Anti-TL1A antibody compositions and methods for treating skin

Abstract

Described herein are humanized anti-TL1A antibodies and pharmaceutical compositions for the treatment of diseases and / or conditions of the skin, including hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, and alopecia areata, as well as other diseases and / or conditions provided herein.

Description

Cross Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 485,815, filed February 17, 2023.

[0002] Reference to the Sequence Listing Submitted Electronically The instant application contains a Sequence Listing which has been submitted electronically in XML format and which is hereby incorporated by reference in its entirety. The XML file, created on February 2, 2024, is named 25814-WO-PCT_SL.xml and is 380,462 bytes in size. 1. BACKGROUND TL1A is a cytokine secreted by antigen presenting cells, T cells, and endothelial cells. TL1A signaling is through Death Receptor 3 (DR3), a TNF family receptor that is predominantly present on T cells, natural killer (NK) and NK-T cells, innate lymphoid cells (ILCs), fibroblasts, and epithelial cells, and is effective in driving Th1, Th2, Th9, and Th17 responses. Additionally, it is induced in antigen presenting cells by toll-like receptor (TLR) ligands and FcR cross-linking, and in T cells by T cell receptor (TCR) stimulation. TL1A has been shown to be upregulated in the mucosa and serum of patients with inflammatory bowel disease. Antibodies to TL1A led to reduced inflammation and reversal of fibrosis in dextran sulfate sodium (DSS) and adoptive transfer mouse models, even when treatment was administered later in the disease process, after inflammation and fibrosis had been established. 2. SUMMARY The present disclosure provides tumor necrosis factor ligand 1A (TL1A) binding antibodies and antigen-binding fragments thereof, and compositions thereof, for use in treating inflammation and / or fibrosis, including diseases or conditions manifested in the skin of a subject, and / or systemic sclerosis. In aspects, the antibodies and antigen-binding fragments thereof described herein have features useful for therapeutic applications, such as low immunogenicity; and / or features that facilitate antibody or antigen-binding fragment preparation, such as a high percentage of monomeric fractions as measured by size exclusion chromatography; and / or high expression. In further aspects, the antibodies and antigen-binding fragments thereof described herein have features useful for subcutaneous administration, such as low viscosity at high antibody or antigen-binding fragment concentration. Additional aspects of the antibodies and antigen-binding fragments, and formulations thereof, can include high solubility, low sub-visible particles, low opalescence, absence of visible particulates, and any combination thereof.

[0005] In one aspect, provided herein is a method of treating inflammation in a subject in need thereof, comprising administering to the subject an antibody or antigen-binding fragment that binds to tumor necrosis factor-like protein 1A (anti-TL1A antibody). In some embodiments, the subject has inflammation of the skin. Further provided is a method of treating fibrosis in a subject in need thereof, comprising administering to the subject an antibody or antigen-binding fragment that binds to tumor necrosis factor-like protein 1A (anti-TL1A antibody). In some embodiments, the subject has fibrosis of the skin. Further provided is a method of treating a disease and / or condition in the skin in a subject in need thereof, comprising administering to the subject an antibody or antigen-binding fragment that binds to tumor necrosis factor-like protein 1A (anti-TL1A antibody).

[0006] In some embodiments, the subject has a chronic skin disorder. In some embodiments, the subject has systemic sclerosis. In some embodiments, the subject having systemic sclerosis has a cutaneous manifestation of systemic sclerosis. In some embodiments, the subject having systemic sclerosis has systemic sclerosis-associated interstitial lung disease. In some embodiments, the subject has scleroderma. In some embodiments, the subject has psoriasis. In some embodiments, the subject has lupus. In some embodiments, the subject has eczema. In some embodiments, the subject has dermatomyositis. In some embodiments, the subject has systemic sclerosis or scleroderma, psoriasis, lupus, dermatomyositis, eczema, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, or a combination thereof. In some embodiments, the subject has hidradenitis suppurativa. In some embodiments, the subject has atopic dermatitis. In some embodiments, the subject has vitiligo. In some embodiments, the subject has alopecia areata. In some embodiments, the subject has alopecia areata. In some embodiments, the skin inflammation is hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, or alopecia areata. In some embodiments, the skin fibrosis is hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, or alopecia areata. In some embodiments, the skin disease and / or condition in the skin is hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, or alopecia areata.

[0007] In one aspect, provided herein is a method of treating hidradenitis suppurativa in a subject in need thereof, comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to Tumor Necrosis Factor-like protein 1A. In another aspect, provided herein is a method of treating atopic dermatitis in a subject in need thereof, comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to Tumor Necrosis Factor-like protein 1A. In another aspect, provided herein is a method of treating psoriasis in a subject in need thereof, comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to Tumor Necrosis Factor-like protein 1A. In yet another aspect, provided herein is a method of treating vitiligo in a subject in need thereof, comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to Tumor Necrosis Factor-like protein 1A. In another aspect, provided herein is a method of treating alopecia areata in a subject in need thereof, comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to Tumor Necrosis Factor-like protein 1A.

[0008] In some embodiments, the anti-TLl A antibody or antigen binding fragment is administered in a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises the anti-TLl A antibody or antigen binding fragment at a concentration greater than about 150 mg / mL. In some embodiments, the concentration is greater than about 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg / mL. In some embodiments, the concentration is about 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, or 225 mg / mL. In some embodiments, the concentration is about 150 mg / mL to about 250 mg / mL. In some embodiments, the concentration is about 175 mg / mL to about 225 mg / mL. In an aspect, provided herein is a pharmaceutical composition comprising an antibody or antigen binding fragment that binds to Tumor Necrosis Factor-like protein 1A (anti-TLl A antibody) at a concentration greater than about 50 mg / mL. In some embodiments, the concentration is greater than about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, or 145 mg / mL. In certain embodiments, the concentration is about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, or 145 mg / mL. In some embodiments, the pharmaceutical composition is administered subcutaneously. In some embodiments, about 150 mg to about 500 mg of the anti-TLl A antibody or antigen binding fragment is present in the composition. In some embodiments, the total volume of the composition is less than or equal to about 2 mL. In some embodiments, the total volume of the composition is less than or equal to about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9 mL. In some embodiments, the pharmaceutical composition comprises a therapeutically effective dose of an anti-TLl A antibody or antigen binding fragment.In some embodiments, the total volume of the composition is less than or equal to about 9.0, 8.9, 8.8, 8.7, 8.6, 8.5, 8.4, 8.3, 8.2, 8.1, 8.0, 7.9, 7.8, 7.7, 7.6, 7.5, 7.4, 7.3, 7.2, 7.1, 7.0, 6.9, 6.8, 6.7, 6.6, 6.5, 6.4, 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, or 0.8 mL. In some embodiments, the total volume of the composition is about 0.5 mL to about 1.5 mL. In some embodiments, the total volume of the compositions herein is about 0.5 mL to about 2.5 mL. In some embodiments, the total volume of the compositions herein is about 0.5 mL to about 3.5 mL. In some embodiments, the total volume of the compositions herein is about 0.5 mL to about 4.5 mL. In some embodiments, the total volume of the compositions herein is about 1 mL to about 1.5 mL. In some embodiments, the total volume of the compositions herein is about 1 mL to about 2.5 mL. In some embodiments, the total volume of the compositions herein is about 1 mL to about 3.5 mL. In some embodiments, the total volume of the compositions herein is about 1 mL to about 4.5 mL. In some embodiments, the viscosity of the composition is less than about 20 cP. In some embodiments, the viscosity of the composition is less than about 15 cP. In some embodiments, the viscosity of the composition is less than about 10 cP. In some embodiments, the viscosity of the composition is less than about 9, 8, 7, 6, or 5 cP. In some embodiments, the viscosity of the composition is about 1 cP to about 7 cP, about 1 cP to about 2 cP, or about 10 cP to about 20 cP. In some embodiments, the viscosity of the composition is about 1 cP to about 10 cP. In some embodiments, the viscosity of the composition is about 1 cP to about 15 cP. In some embodiments, the viscosity of the composition is about 1 cP to about 20 cP. In some embodiments, the percentage of aggregation of the anti-TLl A antibody or antigen-binding fragment in the pharmaceutical composition, as measured by size exclusion chromatography, is less than about 5% of the total anti-TLl A antibody or antigen-binding fragment in the composition.In some embodiments, the aggregation is less than about 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5%. In some embodiments, the composition comprises a surfactant. In some embodiments, the surfactant comprises a non-ionic surfactant. In some embodiments, the non-ionic surfactant comprises polysorbate-20. In some embodiments, the surfactant is present at a concentration of about 0.005% to about 0.05% of the composition. In some embodiments, the surfactant is present at a concentration of about 0.01% to about 0.02% of the composition. In some embodiments, the surfactant is present at a concentration of about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about 0.014%, about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, about 0.02%, about 0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.025%, about 0.026%, about 0.027%, about 0.028%, about 0.029%, or about 0.03% (v / v) of the composition. In some embodiments, the composition comprises a salt. In some embodiments, the salt comprises sodium chloride, glycine, lysine-hydrochloride, arginine-hydrochloride, arginine glutamate, potassium chloride, magnesium chloride, or calcium chloride, or a combination thereof. In some embodiments, the salt comprises sodium chloride. In some embodiments, the salt comprises lysine-HCl. In some embodiments, the salt is present in the composition at a concentration of about 10 mM to about 100 mM. In some embodiments, the salt is present in the composition at a concentration of about 25 mM. In some embodiments, the salt is present in the composition at a concentration of about 40 mM. In some embodiments, the composition comprises a stabilizer. In some embodiments, the stabilizer comprises a sugar, a polyol, an amino acid or a polymer, a cyclodextrin (e.g., HP-b-CD), or a combination thereof. In some embodiments, the stabilizer comprises a sugar. In some embodiments, the sugar comprises sucrose, glucose, trehalose, maltose, or lactose, or a combination thereof. In some embodiments, the sugar comprises sucrose. In some embodiments, the amino acid comprises glycine. In some embodiments, the stabilizer is present in the composition at a concentration of about 50 mM to about 300 mM. In some embodiments, the stabilizer is present at a concentration of about 200 mM to about 280 mM. In some embodiments, the stabilizer is present at a concentration of about 220 to about 240 mM.In certain embodiments, the stabilizer is present at a concentration of about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM, or about 250 mM. In some embodiments, the stabilizer comprises sucrose and glycine. In certain embodiments, the sucrose is present at a concentration of about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM, or about 250 mM. In some embodiments, the glycine is present at a concentration of about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, about 100 mM, about 105 mM, about 110 mM, about 115 mM, or about 120 mM. In some embodiments, the composition comprises a buffer. In some embodiments, the buffer comprises acetate, phosphate, citrate, glutamate, succinate, gluconate, histidine, bicine, citric acid, Tris (tris(hydroxymethyl)aminomethane), or diethanolamine, or a combination thereof. In some embodiments, the buffer comprises acetate. In some embodiments, the buffer comprises phosphate. In some embodiments, the buffer is present in the composition at a concentration of about 10 mM to about 50 mM. In some embodiments, the composition comprises about 20 mM of the buffer. In some embodiments, the pH of the composition is about 4.5 to about 8.0. In some embodiments, the pH of the composition is about 4.5 to about 7.5. In some embodiments, the pH of the composition is about 6 to about 7. In some embodiments, the pH of the composition is about 6.5. In some embodiments, the pH of the composition is about 5 to about 5.5. In some embodiments, the pH of the composition is about 5.3.

[0009] In some embodiments, the anti-TLl A antibody or antigen binding fragment is administered to the subject at a first dose of up to about 1000 mg. In some embodiments, the anti-TLl A antibody or antigen binding fragment is administered to the subject at a first dose of about 150 mg to about 1000 mg. In some embodiments, the first dose is about 500 mg to about 1000 mg. In some embodiments, the first dose is about 500 mg or about 800 mg. In some embodiments, the first dose is administered to the subject at a first time point, and a second dose is administered to the subject at a second time point. In some embodiments, the second time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the first time point. In some embodiments, the second time point is about 1, 2, 3, or 4 weeks after the first time point. In some embodiments, the second dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen binding fragment. In some embodiments, the second dose comprises about 150 mg to about 1000 mg. In some embodiments, the second dose comprises about 150 mg to about 600 mg. In some embodiments, a third dose of the anti-TLl A antibody or antigen binding fragment is administered to the subject at a third time point. In some embodiments, the third time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the second time point. In some embodiments, the third time point is about 1, 2, 3, or 4 weeks after the second time point. In some embodiments, the third dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen binding fragment. In some embodiments, the third dose comprises about 150 mg to about 1000 mg. In some embodiments, the third dose comprises about 150 mg to about 600 mg. In some embodiments, a fourth dose of the anti-TLl A antibody or antigen binding fragment is administered to the subject at a fourth time point. In some embodiments, the fourth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the third time point. In some embodiments, the fourth time point is about 1, 2, 3, or 4 weeks after the third time point.In some embodiments, the fourth dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen-binding fragment. In some embodiments, the fourth dose comprises about 150 mg to about 1000 mg. In some embodiments, the fourth dose comprises about 150 mg to about 600 mg. In some embodiments, a fifth dose of the anti-TLl A antibody or antigen-binding fragment is administered to the subject at a fifth time point. In some embodiments, the fifth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the fourth time point. In some embodiments, the fifth time point is about 1, 2, 3, or 4 weeks after the fourth time point. In some embodiments, the fifth dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen-binding fragment. In some embodiments, the fifth dose comprises about 150 mg to about 1000 mg. In some embodiments, the fifth dose comprises about 150 mg to about 600 mg. In some embodiments, a sixth dose of the anti-TLl A antibody or antigen-binding fragment is administered to the subject at a sixth time point. In some embodiments, the sixth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the fifth time point. In some embodiments, the sixth time point is about 1, 2, 3, or 4 weeks after the fifth time point. In some embodiments, the sixth dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen-binding fragment. In some embodiments, the sixth dose comprises about 150 mg to about 1000 mg. In some embodiments, the sixth dose comprises about 150 mg to about 600 mg.

[0010] In some embodiments, an additional dose of the anti-TLl A antibody or antigen binding fragment is administered to the subject at one or more additional time points. In some embodiments, the one or more additional time points comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 additional time points. In some embodiments, the composition is administered to the subject at about 12 additional time points. In some embodiments, each additional time point is independently about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the preceding time point. In some embodiments, each additional time point is independently about 1, 2, 3, or 4 weeks after the preceding time point. In some embodiments, at least one of the additional time points is about 2 weeks after the preceding time point. In some embodiments, the additional dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen binding fragment. In some embodiments, the additional dose comprises about 150 mg to about 1000 mg of the anti-TLl A antibody or antigen binding fragment. In some embodiments, the additional dose is about 175 mg to about 300 mg of the anti-TLl A antibody or antigen binding fragment.

[0011] In an aspect, provided herein is an antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1A (“TL1A”, and such antibodies or antigen binding fragments thereof, i.e., “anti-TLl A antibodies or antigen binding fragments”) wherein the antibody or antigen binding fragment binds to both monomeric TL1A and trimeric TL1A.

[0012] In some embodiments, the antibody or antigen binding fragment blocks the interaction of TL1A with death receptor 3 (“DR3”). In some embodiments, the antibody or antigen binding fragment blocks the interaction of TL1A with DR3 with a dissociation constant (K D-单体 ) measured as described herein. In some embodiments, the antibody or antigen binding fragment binds to monomeric TL1A with a binding affinity comparable to the binding affinity of the antibody or antigen binding fragment to trimeric TL1A as measured by a dissociation constant (K D-三聚体 ) measured as described herein. In some embodiments, the K D-单体 is within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold of the K D-三聚体 . In some embodiments, the K D-单体 is no more than 0.06 nM. In some embodiments, the K D-三聚体 is no more than 0.06 nM 。

[0013] In an aspect, provided herein is a method of neutralizing monomeric TL1A and trimeric TL1A in a subject having skin inflammation and / or skin fibrosis, the method comprising (a) administering to the subject an effective dose of an anti-TL1A antibody or antigen binding fragment, wherein the antibody or antigen binding fragment binds to both monomeric TL1A and trimeric TL1A, wherein the antibody or antigen binding fragment blocks the interaction of TL1A with DR3, wherein the concentration of TL1A in a diseased tissue in the subject is reduced below the concentration of TL1A in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, and wherein the diseased tissue comprises any one or more selected from the group consisting of epidermis, dermis, subcutaneous tissue, skin connective tissue, skin fibrotic tissue, other tissue having skin inflammation and / or skin fibrosis, and other tissue having a pathogenesis of the skin inflammation and / or skin fibrosis. In some embodiments, the subject has one or more inflammatory conditions selected from the group consisting of chronic skin disorder, systemic sclerosis, psoriasis, lupus, eczema, and dermatomyositis. In some embodiments, the subject has systemic sclerosis, psoriasis, lupus, dermatomyositis, eczema, epidermolysis bullosa, mastocytosis, keloid, acne, rosacea, or bullous pemphigoid, or a combination thereof. In some embodiments, the subject has hidradenitis suppurativa. In some embodiments, the subject has atopic dermatitis. In some embodiments, the subject has vitiligo. In some embodiments, the subject has alopecia areata. In some embodiments, the subject has alopecia areata. In some embodiments, the skin inflammation and / or skin fibrosis is hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, or alopecia areata. In some embodiments, the skin inflammation and / or skin fibrosis is hidradenitis suppurativa. In some embodiments, the skin inflammation and / or skin fibrosis is atopic dermatitis. In some embodiments, the skin inflammation and / or skin fibrosis is psoriasis. In some embodiments, the skin inflammation and / or skin fibrosis is vitiligo. In some embodiments, the skin inflammation and / or skin fibrosis is alopecia areata.

[0014] In an aspect, provided herein is a method of reducing the concentration of TL1A in a diseased tissue in a subject having skin inflammation and / or skin fibrosis, the method comprising (a) administering to the subject an effective dose of an anti-TL1A antibody or antigen binding fragment, whereby the concentration of TL1A in the diseased tissue in the subject is reduced below the concentration of TL1A in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, wherein diseased tissue comprises any one or more selected from the group consisting of epidermis, dermis, subcutaneous tissue, skin connective tissue, skin fibrotic tissue, other tissue having skin inflammation and / or skin fibrosis, and other tissue having a pathogenesis of the skin inflammation and / or skin fibrosis.

[0015] In an aspect, provided herein is a method of treating skin inflammation and / or skin fibrosis in a subject in need thereof, the method comprising (a) administering to the subject an anti-TL1A antibody or antigen binding fragment, wherein the anti-TL1A antibody or antigen binding fragment is administered in an effective dose such that after step (a), the concentration of TL1A in a diseased tissue in the subject is below the concentration of TL1A in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, and wherein diseased tissue comprises any one or more selected from the group consisting of epidermis, dermis, subcutaneous tissue, skin connective tissue, skin fibrotic tissue, other tissue having skin inflammation and / or skin fibrosis, and other tissue having a pathogenesis of the skin inflammation and / or skin fibrosis.

[0016] In an aspect, provided herein is a method of treating skin inflammation and / or skin fibrosis in a subject in need thereof, the method comprising: (a) administering to the subject an anti-TL1A antibody or antigen binding fragment in an effective dose, and (b) reducing the concentration of TL1A in a diseased tissue in the subject below the concentration of TL1A in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, wherein diseased tissue comprises any one or more selected from the group consisting of epidermis, dermis, subcutaneous tissue, skin connective tissue, skin fibrotic tissue, other tissue having skin inflammation and / or skin fibrosis, and other tissue having a pathogenesis of the skin inflammation and / or skin fibrosis.

[0017] In some embodiments, the effective dose comprises an induction regimen.

[0018] In some embodiments, the method further comprises (c) maintaining the concentration of TL1A in the diseased tissue in the subject below the concentration of TL1A in the corresponding tissue in the control subject.

[0019] In some embodiments, the TL1A in the diseased tissue in the subject is maintained with a maintenance regimen of the anti-TL1A antibody or antigen binding fragment. In some embodiments, the induction regimen and the maintenance regimen are the same. In some embodiments, the induction regimen and the maintenance regimen are different. In some embodiments, the maintenance regimen is administered after the induction regimen. In some embodiments, during the induction regimen, the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100-fold or more of the TL1A produced by the corresponding tissue in the control subject. In some embodiments, within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen, the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100-fold or more of the TL1A produced by the corresponding tissue in the control subject. In some embodiments, the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100-fold or more of the TL1A produced by the corresponding tissue in the control subject.

[0020] In some embodiments, the induction regimen comprises one administration of the anti-TL1A antibody or antigen binding fragment. In some embodiments, the anti-TL1A antibody or antigen binding fragment is administered at 200 mg / dose, 250 mg / dose, 300 mg / dose, 350 mg / dose, 400 mg / dose, 450 mg / dose, 500 mg / dose, 550 mg / dose, 600 mg / dose, 650 mg / dose, 700 mg / dose, 750 mg / dose, 800 mg / dose, 850 mg / dose, 900 mg / dose, 950 mg / dose, 1000 mg / dose, 1100 mg / dose, 1200 mg / dose, 1250 mg / dose, 1300 mg / dose, 1400 mg / dose, 1500 mg / dose, 1600 mg / dose, 1700 mg / dose, 1750 mg / dose, 1800 mg / dose, 1900 mg / dose, or 2000 mg / dose.

[0021] In some embodiments, the induction regimen comprises multiple administrations of the anti-TLl A antibody or antigen binding fragment. In some embodiments, the induction regimen comprises: (i) 1000 mg / dose at week 0, 1000 mg / dose at week 2, 1000 mg / dose at week 6, and 1000 mg / dose at week 10; (ii) 500 mg / dose at week 0, 500 mg / dose at week 2, 500 mg / dose at week 6, and 500 mg / dose at week 10; (iii) 1000 mg / dose at week 0, 1000 mg / dose at week 2, 1000 mg / dose at week 6, and 500 mg / dose at week 10; (iv) 1000 mg / dose at week 0, 1000 mg / dose at week 2, 500 mg / dose at week 6, and 500 mg / dose at week 10; or (v) 1000 mg / dose at week 0, 500 mg / dose at week 2, 500 mg / dose at week 6, and 500 mg / dose at week 10.

[0022] In some embodiments, the induction regimen comprises administration of 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, or 200 mg / dose. In some embodiments, the induction regimen comprises administration once every 2, 4, 6, or 8 weeks. In some embodiments, the induction regimen comprises administration once every 2 or 4 weeks for the first 2 administrations, and then once every 2, 4, 6, or 8 weeks for the remaining induction regimen.

[0023] In some embodiments, the diseased tissue in the subject produces TL1A that is at most 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more of the TL1A produced by the corresponding tissue in the control subject. In some embodiments, during the maintenance regimen, the diseased tissue in the subject produces TL1A that is at most 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more of the TL1A produced by the corresponding tissue in the control subject. In some embodiments, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks or more from the start of the maintenance regimen, the diseased tissue in the subject produces TL1A that is at most 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more of the TL1A produced by the corresponding tissue in the control subject.

[0024] In some embodiments, the maintenance regimen comprises multiple administrations of the anti-TLl A antibody or antigen binding fragment. In some embodiments, the maintenance regimen comprises administering the anti-TLl A antibody or antigen binding fragment at (i) 500 mg / dose every 2 weeks; (ii) 400 mg / dose every 2 weeks; (iii) 300 mg / dose every 2 weeks; (iv) 250 mg / dose every 2 weeks; (v) 200 mg / dose every 2 weeks; (vi) 150 mg / dose every 2 weeks; (vii) 100 mg / dose every 2 weeks; (viii) 50 mg / dose every 2 weeks; (ix) 500 mg / dose every 4 weeks; (x) 400 mg / dose every 4 weeks; (xi) 300 mg / dose every 4 weeks; (xii) 250 mg / dose every 4 weeks; (xiii) 200 mg / dose every 4 weeks; (xiv) 150 mg / dose every 4 weeks; (xv) 100 mg / dose every 4 weeks; (xvi) 50 mg / dose every 4 weeks; (xvii) 500 mg / dose every 6 weeks; (xviii) 400 mg / dose every 6 weeks; (xix) 300 mg / dose every 6 weeks; (xx) 250 mg / dose every 6 weeks; (xxi) 200 mg / dose every 6 weeks; (xxii) 150 mg / dose every 6 weeks; (xxiii) 100 mg / dose every 6 weeks; (xxiv) 50 mg / dose every 6 weeks; (xxv) 500 mg / dose every 8 weeks; (xxvi) 400 mg / dose every 8 weeks; (xxvii) 300 mg / dose every 8 weeks; (xxviii) 250 mg / dose every 8 weeks; (xxix) 200 mg / dose every 8 weeks; (xxx) 150 mg / dose every 8 weeks; (xxxi) 100 mg / dose every 8 weeks; or (xxxii) 50 mg / dose every 8 weeks.

[0025] In some embodiments, the maintenance regimen includes administering the anti-TL1A antibody or antigen-binding fragment at doses of 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 mg. In some embodiments, the maintenance regimen includes administering the anti-TL1A antibody or antigen-binding fragment every 2, 4, 6, 8, 10, or 12 weeks. In some embodiments, the maintenance regimen includes administering the anti-TL1A antibody or antigen-binding fragment at a dose of 250 mg every 4 weeks. In some embodiments, the maintenance regimen includes administering the anti-TL1A antibody or antigen-binding fragment at a dose of 100 mg every 4 weeks. In some implementations, the maintenance program lasts for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, or 52 weeks.

[0026] In some embodiments, the antibody or antigen-binding fragment binds to both monomeric TL1A and trimeric TL1A, and wherein the antibody or antigen-binding fragment blocks the binding of TL1A to DR3. In some embodiments, at least 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the monomeric TL1A in the subject's blood is occupied by the anti-TL1A antibody or antigen-binding fragment. In some embodiments, at least 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the trimeric TL1A in the subject's blood is occupied by the anti-TL1A antibody or antigen-binding fragment.

[0027] In some implementations, such as by dissociating the equilibrium constant (K) D-单体 The binding affinity of the antibody or antigen-binding fragment to monomer TL1A, as measured by the dissociation equilibrium constant (K0), is related to the affinity of the antibody or antigen-binding fragment to monomer TL1A. D-三聚体 The measured antibody or antigen-binding fragment has a binding affinity comparable to that of the trimer TL1A. In some embodiments, K D-单体 In the K D-三聚体 Within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times. In some implementations, K... D-单体 Not exceeding 0.06 nM. In some implementations, the K... D-三聚体 Not exceeding 0.06 nM.

[0028] In some embodiments, the subject has one or more skin inflammation and / or skin fibrosis conditions selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo or alopecia areata, chronic skin disorder, systemic sclerosis, lupus, eczema, and dermatomyositis.

[0029] In some embodiments, the subject has systemic sclerosis, psoriasis, lupus, dermatomyositis, eczema, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, or a combination thereof.

[0030] In some embodiments, the subject has hidradenitis suppurativa.

[0031] In some embodiments, the subject has atopic dermatitis.

[0032] In some embodiments, the subject has vitiligo.

[0033] In some embodiments, the subject has alopecia areata.

[0034] In some embodiments, the subject has alopecia areata.

[0035] In some embodiments of the methods provided herein, the skin inflammation and / or skin fibrosis is hidradenitis suppurativa. In some embodiments, the skin inflammation and / or skin fibrosis is atopic dermatitis. In some embodiments, the skin inflammation and / or skin fibrosis is psoriasis. In some embodiments, the skin inflammation and / or skin fibrosis is vitiligo. In some embodiments, the skin inflammation and / or skin fibrosis is alopecia areata. In some embodiments, the skin inflammation and / or skin fibrosis is selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo or alopecia areata, chronic skin disorder, systemic sclerosis, lupus, eczema, and dermatomyositis.

[0036] In some embodiments of the methods provided herein, the skin inflammation and / or skin fibrosis is skin inflammation. In some embodiments, the skin inflammation is hidradenitis suppurativa. In some embodiments, the skin inflammation is atopic dermatitis. In some embodiments, the skin inflammation is psoriasis. In some embodiments, the skin inflammation is vitiligo. In some embodiments, the skin inflammation is alopecia areata. In some embodiments, the skin inflammation is selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo or alopecia areata, chronic skin disorder, systemic sclerosis, lupus, eczema, and dermatomyositis.

[0037] In some embodiments of the methods provided herein, the skin inflammation and / or skin fibrosis is skin inflammation. In some embodiments, the skin inflammation is hidradenitis suppurativa. In some embodiments, the skin inflammation is atopic dermatitis. In some embodiments, the skin inflammation is psoriasis. In some embodiments, the skin inflammation is vitiligo. In some embodiments, the skin inflammation is alopecia areata. In some embodiments, the skin inflammation is selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo or alopecia areata, chronic skin disorder, systemic sclerosis, lupus, eczema, and dermatomyositis.

[0038] In some embodiments of the methods provided herein, the skin inflammation and / or skin fibrosis is skin fibrosis. In some embodiments, the skin fibrosis is hidradenitis suppurativa. In some embodiments, the skin fibrosis is atopic dermatitis. In some embodiments, the skin fibrosis is psoriasis. In some embodiments, the skin fibrosis is vitiligo. In some embodiments, the skin fibrosis is alopecia areata. In some embodiments, the skin fibrosis is selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo or alopecia areata, chronic skin disorder, systemic sclerosis, lupus, eczema, and dermatomyositis.

[0039] In some embodiments, the effective dose or induction regimen is determined by a dose determination method, wherein the dose determination method comprises: (i) receiving a parameter of TL1A overproduction in a diseased tissue compared to TL1A production in a normal reference tissue; (ii) integrating the parameter received in (a) into a physiologically integrated whole-body based pharmacokinetic (PBPK) model or population pharmacokinetic (popPK) model; and (iii) determining an effective dose or induction regimen such that after step (a), the concentration of TL1A in the diseased tissue in the subject is lower than the concentration of TL1A in the corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis. In some embodiments, the overproduction of the parameter of TL1A overproduction is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200-fold or more of the TL1A production in the normal reference tissue.

[0040] In some embodiments, the maintenance regimen is determined by a dose determination method, wherein the dose determination method comprises: (i) receiving a parameter of TL1A overproduction in a diseased tissue compared to TL1A production in a normal reference tissue; (ii) integrating the parameter received in (i) into a physiologically integrated whole-based pharmacokinetic (PBPK) model or a population pharmacokinetic (popPK) model; and (iii) determining the maintenance regimen such that after step (c), the concentration of TL1A in the diseased tissue in the subject is lower than the concentration of TL1A in the corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis. In some embodiments, the overproduction of the parameter of TL1A overproduction is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100-fold or more of TL1A production in the normal reference tissue.

