EP4676971A2 - Compositions d'anticorps anti-tl1a et méthodes de traitement de la sarcoïdose - Google Patents

Compositions d'anticorps anti-tl1a et méthodes de traitement de la sarcoïdose

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Publication number
EP4676971A2
EP4676971A2 EP24767755.2A EP24767755A EP4676971A2 EP 4676971 A2 EP4676971 A2 EP 4676971A2 EP 24767755 A EP24767755 A EP 24767755A EP 4676971 A2 EP4676971 A2 EP 4676971A2
Authority
EP
European Patent Office
Prior art keywords
tl1a
dose
antibody
sarcoidosis
fcrn
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24767755.2A
Other languages
German (de)
English (en)
Inventor
Ernesto J. MUNOZ
Heather LLEWELLYN
Yong Wang
Jaclyn Kay ANDERSON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Prometheus Biosciences Inc
Original Assignee
Merck Sharp and Dohme LLC
Prometheus Biosciences Inc
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Filing date
Publication date
Application filed by Merck Sharp and Dohme LLC, Prometheus Biosciences Inc filed Critical Merck Sharp and Dohme LLC
Publication of EP4676971A2 publication Critical patent/EP4676971A2/fr
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/71—Decreased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/734—Complement-dependent cytotoxicity [CDC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • Sarcoidosis is a disease characterized by the growth of aggregations of inflammatory cells in parts of patients’ body, most commonly in the lungs, lymph nodes and skin, and presents itself as small patches of swollen tissue, called granulomas, in these affected organs of the body.
  • Sarcoidosis in the lung is known as pulmonary sarcoidosis.
  • Sarcoidosis in the skin is known as cutaneous sarcoidosis.
  • 9 out of 10 sarcoidosis patients develop pulmonary sarcoidosis, the symptoms of which include shortness of breath and a persistent dry cough and may also include pain and discomfort in their chest.
  • the cutaneous sarcoidosis further includes lupus pernio, papular sarcoidosis, nodular sarcoidosis, subcutaneous sarcoidosis (also known and referred to herein as Darier-Roussy sarcoidosis), maculopapular sarcoidosis, plaque sarcoidosis, hypopigmented sarcoidosis, and atrophic and ulcerative sarcoidosis.
  • Plaque sarcoidosis further includes angiolupoid sarcoidosis, psoriasiform sarcoidosis, and verrucous sarcoidosis.
  • sarcoidosis includes neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichthyosiform sarcoidosis, erythrodermic sarcoidosis, and perforating sarcoidosis.
  • Sarcoidosis including pulmonary sarcoidosis and cutaneous sarcoidosis, among others, is currently treated with over the counter painkillers, and in some instances, with steroids.
  • an anti-TL1A antagonistic monoclonal antibody provided herein can treat sarcoidosis, including pulmonary sarcoidosis and/or cutaneous sarcoidosis.
  • T1A tumor necrosis factor ligand 1A
  • T1A tumor necrosis factor ligand 1A
  • antibodies described herein possess features useful for therapeutic application such as low immunogenicity, and/or features that facilitate antibody manufacture, such as high percentage of monomeric fraction as measured by size-exclusion chromatography, and/or high expression.
  • antibodies described herein possess features useful for subcutaneous administration, such as low viscosity at high antibody concentration. Further aspects of the antibodies and antibody formulations may include high solubility, low subvisible particles, low opalescence, no visible particulates, and any combination thereof.
  • a method of treating sarcoidosis 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-TL1A antibody or antigen binding fragment).
  • the sarcoidosis is pulmonary sarcoidosis.
  • the sarcoidosis is cutaneous sarcoidosis.
  • the cutaneous sarcoidosis is lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, plaque sarcoidosis, hypopigmented sarcoidosis, or atrophic and ulcerative sarcoidosis.
  • the sarcoidosis is neurologic sarcoidosis.
  • the sarcoidosis is cardiac sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is gastrointestinal sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is hepatic sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is pancreatic sarcoidosis.
  • the sarcoidosis is peritoneal sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is sarcoidosis of bones. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is sarcoid arthropathy. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is plaque sarcoidosis.
  • the plaque sarcoidosis is angiolupoid sarcoidosis, psoriasiform sarcoidosis, or verrucous sarcoidosis.
  • the sarcoidosis is ichthyosiform sarcoidosis.
  • the sarcoidosis is erythrodermic sarcoidosis.
  • the sarcoidosis is perforating sarcoidosis.
  • the anti-TL1A antibody or antigen binding fragment is administered in a pharmaceutical composition.
  • the pharmaceutical composition comprises anti-TL1A antibody or antigen binding fragment at a concentration greater than about 150 mg/mL.
  • the pharmaceutical composition comprises anti-TL1A antibody or antigen binding fragment at a concentration greater than about 160 mg/ml, about 165 mg/ml, about 170 mg/ml, about 175 mg/ml, about 180 mg/ml, about 185 mg/ml, about 190 mg/ml, about 195 mg/ml, about 200 mg/ml, about 205 mg/ml, about 210 mg/ml, about 215 mg/ml, about 220 mg/ml, about 225 mg/ml, about 230 mg/ml, about 235 mg/ml, about 240 mg/ml, about 245 mg/ml, or about 250 mg/mL.
  • the pharmaceutical composition comprises anti-TL1A antibody or antigen binding fragment at a concentration about 125 mg/mL to about 175 mg/mL, about 125 mg/mL to about 200 mg/mL, about 125 mg/mL to about 225 mg/mL, about 150 mg/mL to about 200 mg/mL, about 150 mg/mL to about 225 mg/mL, about 150 mg/mL to about 250 mg/mL, about 175 mg/mL to about 225 mg/mL, about 175 mg/mL to about 250 mg/mL, about 175 mg/mL to about 275 mg/mL, about 200 mg/mL to about 250 mg/mL, or about 200 mg/mL to about 275 mg/mL.
  • the pharmaceutical composition is administered subcutaneously.
  • the pharmaceutical composition is administered intravenously.
  • the pharmaceutical composition comprises about 150 mg to about 1000 mg of the anti-TL1A antibody or antigen binding fragment.
  • the pharmaceutical composition has a total volume of less than or equal to about 2 mL, about 1.9 ml, about 1.8 ml, about 1.7 ml, about 1.6 ml, about 1.5 ml, about 1.4 ml, about 1.3 ml, about 1.2 ml, about 1.1 ml, about 1.0 ml, about 0.9 ml, or about 0.8 mL.
  • the pharmaceutical composition comprises a therapeutically effective dose of the anti-TL1A antibody or antigen binding fragment.
  • the pharmaceutical composition has a viscosity of less than about 20cP, less than about 19cP, less than about 18cP, less than about 17cP, less than about 16cP, less than about 15cP, less than about 14cP, less than about 13cP, less than about 12cP, less than about 11cP, less than about 10cP, less than about 9cP, less than about 8cP, less than about 7cP, less than about 6cP, or less than about 5 cP.
  • the pharmaceutical composition comprises a surfactant, a salt, a stabilizer, and/or a buffering agent.
  • the surfactant comprises polysorbate-20, and wherein optionally the surfactant is present at a concentration of about 0.02% in the pharmaceutical composition.
  • the salt comprises NaCl, and wherein optionally the NaCl is at a concentration of about 40 mM in the pharmaceutical composition.
  • the stabilizer comprises sucrose, wherein optionally the sucrose is at a concentration of about 220 mM in the pharmaceutical composition.
  • the buffering agent comprises sodium acetate, wherein optionally the sodium acetate is at a concentration of about 20 mM in the pharmaceutical composition.
  • the pharmaceutical composition has a pH of about 5.3.
  • the anti-TL1A antibody or antigen binding fragment is administered to the subject at a second dose up to about 1000 mg. In some embodiments, the anti-TL1A antibody or antigen binding fragment is administered to the subject at a second dose of about 500 mg. [0021] In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the first dose is administered to the subject at a first time point, and the second dose is administered to the subject at a second time point.
  • the first dose and the second dose is different or wherein the first dose and the second dose is identical.
  • 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.
  • the anti-TL1A antibody or antigen binding fragment is administered to the subject at an induction regimen.
  • the induction regimen comprises 500 mg/dose once every 4 weeks.
  • the anti-TL1A antibody or antigen binding fragment is administered to the subject at a maintenance regimen.
  • the maintenance regimen comprises 500 mg/dose once every 4 weeks.
  • the induction regimen and the maintenance regimen are identical.
  • the induction regimen and the maintenance regimen are different.
  • the maintenance regimen 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 induction regimen.
  • a method of neutralizing monomeric TL1A and trimeric TL1A in a subject having sarcoidosis comprising (a) administering an effective dose of anti-TL1A antibody or antigen binding fragment to the subject, wherein the antibody or antigen binding fragment binds to both monomeric TL1A and trimeric TL1A, wherein the antibody or antigen binding fragment blocks interaction of TL1A to 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 without sarcoidosis, and wherein diseased tissue comprises any one or more selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, and other tissues afflicted by sarcoidosis.
  • a method of reducing the concentration of TL1A in a diseased tissue in a subject with sarcoidosis comprising (a) administering an effective dose of anti-TL1A antibody or antigen binding fragment to the subject, thereby reducing the concentration of TL1A in the diseased tissue in the subject below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis, wherein diseased tissue comprises any one or more selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, other and tissues afflicted by sarcoidosis.
  • a method of treating sarcoidosis in a subject in need thereof comprising (a) administering an anti-TL1A antibody or antigen binding fragment to the subject, wherein the anti-TL1A antibody or antigen binding fragment is administered at an effective dose such that the concentration of TL1A in a diseased tissue in the subject after step (a) is below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis, and wherein diseased tissue comprises any one or more selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, and other tissues afflicted by sarcoidosis.
  • a method of treating sarcoidosis in a subject in need thereof comprising (a) administering an anti-TL1A antibody or antigen binding fragment to the subject at 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 without sarcoidosis, wherein diseased tissue comprises any one or more selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, and other tissues afflicted by sarcoidosis.
  • the sarcoidosis is pulmonary sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is cutaneous sarcoidosis.
  • the cutaneous sarcoidosis is lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, plaque sarcoidosis, hypopigmented sarcoidosis, or atrophic and ulcerative sarcoidosis.
  • the sarcoidosis is neurologic sarcoidosis.
  • the sarcoidosis is cardiac sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is gastrointestinal sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is hepatic sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is pancreatic sarcoidosis.
  • the sarcoidosis is peritoneal sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is sarcoidosis of bones. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is sarcoid arthropathy. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is plaque sarcoidosis.
  • the plaque sarcoidosis is angiolupoid sarcoidosis, psoriasiform sarcoidosis, or verrucous sarcoidosis.
  • the sarcoidosis is ichthyosiform sarcoidosis.
  • the sarcoidosis is erythrodermic sarcoidosis.
  • the sarcoidosis is perforating sarcoidosis.
  • the effective dose comprises an induction regimen.
  • the method further comprises (c) maintaining TL1A in the diseased tissue in the subject at a concentration below the concentration of TL1A in the corresponding tissue in the control subject.
  • the TL1A in the diseased tissue in the subject is maintained with a maintenance regimen of the anti-TL1A antibody or antigen binding fragment.
  • the induction regimen and the maintenance regimen are identical.
  • the induction regimen and the maintenance regimen are different.
  • the maintenance regimen is administered after the induction regimen.
  • the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen. In some embodiments, the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of start of the induction regimen. In some embodiments, the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1A compared to the corresponding tissue in the control subject.
  • the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment.
  • the one-time administration of the anti-TL1A antibody or antigen binding fragment comprises an administration 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 25746 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.
  • the induction regimen comprises multiple administrations of the anti-TL1A antibody or antigen binding fragment.
  • the induction regimen comprises administrations of (i) 1000 mg/dose on week 0, 1000 mg/dose on week 2, 1000 mg/dose on week 6, and 1000 mg/dose on week 10; (ii) 500 mg/dose on week 0, 500 mg/dose on week 2, 500 mg/dose on week 6, and 500 mg/dose on week 10; (iii) 1000 mg/dose on week 0, 1000 mg/dose on week 2, 1000 mg/dose on week 6, and 500 mg/dose on week 10; (iv) 1000 mg/dose on week 0, 1000 mg/dose on week 2, 500 mg/dose on week 6, and 500 mg/dose on week 10; or (v) 1000 mg/dose on week 0, 500 mg/dose on week 2, 500 mg/dose on week 6, and 500 mg/dose/dose on week 10; or (v) 1000 mg/dose on week 0, 500 mg/dose on week 2, 500 mg/dose on week 6, and 500 mg/dose/
  • 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.
  • the induction regimen comprises administration once every 2, 4, 6, or 8 weeks.
  • 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.
  • the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more fold of TL1A compared to the corresponding tissue in the control subject.
  • the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more fold of TL1A compared to the corresponding tissue in the control subject 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 longer of start of the maintenance regimen.
  • the maintenance regimen comprises multiple administrations of the anti-TL1A antibody or antigen binding fragment.
  • the maintenance regimen comprises administrations of 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, (xi) 400 mg/dose every 2 weeks, (iii) 300 mg/dose every 2 weeks, (iv) 250 mg
  • the maintenance regimen comprises administration of the anti-TL1A 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.
  • the maintenance regimen comprises administration of the anti-TL1A antibody or antigen binding fragment once every 2, 4, 6, 8, 10, or 12 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at 250 mg/dose every 4 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at 100 mg/dose every 4 weeks.
  • the maintenance regimen continues for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, or 52 weeks.
  • the antibody or antigen binding fragment binds to both monomeric TL1A and trimeric TL1A and wherein the antibody or antigen binding fragment blocks binding of TL1A to DR3.
  • 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 blood of the subject is occupied by the anti-TL1A antibody or antigen binding fragment.
  • 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 blood of the subject is occupied by the anti-TL1A antibody or antigen binding fragment.
  • the binding affinity of the antibody or antigen binding fragment to monomeric TL1A as measured by dissociation equilibrium constant (KD- monomer) is comparable to binding affinity of the antibody or antigen binding fragment to trimeric TL1A as measured by dissociation equilibrium constant (KD-trimer).
  • KD- monomer the binding affinity of the antibody or antigen binding fragment to monomeric TL1A as measured by dissociation equilibrium constant
  • KD-trimer dissociation equilibrium constant
  • the KD-monomer is within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold of the KD-trimer. In some embodiments, the KD-monomer is no more than 0.06 nM.
  • the KD-trimer is no more than 0.06 nM.
  • 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 over-production in the diseased tissue comparing to TL1A production in a normal reference tissue; (ii) integrating the parameters received in (a) to an integrated whole-body physiologically based pharmacokinetic (PBPK) model or a population pharmacokinetic model (popPK); and (iii) determining the effective dose or the induction regimen such that the concentration of TL1A in diseased tissue in the subject after step (a) is below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis [0054] In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the parameter of TL
  • the maintenance regimen is determined by a dose determination method, wherein the dose determination method comprises: (i) receiving a parameter of TL1A over-production in the diseased tissue comparing to TL1A production in a normal reference tissue; (ii) integrating the parameter received in (i) to an integrated whole- body physiologically based pharmacokinetic (PBPK) model or a population pharmacokinetic model (popPK); and (iii) determining the maintenance regimen such that the concentration of TL1A in diseased tissue in the subject after step (c) is below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis.
  • PBPK whole- body physiologically based pharmacokinetic
  • popPK population pharmacokinetic model
  • the parameter of TL1A over-production is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, or more fold over-production comparing to TL1A production in the normal reference tissue.
  • the step (i) in the dose determination method further comprises receiving association rate of the antibody to TL1A (kon-mAb), dissociation rate of the antibody from TL1A (koff-mAb), synthesis rate of TL1A in normal tissue (ksyn-normal), synthesis rate of TL1A in diseased tissue (ksyn-disease), and/or degradation rate of TL1A (kdeg- total-TL1A ).
  • the association rate of the antibody to TL1A comprises the association rate of the antibody to monomeric TL1A (kon-monomer) and association rate of the antibody to trimeric TL1A (k on-trimer ), wherein the dissociation rate of the antibody from TL1A (koff-mAb) comprises the dissociation rate of the antibody from monomeric TL1A (k off-monomer ) and dissociation rate of the antibody from trimeric TL1A (k off- trimer), and/or wherein the degradation rate of TL1A (kdeg-total-TL1A) comprises degradation rate of monomeric TL1A (k deg-TL1A-monomer ) and degradation rate of trimeric TL1A (k deg-TL1A-trimer ).
  • the step (i) in the dose determination method further comprises receiving association rate of the antibody to FcRn receptor (kon-mAb-FcRn), dissociation rate of the antibody from FcRn (k off- mAb-FcRn ), association rate of the antibody- TL1A complex to FcRn receptor (kon-(mAb-TL1A)-FcRn), and/or dissociation rate of the antibody- TL1A complex from FcRn (k off-(mAb-TL1A)-FcRn ).
  • the association rate of the antibody- TL1A complex to FcRn receptor comprises association rate of the antibody-monomeric-TL1A complex to FcRn receptor (k on-(mAb-monoTL1A)-FcRn ) and association rate of the antibody- trimeric-TL1A complex to FcRn receptor (kon-(mAb-triTL1A)-FcRn), and/or wherein the dissociation rate of the antibody- TL1A complex from FcRn (k off-(mAb-TL1A)-FcRn ) comprises dissociation rate of the antibody-monomeric-TL1A complex from FcRn (koff-(mAb-monoTL1A)- FcRn ) and dissociation rate of the antibody-trimeric-TL1A complex from FcR
  • the step (i) in the dose determination method further comprises receiving clearance rate of FcRn receptor bound by the antibody (k deg-mAb-FcRn ).
  • the clearance rate of FcRn receptor bound by the antibody comprises clearance rate of the antibody to FcRn bound by the antibody- monomeric-TL1A complex (kdeg-(mAb-monoTL1A)-FcRn) and clearance rate of FcRn receptor bound by the antibody-trimeric-TL1A complex (kdeg-(mAb-triTL1A)-FcRn).
  • k on-monomer and k on-trimer are identical or different; (2) koff-monomer and koff-trimer are identical or different; (3) kdeg-monomer and k deg-trimer are identical or different; (4) k on-(mAb-monoTL1A)-FcRn and k on-(mAb-triTL1A)-FcRn are identical or different; (5) kon-mAb-FcRn and kon-(mAb-monoTL1A)-FcRn are identical or different; (6) k on-mAb-FcRn and k on-(mAb-triTL1A)-FcRn are identical or different; (7) k off-(mAb-monoTL1A)-FcRn and k off- (mAb-triTL1A)-FcRn are
  • ksyn-disease is up to 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, or more fold of ksyn-normal.
  • the step (i) in the dose determination method further 25746 comprises receiving rate of TL1A trimerization (kon-TL1A-monomer-to-trimer) and/or rate of TL1A monomerization (k off-TL1A-trimer-to-monomer ).
  • a method of determining an effective dose regimen for administering an anti-TL1A antibody to a subject having sarcoidosis comprises: (a) receiving a parameter of TL1A over-production in the diseased tissue comparing to TL1A production in a normal reference tissue; (b) integrating the parameter received in (a) to an integrated whole-body physiologically based pharmacokinetic (PBPK) model; and (c) determining the effective dose regimen of the anti-TL1A antibody with the PBPK model from (b) such that after administration of the effective dose regimen the concentration of TL1A in a diseased tissue in the subject having sarcoidosis is below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis, wherein the diseased tissue comprises any one or more selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the
  • a method of determining an effective dose regimen for administering an anti-TL1A antibody to a subject having sarcoidosis comprises: (a) receiving a parameter of TL1A over-production in the diseased tissue comparing to TL1A production in a normal reference tissue; (b) integrating the parameter received in (a) to a population pharmacokinetic (popPK) model; and (c) determining the effective dose regimen of the anti-TL1A antibody with the popPK model from (b) such that after administration of the effective dose regimen the concentration of TL1A in a diseased tissue in the subject having sarcoidosis is below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis, wherein the diseased tissue comprises any one or more selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, other tissues with s
  • the sarcoidosis is pulmonary sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is cutaneous sarcoidosis.
  • the cutaneous sarcoidosis is lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, plaque sarcoidosis, hypopigmented sarcoidosis, or atrophic and ulcerative sarcoidosis.
  • the sarcoidosis is neurologic sarcoidosis.
  • the sarcoidosis is cardiac sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is gastrointestinal sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is hepatic sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is pancreatic sarcoidosis.
  • the sarcoidosis is peritoneal sarcoidosis. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is sarcoidosis of bones. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is sarcoid arthropathy. In some embodiments of the various methods provided herein, including in Sections 2, [0456], and [0551], the sarcoidosis is plaque sarcoidosis.
  • the plaque sarcoidosis is angiolupoid sarcoidosis, psoriasiform sarcoidosis, or verrucous sarcoidosis.
  • the sarcoidosis is ichthyosiform sarcoidosis.
  • the sarcoidosis is erythrodermic sarcoidosis.
  • the sarcoidosis is perforating sarcoidosis.
  • the parameter of TL1A over-production 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 or more fold over-production comparing to TL1A production in the normal reference tissue.
  • the step (a) further comprises receiving association rate of the antibody to TL1A (kon-mAb), dissociation rate of the antibody from TL1A (k off-mAb ), synthesis rate of TL1A in normal tissue (k syn-normal ), synthesis rate of TL1A in diseased tissue (ksyn-disease), and/or degradation rate of TL1A (kdeg- total-TL1A ).
  • the association rate of the antibody to TL1A comprises the association rate of the antibody to monomeric TL1A (kon-monomer) and association rate of the antibody to trimeric TL1A (k on-trimer ), wherein the dissociation rate of the antibody from TL1A (koff-mAb) comprises the dissociation rate of the antibody from monomeric TL1A (k off-monomer ) and dissociation rate of the antibody from trimeric TL1A (k off- trimer), and/or wherein the degradation rate of TL1A (kdeg-total-TL1A) comprises degradation rate of monomeric TL1A (k deg-TL1A-monomer ) and degradation rate of trimeric TL1A (k deg-TL1A-trimer ).
  • the step (a) comprises receiving association rate of the antibody to FcRn receptor (kon-mAb-FcRn), dissociation rate of the antibody from FcRn (k off- mAb-FcRn ), association rate of the antibody-TL1A complex to FcRn receptor (kon-(mAb-TL1A)-FcRn), and/or dissociation rate of the antibody-TL1A complex from FcRn (k off-(mAb-TL1A)-FcRn ).
  • the association rate of the antibody- TL1A complex to FcRn receptor comprises association rate of the antibody-monomeric-TL1A complex to FcRn receptor (kon-(mAb-monoTL1A)-FcRn) and association rate of the antibody- trimeric-TL1A complex to FcRn receptor (k on-(mAb-triTL1A)-FcRn ), and/or wherein the dissociation rate of the antibody- TL1A complex from FcRn (koff-(mAb-TL1A)-FcRn) comprises dissociation rate of the antibody-monomeric-TL1A complex from FcRn (k off-(mAb-monoTL1A)- FcRn) and dissociation rate of the antibody-trimeric-TL1A complex from FcRn (koff-(
  • the step (a) further comprises receiving clearance rate of FcRn receptor bound by the antibody (kdeg-mAb-FcRn).
  • the clearance rate of FcRn receptor bound by the antibody further comprises clearance rate of the antibody to FcRn bound by the antibody-monomeric-TL1A complex (kdeg-(mAb-monoTL1A)-FcRn) and clearance rate of FcRn receptor bound by the antibody-trimeric-TL1A complex (k deg-(mAb- triTL1A)-FcRn).
  • the ksyn-disease is up to 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, or more fold of ksyn-normal.
  • the effective dose regimen comprises an induction regimen of the anti-TL1A antibody or antigen binding fragment.
  • the effective dose regimen comprises a maintenance regimen of the anti-TL1A antibody or antigen binding fragment.
  • the induction regimen and the maintenance regimen are identical.
  • the induction regimen and the maintenance regimen are different.
  • the maintenance regimen is administered after the induction regimen.
  • the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen.
  • the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of start of the induction regimen.
  • the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1A compared to the corresponding tissue in the control subject.
  • the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment.
  • the one-time administration of the anti-TL1A antibody or antigen binding fragment comprises an administration 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.
  • the induction regimen comprises multiple administrations of the anti-TL1A antibody or antigen binding fragment.
  • the induction regimen comprises administrations of (i) 1000 mg/dose on week 0, 1000 mg/dose on week 2, 1000 mg/dose on week 6, and 1000 mg/dose on week 10; (ii) 500 mg/dose on week 0, 500 mg/dose on week 2, 500 mg/dose on week 6, and 500 mg/dose on week 10; (iii) 1000 mg/dose on week 0, 1000 mg/dose on week 2, 1000 mg/dose on week 6, and 500 mg/dose on week 10; (iv) 1000 mg/dose on week 0, 1000 mg/dose on week 2, 500 mg/dose on week 6, and 500 mg/dose on week 10; or (v) 1000 mg/dose on week 0, 500 mg/dose
  • 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.
  • the induction regimen comprises administration once every 2, 4, 6, or 8 weeks.
  • 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.
  • the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more fold of TL1A compared to the corresponding tissue in the control subject. In some embodiments, the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more fold of TL1A compared to the corresponding tissue in the control subject 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 longer of start of the maintenance regimen.
  • the maintenance regimen comprises multiple administrations of the anti-TL1A antibody or antigen binding fragment.
  • the maintenance regimen comprises administrations of 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///
  • the maintenance regimen comprises administration of the anti-TL1A 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.
  • the maintenance regimen comprises administration of the anti-TL1A antibody or antigen binding fragment once every 2, 4, 6, 8, 10, or 12 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at 250 mg/dose every 4 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at 100 mg/dose every 4 weeks.
  • the maintenance regimen continues for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, or 52 weeks.
  • the effective dose regimen maintains the concentration of TL1A in diseased tissue in the subject below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis 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.
  • At least 91%, at least 25746 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 TL1A in the blood of the subject is occupied by the anti-TL1A antibody or antigen binding fragment during the effective dose regimen.
  • 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 TL1A in the blood of the subject is occupied by the anti-TL1A antibody or antigen binding fragment during the effective dose regimen.
  • the step (a) further comprises receiving the rate of TL1A trimerization (kon-TL1A-monomer-to-trimer) and/or rate of TL1A monomerization (k off-TL1A-trimer-to-monomer ).
  • the concentration of TL1A is the concentration of free TL1A.
  • the anti-TL1A antibody comprises a heavy chain variable region comprising: an HCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 2-5, and an HCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 6- 9; and a light chain variable region comprising an LCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 10, an LCDR2 comprising an amino acid sequence set forth by SEQ ID NO: 11, an LCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 12-15.
  • the anti-TL1A antibody comprises the CDRs of antibody J of Table 10. In some cases, the anti-TL1A antibody comprises the CDRs of antibody J2 of Table 10. In some cases, the anti-TL1A antibody comprises the CDRs of antibody K of Table 10.
  • the anti-TL1A 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 25746 comprise no or fewer than nine amino acid modification(s) from the human IGHV1-46*02 framework and the human IGKV3-20 framework.
  • the anti-TL1A antibody comprises a heavy chain variable domain comprising an amino acid sequence at least 96% identical to any one of SEQ ID NOS: 101-169, and a light chain variable domain comprising an amino acid sequence at least 96% identical to any one of SEQ ID NOS: 201-220.
  • the anti-TL1A antibody comprises a heavy chain variable domain comprising an amino acid sequence 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 at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 430.
  • the anti-TL1A antibody comprises a heavy chain variable domain comprising an amino acid sequence 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 at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 431.
  • the anti-TL1A antibody comprises a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 423, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 433.
  • the anti-TL1A antibody comprises a heavy chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 424, and a light chain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 434.
  • the anti-TL1A 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]GIPDR FSGSGSGTDFTLTISRLEPEDFAVYYC[LCDR3]FGGGTKLEIK, wherein each of X1-X11 is independently selected from A, R, N, D, C, Q, E, G, H, I, L, K,
  • the anti-TL1A antibody comprises the CDRs of antibody J of Table 10. In some cases, the anti-TL1A antibody comprises the CDRs of antibody J2 of Table 10. In some cases, the anti-TL1A antibody comprises the CDRs of antibody K of Table 10.
  • the anti-TL1A antibody comprises a heavy chain variable region comprising: an HCDR1 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 401, 407, 413, or 450, an HCDR2 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 402, 408, 414, or 451, and an HCDR3 comprising an 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 an amino acid sequence set forth by any one of SEQ ID NOS: 404, 410, 416, or 453, an LCDR2 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 405, 411, 417, or 454, an LCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 406, 412,
  • the anti-TL1A antibody comprises a heavy chain variable domain comprising an amino acid sequence at least 96% identical to any one of SEQ ID NOS: 420-427, and a light chain variable domain comprising an amino acid sequence at least 96% identical to any one of SEQ ID NOS: 430-437.
  • a heavy chain variable domain comprising an amino acid sequence at least 96% identical to any one of SEQ ID NOS: 420-427
  • a light chain variable domain comprising an amino acid sequence at least 96% identical to any one of SEQ ID NOS: 430-437.
  • Embodiment 2 The anti-TL1A antibody or antigen-binding fragment of embodiment 1, wherein the sarcoidosis is cutaneous sarcoidosis.
  • Embodiment 3. The anti-TL1A antibody or antigen-binding fragment of embodiment 2, wherein the cutaneous sarcoidosis is lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, plaque sarcoidosis, hypopigmented sarcoidosis, or atrophic and ulcerative sarcoidosis.
  • Embodiment 5 The anti-TL1A antibody or antigen-binding fragment of embodiment 1, wherein the sarcoidosis is neurologic sarcoidosis. 25746 [0115] Embodiment 5. The anti-TL1A antibody or antigen-binding fragment of embodiment 1, wherein the sarcoidosis is cardiac sarcoidosis. [0116] Embodiment 6. The anti-TL1A antibody or antigen-binding fragment of embodiment 1, wherein the sarcoidosis is gastrointestinal sarcoidosis. [0117] Embodiment 7. The anti-TL1A antibody or antigen-binding fragment of embodiment 1, wherein the sarcoidosis is hepatic sarcoidosis. [0118] Embodiment 8.
  • Embodiment 9 The anti-TL1A antibody or antigen-binding fragment of embodiment 1, wherein the sarcoidosis is pancreatic sarcoidosis.
  • Embodiment 9 The anti-TL1A antibody or antigen-binding fragment of embodiment 1, wherein the sarcoidosis is peritoneal sarcoidosis.
  • Embodiment 10 The anti-TL1A antibody or antigen-binding fragment of embodiment 1, wherein the sarcoidosis is sarcoidosis of bones.
  • Embodiment 11 The anti-TL1A antibody or antigen-binding fragment of embodiment 1, wherein the sarcoidosis is sarcoid arthropathy.
  • Embodiment 13 The anti-TL1A antibody or antigen-binding fragment of embodiment 1, wherein the sarcoidosis is plaque sarcoidosis.
  • Embodiment 13 The anti-TL1A antibody or antigen-binding fragment of embodiment 12, wherein the plaque sarcoidosis is angiolupoid sarcoidosis, psoriasiform sarcoidosis, or verrucous sarcoidosis.
  • Embodiment 14 The anti-TL1A antibody or antigen-binding fragment of embodiment 1, wherein the sarcoidosis is ichthyosiform sarcoidosis.
  • Embodiment 16 The anti-TL1A antibody or antigen-binding fragment of embodiment 1, wherein the sarcoidosis is perforating sarcoidosis.
  • Embodiment 17. The anti-TL1A antibody or antigen-binding fragment of embodiment 1, wherein the sarcoidosis is pulmonary sarcoidosis.
  • Embodiment 18 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 1 to 17, wherein the anti-TL1A antibody or antigen binding fragment is administered in a pharmaceutical composition.
  • Embodiment 19 The anti-TL1A antibody or antigen-binding fragment of embodiment 18, wherein the pharmaceutical composition comprises anti-TL1A antibody or antigen binding fragment at a concentration greater than about 150 mg/mL. [0130] Embodiment 20.
  • Embodiment 21 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 18 to 20, wherein the pharmaceutical composition comprises anti-TL1A antibody or antigen binding fragment at a concentration about 125 mg/mL to about 175 mg/mL, about 125 mg/mL to about 200 mg/mL, about 125 mg/mL to about 225 mg/mL, about 150 mg/mL to about 200 mg/mL, about 150 mg/mL to about 225 mg/mL, about 150 mg/mL to about 250 mg/mL, about 175 mg/mL to about 225 mg/mL, about 175 mg/mL to about 250 mg/mL, about 175 mg/mL to about 275 mg/mL, about 200 mg/mL to about 250 mg/mL, or about 200 mg/mL to about 275 mg/mL.
  • Embodiment 22 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 18 to 21, wherein the pharmaceutical composition is administered subcutaneously.
  • Embodiment 23 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 18 to 21, wherein the pharmaceutical composition is administered intravenously.
  • Embodiment 24 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 18 to 23, wherein the pharmaceutical composition comprises about 150 mg to about 1000 mg of the anti-TL1A antibody or antigen binding fragment.
  • Embodiment 25 Embodiment 25.
  • Embodiment 26 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 18 to 25, wherein the pharmaceutical composition comprises a therapeutically effective dose of the anti-TL1A antibody or antigen binding fragment.
  • Embodiment 27 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 18 to 26, wherein the pharmaceutical composition has a viscosity of less than about 20cP, less than about 19cP, less than about 18cP, less than about 17cP, less than about 16cP, less than about 15cP, less than about 14cP, less than about 13cP, less than about 12cP, less than about 11cP, less than about 10cP, less than about 9cP, less than about 8cP, less than about 7cP, less than about 6cP, or less than about 5 cP.
  • Embodiment 28 Embodiment 28.
  • Embodiment 29 The anti-TL1A antibody or antigen-binding fragment of embodiment 28, wherein the surfactant comprises polysorbate-20, and wherein optionally the surfactant is present at a concentration of about 0.02% in the pharmaceutical composition.
  • Embodiment 30 The anti-TL1A antibody or antigen-binding fragment of embodiment 28 or 29, wherein the salt comprises NaCl, and wherein optionally the NaCl is at a concentration of about 40 mM in the pharmaceutical composition.
  • Embodiment 31 Embodiment 31.
  • Embodiment 32 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 28 to 31, wherein the buffering agent comprises sodium acetate, wherein optionally the sodium acetate is at a concentration of about 20 mM in the pharmaceutical composition.
  • Embodiment 33 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 28 to 32, wherein the pharmaceutical composition has a pH of about 5.3.
  • Embodiment 34 Embodiment 34.
  • Embodiment 35 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 1 to 34, wherein the anti-TL1A antibody or antigen binding fragment is administered to the subject at a first dose of about 500 mg.
  • Embodiment 36 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 1 to 35, wherein the anti-TL1A antibody or antigen binding fragment is administered to the subject at a second dose up to about 1000 mg.
  • Embodiment 37 Embodiment 37.
  • Embodiment 38 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 1 to 37, wherein the first dose is administered to the subject at a first time point, and the second dose is administered to the subject at a second time point.
  • Embodiment 39 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 1 to 38, wherein the first dose and the second dose is different or wherein the first dose and the second dose is identical.
  • Embodiment 40 Embodiment 40.
  • Embodiment 41 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 1 to 33, wherein the anti-TL1A antibody or antigen binding fragment is administered to the subject at an induction regimen.
  • Embodiment 42 The anti-TL1A antibody or antigen-binding fragment of embodiment 41, wherein the induction regimen comprises 500 mg/dose once every 4 weeks.
  • Embodiment 43 The anti-TL1A antibody or antigen-binding fragment of embodiment 41, wherein the induction regimen comprises 500 mg/dose once every 4 weeks.
  • Embodiment 44 The anti-TL1A antibody or antigen-binding fragment of embodiment 43, wherein the maintenance regimen comprises 500 mg/dose once every 4 weeks.
  • Embodiment 45 The anti-TL1A antibody or antigen-binding fragment of embodiment 43 or 44, wherein the induction regimen and the maintenance regimen are identical.
  • Embodiment 46 The anti-TL1A antibody or antigen-binding fragment of embodiment 43, wherein the induction regimen and the maintenance regimen are different.
  • Embodiment 47 Embodiment 47.
  • An anti-TL1A antibody or antigen-binding fragment for use in neutralizing monomeric TL1A and trimeric TL1A in a subject having sarcoidosis wherein the antibody or antigen binding fragment binds to both monomeric TL1A and trimeric TL1A, 25746 wherein the antibody or antigen binding fragment blocks interaction of TL1A to 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 without sarcoidosis, and wherein diseased tissue comprises any one or more selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, and other tissues afflicted by sarcoidosis.
  • Embodiment 49 An anti-TL1A antibody or antigen-binding fragment for use in reducing the concentration of TL1A in a diseased tissue in a subject with sarcoidosis, wherein the anti-TL1A antibody or antigen binding fragment is formulated in an effective dose for administration to the subject to reduce the concentration of TL1A in the diseased tissue in the subject below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis, wherein diseased tissue comprises any one or more selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, other and tissues afflicted by sarcoidosis.
