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WO2024173865A2 - Compositions d'anticorps anti-tl1a et méthodes de traitement rénales - Google Patents

Compositions d'anticorps anti-tl1a et méthodes de traitement rénales Download PDF

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Publication number
WO2024173865A2
WO2024173865A2 PCT/US2024/016264 US2024016264W WO2024173865A2 WO 2024173865 A2 WO2024173865 A2 WO 2024173865A2 US 2024016264 W US2024016264 W US 2024016264W WO 2024173865 A2 WO2024173865 A2 WO 2024173865A2
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WIPO (PCT)
Prior art keywords
dose
antibody
weeks
fcrn
tlia
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PCT/US2024/016264
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WO2024173865A3 (fr
Inventor
Allison LUO
Olivier Laurent
Janine Bilsborough
Bradley Henkle
Stephan R. Targan
Dermot P. Mcgovern
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Cedars Sinai Medical Center
Prometheus Biosciences Inc
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Cedars Sinai Medical Center
Prometheus Biosciences Inc
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Publication of WO2024173865A2 publication Critical patent/WO2024173865A2/fr
Publication of WO2024173865A3 publication Critical patent/WO2024173865A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • 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
    • 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
    • C07K2317/70—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
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • 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
    • C07K2317/90—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

  • TL1 A is a cytokine that is secreted by antigen-presenting cells, T cells, 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 Thl, Th2, Th9 and Thl7 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 Thl, Th2, Th9 and Thl7 responses.
  • TLR toll like receptor
  • FcR FcR cross-linking
  • T cells T cell receptor
  • TL1 A has been shown to be upregulated in mucosa and serum of patients with inflammatory bowel disease.
  • DSS dextran sodium sulfate
  • TL1 A led to reduced inflammation and reversal of fibrosis, even when treatment was administered late in the course of disease, after inflammation and fibrosis has been established.
  • the present disclosure provides tumor necrosis factor ligand 1A (TL1 A) binding antibodies or antigen binding fragments thereof and compositions thereof for the treatment of inflammation and/or fibrosis, including diseases or conditions that present in the kidney of a subject.
  • T1 A tumor necrosis factor ligand 1A
  • antibodies or antigen binding fragments thereof described herein possess features useful for therapeutic application such as low immunogenicity, and/or features that facilitate antibody or antigen binding fragmentmanufacture, such as high percentage of monomeric fraction as measured by size-exclusion chromatography, and/or high expression.
  • antibodies or antigen binding fragments thereof described herein possess features useful for subcutaneous administration, such as low viscosity at high antibody or antigen binding fragment concentration.
  • antibodies or antigen binding fragments thereof and their formulations may include high solubility, low subvisible particles, low opalescence, no visible particulates, and any combination thereof.
  • a method of treating inflammation in a subject in need thereof comprising administering to the subject an antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1 A (anti-TLl A antibody or antigen binding fragment).
  • the subject has inflammation in the kidney.
  • a method of treating fibrosis in a subject in need thereof comprising administering to the subject an antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1 A (anti-TLl A antibody or antigen binding fragment).
  • the subject has fibrosis in the kidney.
  • a method of treating a disease and/or condition of the kidney 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 1 A (anti-TLl A antibody or antigen binding fragment).
  • the subject has a chronic kidney disorder.
  • the subject has end stage renal disease.
  • the subject has tubulointerstitial renal fibrosis.
  • the subject has nephritis.
  • the subject has diabetic kidney disease.
  • the subject has polycystic kidney disease.
  • the subject has end-stage renal disease, tubulointerstitial renal fibrosis, glomerulonephritis, interstitial nephritis, IgA nephropathy, acute interstitial nephritis, diabetic kidney diseases, lupus nephritis, Alport syndrome, or polycystic kidney disease, or a combination thereof.
  • the anti-TLl A antibody or antigen binding fragment is administered in a pharmaceutical composition.
  • the pharmaceutical composition comprises the anti-TLl A antibody or antigen binding fragment at a concentration greater than about 150 mg/mL.
  • the concentration is greater than about 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg/mL.
  • the concentration is about 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, or 225 mg/mL.
  • the concentration is about 150 mg/mL to about 250 mg/mL.
  • the concentration is about 175 mg/mL to about 225 mg/mL.
  • a pharmaceutical composition comprising an antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1A (anti-TLl A antibody or antigen binding fragment) at a concentration greater than about 50 mg/mL.
  • the concentration is greater than about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, or 145 mg/mL.
  • the concentration is about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, or 145 mg/mL.
  • the pharmaceutical composition is administered subcutaneously. In some embodiments, about 150 mg to about 500 mg of the anti-TLIA antibody or antigen binding fragment is present in the composition. In some embodiments, the composition has a total volume of less than or equal to about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, ,6.5, 7, 7.5, 8, 8.5, or 9 mL. In some embodiments, the pharmaceutical composition comprises a therapeutically effective dose of the anti-TLIA antibody or antigen binding fragment. In some embodiments, the composition has a total volume 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,
  • the composition has a total volume of about 0.5 mL to about 1.5 mL. In some embodiments, a composition herein has a total volume of about 0.5 mL to about 2.5 mL. In some embodiments, a composition herein has a total volume of about 0.5 mL to about 3.5 mL. In some embodiments, a composition herein has a total volume of about 0.5 mL to about 4.5 mL. In some embodiments, a composition herein has a total volume of about 1 mL to about 1.5 mL.
  • a composition herein has a total volume of about 1 mL to about 2.5 mL. In some embodiments, a composition herein has a total volume of about 1 mL to about 3.5 mL. In some embodiments, a composition herein has a total volume of about 1 mL to about 4.5 mL. In some embodiments, the composition has a viscosity of less than about 20 cP. In some embodiments, the composition has a viscosity of less than about 15 cP. In some embodiments, the composition has a viscosity of less than about 10 cP. In some embodiments, the composition has a viscosity of less than about 9, 8, 7, 6, or 5 cP.
  • the composition has a viscosity of about 1 cP to about 7 cP, about 1 cP to about 2 cP, or about 10 cP to about 20 cP. In some embodiments, the composition has a viscosity of about 1 cP to about 10 cP. In some embodiments, the composition has a viscosity of about 1 cP to about 15 cP. In some embodiments, the composition has a viscosity of about 1 cP to about 20 cP.
  • the pharmaceutical composition has a percentage aggregation of anti-TLIA antibody or antigen binding fragment as measured by size exclusion chromatography of less than about 5% of the total anti-TLIA antibody or antigen binding fragment in the composition. In some embodiments, the aggregation is less than about 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5%.
  • the composition comprises a surfactant. In some embodiments, the surfactant comprises a nonionic surfactant. In some embodiments, the nonionic surfactant comprises polysorbate-20. In some embodiments, the surfactant is present at a concentration of about 0.005% to about 0.05% of the composition.
  • the surfactant is present at a concentration of about 0.01% to about 0.02% of the composition. In some embodiments, the surfactant is present at a concentration of about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about 0.014%, about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, about 0.02%, about 0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.025%, about 0.026%, about 0.027%, about 0.028%, about 0.029%, or about 0.03% (v/v) of the composition.
  • the composition comprises a salt.
  • the salt comprises sodium chloride, glycine, lysine-hydrochloride, arginine-hydrochloride, arginine glutamate, potassium chloride, magnesium chloride, or calcium chloride, or a combination thereof.
  • the salt comprises sodium chloride.
  • the salt comprises lysine-HCl.
  • the salt is present at a concentration of about 10 mM to about 100 mM in the composition.
  • the salt is present at a concentration of about 25 mM in the composition.
  • the salt is present at a concentration of about 40 mM in the composition.
  • the composition comprises a stabilizer.
  • the stabilizer comprises a sugar, polyol, amino acid, or polymer, cyclodextrin (e.g., HP-b-CD), or a combination thereof.
  • the stabilizer comprises the sugar.
  • the sugar comprises sucrose, glucose, trehalose, maltose, or lactose, or a combination thereof.
  • the sugar comprises sucrose.
  • the amino acid comprises glycine.
  • the stabilizer is present at a concentration of about 50 mM to about 300 mM in the composition. In some embodiments, the stabilizer is present at a concentration of about 200 mM to about 280 mM.
  • the stabilizer is present at a concentration of about 220 to about 240 mM. In certain embodiments, the stabilizer is present at a concentration of about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM, or about 250 mM. In some embodiments, the stabilizer comprises sucrose and glycine.
  • the sucrose is present at a concentration of about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 210 M, about 220 M, about 230 M, about 240 mM, or about 250 mM.
  • the glycine is present at a concentration of about 10 mM, about 15 m , about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, about 100 mM, about 105 mM, about 110 mM, about 115 mM, or about 120 mM.
  • the composition comprises a buffering agent.
  • the buffering agent comprises acetate, phosphate, citrate, glutamate, succinate, gluconate, histidine, glycylglycine, citric acid, Tris (tris (hydroxymethyl) aminomethane), or diethanolamine, or a combination thereof.
  • the buffering agent comprises acetate.
  • the buffering agent comprises phosphate.
  • the buffering agent is present at a concentration of about 10 mM to about 50 mM in the composition.
  • the composition comprises about 20 mM buffer.
  • the composition has a pH of about 4.5 to about 8.0.
  • the composition has a pH of about 4.5 to about 7.5.
  • the composition has a pH of about 6 to about 7. In some embodiments, the composition has a pH of about 6.5. In some embodiments, the composition has a pH of about 5 to about 5.5. In some embodiments, the composition has a pH of about 5.3.
  • the anti-TLl A antibody or antigen binding fragment is administered to the subject at a first dose up to about 1000 mg. In some embodiments, the anti-TLl A antibody or antigen binding fragment is administered to the subject at a first dose of about 150 mg to about 1000 mg. In some embodiments, the first dose is about 500 mg to about 1000 mg. In some embodiments, the first dose is about 500 mg or about 800 mg. In some embodiments, the first dose is administered to the subject at a first time point, and a second dose is administered to the subject at a second time point.
  • the second time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the first time point. In some embodiments, the second time point is about 1, 2, 3, or 4 weeks after the first time point. In some embodiments, the second dose comprises up to about 1000 mg anti-TLl A antibody or antigen binding fragment. In some embodiments, the second dose comprises about 150 mg to about 1000 mg. In some embodiments, the second dose comprises about 150 mg to about 600 mg. In some embodiments, a third dose of anti-TLl A antibody or antigen binding fragment is administered to the subject at a third time point.
  • the third time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the second time point. In some embodiments, the third time point is about 1, 2, 3, or 4 weeks after the second time point. In some embodiments, the third dose comprises up to about 1000 mg anti-TLl A antibody or antigen binding fragment. In some embodiments, the third dose comprises about 150 mg to about 1000 mg. In some embodiments, the third dose comprises about 150 mg to about 600 mg. In some embodiments, a fourth dose of anti-TLl A antibody or antigen binding fragment is administered to the subject at a fourth time point.
  • the fourth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the third time point. In some embodiments, the fourth time point is about 1, 2, 3, or 4 weeks after the third time point. In some embodiments, the fourth dose comprises up to about 1000 mg anti-TLl A antibody or antigen binding fragment. In some embodiments, the fourth dose comprises about 150 mg to about 1000 mg. In some embodiments, the fourth dose comprises about 150 mg to about 600 mg. In some embodiments, a fifth dose of anti-TLl A antibody or antigen binding fragment is administered to the subject at a fifth time point.
  • the fifth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the fourth time point. In some embodiments, the fifth time point is about 1, 2, 3, or 4 weeks after the fourth time point. In some embodiments, the fifth dose comprises up to about 1000 mg anti-TLl A antibody or antigen binding fragment. In some embodiments, the fifth dose comprises about 150 mg to about 1000 mg. In some embodiments, the fifth dose comprises about 150 mg to about 600 mg. In some embodiments, a sixth dose of anti-TLl A antibody or antigen binding fragment is administered to the subject at a sixth time point.
  • the sixth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the fifth time point. In some embodiments, the sixth time point is about 1, 2, 3, or 4 weeks after the fifth time point. In some embodiments, the sixth dose comprises up to about 1000 mg anti-TLIA antibody or antigen binding fragment. In some embodiments, the sixth dose comprises about 150 mg to about 1000 mg. In some embodiments, the sixth dose comprises about 150 mg to about 600 mg.
  • an additional dose of the anti-TLIA antibody or antigen binding fragment is administered to the subject at one or more additional time points.
  • the one or more additional time points comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 additional time points.
  • the composition is administered to the subject at about 12 additional time points.
  • each additional time point is independently about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after a previous time point.
  • each additional time point is independently about 1, 2, 3, or 4 weeks after a previous time point.
  • the additional dose comprises up to about 1000 mg anti-TLl A antibody or antigen binding fragment. In some embodiments, the additional dose comprises from about 150 mg to about 1000 mg anti-TLIA antibody or antigen binding fragment. In some embodiments, the additional dose is about 175 mg to about 300 mg anti-TLIA antibody or antigen binding fragment.
  • an antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1 A (“TL1 A,” and such antibody or antigen binding fragment thereof, “anti-TLIA antibody or antigen binding fragment”), wherein the antibody or antigen binding fragment binds to both monomeric TL1A and trimeric TL1A.
  • the antibody or antigen binding fragment blocks interaction of TL1 A to Death Receptor 3 (“DR3”).
  • the binding affinity of the antibody or antigen binding fragment to monomeric TL1 A as measured by dissociation equilibrium constant (Ko-monomer) is comparable to binding affinity of the antibody or antigen binding fragment to trimeric TL1 A as measured by dissociation equilibrium constant (Ko-trimer).
  • the KD -monomer is within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold of the KD -trim er.
  • the KD -monomer is no more than 0.06 nM.
  • the Ko-trimer is no more than 0.06 nM.
  • a method of neutralizing monomeric TL1A and trimeric TL1 A in a subject having kidney inflammation and/or kidney fibrosis comprising (a) administering an effective dose of anti-TLIA antibody or antigen binding fragment to the subject, wherein the antibody or antigen binding fragment binds to both monomeric TL1 A and trimeric TL1A, wherein the antibody or antigen binding fragment blocks interaction of TL1 A to DR3, wherein the concentration of TL1 A in a diseased tissue in the subject is reduced below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis, and wherein diseased tissue comprises any one or more selected from the group consisting of renal cortex, renal medulla, renal pyramid, renal column, renal papilla, nephron, renal corpuscle, Bowman’s capsule, glomerulus, a fibrotic tissue in the kidney, other tissues with kidney inflammation and/or kidney fibrosis, and
  • the subject has one or more inflammatory conditions selected from the group consisting of a chronic kidney disorder, end stage renal disease, tubulointerstitial renal fibrosis, nephritis, diabetic kidney disease, and polycystic kidney disease.
  • the subject has glomerulonephritis, interstitial nephritis, IgA nephropathy, acute interstitial nephritis, lupus nephritis, or Alport syndrome, pyelonephritis, or a combination thereof.
  • a method of reducing the concentration of TL1 A in a diseased tissue in a subject with kidney inflammation and/or kidney fibrosis comprising (a) administering an effective dose of anti-TLl A antibody or antigen binding fragment to the subject, thereby reducing the concentration of TL1 A in the diseased tissue in the subject below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis, wherein diseased tissue comprises any one or more selected from the group consisting of renal cortex, renal medulla, renal pyramid, renal column, renal papilla, nephron, renal corpuscle, Bowman’s capsule, glomerulus, a fibrotic tissue in the kidney, other tissues with kidney inflammation and/or kidney fibrosis, and other tissues of pathogenesis for the kidney inflammation and/or kidney fibrosis.
