CN117202932A - anti-TL 1A antibody compositions and methods for treating lung - Google Patents

anti-TL 1A antibody compositions and methods for treating lung Download PDF

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Publication number
CN117202932A
CN117202932A CN202280029342.9A CN202280029342A CN117202932A CN 117202932 A CN117202932 A CN 117202932A CN 202280029342 A CN202280029342 A CN 202280029342A CN 117202932 A CN117202932 A CN 117202932A
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China
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dose
antibody
tl1a
weeks
fcrn
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CN202280029342.9A
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Chinese (zh)
Inventor
艾利森·骆
奥立维尔·劳伦特
恩尼斯托·J·穆诺兹
J·比尔斯伯勒
布拉德利·亨克尔
S·R·塔尔干
D·P·麦戈文
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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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Priority claimed from PCT/US2022/016840 external-priority patent/WO2022178158A1/en
Publication of CN117202932A publication Critical patent/CN117202932A/en
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Abstract

Described herein are humanized anti-TL 1A antibodies and pharmaceutical compositions for use in treating diseases and/or conditions of the lung.

Description

anti-TL 1A antibody compositions and methods for treating lung
Cross Reference to Related Applications
The present application claims U.S. provisional application No. 63/285,785 filed on 3/12/2021; U.S. provisional application No. 63/226,041 filed on 7.27 of 2021; U.S. provisional application No. 63/180,896, filed on 28 at 4 at 2021; and U.S. provisional application No. 63/150,832 filed on 18, 2, 2021. The entire contents of each of the four aforementioned applications are expressly incorporated herein by reference.
Sequence listing
The present application contains a sequence listing that has been electronically submitted in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy created at day 14 of 2 months 2022 is named 56884-788_601_sl.txt and is 356,830 bytes in size.
Background
TL1A is a cytokine secreted by antigen presenting cells, T cells and endothelial cells. TL1A signals through death receptor 3 (DR 3), a TNF family receptor that is primarily present on T cells, natural Killer (NK) and NK-T cells, congenital lymphocytes (ILC), fibroblasts, and epithelial cells, and effectively drives Th1, th2, th9, and Th17 responses. In addition, it is induced in antigen presenting cells by cross-linking of toll-like receptor (TLR) ligands with FcR, and in T cells by T Cell Receptor (TCR) stimulation. TL1A has been demonstrated to be upregulated in the mucosa and serum of patients with inflammatory bowel disease. Antibodies to TL1A resulted in reduced inflammation and reversal of fibrosis in Dextran Sodium Sulfate (DSS) and adoptive transfer mouse models, even after inflammation and fibrosis have been determined, with treatment administered later in the disease course.
Disclosure of Invention
The present disclosure provides tumor necrosis factor ligand 1A (TL 1A) binding antibodies, and compositions thereof, for use in treating inflammation and/or fibrosis, including diseases or conditions present in the lungs of a subject. In various aspects, the antibodies described herein have characteristics that are useful for therapeutic applications, such as low immunogenicity; and/or features that facilitate antibody production, such as a high percentage of monomeric moieties as measured by size exclusion chromatography; and/or high expression. In further aspects, the antibodies described herein have characteristics that are useful for subcutaneous administration, such as low viscosity at high antibody concentrations. Additional aspects of antibodies and antibody formulations may comprise high solubility, low sub-visible particles, low opalescence, no visible microparticles, and any combination thereof.
In one aspect, provided herein is a method of treating inflammation in a subject in need thereof, the method comprising administering to the subject an antibody that binds to tumor necrosis factor-like protein 1A (anti-TL 1A antibody). In some embodiments, the lung of the subject has inflammation. Further provided is a method of treating fibrosis in a subject in need thereof, the method comprising administering to the subject an antibody that binds to tumor necrosis factor-like protein 1A (an anti-TL 1A antibody). In some embodiments, the lung of the subject is fibrotic. Further provided is a method of treating a disease and/or condition of the lung of a subject in need thereof, the method comprising administering to the subject an antibody that binds to tumor necrosis factor-like protein 1A (anti-TL 1A antibody).
In some embodiments, the subject has a chronic pulmonary disorder. In some embodiments, the subject has idiopathic pulmonary fibrosis. In some embodiments, the subject has virus-induced pulmonary fibrosis. In some embodiments, the subject has asthma. In some embodiments, the subject has COPD. In some embodiments, the subject has pneumonia. In some embodiments, the subject has idiopathic interstitial pneumonia, pulmonary sarcoidosis, interstitial lung disease, bronchiolitis, alveolitis, vasculitis, interstitial pneumonia, non-specific interstitial pneumonia, hypersensitivity pneumonitis, cryptogenic mechanized pneumonia, acute interstitial pneumonia, allergic rhinitis, emphysema, chronic bronchitis, primary biliary cholangitis, behcet's disease, systemic sclerosis-associated interstitial lung disease, or cystic fibrosis, or a combination thereof.
In some embodiments, the anti-TL 1A antibody is administered in a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises the anti-TL 1A antibody at a concentration of greater than about 150 mg/mL. In some embodiments, the concentration is greater than about 160, 165, 170, 175, 180, 185, 190, 195, or 200mg/mL. In some embodiments, the concentration is about 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, or 225mg/mL. In some embodiments, the concentration is about 150mg/mL to about 250mg/mL. In some embodiments, the concentration is about 175mg/mL to about 225mg/mL. In one aspect, provided herein is a pharmaceutical composition comprising an antibody that binds tumor necrosis factor-like protein 1A (anti-TL 1A antibody) at a concentration of greater than about 50mg/mL. In some embodiments, the concentration is greater than about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, or 145mg/mL. In certain embodiments, the concentration is about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, or 145mg/mL. In some embodiments, the pharmaceutical composition is administered subcutaneously. In some embodiments, about 150mg to about 500mg of the anti-TL 1A antibody is present in the composition. In some embodiments, the total volume of the composition is less than or equal to about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9mL. In some embodiments, the pharmaceutical composition includes a therapeutically effective dose of an anti-TL 1A antibody. In some embodiments of the present invention, in some embodiments, the total volume of the composition is less than or equal to about 9.0, 8.9, 8.8, 8.7, 8.6, 8.5, 8.4, 8.3, 8.2, 8.1, 8.0, 7.9, 7.8, 7.7, 7.6, 7.5, 7.4, 7.3, 7.2, 7.1, 7.0, 6.9, 6.8, 6.7, 6.6, 6.5, 6.4, 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2 5.1, 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9 or 0.8mL. In some embodiments, the total volume of the composition is from about 0.5mL to about 1.5mL. In some embodiments, the total volume of the compositions herein is from about 0.5mL to about 2.5mL. In some embodiments, the total volume of the compositions herein is from about 0.5mL to about 3.5mL. In some embodiments, the total volume of the compositions herein is from about 0.5mL to about 4.5mL. In some embodiments, the total volume of the compositions herein is from about 1mL to about 1.5mL. In some embodiments, the total volume of the compositions herein is from about 1mL to about 2.5mL. In some embodiments, the total volume of the compositions herein is from about 1mL to about 3.5mL. In some embodiments, the total volume of the compositions herein is from about 1mL to about 4.5mL. In some embodiments, the viscosity of the composition is less than about 20cP. In some embodiments, the viscosity of the composition is less than about 15cP. In some embodiments, the viscosity of the composition is less than about 10cP. In some embodiments, the viscosity of the composition is less than about 9, 8, 7, 6, or 5cP. In some embodiments, the viscosity of the composition is from about 1cP to about 7cP, from about 1cP to about 2cP, or from about 10cP to about 20cP. In some embodiments, the viscosity of the composition is from about 1cP to about 10cP. In some embodiments, the viscosity of the composition is from about 1cP to about 15cP. In some embodiments, the viscosity of the composition is from about 1cP to about 20cP. In some embodiments, the percentage of aggregation of the anti-TL 1A antibodies in the pharmaceutical composition is less than about 5% of the total anti-TL 1A antibodies in the composition, as measured by size exclusion chromatography. In some embodiments, the aggregation is less than about 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5%. In some embodiments, the composition comprises a surfactant. In some embodiments, the surfactant comprises a 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. In some embodiments, the surfactant is present at a concentration of about 0.01% to about 0.02% of the composition. In some embodiments, the surfactant is present at a concentration of about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about 0.014%, about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, about 0.02%, about 0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.025%, about 0.026%, about 0.027%, about 0.028%, about 0.029% or about 0.03% (v/v) of the composition. In some embodiments, the composition comprises a salt. In some embodiments, the salt comprises sodium chloride, glycine, lysine-hydrochloride, arginine glutamate, potassium chloride, magnesium chloride, or calcium chloride, or a combination thereof. In some embodiments, the salt comprises sodium chloride. In some embodiments, the salt comprises lysine-HCl. In some embodiments, the salt is present in the composition at a concentration of about 10mM to about 100 mM. In some embodiments, the salt is present in the composition at a concentration of about 25 mM. In some embodiments, the salt is present in the composition at a concentration of about 40 mM. In some embodiments, the composition includes a stabilizer. In some embodiments, the stabilizing agent comprises a sugar, a polyol, an amino acid or polymer, a cyclodextrin (e.g., HP-b-CD), or a combination thereof. In some embodiments, the stabilizing agent comprises the sugar. In some embodiments, the sugar comprises sucrose, glucose, trehalose, maltose, or lactose, or a combination thereof. In some embodiments, the sugar comprises sucrose. In some embodiments, the amino acid comprises glycine. In some embodiments, the stabilizing agent is present in the composition at a concentration of about 50mM to about 300 mM. In some embodiments, the stabilizing agent is present at a concentration of about 200mM to about 280 mM. In some embodiments, the stabilizing agent is present at a concentration of about 220 to about 240 mM. In certain embodiments, the stabilizing agent is present at a concentration of about 150mM, about 160mM, about 170mM, about 180mM, about 190mM, about 200mM, about 210mM, about 220mM, about 230mM, about 240mM, or about 250 mM. In some embodiments, the stabilizing agent comprises sucrose and glycine. In certain embodiments, the sucrose is present at a concentration of about 150mM, about 160mM, about 170mM, about 180mM, about 190mM, about 200mM, about 210mM, about 220mM, about 230mM, about 240mM, or about 250 mM. In some embodiments, the glycine is present at a concentration of about 10mM, about 15mM, about 20mM, about 25mM, about 30mM, about 35mM, about 40mM, about 45mM, about 50mM, about 55mM, about 60mM, about 65mM, about 70mM, about 75mM, about 80mM, about 85mM, about 90mM, about 95mM, about 100mM, about 105mM, about 110mM, about 115mM, or about 120 mM. In some embodiments, the composition comprises a buffer. In some embodiments, the buffer comprises acetate, phosphate, citrate, glutamate, succinate, gluconate, histidine, glycylglycine, citric acid, tris (hydroxymethyl) aminomethane), or diethanolamine, or a combination thereof. In some embodiments, the buffer comprises acetate. In some embodiments, the buffer comprises phosphate. In some embodiments, the buffer is present in the composition at a concentration of about 10mM to about 50 mM. In some embodiments, the composition comprises about 20mM buffer. In some embodiments, the pH of the composition is from about 4.5 to about 8.0. In some embodiments, the pH of the composition is from about 4.5 to about 7.5. In some embodiments, the pH of the composition is from about 6 to about 7. In some embodiments, the pH of the composition is about 6.5. In some embodiments, the pH of the composition is from about 5 to about 5.5. In some embodiments, the pH of the composition is about 5.3.
In some embodiments, the anti-TL 1A antibody is administered to the subject at a first dose of up to about 1000mg. In some embodiments, the anti-TL 1A antibody is administered to the subject at a first dose of about 150mg to about 1000mg. In some embodiments, the first dose is about 500mg to about 1000mg. In some embodiments, the first dose is about 500mg or about 800mg. In some embodiments, the first dose is administered to the subject at a first time point and the second dose is administered to the subject at a second time point. In some embodiments, the second time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the first time point. In some embodiments, the second time point is about 1, 2, 3, or 4 weeks after the first time point. In some embodiments, the second dose comprises up to about 1000mg of anti-TL 1A. In some embodiments, the second dose comprises about 150mg to about 1000mg. In some embodiments, the second dose comprises about 150mg to about 600mg. In some embodiments, a third dose of anti-TL 1A is administered to the subject at a third time point. In some embodiments, the third time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the second time point. In some embodiments, the third time point is about 1, 2, 3, or 4 weeks after the second time point. In some embodiments, the third dose comprises up to about 1000mg of anti-TL 1A. In some embodiments, the third dose comprises about 150mg to about 1000mg. In some embodiments, the third dose comprises about 150mg to about 600mg. In some embodiments, a fourth dose of anti-TL 1A is administered to the subject at a fourth time point. In some embodiments, the fourth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the third time point. In some embodiments, the fourth time point is about 1, 2, 3, or 4 weeks after the third time point. In some embodiments, the fourth dose comprises up to about 1000mg of anti-TL 1A. In some embodiments, the fourth dose comprises about 150mg to about 1000mg. In some embodiments, the fourth dose comprises about 150mg to about 600mg. In some embodiments, a fifth dose of anti-TL 1A is administered to the subject at a fifth time point. In some embodiments, the fifth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the fourth time point. In some embodiments, the fifth time point is about 1, 2, 3, or 4 weeks after the fourth time point. In some embodiments, the fifth dose comprises up to about 1000mg of anti-TL 1A. In some embodiments, the fifth dose comprises about 150mg to about 1000mg. In some embodiments, the fifth dose comprises about 150mg to about 600mg. In some embodiments, a sixth dose of anti-TL 1A is administered to the subject at a sixth time point. In some embodiments, the sixth time point is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the fifth time point. In some embodiments, the sixth time point is about 1, 2, 3, or 4 weeks after the fifth time point. In some embodiments, the sixth dose comprises up to about 1000mg of anti-TL 1A. In some embodiments, the sixth dose comprises about 150mg to about 1000mg. In some embodiments, the sixth dose comprises about 150mg to about 600mg.
In some embodiments, additional doses of anti-TL 1A antibodies are administered to the subject at one or more additional time points. In some embodiments, the one or more additional time points comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 additional time points. In some embodiments, the composition is administered to the subject at about 12 additional time points. In some embodiments, each additional time point is independently about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days after the previous time point. In some embodiments, each additional time point is independently about 1, 2, 3, or 4 weeks after the previous time point. In some embodiments, at least one of the additional time points is about 2 weeks after the previous time point. In some embodiments, the additional dose comprises up to about 1000mg of anti-TL 1A. In some embodiments, the additional dose comprises about 150mg to about 1000mg of anti-TL 1A. In some embodiments, the additional dose is about 175mg to about 300mg of anti-TL 1A.
In one aspect, provided herein is an antibody or antigen-binding fragment thereof that binds to tumor necrosis factor-like protein 1A ("TL 1A", and such an antibody or antigen-binding fragment thereof, i.e., "anti-TL 1A antibody or antigen-binding fragment"), wherein the antibody or antigen-binding fragment binds to both monomeric TL1A and trimeric TL 1A.
In some embodiments, the antibody or antigen binding fragment blocks interaction of TL1A with death receptor 3 ("DR 3"). In some embodiments, the equilibrium constant (K D-monomer ) The binding affinity of the antibody or antigen binding fragment to monomeric TL1A is measured, e.g. by dissociation equilibrium constant (K D-trimer ) The binding affinity of the antibody or antigen binding fragment measured was comparable to that of trimeric TL 1A. In some embodiments, K D-monomer At said K D-trimer 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times. In some embodiments, the K D-monomer No more than 0.06nM. In some embodiments, the K D-trimer No more than 0.06nM.
In one aspect, provided herein is a method of neutralizing monomeric TL1A and trimeric TL1A in a subject having pulmonary inflammation and/or pulmonary fibrosis, the method comprising (a) administering to the subject an effective dose of an anti-TL 1A antibody or antigen binding fragment, wherein the antibody or antigen binding fragment binds to both monomeric TL1A and trimeric TL1A, wherein the antibody or antigen binding fragment blocks interaction of TL1A with DR3, wherein the concentration of TL1A in diseased tissue in the subject is reduced to a lower concentration than the concentration of TL1A in corresponding tissue in a control subject not having pulmonary inflammation and/or pulmonary fibrosis, and wherein the diseased tissue comprises any one or more selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis. In some embodiments, the subject has one or more inflammatory conditions selected from the group consisting of: systemic sclerosis-related interstitial lung disease, idiopathic pulmonary fibrosis, virus-induced pulmonary fibrosis, asthma, chronic Obstructive Pulmonary Disease (COPD) and pneumonia. In some embodiments, the subject has chronic pulmonary disorder, idiopathic interstitial pneumonia, pulmonary sarcoidosis, interstitial lung disease, bronchiolitis, alveolitis, vasculitis, interstitial pneumonia, non-specific interstitial pneumonia, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, acute interstitial pneumonitis, allergic rhinitis, emphysema, chronic bronchitis, primary cholangitis, behcet's disease, systemic sclerosis-associated interstitial lung disease, or cystic fibrosis, or a combination thereof.
In one aspect, provided herein is a method of reducing the concentration of TL1A in diseased tissue in a subject having pulmonary inflammation and/or pulmonary fibrosis, the method comprising (a) administering to the subject an effective dose of an anti-TL 1A antibody or antigen binding fragment, thereby reducing the concentration of TL1A in the diseased tissue in the subject to a lower concentration than TL1A in corresponding tissue in a control subject not having pulmonary inflammation and/or pulmonary fibrosis, wherein the diseased tissue comprises any one or more selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis.
In one aspect, provided herein is a method of treating pulmonary inflammation and/or pulmonary fibrosis in a subject in need thereof, the method comprising (a) administering to the subject an anti-TL 1A antibody or antigen-binding fragment, wherein the anti-TL 1A antibody or antigen-binding fragment is administered in an effective dose such that after step (a) the concentration of TL1A in diseased tissue in the subject is lower than the concentration of TL1A in corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis, and wherein the diseased tissue comprises any one or more selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis.
In one aspect, provided herein is a method of treating pulmonary inflammation and/or pulmonary fibrosis in a subject in need thereof, the method comprising: (a) Administering an anti-TL 1A antibody or antigen-binding fragment to the subject at an effective dose, and (b) lowering the concentration of TL1A in diseased tissue in the subject relative to the concentration of TL1A in corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis, wherein the diseased tissue comprises any one or more selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis.
In some embodiments, the effective dose comprises an induction regimen.
In some embodiments, the method further comprises (c) maintaining the concentration of TL1A in the diseased tissue in the subject below the concentration of TL1A in the corresponding tissue in the control subject.
In some embodiments, the TL1A in the diseased tissue in the subject is maintained with a maintenance regimen of the anti-TL 1A antibody or antigen binding fragment. In some embodiments, the induction regimen and the maintenance regimen are the same. In some embodiments, the induction regimen and the maintenance regimen are different. In some embodiments, the maintenance regimen is administered after the induction regimen. In some embodiments, during the induction regimen, the diseased tissue in the subject produces TL1A that is up to 50, 60, 70, 80, 90, 100 or more times greater than TL1A produced by the corresponding tissue in the control subject. In some embodiments, the diseased tissue in the subject produces TL1A that is up to 50, 60, 70, 80, 90, 100 times or more greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In some embodiments, the diseased tissue in the subject produces TL1A that is up to 50, 60, 70, 80, 90, 100 or more times greater than TL1A produced by the corresponding tissue in the control subject.
In some embodiments, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment. In some embodiments, the anti-TL 1A 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.
In some embodiments, the induction regimen comprises multiple administrations of the anti-TL 1A antibody or antigen binding fragment. In some embodiments, the induction regimen comprises: (i) 1000 mg/dose at week 0, 1000 mg/dose at week 2, 1000 mg/dose at week 6, and 1000 mg/dose at week 10; (ii) 500 mg/dose at week 0, 500 mg/dose at week 2, 500 mg/dose at week 6, and 500 mg/dose at week 10; (iii) 1000 mg/dose at week 0, 1000 mg/dose at week 2, 1000 mg/dose at week 6, and 500 mg/dose at week 10; (iv) 1000 mg/dose at week 0, 1000 mg/dose at week 2, 500 mg/dose at week 6 and 500 mg/dose at week 10; or (v) 1000 mg/dose at week 0, 500 mg/dose at week 2, 500 mg/dose at week 6, and 500 mg/dose at week 10.
In some embodiments, the induction regimen comprises administration of 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, or 200 mg/dose. In some embodiments, the induction regimen comprises administration every 2, 4, 6, or 8 weeks. In some embodiments, the induction regimen comprises administering once every 2 or 4 weeks for the first 2 administrations, and then administering once every 2, 4, 6 or 8 weeks for the remaining induction regimen.
In some embodiments, the diseased tissue in the subject produces TL1A that is up to 10, 15, 20, 25, 30, 35, 40, 45, 50, or more times greater than the TL1A produced by the corresponding tissue in the control subject. In some embodiments, during the maintenance regimen, the diseased tissue in the subject produces TL1A that is at most 10, 15, 20, 25, 30, 35, 40, 45, 50, or more times greater than TL1A produced by the corresponding tissue in the control subject. In some embodiments, the diseased tissue in the subject produces TL1A that is up to 10, 15, 20, 25, 30, 35, 40, 45, 50 or more times greater than TL1A produced by the corresponding tissue in the control subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48 or 52 weeks or more at the beginning of the maintenance regimen.
In some embodiments, the maintenance regimen comprises multiple administrations of the anti-TL 1A antibody or antigen binding fragment. In some embodiments, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment as follows: (i) 500 mg/dose every 2 weeks; (ii) 400 mg/dose every 2 weeks; (iii) 300 mg/dose every 2 weeks; (iv) 250 mg/dose every 2 weeks; (v) 200 mg/dose every 2 weeks; (vi) 150 mg/dose every 2 weeks; (vii) 100 mg/dose every 2 weeks; (viii) 50 mg/dose every 2 weeks; (ix) 500 mg/dose every 4 weeks; (x) 400 mg/dose every 4 weeks; (xi) 300 mg/dose every 4 weeks; (xii) 250 mg/dose every 4 weeks; (xiii) 200 mg/dose every 4 weeks; (xiv) 150 mg/dose every 4 weeks; (xv) 100 mg/dose every 4 weeks; (xvi) 50 mg/dose every 4 weeks; (xvii) 500 mg/dose every 6 weeks; (xviii) 400 mg/dose every 6 weeks; (xix) 300 mg/dose every 6 weeks; (xx) 250 mg/dose every 6 weeks; (xxi) 200 mg/dose every 6 weeks; (xxii) 150 mg/dose every 6 weeks; (xxiii) 100 mg/dose every 6 weeks; (xxiv) 50 mg/dose every 6 weeks; (xxv) 500 mg/dose every 8 weeks; (xxvi) 400 mg/dose every 8 weeks; (xxvii) 300 mg/dose every 8 weeks; (xxviii) 250 mg/dose every 8 weeks; (xxix) 200 mg/dose every 8 weeks; (xxx) 150 mg/dose every 8 weeks; (xxxi) 100 mg/dose every 8 weeks; or (xxxii) 50 mg/dose every 8 weeks.
In some embodiments, the maintenance regimen comprises administering the anti-TL 1A 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 administering the anti-TL 1A antibody or antigen binding fragment every 2, 4, 6, 8, 10, or 12 weeks. In some embodiments, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at a dose of 250 mg/dose every 4 weeks. In some embodiments, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at a dose of 100 mg/dose every 4 weeks. In some embodiments, the maintenance regimen lasts for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, or 52 weeks.
In some embodiments, the antibody or antigen-binding fragment binds to both monomeric TL1A and trimeric TL1A, and wherein the antibody or antigen-binding fragment blocks binding of TL1A to DR 3. In some embodiments, at least 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the monomeric TL1A in the blood of the subject is occupied by the anti-TL 1A antibody or antigen binding fragment. In some embodiments, at least 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the trimeric TL1A in the blood of the subject is occupied by the anti-TL 1A antibody or antigen binding fragment.
In some embodiments, the equilibrium constant (K D-monomer ) The binding affinity of the antibody or antigen binding fragment to monomeric TL1A is measured, e.g. by dissociation equilibrium constant (K D-trimer ) The binding affinity of the antibody or antigen binding fragment measured was comparable to that of trimeric TL 1A. In some embodiments, K D-monomer At said K D-trimer 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times. In some embodiments, the K D-monomer No more than 0.06nM. In some embodiments, the K D-trimer No more than 0.06nM.
In some embodiments, the subject has one or more inflammatory conditions selected from the group consisting of: systemic sclerosis-related interstitial lung disease, idiopathic pulmonary fibrosis, virus-induced pulmonary fibrosis, asthma, chronic Obstructive Pulmonary Disease (COPD) and pneumonia.
In some embodiments, the subject has chronic pulmonary disorder, idiopathic interstitial pneumonia, pulmonary sarcoidosis, interstitial lung disease, bronchiolitis, alveolitis, vasculitis, interstitial pneumonia, non-specific interstitial pneumonia, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, acute interstitial pneumonitis, allergic rhinitis, emphysema, chronic bronchitis, primary cholangitis, behcet's disease, systemic sclerosis-associated interstitial lung disease, or cystic fibrosis, or a combination thereof.
In some embodiments, the effective dose or induction regimen is determined by a dose determination method, wherein the dose determination method comprises: (i) Receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in the normal reference tissue; (ii) Integrating the parameters received in (a) into a physiologically integrated whole-body based pharmacokinetic (PBPK) model or population pharmacokinetic model (popPK); and (iii) determining an effective dose or induction regimen such that after step (a) the concentration of TL1A in the diseased tissue in the subject is lower than the concentration of TL1A in the corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis. In some embodiments, the overproduction of the TL1A over-generates 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 times the overproduction of TL1A in the normal reference tissue.
In some embodiments, the maintenance regimen is determined by a dose determination method, wherein the dose determination method comprises: (i) Receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in the normal reference tissue; (ii) Integrating the parameters received in (i) into a physiologically integrated whole-body based pharmacokinetic (PBPK) model or population pharmacokinetic model (popPK); and (iii) determining the maintenance regimen such that after step (c) the concentration of TL1A in the diseased tissue in the subject is lower than the concentration of TL1A in the corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis. In some embodiments, the overproduction of the TL1A over-generates 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more times the TL1A in the normal reference tissue.
In some embodiments, step (i) of the dose determination method further comprises receiving the association rate (k on-mAb ) The dissociation rate of the antibody from TL1A (k off-mAb ) Rate of synthesis of TL1A in Normal tissue (k syn-normal ) Rate of synthesis of TL1A in diseased tissue (k syn-disease ) And/or the degradation rate (k) of TL1A deg-Total-TL 1A ). In some embodiments, the rate of association (k on-mAb ) Comprises the association rate (k on-monomer ) And the rate of association (k) of the antibody with trimeric TL1A on-trimer ) Wherein the dissociation rate (k off-mAb ) Comprising the dissociation rate (k off-monomers ) And the dissociation rate (k) of the antibody from trimeric TL1A off-trimer ) And/or wherein the degradation rate (k deg-Total-TL 1A ) Degradation rate (k) including monomer TL1A deg-TL 1A-monomer ) And rate of degradation (k) of trimer TL1A deg-TL 1A-trimer )。
In some embodiments, step (i) of the method of determining a dose further comprises receiving a rate of association (k) of the antibody with the FcRn receptor on-mAb-FcRn ) Dissociation rate of antibody to FcRn (k off-mAb-FcRn ) Rate of association of antibody-TL 1A complex with FcRn receptor (k on-(mAb-TL1A)-FcRn ) And/or the dissociation rate (k) of the antibody-TL 1A complex from FcRn off-(mAb-TL1A)-FcRn ). In some embodiments, the rate of association (k on-(mAb-TL1A)-FcRn ) Comprising the rate of association (k) of the antibody-monomer TL1A complex with the FcRn receptor on-(mAb-monoTL1A)-FcRn ) And the rate of association of the antibody-trimeric TL1A complex with FcRn receptor (k on-(mAb-triTL1A)-FcRn ) And/or wherein the dissociation rate (k) of the antibody-TL 1A complex from FcRn off-(mAb-TL1A)-FcRn ) Comprising the dissociation rate (k) of the antibody-monomer TL1A complex from FcRn off-(mAb-monoTL1A)-FcRn ) And dissociation rate of antibody-trimeric TL1A complex from FcRn (k off-(mAb-triTL1A)-FcRn )。
In some embodiments, step (i) of the dose determination method further comprises receiving the clearance (k deg-mAb-FcRn ). In some embodiments, the FcRn bound by the antibody is subjected toClearance of body (k) deg-mAb-FcRn ) Comprising the clearance (k) of the antibody to FcRn bound by the antibody-monomer TL1A complex deg-(mAb-monoTL1A)-FcRn ) And FcRn receptor clearance bound by the antibody-trimeric TL1A complex (k deg-(mAb-triTL1A)-FcRn ). In some embodiments, in the dose determination method: (1) k (k) on-monomer And k on-trimer The same or different; (2) k (k) off-monomers And k off-trimer The same or different; (3) k (k) deg-monomer And k deg-trimer The same or different; (4) k (k) on-(mAb-monoTL1A)-FcRn And k on-(mAb-triTL1A)-FcRn The same or different; (5) k (k) on-mAb-FcRn And k on-(mAb-monoTL1A)-FcRn The same or different; (6) k (k) on-mAb-FcRn And k on-(mAb-triTL1A)-FcRn The same or different; (7) k (k) off-(mAb-monoTL1A)-FcRn And k off-(mAb-triTL1A)-FcRn The same or different; (8) k (k) off-mAb-FcRn And k off-(mAb-monoTL1A)-FcRn The same or different; (9) k (k) off-mAb-FcRn And k off-(mAb-triTL1A)-FcRn The same or different; (10) k (k) deg-(mAb-monoTL1A)-FcRn And k deg-(mAb-triTL1A)-FcRn The same or different; (11) k (k) deg-mAb-FcRn And k deg-(mAb-triTL1A)-FcRn The same or different; (12) k (k) deg-mAb-FcRn And k deg-(mAb-monoTL1A)-FcRn The same or different; (13) any combination of (1) to (12). In some embodiments, in the dose determination method: k (k) syn-disease Is k syn-normal At most 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 or more times. In some embodiments, step (i) of the dose determination method further comprises receiving a rate (k on-TL 1A-monomer to trimer ) And/or the rate of TL1A monomer (k off-TL 1A-trimer to monomer )。
In one aspect, provided herein is a method of determining an effective dosage regimen for administering an anti-TL 1A antibody to a subject suffering from pulmonary inflammation and/or pulmonary fibrosis, wherein the method comprises: (a) Receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in the normal reference tissue; (b) Integrating the parameters received in (a) into a physiologically integrated whole-body based pharmacokinetic (PBPK) model; and (c) determining the effective dose regimen of the anti-TL 1A antibody with the PBPK model from (b) such that, after administration of the effective dose regimen, the concentration of TL1A in diseased tissue in the subject having pulmonary inflammation and/or pulmonary fibrosis is lower than the concentration of TL1A in corresponding tissue in a control subject not having pulmonary inflammation and/or pulmonary fibrosis, wherein the diseased tissue comprises any one or more selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis.
In one aspect, provided herein is a method of determining an effective dosage regimen for administering an anti-TL 1A antibody to a subject suffering from pulmonary inflammation and/or pulmonary fibrosis, wherein the method comprises: (a) Receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in the normal reference tissue; (b) Integrating the parameters received in (a) into a population pharmacokinetic (popPK) model; and (c) determining the effective dose regimen of the anti-TL 1A antibody with the popPK model from (b), such that after administration of the effective dose regimen, the concentration of TL1A in diseased tissue in the subject having pulmonary inflammation and/or pulmonary fibrosis is lower than the concentration of TL1A in corresponding tissue in a control subject not having pulmonary inflammation and/or pulmonary fibrosis, wherein the diseased tissue comprises any one or more selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis.
In some embodiments of the dose determination method, the overproduction of the TL1A overproduction parameter is the normal parameter TL1A in the tissue is considered to produce 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 times. In some embodiments of the dose-determining method, step (a) further comprises receiving the association rate (k) of the antibody with TL1A on-mAb ) The dissociation rate of the antibody from TL1A (k off-mAb ) Rate of synthesis of TL1A in Normal tissue (k syn-normal ) Rate of synthesis of TL1A in diseased tissue (k syn-disease ) And/or the degradation rate (k) of TL1A deg-Total-TL 1A )。
In some embodiments of the dose determination method, the association rate (k on-mAb ) Comprises the association rate (k on-monomer ) And the rate of association (k) of the antibody with trimeric TL1A on-trimer ) Wherein the dissociation rate (k off-mAb ) Comprising the dissociation rate (k off-monomers ) And the dissociation rate (k) of the antibody from trimeric TL1A off-trimer ) And/or wherein the degradation rate (k deg-Total-TL 1A ) Degradation rate (k) including monomer TL1A deg-TL 1A-monomer ) And rate of degradation (k) of trimer TL1A deg-TL 1A-trimer ). In some embodiments of the dose-determining method, step (a) further comprises receiving the rate of association (k) of the antibody with FcRn receptor on-mAb-FcRn ) Dissociation rate of antibody to FcRn (k off-mAb-FcRn ) Rate of association of antibody-TL 1A complex with FcRn receptor (k on-(mAb-TL1A)-FcRn ) And/or the dissociation rate (k) of the antibody-TL 1A complex from FcRn off-(mAb-TL1A)-FcRn )。
In some embodiments of the dose determination method, the rate of association (k) of the antibody-TL 1A complex with FcRn receptor on-(mAb-TL1A)-FcRn ) Comprising the rate of association (k) of the antibody-monomer TL1A complex with the FcRn receptor on-(mAb-monoTL1A)-FcRn ) And the rate of association of the antibody-trimeric TL1A complex with FcRn receptor (k on-(mAb-triTL1A)-FcRn ) And/or wherein the dissociation rate (k) of the antibody-TL 1A complex from FcRn off-(mAb-TL1A)-FcRn ) Comprising the dissociation rate (k) of the antibody-monomer TL1A complex from FcRn off-(mAb-monoTL1A)-FcRn ) And dissociation rate of antibody-trimeric TL1A complex from FcRn (k off-(mAb-triTL1A)-FcRn )。
In some embodiments of the dose determination method, step (a) further comprises receiving the clearance (k deg-mAb-FcRn ). In some embodiments of the dose determination method, the clearance (k deg-mAb-FcRn ) Further comprising clearance (k) of the antibody to FcRn bound by the antibody-monomer TL1A complex deg-(mAb-monoTL1A)-FcRn ) And FcRn receptor clearance bound by the antibody-trimeric TL1A complex (k deg-(mAb-triTL1A)-FcRn )。
In some embodiments of the dose determination method, the subject has one or more inflammatory conditions selected from the group consisting of: systemic sclerosis-related interstitial lung disease, idiopathic pulmonary fibrosis, virus-induced pulmonary fibrosis, asthma, chronic Obstructive Pulmonary Disease (COPD) and pneumonia. In some embodiments of the dose determination method, the subject has chronic pulmonary disorder, idiopathic interstitial pneumonia, pulmonary sarcoidosis, interstitial pulmonary disease, bronchiolitis, alveolitis, vasculitis, interstitial pneumonia, nonspecific interstitial pneumonia, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, acute interstitial pneumonia, allergic rhinitis, emphysema, chronic bronchitis, primary cholangitis, behcet's disease, systemic sclerosis-related interstitial pulmonary disease, or cystic fibrosis, or a combination thereof.
In some embodiments of the dose determination method, in the dose determination method, wherein: (1) k (k) on-monomer And k on-trimer The same or different; (2) k (k) off-monomers And k off-trimer The same or different; (3) k (k) deg-monomer And k deg-trimer The same or different; (4) k (k) on-(mAb-monoTL1A)-FcRn And k on-(mAb-triTL1A)-FcRn The same or different; (5) k (k) on-mAb-FcRn And k on-(mAb-monoTL1A)-FcRn The same or different; (6) k (k) on-mAb-FcRn And k on-(mAb-triTL1A)-FcRn The same or different; (7) k (k) off-(mAb-monoTL1A)-FcRn And k off-(mAb-triTL1A)-FcRn The same or different; (8) k (k) off-mAb-FcRn And k off-(mAb-monoTL1A)-FcRn The same or different; (9) k (k) off-mAb-FcRn And k off-(mAb-triTL1A)-FcRn The same or different; (10) k (k) deg-(mAb-monoTL1A)-FcRn And k deg-(mAb-triTL1A)-FcRn The same or different; (11) k (k) deg-mAb-FcRn And k deg-(mAb-triTL1A)-FcRn The same or different; (12) k (k) deg-mAb-FcRn And k deg-(mAb-monoTL1A)-FcRn The same or different; or (13) any combination of (1) to (12).
In some embodiments of the method of dose determination, in the method of dose determination, wherein K syn-disease Is k syn-normal At most 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 or more times.
In some embodiments of the dose determination method, the effective dose regimen comprises an induction regimen of the anti-TL 1A antibody or antigen binding fragment. In some embodiments of the dose determination method, the effective dose regimen comprises a maintenance regimen of the anti-TL 1A antibody or antigen binding fragment. In some embodiments of the dose determination method, the induction regimen and the maintenance regimen are the same. In some embodiments of the dose determination method, the induction regimen and the maintenance regimen are different. In some embodiments of the dose determination method, the maintenance regimen is administered after the induction regimen.
In some embodiments of the dose determination method, the diseased tissue in the subject produces TL1A that is at most 50, 60, 70, 80, 90, 100 or more times greater than TL1A produced by the corresponding tissue in the control subject during the induction regimen. In some embodiments of the dose determination method, the diseased tissue in the subject produces TL1A that is up to 50, 60, 70, 80, 90, 100 or more times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5 or 6 weeks of the initiation of the induction regimen. In some embodiments of the dose determination method, the diseased tissue in the subject produces TL1A that is at most 50, 60, 70, 80, 90, 100 or more times greater than TL1A produced by the corresponding tissue in the control subject. In some embodiments of the dose-determining method, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen-binding fragment. In some embodiments of the dose determination method, the anti-TL 1A 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.
In some embodiments of the dose determination method, the induction regimen comprises multiple administrations of the anti-TL 1A antibody or antigen binding fragment. In some embodiments of the dose determination method, the induction regimen comprises: (i) 1000 mg/dose at week 0, 1000 mg/dose at week 2, 1000 mg/dose at week 6, and 1000 mg/dose at week 10; (ii) 500 mg/dose at week 0, 500 mg/dose at week 2, 500 mg/dose at week 6, and 500 mg/dose at week 10; (iii) 1000 mg/dose at week 0, 1000 mg/dose at week 2, 1000 mg/dose at week 6, and 500 mg/dose at week 10; (iv) 1000 mg/dose at week 0, 1000 mg/dose at week 2, 500 mg/dose at week 6 and 500 mg/dose at week 10; or (v) 1000 mg/dose at week 0, 500 mg/dose at week 2, 500 mg/dose at week 6, and 500 mg/dose at week 10.
In some embodiments of the dose determination method, the induction regimen comprises administration of 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, or 200 mg/dose. In some embodiments of the dose determination method, the induction regimen comprises administration every 2, 4, 6, or 8 weeks. In some embodiments of the dose-determining method, 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.
In some embodiments of the dose determination method, the diseased tissue in the subject produces TL1A that is at most 10, 15, 20, 25, 30, 35, 40, 45, 50 or more times greater than TL1A produced by the corresponding tissue in the control subject. In some embodiments of the dose determination method, the diseased tissue in the subject produces TL1A that is at most 10, 15, 20, 25, 30, 35, 40, 45, 50 or more times greater than TL1A produced by the corresponding tissue in the control subject during the maintenance regimen. In some embodiments of the dose determination method, the diseased tissue in the subject produces TL1A that is up to 10, 15, 20, 25, 30, 35, 40, 45, 50 or more times greater than TL1A produced by the corresponding tissue in the control subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48 or 52 weeks or more at the beginning of the maintenance regimen.
In some embodiments of the dose determination method, the maintenance regimen comprises multiple administrations of the anti-TL 1A antibody or antigen binding fragment. In some embodiments of the dose determination method, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment as follows: (i) 500 mg/dose every 2 weeks; (ii) 400 mg/dose every 2 weeks; (iii) 300 mg/dose every 2 weeks; (iv) 250 mg/dose every 2 weeks; (v) 200 mg/dose every 2 weeks; (vi) 150 mg/dose every 2 weeks; (vii) 100 mg/dose every 2 weeks; (viii) 50 mg/dose every 2 weeks; (ix) 500 mg/dose every 4 weeks; (x) 400 mg/dose every 4 weeks; (xi) 300 mg/dose every 4 weeks; (xii) 250 mg/dose every 4 weeks; (xiii) 200 mg/dose every 4 weeks; (xiv) 150 mg/dose every 4 weeks; (xv) 100 mg/dose every 4 weeks; (xvi) 50 mg/dose every 4 weeks; (xvii) 500 mg/dose every 6 weeks; (xviii) 400 mg/dose every 6 weeks; (xix) 300 mg/dose every 6 weeks; (xx) 250 mg/dose every 6 weeks; (xxi) 200 mg/dose every 6 weeks; (xxii) 150 mg/dose every 6 weeks; (xxiii) 100 mg/dose every 6 weeks; (xxiv) 50 mg/dose every 6 weeks; (xxv) 500 mg/dose every 8 weeks; (xxvi) 400 mg/dose every 8 weeks; (xxvii) 300 mg/dose every 8 weeks; (xxviii) 250 mg/dose every 8 weeks; (xxix) 200 mg/dose every 8 weeks; (xxx) 150 mg/dose every 8 weeks; (xxxi) 100 mg/dose every 8 weeks; or (xxxii) 50 mg/dose every 8 weeks.
In some embodiments of the dose determination method, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 mg/dose. In some embodiments of the dose determination method, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment every 2, 4, 6, 8, 10, or 12 weeks. In some embodiments of the dose determination method, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at 250 mg/dose every 4 weeks. In some embodiments of the dose determination method, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at 100 mg/dose every 4 weeks. In some embodiments of the dose determination method, the maintenance regimen lasts for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, or 52 weeks.
In some embodiments of the dose determination method, the effective dose regimen maintains a concentration of TL1A in diseased tissue in the subject that is lower than a concentration of TL1A in corresponding tissue in a control subject that does not have pulmonary inflammation and/or pulmonary 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.
In some embodiments of the dose determination method, step (a) further comprises receiving a rate (k on-TL 1A-monomer to trimer ) And/or the rate of TL1A monomer (k off-TL 1A-trimerMonomer(s) )。
In some embodiments of the methods provided herein, including the use/treatment methods and dose determination methods provided herein, the concentration of TL1A is the concentration of free TL 1A.
In some embodiments, the anti-TL 1A antibody comprises: a heavy chain variable region comprising: HCDR1, said HCDR1 comprising a sequence consisting of SEQ ID NO:1, and a polypeptide sequence shown in the specification; HCDR2, said HCDR2 comprising a sequence consisting of SEQ ID NO:2-5, and a polypeptide comprising the amino acid sequence shown in any one of 2-5; and HCDR3, said HCDR3 comprising a sequence consisting of SEQ ID NO: 6-9; and a light chain variable region comprising: LCDR1, said LCDR1 comprising a sequence consisting of SEQ ID NO:10, and a polypeptide comprising the amino acid sequence shown in seq id no; LCDR2, said LCDR2 comprising a nucleotide sequence consisting of SEQ ID NO:11, and a polypeptide comprising the amino acid sequence shown in seq id no; LCDR3, said LCDR3 comprising a nucleotide sequence consisting of SEQ ID NO: 12-15. In certain embodiments, the anti-TL 1A antibody comprises HCDR1, as defined by SEQ ID NO: 401. 407, 413 or 450. In certain embodiments, the anti-TL 1A antibody comprises HCDR2 as defined by SEQ ID NO: 402. 408, 414 or 451. In certain embodiments, the anti-TL 1A antibody comprises HCDR3 as defined by SEQ ID NO: 403. 409, 415 or 452. In certain embodiments, the anti-TL 1A antibody comprises LCDR1 as defined by SEQ ID NO: 404. 410, 416 or 453. In certain embodiments, the anti-TL 1A antibody comprises LCDR2 as defined by SEQ ID NO: 405. 411, 417 or 454. In certain embodiments, the anti-TL 1A antibody comprises LCDR3 as defined by SEQ ID NO: 406. 412, 418 or 455.
In some embodiments, the anti-TL 1A antibody comprises: a heavy chain variable framework region comprising a human IGHV1-46 x 02 framework or a modified human IGHV1-46 x 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 together comprise no or less than nine amino acid modifications from the human IGHV1-46 x 02 framework and the human IGKV3-20 framework.
In some embodiments, the anti-TL 1A antibody comprises: a heavy chain variable domain comprising a sequence identical to SEQ ID NO:101-169 or 420-427, at least 96% identical to any one of the amino acid sequences; and a light chain variable domain comprising a sequence identical to SEQ ID NO:201-220 or 430-437, at least 96% identical.
In some embodiments, the anti-TL 1A antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:301
X1VQLVQSGAEVKKPGASVKVSCKAS [ HCDR1] WVX2QX3PGQGLEWX4G [ HCDR2] RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTAVYYCAR [ HCDR3] WGQGTTVTVSS, and a light chain variable region comprising SEQ ID NO:303
EIVLTQSPGTLSLSPGERATLSC [ LCDR1] WYQKPGQAPRX 10X11IY [ LCDR2] GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC [ LCDR3] FGGGTKLEIK, wherein each of X1-X11 is independently selected from A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y or V, wherein HCDR1 comprises a polypeptide consisting of SEQ ID NO:1, and HCDR2 comprises an amino acid sequence represented by SEQ ID NO:2-5, HCDR3 comprises an amino acid sequence represented by any one of SEQ ID NOs: 6-9, LCDR1 comprises an amino acid sequence represented by any one of SEQ ID NOs: 10, LCDR2 comprises an amino acid sequence represented by SEQ ID NO:11, and LCDR3 comprises an amino acid sequence represented by SEQ ID NO:12 or 13.
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The patent or application document contains at least one drawing in color. Upon request and payment of the necessary fee, the authority will provide a copy of the disclosure of this patent or patent application with the color drawings.
Exemplary embodiments are illustrated in the referenced figures. It is intended that the embodiments and figures disclosed herein are to be regarded as illustrative rather than restrictive.
FIGS. 1A-1C show chromatograms of analytical size exclusion chromatography of anti-TL 1A antibodies. The large peak (main peak) corresponds to the monomer portion. The percentage of monomer samples represents each antibody. FIG. 1A shows the chromatograms of antibodies A193, A194, and A195. Fig. 1B shows the chromatograms of antibodies a196, a197, and a 198. Fig. 1C shows the chromatograms of antibodies a199, a200 and a 201.
FIG. 2 depicts the inhibition of interferon gamma in human blood with anti-TL 1A antibodies.
Fig. 3A depicts a comparison between predicted and measured viscosities. FIGS. 3B-3D depict PLS models demonstrating the effect of pH and protein concentration on viscosity. Fig. 3B shows a PLS plot (for PLS plot, x-axis is pH, y-axis is protein concentration (mg/mL), z-axis is viscosity (mPa-s)), fig. 3C shows a model of predicted viscosity (y-axis, mPa-s) versus anti-TL 1A antibody concentration in mg/mL (x-axis), and fig. 3D shows a model of estimated viscosity (y-axis, mPa-s) versus actual viscosity (x-axis, mPa-s). Fig. 3E depicts the effect of pH on viscosity versus acetate concentration. Fig. 3F shows the effect of sucrose on viscosity relative to NaCl. FIG. 3G depicts the effect of Arg-HCl on viscosity relative to Lys-HCl. The viscosity unit is mPa-s. The arrows point to the areas of highest viscosity. The star shape corresponds to the region of lowest viscosity.
FIG. 4A depicts the effect of PLS1 model on High Molecular Weight (HMW) aggregates. Fig. 4B depicts the effect of pH on aggregation relative to acetate. Fig. 4C depicts the effect of sucrose on NaCl concentration. FIG. 4D depicts the effect of Arg-HCl on aggregation relative to Lys-HCl. FIG. 4E depicts the effect of sucrose concentration relative to Lys-HCl concentration.
Fig. 5A depicts predicted relative to measured losses of the main peak at 2 weeks and 25 ℃. Fig. 5B depicts the effect of pH and protein concentration on loss of the main peak in the CEX curve. Fig. 5C depicts the effect of pH and acetate concentration on loss of the main peak in the CEX curve. Fig. 5D depicts the effect of sucrose and NaCl concentration on loss of the main peak in the CEX curve. FIG. 5E depicts the effect of Lys-HCl and sucrose concentrations on loss of the main peak in the CEX curve.
Fig. 6A depicts the loss of monomer by SEC under agitation. Fig. 6B depicts the loss of monomer by SEC at freeze-thawing.
FIG. 7A depicts binding of anti-TL 1A antibodies to cynomolgus monkey and human TL1A, but not to mouse or rat TL 1A. At least three ELISA runs were performed for each protein. Data from representative experiments are shown and are mean ± SD. Abbreviations: a = absorbance, ab = antibody, cyno = cynomolgus monkey, nM = nM, nM = nanomole. Fig. 7B depicts the average level of sTL1A increasing with increasing IV dose of anti-TL 1A to cynomolgus monkeys as measured in ELISA. In two separate occasions, the samples were assayed in triplicate. The data presented are the mean TL1A concentration ± SD of three animals per group. Samples collected from animals administered isotype control antibodies are shown as circles and samples collected from animals administered anti-TL 1A are shown as triangles and squares. Abbreviations: hr=hours, kg=kg, mg=mg, ml=ml, ng=nanogram; TL1A = tumor necrosis factor-like cytokine 1A.
Figure 8 shows TL1A drives inflammation and fibrosis by binding to DR 3.
Figures 9A-9C show Size Exclusion Chromatography (SEC) curves for recombinant human TL1A (rhTL 1A). Briefly, rhTL1A was labeled with Alexa fluor 488 (AF 488) and added to Normal Human Serum (NHS). In fig. 9A, the rhTL1A SEC curve shows two peaks on SEC when injected alone, representing the trimeric and monomeric forms of TL 1A. In fig. 9B, when rhTL1A was preincubated with control reference antibody, the trimer peak shifted left, indicating the larger complex formation of reference antibody and trimeric rhTL 1A. There was no shift in the monomer peak, indicating that the reference antibody only bound to trimeric rhTL 1A. In fig. 9C, when rhTL1A was pre-incubated with a219, both the trimer and monomeric rhTL1A peaks were shifted, thus indicating that a219 bound to both the trimeric and monomeric forms of TL 1A.
Fig. 10A depicts a whole body physiological-based pharmacokinetic (PBPK) model. Fig. 10B depicts a tissue-level diagram of a systemic PBPK model for characterizing the integration of monoclonal antibodies (mabs), ligands, and complexes between mabs and ligands.
Fig. 11A depicts a comparison of the pharmacokinetics of the mAb as predicted by integrated systemic PBPK (solid line) with the pharmacokinetics of the mAb as observed in normal healthy volunteers (multiple spots, and spots from the same subject shown in the same format) in each case after injection of a219 at the indicated dose. Fig. 11B depicts a comparison of TL1A concentration as predicted by integrated systemic PBPK with TL1A concentration as observed in normal healthy volunteers in each case after injection of a219 at the indicated dose.
Fig. 12A depicts the observed concentrations of TL1A in serum after injection of: (i) anti-TL 1A antibody a219 that binds to both TL1A monomer and trimer (represented in red, top of 2 curves, and data points observed with such curves) and (ii) control reference anti-TL 1A antibody that binds only to TL1A trimer (represented in blue, bottom of 2 curves, and data points observed with such curves). In fig. 12A, solid lines depict predictions from the model, and various points depict observations from subjects injected with the indicated antibodies. Fig. 12B depicts predicted total TL1A concentrations (monomer and trimer, solid line curves, and observed data points accompanying such curves), monomer TL1A concentrations (thin dashed line), and trimer TL1A concentrations (thick dashed line) at basal levels (without any injection of anti-TL 1A antibodies) in each case. Fig. 12C depicts serum TL1A concentrations in Normal Healthy Volunteers (NHV) and UC patients, as predicted by the systemic PBPK model (solid line, upper line of UC patients and lower line of NHV) and as observed (multiple points).
Fig. 13A-13B illustrate the suitability of the model. Fig. 13A depicts the observed concentrations (dots) of TL1A in serum of NHV after injection of anti-TL 1A antibodies that bind only to TL1A trimers, as well as predictions (solid line) that fit the model of observations at the indicated doses. Q2wx3=last three times every 2 weeks. Fig. 13B depicts the observed concentrations (dots) of TL1A in serum of UC patients after injection of anti-TL 1A antibodies that bind only to TL1A trimers, as well as predictions (solid line) that fit the model of observations at the indicated doses. Q2wx7 = seven times every 2 weeks. Fig. 13C depicts the concentration of TL1A in the intestine of NHV (as predicted by the model and observed data points accompanying such lines, black, solid, down line for both lines) and the concentration of TL1A in the intestine of UC patient (red, solid, up line for both lines).
FIGS. 14A-14B depict baseline concentrations of TL1A based on various parameters of TL1A production in the intestine (14A) and serum (14B). In FIGS. 14A-14B, 1X would be the baseline in NHV; 25×, 50×, 75×, and 100× indicate various parameters that are overproducing TL1A in the intestine.
Figures 15A-15V depict the concentration of free soluble TL1A in tissues as determined by the systemic PBPK model according to various parameters of TL1A overproduction at various dosage regimens of anti-TL 1A antibody a219 as shown. FIG. 15W depicts free soluble TL1A in tissue as determined by a systemic PBPK model according to various parameters of TL1A overproduction at a dose regimen of reference anti-TL 1A antibody as shown. Figures 15X-15Z depict a comparison of modeled free soluble TL1A concentrations in subjects treated with reference anti-TL 1A antibodies (red, upper of two curves) or a219 (green, lower of two curves). In FIGS. 15W-15Z, the reference antibody light chain sequence is SEQ ID NO:382, the heavy chain sequence is SEQ ID NO:383, and the systemic PBPK model uses a rapid equilibrium between monomeric and trimeric forms of TL1A, with monomers and trimers having, as observed, consecutive 60:40 ratio. The black solid lines in FIGS. 15A-15Z indicate TL1A concentration in the tissue of NHV. Q2w=every 2 weeks. Q4w=every 4 weeks. Sc=subcutaneous. LD = loading dose (first dose). 4W = week 4. D1 Day 1. W2, 6, 10=week 2, week 6 and week 10. W2, 4, 6, 10=week 2, week 4, week 6 and week 10. Eow=every other week. W4, 8, 12 = week 4, week 8 and week 12. W2, 4, 8, 12 = week 2, week 4, week 8 and week 12. stl1a=soluble TL1A.
FIGS. 16A-16H depict a goodness-of-fit plot for A219 with a population PK model.
Fig. 17A depicts a visual predictive check of a219 concentration predicted from the popPK model for observed a219 concentration. Fig. 17B depicts the induction dose selected in the popPK model to rapidly reach steady state concentrations.
Figure 18 depicts osmotic pressure at 5 ℃ as measured by stability of a219 samples for various formulations at T0, 3 and 6 months.
Figure 19 depicts the concentration of a219 protein at 5 ℃ measured at T0, 3 and 6 months for assessing the stability of a219 samples of various formulations.
Fig. 20 depicts the pH at 5 ℃ measured at T0, 3 and 6 months for evaluating the stability of a219 samples of various formulations.
Fig. 21A depicts viscosity data for T0 and 3M for formulations 1 to 5 at 25 ℃; fig. 21B depicts viscosity data for T0 and 3M for formulations 6 to 8 at 25 ℃.
FIG. 22A depicts the monomer content of the formulation at 5℃as measured by SEC; fig. 22B depicts the loss of monthly monomer (main peak) of the formulation at 5 ℃ as determined by SEC; fig. 22C depicts the monomer content of the formulation at 25 ℃ as measured by SEC; fig. 22D depicts the loss of monthly monomer (main peak) of the formulation at 5 ℃ as determined by SEC.
Fig. 23A depicts the relative area (%) of the main peak of the formulation at 5 ℃ as characterized by cation exchange chromatography; fig. 23B depicts the loss of the main peak of the formulation at 5 ℃ (monthly relative area (%)) as determined by cation exchange chromatography; fig. 23C depicts the relative area (%) of the main peak of the formulation at 25 ℃ as characterized by cation exchange chromatography; fig. 23D depicts the loss of the main peak (monthly relative area (%)) of the formulation at 25 ℃ as determined by cation exchange chromatography.
FIG. 24A depicts predicted relative measured values of monomer loss by SEC using the PLS model for samples stored at 25℃for 2 months as an endpoint; fig. 24B depicts the effect of using monomer loss by SEC on pH and protein according to PLS model for samples stored at 25 ℃ for 2 months as endpoint. In FIG. 24B, sucrose concentration was fixed at 200mM. Fig. 24C depicts the effect of using monomer loss by SEC on pH and acetate according to PLS model for samples stored at 25 ℃ for 2 months as endpoint. In FIG. 24C, sucrose concentration was fixed at 200mM. Fig. 24D depicts the effect of using monomer loss by SEC on sucrose and lysine according to PLS model for samples stored at 25 ℃ for 2 months as endpoint. In FIG. 24D, protein concentration was fixed at 150mg/mL, pH was fixed at 5.5 and acetate was fixed at 20 mM. Fig. 24E depicts the effect of using monomer loss by SEC on glycine and NaCl according to PLS model for samples stored at 25 ℃ for 2 months as endpoint. In FIG. 24E, protein concentration was fixed at 150mg/mL, pH was fixed at 5.5 and acetate was fixed at 20 mM.
In FIGS. 18, 19, 20, 21A-21B, 22A-22D, 23A-23D, and 24A-24E, formulations 1-8 (F01-F08, formulations 1-8, or simply 1-8) are those described in Table 31 of example 31.
Fig. 25 shows a regimen of a double-blind, randomized, placebo-controlled clinical study to evaluate the efficacy and safety of a219 in subjects with systemic sclerosis-related interstitial lung disease (SSc-ILD).
Figure 26A shows the geometric mean serum a219 concentration versus time curve (linear scale) after a single dose of a219 was administered as IV infusion (SAD study). Figure 26B shows geometric mean serum a219 concentration-time curve-day 29 (linear scale) after administration of multiple doses of a 219Q 2W as IV infusion (MAD study). Q2w=every 2 weeks.
Figure 27A shows geometric mean serum sTL1A concentration versus nominal time (semi-logarithmic scale) after single dose a219 administration as IV infusion (SAD study). Figure 27B geometric mean serum sTL1A concentration versus nominal time (semi-logarithmic scale) following administration of multiple doses of a 219Q 2W as IV infusion (MAD study).
