Methods and systems for the selection and treatment of patients with inflammatory diseases

Abstract

To provide compositions for use in treatment of patient with at least one of an inflammatory disease, a fibrostenotic disease, and a fibrotic disease.SOLUTION: The present invention relates to a composition comprising an inhibitor of CD30 ligand for use for inhibiting or reducing CD30 ligand activity or expression in a subject, the compound comprising: identifying the subject as being a carrier of a genotype comprising an "A" allele in rs911605 or a "G" allele in rs1006026; and the inhibitors of CD30 ligand activity or expression being antibodies or antigen-binding fragments, or combinations thereof, that target the CD30 ligand or CD30.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] cross reference This application claims the benefits under U.S. Provisional Patent Application No. 62 / 664,720 filed April 30, 2018, U.S. Provisional Patent Application No. 62 / 681,557 filed June 6, 2018, and U.S. Provisional Patent Application No. 62 / 784,179 filed December 21, 2018, all of which are incorporated herein by reference in their entirety.

[0002] Sequence List This application includes a sequence listing filed electronically in ASCII format and cited herein by reference. The name of the ASCII copy created on April 19, 2019, is 52388-740_601_SL.txt, and its size is 7,862,716 bytes. [Background technology]

[0003] Due to the enormous number of individuals affected, as well as heterogeneous disease etiologies and diverse clinical manifestations, inflammatory diseases, fibrous strictures, and fibrous diseases pose a significant health burden worldwide. One such disease is inflammatory bowel disease (IBD), which has two common forms: Crohn's disease (CD) and ulcerative colitis (UC). IBD consists of chronic, relapsing inflammatory disorders of the gastrointestinal tract. IBD outbreaks are epidemic, affecting nearly 3 million individuals in the United States alone. Each of these forms has various secondary conditions known as subclinical phenotypes present in subpopulations of CD and UC patients. One such disease is obstructive Crohn's disease, which can be caused by chronic inflammation that can lead to scar tissue formation (fibrostenosis) and bloating within the intestinal wall. Both outcomes can lead to stricture, or obstruction. These are known as either fibrous or inflammatory strictures. In severe cases of stricture, the intestine can become blocked, causing abdominal pain, bloating, nausea, and constipation.

[0004] There are few treatment options for patients suffering from inflammatory diseases, fibrous strictures, and fibrotic diseases. Existing anti-inflammatory drugs such as steroids and tumor necrosis factor (TNF) inhibitors are typically used as first-line treatments for IBD. Unfortunately, a significant number of patients experience a lack of or loss of response to existing anti-inflammatory drugs, particularly TNF inhibitors. These patients are treated with ineffective anti-inflammatory drugs, but their disease worsens. Surgery, in the form of structureplasty (reconstruction of the bowel) or resection (removal of the bowel), is the only treatment option for patients who do not respond to first-line treatment. Surgical intervention for IBD is invasive and carries postoperative risks in an estimated one-third of patients undergoing surgery, including anastomotic leakage, infection, and bleeding.

[0005] The pathogenesis of inflammatory diseases such as IBD, fibrous stenosis, and fibrous diseases is thought to involve unregulated immune responses that may be triggered by certain environmental factors in genetically susceptible hosts. The heterogeneity of disease etiology and clinical course, along with the diverse responses to treatments and their associated side effects, suggests that personalized medicine approaches are the best treatment strategies for these diseases. However, only a limited number of personalized therapies are available to patients. Therefore, there is a need to identify targeted approaches for the treatment of inflammatory diseases, fibrous stenosis, and fibrous diseases, as well as their subclinical phenotypes, and there is a further need to develop reliable methods for identifying patients based on their genotype who may respond to any treatment approach. The methods needed also identify subjects who have not yet been diagnosed as being at risk of disease progression. To this end, preventive interventions can be prescribed to reduce the increasing health burden. [Overview of the project]

[0006] CD30 ligand (CD30L) is a ligand for CD30 encoded by the tumor necrosis factor receptor superfamily 8, namely (TNFSF8). CD30L is a member of the tumor necrosis factor superfamily and is considered important in the co-stimulation of immune cells that 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 leading pathway in the pathogenesis of inflammatory, fibrous, and fibrous stenosing diseases such as IBD, particularly in a subset of patients with complex disease phenotypes (e.g., stenosing, invasive, or obstructive disease phenotypes).

[0007] Aspects of this application provide methods and systems for treating inflammatory diseases in subjects with CD30L inhibitors. In some cases, these CD30L inhibitors inhibit, attenuate, or otherwise interfere with the biological response associated with the interaction of CD30L with the congener antigen CD30. Therefore, treatment with CD30L inhibitors may in some cases be useful for treating diseases associated with the expression or activity of CD30 ligands or CD30.

[0008] This specification also describes polymorphisms and haplotypes of the TNFSF8 gene or locus associated with inflammatory, fibrous, or fibrous stenotic diseases. TNFSF8 polymorphisms may be associated with inflammatory bowel disease (IBD) and various subclinical phenotypes of IBD. In addition, these polymorphisms affect the expression of CD30L and, in some cases, CD30. Genotypes containing the TNFSF8 polymorphisms described herein can be detected in samples obtained from subjects diagnosed with or undiagnosed with IBD. Genotype detection is facilitated by existing genotyping assays and can be performed at the time of need or in a healthcare facility. Typical genotyping assays require a hybridization assay using nucleic acid probes specific to the polymorphisms.

[0009] The practical application of the association between the genotypes described herein and the occurrence of clinical and subclinical phenotypes in a given population of individuals is provided herein. For example, the genotypes disclosed herein can be used to predict the risk of a subject progressing to inflammatory disease, fibrous stenosis, or fibrous disease. These genotypes are also useful in predicting whether a patient diagnosed with certain forms of inflammatory, fibrous, or fibrous stenosis will progress to more severe disease, such as a subclinical phenotype. Furthermore, or alternatively, the genotypes disclosed herein are related to variations in CD30 or CD30L expression, which means that these genotypes can be used to identify patients who are suitable for treatment with targeted CD30L therapy (for example, patients carrying genotypes associated with increased CD30L may be suitable for treatment with anti-CD30L or anti-CD30 therapeutics). Typical diseases include both Crohn's disease (CD) and primary sclerosing cholangitis. In some cases, if the phenotype disclosed herein is detected in a sample obtained from a subject, a therapeutic agent (e.g., a CD30L inhibitor, a TL1A inhibitor) is administered to the subject. Further examples of the practical applications disclosed herein include laboratory-based methods for detecting the target genotype, such as quantitative PCR (qPCR) and sequencing methods.

[0010] Embodiments disclosed herein provide a method for inhibiting or reducing the CD30 ligand activity or expression of a subject, the method comprising: (a) selecting a subject having or suspected of having at least one of inflammatory diseases, fibrous stenotic diseases, and fibrous diseases; (b) identifying the subject as a carrier of a genotype comprising at least one polymorphism of rs911605 and rs1006026; and (c) administering to the subject an effective amount of a CD30 ligand inhibitor to inhibit or reduce the CD30 ligand activity or expression of the subject. In some embodiments, the rs911605 polymorphism comprises an "A" allele at nucleic acid base 501 in rs911605 (SEQ ID NO: 1), and the rs1006026 polymorphism comprises a "G" allele at nucleic acid base 501 in rs1006026 (SEQ ID NO: 3). In some embodiments, the genotype includes the rs911605 polymorphism and the rs1006026 polymorphism. In some embodiments, the rs911605 (SEQ ID NO:1) polymorphism includes an "A" allele at nucleic acid base 501 in rs911605, and the rs1006026 polymorphism includes a "G" allele at nucleic acid base 501 in rs1006026 (SEQ ID NO:3). In some embodiments, the step of identifying the subject as a carrier of the genotype includes (a) contacting a sample obtained from a subject containing genetic material with a nucleic acid sequence capable of hybridizing to at least 10 adjacent nucleic acid bases between at least one nucleic acid base 400 and nucleic acid base 600 of SEQ ID NO:1 and SEQ ID NO:3 under standard hybridization conditions, wherein the at least 10 adjacent nucleic acid bases include a nucleic acid base at at least one position 501 of SEQ ID NO:1 and SEQ ID NO:3; and (b) detecting the binding of the nucleic acid sequence to at least 10 adjacent nucleic acid bases between at least one nucleic acid base 400 and nucleic acid base 600 of SEQ ID NO:1 and SEQ ID NO:2. In some embodiments, the CD30 ligand inhibitor is an antibody or antigen-binding fragment that targets the 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 modulator of gene expression, or the expression or activity of a gene expression product, wherein the gene is mitogen-activated protein kinase kinase kinase kinase (MAP4K4), prostaglandin E receptor 4 (PTGER4), interleukin 18 receptor 1 (IL18R1), 6-phosphofructo-2-kinase / fructose-2, six-bisphosphatase 3 (PFKFB3), interleukin 18 receptor accessory protein (IL18RAP), adenylate cyclase 7 (ADCY7), B lymphocyte tyrosine kinase (BLK), G protein-coupled receptor 65 (GPR65), Sprouty-related EVH1 domain-containing 2 (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 receptor 35 (GPR35), and gasdermin B (GSDMB) is selected from the group consisting of. In some embodiments, the method further comprises administering to the subject an effective amount of an inhibitor of tumor necrosis factor ligand superfamily member 15 (TL1A). In some embodiments, the inhibitor of TL1A is an antagonist of an antibody or antigen-binding fragment that targets TL1A. In some embodiments, the antibody or antigen-binding fragment that targets TL1A is shown in Table 15.

[0011] Embodiments disclosed herein provide a method for treating a subject with moderate to severe Crohn's disease, the method comprising the steps of (a) identifying a subject with Crohn's disease (CD) as being a carrier of a genotype comprising at least one polymorphism of rs911605 and rs1006026, wherein the genotype is associated with the risk of the subject progressing to moderate to severe forms of CD, including obstructive CD, and (b) administering the subject a therapeutically effective amount of an inhibitor of CD30 ligand activity or expression. In some embodiments, the method further comprises the step of determining whether the subject has at least one of no response or loss of response to a standard treatment, or progresses to such response. In some embodiments, the standard treatment is selected from the group consisting of glucocorticosteroids, anti-TNF agents, anti--α4-β7 agents (vedolizumab), anti-IL12p40 agents (ustekinumab), thalidomide, and cytoxin. In some embodiments, the rs911605 polymorphism includes an "A" allele at nucleic acid base 501 in rs911605 (SEQ ID NO: 1), and the rs1006026 polymorphism includes a "G" allele at nucleic acid base 501 in rs1006026 (SEQ ID NO: 3). In some embodiments, the genotype includes the polymorphisms of rs911605 and rs1006026. In some embodiments, the CD30 ligand activity inhibitor is an antibody or antigen-binding fragment that targets the CD30 ligand, 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 modulator of gene expression, or the expression or activity of a gene expression product, wherein the gene is mitogen-activated protein kinase kinase kinase kinase (MAP4K4), prostaglandin E receptor 4 (PTGER4), interleukin-18 receptor 1 (IL18R1), 6-phosphofructo-2-kinase / fructose-2, 6-biphosphatase 3 (PFKFB3), interleukin-18 receptor accessory protein (IL18RAP), adenyle The group consists of tocyclase 7 (ADCY7), B lymphocyte tyrosine kinase (BLK), G protein-binding receptor 65 (GPR65), Sprouty-associated EVH1 domain-containing protein 2 (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 receptor 35 (GPR35), and gasdermin B (GSDMB). In some embodiments, the method further comprises administering an effective amount of an inhibitor of tumor necrosis factor ligand superfamily member 15 (TL1A) to the subject. In some embodiments, the inhibitor of TL1A is an antagonist of an antibody or antigen-binding fragment that targets TL1A. In some embodiments, antibodies or antigen-binding fragments that target TL1A are shown in Table 15.

[0012] Embodiments disclosed herein provide a method for characterizing an inflammatory disease in a subject, the method comprising: (a) analyzing genetic material in a sample obtained from a patient with an inflammatory disease to detect the presence or absence of a genotype comprising at least one of rs911605 and rs1006026; and (b) characterizing the inflammatory disease as Crohn's disease (CD) if the presence of the genotype is detected in step (a). In some embodiments, the step of analyzing genetic material in a sample in step (a) comprises: (a) amplifying at least 15 nucleic acid bases in SEQ ID NO: 5 or SEQ ID NO: 6 from the genetic material, wherein the at least 15 nucleic acid bases include nucleic acid bases at the positions indicated by [A / G] in SEQ ID NO: 5 or [A / G] in SEQ ID NO: 6; and (b) hybridizing the genetic material with a nucleic acid comprising a nucleic acid sequence comprising at least one of SEQ ID NO: 5 and SEQ ID NO: 6. In some embodiments, the step of analyzing the genetic material in the sample in step (a) includes (a) amplifying at least 15 nucleic acid bases in SEQ ID NO:7 or SEQ ID NO:8 from the genetic material, wherein the at least 15 nucleic acid bases include nucleic acid bases at the position indicated by [A / G] in SEQ ID NO:7 or [A / G] in SEQ ID NO:8, and (b) hybridizing the genetic material with a nucleic acid comprising a nucleic acid sequence comprising at least one of SEQ ID NO:7 and SEQ ID NO:8. In some embodiments, the nucleic acid comprises a detectable molecule. In some embodiments, the method further includes administering a CD30 ligand activity or expression inhibitor 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 that targets the CD30 ligand or CD30, or a combination thereof.In some embodiments, the step of characterizing the inflammatory disease of step (b) as CD comprises characterizing the inflammatory disease as ineffective to standard treatments selected from the group consisting of glucocorticoids, anti-TNF therapeutic agents, anti-a4-b7 therapeutic agents (vedolizumab), anti-IL12p40 therapeutic agents (ustekinumab), thalidomide, and cytokines. In some embodiments, the CD is further characterized as obstructive CD. In some embodiments, the method further comprises the step of administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is a modulator of gene expression, or the expression or activity of a gene expression product, and the gene is mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), prostaglandin E receptor 4 (PTGER4), interleukin 18 receptor 1 (IL18R1), 6-phosphofructo-2-kinase / fructose-2,6-bisphosphatase 3 (PFKFB3), interleukin 18 receptor accessory protein (IL18RAP), adenylate cyclase 7 (ADCY7), B lymphocyte tyrosine kinase (BLK), G protein-coupled receptor 65 (GPR65), Sprouty-related EVH1 domain-containing 2 (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), and is selected from the group consisting of. In some embodiments, the method further comprises the step of administering to the subject an effective amount of an inhibitor of tumor necrosis factor ligand superfamily member 15 (TL1A). In some embodiments, the inhibitor of TL1A is an antagonist of an antibody or antigen-binding fragment targeting TL1A. In some embodiments, the antibody or antigen-binding fragment targeting TL1A is shown in Table 15.

[0013] Use of compounds comprising CD30 ligand inhibitors to treat subjects identified as carriers of a genotype containing the "A" allele at nucleoposition 501 in SEQ ID NO:2, the "G" allele at nucleoposition 501 in SEQ ID NO:4, or a combination thereof. In some embodiments, the subjects are identified as having, or suspected of progressing to, at least one of no response or loss of response to standard treatment selected from the group consisting of glucocorticosteroids, anti-TNF agents, anti-α4-β7 agents (vedolizumab), anti-IL12p40 agents (ustekinumab), thalidomide, and cytoxin.

[0014] Use of combination therapy comprising a CD30 ligand inhibitor and a tumor necrosis factor ligand superfamily member 15 (TL1A) inhibitor to treat subjects identified as carriers of a genotype containing the "A" allele at nucleoposition 501 in SEQ ID NO:2, the "G" allele at nucleoposition 501 in SEQ ID NO:4, or a combination thereof. In some embodiments, the CD30 ligand inhibitor and the TL1A inhibitor are administered to the subject individually. In some embodiments, the subject is identified as having, or suspected of progressing to, at least one of no response or loss of response to standard treatment selected from the group consisting of glucocorticosteroids, anti-TNF agents, anti-α4-β7 agents (vedolizumab), anti-IL12p40 agents (ustekinumab), thalidomide, and cytoxin. In some embodiments, the TL1A inhibitor is an antibody or antigen-binding fragment that targets TL1A. In some embodiments, antibodies or antigen-binding fragments targeting TL1A are shown in Table 15. [Brief explanation of the drawing]

[0015] [Figure 1]Compared to individuals not carrying the risk allele ("non-risk, GG"), the risk allele "A" within rs911605 (P=4.41×10⁻⁴) (rs911605A or rs911605AA) is associated with increased expression of tumor necrosis factor receptor superfamily 8 (TNFSF8) mRNA in the small intestine using cis-eQTLs. [Figure 2] This study demonstrates that CD30L protein expression is upregulated in T cells and B cells from samples obtained from subjects carrying the rs911605A or rs911605AA risk genotype, compared to non-risk ("NR") individuals that do not express the risk genotype. [Figure 3] This shows increased expression of interferon-gamma (IFN-gamma or IFNg) in samples obtained from subjects compared to non-risk ("NR") individuals that do not express the risk genotype. [Figure 4] Compared to non-risk individuals ("NR") that do not express the risk genotype, samples obtained from test subjects show increased expression of tumor necrosis factor α (TNFa). [Figure 5] This shows increased expression of interleukin-6 (IL-6) in samples obtained from subjects compared to non-risk individuals ("NR") that do not express the risk genotype. [Figure 6] This study demonstrates that CD30L expression correlates with levels of soluble CD30 (sCD30) in a patient population carrying various genotypes, including rs911605AA and rs1006026 AA / GA / GG genotypes (A), rs911605AA and rs1006026GA / GG genotypes (B), and rs911605AA and rs1006026GG genotypes (C). [Figure 7] This study shows that the risk genotypes rs911605AA and rs1006026AA / GA / GG(A), rs911605AA and rs1006026GA / GG(B), and rs911605AA and rs1006026GG(C) are correlated with sCD30 levels and CD30L percentages in B cells. [Modes for carrying out the invention]

[0016] This disclosure provides methods and systems for detecting the presence or absence of a particular genotype in a subject. These may be useful in selecting subjects for specific treatment of a disease or illness, identifying the risk of developing a clinical or subclinical phenotype, or a combination thereof. In some embodiments, the genotype includes the polymorphism of rs911605 (SEQ ID NO: 1) and optionally the polymorphism of rs1006026 (SEQ ID NO: 3). As an example, the genotype is a haplotype that includes polymorphisms in both rs911605 and rs1006026. In some cases, the presence of a particular genotype indicates elevated expression of CD30 ligand (CD30L) in the subject. In some cases, the presence of a particular genotype indicates elevated levels of soluble CD30 in the subject. In some cases, the presence of a particular genotype indicates elevated expression of tumor necrosis factor (TNF) family cytokine TL1A (TNFSF15) in the subject. Therefore, subjects positive for the aforementioned genotype may be suitable for treatment with CD30L inhibitors, such as anti-CD30L antibodies. Subjects positive for the aforementioned genotype may also be suitable for treatment with TL1A inhibitors. For example, CD30L inhibitors and TL1A inhibitors may be useful in treating diseases or conditions associated with CD30L / CD30 or TL1A activity, such as inflammatory diseases, fibrous strictures, and fibrous diseases, at least one of these. Non-limiting examples of inflammatory diseases include diseases of the gastrointestinal tract, liver, and gallbladder, and Crohn's disease (CD). A typical fibrous disease is primary sclerosing cholangitis (PSC).

[0017] In some embodiments, methods and systems are provided for identifying whether a subject has polymorphisms in rs911605 and / or rs1006026. In some cases, the polymorphism includes an "A" allele at position 501 of rs911605 (SEQ ID NO: 2). In some cases, the polymorphism includes a "G" allele at position 501 of rs1006026 (SEQ ID NO: 4). A typical method is a hybridization assay, which includes the step of contacting the subject's genetic material with a probe containing a nucleic acid sequence that can hybridize to at least a portion (e.g., at least about 10 nucleic acid bases) of the nucleic acid sequence containing the polymorphism. As an example, the method includes the step of contacting the genetic material with a probe containing at least about 10 adjacent nucleic acid bases of rs911605 (SEQ ID NO: 1 or SEQ ID NO: 2), wherein the probe contains at least one nucleic acid base at position 501. As another example, the method includes contacting the gene material with a probe containing at least about 10 adjacent nucleic acid bases of rs1006026 (SEQ ID NO:3 or SEQ ID NO:4), wherein the probe contains at least one nucleic acid base at position 501. Additional probes include probes having sequences that are inversely complementary to the sequences described herein, for example, inversely complementary to any of SEQ ID NO:1-4. In some cases, the method includes a multiplex assay comprising contacting the gene material with two or more probes, for example, one or more probes specific to the polymorphism of rs911605 and one or more probes specific to the polymorphism of rs1006026. A suitable hybridization assay is quantitative polymerase chain reaction (qPCR). For example, qPCR is the TaqMan® assay.

[0018] Furthermore, compositions and kits are provided for detecting the presence of polymorphisms of specific genotypes or haplotypes, such as rs911605 and / or rs1006026. In some cases, the kit includes reagents such as primers and / or probes configured to amplify and / or detect the genotype of a subject's genetic sample. In some cases, the kit includes a sample collection device. Some such devices are useful for obtaining a sample containing the subject's genetic material. A typical collection device is a cotton swab. For use in sample collection, one method includes the step of bringing the cotton swab into contact with the surface of the subject to be examined, for example, inside the cheek. Another typical collection device is a tube for collecting a blood sample from a subject. In some cases, the tube contains additives for preservation and / or to facilitate analysis. For example, the tube may contain heparin, potassium oxalate, sodium fluoride, ethylenediaminetetraacetic acid (EDTA), sodium citrate, reagents to activate or reduce coagulation, reagents to separate serum, or combinations thereof.

[0019] Furthermore, other therapeutic agents, such as CD30L inhibitors, are provided, which may be administered to patients with inflammatory diseases, fibrous stenotic diseases, and / or fibrotic diseases. In some cases, the other therapeutic agents may include TL1A inhibitors. Non-limiting examples of CD30L inhibitors are anti-CD30L antibodies, such as the antibodies disclosed elsewhere in this specification. Non-limiting examples of TL1A inhibitors are anti-TL1A antibodies, such as the antibodies disclosed herein. In some embodiments, the patients include polymorphisms of the genotypes disclosed herein, e.g., rs911605 and / or rs1006026.

[0020] overview Embodiments disclosed herein provide a genotype of a subject. This genotype may be detected in a sample obtained from the subject by analyzing the genetic material in the sample. The genotypes disclosed herein may be associated with a disease or illness, or a subclinical phenotype of a disease or illness. The genotypes disclosed herein may be associated with gene expression, or an increase or decrease in gene expression products expressed from such gene. The genotypes may further be associated with the presence of other biomarkers, such as serological markers.

[0021] The determination of the presence of the genotypes disclosed herein may be useful in at least one of the diagnosis, prediction, monitoring, prevention, and treatment of subjects with the disease or illness, or its subclinical phenotype or symptoms. The genotypes disclosed herein may also be useful in identifying subjects who are likely to be unresponsive or lose response to a standard treatment, such as a first-line treatment (e.g., anti-TNF therapy, steroids, or other immunomodulators). Similarly, the genotypes disclosed herein can be used to identify subjects who are likely to show a positive (e.g., therapeutic) response to the therapeutic agents or additional therapeutic agents disclosed herein (e.g., anti-TL1A therapeutic agents).

[0022] Subject

[0023] The subjects disclosed herein may be mammals, such as mice, rats, guinea pigs, rabbits, non-human primates, or livestock. In some examples, the subjects are human. In some examples, the subjects are patients diagnosed with the diseases or illnesses disclosed herein. In some examples, the subjects are not diagnosed with the diseases or illnesses. In some examples, the subjects have symptoms associated with the diseases or illnesses disclosed herein (e.g., abdominal pain, convulsions, diarrhea, rectal bleeding, fever, weight loss, fatigue, loss of appetite, dehydration, and malnutrition, anemia, or ulcers). In some embodiments, the subjects are highly sensitive to or suffer from thiopurine toxicity or diseases caused by thiopurine toxicity (such as pancreatitis or leukopenia). The subject is either unresponsive, loses response, or is suspected to be unresponsive to standard treatment (e.g., anti-TNFα therapy, anti-α4-β7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), thalidomide, or cytoxin).

[0024] Disease or illness

[0025] The diseases or illnesses disclosed herein are at least one of inflammatory diseases, fibrous strictures, and fibrous diseases. Non-exclusive examples of inflammatory diseases include diseases of the gastrointestinal (GI) tract, liver, gallbladder, and joints. In some cases, the inflammatory disease is inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis, systemic lupus erythematosus (SLE), or rheumatoid arthritis. Subjects may have fibrosis, fibrous strictures, or fibrous diseases alone or in combination with inflammatory diseases. In some cases, the CD is obstructive CD. Obstructive CD may result from inflammation causing scarring (fibrous strictures) and / or bulging of the intestinal wall. In some cases, the CD is characterized by the presence of fibrosis and / or inflammatory strictures. The strictures can be identified by computed tomography (CTE) and magnetic resonance imaging (MRE) intestinal motility recordings. In some embodiments, the disease is primary sclerosing cholangitis (PSC). Typical methods for diagnosing PSC include magnetic resonance cholangiopancreatography (MRCP), liver function tests, and histological examinations. Liver function tests are evaluable by laboratory testing and may include measurement of serum alkaline phosphatase levels, serum aminotransferase levels, gamma-glutamyl transpeptidase levels, and the presence of hypergammaglobulinemia. The disease or illness may include thiopurine toxicity or diseases caused by thiopurine toxicity (such as pancreatitis or leukopenia). In further embodiments provided, the subject is unresponsive to induction of treatment or loses response to treatment after successful induction of treatment. Non-limiting examples of standard treatments include glucocorticosteroids, anti-TNF agents, anti-α4-β7 agents (vedolizumab), anti-IL12p40 agents (ustekinumab), thalidomide, and cytoxin.

[0026] Genotype

[0027] This specification discloses, in some embodiments, genotypes detected in a sample by analyzing genetic material obtained from a subject. In some examples, the subject may be a human. In some embodiments, the genetic material is obtained from a subject suffering from a disease or illness disclosed herein. In some cases, the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, or urine by techniques known to those skilled in the art. In some cases, the genetic material is obtained for biopsy, for example, from the digestive tract of a subject.

[0028] The genotypes of this disclosure comprise genetic material that is deoxyribonucleic acid (DNA). In some examples, the genotype comprises a denatured DNA molecule or a fragment thereof. In some examples, the genotype comprises 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 examples, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denatured double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may be cleaved or fragmented.