  • a method of treating kidney inflammation and/or kidney fibrosis in a subject in need thereof comprising (a) administering an anti-TLl A antibody or antigen binding fragment to the subject, wherein the anti-TLl A antibody or antigen binding fragment is administered at an effective dose such that the concentration of TL1 A in a diseased tissue in the subject after step (a) is below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis, and wherein diseased tissue comprises any one or more selected from the group consisting of renal cortex, renal medulla, renal pyramid, renal column, renal papilla, nephron, renal corpuscle, Bowman’s capsule, glomerulus, a fibrotic tissue in the kidney, other tissues with kidney inflammation and/or kidney fibrosis, and other tissues of pathogenesis for the kidney inflammation and/or kidney fibrosis.
  • kidney inflammation and/or kidney fibrosis in a subject in need thereof comprising (a) administering an anti-TLIA antibody or antigen binding fragment to the subject at an effective dose, and (b) reducing the concentration of TL1 A in a diseased tissue in the subject below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis, wherein diseased tissue comprises any one or more selected from the group consisting of renal cortex, renal medulla, renal pyramid, renal column, renal papilla, nephron, renal corpuscle, Bowman’s capsule, glomerulus, a fibrotic tissue in the kidney, other tissues with kidney inflammation and/or kidney fibrosis, and other tissues of pathogenesis for the kidney inflammation and/or kidney fibrosis.
  • the effective dose comprises an induction regimen.
  • the method further comprises (c) maintaining TL1 A in the diseased tissue in the subject at a concentration below the concentration of TL1 A in the corresponding tissue in the control subject.
  • the TL1 A in the diseased tissue in the subject is maintained with a maintenance regimen of the anti-TLIA 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 TL1 A 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 TL1 A 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 TL1 A compared to the corresponding tissue in the control subject.
  • the induction regimen comprises a one-time administration of the anti-TLIA antibody or antigen binding fragment.
  • the anti- TLIA antibody or antigen binding fragment is administered at 200 mg/dose, 250 mg/dose, 300 mg/dose, 350 mg/dose, 400 mg/dose, 450 mg/dose, 500 mg/dose, 550 mg/dose, 600 mg/dose, 650 mg/dose, 700 mg/dose, 750 mg/dose, 800 mg/dose, 850 mg/dose, 900 mg/dose, 950 mg/dose, 1000 mg/dose, 1100 mg/dose, 1200 mg/dose, 1250 mg/dose, 1300 mg/dose, 1400 mg/dose, 1500 mg/dose, 1600 mg/dose, 1700 mg/dose, 1750 mg/dose, 1800 mg/dose, 1900 mg/dose, or 2000 mg/dose.
  • the induction regimen comprises multiple administrations of the anti-TLIA 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 on week 10.
  • 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 TL1 A 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 TL1 A 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 TL1 A 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-TLl A antibody or antigen binding fragment.
  • the maintenance regimen comprises administrations of the anti-TLIA 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 dose every 2 weeks, and (iii)
  • the maintenance regimen comprises administration of the anti-TLl A antibody or antigen binding fragment at 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 mg/dose. In some embodiments, the maintenance regimen comprises administration of the anti-TLl A antibody or antigen binding fragment once every 2, 4, 6, 8, 10, or 12 weeks. In some embodiments, the maintenance regimen comprises administrations of the anti-TLl A antibody or antigen binding fragment at 250 mg/dose every 4 weeks. In some embodiments, the maintenance regimen comprises administrations of the anti-TLl A antibody or antigen binding fragment at 100 mg/dose every 4 weeks. In some embodiments, 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 TL1 A and trimeric TL1 A and wherein the antibody or antigen binding fragment blocks binding of TL1 A 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-TLIA 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-TLIA antibody or antigen binding fragment.
  • the binding affinity of the antibody or antigen binding fragment to monomeric TL1A as measured by dissociation equilibrium constant (Ko-monomer) is comparable to binding affinity of the antibody or antigen binding fragment to trimeric TL1A as measured by dissociation equilibrium constant (Ko-trimer).
  • the KD -monomer is within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold of the Ko-trimer.
  • the KD -monomer is no more than 0.06 nM. In some embodiments, the KD -trimer is no more than 0.06 nM.
  • the subject has one or more inflammatory conditions selected from the group consisting of a chronic kidney disorder, end stage renal disease, tubulointerstitial renal fibrosis, nephritis, diabetic kidney disease, and polycystic kidney disease.
  • the subject has glomerulonephritis, interstitial nephritis, IgA nephropathy, acute interstitial nephritis, lupus nephritis, or Alport syndrome, pyelonephritis, or a combination thereof.
  • 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 TL1 A over-production in the diseased tissue comparing to TL1 A 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 TL1 A in diseased tissue in the subject after step (a) is below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis.
  • PBPK physiologically based pharmacokinetic
  • popPK population pharmacokinetic model
  • the parameter of TL1 A 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 maintenance regimen is determined by a dose determination method, wherein the dose determination method comprises: (i) receiving a parameter of TL1 A over-production in the diseased tissue comparing to TL1 A 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 TL1 A in diseased tissue in the subject after step (c) is below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis.
  • PBPK integrated 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 (k on -mAb), dissociation rate of the antibody from TL1 A (koff-mAb), synthesis rate of TL1 A in normal tissue (k S yn-normai), synthesis rate of TL1 A in diseased tissue (k sy n-disease), and/or degradation rate of TL1 A (kdeg- totai-TLiA).
  • 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 (k on -trimer), wherein the dissociation rate of the antibody from TL1A (koff-mAb) comprises the dissociation rate of the antibody from monomeric TL1 A (k o ff-monomer) and dissociation rate of the antibody from trimeric TL1 A (k o ff- trimer), and/or wherein the degradation rate of TL1A (kdeg-totai-TLiA) comprises degradation rate of monomeric TL1 A (kdeg-TLiA-monomer) and degradation rate of trimeric TL1 A (kdeg-TLiA-trimer).
  • 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- TL1 A complex to FcRn receptor (k on -(mAb-TLiA)-FcRn), and/or dissociation rate of the antibody- TL1 A complex from FcRn (koff-(mAb-TLiA)-FcRn).
  • the association rate of the antibody- TL1 A complex to FcRn receptor comprises association rate of the antibody-monomeric-TLl A complex to FcRn receptor (k on -(mAb-monoTLiA)-FcRn) and association rate of the antibody-trimeric-TLl A complex to FcRn receptor (kon-(mAb-triTLiA)- FcRn), and/or wherein the dissociation rate of the antibody- ILIA complex from FcRn (k o ff- (mAb-TLi A)-FcRn) comprises dissociation rate of the antibody-monomeric-TLIA complex from FcRn (koff-(mAb-monoTLiA)-FcRn) and dissociation rate of the antibody-trimeric-TLl A complex from FcRn (koff-(mAb-triTLlA)-FcRn).
  • the step (i) in the dose determination method 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 (kdeg-mAb-FcRn) comprises clearance rate of the antibody to FcRn bound by the antibody-monomeric-TLIA complex (kdeg-(mAb-monoTLiA)-FcRn) and clearance rate of FcRn receptor bound by the antibody- trimeric-TLl A complex (kdeg-(mAb-triTLiA)-FcRn).
  • 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-monoTLlA)-FcRn and k O n-(mAb-triTLiA FcRn are identical or different; (5) kon-mAb-FcRn and kon- (mAb-monoTLiA>FcRn are identical or different; (6) kon-mAb-FcRn and kon-(mAb-triTLiA)-FcRn are identical or different; (7) k o ff-(mAb-monoTLiA)-FcRn and k o ff-(mAb-triTLiA)-FcRn are identical or different; (8) k o ff- mAb-FcRn and koff-(m
  • k sy n-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 k S yn-normai.
  • the step (i) in the dose determination method further comprises receiving rate of TL1 A trimerization (k on -TLiA- monomer-to-trimer ) and/or rate of TL1 A monomerization (k o ff-TLiA-trimer-to-monomer).
  • a method of determining an effective dose regimen for administering an anti-TLl A antibody to a subject having kidney inflammation and/or kidney fibrosis comprises: (a) receiving a parameter of TL1 A 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-TLl A antibody with the PBPK model from (b) such that after administration of the effective dose regimen the concentration of TL1 A in a diseased tissue in the subject having kidney inflammation and/or kidney fibrosis is below the concentration of TL1A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis, wherein the diseased tissue comprises any one or more selected from the group consisting of renal cortex, renal medulla, renal pyramid, renal column, renal papilla
  • a method of determining an effective dose regimen for administering an anti-TLl A antibody to a subject having kidney inflammation and/or kidney fibrosis comprises: (a) receiving a parameter of TL1 A 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-TLIA antibody with the popPK model from (b) such that after administration of the effective dose regimen the concentration of TL1 A in a diseased tissue in the subject having kidney inflammation and/or kidney fibrosis is below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis, wherein the diseased tissue comprises any one or more selected from the group consisting of renal cortex, renal medulla, renal pyramid, renal column, renal papilla, nephron,
  • the parameter of TL1 A 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 (k on -mAb), dissociation rate of the antibody from TL1A (k o ff-mAb), synthesis rate of TL1 A in normal tissue (k S yn-normai), synthesis rate of TL1 A in diseased tissue (k sy n- disease), and/or degradation rate of TL1 A (kdeg-totai-TLiA).
  • the association rate of the antibody to TL1 A comprises the association rate of the antibody to monomeric TL lA (k on-monomer ) and association rate of the antibody to trimeric TL1 A (k on -trimer), wherein the dissociation rate of the antibody from TL1 A (k o ff-mAb) comprises the dissociation rate of the antibody from monomeric TL1A (k o ff-monomer) and dissociation rate of the antibody from trimeric TL1 A (k o ff-trimer), and/or wherein the degradation rate of TL1 A (kdeg-totai-TLiA) comprises degradation rate of monomeric TL1A (kdeg-TLiA -monomer ) and degradation rate of trimeric TL1A (kdeg-TLiA-trima-).
  • the step (a) comprises receiving association rate of the antibody to FcRn receptor (k on -mAb-FcRn), dissociation rate of the antibody from FcRn (k o ff- mAb-FcRn), association rate of the antibody- TL1 A complex to FcRn receptor (k on -(mAb-TLiA)-FcRn), and/or dissociation rate of the antibody- TL1 A complex from FcRn (koff-(mAb-TLiA)-FcRn).
  • the association rate of the antibody- TL1 A complex to FcRn receptor comprises association rate of the antibody-monomeric-TLl A complex to FcRn receptor (k on -(mAb-monoTLiA)-FcRn) and association rate of the antibody-trimeric-TLl A complex to FcRn receptor (k on -(mAb-triTLiA)- FcRn), and/or wherein the dissociation rate of the antibody- ILIA complex from FcRn (k o ff- (mAb-TLi A)-FcRn) comprises dissociation rate of the antibody-monomeric-TLIA complex from FcRn (koff-(mAb-monoTLiA)-FcRn) and dissociation rate of the antibody-trimeric-TLl A complex from FcRn (koff-(mAb-triTLlA)-
  • 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 (kdeg-mAb-FcRn) further comprises clearance rate of the antibody to FcRn bound by the antibody-monomeric-TLIA complex (kdeg-(mAb-monoTLiA)-FcRn) and clearance rate of FcRn receptor bound by the antibody-trimeric-TLl A complex (kdeg-(mAb-triTLiA)-FcRn).
  • the subject has one or more inflammatory conditions selected from the group consisting of a chronic kidney disorder, end stage renal disease, tubulointerstitial renal fibrosis, nephritis, diabetic kidney disease, and polycystic kidney disease.
  • the subject has glomerulonephritis, interstitial nephritis, IgA nephropathy, acute interstitial nephritis, lupus nephritis, or Alport syndrome, pyelonephritis, or a combination thereof.
  • k sy n-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-TLIA antibody or antigen binding fragment. In some embodiments of the dose determination methods, the effective dose regimen comprises a maintenance regimen of the anti-TLIA antibody or antigen binding fragment. In some embodiments of the dose determination methods, the induction regimen and the maintenance regimen are identical. In some embodiments of the dose determination methods, the induction regimen and the maintenance regimen are different. In some embodiments of the dose determination methods, 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 TL1 A compared to the corresponding tissue in the control subject during the induction regimen. In some embodiments of the dose determination methods, the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1 A 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 of the dose determination methods, the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1 A compared to the corresponding tissue in the control subject.
  • the induction regimen comprises a one-time administration of the anti-TLIA antibody or antigen binding fragment.
  • the anti-TLIA antibody or antigen binding fragment is administered at 200 mg/dose, 250 mg/dose, 300 mg/dose, 350 mg/dose, 400 mg/dose, 450 mg/dose, 500 mg/dose, 550 mg/dose, 600 mg/dose, 650 mg/dose, 700 mg/dose, 750 mg/dose, 800 mg/dose, 850 mg/dose, 900 mg/dose, 950 mg/dose, 1000 mg/dose, 1100 mg/dose, 1200 mg/dose, 1250 mg/dose, 1300 mg/dose, 1400 mg/dose, 1500 mg/dose, 1600 mg/dose, 1700 mg/dose, 1750 mg/dose, 1800 mg/dose, 1900 mg/dose, or 2000 mg/dose.
  • the induction regimen comprises multiple administrations of the anti-TLIA 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 on week 10.
  • 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 TL1 A compared to the corresponding tissue in the control subject. In some embodiments of the dose determination methods, the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more fold of TL1 A 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 TL1 A 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-TLIA antibody or antigen binding fragment. In some embodiments of the dose determination methods, the maintenance regimen comprises administrations of the anti-TLIA 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, at (i) 500 mg/dose every 2 weeks,
  • the maintenance regimen comprises administration of the anti-TLIA antibody or antigen binding fragment at 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 mg/dose. In some embodiments of the dose determination methods, the maintenance regimen comprises administration of the anti-TLIA antibody or antigen binding fragment once every 2, 4, 6, 8, 10, or 12 weeks. In some embodiments of the dose determination methods, the maintenance regimen comprises administrations of the anti-TLIA antibody or antigen binding fragment at 250 mg/dose every 4 weeks.
  • the maintenance regimen comprises administrations of the anti-TLIA antibody or antigen binding fragment at 100 mg/dose every 4 weeks. In some embodiments of the dose determination methods, 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 TL1 A in diseased tissue in the subject below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis for at least 4 weeks, 8 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 2 years, and longer.
  • the step (a) further comprises receiving the rate of TL1 A trimerization (k on -TLiA-monomer-to-trimer) and/or rate of TL1A monomerization (koff-TLIA-trimer-to-monomer).
  • the concentration of TL1A is the concentration of free TL1A.
  • the anti-TLl A 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-TLIA antibody comprises the CDRs of antibody J of Table 10. In some cases, the anti-TLIA antibody comprises the CDRs of antibody J2 of Table 10. In some cases, the anti-TLIA antibody comprises the CDRs of antibody K of Table 10. In some cases, the anti-TLIA antibody comprises the CDRs of antibody M of Table 10. In some cases, the anti-TLIA antibody comprises the CDRs of antibody N of Table 10.
  • the anti-TLIA 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 IGHV 1 -46*02 framework and the human IGKV3-20 framework.
  • the anti-TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA antibody comprises a heavy chain variable region comprising SEQ ID NO: 301
  • the anti-TLIA antibody comprises the CDRs of antibody J of Table 10. In some cases, the anti-TLIA antibody comprises the CDRs of antibody J2 of Table 10. In some cases, the anti-TLIA antibody comprises the CDRs of antibody K of Table 10. In some cases, the anti-TLIA antibody comprises the CDRs of antibody M of Table 10. In some cases, the anti-TLIA antibody comprises the CDRs of antibody N of Table 10.
