 and 60-95, provided that X4 of SEQ ID NO:100155 is T.

[0328] 103. An antibody or antigen-binding fragment of any one of the implementation schemes 1-102, provided that the antibody or antigen-binding fragment specifically binds to human TL1A.

[0329] 104. The antibody or antigen-binding fragment of embodiment 103, wherein the antibody or antigen-binding fragment is in a 1x10-1 ratio. -9 M or lower K d It specifically binds to human TL1A.

[0330] 105. The antibody or antigen-binding fragment of embodiment 104, wherein the K is measured using a method selected from standard ELISA assays and SPR. d .

[0331] 106. An antibody or antigen-binding fragment of any one of embodiments 1-105, provided that the antibody or antigen-binding fragment inhibits the binding of DR3 to human TL1A.

[0332] 107. An antibody or antigen-binding fragment of any one of embodiments 1-106, provided that the antibody or antigen-binding fragment inhibits the binding of DcR3 to human TL1A.

[0333] 108. An antibody or antigen-binding fragment of any one of the implementation schemes 1-107, provided that the antibody or antigen-binding fragment is a humanized antibody, a CDR-transplanted antibody, a chimeric antibody, Fab, ScFv, or a combination thereof.

[0334] 109. An antibody or antigen-binding fragment comprising any one of embodiments 1-108, wherein the antibody or antigen-binding fragment contains a human CH1 domain.

[0335] 110. An antibody or antigen-binding fragment comprising any one of embodiments 1-109, wherein the antibody or antigen-binding fragment contains a human CH2 domain.

[0336] 111. An antibody or antigen-binding fragment of embodiment 110, wherein the CH2 domain contains at least one mutation selected from L234A, L235A and G237A using Kabat numbering.

[0337] 112. An antibody or antigen-binding fragment comprising any one of embodiments 1-111, wherein the antibody or antigen-binding fragment contains a human CH3 domain.

[0338] 113. A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment of any one of embodiments 1-112, and a pharmaceutically acceptable carrier.

[0339] 114. A method for treating an inflammatory disease in a subject in need, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment of any one of embodiments 1-113.

[0340] 115. The method of implementing 114, wherein the inflammatory disease is inflammatory bowel disease.

[0341] 116. The method of implementation scheme 115, wherein the inflammatory bowel disease includes Crohn's disease.

[0342] 117. The method of implementation scheme 116, provided that it has been determined that the subject is unresponsive to anti-TNFα therapy.

[0343] 118. The method of implementation scheme 116 or implementation scheme 117, wherein the subject has been determined to have a disease phenotype including non-stenotic / non-penetrating, stenotic, stenotic and penetrating, or isolated internal penetrating.

[0344] 119. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0345] The heavy chain variable region comprises four heavy chain framework regions (HFR1, HFR2, HFR3, and HFR4) containing SEQ ID NO:100100-100103 and three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), and includes:

[0346] (a) HCDR1, selected from: (i) HCDR1 containing SEQ ID NO:1009, (ii) HCDR1 containing SEQ ID NO:100150, wherein X1 is selected from D and E, X2 is selected from I, P and V, X3 is selected from G, Q, S and V, X4 is selected from F and Y, and X5 is selected from I and M, (iii) HCDR1 selected from SEQ ID NO:100200-100295, and (iv) HCDR1 containing an amino acid sequence that differs from the sequence selected from SEQ ID NO:1009, 100150 and 100200-100295 by a maximum of five, four, three or two amino acids.

[0347] (b) HCDR2, selected from: (i) HCDR2 comprising SEQ ID NO:10012, and (ii) HCDR2 comprising an amino acid sequence differing from SEQ ID NO:10012 by a maximum of five, four, three, or two amino acids, and

[0348] (c) HCDR3, selected from (i) HCDR3 comprising SEQ ID NO: 10015, (ii) HCDR3 comprising SEQ ID NO: 100152, wherein X1 is selected from L and M, and X2 is selected from E, I, K, L, M, Q, T, V, W, and Y, (iii) HCDR3 comprising SEQ ID NO: 100296-100314, and (iv) HCDR3 comprising an amino acid sequence differing from the sequence selected from SEQ ID NO: 10015, 100152, and 100296-100314 by a maximum of five, four, three, or two amino acids, and

[0349] The light chain variable region comprises four light chain framework regions (LFR1, LFR2, LFR3, and LFR4) containing SEQ ID NO:100104-100107 and three light chain complementarity determination regions (LCDR1, LCDR2, and LCDR3), which include:

[0350] (a) LCDR1, selected from: (i) LCDR1 containing SEQ ID NO:10018, and (ii) LCDR1 containing an amino acid sequence that differs from SEQ ID NO:10018 by a maximum of five, four, three, or two amino acids.

[0351] (b) LCDR2, selected from: (i) LCDR2 comprising SEQ ID NO:10021, and (ii) LCDR2 comprising an amino acid sequence differing from SEQ ID NO:10021 by a maximum of five, four, three, or two amino acids, and

[0352] (c) LCDR3 selected from (i) LCDR3 comprising SEQ ID NO:10024, (ii) LCDR3 comprising SEQ ID NO:100155, wherein X1 is selected from Q and N, X2 is selected from D, E, H, N, Q and S, X3 is selected from A and G, and X4 is selected from D, F, K, N, R, S and T, (iii) LCDR3 selected from SEQ ID NO:100315-100482, and (iv) LCDR3 comprising an amino acid sequence differing from the sequence selected from SEQ ID NO:10024, 100155 and 100315-100482 by a maximum of five, four, three or two amino acids.

[0353] 120. The antibody or antigen-binding fragment of embodiment 119, wherein the HCDR1 contains SEQ ID NO:1009.

[0354] 121. The antibody or antigen-binding fragment of embodiment 119, wherein the HCDR1 contains SEQ ID NO:100150.

[0355] 122. The antibody or antigen-binding fragment of implementation scheme 121, provided that X1 is E.

[0356] 123. An antibody or antigen-binding fragment of implementation scheme 121 or implementation scheme 122, wherein X2 is selected from P and V.

[0357] 124. An antibody or antigen-binding fragment of any one of the implementation schemes 121-123, wherein X3 is selected from G, S and V.

[0358] 125. An antibody or antigen-binding fragment of any one of the implementation schemes 121-124, provided that X4 is F.

[0359] 126. An antibody or antigen-binding fragment of any one of the implementation schemes 121-125, provided that X5 is I.

[0360] 127. The antibody or antigen-binding fragment of embodiment 119, wherein the HCDR1 comprises an amino acid sequence selected from SEQ ID NO:100200-100295.

[0361] 128. An antibody or antigen-binding fragment of any one of embodiments 119-127, wherein the HCDR2 contains SEQ ID NO:10012.

[0362] 129. An antibody or antigen-binding fragment of any one of embodiments 119-127, wherein the HCDR2 comprises an amino acid sequence that differs from SEQ ID NO:10012 by a maximum of five, four, three, or two amino acids.

[0363] 130. An antibody or antigen-binding fragment of any one of embodiments 119-129, wherein the HCDR3 contains SEQ ID NO:10015.

[0364] 131. An antibody or antigen-binding fragment of any one of embodiments 119-129, wherein the HCDR3 contains SEQ ID NO:100152.

[0365] 132. The antibody or antigen-binding fragment of implementation scheme 131, provided that X1 is M.

[0366] 133. An antibody or antigen-binding fragment of implementation scheme 131 or implementation scheme 132, wherein X2 is selected from E, I, K, L, M, Q, T, W and Y.

[0367] 134. An antibody or antigen-binding fragment of any one of embodiments 119-129, wherein the HCDR3 comprises a sequence selected from SEQ ID NO:100296-100314.

[0368] 135. An antibody or antigen-binding fragment of any one of embodiments 119-134, wherein the LCDR1 contains SEQ ID NO:10018.

[0369] 136. An antibody or antigen-binding fragment of any one of embodiments 119-134, wherein the LCDR1 contains an amino acid sequence that differs from SEQ ID NO:10018 by a maximum of five, four, three, or two amino acids.

[0370] 137. An antibody or antigen-binding fragment of any one of embodiments 119-136, wherein the LCDR2 contains SEQ ID NO:10021.

[0371] 138. An antibody or antigen-binding fragment of any one of embodiments 119-136, wherein the LCDR2 comprises an amino acid sequence that differs from SEQ ID NO:10021 by a maximum of five, four, three, or two amino acids.

[0372] 139. An antibody or antigen-binding fragment of any one of embodiments 119-138, wherein the LCDR3 contains SEQ ID NO:10024.

[0373] 140. An antibody or antigen-binding fragment of any one of embodiments 119-138, wherein the LCDR3 contains SEQ ID NO:100155.

[0374] 141. Implement the antibody or antigen-binding fragment of scheme 140, provided that X1 is N.

[0375] 142. An antibody or antigen-binding fragment of implementation scheme 140 or implementation scheme 141, wherein X2 is selected from D, E, H, N and Q.

[0376] 143. An antibody or antigen-binding fragment of any one of the implementation schemes 140-142, provided that X3 is A.

[0377] 144. An antibody or antigen-binding fragment of any one of the implementation schemes 140-143, wherein X4 is selected from D, F, K, R, S and T.

[0378] 145. An antibody or antigen-binding fragment of any one of embodiments 119-138, wherein the LCDR3 comprises an amino acid sequence selected from SEQ ID NO:100315-100482.

[0379] 146. The antibody or antigen-binding fragment of embodiment 119, wherein the HCDR1 contains SEQ ID NO:1009, the HCDR2 contains SEQ ID NO:10012, the HCDR3 contains SEQ ID NO:10015, the LCDR1 contains SEQ ID NO:10018, the LCDR2 contains SEQ ID NO:10021, and the LCDR3 contains SEQ ID NO:10024.

[0380] 147. The antibody or antigen-binding fragment of embodiment 119, wherein the HCDR1 contains SEQ ID NO:100150, the HCDR2 contains SEQ ID NO:10012, the HCDR3 contains SEQ ID NO:100152, the LCDR1 contains SEQ ID NO:10018, the LCDR2 contains SEQ ID NO:10021, and the LCDR3 contains SEQ ID NO:100155.

[0381] 148. The antibody or antigen-binding fragment of embodiment 119 or embodiment 147, provided that X1 of SEQ ID NO:100150 is D.

[0382] 149. An antibody or antigen-binding fragment of embodiment 119 or embodiment 147, provided that X1 of SEQ ID NO:100150 is E.

[0383] 150. An antibody or antigen-binding fragment of any one of embodiments 119, 147-149, provided that X2 of SEQ ID NO:100150 is I.

[0384] 151. An antibody or antigen-binding fragment of any one of embodiments 119, 147-149, provided that X2 of SEQ ID NO:100150 is P.

[0385] 152. An antibody or antigen-binding fragment of any one of embodiments 119, 147-149, provided that X2 of SEQ ID NO:100150 is V.

[0386] 153. An antibody or antigen-binding fragment of any one of embodiments 119, 147-152, provided that X3 of SEQ ID NO:100150 is G.

[0387] 154. An antibody or antigen-binding fragment of any one of embodiments 119, 147-152, provided that X3 of SEQ ID NO:100150 is Q.

[0388] 155. An antibody or antigen-binding fragment of any one of embodiments 119, 147-152, provided that X3 of SEQ ID NO:100150 is S.

[0389] 156. An antibody or antigen-binding fragment of any one of embodiments 119, 147-152, provided that X3 of SEQ ID NO:100150 is V.

[0390] 157. An antibody or antigen-binding fragment of any one of embodiments 119, 147-156, provided that X4 of SEQ ID NO:100150 is F.

[0391] 158. An antibody or antigen-binding fragment of any one of embodiments 119, 147-156, provided that X4 of SEQ ID NO:100150 is Y.

[0392] 159. An antibody or antigen-binding fragment of any one of embodiments 119, 147-158, provided that X5 of SEQ ID NO:100150 is I.

[0393] 160. An antibody or antigen-binding fragment of any one of embodiments 119, 147-158, provided that X5 of SEQ ID NO:100150 is M.

[0394] 161. An antibody or antigen-binding fragment of any one of embodiments 119, 147-160, provided that X1 of SEQ ID NO:100152 is L.

[0395] 162. An antibody or antigen-binding fragment of any one of embodiments 119, 147-160, provided that X1 of SEQ ID NO:100152 is M.

[0396] 163. An antibody or antigen-binding fragment of any one of embodiments 119, 147-162, provided that X2 of SEQ ID NO:100152 is E.

[0397] 164. An antibody or antigen-binding fragment of any one of embodiments 119, 147-162, provided that X2 of SEQ ID NO:100152 is I.

[0398] 165. An antibody or antigen-binding fragment of any one of embodiments 119, 147-162, provided that X2 of SEQ ID NO:100152 is K.

[0399] 166. An antibody or antigen-binding fragment of any one of embodiments 119, 147-162, provided that X2 of SEQ ID NO:100152 is L.

[0400] 167. An antibody or antigen-binding fragment of any one of embodiments 119, 147-162, provided that X2 of SEQ ID NO:100152 is M.

[0401] 168. An antibody or antigen-binding fragment of any one of embodiments 119, 147-162, provided that X2 of SEQ ID NO:100152 is Q.

[0402] 169. An antibody or antigen-binding fragment of any one of embodiments 119, 147-162, provided that X2 of SEQ ID NO:100152 is T.

[0403] 170. An antibody or antigen-binding fragment of any one of embodiments 119, 147-162, provided that X2 of SEQ ID NO:100152 is V.

[0404] 171. An antibody or antigen-binding fragment of any one of embodiments 119, 147-162, provided that X2 of SEQ ID NO:100152 is W.

[0405] 172. An antibody or antigen-binding fragment of any one of embodiments 119, 147-162, provided that X2 of SEQ ID NO:100152 is Y.

[0406] 173. An antibody or antigen-binding fragment of any one of embodiments 119, 147-172, provided that X1 of SEQ ID NO:100155 is Q.

[0407] 174. An antibody or antigen-binding fragment of any one of embodiments 119, 147-172, provided that X1 of SEQ ID NO:100155 is N.

[0408] 175. An antibody or antigen-binding fragment of any one of embodiments 119, 147-174, provided that X2 of SEQ ID NO:100155 is D.

[0409] 176. An antibody or antigen-binding fragment of any one of embodiments 119, 147-174, provided that X2 of SEQ ID NO:100155 is E.

[0410] 177. An antibody or antigen-binding fragment of any one of embodiments 119, 147-174, provided that X2 of SEQ ID NO:100155 is H.

[0411] 178. An antibody or antigen-binding fragment of any one of embodiments 119, 147-174, provided that X2 of SEQ ID NO:100155 is N.

[0412] 179. An antibody or antigen-binding fragment of any one of embodiments 119, 147-174, provided that X2 of SEQ ID NO:100155 is Q.

[0413] 180. An antibody or antigen-binding fragment of any one of embodiments 119, 147-174, provided that X2 of SEQ ID NO:100155 is S.

[0414] 181. An antibody or antigen-binding fragment of any one of embodiments 119, 147-180, provided that X3 of SEQ ID NO:100155 is A.

[0415] 182. An antibody or antigen-binding fragment of any one of embodiments 119, 147-180, provided that X3 of SEQ ID NO:100155 is G.

[0416] 183. An antibody or antigen-binding fragment of any one of embodiments 119, 147-182, provided that X4 of SEQ ID NO:100155 is D.

[0417] 184. An antibody or antigen-binding fragment of any one of embodiments 119, 147-182, provided that X4 of SEQ ID NO:100155 is F.

[0418] 185. An antibody or antigen-binding fragment of any one of embodiments 119, 147-182, provided that X4 of SEQ ID NO:100155 is K.

[0419] 186. An antibody or antigen-binding fragment of any one of embodiments 119, 147-182, provided that X4 of SEQ ID NO:100155 is N.