[0029] The genotypes disclosed herein include at least one polymorphism in a gene or locus described herein. In some examples, the gene or locus includes tumor necrosis factor (ligand) superfamily member 8 (TNFSF8). In some examples, the gene or locus includes TNF superfamily member 15 (TNFSF15). In some examples, the polymorphism is present in a locus between genes and spans both TNFSF8 and TNFSF15. The genotypes disclosed herein are, in some cases, haplotypes. In some examples, the genotype includes a specific polymorphism, a polymorphism in linkage disequilibrium (LD) with that polymorphism, or a combination thereof. In some cases, the LD is at least or about 0.70, 0.75, 0.80, 0.85, 0.90, or 0.1 r 2The genotypes disclosed herein may include at least 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, or 30 or more polymorphisms.

[0030] The polymorphisms described herein may be single nucleotide polymorphisms or indels (insertions / deletions). In some examples, the polymorphism is an insertion or deletion of at least one nucleic acid base (e.g., an indel). In some examples, the genotype may include copy number variations (CNVs), which are variations in many nucleic acid sequences between individuals in a given population. In some examples, the CNVs include at least or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, or 50 nucleic acid molecules. In some examples, the genotype is heterozygous. In some examples, the genotype is homozygous.

[0031] The genotypes provided herein may, in some cases, be associated with the presence of serological markers. Serological markers are a type of biomarker, such as autoantigens, that represent a serological response to microbial antigens in the body of a subject. Non-exclusive examples of serological markers include anti-neutrophil cytoplasmic antibodies (ANCA), anti-Saccharomyces cerevisiae antibodies (ASCA), anti-flagellin (CBir1) antibodies, and E. coli outer membrane porin protein C (OmpC). The serological markers disclosed herein are useful for patient selection for treatment, either alone or in combination with the genotypes disclosed herein. The serological markers disclosed herein are further useful, either alone or in combination with the genotypes disclosed herein, for the diagnosis, prediction, prevention, treatment, and / or monitoring of the diseases or illnesses disclosed herein.

[0032] In some examples, the genotype includes one or more polymorphisms in the gene or locus 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: 1. A genotype that contains at least one polymorphism in a gene or gene locus. 2. The genotype of Embodiment 1, comprising the polymorphisms shown in Table 1, or polymorphisms that are in linkage disequilibrium (LD) with said polymorphisms. 3. Genotypes of Embodiment 1 or 2, comprising the polymorphisms shown in Table 2, or said polymorphisms and the polymorphisms in LD. 4. A genotype according to any of Embodiments 1 to 3, which includes the polymorphisms shown in Table 3, or the polymorphisms shown in LD. 5. A genotype according to any of Embodiments 1 to 4, comprising the polymorphisms shown in Table 4, or the polymorphisms shown in LD. 6. A genotype according to any of Embodiments 1 to 5, which includes the polymorphisms shown in Table 5, or the polymorphisms shown in LD. 7. A genotype according to any of Embodiments 1 to 6, comprising the polymorphisms shown in Table 6, or the polymorphisms shown in LD. 8. A genotype according to any of Embodiments 1 to 7, comprising the polymorphisms shown in Table 7, or said polymorphisms and the polymorphisms in LD. 9. A genotype of any of Embodiments 1 to 8, comprising the polymorphisms shown in Table 8, or said polymorphisms and the polymorphisms in LD. 10. A genotype according to any of Embodiments 1 to 9, comprising the polymorphisms shown in Table 9, or the polymorphisms shown in LD. 11. Any genotype of Embodiments 1 to 10, comprising the polymorphisms shown in Table 10, or said polymorphisms and the polymorphisms in LD. 12. Any genotype of Embodiments 1 to 11, comprising the polymorphisms shown in Table 11, or said polymorphisms and the polymorphisms in LD. 13. Any genotype of Embodiments 1 to 12, comprising the polymorphisms shown in Table 12, or said polymorphisms and the polymorphisms in LD. 14. Any genotype of Embodiments 1 to 13, comprising the polymorphisms shown in Table 13, or said polymorphisms and the polymorphisms in LD. 15. Any genotype of Embodiments 1 to 14, comprising the polymorphisms shown in Table 14, or said polymorphisms and the polymorphisms in LD. 16. Any genotype of Embodiments 1 to 15, comprising a single nucleotide polymorphism (SNP) in rs911605. 17. The genotype of Embodiment 16, in which the SNP rs911605 is provided as SEQ ID NO:1. 18. The genotype of Example 16 in which the SNP of rs911605 contains an "A" allele at position 501 of SEQ ID NO:2. 19. A heterozygous genotype of any of embodiments 16 to 18. 20. A homozygous genotype of any of embodiments 16 to 18. 21. Any genotype of Embodiments 1 to 20, comprising the SNP rs1006026. 22. The genotype of Embodiment 21, in which the SNP rs1006026 is provided as SEQ ID NO:3. 23. The genotype of Example 21, in which the SNP of rs100602 contains a "G" allele at position 501 of SEQ ID NO:4. 24. A heterozygous genotype of any of embodiments 21 to 23. 25. A homozygous genotype of any of embodiments 21 to 23.

[0033] Embodiments disclosed herein provide genotypes associated with and representing subjects who progress to or are suspected of progressing to, and therefore at risk of progressing to, a particular disease or illness or its subclinical phenotype. Table 1 shows typical polymorphisms associated with CD. Table 2 shows typical polymorphisms associated with UC. Table 3 shows typical polymorphisms associated with IBD. Table 4 shows typical polymorphisms associated with anti-TNF response loss. Table 5 shows typical polymorphisms associated with primary sclerosing cholangitis (PSC). Table 6 shows typical polymorphisms associated with the presence of ASCA. Table 7 shows typical polymorphisms associated with the presence of an antigenic response to Cbir1 flagellin.

[0034] Table 1-1

[0035] Table 1-2

[0036] Table 1-3

[0037] Table 2-1

[0038] Table 2-2

[0039] Table 2-3

[0040] Table 3-1

[0041] Table 3-2

[0042] Table 4

[0043] Table 5

[0044] Table 6

[0045] Table 7

[0046] In one embodiment, the genotypes disclosed herein are associated with and thus indicate subjects who have or develop a specific subclinical phenotype of a disease or illness. A subclinical phenotype may be a specific phenotype associated with a disease or illness, or a metric that measures disease progression, which is a characteristic of a severe or abnormal form of the disease. In some cases, the subclinical phenotype is diagnosable. In some cases, the subclinical phenotype is not diagnosable. Non-limiting examples of IBD subclinical phenotypes include, but are not limited to, non-stenotic disease, stenotic disease, stenotic-permeable disease, perianal Crohn's disease (pCD), Paneth cell deficiency, PSC, and the development of blood clots (e.g., thrombi). Time to first surgery and time to subsequent surgery are subclinical phenotypes used to identify subjects at risk of severe forms of the disease. In the context of inflammatory bowel disease, time to first surgery may be the time from the onset of symptoms of inflammatory bowel disease to surgery. Time to first surgery may be the time from the initial diagnosis of IBD to the time of the first surgery. The time to the next surgery may be the time from the first surgery to the next surgery. The first and / or subsequent surgeries may involve surgery on at least a portion of the subject's gastrointestinal tract. Non-limiting examples of surgeries include bowel resection, colectomy, perianal surgery, and strictureplasty. The symptoms may be any symptoms described herein. The portion of the gastrointestinal tract may be selected from the anus, colon, large intestine, small intestine, stomach, and esophagus. Table 8 shows typical polymorphisms associated with the time to the first surgery. Table 9 shows typical polymorphisms associated with the time to the next surgery. Table 10 shows typical polymorphisms associated with various Paneth cell phenotypes. Table 11 shows typical SNPs associated with thrombus progression. Table 12 shows typical polymorphisms associated with non-stenotic and non-penetrating disease or stenotic and penetrating disease in various parts of the small intestine.

[0047] [Table 8]

[0048] [Table 9]

[0049] [Table 10]

[0050] [Table 11]

[0051] [Table 12]

[0052] 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, and both belong to the tumor necrosis factor (TNF) family. In some embodiments, the presence of a genotype containing one or more polymorphisms from Table 13 is associated with decreased CD30 values ​​compared to individuals lacking this genotype. In some embodiments, the presence of a genotype containing one or more polymorphisms from Table 14 is associated with increased CD30 values ​​compared to individuals lacking this genotype. In some examples, detection of a genotype associated with decreased CD30 in a sample obtained from a subject indicates decreased CD30 values ​​in the subject compared to individuals lacking this genotype. In some examples, detection of a genotype associated with increased CD30 in a sample obtained from a subject indicates increased CD30 values ​​in the subject compared to individuals lacking this genotype. An increase or decrease in CD30 may be shown to correspond to an increase or decrease in its ligand, CD30L.

[0053] In some examples, an increase or decrease in CD30 or CD30L is expressed as a fold change. In this specification, “fold change” refers to a change in the amount or level of expression of a gene or its gene expression product from an initial value to a final value. A fold change may be measured over a period of time, at one point in time, or a combination thereof. A fold change may be an increase or 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), a protein, or both. In some embodiments, the RNA comprises messenger RNA (mRNA). In some embodiments, an increase or decrease in the meristem ratio of CD30 or CD30L includes increases of 1.1x, 1.2x, 1.3x, 1.4x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, 2.0x, 2.1x, 2.2x, 2.3x, 2.4x, 2.5x, 2.6x, 2.7x, 2.8x, 2.0x, 3.0x, 3.1x, 3.2x, 3.3x, 3.4x, 3.5x, 4x, 5x, 10x, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, or 100x or more between the expression of CD30 or CD30L in a sample obtained from a subject and in an individual that does not have the genotype associated with the meristem ratio change.

[0054] In some embodiments, an increase or decrease in a subject's CD30 or CD30L indicates that the subject has or is progressing a particular disease or illness. In some examples, subjects with a particular disease or illness associated with the presence of a genotype related to an increase in the subject's CD30 or CD30L levels are suitable for treatment with CD30L inhibitors, such as anti-CD30L antibodies. In some examples, subjects with a particular disease or illness associated with the presence of a genotype related to a decrease in the subject's CD30 or CD30L levels are suitable for treatment with CD30L or CD30 agonists.

[0055] [Table 13-1]

[0056] Table 13-2

[0057] Table 14-1

[0058] Table 14-2

[0059] Table 14-3

[0060] Table 14-4

[0061] In some embodiments, the genotype is homozygous, meaning there are two copies of the same allele at the same SNP. In some embodiments, the genotype is heterozygous, meaning there is one copy of the allele at the same SNP. In some embodiments, the genotype contains a polymorphism in rs911605 (SEQ ID NO: 1). For example, as shown by SEQ ID NO: 2, the genotype contains the "A" allele at position 501 in rs911605. In some cases, subjects with this genotype are homozygous for the "A" allele (rs911605AA). In some cases, subjects with this genotype are heterozygous (rs911605A). In some embodiments, the genotype contains a polymorphism in rs1006026 (SEQ ID NO: 3). For example, as shown by SEQ ID NO: 4, the genotype contains the "G" allele at position 501 in rs1006026. In some cases, subjects with this genotype are homozygous for the "G" allele (rs1006026GG). In other cases, subjects with this genotype are heterozygous (rs1006026G).

[0062] Furthermore, haplotypes containing polymorphisms in rs911605 (SEQ ID NO: 1) and rs1006026 (SEQ ID NO: 3) are provided. In this specification, “haplotype” refers, in some examples, to a set of polymorphisms that both tend to be heritable. In some cases, as indicated by SEQ ID NO: 2, the polymorphism of rs911605 contains an “A” allele at position 501 within rs911605. In some cases, as indicated by SEQ ID NO: 4, the polymorphism of rs1006026 contains a “G” allele at position 501 within rs1006026. In some cases, the haplotype includes rs911605AA and rs1006026GG.

[0063] method Methods for detecting genotype

[0064] A method disclosed herein for detecting a genotype in a sample of a subject comprises the step of analyzing the genetic material in the sample to detect at least one of the presence, absence, and amount of a nucleic acid sequence comprising the genotype of interest. In some cases, the nucleic acid sequence comprises DNA. In some examples, the nucleic acid sequence comprises a denatured DNA molecule or a fragment thereof. In some examples, the nucleic acid sequence comprises 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 examples, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denatured double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may be cleaved or fragmented. In some examples, the nucleic acid sequence comprises RNA. In some examples, the nucleic acid sequence comprises fragmented RNA. In some examples, the nucleic acid sequence comprises partially degraded RNA. In some examples, the nucleic acid sequence comprises microRNA or a portion thereof. In some examples, the nucleic acid sequence includes RNA molecules or fragmented RNA molecules (RNA fragments) selected from microRNA (miRNA), pre-miRNA, pri-miRNA, mRNA, pre-mRNA, viral RNA, viroid RNA, circular RNA (circRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), pre-tRNA, long non-coding RNA (lncRNA), small nuclear RNA (snRNA), circulating RNA, cell-free RNA, exosomal RNA, vector-expressed RNA, RNA transcripts, synthetic RNA, and combinations thereof.

[0065] Nucleic acid-based detection techniques that may be useful with the methods described herein include quantitative polymerase chain reaction (qPCR), gel electrophoresis, immunochemistry, insight hybridization such as fluorescence insight hybridization (FISH), cytochemistry, and next-generation sequencing. In some embodiments, the methods include TaqMan® qPCR, which involves a nucleic acid amplification reaction with a specific primer pair and hybridization of the amplified nucleic acid with a hydrolyzable probe specific to the target nucleic acid. This disclosure provides typical probes capable of hybridizing to a target nucleic acid sequence within rs911605. This disclosure also provides typical probes capable of hybridizing to a target nucleic acid sequence within rs1006026.

[0066] In some examples, the methods include hybridization and / or amplification assays, including but not limited to Southern blot or Northern blot analysis, polymerase chain reaction analysis, and probe arrays. Non-limiting amplification reactions include qPCR, self-sequence replication, transcription amplification systems, Q-β replicases, rolling circle replication, or any other nucleic acid amplification known in the art. As described herein, references to qPCR include the use of the TaqMan® method. Further typical hybridization assays include the use of nucleic acid probes conjugated to beads, multiwell plates, or other substrates, or otherwise immobilized. Here, the nucleic acid probes are configured to hybridize with target nucleic acid sequences of the genotypes provided herein. Non-limiting methods are those utilized in Anal Chem. 2013 Feb 5;85(3):1932-9.

[0067] In some embodiments, the detection of the presence or absence of a genotype includes the step of sequencing the genetic material of the subject. Sequencing can be performed using any suitable sequencing technique, including but not limited to single-molecule real-time (SMRT) sequencing, Polony sequencing, ligation sequencing, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain arrest (e.g., Sanger) sequencing, +S sequencing, or synthesis sequencing. Sequencing methods also include modern sequencing techniques such as next-generation sequencing, e.g., Illumina sequencing (e.g., Solexa), Roche 454 sequencing, ion torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing is involved in high-throughput sequencing methods. Further sequencing methods available to those skilled in the art may be utilized.

[0068] In some examples, the number of sequenced nucleotides 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 examples, the number of sequenced nucleotides is 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 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, and approximately 10 to 100 nucleotides. , 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 10,000 nucleotides, approximately 30 to approximately 1,000 nucleotides, approximately 30 to approximately 500 The nucleotides fall within the range of approximately 30 to 300 nucleotides, approximately 30 to 200 nucleotides, approximately 30 to 100 nucleotides, approximately 50 to 100,000 nucleotides, approximately 50 to 10,000 nucleotides, approximately 50 to 1,000 nucleotides, approximately 50 to 500 nucleotides, approximately 50 to 300 nucleotides, approximately 50 to 200 nucleotides, or approximately 50 to 100 nucleotides.

[0069] In some cases, the methods provided herein include the step of determining the presence, absence, and / or quantity of a nucleic acid sequence from a particular genotype. In some embodiments, a genotype detection method is provided, which includes the step of determining the presence, absence, and / or quantity of a nucleic acid sequence or portion thereof selected from SEQ ID NO: 5-8, or combinations thereof. In some cases, the portion of a nucleic acid sequence provided herein includes at least about 10, 15, 20, 25, 30, 35, 40, 45, or 50 adjacent nucleic acid bases. In some cases, the portion of a nucleic acid sequence provided herein includes about 10-50 adjacent nucleic acid bases, about 10-40 adjacent nucleic acid bases, about 15-50 adjacent nucleic acid bases, about 15-40 adjacent nucleic acid bases, about 20-50 adjacent nucleic acid bases, and about 20-40 adjacent nucleic acid bases. In some cases, portions of nucleic acid sequences 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 adjacent nucleic acid bases. In some cases, portions of nucleic acid sequences containing SEQ ID NO: 5 contain the "A" allele at the position enclosed in parentheses. In some cases, portions of nucleic acid sequences containing SEQ ID NO: 5 contain the "G" allele at the position enclosed in parentheses. In some cases, portions of nucleic acid sequences containing SEQ ID NO: 6 contain the "A" allele at the position enclosed in parentheses. In some cases, a portion of the nucleic acid sequence containing SEQ ID NO:6 contains the "G" allele at the position enclosed in parentheses. In some cases, a portion of the nucleic acid sequence containing SEQ ID NO:7 contains the "A" allele at the position enclosed in parentheses. In some cases, a portion of the nucleic acid sequence containing SEQ ID NO:7 contains the "G" allele at the position enclosed in parentheses. In some cases, a portion of the nucleic acid sequence containing SEQ ID NO:8 contains the "A" allele at the position enclosed in parentheses. In some cases, a portion of the nucleic acid sequence containing SEQ ID NO:8 contains the "G" allele at the position enclosed in parentheses.

[0070] In some embodiments, the method includes a step of determining the presence or absence of the rs911605A genotype in a sample of a subject's genetic material, which is determined 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, the subject is administered a CD30L inhibitor. In some cases, if the subject is homozygous for rs911605A, the subject is administered a CD30L inhibitor.

[0071] In some embodiments, the method includes a step of determining the presence or absence of the rs911605A genotype in a sample of a subject's genetic material, which is determined by detecting the presence or absence of nucleic acid sequences that are 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 combinations thereof. In some cases, if the subject contains the rs911605A genotype, the subject is administered a CD30L inhibitor. In some cases, if the subject is homozygous for rs911605A, the subject is administered a CD30L inhibitor.

[0072] In some embodiments, the method includes a step of determining the presence or absence of the rs911605A genotype in a sample of a subject's genetic material, which is determined by detecting the presence or absence of nucleic acid sequences that are 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 combinations thereof. In some cases, if the subject contains the rs911605A genotype, the subject is administered a CD30L inhibitor. In some cases, if the subject is homozygous for rs911605A, the subject is administered a CD30L inhibitor.

[0073] In some embodiments, the method includes a step of determining the presence or absence of the rs1006026G genotype in a sample of a subject's genetic material, which is determined 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, the subject is administered a CD30L inhibitor. In some cases, if the subject is homozygous for rs1006026G, the subject is administered a CD30L inhibitor.

[0074] In some embodiments, the method includes a step of determining the presence or absence of the rs1006026G genotype in a sample of the subject's genetic material, which is determined by detecting the presence or absence of nucleic acid sequences that are 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 combinations thereof. In some cases, if the subject contains the rs1006026G genotype, the subject is administered a CD30L inhibitor. In some cases, if the subject is homozygous for rs1006026G, the subject is administered a CD30L inhibitor.

[0075] In some embodiments, the method includes determining the presence or absence of the rs1006026G genotype in a sample of a subject's genetic material, which is determined by detecting the presence or absence of nucleic acid sequences that are 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 combinations thereof. In some cases, if the subject contains the rs1006026G genotype, the subject is administered a CD30L inhibitor. In some cases, if the subject is homozygous for rs1006026G, the subject is administered a CD30L inhibitor.

[0076] In some embodiments, the method includes determining the presence or absence of haplotypes including rs911605A and rs1006026G in a sample of the subject's genetic material, determined by detecting the presence or absence of (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 the genetic material. In some cases, if the subject contains rs911605A and rs1006026G, the subject is administered a CD30L inhibitor. In some cases, if the subject is homozygous for rs911605A and homozygous for rs1006026G, the subject is administered a CD30L inhibitor.

[0077] In some embodiments, the method includes determining the presence or absence of haplotypes containing rs911605A and rs1006026G in a sample of the subject's genetic material, which is determined by detecting the presence or absence of (a) nucleic acid sequences that are 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 combinations thereof, and (b) nucleic acid sequences that are 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 combinations thereof in the genetic material. In some cases, if the subject contains rs911605A and rs1006026G, the subject is administered a CD30L inhibitor. In some cases, if a subject is homozygous for both rs911605A and rs1006026G, the subject will be administered a CD30L inhibitor.

[0078] In some embodiments, the method includes determining the presence or absence of haplotypes containing rs911605A and rs1006026G in a sample of the subject's genetic material, determined by detecting the presence or absence of (a) nucleic acid sequences that are 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 combinations thereof, and (b) nucleic acid sequences that are 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 combinations thereof in the genetic material. In some cases, if the subject contains rs911605A and rs1006026G, the subject is administered a CD30L inhibitor. In some cases, if a subject is homozygous for both rs911605A and rs1006026G, the subject will be administered a CD30L inhibitor.

[0079] In some examples, a method for detecting a genotype includes contacting nucleic acids from a sample of the subject with a nucleic acid polymer that hybridizes to a region of a target nucleic acid sequence. In some cases, the target nucleic acid sequence is a sequence containing at least about 30, 40, 50, 60, 70, 80, 90, 100, or all of SEQ ID NO:1, where the target nucleic acid sequence contains a nucleic acid base at position 501. In some cases, the region of the target nucleic acid sequence contains a nucleic acid base at position 501 of SEQ ID NO:1. In some cases, the target nucleic acid sequence is a sequence containing at least about 30, 40, 50, 60, 70, 80, 90, 100, or all of SEQ ID NO:2, where the target nucleic acid sequence contains a nucleic acid base at position 501. In some cases, the region of the target nucleic acid sequence contains a nucleic acid base at position 501 of SEQ ID NO:2. In some cases, the target nucleic acid sequence is a sequence containing at least about 30, 40, 50, 60, 70, 80, 90, 100, or all of SEQ ID NO:3, where the target nucleic acid sequence contains a nucleic acid base at position 501. In some cases, the region of the target nucleic acid sequence contains a nucleic acid base at position 501 of SEQ ID NO:3. In some cases, the target nucleic acid sequence is a sequence containing at least about 30, 40, 50, 60, 70, 80, 90, 100, or all of SEQ ID NO:4, where the target nucleic acid sequence contains a nucleic acid base at position 501. In some cases, the region of the target nucleic acid sequence contains a nucleic acid base 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 the step of detecting a target nucleic acid sequence containing a nucleic acid base at position 501 of SEQ ID NO:1 and a target nucleic acid sequence containing a nucleic acid base at position 501 of SEQ ID NO:3. As another example, the method includes the step of detecting a target nucleic acid sequence containing a nucleic acid base at position 501 of SEQ ID NO:2, and a target nucleic acid sequence containing a nucleic acid base at position 501 of SEQ ID NO:4.

[0080] The nucleic acid polymer may contain oligonucleotides having nucleic acid base lengths of at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, or 100 or more, and sufficient to specifically hybridize to a target nucleic acid sequence as described herein. In some examples, the nucleic acid polymer may contain approximately 10 to approximately 100 nucleotides, approximately 10 to approximately 75 nucleotides, approximately 10 to approximately 50 nucleotides, approximately 15 to approximately 100 nucleotides, approximately 15 to approximately 75 nucleotides, approximately 15 to approximately 50 nucleotides, approximately 20 to approximately 100 nucleotides, approximately 20 to approximately 75 nucleotides, approximately 20 to approximately 50 nucleotides, approximately 25 to approximately 100 nucleotides, approximately 25 to approximately 75 nucleotides, or approximately 25 to approximately 50 nucleotides. In some examples, the nucleic acid polymer hybridizes to a region of at least one target nucleic acid sequence among SEQ ID NO: 1 to 8. In some examples, the nucleic acid polymer hybridizes to a target nucleic acid sequence containing SEQ ID NO:1. In some examples, the nucleic acid polymer hybridizes to a target nucleic acid sequence containing SEQ ID NO:2. In some examples, the nucleic acid polymer hybridizes to a target nucleic acid sequence containing SEQ ID NO:3. In some examples, the nucleic acid polymer hybridizes to a target nucleic acid sequence containing SEQ ID NO:4. In some examples, the nucleic acid polymer hybridizes to a target nucleic acid sequence containing SEQ ID NO:5. In some examples, the nucleic acid polymer hybridizes to a target nucleic acid sequence containing SEQ ID NO:6. In some examples, the nucleic acid polymer hybridizes to a target nucleic acid sequence containing SEQ ID NO:7. In some examples, the nucleic acid polymer hybridizes to a target nucleic acid sequence containing SEQ ID NO:8. Hybridization may be performed in standard PCR buffer at a standard hybridization temperature, for example, about 35°C to about 65°C.

[0081] Furthermore, primers useful for amplifying the nucleic acids of the target nucleic acids described herein are provided. For example, primers for use in amplification assays such as qPCR are provided. In some examples, the primers hybridize to at least a portion of one of SEQ ID NO: 1 to 8. In some examples, a forward primer is provided that hybridizes to at least about 10 adjacent bases of SEQ ID NO: 1, and a reverse primer is provided that hybridizes to at least 10 adjacent bases of SEQ ID NO: 1, so that the forward and reverse primers are adjacent to the nucleic acid base at position 501 of SEQ ID NO: 1. In some examples, a forward primer is provided that hybridizes to at least about 10 adjacent bases of SEQ ID NO: 2, and a reverse primer is provided that hybridizes to at least 10 adjacent bases of SEQ ID NO: 2, so that the forward and reverse primers are adjacent to the nucleic acid base at position 501 of SEQ ID NO: 2. In some examples, a forward primer is provided that hybridizes to at least about 10 adjacent bases of SEQ ID NO:3, and a reverse primer is provided that hybridizes to at least 10 adjacent bases of SEQ ID NO:3, so that the forward and reverse primers are adjacent to the nucleic acid base at position 501 of SEQ ID NO:3. In some examples, a forward primer is provided that hybridizes to at least about 10 adjacent bases of SEQ ID NO:4, and a reverse primer is provided that hybridizes to at least 10 adjacent bases of SEQ ID NO:4, so that the forward and reverse primers are adjacent to the nucleic acid base at position 501 of SEQ ID NO:4.

[0082] In some cases, a forward primer containing SEQ ID NO:9 is provided. In some cases, a forward primer containing at least approximately 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:9 is provided. In some cases, a reverse primer containing SEQ ID NO:10 is provided. In some cases, a reverse primer containing at least approximately 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:10 is provided. In some cases, a primer pair is provided, comprising a forward primer containing SEQ ID NO:9 and a reverse primer containing SEQ ID NO:10. In some cases, a primer pair is provided comprising a forward primer containing at least approximately 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:9, and a reverse primer containing at least approximately 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:10.