[0041] In some embodiments, step (i) in the dose determination method further comprises receiving an association rate of the antibody to TL1A (k on-mAb ), a dissociation rate of the antibody to TL1A (k off-mAb ), a synthesis rate of TL1A in normal tissue (k syn-正常 ), a synthesis rate of TL1A in diseased tissue (k syn-疾病 ), and / or a degradation rate of TL1A (k deg-总-TL1A ). In some embodiments, the association rate of the antibody to TL1A (k on-mAb ) comprises an association rate of the antibody to monomeric TL1A (k on-单体 ) and an association rate of the antibody to trimeric TL1A (k on-三聚体 ), wherein the dissociation rate of the antibody to TL1A (k off-mAb ) comprises a dissociation rate of the antibody to monomeric TL1A (k off-单体 ) and a dissociation rate of the antibody to trimeric TL1A (k off-三聚体 ), and / or wherein the degradation rate of TL1A (k deg-总-TL1A ) comprises a degradation rate of monomeric TL1A (k deg-TL1A-单体 ) and a degradation rate of trimeric TL1A (k deg-TL1A-三聚体 ).

[0042] In some embodiments, step (i) in the dose determination method further comprises receiving an association rate of the antibody to FcRn receptor (k on-mAb-FcRn ), a dissociation rate of the antibody to FcRn (k off-mAb-FcRn ), an association rate of the antibody-TL1A complex to FcRn receptor (k on-(mAb-TL1A)-FcRn) and / or the dissociation rate of the antibody-TL1A complex from the FcRn (k off-(mAb-TL1A)-FcRn ) and the association rate of the antibody-TL1A complex with the FcRn receptor (k on-(mAb-TL1A)-FcRn ) includes the association rate of the antibody-monomer TL1A complex with the FcRn receptor (k on-(mAb-monoTL1A)-FcRn ) and the association rate of the antibody-trimer TL1A complex with the FcRn receptor (k on-(mAb-triTL1A)-FcRn ), and / or the dissociation rate of the antibody-TL1A complex from the FcRn (k off-(mAb-TL1A)-FcRn ) and the dissociation rate of the antibody-TL1A complex from the FcRn (k off-(mAb-monoTL1A)-FcRn ) includes the dissociation rate of the antibody-monomer TL1A complex from the FcRn (k off-(mAb-triTL1A)-FcRn ).

[0043] In some embodiments, step (i) of the dose determination method further comprises receiving the clearance rate of the FcRn receptor bound by the antibody (k deg-mAb-FcRn ) and the clearance rate of the FcRn receptor bound by the antibody-trimer TL1A complex (k deg-mAb-FcRn ) includes the clearance rate of the FcRn bound by the antibody-monomer TL1A complex (k deg-(mAb-monoTL1A)-FcRn ) and the clearance rate of the FcRn receptor bound by the antibody-trimer TL1A complex (k deg-(mAb-triTL1A)-FcRn ) In some embodiments, in the dose determination method: (1) k on-单体 and k on-三聚体 are the same or different; (2) k off-单体 and k off-三聚体 are the same or different; (3) k deg-单体 and k deg-三聚体 are the same or different; (4) k on-(mAb-monoTL1A)-FcRn and k on-(mAb-triTL1A)-FcRn are the same or different; (5) k on-mAb-FcRn and k on-(mAb-monoTL1A)-FcRn are the same or different; (6) k on- mAb-FcRn and k on-(mAb-triTL1A)-FcRn are the same or different; (7) k off-(mAb-monoTL1A)-FcRn and k off-(mAb-triTL1A)-FcRn are the same or different; (8) k off-mAb-FcRn and k off-(mAb-monoTL1A)-FcRn are the same or different; (9) k off-mAb-FcRn and k off-(mAb-triTL1A)-FcRn are the same or different; (10) k deg-(mAb-monoTL1A)-FcRn and k deg-(mAb-triTL1A)-FcRn are the same or different; (11) k deg-mAb-FcRn and k deg-(mAb-triTL1A)-FcRn are the same or different; (12) k deg-mAb-FcRn and kdeg-(mAb-monoTL1A)-FcRn Same or different; (13) any combination of (1) to (12). In some embodiments, in the dosage determination method: k syn-疾病 It is k syn-正常 The dose determination method may be 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 times or more. In some embodiments, step (i) of the dose determination method further includes the rate (k) of receiving TL1A trimerization. on-TL1A-单体至三聚体 ) and / or the rate of TL1A monomerization (k off-TL1A-三聚体至单体 ).

[0044] On one hand, this article provides a method for determining an effective dosing regimen for administering an anti-TL1A antibody to a subject suffering from skin inflammation and / or skin fibrosis, wherein the method comprises: (a) receiving a parameter of excessive TL1A production in diseased tissue compared to TL1A production in normal reference tissue; (b) integrating the parameter received in (a) into a physiologically integrated systemic pharmacokinetic (PBPK) model; and (c) determining the effective dosing regimen of the anti-TL1A antibody using the PBPK model from (b) such that, after administration of the effective dosing regimen, the concentration of TL1A in the diseased tissue of the subject suffering from skin inflammation and / or skin fibrosis is lower than the concentration of TL1A in the corresponding tissue of a control subject without skin inflammation, wherein the diseased tissue comprises any one or more of the following groups: epidermis, dermis, subcutaneous tissue, connective tissue of the skin, fibrotic tissue of the skin, other tissues having skin inflammation and / or skin fibrosis, and other tissues having the pathogenesis of said skin inflammation and / or skin fibrosis.

[0045] In an aspect, provided herein is a method of determining an effective dosage regimen for administering an anti-TLl A antibody to a subject having skin inflammation and / or skin fibrosis, wherein the method comprises: (a) receiving a parameter of TLl A overproduction in a diseased tissue compared to TLl A production in a normal reference tissue; (b) integrating the parameter received in (a) into a population pharmacokinetic (popPK) model; and (c) determining the effective dosage regimen of the anti-TLl A antibody with the popPK model from (b) such that, after administration of the effective dosage regimen, the concentration of TLl A in a diseased tissue in the subject having skin inflammation and / or skin fibrosis is lower than the concentration of TLl A in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, wherein the diseased tissue comprises any one or more selected from the group consisting of epidermis, dermis, subcutaneous tissue, skin connective tissue, skin fibrotic tissue, other tissue with skin inflammation and / or skin fibrosis, and other tissue with pathogenesis of the skin inflammation and / or skin fibrosis.

[0046] In some embodiments of the dosage determination method, the overproduction of the parameter of TLl A overproduction is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200-fold or more of TLl A production in the normal reference tissue. In some embodiments of the dosage determination method, step (a) further comprises receiving an association rate of the antibody to TLl A (k on-mAb ), a dissociation rate of the antibody to TLl A (k off-mAb ), a synthesis rate of TLl A in normal tissue (k syn-正常 ), a synthesis rate of TLl A in diseased tissue (k syn-疾病 ), and / or a degradation rate of TLl A (k deg-总-TL1A ).

[0047] In some embodiments of the dosage determination method, the association rate of the antibody to TLl A (k on-mAb ) comprises an association rate of the antibody to monomeric TLl A (k on-单体 ) and an association rate of the antibody to trimeric TLl A (k on-三聚体 ), wherein the dissociation rate of the antibody to TLl A (k off-mAb ) comprises a dissociation rate of the antibody to monomeric TLl A (k off-单体 ) and a dissociation rate of the antibody to trimeric TLl A (k off-三聚体 ), and / or wherein the degradation rate of TLl A (kdeg-总-TL1A ) the degradation rate (k deg-TL1A-单体 ) of monomeric TL1A and the degradation rate (k deg-TL1A-三聚体 ) of trimeric TL1A. In some embodiments of the dose determination method, step (a) further comprises receiving the association rate (k on-mAb-FcRn ) of the antibody with the FcRn receptor, the dissociation rate (k off-mAb-FcRn ) of the antibody with the FcRn, the association rate (k on-(mAb-TL1A)-FcRn ) of the antibody-TL1A complex with the FcRn receptor, and / or the dissociation rate (k off-(mAb-TL1A)-FcRn ) of the antibody-TL1A complex with the FcRn.

[0048] In some embodiments of the dose determination method, the association rate (k on-(mAb-TL1A)-FcRn ) of the antibody-TL1A complex with the FcRn receptor comprises the association rate (k on-(mAb-monoTL1A)-FcRn ) of the antibody-monomer TL1A complex with the FcRn receptor and the association rate (k on-(mAb-triTL1A)-FcRn ) of the antibody-trimeric TL1A complex with the FcRn receptor, and / or wherein the dissociation rate (k off-(mAb-TL1A)-FcRn ) of the antibody-TL1A complex with the FcRn comprises the dissociation rate (k off-(mAb-monoTL1A)-FcRn ) of the antibody-monomer TL1A complex with the FcRn and the dissociation rate (k off-(mAb-triTL1A)-FcRn ) of the antibody-trimeric TL1A complex with the FcRn.

[0049] In some embodiments of the dose determination method, step (a) further comprises receiving the clearance rate (k deg-mAb-FcRn ) of the FcRn receptor bound by the antibody. In some embodiments of the dose determination method, the clearance rate (k deg-mAb-FcRn ) of the FcRn receptor bound by the antibody further comprises the clearance rate (k deg-(mAb-monoTL1A)-FcRn ) of the FcRn bound by the antibody-monomer TL1A complex and the clearance rate (k deg-(mAb-triTL1A)-FcRn ) of the FcRn receptor bound by the antibody-trimeric TL1A complex.

[0050] In some embodiments of the dose determination method, the subject has one or more inflammatory conditions selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, alopecia areata, a chronic skin disorder, systemic sclerosis, lupus, eczema, and dermatomyositis. In some embodiments of the dose determination method, the subject has hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, alopecia areata, systemic sclerosis, lupus, dermatomyositis, eczema, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, or a combination thereof.

[0051] In some embodiments of the dose determination method, in the dose determination method, wherein: (1) k on-单体 and k on-三聚体 are the same or different; (2) k off-单体 and k off-三聚体 are the same or different; (3) k deg-单体 and k deg-三聚体 are the same or different; (4) k on-(mAb-monoTL1A)-FcRn and k on-(mAb-triTL1A)-FcRn are the same or different; (5) k on-mAb-FcRn and k on-(mAb-monoTL1A)-FcRn相同 are the same or different; (6) k on-mAb-FcRn and k on-(mAb-triTL1A)-FcRn are the same or different; (7) k off-(mAb-monoTL1A)-FcRn and k off-(mAb-triTL1A)-FcRn are the same or different; (8) k off-mAb-FcRn and k off-(mAb-monoTL1A)-FcRn are the same or different; (9) k off-mAb-FcRn and k off-(mAb-triTL1A)-FcRn are the same or different; (10) k deg-(mAb-monoTL1A)-FcRn and k deg-(mAb-triTL1A)-FcRn are the same or different; (11) k deg-mAb-FcRn and k deg-(mAb-triTL1A)-FcRn are the same or different; (12) k deg-mAb-FcRn and k deg-(mAb-monoTL1A)-FcRn are the same or different; or (13) any combination of (1) to (12).

[0052] In some embodiments of the dose determination method, in the dose determination method, wherein K syn-疾病 is at most 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200-fold or more-fold of k syn-正常 .

[0053] In some embodiments of the dose determination method, the effective dosage regimen comprises an induction regimen of the anti-TLl A antibody or antigen binding fragment. In some embodiments of the dose determination method, the effective dosage regimen comprises a maintenance regimen of the anti-TLl A antibody or antigen binding fragment. In some embodiments of the dose determination method, the induction regimen and the maintenance regimen are the same. In some embodiments of the dose determination method, the induction regimen and the maintenance regimen are different. In some embodiments of the dose determination method, the maintenance regimen is administered after the induction regimen.

[0054] In some embodiments of the dose-determination method, the diseased tissue in the subject produces TL1A that is at most 50, 60, 70, 80, 90, 100-fold or more of the TL1A produced by the corresponding tissue in the control subject during the induction regimen. In some embodiments of the dose-determination method, the diseased tissue in the subject produces TL1A that is at most 50, 60, 70, 80, 90, 100-fold or more of the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen. In some embodiments of the dose-determination method, the diseased tissue in the subject produces TL1A that is at most 50, 60, 70, 80, 90, 100-fold or more of the TL1A produced by the corresponding tissue in the control subject. In some embodiments of the dose-determination method, the induction regimen comprises one administration of the anti-TL1A antibody or antigen-binding fragment. In some embodiments of the dose-determination method, the anti-TL1A antibody or antigen-binding fragment is administered at 200 mg / dose, 250 mg / dose, 300 mg / dose, 350 mg / dose, 400 mg / dose, 450 mg / dose, 500 mg / dose, 550 mg / dose, 600 mg / dose, 650 mg / dose, 700 mg / dose, 750 mg / dose, 800 mg / dose, 850 mg / dose, 900 mg / dose, 950 mg / dose, 1000 mg / dose, 1100 mg / dose, 1200 mg / dose, 1250 mg / dose, 1300 mg / dose, 1400 mg / dose, 1500 mg / dose, 1600 mg / dose, 1700 mg / dose, 1750 mg / dose, 1800 mg / dose, 1900 mg / dose, or 2000 mg / dose.

[0055] In some embodiments of the dose-determination method, the induction regimen comprises multiple administrations of the anti-TLlRA antibody or antigen binding fragment. In some embodiments of the dose-determination method, the induction regimen comprises: (i) 1000 mg / dose at week 0, 1000 mg / dose at week 2, 1000 mg / dose at week 6, and 1000 mg / dose at week 10; (ii) 500 mg / dose at week 0, 500 mg / dose at week 2, 500 mg / dose at week 6, and 500 mg / dose at week 10; (iii) 1000 mg / dose at week 0, 1000 mg / dose at week 2, 1000 mg / dose at week 6, and 500 mg / dose at week 10; (iv) 1000 mg / dose at week 0, 1000 mg / dose at week 2, 500 mg / dose at week 6, and 500 mg / dose at week 10; or (v) 1000 mg / dose at week 0, 500 mg / dose at week 2, 500 mg / dose at week 6, and 500 mg / dose at week 10.

[0056] In some embodiments of the dose-determination method, the induction regimen comprises administration of 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, or 200 mg / dose. In some embodiments of the dose-determination method, the induction regimen comprises administration once every 2, 4, 6, or 8 weeks. In some embodiments of the dose-determination method, the induction regimen comprises administration once every 2 or 4 weeks for the first 2 administrations, and then administration once every 2, 4, 6, or 8 weeks for the remaining induction regimen.

[0057] In some embodiments of the dose determination method, the diseased tissue in the subject produces TL1A that is up to 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more of the TL1A produced by the corresponding tissue in the control subject. In some embodiments of the dose determination method, during the maintenance regimen, the diseased tissue in the subject produces TL1A that is up to 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more of the TL1A produced by the corresponding tissue in the control subject. In some embodiments of the dose determination method, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks or more after the start of the maintenance regimen, the diseased tissue in the subject produces TL1A that is up to 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more of the TL1A produced by the corresponding tissue in the control subject.

[0058] In some embodiments of the dose determination method, the maintenance regimen comprises multiple administrations of the anti-TLlRA antibody or antigen binding fragment. In some embodiments of the dose determination method, the maintenance regimen comprises administering the anti-TLlRA antibody or antigen binding fragment at (i) 500 mg / dose every 2 weeks; (ii) 400 mg / dose every 2 weeks; (iii) 300 mg / dose every 2 weeks; (iv) 250 mg / dose every 2 weeks; (v) 200 mg / dose every 2 weeks; (vi) 150 mg / dose every 2 weeks; (vii) 100 mg / dose every 2 weeks; (viii) 50 mg / dose every 2 weeks; (ix) 500 mg / dose every 4 weeks; (x) 400 mg / dose every 4 weeks; (xi) 300 mg / dose every 4 weeks; (xii) 250 mg / dose every 4 weeks; (xiii) 200 mg / dose every 4 weeks; (xiv) 150 mg / dose every 4 weeks; (xv) 100 mg / dose every 4 weeks; (xvi) 50 mg / dose every 4 weeks; (xvii) 500 mg / dose every 6 weeks; (xviii) 400 mg / dose every 6 weeks; (xix) 300 mg / dose every 6 weeks; (xx) 250 mg / dose every 6 weeks; (xxi) 200 mg / dose every 6 weeks; (xxii) 150 mg / dose every 6 weeks; (xxiii) 100 mg / dose every 6 weeks; (xxiv) 50 mg / dose every 6 weeks; (xxv) 500 mg / dose every 8 weeks; (xxvi) 400 mg / dose every 8 weeks; (xxvii) 300 mg / dose every 8 weeks; (xxviii) 250 mg / dose every 8 weeks; (xxix) 200 mg / dose every 8 weeks; (xxx) 150 mg / dose every 8 weeks; (xxxi) 100 mg / dose every 8 weeks; or (xxxii) 50 mg / dose every 8 weeks.

[0059] In some embodiments of the dose determination method, the maintenance regimen comprises administering the anti-TLl A antibody or antigen binding fragment at 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 mg / dose. In some embodiments of the dose determination method, the maintenance regimen comprises administering the anti-TLl A antibody or antigen binding fragment every 2, 4, 6, 8, 10, or 12 weeks. In some embodiments of the dose determination method, the maintenance regimen comprises administering the anti-TLl A antibody or antigen binding fragment at 250 mg / dose every 4 weeks. In some embodiments of the dose determination method, the maintenance regimen comprises administering the anti-TLl A antibody or antigen binding fragment at 100 mg / dose every 4 weeks. In some embodiments of the dose determination method, the maintenance regimen lasts for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, or 52 weeks.

[0060] In some embodiments of the dose determination method, the effective dose regimen maintains the concentration of TLl A in the diseased tissue in the subject below the concentration of TLl A in the corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis for at least 4 weeks, 8 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years, and longer.

[0061] In some embodiments of the dose determination method, step (a) further comprises receiving the rate of TLl A trimerization (k on-TL1A-单体至三聚体 ) and / or the rate of TLl A monomerization (k off-TL1A-三聚体至单体 ).

[0062] In some embodiments of the methods provided herein, including the methods of using / treating and the methods of dose determination provided herein, the concentration of TLl A is the concentration of free TLl A.

[0063] In some embodiments, the anti-TLl A antibody comprises: a heavy chain variable region comprising: a HCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 1; a HCDR2 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 2-5; and a HCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 6-9; and a light chain variable region comprising: a LCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 10; a LCDR2 comprising an amino acid sequence set forth by SEQ ID NO: 11; and a LCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 12-15. In some cases, the anti-TLl A antibody comprises the CDRs of antibody J of Table 10. In some cases, the anti-TLl A antibody comprises the CDRs of antibody J2 of Table 10. In some cases, the anti-TLl A antibody comprises the CDRs of antibody K of Table 10. In some cases, the anti-TLl A antibody comprises the CDRs of antibody M of Table 10. In some cases, the anti-TLl A antibody comprises the CDRs of antibody N of Table 10.

[0064] In some embodiments, the anti-TLl A antibody comprises: a heavy chain variable framework region comprising a human IGHVl-46 02 framework or a modified human IGHVl-46 02 framework; and a light chain variable framework region comprising a human IGKV3-20 framework or a modified human IGKV3-20 framework; wherein the heavy chain variable framework region and the light chain variable framework region collectively comprise zero or fewer than nine amino acid modifications from the human IGHVl-46 02 framework and the human IGKV3-20 framework.

[0065] In some embodiments, the anti-TLl A antibody comprises: a heavy chain variable domain comprising an amino acid sequence that is at least 96% identical to any one of SEQ ID NOs: 101-169; and a light chain variable domain comprising an amino acid sequence that is at least 96% identical to any one of SEQ ID NOs: 201-220. In some cases, the anti-TLl A antibody comprises: a heavy chain variable domain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 420; and a light chain variable domain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 430. In some cases, the anti-TLl A antibody comprises: a heavy chain variable domain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 421; and a light chain variable domain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 431. In some cases, the anti-TLl A antibody comprises a heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 423, and a light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 433. In some cases, the anti-TLl A antibody comprises a heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 424, and a light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 434.

[0066] In some embodiments, the anti-TLl A antibody comprises a heavy chain variable region comprising SEQ ID NO: 301 X1VQLVQSGAEVKKPGASVKVSCKAS[HCDR1]WVX2QX3PGQGLEWX4G[HCDR2]RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTAVYYCAR[HCDR3]WGQGTTVTVSS, and a light chain variable region comprising SEQ ID NO: 303 EIVLTQSPGTLSLSPGERATLSC[LCDR1]WYQQKPGQAPRX10X11IY[LCDR2]GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC[LCDR3]FGGGTKLEIK, wherein each of X1-X11 is independently selected from A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, or V, wherein HCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 1, HCDR2 comprises the amino acid sequence set forth by any one of SEQ ID NOs: 2-5, HCDR3 comprises the amino acid sequence set forth by any one of SEQ ID NOs: 6-9, LCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 10, LCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 11, and LCDR3 comprises the amino acid sequence set forth by any one of SEQ ID NOs: 12 or 13. In some cases, the anti-TLl A antibody comprises the CDRs of antibody J of Table 10. In some cases, the anti-TLl A antibody comprises the CDRs of antibody J2 of Table 10. In some cases, the anti-TLl A antibody comprises the CDRs of antibody K of Table 10. In some cases, the anti-TLl A antibody comprises the CDRs of antibody M of Table 10. In some cases, the anti-TLl A antibody comprises the CDRs of antibody N of Table 10.

[0067] In some embodiments, the anti-TLl A antibody comprises a heavy chain variable region comprising: an HCDR1 comprising the amino acid sequence set forth by any one of SEQ ID NOs: 401, 407, 413, or 450; an HCDR2 comprising the amino acid sequence set forth by any one of SEQ ID NOs: 402, 408, 414, or 451; and an HCDR3 comprising the amino acid sequence set forth by any one of SEQ ID NOs: 403, 409, 415, or 452; and a light chain variable region comprising: an LCDR1 comprising the amino acid sequence set forth by any one of SEQ ID NOs: 404, 410, 416, or 453; an LCDR2 comprising the amino acid sequence set forth by any one of SEQ ID NOs: 405, 411, 417, or 454; and an LCDR3 comprising the amino acid sequence set forth by any one of SEQ ID NOs: 406, 412, 418, or 455.

[0068] In some embodiments, the anti-TLl A antibody comprises a heavy chain variable domain comprising an amino acid sequence that is at least 96% identical to any one of SEQ ID NOs: 420-427; and a light chain variable domain comprising an amino acid sequence that is at least 96% identical to any one of SEQ ID NOs: 430-437.

[0069] Additional numbered embodiments are provided in the following paragraphs of this section.

[0070] Embodiment 1. An antibody or antigen-binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TLl A antibody or antigen-binding fragment) for use in treating inflammation in a subject in need thereof.

[0071] Embodiment 2. The anti-TLl A antibody or antigen-binding fragment for use of embodiment 1, wherein the subject has cutaneous inflammation.

[0072] Embodiment 3. An antibody or antigen-binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TLl A antibody or antigen-binding fragment) for use in treating fibrosis in a subject in need thereof.

[0073] Embodiment 4. The anti-TLl A antibody or antigen-binding fragment for use of embodiment 3, wherein the subject has cutaneous fibrosis.

[0074] Embodiment 5. An antibody or antigen-binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TL1A antibody or antigen-binding fragment) for use in treating a disease and / or condition of the skin in a subject in need thereof.

[0075] Embodiment 6. The anti-TL1A antibody or antigen-binding fragment for use of any one of embodiments 1-5, wherein the subject has a chronic skin disorder.

[0076] Embodiment 7. The anti-TL1A antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has systemic sclerosis.

[0077] Embodiment 8. The anti-TL1A antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has psoriasis.

[0078] Embodiment 9. The anti-TL1A antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has lupus.

[0079] Embodiment 10. The anti-TL1A antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has eczema.

[0080] Embodiment 11. The anti-TL1A antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has dermatomyositis.

[0081] Embodiment 12. The anti-TL1A antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has systemic sclerosis or scleroderma, psoriasis, lupus, dermatomyositis, eczema, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, or a combination thereof.

[0082] Embodiment 13. The anti-TL1A antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has hidradenitis suppurativa.

[0083] Embodiment 14. The anti-TL1A antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has atopic dermatitis.

[0084] Embodiment 15. The anti-TL1A antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has vitiligo.

[0085] Embodiment 16. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 1-6, wherein the subject has alopecia areata.

[0086] Embodiment 17. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 1-2 and 6, wherein the skin inflammation is hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, or alopecia areata.

[0087] Embodiment 18. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 3-4 and 6, wherein the skin fibrosis is hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, or alopecia areata.

[0088] Embodiment 19. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 5-6, wherein the skin disease and / or condition in the skin is hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, or alopecia areata.

[0089] Embodiment 20. A method of treating hidradenitis suppurativa in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TLlA antibody or antigen binding fragment).

[0090] Embodiment 21. A method of treating atopic dermatitis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TLlA antibody or antigen binding fragment).

[0091] Embodiment 22. A method of treating psoriasis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TLlA antibody or antigen binding fragment).

[0092] Embodiment 23. A method of treating vitiligo in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TLlA antibody or antigen binding fragment).

[0093] Embodiment 24. A method of treating alopecia areata in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TLlA antibody or antigen binding fragment).

[0094] Embodiment 25. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 1-24, wherein the anti-TLl A antibody or antigen binding fragment is administered in a pharmaceutical composition.

[0095] Embodiment 26. The anti-TLl A antibody or antigen binding fragment for use of embodiment 26, wherein the pharmaceutical composition comprises the anti-TLl A antibody or antigen binding fragment at a concentration greater than about 150 mg / mL.

[0096] Embodiment 27. The anti-TLl A antibody or antigen binding fragment for use of embodiment 26, wherein the concentration is greater than about 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, or 250 mg / mL.

[0097] Embodiment 28. The anti-TLl A antibody or antigen binding fragment for use of embodiment 26, wherein the concentration is about 150 mg / mL to about 250 mg / mL.

[0098] Embodiment 29. The anti-TLl A antibody or antigen binding fragment for use of embodiment 26, wherein the concentration is about 175 mg / mL to about 225 mg / mL.

[0099] Embodiment 30. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 25-29, wherein the pharmaceutical composition is administered subcutaneously.

[0100] Embodiment 31. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 25-30, wherein about 150 mg to about 500 mg of the anti-TLl A antibody or antigen binding fragment is present in the composition.

[0101] Embodiment 32. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 25-31, wherein the total volume of the composition is less than or equal to about 2 mL.

[0102] Embodiment 33. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 25-32, wherein the pharmaceutical composition comprises a therapeutically effective dose of the anti-TLl A antibody or antigen binding fragment.

[0103] Embodiment 34. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 25-33, wherein the total volume of the composition is less than or equal to about 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, or 0.8 mL.

[0104] Embodiment 35. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 25-34, wherein the total volume of the composition is about 0.5 mL to about 1.5 mL.

[0105] Embodiment 36. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 25-35, wherein the viscosity of the composition is less than about 20 cP.

[0106] Embodiment 37. The anti-TLl A antibody or antigen-binding fragment for use of embodiment 36, wherein the viscosity of the composition is less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 cP.

[0107] Embodiment 38. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 25-37, wherein the viscosity of the composition is about 1 cP to about 20 cP.

[0108] Embodiment 39. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 25-38, wherein the percent aggregation of the anti-TLl A antibody or antigen-binding fragment in the pharmaceutical composition, as measured by size exclusion chromatography, is less than about 5% of the total anti-TLl A antibody or antigen-binding fragment in the composition.

[0109] Embodiment 40. The anti-TLl A antibody or antigen-binding fragment for use of embodiment 39, wherein the aggregation is less than about 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5%.

[0110] Embodiment 41. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 25-39, wherein the composition comprises a surfactant.

[0111] Embodiment 42. The anti-TLl A antibody or antigen-binding fragment for use of embodiment 41, wherein the surfactant comprises a non-ionic surfactant.

[0112] Embodiment 43. The anti-TLl A antibody or antigen-binding fragment for use of embodiment 42, wherein the non-ionic surfactant comprises polysorbate-20.

[0113] Embodiment 44. The anti-TLlA antibody or antigen-binding fragment for use of any of embodiments 41-43, wherein the surfactant is present at a concentration of about 0.005% to about 0.05% of the composition.

[0114] Embodiment 45. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 44, wherein the surfactant is present at a concentration of about 0.01% to about 0.02% of the composition.

[0115] Embodiment 46. The anti-TLlA antibody or antigen-binding fragment for use of any of embodiments 25-45, wherein the composition comprises a salt.

[0116] Embodiment 47. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 46, wherein the salt comprises sodium chloride, glycine, lysine-hydrochloride, arginine-hydrochloride, arginine glutamate, potassium chloride, magnesium chloride, or calcium chloride, or a combination thereof.

[0117] Embodiment 48. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 47, wherein the salt comprises sodium chloride.

[0118] Embodiment 49. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 47, wherein the salt comprises lysine-HCl.

[0119] Embodiment 50. The anti-TLlA antibody or antigen-binding fragment for use of any of embodiments 46-49, wherein the salt is present in the composition at a concentration of about 10 mM to about 100 mM.

[0120] Embodiment 51. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 50, wherein the salt is present in the composition at a concentration of about 25 mM.

[0121] Embodiment 52. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 50, wherein the salt is present in the composition at a concentration of about 40 mM.

[0122] Embodiment 53. The anti-TLlA antibody or antigen-binding fragment for use of any of embodiments 25-52, wherein the composition comprises a stabilizer.

[0123] Embodiment 54. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 53, wherein the stabilizer comprises a sugar, a polyol, an amino acid or a polymer, a cyclodextrin (e.g., HP-b-CD), or a combination thereof.

[0124] Embodiment 55. The anti-TLlA antibody or antigen binding fragment for use of embodiment 54, wherein the stabilizer comprises the sugar.

[0125] Embodiment 56. The anti-TLlA antibody or antigen binding fragment for use of embodiment 55, wherein the sugar comprises sucrose, glucose, trehalose, maltose, or lactose, or a combination thereof.