[0420] 187. An antibody or antigen-binding fragment of any one of embodiments 119, 147-182, provided that X4 of SEQ ID NO:100155 is R.

[0421] 188. An antibody or antigen-binding fragment of any one of embodiments 119, 147-182, provided that X4 of SEQ ID NO:100155 is S.

[0422] 189. An antibody or antigen-binding fragment of any one of embodiments 119, 147-182, provided that X4 of SEQ ID NO:100155 is T.

[0423] 190. An antibody or antigen-binding fragment of any one of embodiments 119-189, provided that the antibody or antigen-binding fragment specifically binds to human TL1A.

[0424] 191. The antibody or antigen-binding fragment of embodiment 190, wherein the antibody or antigen-binding fragment is in a 1x10-1 ratio. -9 M or lower K d It specifically binds to human TL1A.

[0425] 192. The antibody or antigen-binding fragment of embodiment 191, wherein the K is measured using a method selected from standard ELISA assays and SPR. d .

[0426] 193. An antibody or antigen-binding fragment of any one of embodiments 119-192, provided that the antibody or antigen-binding fragment inhibits the binding of DR3 to human TL1A.

[0427] 194. An antibody or antigen-binding fragment of any one of embodiments 119-193, provided that the antibody or antigen-binding fragment inhibits the binding of DcR3 to human TL1A.

[0428] 195. An antibody or antigen-binding fragment of any one of embodiments 119-194, wherein the antibody or antigen-binding fragment is a humanized antibody, a CDR-transplanted antibody, a chimeric antibody, Fab, ScFv, or a combination thereof.

[0429] 196. An antibody or antigen-binding fragment comprising any one of embodiments 119-195, wherein the antibody or antigen-binding fragment contains a human CH1 domain.

[0430] 197. An antibody or antigen-binding fragment comprising any one of embodiments 119-196, wherein the antibody or antigen-binding fragment contains a human CH2 domain.

[0431] 198. An antibody or antigen-binding fragment according to embodiment 197, wherein the CH2 domain contains at least one mutation selected from L234A, L235A and G237A using Kabat numbering.

[0432] 199. An antibody or antigen-binding fragment comprising any one of embodiments 119-198, wherein the antibody or antigen-binding fragment contains a human CH3 domain.

[0433] 200. A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment of any one of embodiments 119-199, and a pharmaceutically acceptable carrier.

[0434] 201. A method for treating an inflammatory disease in a subject in need, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment of any one of embodiments 119-199.

[0435] 202. The method of implementation scheme 201, wherein the inflammatory disease is inflammatory bowel disease.

[0436] 203. The method of implementation scheme 202, wherein the inflammatory bowel disease includes Crohn's disease.

[0437] 204. The method of implementation scheme 203, wherein it has been determined that the subject is unresponsive to anti-TNFα therapy.

[0438] 205. The method of implementation scheme 203 or implementation scheme 204, wherein the subject has been determined to have a disease phenotype including non-stenotic / non-penetrating, stenotic, stenotic and penetrating, or isolated internal penetrating.

[0439] 206. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0440] The heavy chain variable region comprises four heavy chain framework regions (HFR1, HFR2, HFR3, and HFR4) containing SEQ ID NO: 100108, 100101, 100109, and 100103 respectively, and three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), which include:

[0441] (a) HCDR1, selected from: (i) HCDR1 containing SEQ ID NO:1009, (ii) HCDR1 containing SEQ ID NO:100150, wherein X1 is selected from D and E, X2 is selected from I, P and V, X3 is selected from G, Q, S and V, X4 is selected from F and Y, and X5 is selected from I and M, (iii) HCDR1 selected from SEQ ID NO:100200-100295, and (iv) HCDR1 containing an amino acid sequence that differs from the sequence selected from SEQ ID NO:1009, 100150 and 100200-100295 by a maximum of five, four, three or two amino acids.

[0442] (b) HCDR2, selected from: (i) HCDR2 comprising SEQ ID NO:10012, and (ii) HCDR2 comprising an amino acid sequence differing from SEQ ID NO:10012 by a maximum of five, four, three, or two amino acids, and

[0443] (c) HCDR3, selected from (i) HCDR3 comprising SEQ ID NO: 10015, (ii) HCDR3 comprising SEQ ID NO: 100152, wherein X1 is selected from L and M, and X2 is selected from E, I, K, L, M, Q, T, V, W, and Y, (iii) HCDR3 comprising SEQ ID NO: 100296-100314, and (iv) HCDR3 comprising an amino acid sequence differing from the sequence selected from SEQ ID NO: 10015, 100152, and 100296-100314 by a maximum of five, four, three, or two amino acids, and

[0444] The light chain variable region comprises four light chain framework regions (LFR1, LFR2, LFR3, and LFR4) containing SEQ ID NO: 100104, 100105, 100110, and 100107 respectively, and three light chain complementarity determination regions (LCDR1, LCDR2, and LCDR3), which include:

[0445] (a) LCDR1, selected from: (i) LCDR1 containing SEQ ID NO:10018, and (ii) LCDR1 containing an amino acid sequence that differs from SEQ ID NO:10018 by a maximum of five, four, three, or two amino acids.

[0446] (b) LCDR2, selected from: (i) LCDR2 comprising SEQ ID NO:10021, and (ii) LCDR2 comprising an amino acid sequence differing from SEQ ID NO:10021 by a maximum of five, four, three, or two amino acids, and

[0447] (c) LCDR3 selected from (i) LCDR3 comprising SEQ ID NO:10024, (ii) LCDR3 comprising SEQ ID NO:100155, wherein X1 is selected from Q and N, X2 is selected from D, E, H, N, Q and S, X3 is selected from A and G, and X4 is selected from D, F, K, N, R, S and T, (iii) LCDR3 selected from SEQ ID NO:100315-100482, and (iv) LCDR3 comprising an amino acid sequence differing from the sequence selected from SEQ ID NO:10024, 100155 and 100315-100482 by a maximum of five, four, three or two amino acids.

[0448] 207. The antibody or antigen-binding fragment of embodiment 206, wherein the HCDR1 contains SEQ ID NO:1009.

[0449] 208. The antibody or antigen-binding fragment of embodiment 206, wherein the HCDR1 contains SEQ ID NO:100150.

[0450] 209. The antibody or antigen-binding fragment of implementation scheme 208, provided that X1 is E.

[0451] 210. An antibody or antigen-binding fragment of implementation scheme 208 or implementation scheme 209, wherein X2 is selected from P and V.

[0452] 211. An antibody or antigen-binding fragment of any one of the implementation schemes 208-210, wherein X3 is selected from G, S and V.

[0453] 212. An antibody or antigen-binding fragment of any one of the implementation schemes 208-211, provided that X4 is F.

[0454] 213. An antibody or antigen-binding fragment of any one of the implementation schemes 208-212, provided that X5 is I.

[0455] 214. The antibody or antigen-binding fragment of embodiment 206, wherein the HCDR1 comprises an amino acid sequence selected from SEQ ID NO:100200-100295.

[0456] 215. An antibody or antigen-binding fragment of any one of embodiments 206-214, wherein the HCDR2 contains SEQ ID NO:10012.

[0457] 216. An antibody or antigen-binding fragment of any of embodiments 206-214, wherein the HCDR2 comprises an amino acid sequence that differs from SEQ ID NO:10012 by a maximum of five, four, three, or two amino acids.

[0458] 217. An antibody or antigen-binding fragment of any one of embodiments 206-216, wherein the HCDR3 contains SEQ ID NO:10015.

[0459] 218. An antibody or antigen-binding fragment of any one of embodiments 206-216, wherein the HCDR3 contains SEQ ID NO:100152.

[0460] 219. The antibody or antigen-binding fragment of implementation scheme 218, provided that X1 is M.

[0461] 220. An antibody or antigen-binding fragment of implementation scheme 218 or implementation scheme 219, wherein X2 is selected from E, I, K, L, M, Q, T, W and Y.

[0462] 221. An antibody or antigen-binding fragment of any one of embodiments 206-220, wherein the HCDR3 comprises a sequence selected from SEQ ID NO:100296-100314.

[0463] 222. An antibody or antigen-binding fragment of any one of embodiments 206-221, wherein the LCDR1 contains SEQ ID NO:10018.

[0464] 223. An antibody or antigen-binding fragment of any of embodiments 206-221, wherein the LCDR1 contains an amino acid sequence that differs from SEQ ID NO:10018 by a maximum of five, four, three, or two amino acids.

[0465] 224. An antibody or antigen-binding fragment of any one of embodiments 206-223, wherein the LCDR2 contains SEQ ID NO:10021.

[0466] 225. An antibody or antigen-binding fragment of any one of embodiments 206-223, wherein the LCDR2 comprises an amino acid sequence that differs from SEQ ID NO:10021 by a maximum of five, four, three, or two amino acids.

[0467] 226. An antibody or antigen-binding fragment of any one of embodiments 206-225, wherein the LCDR3 contains SEQ ID NO:10024.

[0468] 227. An antibody or antigen-binding fragment of any one of embodiments 206-225, wherein the LCDR3 contains SEQ ID NO:100155.

[0469] 228. The antibody or antigen-binding fragment of implementation scheme 227, provided that X1 is N.

[0470] 229. An antibody or antigen-binding fragment of implementation scheme 227 or implementation scheme 228, wherein X2 is selected from D, E, H, N and Q.

[0471] 230. An antibody or antigen-binding fragment of any one of the implementation schemes 227-229, provided that X3 is A.

[0472] 231. An antibody or antigen-binding fragment of any one of the implementation schemes 227-230, wherein X4 is selected from D, F, K, R, S and T.

[0473] 232. An antibody or antigen-binding fragment of any one of embodiments 227-231, wherein the LCDR3 comprises an amino acid sequence selected from SEQ ID NO:100315-100482.

[0474] 233. The antibody or antigen-binding fragment of embodiment 206, wherein the HCDR1 contains SEQ ID NO:1009, the HCDR2 contains SEQ ID NO:10012, the HCDR3 contains SEQ ID NO:10015, the LCDR1 contains SEQ ID NO:10018, the LCDR2 contains SEQ ID NO:10021, and the LCDR3 contains SEQ ID NO:10024.

[0475] 234. The antibody or antigen-binding fragment of embodiment 206, wherein the HCDR1 contains SEQ ID NO:100150, the HCDR2 contains SEQ ID NO:10012, the HCDR3 contains SEQ ID NO:100152, the LCDR1 contains SEQ ID NO:10018, the LCDR2 contains SEQ ID NO:10021, and the LCDR3 contains SEQ ID NO:100155.

[0476] 235. The antibody or antigen-binding fragment of embodiment 206 or embodiment 234, provided that X1 of SEQ ID NO:100150 is D.

[0477] 236. The antibody or antigen-binding fragment of embodiment 206 or embodiment 234, provided that X1 of SEQ ID NO:100150 is E.

[0478] 237. An antibody or antigen-binding fragment of any one of embodiments 206, 234-236, provided that X2 of SEQ ID NO:100150 is I.

[0479] 238. An antibody or antigen-binding fragment of any one of embodiments 206, 234-236, provided that X2 of SEQ ID NO:100150 is P.

[0480] 239. An antibody or antigen-binding fragment of any one of embodiments 206, 234-236, provided that X2 of SEQ ID NO:100150 is V.

[0481] 240. An antibody or antigen-binding fragment of any one of embodiments 206, 234-239, provided that X3 of SEQ ID NO:100150 is G.

[0482] 241. An antibody or antigen-binding fragment of any one of embodiments 206, 234-239, provided that X3 of SEQ ID NO:100150 is Q.

[0483] 242. An antibody or antigen-binding fragment of any one of embodiments 206, 234-239, provided that X3 of SEQ ID NO:100150 is S.

[0484] 243. An antibody or antigen-binding fragment of any one of embodiments 206, 234-239, provided that X3 of SEQ ID NO:100150 is V.

[0485] 244. An antibody or antigen-binding fragment of any one of embodiments 206, 234-243, provided that X4 of SEQ ID NO:100150 is F.

[0486] 245. An antibody or antigen-binding fragment of any one of embodiments 206, 234-243, provided that X4 of SEQ ID NO:100150 is Y.

[0487] 246. An antibody or antigen-binding fragment of any one of embodiments 206, 234-245, provided that X5 of SEQ ID NO:100150 is I.

[0488] 247. An antibody or antigen-binding fragment of any one of embodiments 206, 234-245, provided that X5 of SEQ ID NO:100150 is M.

[0489] 248. An antibody or antigen-binding fragment of any one of embodiments 206, 234-247, provided that X1 of SEQ ID NO:100152 is L.

[0490] 249. An antibody or antigen-binding fragment of any one of embodiments 206, 234-247, provided that X1 of SEQ ID NO:100152 is M.

[0491] 250. An antibody or antigen-binding fragment of any one of embodiments 206, 234-249, provided that X2 of SEQ ID NO:100152 is E.

[0492] 251. An antibody or antigen-binding fragment of any one of embodiments 206, 234-249, provided that X2 of SEQ ID NO:100152 is I.

[0493] 252. An antibody or antigen-binding fragment of any one of embodiments 206, 234-249, provided that X2 of SEQ ID NO:100152 is K.

[0494] 253. An antibody or antigen-binding fragment of any one of embodiments 206, 234-249, provided that X2 of SEQ ID NO:100152 is L.

[0495] 254. An antibody or antigen-binding fragment of any one of embodiments 206, 234-249, provided that X2 of SEQ ID NO:100152 is M.

[0496] 255. An antibody or antigen-binding fragment of any one of embodiments 206, 234-249, provided that X2 of SEQ ID NO:100152 is Q.

[0497] 256. An antibody or antigen-binding fragment of any one of embodiments 206, 234-249, provided that X2 of SEQ ID NO:100152 is T.

[0498] 257. An antibody or antigen-binding fragment of any one of embodiments 206, 234-249, provided that X2 of SEQ ID NO:100152 is V.

[0499] 258. An antibody or antigen-binding fragment of any one of embodiments 206, 234-249, provided that X2 of SEQ ID NO:100152 is W.

[0500] 259. An antibody or antigen-binding fragment of any one of embodiments 206, 234-249, provided that X2 of SEQ ID NO:100152 is Y.

[0501] 260. An antibody or antigen-binding fragment of any one of embodiments 206, 234-259, provided that X1 of SEQ ID NO:100155 is Q.

[0502] 261. An antibody or antigen-binding fragment of any one of embodiments 206, 234-259, provided that X1 of SEQ ID NO:100155 is N.

[0503] 262. An antibody or antigen-binding fragment of any one of embodiments 206, 234-261, provided that X2 of SEQ ID NO:100155 is D.

[0504] 263. An antibody or antigen-binding fragment of any one of embodiments 206, 234-261, provided that X2 of SEQ ID NO:100155 is E.

[0505] 264. An antibody or antigen-binding fragment of any one of embodiments 206, 234-261, provided that X2 of SEQ ID NO:100155 is H.

[0506] 265. An antibody or antigen-binding fragment of any one of embodiments 206, 234-261, provided that X2 of SEQ ID NO:100155 is N.

[0507] 266. An antibody or antigen-binding fragment of any one of embodiments 206, 234-261, provided that X2 of SEQ ID NO:100155 is Q.

[0508] 267. An antibody or antigen-binding fragment of any one of embodiments 206, 234-261, provided that X2 of SEQ ID NO:100155 is S.

[0509] 268. An antibody or antigen-binding fragment of any one of embodiments 206, 234-267, provided that X3 of SEQ ID NO:100155 is A.

[0510] 269. An antibody or antigen-binding fragment of any one of embodiments 206, 234-267, provided that X3 of SEQ ID NO:100155 is G.

[0511] 270. An antibody or antigen-binding fragment of any one of embodiments 206, 234-269, provided that X4 of SEQ ID NO:100155 is D.