[0083] In some cases, a forward primer containing SEQ ID NO:11 is provided. In some cases, a forward primer containing at least approximately 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:11 is provided. In some cases, a reverse primer containing SEQ ID NO:12 is provided. In some cases, a reverse primer containing at least approximately 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:12 is provided. In some cases, a primer pair is provided, comprising a forward primer containing SEQ ID NO:11 and a reverse primer containing SEQ ID NO:12. In some cases, a primer pair is provided comprising a forward primer containing at least approximately 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:11, and a reverse primer containing at least approximately 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:12.

[0084] Furthermore, probe or reporter sequences that hybridize to target nucleic acids described herein are provided. Non-limiting examples include the target nucleic acids rs911605 and / or rs1006026. In some cases, the probe is a reporter comprising a dye label at one end and a quencher at the other. When the probe hybridizes to the target nucleic acid, an added DNA polymerase can increase the fluorescence of the reporter by cleaving the hybridized probe and separating the reporter dye from the quencher. In some cases, a probe comprising the nucleic acid polymer sequences described above is provided. This probe may be used to detect and / or quantify the presence of the target nucleic acid in a given sample.

[0085] In some examples, a probe containing SEQ ID NO:13 is provided. In some examples, a probe containing at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:13 is provided. In some examples, a probe containing SEQ ID NO:14 is provided. In some examples, a probe containing at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:14 is provided. In some examples, a probe containing SEQ ID NO:15 is provided. In some examples, probes are provided that contain at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity for SEQ ID NO:15. In some examples, probes are provided that contain SEQ ID NO:16. In some examples, probes are provided that contain at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity for SEQ ID NO:16.

[0086] 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 that can selectively bind to a specifically intended target nucleic acid sequence. In some examples, probes are specifically designed to be labeled with, for example, radioactive labels, fluorescent labels, enzymes, chemiluminescent tags, colorimetric quantitative tags, or other labels or tags known in the art. In some examples, the fluorescent labels include fluorophores. In some examples, the fluorophores are aromatic compounds or heteroaromatic compounds. In some examples, the fluorophores are pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzindole, oxazole, thiazole, benzothiazole, canine, carbocyanine, salicylates, anthranilates, xanthenes, dyes, and coumarins. Typical xanthene dyes include, for example, fluorescein and rhodamine. Examples of 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 with an amino group at the α or β position. Examples of naphthylamino compounds include 1-dimethylaminonaphthyl-5-sulfonate, 1-anilino-8-naphthalene sulfonate, and 2-p-toluidinyl-6-naphthalene sulfonate, and 5-(2'-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS).Typical coumarins include, for example, 3-phenyl-7-isocyanatocoumarin; acridines such as 9-isothiantoacricidine and acridine orange; N-(p-(2-benzoxazolyl)phenyl)maleimide; cyanines, such as indodicarbocyanin 3 (Cy3), indodicarbocyanin 5 (Cy5), indodicarbocyanin 5.5 (Cy5.5), and 3-(-carboxypentyl)-3'- Examples include ethyl-5,5'-dimethyloxacarbocyanine (CyA); 1H,5H,11H,15H-Xantheno[2,3,4-ij:5,6,7-i'j']diquinoridine-18-ium, 9-[2(or 4)-[[[6-[2,5-dioxo-1-pyrrolidinyl)oxy]-6-oxohexyl]amino]sulfonyl]-4(or 2)-sulfophenyl]-2,3,6,7,12,13,16,17-octahydro-intramolecular salt (TR or Texas Red); or BODIPY™ dyes. In some cases, the probe contains FAM as a dye label.

[0087] In some cases, the primers and / or probes described herein for detecting target nucleic acids are used in amplification reactions. In some cases, this amplification reaction is qPCR. A typical qPCR is a method that utilizes the TaqMan® assay.

[0088] In some cases, qPCR involves the use of an intercalating dye. Examples of intercalating 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 intercalating dye is SYBR.

[0089] In some cases, the number of amplification cycles used to detect the target nucleic acid in an amplification assay is approximately 5 to 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 10, 5 to 15, 5 to 20, 5 to 25, 5 to 30, 10 to 15, 10 to 20, 10 to 25, 10 to 30, 15 to 20, 15 to 25, 15 to 30, 20 to 25, 20 to 30, or 25 to 30 cycles.

[0090] In one embodiment, the methods provided herein for determining the presence, absence, and / or quantity of nucleic acid sequences from a particular genotype include amplification reactions such as qPCR. In a typical method, the genetic material is obtained from a sample of the subject, e.g., a blood or serum sample. In some embodiments, if nucleic acids are to be extracted, this nucleic acid is extracted using any technique that does not interfere with subsequent analysis. In some embodiments, this technique uses an alcohol precipitation reaction using ethanol, methanol, or isopropyl alcohol. In some embodiments, this technique uses phenol, chloroform, or any combination thereof. In some embodiments, this technique uses cesium chloride. In some embodiments, this technique uses sodium, potassium, ammonium acetate, or any other salt commonly used for DNA coagulation. In some embodiments, this technique utilizes a column or resin-based nucleic acid purification scheme, such as those commonly available on the market. One non-limiting example is the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In some embodiments, after extraction, the nucleic acid is stored in water, Tris buffer, or Tris EDTA buffer before analysis. In a typical embodiment, this nucleic acid material is extracted in water. In some cases, the extraction process does not involve nucleic acid purification.

[0091] In a typical qPCR assay, a nucleic acid sample is combined with primers and probes specific to the target nucleic acid, which may or may not be present in the sample and DNA polymerase. The amplification reaction is performed in a thermal cycler, which warms and cools the sample for nucleic acid amplification, excites fluorophores on the probe by irradiating the sample at a specific wavelength, and detects the emitted fluorescence. In the TaqMan® method, the probe may also be a hydrolyzable probe containing fluorophores and quenchers that are hydrolyzed by DNA polymerase when hybridized to the target nucleic acid. In some cases, the presence of the target nucleic acid is determined when the number of amplification cycles to reach a threshold is 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or less than 20. In some cases, the target nucleic acid contains SEQ ID NO: 5, and the presence of the target nucleic acid indicates the rs911605A genotype. In some cases, the target nucleic acid contains SEQ ID NO: 6, and the presence of the target nucleic acid indicates the rs911605A genotype. In some cases, the target nucleic acid includes SEQ ID NO:7, and the presence of the target nucleic acid indicates the rs1006026G genotype. In some cases, the target nucleic acid includes SEQ ID NO:8, and the presence of the target nucleic acid indicates the rs1006026G genotype. The primers and probes in the assay may include any combination of primers and probes described herein. Therefore, if haplotypes including rs911605A and rs1006026G are detectable in the assay, multiple assays may be performed.

[0092] Method for detecting and quantifying soluble CD30

[0093] Embodiments provided herein are methods for analyzing the CD30 protein level of a subject by detecting and quantifying the CD30 protein level from a sample of the subject. Non-limiting examples of sample materials include serum, plasma, and / or whole blood. When an anti-CD30 antibody is used, CD30 may be detected by the use of an antibody-based assay. In an antibody-based detection method, the anti-CD30 antibody may bind to any region of CD30. In some cases, the anti-CD30 antibody binds to a region of the CD30 protein having the sequence of SEQ ID NO:17, SEQ ID NO:18, or any CD30 protein coding isoform (e.g., against P28908). In some cases, the anti-CD30 antibody binds to a region of the CD30 protein having at least or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO:17. A typical analytical method involves performing an enzyme-linked immunosorbent assay (ELISA). The ELISA assay may be a sandwich ELISA or a direct ELISA. Other typical detection methods include immunohistochemical testing and lateral flow assays.

[0094] In some cases, the CD30 protein may be detected by detecting the binding between CD30 and CD30L. Methods for analyzing the binding between CD30 and CD30L include the step of performing an assay in vivo, in vitro, or ex vivo. In some examples, the assay may include co-immunoprecipitation (co-IP), pull-down, cross-linked protein interaction analysis, labeled transfer protein interaction analysis, or far-western blot analysis, FRET-based assays such as FRET-FLIM, yeast two-hybrid assay (BiFC), or split ciferase assay.

[0095] Methods for characterizing diseases, illnesses, or their subtypes

[0096] This specification discloses methods for characterizing a disease, illness, or subtype of said disease in a subject. In some cases, said disease or illness is at least one of inflammatory diseases, fibrous stricture diseases, and fibrous diseases. In some examples, said inflammatory disease is Crohn's disease (CD). In some examples, said inflammatory disease is ulcerative colitis (UC). In some examples, said inflammatory disease is systemic lupus erythematosus (SLE). In some examples, said inflammatory disease is rheumatoid arthritis (RA). In some examples, said fibrous disease is primary sclerosing cholangitis (PSC). The subject may be diagnosed with said disease or illness, and embodiments disclosed herein provide methods for characterizing said disease or illness as a severe form of said disease or illness (e.g., refractory disease). In some cases, the severe form of the disease is characterized by the presence or suspected progression of a subclinical phenotype of a disease or illness, such as perianal disease (e.g., pCD), stricture disease, osmotic disease, stricture-osmotic disease, ileal disease, or ileocolonic disease.

[0097] Embodiments disclosed herein are methods for characterizing a disease, illness, or subtype of said disease, the method comprising (a) applying a sample obtained from a subject to an assay configured to detect the presence, absence, or level of a genotype, and (b) characterizing the disease as a severe form of said disease if the presence or level of said genotype is detected in the sample obtained from the subject. In some examples, the genotype comprises at least one polymorphism selected from Tables 1 to 14. In some cases, the genotype comprises the rs911605A genotype (for example, containing the "A" allele at position 501 of rs911605). In some cases, the genotype is a haplotype containing the rs911605A genotype (e.g., containing the "A" allele at position 501 of rs911605), and the rs1006026G genotype (e.g., containing the "G" allele at position 501 of rs1006026) is detected in a sample obtained from a subject. In some cases, the genotype contains the rs1006026G genotype (e.g., containing the "G" allele at position 501 of rs1006026). In some cases, the disease or subtype of illness includes a subclinical phenotype selected from the group consisting of non-stenotic disease, stenotic disease, stenotic-penetrating disease, perianal Crohn's disease (pCD), Paneth cell deficiency, PSC, and progression of blood clots (e.g., thrombi). In some cases, if the presence of the genotype is detected in a sample obtained from a subject, a therapeutic agent is administered to the subject. In some cases, the therapeutic agent is an inhibitor of a CD30 ligand, TL1A, or a combination thereof. In some cases, the genotype is detected in a sample obtained from a subject using a method described herein, such as a genotyping device (e.g., qPCR, sequencer, microarray, etc.).

[0098] Methods of diagnosis and prediction

[0099] This specification discloses methods for diagnosing or determining (e.g., delivering a prediction) a subject's disease, illness, or suspected progression of said disease or subtype or symptom thereof. In some cases, said disease or illness is at least one of inflammatory diseases, fibrous strictures, and fibrous diseases. In some examples, said inflammatory disease is Crohn's disease (CD). In some examples, said inflammatory disease is ulcerative colitis (UC). In some examples, said inflammatory disease is systemic lupus erythematosus (SLE). In some examples, said inflammatory disease is rheumatoid arthritis (RA). In some examples, said fibrous disease is primary sclerosing cholangitis (PSC). The subject may be diagnosed with said disease or illness, and embodiments disclosed herein provide methods for characterizing said disease or illness as a severe form of said disease or illness (e.g., a refractory disease). In some cases, the severe form of the disease is characterized by the presence or suspected progression of a subclinical phenotype of a disease or illness, such as perianal disease (e.g., pCD), stricture disease, osmotic disease, stricture-osmotic disease, ileal disease, or ileocolonic disease.

[0100] Embodiments disclosed herein are methods for diagnosing a disease, illness, or subtype of said disease in a subject, the method comprising (a) applying a sample obtained from the subject to an assay configured to detect the presence, absence, or level of a genotype, and (b) diagnosing said disease as a severe form of said disease if the presence or level of said genotype is detected in the sample obtained from the subject.

[0101] This specification further provides a method for determining whether a subject has a disease, illness, or is suspected of progressing the disease or a subtype thereof, the method comprising (a) applying a sample obtained from a subject to an assay configured to detect the presence, absence, or level of a genotype, and (b) determining, if the presence or level of the genotype is detected in the sample obtained from the subject, whether the subject has a disease, illness, or is suspected of progressing the disease or a subtype thereof.

[0102] In some cases, the genotype includes at least one polymorphism selected from Tables 1-14. In some cases, the genotype includes the rs911605A genotype (e.g., including the "A" allele at position 501 of rs911605). In some cases, the genotype is a haplotype including the rs911605A genotype (e.g., including the "A" allele at position 501 of rs911605), and the rs1006026G genotype (e.g., including the "G" allele at position 501 of rs1006026) is detected in a sample obtained from a subject. In some cases, the genotype includes the rs1006026G genotype (e.g., including the "G" allele at position 501 of rs1006026). In some cases, the disease or subtype of the disease includes a subclinical phenotype selected from the group consisting of non-stenotic disease, stenotic disease, stenotic-penetrating disease, perianal Crohn's disease (pCD), Paneth cell deficiency, PSC, and progression of blood clots (e.g., thrombi). In some cases, the presence of the genotype is accompanied by increased CD30 ligand levels in the subject compared to individuals not carrying 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 a method described herein, such as a genotyping device (e.g., qPCR, sequencer, microarray, etc.).

[0103] Treatment method

[0104] This specification further provides methods for treating a disease or illness in a subject. In some cases, the disease or illness is at least one of inflammatory diseases, fibrous stricture diseases, and fibrous diseases. In some examples, the inflammatory disease is Crohn's disease (CD). In some examples, the inflammatory disease is ulcerative colitis (UC). In some examples, the inflammatory disease is systemic lupus erythematosus (SLE). In some examples, the inflammatory disease is rheumatoid arthritis (RA). In some examples, the fibrous disease is primary sclerosing cholangitis (PSC).

[0105] This specification discloses a method for treating a disease or illness disclosed herein in a subject by administering a CD30L inhibitor to the subject when the genotype disclosed herein is detected in a sample obtained from the subject. The genotype may be any of the genotypes described in the embodiments provided herein, including, but not limited to, any one of the polymorphisms in Tables 1 to 14, or any combination thereof. In some cases, the genotype includes the rs911605A genotype (for example, including the "A" allele at position 501 of rs911605). In some cases, this specification discloses a method for treating a subject suffering from a disease or illness disclosed herein by administering a CD30L inhibitor to the subject when haplotypes including 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 rs1006026) are detected in a sample obtained from the subject. In some cases, the genotypes are detected in a sample obtained from the subject using the detection method disclosed herein.

[0106] Embodiments disclosed herein provide a method for monitoring the progress of treatment of a subject with a CD30L inhibitor. In some examples, the monitoring includes the step of quantifying the amount of soluble CD30 or CD30L in a sample of the subject before and after administration of the CD30L inhibitor. The foregoing also discloses a method for optimizing the treatment of a subject, which includes the steps of determining the amount of CD30 and / or CD30L in a sample of the treated subject, and modifying, discontinuing, or continuing the treatment based on the amount.

[0107] CD30L inhibitors

[0108] In some examples, the treatment includes administering a therapeutic agent containing a CD30L inhibitor to an individual. In some embodiments, the CD30L inhibitor specifically binds directly or indirectly to CD30L, CD30, or a molecule that directly or indirectly interferes with the binding of CD30L to CD30. In some embodiments, the CD30L inhibitor as used herein includes an agent that modulates at least one functional activity of CD30L, such as binding to CD30. Non-limiting examples of CD30L inhibitors include polypeptides such as anti-CD30L antibodies or their antigen-binding fragments, as well as agents that specifically bind to CD30L, including nucleic acids, such as antisense constructs, siRNAs, and ribozymes. Antisense constructs include expression plasmids that, when transcribed into 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 includes a non-polypeptide or non-nucleic acid moiety as an active agent that binds to and inhibits CD30L activity.

[0109] In some embodiments, the CD30L inhibitor is a polypeptide that binds to CD30L and / or CD30. In some cases, the polypeptide is a CD30 polypeptide or a portion thereof, which retains the ability to bind to CD30L. The portion of the CD30 polypeptide contains about 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids that have at least about 85%, 90%, or 95% identity with human CD30 having SEQ ID NO: 17 or SEQ ID NO: 18. For example, the CD30L inhibitor contains a CD30 polypeptide that includes 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, that have 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. In non-limiting examples, viral CD30 polypeptides include viral CD30 derived from poxviruses such as Ectromelia virus or cowpox virus.

[0110] In non-limiting examples, the inhibitor is an anti-CD30L antibody or an anti-CD30 antibody. In this specification, the antibody comprises a full-length antigen-binding fragment of the antibody, e.g., 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 three complementarity-determining regions, HCDR1, HCDR2, and HCDR3, and a light chain containing 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] In some embodiments, the anti-CD30L antibody includes 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.

[0116] 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, anti-CD30L antibodies contain a heavy chain (HC) variable domain including SEQ ID NO:151 and a light chain (LC) variable domain including SEQ ID NO:154.In some cases, the anti-CD30L antibody contains a heavy chain (HC) variable domain containing SEQ ID NO: 152 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: 153 and a light chain (LC) variable domain containing SEQ ID NO: 154.

[0117] In some embodiments, the anti-CD30 antibody includes 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.

[0118] In some embodiments, the CD30L conjugate comprises an anti-CD30L antibody containing at least one amino acid, and a conjugation moiety bound to at least one amino acid. In some embodiments, the at least one amino acid is located near the N-terminus (e.g., near the N-terminal residue). For example, the at least one amino acid is optionally located within the first 10, 20, 30, 40, or 50 residues from the N-terminus. In some cases, the at least one amino acid is located at the N-terminus (i.e., the at least one amino acid is the N-terminal residue of the CD30L polypeptide). In other embodiments, the at least one amino acid is located near the C-terminus (e.g., near the C-terminal residue). For example, the at least one amino acid is optionally located within the first 10, 20, 30, 40, or 50 residues from the C-terminus. In some cases, the at least one amino acid is located at the C-terminus (i.e., the at least one amino acid is the C-terminal residue of the CD30L polypeptide). In some examples, the plasma half-life of the CD30L conjugate, e.g., the half-life described herein, has been improved. In some embodiments, the CD30L conjugate is functionally active (e.g., retains activity). In some embodiments, the CD30L conjugate is not functionally active (e.g., lacks activity). In some embodiments, the conjugation portion comprises a polymer containing polyethylene glycol (PEG). In some embodiments, the conjugation portion is a drug, such as an additional therapeutic agent disclosed herein. In some embodiments, the anti-CD30 antibody comprises an antibody-drug conjugate. As a non-limiting example, the antibody-drug conjugate is an anti-CD30 antibody conjugated to brentuximab, i.e., monomethyl auristatin E.

[0119] Additional medications

[0120] Treatments useful for the methods described herein include therapeutic agents that can be used alone or in combination with a CD30L inhibitor. In some embodiments, the treatment includes administering a first therapeutic agent, followed by a CD30L inhibitor. In some embodiments, the treatment includes administering the first therapeutic agent and the CD30L inhibitor integrally. In some embodiments, the treatment includes administering a CD30L inhibitor, followed by the first therapeutic agent. The combination therapy agents may be administered on the same day, or with intervals of one day, one week, one month, or more than one year. In some cases, a CD30L inhibitor may be administered when the subject is determined not to respond to first-line treatment, such as a TNF inhibitor and / or steroid. Such determination may be made by monitoring the treatment with first-line therapy and the disease state and / or diagnosis of the subject not responding to the first-line therapy.

[0121] In some embodiments, the therapeutic agent includes an anti-TNF agent, such as an anti-TNFα agent. In some embodiments, the therapeutic agent includes a second-line treatment for 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 immunosuppressant therapeutic agents include STELARA® (ustekinumab) azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate, and cyclosporine A (CsA).

[0122] In some embodiments, the therapeutic agent includes a class of selective anti-inflammatory drugs or drugs that specifically target pro-inflammatory molecules in the body. In some embodiments, the anti-inflammatory drug includes an antibody. In some embodiments, the anti-inflammatory drug includes a small molecule. Non-limiting examples of anti-inflammatory drugs include ENTYVIO (vedolizumab), corticosteroids, aminosalicylates, mesalamine, valsalazid (Colazal), and orsalazine (Dipentum).

[0123] In some embodiments, the therapeutic agent includes a stem cell therapeutic agent. The stem cell therapeutic agent may be embryonic or somatic stem cells. The stem cells may be isolated from a donor (allogeneic) or from a subject (autologous). The stem cells may be expanded adipose-derived stem cells (eASCs), hematopoietic stem cells (HSCs), mesenchymal stem (stromal) cells (MSCs), or induced pluripotent stem cells (iPSCs) derived from subject cells. In some embodiments, the therapeutic agent includes Cx601 / Alofisel® (Dalvadstrocell).

[0124] In some embodiments, the therapeutic agent comprises a small molecule. The small molecule may be used to treat inflammatory diseases or conditions, fibrous stenotic diseases, or fibrous diseases. Non-limiting examples of small molecules include Otezla® (apremilast), aricahorsen, or ozanimod (RPC-1063).

[0125] In some embodiments, the therapeutic agent is mitogen-activated protein kinase kinase kinase 4 (MAP4K4), prostaglandin E receptor 4 (PTGER4), interleukin-18 receptor 1 (IL18R1), 6-phosphofructo-2-kinase / fructose-2,6-biphosphatase 3 (PFKFB3), interleukin-18 receptor accessory protein (IL18RAP), adenylate cyclase 7 (ADCY7), B lymphocyte tyrosine kinase (BLK), and G protein binding. The therapeutic agent comprises receptor 65 (GPR65), Sprouty-associated EVH1 domain-containing 2 (SPRED2), Src kinase-associated phosphoprotein 2 (SKAP2), receptor-interacting serine / threonine kinase 2 (RIPK2), and TNF ligand superfamily member 15 (TL1A), Janus kinase 1 (JAK1) G protein-binding receptor 35 (GPR35), gasdermin B (GSDMB), and agonists of gene expression products derived from genes involved in the pathogenesis of inflammatory, fibrous, or fibrous stenotic diseases. The therapeutic agent may also be an allosteric modulator of MAP4K4, PTGER4, IL18R1, PFKFB3, IL18RAP, ADCY7, GPR65, SPRED2, SKAP2, RIPK2, TL1A, JAK1, GPR35, and GSDMB, and gene expression products derived from genes involved in the pathogenesis of inflammatory, fibrous, or fibrous stenotic diseases.

[0126] In some embodiments, the therapeutic agent comprises an antagonist. The antagonist may be an inhibitor of the activity and expression of MAP4K4, PTGER4, IL18R1, PFKFB3, IL18RAP, ADCY7, GPR65, SPRED2, SKAP2, RIPK2, TL1A, JAK1, GPR35, and GSDMB, as well as a gene expression product derived from a gene involved in the pathogenesis of inflammatory, fibrous, or fibrous stenotic diseases. Non-exclusive examples of JAK1 inhibitors include ruxolitinib (INCB018424), S-ruxolitinib (INCB018424), baricitinib (LY3009104, INCB028050), filgotinib (GLPG0634), momerotinib (CYT387), celduratinib (PRT062070, PRT2070), LY2784544, NVP-BSK805, 2HCl, tofacitinib (CP-690550, tasocitinib), XL019, pacritinib (SB1518), or ZM 39923 HCl.

[0127] In some embodiments, additional therapeutic agents include inhibitors of TL1A expression or activity. In some cases, such inhibitors of TL1A expression or activity are effective in inhibiting TL1A-DR3 binding. In some embodiments, such inhibitors of TL1A expression or activity include allosteric modulators of TL1A. Allosteric modulators of TL1A may indirectly affect TL1A on DR3, or TR6 / DcR3 on TL1A or DR3. Inhibitors of TL1A expression or activity may be direct or indirect inhibitors. Non-limiting examples of inhibitors of TL1A expression include RNA-protein TL1A translation inhibitors, antisense oligonucleotides targeting TNFSF15 mRNA (such as miRNA or siRNA), and epigenome editing (such as targeting the DNA-binding domain of TNFSF15, or post-translational modifications of histone tails and / or DNA molecules). Non-limiting examples of inhibitors of TL1A activity include antagonists to the TL1A receptor (DR3 and TR6 / DcR3), antagonists to the TL1A antigen, and antagonists to gene expression products involved in TL1A-mediated diseases. Antagonists as described herein include, but are not limited to, anti-TL1A antibodies, anti-TL1A-binding antibody fragments, or small molecules. The small molecules may be small molecules that bind to TL1A or DR3. The anti-TL1A antibodies may be monoclonal or polyclonal antibodies. The anti-TL1A antibodies may be humanized or chimeric antibodies. The anti-TL1A antibodies may be fusion proteins. The anti-TL1A antibodies may be blocking anti-TL1A antibodies. A blocking antibody blocks the binding of two proteins, for example, a ligand and its receptor. Therefore, TL1A blocking antibodies include antibodies that prevent TL1A from binding to the DR3 or TR6 / DcR3 receptor. In non-limiting examples, 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.

[0128] The anti-TL1A antibody may contain one or more antibody sequences from Table 16 and / or Table 17. The anti-DR3 antibody may contain an amino acid sequence that is at least 85% identical to any one of SEQ ID NO: 200258 to 200270 and an amino acid sequence that is at least 85% identical to any one of SEQ ID NO: 200271 to 200275. The anti-DR3 antibody may contain an amino acid sequence that includes the HCDR1, HCDR2, and HCDR3 domains of any one of SEQ ID NO: 200258 to 200270 and the LCDR1, LCDR2, and LCDR3 domains of any one of SEQ ID NO: 200271 to 200275.

[0129] In some embodiments, the anti-TL1A antibody comprises a heavy chain containing three complementarity-determining regions, HCDR1, HCDR2, and HCDR3, and a light chain containing three complementarity-determining regions, LCDR1, LCDR2, and LCDR3. In some embodiments, the anti-TL1A antibody comprises HCDR1 containing SEQ ID NO:200109, HCDR2 containing SEQ ID NO:200110, HCDR3 containing SEQ ID NO:200111, LCDR1 containing SEQ ID NO:200112, LCDR2 containing SEQ ID NO:200113, and LCDR3 containing SEQ ID NO:200114. In some cases, the anti-TL1A antibody comprises a heavy chain (HC) variable domain containing SEQ ID NO:200115 and a light chain (LC) variable domain containing SEQ ID NO:200116.

[0130] 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.

[0131] 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.

[0132] In some embodiments, the anti-TL1A antibody includes 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 embodiments, the anti-TL1A antibody includes HCDR1 containing SEQ ID NO:2000136, 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.

[0133] 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.

[0134] 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.

[0135] 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, the anti-TL1A antibody contains 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, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200171 and a light chain (LC) variable domain containing SEQ ID NO:200178.

[0136] 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, the anti-TL1A antibody contains 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, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200171 and a light chain (LC) variable domain containing SEQ ID NO:200182.