  • Embodiment 50 An anti-TL1A antibody or antigen-binding fragment for use in the treatment of sarcoidosis in a subject in need thereof, wherein the anti-TL1A antibody or antigen binding fragment is administered at an effective dose such that the concentration of TL1A in a diseased tissue in the subject after the administration is below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis, and wherein diseased tissue comprises any one or more selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, and other tissues afflicted by sarcoidosis.
  • Embodiment 51 Embodiment 51.
  • Embodiment 52 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 48 to 51, wherein the sarcoidosis is cutaneous sarcoidosis.
  • Embodiment 53 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 48 to 51, wherein the sarcoidosis is pulmonary sarcoidosis.
  • Embodiment 54 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 48 to 53, wherein the effective dose comprises an induction regimen.
  • Embodiment 55 Embodiment 55.
  • Embodiment 56 The anti-TL1A antibody or antigen-binding fragment of embodiment 55, 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.
  • Embodiment 57 The anti-TL1A antibody or antigen-binding fragment of embodiment 56, wherein the induction regimen and the maintenance regimen are identical.
  • Embodiment 58 The anti-TL1A antibody or antigen-binding fragment of embodiment 56, wherein the induction regimen and the maintenance regimen are different.
  • Embodiment 59 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 56 to 58, wherein the maintenance regimen is administered after the induction regimen.
  • Embodiment 60 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 48 to 59, wherein the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen.
  • Embodiment 61 Embodiment 61.
  • the anti-TL1A antibody or antigen-binding fragment of any one of embodiments 48 to 59 wherein the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of start of the induction regimen.
  • Embodiment 62 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 48 to 59, wherein the diseased tissue in the subject produces up to 50, 25746 60, 70, 80, 90, 100, or more fold of TL1A compared to the corresponding tissue in the control subject.
  • Embodiment 63 Embodiment 63.
  • Embodiment 64 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 54 to 62, wherein the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment.
  • Embodiment 64 The anti-TL1A antibody or antigen-binding fragment of embodiment 63, wherein one-time administration of the anti-TL1A antibody or antigen binding fragment comprises an administration 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
  • Embodiment 65 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 54 to 62, wherein the induction regimen comprises multiple administrations of the anti-TL1A antibody or antigen binding fragment.
  • Embodiment 66 Embodiment 66.
  • Embodiment 67 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 54 to 62 or 65, 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.
  • Embodiment 68 Embodiment 68.
  • Embodiment 70 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 54 to 62, 65, or 67, wherein the induction regimen comprises administration once every 2, 4, 6, or 8 weeks. 25746 [0179] Embodiment 69. The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 54 to 62, 65, or 67, wherein 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. [0180] Embodiment 70.
  • Embodiment 71 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 55 to 66, wherein the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more fold of TL1A compared to the corresponding tissue in the control subject.
  • Embodiment 72 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 55 to 66, wherein the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • Embodiment 75 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 56 to 73, wherein the maintenance regimen comprises administration of the anti-TL1A 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.
  • Embodiment 76 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 56 to 73 or 75, wherein the maintenance regimen comprises administration of the anti-TL1A antibody or antigen binding fragment once every 2, 4, 6, 8, 10, or 12 weeks.
  • Embodiment 77 Embodiment 77.
  • Embodiment 78 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 56 to 76, wherein the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at 100 mg/dose every 4 weeks.
  • Embodiment 79 Embodiment 79.
  • Embodiment 80 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 49 to 79, wherein the antibody or antigen binding fragment binds to both monomeric TL1A and trimeric TL1A and wherein the antibody or antigen binding fragment blocks binding of TL1A to DR3.
  • Embodiment 81 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 56 to 78, wherein the maintenance regimen continues for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, or 52 weeks.
  • Embodiment 80 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 49 to 79, wherein the antibody or antigen binding fragment binds to both monomeric TL1A and trimeric TL1A and wherein the antibody or antigen binding fragment blocks binding of TL1A to DR3.
  • Embodiment 82 Embodiment 82.
  • the anti-TL1A antibody or antigen-binding fragment of any one of embodiments 48 to 82 wherein binding affinity of the antibody or antigen binding fragment to monomeric TL1A as measured by dissociation equilibrium constant (KD- monomer) is comparable to binding affinity of the antibody or antigen binding fragment to trimeric TL1A as measured by dissociation equilibrium constant (KD-trimer).
  • KD- monomer monomeric TL1A as measured by dissociation equilibrium constant
  • KD-trimer dissociation equilibrium constant
  • Embodiment 84 The anti-TL1A antibody or antigen-binding fragment of embodiment 83, wherein the KD-monomer is within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold of the KD-trimer.
  • Embodiment 86 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 83 to 85, wherein the KD-trimer is no more than 0.06 nM.
  • Embodiment 87 Embodiment 87.
  • 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 over-production in the diseased tissue comparing to TL1A production in a normal reference tissue; (ii) integrating the parameters received in (a) to an integrated whole-body physiologically based pharmacokinetic (PBPK) model or a population pharmacokinetic model (popPK); and (iii) determining the effective dose or the induction regimen such that the concentration of TL1A in diseased tissue in the subject after step (a) is below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis [0198]
  • Embodiment 88 Embodiment 88.
  • the anti-TL1A antibody or antigen-binding fragment of embodiment 87 wherein the parameter of TL1A over-production 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, or more fold over-production comparing to TL1A production in the normal reference tissue.
  • Embodiment 89 Embodiment 89.
  • the maintenance regimen is determined by a dose determination method, wherein the dose determination method comprises: (i) receiving a parameter of TL1A over-production in the diseased tissue comparing to TL1A production in a normal reference tissue; 25746 (ii) integrating the parameter received in (i) to an integrated whole-body physiologically based pharmacokinetic (PBPK) model or a population pharmacokinetic model (popPK); and (iii) determining the maintenance regimen such that the concentration of TL1A in diseased tissue in the subject after step (c) is below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis.
  • PBPK physiologically based pharmacokinetic
  • popPK population pharmacokinetic model
  • Embodiment 90 The anti-TL1A antibody or antigen-binding fragment of embodiment 89, wherein the parameter of TL1A over-production is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, or more fold over-production comparing to TL1A production in the normal reference tissue.
  • Embodiment 91 Embodiment 91.
  • the anti-TL1A antibody or antigen-binding fragment of embodiment to 91 wherein the association rate of the antibody to TL1A (kon-mAb) comprises the association rate of the antibody to monomeric TL1A (k on-monomer ) and association rate of the antibody to trimeric TL1A (kon-trimer), wherein the dissociation rate of the antibody from TL1A (k off-mAb ) comprises the dissociation rate of the antibody from monomeric TL1A (k off- monomer) and dissociation rate of the antibody from trimeric TL1A (koff-trimer), and/or wherein the degradation rate of TL1A (k deg-total-TL1A ) comprises degradation rate of monomeric TL1A (kdeg-TL1A-monomer) and degradation rate of trimeric TL1A (kdeg-TL1A-trimer).
  • Embodiment 93 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 87 to 92, wherein the step (i) in the dose determination method further comprises receiving association rate of the antibody to FcRn receptor (k on-mAb-FcRn ), dissociation rate of the antibody from FcRn (koff- mAb-FcRn), association rate of the antibody- TL1A complex to FcRn receptor (k on-(mAb-TL1A)-FcRn ), and/or dissociation rate of the antibody- TL1A complex from FcRn (koff-(mAb-TL1A)-FcRn).
  • Embodiment 94 Embodiment 94.
  • the anti-TL1A antibody or antigen-binding fragment of embodiment 93 wherein the association rate of the antibody- TL1A complex to FcRn receptor (k on-(mAb-TL1A)-FcRn ) comprises association rate of the antibody-monomeric-TL1A complex to FcRn receptor (kon-(mAb-monoTL1A)-FcRn) and association rate of the antibody- 25746 trimeric-TL1A complex to FcRn receptor (kon-(mAb-triTL1A)-FcRn), and/or wherein the dissociation rate of the antibody- TL1A complex from FcRn (k off-(mAb-TL1A)-FcRn ) comprises dissociation rate of the antibody-monomeric-TL1A complex from FcRn (koff-(mAb-monoTL1A)- FcRn ) and dissociation rate of the antibody-trimeric-TL1A complex from FcRn (k off-(mAb- tri
  • Embodiment 95 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 87 to 94, wherein the step (i) in the dose determination method further comprises receiving clearance rate of FcRn receptor bound by the antibody (k deg-mAb-FcRn ).
  • Embodiment 96 Embodiment 96.
  • the anti-TL1A antibody or antigen-binding fragment of embodiment 95 wherein the clearance rate of FcRn receptor bound by the antibody (k deg-mAb- FcRn) comprises clearance rate of the antibody to FcRn bound by the antibody-monomeric- TL1A complex (k deg-(mAb-monoTL1A)-FcRn ) and clearance rate of FcRn receptor bound by the antibody-trimeric-TL1A complex (kdeg-(mAb-triTL1A)-FcRn).
  • the clearance rate of FcRn receptor bound by the antibody comprises clearance rate of the antibody to FcRn bound by the antibody-monomeric- TL1A complex (k deg-(mAb-monoTL1A)-FcRn ) and clearance rate of FcRn receptor bound by the antibody-trimeric-TL1A complex (kdeg-(mAb-triTL1A)-FcRn).
  • the anti-TL1A antibody or antigen-binding fragment of any one of embodiments 91 to 96 wherein in the dose determination method: (1) kon-monomer and kon-trimer are identical or different; (2) koff-monomer and koff-trimer are identical or different; (3) kdeg- monomer and kdeg-trimer are identical or different; (4) kon-(mAb-monoTL1A)-FcRn and kon-(mAb-triTL1A)-FcRn are identical or different; (5) kon-mAb-FcRn and kon-(mAb-monoTL1A)-FcRn are identical or different; (6) k on-mAb-FcRn and k on-(mAb-triTL1A)-FcRn are identical or different; (7) k off-(mAb-monoTL1A)-FcRn and koff-(mAb-triTL1A)-FcRn are identical or different; (8) koff-
  • Embodiment 98 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 87 to 97, wherein in the dose determination method: k syn-disease is up to 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, or more fold of ksyn-normal.
  • Embodiment 99 Embodiment 99.
  • step (i) in the dose determination method further comprises receiving rate of TL1A trimerization (k on-TL1A-monomer-to-trimer ) and/or rate of TL1A monomerization (koff-TL1A-trimer-to-monomer).
  • step (i) in the dose determination method further comprises receiving rate of TL1A trimerization (k on-TL1A-monomer-to-trimer ) and/or rate of TL1A monomerization (koff-TL1A-trimer-to-monomer).
  • a heavy chain 25746 variable region comprising: an HCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 1, an HCDR2 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 2-5, and an HC
  • Embodiment 101 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 1 to 100, wherein the anti-TL1A 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 no or fewer than nine amino acid modification(s) from the human IGHV1-46*02 framework and the human IGKV3-20 framework.
  • Embodiment 102 Embodiment 102.
  • Embodiment 103 Embodiment 103.
  • Embodiment 104 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 1 to 99, wherein the anti-TL1A antibody comprises a heavy chain variable region comprising: an HCDR1 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 401, 407, 413, or 450, an HCDR2 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 402, 408, 414, or 451, and an HCDR3 comprising an 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 an amino acid sequence set forth by any one of SEQ ID NOS: 404, 410, 416, or 453, an LCDR2 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 405, 411, 417, or 454, an LCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 401
  • Embodiment 105 The anti-TL1A antibody or antigen-binding fragment of any one of embodiments 1 to 99 or embodiment 104, wherein the anti-TL1A antibody comprises a heavy chain variable domain comprising an amino acid sequence at least 96% identical to any one of SEQ ID NOS: 420-427, and a light chain variable domain comprising an amino acid sequence at least 96% identical to any one of SEQ ID NOS: 430-437.
  • BRIEF DESCRIPTION OF THE FIGURES [0216] 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. [0217] Exemplary embodiments are illustrated in referenced figures.
  • FIGS.1A-1C show chromatograms for analytical size exclusion chromatography of anti-TL1A antibodies. The large peaks (main peak) correspond to monomeric fraction. The percentage of monomeric sample is indicated for each antibody.
  • FIG.1A shows chromatographs for antibodies A193, A194, and A195.
  • FIG.1B shows chromatographs for antibodies A196, A197, and A198.
  • FIG.1C shows chromatographs for antibodies A199, A200, and A201.
  • FIG.2 depicts inhibition of interferon gamma in human blood with anti-TL1A antibodies.
  • FIG.3A depicts the comparison between the predicted and measured viscosity.
  • FIG.3B shows a PLS graph (x-axis is pH, y-axis is protein concentration (mg/ml), z-axis is viscosity (mPa-s) for the PLS graphs),
  • FIG.3C shows a model of the predicted viscosity (y-axis, mPa-s) versus anti-TL1A antibody concentration (x- axis) in mg/mL, and
  • FIG.3D shows a model of the estimated viscosity (y-axis, mPa-s) versus actual viscosity (x-axis, mPa-s).
  • FIG.3E depicts the effects of pH versus acetate concentration on viscosity.
  • FIG.3F shows the effect of sucrose versus NaCl on viscosity.
  • FIG.3G depicts the effect of Arg-HCl versus Lys-HCl on viscosity. Viscosity units are in mPa-s. The arrow points to the region of highest viscosity. The star corresponds to the region of lowest viscosity.
  • FIG.4A depicts the PLS1 model for the effect on high molecular weight (HMW) aggregates.
  • FIG.4B depicts the effect of pH versus acetate on aggregation.
  • FIG. 4C depicts the effect of sucrose versus NaCl concentration.
  • FIG.4D depicts the effect of Arg-HCl versus Lys-HCl on aggregation.
  • FIG.4E depicts the effect of sucrose concentration versus Lys-HCl concentration.
  • FIG.5A depicts the predicted versus measured loss of main peak at 2 weeks and 25°C.
  • FIG.5B depicts the effect of pH and protein concentration on the loss of main peak in the CEX profile.
  • FIG.5C depicts the effect of pH and acetate concentration on the loss of main peak in the CEX profile.
  • FIG.5D depicts the effect of sucrose and NaCl concentration on the loss of main peak in the CEX profile.
  • FIG.5E depicts the effect of Lys- HCl and sucrose concentration on the loss of main peak in the CEX profile.
  • FIG.6A depicts the loss of monomer by SEC with agitation.
  • FIG.6B depicts the loss of monomer by SEC with freeze-thaw.
  • FIG.8 demonstrates that TL1A drives inflammation and fibrosis through binding to DR3.
  • FIGS.9A-9C demonstrates size-exclusion chromatography (SEC) profiles of recombinant human TL1A (rhTL1A). Briefly, rhTL1A was labeled with Alexa fluor 488 (AF488) and spiked into normal human serum (NHS). In FIG.9A, when injected alone, rhTL1A SEC profile shows two peaks on SEC, representing trimeric and monomeric forms of TL1A.
  • SEC size-exclusion chromatography
  • FIG.9B when rhTL1A is pre-incubated with a control reference antibody, the trimeric peak was shifted leftward, indicating a larger complex formation of the reference antibody and trimeric rhTL1A. There was no shift in the monomeric peak, indicating that the reference antibody only binds to the trimeric rhTL1A.
  • FIG.9C when rhTL1A is pre- incubated with A219, both the trimeric and the monomeric rhTL1A peaks were shifted, thus indicating that A219 binds both trimeric and monomeric forms of TL1A.
  • FIG.10A depicts a whole-body physiologically based pharmacokinetic (PBPK) model.
  • FIG.10B depicts a tissue-level diagram of the integrated whole-body PBPK model used to characterize the PK of the monoclonal antibody (mAb), ligand, and complex between mAb and ligand.
  • FIG.11A depicts the comparison of the pharmacokinetics of the mAb as predicted by the integrated whole-body PBPK (solid curve) with the pharmacokinetics of the mAb as observed in normal healthy volunteers (various points with points from the same subject shown by the same format), in each case after injection of A219 at the indicated dose.
  • FIG.11B depicts the comparison of the TL1A concentration as predicted by the integrated whole-body PBPK with the TL1A concentration as observed in normal healthy volunteers, in each case after injection of A219 at the indicated dose.
  • FIG.12A depicts the observed concentration of TL1A in serum after injecting (i) an anti-TL1A antibody A219 that binds to both TL1A monomer and trimer (shown in red, top of the 2 curves, and the observed data points accompanying such curve) and (ii) a control reference anti-TL1A antibody that binds to only TL1A trimer (shown in blue, bottom of the 2 curves, and the observed data points accompanying such curve).
  • FIG.12A solid curves depict the prediction from the model and various dots depict the observations from subjects injected with the indicated antibodies.
  • FIG.12B depicts the predicted total TL1A concentration (monomer and trimer, solid curve and the observed data points accompanying such curve), the monomer TL1A concentration (fine dotted line), and the trimer TL1A 25746 concentration (coarse dotted line), in each case at the basal level (no injection of any anti- TL1A antibodies).
  • FIG.12C depicts the serum TL1A concentration in normal healthy volunteers (NHV) and UC patients, as predicted by the whole-body PBPK model (solid lines, upper line for UC patient and lower line for NHV) and as observed (various points).
  • FIGS.13A-13B demonstrate the fitness of the model.
  • FIG.13A depicts the observed concentration of TL1A in serum of NHVs after injecting an anti-TL1A antibody that binds to only TL1A trimer (dots) and the prediction of the model (solid curve) that fits the observations at the indicated dose.
  • Q2WX3 every 2 weeks for three times.
  • FIG.13B depicts the observed concentration of TL1A in serum of UC patients after injecting an anti- TL1A antibody that binds to only TL1A trimer (dots) and the prediction of the model (solid curve) that fits the observations at the indicated dose.
  • Q2WX7 every 2 weeks for seven times.
  • FIG.13C depicts the concentration of TL1A in intestine of NHV (black, solid, lower line of the two lines as predicted from the model and the observed data points accompanying such line) and the concentration of TL1A in the intestine of UC patient (red, solid, upper line of the two lines).
  • FIGS.14A-14B depict the baseline concentration of TL1A based on various parameters of TL1A production in intestine (14A) and in serum (14B). In FIGS.14A-14B, 1 ⁇ would be the baseline in NHV; 25 ⁇ , 50 ⁇ , 75 ⁇ , and 100 ⁇ indicate various parameters of TL1A over-production in intestine.
  • FIGS 15A-15V depict the concentration of free soluble TL1A in tissue as determined by the whole-body PBPK model according to various parameters of TL1A overproduction under various dose regimen of anti-TL1A antibody A219 as indicated.
  • FIG. 15W depicts the free soluble TL1A in tissue as determined by the whole-body PBPK model according to various parameters of TL1A overproduction under the dose regimen of a reference anti-TL1A antibody as indicated.
  • FIGS.15X-15Z depict the comparison of the modeled free soluble TL1A concentration in subjects treated with a reference anti-TL1A antibody (red, the upper curve of the two curves) or A219 (green, the lower curve of the two curves).
  • reference antibody light chain sequence is SEQ ID NO: 382
  • heavy chain sequence is SEQ ID NO: 383
  • the whole-body PBPK model uses a rapid equilibrium between the monomeric and trimeric form of TL1A with a continuous 60:40 ratio of monomer and trimer as observed.
  • the black solid lines in FIGS.15A-15Z indicate the TL1A concentration in the tissue of NHV.
  • Q2W every 2 weeks.
  • Q4W every 4 weeks.
  • SC subcutaneous.
  • LD loading dose (the first dose).
  • 4W week 4.
  • D1 day 1.
  • W 2, 6, 10 week 2, week 6, and week 10.
  • FIGS 16A-16H depict the goodness of fit plots for A219 with the population PK model.
  • FIG.17A depicts the visual predictive check for the A219 concentration predicted from the popPK model against the observed A219 concentration.
  • FIG.17B depicts an induction dose selected in the popPK model to rapidly achieve steady state concentration.
  • FIG.18 depicts osmotic pressures at 5°C measured for the stability of A219 samples of various formulations at T0, 3 and 6 months.
  • FIG.19 depicts A219 protein concentration at 5°C measured for evaluating the stability of A219 samples of various formulations at T0, 3 and 6 months.
  • FIG.20 depicts pH at 5°C measured for the evaluating the stability A219 samples of various formulations at T0, 3 and 6 months.
  • FIG.21A depicts viscosity data for T0 and 3M for Formulations 1 to 5 at 25°C;
  • FIG.21B depicts viscosity data for T0 and 3M for Formulations 6 to 8 at 25°C.
  • FIG.22A depicts monomer contents for formulations at 5°C as measured by SEC;
  • FIG.22B depicts loss of monomer (main peak) per month for the formulations at 5°C as determined by SEC;
  • FIG.22C depicts monomer contents for formulations at 25°C as measured by SEC;
  • FIG.22D depicts loss of monomer (main peak) per month for the formulations at 5°C as determined by SEC.
  • FIG.23A depicts the relative area (%) of the main peak for formulations at 5°C as characterized by cation exchange chromatography;
  • FIG.23B depicts the loss of main peak (Rel.
  • FIG.24A depicts predicted vs. measured values according to the PLS model using monomer loss by SEC for samples stored for 2 months at 25°C as the endpoint;
  • FIG. 24B depicts effect of pH and protein according to the PLS model using monomer loss by SEC for samples stored for 2 months at 25°C as the endpoint.
  • FIG.24B the sucrose concentration was fixed at 200 mM.
  • FIG.24C depicts effect of pH and acetate according to the PLS model using monomer loss by SEC for samples stored for 2 months at 25°C as the 25746 endpoint.
  • the sucrose concentration was fixed at 200 mM.
  • FIG.24D depicts effect of sucrose and lysine according to the PLS model using monomer loss by SEC for samples stored for 2 months at 25°C as the endpoint.
  • the protein concentration was fixed at 150 mg/mL, pH at 5.5 and acetate at 20 mM.
  • FIG.24E depicts effect of glycine and NaCl according to the PLS model using monomer loss by SEC for samples stored for 2 months at 25°C as the endpoint.
  • the protein concentration was fixed at 150 mg/mL, pH at 5.5 and acetate at 20 mM.
  • the formulations 1-8 (F01-F08, Form.1-8, or simply 1-8) referenced therein are the formulations 1-8 as described in Table 31 of Example 22.
  • FIG.25 shows the scheme of double blind, randomized, placebo-controlled clinical study to evaluate the efficacy and safety of A219 in subjects with pulmonary sarcoidosis.
  • FIG.26A shows geometric mean serum A219 concentration-time profiles following single doses of A219 administered as IV infusion (Linear Scale) (SAD study).
  • FIG.27A shows geometric mean serum sTL1A concentration versus nominal time following single dose of A219 administered as IV Infusion (semi-log scale) (SAD study).
  • FIG.27B geometric mean serum sTL1A concentration versus nominal time following multiple doses of A219 Q2W administered as IV infusion (semi-log scale) (MAD study).
  • FIG.28A shows total A219 concentration in the central compartment (in circulation) in SAD as predicted by the model (curves) and as determined in the phase I trial (dots).
  • FIG.28B shows total soluble TL1A in the central compartment (circulation) in SAD as predicted by the model (curves) and as determined in the phase I trial.
  • FIG.28C shows total A219 concentration in the central compartment (in circulation) in MAD as predicted by the model (curves) and as determined in the phase I trial (dots).
  • FIG.28D shows total soluble TL1A in the central compartment (circulation) in MAD as predicted by the model (curves) and as determined in the phase I trial (dots). The predicted curves fitted with the measured data points.
  • FIGS.28E-28K show model prediction for and the data of a control reference antibody that binds only to TL1A trimer (light chain SEQ ID NO: 382 and heavy 25746 chain SEQ ID NO: 383) with regard to (1) phase I single ascending dose data (FIGS.28E and 28F), (2) phase I multiple ascending dose data (FIGS.28G and 28H), and (3) phase II data on PK & total sTL1A levels (FIGS.28I and 28J).
  • FIG.29A shows doses of A219 determined from the validated model that can bring the free TL1A concentration in the patient’s diseased tissue to below the TL1A concentration of a healthy subject.
  • FIG.29B shows the percent reduction of the free TL1A in the diseased tissue after administering doses of A219 as determined from the model.
  • IV_4 ⁇ 1000 mg loading dose, 3 ⁇ 500 mg on days 14, 42, 70.
  • FIG.29C shows that, in a head-to-head comparison in the validated model, anti- TL1A antibodies that bind to both TL1A monomer and trimer engaged more (3.5 fold more) TL1A in circulation than anti-TL1A antibodies that only bind to TL1A trimer.
  • FIG.29D shows that, in a head-to-head comparison in the validated model, anti-TL1A antibodies that bind to both TL1A monomer and trimer also resulted in higher percentage of TL1A reduction of TL1A in diseased tissue (about 100%) when compared to anti-TL1A antibodies that only bind to TL1A trimer.
  • FIG.30A shows the diagram of a popPK model.
  • FIG.30B shows the comparison of the A219 concentration predicted from the popPK model and the A219 concentration observed in the population of subjects in phase I clinical trial via a linear regression plot.
  • FIG.30C shows the comparison of the TL1A concentration predicted from the popPK model and the TL1A concentration observed in the population of subjects in phase I clinical trial via a linear regression plot.
  • FIG.30D shows the comparison of the A219 concentration predicted from the popPK model and the A219 concentration observed in the population of subjects in phase I clinical trial via a time series plot.
  • FIG.30E shows the comparison of the TL1A concentration predicted from the popPK model and the TL1A concentration observed in the population of subjects in phase I clinical trial via a time series plot.
  • FIGS.31A-31H show the A219 and TL1A engagement (TL1A concentration in serum) predicted from the validated popPK model under various A219 doses.
  • FIGS.31A and 31B show A219 concentration (31A) and TL1A concentration (31B) in circulation with a dosing regimen of induction with 500 mg Q2W (6 doses) up to week 10 and extension with 500 mg Q2W from week 12 to week 52 (20 doses).
  • FIGS.31C and 31D show A219 25746 concentration (31C) and TL1A concentration (31D) in circulation with a dosing regimen of induction with 500 mg Q2W (6 doses) up to week 10 and extension with 500 mg Q4W from week 12 to week 52 (10 doses).
  • FIGS.31E and 31F show A219 concentration (31E) and TL1A concentration (31F) in circulation with a dosing regimen of induction with 500 mg Q2W (6 doses) up to week 10 and extension with 100 mg Q2W from week 12 to week 52 (20 doses).
  • FIGS.31G and 31H show A219 concentration (31G) and TL1A concentration (31H) with a dosing regimen of induction with 500 mg Q2W (6 doses) up to week 10 and extension with 250 mg Q4W from week 12 to week 52 (10 doses).
  • FIG.32A shows TL1A (TNFSF15) gene expression and upregulation of DR3 (TNFRSF25) gene expression in BAL cells from sarcoidosis patients compared to BAL cells from healthy volunteers.
  • FIGS.33A-33B depict various pathway gene expression signatures evaluated by GSVA score. Th1, Th2, and Th17 (FIG.33A) pathways were elevated in BAL cells from sarcoidosis patients compared to BAL cells from healthy volunteer (FIGS.33A) and in lesional skin samples compared to non-lesional skin from cutaneous sarcoidosis patients or skin samples from healthy control subjects (FIG.33B).
  • FIGS.34A-34B depict fibrosis pathway gene expression signatures evaluated by GSVA score.
  • FIGS.35A-35B depict TL1A induced genes in Th17 cells and TL1A induced genes in IFNg producing cells as evaluated by GSVA score.
  • TL1A induced genes in Th17 cells FIG.35A, left panel
  • TL1A induced genes in IFNg producing cells FIG.35A, right panel
  • FIGS.36A-36B depict TL1A expression profiles of sarcoidosis pathway genes as evaluated by modified GSVA score.
  • TL1A target genes identified from sarcoidosis 25746 disease network (FIG.36A) was upregulated in BAL cells from sarcoidosis patients compared to BAL cells from healthy volunteer.
  • FIGS.37A-37D depict TL1A and DR3 expression in various cell types in the lung.
  • each dot represents one cell where the expression of TNFSF15 gene (top panel) or TNFRSF25 (bottom panel) was detected.
  • the y-axis in FIG.37A indicates gene expression level as normalized to the overall RNA sequencing read.
  • FIG.37A shows that, among the various lung tissues, TL1A (TNFSF15) was expressed by epithelial cells (AT1, AT2, Basal, KRT5-KRT17+, transitional AT2), secretory (SCGB3A2) and immune cells (macrophages and monocytes), and DR3 (TNFRSF25) was highly expressed by T cells and expressed by a lower percentage of other immune cells including macrophages, and NK cells.
  • FIGS.37B-37D dot plots show increased level of protein expression of TL1A ligand in epithelial (FIG.37B) and secretory cells (FIG.37C) and increased level of protein expression of DR3 receptor in T and NK cells (FIG.37D) pulmonary sarcoidosis lung.
  • the color scale represents the expression levels and the diameter represents the percentage, as indicated in the legend at the top.
  • FIGS.38A-38B depict TL1A gene expression as detected by fluorescence in- situ hybridization (FISH) in lung tissues from pulmonary sarcoidosis patients.
  • FISH fluorescence in- situ hybridization
  • FIG.38B shows a zoom-in view of the boxed region indicated in FIG.38A, with TL1A stained in red, autofluorescence in green, and nuclei in blue.
  • the scale bar in FIG.38B is 20 ⁇ m.
  • FIGS.39A-39B depict TL1A and DR3 protein expression as detected in skin tissues from sarcoidosis patients.
  • FIGS.39A-39B The immunohistochemistry staining of sarcoidosis afflicted skin samples reveals TL1A (FIG.39A with anti-TL1A staining shown in brown) and DR3 (FIG.39B with anti-DR3 staining shown in brown) are highly expressed in granuloma cells (FIGS.39A-39B).
  • TL1A FIG.39A with anti-TL1A staining shown in brown
  • DR3 FIG.39B with anti-DR3 staining shown in brown
  • FIGS.39A-39B blue indicates cell nuclei staining by hematoxylin.
  • the scale bar in FIGS.39A-39B is 100 ⁇ m.
  • FIGS.39C-39D depict TL1A (39C) and DR3 (39D) protein expression as detected in healthy control skin tissues.
  • TL1A is a cytokine that is secreted by antigen-presenting cells, T cells, epithelial and endothelial cells.
  • TL1A signals through death receptor 3 (DR3), a TNF-family receptor that is found primarily on T cells, natural killer (NK) and NK-T cells, innate lymphoid cells (ILC), fibroblasts, and epithelial cells and potently drives Th1, Th2, Th9, and Th17 responses.
  • DR3 death receptor 3
  • TNF-family receptor that is found primarily on T cells, natural killer (NK) and NK-T cells, innate lymphoid cells (ILC), fibroblasts, and epithelial cells and potently drives Th1, Th2, Th9, and Th17 responses.
  • TLR toll like receptor
  • FcR FcR cross-linking
  • T cells T cell receptor
  • FIG.8 demonstrates how TL1A binding to DR3 independently drives inflammation and fibrosis.
  • TL1A is a pleiotropic cytokine that can promote secretion of several downstream cytokines including IFN ⁇ , IL1, IL6, IL11, IL17 and TGF ⁇ that are produced by macrophages and T cells.
  • TL1A-DR3 pathway activation on Teffector cells is potentiated by IL12, IL18 cytokines and enhances IFN ⁇ and IL17 production, driving granuloma formation in sarcoidosis.
  • IL1 mediated lung fibrosis is dependent on IL17A, can activate human lung fibroblasts and induces elevated IL6 from sarcoidosis fibroblasts relative to controls.
  • IL6 can also be produced from macrophages and blockade of this pathway attenuates pulmonary fibrosis.
  • IL-11 is a pro-fibrotic cytokine that can be secreted by immune cells, epithelial cells and human primary fibroblasts.
  • IL11 can promote fibroblast activation in an autocrine manner and blockade of this pathway attenuates lung fibrosis in mice.
  • TGF ⁇ can promote fibrosis through activation of fibroblasts.
  • levels of circulating TL1A are low in healthy subjects, the inventors recognize that they are elevated in patients suffering from sarcoidosis, including pulmonary sarcoidosis and/or cutaneous sarcoidosis.
  • sarcoidosis include pulmonary sarcoidosis and/or cutaneous sarcoidosis.
  • provided herein are methods of treating cutaneous sarcoidosis with an anti-TL1A antibody or an antigen binding fragment. In one aspect, provided herein are methods of treating lupus pernio with an anti-TL1A antibody or an antigen binding fragment. In one aspect, provided herein are methods of treating papular sarcoidosis with an anti-TL1A antibody or an antigen binding fragment. In one aspect, provided herein are methods of treating nodular sarcoidosis with an anti-TL1A antibody or an antigen binding fragment. In one aspect, provided herein are methods of treating Darier-Roussy sarcoidosis with an anti-TL1A antibody or an antigen binding fragment.
  • provided herein are methods of treating maculopapular sarcoidosis with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating hypopigmented sarcoidosis with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating atrophic and ulcerative sarcoidosis with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating neurologic sarcoidosis with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating cardiac sarcoidosis with an anti-TL1A antibody or antigen binding fragment.
  • provided herein are methods of treating gastrointestinal sarcoidosis with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating hepatic sarcoidosis with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating pancreatic sarcoidosis with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating peritoneal sarcoidosis with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating sarcoidosis of bones with an anti-TL1A antibody or antigen binding fragment.
  • provided herein are methods of treating sarcoid arthropathy with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating plaque sarcoidosis with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating angiolupoid sarcoidosis with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating psoriasiform sarcoidosis with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating verrucous sarcoidosis with an anti-TL1A antibody or antigen binding fragment.
  • provided herein are methods of treating ichthyosiform sarcoidosis with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating erythrodermic sarcoidosis with an anti-TL1A antibody or antigen binding fragment. In one aspect, provided herein are methods of treating perforating sarcoidosis with an anti-TL1A antibody or antigen binding fragment.
  • the anti-TL1A antibodies bind to membrane-bound and soluble forms of TL1A with high affinity and specificity and block the binding of TL1A to its functional receptor DR3.
  • the term “and/or” as used in a phrase with a list of members is intended to include all members individually and all combination of full or partial list of members.
  • a phrase such as “A and/or B” herein is intended to include both A and B; A or B; 25746 A (alone); and B (alone).
  • the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass 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).
  • TL1A exists in both monomeric and trimeric form in vivo and in vitro.
  • the disclosure provides that although the trimeric form is the 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 accounts for a large fraction of the TL1A pool in a subject. By one of the inventors’ estimates, the monomeric TL1A can be 60% of the total TL1A in the circulating blood.
  • total TL1A refers to both monomeric and trimeric TL1A.
  • the disclosure further provides that, despite monomeric TL1A being biologically inactive, anti-TL1A antibodies binding to both monomeric and trimeric TL1A provide advantages over antibodies binding to only trimeric TL1A.
  • advantages include more efficient reduction of the TL1A concentration in a diseased tissue in a subject including the concentration trimeric TL1A in the diseased tissue, more efficient reduction of the TL1A concentration in the blood in a subject including the concentration trimeric TL1A in the blood, more sustained reduction of TL1A concentration (including trimeric TL1A concentration) in a diseased tissue in a subject, and/or more sustained reduction of TL1A concentration (including trimeric TL1A concentration) in the blood in a subject.
  • antibodies or antigen binding fragments thereof that bind to tumor necrosis factor-like protein 1A (“TL1A,” and such antibody or antigen binding fragment thereof, “anti-TL1A antibody or antigen binding fragment” or “anti-TL1A antibody(ies)” in the specification for simplicity), wherein the antibodies or 25746 antigen binding fragments bind to both monomeric TL1A and trimeric TL1A.
  • T1A tumor necrosis factor-like protein 1A
  • anti-TL1A antibody or antigen binding fragment or anti-TL1A antibody(ies)” in the specification for simplicity
  • Assays for screening, testing, and validating the anti-TL1A antibodies are provided in Section [0379]. Methods for generating, improving, mutating, cloning, expressing, and isolating the anti- TL1A antibodies are provided in Section [0385]. Pharmaceutical compositions for the anti- TL1A antibodies are described and provided in Section [0416]. Methods of using the anti- TL1A antibodies are provided in Section [0456]. Further specific and validated embodiments for the anti-TL1A antibodies and the methods of using the same are provided in Section [0551].
  • the disclosure provides the various combinations of the anti-TL1A antibodies, the pharmaceutical compositions of such anti-TL1A antibodies, the methods of generating the anti-TL1A antibodies, the methods of assaying the anti-TL1A antibodies, and the methods of using the anti-TL1A antibodies for treatment.
  • the antibody or antigen binding fragment blocks binding of TL1A to Death Receptor 3 (“DR3”).
  • the antibody or antigen binding fragment blocks the binding of trimeric TL1A to DR3.