[0512] 271. An antibody or antigen-binding fragment of any one of embodiments 206, 234-269, provided that X4 of SEQ ID NO:100155 is F.

[0513] 272. An antibody or antigen-binding fragment of any one of embodiments 206, 234-269, provided that X4 of SEQ ID NO:100155 is K.

[0514] 273. An antibody or antigen-binding fragment of any one of embodiments 206, 234-269, provided that X4 of SEQ ID NO:100155 is N.

[0515] 274. An antibody or antigen-binding fragment of any one of embodiments 206, 234-269, provided that X4 of SEQ ID NO:100155 is R.

[0516] 275. An antibody or antigen-binding fragment of any one of embodiments 206, 234-269, provided that X4 of SEQ ID NO:100155 is S.

[0517] 276. An antibody or antigen-binding fragment of any one of embodiments 206, 234-269, provided that X4 of SEQ ID NO:100155 is T.

[0518] 277. An antibody or antigen-binding fragment of any one of embodiments 206-276, provided that the antibody or antigen-binding fragment specifically binds to human TL1A.

[0519] 278. The antibody or antigen-binding fragment of implementation scheme 277, wherein the antibody or antigen-binding fragment is in a 1x10-1 ratio. -9 M or lower K dIt specifically binds to human TL1A.

[0520] 279. The antibody or antigen-binding fragment of embodiment 278, wherein the K is measured using a method selected from standard ELISA assays and SPR. d .

[0521] 280. An antibody or antigen-binding fragment of any of embodiments 206-279, provided that the antibody or antigen-binding fragment inhibits the binding of DR3 to human TL1A.

[0522] 281. An antibody or antigen-binding fragment of any one of embodiments 206-280, wherein the antibody or antigen-binding fragment inhibits the binding of DcR3 to human TL1A.

[0523] 282. An antibody or antigen-binding fragment of any one of the implementation schemes 206-281, provided that the antibody or antigen-binding fragment is a humanized antibody, a CDR-transplanted antibody, a chimeric antibody, Fab, ScFv, or a combination thereof.

[0524] 283. An antibody or antigen-binding fragment comprising any one of embodiments 206-282, wherein the antibody or antigen-binding fragment comprises a human CH1 domain.

[0525] 284. An antibody or antigen-binding fragment comprising any one of embodiments 206-283, wherein the antibody or antigen-binding fragment contains a human CH2 domain.

[0526] 285. An antibody or antigen-binding fragment of embodiment 284, wherein the CH2 domain contains at least one mutation selected from L234A, L235A and G237A using Kabat numbering.

[0527] 286. An antibody or antigen-binding fragment comprising any one of embodiments 206-285, wherein the antibody or antigen-binding fragment contains a human CH3 domain.

[0528] 287. A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment of any one of embodiments 206-286, and a pharmaceutically acceptable carrier.

[0529] 288. A method of treating an inflammatory disease in a subject in need, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment of any one of embodiments 206-287.

[0530] 289. The method of implementing 288, wherein the inflammatory disease is inflammatory bowel disease.

[0531] 290. The method of implementation scheme 289, wherein the inflammatory bowel disease includes Crohn's disease.

[0532] 291. The method of implementation scheme 290, wherein it has been determined that the subject is unresponsive to anti-TNFα therapy.

[0533] 292. The method of implementation scheme 290 or implementation scheme 291, wherein the subject has been determined to have a disease phenotype including non-stenotic / non-penetrating, stenotic, stenotic and penetrating, or isolated internal penetrating.

[0534] 293. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0535] The heavy chain variable region comprises four heavy chain framework regions (HFR1, HFR2, HFR3, and HFR4) containing SEQ ID NO: 100108, 100101, 100109, and 100103 respectively, and three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), which include:

[0536] (a) HCDR1, selected from: (i) HCDR1 containing SEQ ID NO:1009, (ii) HCDR1 containing SEQ ID NO:100150, wherein X1 is selected from D and E, X2 is selected from I, P and V, X3 is selected from G, Q, S and V, X4 is selected from F and Y, and X5 is selected from I and M, (iii) HCDR1 selected from SEQ ID NO:100200-100295, and (iv) HCDR1 containing an amino acid sequence that differs from the sequence selected from SEQ ID NO:1009, 100150 and 100200-100295 by a maximum of five, four, three or two amino acids.

[0537] (b) HCDR2, selected from: (i) HCDR2 comprising SEQ ID NO:10012, and (ii) HCDR2 comprising an amino acid sequence differing from SEQ ID NO:10012 by a maximum of five, four, three, or two amino acids, and

[0538] (c) HCDR3, selected from (i) HCDR3 comprising SEQ ID NO: 10015, (ii) HCDR3 comprising SEQ ID NO: 100152, wherein X1 is selected from L and M, and X2 is selected from E, I, K, L, M, Q, T, V, W, and Y, (iii) HCDR3 comprising SEQ ID NO: 100296-100314, and (iv) HCDR3 comprising an amino acid sequence differing from the sequence selected from SEQ ID NO: 10015, 100152, and 100296-100314 by a maximum of five, four, three, or two amino acids, and

[0539] The light chain variable region comprises four light chain framework regions (LFR1, LFR2, LFR3, and LFR4) containing SEQ ID NO:100104-100107 and three light chain complementarity determination regions (LCDR1, LCDR2, and LCDR3), which include:

[0540] (a) LCDR1, selected from: (i) LCDR1 containing SEQ ID NO:10018, and (ii) LCDR1 containing an amino acid sequence that differs from SEQ ID NO:10018 by a maximum of five, four, three, or two amino acids.

[0541] (b) LCDR2, selected from: (i) LCDR2 comprising SEQ ID NO:10021, and (ii) LCDR2 comprising an amino acid sequence differing from SEQ ID NO:10021 by a maximum of five, four, three, or two amino acids, and

[0542] (c) LCDR3 selected from (i) LCDR3 comprising SEQ ID NO:10024, (ii) LCDR3 comprising SEQ ID NO:100155, wherein X1 is selected from Q and N, X2 is selected from D, E, H, N, Q and S, X3 is selected from A and G, and X4 is selected from D, F, K, N, R, S and T, (iii) LCDR3 selected from SEQ ID NO:100315-100482, and (iv) LCDR3 comprising an amino acid sequence differing from the sequence selected from SEQ ID NO:10024, 100155 and 100315-100482 by a maximum of five, four, three or two amino acids.

[0543] 294. The antibody or antigen-binding fragment of embodiment 293, wherein the HCDR1 contains SEQ ID NO:1009.

[0544] 295. The antibody or antigen-binding fragment of embodiment 293, wherein the HCDR1 contains SEQ ID NO:100150.

[0545] 296. The antibody or antigen-binding fragment of implementation scheme 295, provided that X1 is E.

[0546] 297. An antibody or antigen-binding fragment of implementation scheme 295 or implementation scheme 296, wherein X2 is selected from P and V.

[0547] 298. An antibody or antigen-binding fragment of any one of the implementation schemes 295-297, provided that X3 is selected from G, S, and V.

[0548] 299. An antibody or antigen-binding fragment of any one of the implementation schemes 295-298, provided that X4 is F.

[0549] 300. An antibody or antigen-binding fragment of any one of the implementation schemes 295-299, provided that X5 is I.

[0550] 301. The antibody or antigen-binding fragment of embodiment 293, wherein the HCDR1 comprises an amino acid sequence selected from SEQ ID NO:100200-100295.

[0551] 302. An antibody or antigen-binding fragment of any one of embodiments 293-301, wherein the HCDR2 contains SEQ ID NO:10012.

[0552] 303. An antibody or antigen-binding fragment of any one of embodiments 293-301, wherein the HCDR2 comprises an amino acid sequence that differs from SEQ ID NO:10012 by a maximum of five, four, three, or two amino acids.

[0553] 304. An antibody or antigen-binding fragment of any one of embodiments 293-303, wherein the HCDR3 contains SEQ ID NO:10015.

[0554] 305. An antibody or antigen-binding fragment of any one of embodiments 293-303, wherein the HCDR3 contains SEQ ID NO:100152.

[0555] 306. The antibody or antigen-binding fragment of implementation scheme 305, wherein X1 is M.

[0556] 307. An antibody or antigen-binding fragment of embodiment 305 or embodiment 306, wherein X2 is selected from E, I, K, L, M, Q, T, W and Y.

[0557] 308. An antibody or antigen-binding fragment of any one of embodiments 293-303, wherein the HCDR3 comprises a sequence selected from SEQ ID NO:100296-100314.

[0558] 309. An antibody or antigen-binding fragment of any one of embodiments 293-308, wherein the LCDR1 contains SEQ ID NO:10018.

[0559] 310. An antibody or antigen-binding fragment of any one of embodiments 293-308, wherein the LCDR1 contains an amino acid sequence that differs from SEQ ID NO:10018 by a maximum of five, four, three, or two amino acids.

[0560] 311. An antibody or antigen-binding fragment of any one of embodiments 293-310, wherein the LCDR2 contains SEQ ID NO:10021.

[0561] 312. An antibody or antigen-binding fragment of any one of embodiments 293-310, wherein the LCDR2 comprises an amino acid sequence that differs from SEQ ID NO:10021 by a maximum of five, four, three, or two amino acids.

[0562] 313. An antibody or antigen-binding fragment of any one of embodiments 293-312, wherein the LCDR3 contains SEQ ID NO:10024.

[0563] 314. An antibody or antigen-binding fragment of any one of embodiments 293-312, wherein the LCDR3 contains SEQ ID NO:100155.

[0564] 315. The antibody or antigen-binding fragment of implementation scheme 314, provided that X1 is N.

[0565] 316. An antibody or antigen-binding fragment of implementation scheme 314 or implementation scheme 315, wherein X2 is selected from D, E, H, N and Q.

[0566] 317. An antibody or antigen-binding fragment of any one of the implementation schemes 314-316, provided that X3 is A.

[0567] 318. An antibody or antigen-binding fragment of any one of the implementation schemes 314-317, wherein X4 is selected from D, F, K, R, S and T.

[0568] 319. An antibody or antigen-binding fragment of any one of embodiments 314-312, wherein the LCDR3 comprises an amino acid sequence selected from SEQ ID NO:100315-100482.

[0569] 320. The antibody or antigen-binding fragment of embodiment 293, wherein the HCDR1 contains SEQ ID NO:1009, the HCDR2 contains SEQ ID NO:10012, the HCDR3 contains SEQ ID NO:10015, the LCDR1 contains SEQ ID NO:10018, the LCDR2 contains SEQ ID NO:10021, and the LCDR3 contains SEQ ID NO:10024.

[0570] 321. The antibody or antigen-binding fragment of embodiment 293, wherein the HCDR1 contains SEQ ID NO:100150, the HCDR2 contains SEQ ID NO:10012, the HCDR3 contains SEQ ID NO:100152, the LCDR1 contains SEQ ID NO:10018, the LCDR2 contains SEQ ID NO:10021, and the LCDR3 contains SEQ ID NO:100155.

[0571] 322. The antibody or antigen-binding fragment of embodiment 293 or embodiment 321, provided that X1 of SEQ ID NO:100150 is D.

[0572] 323. An antibody or antigen-binding fragment of embodiment 293 or embodiment 321, provided that X1 of SEQ ID NO:100150 is E.

[0573] 324. An antibody or antigen-binding fragment of any one of embodiments 293, 321-323, provided that X2 of SEQ ID NO:100150 is I.

[0574] 325. An antibody or antigen-binding fragment of any one of embodiments 293, 321-323, provided that X2 of SEQ ID NO:100150 is P.

[0575] 326. An antibody or antigen-binding fragment of any one of embodiments 293, 321-323, provided that X2 of SEQ ID NO:100150 is V.

[0576] 327. An antibody or antigen-binding fragment of any one of embodiments 293, 321-326, provided that X3 of SEQ ID NO:100150 is G.

[0577] 328. An antibody or antigen-binding fragment of any one of embodiments 293, 321-326, provided that X3 of SEQ ID NO:100150 is Q.

[0578] 329. An antibody or antigen-binding fragment of any one of embodiments 293, 321-326, provided that X3 of SEQ ID NO:100150 is S.

[0579] 330. An antibody or antigen-binding fragment of any one of embodiments 293, 321-326, provided that X3 of SEQ ID NO:100150 is V.

[0580] 331. An antibody or antigen-binding fragment of any one of embodiments 293, 321-330, provided that X4 of SEQ ID NO:100150 is F.

[0581] 332. An antibody or antigen-binding fragment of any one of embodiments 293, 321-330, provided that X4 of SEQ ID NO:100150 is Y.

[0582] 333. An antibody or antigen-binding fragment of any one of embodiments 293, 321-332, provided that X5 of SEQ ID NO:100150 is I.

[0583] 334. An antibody or antigen-binding fragment of any one of embodiments 293, 321-332, provided that X5 of SEQ ID NO:100150 is M.

[0584] 335. An antibody or antigen-binding fragment of any one of embodiments 293, 321-334, provided that X1 of SEQ ID NO:100152 is L.

[0585] 336. An antibody or antigen-binding fragment of any one of embodiments 293, 321-334, provided that X1 of SEQ ID NO:100152 is M.

[0586] 337. An antibody or antigen-binding fragment of any one of embodiments 293, 321-336, provided that X2 of SEQ ID NO:100152 is E.

[0587] 338. An antibody or antigen-binding fragment of any one of embodiments 293, 321-336, provided that X2 of SEQ ID NO:100152 is I.

[0588] 339. An antibody or antigen-binding fragment of any one of embodiments 293, 321-336, provided that X2 of SEQ ID NO:100152 is K.

[0589] 340. An antibody or antigen-binding fragment of any one of embodiments 293, 321-336, provided that X2 of SEQ ID NO:100152 is L.

[0590] 341. An antibody or antigen-binding fragment of any one of embodiments 293, 321-336, provided that X2 of SEQ ID NO:100152 is M.

[0591] 342. An antibody or antigen-binding fragment of any one of embodiments 293, 321-336, provided that X2 of SEQ ID NO:100152 is Q.

[0592] 343. An antibody or antigen-binding fragment of any one of embodiments 293, 321-336, provided that X2 of SEQ ID NO:100152 is T.

[0593] 344. An antibody or antigen-binding fragment of any one of embodiments 293, 321-336, provided that X2 of SEQ ID NO:100152 is V.

[0594] 345. An antibody or antigen-binding fragment of any one of embodiments 293, 321-336, provided that X2 of SEQ ID NO:100152 is W.

[0595] 346. An antibody or antigen-binding fragment of any one of embodiments 293, 321-336, provided that X2 of SEQ ID NO:100152 is Y.

[0596] 347. An antibody or antigen-binding fragment of any one of embodiments 293, 321-346, provided that X1 of SEQ ID NO:100155 is Q.

[0597] 348. An antibody or antigen-binding fragment of any one of embodiments 293, 321-346, provided that X1 of SEQ ID NO:100155 is N.

[0598] 349. An antibody or antigen-binding fragment of any one of embodiments 293, 321-348, provided that X2 of SEQ ID NO:100155 is D.

[0599] 350. An antibody or antigen-binding fragment of any one of embodiments 293, 321-348, provided that X2 of SEQ ID NO:100155 is E.

[0600] 351. An antibody or antigen-binding fragment of any one of embodiments 293, 321-348, provided that X2 of SEQ ID NO:100155 is H.

[0601] 352. An antibody or antigen-binding fragment of any one of embodiments 293, 321-348, provided that X2 of SEQ ID NO:100155 is N.

[0602] 353. An antibody or antigen-binding fragment of any one of embodiments 293, 321-348, provided that X2 of SEQ ID NO:100155 is Q.

[0603] 354. An antibody or antigen-binding fragment of any one of embodiments 293, 321-348, provided that X2 of SEQ ID NO:100155 is S.