  • the anti-TLIA 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, 418, or 455.
  • the anti-TLl A 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.
  • Embodiment 1 An antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1 A (anti-TLl A antibody or antigen binding fragment) for use in the treatment of inflammation in a subject in need thereof.
  • anti-TLl A antibody or antigen binding fragment an antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1 A
  • Embodiment 2 The anti-TLl A antibody or antigen-binding fragment for use of embodiment 1, wherein the subject has inflammation in the kidney.
  • Embodiment 3 An antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1 A (anti-TLl A antibody or antigen binding fragment) for use in the treatment of fibrosis in a subject in need thereof.
  • Embodiment 4 The anti-TLl A antibody or antigen-binding fragment for use of embodiment 3, wherein the subject has fibrosis in the kidney.
  • Embodiment 5 An antibody or antigen binding fragment thereof that binds to tumor necrosis factor-like protein 1 A (anti-TLl A antibody or antigen binding fragment) for use in the treatment of a disease and/or condition of the kidney in a subject in need thereof.
  • Embodiment 6. The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 1-5, wherein the subject has a chronic kidney disorder.
  • Embodiment 7 The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has end stage renal disease.
  • Embodiment 8 The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has tubulointerstitial renal fibrosis.
  • Embodiment 9 The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has nephritis.
  • Embodiment 10 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has diabetic kidney disease.
  • Embodiment 11 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has polycystic kidney disease.
  • Embodiment 12 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 1-6, wherein the subject has end-stage renal disease, tubulointerstitial renal fibrosis, glomerulonephritis, interstitial nephritis, IgA nephropathy, acute interstitial nephritis, diabetic kidney diseases, lupus nephritis, Alport syndrome, or polycystic kidney disease, or a combination thereof.
  • Embodiment 13 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 1-12, wherein the anti-TLIA antibody or antigen binding fragment is administered in a pharmaceutical composition.
  • Embodiment 14 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 13, wherein the pharmaceutical composition comprises the anti-TLIA antibody or antigen binding fragment at a concentration greater than about 150 mg/mL.
  • Embodiment 15 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 14, wherein the concentration is greater than about 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, or 250 mg/mL.
  • Embodiment 16 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 14, wherein the concentration is about 150 mg/mL to about 250 mg/mL.
  • Embodiment 17 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 14, wherein the concentration is about 175 mg/mL to about 225 mg/mL.
  • Embodiment 18 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 13-17, wherein the pharmaceutical composition is administered subcutaneously.
  • Embodiment 19 The anti-TLIA antibody or antigen-binding fragment for use of embodiment any one of embodiments 13-18, wherein about 150 mg to about 500 mg of the anti-TLIA antibody or antigen binding fragment is present in the composition.
  • Embodiment 20 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 13-19, wherein the composition has a total volume of less than or equal to about 2 mL.
  • Embodiment 21 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 13-20, wherein the pharmaceutical composition comprises a therapeutically effective dose of the anti-TLIA antibody or antigen binding fragment.
  • Embodiment 22 The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 13-21, wherein the composition has a total volume less than or equal to about 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, or 0.8 mL.
  • Embodiment 23 The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 13-22, wherein the composition has a total volume of about 0.5 mL to about 1.5 mL.
  • Embodiment 24 The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 13-23, wherein the composition has a viscosity of less than about 20 cP.
  • Embodiment 25 The anti-TLl A antibody or antigen-binding fragment for use of embodiment 24, wherein the composition has a viscosity of less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 cP.
  • Embodiment 26 The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 13-25, wherein the composition has a viscosity of about 1 cP to about 20 cP.
  • Embodiment 27 The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 13-26, wherein the pharmaceutical composition has a percentage aggregation of anti-TLIA antibody or antigen binding fragment as measured by size exclusion chromatography of less than about 5% of the total anti-TLIA antibody or antigen binding fragment in the composition.
  • Embodiment 28 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 27, wherein the aggregation is less than about 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5%.
  • Embodiment 29 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 13-27, wherein the composition comprises a surfactant.
  • Embodiment 30 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 29, wherein the surfactant comprises a nonionic surfactant.
  • Embodiment 31 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 30, wherein the nonionic surfactant comprises polysorbate-20.
  • Embodiment 32 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 29-31, wherein the surfactant is present at a concentration of about 0.005% to about 0.05% of the composition.
  • Embodiment 33 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 32, wherein the surfactant is present at a concentration of about 0.01% to about 0.02% of the composition.
  • Embodiment 34 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 13-33, wherein the composition comprises a salt.
  • Embodiment 35 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 34, wherein the salt comprises sodium chloride, glycine, lysine-hydrochloride, arginine-hydrochloride, arginine glutamate, potassium chloride, magnesium chloride, or calcium chloride, or a combination thereof.
  • Embodiment 36 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 35, wherein the salt comprises sodium chloride.
  • Embodiment 37 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 35, wherein the salt comprises lysine-HCl.
  • Embodiment 38 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 34-37, wherein the salt is present at a concentration of about 10 mM to about 100 mM in the composition.
  • Embodiment 39 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 38, wherein the salt is present at a concentration of about 25 m in the composition.
  • Embodiment 40 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 38, wherein the salt is present at a concentration of about 40 mM in the composition.
  • Embodiment 41 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 13-40, wherein the composition comprises a stabilizer.
  • Embodiment 42 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 41, wherein the stabilizer comprises a sugar, polyol, amino acid, or polymer, cyclodextrin (e.g., HP-b-CD), or a combination thereof.
  • the stabilizer comprises a sugar, polyol, amino acid, or polymer, cyclodextrin (e.g., HP-b-CD), or a combination thereof.
  • Embodiment 43 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 42, wherein the stabilizer comprises the sugar.
  • Embodiment 44 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 43, wherein the sugar comprises sucrose, glucose, trehalose, maltose, or lactose, or a combination thereof.
  • Embodiment 45 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 44, wherein the sugar comprises sucrose.
  • Embodiment 46 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 41-45, wherein the stabilizer is present at a concentration of about 50 mM to about 300 mM in the composition.
  • Embodiment 47 The anti-TLl A antibody or antigen-binding fragment for use of embodiment 46, wherein the stabilizer is present at a concentration of about 200 mM to about 280 mM.
  • Embodiment 48 The anti-TLl A antibody or antigen-binding fragment for use of embodiment 47, wherein the stabilizer is present at a concentration of about 220 to about 240 mM.
  • Embodiment 49 The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 13-48, wherein the composition comprises a buffering agent.
  • Embodiment 50 The anti-TLl A antibody or antigen-binding fragment for use of embodiment 49, wherein the buffering agent comprises acetate, phosphate, citrate, glutamate, succinate, gluconate, histidine, glycylglycine, citric acid, Tris (tris (hydroxymethyl) aminomethane), or diethanolamine, or a combination thereof.
  • the buffering agent comprises acetate, phosphate, citrate, glutamate, succinate, gluconate, histidine, glycylglycine, citric acid, Tris (tris (hydroxymethyl) aminomethane), or diethanolamine, or a combination thereof.
  • Embodiment 51 The anti-TLl A antibody or antigen-binding fragment for use of embodiment 50, wherein the buffering agent comprises acetate buffer.
  • Embodiment 52 The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 49-51, wherein the buffering agent is present at a concentration of about 10 mM to about 50 mM in the composition.
  • Embodiment 53 The anti-TLl A antibody or antigen-binding fragment for use of embodiment 52, wherein the composition comprises about 20 mM buffer.
  • Embodiment 54 The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 13-53, wherein the composition has a pH of about 4.5 to about 8.0.
  • Embodiment 55 The anti-TLl A antibody or antigen-binding fragment for use of embodiment 54, wherein the composition has a pH of about 4.5 to about 7.5.
  • Embodiment 56 The anti-TLl A antibody or antigen-binding fragment for use of embodiment 55, wherein the composition has a pH of about 5 to about 5.5.
  • Embodiment 57 The anti-TLl A antibody or antigen-binding fragment for use of embodiment 56, wherein the composition has a pH of about 5.3.
  • Embodiment 58 The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 1-57, wherein the anti-TLl A antibody or antigen binding fragment is administered to the subject at a first dose up to about 1000 mg.
  • Embodiment 59 The anti-TLl A antibody or antigen-binding fragment for use of any one of embodiments 1-57, wherein the anti-TLl A antibody or antigen binding fragment is administered to the subject at a first dose of about 150 mg to about 1000 mg.
  • Embodiment 60 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 59, wherein the first dose is about 500 mg to about 1000 mg.
  • Embodiment 61 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 60, wherein the first dose is about 500 mg or about 800 mg.
  • Embodiment 62 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 58-61, wherein the first dose is administered to the subject at a first time point, and a second dose is administered to the subject at a second time point.
  • Embodiment 63 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 62, wherein the second time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the first time point.
  • Embodiment 64 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 62, wherein the second time point is about 1, 2, 3, or 4 weeks after the first time point.
  • Embodiment 65 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 62-64, wherein the second dose comprises up to about 1000 mg anti-TLIA antibody or antigen binding fragment.
  • Embodiment 66 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 62-64, wherein the second dose comprises about 150 mg to about 1000 mg.
  • Embodiment 67 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 66, wherein the second dose comprises about 150 mg to about 600 mg.
  • Embodiment 68 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 62-67, wherein a third dose of anti-TLIA antibody or antigen binding fragment is administered to the subject at a third time point.
  • Embodiment 69 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 68, wherein the third time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the second time point.
  • Embodiment 70 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 68, wherein the third time point is about 1, 2, 3, or 4 weeks after the second time point.
  • Embodiment 71 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 68-70, wherein the third dose comprises up to about 1000 mg anti- TL1 A antibody or antigen binding fragment.
  • Embodiment 72 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 68-70, wherein the third dose comprises about 150 mg to about 1000 mg.
  • Embodiment 73 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 72, wherein the third dose comprises about 150 mg to about 600 mg.
  • Embodiment 74 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 68-73, wherein a fourth dose of anti-TLIA antibody or antigen binding fragment is administered to the subject at a fourth time point.
  • Embodiment 75 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 74, wherein the fourth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the third time point.
  • Embodiment 76 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 74, wherein the fourth time point is about 1, 2, 3, or 4 weeks after the third time point.
  • Embodiment 77 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 74-76, wherein the fourth dose comprises up to about 1000 mg anti- TLIA antibody or antigen binding fragment.
  • Embodiment 78 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 74-76, wherein the fourth dose comprises about 150 mg to about 1000 mg.
  • Embodiment 79 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 78, wherein the fourth dose comprises about 150 mg to about 600 mg.
  • Embodiment 80 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 74-79, wherein a fifth dose of anti-TLIA antibody or antigen binding fragment is administered to the subject at a fifth time point.
  • Embodiment 81 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 80, wherein the fifth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the fourth time point.
  • Embodiment 82 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 80, wherein the fifth time point is about 1, 2, 3, or 4 weeks after the fourth time point.
  • Embodiment 83 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 80-82, wherein the fifth dose comprises up to about 1000 mg anti- TLIA antibody or antigen binding fragment.
  • Embodiment 84 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 80-82, wherein the fifth dose comprises about 150 mg to about 1000 mg.
  • Embodiment 85 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 84, wherein the fifth dose comprises about 150 mg to about 600 mg.
  • Embodiment 86 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 80-85, wherein a sixth dose of anti-TLIA antibody or antigen binding fragment is administered to the subject at a sixth time point.
  • Embodiment 87 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 86, wherein the sixth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the fifth time point.
  • Embodiment 88 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 86, wherein the sixth time point is about 1, 2, 3, or 4 weeks after the fifth time point.
  • Embodiment 89 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 86-88, wherein the sixth dose comprises up to about 1000 mg anti- TLIA antibody or antigen binding fragment.
  • Embodiment 90 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 86-88, wherein the sixth dose comprises about 150 mg to about 1000 mg.
  • Embodiment 91 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 90, wherein the sixth dose comprises about 150 mg to about 600 mg.
  • Embodiment 92 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 58-91, wherein an additional dose of the anti-TLIA antibody or antigen binding fragment is administered to the subject at each of the one or more additional time points.
  • Embodiment 93 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 92, wherein the one or more additional time points comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 additional time points.
  • Embodiment 94 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 92, wherein the composition is administered to the subject at about 12 additional time points.
  • Embodiment 95 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 92-94, wherein each additional time point is independently about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after a previous time point.
  • Embodiment 96 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 92-94, wherein each additional time point is independently about 1, 2, 3, or 4 weeks after a previous time point.
  • Embodiment 97 The anti-TLIA antibody or antigen-binding fragment for use of embodiment 96, wherein at least one of the additional time points is about 2 weeks after the previous time point.
  • Embodiment 98 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 92-97, wherein the additional dose comprises up to about 1000 mg anti-TLIA antibody or antigen binding fragment.
  • Embodiment 99 The anti-TLIA antibody or antigen-binding fragment for use of any one of embodiments 92-97, wherein the additional dose comprises from about 150 mg to about 1000 mg anti-TLIA antibody or antigen binding fragment.
  • Embodiment 100 The anti-TLIA antibody or antigen-binding fragment foruse of embodiment 99, wherein the additional dose is about 175 mg to about 300 mg anti-TLIA antibody or antigen binding fragment.
  • Embodiment 101 An anti-TLIA antibody or antigen binding fragment for use in neutralizing monomeric ILIA and trimeric ILIA in a subject having kidney inflammation and/or kidney fibrosis, wherein the anti-TLIA antibody or antigen binding fragment is formulated in an effective dose for administration to the subject, wherein the antibody or antigen binding fragment binds to both monomeric TL1 A and trimeric TL1A, wherein the antibody or antigen binding fragment blocks interaction of TL1 A to DR3, wherein the concentration of TL1 A in a diseased tissue in the subject is reduced below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis, and wherein diseased tissue comprises any one or more selected from the group consisting of renal cortex, renal medulla, renal pyramid, renal column, renal papilla, nephron, renal corpuscle, Bowman’s capsule, glomerulus, a fibrotic tissue in the kidney, other tissues with kidney
  • Embodiment 102 The anti-TLl A antibody or antigen-binding fragment foruse of embodiment 101, wherein the subject has one or more inflammatory conditions selected from the group consisting of a chronic kidney disorder, end stage renal disease, tubulointerstitial renal fibrosis, nephritis, diabetic kidney disease, and polycystic kidney disease.
  • Embodiment 103 The anti-TLIA antibody or antigen-binding fragment foruse of embodiment 101 or 102, wherein the subject has glomerulonephritis, interstitial nephritis, IgA nephropathy, acute interstitial nephritis, lupus nephritis, or Alport syndrome, pyelonephritis, or a combination thereof.
  • Embodiment 104 An anti-TLIA antibody or antigen binding fragment for use in reducing the concentration of TL1 A in a diseased tissue in a subject with kidney inflammation and/or kidney fibrosis, wherein the anti-TLIA antibody or antigen binding fragment is formulated in an effective dose for administration to the subject to reduce the concentration of TL1 A in the diseased tissue in the subject below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis, wherein diseased tissue comprises any one or more selected from the group consisting of renal cortex, renal medulla, renal pyramid, renal column, renal papilla, nephron, renal corpuscle, Bowman’s capsule, glomerulus, a fibrotic tissue in the kidney, other tissues with kidney inflammation and/or kidney fibrosis, and other tissues of pathogenesis for the kidney inflammation and/or kidney fibrosis.