[0126] Embodiment 57. The anti-TLlA antibody or antigen binding fragment for use of embodiment 56, wherein the sugar comprises sucrose.

[0127] Embodiment 58. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 53-57, wherein the stabilizer is present in the composition at a concentration of about 50 mM to about 300 mM.

[0128] Embodiment 59. The anti-TLlA antibody or antigen binding fragment for use of embodiment 58, wherein the stabilizer is present at a concentration of about 200 mM to about 280 mM.

[0129] Embodiment 60. The anti-TLlA antibody or antigen binding fragment for use of embodiment 59, wherein the stabilizer is present at a concentration of about 220 to about 240 mM.

[0130] Embodiment 61. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 25-60, wherein the composition comprises a buffering agent.

[0131] Embodiment 62. The anti-TLlA antibody or antigen binding fragment for use of embodiment 61, wherein the buffering agent comprises acetate, phosphate, citrate, glutamate, succinate, gluconate, histidine, bicine, citric acid, Tris (tris(hydroxymethyl)aminomethane), or diethanolamine, or a combination thereof.

[0132] Embodiment 63. The anti-TLlA antibody or antigen binding fragment for use of embodiment 62, wherein the buffering agent comprises an acetate buffer.

[0133] Embodiment 64. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 61-63, wherein the buffering agent is present in the composition at a concentration of about 10 mM to about 50 mM.

[0134] Embodiment 65. The anti-TLlA antibody or antigen binding fragment for use of embodiment 64, wherein the composition comprises about 20 mM of the buffering agent.

[0135] Embodiment 66. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 25-65, wherein the pH of the composition is about 4.5 to about 8.0.

[0136] Embodiment 67. The anti-TLlA antibody or antigen binding fragment for use of embodiment 66, wherein the pH of the composition is about 4.5 to about 7.5.

[0137] Embodiment 68. The anti-TLlA antibody or antigen binding fragment for use of embodiment 67, wherein the pH of the composition is about 5 to about 5.5.

[0138] Embodiment 69. The anti-TLlA antibody or antigen binding fragment for use of embodiment 68, wherein the pH of the composition is about 5.3.

[0139] Embodiment 70. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 1-69, wherein the anti-TLlA antibody or antigen binding fragment is administered to the subject at a first dose of up to about 1000 mg.

[0140] Embodiment 71. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 1-69, wherein the anti-TLlA antibody or antigen binding fragment is administered to the subject at a first dose of about 150 mg to about 1000 mg.

[0141] Embodiment 72. The anti-TLlA antibody or antigen binding fragment for use of embodiment 71, wherein the first dose is about 500 mg to about 1000 mg.

[0142] Embodiment 73. The anti-TLlA antibody or antigen binding fragment for use of embodiment 72, wherein the first dose is about 500 mg or about 800 mg.

[0143] Embodiment 74. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 70-73, wherein the first dose is administered to the subject at a first time point and a second dose is administered to the subject at a second time point.

[0144] Embodiment 75. The anti-TLl A antibody or antigen binding fragment for use of embodiment 74, wherein the second time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the first time point.

[0145] Embodiment 76. The anti-TLl A antibody or antigen binding fragment for use of embodiment 74, wherein the second time point is about 1, 2, 3, or 4 weeks after the first time point.

[0146] Embodiment 77. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 74-76, wherein the second dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen binding fragment.

[0147] Embodiment 78. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 74-76, wherein the second dose comprises about 150 mg to about 1000 mg.

[0148] Embodiment 79. The anti-TLl A antibody or antigen binding fragment for use of embodiment 78, wherein the second dose comprises about 150 mg to about 600 mg.

[0149] Embodiment 80. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 74-79, wherein a third dose of the anti-TLl A antibody or antigen binding fragment is administered to the subject at a third time point.

[0150] Embodiment 81. The anti-TLl A antibody or antigen binding fragment for use of embodiment 80, wherein the third time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the second time point.

[0151] Embodiment 82. The anti-TLl A antibody or antigen binding fragment for use of embodiment 80, wherein the third time point is about 1, 2, 3, or 4 weeks after the second time point.

[0152] Embodiment 83. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 80-82, wherein the third dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen binding fragment.

[0153] Embodiment 84. The anti-TLlA antibody or antigen binding fragment for use of any of embodiments 80-82, wherein the third dose comprises about 150 mg to about 1000 mg.

[0154] Embodiment 85. The anti-TLlA antibody or antigen binding fragment for use of embodiment 84, wherein the third dose comprises about 150 mg to about 600 mg.

[0155] Embodiment 86. The anti-TLlA antibody or antigen binding fragment for use of any of embodiments 80-85, wherein a fourth dose of the anti-TLlA antibody or antigen binding fragment is administered to the subject at a fourth time point.

[0156] Embodiment 87. The anti-TLlA antibody or antigen binding fragment for use of embodiment 86, wherein the fourth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the third time point.

[0157] Embodiment 88. The anti-TLlA antibody or antigen binding fragment for use of embodiment 86, wherein the fourth time point is about 1, 2, 3, or 4 weeks after the third time point.

[0158] Embodiment 89. The anti-TLlA antibody or antigen binding fragment for use of any of embodiments 86-88, wherein the fourth dose comprises up to about 1000 mg of the anti-TLlA antibody or antigen binding fragment.

[0159] Embodiment 90. The anti-TLlA antibody or antigen binding fragment for use of any of embodiments 86-88, wherein the fourth dose comprises about 150 mg to about 1000 mg.

[0160] Embodiment 91. The anti-TLlA antibody or antigen binding fragment for use of embodiment 90, wherein the fourth dose comprises about 150 mg to about 600 mg.

[0161] Embodiment 92. The anti-TLlA antibody or antigen binding fragment for use of any of embodiments 86-91, wherein a fifth dose of the anti-TLlA antibody or antigen binding fragment is administered to the subject at a fifth time point.

[0162] Embodiment 93. The anti-TLl A antibody or antigen binding fragment for use of embodiment 92, wherein the fifth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the fourth time point.

[0163] Embodiment 94. The anti-TLl A antibody or antigen binding fragment for use of embodiment 92, wherein the fifth time point is about 1, 2, 3, or 4 weeks after the fourth time point.

[0164] Embodiment 95. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 92-94, wherein the fifth dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen binding fragment.

[0165] Embodiment 96. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 92-94, wherein the fifth dose comprises about 150 mg to about 1000 mg.

[0166] Embodiment 97. The anti-TLl A antibody or antigen binding fragment for use of embodiment 96, wherein the fifth dose comprises about 150 mg to about 600 mg.

[0167] Embodiment 98. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 92-97, wherein a sixth dose of the anti-TLl A antibody or antigen binding fragment is administered to the subject at a sixth time point.

[0168] Embodiment 99. The anti-TLl A antibody or antigen binding fragment for use of embodiment 98, wherein the sixth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the fifth time point.

[0169] Embodiment 100. The anti-TLl A antibody or antigen binding fragment for use of embodiment 98, wherein the sixth time point is about 1, 2, 3, or 4 weeks after the fifth time point.

[0170] Embodiment 101. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 98-100, wherein the sixth dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen binding fragment.

[0171] Embodiment 102. The anti-TLlA antibody or antigen-binding fragment for use of any of embodiments 98-100, wherein the sixth dose comprises about 150 mg to about 1000 mg.

[0172] Embodiment 103. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 102, wherein the sixth dose comprises about 150 mg to about 600 mg.

[0173] Embodiment 104. The anti-TLlA antibody or antigen-binding fragment for use of any of embodiments 70-103, wherein an additional dose of the anti-TLlA antibody or antigen-binding fragment is administered to the subject at each of one or more additional time points.

[0174] Embodiment 105. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 104, wherein the one or more additional time points comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 additional time points.

[0175] Embodiment 106. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 104, wherein the composition is administered to the subject at about 12 additional time points.

[0176] Embodiment 107. The anti-TLlA antibody or antigen-binding fragment for use of any of embodiments 104-106, wherein each additional time point is independently about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the preceding time point.

[0177] Embodiment 108. The anti-TLlA antibody or antigen-binding fragment for use of any of embodiments 104-106, wherein each additional time point is independently about 1, 2, 3, or 4 weeks after the preceding time point.

[0178] Embodiment 109. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 108, wherein at least one of the additional time points is about 2 weeks after the preceding time point.

[0179] Embodiment 110. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 104-109, wherein the additional dose comprises up to about 1000 mg of the anti-TLlA antibody or antigen-binding fragment.

[0180] Embodiment 111. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 104-109, wherein the additional dose comprises about 150 mg to about 1000 mg of the anti-TLlA antibody or antigen-binding fragment.

[0181] Embodiment 112. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 111, wherein the additional dose is about 175 mg to about 300 mg of the anti-TLlA antibody or antigen-binding fragment.

[0182] Embodiment 113. An anti-TLlA antibody or antigen-binding fragment for neutralizing monomeric TLlA and trimeric TLlA in a subject having skin inflammation and / or skin fibrosis, wherein the anti-TLlA antibody or antigen-binding fragment is formulated at an effective dose for administration to the subject, wherein the antibody or antigen-binding fragment binds to both monomeric TLlA and trimeric TLlA, wherein the antibody or antigen-binding fragment blocks the interaction of TLlA with DR3, wherein the concentration of TLlA in a diseased tissue in the subject is reduced below the concentration of TLlA in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, and wherein the diseased tissue comprises any one or more selected from the group consisting of: epidermis, dermis, subcutaneous tissue, cutaneous connective tissue, cutaneous fibrotic tissue, other tissue having skin inflammation and / or skin fibrosis, and other tissue having a pathogenesis of the skin inflammation and / or skin fibrosis.

[0183] Embodiment 114. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 113, wherein the subject has one or more inflammatory conditions selected from the group consisting of: hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, alopecia areata, chronic skin disorder, systemic sclerosis, lupus, eczema, and dermatomyositis.

[0184] Embodiment 115. The anti-TLlA antibody or antigen-binding fragment for use of either of embodiments 113 or 114, wherein the subject has hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, alopecia areata, systemic sclerosis, lupus, dermatomyositis, eczema, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, or a combination thereof.

[0185] Embodiment 116. An anti-TLlA antibody or antigen-binding fragment for reducing the concentration of TLlA in a diseased tissue in a subject having skin inflammation and / or skin fibrosis, wherein the anti-TLlA antibody or antigen-binding fragment is formulated at an effective dose for administration to the subject to reduce the concentration of TLlA in the diseased tissue in the subject to below the concentration of TLlA in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, wherein a diseased tissue comprises any one or more selected from the group consisting of epidermis, dermis, subcutaneous tissue, skin connective tissue, skin fibrotic tissue, other tissue having skin inflammation and / or skin fibrosis, and other tissue having a pathogenesis of the skin inflammation and / or skin fibrosis.

[0186] Embodiment 117. An anti-TLlA antibody or antigen-binding fragment for treating skin inflammation and / or skin fibrosis in a subject in need thereof, wherein the anti-TLlA antibody or antigen-binding fragment is administered at an effective dose such that, following the administration, the concentration of TLlA in a diseased tissue in the subject is below the concentration of TLlA in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, and wherein a diseased tissue comprises any one or more selected from the group consisting of epidermis, dermis, subcutaneous tissue, skin connective tissue, skin fibrotic tissue, other tissue having skin inflammation and / or skin fibrosis, and other tissue having a pathogenesis of the skin inflammation and / or skin fibrosis.

[0187] Embodiment 118. An anti-TLlA antibody or antigen-binding fragment for treating skin inflammation and / or skin fibrosis in a subject in need thereof, wherein the anti-TLlA antibody or antigen-binding fragment is administered in a method: (a) at an effective dose to the subject, and (b) reduces the concentration of TLlA in a diseased tissue in the subject to below the concentration of TLlA in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, wherein the diseased tissue comprises any one or more selected from the group consisting of epidermis, dermis, subcutaneous tissue, cutaneous connective tissue, cutaneous fibrotic tissue, other tissue with cutaneous inflammation and / or cutaneous fibrosis, and other tissue with pathogenesis of said cutaneous inflammation and / or cutaneous fibrosis.

[0188] Embodiment 119. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 113-118, wherein the effective dose comprises an induction regimen.

[0189] Embodiment 120. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 113-119, wherein the anti-TLl A antibody or antigen-binding fragment is also for use in maintaining the concentration of TLl A in the diseased tissue in the subject lower than the concentration of TLl A in the corresponding tissue in the control subject.

[0190] Embodiment 121. The anti-TLl A antibody or antigen-binding fragment for use of embodiment 120, wherein the TLl A in the diseased tissue in the subject is maintained with a maintenance regimen of the anti-TLl A antibody or antigen-binding fragment.

[0191] Embodiment 122. The anti-TLl A antibody or antigen-binding fragment for use of embodiment 121, wherein the induction regimen and the maintenance regimen are the same.

[0192] Embodiment 123. The anti-TLl A antibody or antigen-binding fragment for use of embodiment 121, wherein the induction regimen and the maintenance regimen are different.

[0193] Embodiment 124. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 121-123, wherein the maintenance regimen is administered after the induction regimen.

[0194] Embodiment 125. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 114-124, wherein during the induction regimen, the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100-fold or more of TLl A than the corresponding tissue in the control subject.

[0195] Embodiment 126. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 114-124, wherein the diseased tissue in the subject produces TLl A that is at most 50, 60, 70, 80, 90, 100-fold or more of the TLl A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen.

[0196] Embodiment 127. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 114-124, wherein the diseased tissue in the subject produces TLl A that is at most 50, 60, 70, 80, 90, 100-fold or more of the TLl A produced by the corresponding tissue in the control subject.

[0197] Embodiment 128. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 119-127, wherein the induction regimen comprises one administration of the anti-TLl A antibody or antigen binding fragment.

[0198] Embodiment 129. The anti-TLl A antibody or antigen binding fragment for use of embodiment 128, wherein the anti-TLl A antibody or antigen binding fragment is administered at 200 mg / dose, 250 mg / dose, 300 mg / dose, 350 mg / dose, 400 mg / dose, 450 mg / dose, 500 mg / dose, 550 mg / dose, 600 mg / dose, 650 mg / dose, 700 mg / dose, 750 mg / dose, 800 mg / dose, 850 mg / dose, 900 mg / dose, 950 mg / dose, 1000 mg / dose, 1100 mg / dose, 1200 mg / dose, 1250 mg / dose, 1300 mg / dose, 1400 mg / dose, 1500 mg / dose, 1600 mg / dose, 1700 mg / dose, 1750 mg / dose, 1800 mg / dose, 1900 mg / dose, or 2000 mg / dose.

[0199] Embodiment 130. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 119-127, wherein the induction regimen comprises multiple administrations of the anti-TLl A antibody or antigen binding fragment.

[0200] Embodiment 131. The anti-TLl A antibody or antigen binding fragment for use of any one of embodiments 119-127 and 130, wherein the induction regimen comprises: (i) administration of 1000 mg / dose at Week 0, 1000 mg / dose at Week 2, 1000 mg / dose at Week 6, and 1000 mg / dose at Week 10; (ii) administration of 500 mg / dose at Week 0, 500 mg / dose at Week 2, 500 mg / dose at Week 6, and 500 mg / dose at Week 10; (iii) administration of 1000 mg / dose at Week 0, 1000 mg / dose at Week 2, 1000 mg / dose at Week 6, and 500 mg / dose at Week 10; (iv) administration of 1000 mg / dose at Week 0, 1000 mg / dose at Week 2, 500 mg / dose at Week 6, and 500 mg / dose at Week 10; or (v) administration of 1000 mg / dose at Week 0, 500 mg / dose at Week 2, 500 mg / dose at Week 6, and 500 mg / dose at Week 10.

[0201] Embodiment 132. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 119-127 and 130, wherein the induction regimen comprises administration of 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, or 200 mg / dose.

[0202] Embodiment 133. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 119-127, 130, and 132, wherein the induction regimen comprises administration once every 2, 4, 6, or 8 weeks.

[0203] Embodiment 134. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 119-127, 130, and 132, wherein the induction regimen comprises administration once every 2 or 4 weeks for the first 2 administrations, and then administration once every 2, 4, 6, or 8 weeks for the remaining induction regimen.

[0204] Embodiment 135. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 120-134, wherein the diseased tissue in the subject produces TLl A that is at most 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more of the TLl A produced by the corresponding tissue in the control subject.

[0205] Embodiment 136. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 120-131, wherein during the maintenance regimen, the diseased tissue in the subject produces TLl A that is at most 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more of the TLl A produced by the corresponding tissue in the control subject.

[0206] Embodiment 137. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 120-131, wherein for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks or more after the start of the maintenance regimen, the diseased tissue in the subject produces TLl A that is at most 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more of the TLl A produced by the corresponding tissue in the control subject.

[0207] Embodiment 138. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 121-137, wherein the maintenance regimen comprises multiple administrations of the anti-TLl A antibody or antigen-binding fragment.

[0208] Embodiment 139. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 121-138, wherein the maintenance regimen comprises administering the anti-TLl A antibody or antigen-binding fragment at: (i) 500 mg / dose every 2 weeks, (ii) 400 mg / dose every 2 weeks, (iii) 300 mg / dose every 2 weeks, (iv) 250 mg / dose every 2 weeks, (v) 200 mg / dose every 2 weeks, (vi) 150 mg / dose every 2 weeks, (vii) 100 mg / dose every 2 weeks, (viii) 50 mg / dose every 2 weeks, (ix) 500 mg / dose every 4 weeks, (x) 400 mg / dose every 4 weeks, (xi) 300 mg / dose every 4 weeks, (xii) 250 mg / dose every 4 weeks, (xiii) 200 mg / dose every 4 weeks, (xiv) 150 mg / dose every 4 weeks, (xv) 100 mg / dose every 4 weeks, (xvi) 50 mg / dose every 4 weeks, (xvii) 500 mg / dose every 6 weeks, (xviii) 400 mg / dose every 6 weeks, (xix) 300 mg / dose every 6 weeks, (xx) 250 mg / dose every 6 weeks, (xxi) 200 mg / dose every 6 weeks, (xxii) 150 mg / dose every 6 weeks, (xxiii) 100 mg / dose every 6 weeks, (xxiv) 50 mg / dose every 6 weeks, (xxv) 500 mg / dose every 8 weeks, (xxvi) 400 mg / dose every 8 weeks, (xxvii) 300 mg / dose every 8 weeks, (xxviii) 250 mg / dose every 8 weeks, (xxix) 200 mg / dose every 8 weeks, (xxx) 150 mg / dose every 8 weeks, (xxxi) 100 mg / dose every 8 weeks, or (xxxii) 50 mg / dose every 8 weeks.

[0209] Embodiment 140. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 121 to 138, wherein the maintenance regimen comprises administering the anti-TLlA antibody or antigen binding fragment at 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 mg / dose.

[0210] Embodiment 141. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 121-138 and 140, wherein the maintenance regimen comprises administration of the anti-TLlA antibody or antigen-binding fragment once every 2, 4, 6, 8, 10, or 12 weeks.

[0211] Embodiment 142. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 121-141, wherein the maintenance regimen comprises administration of the anti-TLlA antibody or antigen-binding fragment at 250 mg / dose every 4 weeks.

[0212] Embodiment 143. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 121-141, wherein the maintenance regimen comprises administration of the anti-TLlA antibody or antigen-binding fragment at 100 mg / dose every 4 weeks.

[0213] Embodiment 144. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 121-143, wherein the maintenance regimen is for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, or 52 weeks.

[0214] Embodiment 145. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 116-144, wherein the antibody or antigen-binding fragment binds to both monomeric TLlA and trimeric TLlA, and wherein the antibody or antigen-binding fragment blocks the binding of TLlA to DR3.

[0215] Embodiment 146. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 113-145, wherein at least 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the monomeric TLlA in the blood of the subject is occupied by the anti-TLlA antibody or antigen-binding fragment.

[0216] Embodiment 147. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 113-146, wherein at least 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the trimeric TLlA in the blood of the subject is occupied by the anti-TLlA antibody or antigen-binding fragment.

[0217] Embodiment 148. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 113-147, wherein the binding affinity of the antibody or antigen- binding fragment to monomeric TLlA, as measured by the dissociation equilibrium constant (K D-单体 ) is comparable to the binding affinity of the antibody or antigen-binding fragment to trimeric TLlA, as measured by the dissociation equilibrium constant (K D-三聚体 ).

[0218] Embodiment 149. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 148, wherein the K D-单体 is within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold of the K D-三聚体 .

[0219] Embodiment 150. The anti-TLlA antibody or antigen-binding fragment for use of embodiments 148 or 149, wherein the K D-单体 is no more than 0.06 nM.

[0220] Embodiment 151. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 148-150, wherein the K D-三聚体 is no more than 0.06 nM.

[0221] Embodiment 152. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 115-151, wherein the subject has one or more skin inflammation and / or skin fibrosis condition selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo or alopecia areata, a chronic skin disorder, systemic sclerosis, lupus, eczema, and dermatomyositis.

[0222] Embodiment 153. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 114-152, wherein the subject has systemic sclerosis, psoriasis, lupus, dermatomyositis, eczema, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, or a combination thereof.

[0223] Embodiment 154. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 114-152, wherein the subject has hidradenitis suppurativa.

[0224] Embodiment 155. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 114-152, wherein the subject has atopic dermatitis.

[0225] Embodiment 156. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 114-152, wherein the subject has psoriasis.

[0226] Embodiment 157. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 114-152, wherein the subject has vitiligo.

[0227] Embodiment 158. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 114-152, wherein the subject has alopecia areata.

[0228] Embodiment 159. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 115-151, wherein the skin inflammation and / or skin fibrosis is hidradenitis suppurativa.

[0229] Embodiment 160. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 115-151, wherein the skin inflammation and / or skin fibrosis is atopic dermatitis.

[0230] Embodiment 161. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 115-151, wherein the skin inflammation and / or skin fibrosis is psoriasis.

[0231] Embodiment 162. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 115-151, wherein the skin inflammation and / or skin fibrosis is vitiligo.

[0232] Embodiment 163. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 115-151, wherein the skin inflammation and / or skin fibrosis is alopecia areata.

[0233] Embodiment 164. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 115-151, wherein the skin inflammation and / or skin fibrosis is selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo or alopecia areata, a chronic skin disorder, systemic sclerosis, lupus, eczema, and dermatomyositis.

[0234] Embodiment 165. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 113-164, wherein the effective dose or the induction regimen is determined by a dose determination method, wherein the dose determination method comprises: (i) receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in a normal reference tissue; (ii) integrating the parameter received in (a) into a physiologically integrated whole-body based pharmacokinetic (PBPK) model or population pharmacokinetic model (popPK); and (iii) determining the effective dose or the induction regimen such that after step (a), the concentration of TL1A in the diseased tissue in the subject is lower than the concentration of TL1A in the corresponding tissue in a control subject not suffering from skin inflammation and / or skin fibrosis.

[0235] Embodiment 166. The anti-TL1A antibody or antigen-binding fragment for use of embodiment 165, wherein the overproduction of the parameter of TL1A overproduction is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200-fold or more of TL1A production in the normal reference tissue.

[0236] Embodiment 167. The anti-TL1A antibody or antigen-binding fragment for use of any one of embodiments 121 to 166, wherein the maintenance regimen is determined by a dose determination method, wherein the dose determination method comprises: (i) receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in a normal reference tissue; (ii) integrating the parameter received in (i) into a physiologically integrated whole-body based pharmacokinetic (PBPK) model or population pharmacokinetic model (popPK); and (iii) determining the maintenance regimen such that after step (c), the concentration of TL1A in the diseased tissue in the subject is lower than the concentration of TL1A in the corresponding tissue in a control subject not suffering from skin inflammation and / or skin fibrosis.

[0237] Embodiment 168. The anti-TL1A antibody or antigen-binding fragment for use of embodiment 167, wherein the overproduction of the parameter of TL1A overproduction is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100-fold or more of TL1A production in the normal reference tissue.

[0238] Embodiment 169. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 165-168, wherein step (i) in the dose determination method further comprises receiving an association rate of the antibody to TLlA (k on-mAb ), a dissociation rate of the antibody to TLlA (k off-mAb ), a synthesis rate of TLlA in normal tissue (k syn-正常 ), a synthesis rate of TLlA in diseased tissue (k syn-疾病 ), and / or a degradation rate of TLlA (k deg-总-TL1A ).

[0239] Embodiment 170. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 169, wherein the association rate of the antibody to TLlA (k on-mAb ) comprises an association rate of the antibody to monomeric TLlA (k on-单体 ) and an association rate of the antibody to trimeric TLlA (k on-三聚体 ), wherein the dissociation rate of the antibody to TLlA (k off-mAb ) comprises a dissociation rate of the antibody to monomeric TLlA (k off-单体 ) and a dissociation rate of the antibody to trimeric TLlA (k off-三聚体 ), and / or wherein the degradation rate of TLlA (k deg-总-TL1A ) comprises a degradation rate of monomeric TLlA (k deg-TL1A-单体 ) and a degradation rate of trimeric TLlA (k deg-TL1A-三聚体 ).

[0240] Embodiment 171. The anti-TLlA antibody or antigen-binding fragment for use of any one of embodiments 165-170, wherein step (i) in the dose determination method further comprises receiving an association rate of the antibody to FcRn receptor (k on-mAb-FcRn ), a dissociation rate of the antibody to FcRn (k off-mAb-FcRn ), an association rate of the antibody-TLlA complex to FcRn receptor (k on-(mAb-TL1A)-FcRn ), and / or a dissociation rate of the antibody-TLlA complex to FcRn (k off-(mAb-TL1A)-FcRn ).

[0241] Embodiment 172. The anti-TLlA antibody or antigen-binding fragment for use of embodiment 171, wherein the association rate of the antibody-TLlA complex to FcRn receptor (k on-(mAb-TL1A)-FcRn ) comprises an association rate of the antibody-monomeric TLlA complex to FcRn receptor (k on-(mAb-monoTL1A)-FcRn ) and an association rate of the antibody-trimeric TLlA complex to FcRn receptor (k on-(mAb-triTL1A)-FcRn), and / or wherein the off-rate (k off-(mAb-TL1A)-FcRn ) of the antibody-TL1A complex from FcRn includes the off-rate (k off-(mAb-monoTL1A)-FcRn ) of the antibody-monomer TL1A complex from FcRn and the off-rate (k off-(mAb-triTL1A)-FcRn ) of the antibody-trimer TL1A complex from FcRn.

[0242] Embodiment 173. The anti-TL1A antibody or antigen-binding fragment for use of any one of embodiments 165-172, wherein step (i) in the dose determination method further comprises receiving the clearance rate (k deg-mAb-FcRn ) of the FcRn receptor bound by the antibody.

[0243] Embodiment 174. The anti-TL1A antibody or antigen-binding fragment for use of embodiment 173, wherein the clearance rate (k deg-mAb-FcRn ) of the FcRn receptor bound by the antibody includes the clearance rate (k deg-(mAb-monoTL1A)-FcRn ) of the FcRn receptor bound by the antibody-monomer TL1A complex and the clearance rate (k deg-(mAb-triTL1A)-FcRn ) of the FcRn receptor bound by the antibody-trimer TL1A complex.

[0244] Embodiment 175. The anti-TL1A antibody or antigen-binding fragment for use of any one of embodiments 169-174, wherein in the dose determination method: (1) k on-单体 and k on-三聚体 are the same or different; (2) k off-单体 and k off-三聚体 are the same or different; (3) k deg-单体 and k deg-三聚体 are the same or different; (4) k on-(mAb-monoTL1A)-FcRn and k on-(mAb-triTL1A)-FcRn are the same or different; (5) k on-mAb-FcRn and k on-(mAb-monoTL1A)-FcRn are the same or different; (6) k on-mAb-FcRn and k on-(mAb-triTL1A)-FcRn are the same or different; (7) k off-(mAb-monoTL1A)-FcRn and k off-(mAb-triTL1A)-FcRn are the same or different; (8) k off-mAb-FcRn and k off-(mAb-monoTL1A)-FcRn are the same or different; (9) k off-mAb-FcRn and k off-(mAb-triTL1A)-FcRnthe same or different; (10) k deg-(mAb-monoTL1A)-FcRn and k deg-(mAb-triTL1A)-FcRn the same or different; (11) k deg-mAb-FcRn and k -(mAb-triTL1A)-FcRn the same or different; (12) k deg-mAb-FcRn and k deg-(mAb-monoTL1A)-FcRn the same or different; or (13) any combination of (1) to (12).

[0245] Embodiment 176. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 165 to 175, wherein in the dose determination method: k syn-疾病 is at most 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 fold or more fold of k syn-正常 .

[0246] Embodiment 177. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 165 to 176, wherein step (i) in the dose determination method further comprises receiving a rate of TLlA trimerization (k on-TL1A-单体至三聚体 ) and / or a rate of TLlA monomerization (k off-TL1A-三聚体至单体 ).

[0247] Embodiment 179. The anti-TLlA antibody or antigen binding fragment for use of any one of embodiments 114 to 177, wherein the concentration of TLlA is a concentration of free TLlA.

[0248] Implementations 180. The anti-TLlA antibody or antigen-binding fragment for use of any of implementations 1 to 179, wherein the anti-TLlA antibody comprises: a heavy chain variable region comprising: a HCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 1; a HCDR2 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 2-5; and a HCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 6-9; and a light chain variable region comprising: a LCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 10; a LCDR2 comprising an amino acid sequence set forth by SEQ ID NO: 11; a LCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 12-15.

[0249] Implementations 181. The anti-TLlA antibody or antigen-binding fragment for use of any of implementations 1 to 180, wherein the anti-TLlA antibody comprises: a heavy chain variable framework region comprising a human IGHV1-46 02 framework or a modified human IGHV1-46 02 framework; and a light chain variable framework region comprising a human IGKV3-20 framework or a modified human IGKV3-20 framework; wherein the heavy chain variable framework region and the light chain variable framework region collectively comprise zero or fewer than nine amino acid modifications from the human IGHV1-46 02 framework and the human IGKV3-20 framework.

[0250] Implementations 182. The anti-TLlA antibody or antigen-binding fragment for use of any of implementations 1 to 181, wherein the anti-TLlA antibody comprises: a heavy chain variable domain comprising an amino acid sequence that is at least 96% identical to any one of SEQ ID NOs: 101-169; and a light chain variable domain comprising an amino acid sequence that is at least 96% identical to any one of SEQ ID NOs: 201-220.