[0604] 355. An antibody or antigen-binding fragment of any one of embodiments 293, 321-354, provided that X3 of SEQ ID NO:100155 is A.

[0605] 356. An antibody or antigen-binding fragment of any one of embodiments 293, 321-354, provided that X3 of SEQ ID NO:100155 is G.

[0606] 357. An antibody or antigen-binding fragment of any one of embodiments 293, 321-356, provided that X4 of SEQ ID NO:100155 is D.

[0607] 358. An antibody or antigen-binding fragment of any one of embodiments 293, 321-356, provided that X4 of SEQ ID NO:100155 is F.

[0608] 359. An antibody or antigen-binding fragment of any one of embodiments 293, 321-356, provided that X4 of SEQ ID NO:100155 is K.

[0609] 360. An antibody or antigen-binding fragment of any one of embodiments 293, 321-356, provided that X4 of SEQ ID NO:100155 is N.

[0610] 361. An antibody or antigen-binding fragment of any one of embodiments 293, 321-356, provided that X4 of SEQ ID NO:100155 is R.

[0611] 362. An antibody or antigen-binding fragment of any one of embodiments 293, 321-356, provided that X4 of SEQ ID NO:100155 is S.

[0612] 363. An antibody or antigen-binding fragment of any one of embodiments 293, 321-356, provided that X4 of SEQ ID NO:100155 is T.

[0613] 364. An antibody or antigen-binding fragment of any one of embodiments 293-363, provided that the antibody or antigen-binding fragment specifically binds to human TL1A.

[0614] 365. The antibody or antigen-binding fragment of implementation scheme 364, wherein the antibody or antigen-binding fragment is in a 1x10-1 ratio. -9 M or lower K dIt specifically binds to human TL1A.

[0615] 366. The antibody or antigen-binding fragment of embodiment 365, wherein the K is measured using a method selected from standard ELISA assays and SPR. d .

[0616] 367. An antibody or antigen-binding fragment of any one of embodiments 293-366, provided that the antibody or antigen-binding fragment inhibits the binding of DR3 to human TL1A.

[0617] 368. An antibody or antigen-binding fragment of any one of embodiments 293-367, provided that the antibody or antigen-binding fragment inhibits the binding of DcR3 to human TL1A.

[0618] 369. An antibody or antigen-binding fragment of any one of embodiments 293-368, wherein the antibody or antigen-binding fragment is a humanized antibody, a CDR-transplanted antibody, a chimeric antibody, Fab, ScFv, or a combination thereof.

[0619] 370. An antibody or antigen-binding fragment comprising any one of embodiments 293-369, wherein the antibody or antigen-binding fragment comprises a human CH1 domain.

[0620] 371. An antibody or antigen-binding fragment comprising any one of embodiments 293-370, wherein the antibody or antigen-binding fragment comprises a human CH2 domain.

[0621] 372. An antibody or antigen-binding fragment of embodiment 371, wherein the CH2 domain contains at least one mutation selected from L234A, L235A and G237A using Kabat numbering.

[0622] 373. An antibody or antigen-binding fragment comprising any one of embodiments 293-372, wherein the antibody or antigen-binding fragment contains a human CH3 domain.

[0623] 374. A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment of any one of embodiments 293-373, and a pharmaceutically acceptable carrier.

[0624] 375. A method for treating an inflammatory disease in a subject in need, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment of any one of embodiments 293-373.

[0625] 376. The method of implementing 375, wherein the inflammatory disease is inflammatory bowel disease.

[0626] 377. The method of implementation scheme 376, wherein the inflammatory bowel disease includes Crohn's disease.

[0627] 378. The method of implementation scheme 377, wherein it has been determined that the subject is unresponsive to anti-TNFα therapy.

[0628] 379. The method of implementation scheme 377 or implementation scheme 378, wherein the subject has been determined to have a disease phenotype including non-stenotic / non-penetrating, stenotic, stenotic and penetrating, or isolated internal penetrating.

[0629] 380. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0630] The heavy chain variable region contains three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), which include:

[0631] (a) HCDR1, selected from: (i) HCDR1 containing SEQ ID NO:1009, (ii) HCDR1 containing SEQ ID NO:100150, wherein X1 is selected from D and E, X2 is selected from I, P and V, X3 is selected from G, Q, S and V, X4 is selected from F and Y, and X5 is selected from I and M, (iii) HCDR1 selected from SEQ ID NO:100200-100295, and (iv) HCDR1 containing an amino acid sequence that differs from the sequence selected from SEQ ID NO:1009, 100150 and 100200-100295 by a maximum of five, four, three or two amino acids.

[0632] (b) HCDR2, selected from: (i) HCDR2 comprising SEQ ID NO:10012, and (ii) HCDR2 comprising an amino acid sequence differing from SEQ ID NO:10012 by a maximum of five, four, three, or two amino acids, and

[0633] (c) HCDR3, selected from (i) HCDR3 comprising SEQ ID NO: 10015, (ii) HCDR3 comprising SEQ ID NO: 100152, wherein X1 is selected from L and M, and X2 is selected from E, I, K, L, M, Q, T, V, W, and Y, (iii) HCDR3 comprising SEQ ID NO: 100296-100314, and (iv) HCDR3 comprising an amino acid sequence differing from the sequence selected from SEQ ID NO: 10015, 100152, and 100296-100314 by a maximum of five, four, three, or two amino acids, and

[0634] The light chain variable region, which contains three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), includes:

[0635] (a) LCDR1, selected from: (i) LCDR1 containing SEQ ID NO:10018, and (ii) LCDR1 containing an amino acid sequence that differs from SEQ ID NO:10018 by a maximum of five, four, three, or two amino acids.

[0636] (b) LCDR2, selected from: (i) LCDR2 comprising SEQ ID NO:10021, and (ii) LCDR2 comprising an amino acid sequence differing from SEQ ID NO:10021 by a maximum of five, four, three, or two amino acids, and

[0637] (c) LCDR3 selected from (i) LCDR3 comprising SEQ ID NO:10024, (ii) LCDR3 comprising SEQ ID NO:100155, wherein X1 is selected from Q and N, X2 is selected from D, E, H, N, Q and S, X3 is selected from A and G, and X4 is selected from D, F, K, N, R, S and T, (iii) LCDR3 selected from SEQ ID NO:100315-100482, and (iv) LCDR3 comprising an amino acid sequence differing from the sequence selected from SEQ ID NO:10024, 100155 and 100315-100482 by a maximum of five, four, three or two amino acids.

[0638] 381. The antibody or antigen-binding fragment of embodiment 380, wherein the HCDR1 contains SEQ ID NO:100150, the HCDR2 contains SEQ ID NO:10012, the HCDR3 contains SEQ ID NO:100152, the LCDR1 contains SEQ ID NO:10018, the LCDR2 contains SEQ ID NO:10021, and the LCDR3 contains SEQ ID NO:100155.

[0639] 382. The antibody or antigen-binding fragment of embodiment 380 or embodiment 381, wherein X1 of SEQ ID NO:100150 is D.

[0640] 383. An antibody or antigen-binding fragment of embodiment 380 or embodiment 381, wherein X1 of SEQ ID NO:100150 is E.

[0641] 384. An antibody or antigen-binding fragment of any one of embodiments 380-383, provided that X2 of SEQ ID NO:100150 is I.

[0642] 385. An antibody or antigen-binding fragment of any one of embodiments 380-383, provided that X2 of SEQ ID NO:100150 is P.

[0643] 386. An antibody or antigen-binding fragment of any one of embodiments 380-383, provided that X2 of SEQ ID NO:100150 is V.

[0644] 387. An antibody or antigen-binding fragment of any one of embodiments 380-386, provided that X3 of SEQ ID NO:100150 is G.

[0645] 388. An antibody or antigen-binding fragment of any one of embodiments 380-386, provided that X3 of SEQ ID NO:100150 is Q.

[0646] 389. An antibody or antigen-binding fragment of any one of embodiments 380-386, provided that X3 of SEQ ID NO:100150 is S.

[0647] 390. An antibody or antigen-binding fragment of any one of embodiments 380-386, provided that X3 of SEQ ID NO:100150 is V.

[0648] 391. An antibody or antigen-binding fragment of any one of embodiments 380-390, provided that X4 of SEQ ID NO:100150 is F.

[0649] 392. An antibody or antigen-binding fragment of any one of embodiments 380-390, provided that X4 of SEQ ID NO:100150 is Y.

[0650] 393. An antibody or antigen-binding fragment of any one of embodiments 380-392, provided that X5 of SEQ ID NO:100150 is I.

[0651] 394. An antibody or antigen-binding fragment of any one of embodiments 380-392, provided that X5 of SEQ ID NO:100150 is M.

[0652] 395. An antibody or antigen-binding fragment of any one of embodiments 380-394, provided that X1 of SEQ ID NO:100152 is L.

[0653] 396. An antibody or antigen-binding fragment of any one of embodiments 380-394, provided that X1 of SEQ ID NO:100152 is M.

[0654] 397. An antibody or antigen-binding fragment of any one of embodiments 380-396, provided that X2 of SEQ ID NO:100152 is E.

[0655] 398. An antibody or antigen-binding fragment of any one of embodiments 380-396, provided that X2 of SEQ ID NO:100152 is I.

[0656] 399. An antibody or antigen-binding fragment of any one of embodiments 380-396, provided that X2 of SEQ ID NO:100152 is K.

[0657] 400. An antibody or antigen-binding fragment of any one of embodiments 380-396, provided that X2 of SEQ ID NO:100152 is L.

[0658] 401. An antibody or antigen-binding fragment of any one of embodiments 380-396, provided that X2 of SEQ ID NO:100152 is M.

[0659] 402. An antibody or antigen-binding fragment of any one of embodiments 380-396, provided that X2 of SEQ ID NO:100152 is Q.

[0660] 403. An antibody or antigen-binding fragment of any one of embodiments 380-396, provided that X2 of SEQ ID NO:100152 is T.

[0661] 404. An antibody or antigen-binding fragment of any one of embodiments 380-396, provided that X2 of SEQ ID NO:100152 is V.

[0662] 405. An antibody or antigen-binding fragment of any one of embodiments 380-396, provided that X2 of SEQ ID NO:100152 is W.

[0663] 406. An antibody or antigen-binding fragment of any one of embodiments 380-396, provided that X2 of SEQ ID NO:100152 is Y.

[0664] 407. An antibody or antigen-binding fragment of any one of embodiments 380-406, provided that X1 of SEQ ID NO:100155 is Q.

[0665] 408. An antibody or antigen-binding fragment of any one of embodiments 380-406, provided that X1 of SEQ ID NO:100155 is N.

[0666] 409. An antibody or antigen-binding fragment of any one of embodiments 380-408, provided that X2 of SEQ ID NO:100155 is D.

[0667] 410. An antibody or antigen-binding fragment of any one of embodiments 380-408, provided that X2 of SEQ ID NO:100155 is E.

[0668] 411. An antibody or antigen-binding fragment of any one of embodiments 380-408, provided that X2 of SEQ ID NO:100155 is H.

[0669] 412. An antibody or antigen-binding fragment of any one of embodiments 380-408, provided that X2 of SEQ ID NO:100155 is N.

[0670] 413. An antibody or antigen-binding fragment of any one of embodiments 380-408, provided that X2 of SEQ ID NO:100155 is Q.

[0671] 414. An antibody or antigen-binding fragment of any one of embodiments 380-408, provided that X2 of SEQ ID NO:100155 is S.

[0672] 415. An antibody or antigen-binding fragment of any one of embodiments 380-414, provided that X3 of SEQ ID NO:100155 is A.

[0673] 416. An antibody or antigen-binding fragment of any one of embodiments 380-414, provided that X3 of SEQ ID NO:100155 is G.

[0674] 417. An antibody or antigen-binding fragment of any one of embodiments 380-416, provided that X4 of SEQ ID NO:100155 is D.

[0675] 418. An antibody or antigen-binding fragment of any one of embodiments 380-416, provided that X4 of SEQ ID NO:100155 is F.

[0676] 419. An antibody or antigen-binding fragment of any one of embodiments 380-416, provided that X4 of SEQ ID NO:100155 is K.

[0677] 420. An antibody or antigen-binding fragment of any one of embodiments 380-416, provided that X4 of SEQ ID NO:100155 is N.

[0678] 421. An antibody or antigen-binding fragment of any one of embodiments 380-416, provided that X4 of SEQ ID NO:100155 is R.

[0679] 422. An antibody or antigen-binding fragment of any one of embodiments 380-416, provided that X4 of SEQ ID NO:100155 is S.

[0680] 423. An antibody or antigen-binding fragment of any one of embodiments 380-416, provided that X4 of SEQ ID NO:100155 is T.

[0681] 424. An antibody or antigen-binding fragment of any one of embodiments 380-423, provided that the antibody or antigen-binding fragment specifically binds to human TL1A.

[0682] 425. The antibody or antigen-binding fragment of embodiment 424, wherein the antibody or antigen-binding fragment is in a 1x10-1 ratio. -9 M or lower K d It specifically binds to human TL1A.

[0683] 426. The antibody or antigen-binding fragment of embodiment 425, wherein the K is measured using a method selected from standard ELISA assays and SPR. d .

[0684] 427. An antibody or antigen-binding fragment of any one of embodiments 380-426, provided that the antibody or antigen-binding fragment inhibits the binding of DR3 to human TL1A.

[0685] 428. An antibody or antigen-binding fragment of any one of embodiments 380-427, provided that the antibody or antigen-binding fragment inhibits the binding of DcR3 to human TL1A.

[0686] 429. An antibody or antigen-binding fragment of any one of embodiments 380-428, wherein the antibody or antigen-binding fragment is a humanized antibody, a CDR-transplanted antibody, a chimeric antibody, Fab, ScFv, or a combination thereof.

[0687] 430. An antibody or antigen-binding fragment comprising any one of embodiments 380-429, wherein the antibody or antigen-binding fragment comprises a human CH1 domain.

[0688] 431. An antibody or antigen-binding fragment comprising any one of embodiments 380-430, wherein the antibody or antigen-binding fragment comprises a human CH2 domain.

[0689] 432. An antibody or antigen-binding fragment of embodiment 431, wherein the CH2 domain contains at least one mutation selected from L234A, L235A and G237A using Kabat numbering.

[0690] 433. An antibody or antigen-binding fragment comprising any one of embodiments 380-432, wherein the antibody or antigen-binding fragment comprises a human CH3 domain.

[0691] 434. A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment of any one of embodiments 380-433, and a pharmaceutically acceptable carrier.

[0692] 435. A method for treating an inflammatory disease in a subject in need, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment of any one of embodiments 380-433.

[0693] 436. The method of implementing 435, wherein the inflammatory disease is inflammatory bowel disease.

[0694] 437. The method of implementation scheme 436, wherein the inflammatory bowel disease includes Crohn's disease.

[0695] 438. The method of implementation scheme 437, provided that it has been determined that the subject is unresponsive to anti-TNFα therapy.

[0696] 439. The method of implementation scheme 437 or implementation scheme 438, wherein the subject has been determined to have a disease phenotype including non-stenotic / non-penetrating, stenotic, stenotic and penetrating, or isolated internal penetrating.

[0697] 440. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region comprising SEQ ID NO:10052 or SEQ ID NO:10054, and a light chain variable region comprising SEQ ID NO:10053.

[0698] 441. The antibody or antigen-binding fragment of embodiment 440, wherein the heavy chain variable region contains SEQ ID NO: 10052.

[0699] 442. The antibody or antigen-binding fragment of embodiment 440, wherein the heavy chain variable region contains SEQ ID NO: 10054.

[0700] 443. An antibody or antigen-binding fragment of any one of embodiments 440-442, provided that X1 of SEQ ID NO:10052 or SEQ ID NO:10054 is D.