Fig. 28A shows the total a219 concentration in the central compartment (in the cycle) in the SAD as predicted by the model (curve) and as determined in the phase I test (point). Fig. 28B shows the total solubility TL1A in the central compartment (in circulation) in the SAD as predicted by the model (curve) and as determined in the phase I trial. Fig. 28C shows the total a219 concentration in the central compartment (in circulation) in the MAD as predicted by the model (curve) and as determined in phase I test (spot). Fig. 28D shows the total solubility TL1A in the central compartment (in circulation) in the MAD as predicted by the model (curve) and as determined in phase I test (point). The predictive curve fits the measured data points. FIGS. 28E-28K show model predictions and data (light chain SEQ ID NO:382 and heavy chain SEQ ID NO: 383) for control reference antibodies that bind only to TL1A trimer, relative to single incremental dose data (FIGS. 28E and 28F) for phase (1) I; (2) multiple incremental dose data at stage I (fig. 28G and 28H); and (3) phase II data on PK and total sTL1A levels (fig. 28I and 28J). The IBD-specific parameters were then calibrated to capture free tissue TL1A levels in the intestine (FIG. 28K), as observed with the control reference antibodies (light chain SEQ ID NO:382 and heavy chain SEQ ID NO: 383). Nr=no responders, and r=responders.
Fig. 29A shows a dose of a219 determined from the validation model that can result in a patient having a lower concentration of free TL1A in diseased tissue than in healthy subjects. Fig. 29B shows the percent reduction of free TL1A in diseased tissue after administration of a219 at a dose as determined from the model. Iv_4×= 1000mg loading dose, day 14, day 42, day 70 is 3×500mg. SC was dosed with 240mg of either Q1W or Q2W. Fig. 29C shows that in a face-to-face comparison in the validation model, anti-TL 1A antibodies that bound to both TL1A monomers and trimers bind more (3.5 fold more) TL1A in circulation than anti-TL 1A antibodies that bound to only TL1A trimers. Fig. 29D shows that in a face-to-face comparison in the validation model, the anti-TL 1A antibodies that bind to both TL1A monomers and trimers also resulted in a higher percentage of TL1A reduction (about 100%) in TL1A in diseased tissue when compared to the anti-TL 1A antibodies that bind to only TL1A trimers.
Fig. 30A shows a diagram of the popPK model. Fig. 30B shows a comparison of a219 concentration predicted from the popPK model with a219 concentration observed in a population of subjects in phase I clinical trial via a linear regression plot. Fig. 30C shows a comparison of TL1A concentrations predicted from the popPK model with TL1A concentrations observed in a population of subjects in phase I clinical trial via a linear regression plot. Fig. 30D shows a comparison of a219 concentration predicted from the popPK model with a219 concentration observed in a population of subjects in phase I clinical trial via a time series plot. FIG. 30E shows a comparison of TL1A concentration predicted from the popPK model with TL1A concentration observed in a population of subjects in phase I clinical trials via a time series plot.
FIGS. 31A-31H show A219 and TL1A junctions (TL 1A concentration in serum) predicted by the validated popPK model at various A219 doses. Fig. 31A and 31B show the concentration of a219 (31A) and TL1A (31B) in the circulation, with induction dosing regimen performed with 500mg q2w (6 doses) up to week 10 and expansion with 500mg q2w (20 doses) from week 12 to week 52. Fig. 31C and 31D show the concentration of a219 (31C) and TL1A (31D) in the circulation, with induction dosing regimen performed with 500mg q2w (6 doses) up to week 10 and expansion with 500mg q4w (10 doses) from week 12 to week 52. Fig. 31E and 31F show the concentration of a219 (31E) and TL1A (31F) in the circulation with induction dosing regimen with 500mg q2w (6 doses) up to week 10 and expansion with 100mg q2w from week 12 to week 52 (20 doses). Fig. 31G and 31H show the concentration of a219 (31G) and TL1A (31H) in the circulation, with 500mg q2w (6 doses) for the induction dosing regimen up to week 10 and expansion with 250mg q4w (10 doses) from week 12 to week 52.
FIG. 32 depicts a large number of RNAseq gene expression data (raw data from Skaug B et al, "annual rheumatism (Ann RheumDis.)" 2020;79 (3): 379-86) and analyzed by genomic variation analysis (GSVA). FIG. 32 shows up-regulation of a set of TL 1A-responsive signature genes in tissues from SSc patients compared to tissues from healthy control subjects.
FIG. 33 depicts TL1A and DR3 expression in cells from skin of SSc patients. Gene expression data (RNAseq) from SSc biopsies shows upregulation of TL1A (TNFSF 15) and DR3 (TNFRSF 25) genes at single cell levels in SSc patients. In fig. 33, TL1A is expressed in bone marrow cells, and DR3 is expressed in fibroblasts, endothelial cells, keratinocytes, and T cells.
FIGS. 34A-34B depict TL1A and DR3 expression in cells from the skin of SSc patients. Gene expression data (RNAseq) and epigenetic (chromatin availability via ATAC sequences) from SSc biopsies show up-regulation of TL1A (TNFSF 15) and DR3 (TNFRSF 25) genes at the single cell level. TL1A is expressed in myeloid cells; DR3 is expressed in T cells and myeloid cells.
Detailed Description
TL1A is a cytokine secreted by antigen presenting cells, T cells and endothelial cells. TL1A signals through death receptor 3 (DR 3), a TNF family receptor that is primarily present on T cells, natural Killer (NK) and NK-T cells, congenital lymphocytes (ILC), fibroblasts, and epithelial cells, and effectively drives Th1, th2, th9, and Th17 responses. In addition, it is induced in antigen presenting cells by cross-linking of toll-like receptor (TLR) ligands with FcR, and in T cells by T Cell Receptor (TCR) stimulation.
Figure 8 demonstrates how TL1A and DR3 binding independently drive inflammation and fibrosis. Binding of TL1A to DR3 on innate and T cells results in early cytokine responses (IL-23, IL-1β, IL-17, IL-22, TNF- α, IFN- γ, IL-13 release) which lay the foundation for inflammation and stimulate innate and adaptive immune responses. For example, TL1A potentially drives inflammatory Th1 and Th17 responses by binding to DR 3. In addition, binding of TL1A to DR3 on fibroblasts directly activates fibroblasts and leads to collagen distribution and fibrosis, independent of inflammation. Although circulating TL1A levels are low in healthy subjects, levels are elevated in patients with many autoimmune diseases, and TL1A has been shown to be up-regulated in the mucosa and serum of patients with IBD. In mice, chronic TL1A expression causes a structured disease caused by increased collagen deposition. In Dextran Sodium Sulfate (DSS) and adoptive transfer mouse models, TL1A transgenic mice develop more severe colitis than wild-type animals when challenged with DSS, and antibodies to TL1A lead to reduced inflammation, reduced collagen levels, and reversal of fibrosis, even after inflammation and fibrosis have been determined, treatment is administered later in the course of the disease. In addition, TL1A polymorphisms have been shown to correlate with susceptibility to IBD and disease severity.
Fibrosis is an important clinical phenotype represented by IBD patients. Seventy percent of patients with Crohn's Disease (CD) develop stenosis/perforation, and stenosis is the leading indication for surgery for CD. Unfortunately, the anti-inflammatory agents used in the past decade have not substantially altered the rate at which the disease is structured or the need for surgery. Furthermore, in Ulcerative Colitis (UC), subclinical fibrosis has a significant impact on patient symptoms. For example, subclinical fibrosis may lead to symptoms of diarrhea, abdominal pain, urgency, and urinary incontinence. Subclinical fibrosis is also a potential explanation for persistent symptoms after inflammation resolution. In addition, cleveland office studies on 89 consecutive colectomy samples showed that 100% of the samples had submucosal fibrosis. Thus, the treatment of fibrosis constitutes an unmet need for IBD.
In studies evaluating the effect of anti-TL 1A antibodies in a mouse model of IBD, the potential of TL1A as a therapeutic target for intestinal fibrosis has been demonstrated. In these studies, two mouse models of chronic colitis were used: adoptive T cell transfer and chronic DSS. In both models, the neutralized TL1A monoclonal antibody (mAb) or isotype control antibody was administered twice weekly in mice (T cell transfer n=14; dss n=28) for which colitis has been established. In both disease models, treatment with TL1A mAb reduced colonic collagen deposition levels back to those seen in healthy control mice, indicating that blocking TL1A signaling not only prevented the progression of colonic fibrosis, but also reversed established fibrosis to similar levels measured prior to the onset of inflammation. This data suggests that intestinal fibrosis mediated by increased levels of TL1A can be treated by anti-TL 1A antibodies.
In one aspect, provided herein are methods of treating inflammation and/or fibrosis with an anti-TL 1A antibody. In some embodiments, the treatment of fibrosis is independent of the treatment of inflammation. In some embodiments, the treatment of inflammation is independent of the treatment of fibrosis. In another aspect, provided herein are methods of treating diseases and/or conditions of the lung with an anti-TL 1A antibody. Non-limiting examples of indications for use of anti-TL 1A antibodies herein include idiopathic interstitial pneumonia, pulmonary sarcoidosis, interstitial pulmonary disease, bronchiolitis, alveolitis, vasculitis, interstitial pneumonia, nonspecific interstitial pneumonia, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, acute interstitial pneumonia, allergic rhinitis, emphysema, chronic bronchitis, primary cholangitis, behcet's disease, systemic sclerosis-associated interstitial pulmonary disease, and cystic fibrosis. In certain embodiments, the anti-TL 1A antibodies bind with high affinity and specificity to the membrane-bound and soluble forms of TL1A and block binding of TL1A to its functional receptor DR 3.
The term "and/or" as used in a phrase with a list of members is intended to encompass all members individually, as well as all combinations of all or a portion of the list of members. For example, phrases such as "a and/or B" herein are intended to include a and B; a or B; a (alone); and B (alone). Also, the term "and/or" as used in phrases 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).
4.1 general techniques
The techniques and procedures described or referenced herein include those techniques and procedures commonly understood and/or commonly used by those skilled in the art using conventional methods, such as the widely practiced methods described in the following documents: sambrook et al, molecular cloning: laboratory manual [ ]Molecular Cloning：)》ALaboratory Manual) (3 rd edition 2001); scheme in current molecular biologyCurrent Protocols in Molecular Biology) (Ausubel et al, 2003); therapeutic monoclonal antibody: from the workbench to the clinicTherapeutic Monoclonal Antibodies：)<ex>From Bench to Clinic) (An edit 2009); monoclonal antibody: method and protocol [ ]Monoclonal Antibodies：Methods and Protocols) (Albitar edit 2010); antibody engineering [ ]Antibody Engineering) Volumes 1 and 2 (Kontermann and Dubel editions, 2 nd edition 2010).
4.2 anti-TL 1A antibodies
TL1A exists both in monomeric and trimeric forms in vivo and in vitro. The present disclosure suggests that while the trimeric form is in a biologically active form that binds to physiological receptors, namely death receptor 3 ("DR 3"), and triggers TL 1A-mediated signaling (e.g., zhan, C et al, structure 19:162-171 (2011)), monomer TL1A accounts for a substantial portion of the TL1A pool in a subject. By one of the inventors' estimates, the monomer TL1A may be 60% of the total TL1A in the circulating blood. The term "total TL 1A" refers to both monomeric and trimeric TL 1A. The present disclosure further provides that, although monomeric TL1A is biologically inactive, anti-TL 1A antibodies that bind to both monomeric and trimeric TL1A provide advantages over antibodies that bind to trimeric TL1A only. Such advantages, as provided herein and further illustrated in section 5, include: a more effective decrease in TL1A concentration in diseased tissue of the subject (including concentration of trimeric TL1A in diseased tissue); a more effective decrease in TL1A concentration in the blood of the subject (including concentration trimeric TL1A in the blood); a more sustained decrease in TL1A concentration (including trimeric TL1A concentration) in diseased tissue of a subject and/or a more sustained decrease in TL1A concentration (including trimeric TL1A concentration) in blood of a subject.
In one aspect, provided herein is an antibody or antigen-binding fragment thereof that binds tumor necrosis factor-like protein 1A ("TL 1A", and such antibodies or antigen-binding fragments thereof, "anti-TL 1A antibodies or antigen-binding fragments" or "anti-TL 1A antibodies" in the specification for simplicity, wherein the antibody or antigen-binding fragment binds to both monomeric TL1A and trimeric TL 1A. Additional embodiments of anti-TL 1A antibodies, including embodiments having exemplary CDRs, framework sequences, constant region sequences, fc mutations, variable regions, fc regions, and other properties are further provided in this section (section 4.2). Assays for screening, testing, and validating anti-TL 1A antibodies are provided in section 4.3. Methods for generating, modifying, mutating, cloning, expressing and isolating anti-TL 1A antibodies are provided in section 4.4. Pharmaceutical compositions for anti-TL 1A antibodies are described and provided in section 4.5. Methods of using anti-TL 1A antibodies are provided in section 4.6. Additional specificity and validated examples of anti-TL 1A antibodies and methods of use thereof are provided in section 5. Accordingly, the present disclosure provides various combinations of anti-TL 1A antibodies, pharmaceutical compositions of such anti-TL 1A antibodies, methods of generating anti-TL 1A antibodies, methods of assaying anti-TL 1A antibodies, and methods of using anti-TL 1A antibodies for treatment.
In one embodiment of the various anti-TL 1A antibodies or antigen-binding fragments thereof provided herein, the antibodies or antigen-binding fragments block binding of TL1A to death receptor 3 ("DR 3"). In another embodiment, the antibody or antigen binding fragment blocks binding of trimeric TL1A to DR 3. In further embodiments, the antibody or antigen binding fragment blocks signaling DR3 signaling mediated by TL 1A. In yet another embodiment, the antibody or antigen binding fragment blocks an increase in ifnγ secretion by various immune cells. In particular embodiments, the antibody or antigen binding fragment blocks an increase in ifnγ secretion by peripheral blood mononuclear cells, including various B cells, T cells, natural killer cells, and/or macrophages.
As described herein, the present disclosure provides anti-TL 1A antibodies or antigen-binding fragments for binding to both monomeric and trimeric TL 1A. Thus, in one embodiment of the various anti-TL 1A antibodies or antigen-binding fragments thereof provided herein, the binding agent is administered, e.g., by dissociation equilibrium constants (K D-monomer ) The binding affinity of the antibody or antigen binding fragment to monomeric TL1A is measured, e.g. by dissociation equilibrium constant (K D-trimer ) The binding affinity of the antibody or antigen binding fragment measured was comparable to that of trimeric TL 1A. Such K D-monomer And/or K D-trimer Can be determined by any method known and practiced by those skilled in the art and any suitable assay and method described herein, including in this section (section 4.2) and section 5.
The term "binding" or "binding" refers to interactions between molecules, including, for example, the formation of complexes. The interactions may be, for example, non-covalent interactions, including hydrogen bonding, ionic bonding, hydrophobic interactions, and/or van der Waals interactions (van der Waals interaction). A complex may also comprise two or more molecules held together by covalent or non-covalent bonds, interactions or forces. The strength of the total non-covalent interaction between a single antigen binding site on an antibody and a single epitope of a target molecule, such as TL1A, is the affinity of the antibody or functional fragment for said epitope. Dissociation rate of antibody from monovalent antigen (k off ) With association rate (k) on ) Ratio (k) off /k on ) Is the dissociation constant K D Inversely proportional to affinity. K (K) D The lower the value, the higher the affinity of the antibody. The value of KD varies due to different complexes of antibody and antigen, and depends on k on And k off Both of which are located in the same plane. Dissociation constant K of the antibodies provided herein D May be determined using any of the methods provided herein or any other method known to those of skill in the art. The affinity at one binding site does not always reflect the true strength of the interaction between the antibody and the antigen. When complex antigens containing multiple repeat epitopes, such as multivalent TL1A trimers, are contacted with antibodies containing multiple binding sites, the interaction of the antibodies with the antigen at one site will increase the likelihood of reaction at the second site. The strength of such multiple interactions between multivalent antibodies and antigens is referred to as avidity. The affinity of an antibody may measure its binding capacity better than the affinity of its individual binding sites.
"binding affinity" generally refers to the strength of the sum of non-covalent 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). As used herein, unless otherwise indicated, "binding affinity" refers to an intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibodies and antigens). As described above, the affinity of a binding molecule X for its binding partner Y can generally be determined by the dissociation constant (K D ) And (3) representing. Affinity can be measured by conventional methods known in the art, including those described herein. Low affinity antibodies typically bind slowly to the antigen and tend to dissociate easily, while high affinity antibodies typically bind more rapidly to the antigen and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which may be used for the purposes of this disclosure. Specific illustrative examples include the following examples. In one embodiment, "K D "or" K D The value "may be measured by assays known in the art, for example by binding assays. K (K) D Can be measured in RIA, e.g. with an antibody of interestAnd Fab versions of its antigen (Chen et al 1999, journal of molecular biology (J. Mol Biol) 293:865-81). K (K) D Or K D The value can also be obtained byUsing surface plasmon resonance assays, e.g. using +.>TM-2000 or->TM-3000; or e.g. use +.>The QK384 system was measured by bio-layer interferometry. "on rate" or "rate of association" or "association rate" or "k on "also can be used, for example +.>TM-2000 orTM-3000 or->The QK384 system was determined using the same surface plasmon resonance or biological layer interferometry techniques described above.
Thus, the relative binding affinity of an anti-TL 1A antibody or antigen-binding fragment to TL1A monomer and TL1A trimer can be determined by K D-monomer And K D-trimer Is described and provided. In one embodiment of the various anti-TL 1A antibodies or antigen binding fragments provided herein, K D-monomer At said K D-trimer 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times. In another embodiment of the various anti-TL 1A antibodies or antigen-binding fragments provided herein, K D-monomer At said K D-trimer Within 10%, 20%, 30%, 40% or 50%. As herein mentionedIn further embodiments of the various anti-TL 1A antibodies or antigen-binding fragments provided, K D-trimer At said K D-monomer 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times. In another embodiment of the various anti-TL 1A antibodies or antigen-binding fragments provided herein, K D-trimer At said K D-monomer Within 10%, 20%, 30%, 40% or 50%.
More specifically, in one embodiment of the various anti-TL 1A antibodies or antigen-binding fragments provided herein, K D-monomer At most 5X 10 -12 M, at most 6X 10 -12 M, at most 7X 10 -12 M, at most 8X 10 -12 M, at most 9X 10 -12 M, at most 1X 10 -11 M, at most 2X 10 -11 M, at most 3X 10 -11 M, at most 4X 10 -11 M, at most 5X 10 -11 M, at most 6X 10 -11 M, at most 7X 10 -11 M, at most 8X 10 -11 M, at most 9X 10 -11 M, at most 1X 10 -10 M, at most 2X 10 -10 M, at most 3X 10 -10 M, at most 4X 10 -10 M, at most 5X 10 -10 M, at most 6X 10 -10 M, at most 7X 10 -10 M, at most 8X 10 -10 M, at most 9X 10 -10 M or up to 1X 10 -9 M. In another embodiment, K D-monomer Is about 5X 10 -12 M, about 6X 10 -12 M, about 7X 10 -12 M, about 8X 10 -12 M, about 9X 10 -12 M, about 1X 10 -11 M, about 2X 10 -11 M, about 3X 10 -11 M, about 4X 10 -11 M, about 5X 10 -11 M, about 6X 10 -11 M, about 7X 10 -11 M, about 8X 10 -11 M, about 9X 10 -11 M, about 1X 10 -10 M, about 2X 10 -10 M, about 3X 10 -10 M, about 4X 10 -10 M, about 5X 10 -10 M, about 6X 10 -10 M, about 7X 10 -10 M, about 8X 10 -10 M, about 9X 10 -10 M or about 1X 10 -9 M. In further embodiments of the various anti-TL 1A antibodies or antigen binding fragments provided herein, K D-trimer At most 5X 10 -12 M, at most 6X 10 -12 M, at most 7X 10 -12 M, at most 8X 10 -12 M, at most 9X 10 -12 M, at most 1X 10 -11 M, at most 2X 10 -11 M, at most 3X 10 -11 M, at most 4X 10 -11 M, at most 5X 10 -11 M, at most 6X 10 -11 M, at most 7X 10 -11 M, at most 8X 10 - 11 M, at most 9X 10 -11 M, at most 1X 10 -10 M, at most 2X 10 -10 M, at most 3X 10 -10 M, at most 4X 10 -10 M, at most 5X 10 -10 M, at most 6X 10 -10 M, at most 7X 10 -10 M, at most 8X 10 -10 M, at most 9X 10 -10 M or up to 1X 10 -9 M. In yet another embodiment, K D-trimer Is about 5X 10 -12 M, about 6X 10 -12 M, about 7X 10 -12 M, about 8X 10 -12 M, about 9X 10 -12 M, about 1X 10 -11 M, about 2X 10 -11 M, about 3X 10 -11 M, about 4X 10 -11 M, about 5X 10 -11 M, about 6X 10 -11 M, about 7X 10 -11 M, about 8X 10 -11 M, about 9X 10 -11 M, about 1X 10 -10 M, about 2X 10 -10 M, about 3X 10 -10 M, about 4X 10 -10 M, about 5X 10 -10 M, about 6X 10 -10 M, about 7X 10 -10 M, about 8X 10 -10 M, about 9X 10 -10 M or about 1X 10 -9 M. The present disclosure further provides that K D-monomer And K D-trimer May be K as provided herein D-monomer And K D-trimer Any combination of values or ranges is encompassed by this section (section 4.2) and this paragraph.
In a further particular embodiment, K D-monomer About 59pM. In another particular embodiment, K D-trimer About 59pM. In a further embodiment, K D-monomer About 59pM, and K D-trimer About 59pM. In a particular embodiment, K D-monomer About 60pM. In another particular embodiment, K D-trimer About 60pM. In a further embodiment, K D-monomer About 60pM, and K D-trimer About 60pM. In a specific embodiment, K D-monomer At most 60pM. In another embodiment, K D-trimer At most 60pM. In a further embodiment, K D-monomer At most 60pM, and K D-trimer At most 60pM.
In one aspect, provided herein are antibodies that bind TL 1A. In some embodiments, the antibody comprises an antigen binding fragment, which refers to a portion of an antibody having the epitope variable region of the antibody. Examples of antigen binding fragments include, but are not limited to, fab ', F (ab') 2 And Fv fragments, linear antibodies, single chain antibodies, and multispecific antibodies formed from antibody fragments. In some embodiments, an antibody refers to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination of the foregoing, through at least one antigen recognition site within the variable region of the immunoglobulin molecule. In some embodiments, the antibodies comprise intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (e.g., fab ', F (ab') 2 And Fv fragments), single chain Fv (scFv) mutants, CDR-grafted antibodies, multispecific antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an epitope of an antibody, and any other modified immunoglobulin molecule comprising an antigen recognition site, so long as the antibody exhibits the desired biological activity. Antibodies can have any of five main classes of immunoglobulins: igA, igD, igE, igG and IgM or subclasses (isotypes) thereof (e.g., igG1, igG2, igG3, igG4, igA1, and IgA 2), are referred to as α, δ, ε, γ, and μ, respectively, based on the identity of their heavy chain constant domains. Different classes of immunoglobulins have different and well known subunit structures and three-dimensional configurations. Antibodies may be naked or conjugated to other molecules such as toxins, radioisotopes, etc.
In some embodiments, humanized antibodies refer to a form of non-human (e.g., murine) antibody having specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences. In a non-limiting example, the humanized antibody comprises less than about 40% non-human sequences in the variable region. In some cases, the humanized antibody comprises less than about 20% of the non-human sequences in the full-length antibody sequence. In further non-limiting examples, the humanized antibody comprises less than about 20% of a non-human sequence in the framework region of each of the heavy chain variable region and the light chain variable region. For example, a humanized antibody comprises less than about 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% of a non-human sequence in the framework region of each of the heavy chain variable region and the light chain variable region. As another example, a humanized antibody comprises about or less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 non-human sequences in the framework regions of each of the heavy and light chain variable regions. In some cases, the humanized antibody is a human immunoglobulin in which residues from a Complementarity Determining Region (CDR) are replaced with residues from a CDR of a non-human species (e.g., mouse, rat, rabbit, hamster) having the desired specificity, affinity, and capacity. These humanized antibodies may contain one or more non-human species mutations, for example, 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 regions, 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 regions. The humanized heavy chain variable domain may comprise an IGHV1-46 x 02 framework having no or less than about 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid mutations. The humanized light chain variable domain may comprise an IGKV3-20 framework having no amino acid mutation or having less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutation.
In some embodiments, chimeric antibodies refer to antibodies in which the sequence of an immunoglobulin molecule is derived from two or more species. As a non-limiting example, the variable regions of both the light and heavy chains correspond to the variable regions of antibodies derived from one mammalian species (e.g., mouse, rat, rabbit, etc.) having the desired specificity, affinity, and ability, while the constant regions are homologous to sequences in antibodies derived from another species (typically human) to avoid eliciting an immune response in that species.
The terms "complementarity determining regions" and "CDRs" which are synonymous with "hypervariable regions" or "HVRs" are known in the art to refer to non-contiguous amino acid sequences within the variable regions of antibodies that confer antigen specificity and/or binding affinity. Typically, three CDRs (CDR-H1, CDR-H2, CDR-H3) are present in each heavy chain variable region, and three CDRs (CDR-L1, CDR-L2, CDR-L3) are present in each light chain variable region. "framework region" and "FR" are known in the art to refer to the non-CDR portions of the variable regions of the heavy and light chains. Typically, four FRs (FR-H1, FR-H2, FR-H3 and FR-H4) are present in each full-length heavy chain variable region, and four FRs (FR-L1, FR-L2, FR-L3 and FR-L4) are present in each full-length light chain variable region. The exact amino acid sequence boundaries for a given CDR or FR can be readily determined using any of a number of well known schemes, including those described by the following documents: kabat et al (1991), "protein sequence of immunological significance (Sequences of Proteins of Immunological Interest)," public health service of the national institutes of health of Besseda, maryland, 5 th edition (Public Health Service, national Institutes of Health, bethesda, md.) ("Kabat" numbering scheme); A1-Lazikani et al, (1997) JMB 273, 927-948 ("Chothia" numbering scheme); macCallum et al, journal of molecular biology 262:732-745 (1996), "antibody-antigen interactions: contact analysis and binding site topography (anti-body-antigen interactions: contact analysis and binding site topography) ", journal of molecular science (J.Mol.)" 262, 732-745 "(" Contact "numbering scheme); lefranc MP et al, "IMGT unique numbering of immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains (IMGT unique numbering for immunoglobulin and T cell receptor variabledomains and Ig superfamily V-like domains)", "development and comparative immunology (Dev Comp Immunol)", month 1 2003; 27 (1): 55-77 ("IMGT" numbering scheme); another numbering scheme for honeygger a and pluckthun a, "immunoglobulin variable domains: automatic modeling and analysis tools (Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool) ", journal of molecular biology, month 6, 8, 2001; 309 (3): 657-70, ("Aho" numbering scheme); and Whitelegg NR and Rees AR, "WAM: improved algorithms for modeling antibodies on WEB (WAM: an improved algorithm for modelling antibodies on the WEB), "Protein engineering (Protein eng.)", 12 months 2000; 13 (12): 819-24 ("AbM" numbering scheme). In certain embodiments, the CDRs of an antibody described herein can be defined by a method selected from Kabat, chothia, IMGT, aho, abM or a combination thereof.
In some embodiments, an antibody that specifically binds to a protein indicates that the antibody reacts or associates with the protein more frequently, more rapidly, for a longer duration, with greater affinity, or some combination thereof, than an alternative substance (comprising an unrelated protein).
In some embodiments, the terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer having amino acids of any length. The polymer may be linear or branched, may include modified amino acids, and may be interrupted by non-amino acids. The term also encompasses amino acid polymers that have 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, for example, with a labeling component. Also included within the definition are, for example, one or more analogs (e.g., unnatural amino acids, etc.) that contain an amino acid, as well as other modified polypeptides known in the art.
In some embodiments, the protein (e.g., an antibody as described herein) comprises hydrophobic amino acids. Non-limiting exemplary hydrophobic amino acids include glycine (Gly), proline (Pro), phenylalanine (Phe), alanine (Ala), isoleucine (Ile), leucine (Leu), and valine (Val). In some embodiments, the protein (e.g., an antibody as described herein) comprises a hydrophilic amino acid. Non-limiting exemplary hydrophilic amino acids include serine (Ser), threonine (Thr), aspartic acid (Asp), glutamic acid (Glu), cysteine (Cys), asparagine (Asn), glutamine (gin), arginine (Arg), and histidine (His). In some embodiments, the protein (e.g., an antibody as described herein) comprises an amphiphilic amino acid. Non-limiting exemplary amphiphilic amino acids include lysine (Lys), tryptophan (Trp), tyrosine (Tyr), and methionine (Met). In some embodiments, the protein (e.g., an antibody as described herein) comprises an aliphatic amino acid. Non-limiting exemplary aliphatic amino acids include alanine (Ala), isoleucine (Ile), leucine (Leu), and valine (Val). In some embodiments, the protein (e.g., an antibody as described herein) comprises an aromatic amino acid. Non-limiting exemplary aromatic amino acids include phenylalanine (Phe), tryptophan (Trp), and tyrosine (Tyr). In some embodiments, the protein (e.g., an antibody as described herein) comprises an acidic amino acid. Non-limiting exemplary acidic amino acids include aspartic acid (Asp) and glutamic acid (Glu). In some embodiments, the protein (e.g., an antibody as described herein) comprises a basic amino acid. Non-limiting exemplary basic amino acids include arginine (Arg), histidine (His), and lysine (Lys). In some embodiments, the protein (e.g., an antibody as described herein) comprises a hydroxy amino acid. Non-limiting exemplary hydroxy amino acids include serine (Ser) and threonine (Thr). In some embodiments, the protein (e.g., an antibody as described herein) comprises a sulfur-containing amino acid. Non-limiting exemplary sulfur-containing amino acids include cysteine (Cys) and methionine (Met). In some embodiments, the protein (e.g., an antibody as described herein) comprises an amide amino acid. Non-limiting exemplary amide amino acids include asparagine (Asn) and glutamine (Gln).
In some embodiments, "polynucleotide" or "nucleic acid" as used interchangeably herein refers to a polymer of nucleotides of any length, and comprises DNA and RNA. The nucleotide may be a deoxyribonucleotide, a ribonucleotide, a modified nucleotide or base and/or analogue thereof, or any substituent that can be incorporated into a polymer by a DNA or RNA polymerase. Polynucleotides may include modified nucleotides such as, but not limited to, methylated nucleotides and analogs or non-nucleotide components thereof. The nucleotide structure may be modified before or after assembly of the polymer. The polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.
The percent (%) sequence identity relative to the reference polypeptide sequence is the percent of amino acid residues in the candidate sequence that are identical to 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 the purpose of determining the percentage of amino acid sequences that are identical can be accomplished in a variety of ways that are known, for example using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Suitable parameters for aligning sequences can be determined, including the algorithms required to achieve maximum alignment over the full length of the sequences being compared. However, for purposes herein, the% amino acid sequence identity values were generated using the sequence comparison computer program ALIGN-2. ALIGN-2 sequence comparison computer program was written by GeneTek corporation (Genentech, inc.), and the source code has been submitted using a user document in the United states copyright office, no. 20559, washington, registered with the United states copyright registration No. TXU 510087. ALIGN-2 programs are publicly available from Genntech, inc. (Inc., south San Francisco, calif.) from san Francisco, calif., or may be compiled from source code. The ALIGN-2 program should be compiled for use on a UNIX operating system containing the digital UNIX V4.0D. All sequence comparison parameters were set by the ALIGN-2 program and did not change.
In the case of amino acid sequence comparison using ALIGN-2, the identity of a given amino acid sequence A to, and/or relative to, the amino acid sequence of a given amino acid sequence B (which may alternatively be expressed as the identity of a given amino acid sequence A to, and/or relative to, a given amino acid sequence B having or comprising a certain amino acid sequence) is calculated as follows: 100 by a score X/Y, where X is the number of amino acid residues scored as identical matches by sequence alignment program ALIGN-2 in the alignment of a and B of the program, and where Y is the total number of amino acid residues in B. It will be appreciated that when the length of amino acid sequence a is not equal to the length of amino acid sequence B, the% amino acid sequence identity of a and B will not be equal to the% amino acid sequence identity of B and a. Unless otherwise specifically indicated, all amino acid sequence identical% values used herein are obtained using the ALIGN-2 computer program as described in the immediately preceding paragraph.
In some embodiments, the term "about" means within 10% of the stated amount. For example, an antibody variable region comprising about 80% identity to a reference variable region may have 72% to 88% identity to the reference variable region.
In certain aspects, antibodies that specifically bind to TL1A are described herein (Entrez Gene:9966; uniProtKB: O95150). In some embodiments, the antibody specifically binds to soluble TL 1A. In some embodiments, the antibody specifically binds to membrane-bound TL 1A. In some embodiments, an anti-TL 1A antibody is provided 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-TL 1A antibody can include any of the regions provided herein, e.g., as provided in tables, examples, and sequences.
Exemplary anti-TL 1A CDR
In certain embodiments, the anti-TL 1A antibody comprises HCDR1, as defined by SEQ ID NO: 1. In certain embodiments, the anti-TL 1A antibody comprises HCDR2, as defined by SEQ ID NO: 2-5. In certain embodiments, the anti-TL 1A antibody comprises HCDR3, as defined by SEQ ID NO: 6-9. In certain embodiments, the anti-TL 1A antibody comprises LCDR1, as defined by SEQ ID NO: shown at 10. In certain embodiments, the anti-TL 1A antibody comprises LCDR2 as defined by SEQ ID NO: 11. In certain embodiments, the anti-TL 1A antibody comprises LCDR3 as defined by SEQ ID NO: 12-15. In a non-limiting example, the anti-TL 1A antibody comprises HCDR1 as defined by SEQ ID NO:1, shown in the specification: HCDR2 as defined by SEQ ID NO:2, shown in the specification: HCDR3 as defined by SEQ ID NO: 6: LCDR1, as defined by SEQ ID NO:10, shown in the accompanying drawings: LCDR2 as defined by SEQ ID NO: 11: and LCDR3 as defined by SEQ ID NO: shown at 12.
In certain embodiments, the anti-TL 1A antibody comprises HCDR1, as defined by SEQ ID NO: 401. 407, 413 or 450. In certain embodiments, the anti-TL 1A antibody comprises HCDR2, as defined by SEQ ID NO: 402. 408, 414 or 451. In certain embodiments, the anti-TL 1A antibody comprises HCDR3, as defined by SEQ ID NO: 403. 409, 415 or 452. In certain embodiments, the anti-TL 1A antibody comprises LCDR1, as defined by SEQ ID NO: 404. 410, 416 or 453. In certain embodiments, the anti-TL 1A antibody comprises LCDR2 as defined by SEQ ID NO: 405. 411, 417 or 454. In certain embodiments, the anti-TL 1A antibody comprises LCDR3 as defined by SEQ ID NO: 406. 412, 418 or 455.
In certain embodiments, the anti-TL 1A antibody comprises an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 selected from table 6.
Table 6: exemplary CDR amino acid sequences
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In certain embodiments, the anti-TL 1A antibody comprises a CDR as set forth in antibodies A, B, C, D, E, F, G, H, I, A, B2, C2, D2, E2, F2, G2, H2, I2, J, K, M, or N of table 10.
Table 10: CDR sequences from exemplary anti-TL 1A antibodies
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In certain embodiments, the anti-TL 1A antibody comprises heavy chain CDRs selected from those shown in the antibodies of table 7.
Table 7: exemplary heavy chain variable region sequences
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In certain embodiments, the anti-TL 1A antibody comprises light chain CDRs selected from those shown in the antibodies of table 8.
Table 8: exemplary light chain variable region sequences
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In certain embodiments, the anti-TL 1A antibody comprises the CDRs shown in any one of the antibodies of table 1. For example, the number of the cells to be processed, anti-TL 1A antibodies include antibodies A15, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55, A56, A57, A58, A59, A60, A61, A62, A63, A64, A65, A66, A67, A68, A69, A70, A71, A72, A73, A74, A75, A76, A77, A78 A79, A81, A82, A83, A85, A86, A87, A88, A89, A90, A91, A92, A93, A94, A95, A96, A97, A98, A99, A100, A101, A102, A103, A104, A105, A107, A108, A109, A110, A111, A112, A113, A114, A115, A116, A117, A118, A119, A120, A121, A122, A123, A124, A125, A126, A127, A128, A129, A130, A132, A133 a134, a135, a136, a137, a138, a139, a140, a141, a142, a143, a144, a145, a146, a147, a148, a149, a150, a151, a152, a153, a154, a155, a156, a157, a158, a159, a160, a161, a162, a163, a164, a165, a166, a167, a168, a169, a170, a171, a172, a173, a174, a175, a176, a177, a178, a179, a180, a181, a182, a183, a184, a185, a186, a187, a188, a189, a190, a191, a192, a193, a194, a195, a196, a197, a198, a199, a200, a201, a202, a203, a204, a205, a206, a207, a208, a209, a210, a212, a216, a211, a222, a221, a500, a223, a500, a J, or a CDR 500. In a non-limiting example, the anti-TL 1A antibody includes CDRs of antibody a 219.
Antibody CDRs can be defined by the Aho or Kabat, chothia or IMGT methods.
Exemplary TL1A resistant frame region
In certain embodiments, the anti-TL 1A antibody comprises Heavy Chain (HC) framework 1 (FR 1), as defined by SEQ ID NO: 304. In certain embodiments, the anti-TL 1A antibody comprises HC FR2, as defined by SEQ ID NO:305 or 313. In certain embodiments, the anti-TL 1A antibody comprises HC FR3, as defined by SEQ ID NO:306-307, 314-315. In certain embodiments, the anti-TL 1A antibody comprises HC FR4, as defined by SEQ ID NO: shown at 308. In certain embodiments, the anti-TL 1A antibody comprises LC FR1, as defined by SEQ ID NO: shown at 309. In certain embodiments, the anti-TL 1A antibody comprises LC FR2, as defined by SEQ ID NO: shown at 310. In certain embodiments, the anti-TL 1A antibody comprises LC FR3, as defined by SEQ ID NO: shown at 311. In certain embodiments, the anti-TL 1A antibody comprises LC FR4, as defined by SEQ ID NO: shown at 312. In a non-limiting example, the anti-TL 1A antibody comprises HC FR1, as defined by SEQ ID NO:304, as shown in: HC FR2, as represented by SEQ ID NO:305, as shown in: HC FR3, as represented by SEQ ID NO:306 as shown in: HC FR4, as represented by SEQ ID NO: shown at 308: LC FR1 as defined by SEQ ID NO:309, shown in fig. 309: LC FR2 as defined by SEQ ID NO: shown at 310: LC FR3 as defined by SEQ ID NO: shown at 311: and LC FR4 as defined by SEQ ID NO: shown at 312. In a non-limiting example, the anti-TL 1A antibody comprises HC FR1, as defined by SEQ ID NO:304, as shown in: HC FR2, as represented by SEQ ID NO:305, as shown in: HC FR3, as represented by SEQ ID NO: shown at 307: HC FR4, as represented by SEQ ID NO: shown at 308: LC FR1 as defined by SEQ ID NO:309, shown in fig. 309: LC FR2 as defined by SEQ ID NO: shown at 310: LC FR3 as defined by SEQ ID NO: shown at 311: and LC FR4 as defined by SEQ ID NO: shown at 312.
In certain embodiments, the anti-TL 1A antibody comprises a heavy chain framework region selected from those shown in the antibodies of table 7. In certain embodiments, the anti-TL 1A antibody comprises a light chain framework region selected from those shown in the antibodies of table 8. In certain embodiments, the anti-TL 1A antibody comprises a framework region shown in any one of the antibodies of table 1. For example, the number of the cells to be processed, anti-TL 1A antibodies include antibodies A15, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A54, A55, A56, A57, A58, A59, A60, A61, A62, A63, A64, A65, A66, A67, A68, A69, A70, A71, A72, A73, A74, A75, A76, A77, A78 A79, A81, A82, A83, A85, A86, A87, A88, A89, A90, A91, A92, A93, A94, A95, A96, A97, A98, A99, A100, A101, A102, A103, A104, A105, A107, A108, A109, A110, A111, A112, A113, A114, A115, A116, A117, A118, A119, A120, A121, A122, A123, A124, A125, A126, A127, A128, A129, A130, A132, A133 a region a134, a135, a136, a137, a138, a139, a140, a141, a142, a143, a144, a145, a146, a147, a148, a149, a150, a151, a152, a153, a154, a155, a156, a157, a158, a159, a160, a161, a162, a163, a164, a165, a166, a167, a168, a169, a170, a171, a172, a173, a174, a175, a176, a177, a178, a179, a180, a181, a182, a183, a184, a185, a186, a187, a188, a189, a190, a191, a192, a193, a194, a195, a196, a197, a198, a199, a200, a201, a202, a203, a204, a205, a206, a207, a208, a209, a212, a216, a211, a216, a220, a222, a221, a500, a223, a j, a frame or a 500. In a non-limiting example, the anti-TL 1A antibody includes the framework region of antibody a 219.
Antibody CDRs and framework regions can be defined by the Aho or Kabat, chothia or IMGT methods.
In some embodiments, the anti-TL 1A antibody comprises: a heavy chain variable framework region comprising a human IGHV1-46 x 02 framework or a modified human IGHV1-46 x 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 together comprise no or less than nine amino acid modifications from the human IGHV1-46 x 02 framework and the human IGKV3-20 framework. In some embodiments, the amino acid modification comprises: (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, numbered according to Aho or Kabat; or a combination of two or more modifications selected from (a) to (h). In some embodiments, the amino acid modification comprises (a) R45K, (b) a47R, (c) M55I, (d) V78A, (e) M80I, (f) R82T, (g) V89A, or (h) M91L in the heavy chain variable region, numbered according to Aho or Kabat; or a combination of two or more modifications selected from (a) to (h). In some embodiments, the amino acid modification comprises: A47R. In some embodiments, the amino acid modification comprises: a47R, M55I, V A, M80I, R82T, V89A and M91L; a47R, M I and R82T; a47R, M80I, R T, V89A and M91L; or a47R, M55I, V A, M80I, V89A and M91L. In some embodiments, the amino acid modification comprises: R45K and A47R. In some embodiments, the amino acid modification comprises: R45K, A47R, V a and M91L. In some embodiments, the amino acid modification comprises: R45K and A47R and M80I. In some embodiments, the amino acid modification comprises: R45K, A47R, M I and M91L; R45K, A47R, V A, M80I, V89A and M91L; R45K, A47R, M55I, V78A, M3880I, R82T, V a and M91L; R45K, A47R, M80I, V89A and M91L; R45K, A47R, M55I, M80I, R82T, V89A and M91L; R45K, A47R, M I and V89A; R45K, A47R, M80I, R82T, V89A, M L; or R45K, A47R, M55I, M80I, V89A and M91L. In some embodiments, the amino acid modification comprises: R45K. In some embodiments, the amino acid modification comprises: R45K and V78A. In some embodiments, the amino acid modification comprises: V78A. In some embodiments, the amino acid modification comprises: V78A and V89A; V78A and M80I; or V78A, M I and R82T. In some embodiments, the amino acid modification comprises: V89A. In some embodiments, the amino acid modification comprises: M80I. In some embodiments, the amino acid modification comprises: (a) A modification at amino acid position 54 in the light chain variable region; and/or (b) a modification at amino acid position 55 in the light chain variable region, numbered according to Aho or Kabat. In some embodiments, the amino acid modification comprises L54P in the light chain variable region, numbered according to Aho or Kabat. In some embodiments, the amino acid modification comprises L55W in the light chain variable region, numbered according to Aho or Kabat.
In some embodiments, the anti-TL 1A antibody comprises a heavy chain framework comprising the amino acid sequence of SEQ ID NO:301
(X1 VQLVQSGAEVKKPGASVKVSCKAS [ HCDR1] WVX QX3PGQGLEWX4G [ HCDR2] RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTAVYYCAR [ HCDR3] WGQGTTVTSS) or SEQ ID NO:302
(X1 VQLVQSGAEVKKPGASVKVSCKAS [ HCDR1] WVX QX3PGQGLEWX4G [ HCDR2] RX5TX6TX7DTSTSTX8YX9ELSSLRSEDTAVYYC [ HCDR3] WGQGTTVTVSS). In some cases, X1 is Q. In some cases, x1=e. In some cases, x2=r. In some cases, x2=k. In some cases, x3=a. In some cases, x3=r. In some cases, x4=m. In some cases, x4=i. In some cases, x5=v. In some cases, x5=a. In some cases, x6=m. In some cases, x6=i. In some cases, x7=r. In some cases, x7=t. In some cases, x8=v. In some cases, x8=a. In some cases, x9=m. In some cases, x9=l. In some embodiments, X1 is located at position 1 of IGHV 1-46X 02, as determined by the Aho or Kabat numbering. In some embodiments, X2 is located at position 45 of IGHV 1-46X 02, as determined by the Aho or Kabat numbering. In some embodiments, X3 is located at position 47 of IGHV 1-46X 02, as determined by the Aho or Kabat numbering. In some embodiments, X4 is located at position 55 of IGHV 1-46X 02, as determined by the Aho or Kabat numbering. In some embodiments, X5 is located at position 78 of IGHV 1-46X 02, as determined by the Aho or Kabat numbering. In some embodiments, X6 is located at position 80 of IGHV 1-46X 02, as determined by the Aho or Kabat numbering. In some embodiments, X7 is located at position 82 of IGHV 1-46X 02, as determined by the Aho or Kabat numbering. In some embodiments, X8 is located at position 89 of IGHV 1-46X 02, as determined by the Aho or Kabat numbering. In some embodiments, X9 is located at position 91 of IGHV 1-46X 02, as determined by the Aho or Kabat numbering.
In one aspect, provided herein is a first embodiment of an anti-TL 1A antibody comprising a heavy chain framework comprising IGHV1-46 x 02 or a variant thereof, wherein said 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 the IGHV1-46 x 02 framework. Further embodiments include: (2) The anti-TL 1A of embodiment (1), wherein said heavy chain framework comprises the amino acid sequence of SEQ ID NO:301. (3) anti-TL 1A according to example 2, wherein x1=q. (4) anti-TL 1A according to example 2, wherein x1=e. (5) The anti-TL 1A of any one of embodiments 2 to 4, wherein x2=r. (6) The anti-TL 1A of any one of embodiments 2 to 4, wherein x2=k. (7) The anti-TL 1A of any one of embodiments 2 to 6, wherein x3=a. (8) The anti-TL 1A of any one of embodiments 2 to 6, wherein x3=r. (9) The anti-TL 1A of any one of embodiments 2 to 8, wherein x4=m. (10) The anti-TL 1A of any one of embodiments 2 to 8, wherein x4=i. (11) The anti-TL 1A of any one of embodiments 2 to 10, wherein x5=v. (12) The anti-TL 1A of any one of embodiments 2 to 10, wherein x5=a. (13) The anti-TL 1A of any one of embodiments 2 to 12, wherein x6=m. (14) The anti-TL 1A of any one of embodiments 2 to 12, wherein x6=i. (15) The anti-TL 1A of any one of embodiments 2 to 14, wherein x7=r. (16) The anti-TL 1A of any one of embodiments 2 to 14, wherein x7=t. (17) The anti-TL 1A of any one of embodiments 2 to 16, wherein x8=v. (18) The anti-TL 1A of any one of embodiments 2 to 16, wherein x8=a. (19) The anti-TL 1A of any one of embodiments 2 to 18, wherein x9=m. (20) The anti-TL 1A of any one of embodiments 2 to 4, wherein x9=l. (21) The anti-TL 1A of any one of embodiments 1 to 20, comprising antibody a. (22) The anti-TL 1A of any one of embodiments 1 to 20, comprising antibody B. (23) The anti-TL 1A of any one of embodiments 1 to 20, comprising antibody C. (24) The anti-TL 1A of any one of embodiments 1 to 20, comprising antibody D. (25) The anti-TL 1A of any one of embodiments 1 to 20, comprising antibody E. (26) The anti-TL 1A of any one of embodiments 1 to 20, comprising antibody F. (27) The anti-TL 1A of any one of embodiments 1 to 20, comprising an antibody G or I. (28) The anti-TL 1A of any one of embodiments 1 to 20, comprising antibody H. (34) The anti-TL 1A of any one of embodiments 1 to 33, comprising a light chain framework comprising IGKV3-20 x 01 or a variant thereof, wherein said variant comprises between about 1 and about 2 substitutions in the framework, 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. (35) The anti-TL 1A antibody of embodiment 34, wherein X10 is L. (36) The anti-TL 1A antibody of example 34, wherein X10 is P. (37) The anti-TL 1A antibody of any one of embodiments 34 to 36, wherein X11 is L. (38) The anti-TL 1A antibody of any one of embodiments 34 to 36, wherein X11 is W.
In some embodiments, the anti-TL 1A antibody comprises a light chain framework comprising the amino acid sequence of SEQ ID NO:303
(EIVLTQSPGTLSLSPGERATLSC [ LCDR1] WYQKPGQAPRX 10X11IY [ LCDR2] GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC [ LCDR3] FGGGTKLEIK). In some cases, X10 is L. In some cases, X10 is P. In some cases, X11 is L. In some cases, X11 is W. In some embodiments, X10 is located at position 54 of IGKV 3-20X 01, as determined by the Aho or Kabat numbering. In some embodiments, X11 is located at position 55 of IGKV 3-20X 01, as determined by the Aho or Kabat numbering.
In some embodiments, the anti-TL 1A antibody comprises a heavy chain framework comprising IGHV1-46 x 02. In some embodiments, the anti-TL 1A antibody comprises a heavy chain framework comprising a variant of IGHV1-46 x 02 comprising a sequence from SEQ ID NO:316 between about 1 and about 20 amino acid substitutions. In some embodiments, the anti-TL 1A antibody comprises a heavy chain framework comprising a variant of IGHV1-46 x 02 comprising a sequence from SEQ ID NO:316 between about 1 and about 9 amino acid substitutions. In some embodiments, the anti-TL 1A antibody comprises a heavy chain framework comprising variants of IGHV1-46 x 02 comprising the amino acid sequence from SEQ ID NO:316 of 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 some cases, the heavy chain framework substitution includes Q1E, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitution includes R45K, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitution includes a47R, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitution includes M55I, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitution comprises V78A, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitution includes M80I, as determined by Aho or Kabat numbering. In some cases, the heavy chain framework substitution includes 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 includes M91L, as determined by Aho or Kabat numbering.
In some embodiments, the anti-TL 1A antibody comprises a light chain framework comprising IGKV3-20 x 01. In some embodiments, the anti-TL 1A antibody comprises a variant of IGKV3-20 x 01 comprising a sequence derived from SEQ ID NO:317 between about 1 and about 20 amino acid substitutions. In some embodiments, the anti-TL 1A antibody comprises a variant of IGKV3-20 x 01 comprising a sequence derived from SEQ ID NO:317 of about 1 amino acid. In some embodiments, the anti-TL 1A antibody comprises a light chain framework comprising a variant of IGKV3-20 x 01 comprising a sequence derived from SEQ ID NO:317 of about 2 amino acid substitutions. In some embodiments, an anti-TL 1A antibody comprises a light chain framework comprising a variant of IGKV3-20 x 01 comprising the amino acid sequence from SEQ ID NO:317 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 some cases, the light chain framework substitution includes Q1E, as determined by Aho or Kabat numbering. In some cases, the light chain framework substitution includes R45K, as determined by Aho or Kabat numbering.
In some embodiments, the anti-TL 1A antibody comprises a heavy chain FR1, as defined by SEQ ID NO: 304. In some embodiments, the anti-TL 1A antibody comprises a heavy chain FR2, as defined by SEQ ID NO: indicated at 305. In some embodiments, the anti-TL 1A antibody comprises a heavy chain FR2, as defined by SEQ ID NO: 313. In some embodiments, the anti-TL 1A antibody comprises a heavy chain FR3, as defined by SEQ ID NO: as indicated at 306. In some embodiments, the anti-TL 1A antibody comprises a heavy chain FR3, as defined by SEQ ID NO: shown at 307. In some embodiments, the anti-TL 1A antibody comprises a heavy chain FR3, as defined by SEQ ID NO: 314. In some embodiments, the anti-TL 1A antibody comprises a heavy chain FR3, as defined by SEQ ID NO: shown at 315. In some embodiments, the anti-TL 1A antibody comprises a heavy chain FR4, as defined by SEQ ID NO: shown at 308. In some embodiments, the anti-TL 1A antibody comprises a light chain FR1, as defined by SEQ ID NO: shown at 309. In some embodiments, the anti-TL 1A antibody comprises a light chain FR2, as defined by SEQ ID NO: shown at 310. In some embodiments, the anti-TL 1A antibody comprises a light chain FR3, as defined by SEQ ID NO: shown at 311. In some embodiments, the anti-TL 1A antibody comprises a light chain FR4, as defined by SEQ ID NO: shown at 312.
In some embodiments, the anti-TL 1A antibody comprises the framework regions of table 9A.
Table 9A: example framework sequence
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Exemplary anti-TL 1A variable region
In one aspect, provided herein is an anti-TL 1A antibody comprising a heavy chain variable region comprising an amino acid sequence that hybridizes to SEQ ID NO:101-169 or 420-427, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical amino acid sequence; and a light chain variable region that hybridizes to SEQ ID NO: any of 201-220 or 430-437 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
Further provided herein are first embodiments of anti-TL 1A antibodies comprising a heavy chain variable region and a light chain variable region. Additional non-limiting embodiments include: (example 2) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:101 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical or identical to SEQ ID NO:101 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 3) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:102 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:102 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 4) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:103 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:103 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 5) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:104 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:104 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 6) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:105 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:105 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 7) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:106 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:106 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 8) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:107 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:107 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 9) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:108 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:108 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 10) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:109 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:109 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 11) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:110, or the heavy chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:110 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 12) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:111 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:111 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 13) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:112 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:112 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 14) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:113 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:113 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 15) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:114, or 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 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 16) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:115 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:115 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 17) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:116 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:116 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 18) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:117 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:117 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 19) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:118 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:118 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 20) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence which hybridizes to SEQ ID NO:119, or 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:119 to a sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 21) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:120, or 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:120 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to the sequence. (example 22) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:121, or 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:121 has a sequence of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 23) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:122, or the heavy chain variable region comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:122 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 24) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:123, or 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 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 25) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:124 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:124 having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 26) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:125 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:125 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 27) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:126 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:126 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 28) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:127 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:127 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 29) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:128 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:128 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 30) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:129 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:129 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 31) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:130 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:130 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 32) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:131 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:131 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 33) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:132 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:132 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 34) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:133, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:133 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to the sequence. (example 35) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:134 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:134 having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 36) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:135 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:135 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 37) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:136 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:136 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 38) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:137 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:137 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 39) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:138 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:138 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 40) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:139 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:139 has a sequence of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to the sequence. (example 41) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:140 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:140 having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 42) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:141 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:141 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 43) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:142 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:142 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 44) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:143 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:143 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 45) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:144 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:144 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 46) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:145 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:145 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 47) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:146 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:146 has a sequence of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to the sequence. (example 48) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:147 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:147 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 49) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:148 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:148 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 50) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:149 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence of SEQ ID NO:149 has a sequence of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 51) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:150 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:150 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 52) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:151 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:151 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to the sequence. (example 53) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:152 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:152 has a sequence of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 54) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:153 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:153 with about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 55) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:154, or 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:154 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 56) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:155, or 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:155 having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 57) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:156, or 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:156 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 58) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:157, or 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:157 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 59) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:158, or 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:158 has a sequence of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 60) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:159 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:159 has a sequence of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to the sequence. (example 61) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:160 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:160 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 62) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:161 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:161 has a sequence of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 63) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:162 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:162 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 64) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:163 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:163 have a sequence of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 65) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:164 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:164 has a sequence of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 66) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:165 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:165 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 67) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:166 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:166 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 68) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:167 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:167 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 69) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:168 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:168 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (example 70) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:169 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the heavy chain variable region comprises a sequence identical to SEQ ID NO:169 have a sequence of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions.
(embodiment 71) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:201 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:201 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 72) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:202 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:202 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 73) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:203 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:203 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 74) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:204 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:204 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 75) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:205 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:205 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 76) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:206 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:206 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 77) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:207, or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:207 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 78) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein the light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:208 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:208 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 79) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:209 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:209 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 80) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:210 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:210 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to the sequence. (embodiment 81) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:211 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:211 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 82) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein the light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:212 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence that hybridizes to SEQ ID NO:212 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 83) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein the light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:213 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:213 has about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions or deletions. (embodiment 84) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein the light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:214 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:214 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 85) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:215 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:215 have about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 86) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein the light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:216, or 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 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 87) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:217 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:217 has a sequence of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions compared to the sequence. (embodiment 88) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:218 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:218 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 89) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:219 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:219 has a sequence of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions. (embodiment 90) the anti-TL 1A antibody of any one of embodiments 1 to 70, wherein said light chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:220 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, or the light chain variable region comprises a sequence identical to SEQ ID NO:220 has about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions or deletions.
(example 91) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:101 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 92) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:102 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 93) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:103 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:202 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 94) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:104 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 95) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:105 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
(example 96) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:103 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 97) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:106 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 98) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:107 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:202 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 99) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:108 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:202 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 100) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:109 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:202 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
(example 101) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:108 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 102) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:109 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 103) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:108 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:203 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 104) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:108 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:204 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 105) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:107 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:204 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
(example 106) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:107 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:202 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 107) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:110 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:204 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 108) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:111 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 109) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:112 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 110) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:113 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:204 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
(example 111) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:114, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 112) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:115 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:202 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 113) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:116 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 114) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:117 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 115) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:118 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:204 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
(example 116) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:114, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:204 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 117) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:102 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:204 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 118) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:104 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:204 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 119) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:119, 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 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 120) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:119, 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 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
(example 121) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:101 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:204 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 122) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:105 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:204 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 123) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:120 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:204 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 124) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:121, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:202 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 125) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:122 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:202 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
(example 126) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:122 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:207 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 127) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:123 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:202 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 128) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:124 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:202 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 129) the anti-TL 1A antibody of example 1, wherein the heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:125 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 130) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:116 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
(example 131) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:117 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 132) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:126 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 133) the anti-TL 1A antibody of example 1, wherein the heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:127 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 134) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:127 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 135) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:121, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
(example 136) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:122 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 137) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:122 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 138) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:122 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:206 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 139) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:124 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 140) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:124 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
(example 141) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:128 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 142) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:128 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:206 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 143) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:129 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 144) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:130 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 145) the anti-TL 1A antibody of example 1, wherein the heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:131 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
(example 146) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:132 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 147) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:133 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 148) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:134 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 149) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:135 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:205, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 150) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:126 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 151) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:130 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 152) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:132 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:201 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 153) the anti-TL 1A antibody of example 1, comprising a500. (example 154) the anti-TL 1A antibody of example 1, comprising a501. (example 155) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes 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 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 156) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:421 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:431 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 157) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:422 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:432 is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 158) the anti-TL 1A antibody of example 1, wherein said heavy chain variable region comprises an amino acid sequence that hybridizes to SEQ ID NO:427, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises a sequence identical to SEQ ID NO:437 are at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
Exemplary anti-TL 1A constant region
In some embodiments, one or more amino acid modifications may be introduced to the crystallizable fragment (Fc) region of a human or humanized antibody, thereby producing an Fc region variant. The Fc region may include the C-terminal region of an immunoglobulin heavy chain, which includes a hinge region, a CH2 domain, a CH3 domain, or any combination thereof. As used herein, an Fc region comprises a native sequence Fc region and a variant Fc region. The Fc region variant may include a human Fc region sequence (e.g., a human IgG1, igG2, igG3, or IgG4 Fc region) that includes amino acid modifications (e.g., substitutions, additions, or deletions) at one or more amino acid positions. In an exemplary embodiment, the Fc region comprises SEQ ID NO: 320-367. In some embodiments, the anti-TL 1A antibody comprises a constant region comprising the amino acid sequence of SEQ ID NO: 319. 368-381.