  • the antibody or antigen binding fragment blocks the signaling DR3 signaling mediated by TL1A.
  • the antibody or antigen binding fragment blocks the increase of IFN ⁇ secretion by various immune cells.
  • the antibody or antigen binding fragment blocks the increase of IFN ⁇ secretion by peripheral blood mononuclear cells, including various B cells, T cells, natural killer cells, and/or macrophages.
  • peripheral blood mononuclear cells including various B cells, T cells, natural killer cells, and/or macrophages.
  • binding affinity of the antibody or antigen binding fragment to monomeric TL1A as measured by dissociation equilibrium constant (KD-monomer) is comparable to binding affinity of the antibody or antigen binding fragment to trimeric TL1A as measured by dissociation equilibrium constant (KD-trimer).
  • KD-monomer and/or KD-trimer can be determined via any of the and practice by a in the field and via any of the applicable assays and methods described herein, including in this Section (Section [0265]) and Section [0551]. 25746 [0267]
  • the terms “binds” or “binding” refer to an interaction between molecules including, for example, to form a complex.
  • Interactions can be, for example, non-covalent interactions including hydrogen bonds, ionic bonds, hydrophobic interactions, and/or van der Waals interactions.
  • a complex can also include the binding of two or more molecules held together by covalent or non-covalent bonds, interactions, or forces.
  • the strength of the total non-covalent interactions between a single antigen-binding site on an antibody and a single epitope of a target molecule, such as TL1A is the affinity of the antibody or functional fragment for that epitope.
  • the ratio of dissociation rate (k off ) to association rate (k on ) of an antibody to a monovalent antigen (koff/kon) is the dissociation constant KD, which is inversely related to affinity.
  • K D the affinity of the antibody.
  • KD the affinity of an antibody provided herein
  • the affinity at one binding site does not always reflect the true strength of the interaction between an antibody and an antigen.
  • complex antigens containing multiple, repeating antigenic determinants such as a polyvalent TL1A trimer, come in contact with antibodies containing multiple binding sites, the interaction of antibody with antigen at one site will increase the probability of a reaction at a second site.
  • the strength of such multiple interactions between a multivalent antibody and antigen is called the avidity.
  • Binding affinity generally refers to the strength of the sum total of 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., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). As described above, the affinity of a binding molecule X for its binding partner Y can generally be represented by the dissociation constant (K D ).
  • Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster 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 purposes of the present disclosure. Specific illustrative embodiments include the following.
  • the “KD” or “K D value” can be measured by assays known in the art, for example by a binding assay. The KD can be measured in a RIA, for example, performed with the Fab version of an antibody of 25746 interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81).
  • the KD or KD value can also be measured by using surface plasmon resonance assays by Biacore ® , using, for example, a Biacore ® TM-2000 or a Biacore ® TM-3000, or by biolayer interferometry using, for example, the Octet ® QK384 system.
  • An “on-rate” or “rate of association” or “association rate” or “kon” can also be determined with the same surface plasmon resonance or biolayer interferometry techniques described above using, for example, a Biacore ® TM-2000 or a Biacore ® TM-3000, or the Octet ® QK384 system.
  • the relative binding affinity of the anti-TL1A antibody or antigen binding fragment for the TL1A monomer and TL1A trimer can be described and provided by K D-monomer and K D-trimer .
  • the KD-monomer is within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold of the K D-trimer .
  • the KD-monomer is within 10%, 20%, 30%, 40%, or 50% of the K D-trimer .
  • the KD-trimer is within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold of the KD- monomer. In another embodiment of the various anti-TL1A antibodies or antigen binding fragments provided herein, the KD-trimer is within 10%, 20%, 30%, 40%, or 50% of the KD- monomer.
  • KD-monomer is at most 5 ⁇ 10 -12 M, at most 6 ⁇ 10 -12 M, at most 7 ⁇ 10 -12 M, at most 8 ⁇ 10 -12 M, at most 9 ⁇ 10 -12 M, at most 1 ⁇ 10 -11 M, at most 2 ⁇ 10 -11 M, at most 3 ⁇ 10 -11 M, at most 4 ⁇ 10 -11 M, at most 5 ⁇ 10 -11 M, at most 6 ⁇ 10 -11 M, at most 7 ⁇ 10 -11 M, at most 8 ⁇ 10 -11 M, at most 9 ⁇ 10 -11 M, at most 1 ⁇ 10 -10 M, at most 2 ⁇ 10 -10 M, at most 3 ⁇ 10 -10 M, at most 4 ⁇ 10 -10 M, at most 5 ⁇ 10 -10 M, at most 6 ⁇ 10 -10 M, at most 7 ⁇ 10 -10 M, at most 8 ⁇ 10 -10 M, at most 9 ⁇ 10 -10 M, or at most 1 ⁇ 10 -9 M.
  • K D- monomer is about 5 ⁇ 10 -12 M, about 6 ⁇ 10 -12 M, about 7 ⁇ 10 -12 M, about 8 ⁇ 10 -12 M, about 9 ⁇ 10 -12 M, about 1 ⁇ 10 -11 M, about 2 ⁇ 10 -11 M, about 3 ⁇ 10 -11 M, about 4 ⁇ 10 -11 M, about 5 ⁇ 10 -11 M, about 6 ⁇ 10 -11 M, about 7 ⁇ 10 -11 M, about 8 ⁇ 10 -11 M, about 9 ⁇ 10 -11 M, about 1 ⁇ 10 -10 M, about 2 ⁇ 10 -10 M, about 3 ⁇ 10 -10 M, about 4 ⁇ 10 -10 M, about 5 ⁇ 10 -10 M, about 6 ⁇ 10 -10 M, about 7 ⁇ 10- 10 M, about 8 ⁇ 10 -10 M, about 9 ⁇ 10 -10 M, or about 1 ⁇ 10 -9 M.
  • K D-trimer is at most 5 ⁇ 10 -12 M, at most 6 ⁇ 10 -12 M, at most 7 ⁇ 10 -12 M, at most 8 ⁇ 10 -12 M, at most 9 ⁇ 10 -12 M, at most 1 ⁇ 10 -11 M, at most 2 ⁇ 10 -11 M, at most 3 ⁇ 10 -11 M, at most 4 ⁇ 10 -11 M, at most 5 ⁇ 10 -11 M, at most 6 ⁇ 10 -11 M, at most 7 ⁇ 10 -11 M, at most 8 ⁇ 10 -11 M, at most 9 ⁇ 10 -11 M, at most 25746 1 ⁇ 10 -10 M, at most 2 ⁇ 10 -10 M, at most 3 ⁇ 10 -10 M, at most 4 ⁇ 10 -10 M, at most 5 ⁇ 10 -10 M, at most 6 ⁇ 10 -10 M, at most 7 ⁇ 10 -10 M, at most 8 ⁇ 10 -10 M, at most 9 ⁇ 10 -10 M, or at most 1 ⁇ 10 -9 M.
  • KD-trimer is about 5 ⁇ 10 -12 M, about 6 ⁇ 10 -12 M, about 7 ⁇ 10 -12 M, about 8 ⁇ 10 -12 M, about 9 ⁇ 10 -12 M, about 1 ⁇ 10 -11 M, about 2 ⁇ 10 -11 M, about 3 ⁇ 10 -11 M, about 4 ⁇ 10 -11 M, about 5 ⁇ 10 -11 M, about 6 ⁇ 10 -11 M, about 7 ⁇ 10 -11 M, about 8 ⁇ 10 -11 M, about 9 ⁇ 10 -11 M, about 1 ⁇ 10 -10 M, about 2 ⁇ 10 -10 M, about 3 ⁇ 10 -10 M, about 4 ⁇ 10 -10 M, about 5 ⁇ 10- 10 M, about 6 ⁇ 10 -10 M, about 7 ⁇ 10 -10 M, about 8 ⁇ 10 -10 M, about 9 ⁇ 10 -10 M, or about 1 ⁇ 10 -9 M.
  • the K D-monomer and K D-trimer can be any combination of the KD-monomer and KD-trimer value or range as provided herein, including in this Section (Section [0265]) and this paragraph. [0271]
  • the KD-monomer is about 59 pM.
  • the K D-trimer is about 59 pM.
  • the K D-monomer is about 59 pM and the KD-trimer is about 59 pM.
  • the KD-monomer is about 60 pM.
  • the K D-trimer is about 60 pM.
  • the KD-monomer is about 60 pM and the KD-trimer is about 60 pM. In one specific embodiment, the KD-monomer is at most 60 pM. In another specific embodiment, the KD-trimer is at most 60 pM. In a further embodiment, the KD-monomer is at most 60 pM and the KD-trimer is at most 60 pM. [0272] 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 the desired biological or binding activity.
  • the basic antibody structural unit comprises a tetramer.
  • Each tetramer includes 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 may define a constant region primarily responsible for effector function.
  • human light chains are classified as kappa and lambda light chains.
  • human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
  • the variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy 25746 chain also including a “D” region of about 10 more amino acids. See generally, Fundamental Immunology Ch.7 (Paul, W., ed., 2nd ed. Raven Press, N.Y.
  • variable regions of each light/heavy chain pair form the antibody binding site.
  • an intact antibody has two binding sites.
  • the two binding sites are, in general, the same.
  • the variable domains of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • the CDRs are usually aligned by the framework regions, enabling binding to a specific epitope.
  • both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • antibody fragment As used herein, unless otherwise indicated, “antibody fragment,” “antigen- binding fragment,” and “antigen binding fragment” are used interchangeably to refer to antigen binding fragments of antibodies, i.e., antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g., fragments that retain one or more CDR regions.
  • antibody binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., sc-Fv; nanobodies and multispecific antibodies formed from antibody fragments.
  • an antibody comprises an antigen-binding fragment that refers to a portion of an antibody having antigenic determining variable regions of an antibody.
  • antigen-binding fragments include, but are not limited to Fab, Fab’, F(ab’)2, and Fv fragments, linear antibodies, single chain antibodies, and multispecific antibodies formed from antibody fragments.
  • 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.
  • an antibody includes intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Fab, Fab’, F(ab’)2, and Fv fragments), 25746 single chain Fv (scFv) mutants, a CDR-grafted antibody, multispecific antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antigen determination portion of an antibody, and any other modified immunoglobulin molecule comprising an antigen recognition site so long as the antibodies exhibit the desired biological activity.
  • antibody fragments such as Fab, Fab’, F(ab’)2, and Fv fragments
  • scFv 25746 single chain Fv mutants
  • CDR-grafted antibody multispecific antibodies
  • chimeric antibodies humanized antibodies
  • human antibodies fusion proteins comprising an antigen determination portion of an antibody
  • any other modified immunoglobulin molecule comprising an antigen recognition site so long as the antibodies exhibit the desired biological activity.
  • An antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively.
  • the 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, etc.
  • a humanized antibody refers to forms of non-human (e.g., murine) antibodies having specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences.
  • a humanized antibody comprises less than about 40% non-human sequence in the variable region.
  • a humanized antibody comprises less than about 20% non-human sequence in a full-length antibody sequence.
  • a humanized antibody comprises less than about 20% non-human sequence in the framework region of each of the heavy chain and light chain variable regions.
  • the 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 sequence in the framework region of each of the heavy chain and light chain variable regions.
  • the 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 and light chain variable regions.
  • humanized antibodies are human immunoglobulins in which residues from the complementarity determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g., mouse, rat, rabbit, hamster) that have the desired specificity, affinity, and capability.
  • CDR complementarity determining region
  • non-human species e.g., mouse, rat, rabbit, hamster
  • These humanized antibodies may contain one or more non-human species mutations, e.g., the heavy chain comprises 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 the light chain comprises 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.
  • the humanized heavy chain variable domain may comprise IGHV1-46*02 framework with no or fewer than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations.
  • the humanized light chain variable domain may comprise 25746 IGKV3-20 framework with no or fewer than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations.
  • chimeric antibodies refer to antibodies wherein the sequence of the immunoglobulin molecule is derived from two or more species.
  • variable region of both light and heavy chains corresponds to the variable region of antibodies derived from one species of mammals (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and capability while the constant regions are homologous to the sequences in antibodies derived from another (usually human) to avoid eliciting an immune response in that species.
  • CDR complementarity determining region
  • HVR hypervariable region
  • CDR-H1, CDR-H2, CDR-H3 there are three CDRs in each heavy chain variable region
  • CDR-L1, CDR-L2, CDR-L3 CDRs in each light chain variable region
  • “Framework regions” and “FR” are known in the art to refer to the non-CDR portions of the variable regions of the heavy and light chains.
  • FR-H1, FR-H2, FR-H3, and FR-H4 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 CDRs of the antibodies described herein can be defined by a method selected from Kabat, Chothia, IMGT, Aho, AbM, or combinations thereof. 25746
  • an antibody that specifically binds to a protein indicates that the antibody reacts or associates more frequently, more rapidly, with greater duration, with greater affinity, or with some combination of the above to the protein than with alternative substances, including unrelated proteins.
  • the terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids.
  • 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 (Ile), leucine (Leu), and valine (Val).
  • 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 (Gln), arginine (Arg), and histidine (His).
  • 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).
  • a protein such as an antibody described herein comprises an aliphatic amino acid.
  • Non-limiting exemplary aliphatic amino acids include alanine (Ala), isoleucine (Ile), leucine (Leu) and valine (Val).
  • 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).
  • 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).
  • 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).
  • a protein such as an antibody described herein comprises a hydroxylic amino acid.
  • Non- limiting exemplary hydroxylic amino acids include serine (Ser) and threonine (Thr).
  • 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).
  • a protein such as an antibody described herein comprises an amidic amino acid.
  • Non-limiting exemplary amidic amino acids include asparagine (Asn) and glutamine (Gln).
  • polynucleotide or “nucleic acid,” as used interchangeably herein, refer to polymers of nucleotides of any length, and include DNA and RNA.
  • the nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase.
  • a polynucleotide may comprise modified nucleotides, such as, but not limited to methylated nucleotides and their analogs or non-nucleotide components. Modifications to the nucleotide structure may be imparted before or after assembly of the polymer.
  • a polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.
  • 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 various ways that are known for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • % 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 user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may 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.
  • the % amino acid sequence identity of a given amino acid sequence A to, with, or against 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 scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B.
  • an anti-TL1A antibody having a heavy chain comprising four heavy chain framework regions (HCFR) and three heavy chain complementarity-determining regions (HCDR): HCFR1, HCDR1, HCFR2, HCDR2, HCFR3, HCDR3, and HCFR4; and a light chain comprising four light chain framework regions (LCFR) and three light chain complementarity-determining regions (LCDR): LCFR1, LCDR1, LCFR2, LCDR2, LCFR3, LCDR3, and LCFR4.
  • HCFR heavy chain framework regions
  • HCDR2 heavy chain complementarity-determining regions
  • LCFR3 light chain complementarity-determining regions
  • an anti-TL1A antibody may comprise any region provided herein, for example, as provided in the tables, the examples, and the sequences.
  • Exemplary anti-TL1A CDRs [0289]
  • an anti-TL1A antibody comprises a HCDR1 as set forth by SEQ ID NO: 1.
  • an anti-TL1A antibody comprises a HCDR2 as set forth by any one of SEQ ID NOS: 2-5.
  • an anti-TL1A antibody comprises a HCDR3 as set forth by any one of SEQ ID NOS: 6-9.
  • an anti-TL1A antibody comprises a LCDR1 as set forth by SEQ ID NO: 10.
  • an anti-TL1A antibody comprises a LCDR2 as set forth by SEQ ID NO: 11.
  • an anti-TL1A antibody comprises a LCDR3 as set forth by any one of SEQ ID NOS: 12-15.
  • an anti-TL1A 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.
  • an anti-TL1A antibody comprises the CDRs of antibody J of Table 10. In some cases, the anti-TL1A antibody comprises the CDRs of antibody J2 of Table 10. In some cases, the anti-TL1A antibody comprises the CDRs of antibody K of Table 10. [0290] In certain embodiments, an anti-TL1A antibody comprises a HCDR1 as set forth by SEQ ID NOS: 401, 407, 413, or 450. In certain embodiments, an anti-TL1A antibody comprises a HCDR2 as set forth by SEQ ID NOS: 402, 408, 414, or 451. In certain embodiments, an anti-TL1A antibody comprises a HCDR3 as set forth by SEQ ID NOS: 403, 409, 415, or 452.
  • an anti-TL1A antibody comprises a LCDR1 as set forth by SEQ ID NOS: 404, 410, 416, or 453.
  • an anti-TL1A antibody comprises a LCDR2 as set forth by SEQ ID NOS: 405, 411, 417, or 454.
  • an anti-TL1A antibody comprises a LCDR3 as set forth by SEQ ID NOS: 406, 412, 418, or 455.
  • an anti-TL1A antibody comprises a HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 selected from Table 6. Table 6.
  • Example light chain variable region sequences 25746 SEQ Description Sequence ID NO Q Q S Q S Q S Q S Q S 25746 196 VL, 172 VL, 75 VL, 174 VL, 109 VL, 198 VL, Q Q S Q L Q S L Q T Q T Q L Q T Q T Q S Q S 25746 218 88 VL EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQ KPGQAPRLLIYATSNLASGIPDRFSGSGSGTDYTLTIS RVEPEDFAVYYCQQWEGNPRTFGGGTKLEIK I I Q TI W S L Y T EI Q TI A W W S L A L I I W S ce a e o e s, a a - a o y co p ses e s se orth in any one of the antibodies of Table 1.
  • an anti-TL1A 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, 2
  • an anti-TL1A antibody comprises the CDRs of antibody A219.
  • Antibody CDRs may be defined by the Aho, Kabat, Chothia, or IMGT methods.
  • Exemplary anti-TL1A Framework Regions [0296]
  • an anti-TL1A antibody comprises a heavy chain (HC) framework 1 (FR1) as set forth by SEQ ID NO: 304.
  • an anti-TL1A antibody comprises a HC FR2 as set forth by any one of SEQ ID NOS: 305 or 313.
  • an anti-TL1A antibody comprises a HC FR3 as set forth by any one of SEQ ID NOS: 306-307, 314-315.
  • an anti-TL1A antibody comprises a HC FR4 as set forth by SEQ ID NO: 308. In certain embodiments, an anti-TL1A antibody comprises a LC FR1 as set forth by SEQ ID NO: 309. In certain embodiments, an anti-TL1A antibody comprises a LC FR2 as set forth by SEQ ID NO: 310. In certain embodiments, an anti-TL1A antibody comprises a LC FR3 as set forth by SEQ ID NO: 311. In certain embodiments, an anti-TL1A antibody comprises a LC FR4 as set forth by SEQ ID NO: 312.
  • an anti-TL1A 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.
  • an anti-TL1A 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.
  • an anti-TL1A antibody comprises the heavy chain framework regions set forth in an antibody selected from Table 7. In certain embodiments, an anti-TL1A antibody comprises the light chain framework regions set forth in an antibody selected from Table 8. In certain embodiments, an anti-TL1A antibody comprises the framework regions set forth in any one of the antibodies of Table 1.
  • an anti- TL1A 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, A
  • an anti-TL1A antibody comprises the framework region of antibody A219.
  • the anti-TL1A antibody comprises the framework region of an antibody comprising SESQ ID NOS: 420 and 430.
  • the anti-TL1A antibody comprises the framework region of an antibody comprising SESQ ID NOS: 421 and 431.
  • the anti-TL1A antibody comprises the framework region of an antibody comprising SESQ ID NOS: 424 and 434.
  • Antibody CDR and framework regions may be defined by the Aho, Kabat, Chothia, or IMGT methods.
  • an anti-TL1A 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 no or fewer than nine amino acid modification(s) from the human 25746 IGHV1-46*02 framework and the human IGKV3-20 framework.
  • the amino acid modification(s) 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, per Aho or Kabat numbering; or a combination of two or more modifications selected from (a) to (h).
  • the amino acid modification(s) comprise (a) R45K, (b) A47R, (c) M55I, (d) V78A, (e) M80I, (f) R82T, (g) V89A, or (h) M91L in the heavy chain variable region, per Aho or Kabat numbering; or a combination of two or more modifications selected from (a) to (h).
  • the amino acid modification(s) comprise: A47R.
  • the amino acid modification(s) 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.
  • the amino acid modification(s) comprise: R45K and A47R.
  • the amino acid modification(s) comprise: R45K, A47R, V89A, and M91L.
  • the amino acid modification(s) comprise: R45K and A47R, and M80I.
  • the amino acid modification(s) 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, and V89A; R45K, A47R, M80I, R82T, V89A, M91L; or R45K, A47R, M55I, M80I, V89A, and M91L.
  • the amino acid modification(s) comprise: R45K. In some embodiments, the amino acid modification(s) comprise: R45K and V78A. In some embodiments, the amino acid modification(s) comprise: V78A. In some embodiments, the amino acid modification(s) comprise: V78A and V89A; V78A and M80I; or V78A, M80I, and R82T. In some embodiments, the amino acid modification(s) comprise: V89A. In some embodiments, the amino acid modification(s) comprise: M80I.
  • the amino acid modification(s) 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, per Aho or Kabat numbering.
  • the amino acid modification(s) comprises L54P in the light chain variable region, per Aho or Kabat 25746 numbering.
  • the amino acid modification(s) comprises L55W in the light chain variable region, per Aho or Kabat numbering.
  • an anti-TL1A antibody comprises a heavy chain framework comprising SEQ ID NO: 301 (X1VQLVQSGAEVKKPGASVKVSCKAS[HCDR1]WVX2QX3PGQGLEWX4G[HCDR2] RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTAVYYCAR[HCDR3]WGQGTTVTVSS) or SEQ ID NO: 302 (X1VQLVQSGAEVKKPGASVKVSCKAS[HCDR1]WVX2QX3PGQGLEWX4G[HCDR2] RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTAVYYC[HCDR3]WGQGTTVTVSS).
  • SEQ ID NO: 301 X1VQLVQSGAEVKKPGASVKVSCKAS[HCDR1]WVX2QX3PGQGLEWX4G[HCDR2] RX5TX6TX7DTSTST
  • X1 is at position 1 of IGHV1-46*02 as determined by Aho or Kabat numbering.
  • X2 is at position 45 of IGHV1-46*02 as determined by Aho or Kabat numbering.
  • X3 is at position 47 of IGHV1-46*02 as determined by Aho or Kabat numbering.
  • X4 is at position 55 of IGHV1-46*02 as determined by Aho or Kabat numbering.
  • X5 is at position 78 of IGHV1-46*02 as determined by Aho or Kabat numbering.
  • X6 is at position 80 of IGHV1-46*02 as determined by Aho or Kabat numbering.
  • X7 is at position 82 of IGHV1-46*02 as determined by Aho or Kabat numbering.
  • X8 is at position 89 of IGHV1-46*02 as determined by Aho or Kabat numbering.
  • X9 is at position 91 of IGHV1-46*02 as determined by Aho or Kabat numbering.
  • an anti-TL1A antibody comprising a heavy chain framework comprising IGHV1-46*02, or a variant thereof, wherein the variant comprises between about 1 and about 9 amino acid substitutions, or between about 1 and 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 from IGHV1-46*02 framework.
  • an anti-TL1A antibody comprises a light chain framework comprising SEQ ID NO: 303 (EIVLTQSPGTLSLSPGERATLSC[LCDR1]WYQQKPGQAPRX10X11IY[LCDR2]GIPDR FSGSGSGTDFTLTISRLEPEDFAVYYC[LCDR3]FGGGTKLEIK).
  • SEQ ID NO: 303 EIVLTQSPGTLSLSPGERATLSC[LCDR1]WYQQKPGQAPRX10X11IY[LCDR2]GIPDR FSGSGSGTDFTLTISRLEPEDFAVYYC[LCDR3]FGGGTKLEIK.
  • X10 is L.
  • X10 is P.
  • X11 is L.
  • an anti-TL1A antibody comprises a heavy chain framework comprising IGHV1-46*02. In some embodiments, an anti-TL1A antibody comprises a heavy chain framework comprising a variant of IGHV1-46*02 comprising between about 1 and about 20 amino acid substitutions from SEQ ID NO: 316.
  • an anti-TL1A antibody comprises a heavy chain framework comprising a variant of IGHV1-46*02 comprising between about 1 and about 9 amino acid substitutions from SEQ ID NO: 316.
  • an anti-TL1A antibody comprises a heavy chain framework comprising a variant of IGHV1-46*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.
  • the heavy chain framework substitution comprises Q1E, as determined by Aho or Kabat numbering.
  • the heavy chain framework substitution comprises R45K, as determined by Aho or Kabat numbering.
  • the heavy chain framework substitution comprises A47R, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitution comprises M55I, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitution comprises V78A, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitution comprises M80I, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitution comprises R82T, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitution comprises V89A, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitution comprises M91L, as determined by Aho or Kabat numbering.
  • an anti-TL1A antibody comprises a light chain framework comprising IGKV3-20*01. In some embodiments, an anti-TL1A antibody comprises a variant of IGKV3-20*01 comprising between about 1 and about 20 amino acid substitutions from SEQ ID NO: 317. In some embodiments, an anti-TL1A antibody comprises a variant of IGKV3-20*01 comprising about 1 amino acid substitution from SEQ ID NO: 317. In some embodiments, an anti-TL1A antibody comprises a light chain framework comprising a variant of IGKV3-20*01 comprising about 2 amino acid substitutions from SEQ ID NO: 317.
  • an anti-TL1A antibody comprises a light chain framework comprising a variant of IGKV3-20*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 from SEQ ID NO: 317 in the framework.
  • the light chain framework substitution comprises Q1E, as determined by Aho or Kabat numbering.
  • the 25746 light chain framework substitution comprises R45K, as determined by Aho or Kabat numbering.
  • an anti-TL1A antibody comprises a heavy chain FR1 as set forth by SEQ ID NO: 304.
  • an anti-TL1A antibody comprises a heavy chain FR2 as set forth by SEQ ID NO: 305. In some embodiments, an anti-TL1A antibody comprises a heavy chain FR2 as set forth by SEQ ID NO: 313. In some embodiments, an anti-TL1A antibody comprises a heavy chain FR3 as set forth by SEQ ID NO: 306. In some embodiments, an anti-TL1A antibody comprises a heavy chain FR3 as set forth by SEQ ID NO: 307. In some embodiments, an anti-TL1A antibody comprises a heavy chain FR3 as set forth by SEQ ID NO: 314. In some embodiments, an anti-TL1A antibody comprises a heavy chain FR3 as set forth by SEQ ID NO: 315.
  • an anti-TL1A antibody comprises a heavy chain FR4 as set forth by SEQ ID NO: 308. In some embodiments, an anti-TL1A antibody comprises a light chain FR1 as set forth by SEQ ID NO: 309. In some embodiments, an anti-TL1A antibody comprises a light chain FR2 as set forth by SEQ ID NO: 310. In some embodiments, an anti-TL1A antibody comprises a light chain FR3 as set forth by SEQ ID NO: 311. In some embodiments, an anti-TL1A antibody comprises a light chain FR4 as set forth by SEQ ID NO: 312. In some embodiments, an anti-TL1A antibody comprises a framework region of Table 9A. Table 9A. Example framework sequences
  • an anti-TL1A antibody comprising a heavy chain variable region comprising an amino acid sequence 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 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
  • an anti-TL1A antibody comprising a heavy chain variable region and a light chain variable region.
  • Non-limiting additional embodiments include: (Embodiment 2) The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 101.
  • (Embodiment 60) The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 159.
  • (Embodiment 65) The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 164.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 201.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 202.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 203.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 204.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 205.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 206.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 208.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 209.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 211.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 212.
  • the anti-TL1A antibody of any one of 25746 embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 214.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 215.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 216.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 217.
  • the anti-TL1A antibody of any one of embodiments 1-70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 218.
  • the anti-TL1A antibody of any one of embodiments 1- 70 wherein the light chain variable region comprises a sequence 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 having about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions as compared to SEQ ID NO: 219 or 220.
  • (Embodiment 102) The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 25746 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 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 104) The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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 106 The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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 111 The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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 121) The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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 126) The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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 131 The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 25746 100% identical to SEQ ID NO: 117, and the light chain variable region comprises a sequence 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 141 The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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- TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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.
  • the anti-TL1A antibody of embodiment 1 comprising A500.
  • the anti-TL1A antibody of embodiment 1 wherein the heavy chain variable region comprises a sequence 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 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 157) The anti-TL1A antibody of embodiment 1, wherein the heavy chain variable region comprises a sequence 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 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.
  • one or more amino acid modifications may be introduced into the Fragment crystallizable (Fc) region of a human or humanized antibody, thereby generating an Fc region variant.
  • An Fc region may comprise a C-terminal region of an immunoglobulin heavy chain that comprises a hinge region, CH2 domain, CH3 domain, or any combination thereof.
  • an Fc region includes native sequence Fc regions and variant Fc regions.
  • the Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, 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.
  • the Fc region comprises any one of SEQ ID NOS: 320-367.
  • the anti-TL1A antibody comprises a constant region comprising any one of SEQ ID NOS: 319, 368-381.
  • antibodies of this disclosure have a reduced effector function as compared to a human IgG.
  • Effector function refers to a biological event resulting from the interaction of an antibody Fc region with an Fc receptor or ligand.
  • Non-limiting effector functions include C1q 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, down regulation of cell surface receptors (e.g., B cell receptor), and B cell activation.
  • antibody-dependent cell-mediated 25746 cytotoxicity refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing Fc receptors (e.g., natural killer cells, neutrophils, macrophages) recognize bound antibody on a target cell, subsequently causing lysis of the target cell.
  • complement dependent cytotoxicity refers to lysing of a target cells in the presence of complement, where the complement action pathway is initiated by the binding of C1q to antibody bound with the target.
  • Fc regions have a natural lack of effector function, and some Fc regions can comprise mutations that reduce effector functions. For instance, IgG4 has low ADCC and CDC activities and IgG2 has low ADCC activity.
  • the disclosure provides antibodies comprising Fc regions characterized by exhibiting ADCC that is reduced by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70% or more as compared to an antibody comprising a non-variant Fc region, i.e., an antibody with the same sequence identity but for the substitution(s) that decrease ADCC (such as human IgG1, SEQ ID NO: 320).
  • the disclosure provides antibodies comprising Fc regions characterized by exhibiting CDC that is reduced by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70% or more as compared to an antibody comprising a non-variant Fc region, i.e., an antibody with the same sequence identity but for the substitution(s) that decrease CDC (such as human IgG1, SEQ ID NO: 320).
  • the antibodies of this disclosure have reduced effector function as compared with human IgG1.
  • antibodies herein have no detectable ADCC activity.
  • the reduction and/or abatement of ADCC activity may be attributed to the reduced affinity antibodies of the invention exhibit for Fc ligands and/or receptors.
  • antibodies herein exhibit no detectable CDC activities.
  • the reduction and/or abatement of CDC activity may be attributed to the reduced affinity antibodies of the invention exhibit for Fc ligands and/or receptors. Measurement of effector function may be performed as described in Example 3.
  • antibodies comprising Fc regions described herein exhibit decreased affinities to C1q relative to an unmodified antibody (e.g., human IgG1 having SEQ ID NO: 320).
  • antibodies herein exhibit affinities for C1q receptor that are 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 less than an unmodified antibody.
  • antibodies herein 25746 exhibit affinities for C1q that are 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% less than an unmodified antibody.
  • the antibodies of this disclosure are variants that possess some but not all effector functions, which make it a desirable candidate for applications in which the half-life of the antibody in vivo is important yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious.
  • In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities.
  • Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks Fc ⁇ R binding (hence likely lacking ADCC activity) but retains FcRn binding ability. Measurement of effector function may be performed as described in Example 3.
  • antibodies are tested for binding to Fc ⁇ receptors and complement C1q by ELISA. In some embodiments, antibodies are tested for the ability to activate primary human immune cells in vitro, for example, by assessing their ability to induce expression of activation markers.
  • assessment of ADCC activity of an anti-TL1A antibody comprises adding the antibody to target cells in combination with immune effector cells, which may be activated by the antigen antibody complexes resulting in cytolysis of the target cell. Cytolysis may be detected by the release of label (e.g. radioactive substrates, fluorescent dyes or natural intracellular proteins) from the lysed cells.
  • label e.g. radioactive substrates, fluorescent dyes or natural intracellular proteins
  • PBMC peripheral blood mononuclear cells
  • NK Natural Killer
  • ADCC activity of the antibody of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al., 1998, PNAS USA 95:652-656.
  • an assessment of complement activation, a CDC assay may be performed as described in Gazzano-Santoro et al., 1996, J. Immunol. Methods, 202:163.
  • Non-limiting examples of Fc mutations in IgG1 that may reduce ADCC and/or CDC include substitutions at one or more of positions: 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 in 25746 IgG1, where the numbering system of the constant region is that of the EU index as set forth by Kabat.
  • the antibodies of this disclosure have reduced effector function as compared with human IgG1.
  • an antibody comprises an IgG1 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,
  • an antibody comprises a Fc region selected from the representative sequences disclosed in Table 3, Table 13, and Table 9B.
  • an antibody comprises an IgG1 Fc region comprising E233P, according to the Kabat numbering system.
  • an antibody comprises an IgG4 Fc region comprising S228P and L235E.
  • an antibody comprises an IgG1 Fc region comprising L235E, according to the Kabat numbering system.
  • an antibody comprises an IgG1 Fc region comprising L234A and L235A, according to the Kabat numbering system.
  • an antibody comprises an IgG1 Fc region comprising L234A, L235A, and G237A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising L234A, L235A, P329G, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising L234F, L235E, and P331S, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising L234A, L235E, and G237A, according to the Kabat numbering system.
  • an antibody comprises an IgG1 Fc region comprising L234A, L235E, G237A, and P331S, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising L234A, L235A, G237A, P238S, H268A, A330S, and P331S (IgG1 ⁇ ), according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising L234A, L235A, and P329A, according to the Kabat numbering system.
  • an antibody comprises an IgG1 Fc region 25746 comprising G236R and L328R, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising G237A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising F241A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising V264A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising D265A, according to the Kabat numbering system.
  • an antibody comprises an IgG1 Fc region comprising D265A and N297A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising D265A and N297G, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising D270A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising N297A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising N297G, according to the Kabat numbering system.
  • an antibody comprises an IgG1 Fc region comprising N297D, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising N297Q, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising P329A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising P329G, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising P329R, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising A330L, according to the Kabat numbering system.
  • an antibody comprises an IgG1 Fc region comprising P331A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG1 Fc region comprising P331S, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG2 Fc region. In some embodiments, an antibody comprises an IgG4 Fc region. In some embodiments, an antibody comprises an IgG4 Fc region comprising S228P, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG4 Fc region comprising S228P, F234A, and L235A, according to the Kabat numbering system.
  • an antibody comprises an IgG2-IgG4 cross-subclass (IgG2/G4) Fc region. In some embodiments, an antibody comprises an IgG2-IgG3 cross-subclass Fc region. In some embodiments, an antibody comprises an IgG2 Fc region comprising H268Q, V309L, A330S, and P331S, according to the Kabat numbering system. In some embodiments, an antibody comprises an 25746 IgG2 Fc region comprising V234A, G237A, P238S, H268A, V309L, A330S, and P331S, according to the Kabat numbering system. In some embodiments, an antibody comprises a Fc region comprising high mannose glycosylation.
  • an antibody comprises an IgG4 Fc region comprising a S228P substitution, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG4 Fc region comprising an A330S substitution, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG4 Fc region comprising a P331S substitution, according to the Kabat numbering system. [0334] In some embodiments, an antibody comprises an IgG2 Fc region comprising an A330S substitution, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG2 Fc region comprising an P331S substitution, according to the Kabat numbering system.
  • an antibody comprises an IgG2 Fc region comprising an 234A substitution, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgG2 Fc region comprising an 237A substitution, according to the Kabat numbering system.
  • an anti-TL1A described herein comprises a Fc region as shown in Table 13. Table 13. Exemplary Fc Mutations M utations Constant Region (SEQ ID NO) K DL R EM K EM mprises a Fc region comprising a sequence from Table 9B.
  • an anti-TL1A 25746 antibody described herein comprises a Fc region comprising any one 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 one of SEQ ID NOS: 320-367 [0337]
  • anti-TL1A described herein comprise 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.
  • an anti-TL1A antibody includes an anti-TL1A antigen binding fragment.
  • Non-limiting additional embodiments include: (Embodiment 2) The anti-TL1A 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.
  • 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, 40
  • the anti-TL1A antibody of any one of embodiments 1-10 comprising a LCDR1 comprising SEQ ID NO: 10.
  • the anti-TL1A antibody of any one of embodiments 1-11 comprising a LCDR2 comprising SEQ ID NO: 11.
  • the anti-TL1A antibody of any one of embodiments 1-12 comprising a LCDR3 comprising SEQ ID NO: 12.
  • the anti-TL1A 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).