[0251] Implementations 183. The anti-TLlA antibody or antigen-binding fragment for use of any of implementations 1 to 182, wherein the anti-TLlA antibody comprises a heavy chain variable region comprising SEQ ID NO: 301 X1VQLVQSGAEVKKPGASVKVSCKAS[HCDR1]WVX2QX3PGQGLEWX4G[HCDR2]RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTAVYYCAR[HCDR3]WGQGTTVTVSS, and a light chain variable region comprising SEQ ID NO: 303 EIVLTQSPGTLSLSPGERATLSC[LCDR1]WYQQKPGQAPRX10X11IY[LCDR2]GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC[LCDR3]FGGGTKLEIK, wherein each of X1-X11 is independently selected from A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, or V, wherein HCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 1, HCDR2 comprises the amino acid sequence set forth by any one of SEQ ID NOs: 2-5, HCDR3 comprises the amino acid sequence set forth by any one of SEQ ID NOs: 6-9, LCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 10, LCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 11, and LCDR3 comprises the amino acid sequence set forth by any one of SEQ ID NOs: 12 or 13. 3. BRIEF DESCRIPTION OF DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0253] The exemplary embodiments are illustrated in referenced drawings. It is intended that the embodiments and figures disclosed herein be considered illustrative rather than restrictive.

[0254] Figures 1A-1C Chromatograms of analytical size exclusion chromatography of anti-TL1A antibodies are shown. The large peak (main peak) corresponds to the monomeric fraction. The percentage of monomeric sample is indicated for each antibody. Figure 1A Chromatograms of antibodies A193, A194, and A195 are shown. Figure 1B Chromatograms of antibodies A196, A197, and A198 are shown. Figure 1C Chromatograms of antibodies A199, A200, and A201 are shown.

[0255] Figure 2 Inhibition of interferon gamma in human blood with anti-TL1A antibodies is described.

[0256] Figure 3AA comparison between predicted and measured viscosity is depicted. Figures 3B-3D A PLS model is depicted showing the effect of pH and protein concentration on viscosity. Figure 3B A PLS plot is shown (for the PLS plot, the x-axis is pH, the y-axis is protein concentration (mg / ml), and the z-axis is viscosity (mPa-s)), Figure 3C A model of predicted viscosity (y-axis, mPa-s) versus anti-TLlA antibody concentration in mg / mL (x-axis) is shown, and Figure 3D A model of estimated viscosity (y-axis, mPa-s) versus actual viscosity (x-axis, mPa-s) is shown. Figure 3E The effect of pH versus acetate concentration on viscosity is depicted. Figure 3F The effect of sucrose versus NaCl on viscosity is shown. Figure 3G The effect of Arg-HCl versus Lys-HCl on viscosity is depicted. The viscosity units are mPa-s. The arrow points to the region of highest viscosity. The star corresponds to the region of lowest viscosity.

[0257] Figure 4A The effect of a PLS1 model on high molecular weight (HMW) aggregates is depicted. Figure 4B The effect of pH versus acetate on aggregation is depicted. Figure 4C The effect of sucrose versus NaCl concentration is depicted. Figure 4D The effect of Arg-HCl versus Lys-HCl on aggregation is depicted. Figure 4E The effect of sucrose concentration versus Lys-HCl concentration is depicted.

[0258] Figure 5A The predicted versus measured loss of the main peak at 2 weeks and 25°C is depicted. Figure 5B The effect of pH and protein concentration on the loss of the main peak in CEX profiles is depicted. Figure 5C The effect of pH and acetate concentration on the loss of the main peak in CEX profiles is described. Figure 5D The effect of sucrose and NaCl concentration on the loss of the main peak in CEX profiles is depicted. Figure 5E The effect of Lys-HCl and sucrose concentration on the loss of the main peak in CEX profiles is depicted.

[0259] Figure 6A The loss of monomer by SEC under agitation is depicted. Figure 6B The loss of monomer by SEC under freeze-thaw is depicted.

[0260] Figure 7ABinding of anti-TL1A antibodies to cynomolgus and human TL1A, but not to mouse or rat TL1A, is depicted. At least three ELISAs were performed for each protein. Data from a representative experiment are shown, and are mean ± SD. Abbreviations: A = absorbance, Ab = antibody, Cyno = cynomolgus, nm = nanometer, nM = nanomolar. Figure 7B Mean levels of sTL1A, as measured in ELISA, are depicted as IV doses of anti-TL1A to cynomolgus monkeys are increased. Samples were assayed in triplicate on two separate occasions. Data presented are mean TL1A concentrations ± SD for each group of three animals. Samples collected from animals administered isotype control antibody are shown as circles, and samples collected from animals administered anti-TL1A are shown as triangles and squares. Abbreviations: hr = hour, kg = kilogram, mg = milligram, mL = milliliter, ng = nanogram; TL1A = Tumor necrosis factor-like cytokine 1A.

[0261] Figure 8 TL1A is shown to drive inflammation and fibrosis through binding to DR3.

[0262] Figures 9A-9C Size exclusion chromatography (SEC) profiles of recombinant human TL1A (rhTL1A) are shown. Briefly, rhTL1A was labeled with Alexa fluor 488 (AF488) and spiked into normal human serum (NHS). In Figure 9A When injected alone, rhTL1A SEC profiles showed two peaks on SEC, representing the trimeric and monomeric forms of TL1A. In Figure 9B When rhTL1A was pre-incubated with control reference antibody, the trimeric peak shifted left, indicating the formation of a larger complex of reference antibody and trimeric rhTL1A. There was no shift in the monomeric peak, indicating that the reference antibody only bound to trimeric rhTL1A. In Figure 9C When rhTL1A was pre-incubated with A219, both the trimeric and monomeric rhTL1A peaks shifted, thus indicating that A219 binds to both the trimeric and monomeric forms of TL1A.

[0263] Figure 10A A whole-body physiologically-based pharmacokinetic (PBPK) model is depicted. Figure 10B An organizational level diagram of an integrated whole-body PBPK model for characterizing the PK of a monoclonal antibody (mAb), a ligand, and a complex between the mAb and the ligand is depicted.

[0264] Figure 11ADepicted is the comparison of the pharmacokinetics of the mAb as predicted by the integrated whole-body PBPK (solid lines) to the pharmacokinetics of the mAb as observed in normal healthy volunteers (multiple points, and points from the same subject are shown in the same format) for each case after injection of A219 at the indicated doses. Figure 11B Depicted is the comparison of the TL1A concentrations as predicted by the integrated whole-body PBPK to the TL1A concentrations as observed in normal healthy volunteers for each case after injection of A219 at the indicated doses.

[0265] Figure 12A Depicted are the observed concentrations of TL1A in serum after injection of (i) anti-TL1A antibody A219, which binds to both TL1A monomer and trimer (shown in red, top of the 2 curves, and observed data points accompanying such curves), and (ii) a control reference anti-TL1A antibody, which binds only to TL1A trimer (shown in blue, bottom of the 2 curves, and observed data points accompanying such curves). In Figure 12A In, the solid lines depict the predictions from the model, and the various points depict observations from subjects injected with the indicated antibodies. Figure 12B Depicted is the predicted total TL1A concentration (monomer and trimer, solid line curves, and observed data points accompanying such curves), monomer TL1A concentration (thin dashed line), and trimer TL1A concentration (thick dashed line) for each case at baseline levels (no injection of any anti-TL1A antibody). Figure 12C Depicted are serum TL1A concentrations in normal healthy volunteers (NHV) and UC patients, as predicted by the whole-body PBPK model (solid lines, upper line for UC patients and lower line for NHV) and as observed (multiple points).

[0266] Figures 13A-13B Demonstrated is the fitness of the model. Figure 13A Depicted are the observed concentrations of TL1A in serum in NHV (points) after injection of an anti-TL1A antibody that binds only to TL1A trimer, and the predictions of the model that fit the observations at the indicated doses (solid lines). Q2WX3 = three times every 2 weeks. Figure 13B Depicted are the observed concentrations of TL1A in serum in UC patients (points) after injection of an anti-TL1A antibody that binds only to TL1A trimer, and the predictions of the model that fit the observations at the indicated doses (solid lines). Q2WX7 = seven times every 2 weeks. Figure 13C Depicted are the concentrations of TL1A in the gut of NHV (as predicted by the model and observed data points accompanying such lines, black, solid, lower line of the 2 lines) and UC patients (red, solid, upper line of the 2 lines).

[0267] Figures 14A-14B Baseline concentrations of TL1A are depicted based on various parameters of TL1A production in the intestine (14A) and serum (14B). In Figures 14A-14B In the middle, 1x would be the baseline in the NHV; 25x, 50x, 75x, and 100x indicate various parameters of TL1A overproduction in the intestine.

[0268] Figures 15A-15V Concentrations of free soluble TL1A in tissues as determined by the whole-body PBPK model are depicted under various dose regimens of anti-TL1A antibody A219 as indicated. Figure 15W Concentrations of free soluble TL1A in tissues as determined by the whole-body PBPK model are depicted under dose regimens of a reference anti-TL1A antibody as indicated. Figures 15X-15Z A comparison of modeled free soluble TL1A concentrations in subjects treated with a reference anti-TL1A antibody (red, upper curve of two curves) or A219 (green, lower curve of two curves) is depicted. In Figures 15W-15Z In the middle, the reference antibody light chain sequence is SEQ ID NO: 382 and the heavy chain sequence is SEQ ID NO: 383, and the whole-body PBPK model uses rapid equilibration between monomer and trimer forms of TL1A, with a continuous 60:40 ratio of monomer and trimer as observed. Figures 15A-15Z The black solid line in indicates TL1A concentrations in tissues of the NHV. Q2W = every 2 weeks. Q4W = every 4 weeks. SC = subcutaneous. LD = loading dose (first dose). 4W = week 4. D1 = day 1. W 2, 6, 10 = weeks 2, 6, and 10. W 2, 4, 6, 10 = weeks 2, 4, 6, and 10. EOW = every other week. W 4, 8, 12 = weeks 4, 8, and 12. W 2, 4, 8, 12 = weeks 2, 4, 8, and 12. sTL1A = soluble TL1A.

[0269] Figures 16A-16H A goodness of fit plot for A219 with a population PK model is depicted.

[0270] Figure 17A A visual predictive check of A219 concentrations predicted from the popPK model against observed A219 concentrations is depicted. Figure 17B An induction dose selected in the popPK model to rapidly reach steady state concentrations is depicted.

[0271] Figure 18Depicted is the osmolality at 5°C measured for the stability of A219 samples for various formulations at T0, 3 and 6 months.

[0272] Figure 19 Depicted is the A219 protein concentration at 5°C measured for the stability of A219 samples for various formulations at T0, 3 and 6 months.

[0273] Figure 20 Depicted is the pH at 5°C measured for the stability of A219 samples for various formulations at T0, 3 and 6 months.

[0274] Figure 21A Depicted is the viscosity data for Formulations 1 to 5 at T0 and 3M at 25°C; Figure 21B Depicted is the viscosity data for Formulations 6 to 8 at T0 and 3M at 25°C.

[0275] Figure 22A Depicted is the monomer content of the formulations at 5°C as measured by SEC; Figure 22B Depicted is the loss of monomer (main peak) per month of the formulations at 5°C as determined by SEC; Figure 22C Depicted is the monomer content of the formulations at 25°C as measured by SEC; Figure 22D Depicted is the loss of monomer (main peak) per month of the formulations at 5°C as determined by SEC.

[0276] Figure 23A Depicted is the relative area (%) of the main peak of the formulations at 5°C as characterized by cation exchange chromatography; Figure 23B Depicted is the loss of the main peak (relative area (%) per month) of the formulations at 5°C as determined by cation exchange chromatography; Figure 23C Depicted is the relative area (%) of the main peak of the formulations at 25°C as characterized by cation exchange chromatography; Figure 23D Depicted is the loss of the main peak (relative area (%) per month) of the formulations at 25°C as determined by cation exchange chromatography.

[0277] Figure 24A Depicted is the prediction of monomer loss according to the PLS model versus the measured values by SEC for samples stored at 25°C for 2 months as endpoint; Figure 24B Depicted is the impact of pH and protein according to the PLS model by SEC for samples stored at 25°C for 2 months as endpoint. Figure 24B In the model, the sucrose concentration was fixed at 200 mM. Figure 24CThe impact of pH and acetate according to the PLS model using monomer loss by SEC is depicted for samples stored at 25°C for 2 months as end point. Figure 24C In the Figure 24D The impact of sucrose and lysine according to the PLS model using monomer loss by SEC is depicted for samples stored at 25°C for 2 months as end point. Figure 24D In the Figure 24E The impact of glycine and NaCl according to the PLS model using monomer loss by SEC is depicted for samples stored at 25°C for 2 months as end point. Figure 24E In the

[0278] In Figure 18 , 19 , 20, 21A-21B, 22A-22D, 23A-23D and 24A-24E, wherein Formulations 1-8 (F01-F08, Formulations 1-8 or simply 1-8) mentioned therein are Formulations 1-8 as described in Table 31 of Example 24.

[0279] Figure 25A Geometric mean serum A219 concentration-time profile (linear scale) following a single dose of A219 administered as an IV infusion is shown (SAD study). Figure 25B Geometric mean serum A219 concentration-time profile - Day 29 (linear scale) following multiple doses of A219 Q2W administered as an IV infusion is shown (MAD study). Q2W = every 2 weeks.

[0280] Figure 26A Geometric mean serum sTL1A concentration versus nominal time (semi-log scale) following a single dose of A219 administered as an IV infusion is shown (SAD study). Figure 26B Geometric mean serum sTL1A concentration versus nominal time (semi-log scale) following multiple doses of A219 Q2W administered as an IV infusion is shown (MAD study).

[0281] Figure 27A Total A219 concentration in the central compartment (circulating) in SAD as predicted by the model (curve) and as determined in the Phase I trial (points) is shown. Figure 27B Total soluble TL1A in the central compartment (circulating) in SAD as predicted by the model (curve) and as determined in the Phase I trial is shown. Figure 27CTotal A219 concentration in the central compartment (in circulation) in MAD is shown as predicted by the model (curve) and as determined in the Phase I trial (points). Figure 27D Total soluble TL1A in the central compartment (in circulation) in MAD is shown as predicted by the model (curve) and as determined in the Phase I trial (points). The predicted curve fits the measured data points. Figures 27E-27K Model predictions and data for a control reference antibody that binds only to TL1A trimers (light chain SEQ ID NO: 382 and heavy chain SEQ ID NO: 383) are shown relative to (1) Phase I single ascending dose data ( Figure 27E and Figure 27F ); (2) Phase I multiple ascending dose data ( Figure 27G and Figure 27H ); and (3) Phase II data on PK and total sTL1A levels ( Figure 27I and Figure 27J ). The IBD-specific parameters are then calibrated to capture free tissue TL1A levels in the gut ( Figure 27K ), as observed with the control reference antibody (light chain SEQ ID NO: 382 and heavy chain SEQ ID NO: 383). NR = non-responder, and R = responder.

[0282] Figure 28A A219 doses determined from the validation model are shown that can bring free TL1A concentration in the diseased tissue of a patient below TL1A concentration in a healthy subject. Figure 28B Percent reduction of free TL1A in the diseased tissue after administration of A219 at doses determined from the model is shown. IV_4x = 1000 mg loading dose, 3 x 500 mg at day 14, day 42, day 70. SC dosing 240 mg Q1W or Q2W. Figure 28C In a head-to-head comparison in the validation model, an anti-TL1A antibody that binds to both TL1A monomer and trimer engages more (3.5 times more) TL1A in circulation than an anti-TL1A antibody that binds only to TL1A trimer is shown. Figure 28D In a head-to-head comparison in the validation model, an anti-TL1A antibody that binds to both TL1A monomer and trimer also results in a higher percent reduction of TL1A in the diseased tissue (about 100%) when compared to an anti-TL1A antibody that binds only to TL1A trimer is shown.

[0283] Figure 29A A plot of the popPK model is shown. Figure 29BA comparison of A219 concentrations predicted from the popPK model versus observed in a population of subjects in a Phase I clinical trial via a linear regression plot is shown. Figure 29C A comparison of TL1A concentrations predicted from the popPK model versus observed in a population of subjects in a Phase I clinical trial via a linear regression plot is shown. Figure 29D A comparison of A219 concentrations predicted from the popPK model versus observed in a population of subjects in a Phase I clinical trial via a time series plot is shown. Figure 29E A comparison of TL1A concentrations predicted from the popPK model versus observed in a population of subjects in a Phase I clinical trial via a time series plot is shown.

[0284] Figures 30A-30H A219 and TL1A engagement (TL1A concentration in serum) predicted by the validated popPK model at various A219 doses is shown. Figure 30A and Figure 30B A219 concentration (30A) and TL1A concentration (30B) in circulation is shown, where an induction dosing regimen of 500 mg Q2W (6 doses) is performed until Week 10, and an expansion of 500 mg Q2W (20 doses) is performed from Week 12 to Week 52. Figure 30C and Figure 30D A219 concentration (30C) and TL1A concentration (30D) in circulation is shown, where an induction dosing regimen of 500 mg Q2W (6 doses) is performed until Week 10, and an expansion of 500 mg Q4W (10 doses) is performed from Week 12 to Week 52. Figure 30E and Figure 30F A219 concentration (30E) and TL1A concentration (30F) in circulation is shown, where an induction dosing regimen of 500 mg Q2W (6 doses) is performed until Week 10, and an expansion of 100 mg Q2W (20 doses) is performed from Week 12 to Week 52. Figure 30G and Figure 30H A219 concentration (31G) and TL1A concentration (30H) in circulation is shown, where an induction dosing regimen of 500 mg Q2W (6 doses) is performed until Week 10, and an expansion of 250 mg Q4W (10 doses) is performed from Week 12 to Week 52.

[0285] Figures 31A-31B TNFSF15 (30A) and TNFRSF25 (30B) gene expression levels in lesional hidradenitis suppurativa HS and healthy control skin are shown. Figure 31A ) and TNFRSF25 ( Figure 31B ) gene expression levels in lesional hidradenitis suppurativa HS and healthy control skin are shown.

[0286] Figures 32A-32C Gene set variation analysis (GSVA) of Thl, Thl7, and Th2 pathways in lesional HS and healthy control skin shows upregulation of Thl, Thl7, and Th2 pathway genes in lesional HS tissue compared to healthy control skin. Th = T helper cell.

[0287] Figures 33A-33B GSVA of fibrosis genes enriched in fibroblasts (set 1.1) and fibrosis genes expressed by stromal and immune cells (set 1.2) in lesional HS and healthy control skin shows upregulation of fibrosis genes in lesional HS tissue compared to healthy control skin.

[0288] Figures 34A-34B GSVA of TL1A-induced genes in IFNg-producing cells and Thl7 T cells in lesional HS and healthy control skin shows upregulation of TL1A-induced genes in lesional HS tissue compared to healthy control skin.

[0289] Figure 35A Upregulation of TNFSF15 regulatory factor activity of target genes identified from healthy skin gene regulatory networks in lesional HS skin compared to control skin from healthy subjects, and Figure 35B TNFSF15 is shown as a top master regulator in differential master regulator analysis in HS dataset.

[0290] Figure 36A Normalized gene expression levels of TNFRSF25 in single cells grouped by cell type in lesional HS skin (N=8) and controls (N=10) by single cell RNAseq analysis of Kim Figure 36B Normalized gene expression levels of TNFSF15 in single cells grouped by cell type in lesional HS skin (N=4) and lesional HS skin (N=3) controls (N=1) by single cell RNAseq analysis of Gudjonsson and Mariottoni

[0291] Figures 37A-37E Fluorescence in situ hybridization to detect TL1A transcript in lesional HS (37A and 37B) and healthy control (37C and 37D) skin tissue. Figure 37B Enlargement of the boxed area in 60X in Figure 37A Figure 37D Enlargement of the boxed area in 60X in Figure 37C ​​​​Magnified view of the boxed area at 60x. Figure 37E Negative control probe targeting the DapB gene from Bacillus subtilis strain SMY, a soil bacterium; larger image not shown. Blue = dapi, green = autofluorescence, red = TL1A probe. Representative n = 3. Scale bar = 20um. Figure 37A and Figure 37C show autofluorescence; and Figure 37B and Figure 37D show TL1A FISH.

[0292] Figures 38A-38D show TL1A (left) and DR3 protein (right) immunohistochemical detection in lesional HS (top) or healthy control (bottom) skin tissue, confirming strong expression in HS nodules and surrounding tunnels and almost no staining in healthy controls. Figure 38A and Figure 38C ) and DR3 protein ( Figure 38B and Figure 38D ) in lesional HS (top) or healthy control (bottom) skin tissue, confirming strong expression in HS nodules and surrounding tunnels and almost no staining in healthy controls. Figure 38A and Figure 38B ) and HS lesion tunnel skin tissue (bottom). Figure 38C and Figure 38D ) and HS lesion tunnel skin tissue (bottom). Figures 38A-38D Representative images of n = 5 are shown.

[0293] Figures 39A-39D show immunofluorescence detection of DR3 (red) and T cells (CD3, green) in acute HS lesion samples (top) and HS lesion tunnel skin tissue (bottom). Figure 39A and Figure 39B show low magnification images of composite images of anti-DR3 (red), anti-CD3 (green) and dapi (blue); and Figure 39C and Figure 39D show Figure 39A and Figure 39C show Figure 39B and Figure 39D show Figure 39A and Figure 39C show magnified boxed areas in single channels (left and middle panels) and merged (right panels). Figure 39B and Figure 39D confirm co-localization of DR3 and CD3 (asterisks), and DR3+ expression by non-T cells (CD3- cells). Figure 39B and Figure 39D confirm co-localization of DR3 and CD3 (asterisks), and DR3+ expression by non-T cells (CD3- cells). Figures 39A-39D Representative images of n = 5. Figures 39A-39D

[0294] Figure 40 ​Soluble levels of IL6, IL1b, IL17A, IL17F, TL1a, and TNFa in HS skin tissue lysates and healthy control lysates quantified by immunoassay (Meso Scale Discovery) showing elevated levels of TL1A in HS skin tissue lysates compared to skin tissue from normal healthy volunteers (NHV).

[0295] Figures 41A-41B Gene set variation analysis (GSVA) of TL1A induced genes in Th17 T cells and TL1A induced genes in IFNg producing cells in lesional atopic dermatitis (“AD”) skin and healthy control skin is shown. Th = T helper cell.

[0296] Figure 42A TNFSF15 regulatory factor activity of target genes identified from healthy skin regulatory networks in lesional AD skin compared to control skin from healthy subjects is shown. Figure 42B TNFSF15 in differential master regulator analysis in AD compared to controls in transcriptomic datasets is shown.

[0297] Figure 43 Normalized gene expression levels of TNFRSF25 and proportion of TNFRSF25 expressing cells in T / NKT clusters in lesional and non-lesional AD skin (N=5 patients) and healthy controls (N=7) analyzed from single cell RNAseq datasets (GSE147424) is shown.

[0298] Figures 44A-44B TL1A (44A) and DR3 (44B) protein detected by immunohistochemistry in lesional AD skin tissue demonstrating elevated TL1A expression and enhanced DR3 expression in nodules and surrounding tunnels in AD. Representative images of N=8 AD and N=5 healthy controls. 4. DETAILED DESCRIPTION TL1A is a cytokine secreted by antigen presenting cells, T cells, and endothelial cells. TL1A signaling is through death receptor 3 (DR3), a TNF family receptor that is predominantly present on T cells, natural killer (NK) and NK-T cells, innate lymphoid cells (ILCs), fibroblasts, and epithelial cells, and is effective in driving Th1, Th2, Th9, and Th17 responses. Additionally, it is induced in antigen presenting cells by toll-like receptor (TLR) ligands and FcR cross-linking, and in T cells by T cell receptor (TCR) stimulation. Figure 8It is shown how TL1 A binding to DR3 independently drives inflammation and fibrosis. TL1 A binding to DR3 on innate and T cells leads to early cytokine responses (release of IL-23, IL-1 β, IL-17, IL-22, TNF-a, IFN-γ, IL-13) that lay the foundation for inflammation and stimulate innate and adaptive immune responses. For example, through binding to DR3, TL1 A potentially drives inflammatory Th1 and Th17 responses. In addition, TL1 A binding to DR3 on fibroblasts directly activates fibroblasts and leads to collagen deposition and fibrosis independent of inflammation. While levels of circulating TL1 A are low in healthy subjects, levels are elevated in patients with many autoimmune diseases and TL1 A has been shown to be upregulated in the mucosa and serum of patients with IBD. In mice, chronic TL1 A expression causes structuralized disease from increased collagen deposition. In a dextran sulfate sodium (DSS) and adoptive transfer mouse model, TL1 A transgenic mice develop more severe colitis than wild type animals when challenged with DSS and antibodies to TL1 A lead to reduced inflammation, decreased collagen levels and reversal of fibrosis even when treatment is administered later in the disease course after inflammation and fibrosis have been established. In addition, TL1 A polymorphisms have been shown to be associated with susceptibility to and disease severity of IBD.

[0300] Fibrosis is an important clinical phenotype exhibited by IBD patients. Seventy percent of Crohn's disease (CD) patients develop strictures / penetrations and stricture is the leading indication for surgery in CD. Unfortunately, the anti-inflammatory agents used over the past decade have not substantially changed the rate of disease structuralization or the need for surgery. In addition, in ulcerative colitis (UC), subclinical fibrosis has a significant impact on patient symptoms. For example, subclinical fibrosis can cause symptoms of diarrhea, abdominal pain, urinary urgency, and urinary incontinence. Subclinical fibrosis is also a potential explanation for persistent symptoms after inflammation has resolved. Additionally, a Cleveland Clinic study of 89 consecutive colectomy specimens showed that 100% of the specimens had submucosal fibrosis. Thus, treatment of fibrosis constitutes an unmet need in IBD.

[0301] Studies evaluating the effects of anti-TL1A antibodies in mouse models of IBD have demonstrated the potential of TL1A as a therapeutic target for intestinal fibrosis. In these studies, two mouse models of chronic colitis were used: adoptive T-cell metastasis and chronic DSS. In both models, neutralizing TL1A monoclonal antibodies (mAbs) or isotype control antibodies were administered twice weekly to mice with confirmed colitis (T-cell metastasis n=14; DSS n=28). In both disease models, treatment with TL1AmAbs reduced colonic collagen deposition levels back to those seen in healthy control mice, indicating that blocking TL1A signaling not only prevents the progression of colonic fibrosis but also reverses confirmed fibrosis to similar levels measured before the onset of inflammation. This data suggests that TL1A-mediated intestinal fibrosis can be treated with anti-TL1A antibodies.

[0302] On one hand, this article provides methods for treating inflammation and / or fibrosis with anti-TL1A antibodies. In some embodiments, the treatment of fibrosis is independent of the treatment of inflammation. In some embodiments, the treatment of inflammation is independent of the treatment of fibrosis. On one hand, this article provides methods for treating skin diseases and / or disorders with anti-TL1A antibodies. On one hand, this article provides methods for treating systemic sclerosis with anti-TL1A antibodies. Systemic scleroderma is primarily a fibrotic disease. In some cases, treatment of systemic sclerosis includes treatment of fibrosis. In some cases, treatment of fibrosis includes treatment of systemic sclerosis. In some cases, treatment of systemic sclerosis is independent of treatment of fibrosis, and vice versa. Non-limiting examples of indications for using the anti-TL1A antibodies of this article include hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, alopecia areata, systemic sclerosis or scleroderma, lupus, dermatomyositis, eczema, epidermolysis bullosa, and bullous pemphigoid. In some embodiments, the subject with systemic sclerosis has skin manifestations of systemic sclerosis. In some embodiments, the subject with systemic sclerosis has systemic sclerosis-associated interstitial lung disease. In some embodiments, the subject has scleroderma. In some embodiments, the anti-TL1A antibody binds to the membrane-bound and soluble form of TL1A with high affinity and specificity and blocks the binding of TL1A to its functional receptor DR3.

[0303] The term "and / or" as used in phrases containing a list of members is intended to include, individually, all members and all combinations of the entire or partial list of members. For example, phrases such as "A and / or B" are intended to include A and B; A or B; A (alone); and B (alone). Similarly, the term "and / or" as used in phrases such as "A, B and / or C" is intended to cover each of the following embodiments: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0304] 4.1 General Technology The techniques and procedures described or referenced herein include those generally understood and / or commonly used by those skilled in the art using conventional methods, such as the widely employed methods described in the following literature: Sambrook et al., Molecular Cloning: A Laboratory Manual (…). Molecular Cloning: A Laboratory Manual (3rd edition, 2001); Current protocols in molecular biology ( Current Protocols in Molecular Biology (Ausubel et al., eds., 2003); Therapeutic Monoclonal Antibodies: From the Workbench to the Clinic ( Therapeutic Monoclonal Antibodies: From Bench to Clinic (An edited 2009); Monoclonal antibodies: methods and protocols ( Monoclonal Antibodies: Methods and Protocols (Albitar, 2010); and Antibody Engineering ( Antibody Engineering Volumes 1 and 2 of the book (edited by Kontermann and Dübel, 2nd edition 2010).

[0305] 4.2 Anti-TL1A antibody TL1A exists in both monomeric and trimeric forms in vivo and in vitro. The present disclosure proposes that, while the trimeric form is in a biologically active form that can bind to the physiological receptor, death receptor 3 (“DR3”), and trigger TL1A-mediated signaling (e.g., Zhan, C, et al., Structure 19: 162-171 (2011)), monomeric TL1A makes up a significant portion of the TL1A pool in a subject. By one of the inventors’ estimates, monomeric TL1A can be 60% of the total TL1A in circulating blood. The term “total TL1A” refers to both monomeric and trimeric TL1A. The present disclosure further provides that, while monomeric TL1A is biologically inactive, an anti-TL1A antibody that binds to both monomeric and trimeric TL1A provides advantages over an antibody that binds only to trimeric TL1A. Such advantages include, as provided herein and further demonstrated in Section 5, more effective reduction of TL1A concentration in a subject’s diseased tissue (including concentration of trimeric TL1A in the diseased tissue), more effective reduction of TL1A concentration in a subject’s blood (including concentration of trimeric TL1A in the blood), more sustained reduction of TL1A concentration in a subject’s diseased tissue (including trimeric TL1A concentration), and / or more sustained reduction of TL1A concentration in a subject’s blood (including trimeric TL1A concentration).