[0701] 444. An antibody or antigen-binding fragment of any one of embodiments 440-442, provided that X1 of SEQ ID NO:10052 or SEQ ID NO:10054 is E.

[0702] 445. An antibody or antigen-binding fragment of any one of embodiments 440-444, provided that X2 of SEQ ID NO:10052 or SEQ ID NO:10054 is I.

[0703] 446. An antibody or antigen-binding fragment of any one of embodiments 440-444, provided that X2 of SEQ ID NO:10052 or SEQ ID NO:10054 is P.

[0704] 447. An antibody or antigen-binding fragment of any one of embodiments 440-444, provided that X2 of SEQ ID NO:10052 or SEQ ID NO:10054 is V.

[0705] 448. An antibody or antigen-binding fragment of any one of embodiments 440-447, provided that X3 of SEQ ID NO:10052 or SEQ ID NO:10054 is G.

[0706] 449. An antibody or antigen-binding fragment of any one of embodiments 440-447, provided that X3 of SEQ ID NO:10052 or SEQ ID NO:10054 is Q.

[0707] 450. An antibody or antigen-binding fragment of any one of embodiments 440-447, provided that X3 of SEQ ID NO:10052 or SEQ ID NO:10054 is S.

[0708] 451. An antibody or antigen-binding fragment of any one of embodiments 440-447, provided that X3 of SEQ ID NO:10052 or SEQ ID NO:10054 is V.

[0709] 452. An antibody or antigen-binding fragment of any one of embodiments 440-451, provided that X4 of SEQ ID NO:10052 or SEQ ID NO:10054 is F.

[0710] 453. An antibody or antigen-binding fragment of any one of embodiments 440-451, provided that X4 of SEQ ID NO:10052 or SEQ ID NO:10054 is Y.

[0711] 454. An antibody or antigen-binding fragment of any one of embodiments 440-453, provided that X5 of SEQ ID NO:10052 or SEQ ID NO:10054 is I.

[0712] 455. An antibody or antigen-binding fragment of any one of embodiments 440-453, provided that X5 of SEQ ID NO:10052 or SEQ ID NO:10054 is M.

[0713] 456. An antibody or antigen-binding fragment of any one of embodiments 440-455, provided that X6 of SEQ ID NO:10052 or SEQ ID NO:10054 is L.

[0714] 457. An antibody or antigen-binding fragment of any one of embodiments 440-455, provided that X6 of SEQ ID NO:10052 or SEQ ID NO:10054 is M.

[0715] 458. An antibody or antigen-binding fragment of any one of embodiments 440-457, provided that X7 of SEQ ID NO:10052 or SEQ ID NO:10054 is E.

[0716] 459. An antibody or antigen-binding fragment of any one of embodiments 440-457, provided that X7 of SEQ ID NO:10052 or SEQ ID NO:10054 is I.

[0717] 460. An antibody or antigen-binding fragment of any one of embodiments 440-457, provided that X7 of SEQ ID NO:10052 or SEQ ID NO:10054 is K.

[0718] 461. An antibody or antigen-binding fragment of any one of embodiments 440-457, provided that X7 of SEQ ID NO:10052 or SEQ ID NO:10054 is L.

[0719] 462. An antibody or antigen-binding fragment of any one of embodiments 440-457, provided that X7 of SEQ ID NO:10052 or SEQ ID NO:10054 is M.

[0720] 463. An antibody or antigen-binding fragment of any one of embodiments 440-457, provided that X7 of SEQ ID NO:10052 or SEQ ID NO:10054 is Q.

[0721] 464. An antibody or antigen-binding fragment of any one of embodiments 440-457, provided that X7 of SEQ ID NO:10052 or SEQ ID NO:10054 is T.

[0722] 465. An antibody or antigen-binding fragment of any one of embodiments 440-457, provided that X7 of SEQ ID NO:10052 or SEQ ID NO:10054 is V.

[0723] 466. An antibody or antigen-binding fragment of any one of embodiments 440-457, provided that X7 of SEQ ID NO:10052 or SEQ ID NO:10054 is W.

[0724] 467. An antibody or antigen-binding fragment of any one of embodiments 440-457, provided that X7 of SEQ ID NO:10052 or SEQ ID NO:10054 is Y.

[0725] 468. An antibody or antigen-binding fragment of any one of embodiments 440-467, provided that X1 of SEQ ID NO:10053 is Q.

[0726] 469. An antibody or antigen-binding fragment of any one of embodiments 440-467, provided that X1 of SEQ ID NO:10053 is N.

[0727] 470. An antibody or antigen-binding fragment of any one of embodiments 440-469, provided that X2 of SEQ ID NO:10053 is D.

[0728] 471. An antibody or antigen-binding fragment of any one of embodiments 440-469, provided that X2 of SEQ ID NO:10053 is E.

[0729] 472. An antibody or antigen-binding fragment of any one of embodiments 440-469, provided that X2 of SEQ ID NO:10053 is H.

[0730] 473. An antibody or antigen-binding fragment of any one of embodiments 440-469, provided that X2 of SEQ ID NO:10053 is N.

[0731] 474. An antibody or antigen-binding fragment of any one of embodiments 440-469, provided that X2 of SEQ ID NO:10053 is Q.

[0732] 475. An antibody or antigen-binding fragment of any one of embodiments 440-469, provided that X2 of SEQ ID NO:10053 is S.

[0733] 476. An antibody or antigen-binding fragment of any one of embodiments 440-475, provided that X3 of SEQ ID NO:10053 is A.

[0734] 477. An antibody or antigen-binding fragment of any one of embodiments 440-475, provided that X3 of SEQ ID NO:10053 is G.

[0735] 478. An antibody or antigen-binding fragment of any one of embodiments 440-477, provided that X4 of SEQ ID NO:10053 is D.

[0736] 479. An antibody or antigen-binding fragment of any one of embodiments 440-477, provided that X4 of SEQ ID NO:10053 is F.

[0737] 480. An antibody or antigen-binding fragment of any one of embodiments 440-477, provided that X4 of SEQ ID NO:10053 is K.

[0738] 481. An antibody or antigen-binding fragment of any one of embodiments 440-477, provided that X4 of SEQ ID NO:10053 is N.

[0739] 482. An antibody or antigen-binding fragment of any one of embodiments 440-477, provided that X4 of SEQ ID NO:10053 is R.

[0740] 483. An antibody or antigen-binding fragment of any one of embodiments 440-477, provided that X4 of SEQ ID NO:10053 is S.

[0741] 484. An antibody or antigen-binding fragment of any one of embodiments 440-477, provided that X4 of SEQ ID NO:10053 is T.

[0742] 485. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: the heavy chain variable region of SEQ ID NO:10036 and the light chain variable region of SEQ ID NO:10038.

[0743] 486. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: the heavy chain variable region of SEQ ID NO:10040 and the light chain variable region of SEQ ID NO:10042.

[0744] 487. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: the heavy chain variable region of SEQ ID NO:10040 and the light chain variable region of SEQ ID NO:10038.

[0745] 488. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO:10044 and a light chain variable region of SEQ ID NO:10038.

[0746] 489. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO:10043 and a light chain variable region of SEQ ID NO:10038.

[0747] 490. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO:10045 and a light chain variable region of SEQ ID NO:10038.

[0748] 491. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO:10046 and a light chain variable region of SEQ ID NO:10038.

[0749] 492. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO:10040 and a light chain variable region of SEQ ID NO:10047.

[0750] 493. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: the heavy chain variable region of SEQ ID NO:10040 and the light chain variable region of SEQ ID NO:10048.

[0751] 494. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO:10040 and a light chain variable region of SEQ ID NO:10049.

[0752] 495. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: the heavy chain variable region of SEQ ID NO:10040 and the light chain variable region of SEQ ID NO:10050.

[0753] 496. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising: a heavy chain variable region of SEQ ID NO:10040 and a light chain variable region of SEQ ID NO:10051.

[0754] 497. An antibody or antigen-binding fragment of any one of embodiments 440-496, provided that the antibody or antigen-binding fragment specifically binds to human TL1A.

[0755] 498. The antibody or antigen-binding fragment of embodiment 497, wherein the antibody or antigen-binding fragment is in a 1x10-1 ratio. -9 M or lower K d It specifically binds to human TL1A.

[0756] 499. The antibody or antigen-binding fragment of embodiment 498, wherein the K is measured using a method selected from standard ELISA assays and SPR. d .

[0757] 500. An antibody or antigen-binding fragment of any one of embodiments 440-499, provided that the antibody or antigen-binding fragment inhibits the binding of DR3 to human TL1A.

[0758] 501. An antibody or antigen-binding fragment of any one of embodiments 440-500, wherein the antibody or antigen-binding fragment inhibits the binding of DcR3 to human TL1A.

[0759] 502. An antibody or antigen-binding fragment of any one of embodiments 440-501, wherein the antibody or antigen-binding fragment is a humanized antibody, a CDR-transplanted antibody, a chimeric antibody, Fab, ScFv, or a combination thereof.

[0760] 503. An antibody or antigen-binding fragment comprising any one of embodiments 440-502, wherein the antibody or antigen-binding fragment comprises a human CH1 domain.

[0761] 504. An antibody or antigen-binding fragment comprising any one of embodiments 440-503, wherein the antibody or antigen-binding fragment comprises a human CH2 domain.

[0762] 505. An antibody or antigen-binding fragment of embodiment 504, wherein the CH2 domain contains at least one mutation selected from L234A, L235A and G237A using Kabat numbering.

[0763] 506. An antibody or antigen-binding fragment comprising any one of embodiments 440-505, wherein the antibody or antigen-binding fragment comprises a human CH3 domain.

[0764] 507. A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment of any one of embodiments 440-506, and a pharmaceutically acceptable carrier.

[0765] 508. A method for treating an inflammatory disease in a subject in need, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment of any one of embodiments 440-506.

[0766] 509. The method of implementation plan 508, wherein the inflammatory disease is inflammatory bowel disease.

[0767] 510. The method of implementation scheme 509, wherein the inflammatory bowel disease includes Crohn's disease.

[0768] 511. The method of implementation scheme 510, wherein it has been determined that the subject is unresponsive to anti-TNFα therapy.

[0769] 512. The method of implementation scheme 510 or implementation scheme 511, wherein the subject has been determined to have a disease phenotype including non-stenotic / non-penetrating, stenotic, stenotic and penetrating, or isolated internal penetrating.

[0770] 513. An antibody or antigen-binding fragment of any one of implementation schemes 1-112, 119-199, 206-286, 293-373, 380-433 and 440-506 that binds to the same region of human TL1A as the reference antibody.

[0771] 514. An antibody or antigen-binding fragment that binds to the same region of human TL1A as a reference antibody, comprising the heavy chain variable region of SEQ ID NO:10036 and the light chain variable region of SEQ ID NO:10038.

[0772] 515. An antibody or antigen-binding fragment that binds to the same region of human TL1A as a reference antibody, comprising the heavy chain variable region of SEQ ID NO:10040 and the light chain variable region of SEQ ID NO:10042.

[0773] 516. An antibody or antigen-binding fragment that binds to the same region of human TL1A as a reference antibody, comprising the heavy chain variable region of SEQ ID NO:10040 and the light chain variable region of SEQ ID NO:10038.

[0774] 517. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0775] Heavy chain variable region, which includes:

[0776] (a) HCDR1 containing the amino acid sequence shown in SEQ ID NO:553;

[0777] (b) HCDR2 comprising the amino acid sequence shown in any one of SEQ ID NO: 554 to 564 or 574 to 577; and

[0778] (c) HCDR3 comprising the amino acid sequence shown in any one of SEQ ID NO: 565 to 568 or 578 to 581; and

[0779] The light chain variable region, which includes:

[0780] (d) LCDR1 containing the amino acid sequence shown in either SEQ ID NO:569 or 570;

[0781] (e) LCDR2 comprising the amino acid sequence shown in SEQ ID NO:488; and

[0782] (f) LCDR3 comprising the amino acid sequence shown in any one of SEQ ID NO:571 to 573 or 582 to 585.

[0783] 518. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0784] Heavy chain variable region, which includes:

[0785] (a) HCDR1 containing the amino acid sequence shown in SEQ ID NO:553;

[0786] (b) HCDR2 comprising the amino acid sequence shown in SEQ ID NO:559; and

[0787] (c) HCDR3 comprising the amino acid sequence shown in SEQ ID NO:567; and

[0788] The light chain variable region, which includes:

[0789] (d) LCDR1 containing the amino acid sequence shown in SEQ ID NO:569;

[0790] (e) LCDR2 comprising the amino acid sequence shown in SEQ ID NO:488; and

[0791] (f) LCDR3 containing the amino acid sequence shown in SEQ ID NO:573.

[0792] 519. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0793] Heavy chain variable region, which includes:

[0794] (a) HCDR1 containing the amino acid sequence shown in SEQ ID NO:553;

[0795] (b) HCDR2 comprising the amino acid sequence shown in SEQ ID NO:563; and

[0796] (c) HCDR3 comprising the amino acid sequence shown in SEQ ID NO:568; and

[0797] The light chain variable region, which includes:

[0798] (d) LCDR1 containing the amino acid sequence shown in SEQ ID NO:569;

[0799] (e) LCDR2 comprising the amino acid sequence shown in SEQ ID NO:488; and

[0800] (f) LCDR3 containing the amino acid sequence shown in SEQ ID NO:572.

[0801] 520. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0802] Heavy chain variable region, which includes:

[0803] (a) HCDR1 containing the amino acid sequence shown in SEQ ID NO:553;

[0804] (b) HCDR2 comprising the amino acid sequence shown in SEQ ID NO:555; and

[0805] (c) HCDR3 comprising the amino acid sequence shown in SEQ ID NO:566; and

[0806] The light chain variable region, which includes:

[0807] (d) LCDR1 containing the amino acid sequence shown in SEQ ID NO:569;

[0808] (e) LCDR2 comprising the amino acid sequence shown in SEQ ID NO:488; and

[0809] (f) LCDR3 containing the amino acid sequence shown in SEQ ID NO:572.

[0810] 521. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0811] Heavy chain variable region, which includes:

[0812] (a) HCDR1 containing the amino acid sequence shown in SEQ ID NO:553;

[0813] (b) HCDR2 comprising the amino acid sequence shown in SEQ ID NO:558; and

[0814] (c) HCDR3 comprising the amino acid sequence shown in SEQ ID NO:566; and

[0815] The light chain variable region, which includes:

[0816] (d) LCDR1 containing the amino acid sequence shown in SEQ ID NO:569;

[0817] (e) LCDR2 comprising the amino acid sequence shown in SEQ ID NO:488; and

[0818] (f) LCDR3 containing the amino acid sequence shown in SEQ ID NO:572.

[0819] 522. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0820] Heavy chain variable region, which includes:

[0821] (a) HCDR1 containing the amino acid sequence shown in SEQ ID NO:553;

[0822] (b) HCDR2 comprising the amino acid sequence shown in SEQ ID NO:564; and

[0823] (c) HCDR3 comprising the amino acid sequence shown in SEQ ID NO:568; and

[0824] The light chain variable region, which includes:

[0825] (d) LCDR1 containing the amino acid sequence shown in SEQ ID NO:569;

[0826] (e) LCDR2 comprising the amino acid sequence shown in SEQ ID NO:488; and

[0827] (f) LCDR3 containing the amino acid sequence shown in SEQ ID NO:572.

[0828] 523. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0829] (a) A heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 from any one of SEQ ID NO: 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, or 541; and

[0830] (b) A light chain variable region comprising LCDR1, LCDR2, and LCDR3 from any one of SEQ ID NO: 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, or 540; wherein the CDR is defined by the Kabat, Chothia, or IMGT method or a combination thereof.