[0137] 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, the anti-TL1A antibody contains a heavy chain (HC) variable domain including SEQ ID NO:200172 and a light chain (LC) variable domain including SEQ ID NO:200177. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain including SEQ ID NO:200172 and a light chain (LC) variable domain including SEQ ID NO:200178.

[0138] 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, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200172 and a light chain (LC) variable domain containing SEQ ID NO:200181.

[0139] 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 including SEQ ID NO:200173 and a light chain (LC) variable domain including SEQ ID NO:200177. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain including SEQ ID NO:200173 and a light chain (LC) variable domain including SEQ ID NO:200178. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain including SEQ ID NO:200173 and a light chain (LC) variable domain including SEQ ID NO:200179. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain including SEQ ID NO:200173 and a light chain (LC) variable domain including SEQ ID NO:200180. In some cases, the anti-TL1A antibody contains 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, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200173 and a light chain (LC) variable domain containing SEQ ID NO:200182.

[0140] 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 containing SEQ ID NO:200174 and a light chain (LC) variable domain containing SEQ ID NO:200181. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200174 and a light chain (LC) variable domain containing SEQ ID NO:200182. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200174 and a light chain (LC) variable domain containing SEQ ID NO:200175. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200174 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 containing SEQ ID NO:200174 and a light chain (LC) variable domain containing SEQ ID NO:200177. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200174 and a light chain (LC) variable domain containing SEQ ID NO:200178.

[0141] 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 containing SEQ ID NO:200189 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 containing SEQ ID NO:200189 and a light chain (LC) variable domain containing SEQ ID NO:200197. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200190 and a light chain (LC) variable domain containing SEQ ID NO:200194. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200190 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 containing SEQ ID NO:200190 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 containing SEQ ID NO:200190 and a light chain (LC) variable domain containing SEQ ID NO:200197. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200191 and a light chain (LC) variable domain containing SEQ ID NO:200194.In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200191 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 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 containing SEQ ID NO:200191 and a light chain (LC) variable domain containing SEQ ID NO:200197. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200192 and a light chain (LC) variable domain containing SEQ ID NO:200194. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200192 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 containing SEQ ID NO:200192 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 containing SEQ ID NO:200192 and a light chain (LC) variable domain containing SEQ ID NO:200197. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200193 and a light chain (LC) variable domain containing SEQ ID NO:200194. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200193 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 containing SEQ ID NO:200193 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 containing SEQ ID NO:200193 and a light chain (LC) variable domain containing SEQ ID NO:200197.

[0142] 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 containing SEQ ID NO:200208 and a light chain (LC) variable domain containing SEQ ID NO:200209. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200210 and a light chain (LC) variable domain containing SEQ ID NO:200211. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200212 and a light chain (LC) variable domain containing SEQ ID NO:200213. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200214 and a light chain (LC) variable domain containing SEQ ID NO:200215. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200216 and a light chain (LC) variable domain containing SEQ ID NO:200217. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200218 and a light chain (LC) variable domain containing SEQ ID NO:200219. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain containing SEQ ID NO:200220 and a light chain (LC) variable domain containing SEQ ID NO:200221.In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain including SEQ ID NO:200222 and a light chain (LC) variable domain including SEQ ID NO:200223. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain including SEQ ID NO:200224 and a light chain (LC) variable domain including SEQ ID NO:200225. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain including SEQ ID NO:200226 and a light chain (LC) variable domain including SEQ ID NO:200227.

[0143] 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.

[0144] 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.

[0145] 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, the anti-TL1A antibody contains a heavy chain (HC) variable domain including SEQ ID NO:200254 and a light chain (LC) variable domain including SEQ ID NO:200255. In some cases, the anti-TL1A antibody contains a heavy chain (HC) variable domain including SEQ ID NO:200256 and a light chain (LC) variable domain including SEQ ID NO:200257.

[0146] 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.

[0147] 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.

[0148] In some embodiments, the anti-TL1A antibody comprises one or more of A101 to 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.

[0149] 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 embodiments, the anti-DR3 is A242.

[0150] [Table 15-1]

[0151] [Table 15-2]

[0152] [Table 15-3]

[0153] In some cases, the anti-TL1A antibody binds to at least one of the remaining human TL1A molecules, the same as those of the antibodies described herein. For example, the anti-TL1A antibody binds to at least one of the remaining human TL1A molecules, the same as those of the antibody selected from A100 to A177 in Table 17. In some cases, the anti-TL1A antibody binds to the same human TL1A epitope as the antibody selected from A100 to A177. In some cases, the anti-TL1A antibody binds to the same human TL1A region as the antibody selected from A100 to A177.

[0154] In one embodiment, the anti-TL1A antibody or antigen-binding fragment has a heavy chain variable region containing at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical amino acid sequence 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 (b) SEQ ID NO:Includes a light chain variable region containing at least approximately 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical amino acid sequence to any one of 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.