In some embodiments, the antibodies of the disclosure have reduced effector function compared to human IgG. Effector function refers to a biological event resulting from the interaction of an antibody Fc region with an Fc receptor or ligand. Non-limiting effector functions include C1q binding, complement Dependent Cytotoxicity (CDC), fc receptor binding, antibody dependent cell-mediated cytotoxicity (ADCC), antibody Dependent Cell Phagocytosis (ADCP), cytokine secretion, immune complex-mediated antigen uptake by antigen presenting cells, down-regulation of cell surface receptors (e.g., B cell receptors), and B cell activation. In some cases, antibody-dependent cell-mediated cytotoxicity (ADCC) 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, which in turn results in lysis of the target cell. In some cases, complement Dependent Cytotoxicity (CDC) refers to lysis of target cells in the presence of complement, where the complement pathway is initiated by the binding of C1q to antibodies that bind to the target.
Some Fc regions naturally lack effector function, and some Fc regions may include mutations that reduce effector function. For example, igG4 has low ADCC and CDC activity, and IgG2 has low ADCC activity.
The disclosure provides antibodies comprising an Fc region characterized as exhibiting at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70% or more reduced ADCC as compared to antibodies comprising a non-variant Fc region, i.e., substituted antibodies having the same sequence but for reduced ADCC (e.g., human IgG1, SEQ ID NO: 320). The disclosure provides antibodies comprising an Fc region characterized as exhibiting a reduction in CDC of 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 having the same sequence but a substitution for reducing CDC (e.g., human IgG1, SEQ ID NO: 320). In certain embodiments, the antibodies of the disclosure have reduced effector function compared to human IgG 1. In certain embodiments, the antibodies herein have no detectable ADCC activity. In certain embodiments, the decrease and/or attenuation of ADCC activity may be due to a decrease in affinity of the antibodies of the invention for Fc ligands and/or receptors. In certain embodiments, the antibodies herein do not exhibit detectable CDC activity. In some embodiments, the decrease and/or attenuation of CDC activity may be due to a decrease in affinity of an antibody of the invention for an Fc ligand and/or receptor. Measurement of effector functions can be performed as described in example 3.
In some embodiments, antibodies comprising an Fc region as described herein exhibit reduced affinity for C1q relative to an unmodified antibody (e.g., human IgG1 having SEQ ID NO: 320). In some embodiments, the antibodies herein exhibit at least 2-fold, or at least 3-fold, or at least 5-fold, or at least 7-fold, or at least 10-fold, or at least 20-fold, or at least 30-fold, or at least 40-fold, or at least 50-fold, or at least 60-fold, or at least 70-fold, or at least 80-fold, or at least 90-fold, or at least 100-fold, or at least 200-fold lower affinity for the C1q receptor than the unmodified antibody. In some embodiments, the antibodies herein exhibit an affinity for C1q that is at least 90%, at least 80%, at least 70%, at least 60%, at least 50%, at least 40%, at least 30%, at least 20%, at least 10%, or at least 5% lower than that of the unmodified antibody.
In some embodiments, the antibodies of the present disclosure are variants with some, but not all, effector functions, which makes the antibodies ideal candidates for use, where in vivo antibody half-life is important, but some effector functions (such as complement and ADCC) are unnecessary or detrimental.
In vitro and/or in vivo cytotoxicity assays may be performed to confirm a reduction/depletion of CDC and/or ADCC activity. For example, an Fc receptor (FcR) binding assay may be performed to ensure that the antibody lacks fcγr binding (and thus may lack ADCC activity), but retains FcRn binding capacity. Measurement of effector functions can be performed as described in example 3.
In some embodiments, antibodies are tested for binding to fcγ receptor and complement C1q by ELISA. In some embodiments, the ability of an antibody to activate primary human immune cells in vitro is tested, for example, by assessing the ability of the antibody to induce expression of an activation marker.
In some embodiments, the assessment of ADCC activity of an anti-TL 1A antibody comprises adding the antibody to a combination of target cells and immune effector cells that can be activated by antigen-antibody complexes that result in cell lysis of the target cells. Cell lysis can be detected by releasing a label (e.g., a radioactive substrate, fluorescent dye, or native intracellular protein) from the lysed cells. Useful effector cells for such assays include Peripheral Blood Mononuclear Cells (PBMC) and Natural Killer (NK) cells. Specific examples of in vitro ADCC assays are described in the following documents: wisecarver et al, 1985 79:277-282; bruggemann et al, 1987, journal of experimental medicine (J Exp Med) 166:1351-1361; wilkinson et al, 2001, journal of immunological methods (J Immunol Methods) 258:183-191; patel et al, 1995 J.Immunol.method.184: 29-38. Alternatively, or in addition, the ADCC activity of the antibody of interest may be in vivo, for example in an animal model, as in Clynes et al, 1998, proc. Natl. Acad. Sci. USAS (USA) 95: the evaluation was performed in an animal model as disclosed in 652-656.
In some embodiments, the assessment of complement activation, i.e., CDC assay, may be as described in Gazzano-Santoro et al, 1996, J immunological methods, 202: 163.
Non-limiting examples of Fc mutations in IgG1 that may reduce ADCC and/or CDC include substitutions at one or more of the following 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 IgG1, wherein the numbering system of the constant regions is that of the EU index as set forth by Kabat. In certain embodiments, the antibodies of the disclosure have reduced effector function compared to human IgG 1.
In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region comprising one or more of the following substitutions: N297A, N297Q, N297D, D265A, S228P, L A, L237A, L234A, E233P, L234V, C236, P238A, A327Q, P329A, P329G, L E, P331S, L37234F, 235G, 235Q, 235R, 235S, 236F, 236R, 237E, 237K, 237N, 237R, 238A, 238E, 238G, 238H, 238I, 238V, 238W, 238Y, 248A, 254D, 254E, 254G, 254H, 254I, 254N, 254P, 254Q, 254T, 254V, 255N, 256H, 256K, 256R, 256V, 264S, 265H, 265K, 265S, 265Y, 267G, 267H, 267I, 267K, 268K, 269N, 269Q, 270A 270G, 270M, 270N, 271T, 272N, 279F, 279K, 279L, 292E, 292F, 292G, 292I, 293S, 301W, 304E, 311G, 311S, 316F, 327T, 328V, 329Y, 330R, 339E, 339L, 343I, 343V, 373A, 373G, 373S, 376E, 376W, 376Y, 380D, 382P, 385P, 424H, 424M, 424V, 434I, 438G, 439E, 439H, 439Q, 440A, 440D, 440E, 440F, 440M, 440T, 440V.
In some embodiments, the antibody comprises an Fc region selected from the representative sequences disclosed in table 3, table 13, and table 9B. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, said IgG1 Fc region comprising E233P. In some embodiments, the antibody comprises an IgG4 Fc region, which comprises S228P and L235E. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, which IgG1 Fc region comprises L235E. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, which IgG1 Fc region comprises L234A and L235A. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region comprising L234A, L235A and G237A. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region comprising L234A, L235A, P329G. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region comprising L234F, L235E and P331S. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region comprising L234A, L235E and G237A. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region comprising L234A, L235E, G237A and P331S. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region comprising L234A, L235A, G237A, P238S, H268A, A S and P331S (igg1σ). In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region comprising L234A, L235A and P329A. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, which IgG1 Fc region comprises G236R and L328R. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, which IgG1 Fc region comprises G237A. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, said IgG1 Fc region comprising F241A. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, which IgG1 Fc region comprises V264A. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, which IgG1 Fc region comprises D265A. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, which IgG1 Fc region comprises D265A and N297A. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, which IgG1 Fc region comprises D265A and N297G. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, which IgG1 Fc region comprises D270A. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, said IgG1 Fc region comprising N297A. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, said IgG1 Fc region comprising N297G. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, said IgG1 Fc region comprising N297D. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, said IgG1 Fc region comprising N297Q. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, said IgG1 Fc region comprising P329A. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, said IgG1 Fc region comprising P329G. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, said IgG1 Fc region comprising P329R. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, which IgG1 Fc region comprises a330L. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, said IgG1 Fc region comprising P331A. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG1 Fc region, said IgG1 Fc region comprising P331S. In some embodiments, the antibody comprises an IgG2 Fc region. In some embodiments, the antibody comprises an IgG4 Fc region. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG4 Fc region, said IgG4 Fc region comprising S228P. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG4 Fc region, which IgG4 Fc region comprises S228P, F234A and L235A. In some embodiments, the antibody comprises an IgG2-IgG4 cross-subclass (IgG 2/G4) Fc region. In some embodiments, the antibody comprises an IgG2-IgG3 cross subclass Fc region. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG2 Fc region comprising H268Q, V309L, A S and P331S. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG2 Fc region comprising V234A, G237A, P238S, H268A, V309L, A S and P331S. In some embodiments, the antibody comprises an Fc region comprising high mannose glycosylation.
In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG4 Fc region, said IgG4 Fc region comprising an S228P substitution. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG4 Fc region, said IgG4 Fc region comprising an a330S substitution. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG4 Fc region, said IgG4 Fc region comprising a P331S substitution.
In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG2 Fc region, said IgG2 Fc region comprising an a330S substitution. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG2 Fc region, said IgG2 Fc region comprising a P331S substitution. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG2 Fc region, said IgG2 Fc region comprising 234A substitutions. In some embodiments, according to the Kabat numbering system, the antibody comprises an IgG2 Fc region, said IgG2 Fc region comprising a 237A substitution.
In certain embodiments, an anti-TL 1A described herein comprises an Fc region as shown in table 13.
Table 13: exemplary Fc mutations
In certain embodiments, an anti-TL 1A antibody described herein comprises an Fc region comprising a sequence selected from table 9B. In certain embodiments, an anti-TL 1A antibody described herein comprises an Fc region comprising the amino acid sequence of SEQ ID NO:320-367 or with any one of SEQ ID NOs: 320-367, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical.
In some embodiments, an anti-TL 1A described herein comprises a light chain constant region comprising the amino acid sequence of SEQ ID NO:319 or with SEQ ID NO:319 at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.
Additional non-limiting examples of anti-TL 1A antibody examples
CDR examples
In one aspect, provided herein are first embodiments of anti-TL 1A antibodies. As used herein, anti-TL 1A antibodies comprise anti-TL 1A antigen binding fragments. Additional non-limiting embodiments include: (example 2) an anti-TL 1A antibody according to example 1, comprising: a heavy chain comprising: HCDR1, said HCDR1 comprising SEQ ID NO:1. 401, 407, 413, or 450; HCDR2, said HCDR2 comprising SEQ ID NO:2. 3, 4, 5, 402, 408, 414, or 451; and HCDR3, said HCDR3 comprising SEQ ID NO:6. 7, 8, 9, 403, 409, 415, or 452; and a light chain comprising: LCDR1, said LCDR1 comprising SEQ ID NO:10. 404, 410, 416 or 453; LCDR2, said LCDR2 comprising SEQ ID NO:11. 405, 411, 417 or 454, and LCDR3, said LCDR3 comprising SEQ ID NO:12. 13, 14, 15, 406, 412, 418, or 455. (example 3) an anti-TL 1A antibody according to example 1, comprising: HCDR1, said HCDR1 comprising SEQ ID NO:1. (example 4) the anti-TL 1A antibody of example 1 or example 2, comprising HCDR2, said HCDR2 comprising the amino acid sequence of SEQ ID NO:2. (example 5) the anti-TL 1A antibody of example 1 or example 2, comprising HCDR2, said HCDR2 comprising the amino acid sequence of SEQ ID NO:3. (example 6) the anti-TL 1A antibody of example 1 or example 2, comprising HCDR2, said HCDR2 comprising the amino acid sequence of SEQ ID NO:4. (example 7) the anti-TL 1A antibody of example 1 or example 2, comprising HCDR2, said HCDR2 comprising the amino acid sequence of SEQ ID NO:5. (embodiment 8) the anti-TL 1A antibody of any one of embodiments 1 to 6, comprising: HCDR3, said HCDR3 comprising SEQ ID NO:6. (embodiment 9) the anti-TL 1A antibody of any one of embodiments 1 to 6, comprising: HCDR3, said HCDR3 comprising SEQ ID NO:7. (embodiment 10) the anti-TL 1A antibody of any one of embodiments 1 to 6, comprising: HCDR3, said HCDR3 comprising SEQ ID NO:8. (embodiment 11) the anti-TL 1A antibody of any one of embodiments 1 to 6, comprising: HCDR3, said HCDR3 comprising SEQ ID NO:9. (example 12) the anti-TL 1A antibody of any one of examples 1 to 10, comprising LCDR1, said LCDR1 comprising the amino acid sequence of SEQ ID NO:10. (example 13) the anti-TL 1A antibody of any one of examples 1 to 11, comprising LCDR2, said LCDR2 comprising the amino acid sequence of SEQ ID NO:11. (example 14) the anti-TL 1A antibody of any one of examples 1 to 12, comprising LCDR3, said LCDR3 comprising the amino acid sequence of SEQ ID NO:12. (embodiment 15) the anti-TL 1A antibody of any one of embodiments 1 to 12, comprising: LCDR3, said LCDR3 comprising SEQ ID NO:13. (example 16) the anti-TL 1A antibody of any one of examples 1 to 12, comprising LCDR3, said LCDR3 comprising the amino acid sequence of SEQ ID NO:14 or 15. (example 17) the anti-TL 1A antibody of example 1, which comprises CDRs of antibodies A, B, C, D, E, F, G, H, I, A, B2, C2, D2, E2, F2, G2, H2, I2, J, K, M or N (table 10). (example 18) the anti-TL 1A antibody of example 1, comprising a heavy chain variable region comprising: (a) HCDR1, said HCDR1 comprising a sequence consisting of SEQ ID NO:1, and a polypeptide sequence shown in the specification; (b) HCDR2, said HCDR2 comprising a sequence consisting of SEQ ID NO:2-5, and a polypeptide comprising the amino acid sequence shown in any one of 2-5; and (c) HCDR3, said HCDR3 comprising a sequence consisting of SEQ ID NO: 6-9; and a light chain variable region comprising: (d) LCDR1, said LCDR1 comprising a sequence consisting of SEQ ID NO:10, and a polypeptide comprising the amino acid sequence shown in seq id no; (e) LCDR2, said LCDR2 comprising a nucleotide sequence consisting of SEQ ID NO:11, and a polypeptide comprising the amino acid sequence shown in seq id no; and (f) LCDR3, said LCDR3 comprising a sequence consisting of SEQ ID NO: 12-15. (example 19) the anti-TL 1A antibody of example 1, comprising: HCDR1, as defined by SEQ ID NO:1, shown in the specification: HCDR2 as defined by SEQ ID NO:2, shown in the specification: HCDR3 as defined by SEQ ID NO: 6: LCDR1, as defined by SEQ ID NO:10, shown in the accompanying drawings: LCDR2 as defined by SEQ ID NO: 11: and LCDR3 as defined by SEQ ID NO: shown at 12
Frame embodiment
(embodiment 20) the anti-TL 1A antibody of any one of embodiments 1 to 19, comprising a heavy chain framework comprising IGHV1-46 x 02. (embodiment 21) the anti-TL 1A antibody of any one of embodiments 1 to 19, comprising a heavy chain framework comprising a variant of IGHV1-46 x 02 comprising a sequence from SEQ ID NO:316 between about 1 and about 20 amino acid substitutions. (embodiment 22) the anti-TL 1A antibody of any one of embodiments 1 to 19, comprising a heavy chain framework comprising a variant of IGHV1-46 x 02 comprising a sequence from SEQ ID NO:316 between about 1 and about 9 amino acid substitutions. (example 23) the anti-TL 1A antibody of any one of examples 1 to 19, comprising a heavy chain framework comprising a variant of IGHV1-46 x 02 comprising the amino acid sequence of SEQ ID NO:316 of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. (embodiment 24) the anti-TL 1A antibody of any one of embodiments 21 to 23, wherein said heavy chain framework substitution comprises Q1E, as determined by Aho or Kabat numbering. (embodiment 25) the anti-TL 1A antibody of any one of embodiments 21 to 24, wherein said heavy chain framework substitution comprises R45K, as determined by Aho or Kabat numbering. (embodiment 26) the anti-TL 1A antibody of any one of embodiments 21 to 25, wherein said heavy chain framework substitution comprises a47R, as determined by Aho or Kabat numbering. (embodiment 27) the anti-TL 1A antibody of any one of embodiments 21 to 26, wherein said heavy chain framework substitution comprises M55I, as determined by Aho or Kabat numbering. (embodiment 28) the anti-TL 1A antibody of any one of embodiments 21 to 27, wherein said heavy chain framework substitution comprises V78A, as determined by Aho or Kabat numbering. (embodiment 29) the anti-TL 1A antibody of any one of embodiments 21 to 28, wherein said heavy chain framework substitution comprises M80I, as determined by Aho or Kabat numbering. (embodiment 30) the anti-TL 1A antibody of any one of embodiments 21 to 29, wherein said heavy chain framework substitution comprises R82T, as determined by Aho or Kabat numbering. (embodiment 31) the anti-TL 1A antibody of any one of embodiments 21 to 30, wherein said heavy chain framework substitution comprises V89A, as determined by Aho or Kabat numbering. (embodiment 32) the anti-TL 1A antibody of any one of embodiments 21 to 31, wherein said heavy chain framework substitution comprises M91L, as determined by Aho or Kabat numbering.
(embodiment 33) the anti-TL 1A antibody of any one of embodiments 1 to 19, comprising a heavy chain framework comprising the amino acid sequence of SEQ ID NO:301. (example 34) the anti-TL 1A antibody of example 33, wherein X1 is Q. (example 35) the anti-TL 1A of example 33, wherein x1=e. (embodiment 36) the anti-TL 1A of any one of embodiments 33 to 35, wherein x2=r. (embodiment 37) the anti-TL 1A of any one of embodiments 33 to 35, wherein x2=k. (embodiment 38) the anti-TL 1A of any one of embodiments 33 to 37, wherein x3=a. (embodiment 39) the anti-TL 1A of any one of embodiments 33 to 37, wherein x3=r. (embodiment 40) the anti-TL 1A of any one of embodiments 33 to 39, wherein x4=m. (embodiment 41) the anti-TL 1A of any one of embodiments 33 to 39, wherein x4=i. (embodiment 42) the anti-TL 1A of any one of embodiments 33 to 41, wherein x5=v. (embodiment 43) the anti-TL 1A of any one of embodiments 33 to 41, wherein x5=a. (embodiment 44) the anti-TL 1A of any one of embodiments 33 to 43, wherein x6=m. (embodiment 45) the anti-TL 1A of any one of embodiments 33 to 43, wherein x6=i. (embodiment 46) the anti-TL 1A of any one of embodiments 33 to 45, wherein x7=r. (embodiment 47) the anti-TL 1A of any one of embodiments 33 to 45, wherein x7=t. (embodiment 48) the anti-TL 1A of any one of embodiments 33 to 47, wherein x8=v. (embodiment 49) the anti-TL 1A of any one of embodiments 33 to 47, wherein x8=a. (embodiment 50) the anti-TL 1A of any one of embodiments 33 to 49, wherein x9=m. (embodiment 51) the anti-TL 1A of any one of embodiments 33 to 49, wherein x9=l.
(embodiment 52) the anti-TL 1A antibody of any one of embodiments 1 to 51, comprising a light chain framework comprising IGKV3-20 x 01. (example 53) the anti-TL 1A antibody of any one of examples 1 to 51, comprising a light chain framework comprising a variant of IGKV3-20 x 01 comprising a sequence from SEQ ID NO:317 between about 1 and about 20 amino acid substitutions. (embodiment 54) the anti-TL 1A antibody of any one of embodiments 1 to 51, comprising a light chain framework comprising a variant of IGKV3-20 x 01 comprising a sequence from SEQ ID NO:317 of about 1 amino acid. (embodiment 55) the anti-TL 1A antibody of any one of embodiments 1 to 51, comprising a light chain framework comprising a variant of IGKV3-20 x 01 comprising a sequence from SEQ ID NO:317 of about 2 amino acid substitutions. (example 56) the anti-TL 1A antibody of any one of examples 1 to 51, comprising a light chain framework comprising a variant of IGKV3-20 x 01 comprising the amino acid sequence of SEQ ID NO:317 about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acid substitutions. (embodiment 57) the anti-TL 1A antibody of any one of embodiments 53 to 56, wherein said light chain framework substitution comprises Q1E, as determined by Aho or Kabat numbering. (embodiment 58) the anti-TL 1A antibody of any one of embodiments 53 to 57, wherein the light chain framework substitution comprises R45K, as determined by Aho or Kabat numbering.
(embodiment 59) the anti-TL 1A antibody of any one of embodiments 1 to 51, comprising a light chain framework comprising the amino acid sequence of SEQ ID NO:303. (example 60) the anti-TL 1A antibody of example 59, wherein X10 is L. (example 61) the anti-TL 1A antibody of example 59, wherein X10 is P. (embodiment 62) the anti-TL 1A antibody of any one of embodiments 59 to 61, wherein X11 is L. (embodiment 63) the anti-TL 1A antibody of any one of embodiments 59 to 61, wherein X11 is W.
(embodiment 64) the anti-TL 1A antibody of any one of embodiments 1 to 19, comprising: a heavy chain variable framework region comprising a modified human IGHV1-46 x 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 together comprise at least one amino acid modification compared to the human IGHV1-46 x 02 framework and the human IGKV3-20 framework. (embodiment 65) the antibody of embodiment 64, wherein the at least one amino acid modification is no more than about 13, 12, 11, 10, 9, or 8 amino acid modifications. (embodiment 66) the antibody of embodiment 64 or embodiment 65, wherein the amino acid modification comprises: a modification at amino acid position 45 in the heavy chain variable region. (embodiment 67) the antibody of any one of embodiments 64-66, wherein the amino acid modification comprises a modification at amino acid position 47 in the heavy chain variable region. (embodiment 68) the antibody of any one of embodiments 64-67, wherein the amino acid modification comprises a modification at amino acid position 55 in the heavy chain variable region. (embodiment 69) the antibody of any one of embodiments 64-68, wherein the amino acid modification comprises a modification at amino acid position 78 in the heavy chain variable region. (embodiment 70) the antibody of any one of embodiments 64-69, wherein the amino acid modification comprises a modification at amino acid position 80 in the heavy chain variable region. (embodiment 71) the antibody of any one of embodiments 64-70, wherein the amino acid modification comprises a modification at amino acid position 82 in the heavy chain variable region. (embodiment 72) the antibody of any one of embodiments 64-71, wherein the amino acid modification comprises a modification at amino acid position 89 in the heavy chain variable region. (embodiment 73) the antibody of any one of embodiments 64-72, wherein the amino acid modification comprises a modification at amino acid position 91 in the heavy chain variable region, numbered according to Aho or Kabat. (embodiment 74) the antibody of any one of embodiments 64-65, wherein the amino acid modification comprises in the heavy chain variable region: (a) R45K, (b) A47R, (c) M55I, (d) V78A, (e) M80I, (f) R82T, (g) V89A or (h) M91L, numbered according to Aho or Kabat; or a combination of two or more modifications selected from (a) to (h). (embodiment 75) the antibody of embodiment 74, wherein the amino acid modification comprises: A47R. (embodiment 76) the antibody of embodiment 74, wherein the amino acid modification comprises: a47R, M55I, V A, M80I, R82T, V89A and M91L; a47R, M I and R82T; a47R, M80I, R T, V89A and M91L; or a47R, M55I, V A, M80I, V89A and M91L. (embodiment 77) the antibody of embodiment 74, wherein the amino acid modification comprises: R45K and A47R. (embodiment 78) the antibody of embodiment 74, wherein the amino acid modification comprises: R45K, A47R, V a and M91L. (embodiment 79) the antibody of embodiment 74, wherein the amino acid modification comprises: R45K and A47R and M80I. (embodiment 80) the antibody of embodiment 74, wherein the amino acid modification comprises: R45K, A47R, M I and M91L; R45K, A47R, V A, M80I, V89A and M91L; R45K, A47R, M55I, V78A, M3880I, R82T, V a and M91L; R45K, A47R, M80I, V89A and M91L; R45K, A47R, M55I, M80I, R82T, V89A and M91L; R45K, A47R, M I and V89A; R45K, A47R, M80I, R82T, V89A, M L; or R45K, A47R, M55I, M80I, V89A and M91L. (embodiment 81) the antibody of embodiment 74, wherein the amino acid modification comprises: R45K. (embodiment 82) the antibody of embodiment 74, wherein the amino acid modification comprises: R45K and V78A. (embodiment 83) the antibody of embodiment 74, wherein the amino acid modification comprises: V78A. (embodiment 84) the antibody of embodiment 74, wherein the amino acid modification comprises: V78A and V89A; V78A and M80I; or V78A, M I and R82T. (embodiment 85) the antibody of embodiment 74, wherein the amino acid modification comprises: V89A. (embodiment 86) the antibody of embodiment 74, wherein the amino acid modification comprises: M80I. (embodiment 87) the antibody of any one of embodiments 64-86, wherein the amino acid modification comprises: (a) A modification at amino acid position 54 in the light chain variable region; and/or (b) a modification at amino acid position 55 in the light chain variable region, numbered according to Aho or Kabat. (example 88) the antibody of example 87, wherein the amino acid modification comprises L54P in the light chain variable region, numbered according to Aho or Kabat. (example 89) the antibody of example 87 or 88, wherein the amino acid modification comprises L55W in the light chain variable region, numbered according to Aho or Kabat.
(embodiment 90) the antibody of any one of embodiments 1 to 19, comprising a heavy chain FR1, as defined by SEQ ID NO: 304. (embodiment 91) the antibody of any one of embodiments 1 to 19 or 90 comprising a heavy chain FR2 as defined by SEQ ID NO: indicated at 305. (embodiment 92) the antibody of any one of embodiments 1 to 19 or 90 comprising a heavy chain FR2 as defined by SEQ ID NO: 313. (embodiment 93) the antibody of any one of embodiments 1-19 or 90-92 comprising heavy chain FR3 as defined by SEQ ID NO: as indicated at 306. (embodiment 94) the antibody of any one of embodiments 1-19 or 90-92 comprising heavy chain FR3 as defined by SEQ ID NO: shown at 307. (embodiment 95) the antibody of any one of embodiments 1 to 19 or 90 to 92 comprising heavy chain FR3 as defined by SEQ ID NO: 314. (example 96) the antibody of any one of examples 1-19 or 90-92 comprising heavy chain FR3 as defined by SEQ ID NO: shown at 315. (embodiment 97) the antibody of any one of embodiments 1 to 19 or 90 to 96 comprising heavy chain FR4 as defined by SEQ ID NO: shown at 308. (embodiment 98) the antibody of any one of embodiments 1-19 or 90-97 comprising a light chain FR1, as defined by SEQ ID NO: shown at 309. (embodiment 99) the antibody of any one of embodiments 1 to 19 or 90 to 98, comprising a light chain FR2, as defined by SEQ ID NO: shown at 310. (embodiment 100) the antibody of any one of embodiments 1-19 or 90-99 comprising a light chain FR3 as defined by SEQ ID NO: shown at 311. (embodiment 101) the antibody of any one of embodiments 1-19 or 90-100 comprising a light chain FR4 as defined by SEQ ID NO: shown at 312. (embodiment 102) the antibody of any one of embodiments 1-19, comprising: HC FR1, as represented by SEQ ID NO:304, as shown in: HC FR2, as represented by SEQ ID NO:305, as shown in: HC FR3, as represented by SEQ ID NO: shown at 307: HC FR4, as represented by SEQ ID NO: shown at 308: LC FR1 as defined by SEQ ID NO:309, shown in fig. 309: LC FR2 as defined by SEQ ID NO: shown at 310: LC FR3 as defined by SEQ ID NO: shown at 311: and LC FR4 as defined by SEQ ID NO: shown at 312.
Variable region examples
(example 103) the antibody of example 1 comprising a heavy chain variable domain comprising a sequence that hybridizes to SEQ ID NO:101-169 or 420-427, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical amino acid sequence; and a light chain variable domain comprising a sequence identical to SEQ ID NO:201-220 or 430-437 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (example 104) the antibody of example 103, comprising a heavy chain variable domain comprising a sequence that hybridizes to SEQ ID NO:104 at least 96% identical amino acid sequence; and a light chain variable domain comprising a sequence identical to SEQ ID NO:201, at least 97% identical. (example 105) the antibody of example 103, comprising a sequence that hybridizes to SEQ ID NO:104, at least 97% identical. (example 106) the antibody of example 103, comprising an amino acid sequence that hybridizes to SEQ ID NO:104, at least 98% identical. (example 107) the antibody of example 103, comprising an amino acid sequence that hybridizes to SEQ ID NO:104, at least 99% identical. (example 108) the antibody of example 103, comprising SEQ ID NO:104. (embodiment 109) the antibody of any one of embodiments 103-108, comprising a polypeptide that hybridizes to SEQ ID NO:201 is at least 98% identical. (example 110) the antibody of example 109, comprising an amino acid sequence that hybridizes to SEQ ID NO:201 is at least about 99% identical. (example 111) the antibody of example 109 comprising SEQ ID NO:201.
(example 112) the antibody of example 103, comprising a heavy chain variable domain comprising a sequence that hybridizes to SEQ ID NO:104 at least about 97% identical to an amino acid sequence; and a light chain variable domain comprising a sequence identical to SEQ id no:201, and at least about 97% identical. (example 113) the antibody of example 112, wherein the heavy chain variable domain comprises a sequence that hybridizes to SEQ ID NO:104, at least about 98% identical. (embodiment 114) the antibody of embodiment 112, wherein the heavy chain variable domain comprises a sequence that hybridizes to SEQ ID NO:104, and an amino acid sequence that is at least about 99% identical. (example 115) the antibody of example 112, wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:104. (embodiment 116) the antibody of any one of embodiments 112-115, wherein the light chain variable domain comprises a sequence that hybridizes to SEQ ID NO:201 are at least about 98% identical. (embodiment 117) the antibody of any one of embodiments 112-116, wherein the light chain variable domain comprises a sequence that hybridizes to SEQ ID NO:201 is at least about 99% identical. (embodiment 118) the antibody of any one of embodiments 112-117, wherein the light chain variable domain comprises the amino acid sequence of SEQ ID NO:201.
Examples of Fc regions
(embodiment 119) the antibody of any one of embodiments 1-118, comprising a crystallizable fragment (Fc) region. (example 120) the antibody of example 119, comprising reduced antibody-dependent cell-mediated cytotoxicity (ADCC) function as compared to human IgG1 and/or reduced complement-dependent cytotoxicity (CDC) as compared to human IgG 1. (example 121) the antibody of example 120, wherein the human IgG1 comprises the amino acid sequence of SEQ ID NO:320. (example 122) the antibody of example 120 or example 121, wherein ADCC function of the Fc region comprising reduced ADCC is reduced by at least about 50% compared to human IgG 1. (embodiment 123) the antibody of any one of embodiments 120-122, wherein CDC function of the Fc region comprising reduced ADCC is reduced by at least about 50% as compared to human IgG 1. (embodiment 124) the anti-TL 1A antibody of any one of embodiments 119 to 123, comprising a human IgG1 Fc region comprising (a) 297A, 297Q, 297G, or 297D, (b) 279F, 279K, or 279L, (c) 228P, (D) 235A, 235E, 235G, 235Q, 235R, or 235S, (E) 237A, 237E, 237K, 237N, or 237R, (F) 234A, 234V, or 234F, (G) 233P, (H) 328A, (I) 327Q or 327T, (j) 329A, 329G, 329Y, or 329R (K) 331S, (L) 236F or 236R, (m) 238A, 238E, 238G, 238H, 238I, 238V, 238W, or 238Y, (N) 237A, ("V, or 238Y o ) 254D, 254E, 254G, 254H, 254I, 254N, 254P, 254Q, 254T, or 254V, (P) 255N, (Q) 256H, 256K, 256R, or 256V, (R) 264S, (S) 265H, 265K, 265S, 265Y, or 265A, (T) 267G, 267H, 267I, or 267K, (u) 268K, (V) 269N or 269Q, (W) 270A, 270G, 270M, or 270N, (x) 271T, (Y) 272N, (z) 292E, 292F, 292G, or 292I, (aa) 293S, (bb) 301W, (cc) 304E, (dd) 311E, 311G, or 311S, (316F, (ff) 328V, (gg) 330R, (hh) E, or 373, (ii) 343I, or V, (jj) 373A, 267G, or S, (kk) 376E, 376W, or Y, (nn, (380 mm 382D, (P) 382G, or 424, or 292I, (Q) 293G, or (Q) 293I, (Q) 293S, (Q) 301W, (cc) 304E, 311G, or 311S, (P) 316F, (P) 328G, 35G or (G) 339K)(ss) 440A, 440D, 440E, 440F, 440M, 440T or 440V, (tt) E233P, (uu) L235E, (vv) L234A and L235A, (ww) L234A, L A and G237A, (xx) L234A, L A and P329G, (yy) L234F, L235E and P331S, (zz) L234A, L E and G237A, (aaa), L234 52235E, G237A and P331S (bbb) L234A, L235 82348 237A, P238S, H268 56330S and P331S (IgG 1 sigma), (ccc) L234A, L235A and P329A, (ddd) G236R and L328R, (eee) G237A, (fff) F241A, (ggg) V264A, (hhh) D265A, (iii) D265A and N297A, (jjj) D265A and N297G, (kkk) D270A, (11L) A330L, (mmm) P331A or P331S, or (nnn) (any combination of a) - (uu), numbered according to Kabat. (embodiment 125) the anti-TL 1A of any one of embodiments 119 to 123, comprising: (i) a human IgG4 Fc region; or (ii) a human IgG4 Fc region, said human IgG4 Fc region comprising: (a) S228P, (b) S228P, and L235E; or (c) S228P, F234A and L235A, numbered according to Kabat. (embodiment 126) the anti-TL 1A of any one of embodiments 119 to 123, comprising a human IgG2 Fc region; an IgG2-IgG4 cross-subclass Fc region; an IgG2-IgG3 cross-subclass Fc region; igG2, said IgG2 comprising H268Q, V309L, A330S, P331S (IgG 2m 4); or IgG2, said IgG2 comprising V234A, G237A, P238S, H268A, V38309L, A330S, P S (IgG 2) sigma); (embodiment 127) the antibody of any one of embodiments 119-123, comprising a human IgG1, the human IgG1 comprising one or more substitutions selected from the group consisting of: 329A, 329G, 329Y, 331S, 236F, 236R, 238A, 238E, 238G, 238H, 238I, 238V, 238W, 238Y, 248A, 254D, 254E, 254G, 254H, 254I, 254N, 254P, 254Q, 254T, 254V, 264S, 265H, 265K, 265S, 265Y, 265A, 267G, 267H, 267I, 267K, 434I, 438G, 439E, 439H, 439Q, 440A, 440D, 440E, 440F, 440M, 440T and 440V, numbered according to Kabat. (embodiment 128) the anti-TL 1A of any one of embodiments 119 to 123, comprising a heavy chain Fc region comprising an amino acid sequence that hybridizes to SEQ ID NO:320-362, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (embodiment 129) the anti-TL 1A of any one of embodiments 119-123 comprising a heavy chain Fc region The heavy chain Fc region comprises a sequence identical to SEQ ID NO:368-380 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. (embodiment 130) the anti-TL 1A of any one of embodiments 119 to 123, comprising a constant region comprising an amino acid sequence that is identical to SEQ ID NO:381 are at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
Additional antibody characterization
(example 131) the anti-TL 1A antibody of any one of examples 1 to 130, comprising a light chain constant region comprising an amino acid sequence that hybridizes to SEQ ID NO:319 at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
(embodiment 132) the anti-TL 1A antibody of any one of embodiments 1 to 131, 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 moieties, as determined by size exclusion chromatography. (embodiment 133) the antibody of embodiment 132, wherein the size-exclusion chromatography comprises injecting the purified antibody onto a size-exclusion column, wherein the antibody is purified from protein a. (example 134) the antibody of example 132 or 133, wherein the antibody is purified as described in example 2. (embodiment 135) the antibody of any one of embodiments 132-134, wherein the antibody is expressed under the conditions described in example 2. (embodiment 136) the antibody of any one of embodiments 132-135, wherein the size exclusion chromatography column has an inner diameter of 4.6mm. (embodiment 137) the antibody of any one of embodiments 132-136, wherein the size exclusion chromatography column has a length of 150mm. (example 138) according to examples 132 to 137 The antibody of any one of claims, wherein the size exclusion chromatography column has a pore size of(embodiment 139) the antibody of any one of embodiments 132-138, wherein the size exclusion chromatography column has a particle size of 1.7 microns. (embodiment 140) the antibody of any one of embodiments 132-139, wherein the size exclusion chromatography column is an ACQUITY UPLC BEH200 SEC column. (embodiment 141) the antibody of any one of embodiments 132-140, wherein the antibody or antigen-binding fragment is injected in a total volume of 15 μl. (embodiment 142) the antibody of any one of embodiments 132-141, wherein the antibody is injected at a concentration of about 0.1 μg/μl to about 1.0 μg/μl. (embodiment 143) the antibody of any one of embodiments 132-142, wherein the size exclusion chromatography is performed on a Shimadzu (Shimadzu) UPLC instrument. (embodiment 144) the antibody of any one of embodiments 132-143, 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 132-144, wherein the size exclusion chromatography is performed at a column oven temperature of 30 ℃. (embodiment 146) the antibody of any one of embodiments 132-145, wherein the percentage of monomer is calculated using shimadzu software. (embodiment 147) the antibody of any one of embodiments 132-146, wherein the size exclusion chromatography is performed as described in example 2.
(embodiment 148) the anti-TL 1A antibody of any one of embodiments 1 to 147, wherein the anti-TL 1A is expressed as a concentration of at least about 2 μg/mL, between about 2 μg/mL and about 60 μg/mL, between about 5 μg/mL and about 60 μg/mL, between about 10 μg/mL and about 60 μg/mL, at least about 5 μg/mL, at least about 10 μg/mL, at least about 15 μg/mL, at least about 20 μg/mL, between about 2 μg/mL and about 50 μg/mL, between about 2 μg/mL and about 40 μg/mL, between about 2 μg/mL and about 30 μg/mL, between about 2 μg/mL and about 20 μg/mL, between about 5 μg/mL and about 50 μg/mL, between about 5 μg/mL and about 40 μg/mL, between about 5 μg/mL and about 30 μg/mL, between about 10 μg/mL and about 10 μg/mL, between about 10 μg/mL and about 40 μg/mL, or between about 10 μg/mL. (embodiment 149) the anti-TL 1A antibody of any one of embodiments 1 to 147, wherein said 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 μg/mL, as determined by the methods disclosed herein. (example 150) the antibody of example 148 or example 149, wherein the antibody is expressed in a FreeStyle 293-F cell. (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 an enzyme-linked immunosorbent assay (ELISA). (example 153) the antibody of example 152, wherein the ELISA comprises coating the surface of the substrate with a capture antibody that binds to a human or humanized antibody, applying an anti-TL 1A antibody to the substrate, and applying a second antibody that binds to a human or humanized antibody to the substrate. (embodiment 154) the antibody of embodiment 153, wherein the capture antibody comprises an anti-kappa antibody. (embodiment 155) the antibody of embodiment 153 or embodiment 154, wherein the second antibody comprises an anti-Fc antibody. (embodiment 156) the antibody of any one of embodiments 152-155, wherein the ELISA is performed as described in example 2.
(embodiment 157) a method of treating a disease and/or condition of the lung of a subject in need thereof, the method comprising administering to the subject the 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 lung comprises idiopathic pulmonary fibrosis, virus-induced pulmonary fibrosis, asthma, or COPD, 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 the 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. (example 162) a vector comprising the nucleic acid of example 161. (example 163) a cell comprising a nucleic acid according to example 161. Example 164 a cell comprising the vector of example 162.
Antibody Properties
The anti-TL 1A antibodies described herein bind to a specific region or epitope of human TL 1A. In various embodiments, an anti-TL 1A antibody provided herein has a binding affinity for human TL1A of less than about 1E -7 、1E -8 、1E -9 Or 1E -10 Kd. In some cases, the binding affinity is about 1E -9 To about 1E -10 Kd. In some embodiments, an anti-TL 1A antibody provided herein has a binding affinity for human TL1A and/or rat TL1A of less than about 1E -7 、1E -8 、1E -9 、1E -10 Or 1E -11 Kd. Methods for determining binding affinity are exemplified herein, including in example 2.
In various embodiments, the anti-TL 1A antibodies provided herein are antagonists of TL1A receptors, such as, but not limited to DR3 and TR6/DcR3. In certain embodiments, the antibody inhibits one or more activities of a bound TL1A receptor by 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%. In certain embodiments, the anti-TL 1A antibody inhibits TL1A activation as measured by release of interferon gamma in human blood. In certain embodiments, the antibodies are in an IC of between about 1 nanomolar and about 30 picomolar 50 Inhibiting release of interferon gamma in human blood. In certain embodiments, the antibodies are present in an IC of between about 500 picomoles and about 30 picomoles 50 Inhibiting release of interferon gamma in human blood. In certain embodiments, the antibodies are in an IC of between about 200 picomoles and about 30 picomoles 50 Inhibiting release of interferon gamma in human blood. In certain embodiments, the antibodies are in an IC of less than or equal to about 200 picomoles 50 Inhibiting release of interferon gamma in human blood. In certain embodiments, the antibodies are raised to an IC of less than or equal to about 100 picomoles 50 Inhibiting release of interferon gamma in human blood.
In various embodiments, an anti-TL 1A antibody provided herein comprises at least about 80% monomeric moieties after expression and purification as described in example 2 or elsewhere herein. In various embodiments, an anti-TL 1A antibody provided herein comprises at least about 85% monomeric moieties after expression and purification as described in example 2 or elsewhere herein. In various embodiments, an anti-TL 1A antibody provided herein comprises at least about 90% monomeric moieties after expression and purification as described in example 2 or elsewhere herein. In various embodiments, an anti-TL 1A antibody provided herein comprises at least about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% monomeric moieties after expression and purification as described in example 2 or elsewhere herein.
In various embodiments, the anti-TL 1A antibodies provided herein are expressed at least about 2 μg/mL as determined by the methods disclosed herein. In some embodiments, the anti-TL 1A antibody has an expression of about 2 μg/mL to about 60 μg/mL, as determined by the methods disclosed herein. In some embodiments, the anti-TL 1A antibody has an expression of about 5 μg/mL to about 60 μg/mL, as determined by the methods disclosed herein. In some embodiments, the anti-TL 1A antibody has an expression of about 10 μg/mL to about 60 μg/mL, as determined by the methods disclosed herein. In some embodiments, the anti-TL 1A antibody is expressed at least about 5 μg/mL as determined by the methods disclosed herein. In some embodiments, the anti-TL 1A antibody is expressed at least about 10 μg/mL as determined by the methods disclosed herein. In some embodiments, the anti-TL 1A antibody is expressed at least about 15 μg/mL as determined by the methods disclosed herein. In some embodiments, the anti-TL 1A antibody is expressed at least about 20 μg/mL as determined by the methods disclosed herein. In some embodiments, the anti-TL 1A antibody is expressed between about 2 μg/mL and about 50 μg/mL, between about 2 μg/mL and about 40 μg/mL, between about 2 μg/mL and about 30 μg/mL, between about 2 μg/mL and about 20 μg/mL, between about 5 μg/mL and about 50 μg/mL, between about 5 μg/mL and about 40 μg/mL, between about 5 μg/mL and about 30 μg/mL, between about 10 μg/mL and about 50 μg/mL, between about 10 μg/mL and about 40 μg/mL, or between about 10 μg/mL and about 30 μg/mL, as determined by the methods disclosed herein. In some embodiments, the anti-TL 1A antibody has an expression of 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 μg/mL as determined by the methods disclosed herein. The methods disclosed herein include those described in example 2.
In various embodiments, the anti-TL 1A antibodies provided herein are humanized and have less than about 20% non-human sequences in the framework regions of each of the heavy and light chain variable regions. For example, a humanized antibody comprises less than about 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% of a non-human sequence in the framework region of each of the heavy chain variable region and the light chain variable region. As another example, a humanized antibody comprises about or less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 non-human sequences in the framework regions of each of the heavy and light chain variable regions. The humanized heavy chain variable domain may comprise no or less than about 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 non-human mutated IGHV1-46 x 02 framework. The humanized light chain variable domain may comprise no or less than about 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 IGKV3-20 frames that are non-human mutated.
Epitope(s)
Various embodiments provide anti-TL 1A antibodies (anti-TL 1A antibodies as described herein) that bind to the same region of a TL1A protein or part thereof as a reference antibody. In some embodiments, the reference antibody comprises antibody A, B, C, D, E, F, G, H, A, B2, C2, D2, E2, F2, G2, or H2, or a combination thereof. In some embodiments, provided herein are anti-TL 1A antibodies that specifically bind to the same region of TL1A as a reference antibody, comprising: a heavy chain sequence that hybridizes to SEQ ID NO:104 at least about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical; and a light chain comprising a sequence identical to SEQ ID NO:201 is at least about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. In some embodiments, provided herein are anti-TL 1A antibodies that specifically bind to the same region of TL1A as a reference antibody, comprising: a heavy chain sequence that hybridizes to SEQ ID NO:107 is at least about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical; and a light chain comprising a sequence identical to SEQ ID NO:201 is at least about 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
Non-limiting methods for determining whether an anti-TL 1A antibody (i.e., a test antibody) binds to the same region of a TL1A protein or portion thereof as an antibody described herein are provided. Exemplary embodiments include competition assays. For example, the method includes determining whether the test antibody can compete for binding between the reference antibody and the TL1A protein or portion thereof, or determining whether the reference antibody can compete for binding between the test antibody and the TL1A protein or portion thereof. An exemplary method comprises using surface plasmon resonance to assess whether an anti-TL 1A antibody can compete for binding between TL1A and another anti-TL 1A antibody. In some cases, surface plasmon resonance is used for competition assays. Non-limiting methods are described in the examples.
In certain embodiments, disclosed herein are antibodies that compete with the antibodies described herein for binding to TL 1A. In certain embodiments, disclosed herein are antibodies that bind discrete epitopes that overlap with epitopes of TL1A bound by antibodies described herein. In certain embodiments, disclosed herein are antibodies that bind to the same epitope of TL1A, overlap the epitope of TL1A by one or more amino acid residues, or compete with antibodies or fragments thereof, which comprise a heavy chain variable region comprising: SEQ ID NO:104, an amino acid sequence of seq id no; and a light chain variable region comprising: SEQ ID NO:201, amino acid. In certain embodiments, disclosed herein are antibodies that bind to the same epitope of TL1A, overlap the epitope of TL1A by one or more amino acid residues, or compete with antibodies or fragments thereof, which comprise a heavy chain variable region comprising: SEQ ID NO:107, amino acid sequence; and a light chain variable region comprising: SEQ ID NO:201, amino acid.
4.3 measurement
An exemplary screening paradigm for identifying antibody variants that express well in mammalian cells and retain TL1A binding activity while minimizing the propensity of the antibody to aggregate includes a five-step process. This screening is 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 plates) transfection, (2) expression levels of antibodies were assessed in culture supernatants 96-120 hours after transfection with antibody quantitative ELISA, (3) supernatant antibody variants were assessed for binding to human TL1A by ELISA, (4) antibodies were purified using protein a in a single step, and (5) materials were analyzed by analytical SEC to assess monomer/aggregate content. This method enables the identification of variants that are well expressed, retain binding to TL1A and exhibit high monomer content.
Further provided herein are methods for analyzing antibody solubility based on the percentage of monomeric moieties. For example, as described in example 2.
Further provided herein are assays for quantifying antibody expression. For example, as described in example 2.
Further provided herein are assays for quantifying the immunogenicity of antibodies.
Specific binding of an antibody described herein can be determined by any method known in the art. Immunoassays that can be used include, but are not limited to, competitive and non-competitive assay systems using the following techniques: such as BIAcore analysis, FACS analysis, immunofluorescence, immunocytochemistry, western blotting, radioimmunoassay, ELISA, "sandwich" immunoassays, immunoprecipitation assays, precipitation reactions, gel diffusion precipitant reactions, immunodiffusion assays, agglutination assays, complement fixation assays, immunoradiometric assays, fluorescent immunoassays, and protein A immunoassays. Such assays are provided, for example, in Ausubel et al, 1994, current protocols in molecular biology (Current Protocols in Molecular Biology), volume 1, john Willi parent-child publishing company, N.Y. (John Wiley & Sons, inc., new York).
4.4 methods of producing antibodies
In various embodiments, monoclonal antibodies are prepared using methods known in the art, such as, but not limited to, hybridoma methods, wherein a host animal is immunized to elicit the production of lymphocytes of the antibody that will specifically bind to an immune antigen (Kohler and Milstein (1975), nature (Nature) 256:495). Hybridomas produce monoclonal antibodies specific for the selected antigen. When transmitted in vitro or in vivo, monoclonal antibodies are purified from the culture medium or ascites fluid by techniques known in the art.
In some embodiments, monoclonal antibodies are prepared using recombinant DNA methods. Polynucleotides encoding monoclonal antibodies 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 upon transfection into host cells, e.g., e.coli (e.coli) cells, simian COS cells, chinese Hamster Ovary (CHO) cells, or myeloma cells, produce monoclonal antibodies. Polynucleotides encoding monoclonal antibodies can be further modified in a number of different ways using recombinant DNA techniques to produce alternative antibodies.
In various embodiments, chimeric antibodies can be generated, i.e., molecules 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., a humanized antibody).
In some embodiments, the anti-TL 1A monoclonal antibody is a humanized antibody to reduce antigenicity and HAMA (human anti-mouse antibody) response when administered to a human subject. Various techniques known in the art may be used to produce humanized antibodies. For example, an antibody is humanized by: (1) Determining the nucleotide and predicted amino acid sequences of the light and heavy variable domains of the starting antibody; (2) Humanized antibodies are designed, for example, to determine which antibody framework regions to use in the humanization process; (3) actual humanization methods/techniques; and (4) transfection and expression of humanized antibodies. In various embodiments, the humanized antibodies may be further optimized to reduce potential immunogenicity while maintaining functional activity for use in therapy in humans.
Humanized antibodies can also be prepared in transgenic mice containing human immunoglobulin loci that are capable of producing a complete repertoire of human antibodies upon immunization in the absence of endogenous immunoglobulin production. Humanized antibodies can also be obtained by genetic engineering methods that are capable of producing affinity matured human-like polyclonal antibodies in large animals.
Fully humanized antibodies can be created by first designing variable region amino acid sequences that contain CDRs embedded in a human-derived framework sequence that are non-human (e.g., rodent-derived). The non-human CDRs provide the desired specificity. Thus, in some cases, these residues are included in the design of the substantially unchanged, reconstructed variable region. In some cases, the modification should therefore be limited to a minimum in the specificity and affinity of the antibody and closely observe the changes. On the other hand, the theoretical framework residues may be derived from any human variable region. Human framework sequences that are also suitable for producing the recombinant variable regions and for maintaining the affinity of the antibody should be selected in order to produce a recombinant antibody that exhibits acceptable or 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 skilled in the art, such as, but not limited to, phage display of libraries of human antibodies, transgenic mice, human-human hybridomas, B cell immortalization and cloning, single cell RT-PCR or HuRAb techniques, and the like, can be used to generate humanized antibodies having hybrid DNA sequences containing human frameworks and non-human CDRs.
In certain embodiments, the anti-TL 1A antibody is a human antibody. Human antibodies can be prepared directly using a variety of techniques known in the art. Immortalized human B lymphocytes may be generated for immunization in vitro or isolated from an immunized individual producing antibodies to a target antigen.
Chimeric, humanized and human antibodies may be produced by recombinant expression. Recombinant polynucleotide constructs typically comprise expression control sequences, including naturally-associated or heterologous promoter regions, operably linked to the coding sequence of the antibody chain. In certain embodiments, amino acid sequence variants that produce these humanized antibodies may be desirable, particularly when the variants improve the binding affinity or other biological properties of the antibodies.
In certain embodiments, the antibody fragments are used to treat and/or ameliorate inflammation and/or fibrosis. In certain embodiments, the antibody fragments are used to treat and/or ameliorate diseases and/or conditions of the lung. Various techniques are known for the production of antibody fragments. Typically, these fragments are obtained by proteolytic digestion of the intact antibody (e.g., morimoto et al, 1993, journal of Biochemical and biophysical methods (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 generating antibody fragments will be apparent to those skilled in the art.
In accordance with the present disclosure, the techniques may be adapted to produce single chain antibodies specific for TL1A. Furthermore, the methods may be adapted to construct Fab expression libraries to allow for the rapid and efficient identification of monoclonal Fab fragments, or derivatives, fragments, analogs, or homologs thereof, having the desired specificity for TL1A. Antibody fragments may be generated by techniques in the art, including but not limited to: (a) F (ab') 2 fragments produced by pepsin digestion of antibody molecules; (b) Fab fragments generated by reduction of disulfide bonds of F (ab') 2 fragments; (c) A Fab fragment produced by treating an antibody molecule with papain and a reducing agent, and (d) an Fv fragment.
Also provided herein are modified antibodies comprising any type of variable region that provides for association of the antibody with TL1A. Those skilled in the art will appreciate that modified antibodies can include antibodies (e.g., full length antibodies or immunoreactive fragments thereof) in which at least a portion of one or more of the constant region structures has been deleted or otherwise altered in order to provide the desired biochemical characteristics, such as reduced TL1A. In certain embodiments, the variable regions in both the heavy and light chains are altered by at least partial substitution of one or more CDRs and, if desired, partial framework region substitutions and sequence alterations. In some embodiments, the substituted CDRs may be derived from antibodies of the same class, subclass, from different classes of antibodies, e.g., from different species and/or combinations thereof. In some embodiments, the constant region of the modified antibody will comprise a human constant region. Modifications to constant regions compatible with the present disclosure include additions, deletions, or substitutions of one or more amino acids in one or more domains.
In various embodiments, expression of an antibody or antigen binding fragment thereof as described herein may occur in a prokaryotic cell or eukaryotic cell. Suitable hosts include bacterial or eukaryotic hosts, including yeast, insect, fungal, avian and mammalian cells, in vivo or in situ, or host cells of mammalian, insect, avian or yeast origin. The mammalian cells or tissues may be of human, primate, hamster, rabbit, rodent, cow, pig, sheep, horse, goat, dog or cat origin, but any other mammalian cell may be used. In other embodiments, an antibody or antigen fragment thereof as described herein may be transfected into a host.
In some embodiments, the expression vector is transfected into a recipient cell line for the production of chimeric, humanized or composite human antibodies described herein. In various embodiments, mammalian cells may be used as hosts for the production of antibody proteins, which may include, but are not limited to, fibroblasts-derived cells, such as Vero (ATCC CRL 81) or CHO-K1 (ATCC CRL 61) cells, heLa cells, and L cells. Can be used forExemplary eukaryotic cells for expressing the polypeptide include, but are not limited to: COS cells, comprising COS 7 cells; 293 cells, comprising 293-6E cells; CHO cells comprising CHO-S and DG44 cells; PER.C6 TM Cells (Crucell); and NSO cells. In some embodiments, a particular eukaryotic host cell is selected based on its ability to make a desired post-translational modification of the heavy and/or light chain.
Many 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.
Expression vectors carrying chimeric, humanized or composite human antibody constructs, antibodies or antigen binding fragments thereof as described herein may be introduced into suitable host cells 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 those of ordinary skill in the art. Expression vectors for these cells may contain expression control sequences such as replication origin sites, promoters, enhancers and necessary processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites and transcription terminator sequences.
In various embodiments, yeast may also be used as a host for producing the antibody molecules or peptides described herein. In various other embodiments, bacterial strains may also be used as hosts for the production of antibody molecules or peptides described herein. Examples of bacterial strains include, but are not limited to, E.coli, bacillus (Bacillus) strains, E.coli (Enterobacteria) and various Pseudomonas (Pseudomonas) strains.
In some embodiments, one or more antibodies or antigen binding fragments thereof as described herein may 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. To produce a transgenic animal, the transgene may be microinjected into fertilized oocytes, or the transgene may be incorporated into the genome of embryonic stem cells, and the nucleus of such cells transferred into enucleated oocytes. Once expressed, the antibodies can be purified according to standard procedures in the art, including HPLC purification, column chromatography, gel electrophoresis, and the like (see generally, scens, protein purification (Protein Purification) (Springer-Verlag, N.Y., 1982)).
Once expressed in the host, the intact antibodies, antibody fragments (e.g., individual light and heavy chains) or other immunoglobulin forms of the present disclosure can be prepared by known techniques, such as immunoabsorbent or immunoaffinity chromatography; chromatography, such as HPLC (high performance liquid chromatography); precipitating ammonium sulfate; gel electrophoresis or any combination of these methods. See generally, scope, PROTEIN purification (PROTEIN purification.) (Springer-Verlag, N.Y., 1982). Substantially pure immunoglobulins of at least about 90% to 95% homogeneity are advantageous, as are those immunoglobulins having 98% to 99% or more homogeneity, in particular for pharmaceutical use. Once partially purified or purified to homogeneity as desired, the humanized or composite human antibodies can then be used therapeutically or for developing and performing assay procedures, immunofluorescent staining, and the like. See generally, volumes I and II, methods of immunology (immunol. Meth.) (Lefkovits and Pemis editors, academic Press, N.Y., 1979 and 1981).
Various embodiments provide genetic constructs comprising nucleic acids encoding anti-TL 1A antibodies or fragments provided herein. The genetic construct of the antibody may be in the form of an expression cassette, which may be suitable for expression of the encoded anti-TL 1A antibody or fragment. The gene construct may be introduced into a host cell with or without incorporation into a vector. For example, the genetic construct may be incorporated into a liposome or viral particle. Alternatively, the purified nucleic acid molecule may be inserted directly into a host cell by methods known in the art. The gene construct may be introduced directly into the cells of the host subject by transfection, infection, electroporation, cell fusion, protoplast fusion, microinjection or ballistic bombardment.