  • Embodiment 105 An anti-TLIA antibody or antigen binding fragment for use in the treatment of kidney inflammation and/or kidney fibrosis in a subject in need thereof, wherein the anti-TLIA antibody or antigen binding fragment is administered at an effective dose such that the concentration of TL1 A in a diseased tissue in the subject after the administration is below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis, and wherein diseased tissue comprises any one or more selected from the group consisting of renal cortex, renal medulla, renal pyramid, renal column, renal papilla, nephron, renal corpuscle, Bowman’s capsule, glomerulus, a fibrotic tissue in the kidney, other tissues with kidney inflammation and/or kidney fibrosis, and other tissues of pathogenesis for the kidney inflammation and/or kidney fibrosis.
  • Embodiment 106 An anti-TLl A antibody or antigen binding fragment for use in the treatment of kidney inflammation and/or kidney fibrosis in a subject in need thereof, wherein the anti-TLl A antibody or antigen binding fragment is administered in a method comprising:
  • diseased tissue comprises any one or more selected from the group consisting of renal cortex, renal medulla, renal pyramid, renal column, renal papilla, nephron, renal corpuscle, Bowman’s capsule, glomerulus, a fibrotic tissue in the kidney, other tissues with kidney inflammation and/or kidney fibrosis, and other tissues of pathogenesis for the kidney inflammation and/or kidney fibrosis.
  • Embodiment 107 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 101 to 106, wherein the effective dose comprises an induction regimen.
  • Embodiment 108 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 101 to 107, wherein anti-TLl A antibody or antigen -binding fragment is also for use in the maintenance of ILIA in the diseased tissue in the subject at a concentration below the concentration of ILIA in the corresponding tissue in the control subject.
  • Embodiment 109 The anti-TLl A antibody or antigen-binding fragment foruse of embodiment 108, wherein the ILIA in the diseased tissue in the subject is maintained with a maintenance regimen of the anti-TLl A antibody or antigen binding fragment.
  • Embodiment 110 The anti-TLl A antibody or antigen-binding fragment foruse of embodiment 109, wherein the induction regimen and the maintenance regimen are identical.
  • Embodiment 111 The anti-TLl A antibody or antigen-binding fragment foruse of embodiment 109, wherein the induction regimen and the maintenance regimen are different.
  • Embodiment 112. The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 109 to 111, wherein the maintenance regimen is administered after the induction regimen.
  • Embodiment 113 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 102 to 112, wherein the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1 A compared to the corresponding tissue in the control subject during the induction regimen.
  • Embodiment 114 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 102 to 112, wherein the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1 A 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 115 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 102 to 112, wherein the diseased tissue in the subject produces up to 50, 60, 70, 80, 90, 100, or more fold of TL1 A compared to the corresponding tissue in the control subject.
  • Embodiment 116 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 107 to 115, wherein the induction regimen comprises a one-time administration of the anti-TLl A antibody or antigen binding fragment.
  • Embodiment 117 The anti-TLl A antibody or antigen-binding fragment foruse of embodiment 116, wherein the anti-TLl A antibody or antigen binding fragment is administered at 200 mg/dose, 250 mg/dose, 300 mg/dose, 350 mg/dose, 400 mg/dose, 450 mg/dose, 500 mg/dose, 550 mg/dose, 600 mg/dose, 650 mg/dose, 700 mg/dose, 750 mg/dose, 800 mg/dose, 850 mg/dose, 900 mg/dose, 950 mg/dose, 1000 mg/dose, 1100 mg/dose, 1200 mg/dose, 1250 mg/dose, 1300 mg/dose, 1400 mg/dose, 1500 mg/dose, 1600 mg/dose, 1700 mg/dose, 1750 mg/dose, 1800 mg/dose, 1900 mg/dose, or 2000 mg/dose.
  • Embodiment 118 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 107 to 115, wherein the induction regimen comprises multiple administrations of the anti-TLl A antibody or antigen binding fragment.
  • Embodiment 119 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 107 to 115 and 118, wherein the induction regimen comprises administrations of
  • Embodiment 120 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 107 to 115 and 118, 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 121 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 107 to 115, 118, and 120, wherein the induction regimen comprises administration once every 2, 4, 6, or 8 weeks.
  • Embodiment 122 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 107 to 115, 118, and 120, 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.
  • Embodiment 123 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 108 to 122, wherein the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more fold of TL1 A compared to the corresponding tissue in the control subject.
  • Embodiment 124 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 108 to 119, wherein the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more fold of TL1 A compared to the corresponding tissue in the control subject during the maintenance regimen.
  • Embodiment 125 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 108 to 119, wherein the diseased tissue in the subject produces up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more fold of TL1 A 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.
  • Embodiment 126 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 109 to 125, wherein the maintenance regimen comprises multiple administrations of the anti-TLIA antibody or antigen binding fragment.
  • Embodiment 127 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 109 to 126, wherein the maintenance regimen comprises administrations of the anti-TLIA antibody or antigen binding fragment at
  • Embodiment 128 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 109 to 126, wherein the maintenance regimen comprises administration of the anti-TLl A antibody or antigen binding fragment at 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 mg/dose.
  • Embodiment 129 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 109 to 126 and 128, wherein the maintenance regimen comprises administration of the anti-TLl A antibody or antigen binding fragment once every 2, 4, 6, 8, 10, or 12 weeks.
  • Embodiment 130 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 109 to 129, wherein the maintenance regimen comprises administrations of the anti-TLl A antibody or antigen binding fragment at 250 mg/dose every 4 weeks.
  • Embodiment 131 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 109 to 129, wherein the maintenance regimen comprises administrations of the anti-TLl A antibody or antigen binding fragment at 100 mg/dose every 4 weeks.
  • Embodiment 132 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 109 to 131, 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 133 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 104 to 132, wherein the antibody or antigen binding fragment binds to both monomeric ILIA and trimeric ILIA and wherein the antibody or antigen binding fragment blocks binding of ILIA to DR3.
  • Embodiment 134 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 101 to 133, wherein at least 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the monomeric ILIA in the blood of the subject is occupied by the anti-TLIA antibody or antigen binding fragment.
  • Embodiment 135. The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 101 to 134, wherein at least 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the trimeric TL1 A in the blood of the subject is occupied by the anti-TLIA antibody or antigen binding fragment.
  • Embodiment 136 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 101 to 135, wherein binding affinity of the antibody or antigen binding fragment to monomeric ILIA 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 (Ko-trimer).
  • Embodiment 137 The anti-TLl A antibody or antigen-binding fragment foruse of embodiment 136, wherein the KD -monomer is within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold of the KD -trim er.
  • Embodiment 138 The anti-TLl A antibody or antigen-binding fragment foruse of embodiment 136 or 137, wherein the KD -monomer is no more than 0.06 nM.
  • Embodiment 139 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 136 to 138, wherein the Ko-trimer is no more than 0.06 nM.
  • Embodiment 140 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 103 to 139, wherein the subject has one or more inflammatory conditions selected from the group consisting of a chronic kidney disorder, end stage renal disease, tubulointerstitial renal fibrosis, nephritis, diabetic kidney disease, and polycystic kidney disease.
  • Embodiment 141 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 102 to 140, wherein the subject has glomerulonephritis, interstitial nephritis, IgA nephropathy, acute interstitial nephritis, lupus nephritis, or Alport syndrome, pyelonephritis, or a combination thereof.
  • Embodiment 142 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 101 to 141, wherein the effective dose or the induction regimen is determined by a dose determination method, wherein the dose determination method comprises:
  • step (iii) determining the effective dose or the induction regimen such that the concentration of TL1 A in diseased tissue in the subject after step (a) is below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis.
  • Embodiment 143 The anti-TLIA antibody or antigen-binding fragment foruse of embodiment 142, wherein the parameter of TL1 A 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 TL1 A production in the normal reference tissue.
  • Embodiment 144 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 109 to 143, wherein the maintenance regimen is determined by a dose determination method, wherein the dose determination method comprises:
  • Embodiment 145 The anti-TLl A antibody or antigen-binding fragment foruse of embodiment 144, wherein the parameter of TL1 A 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 146 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 142 to 145, wherein the step (i) in the dose determination method further comprises receiving association rate of the antibody to TL1 A (k on -mAb), dissociation rate of the antibody from TL1 A (koff-mAb), synthesis rate of TL1 A in normal tissue (k S yn-normai), synthesis rate of TL1 A in diseased tissue (k sy n-disease), and/or degradation rate of TL1 A (kdeg- total-TLlA).
  • Embodiment 147 The anti-TLl A antibody or antigen-binding fragment foruse of embodiment to 146, wherein the association rate of the antibody to TL1 A (kon-mAb) comprises the association rate of the antibody to monomeric ILIA (k on-monomer ) and association rate of the antibody to trimeric TL1 A (k on -trimer), wherein the dissociation rate of the antibody from TL1 A (koff-mAb) comprises the dissociation rate of the antibody from monomeric TL1 A (k o ff- monomer) and dissociation rate of the antibody from trimeric TL1A (k o ff-trimer), and/or wherein the degradation rate of TL1 A (kdeg-totai-TLiA) comprises degradation rate of monomeric TL1 A (kdeg-TLIA -monomer ) and degradation rate of trimeric ILIA (kdeg-TLiA-trimer).
  • the association rate of the antibody to TL1 A comprises the association
  • Embodiment 148 The anti-TLl A antibody or antigen-binding fragment foruse of any one of embodiments 142 to 147, 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 (k o ff- mAb-FcRn), association rate of the antibody- TL1 A complex to FcRn receptor (kon-(mAb-TLiA)-FcRn), and/or dissociation rate of the antibody- TL1 A complex from FcRn (koff-(mAb-TLiA)-FcRn).
  • association rate of the antibody to FcRn receptor k on -mAb-FcRn
  • dissociation rate of the antibody from FcRn k o ff- mAb-FcRn
  • association rate of the antibody- TL1 A complex to FcRn receptor kon-(mAb
  • Embodiment 149 The anti-TLl A antibody or antigen-binding fragment foruse of embodiment 148, wherein the association rate of the antibody- TL1 A complex to FcRn receptor (kon-(mAb-TLiA)-FcRn) comprises association rate of the antibody-monomeric-TLIA complex to FcRn receptor (k on -(mAb-monoTLiA)-FcRn) and association rate of the antibody- trimeric-TLlA complex to FcRn receptor (kon-(mAb-triTLiA)-FcRn), and/or wherein the dissociation rate of the antibody- TL1A complex from FcRn (koff-(mAb-TLiA)-FcRn) comprises dissociation rate of the antibody-monomeric-TLIA complex from FcRn (koff-(mAb-monoTLiA)- FcRn) and dissociation rate of the antibody-trimeric-TLl A complex from FcRn (
  • Embodiment 150 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 142 to 149, wherein the step (i) in the dose determination method further comprises receiving clearance rate of FcRn receptor bound by the antibody (kdeg-mAb- FcRn).
  • Embodiment 151 The anti-TLIA antibody or antigen-binding fragment foruse of embodiment 150, wherein the clearance rate of FcRn receptor bound by the antibody (kdeg- mAb-FcRn) comprises clearance rate of the antibody to FcRn bound by the antibody-monomeric- TLIA complex (kdeg-(mAb-monoTLiA)-FcRn) and clearance rate of FcRn receptor bound by the antibody-trimeric-TLl A complex (kdeg-(mAb-triTLiA)-FcRn).
  • the clearance rate of FcRn receptor bound by the antibody comprises clearance rate of the antibody to FcRn bound by the antibody-monomeric- TLIA complex (kdeg-(mAb-monoTLiA)-FcRn) and clearance rate of FcRn receptor bound by the antibody-trimeric-TLl A complex (kdeg-(mAb-triTLiA)-FcRn).
  • Embodiment 152 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 146 to 151, wherein in the dose determination method:
  • k o ff-(mAb-monoTLiA)-FcRn and k o ff-( m Ab-triTLiA)-FcRn are identical or different;
  • koff- mAb-FcRn and k o ff-(mAb-monoTLi A)-FcRn are identical or different;
  • kdeg-mAb-FcRn and kde g -(mAb-triTLi A)-FcRn are identical or different;
  • kdeg-mAb-FcRn and kdeg-(mAb-monoTLi A)-FcRn are identical or different; (13) any combination of (1) to (12).
  • Embodiment 153 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 142 to 152, wherein in the dose determination method: 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 k sy n-normai.
  • Embodiment 154 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 142 to 153, wherein step (i) in the dose determination method further comprises receiving rate of TL1 A trimerization (k on -TLiA-monomer-to-trimer) and/or rate of TL1A monomerization (koff-TLIA-trimer-to-monomer).
  • Embodiment 155 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 102 to 154, wherein the concentration of TL1 A is the concentration of free ILIA.
  • Embodiment 156 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 1 to 155, wherein the anti-TLIA 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.
  • 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,
  • Embodiment 157 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 1 to 156, wherein the anti-TLIA 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 158 The anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 1 to 157, wherein the anti-TLIA 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.
  • Embodiment 159 Embodiment 159.
  • anti-TLIA antibody or antigen-binding fragment foruse of any one of embodiments 1 to 158, wherein the anti-TLIA 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
  • each of XI -XI 1 is independently selected from A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, or V
  • HCDR1 comprises an amino acid sequence set forth by SEQ ID NO: 1
  • HCDR2 comprises an amino acid sequence set forth by any one of SEQ ID NOS: 2-5
  • HCDR3 comprises an amino acid sequence set forth by any one of SEQ ID NOS: 6-9
  • LCDR1 comprises an amino acid sequence set forth by SEQ ID NO: 10
  • LCDR2 comprises an amino acid sequence set forth by SEQ ID NO: 11
  • LCDR3 comprises an amino acid sequence set forth by any one of SEQ ID NOS:
  • FIGS. 1A-1C show chromatograms for analytical size exclusion chromatography of anti-TLIA 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. IB 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-TLIA 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-TLIA antibody concentration (x-axis) in mg/mL, and FIG.
  • 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 PLS 1 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. 7A depicts the binding of an anti-TLIA antibody to cynomolgus and human TL1 A, but not to mouse or rat ILIA.
  • ELISA for each protein was performed at least three times. The data from a representative experiment are shown and are mean ⁇ SD.
  • FIG. 7B depicts mean levels of sTLIA increased with increasing IV doses of anti-TLIA to cynomolgus monkeys, as measured in an ELISA. Samples were assayed in triplicate, on two separate occasions. Data presented are the mean ILIA concentrations of three animals per group ⁇ SD. Samples collected from animals administered isotype control antibody are shown in circles, samples collected from animals administered anti-TLIA are shown in the triangles and square.
  • FIG. 8 demonstrates that TL1 A drives inflammation and fibrosis through binding to DR3.
  • FIGS. 9A-9C demonstrates size-exclusion chromatography (SEC) profiles of recombinant human TL1 A (rhTLl A). Briefly, rhTLl A was labeled with Alexa fluor 488 (AF488) and spiked into normal human serum (NHS). In FIG. 9A, when injected alone, rhTLl A SEC profile shows two peaks on SEC, representing trimeric and monomeric forms of TL1A. In FIG.
  • 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.
  • mAb monoclonal antibody
  • ligand ligand
  • complex between mAb and ligand mAb
  • 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 TL1 A concentration as predicted by the integrated whole-body PBPK with the TL1 A 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 TL1 A in serum after injecting (i) an anti-TLl A antibody A219 that binds to both TL1 A 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-TLIA antibody that binds to only TL1A trimer (shown in blue, bottom of the 2 curves, and the observed data points accompanying such curve).
  • 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 TL1 A concentration (monomer and trimer, solid curve and the observed data points accompanying such curve), the monomer TL1 A concentration (fine dotted line), and the trimer TL1 A concentration (coarse dotted line), in each case at the basal level (no injection of any anti- TLIA antibodies).