  • the anti-TL1A antibody of embodiment 1 comprising a heavy chain variable region comprising: (a) an HCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 1; (b) an HCDR2 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 2-5; and (c) an HCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 6-9; and the light chain variable region comprises: (d) an LCDR1 comprising an amino acid sequence set forth by SEQ ID NO: 10; (e) an LCDR2 comprising an amino acid sequence set forth by SEQ ID NO: 11; and (f) an LCDR3 comprising an amino acid sequence set forth by any one of SEQ ID NOS: 12-15.
  • the anti-TL1A 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 [0339] (Embodiment 20) The anti-TL1A antibody of any one of embodiments 1-19, comprising a heavy chain framework comprising IGHV1-46*02.
  • the anti- TL1A antibody of any one of embodiments 1-19 comprising a heavy chain framework comprising a variant of IGHV1-46*02 comprising between about 1 and about 20 amino acid substitutions from SEQ ID NO: 316.
  • the anti-TL1A antibody of any one of embodiments 1-19 comprising a heavy chain framework comprising a variant of IGHV1- 46*02 comprising between about 1 and about 9 amino acid substitutions from SEQ ID NO: 316.
  • the anti-TL1A antibody of any one of embodiments 1-19 comprising a heavy chain framework comprising a variant of IGHV1-46*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.
  • Embodiment 24 The anti-TL1A antibody of any one of embodiments 21-23, wherein the heavy chain framework substitution comprises Q1E, as determined by Aho or Kabat numbering.
  • the heavy chain framework substitution comprises R45K, as determined by Aho or Kabat numbering.
  • (Embodiment 26) The anti-TL1A 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- 25746 TL1A 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-TL1A 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-TL1A 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-TL1A 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-TL1A 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-TL1A antibody of any one of embodiments 21-31, wherein the heavy chain framework substitution comprises M91L, as determined by Aho or Kabat numbering.
  • (Embodiment 33) The anti-TL1A antibody of any one of embodiments 1-19, comprising a heavy chain framework comprising SEQ ID NO: 301.
  • (Embodiment 34) The anti-TL1A antibody of embodiment 33, wherein X1 is Q.
  • the anti-TL1A antibody of any one of embodiments 1-51 comprising a light chain framework comprising a variant of IGKV3- 20*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 from SEQ ID NO: 317 in the framework.
  • Embodiment 57 The anti-TL1A antibody of any one of embodiments 53-56, wherein the light chain framework substitution comprises Q1E, as determined by Aho or Kabat numbering.
  • the light chain framework substitution comprises R45K, as determined by Aho or Kabat numbering.
  • (Embodiment 59) The anti-TL1A 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-TL1A antibody of embodiment 59, wherein X10 is L.
  • Embodiment 61) The anti-TL1A antibody of embodiment 59, wherein X10 is P.
  • (Embodiment 62) The anti-TL1A antibody of any one of embodiments 59-61, wherein X11 is L.
  • (Embodiment 63) The anti-TL1A antibody of any one of embodiments 59-61, wherein X11 is W.
  • (Embodiment 64) The anti-TL1A 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 heavy chain variable framework region and the light chain variable framework region collectively comprise at least one amino acid modification(s) as compared to the human IGHV1-46*02 framework and the human IGKV3-20 framework.
  • the at least one amino acid modification(s) 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(s) comprise: a modification at amino 25746 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(s) comprise 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(s) comprise 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(s) comprise 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(s) comprise 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(s) comprise 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(s) comprise 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(s) comprise a modification at amino acid position 91 in the heavy chain variable region, per Aho or Kabat numbering.
  • (Embodiment 74) The antibody of any one of embodiments 64-65, wherein the amino acid modification(s) comprise (a) R45K, (b) A47R, (c) M55I, (d) V78A, (e) M80I, (f) R82T, (g) V89A, or (h) M91L in the heavy chain variable region, per 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(s) comprise: A47R.
  • (Embodiment 76) The antibody of embodiment 74, wherein the amino acid modification(s) 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.
  • (Embodiment 77) The antibody of embodiment 74, wherein the amino acid modification(s) comprise: R45K and A47R.
  • Embodiment 86 The antibody of embodiment 74, wherein the amino acid modification(s) comprise: M80I.
  • Embodiment 87 The antibody of any one of embodiments 64-86, wherein the amino acid modification(s) 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, per Aho or Kabat numbering.
  • Embodiment 88 The antibody of embodiment 87, wherein the amino acid modification(s) comprises L54P in the light chain variable region, per Aho or Kabat numbering.
  • (Embodiment 89) The antibody of embodiment 87 or 88, wherein the amino acid modification(s) comprises L55W in the light chain variable region, per Aho or Kabat numbering.
  • (Embodiment 90) The antibody of any one of embodiments 1-19, comprising a heavy chain FR1 as set forth by SEQ ID NO: 304.
  • (Embodiment 91) The antibody of any one of embodiments 1-19 or 90, comprising a heavy chain FR2 as set forth by SEQ ID NO: 305.
  • (Embodiment 92) The antibody of any one of embodiments 1-19 or 90, comprising a heavy chain FR2 as set forth by SEQ ID NO: 313.
  • Embodiment 93 The antibody of any one of embodiments 1-19 or 90-92, comprising a heavy chain FR3 as set forth by SEQ ID NO: 306.
  • Embodiment 94 The antibody of any one of embodiments 1-19 or 90-92, comprising a heavy chain FR3 as set forth by SEQ ID NO: 307.
  • Embodiment 95 The antibody of any one of embodiments 1-19 or 90-92, comprising a heavy chain FR3 as set forth by SEQ ID NO: 314.
  • Embodiment 96 The antibody of any one of embodiments 1-19 or 90-92, comprising a heavy chain FR3 as set forth by SEQ ID NO: 315.
  • (Embodiment 97) The antibody of any one of embodiments 1-19 or 90-96, comprising a heavy chain FR4 as set forth by SEQ ID NO: 308.
  • (Embodiment 98) The antibody of any one of embodiments 1-19 or 90-97, comprising a light chain FR1 as set forth by SEQ ID NO: 309.
  • (Embodiment 99) The antibody of any one of embodiments 1-19 or 90-98, comprising a light chain FR2 as set forth by SEQ ID NO: 310.
  • (Embodiment 100) The antibody of any one of embodiments 1-19 or 90-99, comprising a light chain FR3 as set forth by SEQ ID NO: 311.
  • (Embodiment 101) The antibody of any one of embodiments 1-19 or 90-100, comprising a light chain FR4 as set forth by SEQ ID NO: 312.
  • (Embodiment 102) The antibody of any one of embodiments 1-19, comprising a 25746 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.
  • Embodiment 103 The antibody of embodiment 1, comprising a heavy chain variable domain comprising an amino acid sequence 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 domain comprising an amino acid sequence 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.
  • the antibody of embodiment 103 comprising a heavy chain variable domain comprising an amino acid sequence at least 96% identical to SEQ ID NO: 104, and a light chain variable domain comprising an amino acid sequence at least 97% identical to SEQ ID NO: 201.
  • the antibody of embodiment 103 comprising an amino acid sequence at least 97% identical to SEQ ID NO: 104.
  • the antibody of embodiment 103 comprising an amino acid sequence at least 98% identical to SEQ ID NO: 104.
  • the antibody of embodiment 103 comprising an amino acid sequence at least 99% identical to SEQ ID NO: 104.
  • (Embodiment 112) The antibody of embodiment 103, comprising a heavy chain variable domain comprising an amino acid sequence at least about 97% identical to SEQ ID NO: 104, and a light chain variable domain comprising an amino acid sequence at least about 97% identical to SEQ ID NO: 201.
  • Embodiment 113 The antibody of embodiment 112, wherein the heavy chain variable domain comprises an amino acid sequence at least about 98% identical to SEQ ID NO: 104.
  • (Embodiment 114) The antibody of embodiment 112, wherein the heavy chain variable domain comprises an amino acid sequence at least about 99% identical to SEQ ID NO: 104.
  • (Embodiment 115) The antibody of embodiment 112, wherein the heavy chain variable domain comprises SEQ ID NO: 104.
  • the antibody of embodiment 103 comprising a heavy chain variable domain comprising an amino acid sequence 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 a light chain variable domain comprising an amino acid sequence 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 120 The antibody of embodiment 103, comprising a heavy chain variable domain comprising an amino acid sequence 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 a light chain variable domain comprising an amino acid sequence 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.
  • Embodiments [0347] (Embodiment 121) The antibody of any one of embodiments 1-120, comprising a fragment crystallizable (Fc) region.
  • Embodiment 122 The antibody of embodiment 121, comprising reduced antibody-dependent cell-mediated cytotoxicity (ADCC) function as compared to human IgG1 and/or reduced complement-dependent cytotoxicity (CDC) as compared to human IgG1.
  • Embodiment 123 The antibody of embodiment 122, wherein the human IgG1 comprises SEQ ID NO: 320.
  • the antibody of embodiment 120 or embodiment 123, wherein the ADCC function of the Fc region comprising reduced ADCC is at least about 50% reduced as compared to human IgG1.
  • (Embodiment 127) The anti-TL1A of any one of embodiments 121-125, comprising a (i) human IgG4 Fc region or (ii) a human IgG4 Fc region comprising (a) S228P, (b) S228P and L235E, or (c) S228P, F234A, and L235A, per Kabat numbering.
  • the anti-TL1A of any one of embodiments 121-125 comprising a human IgG2 Fc region; IgG2-IgG4 cross-subclass Fc region; IgG2-IgG3 cross- subclass Fc region; IgG2 comprising H268Q, V309L, A330S, P331S (IgG2m4); or IgG2 comprising V234A, G237A, P238S, H268A, V309L, A330S, P331S (IgG2 ⁇ ⁇ ⁇ (Embodiment 129)
  • the anti-TL1A of any one of embodiments 121-125 comprising a heavy chain Fc region comprising a sequence 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: 320-362.
  • (Embodiment 131) The anti-TL1A of any one of embodiments 121-125, comprising a heavy chain Fc region comprising a sequence 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 25746 to any one of SEQ ID NOS: 368-380.
  • Embodiment 132 The anti-TL1A of any one of embodiments 121-125, comprising a constant region comprising a sequence 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: 381.
  • the anti-TL1A antibody of any one of embodiments 1- 132 comprising a light chain constant region comprising a sequence 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: 319.
  • the anti-TL1A antibody of any one of embodiments 1- 133 comprising at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% monomeric fraction as determined by size exclusion chromatography.
  • the antibody of embodiment 134, wherein the size exclusion chromatography comprises injecting purified antibody onto a size exclusion column, wherein the antibody is purified by protein A.
  • Embodiment 137 The antibody of any one of embodiments 134- 136, wherein the antibody is expressed under conditions described in Example 2.
  • Embodiment 138 The antibody of any one of embodiments 134-137, wherein the size exclusion chromatography column has an inner diameter of 4.6 mm.
  • Embodiment 139 The antibody of any one of embodiments 134-138, wherein the size exclusion chromatography column has a length of 150 mm.
  • Embodiment 140 The antibody of any one of embodiments 134-139, wherein the size exclusion chromatography column has a pore size of 200 ⁇ .
  • Embodiment 141 The antibody of any one of embodiments 134-140, wherein the size exclusion chromatography column has a particle size of 1.7 micrometer.
  • Embodiment 142 The antibody of any one of embodiments 134-141, wherein the size exclusion chromatography column is ACQUITY UPLC BEH200 SEC column.
  • Embodiment 143 The antibody of any one of embodiments 134-142, wherein the antibody or antigen binding fragment is injected at a total volume of 15 ⁇ L.
  • Embodiment 144) The antibody of any one of embodiments 134-143, wherein the antibody is injected at a concentration of about 0.1 ⁇ g/ ⁇ L to about 1.0 ⁇ g/ ⁇ L.
  • (Embodiment 149) The antibody of any one of embodiments 134-148, wherein the size exclusion chromatography is performed as described in Example 2.
  • (Embodiment 150) The anti-TL1A antibody of any one of embodiments 1- 149, wherein the anti-TL1A is expressed at a concentration of at least about 2 ⁇ g/mL, between about 2 ⁇ g/mL and about 60 ⁇ g/mL, between about 5 ⁇ g/mL and about 60 ⁇ g/mL, between about 10 ⁇ g/mL and about 60 ⁇ g/mL, at least about 5 ⁇ g/mL, at least about 10 ⁇ g/mL, at least about 15 ⁇ g/mL, at least about 20 ⁇ g/mL, between about 2 ⁇ g/mL and about 50 ⁇ g/mL, between about 2 ⁇ g/mL and about 40 ⁇ g/mL, between about 2 ⁇ g/mL and about 30 ⁇ g/mL, between about 2 ⁇
  • (Embodiment 151) The anti-TL1A antibody of any one of embodiments 1-149, wherein the expression level is at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 ⁇ g/mL as determined by a method disclosed herein.
  • (Embodiment 152) The antibody of embodiment 150 or embodiment 151, wherein the antibody is expressed in FreeStyle 293-F cells.
  • (Embodiment 153) The antibody of any one of embodiments 150-152, wherein the antibody is expressed as described in Example 2.
  • (Embodiment 154) The antibody of any one of embodiments 150-153, wherein the antibody expression level is quantified using Enzyme- Linked Immunosorbent assay (ELISA).
  • ELISA Enzyme- Linked Immunosorbent assay
  • Embodiment 155 The antibody of embodiment 154, wherein the ELISA comprises coating a surface of a substrate with a capture antibody that binds to a human or humanized antibody, applying the anti-TL1A antibody to the substrate, and applying to the substrate a second antibody that binds to a human or humanized antibody.
  • Embodiment 156 The antibody of embodiment 155, where the capture antibody comprises an anti-kappa antibody.
  • Embodiment 157 The antibody of embodiment 155 or embodiment 156, where the second antibody comprises an anti-Fc antibody.
  • Embodiment 158 The antibody of any one of embodiments 154-157, where the ELISA is performed as described in Example 2.
  • Embodiment 159 A method of treating sarcoidosis (such as pulmonary sarcoidosis and/or cutaneous sarcoidosis) in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment of any one of embodiments 1-158.
  • sarcoidosis such as pulmonary sarcoidosis and/or cutaneous sarcoidosis
  • Embodiment 160 A method of treating pulmonary sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment of any one of embodiments 1-158.
  • (Embodiment 161) A method of treating cutaneous sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment of any one of embodiments 1-158; a method of treating lupus pernio in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment of any one of embodiments 1-158; a method of treating papular sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment of any one of embodiments 1-158; a method of treating nodular sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment of any one of embodiments 1-158; a method of treating Darier- Roussy sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment of any one of embodiments 1-158; a method of treating maculopapular
  • Embodiment 162 A nucleic acid encoding the antibody of any one of embodiments 1-158.
  • Embodiment 163 A vector comprising the nucleic acid of embodiment 162.
  • Embodiment 164) A cell comprising the nucleic acid of embodiment 162.
  • Embodiment 165) A cell comprising the vector of embodiment 163.
  • Antibody Properties [0353] Anti-TL1A antibodies described herein bind to specific regions or epitopes of human TL1A. In various embodiments, an anti-TL1A antibody provided herein has a binding affinity to human TL1A of less than about 1E -7 , 1E -8 , 1E -9 , or 1E -10 Kd.
  • an anti-TL1A antibody provided herein has a binding affinity to murine TL1A and/or rat TL1A of less than about 1E -7 , 1E -8 , 1E -9 , 1E -10 , or 1E -11 Kd. Methods for determining binding affinity are exemplified herein, including in Example 2. [0354] In various embodiments, an anti-TL1A antibody provided herein is an antagonist of a TL1A receptor, such as, but not limited to, DR3 and TR6/DcR3.
  • the antibody inhibits at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 90%, or about 100% of one or more activity of the bound TL1A receptor.
  • the anti-TL1A antibody inhibits TL1A activation as measured by interferon gamma release in human blood.
  • the antibody inhibits interferon gamma release in human blood at an IC50 of between about 1 nanomolar and about 30 picomolar.
  • the antibody inhibits interferon gamma release in human blood at an IC50 of between about 500 picomolar and about 30 picomolar.
  • an anti-TL1A antibody provided herein comprises at least about 80% monomeric fraction after expression and purification as described in Example 2 or elsewhere herein.
  • an anti-TL1A antibody provided herein comprises at least about 85% monomeric fraction after expression and purification as described in Example 2 or elsewhere herein. In various embodiments, an anti-TL1A antibody provided herein comprises at least about 90% monomeric fraction after expression and purification as described in Example 2 or elsewhere herein. In various embodiments, an anti- TL1A antibody provided herein comprises at least about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% monomeric fraction after expression and purification as described in Example 2 or elsewhere herein. [0356] In various embodiments, an anti-TL1A antibody provided herein has at least about 2 ⁇ g/mL expression as determined by the method disclosed herein.
  • the anti-TL1A antibody has about 2 ⁇ g/mL to about 60 ⁇ g/mL expression as determined by the method disclosed herein. In some embodiments, the anti-TL1A antibody has about 5 ⁇ g/mL to about 60 ⁇ g/mL expression as determined by the method disclosed 25746 herein. In some embodiments, the anti-TL1A antibody has about 10 ⁇ g/mL to about 60 ⁇ g/mL expression as determined by the method disclosed herein. In some embodiments, the anti-TL1A antibody has at least about 5 ⁇ g/mL expression as determined by the method disclosed herein. In some embodiments, the anti-TL1A antibody has at least about 10 ⁇ g/mL expression as determined by the method disclosed herein.
  • the anti- TL1A antibody has at least about 15 ⁇ g/mL expression as determined by the method disclosed herein. In some embodiments, the anti-TL1A antibody has at least about 20 ⁇ g/mL expression as determined by the method disclosed herein.
  • the anti- TL1A antibody expresses between about 2 ⁇ g/mL and about 50 ⁇ g/mL, between about 2 ⁇ g/mL and about 40 ⁇ g/mL, between about 2 ⁇ g/mL and about 30 ⁇ g/mL expression, between about 2 ⁇ g/mL and about 20 ⁇ g/mL, between about 5 ⁇ g/mL and about 50 ⁇ g/mL, between about 5 ⁇ g/mL and about 40 ⁇ g/mL, between about 5 ⁇ g/mL and about 30 ⁇ g/mL, between about 10 ⁇ g/mL and about 50 ⁇ g/mL, between about 10 ⁇ g/mL and about 40 ⁇ g/mL, or between about 10 ⁇ g/mL and about 30 ⁇ g/mL as determined by the method disclosed herein.
  • the anti-TL1A antibody has about 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 ⁇ g/mL expression as determined by the method disclosed herein. Methods disclosed herein include those described in Example 2. [0357] In various embodiments, an anti-TL1A antibody provided herein is humanized and has less than about 20% non-human sequence in the framework region of each of the heavy chain and light chain variable regions.
  • the 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 sequence in the framework region of each of the heavy chain and light chain variable regions.
  • the 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 and light chain variable regions.
  • the humanized heavy chain variable domain may comprise IGHV1-46*02 framework with no or fewer than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 non-human mutations.
  • the humanized light chain variable domain may comprise IGKV3-20 framework with no or fewer than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 non-human mutations.
  • Epitope Various embodiments provide for an anti-TL1A antibody that binds to the same region of a TL1A protein or portion thereof as a reference antibody such as the anti- TL1A antibodies described herein.
  • the reference antibody comprises 25746 antibody A, B, C, D, E, F, G, H, A2, B2, C2, D2, E2, F2, G2, H2, J, J2, or K, or a combination thereof.
  • an anti-TL1A antibody that binds specifically to the same region of TL1A as a reference antibody comprising a heavy chain sequence at least about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 104, and a light chain comprising a sequence at least about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 201.
  • an anti-TL1A antibody that binds specifically to the same region of TL1A as a reference antibody comprising a heavy chain sequence at least about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 107, and a light chain comprising a sequence at least about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 201.
  • an anti-TL1A antibody that binds specifically to the same region of TL1A as a reference antibody comprising a heavy chain sequence at least about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 420, and a light chain comprising a sequence at least about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 430.
  • an anti-TL1A antibody that binds specifically to the same region of TL1A as a reference antibody comprising a heavy chain sequence at least about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 421, and a light chain comprising a sequence at least about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 431.
  • Non-limiting methods for determining whether an anti-TL1A antibody i.e. test antibody
  • binds to the same region of a TL1A protein or portion thereof as an antibody described herein are provided.
  • An exemplary embodiment comprises a competition assay.
  • the method comprises determining whether the test antibody can compete with binding between the reference antibody and the TL1A protein or portion thereof, or determining whether the reference antibody can compete with binding between the test antibody and the TL1A protein or portion thereof.
  • Exemplary methods include use of surface plasmon resonance to evaluate whether an anti-TL1A antibody can compete with the binding between TL1A and another anti-TL1A antibody. In some cases, surface plasmon resonance is utilized in the competition assay. Non-limiting methods are described in the examples. [0360] In certain embodiments, disclosed herein are antibodies that compete for binding TL1A with the antibodies described herein.
  • antibodies that bind a discrete epitope that overlaps with an epitope of TL1A bound by an 25746 antibody described herein are antibodies that bind the same epitope of TL1A, overlap with the epitope of TL1A by one or more amino acid residues, or that compete for binding to an epitope of TL1A with an antibody or fragment thereof that comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104; and a light chain variable region comprising the amino acid of SEQ ID NO: 201.
  • antibodies that bind the same epitope of TL1A, overlap with the epitope of TL1A by one or more amino acid residues, or that compete for binding to an epitope of TL1A with an antibody or fragment thereof that comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 107; and a light chain variable region comprising the amino acid of SEQ ID NO: 201.
  • antibodies that bind the same epitope of TL1A, overlap with the epitope of TL1A by one or more amino acid residues, or that compete for binding to an epitope of TL1A with an antibody or fragment thereof that comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 420; and a light chain variable region comprising the amino acid of SEQ ID NO: 421.
  • antibodies that bind the same epitope of TL1A, overlap with the epitope of TL1A by one or more amino acid residues, or that compete for binding to an epitope of TL1A with an antibody or fragment thereof that comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 421; and a light chain variable region comprising the amino acid of SEQ ID NO: 431.
  • Assays [0361] An exemplary screening paradigm for identification of antibody variants that express well in mammalian cells and preserve TL1A binding activity while minimizing the propensity of the antibody to aggregate comprises a five-step process. This screen was performed as detailed in the examples.
  • variants were cloned and transiently expressed as intact Ig in 293 cells using small-scale (3 mL, 6-well culture plates) transfections, (2) the expression level of the antibody was assessed in the culture supernatant 96-120 hours after transfection using an antibody quantitation ELISA, (3) the binding of the supernatant antibody variants to human TL1A was assessed by ELISA, (4) the antibody was purified in a single step using Protein A and (5) the material was analyzed by analytical SEC to assess monomer/aggregate content. This approach enabled identification of variants that expressed well, preserved binding to TL1A, and displayed high monomer content. [0362] Further provided herein are methods for analyzing antibody solubility based on percentage of monomeric fraction.
  • the immunoassays which can be used include, but are not limited to, competitive and non-competitive assay systems using techniques such as BIAcore analysis, FACS analysis, immunofluorescence, immunocytochemistry, Western blots, radioimmunoassays, ELISA, “sandwich” immunoassays, immunoprecipitation assays, precipitation reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and protein A immunoassays.
  • BIAcore analysis FACS analysis, immunofluorescence, immunocytochemistry, Western blots, radioimmunoassays, ELISA, “sandwich” immunoassays, immunoprecipitation assays, precipitation reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric as
  • monoclonal antibodies are prepared using methods known in the art, such as, but not limited to the hybridoma method, where a host animal is immunized to elicit the production by lymphocytes of antibodies that will specifically bind to an immunizing antigen (Kohler and Milstein (1975) Nature 256:495). Hybridomas produce monoclonal antibodies directed specifically against a chosen antigen.
  • monoclonal antibodies are purified from the culture medium or ascites fluid by techniques known in the art, when propagated either in vitro or in vivo.
  • monoclonal antibodies are made using recombinant DNA methods.
  • the polynucleotides encoding a monoclonal antibody are isolated from mature B-cells or hybridoma cells.
  • the isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors, which when transfected into host cells (e.g., E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells) generate monoclonal antibodies.
  • host cells e.g., E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells
  • the polynucleotide(s) encoding a monoclonal antibody can further be modified in a number of different manners using recombinant DNA technology to generate alternative antibodies.
  • a chimeric antibody a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region (e.g., humanized antibodies) can be generated.
  • the anti-TL1A monoclonal antibody is a humanized antibody, to reduce antigenicity and HAMA (human anti-mouse antibody) responses when administered to a human subject.
  • Humanized antibodies can be produced using various techniques known in the art.
  • an antibody is humanized by (1) determining the nucleotide and predicted amino acid sequence of the starting antibody light and heavy variable domains; (2) designing the humanized antibody, e.g., deciding which antibody framework region to use during the humanizing process; (3) the actual humanizing methodologies/techniques; and (4) the transfection and expression of the humanized antibody.
  • a humanized antibody can be further optimized to decrease potential immunogenicity, while maintaining functional activity, for therapy in humans.
  • Humanized antibodies can also be made in transgenic mice containing human immunoglobulin loci that are capable, upon immunization, of producing the full repertoire of human antibodies in the absence of endogenous immunoglobulin production.
  • a humanized antibody may also be obtained by a genetic engineering approach that enables production of affinity-matured human-like polyclonal antibodies in large animals.
  • a fully humanized antibody may be created by first designing a variable region amino acid sequence that contains non-human, e.g., rodent-derived CDRs, embedded in human-derived framework sequences.
  • the non-human CDRs provide the desired specificity. Accordingly, in some cases these residues are included in the design of the reshaped variable region essentially unchanged. In some cases, modifications should therefore be restricted to a minimum and closely watched for changes in the specificity and affinity of the antibody.
  • framework residues in theory can be derived from any human variable region.
  • a human framework sequences should be chosen, which is equally suitable for creating a reshaped variable region and for retaining antibody affinity, in order to create a reshaped antibody which shows an acceptable or an even improved affinity.
  • the human framework may be of germline origin, or may be derived from non-germline (e.g., mutated or affinity matured) sequences.
  • Genetic engineering techniques well known to those in the art, for example, but not limited to, phage display of libraries of human antibodies, transgenic mice, human-human hybridoma, hybrid hybridoma, B cell immortalization and cloning, single-cell RT–PCR or HuRAb Technology, may be used to generate a humanized antibody with a hybrid DNA sequence containing a human framework and a non-human CDR.
  • the anti-TL1A antibody is a human antibody.
  • Human antibodies can be directly prepared using various techniques known in the art. Immortalized human B lymphocytes immunized in vitro or isolated from an immunized individual that produce an antibody directed against a target antigen can be generated.
  • Chimeric, humanized and human antibodies may be produced by recombinant expression.
  • Recombinant polynucleotide constructs typically include an expression control sequence operably linked to the coding sequences of antibody chains, including naturally associated or heterologous promoter regions. In certain embodiments, it may be desirable to generate amino acid sequence variants of these humanized antibodies, particularly where these improve the binding affinity or other biological properties of the antibody.
  • an antibody fragment is used to treat and/or ameliorate sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichth
  • Antibody fragments may be produced by techniques in the art including, but not limited to: (a) a F(ab’)2 fragment produced by pepsin digestion of an antibody molecule; (b) a Fab fragment generated by reducing the disulfide bridges of an F(ab’)2 fragment, (c) a Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent, and (d) Fv fragments.
  • modified antibodies comprising any type of variable region that provides for the association of the antibody with TL1A.
  • modified antibodies may comprise antibodies (e.g., full-length antibodies or immunoreactive fragments thereof) in which at least a fraction of one or more of the constant region domains has been deleted or otherwise altered so as to provide desired biochemical characteristics such as decreasing TL1A.
  • the variable regions in both the heavy and light chains are altered by at least partial replacement of one or more CDRs and, if necessary, by partial framework region replacement and sequence changing.
  • the replaced CDRs may be derived from an antibody of the same class, subclass, from an antibody of a different class, for instance, from an antibody from a different species and/or a combination thereof.
  • the constant region of the modified antibodies will comprise a human constant region. Modifications to the constant region compatible with this disclosure comprise additions, deletions or substitutions of one or more amino acids in one or more domains. [0377] In various embodiments, the expression of an antibody or antigen-binding fragment thereof as described herein can occur in either prokaryotic or eukaryotic cells.
  • Suitable hosts include bacterial or eukaryotic hosts, including yeast, insects, fungi, bird and mammalian cells either in vivo, or in situ, or host cells of mammalian, insect, bird or yeast origin.
  • the mammalian cell or tissue can be of human, primate, hamster, rabbit, rodent, cow, pig, sheep, horse, goat, dog or cat origin, but any other mammalian cell may be used.
  • the antibody or antigen-fragment thereof as described herein may be transfected into the host.
  • the expression vectors are transfected into the recipient cell line for the production of the chimeric, humanized, or composite human antibodies described herein.
  • mammalian cells can be useful as hosts for the production of antibody proteins, which can include, but are not limited to cells of fibroblast origin, such as Vero (ATCC CRL 81) or CHO-K1 (ATCC CRL 61) cells, HeLa cells and L cells.
  • exemplary eukaryotic cells that can be used to express polypeptides include, but are not limited to, COS cells, including COS 7 cells; 293 cells, including 293-6E cells; CHO cells, including CHO— S and DG44 cells; PER.C6TM cells (Crucell); and NSO cells.
  • a particular eukaryotic host cell is selected based on its ability to make desired post-translational modifications to the heavy chains and/or light chains.
  • a number of suitable host cell lines capable of secreting intact heterologous proteins have been developed in the art, and include, but are not limited to CHO cell lines, various COS cell lines, HeLa cells, L cells and multiple myeloma cell lines.
  • An expression vector carrying a chimeric, humanized, or composite human antibody construct, antibody or antigen-binding fragment thereof as described herein can be introduced into an appropriate host cell by any of a variety of suitable means, depending on the type of cellular host including, but not limited to transformation, transfection, lipofection, conjugation, electroporation, direct microinjection, and microprojectile bombardment, as known to one of ordinary skill in the art.
  • Expression vectors for these cells can include expression control sequences, such as an origin of replication sites, a promoter, an enhancer and necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional terminator sequences.
  • yeast can also be utilized as hosts for the production of the antibody molecules or peptides described herein.
  • bacterial strains can also be utilized as hosts for the production of the antibody molecules or peptides described herein. Examples of bacterial strains include, but are not limited to E. coli, Bacillus species, enterobacteria, and various Pseudomonas species.
  • one or more antibodies or antigen-binding fragments thereof as described herein can be produced in vivo in an animal that has been engineered (transgenic) or transfected with one or more nucleic acid molecules encoding the polypeptides, according to any suitable method.
  • transgenes can be microinjected into fertilized oocytes, or can be incorporated into the genome of embryonic stem cells, and the nuclei of such cells transferred into enucleated oocytes.
  • antibodies can be purified according to standard procedures of the art, including HPLC purification, column chromatography, gel electrophoresis and the like (see generally, Scopes, Protein Purification (Springer-Verlag, NY, 1982)).
  • the whole antibodies, antibody-fragments (e.g., individual light and heavy chains), or other immunoglobulin forms of the present disclosure can be recovered and purified by known techniques, e.g., immunoabsorption or immunoaffinity chromatography, chromatographic methods such as HPLC (high performance liquid chromatography), ammonium sulfate precipitation, gel electrophoresis, or any combination of these. See generally, Scopes, PROTEIN PURIF. (Springer- Verlag, NY, 1982). Substantially pure immunoglobulins of at least about 90% to 95% homogeneity are advantageous, as are those with 98% to 99% or more homogeneity, particularly for 25746 pharmaceutical uses.
  • a humanized or composite human antibody can then be used therapeutically or in developing and performing assay procedures, immunofluorescent stainings, etc. See generally, Vols. I & II Immunol. Meth. (Lefkovits & Pernis, eds., Acad. Press, NY, 1979 and 1981).
  • Various embodiments provide for a genetic construct comprising a nucleic acid encoding an anti-TL1A antibody or fragment provided herein. Genetic constructs of the antibody can be in the form of expression cassettes, which can be suitable for expression of the encoded anti-TL1A antibody or fragment. The genetic construct may be introduced into a host cell with or without being incorporated in a vector.
  • the genetic construct can be incorporated within a liposome or a virus particle.
  • a purified nucleic acid molecule can be inserted directly into a host cell by methods known in the art.
  • the genetic construct can be introduced directly into cells of a host subject by transfection, infection, electroporation, cell fusion, protoplast fusion, microinjection or ballistic bombardment.
  • Various embodiments provide a recombinant vector comprising the genetic construct of an antibody provided herein.
  • the recombinant vector can be a plasmid, cosmid or phage.
  • the recombinant vectors can include other functional elements; for example, a suitable promoter to initiate gene expression.
  • a host cell comprising a genetic construct and/or recombinant vector described herein.
  • Various host systems are also advantageously employed to express recombinant protein. Examples of suitable mammalian host cell lines include the COS-7 lines of monkey kidney cells, and other cell lines capable of expressing an appropriate vector including, for example, L cells, C127, 3T3, Chinese hamster ovary (CHO), HeLa and BHK cell lines.
  • Mammalian expression vectors can comprise non-transcribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, and other 5’ or 3’ flanking non-transcribed sequences, and 5’ or 3’ non-translated sequences, such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and transcriptional termination sequences.
  • the proteins produced by a transformed host can be purified according to any suitable method. Such standard methods include chromatography (e.g., ion exchange, affinity and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for protein purification.
  • Affinity tags such as hexahistidine (SEQ ID NO: 391), maltose binding domain, influenza coat sequence and glutathione-S-transferase can be 25746 attached to the protein to allow easy purification by passage over an appropriate affinity column.
  • Isolated proteins can also be physically characterized using such techniques as proteolysis, nuclear magnetic resonance and x-ray crystallography. Recombinant protein produced in bacterial culture can be isolated.
  • a given amino acid can be replaced by a residue having similar physiochemical characteristics, e.g., substituting one aliphatic residue for another (such as He, Val, Leu, or Ala for one another), or substitution of one polar residue for another (such as between Lys and Arg; Glu and Asp; or Gln and Asn).
  • Other such conservative substitutions e.g., substitutions of entire regions having similar hydrophobicity characteristics, are well known.
  • Polypeptides comprising conservative amino acid substitutions can be tested in any one of the assays described herein to confirm that a desired activity, e.g. antigen-binding activity and specificity of a native or reference polypeptide is retained.
  • Particular conservative substitutions include, for example; Ala into Gly or into Ser; Arg into Lys; Asn into Gin or into H is; Asp into Glu; Cys into Ser; Gin into Asn; Glu into Asp; Gly into Ala or into Pro; His into Asn or into Gin; lie into Leu or into Val; Leu into lie or into Val; Lys into Arg, into Gin or into Glu; Met into Leu, into Tyr or into lie; Phe into Met, into Leu or into Tyr; Ser into Thr; Thr into Ser; Trp into Tyr; Tyr into Trp; and/or Phe into Val, into lie or into Leu.
  • the antibody and/or antigen-binding fragment thereof described herein can be a variant of a sequence described herein, e.g., a conservative substitution variant of an antibody polypeptide.
  • the variant is a conservatively modified variant.
  • a variant may refer to a polypeptide substantially homologous to a native or reference polypeptide, but which has an amino acid sequence different from that of the native or reference polypeptide because of one or a plurality of deletions, insertions or substitutions.
  • Variant polypeptide-encoding DNA sequences encompass sequences that comprise one or more additions, deletions, or substitutions of nucleotides when compared to a native or reference DNA sequence, but that encode a variant 25746 protein or fragment thereof that retains activity, e.g., antigen-specific binding activity for the relevant target polypeptide.
  • Alterations of the native amino acid sequence can be accomplished by any of a number of techniques known to one of skill in the art. Mutations can be introduced at particular loci or by oligonucleotide-directed site-specific mutagenesis procedures. Techniques for making such alterations are very well established and include, for example, those disclosed by Walder et al. (Gene 42: 133, 1986); Bauer et al.
  • Nucleic acid molecules encoding amino acid sequence variants of antibodies are prepared by a variety of methods known in the art. These methods include, but are not limited to, preparation by oligonucleotide-mediated (or site-directed) mutagenesis, PCR mutagenesis, and cassette mutagenesis of an earlier prepared variant or a non-variant version of the antibody.
  • a nucleic acid sequence encoding at least one antibody, portion or polypeptide as described herein can be recombined with vector DNA in accordance with conventional techniques, including but not limited to, blunt-ended or staggered-ended termini for ligation and restriction enzyme digestion. Techniques for such manipulations are disclosed, e.g., by Maniatis et al., Molecular Cloning, Lab. Manual (Cold Spring Harbor Lab. Press, NY, 1982 and 1989), and can be used to construct nucleic acid sequences which encode a monoclonal antibody molecule or antigen-binding region. [0395]
  • a nucleic acid encoding an antibody or antigen-binding fragment thereof as described herein is comprised by a vector.