Various embodiments provide recombinant vectors comprising the genetic constructs of the antibodies provided herein. The recombinant vector may be a plasmid, cosmid or phage. Recombinant vectors may contain other functional elements; for example, a suitable promoter for promoting gene expression.
Various embodiments provide host cells comprising the genetic constructs and/or recombinant vectors described herein.
Various host systems are also advantageously used for expression of recombinant proteins. Examples of suitable mammalian host cell lines include the COS-7 line of monkey kidney cells, as well as other cell lines capable of expressing suitable vectors, including, for example, L cell, C127, 3T3, chinese Hamster Ovary (CHO), heLa, and BHK cell lines. Mammalian expression vectors may include non-transcriptional elements such as origins of replication, suitable promoters and enhancers linked to the gene to be expressed, and other 5 'or 3' flanking non-transcribed and 5 'or 3' non-translated sequences such as necessary ribosome binding sites, polyadenylation sites, splice donor and acceptor sites, and transcription termination sequences.
The protein produced by the transformed host may be purified according to any suitable method. Such standard methods include chromatography (e.g., ion exchange, affinity and fractionation column chromatography), centrifugation, differential solubility, or by any other standard technique for protein purification. Affinity tags, such as hexahistidine (SEQ ID NO: 391), maltose binding domain, influenza coat sequence, and glutathione-S-transferase, can be attached to the protein to allow for simple purification by passage through a suitable affinity column. The isolated proteins may also be physically characterized using techniques such as proteolysis, nuclear magnetic resonance, and x-ray crystallography. Recombinant proteins produced in bacterial culture can be isolated.
One of skill in the art will recognize that a single substitution, deletion, or addition of a nucleic acid, peptide, polypeptide, or protein sequence that alters a single amino acid or a small portion of an amino acid in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid and retains the ability to specifically bind to the target antigen. Such conservatively modified variants are the supplementation of polymorphic variants, interspecies homologs, and alleles, and do not exclude polymorphic variants, interspecies homologs, and alleles, consistent with the present disclosure.
A given amino acid may be substituted with a residue having similar physiochemical characteristics, e.g., one aliphatic residue is substituted with another aliphatic residue (e.g., he, val, leu or Ala is substituted with each other), or one polar residue is substituted with another polar residue (e.g., between Lys and Arg, between Glu and Asp, or between gin and Asn). Other such conservative substitutions, for example substitutions of the entire region with similar hydrophobic character, are well known. Polypeptides comprising conservative amino acid substitutions may be tested in any of the assays described herein to confirm that the desired activity, e.g., antigen binding activity and specificity of the native or reference polypeptide, is retained.
Specific conservative substitutions include, for example: substitution of Ala to Gly or Ser; arg is substituted by Lys; asn is substituted with Gin or with His; asp is substituted with Glu; cys is substituted by Ser; gin is substituted with Asn; glu is substituted with Asp; substitution of Gly to Ala or to Pro; his is substituted by Asn or Gin; lie is substituted with Leu or with Val; leu is substituted into lie or into Val; lys is substituted with Arg, gin or Glu; substitution of Met to Leu, to Tyr, or to lie; phe is substituted with Met, with Leu or with Tyr; substitution of Ser to Thr; thr is substituted by Ser; trp is substituted with Tyr; tyr is substituted to Trp; and/or Phe to Val, to lie or to Leu.
In some embodiments, an antibody and/or antigen binding fragment thereof described herein can be a variant of a sequence described herein, e.g., a conservatively substituted variant of an antibody polypeptide. In some embodiments, the variant is a conservatively modified variant. A variant may refer to a polypeptide that is substantially homologous to a native or reference polypeptide, but which differs in amino acid sequence from the native or reference polypeptide by one or more deletions, insertions or substitutions. DNA sequences encoding variant polypeptides encompass sequences that include one or more additions, deletions, or substitutions of nucleotides when compared to the native or reference DNA sequence, but encode variant proteins or fragments thereof that retain activity, e.g., antigen-specific binding activity of the relevant target polypeptide.
The alteration of the natural amino acid sequence may be accomplished by any of a number of techniques known to those skilled in the art. Mutations may be introduced at specific loci or by oligonucleotide-directed site-specific mutagenesis procedures. Techniques for making such changes are well established and include, for example, those disclosed in the following documents: walder et al (Gene 42:133, 1986); bauer et al (Gene 37:73, 1985); craik (biotechnology (BioTechniques), month 1, 1985, 12-19); smith et al (Gene engineering: principle and methods (Genetic Engineering: principles and Methods), proneome Press, 1981).
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 variant or non-variant forms of the early preparation of antibodies. The nucleic acid sequence encoding at least one antibody, moiety or polypeptide as described herein may be recombined with vector DNA according to conventional techniques including, but not limited to, blunt-ended or staggered-ended termini for ligation and restriction enzyme digestion. Techniques for such operations are disclosed, for example, by the following documents: maniatis et al, molecular cloning: laboratory Manual (Cold spring harbor laboratory Press, N.Y. (Cold Spring Harbor Lab. Press, N.Y.), 1982 and 1989) and can be used to construct nucleic acid sequences encoding monoclonal antibody molecules or antigen binding regions.
In some embodiments, a nucleic acid encoding an antibody or antigen binding fragment thereof as described herein is included in a vector. In some aspects described herein, 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. As used herein, the term "vector" refers to a nucleic acid construct designed for delivery to a host cell or for transfer between different host cells. As used herein, a vector may be viral or non-viral. The term "vector" encompasses any genetic element that is capable of replication when associated with an appropriate control element, and that can transfer a gene sequence to a cell. Vectors may include, but are not limited to, cloning vectors, expression vectors, plasmids, phages, transposons, cosmids, chromosomes, viruses, virions, and the like.
As used herein, the term "expression vector" refers to a vector that directs the expression of RNA or a polypeptide from a sequence linked to a transcriptional regulatory sequence on the vector. The term "expression" refers to cellular processes involved in the production of RNA and proteins and, where appropriate, proteins, including, but not limited to, transcription, transcript processing, translation and protein folding, modification and processing, as applicable. An "expression product" comprises RNA transcribed from a gene and a polypeptide obtained by translation of mRNA transcribed from the gene. The term "gene" means a nucleic acid sequence that, when operably linked to appropriate regulatory sequences, transcribes (DNA) into RNA in vitro or in vivo. The gene may or may not comprise regions preceding and following the coding region, for example, 5' untranslated (5 ' UTR) or "leader" sequences and 3' UTR or "trailer" sequences, as well as intervening sequences (introns) between individual coding segments (exons).
As used herein, the term "viral vector" refers to a nucleic acid vector construct comprising at least one viral-derived element and having the ability to be packaged into viral vector particles. The viral vector may contain a nucleic acid encoding an antibody or antigen binding portion thereof as described herein in place of the non-essential viral genes. The vector and/or particle may be used for the purpose of transferring any nucleic acid into a cell in vitro or in vivo. Various forms of viral vectors are known in the art.
"recombinant vector" means that the vector comprises a heterologous nucleic acid sequence or "transgene" capable of expression in vivo.
4.5 pharmaceutical compositions
In one aspect, the anti-TL 1A antibodies provided herein are formulated as 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 method of use may be in vitro, ex vivo or in vivo. In certain embodiments, the disease and/or condition treated with an anti-TL 1A antibody is a disease and/or condition of the lung.
In various embodiments, the pharmaceutical composition is formulated for delivery by any route of administration. "route of administration" includes any route of administration known in the art including, but not limited to, intravenous, subcutaneous, aerosol, nasal, oral, transmucosal, transdermal, and parenteral. In an exemplary embodiment, the route of administration is subcutaneous.
The pharmaceutical composition may contain any pharmaceutically acceptable carrier. "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle that involves 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. For example, 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. The component must also be suitable for contacting any tissue or organ with which it may be in contact, meaning that the component must not carry the risk of toxicity, irritation, allergic response, immunogenicity, or any other complication beyond its therapeutic benefit.
In various embodiments, pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of an anti-TL 1A antibody are provided. By "pharmaceutically acceptable excipient" is meant an excipient that can be used to prepare generally safe, non-toxic, and desirable pharmaceutical compositions, and which comprises excipients that are acceptable for veterinary as well as human pharmaceutical use. The active ingredient may be admixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for the therapeutic methods described herein. Such excipients may be solid, liquid, semi-solid, or gaseous in the case of an aerosol composition. Suitable excipients for different routes of administration (e.g., subcutaneous, intravenous, oral) may be selected. Non-limiting examples include, for example: starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, water, physiological saline, dextrose, propylene glycol, glycerol, ethanol, mannitol, polysorbate and the like and combinations thereof. In addition, if desired, the compositions may 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. The therapeutic compositions as described herein may comprise pharmaceutically acceptable salts. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric or phosphoric acid, organic acids such as acetic, tartaric or mandelic acid, salts formed with inorganic bases such as sodium, potassium, ammonium, calcium or ferric hydroxides, and salts formed with organic bases such as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine (procaine) and the like. The liquid compositions may contain aqueous and non-aqueous liquid phases such as glycerin, vegetable oils such as cottonseed oil, and aqueous oil emulsions. Physiologically tolerable carriers are well known in the art. The amount of antibody used that will be effective in treating 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 using standard clinical techniques.
Non-limiting exemplary compositions
In certain embodiments, provided herein are pharmaceutical compositions comprising an anti-TL 1A antibody formulated for intravenous administration.
In certain embodiments, provided herein are pharmaceutical compositions comprising an anti-TL 1A antibody formulated for subcutaneous administration.
In certain embodiments, provided herein are pharmaceutical compositions comprising an anti-TL 1A antibody at a concentration of about or greater than about 150 mg/mL. In some embodiments, the concentration is up to about 300mg/mL. In some embodiments, the concentration is about or greater than about 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200mg/mL. In some embodiments, the concentration is about 150mg/mL to about 300mg/mL, about 150mg/mL to about 250mg/mL, about 150mg/mL to about 225mg/mL, about 150mg/mL to about 220mg/mL, about 150mg/mL to about 210mg/mL, about 150mg/mL to about 200mg/mL, about 150mg/mL to about 190mg/mL, about 150mg/mL to about 180mg/mL, about 160mg/mL to about 300mg/mL, about 160mg/mL to about 250mg/mL, about 160mg/mL to about 225mg/mL, about 160mg/mL to about 220mg/mL, about 160mg/mL to about 210mg/mL, about 160mg/mL to about 200mg/mL, about 160mg/mL to about 190mg/mL, about 160mg/mL to about 180mg/mL, about 170mg/mL to about 250mg/mL, about 170mg to about 170mg/mL, about 170mg to about 180mg/mL, about 170mg to about 210 mg/mL. In some embodiments, about 150mg to about 1,000mg of the anti-TL 1A antibody is present in the composition. For example, from about 150mg to about 2000mg, from about 150mg to about 1750mg, from about 150mg to about 1500mg, from about 150mg to about 1250mg, from about 150mg to about 1000mg, from about 150mg to about 750mg, from about 150 to about 500mg, from about 150 to about 300mg, from about 150 to about 200mg or from about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225mg, 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, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000mg of the anti-TL 1A antibody may be present in the composition. Additionally, in some embodiments of the compositions provided herein, the compositions comprise an anti-TL 1A antibody at a concentration of greater than about 50 mg/mL. In some embodiments, the composition includes anti-TL 1A antibody at a concentration of greater than about 55mg/mL, greater than about 60mg/mL, greater than about 65mg/mL, greater than about 70mg/mL, greater than about 75mg/mL, greater than about 80mg/mL, greater than about 85mg/mL, greater than about 90mg/mL, greater than about 95mg/mL, greater than about 100mg/mL, greater than about 105mg/mL, greater than about 110mg/mL, greater than about 115mg/mL, greater than about 120mg/mL, greater than about 125mg/mL, greater than about 130mg/mL, greater than about 135mg/mL, greater than about 140mg/mL, or greater than about 145 mg/mL. In some embodiments, the composition includes anti-TL 1A antibody at a concentration of about 55mg/mL, about 60mg/mL, about 65mg/mL, about 70mg/mL, about 75mg/mL, about 80mg/mL, about 85mg/mL, about 90mg/mL, about 95mg/mL, about 100mg/mL, about 105mg/mL, about 110mg/mL, about 115mg/mL, about 120mg/mL, about 125mg/mL, about 130mg/mL, about 135mg/mL, about 140mg/mL, or about 145 mg/mL. In some embodiments of the present invention, in some embodiments, the composition comprises a pharmaceutical composition in the form of about 50mg/mL to about 250mg/mL, about 55mg/mL to about 250mg/mL, about 60mg/mL to about 250mg/mL, about 65mg/mL to about 250mg/mL, about 70mg/mL to about 250mg/mL, about 75mg/mL to about 250mg/mL, about 80mg/mL to about 250mg/mL, about 85mg/mL to about 250mg/mL, about 90mg/mL to about 250mg/mL, about 95mg/mL to about 250mg/mL, about 100mg/mL to about 250mg/mL, about 105mg/mL to about 250mg/mL, about 110mg/mL to about 250mg/mL, about 115mg/mL to about 250mg/mL, about 120mg/mL to about 250mg/mL, about 125mg/mL to about 250mg/mL, about 130mg/mL, about 135mg/mL about 140mg/mL to about 250mg/mL, about 145mg/mL to about 250mg/mL, about 150mg/mL to about 250mg/mL, about 155mg/mL to about 250mg/mL, about 160mg/mL to about 250mg/mL, about 165mg/mL to about 250mg/mL, about 170mg/mL to about 250mg/mL, about 175mg/mL to about 250mg/mL, about 180mg/mL to about 250mg/mL, about 185mg/mL to about 250mg/mL, about 190mg/mL to about 250mg/mL, about 195mg/mL to about 250mg/mL, about 200mg/mL to about 250mg/mL, about 205mg/mL to about 250mg/mL, about 210mg/mL to about 250mg/mL, about 215mg/mL to about 250mg/mL, about 220mg/mL to about 250mg/mL, about 225mg/mL to about 250mg/mL, about 230mg/mL to about 250mg/mL, about 235mg/mL to about 250mg/mL, about 240mg/mL to about 250mg/mL, about 245mg/mL to about 250mg/mL, about 50mg/mL to about 240mg/mL, about 55mg/mL to about 240mg/mL, about 60mg/mL to about 240mg/mL, about 65mg/mL to about 240mg/mL, about 70mg/mL to about 240mg/mL, about 75mg/mL to about 240mg/mL, about 80mg/mL to about 240mg/mL, about 85mg/mL to about 240mg/mL, about 90mg/mL to about 240mg/mL, about 95mg/mL to about 240mg/mL, about 100mg/mL to about 240mg/mL, about 105mg/mL to about 240mg/mL, about 110mg/mL to about 240mg/mL, about 115mg/mL to about 240mg/mL, about 120mg/mL, about 240mg/mL to about 240mg/mL about 125mg/mL to about 240mg/mL, about 130mg/mL to about 240mg/mL, about 135mg/mL to about 240mg/mL, about 140mg/mL to about 240mg/mL, about 145mg/mL to about 240mg/mL, about 150mg/mL to about 240mg/mL, about 155mg/mL to about 240mg/mL, about 160mg/mL to about 240mg/mL, about 165mg/mL to about 240mg/mL, about 170mg/mL to about 240mg/mL, about 175mg/mL to about 240mg/mL, about 180mg/mL to about 240mg/mL, about 185mg/mL to about 240mg/mL, about 190mg/mL to about 240mg/mL, about 195mg/mL to about 240mg/mL, about 200mg/mL to about 240mg/mL, about 205mg/mL to about 240mg/mL, about 210mg/mL to about 240mg/mL, about 215mg/mL to about 240mg/mL, about 220mg/mL to about 240mg/mL, about 225mg/mL to about 240mg/mL, about 230mg/mL to about 240mg/mL, about 235mg/mL to about 240mg/mL, about 50mg/mL to about 230mg/mL, about 55mg/mL to about 230mg/mL, about 60mg/mL to about 230mg/mL, about 65mg/mL to about 230mg/mL, about 70mg/mL to about 230mg/mL, about 75mg/mL to about 230mg/mL, about 80mg/mL to about 230mg/mL, about 85mg/mL to about 230mg/mL, about 90mg/mL to about 230mg/mL, about 95mg/mL to about 230mg/mL, about 100mg/mL to about 230mg/mL, about 105mg/mL to about 230mg/mL, about 110mg/mL to about 230mg/mL, about 115mg/mL to about 230mg/mL about 120mg/mL to about 230mg/mL, about 125mg/mL to about 230mg/mL, about 130mg/mL to about 230mg/mL, about 135mg/mL to about 230mg/mL, about 140mg/mL to about 230mg/mL, about 145mg/mL to about 230mg/mL, about 150mg/mL to about 230mg/mL, about 155mg/mL to about 230mg/mL, about 160mg/mL to about 230mg/mL, about 165mg/mL to about 230mg/mL, about 170mg/mL to about 230mg/mL, about 175mg/mL to about 230mg/mL, about 180mg/mL to about 230mg/mL, about 185mg/mL to about 230mg/mL, about 190mg/mL to about 230mg/mL, about 195mg/mL to about 230mg/mL, about 200mg/mL to about 230mg/mL, about 205mg/mL to about 230mg/mL, about 210mg/mL to about 230mg/mL, about 215mg/mL to about 230mg/mL, about 220mg/mL to about 230mg/mL, about 225mg/mL to about 230mg/mL, about 50mg/mL to about 220mg/mL, about 55mg/mL to about 220mg/mL, about 60mg/mL to about 220mg/mL, about 65mg/mL to about 220mg/mL, about 70mg/mL to about 220mg/mL, about 75mg/mL to about 220mg/mL, about 80mg/mL to about 220mg/mL, about 85mg/mL to about 220mg/mL, about 90mg/mL to about 220mg/mL, about 95mg/mL to about 220mg/mL, about 100mg/mL to about 220mg/mL, about 105mg/mL to about 220mg/mL, about 110mg/mL to about 220mg/mL, about 115mg/mL to about 220mg/mL, about 120mg/mL about 125mg/mL to about 220mg/mL, about 130mg/mL to about 220mg/mL, about 135mg/mL to about 220mg/mL, about 140mg/mL to about 220mg/mL, about 145mg/mL to about 220mg/mL, about 150mg/mL to about 220mg/mL, about 155mg/mL to about 220mg/mL, about 160mg/mL to about 220mg/mL, about 165mg/mL to about 220mg/mL, about 170mg/mL to about 220mg/mL, about 175mg/mL to about 220mg/mL, about 180mg/mL to about 220mg/mL, about 185mg/mL to about 220mg/mL, about 190mg/mL to about 220mg/mL, about 195mg/mL to about 220mg/mL, about 200mg/mL to about 220mg/mL, about 205mg/mL to about 220mg/mL, about 210mg/mL to about 220mg/mL, about 215mg/mL to about 220mg/mL, about 50mg/mL to about 210mg/mL, about 55mg/mL to about 210mg/mL, about 60mg/mL to about 210mg/mL, about 65mg/mL to about 210mg/mL, about 70mg/mL to about 210mg/mL, about 75mg/mL to about 210mg/mL, about 80mg/mL to about 210mg/mL, about 85mg/mL to about 210mg/mL, about 90mg/mL to about 210mg/mL, about 95mg/mL to about 210mg/mL, about 100mg/mL to about 210mg/mL, about 105mg/mL to about 210mg/mL, about 110mg/mL to about 210mg/mL, about 115mg/mL to about 210mg/mL, about 120mg/mL to about 210mg/mL, about 125mg/mL to about 210mg/mL, about 130mg/mL to about 210mg/mL, about 135mg/mL to about 210mg/mL about 140mg/mL to about 210mg/mL, about 145mg/mL to about 210mg/mL, about 150mg/mL to about 210mg/mL, about 155mg/mL to about 210mg/mL, about 160mg/mL to about 210mg/mL, about 165mg/mL to about 210mg/mL, about 170mg/mL to about 210mg/mL, about 175mg/mL to about 210mg/mL, about 180mg/mL to about 210mg/mL, about 185mg/mL to about 210mg/mL, about 190mg/mL to about 210mg/mL, about 195mg/mL to about 210mg/mL, about 200mg/mL to about 210mg/mL, about 205mg/mL to about 210mg/mL, about 50mg/mL to about 200mg/mL, about 55mg/mL to about 200mg/mL, about 60mg/mL to about 200mg/mL, about 65mg/mL to about 200mg/mL, about 70mg/mL to about 200mg/mL, about 75mg/mL to about 200mg/mL, about 80mg/mL to about 200mg/mL, about 85mg/mL to about 200mg/mL, about 90mg/mL to about 200mg/mL, about 95mg/mL to about 200mg/mL, about 100mg/mL to about 200mg/mL, about 105mg/mL to about 200mg/mL, about 110mg/mL to about 200mg/mL, about 115mg/mL to about 200mg/mL, about 120mg/mL to about 200mg/mL, about 125mg/mL to about 200mg/mL, about 130mg/mL to about 200mg/mL, about 135mg/mL to about 200mg/mL, about 140mg/mL to about 200mg/mL, about 145mg/mL to about 200mg/mL, about 150mg/mL to about 200mg/mL, about 155mg/mL to about 200mg/mL, about 160mg/mL about 165mg/mL to about 200mg/mL, about 170mg/mL to about 200mg/mL, about 175mg/mL to about 200mg/mL, about 180mg/mL to about 200mg/mL, about 185mg/mL to about 200mg/mL, about 190mg/mL to about 200mg/mL, about 195mg/mL to about 200mg/mL, about 50mg/mL to about 190mg/mL, about 55mg/mL to about 190mg/mL, about 60mg/mL to about 190mg/mL, about 65mg/mL to about 190mg/mL, about 70mg/mL to about 190mg/mL, about 75mg/mL to about 190mg/mL, about 80mg/mL to about 190mg/mL, about 85mg/mL to about 190mg/mL, about 90mg/mL to about 190mg/mL, about 95mg/mL to about 190mg/mL, about 100mg/mL to about 190mg/mL, about 105mg/mL to about 190mg/mL, about 110mg/mL to about 190mg/mL, about 115mg/mL to about 190mg/mL, about 120mg/mL to about 190mg/mL, about 125mg/mL to about 190mg/mL, about 130mg/mL to about 190mg/mL, about 135mg/mL to about 190mg/mL, about 140mg/mL to about 190mg/mL, about 145mg/mL to about 190mg/mL, about 150mg/mL to about 190mg/mL, about 155mg/mL to about 190mg/mL, about 160mg/mL to about 190mg/mL, about 165mg/mL to about 190mg/mL, about 170mg/mL to about 190mg/mL, about 175mg/mL to about 190mg/mL, about 180mg/mL to about 190mg/mL, about 185mg/mL, about 50mg/mL to about 180mg/mL, about 55mg/mL to about 180mg/mL about 60mg/mL to about 180mg/mL, about 65mg/mL to about 180mg/mL, about 70mg/mL to about 180mg/mL, about 75mg/mL to about 180mg/mL, about 80mg/mL to about 180mg/mL, about 85mg/mL to about 180mg/mL, about 90mg/mL to about 180mg/mL, about 95mg/mL to about 180mg/mL, about 100mg/mL to about 180mg/mL, about 105mg/mL to about 180mg/mL, about 110mg/mL to about 180mg/mL, about 115mg/mL to about 180mg/mL, about 120mg/mL to about 180mg/mL, about 125mg/mL to about 180mg/mL, about 130mg/mL to about 180mg/mL, about 135mg/mL to about 180mg/mL, about 140mg/mL to about 180mg/mL, about 145mg/mL to about 180mg/mL, about 150mg/mL to about 180mg/mL, about 155mg/mL to about 180mg/mL, about 160mg/mL to about 180mg/mL, about 165mg/mL to about 180mg/mL, about 170mg/mL to about 180mg/mL, about 175mg/mL to about 180mg/mL, about 50mg/mL to about 170mg/mL, about 55mg/mL to about 170mg/mL, about 60mg/mL to about 170mg/mL, about 65mg/mL to about 170mg/mL, about 70mg/mL to about 170mg/mL, about 75mg/mL to about 170mg/mL, about 80mg/mL to about 170mg/mL, about 85mg/mL to about 170mg/mL, about 90mg/mL to about 170mg/mL, about 95mg/mL to about 170mg/mL, about 100mg/mL to about 170mg/mL, about 105mg/mL to about 170mg/mL, about 110mg/mL to about 170mg/mL about 115mg/mL to about 170mg/mL, about 120mg/mL to about 170mg/mL, about 125mg/mL to about 170mg/mL, about 130mg/mL to about 170mg/mL, about 135mg/mL to about 170mg/mL, about 140mg/mL to about 170mg/mL, about 145mg/mL to about 170mg/mL, about 150mg/mL to about 170mg/mL, about 155mg/mL to about 170mg/mL, about 160mg/mL to about 170mg/mL, about 165mg/mL to about 170mg/mL, about 50mg/mL to about 160mg/mL, about 55mg/mL to about 160mg/mL, about 60mg/mL to about 160mg/mL, about 65mg/mL to about 160mg/mL, about 70mg/mL to about 160mg/mL, about 75mg/mL to about 160mg/mL, about 80mg/mL to about 160mg/mL, about 85mg/mL to about 160mg/mL, about 90mg/mL to about 160mg/mL, about 95mg/mL to about 160mg/mL, about 100mg/mL to about 160mg/mL, about 105mg/mL to about 160mg/mL, about 110mg/mL to about 160mg/mL, about 115mg/mL to about 160mg/mL, about 120mg/mL to about 160mg/mL, about 125mg/mL to about 160mg/mL, about 130mg/mL to about 160mg/mL, about 135mg/mL to about 160mg/mL, about 140mg/mL to about 160mg/mL, about 145mg/mL to about 160mg/mL, about 150mg/mL to about 160mg/mL, about 155mg/mL to about 160mg/mL, about 50mg/mL to about 150mg/mL, about 55mg/mL to about 150mg/mL, about 60mg/mL to about 150mg/mL an anti-TL 1A antibody at a concentration of about 65mg/mL to about 150mg/mL, about 70mg/mL to about 150mg/mL, about 75mg/mL to about 150mg/mL, about 80mg/mL to about 150mg/mL, about 85mg/mL to about 150mg/mL, about 90mg/mL to about 150mg/mL, about 95mg/mL to about 150mg/mL, about 100mg/mL to about 150mg/mL, about 105mg/mL to about 150mg/mL, about 110mg/mL to about 150mg/mL, about 115mg/mL to about 150mg/mL, about 120mg/mL to about 150mg/mL, about 125mg/mL to about 150mg/mL, about 130mg/mL to about 150mg/mL, about 135mg/mL to about 150mg/mL, about 140mg/mL to about 150mg/mL, or about 145mg/mL to about 150 mg/mL. In some embodiments, the composition includes anti-TL 1A at a concentration of about 50mg/mL to about 140mg/mL, about 55mg/mL to about 140mg/mL, about 60mg/mL to about 140mg/mL, about 65mg/mL to about 140mg/mL, about 70mg/mL to about 140mg/mL, about 75mg/mL to about 140mg/mL, about 80mg/mL to about 140mg/mL, about 85mg/mL to about 140mg/mL, about 90mg/mL to about 140mg/mL, about 95mg/mL to about 140mg/mL, about 100mg/mL to about 140mg/mL, about 105mg/mL to about 140mg/mL, about 110mg/mL to about 140mg/mL, about 115mg/mL to about 140mg/mL, about 120mg/mL to about 140mg/mL, about 125mg/mL to about 140mg/mL, about 130mg/mL to about 140mg/mL, or about 135mg/mL to about 140 mg/mL. In some embodiments, the composition comprises an anti-TL 1A antibody at a concentration of about 50mg/mL to about 130mg/mL, about 55mg/mL to about 130mg/mL, about 60mg/mL to about 130mg/mL, about 65mg/mL to about 130mg/mL, about 70mg/mL to about 130mg/mL, about 75mg/mL to about 130mg/mL, about 80mg/mL to about 130mg/mL, about 85mg/mL to about 130mg/mL, about 90mg/mL to about 130mg/mL, about 95mg/mL to about 130mg/mL, about 100mg/mL to about 130mg/mL, about 105mg/mL to about 130mg/mL, about 110mg/mL to about 130mg/mL, about 115mg/mL to about 130mg/mL, about 120mg/mL to about 130mg/mL, or about 125mg/mL to about 130 mg/mL. In some embodiments, the composition comprises anti-TL 1A antibodies at a concentration of about 50mg/mL to about 120mg/mL, about 55mg/mL to about 120mg/mL, about 60mg/mL to about 120mg/mL, about 65mg/mL to about 120mg/mL, about 70mg/mL to about 120mg/mL, about 75mg/mL to about 120mg/mL, about 80mg/mL to about 120mg/mL, about 85mg/mL to about 120mg/mL, about 90mg/mL to about 120mg/mL, about 95mg/mL to about 120mg/mL, about 100mg/mL to about 120mg/mL, about 105mg/mL to about 120mg/mL, about 110mg/mL to about 120mg/mL, or about 115mg/mL to about 120 mg/mL. In some embodiments, the composition includes anti-TL 1A antibody at a concentration of about 50mg/mL to about 110mg/mL, about 55mg/mL to about 110mg/mL, about 60mg/mL to about 110mg/mL, about 65mg/mL to about 110mg/mL, about 70mg/mL to about 110mg/mL, about 75mg/mL to about 110mg/mL, about 80mg/mL to about 110mg/mL, about 85mg/mL to about 110mg/mL, about 90mg/mL to about 110mg/mL, about 95mg/mL to about 110mg/mL, about 100mg/mL to about 110mg/mL, or about 105mg/mL to about 110 mg/mL. In some embodiments, the composition includes anti-TL 1A antibody at a concentration of about 50mg/mL to about 100mg/mL, about 55mg/mL to about 100mg/mL, about 60mg/mL to about 100mg/mL, about 65mg/mL to about 100mg/mL, about 70mg/mL to about 100mg/mL, about 75mg/mL to about 100mg/mL, about 80mg/mL to about 100mg/mL, about 85mg/mL to about 100mg/mL, about 90mg/mL to about 100mg/mL, about 95mg/mL to about 100mg/mL, about 100mg/mL to about 100mg/mL, or about 105mg/mL to about 100 mg/mL. In some embodiments, the composition includes an anti-TL 1A antibody at a concentration of about 50mg/mL to about 90mg/mL, about 55mg/mL to about 90mg/mL, about 60mg/mL to about 90mg/mL, about 65mg/mL to about 90mg/mL, about 70mg/mL to about 90mg/mL, about 75mg/mL to about 90mg/mL, about 80mg/mL to about 90mg/mL, or about 85mg/mL to about 90 mg/mL. In some embodiments, the composition includes an anti-TL 1A antibody at a concentration of about 50mg/mL to about 80mg/mL, about 55mg/mL to about 80mg/mL, about 60mg/mL to about 80mg/mL, about 65mg/mL to about 80mg/mL, about 70mg/mL to about 80mg/mL, or about 75mg/mL to about 80mg/mL. In some embodiments, the composition includes an anti-TL 1A antibody at a concentration of about 50mg/mL to about 70mg/mL, about 55mg/mL to about 70mg/mL, about 60mg/mL to about 70mg/mL, or about 65mg/mL to about 70 mg/mL. In some embodiments, the composition includes an anti-TL 1A antibody at a concentration of about 50mg/mL to about 55mg/mL, about 50mg/mL to about 60mg/mL, or about 55mg/mL to about 60 mg/mL. The compositions 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). For example, 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. Additional exemplary viscosities include about 1 to about 2, about 1 to about 3, about 1 to about 4, about 1 to about 5, about 1 to about 6, about 1 to about 7, about 1 to about 8, about 1 to about 9, about 1 to about 10, about 1 to about 11, about 1 to about 12, about 1 to about 13, about 1 to about 14, about 1 to about 15, about 1 to about 16, about 1 to about 17, about 1 to about 18, about 1 to about 19, about 1 to about 20, about 2 to about 5, about 2 to about 6 about 2 to about 7cP, about 2 to about 8cP, about 2 to about 9cP, about 2 to about 10cP, about 2 to about 11cP, about 2 to about 12cP, about 2 to about 13cP, about 2 to about 14cP, about 2 to about 15cP, about 2 to about 16cP, about 2 to about 17cP, about 2 to about 18cP, about 2 to about 19cP, about 2 to about 20cP, about 3 to about 5cP, about 3 to about 6cP, about 3 to about 7cP, about 3 to about 8cP, about 3 to about 9cP, about 3 to about 10cP, about 3 to about 11cP about 3 to about 12cP, about 3 to about 13cP, about 3 to about 14cP, about 3 to about 15cP, about 3 to about 16cP, about 3 to about 17cP, about 3 to about 18cP, about 3 to about 19cP, about 4 to about 20cP, about 4 to about 5cP, about 4 to about 6cP, about 4 to about 7cP, about 4 to about 8cP, about 4 to about 9cP, or about 4 to about 10cP, about 4 to about 11cP, about 4 to about 12cP, about 4 to about 13cP, about 4 to about 14cP, about 4 to about 15cP, about 4 to about 16cP about 4 to about 17cP, about 4 to about 18cP, about 4 to about 19cP, about 4 to about 20cP, about 5 to about 10cP, about 5 to about 11cP, about 5 to about 12cP, about 5 to about 13cP, about 5 to about 14cP, about 5 to about 15cP, about 5 to about 16cP, about 5 to about 17cP, about 5 to about 18cP, about 5 to about 19cP, about 5 to about 20cP, about 6 to about 10cP, about 6 to about 11cP, about 6 to about 12cP, about 6 to about 13cP, about 6 to about 14cP, about 6 to about 15cP, about 6 to about 16, about 6 to about 17, about 6 to about 18, about 6 to about 19, about 6 to about 20, about 7 to about 10, about 7 to about 11, about 7 to about 12, about 7 to about 13, about 7 to about 14, about 7 to about 15, about 7 to about 16, about 7 to about 17, about 7 to about 18, about 7 to about 19, about 7 to about 20, about 8 to about 10, about 8 to about 11, about 8 to about 12, about 8 to about 13, about 8 to about 14, about 8 to about 15, about 8 to about 16, about 8 to about 17, about 8 to about 18, about 8 to about 19, or about 8 to about 20. In some embodiments, centipoise as used herein is millipascal seconds (mpa.s).
In certain embodiments, provided herein are pharmaceutical compositions comprising a therapeutically effective dose of an anti-TL 1A antibody, the total volume of which is less than or equal to about 2.5mL. In some embodiments, the pharmaceutical composition includes a therapeutically effective dose of an anti-TL 1A antibody, the total volume of which is less than or equal to about 2mL. 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 0.8mL. The total volume may be at least about 0.5mL. The total volume may be from about 0.5mL to about 3mL, from about 0.5mL to about 2.9mL, from about 0.5mL to about 2.8mL, from about 0.5mL to about 2.7mL, from about 0.5mL to about 2.6mL, from about 0.5mL to about 2.5mL, from about 0.5mL to about 2.4mL, from about 0.5mL to about 2.3mL, from about 0.5mL to about 2.2mL, from about 0.5mL to about 2.1mL, from about 0.5mL to about 2.0mL, from about 0.5mL to about 1.9mL, from about 0.5mL to about 1.8mL, from about 0.5mL to about 1.7mL, from about 0.5mL to about 1.6mL, from about 0.5mL to about 1.5mL, from about 0.4 mL, from about 0.5mL to about 1.3mL, from about 0.5mL to about 1.2.2 mL, from about 0.5mL to about 1.5mL, from about 0.5mL to about 1.8mL, from about 0.5mL to about 1.5mL, from about 0.5mL about 0.5mL to about 0.9mL, about 0.5mL to about 0.8mL, about 0.6mL to about 3mL, about 0.6mL to about 2.9mL, about 0.6mL to about 2.8mL, about 0.6mL to about 2.7mL, about 0.6mL to about 2.6mL, about 0.6mL to about 2.5mL, about 0.6mL to about 2.4mL, about 0.6mL to about 2.3mL, about 0.6mL to about 2.2mL, about 0.6mL to about 2.1mL, about 0.6mL to about 2.0mL, about 0.6mL to about 1.9mL, about 0.6mL to about 1.8mL, about 0.6mL to about 1.7mL, about 0.6mL to about 1.6mL, about 0.6mL to about 1.5mL, about 0.6mL to about 1.4mL, about 0.6mL to about 1.3mL, about 0.6mL to about 1.6mL, about 1.6mL to about 1.6mL about 0.6mL to about 1.1mL, about 0.6mL to about 1.0mL, about 0.6mL to about 0.9mL, about 0.6mL to about 0.8mL, about 0.7mL to about 3mL, about 0.7mL to about 2.9mL, about 0.7mL to about 2.8mL, about 0.7mL to about 2.7mL, about 0.7mL to about 2.6mL, about 0.7mL to about 2.5mL, about 0.7mL to about 2.4mL, about 0.7mL to about 2.3mL, about 0.7mL to about 2.2mL, about 0.7mL to about 2.1mL, about 0.7mL to about 2.0mL, about 0.7mL to about 1.9mL, about 0.7mL to about 1.8mL, about 0.7mL to about 1.7mL, about 0.7mL to about 1.6mL, about 0.7mL to about 1.7mL, about 1.5mL, about 0.7mL to about 1.4mL about 0.7 to about 1.3mL, about 0.7 to about 1.2mL, about 0.7 to about 1.1mL, about 0.7 to about 1.0mL, about 0.7 to about 0.9mL, about 0.7 to about 0.8mL, about 3 to about 10mL, about 3 to about 9.5mL, about 3 to about 9.0mL, about 3 to about 8.5mL, about 3 to about 8.0mL, about 3 to about 7.5mL, about 3 to about 7.0mL, about 3 to about 6.5mL, about 3 to about 6mL, about 3 to about 5.5mL, about 3 to about 5.0mL, about 3 to about 4.5mL, about 3 to about 4mL, about 3 to about 3.5mL, about 3.5 to about 10mL, about 3.5 to about 9.5mL, about 3.5 to about 9.0mL, about 3.5 to about 8.5mL, about 3.5 to about 8.0mL, about 3.5 to about 7.5mL, about 3.5 to about 7.0mL, about 3.5 to about 6.5mL, about 3.5 to about 6.0mL, about 3.5 to about 5.5mL, about 3.5 to about 5.0mL, about 3.5 to about 4.5mL, about 3.5 to about 4mL, about 4.0 to about 10mL, about 4.0 to about 9.5mL, about 4.0 to about 9.0mL, about 4.0 to about 8.5mL, about 4.0 to about 8.0mL, about 4.0 to about 7.5mL, about 4.0 to about 6.5mL, about 4.0 to about 6.0mL, about 4.0 to about 4.5mL, about 4.0 to about 10mL, about 4.0 to about 4.0mL, about 4.0 to about 4.5mL, about 4.0 to about 5mL, about 4.0 to about 5mL about 4.0 to about 4.5mL, about 4.5 to about 10mL, about 4.5 to about 9.5mL, about 4.5 to about 9.0mL, about 4.5 to about 8.5mL, about 4.5 to about 8.0mL, about 4.5 to about 7.5mL, about 4.5 to about 7.0mL, about 4.5 to about 6.5mL, about 4.5 to about 5.5mL, about 4.5 to about 5.0mL, about 5 to about 10mL, about 5 to about 9.5mL, about 5 to about 9.0mL, about 5 to about 8.5mL, about 5 to about 8.0mL, about 5 to about 7.5mL, about 5 to about 7.0mL, about 5 to about 6.5mL, about 5 to about 5.5mL, about 5 to about 5.0mL, about 5 to about 5.5mL, about 5 about 5.5 to about 10mL, about 5.5 to about 9.5mL, about 5.5 to about 9.0mL, about 5.5 to about 8.5mL, about 5.5 to about 7.0mL, about 5.5 to about 7.5mL, about 5.5 to about 7.0mL, about 5.5 to about 6.5mL, about 6.0 to about 10mL, about 6.0 to about 9.5mL, about 6.0 to about 9.0mL, about 6.0 to about 8.5mL, about 6.0 to about 8.0mL, about 6.0 to about 7.5mL, about 6.0 to about 7.0mL, about 6.0 to about 6.5 to about 10mL, about 6.5 to about 9.5mL, about 6.5 to about 9.0, about 6.0 to about 9.0mL, about 6.0 to about 8.5mL, about 6.0 to about 8.0mL about 6.5mL to about 8.0mL, about 6.5mL to about 7.5mL, about 6.5mL to about 7.0mL, about 7.0mL to about 10mL, about 7.0mL to about 9.5mL, about 7.0mL to about 9.0mL, about 7.0mL to about 8.5mL, about 7.0mL to about 8.0mL, about 7.0mL to about 7.5mL, about 7.5mL to about 10mL, about 7.5mL to about 9.5mL, about 7.5mL to about 9.0mL, about 7.5mL to about 8.5mL, about 7.5mL to about 8.0mL, about 8.0mL to about 10mL, about 8.0mL to about 9.5mL, about 8.0mL to about 9.0mL, about 8.0mL to about 8.5mL, about 8.5mL to about 10mL, about 8.5mL to about 9.5mL, about 7.5mL, about 7.0mL to about 9.0mL, about 7.0mL to about 8.0mL, about 7.0mL, about 8.0mL to about 8.5mL, about 8.0mL to about 9.5mL, about 9mL to about 10mL, about 9mL to about 9.5mL, or about 9.5mL to about 10mL. The composition may have a viscosity of less than or about 10 centipoise (cP). For example, 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. Additional example viscosities include about 1cP to about 2cP, about 1cP to about 3cP, about 1cP to about 4cP, about 1cP to about 5cP, about 1cP to about 6cP, about 1cP to about 7cP, about 1cP to about 8cP, about 1cP to about 9cP, about 1cP to about 10cP, about 2cP to about 5cP, about 2cP to about 6cP, about 2cP to about 7cP, about 2cP to about 8cP, about 2cP to about 9cP, about 2cP to about 10cP, about 3cP to about 5cP, about 3cP to about 6cP, about 3cP to about 7cP, about 3cP to about 8cP, about 3cP to about 10cP, about 4cP to about 5cP, about 4cP to about 6cP, about 4cP to about 7cP, about 4cP to about 8cP, about 4cP to about 9cP, or about 4 to about 10cP. In some embodiments, the therapeutically effective dose is at least about 150mg of the anti-TL 1A antibody. In some cases, the therapeutically effective dose is about or at least about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000mg of anti-TL 1A. In some cases, the therapeutically effective dose is about 150mg to about 2000mg, about 150mg to about 1750mg, about 150mg to about 1500mg, about 150mg to about 1250mg, about 150mg to about 1000mg, about 150mg to about 750mg, about 150mg to about 500mg, about 150mg to about 450mg, about 150mg to about 400mg, about 150mg to about 350mg, about 150mg to about 300mg, about 150mg to about 250mg, or about 150mg to about 200mg of anti-TL 1A. In some embodiments of the present invention, in some embodiments, the pharmaceutical composition comprises about 50mg/mL to about 250mg/mL, about 55mg/mL to about 250mg/mL, about 60mg/mL to about 250mg/mL, about 65mg/mL to about 250mg/mL, about 70mg/mL to about 250mg/mL, about 75mg/mL to about 250mg/mL, about 80mg/mL to about 250mg/mL, about 85mg/mL to about 250mg/mL, about 90mg/mL to about 250mg/mL, about 95mg/mL to about 250mg/mL, about 100mg/mL to about 250mg/mL, about 105mg/mL to about 250mg/mL, about 110mg/mL to about 250mg/mL, about 115mg/mL to about 250mg/mL, about 120mg/mL to about 250mg/mL, about 125mg/mL to about 250mg/mL, about 130mg/mL, about 135mg/mL about 140mg/mL to about 250mg/mL, about 145mg/mL to about 250mg/mL, about 150mg/mL to about 250mg/mL, about 155mg/mL to about 250mg/mL, about 160mg/mL to about 250mg/mL, about 165mg/mL to about 250mg/mL, about 170mg/mL to about 250mg/mL, about 175mg/mL to about 250mg/mL, about 180mg/mL to about 250mg/mL, about 185mg/mL to about 250mg/mL, about 190mg/mL to about 250mg/mL, about 195mg/mL to about 250mg/mL, about 200mg/mL to about 250mg/mL, about 205mg/mL to about 250mg/mL, about 210mg/mL to about 250mg/mL, about 215mg/mL to about 250mg/mL, about 220mg/mL to about 250mg/mL, about 225mg/mL to about 250mg/mL, about 230mg/mL to about 250mg/mL, about 235mg/mL to about 250mg/mL, about 240mg/mL to about 250mg/mL, about 245mg/mL to about 250mg/mL, about 50mg/mL to about 240mg/mL, about 55mg/mL to about 240mg/mL, about 60mg/mL to about 240mg/mL, about 65mg/mL to about 240mg/mL, about 70mg/mL to about 240mg/mL, about 75mg/mL to about 240mg/mL, about 80mg/mL to about 240mg/mL, about 85mg/mL to about 240mg/mL, about 90mg/mL to about 240mg/mL, about 95mg/mL to about 240mg/mL, about 100mg/mL to about 240mg/mL, about 105mg/mL to about 240mg/mL, about 110mg/mL to about 240mg/mL, about 115mg/mL to about 240mg/mL, about 120mg/mL, about 240mg/mL to about 240mg/mL about 125mg/mL to about 240mg/mL, about 130mg/mL to about 240mg/mL, about 135mg/mL to about 240mg/mL, about 140mg/mL to about 240mg/mL, about 145mg/mL to about 240mg/mL, about 150mg/mL to about 240mg/mL, about 155mg/mL to about 240mg/mL, about 160mg/mL to about 240mg/mL, about 165mg/mL to about 240mg/mL, about 170mg/mL to about 240mg/mL, about 175mg/mL to about 240mg/mL, about 180mg/mL to about 240mg/mL, about 185mg/mL to about 240mg/mL, about 190mg/mL to about 240mg/mL, about 195mg/mL to about 240mg/mL, about 200mg/mL to about 240mg/mL, about 205mg/mL to about 240mg/mL, about 210mg/mL to about 240mg/mL, about 215mg/mL to about 240mg/mL, about 220mg/mL to about 240mg/mL, about 225mg/mL to about 240mg/mL, about 230mg/mL to about 240mg/mL, about 235mg/mL to about 240mg/mL, about 50mg/mL to about 230mg/mL, about 55mg/mL to about 230mg/mL, about 60mg/mL to about 230mg/mL, about 65mg/mL to about 230mg/mL, about 70mg/mL to about 230mg/mL, about 75mg/mL to about 230mg/mL, about 80mg/mL to about 230mg/mL, about 85mg/mL to about 230mg/mL, about 90mg/mL to about 230mg/mL, about 95mg/mL to about 230mg/mL, about 100mg/mL to about 230mg/mL, about 105mg/mL to about 230mg/mL, about 110mg/mL to about 230mg/mL, about 115mg/mL to about 230mg/mL about 120mg/mL to about 230mg/mL, about 125mg/mL to about 230mg/mL, about 130mg/mL to about 230mg/mL, about 135mg/mL to about 230mg/mL, about 140mg/mL to about 230mg/mL, about 145mg/mL to about 230mg/mL, about 150mg/mL to about 230mg/mL, about 155mg/mL to about 230mg/mL, about 160mg/mL to about 230mg/mL, about 165mg/mL to about 230mg/mL, about 170mg/mL to about 230mg/mL, about 175mg/mL to about 230mg/mL, about 180mg/mL to about 230mg/mL, about 185mg/mL to about 230mg/mL, about 190mg/mL to about 230mg/mL, about 195mg/mL to about 230mg/mL, about 200mg/mL to about 230mg/mL, about 205mg/mL to about 230mg/mL, about 210mg/mL to about 230mg/mL, about 215mg/mL to about 230mg/mL, about 220mg/mL to about 230mg/mL, about 225mg/mL to about 230mg/mL, about 50mg/mL to about 220mg/mL, about 55mg/mL to about 220mg/mL, about 60mg/mL to about 220mg/mL, about 65mg/mL to about 220mg/mL, about 70mg/mL to about 220mg/mL, about 75mg/mL to about 220mg/mL, about 80mg/mL to about 220mg/mL, about 85mg/mL to about 220mg/mL, about 90mg/mL to about 220mg/mL, about 95mg/mL to about 220mg/mL, about 100mg/mL to about 220mg/mL, about 105mg/mL to about 220mg/mL, about 110mg/mL to about 220mg/mL, about 115mg/mL to about 220mg/mL, about 120mg/mL about 125mg/mL to about 220mg/mL, about 130mg/mL to about 220mg/mL, about 135mg/mL to about 220mg/mL, about 140mg/mL to about 220mg/mL, about 145mg/mL to about 220mg/mL, about 150mg/mL to about 220mg/mL, about 155mg/mL to about 220mg/mL, about 160mg/mL to about 220mg/mL, about 165mg/mL to about 220mg/mL, about 170mg/mL to about 220mg/mL, about 175mg/mL to about 220mg/mL, about 180mg/mL to about 220mg/mL, about 185mg/mL to about 220mg/mL, about 190mg/mL to about 220mg/mL, about 195mg/mL to about 220mg/mL, about 200mg/mL to about 220mg/mL, about 205mg/mL to about 220mg/mL, about 210mg/mL to about 220mg/mL, about 215mg/mL to about 220mg/mL, about 50mg/mL to about 210mg/mL, about 55mg/mL to about 210mg/mL, about 60mg/mL to about 210mg/mL, about 65mg/mL to about 210mg/mL, about 70mg/mL to about 210mg/mL, about 75mg/mL to about 210mg/mL, about 80mg/mL to about 210mg/mL, about 85mg/mL to about 210mg/mL, about 90mg/mL to about 210mg/mL, about 95mg/mL to about 210mg/mL, about 100mg/mL to about 210mg/mL, about 105mg/mL to about 210mg/mL, about 110mg/mL to about 210mg/mL, about 115mg/mL to about 210mg/mL, about 120mg/mL to about 210mg/mL, about 125mg/mL to about 210mg/mL, about 130mg/mL to about 210mg/mL, about 135mg/mL to about 210mg/mL about 140mg/mL to about 210mg/mL, about 145mg/mL to about 210mg/mL, about 150mg/mL to about 210mg/mL, about 155mg/mL to about 210mg/mL, about 160mg/mL to about 210mg/mL, about 165mg/mL to about 210mg/mL, about 170mg/mL to about 210mg/mL, about 175mg/mL to about 210mg/mL, about 180mg/mL to about 210mg/mL, about 185mg/mL to about 210mg/mL, about 190mg/mL to about 210mg/mL, about 195mg/mL to about 210mg/mL, about 200mg/mL to about 210mg/mL, about 205mg/mL to about 210mg/mL, about 50mg/mL to about 200mg/mL, about 55mg/mL to about 200mg/mL, about 60mg/mL to about 200mg/mL, about 65mg/mL to about 200mg/mL, about 70mg/mL to about 200mg/mL, about 75mg/mL to about 200mg/mL, about 80mg/mL to about 200mg/mL, about 85mg/mL to about 200mg/mL, about 90mg/mL to about 200mg/mL, about 95mg/mL to about 200mg/mL, about 100mg/mL to about 200mg/mL, about 105mg/mL to about 200mg/mL, about 110mg/mL to about 200mg/mL, about 115mg/mL to about 200mg/mL, about 120mg/mL to about 200mg/mL, about 125mg/mL to about 200mg/mL, about 130mg/mL to about 200mg/mL, about 135mg/mL to about 200mg/mL, about 140mg/mL to about 200mg/mL, about 145mg/mL to about 200mg/mL, about 150mg/mL to about 200mg/mL, about 155mg/mL to about 200mg/mL, about 160mg/mL about 165mg/mL to about 200mg/mL, about 170mg/mL to about 200mg/mL, about 175mg/mL to about 200mg/mL, about 180mg/mL to about 200mg/mL, about 185mg/mL to about 200mg/mL, about 190mg/mL to about 200mg/mL, about 195mg/mL to about 200mg/mL, about 50mg/mL to about 190mg/mL, about 55mg/mL to about 190mg/mL, about 60mg/mL to about 190mg/mL, about 65mg/mL to about 190mg/mL, about 70mg/mL to about 190mg/mL, about 75mg/mL to about 190mg/mL, about 80mg/mL to about 190mg/mL, about 85mg/mL to about 190mg/mL, about 90mg/mL to about 190mg/mL, about 95mg/mL to about 190mg/mL, about 100mg/mL to about 190mg/mL, about 105mg/mL to about 190mg/mL, about 110mg/mL to about 190mg/mL, about 115mg/mL to about 190mg/mL, about 120mg/mL to about 190mg/mL, about 125mg/mL to about 190mg/mL, about 130mg/mL to about 190mg/mL, about 135mg/mL to about 190mg/mL, about 140mg/mL to about 190mg/mL, about 145mg/mL to about 190mg/mL, about 150mg/mL to about 190mg/mL, about 155mg/mL to about 190mg/mL, about 160mg/mL to about 190mg/mL, about 165mg/mL to about 190mg/mL, about 170mg/mL to about 190mg/mL, about 175mg/mL to about 190mg/mL, about 180mg/mL to about 190mg/mL, about 185mg/mL, about 50mg/mL to about 180mg/mL, about 55mg/mL to about 180mg/mL about 60mg/mL to about 180mg/mL, about 65mg/mL to about 180mg/mL, about 70mg/mL to about 180mg/mL, about 75mg/mL to about 180mg/mL, about 80mg/mL to about 180mg/mL, about 85mg/mL to about 180mg/mL, about 90mg/mL to about 180mg/mL, about 95mg/mL to about 180mg/mL, about 100mg/mL to about 180mg/mL, about 105mg/mL to about 180mg/mL, about 110mg/mL to about 180mg/mL, about 115mg/mL to about 180mg/mL, about 120mg/mL to about 180mg/mL, about 125mg/mL to about 180mg/mL, about 130mg/mL to about 180mg/mL, about 135mg/mL to about 180mg/mL, about 140mg/mL to about 180mg/mL, about 145mg/mL to about 180mg/mL, about 150mg/mL to about 180mg/mL, about 155mg/mL to about 180mg/mL, about 160mg/mL to about 180mg/mL, about 165mg/mL to about 180mg/mL, about 170mg/mL to about 180mg/mL, about 175mg/mL to about 180mg/mL, about 50mg/mL to about 170mg/mL, about 55mg/mL to about 170mg/mL, about 60mg/mL to about 170mg/mL, about 65mg/mL to about 170mg/mL, about 70mg/mL to about 170mg/mL, about 75mg/mL to about 170mg/mL, about 80mg/mL to about 170mg/mL, about 85mg/mL to about 170mg/mL, about 90mg/mL to about 170mg/mL, about 95mg/mL to about 170mg/mL, about 100mg/mL to about 170mg/mL, about 105mg/mL to about 170mg/mL, about 110mg/mL to about 170mg/mL about 115mg/mL to about 170mg/mL, about 120mg/mL to about 170mg/mL, about 125mg/mL to about 170mg/mL, about 130mg/mL to about 170mg/mL, about 135mg/mL to about 170mg/mL, about 140mg/mL to about 170mg/mL, about 145mg/mL to about 170mg/mL, about 150mg/mL to about 170mg/mL, about 155mg/mL to about 170mg/mL, about 160mg/mL to about 170mg/mL, about 165mg/mL to about 170mg/mL, about 50mg/mL to about 160mg/mL, about 55mg/mL to about 160mg/mL, about 60mg/mL to about 160mg/mL, about 65mg/mL to about 160mg/mL, about 70mg/mL to about 160mg/mL, about 75mg/mL to about 160mg/mL, about 80mg/mL to about 160mg/mL, about 85mg/mL to about 160mg/mL, about 90mg/mL to about 160mg/mL, about 95mg/mL to about 160mg/mL, about 100mg/mL to about 160mg/mL, about 105mg/mL to about 160mg/mL, about 110mg/mL to about 160mg/mL, about 115mg/mL to about 160mg/mL, about 120mg/mL to about 160mg/mL, about 125mg/mL to about 160mg/mL, about 130mg/mL to about 160mg/mL, about 135mg/mL to about 160mg/mL, about 140mg/mL to about 160mg/mL, about 145mg/mL to about 160mg/mL, about 150mg/mL to about 160mg/mL, about 155mg/mL to about 160mg/mL, about 50mg/mL to about 150mg/mL, about 55mg/mL to about 150mg/mL, about 60mg/mL to about 150mg/mL, about 65mg/mL to about 150mg/mL about 70mg/mL to about 150mg/mL, about 75mg/mL to about 150mg/mL, about 80mg/mL to about 150mg/mL, about 85mg/mL to about 150mg/mL, about 90mg/mL to about 150mg/mL, about 95mg/mL to about 150mg/mL, about 100mg/mL to about 150mg/mL, about 105mg/mL to about 150mg/mL, about 110mg/mL to about 150mg/mL, about 115mg/mL to about 150mg/mL, about 120mg/mL to about 150mg/mL, about 125mg/mL to about 150mg/mL, about 130mg/mL to about 150mg/mL, about 135mg/mL to about 150mg/mL, about 140mg/mL, about 145mg/mL to about 150mg/mL, about 50mg/mL to about 140mg/mL, about 55mg/mL to about 140mg/mL, about 60mg/mL to about 140mg/mL, about 65mg/mL to about 140mg/mL, about 70mg/mL to about 140mg/mL, about 75mg/mL to about 140mg/mL, about 80mg/mL to about 140mg/mL, about 85mg/mL to about 140mg/mL, about 90mg/mL to about 140mg/mL, about 95mg/mL to about 140mg/mL, about 100mg/mL to about 140mg/mL, about 105mg/mL to about 140mg/mL, about 110mg/mL to about 140mg/mL, about 115mg/mL to about 140mg/mL, about 120mg/mL to about 140mg/mL, about 125mg/mL to about 140mg/mL, about 130mg/mL, about 135mg/mL to about 140mg/mL, about 50mg/mL to about 130mg/mL, about 55mg/mL to about 130mg/mL, about 60mg/mL to about 130mg/mL about 65mg/mL to about 130mg/mL, about 70mg/mL to about 130mg/mL, about 75mg/mL to about 130mg/mL, about 80mg/mL to about 130mg/mL, about 85mg/mL to about 130mg/mL, about 90mg/mL to about 130mg/mL, about 95mg/mL to about 130mg/mL, about 100mg/mL to about 130mg/mL, about 105mg/mL to about 130mg/mL, about 110mg/mL to about 130mg/mL, about 115mg/mL to about 130mg/mL, about 120mg/mL to about 130mg/mL, or about 125mg/mL to about 130mg/mL, about 50mg/mL to about 120mg/mL, about 55mg/mL to about 120mg/mL, about 60mg/mL to about 120mg/mL, about 65mg/mL to about 120mg/mL, about 70mg/mL to about 120mg/mL, about 75mg/mL to about 120mg/mL, about 80mg/mL to about 120mg/mL, about 85mg/mL to about 120mg/mL, about 90mg/mL to about 120mg/mL, about 95mg/mL to about 120mg/mL, about 100mg/mL to about 120mg/mL, about 105mg/mL to about 120mg/mL, about 110mg/mL to about 120mg/mL, about 115mg/mL to about 120mg/mL, about 50mg/mL to about 110mg/mL, about 55mg/mL to about 110mg/mL, about 60mg/mL to about 110mg/mL, about 65mg/mL to about 110mg/mL, about 70mg/mL to about 110mg/mL, about 75mg/mL to about 110mg/mL, about 80mg/mL to about 110mg/mL, about 85mg/mL to about 110mg/mL, about 90mg/mL to about 110mg/mL, about 95mg/mL to about 110mg/mL about 100mg/mL to about 110mg/mL, about 105mg/mL to about 110mg/mL, about 50mg/mL to about 100mg/mL, about 55mg/mL to about 100mg/mL, about 60mg/mL to about 100mg/mL, about 65mg/mL to about 100mg/mL, about 70mg/mL to about 100mg/mL, about 75mg/mL to about 100mg/mL, about 80mg/mL to about 100mg/mL, about 85mg/mL to about 100mg/mL, about 90mg/mL to about 100mg/mL, about 95mg/mL to about 100mg/mL, about 100mg/mL to about 100mg/mL, about 105mg/mL to about 100mg/mL, about 50mg/mL to about 90mg/mL, about 55mg/mL to about 90mg/mL, about 60mg/mL to about 90mg/mL, about 65mg/mL to about 90mg/mL, about 70mg/mL to about 90mg/mL, about 75mg/mL to about 90mg/mL, about 80mg/mL to about 90mg/mL, about 85mg/mL to about 90mg/mL, about 50mg/mL to about 80mg/mL, about 55mg/mL to about 80mg/mL, about 60mg/mL to about 80mg/mL, about 65mg/mL to about 80mg/mL, about 70mg/mL to about 80mg/mL, about 75mg/mL to about 80mg/mL, about 50mg/mL to about 70mg/mL, about 55mg/mL to about 70mg/mL, about 60mg/mL to about 70mg/mL, about 65mg/mL to about 70mg/mL, about 50mg/mL to about 60mg/mL, about 55mg/mL to about 60mg/mL, or about 50mg/mL to about 55mg/mL of anti-TL 1A. In some embodiments, the concentration of the anti-TL 1A 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 300mg/mL.