[0155] In some embodiments, the anti-TL1A antibody comprises one of the following embodiments 1 to 547. 1. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment is It includes a heavy chain variable region comprising four heavy chain framework regions (HFR1, HFR2, HFR3, HFR4) and three heavy chain complementarity determination regions (HCDR1, HCDR2, HCDR3), and this heavy chain variable region is (a)(i) HFR1 containing SEQ ID NO: 100100, (ii) HFR1 containing SEQ ID NO: 100108, and (iii) HFR1 selected from sequences that differ by a maximum of 5, 4, 3, or 2 amino acids from sequences selected from the group consisting of SEQ ID NO: 100100 and 100108, (b) HFR2 selected from (i) HFR2 containing SEQ ID NO: 100100, and (ii) HFR2 containing amino acid sequences that differ from SEQ ID NO: 100100 by a maximum of 5, 4, 3, or 2 amino acids, (c) HFR3 selected from (i) HFR3 containing SEQ ID NO: 100102, (ii) HFR3 containing SEQ ID NO: 100109, and (iii) HFR3 containing amino acid sequences that differ by a maximum of 5, 4, 3, or 2 amino acids from sequences selected from the group consisting of SEQ ID NO: 100102 and 100109, (d)(i) HFR4 containing SEQ ID NO:100103, and (ii) HFR4 selected from HFR4 containing amino acid sequences that differ from SEQ ID NO:100103 by a maximum of 5, 4, 3, or 2 amino acids, (e)(i)HCDR1 containing SEQ ID NO:1009, (ii)HCDR1 containing SEQ ID NO:100150 in which 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 selected from HCDR1 containing amino acid sequences that differ by a maximum of 5, 4, 3, or 2 amino acids from sequences selected from the group consisting of SEQ ID NO:1009, 100150, and 100200~100295, (f)(i)HCDR2 containing SEQ ID NO:10012, and (ii)HCDR2 selected from HCDR2 containing amino acid sequences that differ from SEQ ID NO:10012 by a maximum of 5, 4, 3, or 2 amino acids, (g) (i) HCDR3 containing SEQ ID NO: 10015, (ii) HCDR3 containing SEQ ID NO: 100152 where 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 selected from SEQ ID NO: 100296~100314, and (iv) HCDR3 selected from HCDR3 containing amino acid sequences that differ by a maximum of 5, 4, 3, or 2 amino acids from sequences selected from the group consisting of SEQ ID NO: 10015, 100152, and 100296~100314. The antibody or antigen-binding fragment further comprises a light chain variable region including four light chain framework regions (LFR1, LFR2, LFR3, LFR4) and three light chain complementarity-determining regions (LCDR1, LCDR2, LCDR3), wherein the light chain variable region is (a)(i) LFR1 containing SEQ ID NO:100104, and (ii) LFR1 selected from LFR1 containing amino acid sequences that differ from SEQ ID NO:100104 by a maximum of 5, 4, 3, or 2 amino acids, (b) LFR2 selected from (i) LFR2 containing SEQ ID NO: 100105, and (ii) LFR2 containing amino acid sequences that differ from SEQ ID NO: 100105 by a maximum of 5, 4, 3, or 2 amino acids, (c) LFR3 selected from (i) LFR3 containing SEQ ID NO: 100106, (ii) LFR3 containing SEQ ID NO: 100110, and (iii) LFR3 containing an amino acid sequence that differs by a maximum of 5, 4, 3, or 2 amino acids from the sequence selected from the group consisting of SEQ ID NO: 100106 and 100110, (d)(i) LFR4 containing SEQ ID NO:100107, and (ii) LFR4 selected from LFR4 containing amino acid sequences that differ from SEQ ID NO:100107 by a maximum of 5, 4, 3, or 2 amino acids, (e)(i) LCDR1 containing SEQ ID NO:10018, and (ii) LCDR1 selected from LCDR1 containing amino acid sequences that differ from SEQ ID NO:10018 by a maximum of 5, 4, 3, or 2 amino acids, (f)(i) LCDR2 containing SEQ ID NO:10021, and (ii) LCDR2 selected from LCDR2 containing amino acid sequences that differ from SEQ ID NO:10021 by a maximum of 5, 4, 3, or 2 amino acids, (g) an antibody or antigen-binding fragment comprising (i) an LCDR3 containing SEQ ID NO: 10024, (ii) an LCDR3 containing SEQ ID NO: 100155 in which 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) an LCDR3 selected from SEQ ID NO: 100315 to 100482, and (iv) an LCDR3 containing an amino acid sequence that differs by a maximum of 5, 4, 3, or 2 amino acids from a sequence selected from the group consisting of SEQ ID NO: 10024, 100155, and 100315 to 100482. 2. The antibody or antigen-binding fragment according to Embodiment 1, wherein HFR1 contains SEQ ID NO: 100100. 3. The antibody or antigen-binding fragment according to Embodiment 1, wherein HFR1 contains SEQ ID NO:100108. 4. The antibody or antigen-binding fragment according to Embodiment 1, wherein HFR1 contains an amino acid sequence that differs from SEQ ID NO: 100100 by a maximum of 5, 4, 3, or 2 amino acids. 5. The antibody or antigen-binding fragment according to Embodiment 1, wherein HFR1 contains an amino acid sequence that differs from SEQ ID NO: 100108 by a maximum of 5, 4, 3, or 2 amino acids. 6. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 5, wherein HFR2 contains SEQ ID NO: 100101. 7. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 5, wherein HFR2 contains an amino acid sequence that differs from SEQ ID NO: 100101 by a maximum of 5, 4, 3, or 2 amino acids. 8. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 7, wherein HFR3 contains SEQ ID NO: 100102. 9. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 7, wherein HFR3 comprises SEQ ID NO: 100109. 10. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 7, wherein HFR3 contains an amino acid sequence that differs from SEQ ID NO: 100102 by a maximum of 5, 4, 3, or 2 amino acids. 11. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 7, wherein HFR3 contains an amino acid sequence that differs from SEQ ID NO: 100109 by a maximum of 5, 4, 3, or 2 amino acids. 12. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 11, wherein HFR4 comprises SEQ ID NO: 100103. 13. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 11, wherein HFR4 contains an amino acid sequence that differs from SEQ ID NO: 100103 by a maximum of 5, 4, 3, or 2 amino acids. 14. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 13, wherein HFR4 comprises SEQ ID NO:1009. 15. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 13, wherein HCDR1 comprises SEQ ID NO: 100150. 16. The antibody or antigen-binding fragment according to Embodiment 15, wherein X1 is E. 17. The antibody or antigen-binding fragment according to embodiment 15 or 16, wherein X2 is selected from P and V. 18. The antibody or antigen-binding fragment according to any one of claims 15 to 17, wherein X3 is selected from G, S, and V. 19. The antibody or antigen-binding fragment according to any one of claims 15 to 18, wherein X4 is F. 20. An antibody or antigen-binding fragment according to any one of embodiments 15 to 19, wherein X5 is I. 21. HCDR1 is an antibody or antigen-binding fragment according to any one of Embodiments 1 to 13, comprising an amino acid sequence selected from SEQ ID NO: 100200 to 100295. 22. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 21, wherein HCDR2 comprises SEQ ID NO: 10012. 23. The antibody or antigen-binding fragment according to any one of Embodiments 1 to 21, wherein HCDR2 contains an amino acid sequence that differs from SEQ ID NO: 10012 by a maximum of 5, 4, 3, or 2 amino acids. 24. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 23, wherein HCDR3 contains SEQ ID NO: 10015. 25. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 23, wherein HCDR3 comprises SEQ ID NO: 100152. 26. The antibody or antigen-binding fragment according to Embodiment 25, wherein X1 is M. 27. An antibody or antigen-binding fragment according to either embodiment 25 or 26, wherein X2 is selected from E, I, K, L, M, Q, T, W, and Y. 28. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 23, wherein HCDR3 comprises a sequence selected from SEQ ID NO: 100296 to 100314. 29. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 28, wherein LFR1 contains SEQ ID NO: 100104. 30. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 28, wherein LFR1 contains an amino acid sequence that differs from SEQ ID NO: 100104 by a maximum of 5, 4, 3, or 2 amino acids. 31. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 30, wherein LFR2 contains SEQ ID NO: 100105. 32. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 30, wherein LFR2 contains an amino acid sequence that differs from SEQ ID NO: 100105 by a maximum of 5, 4, 3, or 2 amino acids. 33. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 32, wherein LFR3 contains SEQ ID NO: 100106. 34. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 32, wherein LFR3 contains SEQ ID NO: 100110. 35. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 32, wherein LFR3 contains an amino acid sequence that differs from SEQ ID NO: 100106 by a maximum of 5, 4, 3, or 2 amino acids. 36. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 32, wherein LFR3 contains an amino acid sequence that differs from SEQ ID NO: 100110 by a maximum of 5, 4, 3, or 2 amino acids. 37. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 36, wherein LFR4 contains SEQ ID NO: 100107. 38. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 36, wherein LFR4 contains an amino acid sequence that differs from SEQ ID NO: 100107 by a maximum of 5, 4, 3, or 2 amino acids. 39. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 38, wherein LCDR1 comprises SEQ ID NO: 10018. 40. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 38, wherein LCDR1 contains an amino acid sequence that differs from SEQ ID NO: 10018 by a maximum of 5, 4, 3, or 2 amino acids. 41. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 40, wherein LCDR2 comprises SEQ ID NO: 10021. 42. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 40, wherein LCDR2 contains an amino acid sequence that differs from SEQ ID NO: 10021 by a maximum of 5, 4, 3, or 2 amino acids. 43. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 42, wherein LCDR3 comprises SEQ ID NO: 10024. 44. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 42, wherein LCDR3 contains SEQ ID NO: 100155. 45. The antibody or antigen-binding fragment according to Embodiment 44, wherein X1 is N. 46. ​​The antibody or antigen-binding fragment according to Embodiment 44 or 45, wherein X2 is selected from D, E, H, N, and Q. 47. An antibody or antigen-binding fragment according to any one of embodiments 44 to 46, wherein X3 is A. 48. An antibody or antigen-binding fragment according to any one of embodiments 44 to 47, wherein X4 is selected from D, F, K, R, S, and T. 49. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 42, wherein LCDR3 comprises an amino acid sequence selected from SEQ ID NO: 100315 to 100482. 50. The antibody or antigen-binding fragment according to Embodiment 1, wherein HFR1 contains SEQ ID NO: 100100, HFR2 contains SEQ ID NO: 100101, HFR3 contains SEQ ID NO: 100102, HFR4 contains SEQ ID NO: 100103, LFR1 contains SEQ ID NO: 100104, LFR2 contains SEQ ID NO: 100105, LFR3 contains SEQ ID NO: 100106, and LFR4 contains 100107. 51. The antibody or antigen-binding fragment according to Embodiment 1, wherein HFR1 contains SEQ ID NO: 100108, HFR2 contains SEQ ID NO: 100109, HFR3 contains SEQ ID NO: 100103, HFR4 contains SEQ ID NO: 100103, LFR1 contains SEQ ID NO: 100104, LFR2 contains SEQ ID NO: 100105, LFR3 contains SEQ ID NO: 100110, and LFR4 contains 100107. 52. The antibody or antigen-binding fragment according to Embodiment 1, wherein HFR1 contains SEQ ID NO: 100108, HFR2 contains SEQ ID NO: 100101, HFR3 contains SEQ ID NO: 100109, HFR4 contains SEQ ID NO: 100103, LFR1 contains SEQ ID NO: 100104, LFR2 contains SEQ ID NO: 100105, LFR3 contains SEQ ID NO: 100106, and LFR4 contains 100107. 53. The antibody or antigen-binding fragment according to Embodiment 1 and any one of 50 to 52, wherein HCDR1 comprises SEQ ID NO: 1009, HCDR2 comprises SEQ ID NO: 10012, HCDR3 comprises SEQ ID NO: 10015, LCDR1 comprises SEQ ID NO: 10018, LCDR2 comprises SEQ ID NO: 10021, and LCDR3 comprises SEQ ID NO: 10024. 54. The antibody or antigen-binding fragment according to Embodiment 1 and any one of 50 to 52, wherein HCDR1 comprises SEQ ID NO: 100150, HCDR2 comprises SEQ ID NO: 10012, HCDR3 comprises SEQ ID NO: 100152, LCDR1 comprises SEQ ID NO: 10018, LCDR2 comprises SEQ ID NO: 10021, and LCDR3 comprises SEQ ID NO: 100155. 55. The antibody or antigen-binding fragment according to Embodiment 1, wherein HFR1 contains SEQ ID NO:100100, HFR2 contains SEQ ID NO:100101, HFR3 contains SEQ ID NO:100102, HFR4 contains SEQ ID NO:100103, LFR1 contains SEQ ID NO:100104, LFR2 contains SEQ ID NO:100105, LFR3 contains SEQ ID NO:100106, LFR4 contains 100107, HCDR1 contains SEQ ID NO:1009, HCDR2 contains SEQ ID NO:10012, HCDR3 contains SEQ ID NO:10015, LCDR1 contains SEQ ID NO:10018, LCDR2 contains SEQ ID NO:10021, and LCDR3 contains SEQ ID NO:10024. 56. The antibody or antigen-binding fragment according to Embodiment 1, wherein HFR1 contains SEQ ID NO: 100100, HFR2 contains SEQ ID NO: 100101, HFR3 contains SEQ ID NO: 100102, HFR4 contains SEQ ID NO: 100103, LFR1 contains SEQ ID NO: 100104, LFR2 contains SEQ ID NO: 100105, LFR3 contains SEQ ID NO: 100106, LFR4 contains 100107, HCDR1 contains SEQ ID NO: 100150, HCDR2 contains SEQ ID NO: 10012, HCDR3 contains SEQ ID NO: 100152, LCDR1 contains SEQ ID NO: 10018, LCDR2 contains SEQ ID NO: 10021, and LCDR3 contains SEQ ID NO: 100155. 57. The antibody or antigen-binding fragment according to Embodiment 1, wherein HFR1 contains SEQ ID NO:100108, HFR2 contains SEQ ID NO:100101, HFR3 contains SEQ ID NO:100109, HFR4 contains SEQ ID NO:100103, LFR1 contains SEQ ID NO:100104, LFR2 contains SEQ ID NO:100105, LFR3 contains SEQ ID NO:100110, LFR4 contains 100107, HCDR1 contains SEQ ID NO:1009, HCDR2 contains SEQ ID NO:10012, HCDR3 contains SEQ ID NO:10015, LCDR1 contains SEQ ID NO:10018, LCDR2 contains SEQ ID NO:10021, and LCDR3 contains SEQ ID NO:10024. 58. The antibody or antigen-binding fragment according to Embodiment 1, wherein HFR1 contains SEQ ID NO:100108, HFR2 contains SEQ ID NO:100101, HFR3 contains SEQ ID NO:100109, HFR4 contains SEQ ID NO:100103, LFR1 contains SEQ ID NO:100104, LFR2 contains SEQ ID NO:100105, LFR3 contains SEQ ID NO:100110, LFR4 contains 100107, HCDR1 contains SEQ ID NO:100150, HCDR2 contains SEQ ID NO:10012, HCDR3 contains SEQ ID NO:100152, LCDR1 contains SEQ ID NO:10018, LCDR2 contains SEQ ID NO:10021, and LCDR3 contains SEQ ID NO:100155. 59. The antibody or antigen-binding fragment according to Embodiment 1, wherein HFR1 contains SEQ ID NO:100108, HFR2 contains SEQ ID NO:100101, HFR3 contains SEQ ID NO:100109, HFR4 contains SEQ ID NO:100103, LFR1 contains SEQ ID NO:100104, LFR2 contains SEQ ID NO:100105, LFR3 contains SEQ ID NO:100106, LFR4 contains 100107, HCDR1 contains SEQ ID NO:1009, HCDR2 contains SEQ ID NO:10012, HCDR3 contains SEQ ID NO:10015, LCDR1 contains SEQ ID NO:10018, LCDR2 contains SEQ ID NO:10021, and LCDR3 contains SEQ ID NO:10024. 60. The antibody or antigen-binding fragment according to Embodiment 1, wherein HFR1 contains SEQ ID NO:100108, HFR2 contains SEQ ID NO:100101, HFR3 contains SEQ ID NO:100109, HFR4 contains SEQ ID NO:100103, LFR1 contains SEQ ID NO:100104, LFR2 contains SEQ ID NO:100105, LFR3 contains SEQ ID NO:100106, LFR4 contains 100107, HCDR1 contains SEQ ID NO:100150, HCDR2 contains SEQ ID NO:10012, HCDR3 contains SEQ ID NO:100152, LCDR1 contains SEQ ID NO:10018, LCDR2 contains SEQ ID NO:10021, and LCDR3 contains SEQ ID NO:100155. 61. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60, wherein X1 of SEQ ID NO:100150 is D. 62. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60, wherein X1 of SEQ ID NO:100150 is E. 63. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 62, wherein X2 of SEQ ID NO:100150 is I. 64. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 62, wherein X2 of SEQ ID NO:100150 is P. 65. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 62, wherein X2 of SEQ ID NO:100150 is V. 66. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 65, wherein X3 of SEQ ID NO:100150 is G. 67. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 65, wherein X3 of SEQ ID NO:100150 is Q. 68. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 65, wherein X3 of SEQ ID NO:100150 is S. 69. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 65, wherein X3 of SEQ ID NO:100150 is V. 70. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 69, wherein X4 of SEQ ID NO: 100150 is F. 71. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 69, wherein X4 of SEQ ID NO: 100150 is Y. 72. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 71, wherein X5 of SEQ ID NO:100150 is I. 73. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 71, wherein X5 of SEQ ID NO: 100150 is M. 74. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 73, wherein X1 of SEQ ID NO:100152 is L. 75. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 73, wherein X1 of SEQ ID NO:100152 is M. 76. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 75, wherein X2 of SEQ ID NO: 100152 is E. 77. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 75, wherein X2 of SEQ ID NO:100152 is I. 78. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 75, wherein X2 of SEQ ID NO:100152 is K. 79. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 75, wherein X2 of SEQ ID NO:100152 is L. 80. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 75, wherein X2 of SEQ ID NO:100152 is M. 81. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 75, wherein X2 of SEQ ID NO:100152 is Q. 82. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 75, wherein X2 of SEQ ID NO:100152 is T. 83. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 75, wherein X2 of SEQ ID NO:100152 is V. 84. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 75, wherein X2 of SEQ ID NO: 100152 is W. 85. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 75, wherein X2 of SEQ ID NO: 100152 is Y. 86. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 85, wherein X1 of SEQ ID NO:100155 is Q. 87. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 85, wherein X1 of SEQ ID NO:100155 is N. 88. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 87, wherein X2 of SEQ ID NO:100155 is D. 89. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 87, wherein X2 of SEQ ID NO: 100155 is E. 90. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 87, wherein X2 of SEQ ID NO: 100155 is H. 91. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 87, wherein X2 of SEQ ID NO: 100155 is N. 92. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 87, wherein X2 of SEQ ID NO:100155 is Q. 93. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 87, wherein X2 of SEQ ID NO:100155 is S. 94. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 93, wherein X3 of SEQ ID NO:100155 is A. 95. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 93, wherein X3 of SEQ ID NO:100155 is G. 96. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 95, wherein X4 of SEQ ID NO: 100155 is D. 97. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 95, wherein X4 of SEQ ID NO: 100155 is F. 98. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 95, wherein X4 of SEQ ID NO: 100155 is K. 99. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 95, wherein X4 of SEQ ID NO:100155 is N. 100. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 95, wherein X4 of SEQ ID NO: 100155 is K. 101. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 95, wherein X4 of SEQ ID NO:100155 is S. 102. An antibody or antigen-binding fragment according to any one of Embodiments 1, 54, 56, 58, and 60 to 95, wherein X4 of SEQ ID NO:100155 is T. 103. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 102, which specifically binds to human TL1A. 104. K d is 1 x 10 -9 An antibody or antigen-binding fragment according to Embodiment 103 that specifically binds to human TL1A of M or less. 105. Using a method selected from standard ELISA assays and SPRs, K d The antibody or antigen-binding fragment described in Embodiment 104, which is measured. 106. An antibody or antigen-binding fragment according to any one of embodiments 1 to 105, which inhibits the binding of DR3 to human TL1A. 107. An antibody or antigen-binding fragment according to any one of embodiments 1 to 106, which inhibits the binding of DcR3 to human TL1A. 108. The antibody or antigen-binding fragment according to any one of Embodiments 1 to 107, wherein the antibody or antigen-binding fragment is a humanized antibody, a CDR-transplanted antibody, a chimeric antibody, a Fab, a ScFv, or a combination thereof. 109. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 108, comprising a human CH1 domain. 110. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 109, comprising a human CH2 domain. 111. The antibody or antigen-binding fragment according to Embodiment 110, wherein the CH2 domain comprises at least one mutation selected from L234A, L235A, and G237A, which are numbered using Kabat. 112. An antibody or antigen-binding fragment according to any one of Embodiments 1 to 111, comprising a human CH3 domain. 113. A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment according to any one of Embodiments 1 to 112 and a pharmaceutically acceptable carrier. 114. A method for treating an inflammatory disease in a subject, comprising the step of administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment according to any one of Embodiments 1 to 113. 115. The method according to Embodiment 114, wherein the inflammatory disease is inflammatory bowel disease. 116. The method according to Embodiment 115, wherein the inflammatory bowel disease includes Crohn's disease. 117. The method according to Embodiment 116, wherein the subject is determined not to respond to anti-TNFα treatment. 118. The method according to Embodiment 116 or 117, wherein the subject is determined to have a disease phenotype including non-stenotic / non-penetrating, stenotic, stenotic and penetrating, or isolated internal penetrating. 119. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment includes a heavy chain variable region comprising four heavy chain framework regions (HFR1, HFR2, HFR3, HFR4) including SEQ ID NO: 100100~100103 and three heavy chain complementarity-determining regions (HCDR1, HCDR2, HCDR3), and the heavy chain variable region is (a)(i)HCDR1 containing SEQ ID NO:1009, (ii)HCDR1 containing SEQ ID NO:100150 in which 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 selected from HCDR1 containing amino acid sequences that differ by a maximum of 5, 4, 3, or 2 amino acids from sequences selected from the group consisting of SEQ ID NO:1009, 100150, and 100200~100295, (b) (i) HCDR2 containing SEQ ID NO: 10012, and (ii) HCDR2 selected from HCDR2 containing amino acid sequences that differ from SEQ ID NO: 10012 by a maximum of 5, 4, 3, or 2 amino acids, (c)(i)HCDR3 containing SEQ ID NO:10015, (ii)HCDR3 containing SEQ ID NO:100152 in which 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 selected from SEQ ID NO:100296~100314, and (iv)HCDR3 selected from HCDR3 containing amino acid sequences that differ by a maximum of 5, 4, 3, or 2 amino acids from sequences selected from the group consisting of SEQ ID NO:10015, 100152, and 100296~100314. The antibody or antigen-binding fragment further comprises a light chain variable region comprising four light chain framework regions (LFR1, LFR2, LFR3, LFR4) including SEQ ID NO: 100104~100107 and three light chain complementarity determining regions (LCDR1, LCDR2, LCDR3), wherein the light chain variable region is (a)(i) LCDR1 containing SEQ ID NO:10018, and (ii) LCDR1 selected from LCDR1 containing amino acid sequences that differ from SEQ ID NO:10018 by a maximum of 5, 4, 3, or 2 amino acids. (b) (i) LCDR2 containing SEQ ID NO: 10021, and (ii) LCDR2 selected from LCDR2 containing amino acid sequences that differ from SEQ ID NO: 10021 by a maximum of 5, 4, 3, or 2 amino acids, (c) an antibody or antigen-binding fragment comprising (i) an LCDR3 containing SEQ ID NO: 10024, (ii) an LCDR3 containing SEQ ID NO: 100155 in which 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) an LCDR3 selected from SEQ ID NO: 100315 to 100482, and (iv) an LCDR3 containing an amino acid sequence that differs by a maximum of 5, 4, 3, or 2 amino acids from a sequence selected from the group consisting of SEQ ID NO: 10024, 100155, and 100315 to 100482. 120. The antibody or antigen-binding fragment according to Embodiment 119, wherein HCDR1 contains SEQ ID NO:1009. 121. The antibody or antigen-binding fragment according to Embodiment 119, wherein HCDR1 contains SEQ ID NO: 100150. 122. The antibody or antigen-binding fragment according to Embodiment 121, wherein X1 is E. 123. An antibody or antigen-binding fragment according to Embodiment 121 or 122, wherein X2 is selected from P and V. 124. The antibody or antigen-binding fragment according to any one of claims 121 to 123, wherein X3 is selected from G, S, and V. 125. The antibody or antigen-binding fragment according to any one of claims 121 to 124, wherein X4 is F. 126. An antibody or antigen-binding fragment according to any one of embodiments 121 to 125, wherein X5 is I. 127. HCDR1 is an antibody or antigen-binding fragment according to Embodiment 119, comprising an amino acid sequence selected from SEQ ID NO: 100200~100295. 128. An antibody or antigen-binding fragment according to any one of Embodiments 119 to 127, wherein HCDR2 comprises SEQ ID NO: 10012. 129. An antibody or antigen-binding fragment according to any one of Embodiments 119 to 127, wherein HCDR2 contains an amino acid sequence that differs from SEQ ID NO: 10012 by a maximum of 5, 4, 3, or 2 amino acids. 130. An antibody or antigen-binding fragment according to any one of Embodiments 119 to 129, wherein HCDR3 contains SEQ ID NO: 10015. 131. An antibody or antigen-binding fragment according to any one of Embodiments 119 to 129, wherein HCDR3 comprises SEQ ID NO: 100152. 132. The antibody or antigen-binding fragment according to Embodiment 131, wherein X1 is M. 133. An antibody or antigen-binding fragment according to either embodiment 131 or 132, wherein X2 is selected from E, I, K, L, M, Q, T, W, and Y. 134. An antibody or antigen-binding fragment according to any one of Embodiments 119 to 129, wherein HCDR3 comprises a sequence selected from SEQ ID NO: 100296 to 100314. 135. An antibody or antigen-binding fragment according to any one of embodiments 119 to 134, wherein LCDR1 includes SEQ ID NO:10018. 136. An antibody or antigen-binding fragment according to any one of Embodiments 119 to 134, wherein LCDR1 contains an amino acid sequence that differs from SEQ ID NO: 10018 by a maximum of 5, 4, 3, or 2 amino acids. 137. An antibody or antigen-binding fragment according to any one of embodiments 119 to 136, wherein LCDR2 includes SEQ ID NO: 10021. 138. An antibody or antigen-binding fragment according to any one of Embodiments 119 to 136, wherein LCDR2 contains an amino acid sequence that differs from SEQ ID NO: 10021 by a maximum of 5, 4, 3, or 2 amino acids. 139. An antibody or antigen-binding fragment according to any one of Embodiments 119 to 138, wherein LCDR3 includes SEQ ID NO: 10024. 140. An antibody or antigen-binding fragment according to any one of Embodiments 119 to 138, wherein LCDR3 includes SEQ ID NO: 100155. 141. The antibody or antigen-binding fragment according to Embodiment 140, wherein X1 is N. 142. An antibody or antigen-binding fragment according to Embodiment 140 or 141, wherein X2 is selected from D, E, H, N, and Q. 143. An antibody or antigen-binding fragment according to any one of embodiments 140 to 142, wherein X3 is A. 144. An antibody or antigen-binding fragment according to any one of embodiments 140 to 143, wherein X4 is selected from D, F, K, R, S, and T. 145. An antibody or antigen-binding fragment according to any one of Embodiments 119 to 138, wherein LCDR3 comprises an amino acid sequence selected from SEQ ID NO: 100315 to 100482. 146. The antibody or antigen-binding fragment according to Embodiment 119, wherein HCDR1 comprises SEQ ID NO: 1009, HCDR2 comprises SEQ ID NO: 10012, HCDR3 comprises SEQ ID NO: 10015, LCDR1 comprises SEQ ID NO: 10018, LCDR2 comprises SEQ ID NO: 10021, and LCDR3 comprises SEQ ID NO: 10024. 147. The antibody or antigen-binding fragment according to Embodiment 119, wherein HCDR1 contains SEQ ID NO: 100150, HCDR2 contains SEQ ID NO: 10012, HCDR3 contains SEQ ID NO: 100152, LCDR1 contains SEQ ID NO: 10018, LCDR2 contains SEQ ID NO: 10021, and LCDR3 contains SEQ ID NO: 100155. 148. An antibody or antigen-binding fragment according to Embodiment 119 or 147, wherein X1 of SEQ ID NO:100150 is D. 149. An antibody or antigen-binding fragment according to Embodiment 119 or 147, wherein X1 of SEQ ID NO:100150 is E. 150. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 149, wherein X2 of SEQ ID NO: 100150 is I. 151. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 149, wherein X2 of SEQ ID NO: 100150 is P. 152. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 149, wherein X2 of SEQ ID NO: 100150 is V. 153. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 152, wherein X3 of SEQ ID NO: 100150 is G. 154. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 152, wherein X3 of SEQ ID NO: 100150 is Q. 155. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 152, wherein X3 of SEQ ID NO:100150 is S. 156. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 152, wherein X3 of SEQ ID NO: 100150 is V. 157. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 156, wherein X4 of SEQ ID NO: 100150 is F. 158. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 156, wherein X4 of SEQ ID NO: 100150 is Y. 159. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 158, wherein X5 of SEQ ID NO: 100150 is I. 160. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 158, wherein X5 of SEQ ID NO: 100150 is M. 161. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 160, wherein X1 of SEQ ID NO: 100152 is L. 162. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 160, wherein X1 of SEQ ID NO: 100152 is M. 163. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 162, wherein X2 of SEQ ID NO: 100152 is E. 164. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 162, wherein X2 of SEQ ID NO: 100152 is I. 165. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 162, wherein X2 of SEQ ID NO: 100152 is K. 166. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 162, wherein X2 of SEQ ID NO: 100152 is L. 167. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 162, wherein X2 of SEQ ID NO: 100152 is M. 168. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 162, wherein X2 of SEQ ID NO:100152 is Q. 169. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 162, wherein X2 of SEQ ID NO: 100152 is T. 170. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 162, wherein X2 of SEQ ID NO: 100152 is V. 171. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 162, wherein X2 of SEQ ID NO: 100152 is W. 172. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 162, wherein X2 of SEQ ID NO: 100152 is Y. 173. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 172, wherein X1 of SEQ ID NO:100155 is Q. 174. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 172, wherein X1 of SEQ ID NO: 100155 is N. 175. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 174, wherein X2 of SEQ ID NO: 100155 is D. 176. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 174, wherein X2 of SEQ ID NO: 100155 is E. 177. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 174, wherein X2 of SEQ ID NO: 100155 is H. 178. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 174, wherein X2 of SEQ ID NO: 100155 is N. 179. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 174, wherein X2 of SEQ ID NO: 100155 is Q. 180. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 174, wherein X2 of SEQ ID NO:100155 is S. 181. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 180, wherein X3 of SEQ ID NO: 100155 is A. 182. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 180, wherein X3 of SEQ ID NO: 100155 is G. 183. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 182, wherein X4 of SEQ ID NO: 100155 is D. 184. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 182, wherein X4 of SEQ ID NO: 100155 is F. 185. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 182, wherein X4 of SEQ ID NO: 100155 is K. 186. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 182, wherein X4 of SEQ ID NO: 100155 is N. 187. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 182, wherein X4 of SEQ ID NO:100155 is R. 188. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 182, wherein X4 of SEQ ID NO:100155 is S. 189. An antibody or antigen-binding fragment according to any one of Embodiments 119, 147 to 182, wherein X4 of SEQ ID NO:100155 is T. 190. An antibody or antigen-binding fragment according to any one of embodiments 119 to 189, which specifically binds to human TL1A. 191. K d is 1 x 10 -9 An antibody or antigen-binding fragment according to Embodiment 190 that specifically binds to human TL1A of M or less. 192. Using a method selected from standard ELISA assays and SPRs, K d The antibody or antigen-binding fragment described in Embodiment 104, which is measured. 193. An antibody or antigen-binding fragment according to any one of embodiments 119 to 192, which inhibits the binding of DR3 to human TL1A. 194. An antibody or antigen-binding fragment according to any one of embodiments 119 to 193, which inhibits the binding of DcR3 to human TL1A. 195. The antibody or antigen-binding fragment according to any one of Embodiments 119 to 194, wherein the antibody or antigen-binding fragment is a humanized antibody, a CDR-transplanted antibody, a chimeric antibody, a Fab, a ScFv, or a combination thereof. 196. An antibody or antigen-binding fragment according to any one of embodiments 119 to 195, comprising a human CH1 domain. 197. An antibody or antigen-binding fragment according to any one of embodiments 1 to 196, comprising a human CH2 domain. 198. The antibody or antigen-binding fragment according to embodiment 197, wherein the CH2 domain comprises at least one mutation selected from L234A, L235A, and G237A, numbered using Kabat. 199. An antibody or antigen-binding fragment according to any one of embodiments 119 to 198, comprising a human CH3 domain. 200. A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment according to any one of embodiments 119 to 199 and a pharmaceutically acceptable carrier. 201. A method of treating an inflammatory disease in a subject, the method comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment according to any one of embodiments 119 to 199. 202. The method according to embodiment 201, wherein the inflammatory disease is an inflammatory bowel disease. 203. The method according to embodiment 202, wherein the inflammatory bowel disease includes Crohn's disease. 204. The method according to embodiment 203, wherein the subject has been determined to be non-responsive to anti-TNFα treatment. 205. The method according to embodiment 203 or 204, wherein the subject has been determined to have a disease phenotype including non-stricturing / non-penetrating, stricturing, stricturing and penetrating, or isolated internal penetration. 206. An antibody or antigen-binding fragment that specifically binds to TL1A, the antibody or antigen-binding fragment comprising a heavy chain variable region comprising four heavy chain framework regions (HFR1, HFR2, HFR3, HFR4) each comprising SEQ ID NO: 100108, 100101, 100109, and 100103, and three heavy chain complementarity determining regions (HCDR1, HCDR2, HCDR3), the heavy chain variable region (a)(i) An HCDR1 comprising SEQ ID NO:1009, (ii) an HCDR1 comprising SEQ ID NO:100150, where 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) an HCDR1 selected from SEQ ID NO:100200 - 100295, and (iv) an HCDR1 selected from amino acid sequences that differ from the sequences consisting of SEQ ID NO:1009, 100150, and 100200 - 100295 by at most 5, 4, 3, or 2 amino acids, (b)(i) An HCDR2 comprising SEQ ID NO:10012, and (ii) an HCDR2 selected from amino acid sequences that differ from SEQ ID NO:10012 by at most 5, 4, 3, or 2 amino acids, (c)(i) An HCDR3 comprising SEQ ID NO:10015, (ii) an HCDR3 comprising SEQ ID NO:100152, where X1 is selected from L and M and X2 is selected from E, I, K, L, M, Q, T, V, W, and Y, (iii) an HCDR3 selected from SEQ ID NO:100296 - 100314, and (iv) an HCDR3 selected from amino acid sequences that differ from the sequences consisting of SEQ ID NO:10015, 100152, and 100296 - 100314 by at most 5, 4, 3, or 2 amino acids, The antibody or antigen - binding fragment further comprises a light - chain variable region comprising four light - chain framework regions (LFR1, LFR2, LFR3, LFR4) each comprising SEQ ID NO:100104, 100105, 100110, and 100107, and three light - chain complementarity - determining regions (LCDR1, LCDR2, LCDR3), and the light - chain variable region (a)(i) An LCDR1 comprising SEQ ID NO:10018, and (ii) an LCDR1 selected from amino acid sequences that differ from SEQ ID NO:10018 by at most 5, 4, 3, or 2 amino acids, (b) (i) LCDR2 containing SEQ ID NO: 10021, and (ii) LCDR2 selected from LCDR2 containing amino acid sequences that differ from SEQ ID NO: 10021 by a maximum of 5, 4, 3, or 2 amino acids, (c) an antibody or antigen-binding fragment comprising (i) an LCDR3 containing SEQ ID NO: 10024, (ii) an LCDR3 containing SEQ ID NO: 100155 in which 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) an LCDR3 selected from SEQ ID NO: 100315 to 100482, and (iv) an LCDR3 containing an amino acid sequence that differs by a maximum of 5, 4, 3, or 2 amino acids from a sequence selected from the group consisting of SEQ ID NO: 10024, 100155, and 100315 to 100482. 207. The antibody or antigen-binding fragment according to Embodiment 206, wherein HCDR1 comprises SEQ ID NO:1009. 208. The antibody or antigen-binding fragment according to Embodiment 206, wherein HCDR1 contains SEQ ID NO: 100150. 209. The antibody or antigen-binding fragment according to Embodiment 208, wherein X1 is E. 210. An antibody or antigen-binding fragment according to embodiment 208 or 209, wherein X2 is selected from P and V. 211. The antibody or antigen-binding fragment according to any one of claims 208 to 210, wherein X3 is selected from G, S, and V. 212. The antibody or antigen-binding fragment according to any one of claims 208 to 211, wherein X4 is F. 213. An antibody or antigen-binding fragment according to any one of embodiments 208 to 212, wherein X5 is I. 214. HCDR1 is an antibody or antigen-binding fragment according to Embodiment 206, comprising an amino acid sequence selected from SEQ ID NO: 100200~100295. 215. An antibody or antigen-binding fragment according to any one of embodiments 206 to 214, wherein HCDR2 comprises SEQ ID NO: 10012. 216. An antibody or antigen-binding fragment according to any one of embodiments 206 to 214, wherein HCDR2 contains an amino acid sequence that differs from SEQ ID NO: 10012 by a maximum of 5, 4, 3, or 2 amino acids. 217. An antibody or antigen-binding fragment according to any one of embodiments 206 to 216, wherein HCDR3 comprises SEQ ID NO: 10015. 218. An antibody or antigen-binding fragment according to any one of embodiments 206 to 216, wherein HCDR3 comprises SEQ ID NO: 100152. 219. The antibody or antigen-binding fragment according to Embodiment 218, wherein X1 is M. 220. An antibody or antigen-binding fragment according to either embodiment 218 or 219, wherein X2 is selected from E, I, K, L, M, Q, T, W, and Y. 221. An antibody or antigen-binding fragment according to any one of embodiments 206 to 220, wherein HCDR3 comprises a sequence selected from SEQ ID NO: 100296 to 100314. 222. An antibody or antigen-binding fragment according to any one of embodiments 206 to 221, wherein LCR1 comprises SEQ ID NO: 10018. 223. An antibody or antigen-binding fragment according to any one of Embodiments 206 to 221, wherein LCDR1 contains an amino acid sequence that differs from SEQ ID NO:10018 by a maximum of 5, 4, 3, or 2 amino acids. 224. An antibody or antigen-binding fragment according to any one of embodiments 206 to 223, wherein the LCDR2 comprises SEQ ID NO: 10021. 225. An antibody or antigen-binding fragment according to any one of Embodiments 206 to 223, wherein LCDR2 contains an amino acid sequence that differs from SEQ ID NO: 10021 by a maximum of 5, 4, 3, or 2 amino acids. 226. An antibody or antigen-binding fragment according to any one of embodiments 206 to 225, wherein the LCDR3 comprises SEQ ID NO: 10024. 227. An antibody or antigen-binding fragment according to any one of embodiments 206 to 225, wherein the LCDR3 comprises SEQ ID NO: 100155. 228. The antibody or antigen-binding fragment according to Embodiment 227, wherein X1 is N. 229. An antibody or antigen-binding fragment according to Embodiment 227 or 228, wherein X2 is selected from D, E, H, N, and Q. 230. An antibody or antigen-binding fragment according to any one of embodiments 227 to 229, wherein X3 is A. 231. An antibody or antigen-binding fragment according to any one of embodiments 227 to 230, wherein X4 is selected from D, F, K, R, S, and T. 232. An antibody or antigen-binding fragment according to any one of embodiments 227 to 231, wherein LCDR3 comprises an amino acid sequence selected from SEQ ID NO: 100315 to 100482. 233. The antibody or antigen-binding fragment according to Embodiment 206, wherein HCDR1 comprises SEQ ID NO: 1009, HCDR2 comprises SEQ ID NO: 10012, HCDR3 comprises SEQ ID NO: 10015, LCDR1 comprises SEQ ID NO: 10018, LCDR2 comprises SEQ ID NO: 10021, and LCDR3 comprises SEQ ID NO: 10024. 234. The antibody or antigen-binding fragment according to Embodiment 206, wherein HCDR1 contains SEQ ID NO: 100150, HCDR2 contains SEQ ID NO: 10012, HCDR3 contains SEQ ID NO: 100152, LCDR1 contains SEQ ID NO: 10018, LCDR2 contains SEQ ID NO: 10021, and LCDR3 contains SEQ ID NO: 100155. 235. An antibody or antigen-binding fragment according to Embodiment 206 or 234, wherein X1 of SEQ ID NO:100150 is D. 236. An antibody or antigen-binding fragment according to Embodiment 206 or 234, wherein X1 of SEQ ID NO:100150 is E. 237. An antibody or antigen-binding fragment according to any one of embodiments 206, 234 to 236, wherein X2 of SEQ ID NO:100150 is I. 238. An antibody or antigen-binding fragment according to any one of embodiments 206, 234 to 236, wherein X2 of SEQ ID NO:100150 is P. 239. An antibody or antigen-binding fragment according to any one of embodiments 206, 234 to 236, wherein X2 of SEQ ID NO:100150 is V. 240. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 239, wherein X3 of SEQ ID NO:100150 is G. 241. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 239, wherein X3 of SEQ ID NO:100150 is Q. 242. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 239, wherein X3 of SEQ ID NO:100150 is S. 243. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 239, wherein X3 of SEQ ID NO:100150 is V. 244. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 243, wherein X4 of SEQ ID NO: 100150 is F. 245. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 243, wherein X4 of SEQ ID NO: 100150 is Y. 246. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 245, wherein X5 of SEQ ID NO:100150 is I. 247. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 245, wherein X5 of SEQ ID NO:100150 is M. 248. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 247, wherein X1 of SEQ ID NO:100152 is L. 249. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 247, wherein X1 of SEQ ID NO:100152 is M. 250. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 249, wherein X2 of SEQ ID NO: 100152 is E. 251. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 249, wherein X2 of SEQ ID NO:100152 is I. 252. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 249, wherein X2 of SEQ ID NO:100152 is K. 253. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 249, wherein X2 of SEQ ID NO:100152 is L. 254. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 249, wherein X2 of SEQ ID NO:100152 is M. 255. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 249, wherein X2 of SEQ ID NO: 100152 is O. 256. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 249, wherein X2 of SEQ ID NO:100152 is T. 257. An antibody or antigen-binding fragment according to any one of Embodiments 206, 234 to 249, wherein X2 of SEQ ID NO:100152 is V. 258. An antibody or antigen-binding fragment according to any one of embodiments 206, 234 to 249, wherein X2 of SEQ ID NO: 100152 is W. 259. An antibody or antigen-binding fragment according to any one of embodiments 206, 234 to 249, wherein X2 of SEQ ID NO: 100152 is Y. 260. An antibody or antigen-binding fragment according to any one of embodiments 206, 234 to 259, wherein X1 of SEQ ID NO: 100155 is Q. 261. An antibody or antigen-binding fragment according to any one of embodiments 206, 234 to 259, wherein X1 of SEQ ID NO: 100155 is N. 262. An antibody or antigen-binding fragment according to any one of embodiments 206, 234 to 261, wherein X2 of SEQ ID NO: 100155 is D. 263. An antibody or antigen-binding fragment according to any one of embodiments 206, 234 to 261, wherein X2 of SEQ ID NO: 100155 is E. 264. An antibody or antigen-binding fragment according to any one of embodiments 206, 234 to 261, wherein X2 of SEQ ID NO: 100155 is H. 265. An antibody or antigen-binding fragment according to any one of embodiments 206, 234 to 261, wherein X2 of SEQ ID NO: 100155 is N. 266. An antibody or antigen-binding fragment according to any one of embodiments 206, 234 to 261, wherein X2 of SEQ ID NO: 100155 is Q. <0​​​​269. An antibody or antigen-binding fragment according to any one of embodiments 206 to 267, wherein X3 of SEQ ID NO: 100155 is G. 270. An antibody or antigen-binding fragment according to any one of embodiments 206 to 269, wherein X4 of SEQ ID NO: 100155 is D. 271. An antibody or antigen-binding fragment according to any one of embodiments 206 to 269, wherein X4 of SEQ ID NO: 100155 is F. 272. An antibody or antigen-binding fragment according to any one of embodiments 206 to 269, wherein X4 of SEQ ID NO: 100155 is K. 273. An antibody or antigen-binding fragment according to any one of embodiments 206 to 269, wherein X4 of SEQ ID NO: 100155 is N. 274. An antibody or antigen-binding fragment according to any one of embodiments 206 to 269, wherein X4 of SEQ ID NO: 100155 is R. 275. An antibody or antigen-binding fragment according to any one of embodiments 206 to 269, wherein X4 of SEQ ID NO: 100155 is S. 276. An antibody or antigen-binding fragment according to any one of embodiments 206 to 269, wherein X4 of SEQ ID NO: 100155 is T. 277. An antibody or antigen-binding fragment according to any one of embodiments 206 to 276, which specifically binds to human TL1A. 278. K d is 1 × 10 -9 The antibody or antigen-binding fragment according to embodiment 277, which specifically binds to human TL1A at M or less. 279. K d The antibody or antigen-binding fragment according to embodiment 278, wherein K is measured using a method selected from standard ELISA assays and SPR. 280. An antibody or antigen-binding fragment according to any one of embodiments 206 to 279, which inhibits the binding of DR3 to human TL1A. 281. An antibody or antigen-binding fragment according to any one of embodiments 206 to 280, which inhibits the binding of DcR3 to human TL1A. 282. The antibody or antigen-binding fragment according to any one of embodiments 206 to 281, wherein the antibody or antigen-binding fragment is a humanized antibody, a CDR-transplanted antibody, a chimeric antibody, a Fab, a ScFv, or a combination thereof. 283. An antibody or antigen-binding fragment according to any one of embodiments 206 to 282, comprising a human CH1 domain. 284. An antibody or antigen-binding fragment according to any one of embodiments 206 to 283, comprising a human CH2 domain. 285. The antibody or antigen-binding fragment according to Embodiment 284, wherein the CH2 domain comprises at least one mutation selected from L234A, L235A, and G237A, which are numbered using Kabat. 286. An antibody or antigen-binding fragment according to any one of embodiments 206 to 285, comprising a human CH3 domain. 287. A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment as described in any one of Embodiments 206 to 286, and a pharmaceutically acceptable carrier. 288. A method for treating an inflammatory disease in a subject, comprising the step of administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment according to any one of embodiments 206 to 287. 289. The method according to Embodiment 288, wherein the inflammatory disease is inflammatory bowel disease. 290. The method according to Embodiment 289, wherein the inflammatory bowel disease includes Crohn's disease. 291. The method according to Embodiment 290, wherein the subject is determined not to respond to anti-TNFα treatment. 292. The method according to Embodiment 290 or 291, wherein the subject is determined to have a disease phenotype including non-stenotic / non-penetrating, stenotic, stenotic and penetrating, or isolated internal penetrating. 293. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment includes a heavy chain variable region comprising four heavy chain framework regions (HFR1, HFR2, HFR3, HFR4) containing SEQ ID NO: 100108, 100101, 100109, and 100103 respectively, and three heavy chain complementarity-determining regions (HCDR1, HCDR2, HCDR3), wherein the heavy chain variable region is (a)(i)HCDR1 containing SEQ ID NO:1009, (ii)HCDR1 containing SEQ ID NO:100150 in which 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 selected from HCDR1 containing amino acid sequences that differ by a maximum of 5, 4, 3, or 2 amino acids from sequences selected from the group consisting of SEQ ID NO:1009, 100150, and 100200~100295, (b) (i) HCDR2 containing SEQ ID NO: 10012, and (ii) HCDR2 selected from HCDR2 containing amino acid sequences that differ from SEQ ID NO: 10012 by a maximum of 5, 4, 3, or 2 amino acids, (c)(i)HCDR3 containing SEQ ID NO:10015, (ii)HCDR3 containing SEQ ID NO:100152 in which 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 selected from SEQ ID NO:100296~100314, and (iv)HCDR3 selected from HCDR3 containing amino acid sequences that differ by a maximum of 5, 4, 3, or 2 amino acids from sequences selected from the group consisting of SEQ ID NO:10015, 100152, and 100296~100314. The antibody or antigen-binding fragment further comprises a light chain variable region comprising four light chain framework regions (LFR1, LFR2, LFR3, LFR4) including SEQ ID NO: 100104~100107 and three light chain complementarity determining regions (LCDR1, LCDR2, LCDR3), wherein the light chain variable region is (a)(i) LCDR1 containing SEQ ID NO:10018, and (ii) LCDR1 selected from LCDR1 containing amino acid sequences that differ from SEQ ID NO:10018 by a maximum of 5, 4, 3, or 2 amino acids. (b) (i) LCDR2 containing SEQ ID NO: 10021, and (ii) LCDR2 selected from LCDR2 containing amino acid sequences that differ from SEQ ID NO: 10021 by a maximum of 5, 4, 3, or 2 amino acids, (c) an antibody or antigen-binding fragment comprising (i) an LCDR3 containing SEQ ID NO: 10024, (ii) an LCDR3 containing SEQ ID NO: 100155 in which 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) an LCDR3 selected from SEQ ID NO: 100315 to 100482, and (iv) an LCDR3 containing an amino acid sequence that differs by a maximum of 5, 4, 3, or 2 amino acids from a sequence selected from the group consisting of SEQ ID NO: 10024, 100155, and 100315 to 100482. 294. The antibody or antigen-binding fragment according to Embodiment 293, wherein HCDR1 contains SEQ ID NO:1009. 295. The antibody or antigen-binding fragment according to Embodiment 293, wherein HCDR1 contains SEQ ID NO: 100150. 296. The antibody or antigen-binding fragment according to Embodiment 295, wherein X1 is E. 297. An antibody or antigen-binding fragment according to embodiment 295 or 296, wherein X2 is selected from P and V. 298. The antibody or antigen-binding fragment according to any one of claims 295 to 297, wherein X3 is selected from G, S, and V. 299. The antibody or antigen-binding fragment according to any one of claims 295 to 298, wherein X4 is F. 300. An antibody or antigen-binding fragment according to any one of embodiments 295 to 299, wherein X5 is I. 301. HCDR1 is an antibody or antigen-binding fragment according to Embodiment 293, comprising an amino acid sequence selected from SEQ ID NO: 100200~100295. 302. An antibody or antigen-binding fragment according to any one of Embodiments 293 to 301, wherein HCDR2 comprises SEQ ID NO: 10012. 303. An antibody or antigen-binding fragment according to any one of Embodiments 293 to 301, wherein HCDR2 contains an amino acid sequence that differs from SEQ ID NO: 10012 by a maximum of 5, 4, 3, or 2 amino acids. 304. An antibody or antigen-binding fragment according to any one of Embodiments 293 to 303, wherein HCDR3 contains SEQ ID NO:10015. 305. An antibody or antigen-binding fragment according to any one of Embodiments 293 to 303, wherein HCDR3 comprises SEQ ID NO: 100152. 306. The antibody or antigen-binding fragment according to Embodiment 305, wherein X1 is M. 307. An antibody or antigen-binding fragment according to either embodiment 305 or 306, wherein X2 is selected from E, I, K, L, M, Q, T, W, and Y. 308. An antibody or antigen-binding fragment according to any one of Embodiments 293 to 303, wherein HCDR3 comprises a sequence selected from SEQ ID NO: 100296 to 100314. 309. An antibody or antigen-binding fragment according to any one of Embodiments 293 to 308, wherein LCDR1 comprises SEQ ID NO: 10018. 310. An antibody or antigen-binding fragment according to any one of Embodiments 293 to 308, wherein LCDR1 contains an amino acid sequence that differs from SEQ ID NO: 10018 by a maximum of 5, 4, 3, or 2 amino acids. 311. An antibody or antigen-binding fragment according to any one of embodiments 293 to 310, wherein LCDR2 comprises SEQ ID NO: 10021. 312. An antibody or antigen-binding fragment according to any one of Embodiments 293 to 310, wherein LCDR2 contains an amino acid sequence that differs from SEQ ID NO: 10021 by a maximum of 5, 4, 3, or 2 amino acids. 313. An antibody or antigen-binding fragment according to any one of embodiments 293 to 312, wherein LCDR3 comprises SEQ ID NO: 10024. 314. An antibody or antigen-binding fragment according to any one of embodiments 293 to 312, wherein LCDR3 includes SEQ ID NO: 100155. 315. The antibody or antigen-binding fragment according to Embodiment 314, wherein X1 is N. 316. An antibody or antigen-binding fragment according to embodiment 314 or 315, wherein X2 is selected from D, E, H, N, and Q. 317. An antibody or antigen-binding fragment according to any one of embodiments 314 to 316, wherein X3 is A. 318. An antibody or antigen-binding fragment according to any one of embodiments 314 to 317, wherein X4 is selected from D, F, K, R, S, and T. 319. An antibody or antigen-binding fragment according to any one of embodiments 314 to 312, wherein LCDR3 comprises an amino acid sequence selected from SEQ ID NO: 100315 to 100482. 320. The antibody or antigen-binding fragment according to Embodiment 293, wherein HCDR1 comprises SEQ ID NO:1009, HCDR2 comprises SEQ ID NO:10012, HCDR3 comprises SEQ ID NO:10015, LCDR1 comprises SEQ ID NO:10018, LCDR2 comprises SEQ ID NO:10021, and LCDR3 comprises SEQ ID NO:10024. 321. The antibody or antigen-binding fragment according to Embodiment 293, wherein HCDR1 contains SEQ ID NO: 100150, HCDR2 contains SEQ ID NO: 10012, HCDR3 contains SEQ ID NO: 100152, LCDR1 contains SEQ ID NO: 10018, LCDR2 contains SEQ ID NO: 10021, and LCDR3 contains SEQ ID NO: 100155. 322. An antibody or antigen-binding fragment according to Embodiment 293 or 321, wherein X1 of SEQ ID NO:100150 is D. 323. An antibody or antigen-binding fragment according to Embodiment 293 or 321, wherein X1 of SEQ ID NO:100150 is E. 324. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 323, wherein X2 of SEQ ID NO:100150 is I. 325. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 323, wherein X2 of SEQ ID NO:100150 is P. 326. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 323, wherein X2 of SEQ ID NO:100150 is V. 327. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 326, wherein X3 of SEQ ID NO:100150 is G. 328. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 326, wherein X3 of SEQ ID NO:100150 is Q. 329. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 326, wherein X3 of SEQ ID NO:100150 is S. 330. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 326, wherein X3 of SEQ ID NO:100150 is V. 331. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 330, wherein X4 of SEQ ID NO: 100150 is F. 332. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 330, wherein X4 of SEQ ID NO: 100150 is Y. 333. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 332, wherein X5 of SEQ ID NO:100150 is I. 334. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 332, wherein X5 of SEQ ID NO:100150 is M. 335. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 334, wherein X1 of SEQ ID NO:100152 is L. 336. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 334, wherein X1 of SEQ ID NO:100152 is M. 337. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 336, wherein X2 of SEQ ID NO:100152 is E. 338. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 336, wherein X2 of SEQ ID NO:100152 is I. 339. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 336, wherein X2 of SEQ ID NO:100152 is K. 340. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 336, wherein X2 of SEQ ID NO: 100152 is L. 341. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 336, wherein X2 of SEQ ID NO:100152 is M. 342. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 336, wherein X2 of SEQ ID NO:100152 is Q. 343. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 336, wherein X2 of SEQ ID NO:100152 is T. 344. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 336, wherein X2 of SEQ ID NO:100152 is V. 345. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 336, wherein X2 of SEQ ID NO: 100152 is W. 346. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 336, wherein X2 of SEQ ID NO:100152 is Y. 347. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 346, wherein X1 of SEQ ID NO:100155 is Q. 348. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 346, wherein X1 of SEQ ID NO:100155 is N. 349. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 348, wherein X2 of SEQ ID NO: 100155 is D. 350. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 348, wherein X2 of SEQ ID NO: 100155 is E. 351. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 348, wherein X2 of SEQ ID NO: 100155 is H. 352. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 348, wherein X2 of SEQ ID NO:100155 is N. 353. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 348, wherein X2 of SEQ ID NO:100155 is Q. 354. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 348, wherein X2 of SEQ ID NO:100155 is S. 355. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 354, wherein X3 of SEQ ID NO:100155 is A. 356. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 354, wherein X3 of SEQ ID NO:100155 is G. 357. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 356, wherein X4 of SEQ ID NO: 100155 is D. 358. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 356, wherein X4 of SEQ ID NO: 100155 is F. 359. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 356, wherein X4 of SEQ ID NO: 100155 is K. 360. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 356, wherein X4 of SEQ ID NO: 100155 is N. 361. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 356, wherein X4 of SEQ ID NO:100155 is R. 362. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 356, wherein X4 of SEQ ID NO:100155 is S. 363. An antibody or antigen-binding fragment according to any one of Embodiments 293, 321 to 356, wherein X4 of SEQ ID NO:100155 is T. 364. An antibody or antigen-binding fragment according to any one of embodiments 293 to 363, which specifically binds to human TL1A. 365. K d is 1 x 10 -9 An antibody or antigen-binding fragment according to Embodiment 364, which specifically binds to human TL1A of M or less. 366. Using a method selected from standard ELISA assays and SPRs, K d The antibody or antigen-binding fragment according to Embodiment 365, which is measured. 367. An antibody or antigen-binding fragment according to any one of embodiments 293 to 366, which inhibits the binding of DR3 to human TL1A. 368. An antibody or antigen-binding fragment according to any one of embodiments 293 to 367, which inhibits the binding of DcR3 to human TL1A. 369. The antibody or antigen-binding fragment according to any one of embodiments 293 to 368, wherein the antibody or antigen-binding fragment is a humanized antibody, a CDR-transplanted antibody, a chimeric antibody, a Fab, a ScFv, or a combination thereof. 370. An antibody or antigen-binding fragment according to any one of embodiments 293 to 369, comprising a human CH1 domain. 371. An antibody or antigen-binding fragment according to any one of embodiments 293 to 370, comprising a human CH2 domain. 372. The antibody or antigen-binding fragment according to Embodiment 371, wherein the CH2 domain comprises at least one mutation selected from L234A, L235A, and G237A, which are numbered using Kabat. 373. An antibody or antigen-binding fragment according to any one of embodiments 293 to 372, comprising a human CH3 domain. 374. A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment according to any one of embodiments 293 to 373 and a pharmaceutically acceptable carrier. 375. A method for treating an inflammatory disease in a subject, comprising the step of administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment according to any one of embodiments 293 to 373. 376. The method according to Embodiment 375, wherein the inflammatory disease is inflammatory bowel disease. 377. The method according to embodiment 376, wherein the inflammatory bowel disease includes Crohn's disease. 378. The method according to Embodiment 377, wherein the subject is determined not to respond to anti-TNFα treatment. 379. The method according to Embodiment 377 or 378, wherein the subject is determined to have a disease phenotype including non-stenotic / non-penetrating, stenotic, stenotic and penetrating, or isolated internal penetrating. 380. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region containing three heavy chain complementarity-determining regions (HCDR1, HCDR2, HCDR3), and the heavy chain variable region is (a)(i)HCDR1 containing SEQ ID NO:1009, (ii)HCDR1 containing SEQ ID NO:100150 in which 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 selected from HCDR1 containing amino acid sequences that differ by a maximum of 5, 4, 3, or 2 amino acids from sequences selected from the group consisting of SEQ ID NO:1009, 100150, and 100200~100295, (b) (i) HCDR2 containing SEQ ID NO: 10012, and (ii) HCDR2 selected from HCDR2 containing amino acid sequences that differ from SEQ ID NO: 10012 by a maximum of 5, 4, 3, or 2 amino acids, (c)(i)HCDR3 containing SEQ ID NO:10015, (ii)HCDR3 containing SEQ ID NO:100152 in which 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 selected from SEQ ID NO:100296~100314, and (iv)HCDR3 selected from HCDR3 containing amino acid sequences that differ by a maximum of 5, 4, 3, or 2 amino acids from sequences selected from the group consisting of SEQ ID NO:10015, 100152, and 100296~100314. The antibody or antigen-binding fragment further comprises a light chain variable region including three light chain complementarity-determining regions (LCDR1, LCDR2, LCDR3), the light chain variable region being (a)(i) LCDR1 containing SEQ ID NO:10018, and (ii) LCDR1 selected from LCDR1 containing amino acid sequences that differ from SEQ ID NO:10018 by a maximum of 5, 4, 3, or 2 amino acids. (b) (i) LCDR2 containing SEQ ID NO: 10021, and (ii) LCDR2 selected from LCDR2 containing amino acid sequences that differ from SEQ ID NO: 10021 by a maximum of 5, 4, 3, or 2 amino acids, (c) an antibody or antigen-binding fragment comprising (i) an LCDR3 containing SEQ ID NO: 10024, (ii) an LCDR3 containing SEQ ID NO: 100155 in which 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) an LCDR3 selected from SEQ ID NO: 100315 to 100482, and (iv) an LCDR3 containing an amino acid sequence that differs by a maximum of 5, 4, 3, or 2 amino acids from a sequence selected from the group consisting of SEQ ID NO: 10024, 100155, and 100315 to 100482. 381. The antibody or antigen-binding fragment according to Embodiment 380, wherein HCDR1 comprises SEQ ID NO: 100150, HCDR2 comprises SEQ ID NO: 10012, HCDR3 comprises SEQ ID NO: 100152, LCDR1 comprises SEQ ID NO: 10018, LCDR2 comprises SEQ ID NO: 10021, and LCDR3 comprises SEQ ID NO: 100155. 382. An antibody or antigen-binding fragment according to Embodiment 380 or 381, wherein X1 of SEQ ID NO:100150 is D. 383. An antibody or antigen-binding fragment according to Embodiment 380 or 381, wherein X1 of SEQ ID NO:100150 is E. 384. An antibody or antigen-binding fragment according to any one of embodiments 380 to 383, wherein X2 of SEQ ID NO:100150 is I. 385. An antibody or antigen-binding fragment according to any one of embodiments 380 to 383, wherein X2 of SEQ ID NO:100150 is P. 386. An antibody or antigen-binding fragment according to any one of embodiments 380 to 383, wherein X2 of SEQ ID NO:100150 is V. 387. An antibody or antigen-binding fragment according to any one of embodiments 380 to 386, wherein X3 of SEQ ID NO:100150 is G. 388. An antibody or antigen-binding fragment according to any one of embodiments 380 to 386, wherein X3 of SEQ ID NO:100150 is Q. 389. An antibody or antigen-binding fragment according to any one of embodiments 380 to 386, wherein X3 of SEQ ID NO:100150 is S. 390. An antibody or antigen-binding fragment according to any one of embodiments 380 to 386, wherein X3 of SEQ ID NO:100150 is V. 391. An antibody or antigen-binding fragment according to any one of embodiments 380 to 390, wherein X4 of SEQ ID NO: 100150 is F. 392. An antibody or antigen-binding fragment according to any one of Embodiments 380 to 390, wherein X4 of SEQ ID NO:100150 is Y. 393. An antibody or antigen-binding fragment according to any one of embodiments 380 to 392, wherein X5 of SEQ ID NO:100150 is I. 394. An antibody or antigen-binding fragment according to any one of embodiments 380 to 392, wherein X5 of SEQ ID NO:100150 is M. 395. An antibody or antigen-binding fragment according to any one of embodiments 380 to 394, wherein X1 of SEQ ID NO:100152 is L. 396. An antibody or antigen-binding fragment according to any one of embodiments 380 to 394, wherein X1 of SEQ ID NO:100152 is M. 397. An antibody or antigen-binding fragment according to any one of embodiments 380 to 396, wherein X2 of SEQ ID NO:100152 is E. 398. An antibody or antigen-binding fragment according to any one of embodiments 380 to 396, wherein X2 of SEQ ID NO:100152 is I. 399. An antibody or antigen-binding fragment according to any one of embodiments 380 to 396, wherein X2 of SEQ ID NO:100152 is K. 400. An antibody or antigen-binding fragment according to any one of embodiments 380 to 396, wherein X2 of SEQ ID NO:100152 is L. 401. An antibody or antigen-binding fragment according to any one of embodiments 380 to 396, wherein X2 of SEQ ID NO:100152 is M. 402. An antibody or antigen-binding fragment according to any one of Embodiments 380 to 396, wherein X2 of SEQ ID NO:100152 is Q. 403. An antibody or antigen-binding fragment according to any one of Embodiments 380 to 396, wherein X2 of SEQ ID NO:100152 is T. 404. An antibody or antigen-binding fragment according to any one of embodiments 380 to 396, wherein X2 of SEQ ID NO:100152 is V. 405. An antibody or antigen-binding fragment according to any one of embodiments 380 to 396, wherein X2 of SEQ ID NO:100152 is W. 406. An antibody or antigen-binding fragment according to any one of embodiments 380 to 396, wherein X2 of SEQ ID NO:100152 is Y. 407. An antibody or antigen-binding fragment according to any one of embodiments 380 to 406, wherein X1 of SEQ ID NO:100155 is Q. 408. An antibody or antigen-binding fragment according to any one of embodiments 380 to 406, wherein X1 of SEQ ID NO:100155 is N. 409. An antibody or antigen-binding fragment according to any one of embodiments 380 to 408, wherein X2 of SEQ ID NO:100155 is D. 410. An antibody or antigen-binding fragment according to any one of embodiments 380 to 408, wherein X2 of SEQ ID NO:100155 is E. 411. An antibody or antigen-binding fragment according to any one of embodiments 380 to 408, wherein X2 of SEQ ID NO:100155 is H. 412. An antibody or antigen-binding fragment according to any one of Embodiments 380 to 408, wherein X2 of SEQ ID NO:100155 is N. 413. An antibody or antigen-binding fragment according to any one of embodiments 380 to 408, wherein X2 of SEQ ID NO:100155 is Q. 414. An antibody or antigen-binding fragment according to any one of embodiments 380 to 408, wherein X2 of SEQ ID NO:100155 is S. 415. An antibody or antigen-binding fragment according to any one of embodiments 380 to 414, wherein X3 of SEQ ID NO:100155 is A. 416. An antibody or antigen-binding fragment according to any one of embodiments 380 to 414, wherein X3 of SEQ ID NO:100155 is G. 417. An antibody or antigen-binding fragment according to any one of embodiments 380 to 416, wherein X4 of SEQ ID NO:100155 is D. 418. An antibody or antigen-binding fragment according to any one of embodiments 380 to 416, wherein X4 of SEQ ID NO:100155 is F. 419. An antibody or antigen-binding fragment according to any one of embodiments 380 to 416, wherein X4 of SEQ ID NO:100155 is K. 420. An antibody or antigen-binding fragment according to any one of embodiments 380 to 416, wherein X4 of SEQ ID NO:100155 is N. 421. An antibody or antigen-binding fragment according to any one of embodiments 380 to 416, wherein X4 of SEQ ID NO:100155 is R. 422. An antibody or antigen-binding fragment according to any one of embodiments 380 to 416, wherein X4 of SEQ ID NO:100155 is S. 423. An antibody or antigen-binding fragment according to any one of embodiments 380 to 416, wherein X4 of SEQ ID NO:100155 is T. 424. An antibody or antigen-binding fragment according to any one of embodiments 380 to 423, which specifically binds to human TL1A. 425. K d is 1 x 10 -9 An antibody or antigen-binding fragment according to Embodiment 424 that specifically binds to human TL1A of M or less. 426. Using a method selected from standard ELISA assays and SPRs, K d The antibody or antigen-binding fragment according to Embodiment 425, which is measured. 427. An antibody or antigen-binding fragment according to any one of embodiments 380 to 426, which inhibits the binding of DR3 to human TL1A. 428. An antibody or antigen-binding fragment according to any one of embodiments 380 to 427, which inhibits the binding of DcR3 to human TL1A. 429. The antibody or antigen-binding fragment according to any one of Embodiments 380 to 428, wherein the antibody or antigen-binding fragment is a humanized antibody, a CDR-transplanted antibody, a chimeric antibody, a Fab, a ScFv, or a combination thereof. 430. An antibody or antigen-binding fragment according to any one of embodiments 380 to 429, comprising a human CH1 domain. 431. An antibody or antigen-binding fragment according to any one of embodiments 380 to 430, comprising a human CH2 domain. 432. The antibody or antigen-binding fragment according to Embodiment 431, wherein the CH2 domain contains at least one mutation selected from L234A, L235A, and G237A, which are numbered using Kabat. 433. An antibody or antigen-binding fragment according to any one of embodiments 380 to 432, comprising a human CH3 domain. 434. A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment as described in any one of Embodiments 380 to 433, and a pharmaceutically acceptable carrier. 435. A method for treating an inflammatory disease in a subject, comprising the step of administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment according to any one of embodiments 380 to 433. 436. The method according to Embodiment 435, wherein the inflammatory disease is inflammatory bowel disease. 437. The method according to embodiment 436, wherein the inflammatory bowel disease includes Crohn's disease. 438. The method according to Embodiment 437, wherein the subject is determined not to respond to anti-TNFα treatment. 439. The method according to Embodiment 437 or 438, wherein the subject is determined to have a disease phenotype including non-stenotic / non-penetrating, stenotic, stenotic and penetrating, or isolated internal penetrating. 440. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising a heavy chain variable region containing SEQ ID NO:10052 or SEQ ID NO:10054 and a light chain variable region containing SEQ ID NO:10053. 441. The antibody or antigen-binding fragment according to Embodiment 440, wherein the heavy chain variable region includes SEQ ID NO: 10052. 442. The antibody or antigen-binding fragment according to Embodiment 440, wherein the heavy chain variable region includes SEQ ID NO:10054. 443. An antibody or antigen-binding fragment according to any one of Embodiments 440 to 442, wherein X1 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is D. 444. An antibody or antigen-binding fragment according to any one of embodiments 440 to 442, wherein X1 of SEQ ID NO:10052 or SEQ ID NO:10054 is E. 445. An antibody or antigen-binding fragment according to any one of embodiments 440 to 444, wherein X2 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is I. 446. An antibody or antigen-binding fragment according to any one of embodiments 440 to 444, wherein X2 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is P. 447. An antibody or antigen-binding fragment according to any one of embodiments 440 to 444, wherein X2 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is V. 448. An antibody or antigen-binding fragment according to any one of embodiments 440 to 447, wherein X3 of SEQ ID NO:10052 or SEQ ID NO:10054 is G. 449. An antibody or antigen-binding fragment according to any one of embodiments 440 to 447, wherein X3 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is Q. 450. An antibody or antigen-binding fragment according to any one of embodiments 440 to 447, wherein X3 of SEQ ID NO:10052 or SEQ ID NO:10054 is S. 451. An antibody or antigen-binding fragment according to any one of Embodiments 440 to 447, wherein X3 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is V. 452. An antibody or antigen-binding fragment according to any one of embodiments 440 to 451, wherein X4 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is F. 453. An antibody or antigen-binding fragment according to any one of Embodiments 440 to 451, wherein X4 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is Y. 454. An antibody or antigen-binding fragment according to any one of Embodiments 440 to 453, wherein X5 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is I. 455. An antibody or antigen-binding fragment according to any one of embodiments 440 to 453, wherein X5 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is M. 456. An antibody or antigen-binding fragment according to any one of embodiments 440 to 455, wherein X6 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is L. 457. An antibody or antigen-binding fragment according to any one of embodiments 440 to 455, wherein X6 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is M. 458. An antibody or antigen-binding fragment according to any one of embodiments 440 to 457, wherein X7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is E. 459. An antibody or antigen-binding fragment according to any one of embodiments 440 to 457, wherein X7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is I. 460. An antibody or antigen-binding fragment according to any one of embodiments 440 to 457, wherein X7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is K. 461. An antibody or antigen-binding fragment according to any one of embodiments 440 to 457, wherein X7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is L. 462. An antibody or antigen-binding fragment according to any one of embodiments 440 to 457, wherein X7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is M. 463. An antibody or antigen-binding fragment according to any one of Embodiments 440 to 457, wherein X7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is Q. 464. An antibody or antigen-binding fragment according to any one of Embodiments 440 to 457, wherein X7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is T. 465. An antibody or antigen-binding fragment according to any one of embodiments 440 to 457, wherein X7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is V. 466. An antibody or antigen-binding fragment according to any one of embodiments 440 to 457, wherein X7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is W. 467. An antibody or antigen-binding fragment according to any one of Embodiments 440 to 457, wherein X7 of SEQ ID NO: 10052 or SEQ ID NO: 10054 is Y. 468. An antibody or antigen-binding fragment according to any one of embodiments 440 to 467, wherein X1 of SEQ ID NO:10053 is Q. 469. An antibody or antigen-binding fragment according to any one of embodiments 440 to 467, wherein X1 of SEQ ID NO:10053 is N. 470. An antibody or antigen-binding fragment according to any one of embodiments 440 to 469, wherein X2 of SEQ ID NO:10053 is D. 471. An antibody or antigen-binding fragment according to any one of embodiments 440 to 469, wherein X2 of SEQ ID NO:10053 is E. 472. An antibody or antigen-binding fragment according to any one of embodiments 440 to 469, wherein X2 of SEQ ID NO:10053 is H. 473. An antibody or antigen-binding fragment according to any one of embodiments 440 to 469, wherein X2 of SEQ ID NO:10053 is N. 474. An antibody or antigen-binding fragment according to any one of embodiments 440 to 469, wherein X2 of SEQ ID NO:10053 is Q. 475. An antibody or antigen-binding fragment according to any one of embodiments 440 to 469, wherein X2 of SEQ ID NO:10053 is S. 476. An antibody or antigen-binding fragment according to any one of embodiments 440 to 475, wherein X3 of SEQ ID NO:10053 is A. 477. An antibody or antigen-binding fragment according to any one of embodiments 440 to 475, wherein X3 of SEQ ID NO:10053 is G. 478. An antibody or antigen-binding fragment according to any one of embodiments 440 to 477, wherein X4 of SEQ ID NO:10053 is D. 479. An antibody or antigen-binding fragment according to any one of embodiments 440 to 477, wherein X4 of SEQ ID NO:10053 is F. 480. An antibody or antigen-binding fragment according to any one of embodiments 440 to 477, wherein X4 of SEQ ID NO:10053 is K. 481. An antibody or antigen-binding fragment according to any one of embodiments 440 to 477, wherein X4 of SEQ ID NO:10053 is N. 482. An antibody or antigen-binding fragment according to any one of Embodiments 440 to 477, wherein X4 of SEQ ID NO:10053 is R. 483. An antibody or antigen-binding fragment according to any one of embodiments 440 to 477, wherein X4 of SEQ ID NO:10053 is S. 484. An antibody or antigen-binding fragment according to any one of embodiments 440 to 477, wherein X4 of SEQ ID NO:10053 is T. 485. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising a heavy chain variable region with SEQ ID NO: 10036 and a light chain variable region with SEQ ID NO: 10038. 486. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising a heavy chain variable region with SEQ ID NO: 10040 and a light chain variable region with SEQ ID NO: 10042. 487. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising a heavy chain variable region with SEQ ID NO: 10040 and a light chain variable region with SEQ ID NO: 10038. 488. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising a heavy chain variable region with SEQ ID NO: 10044 and a light chain variable region with SEQ ID NO: 10038. 489. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising a heavy chain variable region with SEQ ID NO: 10043 and a light chain variable region with SEQ ID NO: 10038. 490. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising a heavy chain variable region with SEQ ID NO: 10045 and a light chain variable region with SEQ ID NO: 10038. 491. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising a heavy chain variable region with SEQ ID NO: 10046 and a light chain variable region with SEQ ID NO: 10038. 492. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising a heavy chain variable region with SEQ ID NO: 10040 and a light chain variable region with SEQ ID NO: 10047. 493. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising a heavy chain variable region with SEQ ID NO: 10040 and a light chain variable region with SEQ ID NO: 10048. 494. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising a heavy chain variable region with SEQ ID NO: 10040 and a light chain variable region with SEQ ID NO: 10049. 495. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising a heavy chain variable region with SEQ ID NO: 10040 and a light chain variable region with SEQ ID NO: 10050. 496. An antibody or antigen-binding fragment that specifically binds to TL1A, comprising a heavy chain variable region with SEQ ID NO: 10040 and a light chain variable region with SEQ ID NO: 10051. 497. An antibody or antigen-binding fragment according to any one of embodiments 440 to 496, which specifically binds to human TL1A. 498. K d is 1 x 10 -9 An antibody or antigen-binding fragment according to Embodiment 497 that specifically binds to human TL1A of M or less. 499. Using a method selected from standard ELISA assays and SPRs, K d The antibody or antigen-binding fragment according to Embodiment 498, which is measured. 500. An antibody or antigen-binding fragment according to any one of embodiments 440 to 499, which inhibits the binding of DR3 to human TL1A. 501. An antibody or antigen-binding fragment according to any one of embodiments 440 to 500, which inhibits the binding of DcR3 to human TL1A. 502. The antibody or antigen-binding fragment according to any one of embodiments 440 to 501, wherein the antibody or antigen-binding fragment is a humanized antibody, a CDR-transplanted antibody, a chimeric antibody, a Fab, a ScFv, or a combination thereof. 503. An antibody or antigen-binding fragment according to any one of embodiments 440 to 502, comprising a human CH1 domain. 504. An antibody or antigen-binding fragment according to any one of embodiments 440 to 503, comprising a human CH2 domain. 505. The antibody or antigen-binding fragment according to Embodiment 504, wherein the CH2 domain comprises at least one mutation selected from L234A, L235A, and G237A, which are numbered using Kabat. 506. An antibody or antigen-binding fragment according to any one of embodiments 440 to 505, comprising a human CH3 domain. 507. A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment as described in any one of Embodiments 440 to 506, and a pharmaceutically acceptable carrier. 508. A method for treating an inflammatory disease in a subject, comprising the step of administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment according to any one of embodiments 440 to 506. 509. The method according to Embodiment 508, wherein the inflammatory disease is inflammatory bowel disease. 510. The method according to Embodiment 509, wherein the inflammatory bowel disease includes Crohn's disease. 511. The method according to Embodiment 510, wherein the subject is determined not to respond to anti-TNFα treatment. 512. The method according to Embodiment 510 or 511, wherein the subject is determined to have a disease phenotype including non-stenotic / non-penetrating, stenotic, stenotic and penetrating, or isolated internal penetrating. 513. An antibody or antigen-binding fragment that binds to the same region of a human TL1A antibody, as described in any of Embodiments 1 to 112, 119 to 199, 206 to 286, 293 to 373, 380 to 433, and 440 to 506. 514. An antibody or antigen-binding fragment that binds to the same region of human TL1A as a reference antibody containing the heavy chain variable region of SEQ ID NO:10036 and the light chain variable region of SEQ ID NO:10038. 515. An antibody or antigen-binding fragment that binds to the same region of human TL1A as a reference antibody containing the heavy chain variable region of SEQ ID NO:10040 and the light chain variable region of SEQ ID NO:10042. 516. An antibody or antigen-binding fragment that binds to the same region of human TL1A as a reference antibody, containing the heavy chain variable region of SEQ ID NO:10040 and the light chain variable region of SEQ ID NO:10038. 517. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment includes a heavy chain variable region, and the heavy chain variable region is (a) HCDR1 containing the amino acid sequence described in SEQ ID NO: 553, (b) HCDR2 containing the amino acid sequence described in either SEQ ID NO: 554-564 or 574-577, (c)HCDR3 containing the amino acid sequence described in either SEQ ID NO: 565-568 or 578-581, The antibody or antigen-binding fragment further comprises a light chain variable region, the light chain variable region is (d) LCDR1 containing the amino acid sequence described in SEQ ID NO: 569 or 570, (e)LCDR2 containing the amino acid sequence described in SEQ ID NO:488, (f) An antibody or antigen-binding fragment comprising an LCDR3 containing the amino acid sequence described in any one of SEQ ID NO: 571-573 or 582-585. 518. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment includes a heavy chain variable region, and the heavy chain variable region is (a) HCDR1 containing the amino acid sequence described in SEQ ID NO: 553, (b) HCDR2 containing the amino acid sequence described in SEQ ID NO: 559, (c)HCDR3 containing the amino acid sequence described in SEQ ID NO:567, The antibody or antigen-binding fragment further comprises a light chain variable region, the light chain variable region is (d) LCDR1 containing the amino acid sequence described in SEQ ID NO:569, (e)LCDR2 containing the amino acid sequence described in SEQ ID NO:488, (f) An antibody or antigen-binding fragment comprising LCDR3 containing the amino acid sequence described in SEQ ID NO:573. 519. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment includes a heavy chain variable region, and the heavy chain variable region is (a) HCDR1 containing the amino acid sequence described in SEQ ID NO: 553, (b) HCDR2 containing the amino acid sequence described in SEQ ID NO: 563, (c)HCDR3 containing the amino acid sequence described in SEQ ID NO:568, The antibody or antigen-binding fragment further comprises a light chain variable region, the light chain variable region is (d) LCDR1 containing the amino acid sequence described in SEQ ID NO:569, (e)LCDR2 containing the amino acid sequence described in SEQ ID NO:488, (f) An antibody or antigen-binding fragment comprising LCDR3 containing the amino acid sequence described in SEQ ID NO:572. 520. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment includes a heavy chain variable region, and the heavy chain variable region is (a) HCDR1 containing the amino acid sequence described in SEQ ID NO: 553, (b) HCDR2 containing the amino acid sequence described in SEQ ID NO: 555, (c)HCDR3 containing the amino acid sequence described in SEQ ID NO:566, The antibody or antigen-binding fragment further comprises a light chain variable region, the light chain variable region is (d) LCDR1 containing the amino acid sequence described in SEQ ID NO:569, (e)LCDR2 containing the amino acid sequence described in SEQ ID NO:488, (f) An antibody or antigen-binding fragment comprising LCDR3 containing the amino acid sequence described in SEQ ID NO:572. 521. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment includes a heavy chain variable region, and the heavy chain variable region is (a) HCDR1 containing the amino acid sequence described in SEQ ID NO: 553, (b) HCDR2 containing the amino acid sequence described in SEQ ID NO: 558, (c)HCDR3 containing the amino acid sequence described in SEQ ID NO:566, The antibody or antigen-binding fragment further comprises a light chain variable region, the light chain variable region is (d) LCDR1 containing the amino acid sequence described in SEQ ID NO:569, (e)LCDR2 containing the amino acid sequence described in SEQ ID NO:488, (f) An antibody or antigen-binding fragment comprising LCDR3 containing the amino acid sequence described in SEQ ID NO:572. 522. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment includes a heavy chain variable region, and the heavy chain variable region is (a) HCDR1 containing the amino acid sequence described in SEQ ID NO: 553, (b) HCDR2 containing the amino acid sequence described in SEQ ID NO: 564, (c)HCDR3 containing the amino acid sequence described in SEQ ID NO:568, The antibody or antigen-binding fragment further comprises a light chain variable region, the light chain variable region is (d) LCDR1 containing the amino acid sequence described in SEQ ID NO:569, (e)LCDR2 containing the amino acid sequence described in SEQ ID NO:488, (f) An antibody or antigen-binding fragment comprising LCDR3 containing the amino acid sequence described in SEQ ID NO:572. 523. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment is (a) SEQ ID NO: A heavy chain variable region including HCDR1, HCDR2, and HCDR3 from any one of 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, (b) SEQ ID NO: Includes LCDR1, LCDR2, and LCDR3 from 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, including a light chain variable region, The CDR is an antibody or antigen-binding fragment determined by the Kabat, Chotia, or IMGT method, or a combination thereof. 524. An antibody or antigen-binding fragment according to any one of Embodiments 517 to 523, comprising a human heavy chain framework region 1 that is at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that described in SEQ ID NO: 545. 525. An antibody or antigen-binding fragment according to any one of Embodiments 517 to 524, comprising a human heavy chain framework region 2 that is at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that described in SEQ ID NO: 546. 526. An antibody or antigen-binding fragment according to any one of Embodiments 517 to 525, comprising a human heavy chain framework region 3 that is at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that described in SEQ ID NO: 545, or 586 to 588. 527. An antibody or antigen-binding fragment according to any one of Embodiments 517 to 526, comprising a human heavy chain framework region 4 that is at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that described in SEQ ID NO: 548. 528. An antibody or antigen-binding fragment according to any one of Embodiments 517 to 527, comprising a human light chain framework region 1 that is at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that described in SEQ ID NO: 549. 529. An antibody or antigen-binding fragment according to any one of Embodiments 517 to 528, comprising a human light chain framework region 2 that is at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that described in SEQ ID NO: 550. 530. An antibody or antigen-binding fragment according to any one of Embodiments 517 to 529, comprising a human light chain framework region 3 that is at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that described in SEQ ID NO: 551. 531. An antibody or antigen-binding fragment according to any one of Embodiments 517 to 530, comprising a human light chain framework region 4 that is at least 90%, 95%, 96%, 97%, 98%, or 99% identical to that described in SEQ ID NO: 552. 532.(a) Human heavy chain framework region 1 which is at least 90% identical to the one described in SEQ ID NO:545, (b) Human heavy chain framework region 2 which is at least 90% identical to the one described in SEQ ID NO:546, (c) Human heavy chain framework region 3 that is at least 90% identical to that described in SEQ ID NO: 547, or 586 to 588, (d) Human heavy chain framework region 4 which is at least 90% identical to the one described in SEQ ID NO:548, (e) Human light chain framework region 1 which is at least 90% identical to the one described in SEQ ID NO:549, (f) Human light chain framework region 2 which is at least 90% identical to the one described in SEQ ID NO:550, (g) Human light chain framework region 3 which is at least 90% identical to the one described in SEQ ID NO:551, (h) An antibody or antigen-binding fragment according to any one of embodiments 517 to 513, comprising a human light chain framework region 4 that is at least 90% identical to that described in SEQ ID NO: 552. 533.(a) Human heavy chain framework region 1 which is at least 95% identical to the one described in SEQ ID NO:545, (b) Human heavy chain framework region 2 which is at least 95% identical to the one described in SEQ ID NO:546, (c) Human heavy chain framework region 3 that is at least 95% identical to that described in SEQ ID NO: 547, or 586 to 588, (d) Human heavy chain framework region 4 which is at least 95% identical to the one described in SEQ ID NO:548, (e) Human light chain framework region 1 which is at least 95% identical to the one described in SEQ ID NO:549, (f) Human light chain framework region 2 which is at least 95% identical to the one described in SEQ ID NO:550, (g) Human light chain framework region 3 which is at least 95% identical to the one described in SEQ ID NO:551, (h) The antibody or antigen-binding fragment according to Embodiment 532, comprising a human light chain framework region 4 that is at least 95% identical to that described in SEQ ID NO: 552. 534.(a) Human heavy chain framework region 1 which is at least 97% identical to the one described in SEQ ID NO:545, (b) Human heavy chain framework region 2 that is at least 97% identical to the one described in SEQ ID NO: 546, (c) Human heavy chain framework region 3 that is at least 97% identical to that described in SEQ ID NO: 547, or 586 to 588, (d) Human heavy chain framework region 4 that is at least 97% identical to the one described in SEQ ID NO:548, (e) Human light chain framework region 1 that is at least 97% identical to the one described in SEQ ID NO:549, (f) Human light chain framework region 2 which is at least 97% identical to the one described in SEQ ID NO:550, (g) Human light chain framework region 3 that is at least 97% identical to the one described in SEQ ID NO: 551, (h) The antibody or antigen-binding fragment according to Embodiment 532, comprising a human light chain framework region 4 that is at least 97% identical to that described in SEQ ID NO: 552. 535.(a) Human heavy chain framework region 1 which is at least 98% identical to the one described in SEQ ID NO:545, (b) Human heavy chain framework region 2 that is at least 98% identical to the one described in SEQ ID NO: 546, (c) Human heavy chain framework region 3 that is at least 98% identical to that described in SEQ ID NO: 547, or 586 to 588, (d) Human heavy chain framework region 4 that is at least 98% identical to the one described in SEQ ID NO:548, (e) Human light chain framework region 1 that is at least 98% identical to the one described in SEQ ID NO:549, (f) Human light chain framework region 2 which is at least 98% identical to the one described in SEQ ID NO:550, (g) Human light chain framework region 3 that is at least 98% identical to the one described in SEQ ID NO: 551, (h) The antibody or antigen-binding fragment according to Embodiment 532, comprising a human light chain framework region 4 that is at least 98% identical to that described in SEQ ID NO: 552. 536. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment is (a) A heavy chain variable region containing an amino acid sequence that is at least approximately 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical 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, (b) An antibody or antigen-binding fragment comprising a light chain variable region having an amino acid sequence that is at least approximately 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to 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. 537. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment is (a) A heavy chain variable region containing an amino acid sequence that is at least approximately 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:503, (b) An antibody or antigen-binding fragment comprising a light chain variable region having an amino acid sequence that is at least approximately 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:502. 538. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment is (a) A heavy chain variable region containing an amino acid sequence that is at least approximately 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:511, (b) An antibody or antigen-binding fragment comprising a light chain variable region having an amino acid sequence that is at least approximately 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:510. 539. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment is (a) A heavy chain variable region containing an amino acid sequence that is at least approximately 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:493, (b) An antibody or antigen-binding fragment comprising a light chain variable region having an amino acid sequence that is at least approximately 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:492. 540. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment is (a) A heavy chain variable region containing an amino acid sequence that is at least approximately 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:501, (b) An antibody or antigen-binding fragment comprising a light chain variable region having an amino acid sequence that is at least approximately 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:500. 541. An antibody or antigen-binding fragment that specifically binds to TL1A, wherein the antibody or antigen-binding fragment is (a) A heavy chain variable region containing an amino acid sequence that is at least approximately 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:515, (b) An antibody or antigen-binding fragment comprising a light chain variable region having an amino acid sequence that is at least approximately 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to SEQ ID NO:514. 542. An antibody or antigen-binding fragment according to any one of embodiments 517 to 541, which is a chimeric or humanized form. 543. An antibody or antigen-binding fragment according to any one of embodiments 517 to 541, which is an IgG antibody. 544. An antibody or antigen-binding fragment according to any one of embodiments 517 to 541, comprising Fab, F(ab)2, a single-domain antibody, a single-chain variable fragment (scFv), or a nanobody. 545. An antibody or antigen-binding fragment according to any one of Embodiments 517 to 544, comprising a heavy chain constant region having an amino acid sequence such as that described in SEQ ID NO: 542 or 543. 546. An antibody or antigen-binding fragment according to any one of Embodiments 517 to 544, comprising a heavy chain constant region containing an amino acid sequence such as that described in SEQ ID NO: 542. 547. An antibody or antigen-binding fragment according to any one of Embodiments 517 to 544, comprising a light chain constant region having an amino acid sequence such as that described in SEQ ID NO: 544.