  • FIG. 12C depicts the serum TL1 A 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-13B demonstrate the fitness of the model.
  • FIG. 13A depicts the observed concentration of TL1 A in serum of NHVs after injecting an anti-TLl A antibody that binds to only TL1 A 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- TLl A antibody that binds to only ILIA 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.
  • 13C depicts the concentration of TL1 A 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 TL1 A based on various parameters of ILIA production in intestine (14A) and in serum (14B).
  • l x would be the baseline in NHV; 25x, 50x, 75x, and 100x indicate various parameters of TL1A over-production in intestine.
  • FIGS 15A-15V depict the concentration of free soluble ILIA in tissue as determined by the whole-body PBPK model according to various parameters of ILIA overproduction under various dose regimen of anti-TLl A antibody A219 as indicated.
  • FIG. 15W depicts the free soluble ILIA in tissue as determined by the whole-body PBPK model according to various parameters of ILIA overproduction under the dose regimen of a reference anti-TLl A antibody as indicated.
  • FIGS. 15X-15Z depict the comparison of the modeled free soluble ILIA concentration in subjects treated with a reference anti-TLl A antibody (red, the upper curve of the two curves) or A219 (green, the lower curve of the two curves).
  • red the upper curve of the two curves
  • 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 ILIA 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.
  • Dl day 1.
  • W 2, 6, 10 week 2, week 6, and week 10.
  • W 2, 4, 6, 10 week 2, week 4, week 6, and week 10.
  • EOW every other week.
  • W 4, 8, 12 week 4, week 8, and week 12.
  • W 2, 4, 8, 12 week 2, week 4, week 8, and week 12.
  • sTLl A soluble ILIA.
  • 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 TO, 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 TO, 3 and 6 months.
  • FIG. 20 depicts pH at 5 °C measured for the evaluating the stability A219 samples of various formulations at TO, 3 and 6 months.
  • FIG. 21A depicts viscosity data for TO and 3M for Formulations 1 to 5 at 25°C
  • FIG. 21B depicts viscosity data for TO 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. Area (%) per month) for the formulations at 5 °C as determined by cation exchange chromatography
  • FIG. 23C depicts the relative area (%) of the main peak for formulations at 25°C as characterized by cation exchange chromatography
  • FIG. 23D depicts the loss of main peak (Rel. Area (%) per month) for the formulations at 25 °C as determined by cation exchange chromatography.
  • 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.
  • 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 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.
  • FIG. 25A shows geometric mean serum A219 concentration -time profiles following single doses of A219 administered as IV infusion (Linear Scale) (SAD study).
  • FIG. 26A shows geometric mean serum sTLIA concentration versus nominal time following single dose of A219 administered as IV Infusion (semi-log scale) (SAD study).
  • FIG. 26B geometric mean serum sTLIA concentration versus nominal time following multiple doses of A219 Q2W administered as IV infusion (semi -log scale) (MAD study).
  • FIG. 27A 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. 27B shows total soluble ILIA in the central compartment (circulation) in SAD as predicted by the model (curves) and as determined in the phase I trial.
  • FIG. 27C 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. 27D shows total soluble ILIA in the central compartment (circulation) in MAD as predicted by the model (curves) and as determined in the phase I trial (dots).
  • FIGS. 27E-27K show model prediction for and the data of a control reference antibody that binds only to ILIA trimer (light chain SEQ ID NO: 382 and heavy chain SEQ ID NO: 383) with regard to (1) phase I single ascending dose data (FIGS. 27E and 27F), (2) phase I multiple ascending dose data (FIGS. 27G and 27H), and (3) phase II data on PK & total sTLIA levels (FIGS. 271 and 27 J).
  • the IBD specific parameters were then calibrated to capture free tissue TL1 A levels in the gut (FIG. 27K) as observed with the control reference antibody (light chain SEQ ID NO: 382 and heavy chain SEQ ID NO: 383).
  • FIG. 28A 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. 28B shows the percent reduction of the free TL1 A in the diseased tissue after administering doses of A219 as determined from the model.
  • IV_4* 1000 mg loading dose, 3 x 500 mg on days 14, 42, 70. SC dosing 240 mg Q1W or Q2W.
  • FIG. 28C 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-TLIA antibodies that only bind to TL1A trimer.
  • FIG. 28D shows that, in a head-to-head comparison in the validated model, anti-TLIA antibodies that bind to both I IA monomer and trimer also resulted in higher percentage of I IA reduction of ILIA in diseased tissue (about 100%) when compared to anti-TLIA antibodies that only bind to ILIA trimer.
  • FIG. 29A shows the diagram of a popPK model.
  • FIG. 29B 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. 29C shows the comparison of the ILIA concentration predicted from the popPK model and the ILIA concentration observed in the population of subjects in phase I clinical trial via a linear regression plot.
  • FIG. 29D 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. 29E shows the comparison of the ILIA concentration predicted from the popPK model and the ILIA concentration observed in the population of subjects in phase I clinical trial via a time series plot.
  • FIGS. 30A-30H show the A219 and ILIA engagement (ILIA concentration in serum) predicted from the validated popPK model under various A219 doses.
  • FIGS. 30A and 30B show A219 concentration (30 A) and ILIA concentration (30B) 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. 30C and 30D show A219 concentration (30C) and ILIA concentration (30D) 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. 30E and 30F show A219 concentration (30E) and TL1 A concentration (30F) 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. 30G and 30H show A219 concentration (30G) and ILIA concentration (30H) 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).
  • FIGs. 31A-31D show in-situ hybridization for TNFSF 15 mRNA and TNFRSF25 mRNA in sections of kidney tissues from normal healthy volunteers (FIGs. 31A and 31B) and lupus nephritis (LN) patients (FIGs. 31C and 31D).
  • Glomeruli of normal healthy kidney shows a non-diseased pathology (FIG. 31A).
  • Surrounding the normal glomeruli (FIG. 31B) is a modest expression of TL1 A (lighter grey arrows in FIG. 31B) and DR3 (darker black arrows in FIG. 31B) Glomeruli from a LN donor (FIG.
  • FIG. 31C shows a necrotic pathology demonstrated by significate atrophy of the glomeruli core (indicating glomerulosclerosis).
  • Clustered around the necrotic glomeruli are increased positive cells for both TLA1 and DR3 expression, indicating that increased expression is associated with severe nephritic pathology.
  • FIG. 31B shows the enlarged view of the boxed areas of FIG. 31A
  • FIG. 31D shows the enlarged view of the boxed areas of FIG. 31C.
  • ILIA is a cytokine that is secreted by antigen-presenting cells, T cells, and endothelial cells. ILIA 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 Thl, Th2, Th9 and Thl7 responses. In addition, it is induced in antigen-presenting cells by toll like receptor (TLR) ligands and FcR cross-linking and in T cells by T cell receptor (TCR) stimulation.
  • TLR toll like receptor
  • TCR T cell receptor
  • ILIA binding to DR3 on innate and T cells leads to an early cytokine response (release of IL-23, IL-ip, IL-17, IL- 22, TNF-a, IFN-y, IL-13) that sets the stage for inflammation, and stimulates innate and adaptive immune response. For instance, through binding to DR3, ILIA potentially drives inflammatory Thl and Th 17 responses. Further, binding of ILIA to DR3 on fibroblasts directly activates fibroblasts, and leads to collagen disposition and fibrosis independent of inflammation. While levels of circulating ILIA are low in healthy subjects, they are elevated in patients suffering from many auto-immune diseases, and ILIA has been shown to be upregulated in mucosa and serum of patients with IBD.
  • mice chronic ILIA expression causes structuring disease caused by increased collagen deposition.
  • DSS dextran sodium sulfate
  • ILIA transgenic mice develop more severe colitis than wild-type animals, and antibodies against ILIA led to reduced inflammation, lowered collagen levels, and reversal of fibrosis, even when treatment was administered late in the course of disease, after inflammation and fibrosis has been established.
  • TL1 A polymorphisms have been shown to be associated with susceptibility to IBD and with disease severity.
  • Fibrosis is a significant clinical phenotype exhibited by IBD patients. Seventy percent of Crohn’s disease (CD) patients develop stricture/perforation, and stricture is the leading indication for surgery in CD. Unfortunately, anti-inflammatory agent use over the past decade has not materially changed the rate of structuring disease or need for surgery. Further, in ulcerative colitis (UC), subclinical fibrosis has significant implications on patient symptoms. For instance, subclinical fibrosis could contribute to symptoms of diarrhea, abdominal pain, urgency, and incontinence. Subclinical fibrosis is also the potential explanation for persistent symptoms after resolution of inflammation. In addition, a Cleveland Clinic study of 89 consecutive colectomy specimens revealed submucosal fibrosis in 100% of the specimens. Thus, treatment of fibrosis constitutes an unmet need in IBD .
  • TL1 A As a therapeutic target in intestinal fibrosis has been demonstrated in a study evaluating the effect of anti-TLIA antibodies in mouse models of IBD.
  • provided herein are methods of treating inflammation and/or fibrosis with anti-TLIA antibodies.
  • treatment of fibrosis is independent of treatment of inflammation.
  • treatment of inflammation is independent of treatment of fibrosis.
  • methods of treating a disease and/or condition of the kidney with anti-TLIA antibodies are provided herein.
  • Non-limiting examples of indications for use with the anti-TLIA antibodies herein include end-stage renal disease, tubulointerstitial renal fibrosis, glomerulonephritis, interstitial nephritis, acute interstitial nephritis, diabetic kidney diseases, lupus nephritis, Alport syndrome, and polycystic kidney disease.
  • the anti-TLIA antibodies bind to membrane-bound and soluble forms of TL1 A with high affinity and specificity and block the binding of TL1 A 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; 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).
  • ILIA 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 ILIA mediated signaling (e.g. Zhan, C et al., Structure 19: 162-171 (2011)), monomeric ILIA accounts for a large fraction of the ILIA pool in a subject. By one of the inventors’ estimates, the monomeric ILIA can be 60% of the total ILIA in the circulating blood.
  • the term “total TL1 A” refers to both monomeric and trimeric ILIA.
  • the disclosure further provides that, despite monomeric ILIA being biologically inactive, anti-TLl A antibodies binding to both monomeric and trimeric ILIA provide advantages over antibodies binding to only trimeric TL1 A.
  • advantages include more efficient reduction of the ILIA concentration in a diseased tissue in a subject including the concentration trimeric ILIA in the diseased tissue, more efficient reduction of the ILIA concentration in the blood in a subject including the concentration trimeric ILIA in the blood, more sustained reduction of ILIA concentration (including trimeric ILIA concentration) in a diseased tissue in a subject, and/or more sustained reduction of ILIA concentration (including trimeric ILIA concentration) in the blood in a subject.
  • antibodies or antigen binding fragments thereof that bind to tumor necrosis factor-like protein 1 A (“TL1 A,” and such antibody or antigen binding fragment thereof, “anti-TLl A antibody or antigen binding fragment” or “anti-TLl A antibody(ies)” in the specification for simplicity), wherein the antibodies or antigen binding fragments bind to both monomeric TL1 A and trimeric TL1A.
  • TL1 A tumor necrosis factor-like protein 1 A
  • anti-TLl A antibody or antigen binding fragment or anti-TLl A antibody(ies)” in the specification for simplicity
  • compositions for the anti-TLl A antibodies are described and provided in Section 4.5.
  • Methods of using the anti-TLIA antibodies are provided in Section 4.6. Further specific and validated embodiments for the anti-TLIA antibodies and the methods of using the same are provided in Section 5.
  • the disclosure provides the various combinations of the anti-TLIA antibodies, the pharmaceutical compositions of such anti-TLIA antibodies, the methods of generating the anti-TLIA antibodies, the methods of assaying the anti-TLIA antibodies, and the methods of using the anti-TLIA antibodies for treatment.
  • the antibody or antigen binding fragment blocks binding of TL1 A 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 TL1 A.
  • the antibody or antigen binding fragment blocks the increase of IFNy secretion by various immune cells.
  • the antibody or antigen binding fragment blocks the increase of IFNy secretion by peripheral blood mononuclear cells, including various B cells, T cells, natural killer cells, and/or macrophages.
  • the disclosure provides anti-TLIA antibodies or antigen binding fragments for binding both monomeric and trimeric TL1A. Therefore, in one embodiment of the various anti-TLIA antibodies or antigen binding fragments thereof provided herein, binding affinity of the antibody or antigen binding fragment to monomeric TL1 A as measured by dissociation equilibrium constant (Ko-monomer) is comparable to binding affinity of the antibody or antigen binding fragment to trimeric TL1 A as measured by dissociation equilibrium constant (Ko-trimer).
  • KD -monomer and/or Ko-trimer can be determined via any of the methods known and practice by a skilled artisan in the field and via any of the applicable assays and methods described herein, including in this Section (Section 4.2) and Section 5.
  • binding refers 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 TL1 A, is the affinity of the antibody or functional fragment for that epitope.
  • the ratio of dissociation rate (koff) to association rate (k on ) of an antibody to a monovalent antigen (k o ff/k on ) is the dissociation constant KD, which is inversely related to affinity.
  • KD dissociation constant
  • the value of KD varies for different complexes of antibody and antigen and depends on both k on and koff.
  • the dissociation constant KD for an antibody provided herein can be determined using any method provided herein or any other method well known to those skilled in the art.
  • the affinity at one binding site does not always reflect the true strength of the interaction between an antibody and an antigen.
  • the avidity of an antibody can be a better measure of its binding capacity than is the affinity of its individual binding sites.
  • 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 (KD). Affinity can be measured by common methods known in the art, including those described herein.
  • KD dissociation constant
  • the “KD” or “KD 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 interest and its antigen (Chen etal., 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 “k on ” 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-TLl A antibody or antigen binding fragment for the TL1A monomer and TL1A trimer can be described and provided by Ko-monomer and Ko-trimer.
  • the Ko-monomer is within 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold of the Ko-trimer.
  • the Ko-monomer is within 10%, 20%, 30%, 40%, or 50% of the Ko-trimer.
  • the Ko-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-TLl A antibodies or antigen binding fragments provided herein, the Ko-trimer is within 10%, 20%, 30%, 40%, or 50% of the KD- monomer.
  • KD -monomer is at most 5* IO -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 I MO' 11 M, at most 2x i0' n M, at most 3x l0 -11 M, at most 4x l0 -11 M, at most 5x l0 -11 M, at most 6x l0' n M, at most 7x 10' 11 M, at most 8x l0' n M, at most 9x 10' 11 M, at most l x IO -10 M, at most 2x 1 O' 10 M, at most 3x l0' 10 M, at most 4x lO' 10 M, at most 5x l0' 10 M, at most 6x lO' 10 M, at most 7x lO' 10 M, at most I MO' 11 M, at most 2x i0' n M, at most 3x l0
  • KD- monomer is about 5x l0 -12 M, about 6x 10' 12 M, about 7x 10' 12 M, about 8x l0' 12 M, about 9x 10' 12 M, about I x lO’ 11 M, about 2x l0 -11 M, about 3x l0 -11 M, about 4x l0 -11 M, about 5x l0 -11 M, about 6x l0 -11 M, about 7x l0 -11 M, about 8x l0 -11 M, about 9x l0 -11 M, about Ix lO -10 M, about 2x IO -10 M, about 3x l0' 10 M, about 4x 10' 10 M, about 5x l0' 10 M, about 6x 10' 10 M, about 7x 1 O' 10 M, about 8x 10' 10 M, about 9x 10' 10 M, or about 1 x 10' 9 M.