[0306] In one aspect, provided herein is an antibody or antigen-binding fragment thereof that binds to tumor necrosis factor-like protein 1A (“TL1A,” and such antibody or antigen-binding fragment thereof, for simplicity, “anti-TL1A antibody or antigen-binding fragment” or “anti-TL1A antibody” in the specification), wherein the antibody or antigen-binding fragment binds to both monomeric TL1A and trimeric TL1A. Additional embodiments of anti-TL1A antibodies, including embodiments with exemplary CDRs, framework sequences, constant region sequences, Fc mutations, variable regions, Fc regions, and other properties, are further provided in this section (Section 4.2). Assays for screening, testing, and validating anti-TL1A antibodies are provided in Section 4.3. Methods for generating, modifying, mutating, cloning, expressing, and isolating anti-TL1A antibodies are provided in Section 4.4. Pharmaceutical compositions for anti-TL1A antibodies are described and provided in Section 4.5. Methods of using anti-TL1A antibodies are provided in Section 4.6. Additional specific and validated embodiments of anti-TL1A antibodies and methods of using them are provided in Section 5. Thus, the present disclosure provides various combinations of anti-TL1A antibodies, pharmaceutical compositions of such anti-TL1A antibodies, methods of generating anti-TL1A antibodies, methods of assaying anti-TL1A antibodies, and methods of using anti-TL1A antibodies for therapy.

[0307] In one embodiment of the various anti-TLl A antibodies or antigen-binding fragments thereof provided herein, the antibody or antigen-binding fragment blocks the binding of TLl A to death receptor 3 (“DR3”). In another embodiment, the antibody or antigen-binding fragment blocks the binding of trimeric TLl A to DR3. In further embodiments, the antibody or antigen-binding fragment blocks TLl A-mediated signaling DR3 signaling. In yet another embodiment, the antibody or antigen-binding fragment blocks the increase in IFNy secretion by various immune cells. In particular embodiments, the antibody or antigen-binding fragment blocks the increase in IFNy secretion by peripheral blood mononuclear cells including various B cells, T cells, natural killer cells, and / or macrophages.

[0308] As described herein, the present disclosure provides anti-TLl A antibodies or antigen-binding fragments that bind both monomeric and trimeric TLl A. Accordingly, in one embodiment of the various anti-TLl A antibodies or antigen-binding fragments thereof provided herein, the binding affinity of the antibody or antigen-binding fragment to monomeric TLl A as measured by the dissociation equilibrium constant (K D-单体 ) is comparable to the binding affinity of the antibody or antigen-binding fragment to trimeric TLl A as measured by the dissociation equilibrium constant (K D-三聚体 ). Such K D-单体 and / or K D-三聚体 can be determined by any method known and practiced by one of skill in the art and described herein, including any applicable assays and methods in this section (Section 4.2) and Section 5.

[0309] The term “binds” or “binding” refers to the interaction between molecules, including, for example, the formation of a complex. The interaction can be, for example, a noncovalent interaction including hydrogen bonds, ionic bonds, van der Waals interactions, and / or hydrophobic interactions. A complex can also include the association of two or more molecules held together by covalent or noncovalent bonds, interactions, or forces. The strength of the total noncovalent interaction between a single antigenic binding site on an antibody and a single epitope of a target molecule, such as TLl A, is the affinity of the antibody or functional fragment for that epitope. The ratio of the dissociation rate (k off ) to the association rate (k on ) of an antibody to a monovalent antigen (k off / k on ) is the dissociation constant K D , which is inversely related to the affinity. The lower the K D value, the higher the affinity of the antibody. The value of K D varies for different complexes of antibody and antigen and depends on k onand k off Both. The dissociation constant K D determined using any of the methods provided herein or any other method well known to those of skill in the art. Affinity at one binding site does not always reflect the true strength of the interaction between an antibody and an antigen. When a complex antigen containing multiple repeating antigenic determinants, such as a multivalent TL1A trimer, is contacted with an antibody containing multiple binding sites, the interaction of the antibody with the antigen at one site will increase the likelihood of a reaction occurring at a second site. The strength of such multiple interactions between a multivalent antibody and an antigen is referred to as avidity. Avidity of an antibody can better measure its binding ability than the affinity of its individual binding sites.

[0310] “Binding affinity” generally refers to the strength of the sum of the noncovalent interactions between a single binding site of a molecule (e.g., a binding protein, such as an antibody) and its binding partner (e.g. ， Antigen). Unless otherwise indicated, as used herein, “binding affinity” refers to intrinsic binding affinity reflecting 1:1 interactions between members of a binding pair (e.g., an antibody and an antigen). As noted above, the affinity of a binding molecule X for its binding partner Y can generally be represented by a dissociation constant (K D ). Affinity can be measured by common methods known in the art, including those described herein. Low affinity antibodies will generally bind to an antigen slowly and tend to dissociate easily, while high affinity antibodies will generally bind to an antigen more quickly and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for the purposes of the present disclosure. Particular illustrative embodiments include the following embodiments. In one embodiment, “K D ” or “K D values” can be measured by assays known in the art, for example, by binding assays. K D can be measured in a RIA, for example, performed with a Fab version of the antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81). K D or K D values can also be measured by Biacore ® using a surface plasmon resonance assay, for example, using a Biacore ® TM-2000 or Biacore ® TM-3000; or, for example, using an Octet ® QK384 system by bio-layer interferometry. “Binding rate” or “rate of association” or “association rate” or “k on ” can also be measured using, for example, Biacore® TM-2000 or Biacore ® TM-3000 or Octet ® The QK384 system uses the same surface plasmon resonance or bio-layer interferometry technology described above to determine.

[0311] Accordingly, the relative binding affinity of an anti-TLl A antibody or antigen binding fragment for TLl A monomer and TLl A trimer can be determined by K D-单体 and K D-三聚体 are described and provided. In one embodiment of the various anti-TLl A antibodies or antigen binding fragments provided herein, K D-单体 is within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times the K D-三聚体 In another embodiment of the various anti-TLl A antibodies or antigen binding fragments provided herein, K D-单体 is within 10%, 20%, 30%, 40%, or 50% of the K D-三聚体 In another embodiment of the various anti-TLl A antibodies or antigen binding fragments provided herein, K D-三聚体 is within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times the K D-单体 In another embodiment of the various anti-TLl A antibodies or antigen binding fragments provided herein, K D-三聚体 is within 10%, 20%, 30%, 40%, or 50% of the K D-单体

[0312] More specifically, in one embodiment of the various anti-TLl A antibodies or antigen binding fragments provided herein, K D-单体 is at most 5 x 10 -12 M, at most 6 x 10 -12 M, at most 7 x 10 -12 M, at most 8 x 10 -12 M, at most 9 x 10 -12 M, at most 1 x 10 -11 M, at most 2 x 10 -11 M, at most 3 x 10 -11 M, at most 4 x 10 -11 M, at most 5 x 10 -11 M, at most 6 x 10 -11 M, at most 7 x 10 -11 M, at most 8 x 10 -11 M, at most 9 x 10 -11 M, at most 1 x 10 -10 M, at most 2 x 10 -10 M, at most 3 x 10 - 10 ​M, at most 4 x 10 -10 M, at most 5 x 10 -10 M, at most 6 x 10 -10 M, at most 7 x 10 -10 M, at most 8 x 10 -10 M, at most 9 x 10 -10 M, or at most 1 x 10 -9 M. In another embodiment, K D-单体 is about 5 x 10 -12 M, about 6 x 10 -12 M, about 7 x 10 - 12 M, about 8 x 10 -12 M, about 9 x 10 -12 M, about 1 x 10 -11 M, about 2 x 10 -11 M, about 3 x 10 -11 M, about 4 x 10 -11 M, about 5 x 10 -11 M, about 6 x 10 -11 M, about 7 x 10 -11 M, about 8 x 10 -11 M, about 9 x 10 11 M, about 1 x 10 -10 M, about 2 x 10 -10 M, about 3 x 10 -10 M, about 4 x 10 -10 M, about 5 x 10 -10 M, about 6 x 10 -10 M, about 7 x 10 -10 M, about 8 x 10 -10 M, about 9 x 10 -10 M, or about 1 x 10 -9 M. In further embodiments of the various anti-TLl A antibodies or antigen binding fragments provided herein, K D-三聚体 is at most 5 x 10 -12 M, at most 6 x 10 -12 M, at most 7 x 10 -12 M, at most 8 x 10 -12 M, at most 9 x 10 -12 M, at most 1 x 10 - 11 M, at most 2 x 10 -11 M, at most 3 x 10 -11 M, at most 4 x 10 -11 M, at most 5 x 10 -11 M, at most 6 x 10 -11 M, at most 7 x 10 -11 M, at most 8 x 10 -11M, at most 9 x 10 -11 M, at most 1 x 10 -10 M, at most 2 x 10 -10 M, at most 3 x 10 -10 M, at most 4 x 10 -10 M, at most 5 x 10 -10 M, at most 6 x 10 -10 M, at most 7 x 10 -10 M, at most 8 x 10 -10 M, at most 9 x 10 -10 M, or at most 1 x 10 -9 M. In yet another embodiment, K D-三聚体 is about 5 x 10 -12 M, about 6 x 10 -12 M, about 7 x 10 -12 M, about 8 x 10 -12 M, about 9 x 10 -12 M, about 1 x 10 -11 M, about 2 x 10 -11 M, about 3 x 10 -11 M, about 4 x 10 -11 M, about 5 x 10 -11 M, about 6 x 10 -11 M, about 7 x 10 -11 M, about 8 x 10 -11 M, about 9 x 10 -11 M, about 1 x 10 -10 M, about 2 x 10 -10 M, about 3 x 10 -10 M, about 4 x 10 -10 M, about 5 x 10 -10 M, about 6 x 10 -10 M, about 7 x 10 -10 M, about 8 x 10 -10 M, about 9 x 10 -10 M, or about 1 x 10 -9 M. The present disclosure further provides that K D-单体 and K D-三聚体 may be any combination of K D-单体 and K D-三聚体 values or ranges as provided herein, including in this section (Section 4.2) and in this paragraph.

[0313] In another particular embodiment, K D-单体 is about 59 pM. In another particular embodiment, K D-三聚体 is about 59 pM. In another particular embodiment, K D-单体 is about 59 pM, and K D-三聚体about 59 pM. In a particular embodiment, K D-单体 about 60 pM. In another particular embodiment, K D-三聚体 about 60 pM. In a further embodiment, K D-单体 about 60 pM, and K D-三聚体 about 60 pM. In a particular embodiment, K D-单体 about 60 pM. In another particular embodiment, K D-三聚体 about 60 pM. In a further embodiment, K D-单体 about 60 pM, and K D-三聚体 about 60 pM.

[0314] In one aspect, provided herein are antibodies that bind to TL1A. As used herein, the term "antibody" refers to any form of antibody that exhibits a desired biological or binding activity. Thus, it is used in the broadest sense and specifically encompasses (but is not limited to) monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human, chimeric and camelid-derived single domain antibodies.

[0315] Generally, the basic antibody structural unit comprises a tetramer. Each tetramer contains two identical pairs of polypeptide chains, each pair having one "light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of the heavy chain includes a constant region primarily responsible for effecting binding of the antibody to host tissue receptors. Normally, human light chains are classified as kappa and lambda light chains. Furthermore, human heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define a Fundamental Immunology ) Chapter 7 (Paul, W., ed., 2nd ed., Raven Press, N.Y. (1989).

[0316] The variable region of each pair of light / heavy chains constitutes an antibody binding site. Therefore, in general, an intact antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are typically identical.

[0317] Typically, both heavy and light chain variable domains contain three hypervariable regions, also known as complementarity-determining regions (CDRs), located within relatively conserved framework regions (FRs). CDRs are usually aligned with the framework regions, enabling them to bind to specific epitopes. Generally, from the N-terminus to the C-terminus, both light and heavy chain variable domains contain FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The amino acid sequence of each domain typically conforms to the following definition: [Immunologically significant protein sequences (…]]. Sequences Proteins of Immunological Interest Kabat et al., National Institutes of Health, Bethesda, Md., 5th edition; NIH Publ. No. 91-3242 (1991); Kabat (1978) Advanced Protein Chemistry 32:1-75; Kabat et al., (1977) Journal of Biochemistry 252:6609-6616; Chothia et al., (1987) Journal of Molecular Biology 196:901-917; or Chothia et al., (1989) Nature 342:878-883.

[0318] Unless otherwise stated, as used herein, “antibody fragment” or “antigen-binding fragment” refers to an antigen-binding fragment of an antibody, i.e., an antibody fragment that retains the antigen-specific binding ability to bind to the full-length antibody, such as a fragment retaining one or more CDR regions. Examples of antibody-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; biantibodies; linear antibodies; single-chain antibody molecules, such as sc-Fv; nanobodies; and multispecific antibodies formed from antibody fragments.

[0319] In some embodiments, an antibody includes an antigen-binding fragment, which refers to a portion of an antibody that contains the antigen-determining variable region of an antibody. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, single-chain antibodies, and multi-specific antibodies formed from antibody fragments. In some embodiments, an antibody refers to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing through at least one antigen recognition site within the variable region of the immunoglobulin molecule. In some embodiments, an antibody includes intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments), single-chain Fv (scFv) mutants, CDR-grafted antibodies, multi-specific antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins including an antigen determining portion of an antibody, and any other modified configuration of the immunoglobulin molecule that exhibits the desired biological activity of an antibody. Antibodies can have any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM or subclasses (isotypes) thereof (e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2), referred to as a, δ, ε, γ, and μ respectively, based on the identity of their heavy chain constant domains. Different classes of immunoglobulins have different and well known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules such as toxins, radioisotopes, and the like.

[0320] In some embodiments, a humanized antibody refers to a form of a non-human (e.g., murine) antibody having specific immunoglobulin chains, a chimeric immunoglobulin, or a fragment thereof that contains minimal non-human (e.g., murine) sequences. In non-limiting examples, a humanized antibody comprises less than about 40% non-human sequences in the variable region. In some cases, a humanized antibody comprises less than about 20% non-human sequences in the full-length antibody sequence. In further non-limiting examples, a humanized antibody comprises less than about 20% non-human sequences in the framework region of each of the heavy chain variable region and the light chain variable region. For example, a humanized antibody comprises less than about 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% non-human sequences in the framework region of each of the heavy chain variable region and the light chain variable region. As another example, a humanized antibody comprises about or less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 non-human sequences in the framework region of each of the heavy chain variable region and the light chain variable region. In some cases, a humanized antibody is a human immunoglobulin in which residues from the complementarity determining regions (CDRs) are replaced by residues from the CDRs of an antibody derived from a non-human species (e.g., mouse, rat, rabbit, hamster). These humanized antibodies can contain one or more non-human species mutations, for example, a heavy chain comprising about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 non-human species mutations in the framework region, and a light chain comprising about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 non-human species mutations in the framework region. A humanized heavy chain variable domain can comprise an IGHV1-46 02framework. A humanized light chain variable domain can comprise an IGKV3-20 framework without or with less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations.

[0321] In some embodiments, a chimeric antibody refers to an antibody in which the sequences of the immunoglobulin molecules are derived from two or more species. As a non-limiting example, the variable regions of both the light and heavy chains correspond to those of an antibody derived from one mammalian species (e.g., mouse, rat, rabbit, etc.) having the desired specificity, affinity, and capability, while the constant regions are homologous with those in an antibody derived from another species (typically human) to avoid eliciting an immune response in that species.

[0322] The terms“complementarity determining region” and“CDR,” which are synonymous with“hypervariable region” or“HVR,” are known in the art to refer to non-contiguous sequences of amino acids within the variable region of an antibody that impart antigen specificity and / or binding affinity. Generally, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, CDR-L3).“Framework region” and“FR” are known in the art to refer to the non-CDR portions of the variable regions of the heavy and light chains. Generally, there are four FRs in each full-length heavy chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4) and four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4). The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by: Kabat et al. (1991)“Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme); Al-Lazikani et al. (1997) JMB 273,927-948 (“Chothia” numbering scheme); MacCallum et al. (1996)“Antibody-antigen interactions: Contact analysis and binding site topography,” J. Mol. Biol. 262, 732-745 (“Contact” numbering scheme); Lefranc MP et al. (1999)“IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev. Comp. Immunol. 27, 55-77 (“IMGT” numbering scheme); and Honegger and Plückthun (2001)“Efficient Journal of Molecular Biology retrofitting of CDRs,” J. Mol. Biol. 309, 287-296 (“Aberdeen” numbering scheme). Immunol)》, January 2003;27(1):55-77 (“IMGT” numbering scheme); Honegger A and Plückthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool”, 《 Journal of Molecular Biology 》, June 8, 2001; 309(3):657-70, (“Aho” numbering scheme); and Whitelegg NR and Rees AR, “WAM: animproved algorithm for modelling antibodies on the WEB,” Protein Engineering ( Protein Eng. ). December 2000;13(12):819-24 (“AbM” numbering scheme). In some embodiments, the CDR of the antibody described herein may be defined by a method selected from Kabat, Chothia, IMGT, Aho, AbM or combinations thereof.

[0323] In some implementations, antibodies that specifically bind to proteins indicate that, compared to alternative substances (including unrelated proteins), the antibodies react or associate with proteins more frequently, more rapidly, for longer durations, with greater affinity, or in some combination of the foregoing.

[0324] In some embodiments, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to polymers having amino acids of any length. The polymers may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acid components. The terms also cover amino acid polymers that have been modified naturally or through intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other operation or modification, such as fusion with another polypeptide and / or conjugation, for example, with a labeled component. The definition also includes, for example, one or more analogues containing amino acids (e.g., non-natural amino acids, etc.) and other modified polypeptides known in the art.

[0325] In some embodiments, a protein, such as an antibody described herein, comprises a hydrophobic amino acid. Non-limiting exemplary hydrophobic amino acids include glycine (Gly), proline (Pro), phenylalanine (Phe), alanine (Ala), isoleucine (lie), leucine (Leu), and valine (Val). In some embodiments, a protein, such as an antibody described herein, comprises a hydrophilic amino acid. Non-limiting exemplary hydrophilic amino acids include serine (Ser), threonine (Thr), aspartic acid (Asp), glutamic acid (Glu), cysteine (Cys), asparagine (Asn), glutamine (Gin), arginine (Arg), and histidine (His). In some embodiments, a protein, such as an antibody described herein, comprises an amphipathic amino acid. Non-limiting exemplary amphipathic amino acids include lysine (Lys), tryptophan (Trp), tyrosine (Tyr), and methionine (Met). In some embodiments, a protein, such as an antibody described herein, comprises an aliphatic amino acid. Non-limiting exemplary aliphatic amino acids include alanine (Ala), isoleucine (lie), leucine (Leu), and valine (Val). In some embodiments, a protein, such as an antibody described herein, comprises an aromatic amino acid. Non-limiting exemplary aromatic amino acids include phenylalanine (Phe), tryptophan (Trp), and tyrosine (Tyr). In some embodiments, a protein, such as an antibody described herein, comprises an acidic amino acid. Non-limiting exemplary acidic amino acids include aspartic acid (Asp) and glutamic acid (Glu). In some embodiments, a protein, such as an antibody described herein, comprises a basic amino acid. Non-limiting exemplary basic amino acids include arginine (Arg), histidine (His), and lysine (Lys). In some embodiments, a protein, such as an antibody described herein, comprises a hydroxyl amino acid. Non-limiting exemplary hydroxyl amino acids include serine (Ser) and threonine (Thr). In some embodiments, a protein, such as an antibody described herein, comprises a sulfur-containing amino acid. Non-limiting exemplary sulfur-containing amino acids include cysteine (Cys) and methionine (Met). In some embodiments, a protein, such as an antibody described herein, comprises an amide amino acid. Non-limiting exemplary amide amino acids include asparagine (Asn) and glutamine (Gln).

[0326] In some embodiments, "polynucleotide" or "nucleic acid" as used interchangeably herein refers to polymers of nucleotides of any length and includes DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substitution into the polymeric compounds. The polynucleotide can comprise modified nucleotides, such as, but not limited to, methylated nucleotides and their analogs or non-nucleotide components. Modifications to the nucleotide structure can be made before or after assembly of the polymer. The polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component.

[0327] The percent (%) sequence identity with respect to a reference polypeptide sequence is the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in known ways, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with the U.S. Copyright Office, Washington D.C. 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program can be publicly obtained from Genentech, Inc., South San Francisco, Calif, either as compiled source code or can be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0328] Where amino acid sequence comparisons are made using ALIGN-2, the amino acid sequence identity of a given amino acid sequence A to, and or with or relative to, a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A having or comprising a certain amino acid sequence identity to, and or with or relative to, a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y, where X is the number of amino acid residues in the alignment of the sequences by the sequence alignment program ALIGN-2 in the alignment of A and B by the program, and where Y is the total number of amino acid residues in B. It will be appreciated that where a given amino acid sequence A has a length that is not equal to the length of the given amino acid sequence B, the amino acid sequence identity of A to B will not equal the amino acid sequence identity of B to A. Unless specifically stated otherwise, all amino acid sequence identity values used herein are obtained using the ALIGN-2 computer program as described in the immediately preceding paragraph.

[0329] In some embodiments, the term "about" means within 10% of the stated amount. For example, an antibody variable region comprising a variable region that is about 80% identical to a reference variable region can have between 72% and 88% identity to the reference variable region.

[0330] In certain aspects, described herein are antibodies that specifically bind to TL1A (Entrez Gene: 9966; UniProtKB: 095150). In some embodiments, the antibodies specifically bind to soluble TL1A. In some embodiments, the antibodies specifically bind to membrane-bound TL1A. In some embodiments, provided are anti-TL1A antibodies having a heavy chain comprising four heavy chain framework regions (HCFRs) and three heavy chain complementarity determining regions (HCDRs): HCFR1, HCDR1, HCFR2, HCDR2, HCFR3, HCDR3, and HCFR4; and a light chain comprising four light chain framework regions (LCFRs) and three light chain complementarity determining regions (LCDRs): LCFR1, LCDR1, LCFR2, LCDR2, LCFR3, LCDR3, and LCFR4. Anti-TL1A antibodies can comprise any of the regions provided herein, e.g., as provided in the Tables, Examples, and Sequences.

[0331] Exemplary Anti-TL1A CDRs In certain embodiments, an anti-TLl A antibody comprises a HCDR1 as set forth by SEQ ID NO: 1. In certain embodiments, an anti-TLl A antibody comprises a HCDR2 as set forth by any one of SEQ ID NOs: 2-5. In certain embodiments, an anti-TLl A antibody comprises a HCDR3 as set forth by any one of SEQ ID NOs: 6-9. In certain embodiments, an anti-TLl A antibody comprises a LCDR1 as set forth by SEQ ID NO: 10. In certain embodiments, an anti-TLl A antibody comprises a LCDR2 as set forth by SEQ ID NO: 11. In certain embodiments, an anti-TLl A antibody comprises a LCDR3 as set forth by any one of SEQ ID NOs: 12-15. In a non-limiting example, an anti-TLl A antibody comprises a HCDR1 as set forth by SEQ ID NO: 1: a HCDR2 as set forth by SEQ ID NO: 2: a HCDR3 as set forth by SEQ ID NO: 6: a LCDR1 as set forth by SEQ ID NO: 10: a LCDR2 as set forth by SEQ ID NO: 11 : and a LCDR3 as set forth by SEQ ID NO: 12. In some cases, the anti-TLl A antibody comprises the CDRs of antibody J of Table 10. In some cases, the anti-TLl A antibody comprises the CDRs of antibody J2 of Table 10. In some cases, the anti-TLl A antibody comprises the CDRs of antibody K of Table 10.

[0332] In certain embodiments, an anti-TLl A antibody comprises a HCDR1 as set forth by SEQ ID NO: 401, 407, 413, or 450. In certain embodiments, an anti-TLl A antibody comprises a HCDR2 as set forth by SEQ ID NO: 402, 408, 414, or 451. In certain embodiments, an anti-TLl A antibody comprises a HCDR3 as set forth by SEQ ID NO: 403, 409, 415, or 452. In certain embodiments, an anti-TLl A antibody comprises a LCDR1 as set forth by SEQ ID NO: 404, 410, 416, or 453. In certain embodiments, an anti-TLl A antibody comprises a LCDR2 as set forth by SEQ ID NO: 405, 411, 417, or 454. In certain embodiments, an anti-TLl A antibody comprises a LCDR3 as set forth by SEQ ID NO: 406, 412, 418, or 455.

[0333] In certain embodiments, an anti-TLl A antibody comprises a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 selected from Table 6.

[0334] Table 6. Example CDR Amino Acid Sequences In certain embodiments, the anti-TLl A antibody comprises the CDRs set forth in Antibodies A, B, C, D, E, F, G, H, I, A2, B2, C2, D2, E2, F2, G2, H2, I2, J, J2, K, M, or N of Table 10.

[0335] Table 10. CDR Sequences from Example Anti-TLl A Antibodies In certain embodiments, the anti-TLl A antibody comprises the heavy chain CDRs set forth in an antibody selected from Table 7.

[0336] Table 7. Example Heavy Chain Variable Region Sequences In certain embodiments, the anti-TLl A antibody comprises the light chain CDRs set forth in an antibody selected from Table 8.

[0337] Table 8. Example Light Chain Variable Region Sequences In certain embodiments, an anti-TLl A antibody comprises the CDRs set forth in any one of the antibodies of Table 1. For example, an anti-TLl A antibody comprises the CDRs of antibody A15, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55, A56, A57, A58, A59, A60, A61, A62, A63, A64, A65, A66, A67, A68, A69, A70, A71, A72, A73, A74, A75, A76, A77, A78, A79, A81, A82, A83, A85, A86, A87, A88, A89, A90, A91, A92, A93, A94, A95, A96, A97, A98, A99, A100, A101, A102, A103, A104, A105, A107, A108, A109, A110, A111, A112, A113, A114, A115, A116, A117, A118, A119, A120, A121, A122, A123, A124, A125, A126, A127, A128, A129, A130, A132, A133, A134, A135, A136, A137, A138, A139, A140, A141, A142, A143, A144, A145, A146, A147, A148, A149, A150, A151, A152, A153, A154, A155, A156, A157, A158, A159, A160, A161, A162, A163, A164, A165, A166, A167, A168, A169, A170, A171, A172, A173, A174, A175, A176, A177, A178, A179, A180, A181, A182, A183, A184, A185, A186, A187, A188, A189, A190, A191, A192, A193, A194, A195, A196, A197, A198, A199, A200, A201, A202, A203, A204, A205, A206, A207, A208, A209, A210, A211, A212, A213, A214, A215, A216, A217, A218, A219, A220, A221, A222, A223, A224, A500, A501, AJ, AK, AM, or AN. In a non-limiting example, an anti-TLl A antibody comprises the CDRs of antibody A219.

[0338] Antibody CDRs can be defined by the Aho or Kabat, Chothia, or IMGT method.

[0339] Exemplary Anti-TL1A Framework Regions In certain embodiments, an anti-TLl A antibody comprises a heavy chain (HC) framework 1 (FR1), as set forth by SEQ ID NO: 304. In certain embodiments, an anti-TLl A antibody comprises a HC FR2, as set forth by any one of SEQ ID NOs: 305 or 313. In certain embodiments, an anti-TLl A antibody comprises a HC FR3, as set forth by any one of SEQ ID NOs: 306-307, 314-315. In certain embodiments, an anti-TLl A antibody comprises a HC FR4, as set forth by SEQ ID NO: 308. In certain embodiments, an anti-TLl A antibody comprises a LC FR1, as set forth by SEQ ID NO: 309. In certain embodiments, an anti-TLl A antibody comprises a LC FR2, as set forth by SEQ ID NO: 310. In certain embodiments, an anti-TLl A antibody comprises a LC FR3, as set forth by SEQ ID NO: 311. In certain embodiments, an anti-TLl A antibody comprises a LC FR4, as set forth by SEQ ID NO: 312. In non-limiting examples, an anti-TLl A antibody comprises a HC FR1, as set forth by SEQ ID NO: 304: a HC FR2, as set forth by SEQ ID NO: 305: a HC FR3, as set forth by SEQ ID NO: 306: a HC FR4, as set forth by SEQ ID NO: 308: a LC FR1, as set forth by SEQ ID NO: 309: a LC FR2, as set forth by SEQ ID NO: 310: a LC FR3, as set forth by SEQ ID NO: 311 : and a LC FR4, as set forth by SEQ ID NO: 312. In non-limiting examples, an anti-TLl A antibody comprises a HC FR1, as set forth by SEQ ID NO: 304: a HC FR2, as set forth by SEQ ID NO: 305: a HC FR3, as set forth by SEQ ID NO: 307: a HC FR4, as set forth by SEQ ID NO: 308: a LC FR1, as set forth by SEQ ID NO: 309: a LC FR2, as set forth by SEQ ID NO: 310: a LC FR3, as set forth by SEQ ID NO: 311 : and a LC FR4, as set forth by SEQ ID NO: 312.

[0340] In certain embodiments, an anti-TLl A antibody comprises a heavy chain framework region selected from those shown in the antibodies of Table 7. In certain embodiments, an anti-TLl A antibody comprises a light chain framework region selected from those shown in the antibodies of Table 8. In certain embodiments, an anti-TLl A antibody comprises a framework region shown in any of the antibodies of Table 1.For example, the anti-TLl A antibody comprises the framework regions of antibody A15, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55, A56, A57, A58, A59, A60, A61, A62, A63, A64, A65, A66, A67, A68, A69, A70, A71, A72, A73, A74, A75, A76, A77, A78, A79, A81, A82, A83, A85, A86, A87, A88, A89, A90, A91, A92, A93, A94, A95, A96, A97, A98, A99, A100, A101, A102, A103, A104, A105, A107, A108, A109, A110, A111, A112, A113, A114, A115, A116, A117, A118, A119, A120, A121, A122, A123, A124, A125, A126, A127, A128, A129, A130, A132, A133, A134, A135, A136, A137, A138, A139, A140, A141, A142, A143, A144, A145, A146, A147, A148, A149, A150, A151, A152, A153, A154, A155, A156, A157, A158, A159, A160, A161, A162, A163, A164, A165, A166, A167, A168, A169, A170, A171, A172, A173, A174, A175, A176, A177, A178, A179, A180, A181, A182, A183, A184, A185, A186, A187, A188, A189, A190, A191, A192, A193, A194, A195, A196, A197, A198, A199, A200, A201, A202, A203, A204, A205, A206, A207, A208, A209, A210, A211, A212, A213, A214, A215, A216, A217, A218, A219, A220, A221, A222, A223, A224, A500, A501, AJ, AK, AM, or AN. In a non-limiting example, the anti-TLl A antibody comprises the framework regions of antibody A219.In another non-limiting example, the anti-TLl A antibody comprises a framework region of an antibody comprising SESQ ID NOs: 420 and 430. In another non-limiting example, the anti-TLl A antibody comprises a framework region of an antibody comprising SESQ ID NOs: 421 and 431. In another non-limiting example, the anti-TLl A antibody comprises a framework region of an antibody comprising SESQ ID NOs: 424 and 434.