  • a nucleic acid sequence encoding an antibody or antigen-binding fragment thereof as described herein, or any module thereof is operably linked to a vector.
  • a vector can be viral or non-viral.
  • the term “vector” encompasses any genetic element that is capable of replication when associated with the proper control elements and that can transfer gene sequences to cells.
  • a vector can include, but is not limited to, a cloning vector, an expression vector, a plasmid, phage, transposon, cosmid, chromosome, virus, virion, etc.
  • expression vector refers to a vector that directs expression of an RNA or polypeptide from sequences linked to transcriptional regulatory sequences on the vector.
  • expression refers to the cellular processes involved in producing RNA and proteins and as appropriate, secreting proteins, including where 25746 applicable, but not limited to, for example, transcription, transcript processing, translation and protein folding, modification and processing.
  • “Expression products” include RNA transcribed from a gene, and polypeptides obtained by translation of mRNA transcribed from a gene.
  • gene means the nucleic acid sequence which is transcribed (DNA) to RNA in vitro or in vivo when operably linked to appropriate regulatory sequences.
  • the gene may or may not include regions preceding and following the coding region, e.g., 5’ untranslated (5’UTR) or “leader” sequences and 3’ UTR or “trailer” sequences, as well as intervening sequences (introns) between individual coding segments (exons).
  • the term “viral vector” refers to a nucleic acid vector construct that includes at least one element of viral origin and has the capacity to be packaged into a viral vector particle.
  • the viral vector can contain the nucleic acid encoding an antibody or antigen-binding portion thereof as described herein in place of non-essential viral genes.
  • the vector and/or particle may be utilized for the purpose of transferring any nucleic acids into cells either in vitro or in vivo.
  • Numerous forms of viral vectors are known in the art.
  • recombinant vector it is meant that the vector includes a heterologous nucleic acid sequence, or “transgene” that is capable of expression in vivo.
  • anti-TL1A antibodies provided herein are formulated into pharmaceutical compositions that are useful in a variety of applications including, but not limited to, therapeutic methods, such as the treatment of sarcoidosis, including pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal
  • the methods of use may be in vitro, ex vivo, or in vivo methods.
  • the pharmaceutical compositions are formulated for delivery via any route of administration.
  • Route of administration includes any administration pathway known in the art, including but not limited to intravenous, subcutaneous, aerosol, nasal, oral, transmucosal, transdermal and parenteral. In example embodiments, the route of administration is subcutaneous. 25746 [0401]
  • the pharmaceutical compositions may contain any pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body.
  • the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof.
  • Each component of the carrier must be “pharmaceutically acceptable” in that it must be compatible with the other ingredients of the formulation. It must also be suitable for use in contact with any tissues or organs with which it may come in contact, meaning that does not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits.
  • “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use.
  • the active ingredient can be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in therapeutic methods described herein.
  • excipients may be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous. Suitable excipients may be selected for different routes of administration (e.g., subcutaneous, intravenous, oral).
  • Non- limiting examples include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, water, saline, dextrose, propylene glycol, glycerol, ethanol, mannitol, polysorbate or the like and combinations thereof.
  • the composition can contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance or maintain the effectiveness of the active ingredient.
  • Therapeutic compositions as described herein can include pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts include the acid addition salts formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, organic acids, for example, acetic, tartaric or mandelic, salts formed from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and salts formed from organic bases such as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like.
  • Liquid compositions can contain liquid phases in addition to and in the exclusion of 25746 water, for example, glycerin, vegetable oils such as cottonseed oil, and water-oil emulsions.
  • Physiologically tolerable carriers are well known in the art.
  • the amount of antibody used that will be effective in the treatment of sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichthyosi
  • compositions comprising an anti-TL1A antibody formulated for intravenous administration.
  • pharmaceutical compositions comprising an anti-TL1A antibody formulated for subcutaneous administration.
  • pharmaceutical compositions comprising an anti-TL1A antibody at a concentration of about or greater than about 150 mg/mL. In some embodiments, the concentration is up to about 300 mg/mL. In some embodiments, the concentration is about or greater than about 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg/mL.
  • the concentration is about 150 mg/mL to about 300 mg/mL, about 150 mg/mL to about 250 mg/mL, about 150 mg/mL to about 225 mg/mL, about 150 mg/mL to about 220 mg/mL, about 150 mg/mL to about 210 mg/mL, about 150 mg/mL to about 200 mg/mL, about 150 mg/mL to about 190 mg/mL, about 150 mg/mL to about 180 mg/mL, about 160 mg/mL to about 300 mg/mL, about 160 mg/mL to about 250 mg/mL, about 160 mg/mL to about 225 mg/mL, about 160 mg/mL to about 220 mg/mL, about 160 mg/mL to about 210 mg/mL, about 160 mg/mL to about 200 mg/mL, about 160 mg/mL to about 190 mg/mL, about 160 mg/mL to about 180 mg/mL, about 170 mg/mL to about 300 mg/mL,
  • about 150 mg to about 1,000 mg of the anti-TL1A antibody is present in the composition.
  • the composition comprises an anti- TL1A antibody at a concentration greater than about 50 mg/mL.
  • the composition comprising an anti-TL1A antibody at a concentration greater than about 55 mg/mL, greater than about 60 mg/mL, greater than about 65 mg/mL, greater than about 70 mg/mL, greater than about 75 mg/mL, greater than about 80 mg/mL, greater than about 85 mg/mL, greater than about 90 mg/mL, greater than about 95 mg/mL, greater than about 100 mg/mL, greater than about 105 mg/mL, greater than about 110 mg/mL, greater than about 115 mg/mL, greater than about 120 mg/mL, greater than about 125 mg/mL, greater than about 130 mg/mL, greater than about 135 mg/mL, greater than about 140 mg/mL, or greater than about 145 mg/mL.
  • the composition comprising an anti-TL1A antibody at a concentration of about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 85 mg/mL, about 90 mg/mL, about 95 mg/mL, about 100 mg/mL, about 105 mg/mL, about 110 mg/mL, about 115 mg/mL, about 120 mg/mL, about 125 mg/mL, about 130 mg/mL, about 135 mg/mL, about 140 mg/mL, or about 145 mg/mL.
  • the composition comprising an anti-TL1A antibody at a concentration of about 50 mg/mL to about 250 mg/mL, about 55 mg/mL to about 250 mg/mL, about 60 mg/mL to about 250 mg/mL, about 65 mg/mL to about 250 mg/mL, about 70 mg/mL to about 250 mg/mL, about 75 mg/mL to about 250 mg/mL, about 80 mg/mL to about 250 mg/mL, about 85 mg/mL to about 250 mg/mL, about 90 mg/mL to about 250 mg/mL, about 95 mg/mL to about 250 mg/mL, about 100 mg/mL to about 250 mg/mL, about 105 mg/mL to about 250 mg/mL, about 110 mg/mL to about 250 mg/mL, about 115 mg/mL to about 250 mg/mL, about 120 mg/mL to about 250 mg/mL, about 125 mg/mL to about 250 mg/mL, about 130 mg/mL to
  • the composition comprising an anti-TL1A antibody at a concentration of about 50 mg/mL to about 140 mg/mL, about 55 mg/mL to about 140 mg/mL, about 60 mg/mL to about 140 mg/mL, about 65 mg/mL to about 140 mg/mL, about 70 mg/mL to about 140 mg/mL, about 75 mg/mL to about 140 mg/mL, about 25746 80 mg/mL to about 140 mg/mL, about 85 mg/mL to about 140 mg/mL, about 90 mg/mL to about 140 mg/mL, about 95 mg/mL to about 140 mg/mL, about 100 mg/mL to about 140 mg/mL, about 105 mg/mL to about 140 mg/mL, about 110 mg/mL to about 140 mg/mL, about 115 mg/mL to about 140 mg/mL, about 120 mg/mL to about 140 mg/mL, about 125 mg/mL to about 140 mg/mL, about 130 mg/
  • the composition comprising an anti-TL1A antibody at a concentration of about 50 mg/mL to about 130 mg/mL, about 55 mg/mL to about 130 mg/mL, about 60 mg/mL to about 130 mg/mL, about 65 mg/mL to about 130 mg/mL, about 70 mg/mL to about 130 mg/mL, about 75 mg/mL to about 130 mg/mL, about 80 mg/mL to about 130 mg/mL, about 85 mg/mL to about 130 mg/mL, about 90 mg/mL to about 130 mg/mL, about 95 mg/mL to about 130 mg/mL, about 100 mg/mL to about 130 mg/mL, about 105 mg/mL to about 130 mg/mL, about 110 mg/mL to about 130 mg/mL, about 115 mg/mL to about 130 mg/mL, about 120 mg/mL to about 130 mg/mL, or about 125 mg/mL to about 130 mg/mL.
  • the composition comprising an anti- TL1A antibody at a concentration of about 50 mg/mL to about 120 mg/mL, about 55 mg/mL to about 120 mg/mL, about 60 mg/mL to about 120 mg/mL, about 65 mg/mL to about 120 mg/mL, about 70 mg/mL to about 120 mg/mL, about 75 mg/mL to about 120 mg/mL, about 80 mg/mL to about 120 mg/mL, about 85 mg/mL to about 120 mg/mL, about 90 mg/mL to about 120 mg/mL, about 95 mg/mL to about 120 mg/mL, about 100 mg/mL to about 120 mg/mL, about 105 mg/mL to about 120 mg/mL, about 110 mg/mL to about 120 mg/mL, or about 115 mg/mL to about 120 mg/mL.
  • the composition comprising an anti-TL1A antibody at a concentration of about 50 mg/mL to about 110 mg/mL, about 55 mg/mL to about 110 mg/mL, about 60 mg/mL to about 110 mg/mL, about 65 mg/mL to about 110 mg/mL, about 70 mg/mL to about 110 mg/mL, about 75 mg/mL to about 110 mg/mL, about 80 mg/mL to about 110 mg/mL, about 85 mg/mL to about 110 mg/mL, about 90 mg/mL to about 110 mg/mL, about 95 mg/mL to about 110 mg/mL, about 100 mg/mL to about 110 mg/mL, or about 105 mg/mL to about 110 mg/mL.
  • the composition comprising an anti-TL1A antibody at a concentration of about 50 mg/mL to about 100 mg/mL, about 55 mg/mL to about 100 mg/mL, about 60 mg/mL to about 100 mg/mL, about 65 mg/mL to about 100 mg/mL, about 70 mg/mL to about 100 mg/mL, about 75 mg/mL to about 100 mg/mL, about 80 mg/mL to about 100 mg/mL, about 85 mg/mL to about 100 mg/mL, about 90 mg/mL to about 100 mg/mL, about 95 mg/mL to about 100 mg/mL, about 100 mg/mL to about 100 mg/mL, or about 105 mg/mL to about 100 mg/mL.
  • the composition comprising an anti-TL1A antibody at a concentration 25746 of about 50 mg/mL to about 90 mg/mL, about 55 mg/mL to about 90 mg/mL, about 60 mg/mL to about 90 mg/mL, about 65 mg/mL to about 90 mg/mL, about 70 mg/mL to about 90 mg/mL, about 75 mg/mL to about 90 mg/mL, about 80 mg/mL to about 90 mg/mL, or about 85 mg/mL to about 90 mg/mL.
  • the composition comprising an anti-TL1A antibody at a concentration of about 50 mg/mL to about 80 mg/mL, about 55 mg/mL to about 80 mg/mL, about 60 mg/mL to about 80 mg/mL, about 65 mg/mL to about 80 mg/mL, about 70 mg/mL to about 80 mg/mL, or about 75 mg/mL to about 80 mg/mL.
  • the composition comprising an anti-TL1A antibody at a concentration of about 50 mg/mL to about 70 mg/mL, about 55 mg/mL to about 70 mg/mL, about 60 mg/mL to about 70 mg/mL, or about 65 mg/mL to about 70 mg/mL.
  • the composition comprising an anti-TL1A antibody at a concentration of about 50 mg/mL to about 55 mg/mL, about 50 mg/mL to about 60 mg/mL, or about 55 mg/mL to about 60 mg/mL.
  • the composition provided herein may have a viscosity of less than or about 20 centipoise (cP).
  • the composition may have a viscosity of less than or about 15 centipoise (cP).
  • the composition may have a viscosity of less than or about 10 centipoise (cP).
  • the composition has a viscosity of less than or about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 cP.
  • the composition may have a viscosity of at least about 1, 2 or 3 cP. Further example viscosities include about 1 cP to about 2 cP, about 1 cP to about 3 cP, about 1 cP to about 4 cP, about 1 cP to about 5 cP, about 1 cP to about 6 cP, about 1 cP to about 7 cP, about 1 cP to about 8 cP, about 1 cP to about 9 cP, about 1 cP to about 10 cP, about 1 cP to about 11 cP, about 1 cP to about 12 cP, about 1 cP to about 13 cP, about 1 cP to about 14 cP, about 1 cP to about 15 cP, about 1 cP to about 16 cP, about 1 cP to about 17 cP, about 1 cP to about 18 cP, about 1 cP to about 19 cP, about 1 cP to about 20
  • a centipoise as used herein is a millipascal-second (mPa ⁇ s).
  • a pharmaceutical composition comprising a therapeutically effective dose of an anti-TL1A antibody having a total volume of less than or equal to about 2.5 mL.
  • the pharmaceutical composition comprises a therapeutically effective dose of an anti-TL1A antibody having a total volume of less than or equal to about 2 mL.
  • the total volume may be 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, 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.
  • the total volume may be at least about 0.5 mL.
  • the total volume may be about 0.5 mL to about 3 mL, about 0.5 mL to about 2.9 mL, about 0.5 mL to about 2.8 mL, about 0.5 mL to about 2.7 mL, about 0.5 mL to about 2.6 mL, about 0.5 mL to about 2.5 mL, about 0.5 mL to about 2.4 mL, about 0.5 mL to about 2.3 mL, about 0.5 mL to about 2.2 mL, about 0.5 mL to about 2.1 mL, about 0.5 mL to about 2.0 mL, about 0.5 mL to about 1.9 mL, about 0.5 mL to about 1.8 mL, about 0.5 mL to about 1.7 mL, about 0.5 mL to about 1.6 mL, about 0.5 mL to about 1.5 mL, about 0.5 mL to about 1.4 mL
  • the composition may have a viscosity of less than or about 10 centipoise (cP).
  • cP centipoise
  • the composition has a viscosity of less than or about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 cP.
  • the composition may have a viscosity of at least about 1, 2 or 3 cP.
  • viscosities include about 1 cP to about 2 cP, about 1 cP to about 3 cP, about 1 cP to about 4 cP, about 1 cP to about 5 cP, about 1 cP to about 6 cP, about 1 cP to about 7 cP, about 1 cP to about 8 cP, about 1 cP to about 9 cP, about 1 cP to about 10 cP, about 2 cP to about 5 cP, about 2 cP to about 6 cP, about 2 cP to about 7 cP, about 2 cP to about 8 cP, about 2 cP to about 9 cP, about 2 cP to about 10 cP, about 3 cP to about 5 cP, about 3 cP to about 6 cP, about 3 cP to about 7 cP, about 3 cP to about 8 cP, about 3 cP to about 9 cP, about 3 cP to about 10
  • the therapeutically effective dose is about or at least about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of anti-TL1A.
  • the therapeutically effective dose is about 150 mg to about 2000 mg, about 150 mg to about 1750 mg, about 150 mg to about 25746 1500 mg, about 150 mg to about 1250 mg, about 150 mg to about 1000 mg, about 150 mg to about 750 mg, about 150 mg to about 500 mg, about 150 mg to about 450 mg, about 150 mg to about 400 mg, about 150 mg to about 350 mg, about 150 mg to about 300 mg, about 150 mg to about 250 mg, or about 150 mg to about 200 mg anti-TL1A.
  • the pharmaceutical composition comprises about 50 mg/mL to about 250 mg/mL, about 55 mg/mL to about 250 mg/mL, about 60 mg/mL to about 250 mg/mL, about 65 mg/mL to about 250 mg/mL, about 70 mg/mL to about 250 mg/mL, about 75 mg/mL to about 250 mg/mL, about 80 mg/mL to about 250 mg/mL, about 85 mg/mL to about 250 mg/mL, about 90 mg/mL to about 250 mg/mL, about 95 mg/mL to about 250 mg/mL, about 100 mg/mL to about 250 mg/mL, about 105 mg/mL to about 250 mg/mL, about 110 mg/mL to about 250 mg/mL, about 115 mg/mL to about 250 mg/mL, about 120 mg/mL to about 250 mg/mL, about 125 mg/mL to about 250 mg/mL, about 130 mg/mL to about 250 mg/mL, about 135 mg/
  • the concentration of anti-TL1A is about or greater than about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg/mL.
  • a pharmaceutical composition for subcutaneous administration comprising an anti-TL1A antibody, wherein at least about 150 mg of the anti-TL1A antibody is present in the composition.
  • up to about 2000 mg, up to about 1750 mg, up to about 1500 mg, up to about 1250 mg, up to about 1000 mg, up to 25746 about 750 mg, up to about 500 mg of anti-TL1A is present in the composition.
  • the total volume of the composition may be less than or equal to about 2 mL.
  • the total volume of the composition may be less than or equal to about 2.5 mL.
  • the total volume may be less than about 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, 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.
  • the total volume may be at least about 0.5 mL.
  • the total volume may be about 0.5 mL to about 3 mL, about 0.5 mL to about 2.9 mL, about 0.5 mL to about 2.8 mL, about 0.5 mL to about 2.7 mL, about 0.5 mL to about 2.6 mL, about 0.5 mL to about 2.5 mL, about 0.5 mL to about 2.4 mL, about 0.5 mL to about 2.3 mL, about 0.5 mL to about 2.2 mL, about 0.5 mL to about 2.1 mL, about 0.5 mL to about 2 mL, 0.5 mL to about 1.9 mL, 0.5 mL to about 1.8 mL, 0.5 mL to about 1.7 mL, 0.5 mL to about 1.6 mL, about 0.5 mL to about 1.5 mL, about 0.5 mL to about 1.4 mL, about 0.5
  • the composition may have a viscosity of less than or about 20 centipoise (cP).
  • the composition may have a viscosity of less than or about 15 centipoise (cP).
  • the composition may have a viscosity of less than or about 10 centipoise (cP).
  • the composition has a viscosity of less than or about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 cP.
  • the composition may have a viscosity of at least about 1, 2 or 3 cP.
  • viscosities include about 1 cP to about 2 cP, about 1 cP to about 3 cP, about 1 cP to about 4 cP, about 1 cP to about 5 cP, about 1 cP to about 6 cP, about 1 cP to about 7 cP, about 1 cP to about 8 cP, about 1 cP to about 9 cP, about 1 cP to about 10 cP, about 1 cP to about 11 cP, about 1 cP to about 12 cP, about 1 cP to about 13 cP, about 1 cP to about 14 cP, about 1 cP to about 15 cP, about 1 cP to about 16 cP, about 1 cP to about 17 cP, about 1 cP to about 18 cP, about 1 cP to about 19 cP, about 1 cP to about 20 cP, about 2 cP to about 5 cP, about 2 cP to about 6
  • the concentration of anti-TL1A is about or greater than about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, or 250 mg/mL.
  • a pharmaceutical composition comprising a therapeutically effective dose of an anti-TL1A antibody, wherein the pharmaceutical composition has a viscosity of less than about 20 cP, 15 cP, or 10 cP.
  • the composition may have a viscosity of less than or about 20 cP.
  • the composition may have a viscosity of less than or about 15 cP.
  • the composition may have a viscosity of less than or about 10 cP.
  • the composition has a viscosity of less than or about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 cP.
  • the composition may have a viscosity of at least about 1, 2 or 3 cP.
  • viscosities include about 1 cP to about 2 cP, about 1 cP to about 3 cP, about 1 cP to about 4 cP, about 1 cP to about 5 cP, about 1 cP to about 6 cP, about 1 cP to about 7 cP, about 1 cP to about 8 cP, about 1 cP to about 9 cP, about 1 cP to about 10 cP, about 1 cP to about 11 cP, about 1 cP to about 12 cP, about 1 cP to about 13 cP, about 1 cP to about 14 cP, about 1 cP to about 15 cP, about 1 cP to about 16 cP, about 1 cP to about 17 cP, about 1 cP to about 18 cP, about 1 cP to about 19 cP, about 1 cP to about 20 cP, about 2 cP to about 5 cP, about 2 cP to about 6
  • the therapeutically effective dose is at least about 150 mg anti-TL1A antibody. In some cases, the therapeutically effective dose is about or at least about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of anti-TL1A.
  • the therapeutically effective dose is about 150 mg to about 2000 mg, about 150 mg to about 1750 mg, about 150 mg to about 1500 mg, about 150 mg to about 1250 mg, about 150 mg to about 1000 mg, about 150 mg to about 750 mg, about 150 mg to about 500 mg, about 150 mg to about 450 mg, about 150 mg to about 400 mg, about 150 mg to about 350 mg, about 150 mg to about 300 mg, about 150 mg to about 250 mg, or about 150 mg to about 200 mg anti-TL1A.
  • the total volume of the composition may be less than or equal to about 2 mL.
  • the total volume of the composition may be less than or equal to about 2.5 mL.
  • the total volume may be less than about 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, 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.
  • the total volume may be at least about 0.5 mL.
  • the total volume may be about 0.5 mL to about 3 mL, about 0.5 mL to about 2.9 mL, about 0.5 mL to about 2.8 mL, about 0.5 mL to about 2.7 mL, about 0.5 mL to about 2.6 mL, about 0.5 mL to about 2.5 mL, about 0.5 mL to about 2.4 mL, about 0.5 mL to about 2.3 mL, about 0.5 mL to about 2.2 mL, about 0.5 mL to about 2.1 mL, about 0.5 mL to about 2 mL, 0.5 mL to about 1.9 mL, 0.5 mL to about 1.8 mL, 0.5 mL to about 1.7 mL, 0.5 mL to about 1.6 mL, about 0.5 mL to about 1.5 mL, about 0.5 mL to about 1.4 mL, about 0.5
  • the concentration of anti-TL1A is about or greater than about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, or 250 mg/mL.
  • a pharmaceutical composition comprising a therapeutically effective dose of an anti-TL1A antibody having a percentage aggregation of the anti-TL1A antibody as measured by size exclusion chromatography of less than about 5% of the total anti-TL1A antibody in the composition.
  • the percentage aggregation of anti-TL1A antibody as measured by size exclusion chromatography is less than about 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% of the composition volume.
  • the therapeutically effective dose is at least about 150 mg anti-TL1A antibody.
  • the therapeutically effective dose is about or at least about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of anti-TL1A.
  • the therapeutically effective dose is about 150 mg to about 2000 mg, about 150 mg to about 1750 mg, about 150 mg to about 1500 mg, about 150 mg to about 25746 1250 mg, about 150 mg to about 1000 mg, about 150 mg to about 750 mg, about 150 mg to about 500 mg, about 150 mg to about 450 mg, about 150 mg to about 400 mg, about 150 mg to about 350 mg, about 150 mg to about 300 mg, about 150 mg to about 250 mg, or about 150 mg to about 200 mg anti-TL1A.
  • the total volume of the composition may be less than or equal to about 2 mL.
  • the total volume of the composition may be less than or equal to about 2.5 mL.
  • the total volume may be less than about 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, 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.
  • the total volume may be at least about 0.5 mL.
  • the total volume may be about 0.5 mL to about 3 mL, about 0.5 mL to about 2.9 mL, about 0.5 mL to about 2.8 mL, about 0.5 mL to about 2.7 mL, about 0.5 mL to about 2.6 mL, about 0.5 mL to about 2.5 mL, about 0.5 mL to about 2.4 mL, about 0.5 mL to about 2.3 mL, about 0.5 mL to about 2.2 mL, about 0.5 mL to about 2.1 mL, about 0.5 mL to about 2 mL, 0.5 mL to about 1.9 mL, 0.5 mL to about 1.8 mL, 0.5 mL to about 1.7 mL, 0.5 mL to about 1.6 mL, about 0.5 mL to about 1.5 mL, about 0.5 mL to about 1.4 mL, about 0.5
  • the 25746 concentration of anti-TL1A is about or greater than about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, or 250 mg/mL.
  • the pharmaceutical composition has a volume suitable for injection, such as via subcutaneous administration. In some embodiments, the total volume of the composition may be less than or equal to about 2.5 mL.
  • the total volume of the composition is less than about 2 mL, less than about 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, 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,
  • Antibody therapeutics suitable for injection and/or administration are important to realizing full therapeutic potential. However, administration is generally restricted by volume, for instance, when the therapeutic is delivered subcutaneously. This, in turn, elucidates the importance developing of high concentration antibody formulations of greater than, for example in some cases, 100 mg/ml. Problems associated with antibody development include high solution viscosity and opalescence, which are commonly encountered during the development of high-concentration (e.g., greater than 100 mg/ml). Both viscosity and opalescence impact antibody developability broadly, affecting manufacturability, stability, and delivery.
  • solution viscosities e.g., greater than 30 mPa-s
  • viscous antibody solutions also result in forbidding or incompatible injection forces when administering via injection, including via patient friendly autoinjectors.
  • solution viscosity can be a determining factor for the maximum antibody dose possible via injection.
  • Solution opalescence in therapeutic antibodies can be equally problematic as opalescence can indicate predisposition for liquid-liquid phase separation, precipitation, or aggregation. Further difficulty may occur with blinding of subcutaneous placebo.
  • anti-TL1A antibodies provided herein demonstrate advantageous viscosity and aggregation properties at high antibody concentrations (e.g., greater than about 100, 125, 150, 160, 170, 180, 190, or 200 mg/mL).
  • anti-TL1A antibodies provided herein are characterized by low viscosity (e.g., less than 20 mPa-s) and low aggregation (e.g., less than 5% high molecular weight species) at high concentrations (FIGS.3A-3C).
  • the anti-T1LA antibody is characterized by a viscosity less than about 30, 20, 15, or 10 mPa-s at a concentration greater than about 25746 100 mg/mL, e.g., about 150 mg/mL to about 300 mg/mL, about 150 mg/mL to about 200 mg/mL, about 150 mg/mL to about 225 mg/mL, or about 150 mg/mL to about 250 mg/mL.
  • the antibody comprises a HCDR1 comprising SEQ ID NO: 1, a HCDR2 comprising SEQ ID NO: 2, a HCDR3 comprising SEQ ID NO: 6, a LCDR1 comprising SEQ ID NO: 10, a LCDR2 comprising SEQ ID NO: 11, and a LCDR3 comprising SEQ ID NO: 12, and/or having a heavy chain variable region comprising SEQ ID NO: 104 and a light chain variable region comprising SEQ ID NO: 201.
  • the anti-TL1A antibody comprises 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 less than 9 amino acid modifications from the human IGHV1-46*02 framework and the human IGKV3-20 framework.
  • the composition has a viscosity of less than or about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 cP.
  • the composition may have a viscosity of at least about 1, 2 or 3 cP.
  • the anti-T1LA antibody is characterized by a viscosity about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a concentration greater than or about 150 mg/mL. In some embodiments, the anti-T1LA antibody is characterized by a viscosity about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a concentration greater than or about 160 mg/mL.
  • the anti-T1LA antibody is characterized by a viscosity about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a concentration greater than or about 170 mg/mL. In some embodiments, the anti- T1LA antibody is characterized by a viscosity about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a concentration greater than or about 180 mg/mL.
  • the anti-T1LA antibody is characterized by a viscosity about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a concentration greater than or about 190 mg/mL. In some embodiments, the anti-T1LA antibody is characterized by a viscosity about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a concentration greater than or about 200 mg/mL.
  • the anti-T1LA antibody is characterized by a viscosity about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a concentration greater than or about 210 mg/mL. In some embodiments, the anti-T1LA antibody is characterized by a viscosity about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a concentration greater than or about 220 mg/mL.
  • the anti-T1LA antibody is characterized by a viscosity about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a concentration greater than or about 250 mg/mL. In some embodiments, the anti-T1LA antibody is characterized by a viscosity about or less than about 20, 19, 1817, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 mPa-s at a concentration of about 150 mg/ml to about 250 mg/ml.
  • less than about 20 mPa-s includes from about 2 to about 20 mPa-s, from about 2 to about 19 mPa-s, from about 2 to about 18 mPa-s, from about 2 to about 17 mPa-s, from about 2 to about 16 mPa-s, from about 2 to about 15 mPa-s, from about 2 to about 14 mPa-s, from about 2 to about 13 mPa-s, from about 2 to about 12 mPa-s, from about 2 to about 11 mPa-s, from about 2 to about 10 mPa-s, from about 2 to about 9 mPa-s, from about 2 to about 8 mPa-s, from about 2 to about 7 mPa-s, from about 2 to about 6 mPa-s, from about 2 to about 5 mPa-s, from about 3 to about 20 mPa-s, from about 3 to about 19 mPa-s, from about 3 to about
  • the anti-TL1A antibody is characterized by a turbidity less than 12 Nephelometric Turbidity Units (NTU) when at a concentration greater than about 100 mg/mL e.g., about 150 mg/mL to about 300 mg/mL, about 150 mg/mL to about 200 mg/mL, about 150 mg/mL to about 225 mg/mL, or about 150 mg/mL to about 250 mg/mL.
  • NTU Nephelometric Turbidity Units
  • the antibody comprises a HCDR1 comprising SEQ ID NO: 1, a HCDR2 comprising SEQ ID NO: 2, a HCDR3 comprising SEQ ID NO: 6, a LCDR1 comprising SEQ ID NO: 10, a LCDR2 comprising SEQ ID NO: 11, and a LCDR3 comprising SEQ ID NO: 12, and/or having a heavy chain variable region comprising SEQ ID NO: 104 and a light chain variable region comprising SEQ ID NO: 201.
  • the anti-TL1A antibody comprises 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 less than 9 amino acid modifications from the human IGHV1-46*02 framework and the human IGKV3-20 framework.
  • the anti-TL1A antibody is characterized by a turbidity less than 12 Nephelometric Turbidity Units (NTU) when at a concentration greater than at least about 150 mg/mL.
  • NTU Nephelometric Turbidity Units
  • the anti-TL1A antibody is characterized by a turbidity less than 12 Nephelometric Turbidity Units (NTU) when at a concentration greater than at least about 160 mg/mL. In some embodiments, the anti-TL1A antibody is characterized by a turbidity less than 12 Nephelometric Turbidity Units (NTU) when at a concentration greater than at least about 170 mg/mL. In some embodiments, the anti-TL1A antibody is characterized by a turbidity less than 12 Nephelometric Turbidity Units (NTU) when at a concentration greater than at least about 180 mg/mL.
  • NTU Nephelometric Turbidity Units
  • the anti-TL1A antibody is characterized by a turbidity less than 12 Nephelometric Turbidity Units (NTU) when at a concentration greater than at least about 190 mg/mL. In some embodiments, the anti-TL1A antibody is characterized by a turbidity less than 12 Nephelometric Turbidity Units (NTU) when at a concentration of about 150 mg/mL to about 250 mg/mL. Less than 12 NTU may include about 1, 2, 3, 4, or 5 NTU to about 12 NTU. 25746 [0414] Additionally, anti-TL1A antibodies described herein also demonstrate advantageous aggregation properties.
  • NTU Nephelometric Turbidity Units
  • the anti-TL1A antibody composition is characterized by percent high molecular weight species (e.g., a species having a molecular weight greater than the molecular weight of the monomer) is less than 10% of the composition when the antibody is present in the composition at a concentration greater than about 100 mg/mL, e.g., about 150 mg/mL to about 300 mg/mL, about 150 mg/mL to about 200 mg/mL, about 150 mg/mL to about 225 mg/mL, or about 150 mg/mL to about 250 mg/mL.
  • percent high molecular weight species e.g., a species having a molecular weight greater than the molecular weight of the monomer
  • the antibody comprises a HCDR1 comprising SEQ ID NO: 1, a HCDR2 comprising SEQ ID NO: 2, a HCDR3 comprising SEQ ID NO: 6, a LCDR1 comprising SEQ ID NO: 10, a LCDR2 comprising SEQ ID NO: 11, and a LCDR3 comprising SEQ ID NO: 12, and/or having a heavy chain variable region comprising SEQ ID NO: 104 and a light chain variable region comprising SEQ ID NO: 201.
  • the anti-TL1A antibody comprises 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 less than 9 amino acid modifications from the human IGHV1-46*02 framework and the human IGKV3-20 framework.
  • the anti-TL1A antibody composition is characterized by percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at least about 150 mg/mL.
  • the anti-TL1A antibody composition is characterized by percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at least about 160 mg/mL. In some embodiments, the anti-TL1A antibody composition is characterized by percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at least about 170 mg/mL.
  • the anti-TL1A antibody composition is characterized by percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at least about 180 mg/mL. In some embodiments, the anti-TL1A antibody composition is characterized by percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at least about 190 mg/mL.
  • the anti-TL1A antibody composition is characterized by percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at least about 200 mg/mL.
  • the anti-TL1A antibody 25746 composition is characterized by percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at least about 210 mg/mL.
  • the anti-TL1A antibody composition is characterized by percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at least about 220 mg/mL. In some embodiments, the anti-TL1A antibody composition is characterized by percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at least about 230 mg/mL.
  • the anti-TL1A antibody composition is characterized by percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at least about 240 mg/mL. In some embodiments, the anti-TL1A antibody composition is characterized by percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration greater than at least about 250 mg/mL.
  • the anti-TL1A antibody composition is characterized by percent high molecular weight species less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration of about 150 mg/mL to about 250 mg/mL.
  • provided are pharmaceutical compositions comprising about 150 mg to about 225 mg of anti-TL1A in a total volume of less than or equal to about 1 mL. The composition may be formulated for subcutaneous administration.
  • the composition comprises about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg of anti-TL1A.
  • the total volume may be less than about 1.0, 0.9, or 0.8 mL if less than 300 mg of anti-TL1A.
  • the total volume may be at least about 0.5 mL if less than 300 mg of anti-TL1A.
  • the total volume may be about 0.5 mL to about 3 mL, about 0.5 mL to about 2.9 mL, about 0.5 mL to about 2.8 mL, about 0.5 mL to about 2.7 mL, about 0.5 mL to about 2.6 mL, about 0.5 mL to about 2.5 mL, about 0.5 mL to about 2.4 mL, about 0.5 mL to about 2.3 mL, about 0.5 mL to about 2.2 mL, about 0.5 mL to about 2.1 mL, about 0.5 mL to about 2 mL, 0.5 mL to about 1.9 mL, 0.5 mL to about 1.8 mL, 0.5 mL to about 1.7 mL, 0.5 mL to about 1.6 mL, about 0.5 mL to about 1.0 mL, about 0.5
  • the concentration of anti-TL1A is about or greater than about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, or 250 mg/mL.
  • provided are pharmaceutical compositions comprising about 400 mg to about 1000 mg or about 400 mg to about 2000 mg of anti-TL1A in a total volume of less than or equal to about 15 mL.
  • the composition may be formulated for intravenous administration.
  • the composition may be diluted into about 100 to about 300, or about 250 mL pharmaceutically acceptable solution (e.g., saline) for intravenous administration.
  • the total volume may be at least about 1 mL, at least about 2 mL, at least about 2.5 mL, at least about 3 mL, at least about 4 mL, or at least about 5 mL; and less than or equal to about 15 mL, 14 mL, 13 mL, 11 mL, or 10 mL.
  • the volume may be from about 1 mL to about 15 mL, from about 1 mL to about 14 mL, from about 1 mL to about 13 mL, from about 1 mL to about 12 mL, from about 1 mL to about 11 mL, from about 1 mL to about 10 mL, from about 1 mL to about 9 mL, from about 1 mL to about 8 mL, from about 1 mL to about 7 mL, from about 1 mL to about 6 mL, from about 1 mL to about 5 mL, from about 1 mL to about 4 mL, from about 1 mL to about 3 mL, from about 1 mL to about 2 mL, from about 2 mL to about 15 mL, from about 2 mL to about 14 mL, from about 2 mL to about 13 mL, from about 2 mL to about 12 mL, from about 2 mL to about 11 mL, from
  • a pharmaceutical composition comprising an anti- TL1A antibody comprises a surfactant.
  • a surfactant includes a nonionic surfactant, ionic surfactant, and amphoteric surfactant, and combinations thereof.
  • the surfactant comprises a nonionic surfactant.
  • Non-limiting examples of non-ionic surfactants include polysorbate, polyglycerol alkyl ether, glucosyl dialkyl ether, crownether, ester-linked surfactant, polyoxyethylene alkyl ether, poloxamer 18, Brij, Spans (sorbitan ester), Triton X- 100 (polyethylene glycol p- (1,1,3,3-tetramethylbutyl) -phenyl ether), polyoxyethylene (35) dodecyl ether, polyethylene glycol hexadecyl ether, polyoxyethylene (20) oleyl ether, polyoxyethylene (9) lauryl alcohol, polyethoxylated (35) castor oil, octylphenoxypoly(ethyleneoxy) ethanol, poly(oxyethylene-cooxypropylene) block copolymer, poly(oxyethylene-cooxypropylene) block copolymer, poly(oxyethylene- cooxypropylene) block copolymer, polydimethylsiloxane
  • the surfactant comprises an ionic surfactant.