  • Ko-trimer is at most 5x l0' 12 M, at most 6x l0' 12 M, at most 7xl0' 12 M, at most 8 x 1 O’ 12 M, at most 9xl0' 12 M, at most I x lO’ 11 M, at most 2x l0' n M, at most 3x l0' n M, at most 4x l0' n M, at most 5x l0' n M, at most 6x l0' n M, at most 7x l0' n M, at most 8x l0' n M, at most 9x l0' n M, at most I x lO' 10 M, at most 2x lO' 10 M, at most 3x lO' 10 M, at most 4x lO' 10 M, at most 5x lO' 10 M, at most 6x lO' 10 M, at most 6x lO' 10 M, at most 3x lO' 10 M
  • Ko-trimer is about 5x 10' 12 M, about 6x 10' 12 M, about 7x 10' 12 M, about 8x l0' 12 M, about 9x l0' 12 M, about I x lO' 11 M, about 2x l0' n M, about 3x l0' n M, about 4x l0' n M, about 5x l0' n M, about 6x l0' n M, about 7x l0' n M, about 8x l0' n M, about 9x 10' 11 M, about I x lO' 10 M, about 2x IO' 10 M, about 3x lO' 10 M, about 4x IO' 10 M, about 5x 10' 10 M, about 6x lO' 10 M, about 7x lO' 10 M, about 8x lO' 10 M, about 9x lO' 10 M, or about I x lO' 9 M.
  • the disclosure further provides that the disclosure further
  • the KD -monomer is about 59 pM. In another specific embodiment, the Ko-trimer is about 59 pM. In a further embodiment, the KD -monomer is about 59 pM and the Ko-trimer is about 59 pM. In one specific embodiment, the KD -monomer is about 60 pM. In another specific embodiment, the Ko-trimer is about 60 pM. In a further embodiment, the Ko-monomer is about 60 pM and the Ko-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 Ko-monomer is at most 60 pM and the Ko-trimer is at most 60 pM.
  • antibodies that bind to TL1 A.
  • antibody refers to any form of antibody that exhibits the desired biological or binding activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, chimeric antibodies and camelized single domain antibodies.
  • 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 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. (1989).
  • 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.
  • 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.
  • the assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al:, National Institutes of Health, Bethesda, Md.; 5 th ed.; NIH Publ. No. 91-3242 (1991);
  • antibody fragment or “antigen binding fragment” refers 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), 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 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., IgGl, IgG2, IgG3, IgG4, IgAl 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 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.
  • the 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
  • 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 precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme), Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme);
  • the CDRs of the antibodies described herein can be defined by a method selected from Kabat, Chothia, IMGT, Aho, AbM, or combinations thereof.
  • 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.
  • 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.
  • the terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as fusion with another polypeptide and/or conjugation, e.g., with a labeling component.
  • polypeptides containing one or more analogs of an amino acid for example, unnatural amino acids, etc.
  • a protein such as an antibody described herein comprises a hydrophobic amino acid.
  • hydrophobic amino acids include glycine (Gly), proline (Pro), phenylalanine (Phe), alanine (Ala), isoleucine (He), leucine (Leu), and valine (Vai).
  • a protein such as an antibody described herein comprises a hydrophilic amino acid.
  • Non-limiting exemplary hydrophilic amino acids include serine (Ser), threonine (Thr), aspartic acid (Asp), glutamic acid (Glu), cysteine (Cys), asparagine (Asn), glutamine (Gin), arginine (Arg), and histidine (His).
  • 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 (He), leucine (Leu) and valine (Vai).
  • 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.
  • Nonlimiting 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 (Gin).
  • polynucleotide refers 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.
  • the term “about” means within 10% of the stated amount.
  • an antibody variable region comprising about 80% identity to a reference variable region may comprise 72% to 88% identity to the reference variable region.
  • antibodies are described herein that specifically bind to ILIA (Entrez Gene: 9966; UniProtKB: 095150). In some embodiments, the antibodies specifically bind to soluble ILIA. In some embodiments, the antibodies specifically bind to membrane bound ILIA.
  • an anti-TLl A 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.
  • An anti-TLIA antibody may comprise any region provided herein, for example, as provided in the tables, the examples, and the sequences.
  • an anti-TLIA antibody comprises a HCDRl as set forth by SEQ ID NO: 1.
  • an anti-TLIA antibody comprises a HCDR2 as set forth by any one of SEQ ID NOS: 2-5.
  • an anti-TLIA antibody comprises a HCDR3 as set forth by any one of SEQ ID NOS: 6-9.
  • an anti-TLIA antibody comprises a LCDR1 as set forth by SEQ ID NO: 10.
  • an anti-TLIA antibody comprises a LCDR2 as set forth by SEQ ID NO: 11.
  • an anti-TLIA antibody comprises a LCDR3 as set forth by any one of SEQ ID NOS: 12-15.
  • an anti-TLIA 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.
  • the anti-TLIA antibody comprises the CDRs of antibody J of Table 10.
  • the anti-TLIA antibody comprises the CDRs of antibody J2 of Table 10.
  • the anti-TLIA antibody comprises the CDRs of antibody K of Table 10.
  • an anti-TLIA antibody comprises a HCDRl as set forth by SEQ ID NOS: 401, 407, 413, or 450.
  • an anti-TLIA antibody comprises a HCDR2 as set forth by SEQ ID NOS: 402, 408, 414, or 451.
  • an anti-TLIA antibody comprises a HCDR3 as set forth by SEQ ID NOS: 403, 409, 415, or 452.
  • an anti-TLIA antibody comprises a LCDR1 as set forth by SEQ ID NOS: 404, 410, 416, or 453.
  • an anti-TLIA antibody comprises a LCDR2 as set forth by SEQ ID NOS: 405, 411, 417, or 454. In certain embodiments, an anti-TLIA antibody comprises a LCDR3 as set forth by SEQ ID NOS: 406, 412, 418, or 455.
  • an anti-TLIA antibody comprises a HCDRl, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 selected from Table 6.
  • an anti-TLIA antibody comprises the CDRs set forth in antibody A, B, C, D, E, F, G, H, I, A2, B2, C2, D2, E2, F2, G2, H2, 12, J, J2, K, M, orN of
  • an anti-TLIA antibody comprises the heavy chain CDRs set forth in an antibody selected from Table 7.
  • an anti-TLIA antibody comprises the light chain CDRs set forth in an antibody selected from Table 8. Table 8. Example light chain variable region sequences
  • an anti-TLIA antibody comprises the CDRs set forth in any one of the antibodies of Table 1.
  • an anti-TLIA 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, A
  • Antibody CDRs may be defined by the Aho, Kabat, Chothia, or IMGT methods.
  • an anti-TLl A antibody comprises a heavy chain (HC) framework 1 (FR1) as set forth by SEQ ID NO: 304.
  • an anti-TLIA antibody comprises a HC FR2 as set forth by any one of SEQ ID NOS: 305 or 313.
  • an anti-TLIA antibody comprises a HC FR3 as set forth by any one of SEQ ID NOS: 306-307, 314-315.
  • an anti-TLIA antibody comprises a HC FR4 as set forth by SEQ ID NO: 308.
  • an anti-TLIA antibody comprises a LC FR1 as set forth by SEQ ID NO: 309.
  • an anti-TLIA antibody comprises a LC FR2 as set forth by SEQ ID NO: 310. In certain embodiments, an anti-TLIA antibody comprises a LC FR3 as set forth by SEQ ID NO: 311. In certain embodiments, an anti-TLIA antibody comprises a LC FR4 as set forth by SEQ ID NO: 312.
  • an anti-TLIA 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-TLIA 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-TLIA antibody comprises the heavy chain framework regions set forth in an antibody selected from Table 7. In certain embodiments, an anti-TLl A antibody comprises the light chain framework regions set forth in an antibody selected from Table 8. In certain embodiments, an anti-TLl A antibody comprises the framework regions set forth in any one of the antibodies of Table 1.
  • an anti- TLl A antibody comprises the framework regions of antibody A15, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55, A56, A57, A58, A59, A60, A61, A62, A63, A64, A65, A66, A67, A68, A69, A70, A71, A72, A73, A74, A75, A76, A77, A78, A79, A81, A82, A83, A85, A86, A87, A88, A89, A90, A91, A92, A93, A94, A95, A96, A97, A98, A99, A100, A101, A102, A103, A104, A105, A107, A108, A109, A
  • an anti-TLl A antibody comprises the framework region of antibody A219.
  • the anti-TLl A antibody comprises the framework region of an antibody comprising SESQ ID NOS: 420 and 430.
  • the anti-TLl A antibody comprises the framework region of an antibody comprising SESQ ID NOS: 421 and 431.
  • the anti-TLl A 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-TLl A antibody comprises a heavy chain variable framework region comprising a human IGHV1 -46*02 framework or a modified human IGHV1 -46*02 framework, and a light chain variable framework region comprising a human IGKV3-20 framework or a modified human IGKV3-20 framework; wherein the heavy chain variable framework region and the light chain variable framework region collectively comprise no or fewer than nine amino acid modification(s) from the human IGHV 1 -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 numbering.
  • the amino acid modification(s) comprises L55W in the light chain variable region, per Aho or Kabat numbering.
  • an anti-TLIA 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
  • XI is at position 1 of IGHV 1-46*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-TLIA antibody comprising a heavy chain framework comprising IGHV 1 -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.
  • the anti-TLIA of any one of embodiments 1-20 comprising antibody G or I.
  • the anti-TLIA of any one of embodiments 1-20 comprising antibody H.
  • the anti-TLIA of any one of embodiments 1-33, comprising a light chain comprising a light chain framework comprising IGKV3 -20*01, or a variant thereof, wherein the variant comprises between about 1 and about 2 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 in the framework.
  • the anti-TLIA antibody of embodiment 34 wherein X10 is L.
  • an anti-TLIA antibody comprises a light chain framework comprising SEQ ID NO: 303 (EIVLTQSPGTLSLSPGERATLSC[LCDR1]WYQQKPGQAPRX1OX11IY[LCDR2]GIPDR FSGSGSGTDFTLTISRLEPEDFAVYYC[LCDR3]FGGGTKLEIK).
  • X10 is L.
  • X10 is P.
  • XI 1 is L.
  • XI 1 is W.
  • X10 is at position 54 of IGKV3-20*01 as determined by Aho or Kabat numbering.
  • XI 1 is at position 55 of IGKV3-20*01 as determined by Aho or Kabat numbering.
  • an anti-TLIA antibody comprises a heavy chain framework comprising IGHV1 -46*02. In some embodiments, an anti-TLIA 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. In some embodiments, an anti-TLIA antibody comprises a heavy chain framework comprising a variant of IGHV 1-46*02 comprising between about 1 and about 9 amino acid substitutions from SEQ ID NO: 316.
  • an anti-TLIA 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.
  • the heavy chain framework substitution comprises M55I, as determined by Aho or Kabat numbering.
  • 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-TLIA antibody comprises a light chain framework comprising IGKV3-20*01. In some embodiments, an anti-TLIA 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-TLIA antibody comprises a variant of IGKV3-20*01 comprising about 1 amino acid substitution from SEQ ID NO: 317. In some embodiments, an anti-TLIA 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-TLIA 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 light chain framework substitution comprises R45K, as determined by Aho or Kabat numbering.
  • an anti-TLIA antibody comprises a heavy chain FR1 as set forth by SEQ ID NO: 304.
  • an anti-TLIA antibody comprises a heavy chain FR2 as set forth by SEQ ID NO: 305.
  • an anti-TLIA antibody comprises a heavy chain FR2 as set forth by SEQ ID NO: 313. In some embodiments, an anti-TLIA antibody comprises a heavy chain FR3 as set forth by SEQ ID NO: 306. In some embodiments, an anti-TLIA antibody comprises a heavy chain FR3 as set forth by SEQ ID NO: 307. In some embodiments, an anti-TLIA antibody comprises a heavy chain FR3 as set forth by SEQ ID NO: 314. In some embodiments, an anti-TLIA antibody comprises a heavy chain FR3 as set forth by SEQ ID NO: 315. In some embodiments, an anti-TLIA antibody comprises a heavy chain FR4 as set forth by SEQ ID NO: 308.
  • an anti-TLIA antibody comprises a light chain FR1 as set forth by SEQ ID NO: 309. In some embodiments, an anti-TLIA antibody comprises a light chain FR2 as set forth by SEQ ID NO: 310. In some embodiments, an anti-TLIA antibody comprises a light chain FR3 as set forth by SEQ ID NO: 311. In some embodiments, an anti-TLIA antibody comprises a light chain FR4 as set forth by SEQ ID NO: 312.
  • an anti-TLIA antibody comprises a framework region of Table 9A
  • an anti-TLIA 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 any one of SEQ ID NOS: 201-220 or 430-437.
  • an anti-TLIA antibody comprising a heavy chain variable region and a light chain variable region.
  • Non -limiting additional embodiments include: (Embodiment 2) The anti-TLIA 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 70) The anti-TLIA 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, 421, or 422, 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: 420, 421, or 422.
  • the anti-TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA 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.
  • (Embodiment 80) The anti-TLIA 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: 210 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: 210.
  • the anti-TLIA 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-TLIA 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-TLIA 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: 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-TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA 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.
  • the anti-TLIA 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: 430, 431, or 432 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: 430, 431, or 432.
  • Embodiment 96 The anti-TLIA 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: 103, 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 102) The anti-TLIA 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:
  • 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-TLIA 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-TLIA 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.
  • 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 110) The anti-TLIA 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: 113, 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-TLIA 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-TLIA 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-TLIA 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 127) The anti-TLIA 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-TLIA 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: 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 140) The anti-TLIA 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: 124, 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 141 The anti-TLIA 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-TLIA 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-TLIA 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- TLIA 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-TLIA 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-TLIA antibody of embodiment 1 comprising A500.
  • the anti-TLIA 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 156) The anti- TLIA 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: 421, 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: 431.
  • (Embodiment 157) The anti-TLIA 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 IgGl, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g., a substitution, addition, or deletion) at one or more amino acid positions.
  • the Fc region comprises any one of SEQ ID NOS: 320-367.
  • the anti-TLIA 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 Clq binding, complement dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), antibodydependent 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 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 Clq 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 IgGl, 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 IgGl, SEQ ID NO: 320).
  • the antibodies of this disclosure have reduced effector function as compared with human IgGl.
  • 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 Clq relative to an unmodified antibody (e.g., human IgGl having SEQ ID NO: 320).
  • antibodies herein exhibit affinities for Clq 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 exhibit affinities for Clq 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.
  • Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcyR binding (hence likely lacking ADCC activity) but retains FcRn binding ability. Measurement of effector function may be performed as described in Example 3.
  • antibodies are tested for binding to Fey receptors and complement Clq 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-TLIA 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
  • useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.
  • ADCC assays are described in Wisecarver et al., 1985 79:277- 282; Bruggemann et al., 1987, J Exp Med 166:1351-1361; Wilkinson et al., 2001, J Immunol Methods 258:183-191; Patel et al., 1995 J Immunol Methods 184:29-38.
  • 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 may be performed as described in Gazzano- Santoro et al., 1996, J. Immunol. Methods, 202:163.
  • Non-limiting examples of Fc mutations in IgGl 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 IgGl, 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 IgGl.
  • an antibody comprises an IgGl Fc region comprising one or more of the following substitutions according to the Kabat numbering system: N297A, N297Q, N297D, D265A, S228P, L235A, L237A, L234A, E233P, L234V, C236 deletion, P238A, A327Q, P329A, P329G, L235E, P331S, L234F, 235G, 235Q, 235R, 235S, 236F, 236R, 237E, 237K, 237N, 237R, 238A, 238E, 238G, 238H, 2381, 238V, 238W, 238Y, 248A, 254D, 254E, 254G, 254H, 2541, 254N, 254P, 254Q, 254T, 254V, 255N, 256H, 256K, 256
  • an antibody comprises a Fc region selected from the representative sequences disclosed in Table 3, Table 13, and Table 9B.