In certain embodiments, provided herein are pharmaceutical compositions for subcutaneous administration comprising an anti-TL 1A antibody, wherein at least about 150mg of the anti-TL 1A antibody is present in the composition. For example, from about 150mg to about 2000mg, from about 150mg to about 1750mg, from about 150mg to about 1500mg, from about 150mg to about 1250mg, from about 150mg to about 1000mg, from about 150mg to about 750mg, from about 150 to about 500mg, from about 150 to about 300mg, from about 150 to about 200mg or from 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, 1800, 1900 or 2000mg is present in the composition. In some embodiments, up to about 2000mg, up to about 1750mg, up to about 1500mg, up to about 1250mg, up to about 1000mg, up to about 750mg, up to about 500mg of anti-TL 1A is present in the composition. The total volume of the composition may be less than or equal to about 2mL. The total volume of the composition may be less than or equal to about 2.5mL. 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 0.8mL. The total volume may be at least about 0.5mL. The total volume may be about 0.5 to about 3mL, about 0.5 to about 2.9mL, about 0.5 to about 2.8mL, about 0.5 to about 2.7mL, about 0.5 to about 2.6mL, about 0.5 to about 2.5mL, about 0.5 to about 2.4mL, about 0.5 to about 2.3mL, about 0.5 to about 2.2mL, about 0.5 to about 2.1mL, about 0.5 to about 2.9mL, about 0.5 to about 1.9mL, about 0.5 to about 1.8mL, about 0.5 to about 1.7mL, about 0.5 to about 1.6mL, about 0.5 to about 1.5mL, about 1.3mL, about 0.5 to about 1.2.3 mL, about 0.5 to about 1.5mL, about 1.5 to about 1.1.5 mL, about 1.5 to about 1.3mL, about 0.5 to about 1.1.1 mL, about 0.5 to about 6.1.3 mL, about 0.5 to about 6.1.1 mL, about 0.5 to about 1.5 to about 6.8 mL, about 0.5 to about 1.6.5 mL, about 0.5mL, about 1.5 to about 1.7mL, about 0.5mL, about 1.5 to about 1.8mL, about 1.5mL, about 0.5 to about 1.6.5 mL; about 0.6mL to about 1.0mL, about 0.6mL to about 0.9mL, about 0.6mL to about 0.8mL, about 0.7mL to about 3mL, about 0.7mL to about 2.9mL, about 0.7mL to about 2.8mL, about 0.7mL to about 2.7mL, about 0.7mL to about 2.6mL, about 0.7mL to about 2.5mL, about 0.7mL to about 2.4mL, about 0.7mL to about 2.3mL, about 0.7mL to about 2.2mL, about 0.7mL to about 2.1mL, about 0.7mL to about 2.0mL, about 0.7mL to about 1.9mL, about 0.7mL to about 1.8mL, about 0.7mL to about 1.7mL, about 0.7mL to about 1.6mL, about 0.7mL to about 1.5mL, about 0.7mL to about 1.4mL, about 1.7mL, about 1.3mL to about 1.7mL, about 0.7mL about 0.7 to about 1.2mL, about 0.7 to about 1.1mL, about 0.7 to about 1.0mL, about 0.7 to about 0.9mL, about 0.7 to about 0.8mL, about 3 to about 10mL, about 3 to about 9.5mL, about 3 to about 9.0mL, about 3 to about 8.5mL, about 3 to about 8.0mL, about 3 to about 7.5mL, about 3 to about 7.0mL, about 3 to about 6.5mL, about 3 to about 6mL, about 3 to about 5.5mL, about 3 to about 5.0mL, about 3 to about 4.5mL, about 3 to about 4mL, about 3 to about 3.5mL, about 3.5 to about 10mL, about 3.5 to about 9.5mL, about 3.5 to about 9.0mL, about 3.5mL to about 8.5mL, about 3.5mL to about 8.0mL, about 3.5mL to about 7.5mL, about 3.5mL to about 7.0mL, about 3.5mL to about 6.5mL, about 3.5mL to about 6mL, about 3.5mL to about 5.5mL, about 3.5mL to about 5.0mL, about 3.5mL to about 4.5mL, about 4.0mL to about 10mL, about 4.0mL to about 9.5mL, about 4.0mL to about 9.0mL, about 4.0mL to about 8.5mL, about 4.0mL to about 8.0mL, about 4.0mL to about 7.5mL, about 4.0mL to about 7.0mL, about 4.0mL to about 6mL, about 4.0mL to about 5.5mL, about 4.0mL to about 4.5mL, about 4.0mL to about 4.0mL, about 4.0mL to about 4.5mL, about 4.0mL to about 4.0mL about 4.5 to about 10mL, about 4.5 to about 9.5mL, about 4.5 to about 9.0mL, about 4.5 to about 8.5mL, about 4.5 to about 8.0mL, about 4.5 to about 7.5mL, about 4.5 to about 7.0mL, about 4.5 to about 6.5mL, about 4.5 to about 6mL, about 4.5 to about 5.5mL, about 4.5 to about 5.0mL, about 5 to about 10mL, about 5 to about 9.5mL, about 5 to about 9.0mL, about 5 to about 8.5mL, about 5 to about 8.0mL, about 5 to about 7.5mL, about 5 to about 7.0mL, about 5 to about 6.5mL, about 5 to about 6mL, about 5 to about 5.5mL, about 5 to about 10mL, about 5.5 to about 10mL about 5.5mL to about 9.5mL, about 5.5mL to about 9.0mL, about 5.5mL to about 8.5mL, about 5.5mL to about 8.0mL, about 5.5mL to about 7.5mL, about 5.5mL to about 7.0mL, about 5.5mL to about 6.5mL, about 5.5mL to about 6mL, about 6.0mL to about 10mL, about 6.0mL to about 9.5mL, about 6.0mL to about 9.0mL about 6.0mL to about 8.5mL, about 6.0mL to about 8.0mL, about 6.0mL to about 7.5mL, about 6.0mL to about 7.0mL, about 6.0mL to about 6.5mL, about 6.5mL to about 10mL, about 6.5mL to about 9.5mL, about 6.5mL to about 9.0mL, about 6.5mL to about 8.5mL, about 6.5mL to about 8.0mL about 6.0mL to about 8.5mL, about 6.0mL to about 8.0mL, about 6.0mL to about 7.5mL, about 6.0mL to about 7.0mL, about 6.0mL to about 6.5mL about 6.5mL to about 10mL, about 6.5mL to about 9.5mL, about 6.5mL to about 9.0mL, about 6.5mL to about 8.5mL, about 6.5mL to about 8.0mL, about 9mL to about 9.5mL or about 9.5mL to about 10mL. 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). For example, 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. Additional exemplary viscosities include about 1 to about 2, about 1 to about 3, about 1 to about 4, about 1 to about 5, about 1 to about 6, about 1 to about 7, about 1 to about 8, about 1 to about 9, about 1 to about 10, about 1 to about 11, about 1 to about 12, about 1 to about 13, about 1 to about 14, about 1 to about 15, about 1 to about 16, about 1 to about 17, about 1 to about 18, about 1 to about 19, about 1 to about 20, about 2 to about 5, about 2 to about 6 about 2 to about 7cP, about 2 to about 8cP, about 2 to about 9cP, about 2 to about 10cP, about 2 to about 11cP, about 2 to about 12cP, about 2 to about 13cP, about 2 to about 14cP, about 2 to about 15cP, about 2 to about 16cP, about 2 to about 17cP, about 2 to about 18cP, about 2 to about 19cP, about 2 to about 20cP, about 3 to about 5cP, about 3 to about 6cP, about 3 to about 7cP, about 3 to about 8cP, about 3 to about 9cP, about 3 to about 10cP, about 3 to about 11cP about 3 to about 12cP, about 3 to about 13cP, about 3 to about 14cP, about 3 to about 15cP, about 3 to about 16cP, about 3 to about 17cP, about 3 to about 18cP, about 3 to about 19cP, about 4 to about 20cP, about 4 to about 5cP, about 4 to about 6cP, about 4 to about 7cP, about 4 to about 8cP, about 4 to about 9cP, about 4 to about 10cP, about 4 to about 11cP, about 4 to about 12cP, about 4 to about 13cP, about 4 to about 14cP, about 4 to about 15cP, about 4 to about 16cP about 4 to about 17cP, about 4 to about 18cP, about 4 to about 19cP, about 4 to about 20cP, about 5 to about 10cP, about 5 to about 11cP, about 5 to about 12cP, about 5 to about 13cP, about 5 to about 14cP, about 5 to about 15cP, about 5 to about 16cP, about 5 to about 17cP, about 5 to about 18cP, about 5 to about 19cP, about 5 to about 20cP, about 6 to about 10cP, about 6 to about 11cP, about 6 to about 12cP, about 6 to about 13cP, about 6 to about 14cP, about 6 to about 15cP, about 6 to about 16, about 6 to about 17, about 6 to about 18, about 6 to about 19, about 6 to about 20, about 7 to about 10, about 7 to about 11, about 7 to about 12, about 7 to about 13, about 7 to about 14, about 7 to about 15, about 7 to about 16, about 7 to about 17, about 7 to about 18, about 7 to about 19, about 7 to about 20, about 8 to about 10, about 8 to about 11, about 8 to about 12, about 8 to about 13, about 8 to about 14, about 8 to about 15, about 8 to about 16, about 8 to about 17, about 8 to about 18, about 8 to about 19, or about 8 to about 20. In some embodiments, the concentration of the anti-TL 1A is about or greater than about 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, or 250mg/mL.
In certain embodiments, provided herein are pharmaceutical compositions comprising a therapeutically effective dose of an anti-TL 1A antibody, wherein the pharmaceutical composition has a viscosity of less than about 20cP, 15cP, or 10cP. The composition may have a viscosity of less than or about 20cP. The composition may have a viscosity of less than or about 15 cP. The composition may have a viscosity of less than or about 10cP. For example, 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. Additional exemplary viscosities include about 1 to about 2, about 1 to about 3, about 1 to about 4, about 1 to about 5, about 1 to about 6, about 1 to about 7, about 1 to about 8, about 1 to about 9, about 1 to about 10, about 1 to about 11, about 1 to about 12, about 1 to about 13, about 1 to about 14, about 1 to about 15, about 1 to about 16, about 1 to about 17, about 1 to about 18, about 1 to about 19, about 1 to about 20, about 2 to about 5, about 2 to about 6 about 2 to about 7cP, about 2 to about 8cP, about 2 to about 9cP, about 2 to about 10cP, about 2 to about 11cP, about 2 to about 12cP, about 2 to about 13cP, about 2 to about 14cP, about 2 to about 15cP, about 2 to about 16cP, about 2 to about 17cP, about 2 to about 18cP, about 2 to about 19cP, about 2 to about 20cP, about 3 to about 5cP, about 3 to about 6cP, about 3 to about 7cP, about 3 to about 8cP, about 3 to about 9cP, about 3 to about 10cP, about 3 to about 11cP about 3 to about 12cP, about 3 to about 13cP, about 3 to about 14cP, about 3 to about 15cP, about 3 to about 16cP, about 3 to about 17cP, about 3 to about 18cP, about 3 to about 19cP, about 4 to about 20cP, about 4 to about 5cP, about 4 to about 6cP, about 4 to about 7cP, about 4 to about 8cP, about 4 to about 9cP, about 4 to about 10cP, about 4 to about 11cP, about 4 to about 12cP, about 4 to about 13cP, about 4 to about 14cP, about 4 to about 15cP, about 4 to about 16cP about 4 to about 17cP, about 4 to about 18cP, about 4 to about 19cP, about 4 to about 20cP, about 5 to about 10cP, about 5 to about 11cP, about 5 to about 12cP, about 5 to about 13cP, about 5 to about 14cP, about 5 to about 15cP, about 5 to about 16cP, about 5 to about 17cP, about 5 to about 18cP, about 5 to about 19cP, about 5 to about 20cP, about 6 to about 10cP, about 6 to about 11cP, about 6 to about 12cP, about 6 to about 13cP, about 6 to about 14cP, about 6 to about 15cP, about 6 to about 16, about 6 to about 17, about 6 to about 18, about 6 to about 19, about 6 to about 20, about 7 to about 10, about 7 to about 11, about 7 to about 12, about 7 to about 13, about 7 to about 14, about 7 to about 15, about 7 to about 16, about 7 to about 17, about 7 to about 18, about 7 to about 19, about 7 to about 20, about 8 to about 10, about 8 to about 11, about 8 to about 12, about 8 to about 13, about 8 to about 14, about 8 to about 15, about 8 to about 16, about 8 to about 17, about 8 to about 18, about 8 to about 19, or about 8 to about 20. In some embodiments, the therapeutically effective dose is at least about 150mg of the anti-TL 1A antibody. In some cases, the therapeutically effective dose is about or at least about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000mg of anti-TL 1A. In some cases, the therapeutically effective dose is about 150mg to about 2000mg, about 150mg to about 1750mg, about 150mg to about 1500mg, about 150mg to about 1250mg, about 150mg to about 1000mg, about 150mg to about 750mg, about 150mg to about 500mg, about 150mg to about 450mg, about 150mg to about 400mg, about 150mg to about 350mg, about 150mg to about 300mg, about 150mg to about 250mg, or about 150mg to about 200mg of anti-TL 1A. The total volume of the composition may be less than or equal to about 2mL. The total volume of the composition may be less than or equal to about 2.5mL. 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 0.8mL. The total volume may be at least about 0.5mL. The total volume may be about 0.5 to about 3mL, about 0.5 to about 2.9mL, about 0.5 to about 2.8mL, about 0.5 to about 2.7mL, about 0.5 to about 2.6mL, about 0.5 to about 2.5mL, about 0.5 to about 2.4mL, about 0.5 to about 2.3mL, about 0.5 to about 2.2mL, about 0.5 to about 2.1mL, about 0.5 to about 2.9mL, about 0.5 to about 1.9mL, about 0.5 to about 1.8mL, about 0.5 to about 1.7mL, about 0.5 to about 1.6mL, about 0.5 to about 1.5mL, about 1.4mL, about 0.3 mL, about 0.5 to about 1.2.2 mL, about 1.5 to about 1.2.3 mL, about 1.5 to about 1.5, about 1.5 to about 6.6.6.3.5 to about 6.6.5 to about 2.1mL, about 0.5 to about 6.3 mL, about 0.5 to about 6.6.5 to about 1.6.8 mL, about 0.5 to about 1.5mL, about 0.5 to about 1.7mL, about 1.5 to about 1.6.6 mL, about 0.5 to about 1 mL; about 0.6mL to about 1.1mL, about 0.6mL to about 1.0mL, about 0.6mL to about 0.9mL, about 0.6mL to about 0.8mL, about 0.7mL to about 3mL, about 0.7mL to about 2.9mL, about 0.7mL to about 2.8mL, about 0.7mL to about 2.7mL, about 0.7mL to about 2.6mL, about 0.7mL to about 2.5mL, about 0.7mL to about 2.4mL, about 0.7mL to about 2.3mL, about 0.7mL to about 2.2mL, about 0.7mL to about 2.1mL, about 0.7mL to about 2.0mL, about 0.7mL to about 1.9mL, about 0.7mL to about 1.8mL, about 0.7mL to about 1.7mL, about 0.7mL to about 1.6mL, about 0.7mL to about 1.7mL, about 1.5mL, about 0.7mL to about 1.4mL about 0.7 to about 1.3mL, about 0.7 to about 1.2mL, about 0.7 to about 1.1mL, about 0.7 to about 1.0mL, about 0.7 to about 0.9mL, about 0.7 to about 0.8mL, about 3 to about 10mL, about 3 to about 9.5mL, about 3 to about 9.0mL, about 3 to about 8.5mL, about 3 to about 8.0mL, about 3 to about 7.5mL, about 3 to about 7.0mL, about 3 to about 6.5mL, about 3 to about 6mL, about 3 to about 5.5mL, about 3 to about 5.0mL, about 3 to about 4.5mL, about 3 to about 4mL, about 3 to about 3.5mL, about 3.5 to about 10mL, about 3.5 to about 9.5mL, about 3.5 to about 9.0mL, about 3.5 to about 8.5mL, about 3.5 to about 8.0mL, about 3.5 to about 7.5mL, about 3.5 to about 7.0mL, about 3.5 to about 6.5mL, about 3.5 to about 6.0mL, about 3.5 to about 5.5mL, about 3.5 to about 5.0mL, about 3.5 to about 4.5mL, about 3.5 to about 4mL, about 4.0 to about 10mL, about 4.0 to about 9.5mL, about 4.0 to about 9.0mL, about 4.0 to about 8.5mL, about 4.0 to about 8.0mL, about 4.0 to about 7.5mL, about 4.0 to about 6.5mL, about 4.0 to about 6.0mL, about 4.0 to about 4.5mL, about 4.0 to about 10mL, about 4.0 to about 4.0mL, about 4.0 to about 4.5mL, about 4.0 to about 5mL, about 4.0 to about 5mL about 4.0 to about 4.5mL, about 4.5 to about 10mL, about 4.5 to about 9.5mL, about 4.5 to about 9.0mL, about 4.5 to about 8.5mL, about 4.5 to about 8.0mL, about 4.5 to about 7.5mL, about 4.5 to about 7.0mL, about 4.5 to about 6.5mL, about 4.5 to about 5.5mL, about 4.5 to about 5.0mL, about 5 to about 10mL, about 5 to about 9.5mL, about 5 to about 9.0mL, about 5 to about 8.5mL, about 5 to about 8.0mL, about 5 to about 7.5mL, about 5 to about 7.0mL, about 5 to about 6.5mL, about 5 to about 5.5mL, about 5 to about 5.0mL, about 5 to about 5.5mL, about 5 about 5.5 to about 10mL, about 5.5 to about 9.5mL, about 5.5 to about 9.0mL, about 5.5 to about 8.5mL, about 5.5 to about 7.0mL, about 5.5 to about 7.5mL, about 5.5 to about 7.0mL, about 5.5 to about 6.5mL, about 6.0 to about 10mL, about 6.0 to about 9.5mL, about 6.0 to about 9.0mL, about 6.0 to about 8.5mL, about 6.0 to about 8.0mL, about 6.0 to about 7.5mL, about 6.0 to about 7.0mL, about 6.0 to about 6.5 to about 10mL, about 6.5 to about 9.5mL, about 6.5 to about 9.0, about 6.0 to about 9.0mL, about 6.0 to about 8.5mL, about 6.0 to about 8.0mL about 6.5mL to about 8.0mL, about 6.5mL to about 7.5mL, about 6.5mL to about 7.0mL, about 7.0mL to about 10mL, about 7.0mL to about 9.5mL, about 7.0mL to about 9.0mL, about 7.0mL to about 8.5mL, about 7.0mL to about 8.0mL, about 7.0mL to about 7.5mL, about 7.5mL to about 10mL, about 7.5mL to about 9.5mL, about 7.5mL to about 9.0mL, about 7.5mL to about 8.5mL, about 7.5mL to about 8.0mL, about 8.0mL to about 10mL, about 8.0mL to about 9.5mL, about 8.0mL to about 9.0mL, about 8.0mL to about 8.5mL, about 8.5mL to about 10mL, about 8.5mL to about 9.5mL, about 7.5mL, about 7.0mL to about 9.0mL, about 7.0mL to about 8.0mL, about 7.0mL, about 8.0mL to about 8.5mL, about 8.0mL to about 9.5mL, about 9mL to about 10mL, about 9mL to about 9.5mL, or about 9.5mL to about 10mL. In some embodiments, the concentration of the anti-TL 1A 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 250mg/mL.
In certain embodiments, provided herein are pharmaceutical compositions comprising a therapeutically effective dose of an anti-TL 1A antibody, the percentage of aggregation of which is less than about 5% of the total anti-TL 1A antibodies in the composition, as measured by size exclusion chromatography. In some embodiments, the percentage of aggregation of the anti-TL 1A antibody 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 volume of the composition as measured by size exclusion chromatography. In some embodiments, the therapeutically effective dose is at least about 150mg of the anti-TL 1A antibody. In some cases, the therapeutically effective dose is about or at least about 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000mg of anti-TL 1A. In some cases, the therapeutically effective dose is about 150mg to about 2000mg, about 150mg to about 1750mg, about 150mg to about 1500mg, about 150mg to about 1250mg, about 150mg to about 1000mg, about 150mg to about 750mg, about 150mg to about 500mg, about 150mg to about 450mg, about 150mg to about 400mg, about 150mg to about 350mg, about 150mg to about 300mg, about 150mg to about 250mg, or about 150mg to about 200mg of anti-TL 1A. The total volume of the composition may be less than or equal to about 2mL. The total volume of the composition may be less than or equal to about 2.5mL. 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 0.8mL. The total volume may be at least about 0.5mL. The total volume may be about 0.5 to about 3mL, about 0.5 to about 2.9mL, about 0.5 to about 2.8mL, about 0.5 to about 2.7mL, about 0.5 to about 2.6mL, about 0.5 to about 2.5mL, about 0.5 to about 2.4mL, about 0.5 to about 2.3mL, about 0.5 to about 2.2mL, about 0.5 to about 2.1mL, about 0.5 to about 2.9mL, about 0.5 to about 1.9mL, about 0.5 to about 1.8mL, about 0.5 to about 1.7mL, about 0.5 to about 1.6mL, about 0.5 to about 1.5mL, about 1.4mL, about 0.3 mL, about 0.5 to about 1.2.2 mL, about 1.5 to about 1.2.3 mL, about 1.5 to about 1.5, about 1.5 to about 6.6.6.3.5 to about 6.6.5 to about 2.1mL, about 0.5 to about 6.3 mL, about 0.5 to about 6.6.5 to about 1.6.8 mL, about 0.5 to about 1.5mL, about 0.5 to about 1.7mL, about 1.5 to about 1.6.6 mL, about 0.5 to about 1 mL; about 0.6mL to about 1.1mL, about 0.6mL to about 1.0mL, about 0.6mL to about 0.9mL, about 0.6mL to about 0.8mL, about 0.7mL to about 3mL, about 0.7mL to about 2.9mL, about 0.7mL to about 2.8mL, about 0.7mL to about 2.7mL, about 0.7mL to about 2.6mL, about 0.7mL to about 2.5mL, about 0.7mL to about 2.4mL, about 0.7mL to about 2.3mL, about 0.7mL to about 2.2mL, about 0.7mL to about 2.1mL, about 0.7mL to about 2.0mL, about 0.7mL to about 1.9mL, about 0.7mL to about 1.8mL, about 0.7mL to about 1.7mL, about 0.7mL to about 1.6mL, about 0.7mL to about 1.7mL, about 1.5mL, about 0.7mL to about 1.4mL about 0.7 to about 1.3mL, about 0.7 to about 1.2mL, about 0.7 to about 1.1mL, about 0.7 to about 1.0mL, about 0.7 to about 0.9mL, about 0.7 to about 0.8mL, about 3 to about 10mL, about 3 to about 9.5mL, about 3 to about 9.0mL, about 3 to about 8.5mL, about 3 to about 8.0mL, about 3 to about 7.5mL, about 3 to about 7.0mL, about 3 to about 6.5mL, about 3 to about 6mL, about 3 to about 5.5mL, about 3 to about 5.0mL, about 3 to about 4.5mL, about 3 to about 4mL, about 3 to about 3.5mL, about 3.5 to about 10mL, about 3.5 to about 9.5mL, about 3.5 to about 9.0mL, about 3.5 to about 8.5mL, about 3.5 to about 8.0mL, about 3.5 to about 7.5mL, about 3.5 to about 7.0mL, about 3.5 to about 6.5mL, about 3.5 to about 6.0mL, about 3.5 to about 5.5mL, about 3.5 to about 5.0mL, about 3.5 to about 4.5mL, about 3.5 to about 4mL, about 4.0 to about 10mL, about 4.0 to about 9.5mL, about 4.0 to about 9.0mL, about 4.0 to about 8.5mL, about 4.0 to about 8.0mL, about 4.0 to about 7.5mL, about 4.0 to about 6.5mL, about 4.0 to about 6.0mL, about 4.0 to about 4.5mL, about 4.0 to about 10mL, about 4.0 to about 4.0mL, about 4.0 to about 4.5mL, about 4.0 to about 5mL, about 4.0 to about 5mL about 4.0 to about 4.5mL, about 4.5 to about 10mL, about 4.5 to about 9.5mL, about 4.5 to about 9.0mL, about 4.5 to about 8.5mL, about 4.5 to about 8.0mL, about 4.5 to about 7.5mL, about 4.5 to about 7.0mL, about 4.5 to about 6.5mL, about 4.5 to about 5.5mL, about 4.5 to about 5.0mL, about 5 to about 10mL, about 5 to about 9.5mL, about 5 to about 9.0mL, about 5 to about 8.5mL, about 5 to about 8.0mL, about 5 to about 7.5mL, about 5 to about 7.0mL, about 5 to about 6.5mL, about 5 to about 5.5mL, about 5 to about 5.0mL, about 5 to about 5.5mL, about 5 about 5.5 to about 10mL, about 5.5 to about 9.5mL, about 5.5 to about 9.0mL, about 5.5 to about 8.5mL, about 5.5 to about 7.0mL, about 5.5 to about 7.5mL, about 5.5 to about 7.0mL, about 5.5 to about 6.5mL, about 6.0 to about 10mL, about 6.0 to about 9.5mL, about 6.0 to about 9.0mL, about 6.0 to about 8.5mL, about 6.0 to about 8.0mL, about 6.0 to about 7.5mL, about 6.0 to about 7.0mL, about 6.0 to about 6.5 to about 10mL, about 6.5 to about 9.5mL, about 6.5 to about 9.0, about 6.0 to about 9.0mL, about 6.0 to about 8.5mL, about 6.0 to about 8.0mL about 6.5mL to about 8.0mL, about 6.5mL to about 7.5mL, about 6.5mL to about 7.0mL, about 7.0mL to about 10mL, about 7.0mL to about 9.5mL, about 7.0mL to about 9.0mL, about 7.0mL to about 8.5mL, about 7.0mL to about 8.0mL, about 7.0mL to about 7.5mL, about 7.5mL to about 10mL, about 7.5mL to about 9.5mL, about 7.5mL to about 9.0mL, about 7.5mL to about 8.5mL, about 7.5mL to about 8.0mL, about 8.0mL to about 10mL, about 8.0mL to about 9.5mL, about 8.0mL to about 9.0mL, about 8.0mL to about 8.5mL, about 8.5mL to about 10mL, about 8.5mL to about 9.5mL, about 7.5mL, about 7.0mL to about 9.0mL, about 7.0mL to about 8.0mL, about 7.0mL, about 8.0mL to about 8.5mL, about 8.0mL to about 9.5mL, about 9mL to about 10mL, about 9mL to about 9.5mL, or about 9.5mL to about 10mL. In some embodiments, the concentration of the anti-TL 1A 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 250mg/mL.
In certain embodiments, the pharmaceutical composition has a volume suitable for injection, such as by subcutaneous administration. In some embodiments, the total volume of the composition may be less than or equal to about 2.5mL. In some embodiments of the present invention, in some embodiments, the total volume of the composition is less than about 2mL, 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 0.8mL. Antibody therapy suitable for injection and/or administration is important to achieve full therapeutic potential. However, administration is often limited by volume, for example when the therapy is delivered subcutaneously. This in turn demonstrates the importance of developing high concentration antibody formulations greater than (e.g., in some cases) 100 mg/ml. Problems associated with antibody development include high solution viscosity and opalescence, which are often encountered during development of high concentrations (e.g., greater than 100 mg/ml). Both viscosity and opalescence widely affect antibody developability, affecting manufacturability, stability, and delivery. High solution viscosity (e.g., greater than 30 mPa-s) results in limited backpressure for ultrafiltration/diafiltration during operation of the antibody concentration unit. Likewise, viscous antibody solutions, when administered by injection, including by a patient-friendly auto-injector, can also result in forbidden or incompatible injection forces. In fact, the solution viscosity may be a determinant of the maximum antibody dose possible by injection. Solution opalescence in therapeutic antibodies can also be problematic, as opalescence can indicate a tendency for liquid-liquid phase separation, precipitation, or aggregation. Blinding of subcutaneous placebo can create additional difficulties.
The anti-TL 1A antibodies provided herein exhibit 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). Notably, the anti-TL 1A antibodies provided herein are characterized by low viscosity (e.g., less than 20 mPa-s) and low aggregation (e.g., less than 5% of high molecular weight species) at high concentrations (fig. 3A-3C).
For example, in some embodiments, the anti-T1 LA antibody is characterized by a viscosity of less than about 30, 20, 15, or 10mPa-s at a concentration of greater than about 100mg/mL, e.g., about 150mg/mL to about 300mg/mL, about 150mg/mL to about 200mg/mL, about 150mg/mL to about 225mg/mL, or about 150mg/mL to about 250mg/mL. In some cases, the antibody comprises: HCDR1, said HCDR1 comprising SEQ ID NO:1, a step of; HCDR2, said LCDR2 comprising SEQ ID NO:2; HCDR3, said LCDR2 comprising SEQ ID NO:6, preparing a base material; LCDR1, said LCDR1 comprising SEQ ID NO:10; LCDR2, said LCDR2 comprising SEQ ID NO:11, and LCDR3, said LCDR3 comprising SEQ ID NO:12, and/or has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:104, and a light chain variable region comprising SEQ ID NO:201. in some cases, the anti-TL 1A antibody comprises: human IGHV1-46 x 02 framework or modified human IGHV1-46 x 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 together comprise less than 9 amino acid modifications from the human IGHV1-46 x 02 framework and the human IGKV3-20 framework. For example, 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. Additional example viscosities include about 1cP to about 2cP, about 1cP to about 3cP, about 1cP to about 4cP, about 1cP to about 5cP, about 1cP to about 6cP, about 1cP to about 7cP, about 1cP to about 8cP, about 1cP to about 9cP, about 1cP to about 10cP, about 1cP to about 11cP, about 1cP to about 12cP, about about 1 to about 13cP, about 1 to about 14cP, about 1 to about 15cP, about 1 to about 16cP, about 1 to about 17cP, about 1 to about 18cP, about 1 to about 19cP, about 1 to about 20cP, about 2 to about 5cP, about 2 to about 6cP, about 2 to about 7cP, about 2 to about 8cP, about 2 to about 9cP, about 2 to about 10cP, about 2 to about 11cP, about 2 to about 12cP, about 2 to about 13cP, about 2 to about 14cP, about 2 to about 15cP, about 2 to about 16cP, about 2 to about 17cP about 2 to about 18cP, about 2 to about 19cP, about 2 to about 20cP, about 3 to about 5cP, about 3 to about 6cP, about 3 to about 7cP, about 3 to about 8cP, about 3 to about 9cP, about 3 to about 10cP, about 3 to about 11cP, about 3 to about 12cP, about 3 to about 13cP, about 3 to about 14cP, about 3 to about 15cP, about 3 to about 16cP, about 3 to about 17cP, about 3 to about 18cP, about 3 to about 19cP, about 4 to about 5cP, about 4 to about 6cP about 4 to about 7cP, about 4 to about 8cP, about 4 to about 9cP, about 4 to about 10cP, about 4 to about 11cP, about 4 to about 12cP, about 4 to about 13cP, about 4 to about 14cP, about 4 to about 15cP, about 4 to about 16cP, about 4 to about 17cP, about 4 to about 18cP, about 4 to about 19cP, about 4 to about 20cP, about 5 to about 10cP, about 5 to about 11cP, about 5 to about 12cP, about 5 to about 13cP, about 5 to about 14cP, about 5 to about 15cP, about 5 to about 16cP, about 5 to about 17cP, about 5 to about 18cP, about 5 to about 19cP, about 5 to about 20cP, about 6 to about 10cP, about 6 to about 11cP, about 6 to about 12cP, about 6 to about 13cP, about 6 to about 14cP, about 6 to about 15cP, about 6 to about 16cP, about 6 to about 17cP, about 6 to about 18cP, about 6 to about 19cP, about 6 to about 20cP, about 7 to about 10cP, about 7 to about 11cP, about 7 to about 12cP about 7 to about 13, about 7 to about 14, about 7 to about 15, about 7 to about 16, about 7 to about 17, about 7 to about 18, about 7 to about 19, about 7 to about 20, about 8 to about 10, about 8 to about 11, about 8 to about 12, about 8 to about 13, about 8 to about 14, about 8 to about 15, about 8 to about 16, about 8 to about 17, about 8 to about 18, about 8 to about 19, or about 8 to about 20. In some embodiments, the anti-T1 LA antibody is characterized by a viscosity of about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5mPa-s at a concentration of greater than or about 150 mg/mL. In some embodiments, the anti-T1 LA antibody is characterized by a viscosity of about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5mPa-s at a concentration of greater than or about 160 mg/mL. In some embodiments, the anti-T1 LA antibody is characterized by a viscosity of about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5mPa-s at a concentration of greater than or about 170 mg/mL. In some embodiments, the anti-T1 LA antibody is characterized by a viscosity of about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5mPa-s at a concentration of greater than or about 180 mg/mL. In some embodiments, the anti-T1 LA antibody is characterized by a viscosity of about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5mPa-s at a concentration of greater than or about 190 mg/mL. In some embodiments, the anti-T1 LA antibody is characterized by a viscosity of about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5mPa-s at a concentration of greater than or about 200 mg/mL. In some embodiments, the anti-T1 LA antibody is characterized by a viscosity of about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5mPa-s at a concentration of greater than or about 210 mg/mL. In some embodiments, the anti-T1 LA antibody is characterized by a viscosity of about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5mPa-s at a concentration of greater than or about 220 mg/mL. In some embodiments, the anti-T1 LA antibody is characterized by a viscosity of about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5mPa-s at a concentration of greater than or about 230 mg/mL. In some embodiments, the anti-T1 LA antibody is characterized by a viscosity of about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5mPa-s at a concentration of greater than or about 240 mg/mL. In some embodiments, the anti-T1 LA antibody is characterized by a viscosity of about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5mPa-s at a concentration of greater than or about 250mg/mL. In some embodiments, the anti-T1 LA antibody is characterized by a viscosity of about or less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5mPa-s at a concentration of about 150mg/ml to about 250mg/ml. In some embodiments of the present invention, in some embodiments, less than about 20 mPas comprise about 2 to about 20 mPas, about 2 to about 19 mPas, about 2 to about 18 mPas, about 2 to about 17 mPas, about 2 to about 16 mPas, about 2 to about 15 mPas, about 2 to about 14 mPas, about 2 to about 13 mPas, about 2 to about 12 mPas, about 2 to about 11 mPas, about 2 to about 10 mPas, about 2 to about 9 mPas, about 2 to about 8 mPas, about 2 to about 7 mPas, about 2 to about 6 mPas, about 2 to about 5 mPas, about 3 to about 20 mPas, about 3 to about 19 mPas, about 3 to about 18 mPas, about 3 to about 17 mPas, about 3 to about 16 mPas, about 3 to about 15 mPas, about 3 to about 14 mPas, about 3 to about 12 mPas about 3 to about 11mPa-s, about 3 to about 10mPa-s, about 3 to about 9mPa-s, about 3 to about 8mPa-s, about 3 to about 7mPa-s, about 3 to about 6mPa-s, about 3 to about 5mPa-s, about 4 to about 20mPa-s, about 4 to about 19mPa-s, about 4 to about 18mPa-s, about 4 to about 17mPa-s, about 4 to about 16mPa-s, about 4 to about 15mPa-s, about 4 to about 14mPa-s, about 4 to about 13mPa-s, about 4 to about 12mPa-s, about 4 to about 11mPa-s, about 4 to about 10mPa-s, about 4 to about 9mPa-s, about 4 to about 8mPa-s, about 4 to about 7mPa-s, about 4 to about 6mPa-s, about 4 to about 5mPa-s, about 5 to about 20mPa-s, about 19mPa-s, about 5 to about 18 mPas, about 5 to about 17 mPas, about 5 to about 16 mPas, about 5 to about 15 mPas, about 5 to about 14 mPas, about 5 to about 13 mPas, about 5 to about 12 mPas, about 5 to about 11 mPas, about 5 to about 10 mPas, about 5 to about 9 mPas, about 5 to about 8 mPas, about 5 to about 7 mPas, about 5 to about 6 mPas, about 6 to about 20 mPas, about 6 to about 19 mPas, about 6 to about 18 mPas, about 6 to about 17 mPas, about 6 to about 16 mPas, about 6 to about 15 mPas, about 6 to about 14 mPas, about 6 to about 13 mPas, about 6 to about 12 mPas, about 6 to about 11 mPas, about 6 to about 10 mPas, about 6 to about 6 mPas, about 7 mPas or about 7 mPas. In some embodiments, greater than about 100, 125, 150, 160, 170, 180, 190, or 200mg/ml is at most about 250mg/ml.
Additionally, for example, in some embodiments, the anti-TL 1A antibody is characterized by a turbidity of less than 12 specific turbidity units (NTU) when at a concentration of greater than about 100mg/mL, e.g., about 150mg/mL to about 300mg/mL, about 150mg/mL to about 200mg/mL, about 150mg/mL to about 225mg/mL, or about 150mg/mL to about 250 mg/mL. In some cases, the antibody comprises: HCDR1, said HCDR1 comprising SEQ ID NO:1, a step of; HCDR2, said LCDR2 comprising SEQ ID NO:2; HCDR3, said LCDR2 comprising SEQ ID NO:6, preparing a base material; LCDR1, said LCDR1 comprising SEQ ID NO:10; LCDR2, said LCDR2 comprising SEQ ID NO:11, and LCDR3, said LCDR3 comprising SEQ ID NO:12, and/or has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:104, and a light chain variable region comprising SEQ ID NO:201. in some cases, the anti-TL 1A antibody comprises: human IGHV1-46 x 02 framework or modified human IGHV1-46 x 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 together comprise less than 9 amino acid modifications from the human IGHV1-46 x 02 framework and the human IGKV3-20 framework. In some embodiments, the anti-TL 1A antibody is characterized by a turbidity of less than 12 specific turbidity units (NTU) when at a concentration of greater than at least about 150 mg/mL. In some embodiments, the anti-TL 1A antibody is characterized by a turbidity of less than 12 specific turbidity units (NTU) when at a concentration of greater than at least about 160 mg/mL. In some embodiments, the anti-TL 1A antibody is characterized by a turbidity of less than 12 specific turbidity units (NTU) when at a concentration of greater than at least about 170 mg/mL. In some embodiments, the anti-TL 1A antibody is characterized by a turbidity of less than 12 specific turbidity units (NTU) when at a concentration of greater than at least about 180 mg/mL. In some embodiments, the anti-TL 1A antibody is characterized by a turbidity of less than 12 specific turbidity units (NTU) when at a concentration of greater than at least about 190 mg/mL. In some embodiments, the anti-TL 1A antibody is characterized by a turbidity of less than 12 specific turbidity units (NTU) when at a concentration of about 150mg/mL to about 250 mg/mL. Less than 12 NTUs may comprise about 1, 2, 3, 4, or 5 NTUs to about 12 NTUs.
Additionally, the anti-TL 1A antibodies described herein also exhibit advantageous aggregation properties. In some embodiments, the anti-TL 1A antibody composition is characterized in that when the antibody is present in the composition at a concentration of greater than about 100mg/mL, e.g., from about 150mg/mL to about 300mg/mL, from about 150mg/mL to about 200mg/mL, from about 150mg/mL to about 225mg/mL, or from about 150mg/mL to about 250mg/mL, the percentage of high molecular weight species (e.g., species having a molecular weight greater than the molecular weight of the monomer) is less than 10% of the composition. In some cases, the antibody comprises: HCDR1, said HCDR1 comprising SEQ ID NO:1, a step of; HCDR2, said LCDR2 comprising SEQ ID NO:2; HCDR3, said LCDR2 comprising SEQ ID NO:6, preparing a base material; LCDR1, said LCDR1 comprising SEQ ID NO:10; LCDR2, said LCDR2 comprising SEQ ID NO:11, and LCDR3, said LCDR3 comprising SEQ ID NO:12, and/or has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:104, and a light chain variable region comprising SEQ ID NO:201. in some cases, the anti-TL 1A antibody comprises: human IGHV1-46 x 02 framework or modified human IGHV1-46 x 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 together comprise less than 9 amino acid modifications from the human IGHV1-46 x 02 framework and the human IGKV3-20 framework. In some embodiments, the anti-TL 1A antibody composition is characterized by a high molecular weight species percentage of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% when at a concentration of greater than at least about 150 mg/mL. In some embodiments, the anti-TL 1A antibody composition is characterized by a high molecular weight species percentage of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% when at a concentration of greater than at least about 160 mg/mL. In some embodiments, the anti-TL 1A antibody composition is characterized by a high molecular weight species percentage of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration of greater than at least about 170 mg/mL. In some embodiments, the anti-TL 1A antibody composition is characterized by a high molecular weight species percentage of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% when at a concentration of greater than at least about 180 mg/mL. In some embodiments, the anti-TL 1A antibody composition is characterized by a high molecular weight species percentage of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% when at a concentration of greater than at least about 190 mg/mL. In some embodiments, the anti-TL 1A antibody composition is characterized by a high molecular weight species percentage of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration of greater than at least about 200 mg/mL. In some embodiments, the anti-TL 1A antibody composition is characterized by a high molecular weight species percentage of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration of greater than at least about 210 mg/mL. In some embodiments, the anti-TL 1A antibody composition is characterized by a high molecular weight species percentage of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% when at a concentration of greater than at least about 220 mg/mL. In some embodiments, the anti-TL 1A antibody composition is characterized by a high molecular weight species percentage of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration of greater than at least about 230 mg/mL. In some embodiments, the anti-TL 1A antibody composition is characterized by a high molecular weight species percentage of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% when at a concentration of greater than at least about 240 mg/mL. In some embodiments, the anti-TL 1A antibody composition is characterized by a high molecular weight species percentage of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% when at a concentration of greater than at least about 250 mg/mL. In some embodiments, the anti-TL 1A antibody composition is characterized by a high molecular weight species percentage of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% when at a concentration of about 150mg/mL to about 250 mg/mL.
In some embodiments, a pharmaceutical composition is provided that includes from about 150mg to about 225mg of anti-TL 1A in a total volume of less than or equal to about 1 mL. The composition may be formulated for subcutaneous administration. In some cases, the composition includes 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 2000mg of anti-TL 1A. If less than 300mg of anti-TL 1A is present, the total volume may be less than about 1.0, 0.9 or 0.8mL. If less than 300mg of anti-TL 1A is present, the total volume may be at least about 0.5mL. The total volume may be about 0.5 to about 3mL, about 0.5 to about 2.9mL, about 0.5 to about 2.8mL, about 0.5 to about 2.7mL, about 0.5 to about 2.6mL, about 0.5 to about 2.5mL, about 0.5 to about 2.4mL, about 0.5 to about 3mL, about 0.5 to about 2.2mL, about 0.5 to about 2.1mL, about 0.5 to about 2mL, about 0.5 to about 1.9mL, about 0.5 to about 1.8mL, about 0.5 to about 1.7mL, about 0.5 to about 1.0mL, about 0.5 to about 0.5mL, about 0.8mL, about 0.6 to about 3mL, about 0.6 to about 2.9mL, about 0.9 to about 2.2.2.2.2.1 mL, about 0.5 to about 6.1.1 mL, about 1.1.1.1, about 0.5 to about 1.7mL, about 1.6mL, about 0.3 to about 1.6.3 mL, about 1.1.6 mL, about 0.5 to about 1.7mL, about 1.6mL, about 1.1.5 to about 1.6mL, about 0.5 to about 1.7mL, about 0.5 to about 1.6mL, about 0.5 to about 0.5 mL; about 0.7mL to about 2.9mL, about 0.7mL to about 2.8mL, about 0.7mL to about 2.7mL, about 0.7mL to about 2.6mL, about 0.7mL to about 2.5mL, about 0.7mL to about 2.4mL, about 0.7mL to about 2.3mL, about 0.7mL to about 2.2mL, about 0.7mL to about 2.1mL, about 0.7mL to about 2.0mL, about 0.7mL to about 1.9mL, about 0.7mL to about 1.8mL, about 0.7mL to about 1.7mL, about 0.7mL to about 1.6mL, about 0.7mL to about 1.5mL, about 0.7mL to about 1.4mL, about 0.7mL to about 1.3mL, about 0.7mL to about 1.2mL, about 0.7mL to about 1.1.7 mL, about 0.7mL to about 1.7mL, about 0.7mL to about 1.9mL, about 0.7mL to about 1.7mL about 0.7mL to about 0.8mL, about 3mL to about 10mL, about 3mL to about 9.5mL, about 3mL to about 9.0mL, about 3mL to about 8.5mL, about 3mL to about 8.0mL, about 3mL to about 7.5mL, about 3mL to about 7.0mL, about 3mL to about 6.5mL, about 3mL to about 6mL, about 3mL to about 5.5mL, about 3mL to about 5.0mL, about 3mL to about 4.5mL, about 3mL to about 4mL, about 3mL to about 3.5mL, about 3.5mL to about 10mL, about 3.5mL to about 9.5mL, about 3.5mL to about 9.0mL, about 3.5mL to about 8.5mL, about 3.5mL to about 8.0mL, about 3.5mL to about 7.5mL, about 3.5mL to about 7.0mL, about 3.5 to about 6.5mL, about 3.5 to about 6mL, about 3.5 to about 5.5mL, about 3.5 to about 5.0mL, about 3.5 to about 4.5mL, about 3.5 to about 4mL, about 4.0 to about 10mL, about 4.0 to about 9.5mL, about 4.0 to about 9.0mL, about 4.0 to about 8.5mL, about 4.0 to about 8.0mL, about 4.0 to about 7.5mL, about 4.0 to about 7.0mL, about 4.0 to about 6.5mL, about 4.0 to about 6mL, about 4.0 to about 5.5mL, about 4.0 to about 5.0mL, about 4.0 to about 4.5 to about 10mL, about 4.5 to about 9.5mL, about 4.0 to about 9.0mL about 4.5 to about 8.5mL, about 4.5 to about 8.0mL, about 4.5 to about 7.5mL, about 4.5 to about 7.0mL, about 4.5 to about 6.5mL, about 4.5 to about 6mL, about 4.5 to about 5.5mL, about 4.5 to about 5.0mL, about 5 to about 10mL, about 5 to about 9.5mL, about 5 to about 9.0mL, about 5 to about 8.5mL, about 5 to about 8.0mL, about 5 to about 7.5mL, about 5 to about 7.0mL, about 5 to about 6.5mL, about 5 to about 6mL, about 5 to about 5.5mL, about 5.5 to about 10mL, about 5.5 to about 9.5mL, about 5.5 to about 9.0mL about 5.5mL to about 8.5mL, about 5.5mL to about 8.0mL, about 5.5mL to about 7.5mL, about 5.5mL to about 7.0mL, about 5.5mL to about 6.5mL, about 5.5mL to about 6mL, about 6.0mL to about 10mL, about 6.0mL to about 9.5mL, about 6.0mL to about 9.0mL, about 6.0mL to about 8.5mL, about 6.0mL to about 8.0mL, about 6.0mL to about 7.5mL, about 6.0mL to about 7.0mL, about 6.0mL to about 6.5mL, about 6.5mL to about 10mL, about 6.5mL to about 9.5mL, about 6.5mL to about 9.0mL, about 6.5mL to about 8.5mL, about 8.0mL, about 6.5mL to about 7.5mL, about 7.5mL to about 7.0mL, about 6.0mL about 7.0mL to about 10mL, about 7.0mL to about 9.5mL, about 7.0mL to about 9.0mL, about 7.0mL to about 8.5mL, about 7.0mL to about 8.0mL, about 7.0mL to about 7.5mL, about 7.5mL to about 10mL, about 7.5mL to about 9.5mL, about 7.5mL to about 9.0mL, about 7.5mL to about 8.5mL, about 7.5mL to about 8.0mL, about 8.0mL to about 10mL, about 8.0mL to about 9.5mL, about 8.0mL to about 9.0mL, about 8.5mL to about 10mL, about 8.5mL to about 9.5mL, about 9mL to about 10mL, about 9mL to about 9.5mL, or about 9.5mL to about 10mL. In some embodiments, the concentration of the anti-TL 1A 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 250mg/mL.
In some embodiments, a pharmaceutical composition is provided that includes from about 400mg to about 1000mg or from about 400mg to about 2000mg of anti-TL 1A 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 to about 100 to about 300 or about 250mL of a pharmaceutically acceptable solution (e.g., physiological saline) for intravenous administration. The total volume may be at least about 1mL, at least about 2mL, at least about 2.5mL, at least about 3mL, at least about 4mL, or at least about 5mL; and less than or equal to about 15mL, 14mL, 13mL, 11mL, or 10mL. For example, the number of the cells to be processed, the volume may be from about 1mL to about 15mL, from about 1mL to about 14mL, from about 1mL to about 13mL, from about 1mL to about 12mL, from about 1mL to about 11mL, from about 1mL to about 10mL, from about 1mL to about 9mL, from about 1mL to about 8mL, from about 1mL to about 7mL, from about 1mL to about 6mL, from about 1mL to about 5mL, from about 1mL to about 4mL, from about 1mL to about 3mL, from about 1mL to about 2mL, from about 2mL to about 15mL, from about 2mL to about 14mL, from about 2mL to about 13mL, from about 2mL to about 12mL, from about 2mL to about 11mL, from about 2mL to about 10mL, from about 2mL to about 9mL, from about 2mL to about 8mL, from about 2mL to about 7mL, from about 2mL to about 6mL, from about 2mL to about 5mL, from about 2mL to about 4mL, from about 2mL to about 3mL, from about 15mL, from about 14mL to about 13mL, from about 3mL, from about 13mL about 3mL to about 12mL, about 3mL to about 11mL, about 3mL to about 10mL, about 3mL to about 9mL, about 3mL to about 8mL, about 3mL to about 7mL, about 3mL to about 6mL, about 3mL to about 5mL, about 3mL to about 4mL, about 4mL to about 15mL, about 4mL to about 14mL, about 4mL to about 13mL, about 4mL to about 12mL, about 4mL to about 11mL, about 4mL to about 10mL, about 4mL to about 9mL, about 4mL to about 8mL, about 4mL to about 7mL, about 4mL to about 6mL, about 4mL to about 5mL, about 5mL to about 15mL, about 5mL to about 14mL, about 5mL to about 13mL, about 5mL to about 12mL, about 5mL to about 11mL, about 5mL to about 10mL, about 5mL to about 9mL, about 5mL to about 8mL, about 5mL to about 7mL, or about 5 to about 6mL.
Non-limiting exemplary excipients
In certain embodiments, the pharmaceutical composition comprising an anti-TL 1A antibody comprises a surfactant. The surfactant comprises nonionic surfactants, ionic surfactants, and amphoteric surfactants, and combinations thereof. In some embodiments, the surfactant comprises a nonionic surfactant. Non-limiting examples of nonionic surfactants include polysorbates, polyglycerol alkyl ethers, glucosyldialkyl ethers, crown ethers, ester-linked surfactants, polyoxyethylene alkyl ethers, poloxamer (poloxamer) 18, brij (Brij), span (Spans) (sorbitol esters), tricot (Triton) X-100 (polyethylene glycol p- (1, 3-tetramethylbutyl) -phenyl ether), polyoxyethylene (35) dodecyl ethers, polyethylene glycol cetyl ethers, polyoxyethylene (20) oleyl ethers, polyoxyethylene (9) lauryl alcohol, polyethoxylated (35) castor oil, octylphenoxy poly (ethyleneoxy) ethanol, poly (oxyethylene-peroxypropylene) block copolymers, polydimethylsiloxane methyl ethoxy esters, p-isononylphenoxy-poly (glycidol), 2,4,7, 9-tetramethyl-5-decen-4, 7-diol ethoxy esters, polyethylene glycol-tripropolyethylene glycol and nonylphenol ethoxy esters, and combinations thereof. In some embodiments, the surfactant comprises an ionic surfactant. The ionic surfactants include anionic and cationic surfactants. Non-limiting examples of anionic surfactants include alkyl sulfates, alkyl ether sulfates, docusates, sulfonate fluorosurfactants, alkyl benzene sulfonates, alkyl aryl ether phosphates, alkyl carboxylic esters, and sodium dioctyl-sulfosuccinate, and combinations thereof. Non-limiting examples of cationic surfactants include cetyltrimethylammonium bromide (CTAB), cetyltrimethylammonium chloride (CTAC), cetylpyridinium chloride (CPC), polyethoxylated esterified tallow amine (poe a), benzalkonium chloride (BAC), phenethylammonium chloride (BZT), 5-bromo-5-nitro-1, 3-dioxane, dimethyl octacosanol chloride, and dimethyl dioctadecyl ammonium bromide (DODAB), and combinations thereof. In some embodiments, the surfactant comprises an amphoteric surfactant. Exemplary amphoteric surfactants include ethylenediamine tetra (ethoxy ester-block-propoxy ester) furan.
In an exemplary embodiment, the surfactant comprises a polysorbate. Polysorbates include, but are not limited to, polysorbate-20, polysorbate-60, and polysorbate-80, and combinations thereof. The polysorbate may be polysorbate-20.
In some embodiments of the compositions provided herein, the composition comprises a surfactant, wherein the surfactant comprises or consists of polysorbate-20. In some embodiments of the compositions provided herein, the surfactant comprises or consists of polysorbate-20.
In some embodiments, the surfactant is present in the composition at a concentration of about 0.001-0.1% v/v of the composition. For example, 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. In example embodiments, 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. As further examples, 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. For example, some embodiments of the composition include about 0.01% -0.02%, or about 0.01% or about 0.02% polysorbate. In one embodiment of the compositions provided herein, 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. In one embodiment of the compositions provided herein, the compositions comprise polysorbate-20 at a concentration of about 0.02% v/v of the composition. In one embodiment of the compositions 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. In one embodiment of the compositions provided herein, the compositions comprise polysorbate-60 at a concentration of about 0.02% v/v of the composition. In one embodiment of the compositions provided herein, the composition comprises polysorbate-80 at a concentration of about 0.01% to about 0.05% or about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about 0.014%, about 0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, about 0.02%, about 0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.025%, about 0.026%, about 0.027%, about 0.028%, about 0.029% or about 0.03% v/v of the composition. In one embodiment of the compositions provided herein, the compositions comprise polysorbate-80 at a concentration of about 0.02% v/v of the composition.
In certain embodiments, the pharmaceutical composition comprising an anti-TL 1A antibody comprises a stabilizer. The stabilizers include sugars, polyols, amino acids, polymers, and cyclodextrins (e.g., HP-b-CD), and combinations thereof. In some embodiments, the stabilizing agent comprises a sugar. Non-limiting examples of sugars include sucrose, glucose, trehalose, maltose and lactose, and combinations thereof. In some embodiments, the stabilizer comprises a polyol. Non-limiting examples of polyols include mannitol, sorbitol, raffinose and glycerol, and combinations thereof. In an exemplary embodiment, the stabilizer comprises a sugar, such as sucrose. In some embodiments, the sugar comprises or consists of sucrose. In some embodiments, the stabilizing agent comprises an amino acid. In some embodiments, the amino acid comprises or consists of glycine. In some embodiments, the amino acid comprises or consists of glycine. In some embodiments, the stabilizing agent includes both sugar and amino acids. In some embodiments, the stabilizing agent comprises both sucrose and glycine.