  • Ionic surfactants include anionic and cationic surfactants.
  • anionic surfactants include alkyl sulfate, alkyl ether sulfate, docusate, sulfonate fluorosurfactant, alkyl benzene sulfonate, alkyl aryl ether phosphate, alkyl ether phosphate, alkyl carboxylate, and sodium dioctyl-sulfosuccinate, and combinations thereof.
  • Non-limiting examples of cationic surfactants include cetyltrimethylammonium bromide (CTAB), cetyltrimethylammonium chloride (CTAC), cetylpyridinium chloride (CPC), 25746 polyethoxylated tallow amine (POEA), benzalkonium chloride (BAC), benzethonium chloride (BZT), 5-bromo-5-nitro-1,3-dioxane, dimethyl dioctadecyl ammonium chloride, and dioctadecyl dimethyl ammonium bromide (DODAB), and combinations thereof.
  • the surfactant comprises an amphoteric surfactant.
  • an example amphoteric surfactant includes ethylenediamine tetrakis (ethoxylate-block-propoxylate) tetrol.
  • the surfactant comprises polysorbate.
  • Polysorbate includes, without limitation, polysorbate-20, polysorbate-60, and polysorbate-80, and combinations thereof.
  • the polysorbate may be polysorbate-20.
  • the composition comprises a surfactant, wherein the surfactant comprises or consists of polysorbate-20.
  • the surfactant comprises or consists of polysorbate-20.
  • the surfactant is present in the composition at a concentration of about 0.001-0.1% v/v of the composition.
  • the surfactant is present at a concentration of about 0.005% to about 0.05%, about 0.01% to about 0.05%, about 0.005% to about 0.04%, about 0.01% to about 0.04%, about 0.005% to about 0.03%, about 0.01% to about 0.03%, about 0.005% to about 0.02%, or about 0.01% to about 0.02% v/v of the composition.
  • the surfactant comprises about 0.01% to about 0.05%, or about 0.01%, about 0.02%, about 0.03%, about 0.04%, or about 0.05% v/v of the composition.
  • the surfactant comprises about 0.01% to about 0.05%, or about 0.01%, about 0.02%, about 0.03%, about 0.04%, or about 0.05% polysorbate in the composition.
  • some embodiments of the compositions comprise about 0.01%-0.02%, or about 0.01% or about 0.02% polysorbate.
  • the composition comprises polysorbate-20 at a concentration of about 0.01% to about 0.05%, or 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.
  • the composition comprises polysorbate-20 at a concentration of about 0.02% v/v of the composition. In one embodiment of the composition provided herein, the composition comprises polysorbate-60 at a concentration of about 0.01% to about 0.05%, or 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%, 25746 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.
  • the composition comprises polysorbate-60 at a concentration of about 0.02% v/v of the composition. In one embodiment of the composition provided herein, the composition comprises polysorbate-80 at a concentration of about 0.01% to about 0.05%, or 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.
  • a pharmaceutical composition comprising an anti- TL1A antibody comprises a stabilizer.
  • Stabilizers include sugars, polyols, amino acids, polymers, and cyclodextrin (e.g., HP-b-CD), and combinations thereof.
  • the stabilizer comprises a sugar.
  • Non-limiting examples of sugars include sucrose, glucose, trehalose, maltose, and lactose, and combinations thereof.
  • the stabilizer comprises a polyol.
  • Non-limiting examples of polyols include mannitol, sorbitol, raffinose, and glycerol, and combinations thereof.
  • the stabilizer comprises a sugar, such as sucrose.
  • the sugar comprises or consists of sucrose.
  • the stabilizer comprises an amino acid.
  • the amino acid comprises or consists of glycine.
  • the amino acid comprises or consists of glycine.
  • the stabilizer comprises both a sugar and an amino acid.
  • the stabilizer comprises both sucrose and glycine.
  • the stabilizer is present in the composition at a concentration of about 50 mM to about 300 mM.
  • the stabilizer is present at a concentration of about 50 mM to about 300 mM, about 50 mM to about 290 mM, about 50 mM to about 280 mM, about 50 mM to about 270 mM, about 50 mM to about 260 mM, about 50 mM to about 250 mM, about 50 mM to about 240 mM, about 50 mM to about 220 mM, about 50 mM to about 200 mM, about 75 mM to about 300 mM, about 75 mM to about 290 mM, about 75 mM to about 280 mM, about 75 mM to about 270 mM, about 75 mM to about 260 mM, about 75 mM to about 250 mM, about 75 mM to about 240 mM, about 75 25746
  • the stabilizer is present at concentrations of about 150 mM to about 270 mM, or about 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, or 270 mM stabilizer.
  • the composition comprises about 150 mM to about 270 mM, or about 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, or 270 mM sucrose, for instance, about 220-240 mM, or about 220, about 230, or about 240 mM sucrose.
  • the composition comprises about 50 mM to about 150 mM, or about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150 mM glycine, for instance, 75-100 mM or about 80, about 85, or about 90 mM glycine.
  • the composition comprises about 150 mM to about 270 mM, or about 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, or 270 mM sucrose and comprises 50 mM to about 150 mM, or about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150 mM glycine.
  • a pharmaceutical composition comprising an anti- TL1A antibody comprises a salt.
  • Non-limiting examples of salt include sodium chloride, glycine, lysine-hydrochloride, arginine-hydrochloride, arginine glutamate, potassium chloride, magnesium chloride, and calcium chloride, and combinations thereof.
  • the salt comprises sodium chloride.
  • the salt comprises lysine-HCl.
  • the salt is present in the composition at a concentration of about 10 mM to about 150 mM.
  • the salt is present at a concentration of about 10 mM to about 150 mM, about 10 mM to about 140 mM, about 10 mM to about 130 mM, about 10 mM to about 120 mM, about 10 mM to about 110 mM, about 10 mM to about 100 mM, about 10 mM to about 90 mM, about 10 mM to about 80 mM, about 10 mM to about 70 mM, about 10 mM to about 60 mM, about 10 mM to about 50 mM, about 10 mM to about 40 mM, about 10 mM to about 30 mM, about 20 mM to about 150 mM, about 20 mM to about 140 mM, about 20 mM to about 130 mM, about 20 mM to about 120 mM, about 20 mM to about 110 mM, about 20 mM to about 100 mM, about 20 mM to about 90 mM, about 20 mM
  • the salt is present at concentrations of about 25 mM to about 130 mM.
  • the composition comprises about 40 mM to about 130 mM NaCl.
  • the composition comprises about 40 mM NaCl.
  • the composition comprises 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, about 120 mM, about 125 mM, about 130 mM, about 135 mM, about 140 mM, about 145 mM, or about 150 mM NaCl.
  • a pharmaceutical composition comprising an anti- TL1A antibody comprises a buffering agent.
  • buffering agents include an acetate, phosphate, citrate, glutamate, succinate, gluconate, histidine, 25746 glycylglycine, citric acid, Tris (tris (hydroxymethyl) aminomethane), and diethanolamine, and combinations thereof.
  • the buffering agent comprises acetate.
  • the buffering agent comprises sodium acetate.
  • the buffering agent comprises acetic acid. In some embodiments, the buffering agent comprising acetate comprises acetic acid and sodium acetate. In some embodiments, the buffering agent comprises potassium acetate. In some embodiments, the buffering agent comprises aluminum acetate. In some embodiments, the buffering agent comprises ammonium acetate. In some embodiments, the buffering agent comprises phosphate. In one embodiment, the buffering agent comprising phosphate comprises phosphoric acid and sodium phosphate. In some embodiments, the buffering agent comprises phosphoric acid and potassium phosphate. In some embodiments, the buffering agent comprises sodium phosphate dibasic and sodium phosphate monobasic.
  • the buffering agent comprises phosphoric acid, sodium phosphate dibasic, sodium phosphate monobasic, and/or sodium phosphate. In some embodiments, the buffering agent comprises potassium phosphate dibasic and potassium phosphate monobasic. In some embodiments, the buffering agent comprises phosphoric acid, potassium phosphate dibasic, potassium phosphate monobasic, and/or potassium phosphate. In some embodiments, the buffering agent is present in the composition at a concentration of about 5 mM to about 50 mM.
  • the buffering agent is present at a concentration of about 5 mM to about 50 mM, about 5 mM to about 40 mM, about 5 mM to about 30 mM, about 5 mM to about 20 mM, about 5 mM to about 10 mM, about 10 mM to about 50 mM, about 10 mM to about 40 mM, about 10 mM to about 30 mM, or about 10 mM to about 20 mM.
  • the buffering agent is present at a concentration of about 10 mM to about 20 mM, or about 20 mM.
  • the composition comprises about 10 mM to about 20 mM, or about 10 mM or about 20 mM of acetate. In a further embodiment, the composition comprises about 10 mM to about 20 mM, or about 10 mM or about 20 mM of phosphate.
  • a pharmaceutical composition comprising an anti- TL1A antibody has a pH of 4.0 to 8.0.
  • the pH is about 4.5 to about 8.0, about 4.5 to about 7.8, about 4.5 to about 7.6, about 4.5 to about 7.4, about 4.5 to about 7.2, about 4.5 to about 7.0, about 4.5 to about 6.8, about 4.5 to about 6.6, about 4.5 to about 6.4, about 4.5 to about 6.2, about 4.5 to about 6.0, about 4.5 to about 5.8, about 4.5 to about 5.6, about 4.5 to about 5.4, about 4.5 to about 5.2, or about 4.5 to about 5.0.
  • the pH is about 4.5 to about 6.0, about 4.5 to about 5.9, about 4.5 to about 5.8, about 4.5 to about 5.7, or about 4.5 to about 5.6.
  • the pH is about 4.5 to about 5.5, or 25746 about 4.5 to about 5.4, about 4.5 to about 5.3, about 4.5 to about 5.2, about 4.5 to about 5.1, about 4.5 to about 5.0, 4.6 to about 5.5, about 4.6 to about 5.4, about 4.6 to about 5.3, about 4.6 to about 5.2, about 4.6 to about 5.1, about 4.6 to about 5.0, 4.7 to about 5.5, about 4.7 to about 5.4, about 4.7 to about 5.3, about 4.7 to about 5.2, about 4.7 to about 5.1, about 4.7 to about 5.0, 4.8 to about 5.5, about 4.8 to about 5.4, about 4.8 to about 5.3, about 4.8 to about 5.2, about 4.8 to about 5.1, about 4.8 to about 5.0, 4.9 to about 5.5, about 4.9 to about 5.4, about 4.9 to about 5.3, about 4.9 to about 5.2, about 4.9 to about 5.1, about 4.9 to about 5.0, about 5.0 to about 5.5, about 4.9
  • the pH may be about 4.5 to about 5.5, or about 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5.
  • the pH is about 5.3.
  • the composition comprises an acetate buffer, with a pH of about 4.5 to about 5.5, or about 5.3.
  • the pH is about 6.0 to about 7.0, about 6.0 to about 6.9, about 6.0 to about 6.8, about 6.0 to about 6.7, about 6.0 to about 6.6, about 6.0 to about 6.5, about 6.0 to about 6.4, about 6.0 to about 6.3, about 6.0 to about 6.2, about 6.0 to about 6.1, about 6.1 to about 7.0, about 6.1 to about 6.9, about 6.1 to about 6.8, about 6.1 to about 6.7, about 6.1 to about 6.6, about 6.1 to about 6.5, about 6.1 to about 6.4, about 6.1 to about 6.3, about 6.1 to about 6.2, about 6.2 to about 7.0, about 6.2 to about 6.9, about 6.2 to about 6.8, about 6.2 to about 6.7, about 6.2 to about 6.6, about 6.2 to about 6.5, about 6.2 to about 6.4, about 6.2 to about 6.3, about 6.3 to about 7.0, about 6.3 to about 6.9, about 6.3 to about 6.8, about 6.3 to about 6.7, about
  • the pH can be about 6.0 to about 7.0, or about 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0. As an example, the pH is about 6.5.
  • the composition comprises an phosphate buffer, with a pH of about 6.0 to about 7.0, or about 6.5.
  • a pharmaceutical composition comprising an anti- TL1A antibody comprises one or more of the following: surfactant, stabilizer, salt, and buffering agent.
  • the pharmaceutical composition comprises a surfactant and a stabilizer.
  • the pharmaceutical composition comprises a surfactant and a salt.
  • the pharmaceutical composition comprises a surfactant and a buffering agent.
  • the pharmaceutical composition 25746 comprises a stabilizer and a salt.
  • the pharmaceutical composition comprises a stabilizer and a buffering agent.
  • the pharmaceutical composition comprises a salt and buffering agent.
  • the pharmaceutical composition comprises a surfactant, stabilizer, and salt.
  • the pharmaceutical composition comprises surfactant, salt, and buffering agent.
  • the pharmaceutical composition comprises a surfactant, stabilizer and buffering agent.
  • the pharmaceutical composition comprises a stabilizer, salt, and buffering agent.
  • the pharmaceutical composition comprises a surfactant, stabilizer, salt, and buffering agent.
  • the pharmaceutical composition comprises a surfactant, stabilizer, salt, and buffering agent.
  • Non-limiting example pharmaceutical compositions comprise a nonionic surfactant, sugar, salt and buffering agent.
  • the compositions comprise polysorbate (e.g., polysorbate-20), sucrose, lysine-HCl or sodium chloride, and an acetate buffer.
  • the pH of the composition may be about 4.5 to about 5.5, or about 5.0 to about 5.5.
  • the composition comprises about 10-20 mM acetate at pH 4.5-5.5, 150-270 mM sucrose, 25-50 mM Lys-HCl, and 0.01%-0.05% v/v polysorbate-20.
  • the composition comprises about 20 mM acetate at pH 5.3, about 240 mM sucrose, about 25 mM lysine-HCl, and about 0.02% polysorbate-20.
  • the composition comprises about 10-20 mM acetate at pH 4.5-5.5, 150-270 mM sucrose, 50- 130 mM NaCl, and 0.01%-0.05% v/v polysorbate-20.
  • the composition comprises about 20 mM acetate at pH 5.3, 220 mM sucrose, 40 mM NaCl, and 0.02% polysorbate-20.
  • the compositions comprise polysorbate (e.g., polysorbate-20), sucrose, sodium chloride, and an acetate buffer.
  • the pH of the composition may be about 4.5 to about 5.5, or about 5.0 to about 5.5.
  • the composition comprises about 10-20 mM acetate at pH 4.5-5.5, 150-270 mM sucrose, and 0.01%-0.05% v/v polysorbate-20.
  • the composition comprises about 20 mM acetate at pH 5.3, about 220 mM sucrose, and about 0.02% polysorbate-20.
  • the composition comprises about 10-20 mM acetate at pH 4.5-5.5, 150-270 mM sucrose, 50-130 mM NaCl, and 0.01%-0.05% v/v polysorbate-20.
  • the composition comprises about 20 mM acetate at pH 5.3, 220 mM sucrose, 40 mM NaCl, and 0.02% polysorbate-20.
  • the compositions comprise polysorbate (e.g., polysorbate-20), sucrose, glycine, sodium chloride, and a phosphate buffer.
  • the compositions comprise polysorbate (e.g., polysorbate-20), sucrose, glycine, 25746 and a phosphate buffer.
  • the compositions comprise polysorbate-20, sucrose, glycine, and a phosphate buffer.
  • the pH of the composition may be about 6.0 to about 7.0, or about 6.5 to about 7.0.
  • the composition comprises about 10-20 mM phosphate at pH 6.0-7.0, 75-100 mM glycine, 100-270 mM sucrose, and 0.01%-0.05% v/v polysorbate-20.
  • the composition comprises about 20 mM phosphate at pH 6.5, about 85mM glycine, about 146 mM sucrose, and about 0.02% polysorbate-20.
  • the composition comprises about 10-20 mM phosphate at pH 6.0-7.0, 75-100mM glycine, 2% to 8% (w/v) sucrose, and 0.01%-0.05% v/v polysorbate-20.
  • the composition comprises about 20 mM phosphate at pH 6.5, 5% (w/v) sucrose, 85 mM glycine, and 0.02% polysorbate-20.
  • provided herein is a composition comprising an anti- TL1A antibody provided herein at a concentration of about 200 mg/mL, 20 mM sodium acetate, 220 mM sucrose, 40 mM NaCl, and 0.02% polysorbate-20, at pH 5.3.
  • provided herein is a composition comprising an anti-TL1A antibody provided herein at a concentration of about 100 mg/mL, 20 mM sodium acetate, 220 mM sucrose, 40 mM NaCl, and 0.02% polysorbate-20, at pH 5.3.
  • a composition comprising an anti-TL1A antibody provided herein at a concentration of about 60 mg/mL, 20 mM sodium phosphate, 5% sucrose, 85 mM glycine, and 0.02% polysorbate- 20, at pH 5.3.
  • provided herein is a composition comprising an anti- TL1A antibody provided herein at a concentration described herein, 20 mM sodium acetate, 220 mM sucrose, 40 mM NaCl, and 0.02% polysorbate-20, at pH 5.3.
  • a composition comprising an anti-TL1A antibody provided herein at a concentration described herein, 20 mM sodium acetate, 220 mM sucrose, 40 mM NaCl, and 0.02% polysorbate-20, at pH 5.3.
  • provided herein is a composition comprising an anti-TL1A antibody provided herein at a concentration described herein, 20 mM sodium phosphate, 5% sucrose, 85 mM glycine, and 0.02% polysorbate-20, at pH 5.3.
  • a composition comprising an anti-TL1A antibody provided herein at a concentration of about 150 mg/ml to 250 mg/ml, 20 mM sodium acetate, 220 mM sucrose, 40 mM NaCl, and 0.02% polysorbate-20, at pH 5.3.
  • provided herein is a composition comprising an anti-TL1A antibody provided herein at a concentration of about 100 mg/ml to 200 mg/ml, 20 mM sodium acetate, 220 mM sucrose, 40 mM NaCl, and 0.02% polysorbate-20, at pH 5.3.
  • a composition comprising an anti-TL1A antibody provided 25746 herein at a concentration of about 50 mg/ml to 100 mg/ml, 20 mM sodium phosphate, 5% sucrose, 85 mM glycine, and 0.02% polysorbate-20, at pH 5.3.
  • TL1A is a pro-inflammatory mediator with a broad upstream effect on many inflammatory cells. TL1A can also directly induce fibrosis by stimulating gut fibroblasts.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat sarcoidosis in a subject by 25746 administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat pulmonary sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat cutaneous sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat cutaneous sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat lupus pernio in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat papular sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat nodular sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat Darier- Roussy sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat maculopapular sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical 25746 compositions thereof provided herein can be used in a method to treat hypopigmented sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat atrophic and ulcerative sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat plaque sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat angiolupoid sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat psoriasiform sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat verrucous sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat neurologic sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat cardiac sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat gastrointestinal sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical 25746 compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat hepatic sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat pancreatic sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat peritoneal sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat sarcoidosis of bone in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat sarcoid arthropathy in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat ichthyosiform sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat erythrodermic sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TL1A antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat perforating sarcoidosis in a subject by administering the anti-TL1A antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the sarcoidosis is pulmonary 25746 sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis is cutaneous sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis or the cutaneous sarcoidosis is lupus pernio. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis or the cutaneous sarcoidosis is papular sarcoidosis.
  • the sarcoidosis or the cutaneous sarcoidosis is nodular sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis or the cutaneous sarcoidosis is Darier-Roussy sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis or the cutaneous sarcoidosis is maculopapular sarcoidosis.
  • the sarcoidosis or the cutaneous sarcoidosis is plaque sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis or the cutaneous sarcoidosis is hypopigmented sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis or the cutaneous sarcoidosis is atrophic and ulcerative sarcoidosis.
  • the sarcoidosis is neurologic sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis is cardiac sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis is gastrointestinal sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis is hepatic sarcoidosis.
  • the sarcoidosis is pancreatic sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis is peritoneal sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis is sarcoidosis of bones. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis is sarcoid arthropathy.
  • the sarcoidosis or the plaque sarcoidosis is angiolupoid sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis or the plaque sarcoidosis is psoriasiform sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis or the plaque sarcoidosis is verrucous 25746 sarcoidosis.
  • the sarcoidosis is ichthyosiform sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis is erythrodermic sarcoidosis. In some embodiments of the methods provided herein, including in this Section (Section [0456]), the sarcoidosis is perforating sarcoidosis. [0435] In one aspect provided herein is a method of treating sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen- binding fragment thereof that binds to TL1A.
  • the sarcoidosis is pulmonary sarcoidosis. In some embodiment of the method provided in this paragraph, the sarcoidosis is cutaneous sarcoidosis. In some embodiment of the method provided in this paragraph, the sarcoidosis or the cutaneous sarcoidosis is lupus pernio. In some embodiment of the method provided in this paragraph, the sarcoidosis or the cutaneous sarcoidosis is papular sarcoidosis. In some embodiment of the method provided in this paragraph, the sarcoidosis or the cutaneous sarcoidosis is nodular sarcoidosis.
  • the sarcoidosis or the cutaneous sarcoidosis is Darier-Roussy sarcoidosis. In some embodiment of the method provided in this paragraph, the sarcoidosis or the cutaneous sarcoidosis is maculopapular sarcoidosis. In some embodiment of the method provided in this paragraph, the sarcoidosis or the cutaneous sarcoidosis is plaque sarcoidosis. In some embodiment of the method provided in this paragraph, the sarcoidosis or the cutaneous sarcoidosis is hypopigmented sarcoidosis.
  • the sarcoidosis or the cutaneous sarcoidosis is atrophic and ulcerative sarcoidosis.
  • the sarcoidosis is neurologic sarcoidosis.
  • the sarcoidosis is cardiac sarcoidosis.
  • the sarcoidosis is gastrointestinal sarcoidosis.
  • the sarcoidosis is hepatic sarcoidosis.
  • the sarcoidosis is pancreatic sarcoidosis.
  • the sarcoidosis is peritoneal sarcoidosis. In some embodiment of the method provided in this paragraph, the sarcoidosis is sarcoidosis of bones. In some embodiment of the method provided in this paragraph, the sarcoidosis is sarcoid arthropathy. In some embodiment of the method provided in this paragraph, the sarcoidosis or the plaque sarcoidosis is angiolupoid sarcoidosis. In some embodiment of the method provided in this paragraph, the sarcoidosis or the plaque sarcoidosis is psoriasiform 25746 sarcoidosis.
  • the sarcoidosis or the plaque sarcoidosis is verrucous sarcoidosis. In some embodiment of the method provided in this paragraph, the sarcoidosis is ichthyosiform sarcoidosis. In some embodiment of the method provided in this paragraph, the sarcoidosis is erythrodermic sarcoidosis. In some embodiment of the method provided in this paragraph, the sarcoidosis is perforating sarcoidosis.
  • provided herein is a method of treating pulmonary sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of treating cutaneous sarcoidosis in a subject in need thereof the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of treating lupus pernio in a subject in need thereof the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • provided herein is a method of treating papular sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of treating nodular sarcoidosis in a subject in need thereof the method comprising administering to the subject an antibody or antigen- binding fragment thereof that binds to TL1A.
  • a method of treating Darier-Roussy sarcoidosis in a subject in need thereof the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • provided herein is a method of treating maculopapular sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of treating plaque sarcoidosis in a subject in need thereof the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of treating hypopigmented sarcoidosis in a subject in need thereof the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • provided herein is a method of treating atrophic and ulcerative sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of treating neurologic sarcoidosis in a subject in need thereof the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • provided herein is a method of treating gastrointestinal sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of treating hepatic sarcoidosis in a subject in need thereof the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of treating pancreatic sarcoidosis in a subject in need thereof the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • provided herein is a method of treating peritoneal sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of treating sarcoidosis of bones in a subject in need thereof the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of treating sarcoid arthropathy in a subject in need thereof the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • provided herein is a method of treating angiolupoid sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of treating psoriasiform sarcoidosis in a subject in need thereof the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of treating verrucous sarcoidosis in a subject in need thereof the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • provided herein is a method of treating ichthyosiform sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of treating erythrodermic sarcoidosis in a subject in need thereof the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • provided herein is a method of treating perforating sarcoidosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to TL1A.
  • a method of neutralizing monomeric TL1A and trimeric TL1A in a subject comprising (a) administering an effective dose of anti-TL1A antibody or antigen binding fragment to the subject, wherein the antibody or antigen binding fragment binds to both monomeric TL1A and trimeric TL1A, and wherein the antibody or antigen binding fragment blocks interaction of TL1A to DR3.
  • the subject has sarcoidosis.
  • 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 without sarcoidosis.
  • the subject has pulmonary sarcoidosis.
  • the subject has cutaneous sarcoidosis.
  • the subject has lupus pernio.
  • the subject has papular sarcoidosis.
  • the subject has nodular sarcoidosis.
  • the subject has Darier-Roussy sarcoidosis.
  • the subject has maculopapular sarcoidosis.
  • the subject has plaque sarcoidosis.
  • the subject has hypopigmented sarcoidosis.
  • the subject has atrophic and ulcerative sarcoidosis. In certain embodiments, the subject has neurologic sarcoidosis. In certain embodiments, the subject has cardiac sarcoidosis. In certain embodiments, the subject has gastrointestinal sarcoidosis. In certain embodiments, the subject has hepatic sarcoidosis. In certain embodiments, the subject has pancreatic sarcoidosis. In certain embodiments, the subject has peritoneal sarcoidosis. In certain embodiments, the subject has sarcoidosis of bones. In certain embodiments, the subject has sarcoid arthropathy. In certain embodiments, the subject has angiolupoid sarcoidosis.
  • the subject has psoriasiform sarcoidosis. In certain embodiments, the subject has verrucous sarcoidosis. In certain embodiments, the subject has ichthyosiform sarcoidosis. In certain embodiments, the subject has erythrodermic sarcoidosis. In certain embodiments, the subject has perforating sarcoidosis. In some embodiments, 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 without pulmonary sarcoidosis.
  • 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 without cutaneous sarcoidosis. In some embodiments, 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 without lupus pernio. In some embodiments, the concentration of TL1A in a diseased tissue in the subject is 25746 reduced below the concentration of TL1A in a corresponding tissue in a control subject without papular sarcoidosis.
  • 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 without nodular sarcoidosis. In some embodiments, 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 without Darier-Roussy sarcoidosis. In some embodiments, 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 without maculopapular sarcoidosis.
  • 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 without plaque sarcoidosis. In some embodiments, 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 without hypopigmented sarcoidosis. In some embodiments, 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 without atrophic and ulcerative sarcoidosis.
  • 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 without neurologic sarcoidosis. In some embodiments, 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 without cardiac sarcoidosis. In some embodiments, 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 without gastrointestinal sarcoidosis.
  • 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 without hepatic sarcoidosis. In some embodiments, 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 without pancreatic sarcoidosis. In some embodiments, 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 without peritoneal sarcoidosis.
  • 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 without sarcoidosis of bones. In some embodiments, 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 without sarcoid arthropathy. In some embodiments, the concentration of 25746 TL1A in a diseased tissue in the subject is reduced below the concentration of TL1A in a corresponding tissue in a control subject without angiolupoid sarcoidosis.
  • 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 without psoriasiform sarcoidosis. In some embodiments, 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 without verrucous sarcoidosis. In some embodiments, 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 without ichthyosiform sarcoidosis.
  • 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 without erythrodermic sarcoidosis. In some embodiments, 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 without perforating sarcoidosis.
  • “Neutralizing” TL1A refers to binding to TL1A in such a way that the functional receptor, DR3, can no longer bind to TL1A and/or signal via the ligation with TL1A.
  • an anti-TL1A antibody that blocks TL1A binding to DR3 also neutralizes DR3.
  • a method of reducing the concentration of TL1A in a diseased tissue in a subject with sarcoidosis comprising (a) administering an effective dose of anti-TL1A antibody or antigen binding fragment to the subject, thereby reducing the concentration of TL1A in the diseased tissue in the subject below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis.
  • the sarcoidosis is pulmonary sarcoidosis.
  • the sarcoidosis is cutaneous sarcoidosis. In some embodiments, the sarcoidosis is lupus pernio. In some embodiments, the sarcoidosis is papular sarcoidosis. In some embodiments, the sarcoidosis is nodular sarcoidosis. In some embodiments, the sarcoidosis is Darier-Roussy sarcoidosis. In some embodiments, the sarcoidosis is maculopapular sarcoidosis. In some embodiments, the sarcoidosis is plaque sarcoidosis. In some embodiments, the sarcoidosis is hypopigmented sarcoidosis.
  • the sarcoidosis is atrophic and ulcerative sarcoidosis. In some embodiments, the sarcoidosis is neurologic sarcoidosis. In some embodiments, the sarcoidosis is cardiac sarcoidosis. In some embodiments, the sarcoidosis is gastrointestinal sarcoidosis. In some embodiments, the 25746 sarcoidosis is hepatic sarcoidosis. In some embodiments, the sarcoidosis is pancreatic sarcoidosis. In some embodiments, the sarcoidosis is peritoneal sarcoidosis. In some embodiments, the sarcoidosis is sarcoidosis of bones.
  • the sarcoidosis is sarcoid arthropathy. In some embodiments, the sarcoidosis is angiolupoid sarcoidosis. In some embodiments, the sarcoidosis is psoriasiform sarcoidosis. In some embodiments, the sarcoidosis is verrucous sarcoidosis. In some embodiments, the sarcoidosis is ichthyosiform sarcoidosis. In some embodiments, the sarcoidosis is erythrodermic sarcoidosis. In some embodiments, the sarcoidosis is perforating sarcoidosis.
  • a method of reducing the concentration of TL1A in a diseased tissue in a subject with pulmonary sarcoidosis comprising (a) administering an effective dose of anti-TL1A antibody or antigen binding fragment to the subject, thereby reducing the concentration of TL1A in the diseased tissue in the subject below the concentration of TL1A in a corresponding tissue in a control subject without pulmonary sarcoidosis.
  • a method of reducing the concentration of TL1A in a diseased tissue in a subject with cutaneous sarcoidosis comprising (a) administering an effective dose of anti-TL1A antibody or antigen binding fragment to the subject, thereby reducing the concentration of TL1A in the diseased tissue in the subject below the concentration of TL1A in a corresponding tissue in a control subject without cutaneous sarcoidosis.
  • a method of reducing the concentration of TL1A in a diseased tissue in a subject with sarcoidosis comprising (a) administering an effective dose of anti-TL1A antibody or antigen binding fragment to the subject, thereby reducing the concentration of TL1A in the diseased tissue in the subject below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis, wherein the sarcoidosis is pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, ver
  • a method of treating sarcoidosis in a subject in need thereof comprising (a) administering an anti-TL1A antibody or antigen binding fragment to the subject, wherein the anti-TL1A antibody or antigen binding fragment is administer at an effective dose such that the concentration of TL1A in a diseased tissue in the subject after step (a) is below the concentration of TL1A in a corresponding tissue in a 25746 control subject without sarcoidosis.
  • the sarcoidosis is pulmonary sarcoidosis.
  • the sarcoidosis is cutaneous sarcoidosis.
  • the sarcoidosis is lupus pernio. In some embodiments, the sarcoidosis is papular sarcoidosis. In some embodiments, the sarcoidosis is nodular sarcoidosis. In some embodiments, the sarcoidosis is Darier-Roussy sarcoidosis. In some embodiments, the sarcoidosis is maculopapular sarcoidosis. In some embodiments, the sarcoidosis is plaque sarcoidosis. In some embodiments, the sarcoidosis is hypopigmented sarcoidosis. In some embodiments, the sarcoidosis is atrophic and ulcerative sarcoidosis.
  • the sarcoidosis is neurologic sarcoidosis. In some embodiments, the sarcoidosis is cardiac sarcoidosis. In some embodiments, the sarcoidosis is gastrointestinal sarcoidosis. In some embodiments, the sarcoidosis is hepatic sarcoidosis. In some embodiments, the sarcoidosis is pancreatic sarcoidosis. In some embodiments, the sarcoidosis is peritoneal sarcoidosis. In some embodiments, the sarcoidosis is sarcoidosis of bones. In some embodiments, the sarcoidosis is sarcoid arthropathy.
  • the sarcoidosis is angiolupoid sarcoidosis. In some embodiments, the sarcoidosis is psoriasiform sarcoidosis. In some embodiments, the sarcoidosis is verrucous sarcoidosis. In some embodiments, the sarcoidosis is ichthyosiform sarcoidosis. In some embodiments, the sarcoidosis is erythrodermic sarcoidosis. In some embodiments, the sarcoidosis is perforating sarcoidosis.
  • a method of treating pulmonary sarcoidosis in a subject in need thereof comprising (a) administering an anti-TL1A antibody or antigen binding fragment to the subject, wherein the anti-TL1A antibody or antigen binding fragment is administer at an effective dose such that the concentration of TL1A in a diseased tissue in the subject after step (a) is below the concentration of TL1A in a corresponding tissue in a control subject without pulmonary sarcoidosis.
  • a method of treating cutaneous sarcoidosis in a subject in need thereof comprising (a) administering an anti-TL1A antibody or antigen binding fragment to the subject, wherein the anti-TL1A antibody or antigen binding fragment is administer at an effective dose such that the concentration of TL1A in a diseased tissue in the subject after step (a) is below the concentration of TL1A in a corresponding tissue in a control subject without cutaneous sarcoidosis.
  • a method of treating sarcoidosis in a subject in need thereof comprising (a) administering an anti-TL1A antibody or antigen binding fragment to the subject, wherein the anti-TL1A antibody or antigen binding fragment is administer at an effective dose such that the concentration of TL1A in a diseased tissue in the 25746 subject after step (a) is below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis, wherein the sarcoidosis is pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, ps
  • a method of treating sarcoidosis in a subject in need thereof comprising (a) administering an anti-TL1A antibody or antigen binding fragment to the subject, wherein the anti-TL1A antibody or antigen binding fragment is administered at an effective dose such that the concentration of TL1A in a diseased tissue in the subject after step (a) is below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis.
  • the sarcoidosis is pulmonary sarcoidosis.
  • the sarcoidosis is cutaneous sarcoidosis.
  • the sarcoidosis is lupus pernio. In some embodiments, the sarcoidosis is papular sarcoidosis. In some embodiments, the sarcoidosis is nodular sarcoidosis. In some embodiments, the sarcoidosis is Darier-Roussy sarcoidosis. In some embodiments, the sarcoidosis is maculopapular sarcoidosis. In some embodiments, the sarcoidosis is plaque sarcoidosis. In some embodiments, the sarcoidosis is hypopigmented sarcoidosis. In some embodiments, the sarcoidosis is atrophic and ulcerative sarcoidosis.
  • the sarcoidosis is neurologic sarcoidosis. In some embodiments, the sarcoidosis is cardiac sarcoidosis. In some embodiments, the sarcoidosis is gastrointestinal sarcoidosis. In some embodiments, the sarcoidosis is hepatic sarcoidosis. In some embodiments, the sarcoidosis is pancreatic sarcoidosis. In some embodiments, the sarcoidosis is peritoneal sarcoidosis. In some embodiments, the sarcoidosis is sarcoidosis of bones. In some embodiments, the sarcoidosis is sarcoid arthropathy.
  • the sarcoidosis is angiolupoid sarcoidosis. In some embodiments, the sarcoidosis is psoriasiform sarcoidosis. In some embodiments, the sarcoidosis is verrucous sarcoidosis. In some embodiments, the sarcoidosis is ichthyosiform sarcoidosis. In some embodiments, the sarcoidosis is erythrodermic sarcoidosis. In some embodiments, the sarcoidosis is perforating sarcoidosis.
  • a method of treating pulmonary sarcoidosis in a 25746 subject in need thereof comprising (a) administering an anti-TL1A antibody or antigen binding fragment to the subject, wherein the anti-TL1A antibody or antigen binding fragment is administered at an effective dose such that the concentration of TL1A in a diseased tissue in the subject after step (a) is below the concentration of TL1A in a corresponding tissue in a control subject without pulmonary sarcoidosis.
  • a method of treating cutaneous sarcoidosis in a subject in need thereof comprising (a) administering an anti-TL1A antibody or antigen binding fragment to the subject, wherein the anti-TL1A antibody or antigen binding fragment is administered at an effective dose such that the concentration of TL1A in a diseased tissue in the subject after step (a) is below the concentration of TL1A in a corresponding tissue in a control subject without cutaneous sarcoidosis.
  • a method of treating sarcoidosis in a subject in need thereof comprising (a) administering an anti-TL1A antibody or antigen binding fragment to the subject, wherein the anti-TL1A antibody or antigen binding fragment is administered at an effective dose such that the concentration of TL1A in a diseased tissue in the subject after step (a) is below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis, wherein the sarcoidosis is pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psorias
  • the diseased tissue comprises or consists of a tissue in the lung.