  • an antibody comprises an IgGl 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 IgGl Fc region comprising L235E, according to the Kabat numbering system.
  • an antibody comprises an IgGl Fc region comprising L234A and L235A, according to the Kabat numbering system.
  • an antibody comprises an IgGl Fc region comprising L234A, L235A, and G237A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising L234A, L235A, P329G, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising L234F, L235E, and P331S, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising L234A, L235E, and G237A, according to the Kabat numbering system.
  • an antibody comprises an IgGl Fc region comprising L234A, L235E, G237A, and P331S, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising L234A, L235A, G237A, P238S, H268A, A330S, and P331S (IgGlo), according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising L234A, L235A, and P329A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising G236R and L328R, according to the Kabat numbering system.
  • an antibody comprises an IgGl Fc region comprising G237A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising F241 A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising V264A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising D265A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising D265A and N297A, according to the Kabat numbering system.
  • an antibody comprises an IgGl Fc region comprising D265A and N297G, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising D270A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising N297A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising N297G, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising N297D, according to the Kabat numbering system.
  • an antibody comprises an IgGl Fc region comprising N297Q, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising P329A, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising P329G, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising P329R, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising A330L, according to the Kabat numbering system. In some embodiments, an antibody comprises an IgGl Fc region comprising P331A, according to the Kabat numbering system.
  • an antibody comprises an IgGl 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. In some embodiments, an antibody comprises an IgG2-IgG4 cross-subclass (IgG2/G4) Fc region.
  • 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 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 P331 S substitution, according to the Kabat numbering system.
  • 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. In some embodiments, 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-TLIA described herein comprises a Fc region as shown in Table 13.
  • an anti-TLIA antibody described herein comprises a Fc region comprising a sequence from Table 9B. In certain embodiments, an anti-TLIA 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.
  • anti-TLIA 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-TLIA antibody includes an anti-TLIA antigen binding fragment.
  • Nonlimiting additional embodiments include: (Embodiment 2) The anti-TLIA antibody of embodiment 1, comprising a heavy chain comprising a HCDRl 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 LCDRl 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.
  • the anti-TLIA 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, 12, J, J2, K, M, or N (Table 10).
  • the anti-TLIA 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-TLIA 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 LCDRl 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
  • the anti-TLIA antibody of any one of embodiments 1-19 comprising a heavy chain framework comprising a variant of IGHV1-46*O2 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-TLIA 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-TLIA 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- TLIA 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-TLIA antibody of any one of embodiments 21-27, wherein the heavy chain framework substitution comprises V78A, as determined by Aho or Kabat numbering.
  • (Embodiment 33) The anti-TLIA antibody of any one of embodiments 1-19, comprising a heavy chain framework comprising SEQ ID NO: 301.
  • (Embodiment 34) The anti-TLIA antibody of embodiment 33, wherein XI is Q.
  • (Embodiment 52) The anti-TLIA antibody of any one of embodiments 1-51, comprising a light chain framework comprising IGKV3 -20*01.
  • (Embodiment 53) The anti- TLIA antibody of any one of embodiments 1-51, comprising a light chain framework comprising a variant of IGKV3-20*01 comprising between about 1 and about 20 amino acid substitutions from SEQ ID NO: 317.
  • the anti-TLIA antibody of any one of embodiments 1-51 comprising a light chain framework comprising a variant of IGKV3-20*01 comprising about 2 amino acid substitutions from SEQ ID NO: 317.
  • the anti-TLIA 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 59 The anti-TLIA 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-TLIA antibody of embodiment 59, wherein X10 is L.
  • Embodiment 61 The anti-TLIA antibody of embodiment 59, wherein X10 is P.
  • (Embodiment 64) The anti-TLIA antibody of any one of embodiments 1-19, comprising a heavy chain variable framework region comprising a modified human IGHV 1 - 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 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 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 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 80) The antibody of embodiment 74, wherein 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, and V89A; R45K, A47R, M80I, R82T, V89A, M91L; or R45K, A47R, M55I, M80I, V89A, and M91L.
  • (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 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.
  • Variable Region Embodiments [00351] Variable Region Embodiments [00352] (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.
  • 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 IgGl and/or reduced complement-dependent cytotoxicity (CDC) as compared to human IgGl.
  • Embodiment 123 The antibody of embodiment 122, wherein the human IgGl comprises SEQ ID NO: 320.
  • Embodiment 124) The antibody of embodiment 122 or embodiment 123, wherein the ADCC function of the Fc region comprising reduced ADCC is at least about 50% reduced as compared to human IgGl.
  • (Embodiment 127) The anti-TLIA 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-TLIA 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 (IgG2c>).
  • (Embodiment 131) The anti- TLIA 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: 368-380.
  • Embodiment 132 The anti-TLIA 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-TLIA 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.
  • Embodiment 134 The anti-TLIA 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.
  • Embodiment 135) 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 136 The antibody of embodiment 134 or 135, wherein the antibody is purified as described in Example 2.
  • (Embodiment 139) The antibody of any one of embodiments 134-138, wherein the size exclusion chromatography column has a pore size of 200 A, the size exclusion chromatography column has a particle size of 1.7 micrometer, or the size exclusion chromatography column has a pore size of 200 A and a particle size of 1.7 micrometer.
  • (Embodiment 140) The antibody of any one of embodiments 134-139, wherein the size exclusion chromatography column is ACQUITY UPLC BEH200 SEC column.
  • (Embodiment 141) The antibody of any one of embodiments 134-140, wherein the antibody or antigen binding fragment is injected at a total volume of 15 pL.
  • Embodiment 142 The antibody of any one of embodiments 134-141, wherein the antibody is injected at a concentration of about 0.1 pg/pL to about 1.0 pg/pL.
  • Embodiment 143 The antibody of any one of embodiments 134-142, wherein the size exclusion chromatography is performed on a Shimadzu UPLC instrument.
  • Embodiment 144 The antibody of any one of embodiments 134-143, wherein the size exclusion chromatography is performed at a flow rate of 0.2 mL/min.
  • Embodiment 145) The antibody of any one of embodiments 134-144, wherein the size exclusion chromatography is performed at a column oven temperature of 30°C.
  • (Embodiment 149) The anti-TLIA antibody of any one of embodiments 1- 147, 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 pg/mL as determined by a method disclosed herein.
  • (Embodiment 150) The antibody of embodiment 148 or embodiment 149, wherein the antibody is expressed in FreeStyle 293 -F cells.
  • (Embodiment 151) The antibody of any one of embodiments 148-150, wherein the antibody is expressed as described in Example 2.
  • Embodiment 152 The antibody of any one of embodiments 148-151, wherein the antibody expression level is quantified using Enzyme-Linked Immunosorbent assay (ELISA).
  • ELISA Enzyme-Linked Immunosorbent assay
  • embodiment 153 The antibody of embodiment 152, 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-TLIA antibody to the substrate, and applying to the substrate a second antibody that binds to a human or humanized antibody.
  • the antibody of embodiment 153, where the capture antibody comprises an anti-kappa antibody.
  • Embodiment 155 The antibody of embodiment 153 or embodiment 154, where the second antibody comprises an anti-Fc antibody.
  • Embodiment 156 The antibody of any one of embodiments 152-155, where the ELISA is performed as described in Example 2.
  • (Embodiment 157) A method of treating a disease and/or condition of the kidney in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment of any one of embodiments 1-156.
  • (Embodiment 158) The method of embodiment 157, wherein the disease and/or condition of the kidney comprises end-stage renal disease, tubulointerstitial renal fibrosis, glomerulonephritis, interstitial nephritis, acute interstitial nephritis, diabetic kidney diseases, lupus nephritis, Alport syndrome, or polycystic kidney disease, or a combination thereof.
  • Embodiment 159 A method of treating inflammation and/or fibrosis in a subject in need thereof, the method comprising administering to the subject an antibody or antigen binding fragment of any one of embodiments 1-156. (Embodiment 160) the method of embodiment 159, wherein the subject has inflammatory bowel disease.
  • Embodiment 161 A nucleic acid encoding the antibody of any one of embodiments 1-156.
  • Embodiment 162 A vector comprising the nucleic acid of embodiment 161.
  • Embodiment 163 A cell comprising the nucleic acid of embodiment 161.
  • Embodiment 164 A cell comprising the vector of embodiment 162.
  • Anti-TLl A antibodies described herein bind to specific regions or epitopes of human ILIA.
  • an anti-TLIA antibody provided herein has a binding affinity to human ILIA of less than about IE' 7 , IE' 8 , IE' 9 , or IE' 10 Kd. In some cases, the binding affinity is from about IE -9 to about IE -10 Kd.
  • an anti-TLIA antibody provided herein has a binding affinity to murine TL1 A and/or rat TL1 A of less than about IE -7 , IE -8 , IE -9 , IE -10 , or IE -11 Kd. Methods for determining binding affinity are exemplified herein, including in Example 2.
  • an anti-TLIA antibody provided herein is an antagonist of a TL1 A 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-TLIA 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. In certain embodiments, the antibody inhibits interferon gamma release in human blood at an IC50 of between about 200 picomolar and about 30 picomolar. In certain embodiments, the antibody inhibits interferon gamma release in human blood at an IC50 of less than or equal to about 200 picomolar. In certain embodiments, the antibody inhibits interferon gamma release in human blood at an IC50 of less than or equal to about 100 picomolar.
  • an anti-TLIA antibody provided herein comprises at least about 80% monomeric fraction after expression and purification as described in Example 2 or elsewhere herein. In various embodiments, an anti-TLIA 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-TLl A 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- TE1A 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.
  • an anti-TLIA antibody provided herein has at least about 2 pg/mL expression as determined by the method disclosed herein. In some embodiments, the anti-TLIA antibody has about 2 pg/mL to about 60 pg/mL expression as determined by the method disclosed herein. In some embodiments, the anti-TLIA antibody has about 5 pg/mL to about 60 pg/mL expression as determined by the method disclosed herein. In some embodiments, the anti-TLIA antibody has about 10 pg/mL to about 60 pg/mL expression as determined by the method disclosed herein.
  • the anti-TLIA antibody has at least about 5 pg/mL expression as determined by the method disclosed herein. In some embodiments, the anti-TLIA antibody has at least about 10 pg/mL expression as determined by the method disclosed herein. In some embodiments, the anti-TLIA antibody has at least about 15 pg/mL expression as determined by the method disclosed herein. In some embodiments, the anti-TLIA antibody has at least about 20 pg/mL expression as determined by the method disclosed herein.
  • the anti-TLIA antibody expresses between about 2 pg/mL and about 50 pg/mL, between about 2 pg/mL and about 40 pg/mL, between about 2 pg/mL and about 30 pg/mL expression, between about 2 pg/mL and about 20 pg/mL, between about 5 pg/mL and about 50 pg/mL, between about 5 pg/mL and about 40 pg/mL, between about 5 pg/mL and about 30 pg/mL, between about 10 pg/mL and about 50 pg/mL, between about 10 pg/mL and about 40 pg/mL, or between about 10 pg/mL and about 30 pg/mL as determined by the method disclosed herein.
  • the anti-TLIA 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 pg/mL expression as determined by the method disclosed herein. Methods disclosed herein include those described in Example 2.
  • an anti-TLIA 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.
  • an anti-TLIA antibody that binds to the same region of a TL1 A protein or portion thereof as a reference antibody such as the anti-TLIA antibodies described herein.
  • the reference antibody comprises 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-TLIA antibody that binds specifically to the same region of TL1 A 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-TLIA antibody that binds specifically to the same region of TL1 A 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-TLIA antibody that binds specifically to the same region of TL1 A 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-TLIA antibody that binds specifically to the same region of TL1 A 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-TLIA antibody i.e. test antibody
  • 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 TL1 A protein or portion thereof, or determining whether the reference antibody can compete with binding between the test antibody and the TL1 A protein or portion thereof.
  • Exemplary methods include use of surface plasmon resonance to evaluate whether an anti-TLl A antibody can compete with the binding between TL1A and another anti-TLIA antibody. In some cases, surface plasmon resonance is utilized in the competition assay. Non-limiting methods are described in the examples.
  • antibodies that compete for binding TL1A with the antibodies described herein are antibodies that bind a discrete epitope that overlaps with an epitope of TL1 A bound by an antibody described herein.
  • antibodies that bind the same epitope of TL1 A, overlap with the epitope of TL1 A by one or more amino acid residues, or that compete for binding to an epitope of TL1 A 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 TL1 A, overlap with the epitope of TL1 A by one or more amino acid residues, or that compete for binding to an epitope of TL1 A 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 ILIA, overlap with the epitope of ILIA by one or more amino acid residues, or that compete for binding to an epitope of ILIA 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.
  • 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. Briefly, (1) 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 ILIA 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 ILIA, and displayed high monomer content.
  • the antibodies described herein can be assayed for specific binding by any method known in the art.
  • 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.
  • Such assays are provided in for e.g., Ausubel et al., eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York.
  • monoclonal antibodies are prepared using methods known in the art, such as, but not limited to the hybrid oma 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. The 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-TLIA 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. For example, 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 method ologies/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-TLl A 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.
  • an antibody fragment is used to treat and/or ameliorate inflammation and/or fibrosis. In certain embodiments, an antibody fragment is used to treat and/or ameliorate a disease and/or condition of the kidney.
  • Various techniques are known for the production of antibody fragments. Generally, these fragments are derived via proteolytic digestion of intact antibodies (for example Morimoto et al., 1993, Journal of Biochemical and Biophysical Methods 24:107-117; Brennan et al., 1985, Science, 229:81). Fab, Fv, and scFv antibody fragments can all be expressed in and secreted from E. coli or other host cells, thus allowing the production of large amounts of these fragments. Other techniques for the production of antibody fragments will be apparent to the skilled practitioner.
  • techniques can be adapted for the production of single-chain antibodies specific to TL1A.
  • methods can be adapted for the construction of Fab expression libraries to allow rapid and effective identification of monoclonal Fab fragments with the desired specificity for TL1 A, or derivatives, fragments, analogs or homologs thereof.
  • 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 ILIA.
  • 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.
  • 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, polyad enylation 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. coll. 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 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 & Pemis, eds., Acad. Press, NY, 1979 and 1981).
  • a genetic construct comprising a nucleic acid encoding an anti-TLl A 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-TLl A 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.
  • 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.
  • Various embodiments provide a host cell comprising a genetic construct and/or recombinant vector described herein.
  • 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 polyad enylation 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.
  • 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-transf erase can be 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, Vai, Leu, or Ala for one another), or substitution of one polar residue for another (such as between Lys and Arg; Glu and Asp; or Gin 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 Vai; Leu into lie or into Vai; 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 Vai, 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 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.
  • 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.
  • 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.
  • the term “vector,” as used herein, refers to a nucleic acid construct designed for delivery to a host cell or for transfer between different host cells.
  • a vector can be viral or non-viral.
  • the term “vectof ’ 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 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).
  • 5’ untranslated (5’UTR) or “leader” sequences and 3’ UTR or “trailer” sequences as well as intervening sequences (introns) between individual coding segments (exons).
  • 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-TLIA 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 inflammation and/or fibrosis.
  • the methods of use may be in vitro, ex vivo, or in vivo methods.
  • a disease and/or condition treated with an anti-TLIA antibody is a disease and/or condition of the kidney.
  • 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.
  • the route of administration is subcutaneous.