[0831] 524. An antibody or antigen-binding fragment of any one of embodiments 517 to 523, comprising at least 90%, 95%, 96%, 97%, 98%, or 99% of the same human heavy chain framework region 1 as shown in SEQ ID NO: 545.

[0832] 525. An antibody or antigen-binding fragment of any one of embodiments 517 to 524, comprising at least 90%, 95%, 96%, 97%, 98%, or 99% of the same human heavy chain framework region 2 as shown in SEQ ID NO: 546.

[0833] 526. An antibody or antigen-binding fragment of any one of embodiments 517 to 525, comprising at least 90%, 95%, 96%, 97%, 98%, or 99% of the same human heavy chain framework region 3 as shown in SEQ ID NO: 547 or 586 to 588.

[0834] 527. An antibody or antigen-binding fragment of any one of embodiments 517 to 526, comprising at least 90%, 95%, 96%, 97%, 98%, or 99% of the same human heavy chain framework region 4 as shown in SEQ ID NO: 548.

[0835] 528. An antibody or antigen-binding fragment of any one of embodiments 517 to 527, comprising at least 90%, 95%, 96%, 97%, 98%, or 99% of the same human light chain framework region 1 as shown in SEQ ID NO: 549.

[0836] 529. An antibody or antigen-binding fragment of any one of embodiments 517 to 528, comprising at least 90%, 95%, 96%, 97%, 98%, or 99% of the same human light chain framework region 2 as shown in SEQ ID NO: 550.

[0837] 530. An antibody or antigen-binding fragment of any one of embodiments 517 to 529, comprising at least 90%, 95%, 96%, 97%, 98%, or 99% of the same human light chain framework region 3 as shown in SEQ ID NO: 551.

[0838] 531. An antibody or antigen-binding fragment of any one of embodiments 517 to 530, comprising at least 90%, 95%, 96%, 97%, 98%, or 99% of the same human light chain framework region 4 as shown in SEQ ID NO: 552.

[0839] 532. An antibody or antigen-binding fragment of any one of embodiments 517 to 531, comprising:

[0840] (a) Human heavy chain framework region 1, which is at least 90% identical to that shown in SEQ ID NO:545;

[0841] (b) Human heavy chain framework region 2, which is at least 90% identical to that shown in SEQ ID NO:546;

[0842] (c) Human heavy chain framework region 3, which is at least 90% identical to that shown in SEQ ID NO: 547 or 586 to 588;

[0843] (d) Human heavy chain framework region 4, which is at least 90% identical to that shown in SEQ ID NO:548;

[0844] (e) Human light chain framework region 1, which is at least 90% identical to that shown in SEQ ID NO:549;

[0845] (f) Human light chain framework region 2, which is at least 90% identical to that shown in SEQ ID NO:550;

[0846] (g) a human light chain framework region 3 that is at least 90% identical to that shown in SEQ ID NO:551; and

[0847] (h) is at least 90% identical to the human light chain framework region 4 shown in SEQ ID NO:552.

[0848] 533. The antibody or antigen-binding fragment of embodiment 532, comprising:

[0849] (a) Human heavy chain framework region 1, which is at least 95% identical to that shown in SEQ ID NO:545;

[0850] (b) Human heavy chain framework region 2, which is at least 95% identical to that shown in SEQ ID NO:546;

[0851] (c) Human heavy chain framework region 3, which is at least 95% identical to that shown in SEQ ID NO: 547 or 586 to 588;

[0852] (d) Human heavy chain framework region 4, which is at least 95% identical to that shown in SEQ ID NO:548;

[0853] (e) Human light chain framework region 1, which is at least 95% identical to that shown in SEQ ID NO:549;

[0854] (f) Human light chain framework region 2, which is at least 95% identical to that shown in SEQ ID NO:550;

[0855] (g) a human light chain framework region 3 that is at least 95% identical to that shown in SEQ ID NO:551; and

[0856] (h) is at least 95% identical to the human light chain framework region 4 shown in SEQ ID NO:552.

[0857] 534. The antibody or antigen-binding fragment of embodiment 532, comprising:

[0858] (a) Human heavy chain framework region 1, which is at least 97% identical to that shown in SEQ ID NO:545;

[0859] (b) Human heavy chain framework region 2, which is at least 97% identical to that shown in SEQ ID NO:546;

[0860] (c) Human heavy chain framework region 3, which is at least 97% identical to that shown in SEQ ID NO: 547 or 586 to 588;

[0861] (d) Human heavy chain framework region 4, which is at least 97% identical to that shown in SEQ ID NO:548;

[0862] (e) Human light chain framework region 1, which is at least 97% identical to that shown in SEQ ID NO:549;

[0863] (f) Human light chain framework region 2, which is at least 97% identical to that shown in SEQ ID NO:550;

[0864] (g) a human light chain framework region 3 that is at least 97% identical to that shown in SEQ ID NO:551; and

[0865] (h) is at least 97% identical to the human light chain framework region 4 shown in SEQ ID NO:552.

[0866] 535. The antibody or antigen-binding fragment of embodiment 532, comprising:

[0867] (a) Human heavy chain framework region 1, which is at least 98% identical to that shown in SEQ ID NO:545;

[0868] (b) Human heavy chain framework region 2, which is at least 98% identical to that shown in SEQ ID NO:546;

[0869] (c) Human heavy chain framework region 3, which is at least 98% identical to that shown in SEQ ID NO: 547 or 586 to 588;

[0870] (d) Human heavy chain framework region 4, which is at least 98% identical to that shown in SEQ ID NO:548;

[0871] (e) Human light chain framework region 1, which is at least 98% identical to that shown in SEQ ID NO:549;

[0872] (f) Human light chain framework region 2, which is at least 98% identical to that shown in SEQ ID NO:550;

[0873] (g) a human light chain framework region 3 that is at least 98% identical to that shown in SEQ ID NO:551; and

[0874] (h) is at least 98% identical to the human light chain framework region 4 shown in SEQ ID NO:552.

[0875] 536. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0876] (a) A heavy chain variable region comprising at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical amino acid sequences to any one of SEQ ID NO: 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, or 541; and

[0877] (b) A light chain variable region comprising at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% of the same amino acid sequence as any one of SEQ ID NO: 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, or 540.

[0878] 537. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0879] (a) a heavy chain variable region comprising at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% of the same amino acid sequence as SEQ ID NO:503; and

[0880] (b) Light chain variable region containing at least about 85%, 90%, 95%, 97%, 98%, 99% or 100% of the same amino acid sequence as SEQ ID NO:502.

[0881] 538. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0882] (a) a heavy chain variable region comprising at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% of the same amino acid sequence as SEQ ID NO:511; and

[0883] (b) Light chain variable region containing at least about 85%, 90%, 95%, 97%, 98%, 99% or 100% of the same amino acid sequence as SEQ ID NO:510.

[0884] 539. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0885] (a) a heavy chain variable region comprising at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% of the same amino acid sequence as SEQ ID NO:493; and

[0886] (b) Light chain variable region containing at least about 85%, 90%, 95%, 97%, 98%, 99% or 100% of the same amino acid sequence as SEQ ID NO:492.

[0887] 540. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0888] (a) a heavy chain variable region comprising at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% of the same amino acid sequence as SEQ ID NO:501; and

[0889] (b) Light chain variable region containing at least about 85%, 90%, 95%, 97%, 98%, 99% or 100% of the same amino acid sequence as SEQ ID NO:500.

[0890] 541. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising:

[0891] (a) a heavy chain variable region comprising at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% of the same amino acid sequence as SEQ ID NO:515; and

[0892] (b) Light chain variable region containing at least about 85%, 90%, 95%, 97%, 98%, 99% or 100% of the same amino acid sequence as SEQ ID NO:514.

[0893] 542. An antibody or antigen-binding fragment of any one of embodiments 517 to 541, wherein the antibody or antigen-binding fragment is chimeric or humanized.

[0894] 543. An antibody or antigen-binding fragment of any one of embodiments 517 to 541, wherein the antibody or antigen-binding fragment is an IgG antibody.

[0895] 544. An antibody or antigen-binding fragment of any one of embodiments 517 to 541, wherein the antibody or antigen-binding fragment comprises Fab, F(ab)2, a single-domain antibody, a single-chain variable fragment (scFv), or a nanobody.

[0896] 545. An antibody or antigen-binding fragment of any one of embodiments 517 to 544, comprising a heavy chain constant region containing the amino acid sequence shown in SEQ ID NO: 542 or 543.

[0897] 546. An antibody or antigen-binding fragment of any one of embodiments 517 to 544, comprising a heavy chain constant region containing the amino acid sequence shown in SEQ ID NO: 542.

[0898] 547. An antibody or antigen-binding fragment of any one of embodiments 517 to 544, comprising a light chain constant region containing the amino acid sequence shown in SEQ ID NO: 544.

[0899] Non-limiting methods for determining whether an anti-TL1A antibody binds to the same region as a reference antibody are known in the art. Exemplary methods include competitive assays. For example, the method includes determining whether a reference antibody can compete with a reference antibody for binding to the TL1A protein or a portion thereof, or determining whether a reference antibody can compete with a reference antibody for binding to the TL1A protein or a portion thereof. Exemplary methods include using surface plasmon resonance to evaluate whether an anti-TL1A antibody can compete with another anti-TL1A antibody for binding to TL1A. In some cases, surface plasmon resonance is utilized in this competitive assay.

[0900] Pharmaceutical compositions, formulations and methods of administration

[0901] In one aspect, methods of treating any of the diseases or conditions described herein in subjects requiring such treatment include administering to the subject a pharmaceutical composition comprising a therapeutic agent described herein, such as a CD30L inhibitor, in a therapeutically effective amount. In some embodiments, the therapeutic agents described herein are used to prepare medicaments for treating inflammatory diseases, fibrotic stenosis, and / or fibrotic diseases. Pharmaceutical compositions as used herein include compositions comprising a CD30L inhibitor and optionally additional therapeutic agents.

[0902] In some embodiments, a composition containing the therapeutic agent described herein is administered for prophylactic and / or therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from the disease or condition in an amount sufficient to cure or at least partially stop at least one symptom of the disease or condition. The effective amount for this purpose depends on the severity and course of the disease or condition, prior treatment, the patient's health status, weight, and response to the drug, as well as the judgment of the attending physician. The therapeutically effective amount may optionally be determined by methods including, but not limited to, dose-escalation clinical trials. In some cases, CD30L inhibitors are administered to patients with inflammatory diseases, fibrotic stenosis, and / or fibrotic diseases.

[0903] In prophylactic applications, a composition containing the therapeutic agent described herein is administered to a patient susceptible to or at risk of a specific disease, condition, or ailment, such as an inflammatory disease, fibrotic stenosis, and / or fibrotic disease. Such an amount is defined as a “preventative effective amount or dose.” In this application, the precise amount also depends on the patient’s health status, weight, etc. When used on a patient, the effective amount for this purpose will depend on the severity and progression of the disease, condition, or ailment, prior therapy, the patient’s health status and response to the drug, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing a CD30L inhibitor to a mammal who has previously experienced at least one symptom of a treated disease and is currently in remission, in order to prevent recurrence of the symptoms of the disease or condition.

[0904] In certain implementation plans where the patient’s condition does not improve, the physician may determine that long-term administration of the therapeutic agent is necessary, i.e., a prolonged period of time, including the patient’s entire lifespan, in order to improve or otherwise control or limit the symptoms of the patient’s disease or condition.

[0905] In some implementations where the patient's condition does improve, the dose of the administered therapeutic agent may be temporarily reduced or temporarily suspended for a period of time (i.e., a "withdrawal period"). In specific implementations, the length of the withdrawal period ranges from 2 days to 1 year, including, for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. For example, the dose reduction during the withdrawal period is 10%–100%, including, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0906] In some implementations, the dosage of the drug being administered may be temporarily reduced or temporarily interrupted for a period of time (i.e., "drug diversion"). In specific implementations, the length of drug diversion ranges from 2 days to 1 year, including, for example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. For example only, the dosage reduction during drug diversion is between 10% and 100%, including, for example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. After the appropriate length of time, the normal dosing schedule may optionally be resumed.

[0907] In some implementations, a maintenance dose is administered if necessary once the patient's condition has improved. Subsequently, in certain implementations, the dosage or frequency, or both, is reduced to a level where the improvement in the disease, symptom, or condition is maintained, depending on the symptoms. However, in some implementations, the patient requires long-term intermittent treatment upon any recurrence of symptoms.

[0908] The amount of a given therapeutic agent corresponding to such a dosage varies depending on factors such as the specific therapeutic agent, the disease condition and its severity, and the characteristics of the subject requiring treatment (e.g., weight, sex). However, it can also depend on the specific circumstances of the case, including, for example, the specific agent being administered, the route of administration, the condition being treated, and the subject or individual receiving treatment. Generally, however, the dosage used for adult treatment typically ranges from 0.01 mg to 5000 mg per day. In one aspect, the dosage used for adult treatment is from about 1 mg to about 1000 mg per day. In one embodiment, the required dose is conveniently presented as a single dose or fractional doses, which are administered simultaneously (or over short periods of time) or at appropriate intervals, such as two, three, four, or more sub-dose doses per day.

[0909] In some implementations, when a patient begins a treatment regimen, the patient also begins to discontinue (e.g., by gradually reducing the dose) a second treatment regimen.

[0910] In one embodiment, the daily dose of the CD30L inhibitor suitable for use herein is from about 0.01 to about 10 mg / kg body weight. In specific embodiments, the indicated daily dose for large mammals (including, but not limited to, humans) is in the range of from about 0.5 mg to about 1000 mg, conveniently administered in fractions, including but not limited to up to four times daily. In some embodiments, the daily dose is administered in an extended-release form. In some embodiments, a suitable unit dosage form for oral administration contains about 1 mg to 500 mg of the active ingredient. In some embodiments, the daily dose or the amount of active substance in the dosage form is lower or higher than the range indicated herein, based on several variables relating to a particular treatment regimen. In various embodiments, the daily dose and unit dose vary according to several variables, including but not limited to the activity of the therapeutic agent used, the disease or condition to be treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0911] The toxicity and therapeutic efficacy of such treatment regimens are determined through standard pharmaceutical procedures in cell cultures or laboratory animals, including but not limited to LD50. 50 and ED 50 The determination of toxic effects versus therapeutic effects is the dose ratio, known as the therapeutic index, and is expressed as LD50. 50 With ED 50 The ratio between. In some embodiments, data obtained from cell culture experiments and animal studies are used to determine the therapeutically effective daily dose range and / or therapeutically effective unit dose for mammals, including humans. In some embodiments, the daily dose of the therapeutic agent described herein is within the range of ED. 50 Within the range of circulating concentrations with minimal toxicity. In some embodiments, the daily dose range and / or unit dose vary within this range depending on the dosage form and route of administration used.

[0912] This document discloses therapeutic agents formulated into pharmaceutical compositions. The pharmaceutical composition may contain an inhibitor of anti-CD30L. The pharmaceutical composition may contain an antibody. The pharmaceutical composition may contain an anti-CD30L antibody.

[0913] Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active therapeutic agents into articles suitable for pharmaceutical use. Appropriate formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins, 1999), the contents of which are incorporated herein by reference.

[0914] This document provides pharmaceutical compositions comprising a CD30L inhibitor and at least one pharmaceutically acceptable inactive ingredient. Optionally, the composition comprises other therapeutic agents described herein. In some embodiments, the therapeutic agents described herein are administered as a combination of the therapeutic agent and other active ingredients in the pharmaceutical composition, as in combination therapy. In some embodiments, the pharmaceutical composition comprises other pharmaceutical or medical agents, carriers, adjuvants, preservatives, stabilizers, wetting agents or emulsifiers, solubilizers, salts and / or buffers for adjusting osmotic pressure. In some embodiments, the pharmaceutical composition comprises other substances of therapeutic value.