  • the diseased tissue comprises or consists of 2, 3, 4, 5, 6, 7, 8, or more tissues in the lung.
  • the corresponding tissue or the reference tissue comprises or consists of a tissue in the lung.
  • the corresponding tissue or the reference tissue comprises or consists of 2, 3, 4, 5, 6, 7, 8, or more tissues in the lung.
  • the effective dose used in the methods provided herein, including the methods provided in this Section (Section [0456]), can be or include various dosing regimens.
  • the effective dose comprises an induction regimen.
  • the effective dose consists of an induction regimen.
  • the effective dose comprises a maintenance regimen.
  • the effective dose comprises an induction regimen and a maintenance regimen.
  • the effective dose consists of an induction regimen and a maintenance regimen.
  • the maintenance regimen is administered in a maintenance step as further described below.
  • the methods provided herein, including in this Section (Section [0456]), can include additional steps.
  • the methods further comprises (c) maintaining TL1A in the diseased tissue in the subject at a concentration below the concentration of TL1A in the corresponding tissue in the control subject.
  • the TL1A in the diseased tissue in the subject is maintained with a maintenance regimen of the anti-TL1A antibody or antigen binding fragment.
  • the TL1A in the diseased tissue in the subject is maintained in step (c) with a maintenance regimen of the anti-TL1A antibody or antigen binding fragment.
  • the maintenance regimen is administered after the induction regimen.
  • the induction regimen and the maintenance regimen in the methods provided herein, including in this Section (Section [0456]) can be identical or different in various aspects.
  • the induction regimen and the maintenance regimen are identical.
  • the induction regimen and the maintenance regimen are different.
  • the induction regimen comprises doses of the anti-TL1A antibody or antigen binding fragment higher than the maintenance regimen.
  • the induction regimen comprises doses of the anti-TL1A antibody or antigen binding fragment 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, or more fold higher than the maintenance regimen.
  • the various methods provided herein can reduce the concentration of TL1A in a diseased tissue in the subject below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis.
  • the various methods provided herein can reduce the concentration of TL1A in a diseased tissue in the subject below a reference TL1A level (e.g. a reference concentration). Additionally, the 25746 various methods provided herein can reduce the concentration of TL1A in a diseased tissue in the subject below the concentration of TL1A in a reference tissue in a control subject without carcoidosis. As is already clear from the description above, the diseased tissue in a patient with sarcoidosis overproduces TL1A, which contributes to the cause, phenotypes, and/or symptoms of the patient with sarcoidosis.
  • the various methods provided herein reduces the concentration of TL1A in the diseased tissues of the subject below the concentration of TL1A in a corresponding tissue in a control subject without sarcoidosis, while the diseased tissues (e.g. certain cells in the diseased tissues) of the subject overproduce TL1A.
  • Such reduction of TL1A concentration in the diseased tissues of the subject to below (i) a reference TL1A level or (ii) the concentration of TL1A in a corresponding tissue or a reference tissue in a control subject without sarcoidosis, while the diseased tissue in the subject overproduces TL1A can also be referred to as coverage.
  • a coverage of or covering 100 fold overproduction of TL1A means that TL1A concentration in the diseased tissues of the subject is reduced to below the concentration of TL1A in a corresponding tissue or a reference tissue in a control subject without sarcoidosis, while the diseased tissue overproduces TL1A up to 100 fold comparing to the corresponding tissue or the reference tissue in a control subject without sarcoidosis.
  • the diseased tissue in the subject produces up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 105, up to 110, up to 115, up to 120, up to 125, up to 130, up to 135, up to 140, up to 145, up to 150, up to 155, up to 160, up to 165, up to 170, up to 175, up to 180, up to 185, up to 190, up to 195, up to 200 or up to more fold of TL1A compared to the corresponding tissue in the control subject.
  • the diseased tissue in the subject produces about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200 or about more fold of TL1A compared to the corresponding tissue in the control subject.
  • the diseased tissue in the subject produces 20 to 50, 20 to 55, 20 to 60, 20 to 65, 20 to 70, 20 to 75, 20 to 80, 20 to 85, 20 to 90, 20 to 95, 20 to 100, 20 to 105, 20 to 110, 20 to 115, 20 to 120, 20 to 125, 20 to 130, 20 to 135, 20 to 140, 20 to 145, 20 to 150, 20 to 155, 20 to 160, 20 to 165, 20 to 170, 20 to 175, 20 to 180, 20 to 185, 20 to 190, 20 to 195, 20 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject.
  • the 25746 diseased tissue in the subject produces 30 to 50, 30 to 55, 30 to 60, 30 to 65, 30 to 70, 30 to 75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100, 30 to 105, 30 to 110, 30 to 115, 30 to 120, 30 to 125, 30 to 130, 30 to 135, 30 to 140, 30 to 145, 30 to 150, 30 to 155, 30 to 160, 30 to 165, 30 to 170, 30 to 175, 30 to 180, 30 to 185, 30 to 190, 30 to 195, 30 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject.
  • the diseased tissue in the subject produces 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100, 40 to 105, 40 to 110, 40 to 115, 40 to 120, 40 to 125, 40 to 130, 40 to 135, 40 to 140, 40 to 145, 40 to 150, 40 to 155, 40 to 160, 40 to 165, 40 to 170, 40 to 175, 40 to 180, 40 to 185, 40 to 190, 40 to 195, 40 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject.
  • the diseased tissue in the subject produces 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100, 50 to 105, 50 to 110, 50 to 115, 50 to 120, 50 to 125, 50 to 130, 50 to 135, 50 to 140, 50 to 145, 50 to 150, 50 to 155, 50 to 160, 50 to 165, 50 to 170, 50 to 175, 50 to 180, 50 to 185, 50 to 190, 50 to 195, 50 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject.
  • the diseased tissue in the subject produces 60 to 65, 60 to 70, 60 to 75, 60 to 80, 60 to 85, 60 to 90, 60 to 95, 60 to 100, 60 to 105, 60 to 110, 60 to 115, 60 to 120, 60 to 125, 60 to 130, 60 to 135, 60 to 140, 60 to 145, 60 to 150, 60 to 155, 60 to 160, 60 to 165, 60 to 170, 60 to 175, 60 to 180, 60 to 185, 60 to 190, 60 to 195, 60 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject.
  • the diseased tissue in the subject produces up to or about 50 fold of TL1A compared to the corresponding tissue in the control subject.
  • the diseased tissue in the subject produces up to or about 60 fold of TL1A compared to the corresponding tissue in the control subject. In one specific embodiment, the diseased tissue in the subject produces up to or about 70 fold of TL1A compared to the corresponding tissue in the control subject. In another specific embodiment, the diseased tissue in the subject produces up to or about 80 fold of TL1A compared to the corresponding tissue in the control subject. In one specific embodiment, the diseased tissue in the subject produces up to or about 90 fold of TL1A compared to the corresponding tissue in the control subject. In another specific embodiment, the diseased tissue in the subject produces up to or about 100 fold of TL1A compared to the corresponding tissue in the control subject.
  • the diseased tissue in the subject produces up to or about 110 fold of TL1A compared to the corresponding tissue in the control subject. In another specific embodiment, the diseased tissue in the subject produces up to or about 120 fold of TL1A compared to the corresponding 25746 tissue in the control subject. In yet another specific embodiment, the diseased tissue in the subject produces up to or about 130 fold of TL1A compared to the corresponding tissue in the control subject. In a further embodiment, the diseased tissue in the subject produces up to or about 140 fold of TL1A compared to the corresponding tissue in the control subject. In one embodiment, the diseased tissue in the subject produces up to or about 150 fold of TL1A compared to the corresponding tissue in the control subject.
  • the diseased tissue in the subject produces up to or about 160 fold of TL1A compared to the corresponding tissue in the control subject. In a further embodiment, the diseased tissue in the subject produces up to or about 170 fold of TL1A compared to the corresponding tissue in the control subject. In yet another specific embodiment, the diseased tissue in the subject produces up to or about 180 fold of TL1A compared to the corresponding tissue in the control subject. In one embodiment, the diseased tissue in the subject produces up to or about 190 fold of TL1A compared to the corresponding tissue in the control subject. In another embodiment, the diseased tissue in the subject produces up to or about 200 fold of TL1A compared to the corresponding tissue in the control subject.
  • the diseased tissue in the subject overproduces TL1A as described in this paragraph during the induction regimen. In some other embodiments, the diseased tissue in the subject overproduces TL1A as described in this paragraph before administering the effective dose. In certain embodiments, the diseased tissue in the subject overproduces TL1A as described in this paragraph within 1, 2, 3, 4, 5, or 6 weeks of start of the induction regimen. As is clear from the description, the diseased tissue can overproduce TL1A via any combination of the fold overproduction, timing, and duration as described herein.
  • the disclosure also provides that the method provided herein can cover the TL1A over-production, for the fold overproduction, timing and/or duration, with the effective dose or induction regimen, as described in this paragraph.
  • the diseased tissue in the subject produces up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 105, up to 110, up to 115, up to 120, up to 125, up to 130, up to 135, up to 140, up to 145, up to 150, up to 155, up to 160, up to 165, up to 170, up to 175, up to 180, up to 185, up to 190, up to 195, up to 200 or up to more fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen.
  • the diseased tissue in the subject produces about 50, about 55, about 60, about 65, about 70, 25746 about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200 or about more fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen.
  • the diseased tissue in the subject produces 20 to 50, 20 to 55, 20 to 60, 20 to 65, 20 to 70, 20 to 75, 20 to 80, 20 to 85, 20 to 90, 20 to 95, 20 to 100, 20 to 105, 20 to 110, 20 to 115, 20 to 120, 20 to 125, 20 to 130, 20 to 135, 20 to 140, 20 to 145, 20 to 150, 20 to 155, 20 to 160, 20 to 165, 20 to 170, 20 to 175, 20 to 180, 20 to 185, 20 to 190, 20 to 195, 20 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen.
  • the diseased tissue in the subject produces 30 to 50, 30 to 55, 30 to 60, 30 to 65, 30 to 70, 30 to 75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100, 30 to 105, 30 to 110, 30 to 115, 30 to 120, 30 to 125, 30 to 130, 30 to 135, 30 to 140, 30 to 145, 30 to 150, 30 to 155, 30 to 160, 30 to 165, 30 to 170, 30 to 175, 30 to 180, 30 to 185, 30 to 190, 30 to 195, 30 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen.
  • the diseased tissue in the subject produces 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100, 40 to 105, 40 to 110, 40 to 115, 40 to 120, 40 to 125, 40 to 130, 40 to 135, 40 to 140, 40 to 145, 40 to 150, 40 to 155, 40 to 160, 40 to 165, 40 to 170, 40 to 175, 40 to 180, 40 to 185, 40 to 190, 40 to 195, 40 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen.
  • the diseased tissue in the subject produces 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100, 50 to 105, 50 to 110, 50 to 115, 50 to 120, 50 to 125, 50 to 130, 50 to 135, 50 to 140, 50 to 145, 50 to 150, 50 to 155, 50 to 160, 50 to 165, 50 to 170, 50 to 175, 50 to 180, 50 to 185, 50 to 190, 50 to 195, 50 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen.
  • the diseased tissue in the subject produces 60 to 65, 60 to 70, 60 to 75, 60 to 80, 60 to 85, 60 to 90, 60 to 95, 60 to 100, 60 to 105, 60 to 110, 60 to 115, 60 to 120, 60 to 125, 60 to 130, 60 to 135, 60 to 140, 60 to 145, 60 to 150, 60 to 155, 60 to 160, 60 to 165, 60 to 170, 60 to 175, 60 to 180, 60 to 185, 60 to 190, 60 to 195, 60 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen.
  • the diseased tissue in the subject produces up to or about 50 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen. In another specific embodiment, the diseased tissue in 25746 the subject produces up to or about 60 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 70 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 80 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen.
  • the diseased tissue in the subject produces up to or about 90 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 100 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 110 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 120 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen.
  • the diseased tissue in the subject produces up to or about 130 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen. In a further embodiment, the diseased tissue in the subject produces up to or about 140 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen. In one embodiment, the diseased tissue in the subject produces up to or about 150 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen. In another embodiment, the diseased tissue in the subject produces up to or about 160 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen.
  • the diseased tissue in the subject produces up to or about 170 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen. In yet another specific embodiment, the diseased tissue in the subject produces up to or about 180 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen. In one embodiment, the diseased tissue in the subject produces up to or about 190 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen. In another embodiment, the diseased tissue in the subject produces up to or about 200 fold of TL1A compared to the corresponding tissue in the control subject during the induction regimen.
  • the disclosure also provides that the method provided herein can cover the TL1A over-production, for the 25746 fold overproduction, timing and/or duration, with the effective dose or induction regimen, as described in this paragraph.
  • the diseased tissue in the subject produces up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 105, up to 110, up to 115, up to 120, up to 125, up to 130, up to 135, up to 140, up to 145, up to 150, up to 155, up to 160, up to 165, up to 170, up to 175, up to 180, up to 185, up to 190, up to 195, up to 200 or up to more fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen.
  • the diseased tissue in the subject produces about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200 or about more fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen.
  • the diseased tissue in the subject produces 20 to 50, 20 to 55, 20 to 60, 20 to 65, 20 to 70, 20 to 75, 20 to 80, 20 to 85, 20 to 90, 20 to 95, 20 to 100, 20 to 105, 20 to 110, 20 to 115, 20 to 120, 20 to 125, 20 to 130, 20 to 135, 20 to 140, 20 to 145, 20 to 150, 20 to 155, 20 to 160, 20 to 165, 20 to 170, 20 to 175, 20 to 180, 20 to 185, 20 to 190, 20 to 195, 20 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen.
  • the diseased tissue in the subject produces 30 to 50, 30 to 55, 30 to 60, 30 to 65, 30 to 70, 30 to 75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100, 30 to 105, 30 to 110, 30 to 115, 30 to 120, 30 to 125, 30 to 130, 30 to 135, 30 to 140, 30 to 145, 30 to 150, 30 to 155, 30 to 160, 30 to 165, 30 to 170, 30 to 175, 30 to 180, 30 to 185, 30 to 190, 30 to 195, 30 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen.
  • the diseased tissue in the subject produces 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100, 40 to 105, 40 to 110, 40 to 115, 40 to 120, 40 to 125, 40 to 130, 40 to 135, 40 to 140, 40 to 145, 40 to 150, 40 to 155, 40 to 160, 40 to 165, 40 to 170, 40 to 175, 40 to 180, 40 to 185, 40 to 190, 40 to 195, 40 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen.
  • the diseased tissue in the subject produces 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100, 50 to 105, 50 to 110, 50 to 115, 50 to 120, 50 to 125, 50 to 130, 50 to 135, 50 to 140, 50 to 145, 50 to 150, 50 to 155, 50 to 160, 50 to 165, 50 to 170, 50 to 175, 50 to 180, 50 25746 to 185, 50 to 190, 50 to 195, 50 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen.
  • the diseased tissue in the subject produces 60 to 65, 60 to 70, 60 to 75, 60 to 80, 60 to 85, 60 to 90, 60 to 95, 60 to 100, 60 to 105, 60 to 110, 60 to 115, 60 to 120, 60 to 125, 60 to 130, 60 to 135, 60 to 140, 60 to 145, 60 to 150, 60 to 155, 60 to 160, 60 to 165, 60 to 170, 60 to 175, 60 to 180, 60 to 185, 60 to 190, 60 to 195, 60 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen.
  • the diseased tissue in the subject produces up to or about 50 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 60 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 70 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 80 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen.
  • the diseased tissue in the subject produces up to or about 90 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 100 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 110 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 120 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen.
  • the diseased tissue in the subject produces up to or about 130 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen. In a further embodiment, the diseased tissue in the subject produces up to or about 140 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen. In one embodiment, the diseased tissue in the subject produces up to or about 150 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen. In another embodiment, the diseased tissue in the subject produces up to or about 160 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen.
  • the diseased tissue in the subject produces up to or about 170 fold of TL1A compared to the corresponding tissue in the control 25746 subject before the induction regimen. In yet another specific embodiment, the diseased tissue in the subject produces up to or about 180 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen. In one embodiment, the diseased tissue in the subject produces up to or about 190 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen. In another embodiment, the diseased tissue in the subject produces up to or about 200 fold of TL1A compared to the corresponding tissue in the control subject before the induction regimen.
  • the disclosure also provides that the method provided herein can cover the TL1A over-production, for the fold overproduction, timing and/or duration, with the effective dose or induction regimen, as described in this paragraph.
  • the diseased tissue in the subject produces up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 105, up to 110, up to 115, up to 120, up to 125, up to 130, up to 135, up to 140, up to 145, up to 150, up to 155, up to 160, up to 165, up to 170, up to 175, up to 180, up to 185, up to 190, up to 195, up to 200 or up to more fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen.
  • the diseased tissue in the subject produces about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200 or about more fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen.
  • the diseased tissue in the subject produces 20 to 50, 20 to 55, 20 to 60, 20 to 65, 20 to 70, 20 to 75, 20 to 80, 20 to 85, 20 to 90, 20 to 95, 20 to 100, 20 to 105, 20 to 110, 20 to 115, 20 to 120, 20 to 125, 20 to 130, 20 to 135, 20 to 140, 20 to 145, 20 to 150, 20 to 155, 20 to 160, 20 to 165, 20 to 170, 20 to 175, 20 to 180, 20 to 185, 20 to 190, 20 to 195, 20 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen.
  • the diseased tissue in the subject produces 30 to 50, 30 to 55, 30 to 60, 30 to 65, 30 to 70, 30 to 75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100, 30 to 105, 30 to 110, 30 to 115, 30 to 120, 30 to 125, 30 to 130, 30 to 135, 30 to 140, 30 to 145, 30 to 150, 30 to 155, 30 to 160, 30 to 165, 30 to 170, 30 to 175, 30 to 180, 30 to 185, 30 to 190, 30 to 195, 30 to 200, or more 25746 fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen.
  • the diseased tissue in the subject produces 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100, 40 to 105, 40 to 110, 40 to 115, 40 to 120, 40 to 125, 40 to 130, 40 to 135, 40 to 140, 40 to 145, 40 to 150, 40 to 155, 40 to 160, 40 to 165, 40 to 170, 40 to 175, 40 to 180, 40 to 185, 40 to 190, 40 to 195, 40 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen.
  • the diseased tissue in the subject produces 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100, 50 to 105, 50 to 110, 50 to 115, 50 to 120, 50 to 125, 50 to 130, 50 to 135, 50 to 140, 50 to 145, 50 to 150, 50 to 155, 50 to 160, 50 to 165, 50 to 170, 50 to 175, 50 to 180, 50 to 185, 50 to 190, 50 to 195, 50 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen.
  • the diseased tissue in the subject produces 60 to 65, 60 to 70, 60 to 75, 60 to 80, 60 to 85, 60 to 90, 60 to 95, 60 to 100, 60 to 105, 60 to 110, 60 to 115, 60 to 120, 60 to 125, 60 to 130, 60 to 135, 60 to 140, 60 to 145, 60 to 150, 60 to 155, 60 to 160, 60 to 165, 60 to 170, 60 to 175, 60 to 180, 60 to 185, 60 to 190, 60 to 195, 60 to 200, or more fold of TL1A compared to the corresponding tissue in the control subject 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 or about 50 fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 60 fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 70 fold of TL1A compared to the corresponding tissue in the control subject 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 or about 80 fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 90 fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 100 fold of TL1A compared to the corresponding tissue in the control subject 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 or about 110 fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 120 fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen. In yet another specific embodiment, the diseased tissue in the subject produces up to or about 130 fold of TL1A compared to the corresponding tissue in the control subject 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 or about 140 fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen. In one embodiment, the diseased tissue in the subject produces up to or about 150 fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen. In another embodiment, the diseased tissue in the subject produces up to or about 160 fold of TL1A compared to the corresponding tissue in the control subject 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 or about 170 fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen. In yet another specific embodiment, the diseased tissue in the subject produces up to or about 180 fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen. In one embodiment, the diseased tissue in the subject produces up to or about 190 fold of TL1A compared to the corresponding tissue in the control subject 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 or about 200 fold of TL1A compared to the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the start of the induction regimen.
  • the disclosure also provides that the method provided herein can cover the TL1A over-production, for the fold overproduction, timing and/or duration, with the effective dose or induction regimen, as described in this paragraph.
  • the induction regimen can comprise one or more administrations of the anti- TL1A antibody or antigen binding fragment to reduce the concentration of TL1A in a diseased tissue in the subject.
  • the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment.
  • the induction 25746 regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 150 mg/dose.
  • the induction regimen comprises a one- time administration of the anti-TL1A antibody or antigen binding fragment at about 200 mg/dose.
  • the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 250 mg/dose.
  • the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 300 mg/dose. In yet another embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 350 mg/dose. In one embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 400 mg/dose. In another embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 450 mg/dose. In yet another embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 500 mg/dose.
  • the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 550 mg/dose. In yet another embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 600 mg/dose. In another embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 650 mg/dose. In a further embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 700 mg/dose. In one embodiment, the induction regimen comprises a one-time administration of the anti- TL1A antibody or antigen binding fragment at about 750 mg/dose.
  • the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 800 mg/dose. In one embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 850 mg/dose. In a further embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 900 mg/dose. In one embodiment, the induction regimen comprises a one-time administration of the anti- TL1A antibody or antigen binding fragment at about 950 mg/dose. In yet another embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 1000 mg/dose.
  • the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 1100 mg/dose.
  • the induction regimen 25746 comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 1200 mg/dose.
  • the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 1250 mg/dose.
  • the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 1300 mg/dose.
  • the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 1400 mg/dose.
  • the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 1500 mg/dose. In one embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 1600 mg/dose. In another embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 1700 mg/dose. In a further embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 1750 mg/dose. In yet another embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 1800 mg/dose.
  • the induction regimen comprises a one- time administration of the anti-TL1A antibody or antigen binding fragment at about 1900 mg/dose. In one embodiment, the induction regimen comprises a one-time administration of the anti-TL1A antibody or antigen binding fragment at about 2000 mg/dose. [0452] Alternatively, the induction regimen can comprise multiple administrations of the anti-TL1A antibody or antigen binding fragment. In one embodiment, the induction regimen comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more administrations the anti-TL1A antibody or antigen binding fragments.
  • the induction regimen comprises administration of about 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, or 150 mg/dose.
  • the induction regimen comprises administration of 200 to 2000, 200 to 1950, 200 to 1900, 200 to 1850, 200 to 1800, 200 to 1750, 200 to 1700, 200 to 1650, 200 to 1600, 200 to 1550, 200 to 1500, 200 to 1450, 200 to 1400, 200 to 1350, 200 to 1300, 200 to 1250, 200 to 1200, 200 to 1150, 200 to 1000, 200 to 950, 200 to 900, 200 to 850, 200 to 800, 200 to 750, 200 to 700, 200 to 650, 200 to 600, 200 to 550, 200 to 500, 200 to 450, 200 to 400, 200 to 350, 200 to 300, or 200 to 250 mg/dose.
  • the induction regimen comprises administration of 100 to 2000, 100 to 1950, 100 to 1900, 100 to 25746 1850, 100 to 1800, 100 to 1750, 100 to 1700, 100 to 1650, 100 to 1600, 100 to 1550, 100 to 1500, 100 to 1450, 100 to 1400, 100 to 1350, 100 to 1300, 100 to 1250, 100 to 1200, 100 to 1150, 100 to 1000, 100 to 950, 100 to 900, 100 to 850, 100 to 800, 100 to 750, 100 to 700, 100 to 650, 100 to 600, 100 to 550, 100 to 500, 100 to 450, 100 to 400, 100 to 350, 100 to 300, or 100 to 250 mg/dose.
  • the induction regimen comprises administration of 300 to 2000, 300 to 1950, 300 to 1900, 300 to 1850, 300 to 1800, 300 to 1750, 300 to 1700, 300 to 1650, 300 to 1600, 300 to 1550, 300 to 1500, 300 to 1450, 300 to 1400, 300 to 1350, 300 to 1300, 300 to 1250, 300 to 1200, 300 to 1150, 300 to 1000, 300 to 950, 300 to 900, 300 to 850, 300 to 800, 300 to 750, 300 to 700, 300 to 650, 300 to 600, 300 to 550, 300 to 500, 300 to 450, 300 to 400, or 300 to 350 mg/dose.
  • the induction regimen comprises administration once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks.
  • the induction regimen comprises administration once every 1, 2, 3 or 4 weeks for the first 2 administrations and then once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks for the remaining induction regimen.
  • the induction regimen comprises administration week 0 and week 2 for the first 2 administrations and then once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks for the remaining induction regimen.
  • the duration of the induction regimen is shorter than the duration of the maintenance regimen.
  • the induction regimen continues for 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more weeks.
  • the induction regimen can comprise any combination of the dosing amount, dosing frequency, number of administrations, and/or the duration of the induction regimen.
  • the induction regimen can comprise administration of about 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, or 200 mg/dose for administrations at week 0 and week 2 for the first 2 administrations and then once every 2, 3, 4, 5, 6, 7, or 8 weeks, for a duration of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more weeks for the induction regimen.
  • the induction regimen can comprise administration of about 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, or 200 mg/dose for administrations at week 0 and week 2 for the first 2 administrations and then administration of about 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 25746 or 150 mg/dose once every 2, 3, 4, 5, 6, 7, or 8 weeks, for a duration of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more weeks for the induction regimen.
  • the induction regimen comprises administrations of about 1000 mg/dose on week 0, about 1000 mg/dose on week 2, about 1000 mg/dose on week 6, and about 1000 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 500 mg/dose on week 0, about 500 mg/dose on week 2, about 500 mg/dose on week 6, and about 500 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 1000 mg/dose on week 0, about 1000 mg/dose on week 2, about 1000 mg/dose on week 6, and about 500 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 1000 mg/dose on week 0, about 1000 mg/dose on week 2, about 500 mg/dose on week 6, and about 500 mg/dose on week 10.
  • the induction regimen comprises administrations of about 1000 mg/dose on week 0, about 500 mg/dose on week 2, about 500 mg/dose on week 6, and about 500 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 750 mg/dose on week 0, about 750 mg/dose on week 2, about 750 mg/dose on week 6, and about 750 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 500 mg/dose on week 0, about 500 mg/dose on week 2, about 500 mg/dose on week 6, and about 500 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 750 mg/dose on week 0, about 750 mg/dose on week 2, about 750 mg/dose on week 6, and about 500 mg/dose on week 10.
  • the induction regimen comprises administrations of about 750 mg/dose on week 0, about 750 mg/dose on week 2, about 500 mg/dose on week 6, and about 500 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 750 mg/dose on week 0, about 500 mg/dose on week 2, about 500 mg/dose on week 6, and about 500 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 1500 mg/dose on week 0, about 1500 mg/dose on week 2, about 1500 mg/dose on week 6, and about 1500 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 500 mg/dose on week 0, about 500 mg/dose on week 2, about 500 mg/dose on week 6, and about 500 mg/dose on week 10.
  • the induction regimen comprises administrations of about 1500 mg/dose on week 0, about 1500 mg/dose on week 2, about 1500 mg/dose on week 6, and about 500 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 1500 mg/dose on week 0, about 1500 25746 mg/dose on week 2, about 500 mg/dose on week 6, and about 500 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 1500 mg/dose on week 0, about 500 mg/dose on week 2, about 500 mg/dose on week 6, and about 500 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 750 mg/dose on week 0, about 750 mg/dose on week 2, about 750 mg/dose on week 6, and about 750 mg/dose on week 10.
  • the induction regimen comprises administrations of about 1000 mg/dose on week 0, about 1000 mg/dose on week 2, about 1000 mg/dose on week 6, and about 750 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 1000 mg/dose on week 0, about 1000 mg/dose on week 2, about 750 mg/dose on week 6, and about 750 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 1000 mg/dose on week 0, about 750 mg/dose on week 2, about 750 mg/dose on week 6, and about 750 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 1500 mg/dose on week 0, about 1500 mg/dose on week 2, about 1500 mg/dose on week 6, and about 1500 mg/dose on week 10.
  • the induction regimen comprises administrations of about 750 mg/dose on week 0, about 750 mg/dose on week 2, about 750 mg/dose on week 6, and about 750 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 1500 mg/dose on week 0, about 1500 mg/dose on week 2, about 1500 mg/dose on week 6, and about 750 mg/dose on week 10. In some embodiments, the induction regimen comprises administrations of about 1500 mg/dose on week 0, about 1500 mg/dose on week 2, about 750 mg/dose on week 6, and about 750 mg/dose on week 10.
  • the induction regimen comprises administrations of about 1500 mg/dose on week 0, about 750 mg/dose on week 2, about 750 mg/dose on week 6, and about 750 mg/dose on week 10.
  • the duration of the induction regimen is shorter than the duration of the maintenance regimen.
  • the induction regimen continues for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks.
  • the induction regimen continues for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.
  • the induction regimen continues for 8 weeks.
  • the induction regimen continues for 9 weeks.
  • the induction regimen continues for 10 weeks.
  • the induction regimen continues for 11 weeks.
  • the induction regimen continues for 12 weeks. 25746
  • week 0 means day 1 of the administration of the anti-TL1A antibody or antigen binding fragments.
  • Week 0 of the induction regimen means day 1 of the administration of the anti-TL1A antibody or antigen binding fragments in the induction regimen.
  • Week 0 of the maintenance regimen means day 1 of the administration of the anti- TL1A antibody or antigen binding fragments in the maintenance regimen.
  • the disclosure provides that the diseased tissue in the subject can overproduce and/or continue to overproduce (e.g. cells in the diseased tissue overexpresses) TL1A after the induction regimen.
  • the disclosure further provides a maintenance regimen for the various methods provided herein to maintain the TL1A in the diseased tissue in the subject at a concentration below the concentration of TL1A in the corresponding tissue in the control subject without sarcoidosis.
  • the methods provided herein further comprise a maintenance regimen to maintain the TL1A in the diseased tissue in the subject at a concentration below the concentration of TL1A in a reference tissue in the control subject without sarcoidosis.
  • the methods provided herein further comprise a maintenance regimen to maintain the TL1A in the diseased tissue in the subject at a concentration below a reference TL1A level (e.g. a reference concentration).
  • the sarcoidosis in this paragraph is pulmonary sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is cutaneous sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is lupus pernio. In some embodiments, the sarcoidosis in this paragraph is papular sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is nodular sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is Darier-Roussy sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is maculopapular sarcoidosis.
  • the sarcoidosis in this paragraph is plaque sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is hypopigmented sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is atrophic and ulcerative sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is neurologic sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is cardiac sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is gastrointestinal sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is hepatic sarcoidosis.
  • the sarcoidosis in this paragraph is pancreatic sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is peritoneal sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is sarcoidosis of bones. In some embodiments, the sarcoidosis in this paragraph is sarcoid arthropathy. In some embodiments, the sarcoidosis in this paragraph is angiolupoid sarcoidosis. In some embodiments, the 25746 sarcoidosis in this paragraph is psoriasiform sarcoidosis.
  • the sarcoidosis in this paragraph is verrucous sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is ichthyosiform sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is erythrodermic sarcoidosis. In some embodiments, the sarcoidosis in this paragraph is perforating sarcoidosis.
  • the concentration of TL1A in the diseased tissue of the subject is reduced below (i) a reference TL1A level or (ii) the concentration of TL1A in a corresponding tissue or a reference tissue in in a control subject without sarcoidosis, while the diseased tissues (e.g. certain cells in the diseased tissues) of the subject overproduces TL1A.
  • the reduction of the TL1A in the diseased tissue can be maintained at or during any or all time of the maintenance regimen, while the diseased tissues (e.g. certain cells in the diseased tissues) of the subject overproduces TL1A at various level of overproduction.
  • the diseased tissue in the subject produces up to 10, up to 15, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, or up to more fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • the diseased tissue in the subject produces about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, or about more fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • the diseased tissue in the subject produces 10 to 15, 10 to 20, 10 to 25, 10 to 30, 10 to 35, 10 to 40, 10 to 45, 10 to 50, 10 to 50, 10 to 55, 10 to 60, 10 to 65, 10 to 70, 10 to 75, 10 to 80, 10 to 85, 10 to 90, 10 to 95, 10 to 100 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • the diseased tissue in the subject produces 20 to 25, 20 to 30, 20 to 35, 20 to 40, 20 to 45, 20 to 50, 20 to 50, 20 to 55, 20 to 60, 20 to 65, 20 to 70, 20 to 75, 20 to 80, 20 to 85, 20 to 90, 20 to 95, 20 to 100 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • the diseased tissue in the subject produces 30 to 35, 30 to 40, 30 to 45, 30 to 50, 30 to 50, 30 to 55, 30 to 60, 30 to 65, 30 to 70, 30 to 75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • the diseased tissue in the subject produces 40 to 45, 40 to 50, 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 25746 40 to 85, 40 to 90, 40 to 95, 40 to 100 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • the diseased tissue in the subject produces 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen. In one embodiment, the diseased tissue in the subject produces up to or about 10 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen. In another embodiment, the diseased tissue in the subject produces up to or about 20 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen. In another embodiment, the diseased tissue in the subject produces up to or about 30 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • the diseased tissue in the subject produces up to or about 40 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 50 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 60 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 70 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • the diseased tissue in the subject produces up to or about 80 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 90 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 100 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen. In one embodiment, the diseased tissue in the subject produces up to or about 110 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • the diseased tissue in the subject produces up to or about 120 fold of TL1A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • the sarcoidosis described in various embodiments of this paragraph can be pulmonary sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be cutaneous sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be lupus pernio.
  • the sarcoidosis described in various 25746 embodiments of this paragraph can be papular sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be nodular sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be Darier-Roussy sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be maculopapular sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be plaque sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be hypopigmented sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be atrophic and ulcerative sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be neurologic sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be cardiac sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be gastrointestinal sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be hepatic sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be pancreatic sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be peritoneal sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be sarcoidosis of bones.
  • the sarcoidosis described in various embodiments of this paragraph can be sarcoid arthropathy.
  • the sarcoidosis described in various embodiments of this paragraph can be angiolupoid sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be psoriasiform sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be verrucous sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be ichthyosiform sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be erythrodermic sarcoidosis.
  • the sarcoidosis described in various embodiments of this paragraph can be perforating sarcoidosis.
  • the disclosure also provides that the method provided herein can cover the TL1A over-production, for the fold overproduction, timing and/or duration, with the effective dose or maintenance regimen, as described in this paragraph.
  • the diseased tissue in the subject produces up to 10, up to 15, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, or up to more fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen.
  • the diseased tissue in the subject produces about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, 25746 about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100 or about more fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen.
  • the diseased tissue in the subject produces 10 to 15, 10 to 20, 10 to 25, 10 to 30, 10 to 35, 10 to 40, 10 to 45, 10 to 50, 10 to 50, 10 to 55, 10 to 60, 10 to 65, 10 to 70, 10 to 75, 10 to 80, 10 to 85, 10 to 90, 10 to 95, 10 to 100 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen.
  • the diseased tissue in the subject produces 20 to 25, 20 to 30, 20 to 35, 20 to 40, 20 to 45, 20 to 50, 20 to 50, 20 to 55, 20 to 60, 20 to 65, 20 to 70, 20 to 75, 20 to 80, 20 to 85, 20 to 90, 20 to 95, 20 to 100 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen.
  • the diseased tissue in the subject produces 30 to 35, 30 to 40, 30 to 45, 30 to 50, 30 to 50, 30 to 55, 30 to 60, 30 to 65, 30 to 70, 30 to 75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen.
  • the diseased tissue in the subject produces 40 to 45, 40 to 50, 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen.
  • the diseased tissue in the subject produces 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 10 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 20 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen.
  • the diseased tissue in the subject produces up to or about 30 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 40 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 50 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 60 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen.
  • the diseased tissue in the subject produces up to or about 70 fold of TL1A compared to the corresponding tissue in 25746 the control subject before the maintenance regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 80 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 90 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 100 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen.
  • the diseased tissue in the subject produces up to or about 110 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen. In another specific embodiment, the diseased tissue in the subject produces up to or about 120 fold of TL1A compared to the corresponding tissue in the control subject before the maintenance regimen.
  • the disclosure also provides that the method provided herein can cover the TL1A over-production, for the fold overproduction, timing and/or duration, with the effective dose or maintenance regimen, as described in this paragraph.