  • the pharmaceutical compositions may contain any pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carried’ 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.
  • compositions including a pharmaceutically acceptable excipient along with a therapeutically effective amount of an anti-TLIA antibody.
  • “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).
  • routes of administration e.g., subcutaneous, intravenous, oral.
  • Nonlimiting 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 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 a particular disorder or condition will depend on the nature of the disorder or condition and can be determined by one of skill in the art with standard clinical techniques.
  • compositions comprising an anti-TLIA antibody formulated for intravenous administration.
  • compositions comprising an anti-TLIA antibody formulated for subcutaneous administration.
  • compositions comprising an anti-TLIA 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-TLIA antibody is present in the composition.
  • the composition comprises an anti- TLIA antibody at a concentration greater than about 50 mg/mL.
  • the composition comprising an anti-TLIA 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/rnL, greater than about 80 mg/rnL, 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-TLIA 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-TLIA 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-TLIA 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 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/mL to
  • the composition comprising an anti-TLIA 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-TLl A 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-TLIA 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-TLIA antibody at a concentration 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-TLIA 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-TLIA 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-TLIA 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-TLl A 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-TLl A 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-TLIA.
  • 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-TLIA.
  • 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-TLIA 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-TLIA antibody, wherein at least about 150 mg of the anti-TLIA 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 about 750 mg, up to about 500 mg of anti-TLIA 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,
  • 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
  • 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-TLIA 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-TLIA 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
  • 6 cP to about 14 cP about 6 cP to about 15 cP, about 6 cP to about 16 cP, about 6 cP to about 17 cP, about 6 cP to about 18 cP, about 6 cP to about 19 cP, about 6 cP to about 20 cP, about
  • the therapeutically effective dose is at least about 150 mg anti-TLIA 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-TLIA.
  • 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-TLIA.
  • 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,
  • 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 1.8 mL, 0.5
  • the concentration of anti-TLIA 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-TLIA antibody having a percentage aggregation of the anti-TLIA antibody as measured by size exclusion chromatography of less than about 5% of the total anti-TLIA antibody in the composition.
  • the percentage aggregation of anti-TLIA 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-TLIA 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-TLIA.
  • 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-TLIA.
  • 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-TLIA 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.
  • 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
  • Antibody therapeutics suitable for injection and/or administration are important to realizing full therapeutic potential.
  • administration is generally restricted by volume.
  • the therapeutic when the therapeutic is delivered subcutaneously.
  • This 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-TLl A 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-TLIA 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-TILA antibody is characterized by a viscosity less than about 30, 20, 15, or 10 mPa-s 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.
  • 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-TLIA antibody comprises a human IGHV 1 -46*02 framework or a modified human IGHV 1 -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 IGHV 1-46*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.
  • viscosities include 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 cP, about 2 cP to about 7 cP, about 2 cP to about 8 cP, about 2 cP to about 9
  • the anti-TILA 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-TILA 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 rng/mL. In some embodiments, the anti-TILA 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.
  • the anti- TILA 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. In some embodiments, the anti-TILA 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-TILA 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-TILA 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-TILA 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- TILA 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 230 mg/mL. In some embodiments, the anti-TILA 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 240 mg/mL. In some embodiments, the anti-TILA 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.
  • the anti-TILA 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 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
  • 6 to about 13 mPa-s from about 6 to about 12 mPa-s, from about 6 to about 11 mPa-s, from about 6 to about 10 mPa-s, from about 6 to about 9 mPa-s, from about 6 to about 8 mPa-s, or from about 6 to about 7 mPa-s.
  • greater than about 100, 125, 150, 160, 170, 180, 190, or 200 mg/ml is up to about 250 mg/ml.
  • the anti-TLIA 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 HCDRl 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-TLIA antibody comprises a human IGHV1-46*O2 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 IGHV 1 -46*02 framework and the human IGKV3-20 framework.
  • the anti-TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA 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.
  • anti-TLIA antibodies described herein also demonstrate advantageous aggregation properties.
  • the anti-TLIA 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.
  • 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-TLIA antibody comprises a human IGHV1-46*O2 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 IGHV 1 -46*02 framework and the human IGKV3-20 framework.
  • the anti-TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA 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. In some embodiments, the anti-TLIA 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 210 mg/mL.
  • the anti-TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA 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.
  • compositions comprising about 150 mg to about 225 mg of anti-TLIA 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-TLIA.
  • the total volume may be less than about 1.0, 0.9, or 0.8 mL if less than 300 mg of anti-TLIA.
  • the total volume may be at least about 0.5 mL if less than 300 mg of anti-TLIA.
  • 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
  • the concentration of anti-TLIA 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.
  • compositions comprising about 400 mg to about 1000 mg or about 400 mg to about 2000 mg of anti-TLIA 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
  • a pharmaceutical composition comprising an anti-TLIA 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, poly ethoxylated (35) castor oil, octylphenoxypoly(ethyleneoxy) ethanol, poly(oxyethylene-cooxypropylene) block copolymer, poly(oxyethylene-cooxypropylene) block copolymer, poly(oxyethylene- cooxypropylene) block copolymer, polydimethylsil o
  • the surfactant comprises an ionic surfactant.
  • Ionic surfactants include anionic and cationic surfactants.
  • anionic surfactants include alkyl sulfate, alkyl ether sulfate, docusate, sulfonate fluorosurf actant, 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), polyethoxylated tallow amine (POEA), benzalkonium chloride (BAC), benzethonium chloride (BZT), 5-bromo-5-nitro-l,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. In some embodiments of the composition provided herein, 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%, 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.
  • 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.
  • the composition comprises polysorbate-80 at a concentration of about 0.02% v/v of the composition.
  • a pharmaceutical composition comprising an anti-TLIA 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. In some embodiments, 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 mM
  • 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-TLIA antibody comprises a salt.
  • 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
  • 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.
  • the composition comprises about 25 mM to about 50 mM Lys-HCl.
  • the composition comprises about 25 mM Lys-HCl.
  • a pharmaceutical composition comprising an anti -I’Ll A antibody comprises a buffering agent.
  • buffering agents include an acetate, phosphate, citrate, glutamate, succinate, gluconate, histidine, 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.
  • the buffering agent comprising acetate comprises acetic acid and sodium acetate.
  • the buffering agent comprises potassium acetate.
  • 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. In some embodiments, 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.
  • 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-TLIA 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 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 4.8 to about 5.4, about
  • 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-TLIA 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. In some embodiments, the pharmaceutical composition comprises a stabilizer and a salt. In some embodiments, the pharmaceutical composition comprises a stabilizer and a buffering agent. In some embodiments, the pharmaceutical composition comprises a salt and buffering agent. In some embodiments, the pharmaceutical composition comprises a surfactant, stabilizer, and salt. In some embodiments, the pharmaceutical composition comprises surfactant, salt, and buffering agent. In some embodiments, the pharmaceutical composition comprises a surfactant, stabilizer and buffering agent. In some embodiments, the pharmaceutical composition comprises a stabilizer, salt, and buffering agent. In some embodiments, the pharmaceutical composition comprises a surfactant, stabilizer, salt, and buffering agent. In some embodiments, the pharmaceutical composition comprises a surfactant, stabilizer, salt, and buffering agent. In some embodiments, 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.
  • compositions comprise polysorbate (e.g., polysorbate- 20), sucrose, sodium chloride, and an acetate buffer.
  • the pH of the composition may be about
  • 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. In certain embodiments, the compositions comprise polysorbate (e.g., polysorbate-20), sucrose, glycine, and a phosphate buffer. In some embodiments, 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
  • 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.
  • a composition comprising an anti-TLIA 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-TLIA 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-TLIA 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- TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA 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-TLIA antibody provided 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.
  • compositions provided herein including in this Section (Section 4.5), for example those of the preceding paragraphs
  • further embodiments of the anti-TLIA 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 4.2; assays for screening, testing, and validating the anti-TLIA antibodies are provided in Section 4.3; methods for generating, improving, mutating, cloning, expressing, and isolating the anti-TLIA antibodies are provided in Section 4.4; methods for using the composition are described and provided in Section 4.6; various doses or dosing regimen for using the pharmaceutical composition are provided in Section 4.6 and this Section (Section 4.5); further specific and validated embodiments for the anti- TL1A antibodies and the methods of using the same are provided in Section 5.
  • the disclosure provides the various combinations of the anti-TLIA antibodies, the pharmaceutical compositions of such anti-TLIA antibodies, the doses or the dosing regimens for using such pharmaceutical compositions of anti-TLIA antibodies, the methods of generating the anti- TLIA antibodies, the methods of assaying the anti-TLIA antibodies, and the methods of using the anti-TLIA antibodies for treatment.
  • TL1 A is a pro-inflammatory mediator with a broad upstream effect on many inflammatory cells. TL1 A can also directly induce fibrosis by stimulating gut fibroblasts. [00447] The disclosure provides that the anti-TLIA antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat an inflammatory disease or condition in a subject by administering the anti- TLIA antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the anti-TLIA antibodies or antigen binding fragments and the pharmaceutical compositions thereof provided herein can be used in a method to treat kidney inflammation and/or kidney fibrosis in a subject by administering the anti-TLIA antibodies or antigen binding fragments or the pharmaceutical compositions thereof described herein to the subject.
  • the subject has one or more inflammatory conditions selected from the group consisting of a chronic kidney disorder, end stage renal disease, tubulointerstitial renal fibrosis, nephritis, diabetic kidney disease, and polycystic kidney disease.
  • the subject has glomerulonephritis, interstitial nephritis, IgA nephropathy, acute interstitial nephritis, lupus nephritis, or Alport syndrome, pyelonephritis, or a combination thereof.
  • the kidney inflammation and/or kidney fibrosis comprises or consists of one or more inflammatory conditions selected from the group consisting of a chronic kidney disorder, end stage renal disease, tubulointerstitial renal fibrosis, nephritis, diabetic kidney disease, and polycystic kidney disease.
  • the kidney inflammation and/or kidney fibrosis comprises or consists of glomerulonephritis, interstitial nephritis, IgA nephropathy, acute interstitial nephritis, lupus nephritis, or Alport syndrome, pyelonephritis, or a combination thereof.
  • a method of neutralizing monomeric TL1 A and trimeric TL1A in a subject comprising (a) administering an effective dose of anti-TLIA 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 kidney inflammation and/or kidney fibrosis.
  • the concentration of TL1 A in a diseased tissue in the subject is reduced below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis.
  • TL1 A refers to binding to TL1 A 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-TLIA antibody that blocks TL1A binding to DR3 also neutralizes DR3.
  • a method of reducing the concentration of TL1 A in a diseased tissue in a subject with kidney inflammation and/or kidney fibrosis comprising (a) administering an effective dose of anti-TLIA antibody or antigen binding fragment to the subject, thereby reducing the concentration of TL1 A in the diseased tissue in the subject below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis.
  • a method of treating kidney inflammation and/or kidney fibrosis in a subject in need thereof comprising (a) administering an anti-TLIA antibody or antigen binding fragment to the subject, wherein the anti-TLIA antibody or antigen binding fragment is administer at an effective dose such that the concentration of TL1 A in a diseased tissue in the subject after step (a) is below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis.
  • a method of treating kidney inflammation and/or kidney fibrosis in a subject in need thereof comprising (a) administering an anti-TLIA antibody or antigen binding fragment to the subject, wherein the anti-TLIA antibody or antigen binding fragment is administered at an effective dose such that the concentration of TL1 A in a diseased tissue in the subject after step (a) is below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis.
  • the diseased tissue comprises or consists of a tissue in the kidney.
  • the diseased tissue comprises or consists of 2, 3, 4, 5, 6, 7, 8, or more tissues in the kidney.
  • the corresponding tissue or the reference tissue comprises or consists of a tissue in the kidney.
  • the corresponding tissue or the reference tissue comprises or consists of 2, 3, 4, 5, 6, 7, 8, or more tissues in the kidney.
  • the effective dose used in the methods provided herein, including the methods provided in this Section (Section 4.6), 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 4.6), can include additional steps.
  • the methods further comprises (c) maintaining TL1 A in the diseased tissue in the subject at a concentration below the concentration of TL1 A in the corresponding tissue in the control subject.
  • the TL1 A in the diseased tissue in the subject is maintained with a maintenance regimen of the anti- TL1 A antibody or antigen binding fragment.
  • the TL1 A in the diseased tissue in the subject is maintained in step (c) with a maintenance regimen of the anti- TL1 A antibody or antigen binding fragment.
  • the maintenance regimen is administered after the induction regimen.
  • the disclosure provides that the induction regimen and the maintenance regimen in the methods provided herein, including in this Section (Section 4.6), 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-TLl A antibody or antigen binding fragment higher than the maintenance regimen.
  • the induction regimen comprises doses of the anti-TLl A 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 TL1 A in a diseased tissue in the subject below the concentration of TL1A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis.
  • the various methods provided herein can reduce the concentration of TL1 A in a diseased tissue in the subject below a reference TL1 A level (e.g. a reference concentration).
  • the various methods provided herein can reduce the concentration of TL1 A in a diseased tissue in the subject below the concentration of TL1 A in a reference tissue in a control subject without kidney inflammation and/or kidney fibrosis.
  • the diseased tissue in a patient with kidney inflammation and/or kidney fibrosis overproduces TL1 A, which contributes to the cause, phenotypes, and/or symptoms of the patient with kidney inflammation and/or kidney fibrosis.
  • the various methods provided herein reduces the concentration of TL1 A in the diseased tissues of the subject below the concentration of TL1 A in a corresponding tissue in a control subject without kidney inflammation and/or kidney fibrosis, while the diseased tissues (e.g. certain cells in the diseased tissues) of the subject are overproducing TL1 A.
  • Such reduction of TL1 A concentration in the diseased tissues of the subject to below (i) a reference TL1 A level or (ii) the concentration of TL1 A in a corresponding tissue or a reference tissue in a control subject without kidney inflammation and/or kidney fibrosis, while the diseased tissue in the subject overproduces TL1 A, can also be referred to as coverage.
  • a coverage of or covering 100 fold overproduction of TL1 A means that TL1 A concentration in the diseased tissues of the subject is reduced to below the concentration of TL1 A in a corresponding tissue or a reference tissue in a control subject without kidney inflammation and/or kidney fibrosis, while the diseased tissue overproduces TL1 A up to 100 fold comparing to the corresponding tissue or the reference tissue in a control subject without kidney inflammation and/or kidney fibrosis.
  • 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 TL1 A 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 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 TL1 A compared to the corresponding tissue in the control subject.

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Abstract

Sont décrits dans les présentes des compositions pharmaceutiques et d'anticorps anti-TL1A humanisés pour le traitement de maladies et/ou d'états pathologiques rénaux.
PCT/US2024/016264 2023-02-17 2024-02-16 Compositions d'anticorps anti-tl1a et méthodes de traitement rénales Ceased WO2024173865A2 (fr)

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US12466890B1 (en) 2023-08-11 2025-11-11 Paragon Therapeutics, Inc. TL1A binding proteins and methods of use

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ES2689080T3 (es) * 2013-01-02 2018-11-08 Glenmark Pharmaceuticals S.A. Anticuerpos que se unen a TL1A y sus usos
US20230159649A1 (en) * 2020-04-02 2023-05-25 La Jolla Institute For Immunology Methods and combinations for dual targeting of tnf family members
US20240336691A1 (en) * 2021-02-18 2024-10-10 Prometheus Biosciences, Inc. Anti-tl1a antibody compositions and methods of treatment in the lung

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US12466890B1 (en) 2023-08-11 2025-11-11 Paragon Therapeutics, Inc. TL1A binding proteins and methods of use

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