[0156] Non-limiting methods for determining whether an anti-TL1A antibody binds to the same region of a reference antibody are known in the art. Exemplary methods include competition assays. For example, these methods include the step of determining whether a reference antibody is competitive with the binding of the reference antibody to the TL1A protein or a portion thereof, or the step of determining whether a reference antibody is competitive with the binding of the reference antibody to the TL1A protein or a portion thereof. Exemplary methods include the use of surface plasmon resonance to assess whether an anti-TL1A antibody is competitive with the binding of TL1A to another anti-TL1A antibody. In some cases, surface plasmon resonance is used in competition assays.

[0157] Pharmaceutical composition, formulation, and method of administration In one embodiment, a method for treating any of the diseases or illnesses described herein in a subject requiring treatment comprises administering to the patient a therapeutic agent described herein, for example, a pharmaceutical composition comprising an inhibitor of CD30L, in a therapeutically effective amount. In some embodiments, the therapeutic agents described herein are used in the preparation of agents for treating inflammatory diseases, fibrous stenotic diseases, and / or fibrotic diseases. Pharmaceutical compositions used herein include compositions comprising an inhibitor of CD30L and optionally additional therapeutic agents.

[0158] In some embodiments, compositions comprising the therapeutic agents described herein are administered for prophylactic and / or therapeutic purposes. In some therapeutic uses, the composition is administered to a patient already suffering from a disease or illness in an amount sufficient to cure or at least partially block at least one of the symptoms of the disease or illness. The effective amount for this use depends on the severity and course of the disease or illness, previous treatments, the patient's health status, weight, and response to the drug, as well as the judgment of the physician administering the treatment. The therapeutically effective amount is determined at will by methods including, but not limited to, dose-increase clinical trials. In some cases, inhibitors of CD30L are administered to patients suffering from inflammatory diseases, fibrous stenotic diseases, and / or fibrotic diseases.

[0159] For preventive purposes, compositions comprising the therapeutic agents described herein are administered to patients suspected of or at risk of having a specific disease, disorder, or illness, such as inflammatory diseases, fibrous stenotic diseases, and / or fibrous diseases. Such amounts are defined as “a dose or dosage effective for prevention.” For this use, the exact amount also depends on the patient’s health condition and weight, etc. When administered to a patient, the dose effective for this use depends on the severity and course of the disease, disorder, or illness, previous treatments, the patient’s health condition, and response to the drug, as well as the judgment of the physician administering the treatment. In one embodiment, a preventive treatment includes administering a pharmaceutical composition comprising a CD30L inhibitor to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission, in order to prevent recurrence of the disease or symptoms of the illness.

[0160] In some embodiments where the patient's condition does not improve, the medication may be administered chronically, i.e., over a long period including the patient's entire lifespan, at the physician's discretion, to improve, or otherwise suppress or limit the symptoms of the patient's disease or illness.

[0161] In some embodiments where the patient's condition improves, the dosage of the administered therapeutic agent may be temporarily reduced or temporarily suspended for a period of time (i.e., a “drug-free period”). In certain embodiments, the length of the drug-free period may range from 2 days to 1 year, including, but not limited to, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or 28 days or more. The reduction in dosage during the drug-free period may range from 10% to 100%, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0162] In some embodiments, the dosage of the administered drug may be temporarily reduced or temporarily suspended for a period of time (i.e., “drug diversion”). In certain embodiments, the length of drug diversion may range 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, or 28 days or more. The reduction in dosage during drug diversion may range from 10% to 100%, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. After an appropriate period, the drug may be returned to its normal schedule.

[0163] In some embodiments, once the patient's condition improves, a maintenance dose is administered as needed. Subsequently, in certain embodiments, the dose and / or frequency of administration is reduced, depending on the symptoms, to a level that maintains improvement in the disease, impairment, or illness. However, in some embodiments, the patient requires intermittent treatment over a long period when symptoms recur.

[0164] The amount of a given therapeutic agent corresponding to such a quantity varies depending on factors such as the specific therapeutic agent, the disease state and severity of the subject requiring treatment, and identity (e.g., weight, sex), but nevertheless it can be determined according to the specific environment surrounding the case, including, for example, the specific drug administered, the route of administration, the disease being treated, and the subject or host being treated. However, generally, the dosage used for treating adult humans is usually in the range of 0.01 mg to 5000 mg per day. In one embodiment, the dosage used for treating adults is approximately 1 mg to approximately 1000 mg per day. In one embodiment, the desired dosage is conveniently provided as a single dose, or as divided doses administered simultaneously (or over a short period of time), or at appropriate intervals (e.g., two, three, four, or more lower doses per day).

[0165] In some embodiments, once a patient starts a treatment regimen, the patient discontinues a second treatment regimen (for example, by gradually reducing the dosage).

[0166] In one embodiment, the appropriate daily dose of the CD30L inhibitor as described herein is approximately 0.01 to 10 mg / kg of body weight. In certain embodiments, the indicated daily dose in large mammals, not limited to humans, ranges from approximately 0.5 mg to approximately 1000 mg and is conveniently administered in divided doses, not limited to up to four times a day. In some embodiments, the daily dose is administered in an extended-release form. In some embodiments, a unit dosage form suitable for oral administration contains approximately 1 to 500 mg of the active ingredient. In some embodiments, the daily dose of the active ingredient in the dosage form is less than or higher than the range shown herein, based on many variables relating to the individual treatment regimen. In various embodiments, the daily dose and unit dose are modified depending on many variables, including, but not limited to, the activity of the therapeutic agent used, the disease or illness being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or illness being treated, and the judgment of the attending physician.

[0167] The toxicity and therapeutic effects of these treatment regimens are not limited to the LD50 and ED 50 This is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including the determination of toxicity. The dose-to-toxicity ratio is the therapeutic index, which is the LD50. 50 and ED 50 It is expressed as a ratio to. In some embodiments, data obtained from cell culture assays and animal studies are used to formulate a range of therapeutically effective daily doses and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily dose of the therapeutic agents described herein is the ED with minimal toxicity. 50 The blood concentration range includes [the specified amount]. In some embodiments, the daily dose range and / or unit dose vary within this range depending on the dosage form used and the route of administration utilized.

[0168] This specification discloses therapeutic agents that are formulated into pharmaceutical compositions. The pharmaceutical composition may contain an anti-CD30L inhibitor. The pharmaceutical composition may contain an antibody. The pharmaceutical composition may contain an anti-CD30L antibody.

[0169] The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive components that facilitate the processing of the active therapeutic agent into a pharmaceutically usable formulation. The appropriate formulation depends on the selected route of administration. Summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999), which are cited herein by reference for disclosure.

[0170] This specification provides pharmaceutical compositions comprising an inhibitor of CD30L and at least one pharmaceutically acceptable inactive component. In some cases, the composition comprises other therapeutic agents, such as those described herein. In some embodiments, the therapeutic agents described herein are administered as a pharmaceutical composition in which the therapeutic agents described herein are mixed with other active ingredients, for use in combination therapy. In some embodiments, the pharmaceutical composition comprises other medical agents or pharmaceuticals, carriers, adjuvants, preservatives, stabilizers, wetting agents or emulsifiers, dissolution accelerators, salts for adjusting osmotic pressure, and / or buffers. In some embodiments, the pharmaceutical composition comprises other useful substances.

[0171] In this specification, a pharmaceutical composition refers to a mixture of a therapeutic agent, such as an inhibitor of CD30L, and other chemical components (i.e., pharmaceutically acceptable inert components) such as carriers, excipients, binders, fillers, suspending agents, flavorings, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or combinations thereof. In some cases, the composition comprises two or more therapeutic agents as described herein. When performing a treatment or method of use provided herein, a therapeutically effective amount of the therapeutic agent described herein is included in the pharmaceutical composition and administered to a mammal having the disease, disorder, or illness being treated, such as inflammatory diseases, fibrous stenotic diseases, and / or fibrotic diseases. In some embodiments, the mammal is a human. The therapeutically effective amount varies depending on the severity of the disease, the age and relative health status of the subject, the efficacy of the therapeutic agent used, and other factors. The therapeutic agents described herein may be used individually or in combination with one or more other therapeutic agents as components of a mixture.

[0172] The pharmaceutical formulations described herein are administered to subjects by many routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal. 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, rapid-release formulations, tablets, capsules, pills, delayed-release formulations, extended-release formulations, pulsed-release formulations, multiply particulate formulations, and immediate-mix and controlled-release formulations.

[0173] A therapeutic agent, such as an anti-CD30L inhibitor, is manufactured in a conventional manner using conventional mixing, dissolution, granulation, sugar-coating, crushing, emulsification, encapsulation, or compression processes, among others. In some cases, the composition may also contain other therapeutic agents, such as those described herein.

[0174] The pharmaceutical composition may contain at least one therapeutic agent, such as an anti-CD30L inhibitor, as an active ingredient in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides (where appropriate), crystalline forms, amorphous phases, and active metabolites of the aforementioned compounds having the same type of activity. In some embodiments, the therapeutic agent exists in a non-solvated form or in a solvated form containing a pharmaceutically acceptable solvent such as water or ethanol. The solvated form of the therapeutic agent may also be considered as disclosed herein.

[0175] In some embodiments, therapeutic agents exist as tautomers. All tautomers fall within the range of drugs provided herein. Therefore, it should be understood that therapeutic agents or salts thereof may exhibit the phenomenon of tautomerism, thereby allowing two chemical compounds to readily interconvert by exchanging hydrogen atoms between two atoms and forming a covalent bond with either of them. Since tautomer compounds exist in equilibrium shifts with respect to each other, such compounds may be considered as different isomers of their own.

[0176] In some embodiments, the therapeutic agent exists in the form of an enantiomer, diastereomer, or other stereoisomer. The agents disclosed herein include all enantiomer, diastereomer, and epimer forms, as well as mixtures thereof.

[0177] In some embodiments, the therapeutic agents described herein may be prepared as prodrugs. A “prodrug” refers to a drug that is converted to a parent drug in vivo. Prodrugs are often effective because, depending on the situation, they may be easier to administer than the parent drug. Prodrugs may be bioavailable, for example, by oral administration, while the parent drug is not. Prodrugs may also have improved solubility in the pharmaceutical composition compared to the parent drug. A non-limiting example of a prodrug is the therapeutic agent described herein. The therapeutic agent is administered as an ester (“prodrug”) to facilitate delivery across the cell membrane where water solubility is detrimental to mobility, and is then metabolically hydrolyzed to the active carboxylic acid site once it enters the cell where water solubility is beneficial. Further examples of prodrugs may be short-chain peptides (polyamino acids) bound to an acid group, where the active site is revealed upon metabolism of the peptide. In some embodiments, upon in vivo administration, the prodrug is chemically converted to a biological, pharmaceutical, or therapeutically active form of the therapeutic agent. In one embodiment, the prodrug is enzymatically metabolized into a biological, pharmaceutical, or therapeutically active form of the therapeutic agent by one or more steps or processes.