In some embodiments, the stabilizing agent is present in the composition at a concentration of about 50mM to about 300 mM. For example, the number of the cells to be processed, the stabilizing agent may be present in an amount of about 50mM to about 300mM, about 50mM to about 290mM, about 50mM to about 280mM, about 50mM to about 270mM, about 50mM to about 260mM, about 50mM to about 250mM, about 50mM to about 240mM, about 50mM to about 220mM, about 50mM to about 200mM, about 75mM to about 300mM, about 75mM to about 290mM, about 75mM to about 280mM, about 75mM to about 270mM, about 75mM to about 250mM, about 75mM to about 240mM, about 75mM to about 220mM, about 75mM to about 200mM, about 100mM to about 300mM, about 100mM to about 290mM, about 100mM to about 280mM, about 100mM to about 270mM, about 100mM to about 260mM, about 100mM to about 250mM, about 100mM to about 240mM, about 100mM to about 220mM, about 100mM to about 125mM, about 125mM to about 280mM, about 125mM to about 125mM, about 125mM to about 280 mM. The concentration of about 125mM to about 260mM, about 125mM to about 250mM, about 125mM to about 240mM, about 125mM to about 220mM, about 125mM to about 200mM, about 150mM to about 300mM, about 150mM to about 290mM, about 150mM to about 280mM, about 150mM to about 270mM, about 150mM to about 250mM, about 150mM to about 240mM, about 150mM to about 220mM, about 150mM to about 200mM, about 175mM to about 300mM, about 175mM to about 290mM, about 175mM to about 280mM, about 175mM to about 270mM, about 175mM to about 260mM, about 175mM to about 250mM, about 175mM to about 240mM, about 175mM to about 220mM, about 175mM to about 200mM, about 200mM to about 300mM, about 200mM to about 280mM, about 200mM to about 270mM, about 200mM to about 260mM, about 200mM to about 250mM, about 200mM to about 200mM, or about 240mM to about 200 mM. In example embodiments, the stabilizer is present at a concentration of about 150mM to about 270mM or about 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, or 270mM of stabilizer. As further embodiments, the composition comprises about 150mM to about 270mM, 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 270mM sucrose, for example about 220-240mM or about 220, about 230, or about 240mM sucrose. In yet another embodiment, the composition comprises about 50mM to about 150mM or about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150mM glycine, e.g., 75-100mM or about 80, about 85, or about 90mM glycine. In yet another embodiment, the composition comprises about 150mM to about 270mM, or about 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, or 270mM sucrose, and comprises 50mM to about 150mM, or about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150mM glycine.
In certain embodiments, the pharmaceutical composition comprising an anti-TL 1A antibody comprises a salt. Non-limiting examples of salts include sodium chloride, glycine, lysine-hydrochloride, arginine glutamate, potassium chloride, magnesium chloride, and calcium chloride, and combinations thereof. In some embodiments, the salt comprises sodium chloride. In some embodiments, the salt comprises lysine-HCl.
In some embodiments, the salt is present in the composition at a concentration of about 10mM to about 150 mM. For example, the number of the cells to be processed, the salt is present in an amount of about 10mM to about 150mM, about 10mM to about 140mM, about 10mM to about 130mM, about 10mM to about 120mM, about 10mM to about 110mM, about 10mM to about 100mM, about 10mM to about 90mM, about 10mM to about 80mM, about 10mM to about 70mM, about 10mM to about 60mM, about 10mM to about 50mM, about 10mM to about 40mM, about 10mM to about 30mM, about 20mM to about 150mM, about 20mM to about 140mM, about 20mM to about 130mM, about 20mM to about 120mM, about 20mM to about 110mM, about 20mM to about 100mM, about 20mM to about 90mM, about 20mM to about 80mM, about 20mM to about 70mM, about 20mM to about 60mM, about 20mM to about 50mM, about 20mM to about 40mM, about the concentration of about 20mM to about 30mM, about 30mM to about 150mM, about 30mM to about 140mM, about 30mM to about 130mM, about 30mM to about 120mM, about 30mM to about 110mM, about 30mM to about 100mM, about 30mM to about 90mM, about 30mM to about 80mM, about 30mM to about 70mM, about 30mM to about 60mM, about 30mM to about 50mM, about 30mM to about 40mM, about 40mM to about 150mM, about 40mM to about 140mM, about 40mM to about 130mM, about 40mM to about 120mM, about 40mM to about 110mM, about 40mM to about 100mM, about 40mM to about 90mM, about 40mM to about 80mM, about 40mM to about 70mM, about 40mM to about 60mM, or about 40mM to about 50mM is present. In an exemplary embodiment, the salt is present at a concentration of about 25mM to about 130 mM. As a further example, the composition comprises about 40mM to about 130mM NaCl. For example, the composition comprises about 40mM NaCl. In some embodiments, the composition comprises about 10mM, about 15mM, about 20mM, about 25mM, about 30mM, about 35mM, about 40mM, about 45mM, about 50mM, about 55mM, about 60mM, about 65mM, about 70mM, about 75mM, about 80mM, about 85mM, about 90mM, about 95mM, about 100mM, about 105mM, about 110mM, about 115mM, about 120mM, about 125mM, about 130mM, about 135mM, about 140mM, about 145mM, or about 150mM NaCl. As a further example, the composition comprises about 25mM to about 50mM Lys-HCl. For example, the composition comprises about 25mM Lys-HCl.
In certain embodiments, the pharmaceutical composition comprising an anti-TL 1A antibody comprises a buffer. Non-limiting examples of buffers include acetate, phosphate, citrate, glutamate, succinate, gluconate, histidine, glycylglycine, citric acid, tris (hydroxymethyl) aminomethane) and diethanolamine, and combinations thereof. In an example embodiment, the buffer comprises acetate. In some embodiments, the buffer comprises sodium acetate. In some embodiments, the buffer comprises acetic acid. In some embodiments, the buffer comprising acetate comprises acetic acid and sodium acetate. In some embodiments, the buffer comprises potassium acetate. In some embodiments, the buffer comprises aluminum acetate. In some embodiments, the buffer comprises ammonium acetate. In some embodiments, the buffer comprises phosphate. In one embodiment, the buffer comprising phosphate comprises phosphoric acid and sodium phosphate. In some embodiments, the buffer comprises phosphoric acid and potassium phosphate. In some embodiments, the buffer comprises disodium hydrogen phosphate and sodium dihydrogen phosphate. In some embodiments, the buffer comprises phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, and/or sodium phosphate. In some embodiments, the buffer comprises dipotassium hydrogen phosphate and potassium dihydrogen phosphate. In some embodiments, the buffer comprises phosphoric acid, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and/or potassium phosphate. In some embodiments, the buffer is present in the composition at a concentration of about 5mM to about 50 mM. For example, the buffer is present at a concentration of about 5mM to about 50mM, about 5mM to about 40mM, about 5mM to about 30mM, about 5mM to about 20mM, about 5mM to about 10mM, about 10mM to about 50mM, about 10mM to about 40mM, about 10mM to about 30mM, or about 10mM to about 20 mM. As non-limiting examples, the buffer is present at a concentration of about 10mM to about 20mM or about 20 mM. As further exemplary embodiments, the composition comprises about 10mM to about 20mM or about 10mM or about 20mM acetate. In further embodiments, the composition comprises about 10mM to about 20mM or about 10mM or about 20mM phosphate.
In certain embodiments, the pH of the pharmaceutical composition comprising an anti-TL 1A antibody is 4.0 to 8.0. For example, 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. In some embodiments, 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. In example embodiments, 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, about 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, about 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, about 4.8 to about 5.5, about 4.8 to about 5.3, about 4.8 to about 5.2, about 4.8 to about 5.1, about 4.1, about 4.7 to about 5.3, about 4.3, about 4.7 to about 5.1, about 2.5, about 4.7 to about 5.1, about 4.1, about 4.5 to about 5.3, about 4.8 to about 5.5.5, about 2, about 3 to about 5.1, about 4.7 to about 5.1, about 4.5.1, about 4.8 to about 5.5.5. 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. For example, the pH is about 5.3. In a non-limiting example, the composition includes an acetate buffer and has a pH of about 4.5 to about 5.5 or about 5.3. In certain embodiments, 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 6.2, about 6.1 to about 6.3, about 6.3 to about 6.5, about 6.3 to about 6.6.0, about 6.3 to about 6.5, about 6.3 to about 6.6.6.6.3 to about 6.6.6.6, about 6.2 to about 6.3, about 6.3 to about 6.6.6.6.6.6, about 6.3 to about 6.6.6.6.3 to about 6.6.6.3, about 6.6.6.2 to about 6.3, about 6.6.6.6.6.6.6.3 to about 6.6.3. The pH may 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. For example, the pH is about 6.5. In a non-limiting example, the composition includes a phosphate buffer and has a pH of about 6.0 to about 7.0 or about 6.5.
In some embodiments, the pharmaceutical composition comprising an anti-TL 1A antibody comprises one or more of the following: surfactants, stabilizers, salts and buffers. In some embodiments, the pharmaceutical composition includes a surfactant and a stabilizer. In some embodiments, the pharmaceutical composition includes a surfactant and a salt. In some embodiments, the pharmaceutical composition comprises a surfactant and a buffer. In some embodiments, the pharmaceutical composition includes a stabilizer and a salt. In some embodiments, the pharmaceutical composition comprises a stabilizer and a buffer. In some embodiments, the pharmaceutical composition comprises a salt and a buffer. In some embodiments, the pharmaceutical composition includes a surfactant, a stabilizer, and a salt. In some embodiments, the pharmaceutical composition comprises a surfactant, a salt, and a buffer. In some embodiments, the pharmaceutical composition comprises a surfactant, a stabilizer, and a buffer. In some embodiments, the pharmaceutical composition comprises a stabilizer, a salt, and a buffer. In some embodiments, the pharmaceutical composition comprises a surfactant, a stabilizer, a salt, and a buffer.
Non-limiting exemplary pharmaceutical compositions include nonionic surfactants, sugars, salts, and buffers. For example, the composition includes a polysorbate (e.g., polysorbate-20), sucrose, lysine-HCl, or sodium chloride and an acetate buffer. The pH of the composition may be from about 4.5 to about 5.5 or from about 5.0 to about 5.5. In an exemplary embodiment, the composition comprises about 10-20mM acetate, pH4.5-5.5, 150-270mM sucrose, 25-50mM Lys-HCl, and 0.01% -0.05% v/v polysorbate-20. For example, the composition comprises about 20mM acetate, about 240mM sucrose, about 25mM lysine-HCl, and about 0.02% polysorbate-20 at pH 5.3. As another example embodiment, the composition includes polysorbate-20 at a pH of 4.5-5.5 at about 10-20mM acetate, 150-270mM sucrose, 50-130mM NaCl, and 0.01% -0.05% v/v. For example, the composition comprises about 20mM acetate, 220mM sucrose, 40mM NaCl, and 0.02% polysorbate-20 at pH 5.3.
In some embodiments, the composition comprises a polysorbate (e.g., polysorbate-20), sucrose, sodium chloride, and an acetate buffer. The pH of the composition may be from about 4.5 to about 5.5 or from about 5.0 to about 5.5. In an exemplary embodiment, the composition comprises about 10-20mM acetate, 150-270mM sucrose, and 0.01% -0.05% v/v polysorbate-20 at pH 4.5-5.5. For example, the composition comprises about 20mM acetate, about 220mM sucrose, and about 0.02% polysorbate-20 at pH 5.3. As another example embodiment, the composition includes polysorbate-20 at a pH of 4.5-5.5 at about 10-20mM acetate, 150-270mM sucrose, 50-130mM NaCl, and 0.01% -0.05% v/v. For example, the composition comprises about 20mM acetate, 220mM sucrose, 40mM NaCl, and 0.02% polysorbate-20 at pH 5.3.
In some embodiments, the composition comprises polysorbate (e.g., polysorbate-20), sucrose, glycine, sodium chloride, and phosphate buffer. In certain embodiments, the composition comprises a polysorbate (e.g., polysorbate-20), sucrose, glycine, and a phosphate buffer. In some embodiments, the composition comprises polysorbate-20, sucrose, glycine, and a phosphate buffer. The pH of the composition may be from about 6.0 to about 7.0 or from about 6.5 to about 7.0. In an exemplary embodiment, the composition includes polysorbate-20 at a pH of 6.0-7.0 at about 10-20mM phosphate, 75-100mM glycine, 100-270mM sucrose, and 0.01% -0.05% v/v. For example, the composition comprises about 20mM phosphate, about 85mM glycine, about 146mM sucrose, and about 0.02% polysorbate-20 at pH 6.5. As another example embodiment, the composition includes about 10-20mM phosphate, 75-100mM glycine, 2% to 8% (w/v) sucrose, and 0.01% -0.05% v/v polysorbate-20 at a pH of 6.0-7.0. For example, the composition comprises about 20mM phosphate at pH 6.5, 5% (w/v) sucrose, 85mM glycine, and 0.02% polysorbate-20.
In one embodiment, provided herein is a composition comprising an anti-TL 1A antibody provided herein at a concentration of about 200mg/mL, 20mM sodium acetate, 220mM sucrose, 40mM NaCl, and 0.02% polysorbate-20 at pH 5.3. In another embodiment, provided herein is a composition comprising an anti-TL 1A antibody provided herein at a concentration of about 100mg/mL, 20mM sodium acetate, 220mM sucrose, 40mM NaCl, and 0.02% polysorbate-20 at pH 5.3. In another embodiment, provided herein is a composition comprising an anti-TL 1A antibody provided herein at a concentration of about 60mg/mL, 20mM sodium phosphate, 5% sucrose, 85mM glycine, and 0.02% polysorbate-20 at pH 5.3. In one embodiment, provided herein is a composition comprising an anti-TL 1A antibody provided herein at a pH of 5.3 at the concentrations described herein, 20mM sodium acetate, 220mM sucrose, 40mM NaCl, and 0.02% polysorbate-20. In another embodiment, provided herein is a composition comprising an anti-TL 1A antibody provided herein at a pH of 5.3 at the concentrations described herein, 20mM sodium acetate, 220mM sucrose, 40mM NaCl, and 0.02% polysorbate-20. In another embodiment, provided herein is a composition comprising an anti-TL 1A antibody provided herein at a pH of 5.3 at the concentrations described herein, 20mM sodium phosphate, 5% sucrose, 85mM glycine, and 0.02% polysorbate-20. In one embodiment, provided herein is a composition comprising an anti-TL 1A antibody provided herein at pH 5.3 at a concentration of about 150mg/ml to 250mg/ml, 20mM sodium acetate, 220mM sucrose, 40mM NaCl, and 0.02% polysorbate-20. In another embodiment, provided herein is a composition comprising an anti-TL 1A antibody provided herein at pH 5.3 at a concentration of about 100mg/ml to 200mg/ml, 20mM sodium acetate, 220mM sucrose, 40mM NaCl, and 0.02% polysorbate-20. In another embodiment, provided herein is a composition comprising an anti-TL 1A antibody provided herein at pH 5.3 at a concentration of about 50mg/ml to 100mg/ml, 20mM sodium phosphate, 5% sucrose, 85mM glycine, and 0.02% polysorbate-20.
For the various embodiments of the compositions provided herein, including in this section (section 4.5, e.g., those in the preceding paragraphs), further embodiments of anti-TL 1A antibodies are provided in section 4.2, including embodiments having exemplary CDRs, framework sequences, constant region sequences, fc mutations, variable regions, fc regions, and other properties; assays for screening, testing, and validating anti-TL 1A antibodies are provided in section 4.3; methods for generating, modifying, mutating, cloning, expressing and isolating anti-TL 1A antibodies are provided in section 4.4; methods for using the compositions are described and provided in section 4.6; various dosages or dosing regimens for using the pharmaceutical compositions are provided in section 4.6 and this section (section 4.5); additional specific and validated examples of anti-TL 1A antibodies and methods of their use are provided in section 5. Accordingly, the present disclosure provides various combinations of anti-TL 1A antibodies, pharmaceutical compositions of such anti-TL 1A antibodies, dosages or dosing regimens of such pharmaceutical compositions using anti-TL 1A antibodies, methods of producing anti-TL 1A antibodies, methods of assaying anti-TL 1A antibodies, and methods of treatment using anti-TL 1A antibodies.
4.6 methods of treatment
TL1A is a pro-inflammatory mediator with a broad upstream effect on many inflammatory cells. TL1A can also induce fibrosis directly by stimulating intestinal fibroblasts.
The present disclosure suggests that the anti-TL 1A antibodies or antigen-binding fragments provided herein, and pharmaceutical compositions thereof, may be used in methods to treat an inflammatory disease or condition in a subject by administering the anti-TL 1A antibodies or antigen-binding fragments described herein, or pharmaceutical compositions thereof, to the subject. More specifically, the anti-TL 1A antibodies or antigen-binding fragments provided herein, and pharmaceutical compositions thereof, can be used in methods to treat pulmonary inflammation and/or pulmonary fibrosis in a subject by administering the anti-TL 1A antibodies or antigen-binding fragments described herein, or pharmaceutical compositions thereof, to the subject. In various embodiments, the subject has one or more inflammatory conditions selected from the group consisting of: systemic sclerosis-related interstitial lung disease, idiopathic pulmonary fibrosis, virus-induced pulmonary fibrosis, asthma, chronic Obstructive Pulmonary Disease (COPD) and pneumonia. In certain embodiments, the subject has chronic pulmonary disorders, idiopathic interstitial pneumonia, pulmonary sarcoidosis, interstitial pulmonary disease, bronchiolitis, alveolitis, vasculitis, interstitial pneumonia, non-specific interstitial pneumonia, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, acute interstitial pneumonitis, allergic rhinitis, emphysema, chronic bronchitis, primary cholangitis, behcet's disease, systemic sclerosis-associated interstitial pulmonary disease, or cystic fibrosis, or a combination thereof. In some embodiments of the methods provided herein, including in this section (section 4.6), the pulmonary inflammation and/or pulmonary fibrosis comprises or consists of one or more inflammatory conditions selected from the group consisting of: systemic sclerosis-related interstitial lung disease, idiopathic pulmonary fibrosis, virus-induced pulmonary fibrosis, asthma, chronic Obstructive Pulmonary Disease (COPD) and pneumonia. In certain embodiments of the methods provided herein, including in this section (section 4.6), the pulmonary inflammation and/or pulmonary fibrosis comprises or consists of chronic pulmonary disorders, idiopathic interstitial pneumonia, pulmonary sarcoidosis, interstitial pulmonary disease, bronchiolitis, alveolitis, vasculitis, interstitial pneumonia, nonspecific interstitial pneumonia, hypersensitivity pneumonitis, cryptogenic, acute interstitial pneumonia, allergic rhinitis, emphysema, chronic bronchitis, primary biliary cholangitis, behcet's disease, systemic sclerosis-associated interstitial pulmonary disease, or cystic fibrosis, or a combination thereof.
In one aspect, provided herein is a method of neutralizing monomeric TL1A and trimeric TL1A in a subject, the method comprising (a) administering to the subject an effective dose of an anti-TL 1A antibody or antigen-binding fragment, 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 with DR3. In certain embodiments, the subject has pulmonary inflammation and/or pulmonary fibrosis. In some embodiments, the concentration of TL1A in the diseased tissue in the subject is reduced to a lower concentration than the concentration of TL1A in the corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis.
"neutralizing" TL1A refers to binding to TL1A in such a way that the functional receptor DR3 can no longer bind to TL1A and/or signal by linking to TL 1A. Thus, anti-TL 1A antibodies that block TL1A binding to DR3 also neutralize DR3.
In another aspect, provided herein is a method of reducing the concentration of TL1A in diseased tissue in a subject having pulmonary inflammation and/or pulmonary fibrosis, the method comprising (a) administering to the subject an effective dose of an anti-TL 1A antibody or antigen-binding fragment, thereby reducing the concentration of TL1A in the diseased tissue in the subject to a lower concentration than the concentration of TL1A in corresponding tissue in a control subject not having pulmonary inflammation and/or pulmonary fibrosis.
In yet another aspect, provided herein is a method of treating pulmonary inflammation and/or pulmonary fibrosis in a subject in need thereof, the method comprising (a) administering to the subject an anti-TL 1A antibody or antigen-binding fragment, wherein the anti-TL 1A antibody or antigen-binding fragment is administered in an effective dose such that after step (a) the concentration of TL1A in diseased tissue in the subject is lower than the concentration of TL1A in corresponding tissue in a control subject not having pulmonary inflammation and/or pulmonary fibrosis.
In a further aspect, provided herein is a method of treating pulmonary inflammation and/or pulmonary fibrosis in a subject in need thereof, the method comprising (a) administering to the subject an anti-TL 1A antibody or antigen-binding fragment, wherein the anti-TL 1A antibody or antigen-binding fragment is administered in an effective dose such that after step (a) the concentration of TL1A in diseased tissue in the subject is lower than the concentration of TL1A in corresponding tissue in a control subject not having pulmonary inflammation and/or pulmonary fibrosis.
In some embodiments of the various methods included in this section (section 4.6), the diseased tissue comprises or consists of tissue in the lung. In some embodiments of the various methods included in this section (section 4.6), the diseased tissue comprises or consists of 2, 3, 4, 5, 6, 7, 8 or more tissues in the lung. In some embodiments of the various methods included in this section (section 4.6), the corresponding tissue or reference tissue comprises or consists of tissue in the lung. In some embodiments of the various methods included in this section (section 4.6), the corresponding tissue or reference tissue comprises or consists of 2, 3, 4, 5, 6, 7, 8 or more tissues in the lung.
The methods provided herein, including the methods provided in this section (section 4.6), can be or include a variety of dosing regimens. In some embodiments of the methods provided herein, including methods provided in this section (section 4.6), the effective dose comprises an induction regimen. In certain embodiments, an effective dose consists of an induction regimen. In some further embodiments, an effective dose comprises a maintenance regimen. In certain additional embodiments, an effective dose includes an induction regimen and a maintenance regimen. In one embodiment, the effective dose consists of an induction regimen and a maintenance regimen. In some other embodiments, the maintenance regimen is applied in a maintenance step, as described further below.
The methods provided herein, which are included in this section (section 4.6), may include additional steps. In some embodiments of the methods provided herein, including methods provided in this section (section 4.6), the method further comprises: (c) Maintaining a concentration of TL1A in the diseased tissue in the subject below a concentration of TL1A in the corresponding tissue in the control subject. In certain embodiments, the TL1A in the diseased tissue in the subject is maintained with a maintenance regimen of the anti-TL 1A antibody or antigen binding fragment. In some specific embodiments, the TL1A in the diseased tissue in the subject is maintained in step (c) with a maintenance regimen of the anti-TL 1A antibody or antigen binding fragment. In certain embodiments, the maintenance regimen is administered after the induction regimen.
The present disclosure proposes that the induction and maintenance regimens included in the methods provided herein in this section (section 4.6) may be the same or different in various aspects. In one embodiment of the methods provided herein, which are included in this section (section 4.6), the induction regimen and the maintenance regimen are the same. In another embodiment, the induction regimen and the maintenance regimen are different. In further embodiments, the induction regimen comprises a higher dose of anti-TL 1A antibodies or antigen binding fragments than the maintenance regimen. In yet another embodiment, the induction regimen comprises a dose of anti-TL 1A antibody or antigen binding fragment that is 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-fold or more higher than the maintenance regimen.
As described above and below, the various methods provided herein can reduce the concentration of TL1A in the diseased tissue in the subject to a lower concentration than the concentration of TL1A in the corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis. Alternatively, various methods provided herein can reduce the concentration of TL1A in the diseased tissue in the subject to below a reference TL1A level (e.g., a reference concentration). Additionally, the various methods provided herein can reduce the concentration of TL1A in diseased tissue in a subject to a lower concentration than TL1A in reference tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis. As has been clear from the above description, diseased tissue in patients with pulmonary inflammation and/or pulmonary fibrosis overproduces TL1A, which promotes the etiology, phenotype and/or symptoms of patients with pulmonary inflammation and/or pulmonary fibrosis. Various methods provided herein reduce the concentration of TL1A in diseased tissue of a subject to a lower concentration than the concentration of TL1A in corresponding tissue in a control subject not having pulmonary inflammation and/or pulmonary fibrosis, while diseased tissue of the subject (e.g., certain cells in diseased tissue) overproduces TL1A. Such a decrease in the concentration of TL1A in diseased tissue of the subject is below: (i) Reference TL1A levels or (ii) concentrations of TL1A in corresponding tissues or reference tissues in control subjects not suffering from pulmonary inflammation and/or pulmonary fibrosis, while diseased tissues in the subject overproduce TL1A, may also be referred to as coverage. For example, coverage or coverage of 100-fold overproduction of TL1A means that the concentration of TL1A in diseased tissue of a subject is reduced to a lower concentration than the concentration of TL1A in corresponding tissue or reference tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis, whereas diseased tissue overproduces TL1A by up to 100-fold compared to corresponding tissue or reference tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis.
Thus, in some embodiments of the methods provided herein, including in this section (section 4.6), the diseased tissue in the subject produces TL1A that is at most 50, at most 55, at most 60, at most 65, at most 70, at most 75, at most 80, at most 85, at most 90, at most 95, at most 100, at most 105, at most 110, at most 115, at most 120, at most 125, at most 130, at most 135, at most 140, at most 145, at most 150, at most 155, at most 160, at most 165, at most 170, at most 175, at most 180, at most 185, at most 190, at most 195, at most 200, or at most more times greater than the TL1A produced by the corresponding tissue in the control subject. In certain embodiments, the diseased tissue in the subject produces TL1A that is up to 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 times greater than the corresponding tissue in the control subject. In some embodiments, the diseased tissue in the subject produces TL1A that is up to 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 times or more than the TL1A produced by the corresponding tissue in the control subject. In some embodiments, the diseased tissue in the subject produces TL1A that is up to 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 times or more than the TL1A produced by the corresponding tissue in the control subject. In some embodiments, the diseased tissue in the subject produces TL1A that is up to 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100, 40 to 105, 40 to 110, 40 to 115, 40 to 120, 40 to 125, 40 to 130, 40 to 135, 40 to 140, 40 to 145, 40 to 150, 40 to 155, 40 to 160, 40 to 165, 40 to 170, 40 to 175, 40 to 180, 40 to 185, 40 to 190, 40 to 195, 40 to 200 times or more than the TL1A produced by the corresponding tissue in the control subject. In some embodiments, the diseased tissue in the subject produces TL1A that is up to 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100, 50 to 105, 50 to 110, 50 to 115, 50 to 120, 50 to 125, 50 to 130, 50 to 135, 50 to 140, 50 to 145, 50 to 150, 50 to 155, 50 to 160, 50 to 165, 50 to 170, 50 to 175, 50 to 180, 50 to 185, 50 to 190, 50 to 195, 50 to 200 times or more than the TL1A produced by the corresponding tissue in the control subject. In some embodiments, the diseased tissue in the subject produces TL1A that is up to 60 to 65, 60 to 70, 60 to 75, 60 to 80, 60 to 85, 60 to 90, 60 to 95, 60 to 100, 60 to 105, 60 to 110, 60 to 115, 60 to 120, 60 to 125, 60 to 130, 60 to 135, 60 to 140, 60 to 145, 60 to 150, 60 to 155, 60 to 160, 60 to 165, 60 to 170, 60 to 175, 60 to 180, 60 to 185, 60 to 190, 60 to 195, 60 to 200 times or more greater than the TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, the diseased tissue in the subject produces TL1A up to or about 50 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, the diseased tissue in the subject produces TL1A that is at most or about 60 times greater than TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, the diseased tissue in the subject produces TL1A up to or about 70 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, the diseased tissue in the subject produces TL1A that is at most or about 80 times greater than TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, the diseased tissue in the subject produces TL1A up to or about 90 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, the diseased tissue in the subject produces TL1A up to or about 100 times greater than the TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, the diseased tissue in the subject produces TL1A that is at most or about 110 times greater than TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, the diseased tissue in the subject produces TL1A that is at most or about 120 times greater than TL1A produced by the corresponding tissue in the control subject. In yet another specific embodiment, the diseased tissue in the subject produces TL1A up to or about 130 times greater than TL1A produced by the corresponding tissue in the control subject. In further embodiments, the diseased tissue in the subject produces TL1A that is at most or about 140 times greater than TL1A produced by the corresponding tissue in the control subject. In one embodiment, the diseased tissue in the subject produces TL1A up to or about 150 times greater than the TL1A produced by the corresponding tissue in the control subject. In another embodiment, the diseased tissue in the subject produces TL1A that is at most or about 160 times greater than TL1A produced by the corresponding tissue in the control subject. In further embodiments, the diseased tissue in the subject produces TL1A that is at most or about 170 times greater than TL1A produced by the corresponding tissue in the control subject. In yet another specific embodiment, the diseased tissue in the subject produces TL1A up to or about 180 times greater than the corresponding tissue in the control subject. In one embodiment, the diseased tissue in the subject produces TL1A up to or about 190 times greater than the TL1A produced by the corresponding tissue in the control subject. In another embodiment, the diseased tissue in the subject produces TL1A that is at most or about 200 times greater than TL1A produced by the corresponding tissue in the control subject. In some embodiments, during the induction regimen, diseased tissue in the subject overproduces TL1A as described in this paragraph. In some other embodiments, the TL1A as described in this paragraph is overproduced by diseased tissue in the subject prior to administration of the effective dose. In certain embodiments, the diseased tissue in the subject overproduces TL1A as described in this paragraph within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. As is clear from the description, diseased tissue may overproduce TL1A by any combination of fold overproduction, timing, and duration as described herein. It is also apparent from the above description that by providing a reduction in TL1A in diseased tissue in this paragraph with the methods described, the present disclosure also provides that the methods provided herein can cover TL1A overproduction with an effective dose or induction regimen for fold overproduction, timing and/or duration as described in this paragraph.
More specifically, provided herein, in some embodiments of the methods included in this section (section 4.6), during the induction regimen, the diseased tissue in the subject produces TL1A that is at most 50, at most 55, at most 60, at most 65, at most 70, at most 75, at most 80, at most 85, at most 90, at most 95, at most 100, at most 105, at most 110, at most 115, at most 120, at most 125, at most 130, at most 135, at most 140, at most 145, at most 150, at most 155, at most 160, at most 165, at most 170, at most 175, at most 180, at most 185, at most 190, at most 195, at most 200, or at most more times greater than the corresponding tissue in the control subject. In certain embodiments, during the induction regimen, the diseased tissue in the subject produces TL1A up to 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 times greater than the corresponding tissue in the control subject. In some embodiments, TL1A produced by the diseased tissue in the subject is up to 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 times greater than TL1A produced by the corresponding tissue in the control subject during the induction regimen. In some embodiments, TL1A produced by the diseased tissue in the subject is up to 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 times greater than TL1A produced by the corresponding tissue in the control subject during the induction regimen. In some embodiments, TL1A produced by the diseased tissue in the subject is up to 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100, 40 to 105, 40 to 110, 40 to 115, 40 to 120, 40 to 125, 40 to 130, 40 to 135, 40 to 140, 40 to 145, 40 to 150, 40 to 155, 40 to 160, 40 to 165, 40 to 170, 40 to 175, 40 to 180, 40 to 185, 40 to 190, 40 to 195, 40 to 200 times or more than TL1A produced by the corresponding tissue in the control subject during the induction regimen. In some embodiments, TL1A produced by the diseased tissue in the subject is up to 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100, 50 to 105, 50 to 110, 50 to 115, 50 to 120, 50 to 125, 50 to 130, 50 to 135, 50 to 140, 50 to 145, 50 to 150, 50 to 155, 50 to 160, 50 to 165, 50 to 170, 50 to 175, 50 to 180, 50 to 185, 50 to 190, 50 to 195, 50 to 200 times or more than TL1A produced by the corresponding tissue in the control subject during the induction regimen. In some embodiments, TL1A produced by the diseased tissue in the subject is up to 60 to 65, 60 to 70, 60 to 75, 60 to 80, 60 to 85, 60 to 90, 60 to 95, 60 to 100, 60 to 105, 60 to 110, 60 to 115, 60 to 120, 60 to 125, 60 to 130, 60 to 135, 60 to 140, 60 to 145, 60 to 150, 60 to 155, 60 to 160, 60 to 165, 60 to 170, 60 to 175, 60 to 180, 60 to 185, 60 to 190, 60 to 195, 60 to 200 times or more than TL1A produced by the corresponding tissue in the control subject during the induction regimen. In a specific embodiment, during the induction regimen, the diseased tissue in the subject produces TL1A up to or about 50 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, during the induction regimen, the diseased tissue in the subject produces TL1A up to or about 60 times greater than the TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, during the induction regimen, the diseased tissue in the subject produces TL1A up to or about 70 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, during the induction regimen, the diseased tissue in the subject produces TL1A up to or about 80 times greater than the TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, during the induction regimen, the diseased tissue in the subject produces TL1A up to or about 90 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, during the induction regimen, the diseased tissue in the subject produces TL1A up to or about 100 times greater than the corresponding tissue in the control subject. In a specific embodiment, during the induction regimen, the diseased tissue in the subject produces TL1A up to or about 110 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, during the induction regimen, the diseased tissue in the subject produces TL1A up to or about 120 times greater than the TL1A produced by the corresponding tissue in the control subject. In yet another specific embodiment, during the induction regimen, the diseased tissue in the subject produces TL1A up to or about 130 times greater than the TL1A produced by the corresponding tissue in the control subject. In further embodiments, the TL1A produced by the diseased tissue in the subject is at most or about 140 times greater than the TL1A produced by the corresponding tissue in the control subject during the induction regimen. In one embodiment, during the induction regimen, the diseased tissue in the subject produces TL1A up to or about 150 times greater than the TL1A produced by the corresponding tissue in the control subject. In another embodiment, during the induction regimen, the diseased tissue in the subject produces TL1A up to or about 160 times greater than the TL1A produced by the corresponding tissue in the control subject. In further embodiments, the TL1A produced by the diseased tissue in the subject is at most or about 170 times greater than the TL1A produced by the corresponding tissue in the control subject during the induction regimen. In yet another specific embodiment, during the induction regimen, the diseased tissue in the subject produces TL1A up to or about 180 times greater than the corresponding tissue in the control subject. In one embodiment, during the induction regimen, the diseased tissue in the subject produces TL1A up to or about 190 times greater than the TL1A produced by the corresponding tissue in the control subject. In another embodiment, the TL1A produced by the diseased tissue in the subject is at most or about 200 times greater than the TL1A produced by the corresponding tissue in the control subject during the induction regimen. As is apparent from the above description, by providing a reduction in TL1A in diseased tissue in this paragraph with the methods described, the present disclosure also provides that the methods provided herein can cover TL1A overproduction with an effective dose or induction regimen for fold overproduction, timing, and/or duration as described in this paragraph.
Similarly, in some embodiments of the methods provided herein, including in this section (section 4.6), prior to the induction regimen, the diseased tissue in the subject produces TL1A that is at most 50, at most 55, at most 60, at most 65, at most 70, at most 75, at most 80, at most 85, at most 90, at most 95, at most 100, at most 105, at most 110, at most 115, at most 120, at most 125, at most 130, at most 135, at most 140, at most 145, at most 150, at most 155, at most 160, at most 165, at most 170, at most 175, at most 180, at most 185, at most 190, at most 195, at most 200-fold, or at most more times that of the corresponding tissue in the control subject. In certain embodiments, prior to an induction regimen, the diseased tissue in the subject produces TL1A up to 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 times that of the corresponding tissue in the control subject. In some embodiments, prior to an induction regimen, the subject has TL1A produced by the diseased tissue that is up to 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 times greater than the TL1A produced by the corresponding tissue in the control subject. In some embodiments, prior to an induction regimen, the subject has TL1A produced by the diseased tissue that is up to 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 times greater than the TL1A produced by the corresponding tissue in the control subject. In some embodiments, prior to the induction regimen, the subject has TL1A produced by the diseased tissue that is up to 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100, 40 to 105, 40 to 110, 40 to 115, 40 to 120, 40 to 125, 40 to 130, 40 to 135, 40 to 140, 40 to 145, 40 to 150, 40 to 155, 40 to 160, 40 to 165, 40 to 170, 40 to 175, 40 to 180, 40 to 185, 40 to 190, 40 to 195, 40 to 200, or more times greater than the TL1A produced by the corresponding tissue in the control subject. In some embodiments, prior to the induction regimen, the subject has TL1A produced by the diseased tissue that is up to 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100, 50 to 105, 50 to 110, 50 to 115, 50 to 120, 50 to 125, 50 to 130, 50 to 135, 50 to 140, 50 to 145, 50 to 150, 50 to 155, 50 to 160, 50 to 165, 50 to 170, 50 to 175, 50 to 180, 50 to 185, 50 to 190, 50 to 195, 50 to 200 times or more than the TL1A produced by the corresponding tissue in the control subject. In some embodiments, prior to the induction regimen, the subject has TL1A produced by the diseased tissue that is up to 60 to 65, 60 to 70, 60 to 75, 60 to 80, 60 to 85, 60 to 90, 60 to 95, 60 to 100, 60 to 105, 60 to 110, 60 to 115, 60 to 120, 60 to 125, 60 to 130, 60 to 135, 60 to 140, 60 to 145, 60 to 150, 60 to 155, 60 to 160, 60 to 165, 60 to 170, 60 to 175, 60 to 180, 60 to 185, 60 to 190, 60 to 195, 60 to 200 times or more greater than TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, prior to an induction regimen, the diseased tissue in the subject produces TL1A up to or about 50 times greater than the corresponding tissue in the control subject. In another specific embodiment, prior to an induction regimen, the diseased tissue in the subject produces TL1A up to or about 60 times greater than the TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, prior to an induction regimen, the diseased tissue in the subject produces TL1A up to or about 70 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, prior to an induction regimen, the diseased tissue in the subject produces TL1A up to or about 80 times greater than the TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, prior to an induction regimen, the diseased tissue in the subject produces TL1A up to or about 90 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, prior to an induction regimen, the diseased tissue in the subject produces TL1A up to or about 100 times greater than the corresponding tissue in the control subject. In a specific embodiment, prior to an induction regimen, the diseased tissue in the subject produces TL1A up to or about 110 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, prior to an induction regimen, the diseased tissue in the subject produces TL1A up to or about 120 times greater than the TL1A produced by the corresponding tissue in the control subject. In yet another specific embodiment, prior to the induction regimen, the diseased tissue in the subject produces TL1A up to or about 130 times greater than the corresponding tissue in the control subject. In further embodiments, prior to an induction regimen, the diseased tissue in the subject produces TL1A up to or about 140 times greater than the TL1A produced by the corresponding tissue in the control subject. In one embodiment, prior to an induction regimen, the diseased tissue in the subject produces TL1A up to or about 150 times greater than the TL1A produced by the corresponding tissue in the control subject. In another embodiment, prior to the induction regimen, the diseased tissue in the subject produces TL1A up to or about 160 times greater than the TL1A produced by the corresponding tissue in the control subject. In further embodiments, prior to the induction regimen, the diseased tissue in the subject produces TL1A up to or about 170 times greater than the TL1A produced by the corresponding tissue in the control subject. In yet another specific embodiment, prior to the induction regimen, the diseased tissue in the subject produces TL1A up to or about 180 times greater than the corresponding tissue in the control subject. In one embodiment, prior to an induction regimen, the diseased tissue in the subject produces TL1A up to or about 190 times greater than the TL1A produced by the corresponding tissue in the control subject. In another embodiment, prior to the induction regimen, the diseased tissue in the subject produces TL1A up to or about 200 times greater than the TL1A produced by the corresponding tissue in the control subject. As is apparent from the above description, by providing a reduction in TL1A in diseased tissue in this paragraph with the methods described, the present disclosure also provides that the methods provided herein can cover TL1A overproduction with an effective dose or induction regimen for fold overproduction, timing, and/or duration as described in this paragraph.
Alternatively, provided herein, in some embodiments of the methods included in this section (section 4.6), the diseased tissue in the subject produces TL1A that is at most 50, at most 55, at most 60, at most 65, at most 70, at most 75, at most 80, at most 85, at most 90, at most 95, at most 100, at most 105, at most 110, at most 115, at most 120, at most 125, at most 130, at most 135, at most 140, at most 145, at most 150, at most 155, at most 160, at most 165, at most 170, at most 175, at most 180, at most 185, at most 190, at most 195, at most 200, or at most more times as large as the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks from the start of the induction regimen. In certain embodiments, the TL1A produced by the diseased tissue in the subject is up to 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 times the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In some embodiments, TL1A produced by the diseased tissue in the subject is up to 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 times or more the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In some embodiments, TL1A produced by the diseased tissue in the subject is up to 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 times or more the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In some embodiments, TL1A produced by the diseased tissue in the subject is up to 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100, 40 to 105, 40 to 110, 40 to 115, 40 to 120, 40 to 125, 40 to 130, 40 to 135, 40 to 140, 40 to 145, 40 to 150, 40 to 155, 40 to 160, 40 to 165, 40 to 170, 40 to 175, 40 to 180, 40 to 185, 40 to 190, 40 to 195, 40 to 200, or more times the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In some embodiments, TL1A produced by the diseased tissue in the subject is up to 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100, 50 to 105, 50 to 110, 50 to 115, 50 to 120, 50 to 125, 50 to 130, 50 to 135, 50 to 140, 50 to 145, 50 to 150, 50 to 155, 50 to 160, 50 to 165, 50 to 170, 50 to 175, 50 to 180, 50 to 185, 50 to 190, 50 to 195, 50 to 200 times or more the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In some embodiments, TL1A produced by the diseased tissue in the subject is up to 60 to 65, 60 to 70, 60 to 75, 60 to 80, 60 to 85, 60 to 90, 60 to 95, 60 to 100, 60 to 105, 60 to 110, 60 to 115, 60 to 120, 60 to 125, 60 to 130, 60 to 135, 60 to 140, 60 to 145, 60 to 150, 60 to 155, 60 to 160, 60 to 165, 60 to 170, 60 to 175, 60 to 180, 60 to 185, 60 to 190, 60 to 195, 60 to 200 times or more the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In a specific embodiment, the TL1A produced by the diseased tissue in the subject is no more than or about 50 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In another specific embodiment, the TL1A produced by the diseased tissue in the subject is up to or about 60 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In a specific embodiment, the TL1A produced by the diseased tissue in the subject is no more than or about 70 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In another specific embodiment, the TL1A produced by the diseased tissue in the subject is at most or about 80 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In a specific embodiment, the TL1A produced by the diseased tissue in the subject is no more than or about 90 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In another specific embodiment, the TL1A produced by the diseased tissue in the subject is at most or about 100 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In a specific embodiment, the TL1A produced by the diseased tissue in the subject is up to or about 110 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In another specific embodiment, the TL1A produced by the diseased tissue in the subject is up to or about 120 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In yet another specific embodiment, the diseased tissue in the subject produces TL1A up to or about 130 times greater than the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In further embodiments, the TL1A produced by the diseased tissue in the subject is no more than or about 140 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In one embodiment, the TL1A produced by the diseased tissue in the subject is no more than or about 150 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In another embodiment, the TL1A produced by the diseased tissue in the subject is no more than or about 160 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In further embodiments, the TL1A produced by the diseased tissue in the subject is no more than or about 170 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In yet another specific embodiment, the diseased tissue in the subject produces TL1A up to or about 180 times greater than the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In one embodiment, the TL1A produced by the diseased tissue in the subject is up to or about 190 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. In another embodiment, the TL1A produced by the diseased tissue in the subject is no more than or about 200 times greater than the TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, or 6 weeks of the initiation of the induction regimen. As is apparent from the above description, by providing a reduction in TL1A in diseased tissue in this paragraph with the methods described, the present disclosure also provides that the methods provided herein can cover TL1A overproduction with an effective dose or induction regimen for fold overproduction, timing, and/or duration as described in this paragraph.
The induction regimen may include one or more administrations of an anti-TL 1A antibody or antigen binding fragment to reduce the concentration of TL1A in diseased tissue in the subject. In one embodiment of the methods provided herein, which are encompassed in this section (section 4.6), the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment. In some embodiments, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 150 mg/dose. In one embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 200 mg/dose. In another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 250 mg/dose. In further embodiments, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 300 mg/dose. In yet another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 350 mg/dose. In one embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 400 mg/dose. In another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 450 mg/dose. In yet another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 500 mg/dose. In one embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 550 mg/dose. In yet another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 600 mg/dose. In another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 650 mg/dose. In further embodiments, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 700 mg/dose. In one embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 750 mg/dose. In another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 800 mg/dose. In one embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 850 mg/dose. In further embodiments, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 900 mg/dose. In one embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 950 mg/dose. In yet another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 1000 mg/dose. In yet another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 1100 mg/dose. In one embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 1200 mg/dose. In another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 1250 mg/dose. In further embodiments, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 1300 mg/dose. In yet another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 1400 mg/dose. In yet another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 1500 mg/dose. In one embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 1600 mg/dose. In another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at a dose of about 1700 mg/dose. In further embodiments, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 1750 mg/dose. In yet another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 1800 mg/dose. In yet another embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 1900 mg/dose. In one embodiment, the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment at about 2000 mg/dose.
Alternatively, the induction regimen may comprise multiple administrations of the anti-TL 1A antibody or antigen binding fragment. In one embodiment, the induction regimen comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more administrations of the anti-TL 1A antibody or antigen binding fragment. In another embodiment, the induction regimen comprises administration of about 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, or 150 mg/dose. In one embodiment, the induction regimen comprises administration of 200 to 2000, 200 to 1950, 200 to 1900, 200 to 1850, 200 to 1800, 200 to 1750, 200 to 1700, 200 to 1650, 200 to 1600, 200 to 1550, 200 to 1500, 200 to 1450, 200 to 1400, 200 to 1350, 200 to 1300, 200 to 1250, 200 to 1200, 200 to 1150, 200 to 1000, 200 to 950, 200 to 900, 200 to 850, 200 to 800, 200 to 750, 200 to 700, 200 to 650, 200 to 600, 200 to 550, 200 to 500, 200 to 450, 200 to 400, 200 to 350, 200 to 300, or 200 to 250 mg/dose. In one embodiment, the induction regimen comprises administration of 100 to 2000, 100 to 1950, 100 to 1900, 100 to 1850, 100 to 1800, 100 to 1750, 100 to 1700, 100 to 1650, 100 to 1600, 100 to 1550, 100 to 1500, 100 to 1450, 100 to 1400, 100 to 1350, 100 to 1300, 100 to 1250, 100 to 1200, 100 to 1150, 100 to 1000, 100 to 950, 100 to 900, 100 to 850, 100 to 800, 100 to 750, 100 to 700, 100 to 650, 100 to 600, 100 to 550, 100 to 500, 100 to 450, 100 to 400, 100 to 350, 100 to 300, or 100 to 250 mg/dose. In one embodiment, the induction regimen comprises administration of 300 to 2000, 300 to 1950, 300 to 1900, 300 to 1850, 300 to 1800, 300 to 1750, 300 to 1700, 300 to 1650, 300 to 1600, 300 to 1550, 300 to 1500, 300 to 1450, 300 to 1400, 300 to 1350, 300 to 1300, 300 to 1250, 300 to 1200, 300 to 1150, 300 to 1000, 300 to 950, 300 to 900, 300 to 850, 300 to 800, 300 to 750, 300 to 700, 300 to 650, 300 to 600, 300 to 550, 300 to 500, 300 to 450, 300 to 400, or 300 to 350 mg/dose. In yet another embodiment, the induction regimen comprises administration once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In further embodiments, the induction regimen comprises administration once every 1, 2, 3, or 4 weeks for the first 2 administrations, and then once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks for the remaining induction regimen. In one embodiment, the induction regimen comprises administration at weeks 0 and 2 for the first 2 administrations, and then once every 1, 2, 3, 4, 5, 6, 7 or 8 weeks for the remaining induction regimen. In another embodiment, the duration of the induction regimen is shorter than the duration of the maintenance regimen. In further embodiments, the induction regimen lasts for 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more weeks. The present disclosure further suggests that the induction regimen may include any combination of amount administered, frequency of administration, number of administrations, and/or duration of induction regimen. Thus, and for example, in some embodiments, the induction regimen may comprise administering about 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, or 200 mg/dose of administration at week 0 and week 2 for the first 2 administrations, and then administering once every 2, 3, 4, 5, 6, 7, or 8 weeks for a duration of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more weeks for the induction regimen. Also, in some embodiments, the induction regimen may include administering about 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, or 200 mg/dose of administration at week 0 and week 2 for the first 2 administrations, and then administering once every 2, 3, 4, 5, 6, 7, or 8 weeks for a duration of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more weeks for the induction regimen at about 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1000, 950, 900, 850, 800, 750, 700, 650, b00, 550, 500, 400, 350, 300, 250, 200, or 150 mg/dose of administration.
In particular, in some embodiments, the induction regimen comprises administering about 1000 mg/dose at week 0, about 1000 mg/dose at week 2, about 1000 mg/dose at week 6, and about 1000 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 500 mg/dose at week 0, about 500 mg/dose at week 2, about 500 mg/dose at week 6, and about 500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1000 mg/dose at week 0, about 1000 mg/dose at week 2, about 1000 mg/dose at week 6, and about 500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1000 mg/dose at week 0, about 1000 mg/dose at week 2, about 500 mg/dose at week 6, and about 500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1000 mg/dose at week 0, about 500 mg/dose at week 2, about 500 mg/dose at week 6, and about 500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 750 mg/dose at week 0, about 750 mg/dose at week 2, about 750 mg/dose at week 6, and about 750 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 500 mg/dose at week 0, about 500 mg/dose at week 2, about 500 mg/dose at week 6, and about 500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 750 mg/dose at week 0, about 750 mg/dose at week 2, about 750 mg/dose at week 6, and about 500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 750 mg/dose at week 0, about 750 mg/dose at week 2, about 500 mg/dose at week 6, and about 500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 750 mg/dose at week 0, about 500 mg/dose at week 2, about 500 mg/dose at week 6, and about 500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1500 mg/dose at week 0, about 1500 mg/dose at week 2, about 1500 mg/dose at week 6, and about 1500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 500 mg/dose at week 0, about 500 mg/dose at week 2, about 500 mg/dose at week 6, and about 500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1500 mg/dose at week 0, about 1500 mg/dose at week 2, about 1500 mg/dose at week 6, and about 500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1500 mg/dose at week 0, about 1500 mg/dose at week 2, about 500 mg/dose at week 6, and about 500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1500 mg/dose at week 0, about 500 mg/dose at week 2, about 500 mg/dose at week 6, and about 500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 750 mg/dose at week 0, about 750 mg/dose at week 2, about 750 mg/dose at week 6, and about 750 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1000 mg/dose at week 0, about 1000 mg/dose at week 2, about 1000 mg/dose at week 6, and about 750 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1000 mg/dose at week 0, about 1000 mg/dose at week 2, about 750 mg/dose at week 6, and about 750 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1000 mg/dose at week 0, about 750 mg/dose at week 2, about 750 mg/dose at week 6, and about 750 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1500 mg/dose at week 0, about 1500 mg/dose at week 2, about 1500 mg/dose at week 6, and about 1500 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 750 mg/dose at week 0, about 750 mg/dose at week 2, about 750 mg/dose at week 6, and about 750 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1500 mg/dose at week 0, about 1500 mg/dose at week 2, about 1500 mg/dose at week 6, and about 750 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1500 mg/dose at week 0, about 1500 mg/dose at week 2, about 750 mg/dose at week 6, and about 750 mg/dose at week 10. In some embodiments, the induction regimen comprises administering about 1500 mg/dose at week 0, about 750 mg/dose at week 2, about 750 mg/dose at week 6, and about 750 mg/dose at week 10.
In one embodiment, the duration of the induction regimen is shorter than the duration of the maintenance regimen. In further embodiments, the induction regimen lasts for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In another embodiment, the induction regimen lasts for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In yet another embodiment, the induction regimen lasts for 8 weeks. In one embodiment, the induction regimen lasts for 9 weeks. In one embodiment, the induction regimen lasts for 10 weeks. In one embodiment, the induction regimen lasts for 11 weeks. In one embodiment, the induction regimen lasts 12 weeks.
As used herein, day 0 Zhou Yizhi is day 1 when an anti-TL 1A antibody or antigen binding fragment is administered. Day 0 Zhou Yizhi of the induction regimen the anti-TL 1A antibody or antigen binding fragment was administered in the induction regimen on day 1. Day 0 Zhou Yizhi of the maintenance regimen the anti-TL 1A antibody or antigen binding fragment is administered in the maintenance regimen on day 1.
The present disclosure provides that after an induction regimen, diseased tissue in a subject may overproduce and/or continue to overproduce (e.g., cell over-expression in the diseased tissue) TL1A. Thus, in some embodiments, the present disclosure further provides maintenance protocols for the various methods provided herein to maintain the concentration of TL1A in the diseased tissue in the subject below the concentration of TL1A in corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis. In certain embodiments, the methods provided herein further comprise a maintenance regimen to maintain the concentration of TL1A in the diseased tissue in the subject below the concentration of TL1A in a reference tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis. In some other embodiments, the methods provided herein further comprise a maintenance regimen to maintain the concentration of TL1A in the diseased tissue in the subject below a reference TL1A level (e.g., a reference concentration).
As described herein, the concentration of TL1A in diseased tissue of a subject is reduced below: (i) Reference TL1A levels or (ii) concentrations of TL1A in corresponding tissue or reference tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis, while diseased tissue (e.g., certain cells in diseased tissue) of the subject overproduces TL1A. Thus, a decrease in TL1A in diseased tissue may be maintained during any or all times of the maintenance regimen, while diseased tissue of the subject (e.g., certain cells in diseased tissue) overproduces TL1A at various overproduction levels. In some embodiments of the methods provided herein, including in this section (section 4.6), during the maintenance regimen, the diseased tissue in the subject produces TL1A that is at most 10, at most 15, at most 20, at most 25, at most 30, at most 35, at most 40, at most 45, at most 50, at most 55, at most 60, at most 65, at most 70, at most 75, at most 80, at most 85, at most 90, at most 95, at most 100-fold, or at most more times that of the corresponding tissue in the control subject. In certain embodiments, during the maintenance regimen, the diseased tissue in the subject produces TL1A up to about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, or about more times greater than the corresponding tissue in the control subject. In some embodiments, TL1A produced by the diseased tissue in the subject is up to 10 to 15, 10 to 20, 10 to 25, 10 to 30, 10 to 35, 10 to 40, 10 to 45, 10 to 50, 10 to 55, 10 to 60, 10 to 65, 10 to 70, 10 to 75, 10 to 80, 10 to 85, 10 to 90, 10 to 95, 10 to 100 times greater than TL1A produced by the corresponding tissue in the control subject during the maintenance regimen. In some embodiments, during the maintenance regimen, the diseased tissue in the subject produces TL1A up to 20 to 25, 20 to 30, 20 to 35, 20 to 40, 20 to 45, 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 times greater than the TL1A produced by the corresponding tissue in the control subject. In some embodiments, during the maintenance regimen, the diseased tissue in the subject produces TL1A up to 30 to 35, 30 to 40, 30 to 45, 30 to 50, 30 to 55, 30 to 60, 30 to 65, 30 to 70, 30 to 75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100 fold greater than the TL1A produced by the corresponding tissue in the control subject. In some embodiments, during the maintenance regimen, the diseased tissue in the subject produces TL1A up to 40 to 45, 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100 fold greater than the corresponding tissue in the control subject. In some embodiments, during the maintenance regimen, the diseased tissue in the subject produces TL1A up to 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100 fold greater than the TL1A produced by the corresponding tissue in the control subject. In one embodiment, during the maintenance regimen, the diseased tissue in the subject produces TL1A up to or about 10 times greater than the TL1A produced by the corresponding tissue in the control subject. In another embodiment, the TL1A produced by the diseased tissue in the subject is at most or about 20 times greater than the TL1A produced by the corresponding tissue in the control subject during the maintenance regimen. In another embodiment, the TL1A produced by the diseased tissue in the subject is at most or about 30 times greater than the TL1A produced by the corresponding tissue in the control subject during the maintenance regimen. In another embodiment, during the maintenance regimen, the diseased tissue in the subject produces TL1A that is at most or about 40 times greater than TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, during the maintenance regimen, the diseased tissue in the subject produces TL1A up to or about 50 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, during the maintenance regimen, the diseased tissue in the subject produces TL1A that is at most or about 60 times greater than TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, during the maintenance regimen, the diseased tissue in the subject produces TL1A up to or about 70 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, during the maintenance regimen, the diseased tissue in the subject produces TL1A that is at most or about 80 times greater than TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, during the maintenance regimen, the diseased tissue in the subject produces TL1A up to or about 90 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, during the maintenance regimen, the diseased tissue in the subject produces TL1A up to or about 100 times greater than the TL1A produced by the corresponding tissue in the control subject. In one embodiment, during the maintenance regimen, the diseased tissue in the subject produces TL1A up to or about 110 times greater than the TL1A produced by the corresponding tissue in the control subject. In another embodiment, the TL1A produced by the diseased tissue in the subject is at most or about 120 times greater than the TL1A produced by the corresponding tissue in the control subject during the maintenance regimen. As is apparent from the above description, by providing a reduction in TL1A in diseased tissue in this paragraph with the methods described, the present disclosure also provides that the methods provided herein can cover TL1A overproduction with an effective dosage or maintenance regimen for fold overproduction, timing, and/or duration, as described in this paragraph.
Similarly, in some embodiments of the methods provided herein, including in this section (section 4.6), prior to maintaining a regimen, the diseased tissue in the subject produces TL1A that is at most 10, at most 15, at most 20, at most 25, at most 30, at most 35, at most 40, at most 45, at most 50, at most 55, at most 60, at most 65, at most 70, at most 75, at most 80, at most 85, at most 90, at most 95, at most 100, or at most more times that of the corresponding tissue in the control subject. In certain embodiments, the TL1A produced by the diseased tissue in the subject is up to about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, or about more times greater than the TL1A produced by the corresponding tissue in the control subject prior to maintenance regimen. In some embodiments, prior to maintenance regimens, the subject has TL1A produced by the diseased tissue is up to 10 to 15, 10 to 20, 10 to 25, 10 to 30, 10 to 35, 10 to 40, 10 to 45, 10 to 50, 10 to 55, 10 to 60, 10 to 65, 10 to 70, 10 to 75, 10 to 80, 10 to 85, 10 to 90, 10 to 95, 10 to 100 times greater than TL1A produced by the corresponding tissue in the control subject. In some embodiments, prior to maintenance regimens, the subject has TL1A produced by the diseased tissue is up to 20 to 25, 20 to 30, 20 to 35, 20 to 40, 20 to 45, 20 to 50, 20 to 55, 20 to 60, 20 to 65, 20 to 70, 20 to 75, 20 to 80, 20 to 85, 20 to 90, 20 to 95, 20 to 100 fold greater than TL1A produced by the corresponding tissue in the control subject. In some embodiments, prior to maintenance regimens, the subject has TL1A produced by the diseased tissue is up to 30 to 35, 30 to 40, 30 to 45, 30 to 50, 30 to 55, 30 to 60, 30 to 65, 30 to 70, 30 to 75, 30 to 80, 30 to 85, 30 to 90, 30 to 95, 30 to 100 fold greater than TL1A produced by the corresponding tissue in the control subject. In some embodiments, prior to maintenance regimens, the TL1A produced by the diseased tissue in the subject is up to 40 to 45, 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100 fold greater than the TL1A produced by the corresponding tissue in the control subject. In some embodiments, prior to maintenance regimens, the diseased tissue in the subject produces TL1A up to 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100 fold greater than the TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, prior to maintenance regimens, the diseased tissue in the subject produces TL1A up to or about 10 times greater than the TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, prior to maintenance regimens, the diseased tissue in the subject produces TL1A up to or about 20 times greater than the TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, prior to maintenance regimens, the diseased tissue in the subject produces TL1A up to or about 30 times greater than the TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, prior to maintenance regimens, the diseased tissue in the subject produces TL1A up to or about 40 times greater than the TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, prior to maintenance regimens, the diseased tissue in the subject produces TL1A up to or about 50 times greater than the corresponding tissue in the control subject. In another specific embodiment, prior to maintenance regimens, the diseased tissue in the subject produces TL1A up to or about 60 times greater than the TL1A produced by the corresponding tissue in the control subject. In a specific embodiment, prior to maintenance regimens, the diseased tissue in the subject produces TL1A up to or about 70 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, prior to maintenance regimens, the diseased tissue in the subject produces TL1A up to or about 80 times greater than the corresponding tissue in the control subject. In a specific embodiment, prior to maintenance regimens, the diseased tissue in the subject produces TL1A up to or about 90 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, prior to maintenance regimens, the diseased tissue in the subject produces TL1A up to or about 100 times greater than the corresponding tissue in the control subject. In a specific embodiment, prior to maintenance regimens, the diseased tissue in the subject produces TL1A up to or about 110 times greater than the TL1A produced by the corresponding tissue in the control subject. In another specific embodiment, prior to maintenance regimens, the diseased tissue in the subject produces TL1A up to or about 120 times greater than the TL1A produced by the corresponding tissue in the control subject. As is apparent from the above description, by providing a reduction in TL1A in diseased tissue in this paragraph with the methods described, the present disclosure also provides that the methods provided herein can cover TL1A overproduction with an effective dosage or maintenance regimen for fold overproduction, timing, and/or duration, as described in this paragraph.