[0341] Antibody CDRs and framework regions can be defined by the Aho or Kabat, Chothia, or IMGT method.

[0342] In some embodiments, the anti-TLl A antibody comprises: a heavy chain variable framework region comprising a human IGHVl-46 02 framework or a modified human IGHVl-46 02 framework; and a light chain variable framework region comprising a human IGKV3-20 framework or a modified human IGKV3-20 framework; wherein the heavy chain variable framework region and the light chain variable framework region collectively comprise a human IGHVl-46 02 zero or fewer than nine amino acid modifications of the 02 framework and the human IGKV3-20 framework. In some embodiments, the amino acid modifications comprise: (a) a modification at amino acid position 45 in the heavy chain variable region; (b) a modification at amino acid position 47 in the heavy chain variable region; (c) a modification at amino acid position 55 in the heavy chain variable region; (d) a modification at amino acid position 78 in the heavy chain variable region; (e) a modification at amino acid position 80 in the heavy chain variable region; (f) a modification at amino acid position 82 in the heavy chain variable region; (g) a modification at amino acid position 89 in the heavy chain variable region; or (h) a modification at amino acid position 91 in the heavy chain variable region, according to Aho or Kabat numbering; or a combination of two or more modifications selected from (a) to (h). In some embodiments, the amino acid modifications comprise (a) R45K, (b) A47R, (c) M55I, (d) V78A, (e) M80I, (f) R82T, (g) V89A, or (h) M91L in the heavy chain variable region, according to Aho or Kabat numbering; or a combination of two or more modifications selected from (a) to (h). In some embodiments, the amino acid modifications comprise: A47R. In some embodiments, the amino acid modifications comprise: A47R, M55I, V78A, M80I, R82T, V89A, and M91L; A47R, M80I, and R82T; A47R, M80I, R82T, V89A, and M91L; or A47R, M55I, V78A, M80I, V89A, and M91L. In some embodiments, the amino acid modifications comprise: R45K and A47R. In some embodiments, the amino acid modifications comprise: R45K, A47R, V89A, and M91L. In some embodiments, the amino acid modifications comprise: R45K and A47R and M80I. In some embodiments, the amino acid modifications comprise: R45K, A47R, M80I, and M91L; R45K, A47R, V78A, M80I, V89A, and M91L; R45K, A47R, M55I, V78A, M80I, R82T, V89A, and M91L; R45K, A47R, M80I, V89A, and M91L; R45K, A47R, M55I, M80I, R82T, V89A, and M91L; R45K, A47R, M80I, and V89A; R45K, A47R, M80I, R82T, V89A, M91L; or R45K, A47R, M55I, M80I, V89A, and M91L. In some embodiments, the amino acid modifications comprise: R45K. In some embodiments, the amino acid modifications comprise: R45K and V78A. In some embodiments, the amino acid modifications comprise: V78A.In some embodiments, the amino acid modification comprises: V78A and V89A; V78A and M80I; or V78A, M80I, and R82T. In some embodiments, the amino acid modification comprises: V89A. In some embodiments, the amino acid modification comprises: M80I. In some embodiments, the amino acid modification comprises: (a) a modification at amino acid position 54 in the light chain variable region; and / or (b) a modification at amino acid position 55 in the light chain variable region, according to Aho or Kabat numbering. In some embodiments, the amino acid modification comprises L54P in the light chain variable region, according to Aho or Kabat numbering. In some embodiments, the amino acid modification comprises L55W in the light chain variable region, according to Aho or Kabat numbering.

[0343] In some embodiments, the anti-TL1A antibody comprises a heavy chain framework comprising SEQ ID NO: 301 (X1VQLVQSGAEVKKPGASVKVSCKAS[HCDR1]WVX2QX3PGQGLEWX4G[HCDR2]RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTAVYYCAR [HCDR3]WGQGTTVTSS) or SEQ ID NO: 302 (X1VQLVQSGAEVKKPGASVKVSCKAS[HCDR1]WVX2QX3PGQGLEWX4G[HCDR2]RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTAVYYCAR [HCDR3]WGQGTTVTSS) or SEQ ID NO: 302 02 at position 1, as determined by Aho or Kabat numbering. In some embodiments, X2 is located in IGHV1-46 position 45 of SEQ ID NO: 02, as determined by Aho or Kabat numbering. In some embodiments, X3 is located in IGHV1-46 position 47 of SEQ ID NO: 02, as determined by Aho or Kabat numbering. In some embodiments, X4 is located in IGHV1-46 position 55 of SEQ ID NO: 02, as determined by Aho or Kabat numbering. In some embodiments, X5 is located in IGHV1-46 position 78 of SEQ ID NO: 02, as determined by Aho or Kabat numbering. In some embodiments, X6 is located in IGHV1-46 position 80 of SEQ ID NO: 02, as determined by Aho or Kabat numbering. In some embodiments, X7 is located in IGHV1-46 position 82 of SEQ ID NO: 02, as determined by Aho or Kabat numbering. In some embodiments, X8 is located in IGHV1-46 position 89 of SEQ ID NO: 02, as determined by Aho or Kabat numbering. In some embodiments, X9 is located in IGHV1-46 position 91 of SEQ ID NO: 02, as determined by Aho or Kabat numbering.

[0344] In one aspect, provided herein are first embodiments of anti-TLlA antibodies comprising a heavy chain framework comprising IGHV1-46 SEQ ID NO: 02 or a variant thereof, wherein the variant comprises a substitution at one or more positions of IGHV1-46 02 about 1 to about 9 amino acid substitutions, or about 1 to about 20 amino acid substitutions, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. Additional embodiments include: (2) The anti-TLl A of embodiment (1), wherein the heavy chain framework comprises SEQ ID NO: 301. (3) The anti-TLl A of embodiment 2, wherein X1 = Q. (4) The anti-TLl A of embodiment 2, wherein X1 = E. (5) The anti-TLl A of any one of embodiments 2-4, wherein X2 = R. (6) The anti-TLl A of any one of embodiments 2-4, wherein X2 = K. (7) The anti-TLl A of any one of embodiments 2-6, wherein X3 = A. (8) The anti-TLl A of any one of embodiments 2-6, wherein X3 = R. (9) The anti-TLl A of any one of embodiments 2-8, wherein X4 = M. (10) The anti-TLl A of any one of embodiments 2-8, wherein X4 = I. (11) The anti-TLl A of any one of embodiments 2-10, wherein X5 = V. (12) The anti-TLl A of any one of embodiments 2-10, wherein X5 = A. (13) The anti-TLl A of any one of embodiments 2-12, wherein X6 = M. (14) The anti-TLl A of any one of embodiments 2-12, wherein X6 = I. (15) The anti-TLl A of any one of embodiments 2-14, wherein X7 = R. (16) The anti-TLl A of any one of embodiments 2-14, wherein X7 = T. (17) The anti-TLl A of any one of embodiments 2-16, wherein X8 = V. (18) The anti-TLl A of any one of embodiments 2-16, wherein X8 = A. (19) The anti-TLl A of any one of embodiments 2-18, wherein X9 = M. (20) The anti-TLl A of any one of embodiments 2-4, wherein X9 = L. (21) The anti-TLl A of any one of embodiments 1-20, comprising antibody A. (22) The anti-TLl A of any one of embodiments 1-20, comprising antibody B. (23) The anti-TLl A of any one of embodiments 1-20, comprising antibody C. (24) The anti-TLl A of any one of embodiments 1-20, comprising antibody D. (25) The anti-TLl A of any one of embodiments 1-20, comprising antibody E. (26) The anti-TLl A of any one of embodiments 1-20, comprising antibody F. (27) The anti-TLl A of any one of embodiments 1-20, comprising antibody G or I.(28) The anti-TLl A of any one of embodiments 1-20, comprising antibody H.(34) The anti-TLl A of any one of embodiments 1-33, comprising a light chain comprising a light chain framework comprising IGKV3-20. 01 or a variant thereof, wherein the variant comprises about 1 to about 2 substitutions in the framework, or about 1 to about 20 amino acid substitutions, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions.(35) The anti-TLl A antibody of embodiment 34, wherein X10 is L.(36) The anti-TLl A antibody of embodiment 34, wherein X10 is P.(37) The anti-TLl A antibody of any one of embodiments 34-36, wherein X11 is L.(38) The anti-TLl A antibody of any one of embodiments 34-36, wherein X11 is W.

[0345] In some embodiments, the anti-TLl A antibody comprises a light chain framework comprising SEQ ID NO: 303 (EIVLTQSPGTLSLSPGERATLSC[LCDR1]WYQQKPGQAPRX10X11IY[LCDR2]GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC[LCDR3]FGGG TKLEIK). In some cases, X10 is L. In some cases, X10 is P. In some cases, X11 is L. In some cases, X11 is W. In some embodiments, X10 is at position 54 of IGKV3-20 01, as determined by Aho or Kabat numbering. In some embodiments, X11 is at position 55 of IGKV3-20 01, as determined by Aho or Kabat numbering.

[0346] In some embodiments, the anti-TLl A antibody comprises a heavy chain framework comprising IGHV1-46 02. In some embodiments, the anti-TLl A antibody comprises a heavy chain framework comprising IGHV1-46 02. In some embodiments, the anti-TLl A antibody comprises a heavy chain framework comprising IGHV1-46 a variant of 02 comprising about 1 to about 9 amino acid substitutions from SEQ ID NO: 316. In some embodiments, the anti-TLlA antibody comprises a heavy chain framework comprising IGHV1-46 a variant of 02 comprising about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions from SEQ ID NO: 316 in the framework. In some cases, the heavy chain framework substitutions comprise Q1E, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitutions comprise R45K, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitutions comprise A47R, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitutions comprise M55I, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitutions comprise V78A, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitutions comprise M80I, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitutions comprise R82T, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitutions comprise V89A, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitutions comprise M91L, as determined by Aho or Kabat numbering.

[0347] In some embodiments, the anti-TLlA antibody comprises a light chain framework comprising IGKV3-20 01. In some embodiments, the anti-TLlA antibody comprises IGKV3-20 a variant of 01 comprising about 1 to about 20 amino acid substitutions from SEQ ID NO: 317. In some embodiments, the anti-TLlA antibody comprises IGKV3-20 a variant of 01 comprising about 1 amino acid substitution from SEQ ID NO: 317. In some embodiments, the anti-TLlA antibody comprises a light chain framework comprising IGKV3-20 a variant of 01 comprising about 2 amino acid substitutions from SEQ ID NO: 317. In some embodiments, the anti-TLlA antibody comprises a light chain framework comprising IGKV3-20 a variant of SEQ ID NO: 01 comprising about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions in the framework from SEQ ID NO: 317. In some cases, the light chain framework substitution comprises Q1E, as determined by Aho or Kabat numbering. In some cases, the light chain framework substitution comprises R45K, as determined by Aho or Kabat numbering.

[0348] In some embodiments, the anti-TLl A antibody comprises a heavy chain FR1 as set forth by SEQ ID NO: 304. In some embodiments, the anti-TLl A antibody comprises a heavy chain FR2 as set forth by SEQ ID NO: 305. In some embodiments, the anti-TLl A antibody comprises a heavy chain FR2 as set forth by SEQ ID NO: 313. In some embodiments, the anti-TLl A antibody comprises a heavy chain FR3 as set forth by SEQ ID NO: 306. In some embodiments, the anti-TLl A antibody comprises a heavy chain FR3 as set forth by SEQ ID NO: 307. In some embodiments, the anti-TLl A antibody comprises a heavy chain FR3 as set forth by SEQ ID NO: 314. In some embodiments, the anti-TLl A antibody comprises a heavy chain FR3 as set forth by SEQ ID NO: 315. In some embodiments, the anti-TLl A antibody comprises a heavy chain FR4 as set forth by SEQ ID NO: 308. In some embodiments, the anti-TLl A antibody comprises a light chain FR1 as set forth by SEQ ID NO: 309. In some embodiments, the anti-TLl A antibody comprises a light chain FR2 as set forth by SEQ ID NO: 310. In some embodiments, the anti-TLl A antibody comprises a light chain FR3 as set forth by SEQ ID NO: 311. In some embodiments, the anti-TLl A antibody comprises a light chain FR4 as set forth by SEQ ID NO: 312.

[0349] In some embodiments, the anti-TLl A antibody comprises a framework region of Table 9A.

[0350] Table 9A. Example framework sequences Exemplary Anti-TL1A Variable Regions In one aspect, provided herein is an anti-TL1A antibody comprising a heavy chain variable region comprising an amino acid sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOs: 101-169 or 420-427; and a light chain variable region that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOs: 201-220 or 430-437.

[0351] Further provided herein are first embodiments of an anti-TLl A antibody comprising a heavy chain variable region and a light chain variable region. Additional non-limiting embodiments include: (Embodiment 2) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 101 or a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 101. (Embodiment 3) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 102 or a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 102. (Embodiment 4) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 103 or a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 103. (Embodiment 5) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 104 or a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 104.(Embodiment 6) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 105, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 105. (Embodiment 7) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 106, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 106. (Embodiment 8) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 107, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 107. (Embodiment 9) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 108, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 108.(Embodiment 10) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 109, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 109. (Embodiment 11) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 110, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 110. (Embodiment 12) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 111, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 111. (Embodiment 13) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 112, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 112.(amendment 14) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 113, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 113. (amendment 15) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 114, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 114. (amendment 16) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 115, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 115. (amendment 17) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 116, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 116.(amendment 18) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 117, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 117. (amendment 19) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 118, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 118. (amendment 20) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 119, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 119. (amendment 21) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 120, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 120.(amendment 22) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 121, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 121. (amendment 23) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 122, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 122. (amendment 24) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 123, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 123. (amendment 25) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 124, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 124.(amendment 26) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 125, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 125. (amendment 27) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 126, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 126. (amendment 28) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 127, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 127. (amendment 29) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 128, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 128.(amendment 30) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 129, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 129. (amendment 31) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 130, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 130. (amendment 32) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 131, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 131. (amendment 33) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 132, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 132.(amendment 34) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 133, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 133. (amendment 35) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 134, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 134. (amendment 36) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 135, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 135. (amendment 37) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 136, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 136.(amendment 38) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 137, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 137. (amendment 39) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 138, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 138. (amendment 40) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 139, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 139. (amendment 41) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 140, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 140.(amendment 42) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 141, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 141. (amendment 43) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 142, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 142. (amendment 44) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 143, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 143. (amendment 45) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 144, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 144.(amendment 46) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 145, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 145. (amendment 47) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 146, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 146. (amendment 48) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 147, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 147. (amendment 49) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 148, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 148.(amendment 50) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 149, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 149. (amendment 51) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 150, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 150. (amendment 52) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 151, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 151. (amendment 53) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 152, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 152.(amendment 54) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 153, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 153. (amendment 55) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 154, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 154. (amendment 56) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 155, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 155. (amendment 57) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 156, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 156.(amendment 58) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 157, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 157. (amendment 59) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 158, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 158. (amendment 60) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 159, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 159. (amendment 61) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 160, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 160.(amendment 62) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 161, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 161. (amendment 63) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 162, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 162. (amendment 64) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 163, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 163. (amendment 65) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 164, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 164.(Embodiment 66) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 165, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 165. (Embodiment 67) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 166, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 166. (Embodiment 68) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 167, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 167. (Embodiment 69) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 168 or 169, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 168 or 169.(Embodiment 70) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 420, 421, or 422, or the heavy chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 420, 421, or 422.

[0352] (amendment 71) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 201. (amendment 72) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 202. (amendment 73) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 203, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 203. (amendment 74) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 204.(amendment 75) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 205. (amendment 76) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 206, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 206. (amendment 77) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 207, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 207. (amendment 78) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 208, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 208.(amendment 79) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 209, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 209. (amendment 80) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 210, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 210. (amendment 81) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 211, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 211. (amendment 82) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 212, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 212.(amendment 83) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 213, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 213. (amendment 84) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 214, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 214. (amendment 85) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 215, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 215. (amendment 86) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 216, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 216.(Embodiment 87) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 217, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 217. (Embodiment 88) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 218, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 218. (Embodiment 89) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 219 or 220, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 219 or 220. (Embodiment 90) The anti-TLl A antibody of any one of embodiments 1-70, wherein the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 430, 431, or 432, or the light chain variable region comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to SEQ ID NO: 430, 431, or 432.

[0353] (Embodiment 91) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 101, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 92) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 102, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment 93) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 103, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202.(Embodiment 94) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 104, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 95) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 105, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.

[0354] (Embodiment 96) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 103, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 97) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 106, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 98) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 107, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202.(Embodiment 99) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 108, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202. (Embodiment 100) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 109, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202.

[0355] (Embodiment 101) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 108, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 102) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 109, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 103) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 108, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 203.(Embodiment 104) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 108, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204. (Embodiment 105) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 107, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204.

[0356] (Embodiment 106) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 107, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202. (Embodiment 107) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 110, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204. (Embodiment 108) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 111, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.(Embodiment 109) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 112, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 110) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 113, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204.

[0357] (Embodiment 111) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 114, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 112) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 115, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202. (Embodiment 113) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 116, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.(Embodiment 114) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 117, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 115) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 118, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204.

[0358] (Embodiment 116) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 114, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204. (Embodiment 117) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 102, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204. (Embodiment 118) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 104, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204.(Embodiment 119) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 119, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204. (Embodiment 120) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 119, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.

[0359] (Embodiment 121) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 101, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204. (Embodiment 122) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 105, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204. (Embodiment 123) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 120, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 204.(Embodiment 124) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 121, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202. (Embodiment 125) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 122, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202.

[0360] (Embodiment 126) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 122, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 207. (Embodiment 127) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 123, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202. (Embodiment 128) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 124, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 202.(Embodiment 129) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 125, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment 130) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 116, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205.

[0361] (Embodiment 131) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 117, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment 132) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 126, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment 133) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 127, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205.(Embodiment 134) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 127, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 135) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 121, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.

[0362] (Embodiment 136) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 122, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment 137) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 122, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 138) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 122, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 206.(Embodiment 139) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 124, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment 140) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 124, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.

[0363] (Embodiment 141) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 128, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment 142) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 128, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 206. (Embodiment 143) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 129, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205.(Embodiment 144) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 130, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment 145) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 131, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205.

[0364] (Embodiment 146) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 132, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment 147) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 133, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment 148) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 134, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205.(Embodiment 149) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 135, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 205. (Embodiment 150) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 126, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 151) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 130, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201.(Embodiment 152) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 132, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 201. (Embodiment 153) The anti-TLl A antibody of embodiment 1, comprising A500. (Embodiment 154) The anti-TLl A antibody of embodiment 1, comprising A501. (Embodiment 155) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 420, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 430. (Embodiment 156) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 421, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 431.(Embodiment 157) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 422, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 432. (Embodiment 158) The anti-TLl A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 427, and the light chain variable region comprises a sequence that is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 437.

[0365] Exemplary Anti-TL1A Constant Regions In some embodiments, one or more amino acid modifications can be introduced into a crystallizable fragment (Fc) region of a human or humanized antibody, thereby generating an Fc region variant. An Fc region can comprise the C-terminal region of an immunoglobulin heavy chain, including hinge region, CH2 domain, CH3 domain, or any combination thereof. As used herein, an Fc region encompasses native sequence Fc regions and variant Fc regions. An Fc region variant can comprise a human Fc region sequence (e.g., a human IgGl, IgG2, IgG3, or IgG4 Fc region) comprising an amino acid modification (e.g., a substitution, addition, or deletion) at one or more amino acid positions. In exemplary embodiments, the Fc region comprises any one of SEQ ID NOs: 320-367. In some embodiments, the anti-TLl A antibody comprises a constant region comprising any one of SEQ ID NOs: 319, 368-381.

[0366] In some embodiments, the antibodies of the present disclosure have reduced effector function compared to human IgG. Effector function refers to biological events that result from the interaction of an antibody Fc region with Fc receptors or ligands. Non-limiting effector functions include Clq binding, complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), cytokine secretion, immune complex-mediated antigen uptake by antigen presenting cells, downregulation of cell surface receptors (e.g., B cell receptor), and B cell activation. In some cases, antibody-dependent cell-mediated cytotoxicity (ADCC) refers to a cell-mediated reaction in which nonspecific cytotoxic cells that express Fc receptors (e.g., Natural Killer cells, neutrophils, macrophages) recognize bound antibody on a target cell and subsequently cause target cell lysis. In some cases, complement-dependent cytotoxicity (CDC) refers to lysis of a target cell in the presence of complement, in which the complement action pathway is initiated by the binding of Clq to an antibody bound to a target.

[0367] Some Fc regions naturally lack effector function, and some Fc regions can comprise mutations that reduce effector function. For example, IgG4 has low ADCC and CDC activity, and IgG2 has low ADCC activity.

[0368] The present disclosure provides antibodies comprising an Fc region that exhibit at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70% or more reduction in ADCC compared to an antibody comprising a non-variant Fc region, i.e., an antibody having the same sequence identical but for substitutions to reduce ADCC (e.g., human IgGl, SEQ ID NO: 320). The present disclosure provides antibodies comprising an Fc region that exhibit at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70% or more reduction in CDC compared to an antibody comprising a non-variant Fc region, i.e., an antibody having the same sequence identical but for substitutions to reduce CDC (e.g., human IgGl, SEQ ID NO: 320). In certain embodiments, the antibodies of the present disclosure have reduced effector function compared to human IgGl. In certain embodiments, the antibodies herein do not have detectable ADCC activity. In certain embodiments, the reduction and / or attenuation of ADCC activity is attributable to the reduced affinity exhibited by the antibodies of the present disclosure for Fc ligands and / or receptors. In certain embodiments, the antibodies herein do not exhibit detectable CDC activity. In some embodiments, the reduction and / or attenuation of CDC activity is attributable to the reduced affinity exhibited by the antibodies of the present disclosure for Fc ligands and / or receptors. Measurement of effector function can be performed as described in Example 3.

[0369] In some embodiments, an antibody comprising an Fc region described herein exhibits reduced affinity for Clq relative to an unmodified antibody (e.g., human IgGl with SEQ ID NO: 320). In some embodiments, an antibody herein exhibits at least 2-fold, or at least 3-fold, or at least 5-fold, or at least 7-fold, or at least 10-fold, or at least 20-fold, or at least 30-fold, or at least 40-fold, or at least 50-fold, or at least 60-fold, or at least 70-fold, or at least 80-fold, or at least 90-fold, or at least 100-fold, or at least 200-fold lower affinity for Clq receptor than an unmodified antibody. In some embodiments, an antibody herein exhibits at least 90%, at least 80%, at least 70%, at least 60%, at least 50%, at least 40%, at least 30%, at least 20%, at least 10%, or at least 5% lower affinity for Clq than an unmodified antibody.

[0370] In some embodiments, antibodies of the present disclosure are variants that have some, but not all, effector functions, which make the antibodies desirable candidates for applications where the half-life of the antibody in vivo is important, but certain effector functions (such as complement and ADCC) are unnecessary or deleterious.

[0371] In vitro and / or in vivo cytotoxicity assays can be conducted to confirm reduction / depletion of CDC and / or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. Measurement of effector function can be performed as described in Example 3.

[0372] In some embodiments, the antibody is tested for binding to Fcy receptors and complement Clq by ELISA. In some embodiments, the antibody is tested for the ability to activate primary human immune cells in vitro, for example by assessing the ability of the antibody to induce expression of activation markers.

[0373] In some embodiments, assessment of ADCC activity of an anti-TLlA antibody includes adding the antibody to a combination of target cells and immune effector cells, which can be activated by the antigen-antibody complex to cause cytolysis of the target cells. Cytolysis can be detected by release of a label (e.g., a radioactive substrate, a fluorescent dye, or a native intracellular protein) from the lysed cells. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Particular examples of in vitro ADCC assays are described in Wisecarver et al., 1985 79:277-282; Bruggemann et al., 1987, J Exp Med 166:1351-1361; Wilkinson et al., 2001, J Immunol Methods 258:183-191; Patel et al., 1995 J Immunol Methods 184:29-38. Alternatively, or additionally, ADCC activity of an antibody of interest can be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al., 1998, PNAS USA 95:652-656.

[0374] In some embodiments, assessment of complement activation, i.e., a CDC assay, can be performed as described in Gazzano-Santoro et al., 1996, J Immunol Methods 202:163.

[0375] Non-limiting examples of Fc mutations in IgGl that can reduce ADCC and / or CDC include substitutions at one or more of the following positions in IgGl: 231, 232, 234, 235, 236, 237, 238, 239, 264, 265, 267, 269, 270, 297, 299, 318, 320, 322, 325, 327, 328, 329, 330, and 331, wherein the numbering system of the constant region is that of the EU index as set forth by Kabat. In certain embodiments, the antibodies of the present disclosure have reduced effector function compared to human IgGl.

[0376] In some embodiments, the antibody comprises an IgGl Fc region comprising one or more of the following substitutions according to the Kabat numbering system: N297A, N297Q, N297D, D265A, S228P, L235A, L237A, L234A, E233P, L234V, C236 deletion, P238A, A327Q, P329A, P329G, L235E, P331S, L234F, 235G, 235Q, 235R, 235S, 236F, 236R, 237E, 237K, 237N, 237R, 238A, 238E, 238G, 238H, 238I, 238V, 238W, 238Y, 248A, 254D, 254E, 254G, 254H, 254I, 254N, 254P, 254Q, 254T, 254V, 255N, 256H, 256K, 256R, 256V, 264S, 265H, 265K, 265S, 265Y, 267G, 267H, 267I, 267K, 268K, 269N, 269Q, 270A, 270G, 270M, 270N, 271T, 272N, 279F, 279K, 279L, 292E, 292F, 292G, 292I, 293S, 301W, 304E, 311E, 311G, 311S, 316F, 327T, 328V, 329Y, 330R, 339E, 339L, 343I, 343V, 373A, 373G, 373S, 376E, 376W, 376Y, 380D, 382D, 382P, 385P, 424H, 424M, 424V, 434I, 438G, 439E, 439H, 439Q, 440A, 440D, 440E, 440F, 440M, 440T, 440V.

[0377] In some embodiments, the antibody comprises an Fc region selected from the representative sequences disclosed in Table 3, Table 13, and Table 9B. In some embodiments, the antibody comprises an IgGl Fc region comprising E233P, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgG4 Fc region comprising S228P and L235E. In some embodiments, the antibody comprises an IgGl Fc region comprising L235E, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising L234A and L235A, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising L234A, L235A, and G237A, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising L234A, L235A, P329G, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising L234F, L235E, and P331S, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising L234A, L235E, and G237A, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising L234A, L235E, G237A, and P331S, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising L234A, L235A, G237A, P238S, H268A, A330S, and P331S (IgGl sigma), according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising L234A, L235A, and P329A, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising G236R and L328R, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising G237A, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising F241A, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising V264A, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising D265A, according to the Kabat numbering system.In some embodiments, the antibody comprises an IgGl Fc region comprising D265A and N297A, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising D265A and N297G, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising D270A, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising N297A, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising N297G, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising N297D, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising N297Q, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising P329A, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising P329G, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising P329R, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising A330L, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising P331A, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgGl Fc region comprising P331S, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgG2 Fc region. In some embodiments, the antibody comprises an IgG4 Fc region. In some embodiments, the antibody comprises an IgG4 Fc region comprising S228P, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgG4 Fc region comprising S228P, F234A, and L235A, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgG2-IgG4 cross subclass (IgG2 / G4) Fc region. In some embodiments, the antibody comprises an IgG2-IgG3 cross subclass Fc region. In some embodiments, the antibody comprises an IgG2 Fc region comprising H268Q, V309L, A330S, and P331S, according to the Kabat numbering system.In some embodiments, the antibody comprises an IgG2 Fc region comprising V234A, G237A, P238S, H268A, V309L, A330S, and P331S, according to the Kabat numbering system. In some embodiments, the antibody comprises an Fc region comprising high mannose glycosylation.

[0378] In some embodiments, the antibody comprises an IgG4 Fc region comprising a S228P substitution, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgG4 Fc region comprising a A330S substitution, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgG4 Fc region comprising a P331S substitution, according to the Kabat numbering system.

[0379] In some embodiments, the antibody comprises an IgG2 Fc region comprising a A330S substitution, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgG2 Fc region comprising a P331S substitution, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgG2 Fc region comprising a 234A substitution, according to the Kabat numbering system. In some embodiments, the antibody comprises an IgG2 Fc region comprising a 237A substitution, according to the Kabat numbering system.

[0380] In certain embodiments, the anti-TLl A described herein comprises an Fc region as shown in Table 13.

[0381] Table 13. Exemplary Fc mutations In certain embodiments, the anti-TLl A antibodies described herein comprise an Fc region comprising a sequence selected from Table 9B. In certain embodiments, the anti-TLl A antibodies described herein comprise an Fc region comprising any of SEQ ID NOs: 320-367 or a sequence at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of SEQ ID NOs: 320-367.

[0382] In some embodiments, the anti-TLl A described herein comprises a light chain constant region comprising SEQ ID NO: 319 or a sequence at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 319.