[0178] A prodrug form of a therapeutic agent, in which the prodrug is metabolized in vivo to produce a drug as specified herein, is included in the claims. A prodrug form of a therapeutic agent described herein, in which the prodrug is metabolized in vivo to produce a drug as specified herein, is included in the claims. In some cases, some of the therapeutic agents described herein may be prodrugs for other derivatives or active compounds. In some embodiments described herein, a hydrazone is metabolized in vivo to produce a therapeutic agent.

[0179] In some embodiments, the compositions provided herein include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stable chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridium chloride.

[0180] In some embodiments, the formulations described herein benefit from antioxidants, metal chelating agents, thiol-containing compounds, and other common stabilizers. Examples of such stabilizers include, but are not limited to, (a) glycerol at approximately 0.5% to 2% w / v, (b) methionine at approximately 0.1% to 1% w / v, (c) monothioglycerol at approximately 0.1% to 2% w / v, (d) EDTA at approximately 1 mM to 10 mM, (e) ascorbic acid at approximately 0.01% to 2% w / v, (f) polysorbate 80 at approximately 0.003% to 0.02% w / v, (g) polysorbate 20 at approximately 0.001% to 0.05% w / v, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) heparinoids such as pentosan polysulfate, (m) divalent cations such as magnesium and zinc, or (n) combinations thereof.

[0181] The pharmaceutical compositions described herein, including therapeutic agents such as inhibitors of CD30L, are formulated into any suitable dosage form, but are not limited to, water-soluble oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral dosage forms, aerosols, controlled-release formulations, rapid-release formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, sugar-coated tablets, capsules, delayed-release formulations, extended-release formulations, pulsed-release formulations, multiparticle formulations, and mixtures of immediate-release and controlled-release formulations. In one embodiment, therapeutic agents such as those described herein, for example, inhibitors of CD30L, are formulated into pharmaceutical compositions suitable for intramuscular, subcutaneous, or intravenous injection. In one embodiment, formulations suitable for intramuscular, subcutaneous, or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders that can be reconstituted into sterile injectable or dispersive formulations. Examples of suitable water-soluble and water-insoluble carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, glycerol, and cremophor), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, maintaining the desired particle size in the case of dispersions, and by the use of surfactants. In some embodiments, formulations suitable for subcutaneous injection also contain additives such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial growth can be ensured by various antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, and sorbic acid. In some cases, the inclusion of isotonic agents such as sugars and sodium chloride is desirable. Long-term absorption of injectable dosage forms can be induced by the use of absorption-delaying agents such as aluminum monostearate or gelatin.

[0182] For intravenous injection, infusion, or infusion, the therapeutic agents described herein are formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or buffered saline. For oral mucosal administration, a penetrating agent suitable for the barrier to penetration is used in the formulation. Such penetrating agents are known in the art as a whole. For other parenteral injections, suitable formulations preferably comprise an aqueous solution or a non-aqueous solution together with a physiologically compatible buffer or excipient. Such excipients are known excipients.

[0183] Parenteral administration may require bolus or continuous infusion. Formulations for infusion may be provided in unit dosage forms, for example, in ampoules or multi-dose containers, along with additional preservatives. The pharmaceutical compositions described herein may be in a form suitable for parenteral administration as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain compounding agents such as suspending agents, stabilizers, and / or dispersants. In one embodiment, the active ingredient is in powder form for a suitable vehicle, for example, a composition containing pyrogenically decontaminated distilled water, before use.

[0184] For administration by inhalation, the therapeutic agent is formulated for use as an aerosol, mist, or powder. The pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of pressurized aerosols, the dose unit may be determined by providing a valve to deliver a measured amount. As just one example, capsules and cartridges such as gelatin used in inhalers or injectors may be formulated containing a powder mixture of the therapeutic agent described herein and a suitable powder base such as lactose or starch.

[0185] Typical 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, H.C. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably, these compositions and formulations are prepared with suitable non-toxic, pharmaceutically acceptable components. These components are known to those skilled in the art in the preparation of nasal dosage forms, some of which can be found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005. The selection of a suitable carrier depends on the exact properties of the desired nasal dosage form, e.g., solution, suspension, ointment, or gel. Nasal dosage forms as a whole contain a large amount of water in addition to the active ingredient. Small amounts of other ingredients, such as pH adjusters, emulsifiers or dispersants, preservatives, surfactants, gelling agents, or buffers, as well as other stabilizers and solubilizers, may also be present. The nasal dosage form is preferably isotonic with nasal secretions.

[0186] Oral pharmaceutical preparations are obtained by 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 appropriate adjuvants as needed to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars containing lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or salts of alginic acid such as sodium alginate may be added. In some embodiments, dyes or pigments are added to the coating of tablets or sugar-coated tablets to identify the dosage of active therapeutic agents or to characterize various combinations thereof.

[0187] In some embodiments, the therapeutic drug formulation is in the form of capsules, including push-in capsules made of gelatin, as well as soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-in capsules contain the active ingredient in a mixture 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 drug 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. Capsules may be prepared, for example, by placing a large mixture of the therapeutic drug formulation inside the capsule. In some embodiments, the formulation (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 sprinkle capsule, which is either swallowed whole or opened and the contents are sprinkled onto food before eating.

[0188] All formulations for oral administration are dosage forms suitable for such administration. In one embodiment, a solid oral dosage form is prepared by mixing a therapeutic agent with one or more carrier materials, such as antioxidants, fragrances, and binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents. In some embodiments, the solid dosage forms disclosed herein are in the form of tablets (including suspension tablets, fast-disintegrating tablets, bite-disintegration tablets, rapid-disintegration tablets, effervescent tablets, or caplets), pills, powders, capsules, solid dispersants, solid solutions, biodegradable dosage forms, controlled-release formulations, pulse-release formulations, multiplicity dosage forms, beads, pellets, and granules. In other embodiments, the pharmaceutical formulation is in the form of a powder. Compressed tablets are solid dosage forms prepared by compressing a large mixture of the formulations described above. In various embodiments, the tablets contain one or more fragrances. In other embodiments, the tablet includes a film surrounding the final compressed tablet. In some embodiments, the film coating can slow the release of the therapeutic agent from the formulation. In other embodiments, the film coating assists patient compliance (e.g., Opadry® coating or sugar coating). The film coating, including Opadry®, typically varies from about 1% to about 3% by weight of the tablet. 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 bulk mixture composition. The bulk mixture is readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. In some embodiments, the individual unit doses include a film coating. These formulations are manufactured by conventional formulation techniques.

[0189] In another embodiment, the dosage form includes a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulated material. Typical materials include, but are not limited to, pH adjusters, erosion accelerators, defoamers, antioxidants, flavorings, and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents. Typical useful microencapsulation materials include, but are not limited to, hydroxypropyl cellulose ethers (HPCs) such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPCs), hydroxypropyl methylcellulose ethers (HPMCs) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A, hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS), and Metolose®, ethylcellulose (EC) and its mixtures, for example, E461, Ethocel®, Aqualon®-EC, Surelease®, and Opadry Polyvinyl alcohol (PVA) such as AMB, hydroxyethylcellulose such as Natrosol®, carboxymethylcellulose and carboxymethylcellulose (CMC) salts such as Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol copolymers such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic polymers, and acrylic polymers with Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30DThis includes mixtures with cellulose ethers such as Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, cellulose phthalate acetate, sepifilms (such as mixtures of HPMC and stearic acid), cyclodextrin, and mixtures of these materials.

[0190] The dosage form of an orally administered liquid formulation is optionally, but not limited to, a suspension aqueous solution selected from the group including pharmaceutically acceptable oral dispersion aqueous solutions, emulsions, solutions, elixirs, gels, and syrups. See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002). In addition to the therapeutic agent, the liquid dosage form optionally includes additives such as (a) disintegrants, (b) dispersants, (c) wetting agents, (d) at least one preservative, (e) viscosity enhancers, (f) at least one sweetener, and (g) at least one flavoring agent. In some embodiments, the dispersion aqueous solution further includes a crystal formation inhibitor.

[0191] In some embodiments, the pharmaceutical formulations described herein are self-emulsifying drug delivery systems (SEDDS). An emulsion is a dispersion of one immiscible phase, usually in the form of droplets. Emulsions are typically created by active mechanical dispersion. SEDDS, in contrast to emulsions or microemulsions, spontaneously form emulsions when added to an excess volume of water without requiring any external mechanical dispersion or agitation. The advantage of SEDDS is that only light mixing is required to distribute droplets throughout the solution. In addition, water or the aqueous phase is added as needed immediately before administration, thereby ensuring the stability of unstable or hydrophobic active ingredients. Thus, SEDDS provide an effective delivery system for the oral and parenteral delivery of hydrophobic active ingredients. In some embodiments, SEDDS improve the bioavailability of hydrophobic active ingredients. Methods for producing self-emulsifying dosage forms include, but are not limited to, U.S. Patents 5,858,401, 6,667,048, and 6,960,563.

[0192] Buccal dosage forms containing therapeutic agents are administered using various dosage forms known in the art. Examples of such formulations include, but are not limited to, U.S. Patents 4,229,447, 4,596,795, 4,755,386, and 5,739,136. In addition, the buccal dosage forms described herein may further include 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 conventionally formulated tablets, lozenges, or gels.

[0193] For intravenous injection, the therapeutic agent is formulated in an aqueous solution, preferably in a physiologically compatible buffer such as Hank's solution, Ringer's solution, or buffered saline. For oral mucosal administration, a penetration agent appropriate to the barrier to penetration is used in the formulation. For other parenteral infusions, the appropriate formulation comprises an aqueous solution or non-aqueous solution, preferably with a physiologically compatible buffer or excipient.

[0194] Parenteral administration may optionally include bolus injection or continuous infusion. Formulations for injection may optionally be provided in unit dosage forms, e.g., ampoules or multi-dose containers, along with additional preservatives. In some embodiments, the pharmaceutical compositions described herein are in a form suitable for parenteral injection, such as a sterile suspension, aqueous solution, or emulsion in an oily or water-soluble vehicle, and contain compounding agents such as suspending agents, stabilizers, and / or dispersants. Pharmaceutical formulations for parenteral administration include an aqueous solution of a drug that modulates the activity of the carotid body in aqueous solution form. In addition, suspensions of drugs that modulate the activity of the carotid body may optionally be prepared in a suitable form, e.g., an oily injection suspension.

[0195] Conventional formulation techniques include, for example, one or a combination of the following methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Worcester coating), tangential coating, top spraying, tableting, and extrusion.

[0196] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, and mannitol.

[0197] Suitable fillers for use 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, dextrate, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0198] Suitable disintegrants for use 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 starch glycolate, cellulose, e.g., methylcrystalline cellulose, methylcellulose, microcrystalline cellulose, croscarmellose, or crosslinked cellulose, e.g., crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starch, e.g., sodium starch glycolate, crosslinked polymers, e.g., crospovidone, crosslinked polyvinylpyrrolidone, alginates, e.g., alginic acid or salts of alginic acid, e.g., sodium alginate, gums, e.g., agar, guar, locust bean, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, sodium lauryl sulfate, or sodium lauryl sulfate in combination with starch.

[0199] The binder imparts tackiness to solid oral dosage forms. In powder-filled capsule formulations, the binder assists in forming a stopper that can be filled into soft-shell or hard-shell capsules. In tablet formulations, it ensures that the tablet remains intact after compression and helps ensure uniform mixing before the compression or filling process. Suitable materials for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, and microcrystalline cellulose, microcrystalline dextrose, amylose, aluminum magnesium silicate, polysaccharides, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars such as sucrose, glucose, dextrose, molasses, mannitol, sorbitol, xylitol, lactose, natural or synthetic gums such as acacia, tragacanth, ghati gum, isapole husk mucus, starch, polyvinylpyrrolidone, larch arabogalactan, polyethylene glycol, wax, and sodium alginate.

[0200] Generally, binder levels of 20–70% are used in powder-filled gelatin capsule formulations. The level of binder used in tablet formulations varies depending on whether direct compression, wet granulation, roller compression, or the use of other excipients such as fillers that themselves can act as moderate binders. A maximum binder level of 70% is common in tablet formulations.

[0201] Suitable lubricants or flow enhancers for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol, or methoxypolyethylene glycol, such as Carbowax®, PEG4000, PEG5000, PEG6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium, or sodium lauryl sulfate.

[0202] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrate and bacugadextrin), polyols (including mannitol, xylitol, and sorbitol), and cyclodextrin.

[0203] Suitable wetting agents for use in 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, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium doxate, triacetin, and vitamin E TPGS.

[0204] 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, such as Pluronic® (BASF).

[0205] Suitable suspending agents for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol (e.g., polyethylene glycol having molecular weights of approximately 300 to approximately 6000, approximately 3350 to approximately 4000, or approximately 7000 to approximately 5400), vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Examples include sugars, polysorbate 80, hydroxyethylcellulose, sodium alginate, gums such as tragacanth gum, acacia gum, guar gum, xanthan gum, and xanthan gum, as well as cellulose-based substances such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate 80, sodium alginate, polyethoxylate sorbitan monolauric acid, polyethoxylate sorbitan monolauric acid, and povidone.

[0206] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0207] 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 are merely examples of the types of additives that may be included in the solid dosage forms of the pharmaceutical compositions described herein, and should not be interpreted as limiting. The amount of such additives can be readily determined by those skilled in the art according to the desired specific properties.

[0208] In various embodiments, the particles of the therapeutic agent and one or more excipients are dried and mixed, and compressed into a mass such as a tablet. This mass is hard enough to provide a pharmaceutical composition that substantially decomposes within approximately 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, or 60 minutes after oral administration, thereby releasing the formulation into the gastrointestinal fluid.

[0209] In other embodiments, the powder formulation containing the therapeutic agent is formulated to include one or more pharmaceutical excipients and fragrances. Such powder formulations are prepared, for example, by mixing the therapeutic agent and optionally the pharmaceutical excipients to form a bulk mixture composition. Additional embodiments also include suspending agents and / or wetting agents. This bulk mixture is uniformly subdivided into units of unit dose packages or multi-dose packages.

[0210] In other embodiments, effervescent powders are also prepared. Effervescent salts are used to disperse drugs in water for oral administration.

[0211] In some embodiments, pharmaceutical dosage forms are formulated to provide controlled release of a therapeutic agent. Controlled release refers to the release of a therapeutic agent from a dosage form that is incorporated over a long period of time according to desired properties. Examples of controlled release properties include sustained release, long-acting release, pulsed release, and delayed release. In contrast to immediate-release compositions, controlled-release compositions enable drug delivery to the subject over a long period of time according to predetermined properties. Such release rates allow for the delivery of therapeutically effective levels of the drug over a long period, thus resulting in a longer-lasting pharmacological response while minimizing side effects compared to conventional rapid-release dosage forms. These prolonged responses offer many unique advantages that cannot be achieved with the corresponding short-acting immediate-release preparations.

[0212] In some embodiments, the solid dosage forms described herein are formulated as enteric-coated delayed-release oral dosage forms, i.e., as oral dosage forms of pharmaceutical compositions as described herein that utilize an enteric coating that affects release in the small or large intestine. In one embodiment, the enteric-coated dosage form is a compressed, molded, or extruded tablet / mold (coated or uncoated) containing granules, powders, pellets, beads, or particles of the active ingredient and / or other compositional components, which are coated or uncoated themselves. In one embodiment, the enteric-coated oral dosage form is in the form of a capsule containing pellets, beads, or granules, which contain a coated or uncoated therapeutic agent.

[0213] The coating must be applied to a sufficient thickness so that the entire coating is insoluble in gastrointestinal fluid at pH less than approximately 5, but soluble at pH 5 or higher. The coating is usually selected from one of the following: shellac (this coating dissolves in a medium pH > 7); acrylic polymer (examples of acrylic polymers include methacrylate copolymer and ammonium methacrylate copolymer). Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available to be solubilized in organic solvents, aqueous dispersions, or dry powders. Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but permeable and are primarily used for targeting 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) dissolves at pH > 5 and is not very permeable to water vapor and gastric fluid. Conventional coating techniques, such as spray coating or pan coating, are used to apply the coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until it reaches the desired site of local delivery in the intestinal tract.

[0214] In other embodiments, the formulations described herein are delivered using pulsed dosage forms. Pulsed dosage forms can provide one or more immediate-release pulses at a predetermined time after a controlled delay or at a specific site. Typical pulsed dosage forms and methods for manufacturing them 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 pulsed dosage form comprises at least two groups of particles (i.e., multiparticles), each containing the formulation described herein. The first group of particles provides a therapeutic dose that is substantially immediate after ingestion by a mammal. The first group of particles may be uncoated or may include a coating and / or sealant. In one embodiment, the second group of particles comprises coated particles. The coating on the second group of particles results in a delay of about 2 to about 7 hours after ingestion prior to the release of the second dose. Suitable coatings for pharmaceutical compositions are those described herein or those known in the art.

[0215] In some embodiments, a pharmaceutical formulation is provided comprising a therapeutic agent and at least one dispersant or suspending agent for oral administration to a subject. This formulation may be a powder and / or granules for suspension, and a substantially homogeneous suspension is obtained after mixing with water.

[0216] In some embodiments, particles formulated for controlled release are incorporated into a gel, patch, or wound dressing.

[0217] In one embodiment, the dosage form of a liquid formulation for oral administration and / or topical administration as a detergent is, but is not limited, in the form of an aqueous suspension selected from the group including pharmaceutically acceptable oral dispersion aqueous solutions, emulsions, solutions, elixirs, gels, and syrups. See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002). In addition to the therapeutic particles, the liquid dosage form includes additives such as (a) disintegrants, (b) dispersants, (c) wetting agents, (d) at least one preservative, (e) viscosity enhancers, (f) at least one sweetener, and (g) at least one flavoring. In some embodiments, the dispersion aqueous solution may further include a crystal inhibitor.

[0218] In some embodiments, the liquid formulation also includes water or other solvents, solubilizers, and inert diluents commonly used in the art, such as emulsifiers. Typical emulsifiers include ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, sodium lauryl sulfate, sodium doxate, cholesterol, cholesterol esters, taurocholic acid, phosphatidylcholine, oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, or mixtures of these substances.

[0219] Furthermore, the pharmaceutical composition optionally includes 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 trishydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0220] In addition, the pharmaceutical composition optionally contains one or more salts in amounts necessary to bring the molar osmotic pressure concentration of the pharmaceutical composition within an acceptable range. Examples of such salts include those having a sodium cation, potassium cation, or ammonium cation and a chloride anion, citrate anion, ascorbate anion, borate anion, phosphate anion, bicarbonate anion, sulfate anion, thiosulfate anion, or bisulfite anion. Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0221] Other pharmaceutical compositions optionally include one or more preservatives that inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stable chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridium chloride.

[0222] In one embodiment, the aqueous suspensions and dispersions described herein remain homogeneous for at least 4 hours, as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905). In one embodiment, the aqueous suspension is resuspended into a homogeneous suspension by physical stirring lasting less than 1 minute. In another embodiment, stirring is not required to maintain a homogeneous aqueous dispersion.

[0223] Examples of disintegrants for use 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 starch glycolate; cellulose, such as methylcrystalline cellulose, methylcellulose, croscarmellose, or crosslinked cellulose, such as crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, or crosslinked croscarmellose; crosslinked starches such as sodium starch glycolate; crosslinked polymers such as crospovidone; crosslinked polyvinylpyrrolidone; alginates such as alginic acid or salts of alginic acid such as sodium alginate; gums such as agar, guar, locust bean, karaya, pectin, or tragacanth; sodium starch glycolate; bentonite; natural sponges; surfactants; resins such as cation exchange resins; citrus fruit pulp; sodium lauryl sulfate; and sodium lauryl sulfate in combined starches.

[0224] In some embodiments, suitable dispersants for the aqueous suspensions and dispersions described herein include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone, and carbohydrate-based dispersants such as hydroxypropylcellulose and hydroxypropylcellulose ethers, hydroxypropylmethylcellulose and hydroxypropylmethylcellulose ethers, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymer, ethylene oxide, and 4-(1,1,3,3-tetramethylbutyl)-phenol polymers containing formaldehyde (also known as tyroxapole), poloxamer; and poloxamine. In other embodiments, the dispersant is selected from the group not comprising one of the following: hydrophilic polymers; electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropyl cellulose and hydroxypropyl cellulose ethers; hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers; sodium carboxymethylcellulose; methylcellulose; hydroxyethylcellulose; hydroxypropyl methyl-cellulose phthalate; hydroxypropyl methyl-cellulose acetate stearate; amorphous cellulose; aluminum magnesium silicate; triethanolamine; polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymers containing ethylene oxide and formaldehyde; poloxamer; or poloxamine.

[0225] Suitable wetting agents for the aqueous suspensions and dispersions described herein include, but are not limited to, cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available Tween® products such as Tween 20® and Tween 80®), polyethylene glycol, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium doxate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, and phosphatidylcholine.

[0226] Suitable preservatives for aqueous suspensions or dispersions as described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other esters of para-hydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. The preservative is incorporated into the dosage form at a concentration sufficient to inhibit microbial growth, as used herein.

[0227] Suitable viscosity enhancers for aqueous suspensions or dispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Plasdon® S-630, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, and combinations thereof. The concentration of the viscosity enhancer depends on the selected agent and the desired viscosity.

[0228] Examples of sweeteners suitable for aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, aliterm, aspartame, chocolate, cinnamon, citrus, cocoa, cyclamate, dextrose, fructose, ginger, glycyl retinate, licorice syrup, monoammonium glycyrrhizinate (MagnaSweet®), malitol, mannitol, menthol, neohesperidin DC, neotame, Prosweet® Powder, saccharin, sorbitol, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, sucralose, tagatose, thaumatin, vanilla, xylitol, or any combination thereof.

[0229] In some embodiments, the therapeutic agent is prepared in transdermal dosage form. In some embodiments, the transdermal formulation described herein comprises at least three components: (1) the therapeutic agent, (2) a penetration enhancer, and (3) optionally an aqueous adjuvant. In some embodiments, the transdermal formulation may include additional compounds such as gelling agents, creams, and ointment bases, but are not limited. In some embodiments, the transdermal formulation is provided as a patch or wound dressing. In some embodiments, the transdermal formulation further comprises a woven or non-woven lining to promote absorption and prevent the transdermal formulation from being removed from the skin. In other embodiments, the transdermal formulation described herein may be kept saturated or supersaturated to promote diffusion into the skin.

[0230] In one embodiment, formulations suitable for transdermal administration of the therapeutic agents described herein utilize transdermal delivery devices and transdermal delivery patches, which may be lipid-soluble emulsions or buffered aqueous solutions dissolved and / or dispersed in polymers or adhesives. In one embodiment, such patches are constructed for continuous, pulsed, or on-demand delivery of the drug. Furthermore, transdermal delivery of the therapeutic agents described herein can be achieved by ionophoretic patches, etc. In one embodiment, the transdermal patch delivers the therapeutic agent in a controlled manner. In one embodiment, the transdermal device is in the form of a bandage, comprising a backing member, a reservoir containing the therapeutic agent optionally including a carrier, a rate-limiting barrier for controlled and predetermined delivery of the therapeutic agent to the host's skin over a long period of time, and means for securing the device to the skin.

[0231] In further embodiments, the topical formulation includes a gel formulation (e.g., a gel patch that adheres to the skin). In some such embodiments, the gel composition includes any polyme...

Claims

1. A composition for use in inhibiting or reducing CD30 ligand activity or expression in subjects having or suspected of having at least one of inflammatory diseases, fibrous stenosis, and fibrous diseases, The composition comprises an inhibitor of CD30 ligand activity or expression, The subject was identified as a carrier of a genotype containing the "A" allele in rs911605 or the "G" allele in rs1006026. The inhibitor of CD30 ligand activity or expression is an antibody or antigen-binding fragment that targets the CD30 ligand or CD30, or a combination thereof. composition.

2. The composition according to claim 1, wherein the genotype includes an "A" allele in rs911605 and a "G" allele in rs1006026.

3. The subject as a carrier of the genotype is identified by the following method: This method is a) A step of contacting a sample obtained from the subject containing genetic material with a nucleic acid sequence that can hybridize to at least 10 consecutive nucleic acid bases between at least one nucleic acid base 400 and nucleic acid base 600 of SEQ ID NO: 1 and 3, wherein the at least 10 consecutive nucleic acid bases include a nucleic acid base at at least one position 501 of SEQ ID NO: 1 and 3, b) A step of detecting the binding of the nucleic acid sequence to the at least 10 consecutive nucleic acid bases between at least one nucleic acid base 400 and nucleic acid base 600 from SEQ ID NO: 1 and 3, A composition according to claim 1 or 2, comprising:

4. The composition according to any one of claims 1 to 3, wherein the inhibitor of CD30 ligand activity or expression is an antibody or antigen-binding fragment that targets the CD30 ligand.

5. The composition according to any one of claims 1 to 4, wherein the subject is administered an effective amount of an inhibitor of tumor necrosis factor ligand superfamily member 15 (TL1A), wherein the inhibitor of TL1A is an antibody or antigen-binding fragment that targets TL1A.

6. A composition for use in the treatment of moderate to severe Crohn's disease in subjects with Crohn's disease (CD), The composition comprises an inhibitor of CD30 ligand activity or expression, The subject was identified as a carrier of a genotype associated with the risk of progression of moderate to severe forms of CD, including obstructive CD. The aforementioned genotype includes an "A" allele in rs911605 or a "G" allele in rs1006026. The inhibitor of CD30 ligand activity or expression is an antibody or antigen-binding fragment that targets the CD30 ligand or CD30, or a combination thereof. composition.

7. The composition according to claim 6, wherein the subject has at least one of no response or loss of response to a standard treatment.

8. The composition according to claim 7, wherein the standard treatment is selected from the group consisting of glucocorticosteroids, anti-TNF antibodies or antigen-binding fragments, anti--a4-b7 antibodies or antigen-binding fragments, anti-IL12p40 antibodies or antigen-binding fragments, thalidomide, and cyclophosphamide.

9. The composition according to any one of claims 6 to 8, wherein the genotype comprises an "A" allele in rs911605 and a "G" allele in rs1006026.

10. The composition according to any one of claims 6 to 9, wherein the inhibitor of CD30 ligand activity or expression is an antibody or antigen-binding fragment that targets the CD30 ligand.

11. The composition according to any one of claims 6 to 10, wherein the subject is administered an effective amount of an inhibitor of tumor necrosis factor ligand superfamily member 15 (TL1A), wherein the inhibitor of TL1A is an antibody or antigen-binding fragment that targets TL1A.

12. The composition according to claim 8, wherein the anti-a4-b7 antibody or antigen-binding fragment is vedolizumab.

13. The composition according to claim 8, wherein the anti-IL12p40 antibody or antigen-binding fragment is ustekinumab.

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