Alternatively, provided herein, in some embodiments of the methods included in this section (section 4.6), the diseased tissue in the subject produces TL1A that is at most 10, at most 15, at most 20, at most 25, at most 30, at most 35, at most 40, at most 45, at most 50, at most 55, at most 60, at most 65, at most 70, at most 75, at most 80, at most 85, at most 90, at most 95, at most 100-fold or at most more times greater than TL1A produced by 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, 44, 48, or 52 weeks of the start of the maintenance regimen. In certain embodiments, the diseased tissue in the subject produces TL1A that is up to about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, or about more times greater than the TL1A produced by 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 from the start of the maintenance regimen. In some embodiments, the diseased tissue in the subject produces TL1A that is up to 10 to 15, 10 to 20, 10 to 25, 10 to 30, 10 to 35, 10 to 40, 10 to 45, 10 to 50, 10 to 55, 10 to 60, 10 to 65, 10 to 70, 10 to 75, 10 to 80, 10 to 85, 10 to 90, 10 to 95, 10 to 100 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks beginning with the maintenance regimen. In some embodiments, the diseased tissue in the subject produces TL1A that is up to 20 to 25, 20 to 30, 20 to 35, 20 to 40, 20 to 45, 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 times greater than TL1A produced by 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 beginning with the maintenance regimen. In some embodiments, the diseased tissue in the subject produces TL1A that is up to 30 to 35, 30 to 40, 30 to 45, 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 times greater than TL1A produced by 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 beginning with the maintenance regimen. In some embodiments, the diseased tissue in the subject produces TL1A that is up to 40 to 45, 40 to 50, 40 to 55, 40 to 60, 40 to 65, 40 to 70, 40 to 75, 40 to 80, 40 to 85, 40 to 90, 40 to 95, 40 to 100 times greater than TL1A produced by 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 beginning with the maintenance regimen. In some embodiments, the diseased tissue in the subject produces TL1A that is up to 50 to 55, 50 to 60, 50 to 65, 50 to 70, 50 to 75, 50 to 80, 50 to 85, 50 to 90, 50 to 95, 50 to 100 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of the start of the maintenance regimen. In one embodiment, the diseased tissue in the subject produces TL1A that is up to or about 10 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of the initiation of the maintenance regimen. In one embodiment, the diseased tissue in the subject produces TL1A that is up to or about 20 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of the initiation of the maintenance regimen. In one embodiment, the diseased tissue in the subject produces TL1A that is up to or about 30 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of the initiation of the maintenance regimen. In a specific embodiment, the diseased tissue in the subject produces TL1A that is up to or about 40 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of the initiation of the maintenance regimen. In a specific embodiment, the diseased tissue in the subject produces TL1A up to or about 50 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of the initiation of the maintenance regimen. In another specific embodiment, the diseased tissue in the subject produces TL1A that is up to or about 60 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of the initiation of the maintenance regimen. In a specific embodiment, the diseased tissue in the subject produces TL1A up to or about 70 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of the initiation of the maintenance regimen. In another specific embodiment, the diseased tissue in the subject produces TL1A that is up to or about 80 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of the initiation of the maintenance regimen. In a specific embodiment, the diseased tissue in the subject produces TL1A up to or about 90 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of the initiation of the maintenance regimen. In another specific embodiment, the diseased tissue in the subject produces TL1A up to or about 100 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of the initiation of the maintenance regimen. In a specific embodiment, the diseased tissue in the subject produces TL1A that is up to or about 110 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of the initiation of the maintenance regimen. In another specific embodiment, the diseased tissue in the subject produces TL1A that is up to or about 120 times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks of the initiation of the maintenance regimen. As is apparent from the above description, by providing a reduction in TL1A in diseased tissue in this paragraph with the methods described, the present disclosure also provides that the methods provided herein can cover TL1A overproduction with an effective dosage or maintenance regimen for fold overproduction, timing, and/or duration, as described in this paragraph.
The present disclosure proposes that the maintenance regimen may comprise multiple administrations of an anti-TL 1A antibody or antigen-binding fragment. In one embodiment of the methods provided herein, which are encompassed in this section (section 4.6), the maintenance regimen comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more administrations of the anti-TL 1A antibody or antigen binding fragment. In another embodiment, the maintenance regimen comprises administration of about 2000, 1950, 1900, 1850, 1800, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 mg/dose. In one embodiment, the maintenance regimen comprises administration of about 50 to 1000, 50 to 950, 50 to 900, 50 to 850, 50 to 800, 50 to 750, 50 to 700, 50 to 650, 50 to 600, 50 to 550, 50 to 500, 50 to 450, 50 to 400, 50 to 350, 50 to 300, 50 to 250, 50 to 200, 50 to 150, or 50 to 100 mg/dose. In another embodiment, the maintenance regimen comprises about 100 to 1000, 100 to 950, 100 to 900, 100 to 850, 100 to 800, 100 to 750, 100 to 700, 100 to 650, 100 to 600, 100 to 550, 100 to 500, 100 to 450, 100 to 400, 100 to 350, 100 to 300, 100 to 250, 100 to 200, or 100 to 150 mg/dose of administration. In yet another embodiment, the maintenance regimen comprises administration of about 200 to 1000, 200 to 950, 200 to 900, 200 to 850, 200 to 800, 200 to 750, 200 to 700, 200 to 650, 200 to 600, 200 to 550, 200 to 500, 200 to 450, 200 to 400, 200 to 350, 200 to 300, or 200 to 250 mg/dose. In yet another embodiment, the maintenance regimen comprises administration once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In further embodiments, the maintenance regimen lasts for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, 52 or more weeks. The present disclosure further suggests that the maintenance regimen may include any combination of dosing amount, dosing frequency, number of administrations, and/or duration of induction regimen. Thus, and for example, in some embodiments, the induction regimen may include administering at a frequency of once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks for a duration of 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, 52, or more weeks for administration of about 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, or 50 mg/dose to a maintenance regimen.
In particular, provided herein, in some embodiments of the methods included in this section (section 4.6), the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 500 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 450 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 400 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 350 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 300 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 250 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 200 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 150 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 100 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 50 mg/dose every 2 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 500 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 450 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 400 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 350 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 300 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 250 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 200 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 150 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 100 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 50 mg/dose every 4 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 500 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 450 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 400 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 350 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 300 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 250 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 200 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 150 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 100 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 50 mg/dose every 6 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 500 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 450 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 400 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 350 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 300 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 250 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 200 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 150 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 100 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 50 mg/dose every 8 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 500 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 450 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 400 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 350 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 300 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 250 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 200 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 150 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 100 mg/dose every 10 weeks. In one embodiment, the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at about 50 mg/dose every 10 weeks.
For the various embodiments of the methods provided herein, including in this section (section 4.6, e.g., those in the preceding paragraphs), further embodiments of anti-TL 1A antibodies are provided in section 4.2, including embodiments having exemplary CDRs, framework sequences, constant region sequences, fc mutations, variable regions, fc regions, and other properties; assays for screening, testing, and validating anti-TL 1A antibodies are provided in section 4.3; methods for generating, modifying, mutating, cloning, expressing and isolating anti-TL 1A antibodies are provided in section 4.4; pharmaceutical compositions of anti-TL 1A antibodies are described and provided in section 4.5; additional specific and validated examples of anti-TL 1A antibodies and methods of their use are provided in section 5. Accordingly, the present disclosure provides various combinations of anti-TL 1A antibodies, pharmaceutical compositions of such anti-TL 1A antibodies, methods of generating anti-TL 1A antibodies, methods of assaying anti-TL 1A antibodies, and methods of using anti-TL 1A antibodies for treatment.
The present disclosure provides the advantage of using an anti-TL 1A antibody or antigen-binding fragment that binds to both monomer TL1A and trimer TL1A, as neutralizing both monomer and trimer TL1A can more effectively reduce functional trimer TL1A in diseased tissue. For the various embodiments of the methods provided herein, including in this section (section 4.6, e.g., those in the preceding paragraphs), the antibodies or antigen-binding fragments bind to both monomeric TL1A and trimeric TL1A. In some embodiments of the methods provided herein, an anti-TL 1A antibody or antigen-binding fragment blocks binding of TL1A to DR 3. In certain embodiments of the methods provided herein, an anti-TL 1A antibody or antigen-binding fragment binds to both monomeric TL1A and trimeric TL1A and blocks binding of TL1A to DR 3.
The disclosure also provides that for the methods provided herein, including in this section (section 4.6), the anti-TL 1A antibodies or antigen fragments can neutralize TL1A at different percent levels. In some embodiments of the methods provided herein, at least or about 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of monomeric TL1A in the blood of the subject is neutralized (e.g., occupied and blocked from binding to DR 3) by an anti-TL 1A antibody or antigen binding fragment. In certain embodiments of the methods provided herein, at least or about 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of trimeric TL1A in the blood of a subject is neutralized (e.g., occupied and blocked from binding to DR 3) by an anti-TL 1A antibody or antigen binding fragment. In some further embodiments of the methods provided herein, (i) at least or about 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of monomeric TL1A and (ii) at least or about 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of trimeric TL1A in the blood of the subject is neutralized (e.g., occupied and blocked from binding to DR 3) by an anti-TL 1A antibody or antigen binding fragment. In certain embodiments of the methods provided herein, at least or about 90% of monomeric TL1A in the blood of a subject is neutralized (e.g., occupied and blocked from binding to DR 3) by an anti-TL 1A antibody or antigen-binding fragment. In certain embodiments of the methods provided herein, at least or about 90% of trimeric TL1A in the blood of a subject is neutralized (e.g., occupied and blocked from binding to DR 3) by an anti-TL 1A antibody or antigen binding fragment. In some further embodiments of the methods provided herein, (i) at least or about 90% of monomeric TL1A and (ii) at least or about 90% of trimeric TL1A in the blood of the subject is neutralized (e.g., occupied and blocked from binding to DR 3) by an anti-TL 1A antibody or antigen binding fragment. In certain embodiments of the methods provided herein, at least or about 95% of monomeric TL1A in the blood of a subject is neutralized (e.g., occupied and blocked from binding to DR 3) by an anti-TL 1A antibody or antigen-binding fragment. In certain embodiments of the methods provided herein, at least or about 95% of trimeric TL1A in the blood of a subject is neutralized (e.g., occupied and blocked from binding to DR 3) by an anti-TL 1A antibody or antigen binding fragment. In some further embodiments of the methods provided herein, (i) at least or about 95% of monomeric TL1A and (ii) at least or about 95% of trimeric TL1A in the blood of the subject is neutralized (e.g., occupied and blocked from binding to DR 3) by an anti-TL 1A antibody or antigen binding fragment. In certain embodiments of the methods provided herein, at least or about 99% of monomeric TL1A in the blood of a subject is neutralized (e.g., occupied and blocked from binding to DR 3) by an anti-TL 1A antibody or antigen-binding fragment. In certain embodiments of the methods provided herein, at least or about 99% of trimeric TL1A in the blood of a subject is neutralized (e.g., occupied and blocked from binding to DR 3) by an anti-TL 1A antibody or antigen binding fragment. In some further embodiments of the methods provided herein, (i) at least or about 99% of monomeric TL1A and (ii) at least or about 99% of trimeric TL1A in the blood of the subject is neutralized (e.g., occupied and blocked from binding to DR 3) by an anti-TL 1A antibody or antigen binding fragment.
The diseased tissue described or referenced in the various methods contained in this section (section 4.6) provided herein may be one or more tissues that exhibit pathology in a subject due to pulmonary inflammation and/or pulmonary fibrosis. In one embodiment, the diseased tissue comprises or consists of a bronchus. In some embodiments, the diseased tissue comprises or consists of bronchioles. In certain embodiments, the diseased tissue comprises or consists of an alveolar catheter. In other embodiments, the diseased tissue comprises or consists of alveoli. In yet another embodiment, the diseased tissue comprises or consists of the pleura. In another embodiment, the diseased tissue comprises or consists of fibrotic tissue in the lung. In yet another embodiment, the diseased tissue includes or consists of other tissue having lung inflammation and/or lung fibrosis. In yet another embodiment, the diseased tissue comprises or consists of other tissue having the pathogenesis of the lung inflammation and/or lung fibrosis. In one embodiment, the diseased tissue comprises or consists of any one selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis. In one embodiment, the diseased tissue comprises or consists of any two selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis. In one embodiment, the diseased tissue comprises or consists of any three selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis. In one embodiment, the diseased tissue comprises or consists of any four selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis. In one embodiment, the diseased tissue comprises or consists of any five selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis. In one embodiment, the diseased tissue comprises or consists of any six selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis. In one embodiment, the diseased tissue comprises or consists of any seven selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis. In one embodiment, the diseased tissue comprises or consists of any eight selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis. It is clearly seen that in some embodiments, the diseased tissue comprises or consists of any number of tissues (e.g., one or more) selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis.
By tissue having lung inflammation and/or lung fibrosis is meant tissue that has exhibited a change caused by lung inflammation and/or lung fibrosis. Such significant changes in pulmonary inflammation and/or pulmonary fibrosis may be changes in gene or protein expression profiles (e.g., higher TL1A expression and/or ifnγ expression), histological changes (e.g., changes in the organization and arrangement of various cell types (e.g., damage to layers of epithelial cells), changes in the amount or ratio of various cell types of cells (e.g., loss of certain cells or excessive expansion of some cells), and/or the appearance of cell types that are not normally visible in tissue (e.g., infiltration of monocytes in tissue)).
Other tissues having the pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis refer to tissues that have been shown to cause or lead to changes in the development of pulmonary inflammation and/or pulmonary fibrosis. Such significant changes in pulmonary inflammation and/or pulmonary fibrosis may be changes in gene or protein expression profiles (e.g., higher TL1A expression and/or ifnγ expression), changes in protein or cell trafficking (e.g., increased secretion of TL1A and/or ifnγ or increased migration of monocytes to other tissues of pulmonary inflammation and/or pulmonary fibrosis), and/or other changes that may cause pulmonary inflammation and/or pulmonary fibrosis. The present disclosure proposes that tissue with lung inflammation and/or lung fibrosis is not mutually exclusive to tissue with pathogenesis of lung inflammation and/or lung fibrosis. Thus, some tissues having a pathogenesis of pulmonary inflammation and/or pulmonary fibrosis may also be tissues having pulmonary inflammation and/or pulmonary fibrosis, and some tissues having a pathogenesis of pulmonary inflammation and/or pulmonary fibrosis may also be tissues having a pathogenesis of pulmonary inflammation and/or pulmonary fibrosis.
The corresponding tissue of the various methods provided herein for determining fold overproduction of TL1A in diseased tissue may be the same or equivalent tissue as the diseased tissue, but in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis. For example, when the diseased tissue in a patient suffering from pulmonary inflammation and/or pulmonary fibrosis is alveoli, the corresponding tissue may be alveoli, or one or more portions of alveoli, tissue adjacent to alveoli, or tissue whose TL1A level is correlated with the level in alveoli. Alternatively, the corresponding tissue of the various methods provided herein for determining fold overproduction of TL1A in diseased tissue can be reference tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis. In addition, the corresponding tissue of the various methods provided herein for determining the fold over-production of TL1A in diseased tissue can be a reference tissue that is not affected by pulmonary inflammation and/or pulmonary fibrosis in the same diseased subject. Such reference tissue need not be the same as the diseased tissue, so long as the TL1A concentration in such reference tissue reflects a physiological or basal level of TL1A production as further described in the following paragraphs. Such reference tissue of the control subject may be bronchi, bronchioles, alveolar ducts, alveoli, pleura, and/or tissue (or tissues) without lung inflammation and/or lung fibrosis or abnormal TL1A expression. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of bronchi. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of bronchioles. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of alveolar ducts. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of alveoli. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of the pleura. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of tissue (or tissues) that does not have pulmonary inflammation and/or pulmonary fibrosis or abnormal TL1A expression. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of any combination of 2, 3, 4, 5, 6 or more tissues selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura and/or tissue (or tissues) without lung inflammation and/or pulmonary fibrosis or abnormal TL1A expression. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of any combination of 2 tissues selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura and/or tissue (or tissues) without lung inflammation and/or pulmonary fibrosis or abnormal TL1A expression. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of any combination of 3 tissues selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura and/or tissue (or tissues) without lung inflammation and/or pulmonary fibrosis or abnormal TL1A expression. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of any combination of 4 tissues selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura and/or tissue (or tissues) without lung inflammation and/or pulmonary fibrosis or abnormal TL1A expression. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of any combination of 5 tissues selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura and/or tissue (or tissues) without lung inflammation and/or pulmonary fibrosis or abnormal TL1A expression. In one embodiment, the corresponding tissue or reference tissue in the control subject comprises or consists of any combination of 6 tissues selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura and/or tissue (or tissues) without lung inflammation and/or pulmonary fibrosis or abnormal TL1A expression. In some embodiments of the various methods provided herein, including in this section (section 4.6), the fold overproduction of TL1A in diseased tissue can be determined by reference TL1A levels in control subjects not suffering from pulmonary inflammation and/or pulmonary fibrosis, rather than by TL1A levels in the corresponding tissue. Such reference TL1A levels may be specific concentrations, specific units of TL1A protein, and/or specific proxy measurements of TL 1A.
As used herein, the concentration of TL1A in a corresponding tissue or reference tissue for overproduction of TL1A compared to diseased tissue refers to the concentration of TL1A in such corresponding tissue or reference tissue at physiological or basal levels of TL1A production under normal healthy conditions, i.e., without having pulmonary inflammation and/or pulmonary fibrosis or other diseases or conditions (e.g., inflammatory or immunodeficiency conditions) that increase or inhibit TL1A production. In other words, the corresponding tissue or reference tissue as used herein refers to normal healthy tissue that does not have the pathology or stimulus that results in the production of abnormal TL 1A. Such physiological or basal levels of TL1A may be an average of TL1A concentrations in the corresponding tissue or the reference tissue over a period of time if the TL1A concentration fluctuates with the normal healthy physiological activity of such tissue over said period of time. In some embodiments, the period of time for the average TL1A concentration may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours or 1, 2, 3, 4, 5, 6, 7 days. For clarity, in some descriptions herein, the reference tissue is also referred to as normal reference tissue.
As is apparent from the description herein, a subject that is a target for administration of an anti-TL 1A antibody or antigen-binding fragment in the various methods provided herein may be a subject that has pulmonary inflammation and/or pulmonary fibrosis. In one embodiment, the subject as a target for administration of an anti-TL 1A antibody or antigen binding fragment in the various methods provided herein is a patient with diseased tissue from pulmonary inflammation and/or pulmonary fibrosis (e.g., as described above). In another embodiment, the subject as a target for administration of an anti-TL 1A antibody or antigen binding fragment in the various methods provided herein is a human subject. In another embodiment, the subject as a target for administration of an anti-TL 1A antibody or antigen binding fragment in the various methods provided herein is a patient with pulmonary inflammation and/or pulmonary fibrosis. In further embodiments, the subject as a target for administration of an anti-TL 1A antibody or antigen binding fragment in the various methods provided herein is a patient suffering from ulcerative colitis. In yet another embodiment, the subject as a target for administration of an anti-TL 1A antibody or antigen binding fragment in the various methods provided herein is a patient suffering from crohn's disease. In one embodiment, the subject as a target for administration of an anti-TL 1A antibody or antigen-binding fragment in the various methods provided herein is a patient suffering from ulcerative colitis and crohn's disease.
The present disclosure provides that the effective dose contained in this section (section 4.6) provided herein for use in the method can be determined by a dose determination method as further described in this section (section 4.6, including the following paragraphs). Thus, in various aspects and embodiments, provided herein are methods for determining an effective dose, including an induction regimen, a maintenance regimen, and both an induction regimen and a maintenance regimen.
In one aspect, provided herein is a method of determining an effective dosage regimen for administering an anti-TL 1A antibody, wherein the method comprises: (a) Rate of association of receiver antibody with monomer TL1A (k on-monomer ) Rate of association of antibody with trimeric TL1A (k on-trimer ) The dissociation rate (k) of the antibody from monomer TL1A off-monomers ) The dissociation rate (k) of the antibody from trimeric TL1A off-trimer ) Rate of synthesis of TL1A in Normal tissue (k syn-normal ) Rate of synthesis of TL1A in diseased tissue (k syn-disease ) Degradation rate of monomer TL1A (k deg-monomer ) And rate of degradation (k) of trimer TL1A deg-trimer ) The method comprises the steps of carrying out a first treatment on the surface of the (b) Integrating the rate received in (a) into a population based on a physiologically integrated systemic pharmacokinetic (PBPK) model; and (c) determining the effective dose regimen of the anti-TL 1A antibody with the PBPK model from (b) such that, after administration of the effective dose regimen, the concentration of TL1A in diseased tissue in the subject is lower than the concentration of TL1A in corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis.
In another aspect, provided herein is a method of determining an effective dosage regimen for administering an anti-TL 1A antibody, wherein the method comprises: (a) Receiving antibodies and monomersRate of association (k) of bulk TL1A -monomers ) Rate of association of antibody with trimeric TL1A (k on-trimer ) Dissociation rate of antibody from monomer TL1A (k off-monomers ) Dissociation rate of antibody from trimeric TL1A (k off-trimer ) Rate of synthesis of TL1A in Normal tissue (k syn-normal ) Rate of synthesis of TL1A in diseased tissue (k syn-disease ) Degradation rate of monomer TL1A (k deg-monomer ) And rate of degradation (k) of trimer TL1A deg-trimer ) The method comprises the steps of carrying out a first treatment on the surface of the Integrating the rate received in (a) into a population pharmacokinetic (popPK) model; and determining the effective dose regimen of the anti-TL 1A antibody with the popPK model from (b) such that after administration of the effective dose regimen, the concentration of TL1A in diseased tissue in the subject is lower than the concentration of TL1A in corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis.
In a further aspect, provided herein is a method of determining an effective dosage regimen for administering an anti-TL 1A antibody to a subject suffering from a disease, wherein the method comprises: (a) Receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in the normal reference tissue; (b) Integrating the parameters received in (a) into a physiologically integrated whole-body based pharmacokinetic (PBPK) model; and (c) determining the effective dose regimen of the anti-TL 1A antibody with the PBPK model from (b) such that, after administration of the effective dose regimen, the concentration of TL1A in diseased tissue in the subject is lower than the concentration of TL1A in corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis. In one embodiment of the method of this paragraph, the diseased subject has pulmonary inflammation and/or pulmonary fibrosis.
In yet another aspect, provided herein is a method of determining an effective dosage regimen for administering an anti-TL 1A antibody to a subject suffering from a disease, wherein the method comprises: (a) Receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in the normal reference tissue; (b) Integrating the parameters received in (a) into a population pharmacokinetic (popPK) model; and (c) determining the effective dose regimen of the anti-TL 1A antibody with the popPK model from (b) such that, after administration of the effective dose regimen, the concentration of TL1A in diseased tissue in the subject is lower than the concentration of TL1A in corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis. In one embodiment of the method of this paragraph, the diseased subject has pulmonary inflammation and/or pulmonary fibrosis.
The parameters of TL1A overproduction in the dose determination method reflect the overproduction of TL1A in diseased tissue in affected patients, e.g. in patients with lung disease. In some embodiments, the overproduction of the TL1A over-generates 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 times the overproduction of TL1A in the normal reference tissue. In certain embodiments, the parameters of TL1A overproduction may be various percentages or multiples, reflecting the overproduction of TL1A in diseased tissue in affected patients, e.g., patients with lung disease. In one embodiment, the overproduction of TL1A over-generates up to or about 5 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A is up to or about 10 times greater than the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A is up to or about 15 times greater than the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 20 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 25 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A is up to or about 30 times greater than the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A is up to or about 35 times greater than the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 40 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 45 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 50 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 55 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 60 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 65 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 70 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 75 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 80 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 85 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 90 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 95 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 100 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 110 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 120 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 130 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 140 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 150 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 160 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 170 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 180 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 190 times the overproduction of TL1A in the normal reference tissue. In one embodiment, the overproduction of TL1A over-generates up to or about 200 times the overproduction of TL1A in the normal reference tissue.
Step (a) included in the dose-determining methods provided herein in this section (section 4.6) may receive additional parameters, such as the rate of association and dissociation between the anti-TL 1A antibody and TL 1A. In one embodiment of the method, step (a) further comprises receiving the association rate (k) of the antibody with TL1A on-mAb ) The dissociation rate of the antibody from TL1A (k off-mAb ) Rate of synthesis of TL1A in Normal tissue (k syn-normal ) Rate of synthesis of TL1A in diseased tissue (k syn-disease ) And/or the degradation rate (k) of TL1A deg-Total-TL 1A ). In one embodiment, the rate of association (k on-mAb ) Comprises the association rate (k on-monomer ) And the rate of association (k) of the antibody with trimeric TL1A on-trimer ). In one embodiment, the dissociation rate (k off-mAb ) Comprising the dissociation rate (k off-monomers ) And the dissociation rate (k) of the antibody from trimeric TL1A off-trimer ). In one ofIn the examples, the degradation rate (k deg-Total-TL 1A ) Degradation rate (k) including monomer TL1A deg-TL1A monomer ) And rate of degradation (k) of trimer TL1A deg-TL1A-trimer ). In one embodiment, the rate of association (k on-mAb ) Comprises the association rate (k on-monomer ) And the rate of association (k) of the antibody with trimeric TL1A on-trimer ) And the dissociation rate (k off-mAb ) Comprising the dissociation rate (k off-monomers ) And the dissociation rate (k) of the antibody from trimeric TL1A off-trimer ). In one embodiment, the rate of association (k on-mAb ) Comprises the association rate (k on-monomer ) And the rate of association (k) of the antibody with trimeric TL1A on-trimer ) And the degradation rate of TL1A (k deg-Total-TL 1A ) Degradation rate (k) including monomer TL1A deg-TL 1A-monomer ) And rate of degradation (k) of trimer TL1A deg-TL 1A-trimer ). In one embodiment, the dissociation rate (k off-mAb ) Comprising the dissociation rate (k off-monomers ) And the dissociation rate (k) of the antibody from trimeric TL1A off-trimer ) And the degradation rate of TL1A (k deg-Total-TL 1A ) Degradation rate (k) including monomer TL1A deg-TL 1A-monomer ) And rate of degradation (k) of trimer TL1A deg-TL 1A-trimer ). In one embodiment, the rate of association (k on-mAb ) Comprises the association rate (k on-monomer ) And the rate of association (k) of the antibody with trimeric TL1A on-trimer ) Dissociation rate (k) of the antibody from TL1A off-mAb ) Comprising the dissociation rate (k off-monomers ) And the dissociation rate (k) of the antibody from trimeric TL1A off-trimer ) And/or the degradation rate (k) of TL1A deg-Total-TL 1A ) Degradation rate (k) including monomer TL1A deg-TL 1A-monomer ) And rate of degradation (k) of trimer TL1A deg-TL 1A-trimer )。
Additionally, the dosing method may comprise additional parameters of binding of the anti-TL 1A antibody to proteins other than the TL1A ligand, such as parameters of binding of the anti-TL 1A antibody or antigen binding fragment to FcRn. In some embodiments, step (a) of the dose determination method further comprises receiving a rate of association (k) of the antibody with FcRn receptor on-mAb-FcRn ) Dissociation rate of antibody to FcRn (k off-mAb-FcRn ) Rate of association of antibody-monomer TL1A complex with FcRn receptor (k on-(mAb-monoTL1A)-FcRn ) Dissociation rate of antibody-monomer TL1A complex from FcRn (k off-(mAb-monoTL1A)-FcRn ) Rate of association of antibody-trimeric TL1A complex with FcRn receptor (k on-(mAb-triTL1A)-FcRn ) And/or the dissociation rate (k) of the antibody-trimeric TL1A complex from FcRn off-(mAb-triTL1A)-FcRn ). In one embodiment, step (a) of the dose determination method further comprises receiving the rate of association (k on-mAb-FcRn ) And/or the dissociation rate of antibody from FcRn (k off-mAb-FcRn ). In another embodiment, step (a) of the dosing method further comprises receiving a rate of association (k) of the antibody-monomer TL1A complex with the FcRn receptor on-(mAb-monoTL1A)-FcRn ) And/or the dissociation rate (k) of the antibody-monomer TL1A complex from FcRn off-(mAb-monoTL1A)-FcRn ). In yet another embodiment, step (a) of the dosing method further comprises receiving a rate of association (k on-(mAb-triTL1A)-FcRn ) And/or the dissociation rate (k) of the antibody-trimeric TL1A complex from FcRn off-(mAb-triTL1A)-FcRn ). In further embodiments, step (a) of the dosing method further comprises receiving a rate of association (k) of the antibody-monomer TL1A complex with the FcRn receptor on-(mAb-monoTL1A)-FcRn ) Dissociation rate of antibody-monomer TL1A complex from FcRn (k off-(mAb-monoTL1A)-FcRn ) Rate of association of antibody-trimeric TL1A complex with FcRn receptor (k on-(mAb-triTL1A)-FcRn ) And/or the dissociation rate (k) of the antibody-trimeric TL1A complex from FcRn off-(mAb-triTL1A)-FcRm )。
Alternatively, in some embodiments, aStep (a) of the dose determination method further comprises receiving a rate of association (k) of the antibody with the FcRn receptor om-mAb-FcRn ) Dissociation rate of antibody to FcRn (k off-mAb-FcRn ) Rate of association of antibody-TL 1A complex with FcRn receptor (k on-(mAb-TL1A)-FcRn ) And/or the dissociation rate (k) of the antibody-TL 1A complex from FcRn off-(mAb-TL1A)-FcRn ). In one embodiment, the rate of association (k on-(mAb-TL1A)-FcRn ) Comprising the rate of association (k) of the antibody-monomer TL1A complex with the FcRn receptor on-(mAb-monoTL1A)-FcRn ) And the rate of association of the antibody-trimeric TL1A complex with FcRn receptor (k on-(mAb-triTL1A)-FcRn ). In one embodiment, the dissociation rate (k off-(mAb-TL1A)-FcRn ) Comprising the dissociation rate (k) of the antibody-monomer TL1A complex from FcRn off-(mAb-monoTL1A)-FcRn ) And dissociation rate of antibody-trimeric TL1A complex from FcRn (k off-(mAb-triTL1A)-FcRn ). In another embodiment, the rate of association (k on-(mAb-TL1A)-FcRn ) Comprising the rate of association (k) of the antibody-monomer TL1A complex with the FcRn receptor on-(mAb-monoTL1A)-FcRn ) And the rate of association of the antibody-trimeric TL1A complex with FcRn receptor (k on-(mAb-triTL1A)-FcRn ) And/or wherein the dissociation rate (k) of the antibody-TL 1A complex from FcRn off-(mAb-TL1A)-FcRn ) Comprising the dissociation rate (k) of the antibody-monomer TL1A complex from FcRn off-(mAb-monoTL1A)-FcRn ) And dissociation rate of antibody-trimeric TL1A complex from FcRn (k off-(mAb-triTL1A)-FcRn )。
Similarly, the dosing method may comprise additional parameters, such as parameters of the degradation rate of the complex between the anti-TL 1A antibody or antigen binding fragment and FcRn. In one embodiment, step (a) of the dose determination method further comprises receiving the clearance (k deg-mAb-FcRn ). In one embodiment, the clearance (k deg-mAb-FcRn ) Further comprising clearance (k) of the antibody to FcRn bound by the antibody-monomer TL1A complex deg-(mAb-monoTL1A)-FcRn ) And FcRn receptor clearance bound by the antibody-trimeric TL1A complex (k deg-(mAb-triTL1A)-FcRn )。
Alternatively, in one embodiment, step (a) of the dose determination method further comprises receiving the clearance (k deg-mAb-FcRn ) Clearance of the antibody to FcRn bound by antibody-monomer TL1A complex (k deg-(mAb-monoTL1A)-FcRn ) And/or clearance of FcRn receptor bound by antibody-trimeric TL1A complex (k deg-(mAb-triTL1A)-FcRn ). In one embodiment, step (a) of the dose determination method further comprises receiving the clearance (k deg-mAb-FcRn ). In one embodiment, step (a) of the dose determination method further comprises receiving the clearance (k) of the antibody from FcRn bound by the antibody-monomer TL1A complex deg-(mAb-monoTL1A)-FcRn ). In one embodiment, step (a) of the dose determination method further comprises receiving the clearance (k) of FcRn receptor bound by the antibody-trimeric TL1A complex deg-(mAb-triTL1A)-FcRn ). In one embodiment, step (a) of the dose determination method further comprises receiving the clearance (k deg-mAb-FcRn ) And clearance (k) of the antibody to FcRn bound by the antibody-monomer TL1A complex deg-(mAb-monoTL1A)-FcRn ). In one embodiment, step (a) of the dose determination method further comprises receiving the clearance (k deg-mAb-FcRn ) And FcRn receptor clearance bound by the antibody-trimeric TL1A complex (k deg-(mAb-triTL1A)-FcRn ). In one embodiment, step (a) of the dose determination method further comprises receiving the clearance (k) of the antibody from FcRn bound by the antibody-monomer TL1A complex deg-(mAb-monoTL1A)-FcRn ) And FcRn receptor clearance bound by the antibody-trimeric TL1A complex (k deg-(mAb-triTL1A)-FcRn ). In one embodiment, step (a) of the dose determination method further comprises receiving the clearance (k deg-mAb-FcRn ) Clearance of the antibody to FcRn bound by antibody-monomer TL1A complex (k deg-(mAb-monoTL1A)-FcRn ) And FcRn receptor clearance bound by the antibody-trimeric TL1A complex (k deg-(mAb-triTL1A)-FcRn )。
In addition, in various embodiments of the dose determination methods provided herein, including in this section (section 4.6), step (a) in the dose determination method further comprises receiving a rate (k on-TL 1A-monomer to trimer ) And/or the rate of TL1A monomer (k off-TL 1A-trimer to monomer ). In one embodiment, step (a) of the dose determination method further comprises receiving a rate (k on-TL 1A-monomer to trimer ). In another embodiment, step (a) of the dose determination method further comprises receiving a rate (k) of TL1A singulation off-TL 1A-trimer to monomer ). In yet another embodiment, step (a) of the dose determination method further comprises receiving a rate (k on-TL 1A-monomer to trimer ) And the rate of TL1A monomer (k off-TL 1A-trimer to monomer )。
The term rate of TL1A trimerization refers to the kinetic rate of TL1A monomer self-association to form a TL1A trimer. The term rate of TL1A monomer refers to the kinetic rate of dissociation of TL1A trimer into TL1A monomers.
The various parameters in the dose determination method may be the same or different. The various parameters in the dose determination method may also be related by ranges, multiple differences of values, and/or by specific differences of values. In one embodiment of the various dose determination methods provided herein, k on-monomer And k on-trimer The same or different. In one embodiment of the various dose determination methods provided herein, k off-monomers And k off-trimer The same or different. In one embodiment of the various dose determination methods provided herein, k deg-monomer And k deg-trimer The same or different. In one embodiment of the various dose determination methods provided herein, k on-(mAb-monoTL1A)-FcRn And k on-(mAb-triTL1A)-FcRn The same or different. Provided hereinIn one embodiment of the various dose determination methods, k on-mAb-FcRn And k on-(mAb-monoTL1A)-FcRn The same or different. In one embodiment of the various dose determination methods provided herein, k on-mAb-FcRn And k on-(mAb-triTL1A)-FcRn The same or different. In one embodiment of the various dose determination methods provided herein, k off-(mAb-monoTL1A)-FcRn And k off-(mAb-triTL1A)-FcRn The same or different. In one embodiment of the various dose determination methods provided herein, k off-mAb-FcRn And k off-(mAb-monoTL1A)-FcRn The same or different. In one embodiment of the various dose determination methods provided herein, k off-mAb-FcRn And k off-(mAb-triTL1A)-FcRn The same or different. In one embodiment of the various dose determination methods provided herein, k deg-(mAb-monoTL1A)-FcRn And k deg-(mAb-triTL1A)-FcRn The same or different. In one embodiment of the various dose determination methods provided herein, k deg-mAb-FcRn And k deg-(mAb-triTL1A)-FcRn The same or different. In one embodiment of the various dose determination methods provided herein, k deg-mAb-FcRn And k deg-(mAb-monoTL1A)-FcRn The same or different. In one embodiment of the various dose determination methods provided herein, the parameters received in the dose determination methods may have any combination of the relationships included in this paragraph as described herein.
As is clear from the description herein, diseased tissue overproduces TL1A than normal tissue. As provided above, the diseased tissue overproduces TL1A compared to the normal reference tissue, and the overproduction of the parameter of TL1A 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 times the overproduction of TL1A in the normal reference tissue. Thus, k syn-disease Can be compared with k syn-normal Various percentages or multiples are raised. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 5, 10, 15, 20, 25, 30, 35, 40,45. 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 or more times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 5 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 10 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 15 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 20 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 25 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 30 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 35 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 40 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 45 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 50 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 55 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 60 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 65 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 70 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 75 times greater than the above. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 80 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 85 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 90 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 95 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 100 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 110 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 120 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 130 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 140 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 150 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 160 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 170 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 180 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 190 times. In one embodiment of the dose determination method, k syn-disease Is k syn-normal Up to or about 200 times.
Normal tissue, reference tissue or normal reference tissue in the methods (including the methods provided in this section (section 4.6), such as the use/treatment methods and/or the dose determination methods) refers to tissue that does not have pathology from pulmonary inflammation and/or pulmonary fibrosis and/or does not have abnormal TL1A expression. In some embodiments of the dose-determining method, such normal tissue comprises or consists of healthy tissue from a subject having pulmonary inflammation and/or pulmonary fibrosis (e.g., tissue that does not have pulmonary inflammation and/or pulmonary fibrosis-associated pathology and/or does not have abnormal TL1A expression). In certain embodiments of the dose-determining method, such normal tissue comprises or consists of corresponding or reference tissue from a subject not suffering from pulmonary inflammation and/or pulmonary fibrosis, as provided in this section (section 4.6) and described in further detail.
The various parameters of the systemic physiological-based pharmacokinetics ("PBPK") in the dose determination method, including various rate parameters, may be such parameters that are known and used in systemic PBPK, for example, as described in the following documents: jones H et al, journal of the American society of pharmaceutical sciences (American Association of Pharmaceutical Scientists Journal, AAPS J.); 15 (2): 377-87; dostalek, M et al, cl (Clin Pharmacokinet) in pharmacokinetics, month 2 of 2013; 52 (2): 83-124; li L et al, journal of the American society of pharmaceutical sciences, month 9 of 2014; 16 (5): 1097-109; nestonov I. (Clin pharmacokinetics.) 2003;42 (10): 883-908. In some embodiments, the various systemic PBPK parameters in the end-of-dose method, including the various rate parameters described in this section (section 4.6), may have values as described in section 5. In other embodiments, various systemic PBPK parameters in the end-of-dose method, including various rate parameters described in this section (section 4.6), can be determined as described in section 5.
Alternatively, the various parameters of the population pharmacokinetic ("popPK") model in the dose determination method, including the various rate parameters, may be such parameters known and used in popPK, for example, as described in the following documents: muldulication DR et al, CPT quantitative pharmacology and systemic pharmacology (CPTPharmacometrics Syst pharmacol.) month 4 of 2013; 2 (4): e38; industry group pharmacokinetic guidelines (Guidance for Industry Population Pharmacokinetics), provided by the central pharmaceutical evaluation and research (CDER) center biological product evaluation and research Center (CBER), U.S. health and public service, food and drug administration, month 2 1999. In some embodiments, the various popPK parameters in the end of dose method, including the various rate parameters described in this section (section 4.6), can have values as described in section 5. In other embodiments, various popPK parameters in the end of dose method, including various rate parameters described in this section (section 4.6), can be determined as described in section 5.
A "population pharmacokinetic model" or "popPK model" is a model of a mathematical simulation that integrates the absorption, distribution, metabolism, and elimination of a drug and its metabolites to fit and/or predict drug concentrations in a patient population, where such a model can fit and/or predict observed time courses of drug concentrations between patient populations receiving clinically relevant doses of drug and changes in drug concentrations in such patient populations. Such popPK models can predict the time course of drug concentration in a patient population receiving a given dose, and thus can model and determine the dose of an expected drug level in the patient population. In some embodiments, the popPK model comprises or consists of the popPK model described in section 5.
A "whole-body physiological-based pharmacokinetic model" or "whole-body PBPK model" is a model that integrates and maps the absorption, distribution, metabolism, and elimination of drugs and their metabolites onto physiologically realistic compartment structures, including body tissues, fluids, organs, and/or systems. Such a whole-body PBPK model may have two different sets of parameters: (i) A drug independent subset derived from potential physiological processes (e.g., diffusion and transport), which may be as known and practically available in the field, or specifically determined for a particular patient population as known and practically available in the field; and (ii) a drug-specific subset characterized by pharmacokinetic properties of a particular drug and derived from clinical or preclinical studies. Such systemic PBPK models can fit and/or predict observed time courses of drug concentration in patients receiving clinically relevant doses of drug. Such systemic PBPK models can predict the time course of drug concentration in a patient receiving a given dose, and thus can model and determine the dose of an expected drug level in the patient. In some embodiments, the systemic PBPK model comprises or consists of the systemic PBPK model described in section 5.
As is apparent from the description, the dose determination methods provided herein can be used to determine effective doses, induction regimens, and/or maintenance regimens for various embodiments of methods of treatment, methods of reducing TL1A concentration in diseased tissue, and methods of neutralizing monomeric and trimeric TL1A. Thus, the various embodiments described herein for the elements mentioned in the dose-determining method are also provided for the dose-determining method, including various embodiments with respect to the anti-TL 1A antibody or antigen-binding fragment (e.g., in this section (4.6) and in sections 4.2 and 5), those with respect to an effective dose (e.g., in this section (4.6) and in section 5), those with respect to an induction regimen (e.g., in this section (4.6) and in section 5), those with respect to a maintenance regimen (e.g., in this section (4.6) and in section 5), those with respect to diseased tissue, and/or those with respect to a corresponding or reference tissue (e.g., in this section (4.6) and in section 5).
In some embodiments of the various methods provided herein, including in this section (section 4.6, e.g., each of sections 4.6), the concentration of TL1A is the concentration of free TL1A. In certain embodiments of the various methods provided herein, which are included in this section (section 4.6, e.g., each section of section 4.6), the concentration of TL1A in the diseased tissue referred to in the various methods is the concentration of free TL1A in the diseased tissue. In some embodiments of the various methods provided herein, included in this section (section 4.6, e.g., each of section 4.6), the concentration of TL1A in the corresponding tissue or the reference tissue is the concentration of free TL1A in the corresponding tissue or the reference tissue. In certain other embodiments of the various methods provided herein, which are included in this section (section 4.6, e.g., each section of section 4.6), the concentration of TL1A in the diseased tissue referred to in the various methods is the concentration of free TL1A in the diseased tissue, and the concentration of TL1A in the corresponding tissue or reference tissue is the concentration of free TL1A in the corresponding tissue or reference tissue. As used herein, free TL1A means that TL1A is not neutralized or bound by an anti-TL 1A antibody. Such free TL1A is TL1A that can bind DR3 and trigger TL 1A-mediated signaling or function.
Methods disclosed herein comprise methods of treating an inflammatory disease and/or condition in a subject by administering to the subject an anti-TL 1A antibody described herein. The methods disclosed herein comprise methods of treating a fibrotic disease and/or condition in a subject by administering to the subject an anti-TL 1A antibody described herein. In some embodiments, the method of treating a fibrotic disease and/or condition is independent of the treatment of inflammation.
The methods disclosed herein comprise methods of treating a disease and/or condition of the lung of a subject by administering to the subject an anti-TL 1A antibody described herein. In some embodiments, the disease or condition comprises a chronic pulmonary disorder. Non-limiting examples of diseases and/or conditions include idiopathic interstitial pneumonia, virus-induced pulmonary fibrosis, asthma, COPD, pulmonary sarcoidosis, interstitial pulmonary disease, bronchiolitis, alveolitis, vasculitis, interstitial pneumonia, nonspecific interstitial pneumonia, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, acute interstitial pneumonia, allergic rhinitis, primary cholangitis, behcet's disease, and cystic fibrosis. In some embodiments, the disease and/or condition comprises idiopathic pulmonary fibrosis. In some embodiments, the disease or condition comprises virus-induced pulmonary fibrosis (e.g., during and/or after infection of a subject with a virus, such as a coronavirus, e.g., SARS-CoV-2). In some embodiments, the disease and/or condition comprises asthma. In some embodiments, the disease or condition comprises COPD. In some embodiments, the disease or condition comprises pneumonia. In some embodiments, the disease or condition comprises pneumonia. In some embodiments, the disease or condition comprises bronchitis. In some embodiments, the disease or condition is inflammatory bowel disease. In various embodiments, the subject is determined to have increased TL1A expression. In some embodiments, administration of a therapeutically effective amount of an anti-TL 1A antibody causes a reduction in TL1A in the subject being treated. In example embodiments, the anti-TL 1A antibody comprises any one of the anti-TL 1A antibody embodiments provided herein. In some embodiments, the anti-TL 1A antibody comprises antibody A, B, C, D, E, F, G, H, I, A, B2, C2, D2, E2, F2, G2, H2, I2, J, K, M, or N. In some embodiments, the anti-TL 1A antibody comprises any one of the antibodies of table 1. As a non-limiting example, anti-TL 1A antibodies include antibody a219.
In some embodiments, the disease or condition comprises systemic sclerosis (SSc). In some embodiments, the disease or condition is systemic sclerosis-related interstitial lung disease (SSc-ILD). In some embodiments, the disease or condition comprises sclerosis. SSc is characterized by multiple simultaneous disease processes, differing in severity and impact on the quality of life of the patient. In the United states, about 100,000 people suffer from SSc, which comprises about 50,000 people with SSc-ILD, and the incidence is increasing (clinical epidemiology (Clinical Epidemiology) 2019:11257-273; the Morus registry; the sclerosant Gene). In the united states, ten years have a survival rate of about 54-82%. Without being bound by theory, systemic sclerosis is caused by excessive/progressive collagen deposition in skin/internal organs, severe fibroproliferative vascular lesions of arterioles/arteries, and/or humoral/cellular immune changes. Fibrosis is associated with the following: imbalance of T helper 1/T helper 2 (Th 1/Th 2) cytokines (thus leading to more fibrosis by collagen synthesis, and further promotion of vascular injury and fibrosis (pro-fibrotic and pro-inflammatory cytokines) due to more pro-fibrotic cytokines (TGF-beta, IL-4, IL-5, IL-13), activated macrophages, monocytes and dendritic cells, and activated B cells that produce autoantibodies.
In some embodiments, the method of treating a fibrotic disease and/or condition with an anti-TL 1A antibody comprises treating SSc. In some cases, the method of treating SSc with an anti-TL 1A antibody produces an anti-fibrotic effect.
In some embodiments, the disease or condition comprises systemic sclerosis-related interstitial lung disease (SSc-ILD). In addition to the foregoing, support for SSc-ILD treatment contained data that showed that TL1A injected into wild-type murine lungs promoted DR 3-dependent fibrosis and remodeling (increased collagen deposition in glandular cells and bronchioles, increased myofibroblasts and smooth muscle thickness), and that TL 1A-induced fibrosis was T-cell independent, but required DR3 (RAG 2-/-and RAGyc-/-and WT mice were sensitive to TL1A, whereas DR 3-/-mice were insensitive to TL 1A). Inhibition of DR3 reduced pulmonary fibrosis (bleomycin) and dust mist allergen protein (HDM) in murine models induced pulmonary fibrosis in mice, DR 3-/-mice were resistant to airway remodeling and pulmonary fibrosis in response to bleomycin and HDM, and blocking TL1A using DR3.Fc prevented fibrosis in bleomycin and HDM models. In addition, structural cells from SSc patients express DR3 and can be directly responsive to TL1A (lung fibroblasts from SSc patients express more DR3 than fibroblasts from IPF or healthy subjects when treated with rTLA1A, lung fibroblasts and epithelial cells secrete periostin (fibrotic mediators), and lung fibroblasts synthesize collagen when treated with rTL 1A). In addition, circulating levels of TL1A were elevated in SSc patients. Thus, TL1A directly activates structural lung cells and induces fibrosis independent of inflammation, as demonstrated at least by: instillation of TL1A in murine models was sufficient to induce pulmonary fibrosis in a DR 3-dependent manner, TL1A did not require a functional immune system to trigger pulmonary fibrosis, TL1A stimulated primary fibroblast proliferation, and TL1A induced periostin and collagen expression from structural lung cells.
In some embodiments, the methods comprise treating a patient with an anti-TL 1A antibody comprising a higher level of TL1A as compared to a patient not suffering from a disease or condition herein. In some embodiments, the methods comprise treating a patient with an anti-TL 1A antibody comprising a higher level of DR3 as compared to a patient without a disease or condition herein. For example, a patient without a disease or condition herein is free of inflammation and/or fibrosis. TL1A levels comprise levels of TL1A protein, RNA and/or DNA in a biological sample from a subject.
The anti-TL 1A antibodies described herein can significantly improve the effect in patients susceptible to increased TL1A expression. For example, a patient is selected for treatment with an anti-TL 1A antibody herein based on increased expression of TL1A in the patient as compared to a reference level (e.g., from a subject not suffering from a disease or condition). The patient may be selected for increased TL1A expression as determined by a genotyping assay that determines the presence of a genotype associated with increased TL1A expression. TL1A and nucleic acid encoding TL1A (tumor necrosis factor ligand superfamily member 15 (TNFSF 15)) are provided, as shown by: entrez Gene:9966; uniProtKB: o95150.
In some embodiments, a subject refers to any animal that will be the recipient of a particular treatment, including, but not limited to, humans, non-human primates, rodents, and domestic and hunting animals. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and cynomolgus monkeys, e.g., rhesus monkeys. Rodents include mice, rats, woodchuck, ferrets, rabbits, and hamsters. Domestic animals and hunting animals include cattle, horses, pigs, deer, bison, buffalo, felines (e.g., domestic cats), canines (e.g., dogs, foxes, wolves), avians (e.g., chickens, emus, ostriches), and fish (e.g., trout, catfish, and salmon). In various embodiments, the subject may be a subject that has been previously diagnosed with or identified as suffering from or having a condition in need of treatment. In certain embodiments, the subject is a human. In various embodiments, a subject previously diagnosed with or identified as suffering from or having a condition may or may not have undergone treatment for the condition. In some embodiments, the subject may also be a subject who has not been previously diagnosed as having a condition (i.e., a subject who exhibits one or more risk factors for the condition). A "subject in need of treatment" for a particular condition may be a subject suffering from, diagnosed as suffering from, or at risk of developing the condition. In some embodiments, the subject is a "patient" who has been diagnosed with a disease or condition described herein. In some cases, the subject suffers from symptoms associated with the diseases or conditions disclosed herein (e.g., abdominal pain, cramps, diarrhea, rectal bleeding, fever, weight loss, fatigue, loss of appetite, dehydration, and malnutrition, anemia, or ulcers).
In some embodiments, the term "therapeutically effective amount" refers to an amount of an antibody effective to "treat" a disease or condition in a subject or mammal. In some cases, a therapeutically effective amount of the drug reduces the severity of the symptoms of the disease or condition. In some cases, the disease or condition includes an inflammatory disease or condition. In some cases, the disease or condition includes a fibrotic disease or condition. In some cases, the disease or condition includes a disease or condition of the lung. Non-limiting examples of diseases and/or conditions include idiopathic interstitial pneumonia, virus-induced pulmonary fibrosis, asthma, COPD, pulmonary sarcoidosis, interstitial pulmonary disease, bronchiolitis, alveolitis, vasculitis, interstitial pneumonia, non-specific interstitial pneumonia, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, acute interstitial pneumonia, allergic rhinitis, and cystic fibrosis.
In some embodiments, the term "treatment" or "treatment" as used herein refers to both therapeutic treatment and prophylactic or preventative measures (e.g., disease progression), wherein the object is to prevent or slow down (reduce) a targeted pathological condition. Therapeutic treatment includes alleviating a condition and alleviating a symptom of a condition. In some aspects provided herein, subjects in need of treatment include those already with the disease or condition, as well as those prone to develop the disease or condition. The disease or condition may include an inflammatory disease or condition.
The pharmaceutical composition may be delivered in a therapeutically effective amount. The precise therapeutically effective amount is the amount of the composition that will produce the most effective result in terms of therapeutic efficacy in a given subject. This amount will vary depending on a variety of factors including, but not limited to, the characteristics of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (including age, sex, disease type and stage, general physical condition, responsiveness to a given dose, and drug type), the nature of the pharmaceutically acceptable carrier(s) in the formulation, and the route of administration. Those skilled in the clinical and pharmacological arts will be able to determine a therapeutically effective amount by routine experimentation, for example, by monitoring the subject's response to administration of a compound and adjusting the dosage accordingly. For additional guidance, see, e.g., ramington: pharmaceutical science and practice (remington: the Science and Practice of Pharmacy) (Gennaro edit 20 th edition, wilins Wilkins publishing company (Williams & Wilkins PA, USA) of PA, USA) (2000).
For the treatment of diseases, the appropriate dosage of antibody depends on the type of disease to be treated, the severity and course of the disease, the responsiveness of the disease, whether the antibody is administered for therapeutic or prophylactic purposes, past therapies and the clinical history of the patient. The dosage may also be adjusted by the individual physician and at the discretion of the attending physician in the event of any complications. The optimum dosage, method of administration and repetition rate can be determined by the administering physician. TL1A antibodies may be administered once or for a series of treatments ranging from days to months, or until a cure is achieved or a reduction in the disease state is achieved. The duration of treatment depends on the clinical progress of the subject and the responsiveness to the therapy. In certain embodiments, the dose is 0.01 μg to 100mg per kilogram body weight and may be administered one or more times per day, once per week, once per month, or once per year.
In one aspect, a method of treating an inflammatory disease or condition comprises administering an anti-TL 1A antibody to a subject. In some embodiments, a dose of up to about 1000mg is administered to a subject. In some embodiments, a dose of about 150mg to about 1000mg is administered to a subject. In some of the cases where the number of the cases, the dosage is from about 150mg to about 900mg, from about 150mg to about 800mg, from about 150mg to about 700mg, from about 150mg to about 600mg, from about 150mg to about 500mg, from about 150mg to about 400mg, from about 150mg to about 300mg, from about 150mg to about 200mg, from about 160mg to about 1000mg, from about 160mg to about 900mg, from about 160mg to about 800mg, from about 160mg to about 700mg, from about 160mg to about 600mg, from about 160mg to about 500mg, from about 160mg to about 400mg, from about 160mg to about 300mg, from about 160mg to about 200mg, from about 170mg to about 1000mg, from about 170mg to about 900mg, from about 170mg to about 800mg, from about 170mg to about 700mg, from about 170mg to about 600mg, from about 170mg to about 500mg, from about 170mg to about 300mg, from about 170mg to about 200mg, from about 175mg to about 1000mg, from about 175mg to about 175mg, from about 175mg to about 175mg, from about 700mg, about 800mg, from about 800mg, about about 175mg to about 600mg, about 175mg to about 500mg, about 175mg to about 400mg, about 175mg to about 300mg, about 175mg to about 200mg, about 180mg to about 1000mg, about 180mg to about 900mg, about 180mg to about 800mg, about 180mg to about 700mg, about 180mg to about 600mg, about 180mg to about 500mg, about 180mg to about 400mg, about 180mg to about 300mg, about 180mg to about 200mg, about 190mg to about 1000mg, about 190mg to about 900mg, about 190mg to about 800mg, about 190mg to about 700mg, about 190mg to about 600mg, about 190mg to about 500mg, about 190mg to about 400mg, about 190mg to about 300mg, about 190mg to about 200mg, about 200mg to about 1000mg, about 200mg to about 900mg, about 200mg to about 800mg, about 200mg to about 700mg, about 200mg to about 600mg, about 200mg to about 500mg, or about 400mg to about 300mg. In some cases, the dose is about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg, about 900, about 950mg, or about 1000mg.
In some cases, anti-TL 1A is administered in a fixed dose, e.g., about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg, about 900, about 950mg, or about 1000mg. In some cases, anti-TL 1A is administered based on the weight (kg) of the subject. For example, the anti-TL 1A is administered at a dosage of about 0.15mg/kg to about 20mg/kg or about 0.15mg/kg, about 1.0mg/kg, about 1.5mg/kg, about 2.0mg/kg, about 2.5mg/kg, about 3.0mg/kg, about 3.5mg/kg, about 4.0mg/kg, about 4.5mg/kg, about 5.0mg/kg, about 5.5mg/kg, about 6.0mg/kg, about 6.5mg/kg, about 7.0mg/kg, about 7.5mg/kg, about 8.0mg/kg, about 8.5mg/kg, about 9.0mg/kg, about 9.5mg/kg, about 10.0mg/kg, about 11mg/kg, about 12mg/kg, about 13mg/kg, about 14mg/kg, about 15mg/kg, about 16mg/kg, about 17mg/kg, about 18mg/kg, about 19mg/kg or about 20 mg/kg.
In some embodiments, the dose of anti-TL 1A is administered subcutaneously. In some embodiments, the dose of anti-TL 1A is administered intravenously.