[0915] As used herein, a pharmaceutical composition refers to a mixture of therapeutic agents, such as CD30L inhibitors, with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. Optionally, the composition comprises two or more of the therapeutic agents described herein. When performing the treatment or method of use provided herein, a therapeutically effective amount of the therapeutic agents described herein is administered in the form of a pharmaceutical composition to a mammal suffering from a disease, condition, or ailment to be treated, such as an inflammatory disease, a fibrotic stenosis, and / or a fibrotic disease. In some embodiments, the mammal is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health status of the subject, the potency of the therapeutic agent used, and other factors. These therapeutic agents can be used alone or as components of a mixture in combination with one or more therapeutic agents.

[0916] The pharmaceutical formulations described herein are administered to subjects via appropriate routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, or transdermal routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid dosage forms, powders, immediate-release formulations, controlled-release formulations, rapidly melting formulations, tablets, capsules, pills, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-particle formulations, and hybrid formulations combining immediate-release and controlled-release.

[0917] Pharmaceutical compositions containing therapeutic agents, such as anti-CD30L inhibitors, are prepared in a conventional manner, such as, by way of example only, conventional mixing, dissolving, granulation, dressing-making, grinding, emulsification, encapsulation, embedding, or compression processes. Optionally, the composition contains another therapeutic agent, such as those described herein.

[0918] The pharmaceutical composition may at least comprise a therapeutic agent, such as an anti-CD30L inhibitor, as an active ingredient in the form of a free acid or free base or a pharmaceutically acceptable salt. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides (if appropriate), crystalline forms, amorphous phases, and active metabolites of these compounds having the same type of activity. In some embodiments, the therapeutic agent is present in a non-solvable form or a solvable form with a pharmaceutically acceptable solvent such as water, ethanol, etc. Solvable forms of the therapeutic agent are also considered to be disclosed herein.

[0919] In some embodiments, the therapeutic agent exists as a tautomer. All tautomers are included within the scope of the agents presented herein. Thus, it should be understood that the therapeutic agent or its salts can exhibit tautomerism, whereby two chemical compounds can readily interconvert by exchanging hydrogen atoms between two atoms (with either of them forming a covalent bond). Since tautomers exist in a state of dynamic equilibrium with each other, they can be considered as different isomers of the same compound.

[0920] In some embodiments, the therapeutic agent exists as an enantiomer, diastereomer, or other stereoisomer. The pharmaceutical agents disclosed herein include all enantiomers, diastereomers, and epimers, and mixtures thereof.

[0921] In some embodiments, the therapeutic agents described herein may be prepared as prodrugs. A “prodrug” is a pharmaceutical agent that is converted into a parent drug in vivo. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they may become biologically available through oral administration, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. A non-limiting example of a prodrug is a therapeutic agent described herein administered as an ester (“prodrug”) to facilitate transmembrane transport—water solubility in the cell membrane is detrimental to mobility, but it is subsequently metabolized and hydrolyzed into a carboxylic acid, the active entity, once it is in the intracellular space where water solubility is beneficial. Another example of a prodrug is a short peptide (polyamino acid) bonded to an acid group, wherein the peptide is metabolized to expose the active moiety. In some embodiments, upon administration in vivo, the prodrug is chemically converted into a biologically, pharmaceutically, or therapeutically active form of the therapeutic agent. In some embodiments, the prodrug is enzymatically metabolized into a biologically, pharmaceutically, or therapeutically active form of the therapeutic agent through one or more steps or processes.

[0922] The prodrug form of the therapeutic agent (wherein the prodrug is metabolized in vivo to produce the agent as described herein) is included within the scope of the claims. In some cases, some of the therapeutic agents described herein may be prodrugs of another derivative or active compound. In some embodiments described herein, the hydrazone is metabolized in vivo to produce the therapeutic agent.

[0923] In some embodiments, the compositions provided herein contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as phenylmercuric borate and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, hexadecyltrimethylammonium bromide, and cetylpyridinium chloride.

[0924] In some embodiments, the formulations described herein benefit from antioxidants, metal chelators, thiol-containing compounds, and other common stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol; (b) about 0.1% to about 1% w / v methionine; (c) about 0.1% to about 2% w / v monothioglycerol; (d) about 1 mM to about 10 mM EDTA; (e) about 0.01% to about 2% w / v ascorbic acid; (f) 0.003% to about 0.02% w / v polysorbate 80; (g) 0.001% to about 0.05% w / v polysorbate 20; (h) arginine; (i) heparin; (j) dextran sulfate; (k) cyclodextrin; (l) pentosan polysulfate esters and other heparin-like substances; (m) divalent cations, such as magnesium and zinc; or (n) combinations thereof.

[0925] The pharmaceutical compositions described herein, containing therapeutic agents such as CD30L inhibitors, are formulated into any suitable dosage form, including but not limited to aqueous oral dispersions, liquids, gels, syrups, elixirs, pastes, suspensions, solid oral dosage forms, aerosols, controlled-release formulations, melt-on-demand formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, lozenges, capsules, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-particle formulations, and mixed formulations of immediate-release and controlled-release. In one aspect, the therapeutic agents described herein, such as CD30L inhibitors, are formulated into pharmaceutical compositions suitable for intramuscular, subcutaneous, or intravenous injection. In another aspect, formulations suitable for intramuscular, subcutaneous, or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or media include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin, cremophor, etc.), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters, such as ethyl oleate. For example, by using coatings, such as lecithin, appropriate flowability can be maintained in the case of dispersions by maintaining the desired particle size, and by using surfactants. In some embodiments, formulations suitable for subcutaneous injection also contain additives such as preservatives, wetting agents, emulsifiers, and dispersants. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. In some cases, it is desirable to include isotonic agents such as sugars, sodium chloride, etc. Extended absorption of injectable drug forms can be achieved by using agents with delayed absorption, such as aluminum monostearate and gelatin.

[0926] For intravenous injection, infusion, or transfusion, the therapeutic agents described herein are prepared in an aqueous solution, preferably in a physiologically compatible buffer such as Hanks' solution, Ringer's solution, or saline buffer. For transmucosal administration, a permeabilizing agent suitable for the barrier to be penetrated is used in the formulation. Such permeabilizing agents are generally known in the art. For other parenteral injections, suitable formulations include aqueous or non-aqueous solutions, preferably containing physiologically compatible buffers or excipients. Such excipients are known.

[0927] Parenteral injection can include bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage forms, such as ampoules or multi-dose containers with added preservatives. The pharmaceutical compositions described herein may be in forms suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous media, and may contain conditioning agents such as suspending agents, stabilizers, and / or dispersants. In one aspect, the active ingredient is in powder form for reconstitution with a suitable media such as sterile, pyrogen-free water prior to use.

[0928] For inhalation administration, the therapeutic agent is formulated for use as an aerosol, mist, or powder. The pharmaceutical compositions described herein are conveniently delivered as an aerosol spray from a pressurized package or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by setting a valve to deliver the amount of the metered dose. By way of example only, capsules and cartridges, such as gelatin, can be formulated for use in inhalers or blowpipes, containing the therapeutic agent described herein and a powder mixture of a suitable powder matrix such as lactose or starch.

[0929] Representative intranasal formulations are described, for example, in U.S. Patents 4,476,116, 5,116,817, and 6,391,452. Formulations containing therapeutic agents are prepared as solutions in saline using benzyl alcohol or other suitable preservatives, fluorocarbons, and / or other solubilizers or dispersants known in the art. See, for example, Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th Edition (1995). Preferably, these compositions and formulations are prepared with suitable, non-toxic, pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the art of preparing nasal dosage forms, and some are found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st Edition, 2005. The choice of a suitable carrier depends on the exact nature of the desired nasal dosage form, such as a solution, suspension, ointment, or gel. In addition to the active ingredient, nasal dosage forms typically contain a significant amount of water. Optionally, trace amounts of other ingredients may be present, such as pH adjusters, emulsifiers or dispersants, preservatives, surfactants, gelling agents or buffers, and other stabilizers and solubilizers. Preferably, the nasal dosage form should be isotonic with nasal secretions.

[0930] Pharmaceutical articles for oral use are obtained by the following steps: mixing one or more solid excipients with one or more therapeutic agents described herein, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable excipients (if desired) to obtain a tablet or tablet core. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose products such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other excipients such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, a disintegrant such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginate or its salts such as sodium alginate is added. In some embodiments, dyes or pigments are added to the coating of the tablet or tablet to identify or characterize different combinations of active therapeutic agent doses.

[0931] In some embodiments, the pharmaceutical formulation of the therapeutic agent is in capsule form, including push-fit capsules made of gelatin and sealed soft capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-fit capsules contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active therapeutic agent is dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added. For example, the capsule can be prepared by placing a loose blend of the therapeutic agent formulation within the capsule. In some embodiments, the formulation (a non-aqueous suspension and solution) is placed in a soft gelatin capsule. In other embodiments, the formulation is placed in a standard gelatin capsule or a non-gelatin capsule such as a capsule containing HPMC. In other embodiments, the formulation is placed in a spread capsule, wherein the capsule is swallowed whole or opened before consuming food and the contents are spread onto the food.

[0932] All formulations intended for oral administration are doses suitable for such administration. In one aspect, solid oral dosage forms are prepared by mixing a therapeutic agent with one or more of the following components: antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, humectants, and diluents. In some embodiments, the solid dosage forms disclosed herein are tablets (including suspension tablets, melt-on tablets, chewable disintegrating tablets, rapidly disintegrating tablets, effervescent tablets, or capsules), pellets, powders, capsules, solid dispersions, solid solutions, biodegradable dosage forms, controlled-release formulations, pulse-release formulations, multi-particle formulations, beads, microcapsules, or granules. In other embodiments, the pharmaceutical formulation is in powder form. Compressed tablets are solid dosage forms made by compacting a loose blend of the above-described formulations. In several embodiments, the tablet will contain one or more flavoring agents. In other embodiments, the tablet will contain a film surrounding the ultimately compressed tablet. In some embodiments, film coating can provide delayed release of the therapeutic agent from the formulation. In other embodiments, film coating can contribute to patient compliance (e.g., (Coated or sugar-coated). Contains The film coating typically comprises about 1% to about 3% of the tablet weight. In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing therapeutic agent particles with one or more pharmaceutical excipients to form a loosely compounded composition. Loosely compounded compositions are readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. In some embodiments, individual unit doses contain a film coating. These formulations are prepared using conventional formulation techniques.

[0933] On the other hand, dosage forms include microencapsulated formulations. In some embodiments, one or more other compatible materials are present in the microencapsulated material. Exemplary materials include, but are not limited to, pH adjusters, erosion promoters, defoamers, antioxidants, flavoring agents, and carrier substances such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents. Exemplary useful microencapsulated materials include, but are not limited to, hydroxypropyl cellulose ethers (HPC), such as... Or Nisso HPC; low-substituted hydroxypropyl cellulose ethers (L-HPC); hydroxypropyl methylcellulose ethers (HPMC), such as Seppifilm-LC, Metolose SR OpadryYS, PrimaFlo, Benecel MP824 and Benecel MP843; methylcellulose polymers, such as Hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Ethyl cellulose (EC) and its mixtures, such as E461, Polyvinyl alcohol (PVA), such as Opadry AMB; hydroxyethyl cellulose, such as... Carboxymethyl cellulose and its salts, such as Copolymers of polyvinyl alcohol and polyethylene glycol, such as Kollicoat Monoglycerides (Myverol); triglycerides (KLX); polyethylene glycol; modified edible starch; acrylic polymers and mixtures of acrylic polymers and cellulose ethers, such as... EPO, L30D-55, FS 30D L100-55 L100 S100 RD100 E100 L12.5, S12.5, NE30D and NE 40D; cellulose phthalate acetate; Sepifilm, such as a mixture of HPMC and stearic acid; cyclodextrin; and mixtures of these materials.

[0934] Liquid dosage forms for oral administration are optionally aqueous suspensions selected from, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd edition, pp. 754-757 (2002). In addition to the therapeutic agent, the liquid dosage form optionally contains additives such as: (a) disintegrants; (b) dispersants; (c) humectants; (d) at least one preservative; (e) viscosity enhancers; (f) at least one sweetener; and (g) at least one flavoring agent. In some embodiments, the aqueous dispersion further comprises a crystal formation inhibitor.

[0935] In some embodiments, the pharmaceutical formulations described herein are self-emulsifying drug delivery systems (SEDDS). An emulsion is a dispersion of an immiscible phase in another phase, typically in the form of small droplets. Emulsions are typically formed through vigorous mechanical dispersion. Unlike emulsions or microemulsions, SEDDS spontaneously form an emulsion upon addition to excess water without any external mechanical dispersion or agitation. An advantage of SEDDS is that only gentle mixing is required to disperse the small droplets throughout the solution. Furthermore, the water or aqueous phase is optionally added immediately before administration, ensuring the stability of unstable or hydrophobic active ingredients. Therefore, SEDDS provides an efficient delivery system for oral and parenteral delivery of hydrophobic active ingredients. In some embodiments, SEDDS provides improved bioavailability of the hydrophobic active ingredient. Methods for producing self-emulsifying dosage forms include, for example, U.S. Patents 5,858,401, 6,667,048, and 6,960,563.

[0936] Buccal formulations containing therapeutic agents are administered using a variety of formulations known in the art. Such formulations include, for example, U.S. Patents 4,229,447, 4,596,795, 4,755,386, and 5,739,136. Additionally, the buccal dosage forms described herein may further comprise a biodegradable (hydrolyzable) polymer carrier that also serves to adhere the dosage form to the buccal mucosa. For buccal or sublingual administration, the composition may be in the form of tablets, lozenges, or gels formulated in a conventional manner.

[0937] For intravenous injection, the therapeutic agent is optionally prepared in an aqueous solution, preferably in a physiologically compatible buffer such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, an exfoliating agent suitable for the barrier to be penetrated is used in the formulation. For other parenteral injections, suitable formulations include aqueous or non-aqueous solutions, preferably containing physiologically compatible buffers or excipients.

[0938] Parenteral injection optionally involves bolus or continuous infusion. The formulation for injection is optionally presented in a unit dosage form, such as in an ampoule or multi-dose container with added preservatives. In some embodiments, the pharmaceutical compositions described herein are in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous medium, and contain a conditioning agent, such as a suspending agent, stabilizer, and / or dispersant. Pharmaceutical formulations for parenteral administration include aqueous solutions of an agent in a water-soluble form that modulates carotid body activity. Additionally, suspensions of agents that modulate carotid body activity are optionally prepared as suitable, for example, oily injectable suspensions.

[0939] Conventional formulation techniques include one or a combination of the following methods: (1) dry mixing, (2) direct pressing, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) blending. Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tableting, extrusion, etc.

[0940] Suitable carriers for the solid dosage forms described herein include, but are not limited to, gum arabic, gelatin, colloidal silica, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, sodium caseinate, soybean lecithin, sodium chloride, tricalcium phosphate, dipotassium hydrogen phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, etc.

[0941] Suitable fillers used in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, glucose binder, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, etc.

[0942] Suitable disintegrants used in the solid dosage forms described herein include, but are not limited to, natural starches such as corn starch or potato starch; pregelatinized starch or sodium glycolate starch; celluloses such as methyl crystalline cellulose, methyl cellulose, microcrystalline cellulose, croscarmellose cellulose, or croscarmellose cellulose such as sodium croscarmellose cellulose, croscarmellose cellulose, or cross-linked croscarmellose cellulose; cross-linked starches such as sodium glycolate starch; cross-linked polymers such as crosspovidone, cross-linked polyvinylpyrrolidone; alginic acid such as alginic acid or salts of alginic acid such as sodium alginate; gums such as agar, guar gum, locust bean gum, ark sylvestris gum (Karaya), pectin, or tragacanth gum; sodium glycolate starch; bentonite; sodium lauryl sulfate; sodium lauryl sulfate in combination with starch; and so on.