  • the diseased tissue in the subject produces up to 10, up to 15, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, or up to more fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the diseased tissue in the subject produces about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, or about more fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the diseased tissue in the subject produces 10 to 15, 10 to 20, 10 to 25, 10 to 30, 10 to 35, 10 to 40, 10 to 45, 10 to 50, 10 to 50, 10 to 55, 10 to 60, 10 to 65, 10 to 70, 10 to 75, 10 to 80, 10 to 85, 10 to 90, 10 to 95, 10 to 100 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the diseased tissue in the subject produces 20 to 25, 20 to 30, 20 to 35, 20 to 40, 20 to 45, 20 to 50, 20 to 25746 50, 20 to 55, 20 to 60, 20 to 65, 20 to 70, 20 to 75, 20 to 80, 20 to 85, 20 to 90, 20 to 95, 20 to 100 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the diseased tissue in the subject produces 30 to 35, 30 to 40, 30 to 45, 30 to 50, 30 to 50, 30 to 55, 30 to 60, 30 to 65, 30 to 70, 30 to 75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the diseased tissue in the subject produces 40 to 45, 40 to 50, 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the diseased tissue in the subject produces 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the diseased tissue in the subject produces up to or about 10 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the diseased tissue in the subject produces up to or about 20 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen. In one embodiment, the diseased tissue in the subject produces up to or about 30 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the diseased tissue in the subject produces up to or about 40 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 50 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the diseased tissue in the subject produces up to or about 60 fold of TL1A compared to the 25746 corresponding tissue in the control subject 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 of the start of the maintenance regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 70 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the diseased tissue in the subject produces up to or about 80 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 90 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the diseased tissue in the subject produces up to or about 100 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen. In one specific embodiment, the diseased tissue in the subject produces up to or about 110 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the diseased tissue in the subject produces up to or about 120 fold of TL1A compared to the corresponding tissue in the control subject 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 of the start of the maintenance regimen.
  • the disclosure also provides that the method provided herein can cover the TL1A over-production, for the fold overproduction, timing and/or duration, with the effective dose or maintenance regimen, as described in this paragraph.
  • the maintenance regimen can include multiple administrations of the anti-TL1A antibody or antigen binding fragment.
  • the maintenance regimen comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more administrations the anti-TL1A antibody or antigen binding fragments.
  • the maintenance regimen comprises administration of about 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 25746 1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 mg/dose.
  • the maintenance regimen comprises administration of about 50 to 1000, 50 to 950, 50 to 900, 50 to 850, 50 to 800, 50 to 750, 50 to 700, 50 to 650, 50 to 600, 50 to 550, 50 to 500, 50 to 450, 50 to 400, 50 to 350, 50 to 300, 50 to 250, 50 to 200, 50 to 150, or 50 to 100 mg/dose.
  • the maintenance regimen comprises administration of about 100 to 1000, 100 to 950, 100 to 900, 100 to 850, 100 to 800, 100 to 750, 100 to 700, 100 to 650, 100 to 600, 100 to 550, 100 to 500, 100 to 450, 100 to 400, 100 to 350, 100 to 300, 100 to 250, 100 to 200, or 100 to 150 mg/dose.
  • the maintenance regimen comprises administration of about 200 to 1000, 200 to 950, 200 to 900, 200 to 850, 200 to 800, 200 to 750, 200 to 700, 200 to 650, 200 to 600, 200 to 550, 200 to 500, 200 to 450, 200 to 400, 200 to 350, 200 to 300, or 200 to 250 mg/dose.
  • the maintenance regimen comprises administration once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.
  • the maintenance regimen continues for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, 52, or more weeks.
  • the maintenance regimen can comprise any combination of the dosing amount, dosing frequency, number of administrations, and/or the duration of the induction regimen.
  • the induction regimen can comprise administration of about 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 mg/dose for administrations at a frequency of once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, for a duration of 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, 52, or more weeks for the maintenance regimen.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 500 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 450 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 400 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 350 mg/dose every 2 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 300 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 250 mg/dose every 2 weeks. In 25746 one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 200 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 150 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 100 mg/dose every 2 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 50 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 500 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 450 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 400 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 350 mg/dose every 4 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 300 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 250 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 200 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 150 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 100 mg/dose every 4 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 50 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 500 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 450 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 400 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 350 mg/dose every 6 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A 25746 antibody or antigen binding fragment at about 300 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 250 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 200 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 150 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 100 mg/dose every 6 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 50 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 500 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 450 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 400 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 350 mg/dose every 8 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 300 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 250 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 200 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 150 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 100 mg/dose every 8 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 50 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 500 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 450 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 400 mg/dose every 10 weeks. In one 25746 embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 350 mg/dose every 10 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 300 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 250 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 200 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 150 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 100 mg/dose every 10 weeks.
  • the maintenance regimen comprises administrations of the anti-TL1A antibody or antigen binding fragment at about 50 mg/dose every 10 weeks.
  • further embodiments of the 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 Section [0256]; assays for screening, testing, and validating the anti-TL1A antibodies are provided in Section [0379]; methods for generating, improving, mutating, cloning, expressing, and isolating the anti-TL1A antibodies are provided in Section [0385]; pharmaceutical compositions for the anti-TL1A antibodies are described and provided in Section [0419]; additional dose or route of administration for the anti-TL1A antibodies are described and provided in Section [0419]; further specific and validated embodiments for the anti-TL1A
  • the disclosure provides the various combinations of the anti-TL1A antibodies, the pharmaceutical compositions of such anti-TL1A antibodies, the methods of generating the anti-TL1A antibodies, the methods of assaying the anti-TL1A antibodies, and the methods of using the anti-TL1A antibodies for treatment.
  • the disclosure provides that there is advantage of using anti-TL1A antibody or antigen binding fragments that bind to both monomeric TL1A and trimeric TL1A, as neutralizing both monomeric and trimeric TL1A can more efficiently reduce the functional trimeric TL1A in diseased tissue.
  • the antibody or antigen binding fragment binds to both monomeric TL1A and trimeric TL1A.
  • the anti-TL1A antibody or antigen binding fragment blocks binding of TL1A to DR3.
  • the anti-TL1A antibody or antigen binding fragment binds to both monomeric TL1A and trimeric TL1A and blocks binding of TL1A to DR3.
  • the anti-TL1A antibody or antigen fragments may neutralize TL1A at various percentage levels for the methods provided herein, including in this Section (Section [0456]).
  • at least or about 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 blood of the subject is neutralized (e.g. occupied and blocked for binding with DR3) by the anti-TL1A antibody or antigen binding fragment.
  • At least or about 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 blood of the subject is neutralized (e.g. occupied and blocked for binding with DR3) by the anti-TL1A antibody or antigen binding fragment.
  • At least or about 90% of the monomeric TL1A in the blood of the subject is neutralized (e.g. occupied and blocked for binding with DR3) by the anti-TL1A antibody or antigen binding fragment.
  • at least or about 90% of the trimeric TL1A in the blood of the subject is neutralized (e.g. occupied and blocked for binding with DR3) by the anti-TL1A antibody or antigen binding fragment.
  • At least or about 90% of the monomeric TL1A and (ii) at least or about 90% of the trimeric TL1A in the blood of the subject are neutralized (e.g. occupied and blocked for binding with DR3) by the anti-TL1A antibody or antigen binding fragment.
  • at least or about 95% of the monomeric TL1A in the blood of the subject is neutralized (e.g. occupied and blocked for binding with DR3) by the anti-TL1A antibody or antigen binding fragment.
  • at least or about 95% of the trimeric TL1A in 25746 the blood of the subject is neutralized (e.g.
  • At least or about 95% of the monomeric TL1A and (ii) at least or about 95% of the trimeric TL1A in the blood of the subject are neutralized (e.g. occupied and blocked for binding with DR3) by the anti-TL1A antibody or antigen binding fragment.
  • at least or about 99% of the monomeric TL1A in the blood of the subject is neutralized (e.g. occupied and blocked for binding with DR3) by the anti-TL1A antibody or antigen binding fragment.
  • At least or about 99% of the trimeric TL1A in the blood of the subject is neutralized (e.g. occupied and blocked for binding with DR3) by the anti-TL1A antibody or antigen binding fragment.
  • (i) at least or about 99% of the monomeric TL1A and (ii) at least or about 99% of the trimeric TL1A in the blood of the subject are neutralized (e.g. occupied and blocked for binding with DR3) by the anti-TL1A antibody or antigen binding fragment.
  • the diseased tissue described or referenced in the various methods provided herein, including in this Section can be one or more tissues manifesting pathology of sarcoidosis in the subject.
  • the diseased tissues comprise or consist of bronchi.
  • the diseased tissues comprise or consist of bronchioles.
  • the diseased tissues comprise or consist of alveolar duct.
  • the diseased tissues comprise or consist of alveoli.
  • the diseased tissues comprise or consist of pleura.
  • the diseased tissues comprise or consist of a fibrotic tissue in the lung.
  • the diseased tissues comprise or consist of other tissues afflicted by sarcoidosis.
  • the diseased tissues comprise or consist of other tissues of pathogenesis for sarcoidosis.
  • the diseased tissues comprise or consist of any one selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, other tissues afflicted by sarcoidosis, and other tissues of pathogenesis for sarcoidosis.
  • the diseased tissues comprise or consist of any two selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, other tissues afflicted by sarcoidosis, and other tissues of pathogenesis for sarcoidosis. In one embodiment, the diseased tissues comprise or consist of any three selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, other tissues afflicted by sarcoidosis, and other tissues of pathogenesis for sarcoidosis.
  • the diseased tissues comprise or consist of 25746 any four selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, other tissues afflicted by sarcoidosis, and other tissues of pathogenesis for sarcoidosis. In one embodiment, the diseased tissues comprise or consist of any five selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, other tissues afflicted by sarcoidosis, and other tissues of pathogenesis for sarcoidosis.
  • the diseased tissues comprise or consist of any six selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, other tissues afflicted by sarcoidosis, and other tissues of pathogenesis for sarcoidosis. In one embodiment, the diseased tissues comprise or consist of any seven selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, other tissues afflicted by sarcoidosis, and other tissues of pathogenesis for sarcoidosis.
  • the diseased tissues comprise or consist of any eight selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, other tissues afflicted by sarcoidosis, and other tissues of pathogenesis for sarcoidosis.
  • the diseased tissues comprise or consist of any number of tissues (e.g. one or more), in any combination or permutation, selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, a fibrotic tissue in the lung, other tissues afflicted by sarcoidosis, and other tissues of pathogenesis for sarcoidosis.
  • the sarcoidosis in this paragraph comprises or consists of pulmonary sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of cutaneous sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of lupus pernio. In some embodiments, the sarcoidosis in this paragraph comprises or consists of papular sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of nodular sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of Darier-Roussy sarcoidosis.
  • the sarcoidosis in this paragraph comprises or consists of maculopapular sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of plaque sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of hypopigmented sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of atrophic and ulcerative sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of neurologic sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of cardiac sarcoidosis.
  • the sarcoidosis in this paragraph comprises or consists of gastrointestinal sarcoidosis. In some 25746 embodiments, the sarcoidosis in this paragraph comprises or consists of hepatic sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of pancreatic sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of peritoneal sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of sarcoidosis of bones. In some embodiments, the sarcoidosis in this paragraph comprises or consists of sarcoid arthropathy.
  • the sarcoidosis in this paragraph comprises or consists of angiolupoid sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of psoriasiform sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of verrucous sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of ichthyosiform sarcoidosis. In some embodiments, the sarcoidosis in this paragraph comprises or consists of erythrodermic sarcoidosis.
  • the sarcoidosis in this paragraph comprises or consists of perforating sarcoidosis.
  • the sarcoidosis in this paragraph comprises or consists of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more selected from the group consisting of pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis,
  • sarcoidosis such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichthyosiform sarcoidosis
  • sarcoidosis such as
  • Such manifested changes for sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, 25746 neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichthyosiform sarcoidosis
  • histology changes e.g. changes in the organization and arrangements of the various cell types (such as damages to layers of epithelial cells), changes in the amount or ratio of cell various cells types (such as loss of certain cells or over-amplification of some cells), and/or occurrence of cell types not normally seen in the tissue (such as infiltration of monocytes in the tissue)).
  • sarcoidosis such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichthyosiform sarcoidosis
  • Such manifested changes of sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichthyosiform sarcoidosis, ery
  • TL1A expression and/or IFN ⁇ expression changes in the transportation of proteins or cells (e.g. increased secretion of TL1A and/or IFN ⁇ or increased migration of monocyte to other tissues of such sarcoidosis), and/or other changes that can cause such sarcoidosis.
  • the disclosure provides that the tissues with sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal 25746 sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichthyosiform sarcoidos
  • tissue of pathogenesis for sarcoidosis such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichthyosiform sarcoidosis,
  • the corresponding tissue provided herein for the various methods for determining the fold overproduction of TL1A in the diseased tissue can be the same or equivalent tissue as the diseased tissue but in a control subject without sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal
  • sarcoidosis such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichthyosiform sarc
  • sarcoidosis such as pulmonary
  • the corresponding tissue provided herein for the various methods for determining the fold overproduction of TL1A in the diseased tissue can be a reference tissue in a control subject without sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, 25746 papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis,
  • the corresponding tissue provided herein for the various methods for determining the fold overproduction of TL1A in the diseased tissue can be a reference tissue that is not affected by the sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarc
  • Such reference tissues are not necessarily the same as the diseased tissue, as long as the TL1A concentration in such reference tissue reflects the physiological or basal level of TL1A production as further described in the paragraph below.
  • Such reference tissues in a control subject can be bronchi, bronchioles, alveolar duct, alveoli, pleura, and/or a tissue (or tissues) without sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarc
  • the corresponding tissue or reference tissue in the control subject comprises or consists of bronchi. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of bronchioles. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of alveolar duct. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of alveoli. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of pleura.
  • the corresponding tissue or reference tissue in the 25746 control subject comprises or consists of a tissue (or tissues) without sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarco
  • the corresponding tissue or reference tissue in the control subject comprises or consists of any combination of 2, 3, 4, 5, 6, or more tissues selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, and/or a tissue (or tissues) without sarcoidosis or abnormal TL1A expression.
  • the corresponding tissue or reference tissue in the control subject comprises or consists of any combination of 2 tissues selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, and/or a tissue (or tissues) without sarcoidosis or abnormal TL1A expression.
  • the corresponding tissue or reference tissue in the control subject comprises or consists of any combination of 3 tissues selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, and/or a tissue (or tissues) without sarcoidosis or abnormal TL1A expression.
  • the corresponding tissue or reference tissue in the control subject comprises or consists of any combination of 4 tissues selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, and/or a tissue (or tissues) without sarcoidosis or abnormal TL1A expression.
  • the corresponding tissue or reference tissue in the control subject comprises or consists of any combination of 5 tissues selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, and/or a tissue (or tissues) without sarcoidosis or abnormal TL1A expression.
  • the corresponding tissue or reference tissue in the control subject comprises or consists of any combination of 6 tissues selected from the group consisting of bronchi, bronchioles, alveolar duct, alveoli, pleura, and/or a tissue (or tissues) without sarcoidosis or abnormal TL1A expression.
  • the fold overproduction of TL1A in the diseased tissue can be determined over a reference level of TL1A instead of over the TL1A level in the corresponding tissue in a control subject without sarcoidosis.
  • a reference level of TL1A can be a specific concentration, a specific unit of TL1A protein, and/or a specific proxy measurement of TL1A.
  • the sarcoidosis in this paragraph can 25746 be sarcoidosis selected from the group consisting of pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichthy
  • the TL1A concentration in the corresponding tissue or the reference tissue used for comparing with a diseased tissue for the TL1A over-production refers to the TL1A concentration in such corresponding tissue or reference tissue at the physiological or basal level of TL1A production under normal healthy conditions, i.e. without sarcoidosis or other disease or conditions (e.g. inflammatory or immunodeficient conditions) that increases or suppresses TL1A production.
  • the corresponding tissue or the reference tissue used herein refer to normal healthy tissues without pathology or stimuli that result in abnormal TL1A production.
  • Such physiological or basal level of TL1A can be the average of TL1A concentrations in the corresponding tissue or the reference tissue during a time period, if the TL1A concentration fluctuates with the normal healthy physiological activity of such tissue during the time period.
  • the period of time used to average the TL1A concentration can be, 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 hours, or 1, 2, 3, 4, 5, 6, 7 days.
  • the reference tissue is also referred to as the normal reference tissue in some descriptions herein for clarity.
  • the subject that is the target for administering the anti-TL1A antibodies or antigen binding fragments in the various methods provided herein can be a subject having sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarc
  • sarcoidosis such as pulmonary
  • the subject that is the target for administering the anti- TL1A antibodies or antigen binding fragments in the various methods provided herein is a patient with a diseased tissue (e.g. as described above) from sarcoidosis (such as pulmonary 25746 sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis,
  • the subject that is the target for administering the anti-TL1A antibodies or antigen binding fragments in the various methods provided herein is a human subject.
  • the subject that is the target for administering the anti-TL1A antibodies or antigen binding fragments in the various methods provided herein is a patient with sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis,
  • the subject that is the target for administering the anti-TL1A antibodies or antigen binding fragments in the various methods provided herein is a patient with ulcerative colitis.
  • the subject that is the target for administering the anti- TL1A antibodies or antigen binding fragments in the various methods provided herein is a patient with Crohn’s disease.
  • the subject that is the target for administering the anti-TL1A antibodies or antigen binding fragments in the various methods provided herein is a patient with both ulcerative colitis and Crohn’s disease.
  • the disclosure provides that the effective dose provided herein for the methods, including in this Section (Section [0456]), can be determined by a dose determination methods as further described in this Section (Section [0456]), including the below paragraphs).
  • a method for determining the effective dose including the induction regimen, the maintenance regimen, and both the induction regimen and the maintenance regimen.
  • a method of determining an effective dose regimen for administering an anti-TL1A antibody comprises: (a) receiving association rate of the antibody to monomeric TL1A (kon-monomer), association rate 25746 of the antibody to trimeric TL1A (kon-trimer), dissociation rate of the antibody from monomeric TL1A (k off-monomer ), dissociation rate of the antibody from trimeric TL1A (k off-trimer ), synthesis rate of TL1A in normal tissue (ksyn-normal), synthesis rate of TL1A in diseased tissue (ksyn- disease ), degradation rate of monomeric TL1A (k deg-monomer ), and degradation rate of trimeric TL1A (kdeg-trimer); (b) integrating the rates received in (a) to an integrated whole-body physiologically based pharmacokinetic (PBPK) model; and (c) determining the effective dose regimen of the anti-TL1A antibody
  • a method of determining an effective dose regimen for administering an anti-TL1A antibody comprises: (a) receiving association rate of the antibody to monomeric TL1A (k on-monomer ), association rate of the antibody to trimeric TL1A (kon-trimer), dissociation rate of the antibody from monomeric TL1A (k off-monomer ), dissociation rate of the antibody from trimeric TL1A (k off-trimer ), synthesis rate of TL1A in normal tissue (ksyn-normal), synthesis rate of TL1A in diseased tissue (ksyn- disease ), degradation rate of monomeric TL1A (k deg-monomer ), and degradation rate of trimeric TL1A (kdeg-trimer); integrating the rates received in (a) to a population pharmacokinetic (popPK) model; and determining the effective dose regimen of the anti-TL1A antibody with the popPK model from (b) such that after administration
  • a method of determining an effective dose regimen for administering an anti-TL1A antibody to a diseased subject comprises: (a) receiving a parameter of TL1A over-production in the diseased tissue comparing to TL1A production in a normal reference tissue; (b) integrating the parameter received in (a) to an integrated whole-body physiologically based pharmacokinetic (PBPK) model; and (c) determining the effective dose regimen of the anti-TL1A antibody with the PBPK model from (b) such that after administration of the effective dose regimen 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 without sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarco
  • sarcoidosis such as pulmonary sarcoidosis
  • the diseased subject has sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichthyosiform
  • sarcoidosis such as
  • a method of determining an effective dose regimen for administering an anti-TL1A antibody to a diseased subject comprises: (a) receiving a parameter of TL1A over-production in the diseased tissue comparing to TL1A production in a normal reference tissue; (b) integrating the parameter received in (a) to a population pharmacokinetic (popPK) model; and (c) determining the effective dose regimen of the anti-TL1A antibody with the popPK model from (b) such that after administration of the effective dose regimen the concentration of TL1A in a diseased tissue in the subject is below the concentration of TL1A in a corresponding tissue in a control 25746 subject without sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, macul
  • sarcoidosis such as pulmonary sarcoidos
  • the diseased subject has sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichthyosiform
  • sarcoidosis such as
  • the parameter of TL1A over-production in the dose determination methods reflects the over-production of TL1A in the diseased tissues in affected patients, e.g. sarcoidosis (such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic sarcoidosis, peritoneal sarcoidosis,
  • the parameter of TL1A over-production 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 or more fold over-production comparing to TL1A production in the normal reference tissue.
  • the parameter of TL1A over-production can be various percentages or folds reflecting the over-production of TL1A in the diseased tissues in affected patients, e.g.
  • sarcoidosis such as pulmonary sarcoidosis, cutaneous sarcoidosis, lupus pernio, papular sarcoidosis, nodular sarcoidosis, Darier-Roussy sarcoidosis, maculopapular sarcoidosis, hypopigmented sarcoidosis, atrophic and ulcerative sarcoidosis, plaque sarcoidosis, angiolupoid sarcoidosis, psoriasiform sarcoidosis, verrucous sarcoidosis, neurologic sarcoidosis, cardiac sarcoidosis, gastrointestinal sarcoidosis, hepatic sarcoidosis, pancreatic 25746 sarcoidosis, peritoneal sarcoidosis, sarcoidosis of bone, sarcoid arthropathy, ichthyosiform sarcoidosis, erythrodermic
  • the parameter of TL1A over-production is up to or about 5 fold over-production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 10 fold over-production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 15 fold over-production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 20 fold over-production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 25 fold over-production comparing to TL1A production in the normal reference tissue.
  • the parameter of TL1A over-production is up to or about 30 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 35 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 40 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 45 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 50 fold over- production comparing to TL1A production in the normal reference tissue.
  • the parameter of TL1A over-production is up to or about 55 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 60 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 65 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 70 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 75 fold over- production comparing to TL1A production in the normal reference tissue.
  • the parameter of TL1A over-production is up to or about 80 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 85 fold over- 25746 production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 90 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 95 fold over- production comparing to TL1A production in the normal reference tissue.
  • the parameter of TL1A over-production is up to or about 100 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 110 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 120 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 130 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 140 fold over- production comparing to TL1A production in the normal reference tissue.
  • the parameter of TL1A over-production is up to or about 150 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 160 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 170 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 180 fold over- production comparing to TL1A production in the normal reference tissue. In one embodiment, the parameter of TL1A over-production is up to or about 190 fold over- production comparing to TL1A production in the normal reference tissue.
  • the parameter of TL1A over-production is up to or about 200 fold over- production comparing to TL1A production in the normal reference tissue.
  • the step (a) in the dose determination methods provided herein including in this Section (Section [0456]) can receive additional parameters, such as the rate of association and dissociation between the anti-TL1A antibodies and TL1A.
  • step (a) further comprises receiving association rate of the antibody to TL1A (k on- mAb), dissociation rate of the antibody from TL1A (koff-mAb), synthesis rate of TL1A in normal tissue (k syn-normal ), synthesis rate of TL1A in diseased tissue (k syn-disease ), and/or degradation rate of TL1A (kdeg-total-TL1A).
  • the association rate of the antibody to 25746 TL1A (kon-mAb) comprises the association rate of the antibody to monomeric TL1A (kon- monomer ) and association rate of the antibody to trimeric TL1A (k on-trimer ).
  • the dissociation rate of the antibody from TL1A comprises the dissociation rate of the antibody from monomeric TL1A (k off-monomer ) and dissociation rate of the antibody from trimeric TL1A (koff-trimer).
  • the degradation rate of TL1A comprises degradation rate of monomeric TL1A (k deg-TL1A-monomer ) and degradation rate of trimeric TL1A (kdeg-TL1A-trimer).
  • the association rate of the antibody to TL1A comprises the association rate of the antibody to monomeric TL1A (k on- monomer) and association rate of the antibody to trimeric TL1A (kon-trimer), and the dissociation rate of the antibody from TL1A (k off-mAb ) comprises the dissociation rate of the antibody from monomeric TL1A (koff-monomer) and dissociation rate of the antibody from trimeric TL1A (koff- trimer ).
  • the association rate of the antibody to TL1A comprises the association rate of the antibody to monomeric TL1A (kon-monomer) and association rate of the antibody to trimeric TL1A (k on-trimer ), and the degradation rate of TL1A (k deg-total-TL1A ) comprises degradation rate of monomeric TL1A (kdeg-TL1A-monomer) and degradation rate of trimeric TL1A (kdeg-TL1A-trimer).
  • the dissociation rate of the antibody from TL1A comprises the dissociation rate of the antibody from monomeric TL1A (koff- monomer) and dissociation rate of the antibody from trimeric TL1A (koff-trimer), and the degradation rate of TL1A (k deg-total-TL1A ) comprises degradation rate of monomeric TL1A (kdeg-TL1A-monomer) and degradation rate of trimeric TL1A (kdeg-TL1A-trimer).
  • the association rate of the antibody to TL1A comprises the association rate of the antibody to monomeric TL1A (kon-monomer) and association rate of the antibody to trimeric TL1A (k on-trimer )
  • the dissociation rate of the antibody from TL1A comprises the dissociation rate of the antibody from monomeric TL1A (koff-monomer) and dissociation rate of the antibody from trimeric TL1A (k off-trimer )
  • the degradation rate of TL1A (k deg-total- TL1A) comprises degradation rate of monomeric TL1A (kdeg-TL1A-monomer) and degradation rate of trimeric TL1A (k deg-TL1A-trimer ).
  • the dose determination methods can include additional parameters of the anti-TL1A antibody binding to proteins other than the TL1A ligand, such as the parameters of the anti-TL1A antibodies or antigen binding fragments binding to FcRn.
  • the step (a) of the dose determination methods further comprises receiving association rate of the antibody to FcRn receptor (kon-mAb-FcRn), dissociation rate of the antibody from FcRn (k off- mAb-FcRn ), association rate of the antibody-monomeric-TL1A complex to FcRn receptor (kon-(mAb-monoTL1A)-FcRn), dissociation rate of the antibody- 25746 monomeric-TL1A complex from FcRn (koff-(mAb-monoTL1A)-FcRn), association rate of the antibody-trimeric-TL1A complex to FcRn receptor (k on-(mAb-triTL1A)-FcRn ), and/or dissociation rate
  • the step (a) of the dose determination methods further comprises receiving association rate of the antibody to FcRn receptor (kon-mAb-FcRn), and/or dissociation rate of the antibody from FcRn (k off- mAb-FcRn ).
  • the step (a) of the dose determination methods further comprises receiving association rate of the antibody- monomeric-TL1A complex to FcRn receptor (k on-(mAb-monoTL1A)-FcRn ), and/or dissociation rate of the antibody-monomeric-TL1A complex from FcRn (koff-(mAb-monoTL1A)-FcRn).
  • the step (a) of the dose determination methods further comprises receiving association rate of the antibody-trimeric-TL1A complex to FcRn receptor (kon-(mAb-triTL1A)- FcRn ), and/or dissociation rate of the antibody-trimeric-TL1A complex from FcRn (k off-(mAb- triTL1A)-FcRn).
  • the step (a) of the dose determination methods further comprises receiving association rate of the antibody-monomeric-TL1A complex to FcRn receptor (kon-(mAb-monoTL1A)-FcRn), dissociation rate of the antibody-monomeric-TL1A complex from FcRn (koff-(mAb-monoTL1A)-FcRn), association rate of the antibody-trimeric-TL1A complex to FcRn receptor (kon-(mAb-triTL1A)-FcRn), and/or dissociation rate of the antibody-trimeric-TL1A complex from FcRn (koff-(mAb-triTL1A)-FcRn).
  • the step (a) of the dose determination methods further comprises receiving association rate of the antibody to FcRn receptor (kon- mAb-FcRn ), dissociation rate of the antibody from FcRn (k off- mAb-FcRn ), association rate of the antibody-TL1A complex to FcRn receptor (kon-(mAb-TL1A)-FcRn), and/or dissociation rate of the antibody-TL1A complex from FcRn (k off-(mAb-TL1A)-FcRn ).
  • the association rate of the antibody- TL1A complex to FcRn receptor comprises association rate of the antibody-monomeric-TL1A complex to FcRn receptor (k on-(mAb- monoTL1A)-FcRn) and association rate of the antibody-trimeric-TL1A complex to FcRn receptor (k on-(mAb-triTL1A)-FcRn ).
  • the dissociation rate of the antibody- TL1A complex from FcRn comprises dissociation rate of the antibody- monomeric-TL1A complex from FcRn (k off-(mAb-monoTL1A)-FcRn ) and dissociation rate of the antibody-trimeric-TL1A complex from FcRn (koff-(mAb-triTL1A)-FcRn).
  • the association rate of the antibody- TL1A complex to FcRn receptor comprises association rate of the antibody-monomeric-TL1A complex to FcRn receptor (kon- (mAb-monoTL1A)-FcRn ) and association rate of the antibody-trimeric-TL1A complex to FcRn receptor (kon-(mAb-triTL1A)-FcRn), and/or wherein the dissociation rate of the antibody- TL1A 25746 complex from FcRn (koff-(mAb-TL1A)-FcRn) comprises dissociation rate of the antibody- monomeric-TL1A complex from FcRn (k off-(mAb-monoTL1A)-FcRn ) and dissociation rate of the antibody-trimeric-TL1A complex from FcRn (koff-(mAb-triTL1A)-FcRn).
  • the dose determination methods can include additional parameters such as the parameters of degradation rate of the complex between the anti-TL1A antibodies or antigen binding fragments and FcRn.
  • the step (a) of the dose determination methods further comprises receiving clearance rate of FcRn receptor bound by the antibody (k deg-mAb-FcRn ).
  • the clearance rate of FcRn receptor bound by the antibody further comprises clearance rate of the antibody to FcRn bound by the antibody-monomeric-TL1A complex (k deg-(mAb-monoTL1A)-FcRn ) and clearance rate of FcRn receptor bound by the antibody-trimeric-TL1A complex (kdeg-(mAb-triTL1A)-FcRn).
  • the step (a) of the dose determination methods further comprises receiving clearance rate of FcRn receptor bound by the antibody (k deg-mAb-FcRn ), clearance rate of the antibody to FcRn bound by the antibody-monomeric- TL1A complex (kdeg-(mAb-monoTL1A)-FcRn), and/or clearance rate of FcRn receptor bound by the antibody-trimeric-TL1A complex (kdeg-(mAb-triTL1A)-FcRn). In one embodiment, the step (a) of the dose determination methods further comprises receiving clearance rate of FcRn receptor bound by the antibody (kdeg-mAb-FcRn).
  • the step (a) of the dose determination methods further comprises receiving clearance rate of the antibody to FcRn bound by the antibody-monomeric-TL1A complex (kdeg-(mAb-monoTL1A)-FcRn). In one embodiment, the step (a) of the dose determination methods further comprises receiving clearance rate of FcRn receptor bound by the antibody-trimeric-TL1A complex (kdeg-(mAb- triTL1A)-FcRn ).
  • the step (a) of the dose determination methods further comprises receiving clearance rate of FcRn receptor bound by the antibody (kdeg-mAb-FcRn) and clearance rate of the antibody to FcRn bound by the antibody-monomeric-TL1A complex (kdeg-(mAb-monoTL1A)-FcRn). In one embodiment, the step (a) of the dose determination methods further comprises receiving clearance rate of FcRn receptor bound by the antibody (k deg-mAb- FcRn) and clearance rate of FcRn receptor bound by the antibody-trimeric-TL1A complex (k deg-(mAb-triTL1A)-FcRn ).
  • the step (a) of the dose determination methods further comprises receiving clearance rate of the antibody to FcRn bound by the antibody- monomeric-TL1A complex (k deg-(mAb-monoTL1A)-FcRn ) and clearance rate of FcRn receptor bound by the antibody-trimeric-TL1A complex (kdeg-(mAb-triTL1A)-FcRn).
  • the step (a) of the dose determination methods further comprises receiving clearance rate of FcRn receptor bound by the antibody (kdeg-mAb-FcRn), clearance rate of the antibody to FcRn 25746 bound by the antibody-monomeric-TL1A complex (kdeg-(mAb-monoTL1A)-FcRn), and clearance rate of FcRn receptor bound by the antibody-trimeric-TL1A complex (k deg-(mAb-triTL1A)-FcRn ).
  • the step (a) in the dose determination methods further comprises receiving the rate of TL1A trimerization (kon-TL1A- monomer-to-trimer ) and/or the rate of TL1A monomerization (k off-TL1A-trimer-to-monomer ). In one embodiment, the step (a) in the dose determination methods further comprises receiving the rate of TL1A trimerization (k on-TL1A-monomer-to-trimer ).
  • the step (a) in the dose determination methods further comprises receiving the rate of TL1A monomerization (k off-TL1A-trimer-to-monomer ). In yet another embodiment, the step (a) in the dose determination methods further comprises receiving the rate of TL1A trimerization (kon-TL1A-monomer-to-trimer) and the rate of TL1A monomerization (k off-TL1A-trimer-to-monomer ). [0483] The term rate of TL1A trimerization refers to the kinetic rate at which TL1A monomers self-associate to form TL1A trimer.
  • the term rate of TL1A monomerization refers to the kinetic rate at which TL1A trimer dissociates into TL1A monomers.
  • the various parameters in the dose determination methods can be identical or different.
  • the various parameters in the dose determination methods can also be related by a range, a fold difference in value, and/or by a specific difference in value.
  • k on-monomer and k on-trimer are identical or different.
  • k off-monomer and k off-trimer are identical or different.
  • kdeg-monomer and kdeg-trimer are identical or different.
  • kon-(mAb-monoTL1A)-FcRn and kon-(mAb-triTL1A)-FcRn are identical or different.
  • k on-mAb-FcRn and k on-(mAb-monoTL1A)- FcRn are identical or different.
  • k on-mAb-FcRn and k on-(mAb-triTL1A)-FcRn are identical or different.
  • koff-(mAb-monoTL1A)- FcRn and k off-(mAb-triTL1A)-FcRn are identical or different. In one embodiment of the various dose determination methods provided herein, koff- mAb-FcRn and koff-(mAb-monoTL1A)-FcRn are identical or different. In one embodiment of the various dose determination methods provided herein, koff- mAb-FcRn and koff-(mAb-triTL1A)-FcRn are identical or different.
  • k deg-(mAb-monoTL1A)-FcRn and k deg-(mAb- triTL1A)-FcRn are identical or different.
  • kdeg-mAb-FcRn and kdeg-(mAb-triTL1A)-FcRn are identical or different.
  • k deg-mAb-FcRn and kdeg-(mAb-monoTL1A)-FcRn are identical or different.
  • the parameters received in the dose determination methods can have any combination of the relationship as described herein, including in this paragraph.
  • the diseased tissue overproduces TL1A than a normal tissue.
  • the diseased tissue overproduces TL1A comparing to normal reference tissue and the parameter of TL1A over-production can 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 or more fold over-production comparing to TL1A production in the normal reference tissue.
  • the k syn-disease can be higher than k syn-normal by various percentages or folds.
  • ksyn-disease is up to or about 5, 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, or more fold of ksyn-normal.
  • ksyn-disease is up to or about 5 fold of ksyn-normal.
  • ksyn-disease is up to or about 10 fold of ksyn- normal.
  • ksyn-disease is up to or about 15 fold of k syn-normal . In one embodiment of the dose determination methods, k syn-disease is up to or about 20 fold of ksyn-normal. In one embodiment of the dose determination methods, ksyn-disease is up to or about 25 fold of k syn-normal . In one embodiment of the dose determination methods, ksyn-disease is up to or about 30 fold of ksyn-normal. In one embodiment of the dose determination methods, k syn-disease is up to or about 35 fold of k syn-normal .
  • ksyn-disease is up to or about 40 fold of ksyn-normal. In one embodiment of the dose determination methods, k syn-disease is up to or about 45 fold of k syn-normal . In one embodiment of the dose determination methods, ksyn-disease is up to or about 50 fold of ksyn- normal . In one embodiment of the dose determination methods, k syn-disease is up to or about 55 fold of ksyn-normal. In one embodiment of the dose determination methods, ksyn-disease is up to or about 60 fold of k syn-normal .
  • k syn-disease is up to or about 65 fold of ksyn-normal. In one embodiment of the dose determination methods, k syn-disease is up to or about 70 fold of k syn-normal . In one embodiment of the dose determination methods, ksyn-disease is up to or about 75 fold of ksyn-normal. In one embodiment of the dose determination methods, k syn-disease is up to or about 80 fold of k syn-normal . In one embodiment of the dose determination methods, ksyn-disease is up to or about 85 fold of ksyn-normal.

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Abstract

Des anticorps anti-TL1A humanisés et des compositions pharmaceutiques pour le traitement de la sarcoïdose sont décrits dans la présente invention.
EP24767755.2A 2023-03-09 2024-03-06 Compositions d'anticorps anti-tl1a et méthodes de traitement de la sarcoïdose Pending EP4676971A2 (fr)

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EP2555783A1 (fr) * 2010-04-08 2013-02-13 Anthrogenesis Corporation Traitement de la sarcoïdose au moyen de cellules souches du sang placentaire
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