[0383] Additional Non-limiting Exemplary Anti-TL1A Antibody Embodiments CDR Embodiments In an aspect, provided herein are first embodiments of anti-TLl A antibodies. As used herein, anti-TLl A antibodies include anti-TLl A antigen binding fragments. Additional non-limiting embodiments include: (Embodiment 2) An anti-TLl A antibody of Embodiment 1, comprising: a heavy chain comprising: a HCDR1 comprising SEQ ID NO: 1, 401, 407, 413, or 450; a HCDR2 comprising SEQ ID NO: 2, 3, 4, 5, 402, 408, 414, or 451; and a HCDR3 comprising SEQ ID NO: 6, 7, 8, 9, 403, 409, 415, or 452; and a light chain comprising: a LCDR1 comprising SEQ ID NO: 10, 404, 410, 416, or 453; a LCDR2 comprising SEQ ID NO: 11, 405, 411, 417, or 454, and a LCDR3 comprising SEQ ID NO: 12, 13, 14, 15, 406, 412, 418, or 455. (Embodiment 3) An anti-TLl A antibody of Embodiment 1, comprising: a HCDR1 comprising SEQ ID NO: 1. (Embodiment 4) An anti-TLl A antibody of Embodiment 1 or Embodiment 2, comprising a HCDR2 comprising SEQ ID NO: 2. (Embodiment 5) An anti-TLl A antibody of Embodiment 1 or Embodiment 2, comprising a HCDR2 comprising SEQ ID NO: 3. (Embodiment 6) An anti-TLl A antibody of Embodiment 1 or Embodiment 2, comprising a HCDR2 comprising SEQ ID NO: 4. (Embodiment 7) An anti-TLl A antibody of Embodiment 1 or Embodiment 2, comprising a HCDR2 comprising SEQ ID NO: 5. (Embodiment 8) An anti-TLl A antibody of any one of Embodiments 1-6, comprising: a HCDR3 comprising SEQ ID NO: 6. (Embodiment 9) An anti-TLl A antibody of any one of Embodiments 1-6, comprising: a HCDR3 comprising SEQ ID NO: 7. (Embodiment 10) An anti-TLl A antibody of any one of Embodiments 1-6, comprising: a HCDR3 comprising SEQ ID NO: 8. (Embodiment 11) An anti-TLl A antibody of any one of Embodiments 1-6, comprising: a HCDR3 comprising SEQ ID NO: 9.(Embodiment 12) The anti-TLl A antibody of any one of embodiments 1-10, comprising a LCDR1 comprising SEQ ID NO: 10. (Embodiment 13) The anti-TLl A antibody of any one of embodiments 1-11, comprising a LCDR2 comprising SEQ ID NO: 11. (Embodiment 14) The anti-TLl A antibody of any one of embodiments 1-12, comprising a LCDR3 comprising SEQ ID NO: 12. (Embodiment 15) The anti-TLl A antibody of any one of embodiments 1-12, comprising: a LCDR3 comprising SEQ ID NO: 13. (Embodiment 16) The anti-TLl A antibody of any one of embodiments 1-12, comprising a LCDR3 comprising SEQ ID NO: 14 or 15. (Embodiment 17) The anti-TLl A antibody of embodiment 1, comprising the CDRs of antibody A, B, C, D, E, F, G, H, I, A2, B2, C2, D2, E2, F2, G2, H2, I2, J, K, M, or N (Table 10). (Embodiment 18) The anti-TLl A antibody of embodiment 1, comprising a heavy chain variable region comprising: (a) a HCDR1 comprising the amino acid sequence set forth by SEQ ID NO: 1; (b) a HCDR2 comprising the amino acid sequence set forth by any one of SEQ ID NO: 2-5; and (c) a HCDR3 comprising the amino acid sequence set forth by any one of SEQ ID NO: 6-9; and a light chain variable region comprising: (d) a LCDR1 comprising the amino acid sequence set forth by SEQ ID NO: 10; (e) a LCDR2 comprising the amino acid sequence set forth by SEQ ID NO: 11; and (f) a LCDR3 comprising the amino acid sequence set forth by any one of SEQ ID NO: 12-15. (Embodiment 19) The anti-TLl A antibody of embodiment 1, comprising: a HCDR1 as set forth by SEQ ID NO: 1; a HCDR2 as set forth by SEQ ID NO: 2; a HCDR3 as set forth by SEQ ID NO: 6; a LCDR1 as set forth by SEQ ID NO: 10; a LCDR2 as set forth by SEQ ID NO: 11; and a LCDR3 as set forth by SEQ ID NO: 12. Framework Embodiments (Embodiment 20) The anti-TLl A antibody of any one of embodiments 1-19, comprising a heavy chain framework comprising IGHV1-46 02.(Embodiment 21) The anti-TLl A antibody of any one of embodiments 1-19, comprising a heavy chain framework comprising IGHV1-46 02, comprising about 1 to about 20 amino acid substitutions from SEQ ID NO: 316. (Embodiment 22) The anti-TLl A antibody of any one of embodiments 1-19, comprising a heavy chain framework comprising IGHV1-46 02, comprising about 1 to about 9 amino acid substitutions from SEQ ID NO: 316. (Embodiment 23) The anti-TLl A antibody of any one of embodiments 1-19, comprising a heavy chain framework comprising IGHV1-46 a variant of SEQ ID NO: 316 in the framework comprising about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions.(Embodiment 24) The anti-TLl A antibody of any one of embodiments 21-23, wherein the heavy chain framework substitution comprises Q1E, as determined by Aho or Kabat numbering.(Embodiment 25) The anti-TLl A antibody of any one of embodiments 21-24, wherein the heavy chain framework substitution comprises R45K, as determined by Aho or Kabat numbering.(Embodiment 26) The anti-TLl A antibody of any one of embodiments 21-25, wherein the heavy chain framework substitution comprises A47R, as determined by Aho or Kabat numbering.(Embodiment 27) The anti-TLl A antibody of any one of embodiments 21-26, wherein the heavy chain framework substitution comprises M55I, as determined by Aho or Kabat numbering.(Embodiment 28) The anti-TLl A antibody of any one of embodiments 21-27, wherein the heavy chain framework substitution comprises V78A, as determined by Aho or Kabat numbering.(Embodiment 29) The anti-TLl A antibody of any one of embodiments 21-28, wherein the heavy chain framework substitution comprises M80I, as determined by Aho or Kabat numbering.(Embodiment 30) The anti-TLl A antibody of any one of embodiments 21-29, wherein the heavy chain framework substitution comprises R82T, as determined by Aho or Kabat numbering.(Embodiment 31) The anti-TLl A antibody of any one of embodiments 21-30, wherein the heavy chain framework substitution comprises V89A, as determined by Aho or Kabat numbering.(Embodiment 32) The anti-TLl A antibody of any one of embodiments 21-31, wherein the heavy chain framework substitution comprises M91L, as determined by Aho or Kabat numbering.

[0384] (Embodiment 33) The anti-TLl A antibody of any one of embodiments 1-19, comprising a heavy chain framework comprising SEQ ID NO: 301. (Embodiment 34) The anti-TLl A antibody of embodiment 33, wherein X1 is Q. (Embodiment 35) The anti-TLl A of embodiment 33, wherein X1 = E. (Embodiment 36) The anti-TLl A of any one of embodiments 33-35, wherein X2 = R. (Embodiment 37) The anti-TLl A of any one of embodiments 33-35, wherein X2 = K. (Embodiment 38) The anti-TLl A of any one of embodiments 33-37, wherein X3 = A. (Embodiment 39) The anti-TLl A of any one of embodiments 33-37, wherein X3 = R. (Embodiment 40) The anti-TLl A of any one of embodiments 33-39, wherein X4 = M. (Embodiment 41) The anti-TLl A of any one of embodiments 33-39, wherein X4 = I. (Embodiment 42) The anti-TLl A of any one of embodiments 33-41, wherein X5 = V. (Embodiment 43) The anti-TLl A of any one of embodiments 33-41, wherein X5 = A. (Embodiment 44) The anti-TLl A of any one of embodiments 33-43, wherein X6 = M. (Embodiment 45) The anti-TLl A of any one of embodiments 33-43, wherein X6 = I. (Embodiment 46) The anti-TLl A of any one of embodiments 33-45, wherein X7 = R. (Embodiment 47) The anti-TLl A of any one of embodiments 33-45, wherein X7 = T. (Embodiment 48) The anti-TLl A of any one of embodiments 33-47, wherein X8 = V. (Embodiment 49) The anti-TLl A of any one of embodiments 33-47, wherein X8 = A. (Embodiment 50) The anti-TLl A of any one of embodiments 33-49, wherein X9 = M. (Embodiment 51) The anti-TLl A of any one of embodiments 33-49, wherein X9 = L.

[0385] (Embodiment 52) The anti-TLl A antibody of any one of embodiments 1-51, comprising a light chain framework comprising IGKV3-20 01.(Embodiment 53) The anti-TLl A antibody of any one of embodiments 1-51, comprising a light chain framework comprising IGKV3-20 a variant of SEQ ID NO: 317 comprising about 1 to about 20 amino acid substitutions. (Embodiment 54) The anti-TLlA antibody of any one of embodiments 1-51, comprising a light chain framework comprising IGKV3-20 a variant of SEQ ID NO: 317 comprising about 1 amino acid substitution. (Embodiment 55) The anti-TLlA antibody of any one of embodiments 1-51, comprising a light chain framework comprising IGKV3-20 a variant of SEQ ID NO: 317 comprising about 2 amino acid substitutions. (Embodiment 56) The anti-TLlA antibody of any one of embodiments 1-51, comprising a light chain framework comprising IGKV3-20 a variant of SEQ ID NO: 317 comprising about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions in the framework. (Embodiment 57) The anti-TLlA antibody of any one of embodiments 53-56, wherein the light chain framework substitutions comprise Q1E, as determined by Aho or Kabat numbering. (Embodiment 58) The anti-TLlA antibody of any one of embodiments 53-57, wherein the light chain framework substitutions comprise R45K, as determined by Aho or Kabat numbering.

[0386] (Embodiment 59) The anti-TLlA antibody of any one of embodiments 1-51, comprising a light chain comprising a light chain framework comprising SEQ ID NO: 303. (Embodiment 60) The anti-TLlA antibody of embodiment 59, wherein X10 is L. (Embodiment 61) The anti-TLlA antibody of embodiment 59, wherein X10 is P. (Embodiment 62) The anti-TLlA antibody of any one of embodiments 59-61, wherein X11 is L. (Embodiment 63) The anti-TLlA antibody of any one of embodiments 59-61, wherein X11 is W.

[0387] (Embodiment 64) The anti-TLlA antibody of any one of embodiments 1-19, comprising: a heavy chain variable framework region comprising a modified human IGHV1-46 02 framework; and a light chain variable framework region comprising a human IGKV3-20 framework or a modified human IGKV3-20 framework, wherein the modified human IGHV1-46 02The heavy chain variable framework region and the light chain variable framework region collectively comprise at least one amino acid modification compared to the human IGKV3-20 framework. (Embodiment 65) The antibody of Embodiment 64, wherein the at least one amino acid modification is no more than about 13, 12, 11, 10, 9, or 8 amino acid modifications. (Embodiment 66) The antibody of Embodiment 64 or Embodiment 65, wherein the amino acid modification comprises a modification at amino acid position 45 in the heavy chain variable region. (Embodiment 67) The antibody of any one of Embodiments 64-66, wherein the amino acid modification comprises a modification at amino acid position 47 in the heavy chain variable region. (Embodiment 68) The antibody of any one of Embodiments 64-67, wherein the amino acid modification comprises a modification at amino acid position 55 in the heavy chain variable region. (Embodiment 69) The antibody of any one of Embodiments 64-68, wherein the amino acid modification comprises a modification at amino acid position 78 in the heavy chain variable region. (Embodiment 70) The antibody of any one of Embodiments 64-69, wherein the amino acid modification comprises a modification at amino acid position 80 in the heavy chain variable region. (Embodiment 71) The antibody of any one of Embodiments 64-70, wherein the amino acid modification comprises a modification at amino acid position 82 in the heavy chain variable region. (Embodiment 72) The antibody of any one of Embodiments 64-71, wherein the amino acid modification comprises a modification at amino acid position 89 in the heavy chain variable region. (Embodiment 73) The antibody of any one of Embodiments 64-72, wherein the amino acid modification comprises a modification at amino acid position 91 in the heavy chain variable region, according to Aho or Kabat numbering. (Embodiment 74) The antibody of any one of Embodiments 64-65, wherein the amino acid modification comprises: (a) R45K, (b) A47R, (c) M55I, (d) V78A, (e) M80I, (f) R82T, (g) V89A, or (h) M91L in the heavy chain variable region, according to Aho or Kabat numbering; or a combination of two or more modifications selected from (a) to (h). (Embodiment 75) The antibody of Embodiment 74, wherein the amino acid modification comprises: A47R. (Embodiment 76) The antibody of Embodiment 74, wherein the amino acid modification comprises: A47R, M55I, V78A, M80I, R82T, V89A, and M91L; A47R, M80I, and R82T; A47R, M80I, R82T, V89A, and M91L; or A47R, M55I, V78A, M80I, V89A, and M91L. (Embodiment 77) The antibody of Embodiment 74, wherein the amino acid modification comprises: R45K and A47R.(Embodiment 78) The antibody of embodiment 74, wherein the amino acid modifications comprise: R45K, A47R, V89A, and M91L. (Embodiment 79) The antibody of embodiment 74, wherein the amino acid modifications comprise: R45K and A47R and M80I. (Embodiment 80) The antibody of embodiment 74, wherein the amino acid modifications comprise: R45K, A47R, M80I, and M91L; R45K, A47R, V78A, M80I, V89A, and M91L; R45K, A47R, M55I, V78A, M80I, R82T, V89A, and M91L; R45K, A47R, M80I, V89A, and M91L; R45K, A47R, M55I, M80I, R82T, V89A, and M91L; R45K, A47R, M80I, and V89A; R45K, A47R, M80I, R82T, V89A, M91L; or R45K, A47R, M55I, M80I, V89A, and M91L. (Embodiment 81) The antibody of embodiment 74, wherein the amino acid modifications comprise: R45K. (Embodiment 82) The antibody of embodiment 74, wherein the amino acid modifications comprise: R45K and V78A. (Embodiment 83) The antibody of embodiment 74, wherein the amino acid modifications comprise: V78A. (Embodiment 84) The antibody of embodiment 74, wherein the amino acid modifications comprise: V78A and V89A; V78A and M80I; or V78A, M80I, and R82T. (Embodiment 85) The antibody of embodiment 74, wherein the amino acid mod...

Claims

1. A method of treating inflammation in a subject in need thereof, comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TLl A antibody or antigen-binding fragment).

2. The method of claim 1, wherein the subject has inflammation of the skin.

3. A method of treating fibrosis in a subject in need thereof, comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TLl A antibody or antigen-binding fragment).

4. The method of claim 3, wherein the subject has fibrosis of the skin.

5. A method of treating a disease and / or condition in the skin in a subject in need thereof, comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TLl A antibody or antigen-binding fragment).

6. The method of any one of claims 1-5, wherein the subject has a chronic skin disorder.

7. The method of any one of claims 1-6, wherein the subject has systemic sclerosis.

8. The method of any one of claims 1-6, wherein the subject has psoriasis.

9. The method of any one of claims 1-6, wherein the subject has lupus.

10. The method of any one of claims 1-6, wherein the subject has eczema.

11. The method of any one of claims 1-6, wherein the subject has dermatomyositis.

12. The method of any one of claims 1-6, wherein the subject has systemic sclerosis or scleroderma, psoriasis, lupus, dermatomyositis, eczema, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, or a combination thereof.

13. The method of any one of claims 1-6, wherein the subject has hidradenitis suppurativa.

14. The method of any one of claims 1-6, wherein the subject has atopic dermatitis.

15. The method of any one of claims 1-6, wherein the subject has vitiligo.

16. The method of any one of claims 1-6, wherein the subject has alopecia areata.

17. The method of any one of claims 1-2 and 6, wherein the inflammation of the skin is hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, or alopecia areata.

18. The method of any one of claims 3-4 and 6, wherein the fibrosis of the skin is hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, or alopecia areata.

19. The method of any one of claims 5-6, wherein the disease and / or condition in the skin is hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, or alopecia areata.

20. A method of treating hidradenitis suppurativa in a subject in need thereof, comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TLl A antibody or antigen-binding fragment).

21. A method of treating atopic dermatitis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TL1A antibody or antigen-binding fragment).

22. A method of treating psoriasis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TL1A antibody or antigen-binding fragment).

23. A method of treating vitiligo in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TL1A antibody or antigen-binding fragment).

24. A method of treating alopecia areata in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TL1A antibody or antigen-binding fragment).

25. The method of any one of claims 1-24, wherein the anti-TL1A antibody or antigen-binding fragment is administered in a pharmaceutical composition.

26. The method of claim 26, wherein the pharmaceutical composition comprises the anti-TL1A antibody or antigen-binding fragment at a concentration greater than about 150 mg / mL.

27. The method of claim 26, wherein the concentration is greater than about 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, or 250 mg / mL.

28. The method of claim 26, wherein the concentration is about 150 mg / mL to about 250 mg / mL.

29. The method of claim 26, wherein the concentration is about 175 mg / mL to about 225 mg / mL.

30. The method of any one of claims 25-29, wherein the pharmaceutical composition is administered subcutaneously.

31. The method of any one of claims 25-30, wherein about 150 mg to about 500 mg of the anti-TL1A antibody or antigen-binding fragment is present in the composition.

32. The method of any one of claims 25-31, wherein the total volume of the composition is less than or equal to about 2 mL.

33. The method of any one of claims 25-32, wherein the pharmaceutical composition comprises a therapeutically effective dose of the anti-TL1A antibody or antigen-binding fragment.

34. The method of any one of claims 25-33, wherein the total volume of the composition is less than or equal to about 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, or 0.8 mL.

35. The method of any one of claims 25-34, wherein the total volume of the composition is about 0.5 mL to about 1.5 mL.

36. The method of any one of claims 25-35, wherein the composition has a viscosity of less than about 20 cP.

37. The method of claim 36, wherein the composition has a viscosity of less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 cP.

38. The method of any one of claims 25-37, wherein the composition has a viscosity of about 1 cP to about 20 cP.

39. The method of any one of claims 25-38, wherein the percentage of aggregation of the anti-TLl A antibody or antigen-binding fragment in the pharmaceutical composition, as measured by size exclusion chromatography, is less than about 5% of the total anti-TLl A antibody or antigen-binding fragment in the composition.

40. The method of claim 39, wherein the aggregation is less than about 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5%.

41. The method of any one of claims 25-39, wherein the composition comprises a surfactant.

42. The method of claim 41, wherein the surfactant comprises a non-ionic surfactant.

43. The method of claim 42, wherein the non-ionic surfactant comprises polysorbate-20.

44. The method of any one of claims 41-43, wherein the surfactant is present at a concentration of about 0.005% to about 0.05% of the composition.

45. The method of claim 44, wherein the surfactant is present at a concentration of about 0.01% to about 0.02% of the composition.

46. The method of any one of claims 25-45, wherein the composition comprises a salt.

47. The method of claim 46, wherein the salt comprises sodium chloride, glycine, lysine-hydrochloride, arginine-hydrochloride, arginine glutamate, potassium chloride, magnesium chloride, or calcium chloride, or a combination thereof.

48. The method of claim 47, wherein the salt comprises sodium chloride.

49. The method of claim 47, wherein the salt comprises lysine-HCl.

50. The method of any one of claims 46-49, wherein the salt is present in the composition at a concentration of about 10 mM to about 100 mM.

51. The method of claim 50, wherein the salt is present in the composition at a concentration of about 25 mM.

52. The method of claim 50, wherein the salt is present in the composition at a concentration of about 40 mM.

53. The method of any one of claims 25-52, wherein the composition comprises a stabilizer.

54. The method of claim 53, wherein the stabilizer comprises a sugar, a polyol, an amino acid or a polymer, a cyclodextrin (e.g., HP-b-CD), or a combination thereof.

55. The method of claim 54, wherein the stabilizer comprises the sugar.

56. The method of claim 55, wherein the sugar comprises sucrose, glucose, trehalose, maltose, or lactose, or a combination thereof.

57. The method of claim 56, wherein the sugar comprises sucrose.

58. The method of any one of claims 53-57, wherein the stabilizer is present in the composition at a concentration of about 50 mM to about 300 mM.

59. The method of claim 58, wherein the stabilizer is present at a concentration of about 200 mM to about 280 mM.

60. The method of claim 59, wherein the stabilizer is present at a concentration of about 220 to about 240 mM.

61. The method of any one of claims 25-60, wherein the composition comprises a buffering agent.

62. The method of claim 61, wherein the buffering agent comprises acetate, phosphate, citrate, glutamate, succinate, gluconate, histidine, bicine, citric acid, Tris (tris(hydroxymethyl)aminomethane), or diethanolamine, or a combination thereof.

63. The method of claim 62, wherein the buffering agent comprises an acetate buffer.

64. The method of any one of claims 61-63, wherein the buffering agent is present in the composition at a concentration of about 10 mM to about 50 mM.

65. The method of claim 64, wherein the composition comprises about 20 mM of the buffering agent.

66. The method of any one of claims 25-65, wherein the composition has a pH of about 4.5 to about 8.

0.

67. The method of claim 66, wherein the composition has a pH of about 4.5 to about 7.

5.

68. The method of claim 67, wherein the composition has a pH of about 5 to about 5.

5.

69. The method of claim 68, wherein the composition has a pH of about 5.

3.

70. The method of any one of claims 1-69, wherein the anti-TLl A antibody or antigen binding fragment is administered to the subject at a first dose of up to about 1000 mg.

71. The method of any one of claims 1-69, wherein the anti-TLl A antibody or antigen binding fragment is administered to the subject at a first dose of about 150 mg to about 1000 mg.

72. The method of claim 71, wherein the first dose is about 500 mg to about 1000 mg.

73. The method of claim 72, wherein the first dose is about 500 mg or about 800 mg.

74. The method of any one of claims 70-73, wherein the first dose is administered to the subject at a first time point and a second dose is administered to the subject at a second time point.

75. The method of claim 74, wherein the second time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the first time point.

76. The method of claim 74, wherein the second time point is about 1, 2, 3, or 4 weeks after the first time point.

77. The method of any one of claims 74-76, wherein the second dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen-binding fragment.

78. The method of any one of claims 74-76, wherein the second dose comprises about 150 mg to about 1000 mg.

79. The method of claim 78, wherein the second dose comprises about 150 mg to about 600 mg.

80. The method of any one of claims 74-79, wherein a third dose of the anti-TLl A antibody or antigen-binding fragment is administered to the subject at a third time point.

81. The method of claim 80, wherein the third time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the second time point.

82. The method of claim 80, wherein the third time point is about 1, 2, 3, or 4 weeks after the second time point.

83. The method of any one of claims 80-82, wherein the third dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen-binding fragment.

84. The method of any one of claims 80-82, wherein the third dose comprises about 150 mg to about 1000 mg.

85. The method of claim 84, wherein the third dose comprises about 150 mg to about 600 mg.

86. The method of any one of claims 80-85, wherein a fourth dose of the anti-TLl A antibody or antigen-binding fragment is administered to the subject at a fourth time point.

87. The method of claim 86, wherein the fourth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the third time point.

88. The method of claim 86, wherein the fourth time point is about 1, 2, 3, or 4 weeks after the third time point.

89. The method of any one of claims 86-88, wherein the fourth dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen-binding fragment.

90. The method of any of claims 86-88, wherein the fourth dose comprises about 150 mg to about 1000 mg.

91. The method of claim 90, wherein the fourth dose comprises about 150 mg to about 600 mg.

92. The method of any of claims 86-91, wherein a fifth dose of the anti-TLl A antibody or antigen-binding fragment is administered to the subject at a fifth time point.

93. The method of claim 92, wherein the fifth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the fourth time point.

94. The method of claim 92, wherein the fifth time point is about 1, 2, 3, or 4 weeks after the fourth time point.

95. The method of any of claims 92-94, wherein the fifth dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen-binding fragment.

96. The method of any of claims 92-94, wherein the fifth dose comprises about 150 mg to about 1000 mg.

97. The method of claim 96, wherein the fifth dose comprises about 150 mg to about 600 mg.

98. The method of any of claims 92-97, wherein a sixth dose of the anti-TLl A antibody or antigen-binding fragment is administered to the subject at a sixth time point.

99. The method of claim 98, wherein the sixth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the fifth time point.

100. The method of claim 98, wherein the sixth time point is about 1, 2, 3, or 4 weeks after the fifth time point.

101. The method of any of claims 98-100, wherein the sixth dose comprises up to about 1000 mg of the anti-TLl A antibody or antigen-binding fragment.

102. The method of any of claims 98-100, wherein the sixth dose comprises about 150 mg to about 1000 mg.

103. The method of claim 102, wherein the sixth dose comprises about 150 mg to about 600 mg.

104. The method of any of claims 70-103, wherein an additional dose of the anti-TLl A antibody or antigen-binding fragment is administered to the subject at each of one or more additional time points.

105. The method of claim 104, wherein the one or more additional time points comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 additional time points.

106. The method of claim 104, wherein the composition is administered to the subject at about 12 additional time points.

107. The method of any one of claims 104-106, wherein each additional time point is independently about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the preceding time point.

108. The method of any one of claims 104-106, wherein each additional time point is independently about 1, 2, 3, or 4 weeks after the preceding time point.

109. The method of claim 108, wherein at least one of the additional time points is about 2 weeks after the preceding time point.

110. The method of any one of claims 104-109, wherein the additional dose comprises up to about 1000 mg of the anti-TLlA antibody or antigen-binding fragment.

111. The method of any one of claims 104-109, wherein the additional dose comprises about 150 mg to about 1000 mg of the anti-TLlA antibody or antigen-binding fragment.

112. The method of claim 111, wherein the additional dose is about 175 mg to about 300 mg of the anti-TLlA antibody or antigen-binding fragment.

113. A method of neutralizing monomeric TLlA and trimeric TLlA in a subject having skin inflammation and / or skin fibrosis, the method comprising (a) administering to the subject an effective dose of an anti-TLlA antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment binds to both monomeric TLlA and trimeric TLlA, wherein the antibody or antigen-binding fragment blocks the interaction of TLlA with DR3, wherein the concentration of TLlA in a diseased tissue in the subject is reduced below the concentration of TLlA in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, and wherein a diseased tissue comprises any one or more selected from the group consisting of epidermis, dermis, subcutaneous tissue, cutaneous connective tissue, skin fibrotic tissue, other tissue having skin inflammation and / or skin fibrosis, and other tissue having a pathogenesis of the skin inflammation and / or skin fibrosis.

114. The method of claim 113, wherein the subject has one or more inflammatory conditions selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, alopecia areata, chronic skin disorder, systemic sclerosis, lupus, eczema, and dermatomyositis.

115. The method of claim 113 or 114, wherein the subject has hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, alopecia areata, systemic sclerosis, lupus, dermatomyositis, eczema, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, or a combination thereof.

116. A method of reducing the concentration of TL1A in a diseased tissue in a subject having skin inflammation and / or skin fibrosis, the method comprising (a) administering to the subject an effective dose of an anti-TL1A antibody or antigen binding fragment, such that the concentration of TL1A in the diseased tissue in the subject is reduced below the concentration of TL1A in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, wherein a diseased tissue comprises any one or more selected from the group consisting of epidermis, dermis, subcutaneous tissue, skin connective tissue, skin fibrotic tissue, other tissue having skin inflammation and / or skin fibrosis, and other tissue having a pathogenesis of the skin inflammation and / or skin fibrosis.

117. A method of treating skin inflammation and / or skin fibrosis in a subject in need thereof, the method comprising (a) administering to the subject an anti-TL1A antibody or antigen binding fragment, wherein the anti-TL1A antibody or antigen binding fragment is administered in an effective dose such that after step (a), the concentration of TL1A in a diseased tissue in the subject is below the concentration of TL1A in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, and wherein a diseased tissue comprises any one or more selected from the group consisting of epidermis, dermis, subcutaneous tissue, skin connective tissue, skin fibrotic tissue, other tissue having skin inflammation and / or skin fibrosis, and other tissue having a pathogenesis of the skin inflammation and / or skin fibrosis.

118. A method of treating skin inflammation and / or skin fibrosis in a subject in need thereof, the method comprising: (a) administering to the subject an anti-TL1A antibody or antigen binding fragment in an effective dose, and (b) reducing the concentration of TL1A in a diseased tissue in the subject below the concentration of TL1A in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, wherein a diseased tissue comprises any one or more selected from the group consisting of epidermis, dermis, subcutaneous tissue, skin connective tissue, skin fibrotic tissue, other tissue having skin inflammation and / or skin fibrosis, and other tissue having a pathogenesis of the skin inflammation and / or skin fibrosis.

119. The method of any one of claims 113 to 118, wherein the effective dose comprises an induction regimen.

120. The method of any one of claims 113 to 119, further comprising: (c) maintaining the concentration of TL1A in the diseased tissue in the subject below the concentration of TL1A in the corresponding tissue in the control subject.

121. The method of claim 120, wherein the TL1A in the diseased tissue in the subject is maintained with a maintenance regimen of the anti-TL1A antibody or antigen binding fragment.

122. The method of claim 121, wherein the induction regimen and the maintenance regimen are the same.

123. The method of claim 121, wherein the induction regimen and the maintenance regimen are different.

124. The method of any one of claims 121 to 123, wherein the maintenance regimen is administered after the induction regimen.

125. The method of any one of claims 114 to 124, wherein the diseased tissue in the subject produces TL1A that is at most 50, 60, 70, 80, 90, 100-fold or more of the TL1A produced by the corresponding tissue in the control subject during the induction regimen.

126. The method of any one of claims 114 to 124, wherein the diseased tissue in the subject produces TL1A that is at most 50, 60, 70, 80, 90, 100-fold or more of the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen.

127. The method of any one of claims 114 to 124, wherein the diseased tissue in the subject produces TL1A that is at most 50, 60, 70, 80, 90, 100-fold or more of the TL1A produced by the corresponding tissue in the control subject.

128. The method of any one of claims 119 to 127, wherein the induction regimen comprises one administration of the anti-TL1A antibody or antigen binding fragment.

129. The method of claim 128, wherein the anti-TL1A antibody or antigen binding fragment is administered at 200 mg / dose, 250 mg / dose, 300 mg / dose, 350 mg / dose, 400 mg / dose, 450 mg / dose, 500 mg / dose, 550 mg / dose, 600 mg / dose, 650 mg / dose, 700 mg / dose, 750 mg / dose, 800 mg / dose, 850 mg / dose, 900 mg / dose, 950 mg / dose, 1000 mg / dose, 1100 mg / dose, 1200 mg / dose, 1250 mg / dose, 1300 mg / dose, 1400 mg / dose, 1500 mg / dose, 1600 mg / dose, 1700 mg / dose, 1750 mg / dose, 1800 mg / dose, 1900 mg / dose, or 2000 mg / dose.