[0943] Binders impart binding properties to solid oral dosage forms: for powder-filled capsules, they help form plugs that can be filled into soft-shell or hard-shell capsules; for tablets, they ensure that the tablet remains intact after compression and help guarantee the homogeneity of the mixture before the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate stearate, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose and microcrystalline cellulose, microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, cross-linked povidone, povidone, starch, pregelatinized starch, tragacanth gum, dextrin, sugars (such as sucrose, glucose, dextrose, molasses, mannitol, sorbitol, xylitol, lactose), natural or synthetic gums (such as gum arabic, tragacanth gum, ghattigum, isapol husk mucilage), starch, polyvinylpyrrolidone, larch arabogalactan, polyethylene glycol, waxes, sodium alginate, etc.

[0944] Typically, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. The binder level in tablet formulations varies, whether through direct compression, wet granulation, milling, or the use of other excipients (such as fillers that themselves act as moderate binders). Binder levels of up to 70% are common in tablet formulations.

[0945] Suitable lubricants or flow aids used in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearoyl fumarate, alkali metal and alkaline earth metal salts (such as aluminum, calcium, magnesium, and zinc salts), stearic acid, sodium stearate, magnesium stearate, zinc stearate, waxes, etc. Boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxylated polyethylene glycol (such as Carbowax) TM PEG 4000, PEG 5000, PEG 6000), propylene glycol, sodium oleate, glyceryl betaine, glyceryl palmitoyl stearate, glyceryl benzoate, magnesium lauryl sulfate or sodium lauryl sulfate, etc.

[0946] Suitable diluents used in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including glucose conjugates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, etc.

[0947] Suitable wetting agents for the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, and quaternary ammonium compounds (e.g., Polyquat). ), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E, TPGS, etc.

[0948] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, etc. (BASF), etc.

[0949] Suitable suspending agents for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30; polyethylene glycol, for example, polyethylene glycol may have a molecular weight of about 300 to about 6000 or about 3350 to about 4000 or about 7000 to about 5400; vinylpyrrolidone / vinyl acetate copolymer (S630); sodium carboxymethyl cellulose; and so on. Fiberglass, hydroxypropyl methylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as gum arabic and gum arabic, guar gum, xanthan gum (including xanthan gum), sugar, cellulose products such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, etc.

[0950] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0951] It should be understood that there is considerable overlap among the additives used in the solid dosage forms described herein. Therefore, the additives listed above should be understood as merely exemplary and not as limiting the types of additives that may be included in the solid dosage forms of the pharmaceutical compositions described herein. The amount of such additives can be readily determined by those skilled in the art based on the desired specific properties.

[0952] In several embodiments, the therapeutic agent particles and one or more excipients are dry-mixed and compressed into a block, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration, thereby releasing the formulation into the gastrointestinal fluid.

[0953] In other embodiments, the powder containing the therapeutic agent is formulated to include one or more pharmaceutical excipients and flavoring agents. For example, such a powder is prepared by mixing the therapeutic agent with optional pharmaceutical excipients to form a loose blend composition. Further embodiments include suspending agents and / or wetting agents. The loose blend is then uniformly subdivided into single-dose packages or multi-dose packaging units.

[0954] In another embodiment, an effervescent powder was also prepared. Effervescent salts have been used to disperse the drug in water for oral administration.

[0955] In some embodiments, the drug formulation is designed to provide controlled release of the therapeutic agent. Controlled release refers to the release of the therapeutic agent from its incorporated dosage form over an extended period of time according to a desired curve. Controlled release curves include, for example, sustained release, extended release, pulsatile release, and delayed release curves. In contrast to immediately released compositions, controlled-release compositions allow for the delivery of the drug to the subject over an extended period of time according to a predetermined curve. Such a release rate can provide a therapeutically effective level of the drug over an extended period of time, thereby providing a longer period of pharmacological response compared to conventional rapid-release formulations, while minimizing side effects. This longer period of response provides several inherent benefits that cannot be achieved by corresponding short-acting immediately released formulations.

[0956] In some embodiments, the solid dosage forms described herein are formulated as enteric-coated delayed-release oral dosage forms, i.e., oral dosage forms of the pharmaceutical compositions described herein, which utilize enteric coating to achieve release in the small or large intestine. In one aspect, the enteric-coated dosage form is a compressed, molded, or extruded tablet / mold (coated or uncoated) comprising particles, powders, microcapsules, beads, or granules containing the active ingredient and / or other compositional components, which may or may not be coated. In another aspect, the enteric-coated oral dosage form is in the form of capsules containing coated or uncoated microcapsules, beads, or granules containing a therapeutic agent.

[0957] Any coating should be applied with sufficient thickness so that the entire coating does not dissolve in gastrointestinal fluids with a pH below approximately 5, but dissolves at pH approximately 5 and higher. Coatings are typically selected from any of the following: shellac—this coating dissolves in media with a pH > 7; acrylic polymers—suitable examples of acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available dissolved in organic solvents, as aqueous dispersions, or as dry powders. Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but permeable and primarily targeted to the colon. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D, and S are insoluble in the stomach but soluble in the intestine; polyvinyl acetate phthalate (PVAP)—PVAP dissolves at pH > 5 and has poor permeability to water vapor and gastric juices. Coatings are applied using conventional coating techniques such as spray or pan coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact before reaching the desired local delivery site in the intestine.

[0958] In other embodiments, a pulsatile dosage form is used to deliver the formulation described herein. A pulsatile dosage form is capable of providing one or more immediate release pulses at a predetermined time point after a controlled delay or at a specific site. Exemplary pulsatile dosage forms and methods of their preparation are disclosed in U.S. Patents 5,011,692, 5,017,381, 5,229,135, 5,840,329, and 5,837,284. In one embodiment, the pulsatile dosage form comprises at least two sets of particles (i.e., multiple particles), each set containing the formulation described herein. When ingested by a mammal, the first set of particles provides a substantially immediate dose of the therapeutic agent. The first set of particles may be uncoated or contain a coating and / or sealant. In one aspect, the second set of particles comprises coated particles. The coating on the second set of particles provides a delay of approximately 2 hours to approximately 7 hours from ingestion to the release of a second dose. Suitable coatings for pharmaceutical compositions have been described herein or in the art.

[0959] In some embodiments, a pharmaceutical formulation is provided comprising particles of a therapeutic agent and at least one dispersant or suspending agent for oral administration to a subject. The formulation may be a powder and / or particles for suspension and, when mixed with water, yields a substantially homogeneous suspension.

[0960] In some implementations, particles formulated for controlled release are incorporated into gels, patches, or wound dressings.

[0961] In one aspect, the liquid dosage form for oral administration and / or topical administration as a lotion is in the form of an aqueous suspension selected from, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd edition, pp. 754-757 (2002). In addition to therapeutic particles, the liquid dosage form contains additives such as: (a) disintegrants; (b) dispersants; (c) humectants; (d) at least one preservative; (e) viscosity enhancers; (f) at least one sweetener; and (g) at least one flavoring agent. In some embodiments, the aqueous dispersion may further contain a crystallization inhibitor.

[0962] In some embodiments, the liquid formulation also includes inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers. Exemplary emulsifiers include ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, sodium lauryl sulfate, sodium docusate, cholesterol, cholesterol esters, taurocholic acid, phosphatidylcholine, oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitol, or mixtures of these substances.

[0963] In addition, the pharmaceutical composition optionally comprises one or more pH adjusters or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris(hydroxymethyl)aminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. The amounts of such acids, bases, and buffers required to maintain the pH of the composition within an acceptable range are included.

[0964] Additionally, the pharmaceutical composition optionally comprises one or more salts in the amount required to bring the weight molar osmolality concentration of the composition within an acceptable range. Such salts include those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0965] Other pharmaceutical compositions optionally include one or more preservatives for inhibiting microbial activity. Suitable preservatives include mercury-containing substances such as phenylmercuric borate and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0966] In one embodiment, the aqueous suspension and dispersion described herein are maintained in a homogeneous state for at least 4 hours, as defined in USP Pharmacists' Pharmacopeia (2005 edition, Chapter 905). In one embodiment, the aqueous suspension is resuspended as a homogeneous suspension by physical agitation lasting less than 1 minute. In yet another embodiment, no agitation is required to maintain the homogeneity of the aqueous dispersion.

[0967] Examples of disintegrants used in aqueous suspensions and dispersions include, but are not limited to, starches, such as natural starches like corn starch or potato starch, pregelatinized starch, or sodium glycolate starch; celluloses, such as methyl crystalline cellulose, methyl cellulose, croscarmellose cellulose, or croscarmellose cellulose, such as sodium croscarmellose cellulose, croscarmellose cellulose, or cross-linked croscarmellose cellulose; cross-linked starches, such as sodium glycolate starch; cross-linked polymers, such as crosspovidone; cross-linked polyvinylpyrrolidone; alginic acids, such as alginic acid or salts of alginic acid, such as sodium alginate; gums, such as agar, guar gum, locust bean gum, ark sylvestris gum (Karaya), pectin, or tragacanth gum; sodium glycolate starch; bentonite; natural sponges; surfactants; resins, such as cation exchange resins; citrus pomace; sodium lauryl sulfate; sodium lauryl sulfate in combination with starch; and so on.

[0968] In some embodiments, dispersants suitable for the aqueous suspensions and dispersions described herein include, for example, hydrophilic polymers, electrolytes, 60 or 80, PEG, polyvinylpyrrolidone, and carbohydrate-based dispersants such as hydroxypropyl cellulose and hydroxypropyl cellulose ether, hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ether, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose stearate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymer, polymers of 4-(1,1,3,3-tetramethylbutyl)-phenol with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamer; and poloxamine. In other embodiments, the dispersant is selected from the group excluding one of the following dispersants: hydrophilic polymers; electrolytes; 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropyl cellulose and hydroxypropyl cellulose ether; hydroxypropyl methyl cellulose and hydroxypropyl methyl cellulose ether; sodium carboxymethyl cellulose; methyl cellulose; hydroxyethyl cellulose; hydroxypropyl methyl cellulose phthalate; hydroxypropyl methyl cellulose acetate stearate; amorphous cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); polymers of 4-(1,1,3,3-tetramethylbutyl)phenol with ethylene oxide and formaldehyde; poloxamer; or poloxamine.

[0969] Wetting agents suitable for the aqueous suspensions and dispersions described herein include, but are not limited to, cetyl alcohol, glyceryl monostearate, and polyoxyethylene sorbitan fatty acid esters (e.g., commercially available...). such as Tween and Tween And polyethylene glycol, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphatidylcholine, etc.

[0970] Suitable preservatives for use in the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other esters of parabens (such as butylparaben), alcohols (such as ethanol or benzyl alcohol), phenolic compounds (such as phenol), or quaternary ammonium compounds (such as benzalkonium chloride). Preservatives as used herein are incorporated into the formulation at concentrations sufficient to inhibit microbial growth.

[0971] Suitable viscosity enhancers for the aqueous suspensions or dispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. S-630, carbomer, polyvinyl alcohol, alginate, gum arabic, chitosan, and combinations thereof. The concentration of the viscosity enhancer will depend on the selected agent and the desired viscosity.

[0972] Examples of sweeteners suitable for use in the aqueous suspensions or dispersions described herein include, for example, gum arabic syrup, acesulfame K, alitame, aspartame, chocolate, cinnamon, citrus, cocoa, cyclamate, dextrose, fructose, ginger, glycyrrhizic acid, glycyrrhiza syrup, and monoammonium glyrrhizinate. Maltitol, mannitol, menthol, neohesperidin DC, neotame Powder, saccharin, sorbitol, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, sucralose, tagatose, thaumatin, vanilla, xylitol, or any combination thereof.

[0973] In some embodiments, the therapeutic agent is formulated as a transdermal dosage form. In some embodiments, the transdermal formulation described herein comprises at least three components: (1) a therapeutic agent; (2) a penetration enhancer; and (3) an optional aqueous adjuvant. In some embodiments, the transdermal formulation compris...

Claims

1. Use of one or more binders in the preparation of a medicament for determining inflammatory bowel disease (IBD) in a subject and selecting the subject to receive treatment with an inhibitor of CD30 ligand activity or expression, including an anti-CD30L antibody, wherein the one or more binders specifically detect one or more polymorphisms, wherein the one or more polymorphisms are characterized by an "A" allele at nucleotide 501 in rs911605 as shown in SEQ ID NO:1, a "G" allele at nucleotide 501 in rs1006026 as shown in SEQ ID NO:3, or both.

2. The use according to claim 1, wherein the one or more binding agents further specifically bind to the polymorphism of the "A" allele at 501 of nucleotide 501 in rs911605 as shown in SEQ ID NO:1 and the polymorphism of the "G" allele at 501 of nucleotide 501 in rs1006026 as shown in SEQ ID NO:

3.

3. The use according to claim 1, wherein the one or more binding agents further specifically bind to the polymorphism of the "A" allele characterized at nucleobase 501 in rs911605 as shown in SEQ ID NO:

1.

4. The use according to claim 1, wherein one or more binding agents further specifically bind to the polymorphism of the "G" allele at nucleotide 501 in rs1006026 as shown in SEQ ID NO:

3.

5. The use according to any one of claims 1-4, wherein the subject is identified as a carrier of the polymorphism by the following method: a) Contacting a sample containing genetic material obtained from the subject with a nucleic acid sequence capable of hybridizing with at least 10 consecutive nuclei between nuclei 400 and nuclei 600 of at least one of SEQ ID NO:1 and SEQ ID NO:3 under standard hybridization conditions, wherein the at least 10 consecutive nuclei include the nuclei at position 501 of at least one of SEQ ID NO:1 and SEQ ID NO:3; and b) Detect the binding of the nucleic acid sequence to at least 10 consecutive nucleobases between nucleobases 400 and 600 of at least one of SEQ ID NO:1 and SEQ ID NO:

3.

6. The use according to claim 1, wherein the IBD is ulcerative colitis (UC).

7. The use according to claim 1, wherein the IBD is Crohn's disease (CD).

8. Use of one or more binders in the preparation of a medicament for determining the risk of Crohn's disease (CD) in a subject to select the subject for treatment with an inhibitor of CD30 ligand activity or expression, comprising an anti-CD30L antibody, wherein the one or more binders specifically detect one or more polymorphisms, wherein the one or more polymorphisms are characterized by an "A" allele at nucleotide 501 in rs911605 as shown in SEQ ID NO:1, a "G" allele at nucleotide 501 in rs1006026 as shown in SEQ ID NO:3, or both.

9. The use according to claim 8, wherein the use further comprises determining whether the subject has at least one of non-response or loss of response to standard treatment, wherein the standard treatment is selected from glucocorticoids, anti-TNF therapy, anti-α4-B7 therapy, anti-IL12p40 therapy, thalidomide, and cytotoxic agents.

10. The use according to claim 8, wherein the one or more binding agents further specifically bind to the polymorphism of the "A" allele at 501 of nucleotide 501 in rs911605 as shown in SEQ ID NO:1 and the polymorphism of the "G" allele at 501 of nucleotide 501 in rs1006026 as shown in SEQ ID NO:

3.

11. The use according to claim 8, wherein the one or more binding agents further specifically bind to the polymorphism of the "A" allele characterized at nucleobase 501 in rs911605 as shown in SEQ ID NO:

1.

12. The use according to claim 8, wherein the one or more binding agents further specifically bind to the polymorphism of the "G" allele at nucleotide 501 in rs1006026 as shown in SEQ ID NO:

3.

13. The use according to claim 9, wherein the anti-a4-b7 therapy is vedolizumab.

14. The use according to claim 9, wherein the anti-IL12p40 therapy is ustekinumab.

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