130. The method of any one of claims 119 to 127, wherein the induction regimen comprises multiple administrations of the anti-TL1A antibody or antigen binding fragment.

131. The method of any of claims 119 to 127 and 130, wherein the induction regimen comprises: (i) administration of 1000 mg / dose at Week 0, 1000 mg / dose at Week 2, 1000 mg / dose at Week 6, and 1000 mg / dose at Week 10; (ii) administration of 500 mg / dose at Week 0, 500 mg / dose at Week 2, 500 mg / dose at Week 6, and 500 mg / dose at Week 10; (iii) administration of 1000 mg / dose at Week 0, 1000 mg / dose at Week 2, 1000 mg / dose at Week 6, and 500 mg / dose at Week 10; (iv) administration of 1000 mg / dose at Week 0, 1000 mg / dose at Week 2, 500 mg / dose at Week 6, and 500 mg / dose at Week 10; or (v) administration of 1000 mg / dose at Week 0, 500 mg / dose at Week 2, 500 mg / dose at Week 6, and 500 mg / dose at Week 10.

132. The method of any of claims 119 to 127 and 130, wherein the induction regimen comprises administration of 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, or 200 mg / dose.

133. The method of any of claims 119 to 127, 130, and 132, wherein the induction regimen comprises administration once every 2, 4, 6, or 8 weeks.

134. The method of any of claims 119 to 127, 130, and 132, wherein the induction regimen comprises administration once every 2 or 4 weeks for the first 2 administrations, and then administration once every 2, 4, 6, or 8 weeks for the remaining induction regimen.

135. The method of any of claims 120 to 134, wherein the diseased tissue in the subject produces TL1A that is up to 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more than the TL1A produced by the corresponding tissue in the control subject.

136. The method of any of claims 120 to 131, wherein during the maintenance regimen, the diseased tissue in the subject produces TL1A that is up to 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more than the TL1A produced by the corresponding tissue in the control subject.

137. The method of any of claims 120 to 131, wherein the diseased tissue in the subject produces, at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks or more after initiation of the maintenance regimen, up to 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more of the TL1A produced by the corresponding tissue in the control subject.

138. The method of any of claims 121 to 137, wherein the maintenance regimen comprises multiple administrations of the anti-TL1A antibody or antigen-binding fragment.

139. The method of any of claims 121 to 138, wherein the maintenance regimen comprises administering the anti-TL1A antibody or antigen-binding fragment at: (i) 500 mg / dose every 2 weeks, (ii) 400 mg / dose every 2 weeks, (iii) 300 mg / dose every 2 weeks, (iv) 250 mg / dose every 2 weeks, (v) 200 mg / dose every 2 weeks, (vi) 150 mg / dose every 2 weeks, (vii) 100 mg / dose every 2 weeks, (viii) 50 mg / dose every 2 weeks, (ix) 500 mg / dose every 4 weeks, (x) 400 mg / dose every 4 weeks, (xi) 300 mg / dose every 4 weeks, (xii) 250 mg / dose every 4 weeks, (xiii) 200 mg / dose every 4 weeks, (xiv) 150 mg / dose every 4 weeks, (xv) 100 mg / dose every 4 weeks, (xvi) 50 mg / dose every 4 weeks, (xvii) 500 mg / dose every 6 weeks, (xviii) 400 mg / dose every 6 weeks, (xix) 300 mg / dose every 6 weeks, (xx) 250 mg / dose every 6 weeks, (xxi) 200 mg / dose every 6 weeks, (xxii) 150 mg / dose every 6 weeks, (xxiii) 100 mg / dose every 6 weeks, (xxiv) 50 mg / dose every 6 weeks, (xxv) 500 mg / dose every 8 weeks, (xxvi) 400 mg / dose every 8 weeks, (xxvii) 300 mg / dose every 8 weeks, (xxviii) 250 mg / dose every 8 weeks, (xxix) 200 mg / dose every 8 weeks, (xxx) 150 mg / dose every 8 weeks, (xxxi) 100 mg / dose every 8 weeks, or (xxxii) 50 mg / dose every 8 weeks. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 140. The method of any one of claims 121 to 138, wherein the maintenance regimen comprises administration of the anti-TLl A antibody or antigen-binding fragment at 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 mg / dose.

141. The method of any one of claims 121 to 138 and 140, wherein the maintenance regimen comprises administration of the anti-TLl A antibody or antigen-binding fragment once every 2, 4, 6, 8, 10, or 12 weeks.

142. The method of any one of claims 121 to 141, wherein the maintenance regimen comprises administration of the anti-TLl A antibody or antigen-binding fragment at 250 mg / dose every 4 weeks.

143. The method of any one of claims 121 to 141, wherein the maintenance regimen comprises administration of the anti-TLl A antibody or antigen-binding fragment at 100 mg / dose every 4 weeks.

144. The method of any one of claims 121 to 143, wherein the maintenance regimen is for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, or 52 weeks.

145. The method of any one of claims 116 to 144, wherein the antibody or antigen-binding fragment binds to both monomeric TLl A and trimeric TLl A, and wherein the antibody or antigen-binding fragment blocks the binding of TLl A to DR3.

146. The method of any one of claims 113 to 145, wherein at least 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the monomeric TLl A in the blood of the subject is occupied by the anti-TLl A antibody or antigen-binding fragment.

147. The method of any one of claims 113 to 146, wherein at least 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the trimeric TLl A in the blood of the subject is occupied by the anti-TLl A antibody or antigen-binding fragment.

148. The method of any one of claims 113 to 147, wherein the binding affinity of the antibody or antigen-binding fragment to monomeric TL1A, as measured by the dissociation equilibrium constant (K D-单体 ) is comparable to the binding affinity of the antibody or antigen-binding fragment to trimeric TL1A, as measured by the dissociation equilibrium constant (K D-三聚体 ).

149. The method of claim 148, wherein the K D-单体 within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold of the K D-三聚体 within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold of the K 150. The method of claim 148 or 149, wherein the K D-单体 no more than 0.06 nM.

151. The method of any one of claims 148 to 150, wherein the K D-三聚体 no more than 0.06 nM.

152. The method of any one of claims 115 to 151, wherein the subject has one or more skin inflammation and / or skin fibrosis condition selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo or alopecia areata, a chronic skin disorder, systemic sclerosis, lupus, eczema, and dermatomyositis.

153. The method of any one of claims 114 to 152, wherein the subject has systemic sclerosis, psoriasis, lupus, dermatomyositis, eczema, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, or a combination thereof.

154. The method of any one of claims 114 to 152, wherein the subject has hidradenitis suppurativa.

155. The method of any one of claims 114 to 152, wherein the subject has atopic dermatitis.

156. The method of any one of claims 114 to 152, wherein the subject has psoriasis.

157. The method of any one of claims 114 to 152, wherein the subject has vitiligo.

158. The method of any one of claims 114 to 152, wherein the subject has alopecia areata.

159. The method of any one of claims 115 to 151, wherein the skin inflammation and / or skin fibrosis is hidradenitis suppurativa.

160. The method of any one of claims 115 to 151, wherein the skin inflammation and / or skin fibrosis is atopic dermatitis.

161. The method of any one of claims 115 to 151, wherein the skin inflammation and / or skin fibrosis is psoriasis.

162. The method of any one of claims 115 to 151, wherein the skin inflammation and / or skin fibrosis is vitiligo.

163. The method of any one of claims 115 to 151, wherein the skin inflammation and / or skin fibrosis is alopecia areata.

164. The method of any one of claims 115 to 151, wherein the skin inflammation and / or skin fibrosis is selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo or alopecia areata, a chronic skin disorder, systemic sclerosis, lupus, eczema, and dermatomyositis.

165. The method of any one of claims 113 to 164, wherein the effective dose or the induction regimen is determined by a dose determination method, wherein the dose determination method comprises: (i) receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in a normal reference tissue; (ii) integrating the parameter received in (a) to a physiologically integrated whole-body based pharmacokinetic (PBPK) model or a population pharmacokinetic (popPK) model; and (iii) determining the effective dose or the induction regimen such that after step (a), the concentration of TL1A in the diseased tissue in the subject is lower than the concentration of TL1A in the corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis.

166. The method of claim 165, wherein the overproduction of the parameter of TL1A overproduction is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200-fold or more of TL1A production in the normal reference tissue.

167. The method of any one of claims 121-166, wherein the maintenance regimen is determined by a dose determination method, wherein the dose determination method comprises: (i) receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in a normal reference tissue; (ii) integrating the parameter received in (i) to a physiologically integrated whole-body based pharmacokinetic (PBPK) model or a population pharmacokinetic (popPK) model; and (iii) determining the maintenance regimen such that after step (c), the concentration of TL1A in the diseased tissue in the subject is lower than the concentration of TL1A in the corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis.

168. The method of claim 167, wherein the overproduction of the parameter of TL1A overproduction is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100-fold or more of TL1A production in the normal reference tissue.

169. The method of any one of claims 165 to 168, wherein step (i) in the dose determination method further comprises receiving an association rate of the antibody to TL1A (k on-mAb ), a dissociation rate of the antibody to TL1A (k off-mAb ), a synthesis rate of TL1A in normal tissue (k syn-正常 ), a synthesis rate of TL1A in diseased tissue (k syn-疾病 ), and / or a degradation rate of TL1A (k deg-总-TL1A ).

170. The method of claim 169, wherein the association rate (kJ) between the antibody and TL1A is... on-mAb This includes the association rate (k) between the antibody and the monomer TL1A. on-单体 ) and the association rate (k) of the antibody with trimer TL1A on-三聚体 ), wherein the dissociation rate (k) of the antibody with TL1A off-mAb This includes the dissociation rate (kJ) of the antibody and monomer TL1A. off-单体 ) and the dissociation rate (k) of the antibody with the trimer TL1A off-三聚体 ), and / or the degradation rate (kJ) of said TL1A deg-总-TL1A This includes the degradation rate (kb) of monomer TL1A. deg-TL1A-单体 ) and the degradation rate (k) of trimer TL1A deg-TL1A-三聚体 ).

171. The method of any one of claims 165 to 170, wherein step (i) of the dosage determination method further comprises receiving the association rate (k) between the antibody and the FcRn receptor. on-mAb-FcRn The dissociation rate (k) of the antibody and FcRn off-mAb-FcRn ), the association rate (k) of the antibody-TL1A complex with the FcRn receptor on-(mAb-TL1A)-FcRn ) and / or the dissociation rate (kJ) of the antibody-TL1A complex with FcRn off-(mAb-TL1A)-FcRn ).

172. The method of claim 171, wherein the association rate (kJ) between the antibody-TL1A complex and the FcRn receptor is... on-(mAb-TL1A)-FcRn This includes the association rate (kJ) between the antibody-monomer TL1A complex and the FcRn receptor. on-(mAb-monoTL1A)-FcRn The association rate (kJ) of the antibody-trimeric TL1A complex with the FcRn receptor and the antibody-trimeric TL1A complex with the FcRn receptor. on-(mAb-triTL1A)-FcRn ), and / or the dissociation rate (kJ) of the antibody-TL1A complex with FcRn therein. off-(mAb-TL1A)-FcRn This includes the dissociation rate (kJ) of the antibody-monomer TL1A complex with FcRn. off-(mAb-monoTL1A)-FcRn ) and the dissociation rate (kJ) of the antibody-trimeric TL1A complex with FcRn off-(mAb-triTL1A)-FcRn ).

173. The method of any one of claims 165 to 172, wherein step (i) in the dose determination method further comprises receiving a clearance rate (k deg-mAb-FcRn ) of the FcRn receptor bound by the antibody.

174. The method of claim 173, wherein the clearance rate (k deg-mAb-FcRn ) of the FcRn receptor bound by the antibody comprises the clearance rate (k deg-(mAb-monoTL1A)-FcRn ) of the FcRn by the antibody and the clearance rate (k deg-(mAb-triTL1A)-FcRn ) of the FcRn receptor bound by the antibody-trimeric TL1A complex.

175. The method of any one of claims 169-174, wherein in the dose determination method: (1) k on-单体 and k on-三聚体 are the same or different; (2) k off-单体 and k off-三聚体 are the same or different; (3) k deg-单体 and k deg-三聚体 are the same or different; (4) k on-(mAb-monoTL1A)-FcRn and k on-(mAb-triTL1A)-FcRn are the same or different; (5) k on-mAb-FcRn and k on-(mAb-monoTL1A)-FcRn are the same or different; (6) k on-mAb-FcRn and k on-(mAb-triTL1A)-FcRn are the same or different; (7) k off-(mAb-monoTL1A)-FcRn and k off-(mAb-triTL1A)-FcRn are the same or different; (8) k off-mAb-FcRn and k off-(mAb-monoTL1A)-FcRn are the same or different; (9) k off-mAb-FcRn and k off-(mAb-triTL1A)-FcRn are the same or different; (10) k deg-(mAb-monoTL1A)-FcRn and k deg-(mAb-triTL1A)-FcRn are the same or different; (11) k deg-mAb-FcRn and k -(mAb-triTL1A)-FcRn are the same or different; (12) k deg-mAb-FcRn and k deg-(mAb-monoTL1A)-FcRn are the same or different; or (13) any combination of (1) to (12).

176. The method of any one of claims 165-175, wherein in the dose determination method: k syn-疾病 is at most 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 fold or more of k syn-正常 .

177. The method of any one of claims 165 to 176, wherein step (i) in the dose determination method further comprises receiving a rate of TL1A trimerization (k on-TL1A-单体至三聚体 ) and / or a rate of TL1A monomerization (k off-TL1A-三聚体至单体 ).

178. A method of determining an effective dosage regimen for administering an anti-TL1A antibody to a subject having skin inflammation and / or skin fibrosis, wherein the method comprises: (a) receiving a parameter of TL1A overproduction in a diseased tissue compared to TL1A production in a normal reference tissue; (b) integrating the parameter received in (a) to a physiologically integrated whole-body based pharmacokinetic (PBPK) model; and (c) determining the effective dosage regimen of the anti-TL1A antibody with the PBPK model from (b) such that after administering the effective dosage regimen, the concentration of TL1A in the diseased tissue in the subject having skin inflammation and / or skin fibrosis is lower than the concentration of TL1A in the corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, wherein the diseased tissue comprises any one or more selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, alopecia areata, systemic sclerosis, lupus, dermatomyositis, eczema, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, or a combination thereof.

179. A method of determining an effective dosage regimen of an anti-TLlA antibody for administration to a subject having skin inflammation and / or skin fibrosis, wherein the method comprises: (a) receiving a parameter of TLlA overproduction in a diseased tissue compared to TLlA production in a normal reference tissue; (b) integrating the parameter received in (a) into a population pharmacokinetic (popPK) model; and (c) determining the effective dosage regimen of the anti-TLlA antibody with the popPK model from (b) such that, following administration of the effective dosage regimen, the concentration of TLlA in a diseased tissue in the subject having skin inflammation and / or skin fibrosis is lower than the concentration of TLlA in a corresponding tissue in a control subject not having skin inflammation and / or skin fibrosis, wherein the diseased tissue comprises any one or more selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, alopecia areata, systemic sclerosis, lupus, dermatomyositis, eczema, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, or a combination thereof.

180. The method of claim 178 or 179, wherein the overproduction of the parameter of TLlA overproduction is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200-fold or more of the TLlA production in the normal reference tissue.

181. The method of any one of claims 178 to 180, wherein step (a) further comprises receiving the association rate (k) of the antibody with TL1A. on-mAb ), the dissociation rate (k) of the antibody with TL1A off-mAb ), the synthesis rate of TL1A in normal tissues (k syn-正常 ), the synthesis rate of TL1A in diseased tissue (k syn-疾病 The degradation rate (kJ) of ) and / or TL1A deg-总-TL1A ).

182. The method of claim 181, wherein the association rate (k) between the antibody and TL1A is... on-mAb This includes the association rate (k) between the antibody and the monomer TL1A. on-单体 ) and the association rate (k) of the antibody with trimer TL1A on-三聚体 ), wherein the dissociation rate (k) of the antibody with TL1A off-mAb This includes the dissociation rate (kJ) of the antibody and monomer TL1A. off-单体 ) and the dissociation rate (k) of the antibody with the trimer TL1A off-三聚体 ), and / or the degradation rate (kJ) of said TL1A deg-总-TL1A This includes the degradation rate (kb) of monomer TL1A. deg-TL1A-单体 ) and the degradation rate (k) of trimer TL1A deg-TL1A-三聚体 ).

183. The method of any one of claims 178 to 182, wherein step (a) comprises receiving the association rate (k) of the antibody with the FcRn receptor. on-mAb-FcRn The dissociation rate (k) of the antibody and FcRn off-mAb-FcRn ), the association rate (k) of the antibody-TL1A complex with the FcRn receptor on-(mAb-TL1A)-FcRn ) and / or the dissociation rate (kJ) of the antibody-TL1A complex with FcRn off-(mAb-TL1A)-FcRn ).

184. The method of claim 183, wherein the association rate (k on-(mAb-TL1A)-FcRn ) of the antibody-TL1 A complex with the FcRn receptor comprises the association rate (k on-(mAb-monoTL1A)-FcRn ) of the antibody-monomer TL1 A complex with the FcRn receptor and the association rate (k on-(mAb-triTL1A)-FcRn ) of the antibody-trimer TL1 A complex with the FcRn receptor, and / or wherein the dissociation rate (k off-(mAb-TL1A)-FcRn ) of the antibody-TL1 A complex from the FcRn comprises the dissociation rate (k off-(mAb-monoTL1A)-FcRn ) of the antibody-monomer TL1 A complex from the FcRn and the dissociation rate (k off-(mAb-triTL1A)-FcRn ) of the antibody-trimer TL1 A complex from the FcRn.

185. The method of any one of claims 178 to 184, wherein step (a) further comprises receiving a clearance rate (k deg-mAb-FcRn ) of the FcRn receptor bound by the antibody.

186. The method of claim 185, wherein the clearance rate (k deg-mAb-FcRn ) of the FcRn receptor bound by the antibody is also included. deg-(mAb-monoTL1A)-FcRn ) the clearance rate (k deg-(mAb-triTL1A)-FcRn ) of the FcRn receptor bound by the antibody-trimeric TL1 A complex.

187. The method of any one of claims 178-186, wherein the subject has one or more inflammatory conditions selected from the group consisting of hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, alopecia areata, chronic skin disorder, systemic sclerosis, lupus, eczema, and dermatomyositis.

188. The method of any one of claims 178-187, wherein the subject has hidradenitis suppurativa, atopic dermatitis, psoriasis, vitiligo, alopecia areata, systemic sclerosis, lupus, dermatomyositis, eczema, epidermolysis bullosa, mastocytosis, keloids, acne, rosacea, or bullous pemphigoid, or a combination thereof.

189. The method of any one of claims 178-188, wherein: (1) k on-单体 and k on-三聚体 are the same or different; (2) k off-单体 and k off-三聚体 are the same or different; (3) k deg-单体 and k deg-三聚体 are the same or different; (4) k on-(mAb-monoTL1A)-FcRn and k on-(mAb-triTL1A)-FcRn are the same or different; (5) k on-mAb-FcRn and k on-(mAb-monoTL1A)-FcRn are the same or different; (6) k on-mAb-FcRn and k on-(mAb-triTL1A)-FcRn are the same or different; (7) k off-(mAb-monoTL1A)-FcRn and k off-(mAb-triTL1A)-FcRn are the same or different; (8) k off-mAb-FcRn and k off-(mAb-monoTL1A)-FcRn are the same or different; (9) k off-mAb-FcRn and k off-(mAb-triTL1A)-FcRn are the same or different; (10) k deg-(mAb-monoTL1A)-FcRn and k deg-(mAb-triTL1A)-FcRn are the same or different; (11) k deg-mAb-FcRn and k -(mAb-triTL1A)-FcRn are the same or different; (12) k deg-mAb-FcRn and k deg-(mAb-monoTL1A)-FcRn are the same or different; or (13) any combination of (1)-(12).

190. The method of any one of claims 178-189, wherein: k syn-疾病 is at most 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 fold or more of k syn-正常 .

191. The method of any one of claims 178 to 190, wherein the effective dosage regimen comprises an induction regimen of the anti-TLl A antibody or antigen-binding fragment.

192. The method of any one of claims 178 to 191, wherein the effective dosage regimen comprises a maintenance regimen of the anti-TLl A antibody or antigen-binding fragment.

193. The method of claim 192, wherein the induction regimen and the maintenance regimen are the same.

194. The method of claim 192, wherein the induction regimen and the maintenance regimen are different.

195. The method of any one of claims 192 to 194, wherein the maintenance regimen is administered after the induction regimen.

196. The method of any one of claims 191 to 195, wherein during the induction regimen, the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100-fold or more of TLl A than the corresponding tissue in the control subject.

197. The method of any one of claims 191 to 196, wherein within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen, the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100-fold or more of TLl A than the corresponding tissue in the control subject.

198. The method of any one of claims 178 to 195, wherein the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100-fold or more of TLl A than the corresponding tissue in the control subject.

199. The method of any one of claims 191 to 198, wherein the induction regimen comprises one administration of the anti-TLl A antibody or antigen-binding fragment.

200. The method of claim 199, wherein the anti-TLl A antibody or antigen-binding fragment is administered at 200 mg / dose, 250 mg / dose, 300 mg / dose, 350 mg / dose, 400 mg / dose, 450 mg / dose, 500 mg / dose, 550 mg / dose, 600 mg / dose, 650 mg / dose, 700 mg / dose, 750 mg / dose, 800 mg / dose, 850 mg / dose, 900 mg / dose, 950 mg / dose, 1000 mg / dose, 1100 mg / dose, 1200 mg / dose, 1250 mg / dose, 1300 mg / dose, 1400 mg / dose, 1500 mg / dose, 1600 mg / dose, 1700 mg / dose, 1750 mg / dose, 1800 mg / dose, 1900 mg / dose, or 2000 mg / dose.

201. The method of any one of claims 191 to 198, wherein the induction regimen comprises multiple administrations of the anti-TLl A antibody or antigen binding fragment.

202. The method of any one of claims 191 to 198 and 201, wherein the induction regimen comprises: (i) 1000 mg / dose at Week 0, 1000 mg / dose at Week 2, 1000 mg / dose at Week 6, and 1000 mg / dose at Week 10; (ii) 500 mg / dose at Week 0, 500 mg / dose at Week 2, 500 mg / dose at Week 6, and 500 mg / dose at Week 10; (iii) 1000 mg / dose at Week 0, 1000 mg / dose at Week 2, 1000 mg / dose at Week 6, and 500 mg / dose at Week 10; (iv) 1000 mg / dose at Week 0, 1000 mg / dose at Week 2, 500 mg / dose at Week 6, and 500 mg / dose at Week 10; or (v) 1000 mg / dose at Week 0, 500 mg / dose at Week 2, 500 mg / dose at Week 6, and 500 mg / dose at Week 10.

203. The method of any one of claims 191 to 198 and 201, wherein the induction regimen comprises administration of 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, or 200 mg / dose.

204. The method of any one of claims 191 to 198, 201, and 203, wherein the induction regimen comprises administration once every 2, 4, 6, or 8 weeks.

205. The method of any one of claims 191 to 198, 201, and 203, wherein the induction regimen comprises administration once every 2 or 4 weeks for the first 2 administrations, and then administration once every 2, 4, 6, or 8 weeks for the remaining induction regimen.

206. The method of any one of claims 178 to 195 and 199 to 205, wherein the TLl A produced by the diseased tissue in the subject is up to 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more than the TLl A produced by the corresponding tissue in the control subject.

207. The method of any of claims 192 to 206, wherein during the maintenance regimen, the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more of TL1A than the corresponding tissue in the control subject.

208. The method of any of claims 192 to 207, wherein within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks or more of the start of the maintenance regimen, the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50-fold or more of TL1A than the corresponding tissue in the control subject.

209. The method of any of claims 192 to 208, wherein the maintenance regimen comprises multiple administrations of the anti-TL1A antibody or antigen-binding fragment.

210. The method of any of claims 192 to 209, wherein the maintenance regimen comprises administering the anti-TL1A antibody or antigen-binding fragment at: (i) 500 mg / dose every 2 weeks, (ii) 400 mg / dose every 2 weeks, (iii) 300 mg / dose every 2 weeks, (iv) 250 mg / dose every 2 weeks, (v) 200 mg / dose every 2 weeks, (vi) 150 mg / dose every 2 weeks, (vii) 100 mg / dose every 2 weeks, (viii) 50 mg / dose every 2 weeks, (ix) 500 mg / dose every 4 weeks, (x) 400 mg / dose every 4 weeks, (xi) 300 mg / dose every 4 weeks, (xii) 250 mg / dose every 4 weeks, (xiii) 200 mg / dose every 4 weeks, (xiv) 150 mg / dose every 4 weeks, (xv) 100 mg / dose every 4 weeks, (xvi) 50 mg / dose every 4 weeks, (xvii) 500 mg / dose every 6 weeks, (xviii) 400 mg / dose every 6 weeks, (xix) 300 mg / dose every 6 weeks, (xx) 250 mg / dose every 6 weeks, (xxi) 200 mg / dose every 6 weeks, (xxii) 150 mg / dose every 6 weeks, (xxiii) 100 mg / dose every 6 weeks, (xxiv) 50 mg / dose every 6 weeks, (xxv) 500 mg / dose every 8 weeks, (xxvi) 400 mg / dose every 8 weeks, (xxvii) 300 mg / dose every 8 weeks, (xxviii) 250 mg / dose every 8 weeks, (xxix) 200 mg / dose every 8 weeks, (xxx) 150 mg / dose every 8 weeks, (xxxi) 100 mg / dose every 8 weeks, or (xxxii) 50 mg / dose every 8 weeks.

211. The method of any one of claims 192 to 209, wherein the maintenance regimen comprises administering the anti-TLl A antibody or antigen-binding fragment at 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 mg / dose.

212. The method of any one of claims 192 to 209, and 211, wherein the maintenance regimen comprises administering the anti-TLl A antibody or antigen-binding fragment once every 2, 4, 6, 8, 10, or 12 weeks.

213. The method of any one of claims 192 to 212, wherein the maintenance regimen comprises administering the anti-TLl A antibody or antigen-binding fragment at 250 mg / dose every 4 weeks.

214. The method of any one of claims 192 to 213, wherein the maintenance regimen comprises administering the anti-TLl A antibody or antigen-binding fragment at 100 mg / dose every 4 weeks.

215. The method of any one of claims 192 to 214, wherein the maintenance regimen lasts for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, or 52 weeks.

216. The method of any one of claims 178 to 215, wherein the effective dosage regimen maintains the concentration of TLl A in the diseased tissue in the subject below the concentration of TLl A in the corresponding tissue in a control subject who does not have skin inflammation and / or skin fibrosis for at least 4 weeks, 8 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years, and longer.

217. The method of any one of claims 178 to 216, wherein at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the monomeric TLl A in the blood of the subject is occupied by the anti-TLl A antibody or antigen-binding fragment during the effective dosage regimen.

218. The method of any one of claims 178 to 217, wherein at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the trimeric TLl A in the blood of the subject is occupied by the anti-TLl A antibody or antigen-binding fragment during the effective dosage regimen.

219. The method of any one of claims 178 to 218, wherein step (a) further comprises receiving a rate of TL1A trimerization (k on-TL1A-单体至三聚体 ) and / or a rate of TL1A monomerization (k off-TL1A-三聚体至单体 ).

220. The method of any one of claims 114 to 219, wherein the concentration of TLl A is the concentration of free TLl A.

221. The method of any one of claims 1 to 220, wherein the anti-TLl A antibody comprises: a heavy chain variable region comprising: a HCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 1; a HCDR2 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 2-5; and a HCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 6-9; and a light chain variable region comprising: a LCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 10; a LCDR2 comprising an amino acid sequence set forth by SEQ ID NO: 11; a LCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOs: 12-15.

222. The method of any one of claims 1 to 221, wherein the anti-TLl A antibody comprises: a heavy chain variable framework region comprising a human IGHV1-46 02 framework or a modified human IGHV1-46 02 framework; and a light chain variable framework region comprising a human IGKV3-20 framework or a modified human IGKV3-20 framework; wherein the heavy chain variable framework region and the light chain variable framework region collectively comprise zero or fewer than nine amino acid modifications from the human IGHV1-46 02 framework and the human IGKV3-20 framework.

223. The method of any one of claims 1 to 222, wherein the anti-TLl A antibody comprises: a heavy chain variable domain comprising an amino acid sequence that is at least 96% identical to any one of SEQ ID NOs: 101-169; and a light chain variable domain comprising an amino acid sequence that is at least 96% identical to any one of SEQ ID NOs: 201-220.

224. The method of any one of claims 1 to 223, wherein the anti-TLl A antibody comprises: a heavy chain variable region comprising SEQ ID NO: 301 X1VQLVQSGAEVKKPGASVKVSCKAS[HCDR1]WVX2QX3PGQGLEWX4G[HCDR2]RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTAVYYCAR[HCDR3]WGQGTTVTVSS, and a light chain variable region comprising SEQ ID NO: 303 EIVLTQSPGTLSLSPGERATLSC[LCDR1]WYQQKPGQAPRX10X11IY[LCDR2]GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC[LCDR3]FGGGTKLEIK, wherein each of X1-X11 is independently selected from A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, or V, wherein HCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 1, HCDR2 comprises the amino acid sequence set forth by any one of SEQ ID NOs: 2-5, HCDR3 comprises the amino acid sequence set forth by any one of SEQ ID NOs: 6-9, LCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 10, LCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 11, and LCDR3 comprises the amino acid sequence set forth by any one of SEQ ID NOs: 12 or 13. EIVLTQSPGTLSLSPGERATLSC[LCDR1]WYQQKPGQAPRX10X11IY[LCDR2]GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC[LCDR3]FGGGTKLEIK, wherein each of X1-X11 is independently selected from A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, or V, wherein HCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 1, HCDR2 comprises the amino acid sequence set forth by any one of SEQ ID NOs: 2-5, HCDR3 comprises the amino acid sequence set forth by any one of SEQ ID NOs: 6-9, LCDR1 comprises the amino acid sequence set forth by SEQ ID NO: 10, LCDR2 comprises the amino acid sequence set forth by SEQ ID NO: 11, and LCDR3 comprises the amino acid sequence set forth by any one of SEQ ID NOs: 12 or 13.

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