For subcutaneous injection, the dose may be administered in one or more injections. As a non-limiting example, a dose comprising about 800mg of anti-TL 1A may be administered in about 2, 3, 4, or 5 injections. As a further example, the dose comprising about 800mg of anti-TL 1A antibody is administered in about 4 injections of about 200 mg/mL. In some embodiments, the dose may be administered in one injection. For example, a dose comprising about 175-300mg of anti-TL 1A is administered in one injection of about 175-250 mg/mL. As another example, a dose comprising about 175-300mg of anti-TL 1A is administered in one injection of about 175-200 mg/mL.
In some embodiments, the dose and/or injection of anti-TL 1A is administered in a volume of less than about 3mL, less than about 2.9mL, less than about 2.8mL, less than about 2.7mL, less than about 2.6mL, less than about 2.5mL, less than about 2.4mL, less than about 2.3mL, less than about 2.2mL, less than about 2.1mL, less than about 2mL, less than about 1.9mL, less than about 1.8mL, less than about 1.7mL, less than about 1.6mL, less than about 1.5mL, less than about 1.4mL, less than about 1.3mL, less than about 1.2mL, less than about 1.1mL, less than about 1.0mL, less than about 0.9mL, less than about 0.8mL, or less than about 0.7 mL. The volume may be at least about 0.5mL. The volume may be from about 0.5mL to about 3mL, from about 0.5mL to about 2.9mL, from about 0.5mL to about 2.8mL, from about 0.5mL to about 2.7mL, from about 0.5mL to about 2.6mL, from about 0.5mL to about 2.5mL, from about 0.5mL to about 2.4mL, from about 0.5mL to about 2.3mL, from about 0.5mL to about 2.2mL, from about 0.5mL to about 2.1mL, from about 0.5mL to about 2mL, from about 0.5mL to about 1.9mL, from about 0.5mL to about 1.8mL, from about 0.5mL to about 1.7mL, from about 0.5mL to about 1.6mL, from about 0.5mL to about 1.0mL about 0.5mL to about 0.9mL, about 0.5mL to about 0.8mL, about 0.6mL to about 3mL, about 0.6mL to about 2.9mL, about 0.6mL to about 2.8mL, about 0.6mL to about 2.7mL, about 0.6mL to about 2.6mL, about 0.6mL to about 2.5mL, about 0.6mL to about 2.4mL, about 0.6mL to about 2.3mL, about 0.6mL to about 2.2mL, about 0.6mL to about 2.1mL, about 0.6mL to about 2.0mL, about 0.6mL to about 1.9mL, about 0.6mL to about 1.8mL, about 0.6mL to about 1.7mL about 0.6mL to about 1.6mL, about 0.6mL to about 1.5mL, about 0.6mL to about 1.4mL, about 0.6mL to about 1.3mL, about 0.6mL to about 1.2mL, about 0.6mL to about 1.1mL, about 0.6mL to about 1.0mL, about 0.6mL to about 0.9mL, about 0.6mL to about 0.8mL, about 0.7mL to about 3mL, about 0.7mL to about 2.9mL, about 0.7mL to about 2.8mL, about 0.7mL to about 2.7mL, about 0.7mL to about 2.6mL, about 0.7mL to about 2.5mL, about 0.7mL to about 2.4mL about 0.7mL to about 2.3mL, about 0.7mL to about 2.2mL, about 0.7mL to about 2.1mL, about 0.7mL to about 2.0mL, about 0.7mL to about 1.9mL, about 0.7mL to about 1.8mL, about 0.7mL to about 1.7mL, about 0.7mL to about 1.6mL, about 0.7mL to about 1.5mL, about 0.7mL to about 1.4mL, about 0.7mL to about 1.3mL, about 0.7mL to about 1.2mL, about 0.7mL to about 1.1mL, about 0.7mL to about 1.0mL, about 0.7mL to about 0.9mL, or about 0.7mL to about 0.8mL. In some embodiments, the concentration of anti-TL 1A in each dose and/or injection is about or greater than about 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, or 225mg/mL of anti-TL 1A.
In some embodiments, the method comprises administering more than one dose of anti-TL 1A. Subsequent doses may have the same amount, less than or greater than the first dose of anti-TL 1A. The subsequent dose may be administered 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 previous dose. Subsequent doses may be administered about 1, 2, 3 or 4 weeks after the previous dose. The one or more doses may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses. In a non-limiting example, anti-TL 1A is optionally administered at about 6 doses every other week. In another non-limiting example, the anti-TL 1A is optionally administered at about 12 doses once a week. In some embodiments, one or more doses of anti-TL 1A are administered during the induction period. The induction period may be about 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 weeks. As a non-limiting example, the induction period is about 12 weeks. After the induction period, the subject may be further treated, e.g., with additional doses of anti-TL 1A in a maintenance period. In some embodiments, the maintenance period comprises administering anti-TL 1A every 1, 2, 3, 4, 5, 6, or 7 days or every 1, 2, 3, or 4 weeks. In example embodiments, the maintenance period includes administration of anti-TL 1A every 2 or 4 weeks. In a non-limiting embodiment, the first dose is an intravenous dose and the one or more subsequent doses are subcutaneous doses. In some embodiments, the one or more doses are intravenous doses. In some embodiments, the one or more doses are subcutaneous doses. In some embodiments, the induction period comprises intravenous administration. In some embodiments, the maintenance period comprises subcutaneous administration.
In some embodiments, the method comprises administering to the subject a first dose of anti-TL 1A. In some embodiments, the dose includes about 250mg to about 1000mg of anti-TL 1A, about 400mg to about 600mg, about 700mg to about 800mg, or about 250mg, about 300mg, about 325mg, about 350mg, about 375mg, about 400mg, about 425mg, about 450mg, about 475mg, about 500mg, about 525mg, about 550mg, about 575mg, about 600mg, about 625mg, about 650mg, about 675mg, about 700mg, about 725mg, about 750mg, about 775mg, about 800mg, about 825mg, about 850mg, about 875mg, about 900mg, about 925mg, about 950mg, or about 1000mg of anti-TL 1A. In some embodiments, the first dose comprises about 800mg of anti-TL 1A. In an example embodiment, the first dose comprises about 800mg of anti-TL 1A administered subcutaneously. In an example embodiment, the first dose comprises about 500mg of anti-TL 1A administered intravenously.
In some embodiments, the method comprises administering a first dose of anti-TL 1A to the subject at a first time point, and administering a second dose of anti-TL 1A at a second time point. In some cases, 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 cases, the second time point is about 1, 2, 3, or 4 weeks after the first time point. In some cases, the second dose includes the same amount of anti-TL 1A as the first dose. In some cases, the second dose includes a different amount of anti-TL 1A than the first dose. In some cases, the second dose comprises about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the second dose comprises about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the first dose. In an example embodiment, the second dose includes about 500mg of anti-TL 1A administered intravenously about 2 weeks after the first dose.
In some embodiments, the method comprises administering a third dose of anti-TL 1A to the subject at a third time point. In some cases, 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 cases, the third time point is about 1, 2, 3, or 4 weeks after the second time point. In some cases, the third dose includes the same amount of anti-TL 1A as the second dose. In some cases, the third dose includes a different amount of anti-TL 1A than the second dose. In some cases, the third dose comprises about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the third dose comprises about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the second dose. In an example embodiment, the third dose comprises about 500mg of anti-TL 1A administered intravenously about 2 weeks after the second dose.
In some embodiments, the method comprises administering a fourth dose of anti-TL 1A to the subject at a fourth time point. In some cases, 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 cases, the fourth time point is about 1, 2, 3, or 4 weeks after the third time point. In some cases, the fourth dose includes the same amount of anti-TL 1A as the third dose. In some cases, the fourth dose includes a different amount of anti-TL 1A than the third dose. In some cases, the fourth dose comprises about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the fourth dose comprises about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the third dose. In an example embodiment, the fourth dose comprises about 500mg of anti-TL 1A administered intravenously about 2 weeks after the third dose.
In some embodiments, the method comprises administering a fifth dose of anti-TL 1A to the subject at a fifth time point. In some cases, 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 cases, the fifth time point is about 1, 2, 3, or 4 weeks after the fourth time point. In some cases, the fifth dose includes the same amount of anti-TL 1A as the fourth dose. In some cases, the fifth dose includes a different amount of anti-TL 1A than the fourth dose. In some cases, the fifth dose comprises about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the fifth dose comprises about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the fourth dose. In an example embodiment, the fifth dose comprises about 500mg of anti-TL 1A administered intravenously about 2 weeks after the fourth dose.
In some embodiments, the method comprises administering a sixth dose of anti-TL 1A to the subject at a sixth time point. In some cases, 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 cases, the sixth time point is about 1, 2, 3, or 4 weeks after the fifth time point. In some cases, the sixth dose includes the same amount of anti-TL 1A as the fifth dose. In some cases, the sixth dose includes a different amount of anti-TL 1A than the fifth dose. In some cases, the sixth dose comprises about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the sixth dose comprises about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the fifth dose. In an example embodiment, the sixth dose comprises about 500mg of anti-TL 1A administered intravenously about 2 weeks after the fifth dose.
In some embodiments, the method comprises administering to the subject a seventh dose of anti-TL 1A at a seventh time point. In some cases, the seventh 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 sixth time point. In some cases, the seventh time point is about 1, 2, 3, or 4 weeks after the sixth time point. In some cases, the seventh dose includes the same amount of anti-TL 1A as the sixth dose. In some cases, the seventh dose includes a different amount of anti-TL 1A than the sixth dose. In some cases, the seventh dose comprises about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the seventh dose comprises about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the sixth dose. In an example embodiment, the seventh dose comprises about 500mg of anti-TL 1A administered intravenously about 2 weeks after the sixth dose.
In some embodiments, the method comprises administering an eighth dose of anti-TL 1A to the subject at an eighth time point. In some cases, the eighth 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 seventh time point. In some cases, the eighth time point is about 1, 2, 3, or 4 weeks after the seventh time point. In some cases, the eighth dose includes the same amount of anti-TL 1A as the seventh dose. In some cases, the eighth dose includes a different amount of anti-TL 1A than the seventh dose. In some cases, the eighth dose comprises about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the eighth dose comprises about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the seventh dose. In an example embodiment, the eighth dose comprises about 500mg of anti-TL 1A administered intravenously about 2 weeks after the seventh dose.
In some embodiments, the method comprises administering a ninth dose of anti-TL 1A to the subject at a ninth time point. In some cases, the ninth 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 eighth time point. In some cases, the ninth time point is about 1, 2, 3, or 4 weeks after the eighth time point. In some cases, the ninth dose includes the same amount of anti-TL 1A as the eighth dose. In some cases, the ninth dose includes a different amount of anti-TL 1A than the eighth dose. In some cases, the ninth dose comprises about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the ninth dose comprises about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the eighth dose. In an example embodiment, the ninth dose comprises about 500mg of anti-TL 1A administered intravenously about 2 weeks after the eighth dose.
In some embodiments, the method comprises administering a tenth dose of anti-TL 1A to the subject at a tenth time point. In some cases, the tenth 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 ninth time point. In some cases, the tenth time point is about 1, 2, 3, or 4 weeks after the ninth time point. In some cases, the tenth dose includes the same amount of anti-TL 1A as the ninth dose. In some cases, the tenth dose includes a different amount of anti-TL 1A than the ninth dose. In some cases, the tenth dose comprises about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the tenth dose comprises about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the ninth dose. In an example embodiment, the tenth dose comprises about 500mg of anti-TL 1A administered intravenously about 2 weeks after the ninth dose.
In some embodiments, the method comprises administering an eleventh dose of anti-TL 1A to the subject at an eleventh time point. In some cases, the eleventh 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 tenth time point. In some cases, the eleventh time point is about 1, 2, 3, or 4 weeks after the tenth time point. In some cases, the eleventh dose includes the same amount of anti-TL 1A as the tenth dose. In some cases, the eleventh dose includes a different amount of anti-TL 1A than the tenth dose. In some cases, the eleventh dose comprises about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the eleventh dose comprises about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the tenth dose. In an example embodiment, the eleventh dose comprises about 500mg of anti-TL 1A administered intravenously about 2 weeks after the tenth dose.
In some embodiments, the method comprises administering a twelfth dose of anti-TL 1A to the subject at a twelfth time point. In some cases, the twelfth 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 eleventh time point. In some cases, the twelfth time point is about 1, 2, 3, or 4 weeks after the eleventh time point. In some cases, the twelfth dose includes the same amount of anti-TL 1A as the eleventh dose. In some cases, the twelfth dose includes a different amount of anti-TL 1A than the eleventh dose. In some cases, the twelfth dose includes about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the twelfth dose includes about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the eleventh dose. In an example embodiment, the twelfth dose includes about 500mg of anti-TL 1A administered intravenously about 2 weeks after the eleventh dose.
In some embodiments, the method comprises administering a thirteenth dose of anti-TL 1A to the subject at a thirteenth time point. In some cases, the thirteenth 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 twelfth time point. In some cases, the thirteenth time point is about 1, 2, 3, or 4 weeks after the twelfth time point. In some cases, the thirteenth dose includes the same amount of anti-TL 1A as the twelfth dose. In some cases, the thirteenth dose includes a different amount of anti-TL 1A than the twelfth dose. In some cases, the thirteenth dose includes about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the thirteenth dose includes about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the twelfth dose. In an example embodiment, the thirteenth dose includes about 500mg of anti-TL 1A administered intravenously about 2 weeks after the twelfth dose.
In some embodiments, the method comprises administering a fourteenth dose of anti-TL 1A to the subject at a fourteenth time point. In some cases, the fourteenth 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 thirteenth time point. In some cases, the fourteenth time point is about 1, 2, 3, or 4 weeks after the thirteenth time point. In some cases, the fourteenth dose includes the same amount of anti-TL 1A as the thirteenth dose. In some cases, the fourteenth dose includes a different amount of anti-TL 1A than the thirteenth dose. In some cases, the fourteenth dose includes about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the fourteenth dose includes about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the thirteenth dose. In an example embodiment, the fourteenth dose includes about 500mg of anti-TL 1A administered intravenously about 2 weeks after the thirteenth dose.
In some embodiments, the method comprises administering a fifteenth dose of anti-TL 1A to the subject at a fifteenth time point. In some cases, the fifteenth 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 fourteenth time point. In some cases, the fifteenth time point is about 1, 2, 3, or 4 weeks after the fourteenth time point. In some cases, the fifteenth dose includes the same amount of anti-TL 1A as the fourteenth dose. In some cases, the fifteenth dose comprises a different amount of anti-TL 1A than the fourteenth dose. In some cases, the fifteenth dose comprises about 150mg to about 700mg, about 150mg to about 300mg, about 150mg to about 225mg, about 175mg to about 225mg, about 400mg to about 600mg, about 450mg to about 550mg, about 475mg to about 525mg or about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, or about 700mg of anti-TL 1A. In an exemplary embodiment, the fifteenth dose comprises about 175-300mg of anti-TL 1A administered subcutaneously about 1 week after the fourteenth dose. In an example embodiment, the fifteenth dose comprises about 500mg of anti-TL 1A administered intravenously about 2 weeks after the fourteenth dose.
In some embodiments in which the subject is responsive to treatment, the subject is further treated with anti-TL 1A during the maintenance period. As non-limiting examples, the treatment includes 1 to about 20 doses, 1 to about 12 doses, 1 to about 6 doses, or about 12 doses. In some embodiments, the maintenance period includes administration of anti-TL 1A at one or more doses of about 150mg to about 250mg, about 150mg to about 225mg, about 150mg to about 200mg, about 175mg to about 225mg, about 175 to about 200mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220, about 230mg, about 240mg, or about 250 mg. In some cases, maintaining comprises administering a dose of anti-TL 1A once every 1, 2, 3, or 4 weeks. In some cases, maintaining comprises administering a dose of about 175mg to about 300mg every 2 weeks. In some cases, maintaining comprises administering a dose of about 175mg to about 300mg every 4 weeks. In some cases, administration is subcutaneous. In some cases, the administration is intravenous.
In one aspect, the method of treatment comprises administering to the subject a first dose on day 0, a second dose on day 7, a third dose on day 14, a fourth dose on day 21, a fifth dose on day 28, a sixth dose on day 35, a seventh dose on day 42, an eighth dose on day 49, a ninth dose on day 56, a tenth dose on day 63, an eleventh dose on day 70, a twelfth dose on day 77, and optionally a thirteenth dose on day 84. In some embodiments, the first dose comprises about 500-1000mg or about 800mg of anti-TL 1A. In some embodiments, the second dose comprises about 175-300mg of anti-TL 1A. In some embodiments, the third dose comprises about 175-300mg of anti-TL 1A. In some embodiments, the fourth dose comprises about 175-300mg of anti-TL 1A. In some embodiments, the fifth dose comprises about 175-300mg of anti-TL 1A. In some embodiments, the sixth dose comprises about 175-300mg of anti-TL 1A. In some embodiments, the seventh dose comprises about 175-300mg of anti-TL 1A. In some embodiments, the eighth dose comprises about 175-300mg of anti-TL 1A. In some embodiments, the ninth dose comprises about 175-300mg of anti-TL 1A. In some embodiments, the tenth dose comprises about 175-300mg of anti-TL 1A. In some embodiments, the eleventh dose comprises about 175-300mg of anti-TL 1A. In some embodiments, the twelfth dose comprises about 175-300mg of anti-TL 1A. In some embodiments, the thirteenth dose comprises about 175-300mg of anti-TL 1A. The anti-TL 1A can be administered subcutaneously, e.g., in the compositions disclosed herein. In some embodiments in which the subject is responsive to treatment, the subject is further treated with anti-TL 1A during the maintenance period. In some cases, maintaining comprises administering a dose of about 175mg to about 300mg every 2 weeks. In some cases, maintaining comprises administering a dose of about 175mg to about 300mg every 4 weeks. In some cases, maintenance administration is subcutaneous. In some cases, the maintenance administration is intravenous. In a non-limiting embodiment, the first dose is an intravenous dose and the one or more subsequent doses are subcutaneous doses. For example, in some cases, the induction period comprises intravenous administration and the maintenance period comprises subcutaneous administration.
In one aspect, the method of treatment comprises administering to the subject a first dose on day 0, a second dose on day 14, a third dose on day 28, a fourth dose on day 42, a fifth dose on day 56, a sixth dose on day 70, and optionally a seventh dose on day 84. In some embodiments, the first dose comprises about 400-600mg or about 500mg of anti-TL 1A. In some embodiments, the second dose comprises about 400-600mg of anti-TL 1A. In some embodiments, the third dose comprises about 400-600mg of anti-TL 1A. In some embodiments, the fourth dose comprises about 400-600mg of anti-TL 1A. In some embodiments, the fifth dose comprises about 400-600mg of anti-TL 1A. In some embodiments, the sixth dose comprises about 400-600mg of anti-TL 1A. In some embodiments, the seventh dose comprises about 400-600mg of anti-TL 1A. The anti-TL 1A can be administered intravenously, e.g., by diluting the compositions herein to a suitable volume for administration, e.g., about 250mL. In some cases, maintaining comprises administering a dose of about 175mg to about 300mg every 2 weeks. In some cases, maintaining comprises administering a dose of about 175mg to about 300mg every 4 weeks. In some cases, maintenance administration is subcutaneous. In some cases, the maintenance administration is intravenous. In a non-limiting embodiment, the first dose is an intravenous dose and the one or more subsequent doses are subcutaneous doses. For example, in some cases, the induction period comprises intravenous administration and the maintenance period comprises subcutaneous administration.
5. Examples
The following examples illustrate the embodiments described herein and should not be construed as limiting the scope of the disclosure. To mention specific materials, for illustrative purposes only, and not intended to be limiting. Those skilled in the art can develop equivalent means or reactants without the exercise of inventive capabilities and without departing from the scope of the present disclosure.
Example 1: design of humanized anti-TL 1A antibodies
Two different strategies were employed to identify humanized variants that were fully expressed in mammalian cells, retained TL1A binding and displayed high monomer content.
The first strategy utilized a previously humanized variant called ASX, which showed high monomer content (98%) and was fully expressed (30 μg/mL in small-scale transient culture), as a template for additional mutagenesis. However, ASX contains a large number of murine framework residues, namely eight heavy chain residues and 7 light chain residues, which can pose an immunogenicity risk. ASX heavy and light chain templates were used to systematically mutate murine framework residues to human residues corresponding to the most closely related human germline frameworks. The goal of this strategy is to reduce the total number of murine framework residues while preserving the favorable expression and solubility characteristics of ASX. Since ASX contains 15 murine framework residues, there are 2≡15 (32,768) different variants that can be made and tested (limiting each position to either murine or human residues).
The second strategy utilized a previously humanized variant called c34, which was fully expressed (17 μg/mL in small-scale transient culture) and contained CDRs optimized for binding within the fully human germline framework, as a template for additional mutagenesis. Large scale expression of c34 unexpectedly resulted in suboptimal monomer content (55-60%). c34 heavy and light chain templates were used to systematically mutate certain framework residues to murine residues corresponding to the original murine antibody framework. The goal of this strategy is to improve the solubility (monomer content) of c34 by introducing as few murine framework residues as possible (minimizing the potential risk of immunogenicity) while preserving the favorable expression profile of c 34.
For both strategies, the initial approach is to scan the different framework residues, one at a time, and express and characterize the variants. Thus, the human framework residues were introduced into variant ASX different from c34, and conversely, the murine framework mutations were introduced into variant c34 different from ASX. Initial scans identified certain framework and CDR residues that had minimal impact on the features displayed by the template antibodies, while other mutations had more significant impact, which was advantageous in some cases and disadvantageous in other cases. The information obtained from the position scan is then used in an iterative and combinatorial fashion to identify a plurality of variants with advantageous characteristics. Importantly, by applying stepwise, iterative and combinatorial methods, advantageous variants were identified without the necessity of expression and characterization of 32,768 different variants.
In some cases, the first residue of the heavy chain is evaluated for glutamine to aspartic acid or glutamic acid, alone or in combination with other mutations.
Furthermore, for both strategies, some CDR residues were also mutated to determine the effect on expression and solubility. For example, a limited number of mutations in HCDR2, HCDR3 and LCDR3 were examined. Similar to the method used with frameworks, mutations are primarily limited to original murine CDR residues or mutations previously identified as enhancing binding affinity.
Finally, for both strategies, a "substitution" of the heavy and light chains is used. Specifically, certain human light chains containing small amounts of murine framework residues and having a beneficial effect on the expression of antibodies with higher monomer content were identified early in the process and paired with various engineered heavy chains to accelerate the process of identifying suitable variants.
Examples of certain engineered antibodies are shown in table 1.
Table 1: selection of variable region sequences for anti-TL 1A antibodies
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As used herein, reference to a (number) refers to an antibody of this table. For example, a15 as used herein refers to a15 in table 1.
Example 2: generation and characterization of humanized anti-TL 1A antibodies
Humanized anti-TL 1A antibodies designed in example 1 were prepared and characterized.
Cloning of humanized antibodies
DNA encoding the leader sequence and the heavy and light chain variable regions of the humanized variants of interest were cloned into pFuse1-hIgG1-Fc1 (invitrogen) and pFuse2-CLig-hk (invitogen), respectively. Two different humanized heavy chain templates, designated ASX-HC and c34-HC, and four different humanized light chain templates, designated ASX-LC, cH3-1, c34-LC, cXL3-13-LC and cXL3-15-LC, were cloned.
To introduce mutations into the templates, the QuickChange site-directed mutagenesis kit (Agilent), catalog #200518, was used according to the manufacturer's instructions. Briefly, miniprep double-stranded plasmid DNA, two synthetic oligonucleotide primers containing the desired mutation, and,DNA polymerase and temperature cycler to carry out mutagenesis. After temperature cycling, the product was treated with Dpn I. Nicked vector DNA containing the mutation of interest is used to transform bacteria. Colonies were then picked and the DNA sequenced to confirm mutagenesis and subsequently used to transfect mammalian FreeStyle 293-F cells.
Antibody expression
Small scale (3 mL,6 well) expression of variants in FreeStyle 293-F cells was performed as follows. Cells were passaged one or two days prior to transfection such that the density would be > 1x10 on the day of transfection 6 Individual cells/mL. Typically, this means 6-7x10 a day ago 5 Individual cells/mL or 4x10 two days ago 5 Each cell/mL was passaged. Transfection was only performed with cell viability > 90%. On the day of transfection, opti-MEM medium was warmed to 37℃and cells were resuspended to 1.1X10 6 Each cell/mL, 3.3X10 per 3mL transfection 6 Individual cells. A total of 3. Mu.g of DNA was used for each transfection. Briefly, transfection uses heavy chains: the light chain ratio is 1:3 and light chain plasmids. For 3mL transfection, 4. Mu.L of 293fectin was added to 96. Mu.L of Opti-MEM, combined with 100. Mu.L of the DNA mixture and incubated for 20-30 min at 25 ℃. Subsequently, this mixture was added dropwise to 2.8mL of cells, and the plate was transferred to an incubator and placed on a rotating platform at 175rpm for up to 120 hours. After 96-120 hours, the transfected cells and supernatant were collected by centrifugation at 1200rpm for 5 minutes. The supernatant was transferred to a clean tube and centrifuged again at 3900rpm for 10 minutes to remove any remaining cell debris. The supernatant was filtered through a 0.45mm PES syringe filter and stored at 4 ℃ until the next step.
Quantification of antibody expression
Antibody expression was quantified by ELISA. Briefly, a high binding plate of Corning (Costar 336696 Kong Yuande) was coated overnight at 4℃with 50mL of anti-kappa (2. Mu.g/mL) PBS. Plates were washed 3 times with PBS-0.05% Tween 20 (PBS-T) and blocked with 100. Mu.L of 1% BSA/PBS for 1 hour at 25 ℃. The blockage was removed and culture supernatants diluted 5-fold were added and serially diluted 2-fold on plates. Each plate also contained IgG standards that were serially diluted 3-fold starting at 1 μg/mL. Samples were incubated at 25℃for 1 hour, plates were washed three times with PBS-T, and 50. Mu.L of the solution containing 1:4000 dilution of anti-Fc HRP secondary (southern Biotech) # 2048-05) BSA/PBS lasted 1 hour. Plates were washed three times with PBS-T and incubated for up to 15 minutes after addition of 50. Mu.L of Ultra TMB ELISA substrate (Siemeco. TM. # 34028). The reaction was carried out by adding 50. Mu.L of 2N H 2 SO 4 To terminate and measure a450 nm. The antibody expression levels obtained from 3 mL-sized transfection are shown in table 2.
Table 2: expression, binding and analytical SEC characterization of anti-TL 1A antibodies (ND, undetermined)
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Antibodies that bind to human TL1A
Antibodies that bound to human TL1A (Fitzgerald) were quantified by ELISA. Briefly, corning Costar 336696 Kong Yuande high binding plates were coated overnight at 4deg.C with 50. Mu.L of PBS containing TL1A (1. Mu.g/mL). Plates were washed 3 times with PBS-0.05% Tween 20 (PBS-T) and blocked with 100. Mu.L of 1% BSA/PBS for 1 hour at 25 ℃. The blockage was removed and culture supernatants diluted 5-fold were added and serially diluted 2-fold on plates. Samples were incubated at 25℃for 1 hour, plates were washed three times with PBS-T, and 50. Mu.L of 1:4000 diluted anti-Fc HRP secondary-antibody-containing BSA/PBS was added at 25℃for 1 hour. Plates were washed three times with PBS-T and incubated for up to 15 minutes after addition of 50. Mu.L of Ultra TMB ELISA substrate. The reaction was carried out by adding 50. Mu.L of 2N H 2 SO 4 To terminate and measure a450 nm. The antibody affinities as determined by ELISA titration of human TL1A using unpurified culture supernatant are shown in table 2.
Purification of antibodies
Antibodies were purified in a single step from culture supernatants using immunomagnetic globin a (zemoeimer technologies (ThermoFisher Scientific), catalog number 10002D). First, culture supernatants were concentrated using an Amicon Ultra-4 centrifuge filter (30,000 MWCO; millipore Sigma, catalog # C7719) according to manufacturer's instructions. Immunomagnetic beads were resuspended by gentle vortexing and 100 μl was transferred into Ai Bende (Eppendorf) tubes. The beads were fixed using a magnet, the storage buffer was removed, and the beads were washed with 0.5mL of 20mM sodium phosphate, 150mM NaCl (pH 7.4) (EB, equilibration buffer). A total of up to 24 μg IgG from culture supernatant was added to the beads and gently mixed until the beads were resuspended. Antibody supernatants were diluted with EB, if necessary. The tube was placed sideways on a shaking table and mixed at 500rpm for 10 minutes at 25 ℃. Subsequently, beads were collected at the bottom of the tube using a microcentrifuge at 10,000rpm for 30 seconds. The beads were fixed using a magnet and the supernatant was removed. The beads were washed once with 0.5mL of 20mM sodium phosphate, 500mM NaCl (pH 7.4), followed by another wash with 50mM sodium phosphate (pH 6.0). Beads were collected at the bottom of the tube using a microcentrifuge at 10,000rpm for 30 seconds. Purified antibodies were eluted from the beads using 20 μl of 50mM sodium acetate (pH 3.5) at 25 ℃ and gently mixed for 2 minutes. Using a magnet to retain the beads, the eluate was transferred to a fresh tube containing 1.1. Mu.L of 1M Tris (pH 8.5) to neutralize the pH of the sample. This sample was then centrifuged at 10,000rpm for 2 minutes and transferred to a fresh tube to ensure removal of residual immunomagnetic beads. The concentration of the purified samples was determined using a DeNovix DS-11 spectrophotometer/fluorometer, buffer blank and a mass extinction coefficient of 13.70 at 280nm for a 1% IgG solution.
Size exclusion chromatography
Antibodies were analyzed by Size Exclusion Chromatography (SEC) to determine the percent monomer and identify any large molecular weight aggregated contaminant species. A wottch (Waters) SEC column (Acquity UPLC BEH SEC,1.7 μm, 4.6x150mm) to analyze protein a purified antibody at a concentration of 0.1-1 μg/μl in a total volume of 15 μl. Standard PBS was used as the mobile phase and absorbance at 280nm was used to monitor protein elution. For some of the tested antibody clones exhibiting asymmetric elution profile, PBS buffer supplemented with 350mM NaCl at pH 6.0 was used to reduce non-specific interactions with the column matrix. The Shimadzu software was used to calculate the main peak (monomer) percent value. Representative sample curves are shown in FIGS. 1A-C. The monomer content of the purified antibody variants is shown in table 2.
Example 3: design of humanized anti-TL 1A antibodies with reduced effector function
In some cases, it may be beneficial to reduce the potential effector functions of the antibody. Various strategies have been described to reduce effector function, including point mutations that ablate fcγr and C1q binding, cross-subclass Fc designs that eliminate fcγr and C1q binding, and glycoengineering that ablate fcγr and C1q binding. Representative examples are highlighted in table 3.
Table 3: representative methods of abrogating effector function
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To express antibodies with deleted effector functions, the light chain variable regions of the antibodies disclosed in example 2 and table 1 were cloned with kappa light chain constant regions, while the heavy chain variable regions were cloned with modified IgG1 heavy chain backbones, or modified IgG2 backbones, or modified IgG4 backbones, or unmodified IgG2 or IgG4 backbones, such as those disclosed in table 3, table 13, table 9B, or elsewhere.
The effect of various Fc engineering methods on CDC activity can be assessed using C1q binding and C3 immobilization assays. Purified antibodies were diluted in PBS and serial dilutions were inoculated onto microtiter plates at 4 ℃ for 12-18 hours. Plates were blocked with 5% gelatin/PBS containing 1% (v/v) Tween-20 for 1 hour at 25 ℃. Subsequently, plates were incubated with PBS containing 10% (v/v) human serum and 1 with HRP conjugated rabbit anti-C1 q (boosen inc.): PBS containing 1% (v/v) Tween-20 in 500 dilutions detected C1q binding. To test C3 immobilization, a 1:1000 dilution of rabbit anti-C3 (abcam) was used followed by a 1:2000 dilution of HRP conjugated chicken anti-rabbit IgG (abcam). The incubation plates were quantified for antibodies as in example 1. EC50 values were calculated by fitting data to a log (agonist) and response-variable slope (four parameter) model using GraphPad Prism (Sunnyvale, CA).
In addition, variants can be characterized for binding of isolated C1 q. MaxiSorp 384-well plates (Nunc, simer Feier technologies) were coated with antibodies serially diluted in 50mM carbonate buffer (pH 9.6) (coating buffer) at 4℃for 12-18 hours. Plates were washed with Phosphate Buffered Saline (PBS) containing 0.05% polysorbate 20 (pH 7.4) and blocked with PBS (pH 7.4) containing 0.5% bsa, 0.05% polysorbate 20, 15ppm Proclin, and 10% blocker casein (zemoeimer feichi technologies). After incubation for 1 hour at 25 ℃, the plates were washed. The same buffer containing human C1q (Quidel, san Diego, calif.) was added and incubated for 1.5 hours. Bound C1q was detected by: biotinylated mouse anti-mouse C1q (Hycult biotech; cross-reactive with human C1 q) was added at 20ng/mL for 1.5 hours followed by horseradish peroxidase (HRP) -conjugated streptavidin (general electric medical group Life sciences (GE Healthcare Life Sciences)) for 1 hour. To check coating efficiency, some coated wells received only buffer in the first two incubation steps and goat anti-human Fab'2-HRP when wells used to measure C1q binding received streptavidin-HRP. After each incubation step the plates were washed. Peroxidase activity was detected with the substrate 3,3', 5' -Tetramethylbenzidine (TMB) (Kirkegaard & Perry Laboratories, kekkrad and Peli laboratories). The reaction was terminated with 1M phosphoric acid and absorbance was measured at 450 nm. Dose-response binding curves were fitted with a four-parameter model and EC50 values were calculated using GraphPad Prism (senneviral, california).
The effect of various Fc engineering methods on ADCC activity was assessed using a soluble fcγr receptor binding ELISA. Soluble human fcyri, fcyriib, and fcyriii (which evaluate binding affinity to both F158 and V158 polymorphisms of fcyriii) are expressed as recombinant fusion proteins with Gly-His 6-glutathione-S-transferase (GST) at the C-terminus of the extracellular domain of the receptor. MaxiSorp 384 well plates were coated with 1 μg/ml human FcgammaR in coating buffer. Plates were washed and blocked with PBS containing 0.5% BSA, 15ppm Proclin (pH 7.4). After 1 hour incubation, the plates were washed and 3-fold serial dilutions of antibodies in PBS (pH 7.4) containing 0.5% bsa, 0.05% polysorbate 20, 15ppm Proclin were added to the plates and incubated for 2 hours. Immune complexes are formed using anti-human antibodies for enhanced binding sensitivity due to avidity. Bound antibodies were detected with HRP conjugated goat anti-human kappa (south biotechnology company) using Ultra TMB substrate as described in example 1. The reaction was terminated and the plates were read as described above. The dose-dependent binding curve (without Fc modification) of the wild-type antibody was fitted to a GraphPad Prism (sennivir, california) four-parameter curve fitting program. The relative affinity of the variant relative to the wild type is estimated by dividing by the equivalent ng/ml wild type concentration at the appropriate concentration.
In addition, variants were tested directly in Fc effector bioassays (Promega) as instructed by the manufacturer. These assays include fcyriia-H ADCP bioassays (plakogaz cat No. G9901), ADCC reporter bioassays, fcyriiia F variants (plakogaz cat No. G9798), ADCC reporter bioassays, fcyriiia V variants (plakogaz cat No. G7015). By using anti-huig antibodies to form small ICs, variants were tested both as monomeric Ig and as small Immune Complexes (ICs).
Europium-based ADCC assays were performed. Briefly, peripheral Blood Lymphocyte (PBL) is communicatedSeparation was performed by gradient centrifugation through Ficoll Paque Plus. PBLs were collected, washed with RPMI1640, 10% fcs, and resuspended in cell culture medium. Dilution of cells to 2.5x10 6 Individual cells/ml. Target cells were labeled with BADTA (2, 2':6',2 "-terpyridine-6, 6" -dicarboxylic acid acetoxymethyl ester): cells were harvested by addition of acorase (Ackutase) (Milibo), washed once and diluted to 1X10 6 cells/ml. Next, every 1×10 6 mu.L of BADTA was added to each cell and the mixture was treated with 5% CO at 37 ℃ 2 Incubation was continued for 35 minutes. After labelling, the cells were diluted with 10ml of medium, centrifuged at 200x g for 10 min and the supernatant aspirated. This procedure was repeated 3 times with medium/2 mM p-monobenzoic acid and the samples were diluted 1X10 5 Individual cells/ml, centrifuged at 300x g for 5 min, the supernatant removed and 50 μl was pipetted into wells intended for background control. The final ratio of effector (PBL) to target cells was 25:1.
The control contains: (1) background: 50 μl aliquots, diluted with 100 μl of medium; (2) spontaneous cleavage: mu.L of the labeled target cell suspension was added with 100. Mu.L of a medium and incubated at 37℃for 2 hours; (3) maximum cleavage: mu.L/well of the labeled target cell suspension plus 100. Mu.L of trie X-100 (0.5% in PBS) were incubated for 2 hours at 37 ℃; (4) control lysis without antibody: 50. Mu.L/well of the labeled target cell suspension and 50. Mu.L of medium plus 50. Mu.L of effector cells were incubated at 37℃for 2 hours; (5) control lysis of effector-free cells: 50. Mu.L/well of labelled target cell suspension; 50. Mu.L of medium was added to the antibody used at the highest concentration and incubated at 37℃for 2 hours.
At the end of the incubation period, 96-well plates were centrifuged at 100 rpm. mu.L of each supernatant was transferred to OptiPlate HTRF-96 (Packard) and 200. Mu.L of europium solution was added and incubated on a shaker for 15 minutes. Fluorescence is measured, as is time resolved fluorescence, and spontaneous and specific release is calculated.
CDC measurement was performed. Briefly, target cells were washed and diluted to 1×105 cells/ml, and 100 μl/well (10 4 Individual cells) were added to 96-well flat bottom microtiter plates. A titration curve for the test antibodies was created using serial dilutions, starting at 1 μg/mL. The antibodies were added to the plates, gently mixed, and then placed in a 37 ℃/5% co2 incubator for 30 minutes. Next, 25 μl of freshly dissolved rabbit supplement (Cedarlane CL3441,1ml freeze-dried, freshly diluted in 4ml double distilled water) was added, gently mixed, and the plates were incubated in a 37 ℃/5% co2 incubator for 30 minutes. After the incubation period, 50 μl of supernatant was removed and 100 μl of cell titer glo. Reagent (plagmatogen) was added to the remaining 100 μl of supernatant. The plate was placed on an orbital shaker for 2 minutes, 100 μl/well was transferred into a black luminescence microtiter plate (Costar) and luminescence measured. The control contains: (1) a medium control (target cells plus 50. Mu.L of medium); (2) Maximum lysis control (target cells plus 50. Mu.L of 0.5% trie X-100); (3) Supplement control (target cells plus 25. Mu.L medium plus 25. Mu.L supplement).
As provided and described herein, fc variants are intended to reduce effector function, and then tested for the following capabilities: (i) purified/prepared efficiently (table 11); (ii) Reducing antibody-dependent cell-mediated cytotoxicity (ADCC) and (iii) reducing complement-dependent cytotoxicity. The test article tested comprises a heavy chain SEQ ID NO:368-380. The heavy chain used was paired with a light chain comprising the amino acid sequence of SEQ ID NO:381. ELISA titration curves and EC50 ("EC 50", table 12) were generated for recombinant TL1A antigen. Interestingly, the Fc mutation did affect the purity of the selection mutation/Fc variant as measured by monomer content (table 11, wild type IgG1 control).
Reduction of CDC Activity
The CDC activity of the test article was evaluated on HEK293 target cells expressing TL1A as compared to a negative control human IgG4 isotype control. Rituxan (Rituxan) (anti-CD 20) was used as a positive technical control for Raji cells expressing CD 20. All test articles were used at a final maximum concentration of 10 μg/mL, followed by five-fold serial dilutions (7 spots total) and no treatment control in triplicate. Cells were incubated with test articles for 15 minutes at 37C and then treated with human supplement at a final concentration of 25% for 3 hours at 37C, 5% CO 2. After incubation, cells were washed and resuspended in propidium iodide (p.i.) at a final concentration of 5 μg/mL prior to flow cytometry analysis. Total cells were examined by flow cytometry during sample collection. The data are plotted on an XY plot, the log of the percentage of p.i. positive cells versus concentration is plotted, and fitted to a nonlinear regression curve. Cytotoxicity in the presence of all test articles was indistinguishable from cytotoxicity in the presence of isotype control (table 12). CDC bioactivity was observed on Raji target cells treated with rituximab.
Table 11: testing reduced effector function of anti-TL 1A antibodies
Table 12: effector function of anti-TL 1A antibodies
Reduction of CDC Activity
Antibody-dependent cell-mediated cytotoxicity (ADCC) reporter assays were performed for characterization of HEK 293TL1A cells by test article and IgG4 isotype control. The reporter cell line engineered to express human Fc-gamma-RIIIa V158 (high affinity) was used as an effector cell.
Test articles were evaluated at the highest concentration of 10 μg/mL (log dilution of 7 total points, and no test article control). Treatment conditions were tested in triplicate and effector and target cells were co-cultured at 37C and 5% co2 for 6 hours. Raji target cells were used as positive controls, with treatment with rituximab at the highest concentration of 10 μg/mL, 7-point log serial dilution, and no-treatment controls. Test article 502 treatment resulted in a dose-dependent increase in luciferase reporter activity, and 5044 treatment resulted in an increase in reporter activity at the highest test concentration. The remaining test articles did not induce reporter activity (table 12).
Example 4: characterization of potency and species selectivity in whole blood assays
The relative efficacy of a set of candidate antibodies was first evaluated by determining inhibition of interferon gamma release in human blood using antibodies at 1 and 10 nM. All antibodies showed potent activity, with a219 appearing to be one of the most potent candidates (table 4).
Table 4: inhibition of interferon gamma release in human blood with anti-TL 1A
Cloning Inhibition at 1 nIg% Inhibition at 10 nIg%
A147 51.3 72.4
A212 46.8 71.2
A213 48.6 69.8
A217 46.0 72.2
A219 59.8 75.2
A220 36.9 63.2
Next, inhibition of interferon gamma release in human blood by three variants was characterized using a variety of human blood donors and testing antibodies over a wider concentration range (0.01-100 nM). Representative inhibition curves for variants a212, a213 and a219 are shown in fig. 2. The average IC50 values of these variants and the control antibody designated 1D1 for inhibiting release of interferon gamma from multiple human donors are shown in table 5.
Table 5: IC50 value
Cloning Average value of SD
A212 51.3 72.4
A213 46.8 71.2
A219 48.6 69.8
1D1 46.0 72.2
Example 5: properties of anti-TL 1A antibodies
The physical and chemical properties of anti-TL 1A antibody a219 are shown in table 18. Physical and chemical Properties of A219
1: calculated molecular weight from unglycosylation of amino acid sequences
2: three independent measurements, +/-standard deviation
3: calculated extinction coefficient from amino acid sequence
Example 6: animal model of colitis
Efficacy of anti-TL 1A antibodies in animal models of colitis were performed. Acute colitis induced by intrarectal administration of di-or tri-m-nitrobenzenesulfonic acid (D/TNBS) or oxazolone and by administration of DSS-containing drinking water or CD45RB hi anti-TL 1A antibodies were tested in rodent models of T cell transfer-induced chronic colitis. DNBS and oxazolone induce local ulcers and inflammation. DSS administration induces stable general inflammation of the gut characterized by erosive lesions and inflammatory infiltrates. Symptoms of all these models generally include diarrhea, occult blood, weight loss, and occasional rectal prolapse. In the prophylactic model, antibody treatment begins when administration of a compound that induces colitis begins. In the therapeutic model, antibody treatment was started several days after induction was started. The effect of treatment on body weight, fecal consistency and occult blood was determined as well as minor effects on epithelial integrity and inflammatory infiltrate. Daily clinical scores were performed based on fecal consistency and the presence of occult blood, resulting in Disease Activity Index (DAI) scores.
Example 7: overview of pharmacological, pharmacokinetic and toxicology studies
anti-TL 1A antibody a219 binds human tumor necrosis factor-like cytokine 1A (TL 1A) with high affinity and specificity and neutralizes TL1A functional activity in vitro and ex vivo cell-based assays. A219 binds with similar affinity to both human and cynomolgus TL1A (KD values of 0.06nM and 0.04nM, respectively). In addition, a219 is specific for TL1A and does not bind to other Tumor Necrosis Factor Superfamily (TNFSF) members. In the TF-1 function assay, A219 blocked human TL 1A-induced caspase activation and IC50 was 0.27nM. A219 inhibits TL1A mediated release of interferon gamma from Peripheral Blood Mononuclear Cells (PBMCs) in whole blood from monkeys administered at a dose of ≡0.056 mg/kg. In addition, at all dose levels in these monkeys, a dose-dependent increase in circulating soluble (sTL 1A) concentration was observed. This suggests that systemic sTL1A levels may be a useful PD marker for target engagement by a 219.
The non-clinical Pharmacokinetics (PK) of a219 were characterized in monkeys and supported a planned dosing regimen in humans once every other week. The non-clinical PK of a219 is consistent with what would be expected for target-mediated drug Treatment (TMDD) exhibited by monoclonal antibodies at lower doses and linear PK at higher dose levels, saturating the targeted-mediated clearance pathway.
A219 was administered to monkeys once a week for up to 6 weeks (7 total doses) via IV injection. In 6-week repeat dose toxicity studies, most, if not all, observed following administration of a219 to monkey IV was found to be secondary to ADA production in response to administration of the foreign protein (humanized monoclonal antibody) to the immunocompetent animal. Based on Electrocardiogram (ECG), daily and detailed weekly clinical observations and microscopic evaluation of relevant tissues/organs, no cardiovascular, central Nervous System (CNS) or respiratory effects were observed in monkeys during 6 weeks of IV administration of a219 at weekly IV of up to 300 mg/kg/week. In this study, the clinically relevant level of no visible adverse effects (NOAEL) was considered to be 300 mg/kg/week (highest dose tested). In tissue cross-reactivity studies with human or monkey tissue, off-target binding of a219 was not mentioned. During 6 weeks of repeat dose toxicity study, there was no a 219-associated cytokine release either in human PBMC or whole blood cytokine release assays or in monkeys. In the Fc effector function assay, a219 does not cause Complement Dependent Cytotoxicity (CDC) or antibody dependent cytotoxicity (ADCC) of the target expressing cells.
Example 8: biophysical Properties of high concentrations of anti-TL 1A antibody
Data on the properties of a219 anti-TL 1A antibodies in solution were analyzed together using a chemometric method called Partial Least Squares (PLS). Detailed descriptions of PLS modeling have been published in the following documents, for example: kaz, m.h. "multivariate analysis: clinical practice guidelines (Multivariate Analysis: A Practice Guide for Clinicians), university of Cambridge press, new York, cambridge University Press, pages 158-162 (1999); multivariate data analysis and experimental design in biomedical research (Multivariate data analysis and experimental design in biomedical research) Stahle, l., wold, k.) (pharmaceutical chemistry progression (prog. Med. Chem.)) 1988, 25:291-338; wold S.PLS regression: basic tool for chemometrics (PLS-regression: a basic tool of chemometrics) & lt, chemometrics and Intelligent laboratory System (chemom. Intll. Lab. System) & lt 2001, 58:109-130; martens, h.; martens, M. mass multiplex analysis: introduction (Multivariate Analysis of Quality: an Introduction), john Willi parent-child publishing company, wiley and Sons, chichester, UK, wick (2001). The calibration set (blue line) uses all the data of the model, while the validation set (red line) omits one sample at a time and reconstructs the model to evaluate robustness.
Use of m-VROC by Ruihsen (Rheosense) with A10 chip TM A viscometer measures the viscosity. The shear rate employed was about 1820s-1. The viscometer uses a ThermoCube thermoelectric cooler for temperature control and a Hamilton (Hamilton) 100 μl syringe (81060) to deliver the sample. The accuracy of the instrument was verified using pure isopropanol and measured at 25 ℃. Furthermore, the percentage increase of the HMW fraction as measured by size exclusion chromatography was in the range of 0% to 1.3% increase over the concentration range tested. HMW as used herein refers to a high molecular weight antibody fraction, e.g., an aggregated protein, and which does not comprise monomeric antibodies.
Tables 25 and 26 provide example formulations that have been evaluated.
Table 25: round 1 formulation
Table 26: wheel 2 formulation
Viscosity of the mixture
Fig. 3A depicts a comparison between predicted and measured viscosities, where viscosity is in mPa-s. Figures 3B-3D show viscosity as a function of antibody concentration and pH. The antibody concentration is in the range of greater than about 125mg/mL to greater than about 170 mg/mL. The pH is in the range of less than 5.0 to about 7.5. The concentration dependence is evident and the viscosity is very low (e.g. as indicated by a viscosity of less than 5mPa-s or 7 mPa-s). All formulations showed low viscosity (< 10 mPa-s) even at 170 mg/mL. FIG. 3E depicts the effect of pH on viscosity versus acetate concentration at an antibody concentration of 150 mg/mL. There is a slight pH dependence, with the minimum viscosity approaching pH 6. FIG. 3F shows the effect of sucrose on viscosity relative to NaCl at a pH of 5.5 and an antibody concentration of 150 mg/mL. NaCl helps to reduce the viscosity, while HP-b-CD increases the viscosity significantly. FIG. 3G depicts the effect of ArgHCl relative to LysHCl at a pH of 5.5. ArgHCl slightly increases viscosity, while LysHCl has little effect. The formulated anti-TL 1A antibodies also exhibit low viscosity (less than 16 mPa-s) at 200mg/ml anti-TL 1A.
Aggregation
FIG. 4A depicts the effect of PLS1 model on High Molecular Weight (HMW) aggregates at 2C and 25 ℃. Fig. 4B-4E depict the impact of different parameters on aggregation. The response surface shows an increase in HMW over time. FIG. 4B depicts the effect of pH on aggregation relative to acetate at an antibody concentration of 150 mg/mL. Using the PLS12 model, lower pH resulted in less aggregation (by SEC), including all formulations with increased HMW species (%) by SEC as endpoints. FIG. 4C depicts the effect of sucrose on aggregation relative to NaCl concentration at a pH of 5.5 and an antibody concentration of 150 mg/mL. FIG. 4D depicts the effect of ArgHCl on aggregation relative to LysHCl at a pH of 5.5 and an antibody concentration of 150 mg/mL. FIG. 4E depicts the effect of sucrose concentration versus LysHCl concentration over time at a pH of 5.5 and an antibody concentration of 150mg/mL and acetate of 20 mM. Sucrose, sorbitol and Lys reduce aggregation. The formulated anti-TL 1A antibodies also showed low aggregation at 200mg/ml anti-TL 1A.
Loss of the main peak of CEX by cation exchange chromatography
Fig. 5A depicts predicted relative to measured losses of the main peak at 2 weeks and 25 ℃. Fig. 5B-5E depict the effect of different parameters on the loss of the main peak. The response surface indicates the percent loss of the main peak. Fig. 5B depicts the effect of pH and protein concentration on loss of the main peak in the CEX curve. The optimum pH for loss of the main peak reduced by CEX is between 5 and 6. FIG. 5C depicts the effect of pH and acetate concentration on the loss of the main peak in the CEX curve at an antibody concentration of 150 mg/mL. FIG. 5D depicts the effect of sucrose and NaCl concentrations on the loss of the main peak in the CEX curve at an antibody concentration of 150mg/mL and a pH of 5.5. FIG. 5E depicts the effect of LysHCl and sucrose concentrations on the loss of the main peak in the CEX curve at an antibody concentration of 150mg/mL, pH of 5.5 and acetate concentration of 20 mM. The formulated anti-TL 1A antibodies also showed low levels of loss of major peaks at 200mg/ml of anti-TL 1A.
Example 9: effect of Polysorbate 20 or Polysorbate 80 on storage stability
After two rounds of formulation screening based on storage stability at different temperatures, round 3 was designed to evaluate the interfacial sensitivity of two different base formulations in the presence (and absence) of different amounts of polysorbate: PS20 and PS80. Repeated freeze thawing (F/T) stress and agitation (Ag) were used as stress conditions. Two base formulations were evaluated against TL1A A219 at about 200mg/ml as shown in Table 15.
Table 15: formulation design
The results are depicted in tables 16-17 and FIGS. 6A-6B. Fig. 6A depicts the loss of monomer with agitation by Size Exchange Chromatography (SEC). Fig. 6B depicts the loss of monomer by SEC at freeze-thawing. The results demonstrate that both PS20 and PS80 surfactants provide stability benefits. Very weak concentration dependence was observed for both surfactants. In addition, there were no significant chemical lesions during the short-term stress seen by CEX.
Table 16: visual appearance
Formulations QS (Ag) Control FT
1 Clarifying Cloudiness Clarifying Clarifying
1-A Clarifying Clarifying Clarifying Clarifying
1-B Clarifying Clarifying Clarifying Clarifying
1-C Clarifying Clarifying Clarifying Clarifying
1-D Clarifying Clarifying Clarifying Clarifying
1-E Clarifying Clarifying Clarifying Clarifying
1-F Clarifying Clarifying Clarifying Clarifying
2 Clarifying Cloudiness Clarifying Clarifying
2-A Clarifying Clarifying Clarifying Clarifying
2-B Clarifying Clarifying Clarifying Clarifying
2-C Clarifying Clarifying Clarifying Clarifying
2-D Clarifying Clarifying Clarifying Clarifying
2-E Clarifying Clarifying Clarifying Clarifying
2-F Clarifying Clarifying Clarifying Clarifying
Table 17: SEC results
Example 10: long term stability
Formulation 1 (150, 175 or 200mg/ml anti-TL 1A;20mM acetate; pH5.3; 240mM sucrose; 25mM LysHCl;0.02% PS 20) and formulation 2 (150, 175 or 200mg/ml anti-TL 1A;20mM acetate; pH5.3;220mM sucrose; 40mM NaCl;0.02% PS 20) were tested for long term stability over 6 months. One set of formulations was stored at 5 ℃ and one set of formulations was stored at 25 ℃. pH, osmolarity, protein concentration and viscosity were measured at the beginning of the study and after 6 months. SEC, CEX, flowCAM and visual appearance were used to monitor stability at the beginning of the study and at 1 month, 2 months, 3 months and 6 months after the study.
Example 11: pharmaceutical properties and formulations
Formulations were prepared against TL1AA 219. The a219 formulation was a clear to slightly milky white, colorless to yellowish liquid, which was essentially free of foreign matter, provided as 8.4mL of a 60mg/mL solution in a 10mL SCHOTT Fiolax type I tubular glass bottle sealed with a sibutryl rubber stopper and West Flip-Off.
Qualitative compositions of a219 are provided in table 19 below.
Table 19: exemplary compositions against TL1A
Composition of the components Quality standard Function of
A219 bulk drug cGMP Active ingredient
Sodium phosphate, monobasic monohydrate USP, FCC, endotoxin tested Buffer solution
Sodium phosphate, dibasic heptahydrate USP, FCC, endotoxin tested Buffer solution
Sucrose USP/NF、EP、JP Stabilizing agent
Glycine (Gly) BP、EP、JP、USP Stabilizing agent
Polysorbate-20 NF, multiple pharmacopoeias Surface active agent
Water for injection (WFI) USP/NF Diluent agent
BP = british pharmacopoeia; cGMP = current pharmaceutical production quality management codes; EP = european pharmacopoeia; FCC = food chemical code; NF = national formulary; JP = japanese pharmacopoeia; USP = united states pharmacopeia.
Pharmaceutical product preparation
The solution of a219 may be foamed. Thus, shaking or over-stirring of the vials is avoided. In addition, care is taken to ensure sterility of the prepared solution, as the pharmaceutical product may be free of antimicrobial preservatives or bacteriostats. Each disposable vial may contain a sufficient excess of drug product to account for withdrawal losses.
Dilution of the a219 injections was performed using a sterile disposable latex-free syringe. An 18 gauge, 1.5 inch sterile needle was used to withdraw from the vial. Prior to IV administration, the A219 injection is diluted in polyvinyl chloride (PVC) intravenous bags containing 0.9% sodium chloride injection (normal saline [ NS ]) using aseptic techniques to prepare a dosing solution having an A219 concentration between 0.01 and 8 mg/mL. The product was infused at protocol specific doses and rates through a PVC IV solution infusion set with sterile, heat-free 0.2 μm polyethersulfone in line filter. It is not administered as an IV bolus or bolus.
Storage conditions and use conditions
A219 formulated at 500 mg/vial (60 mg/mL) was stored in a refrigerator at a temperature of 2-8deg.C (38-46F).
Example 12: a219 binding Selectivity
The predicted TL1A protein sequences in humans were compared to mouse, rat and cynomolgus monkey sequences. The mouse, rat and monkey protein sequences have 64%, 66% and 98% homology, respectively, to human TL 1A.
Binding of a219 to mouse, rat, cynomolgus monkey and human recombinant TL1A proteins was assessed in ELISA. As shown in fig. 7A, a219 binds to human and monkey TL1A with sub-nanomolar IC50 values of 0.33nM and 0.47nM, respectively. In contrast, a219 did not bind to mouse or rat TL1A protein.
The a219 binding affinity and kinetics of recombinant human and monkey TL1A proteins were assessed using Surface Plasmon Resonance (SPR). A219 bound to human and cynomolgus TL1A and KD values were 0.06nM and 0.04nM, respectively.
Binding of A219 to membrane-bound TL1A was assessed using human embryonic kidney 293 cells stably transfected with human TL1A (TNFSF 15/HEK293 cells). A219 bound to membrane-bound TL1A expressed on the surface of TNFSF15/HEK293 cells in a dose-dependent manner and the EC50 value was 17.4nM. There was no binding to the parental HEK293 cells.
TL1A is the only known ligand for its functional receptor DR 3. TL1A is also able to bind to decoy receptor 3 (DcR 3), a soluble TNF receptor without a transmembrane domain. Binding of a219 to other known ligands of DcR3, including TNFSF6 (FasL), TNFSF10 (TRAIL) and TNFSF14 (LIGHT) was assessed by ELISA. A219 did not bind to these TNF family members when tested at concentrations approximately 1,000 fold higher than the EC50 of the corresponding positive control antibody.
Example 13: in vitro functional Activity against TL1A
The ability of A219 to prevent activation of caspases mediated by DR3 of human or monkey TL1A was evaluated in cycloheximide-treated TF-1 cells. TF-1 cells are human erythroleukemia cells that naturally express the functional receptor for DR3, TL 1A. Both human and cynomolgus TL1A proteins are able to bind and activate DR3 receptors on human TF-1 cells, resulting in intracellular caspase activation and apoptosis. A219 inhibited human and monkey TL 1A-induced caspase activation in TF-1 cells and IC50 values were 0.27nM and 0.59nM, respectively.
IFN-gamma is released from PBMC from whole blood collected from cynomolgus monkeys when stimulated with immune complexes in the presence of IL-12 and IL-18. This enhancement of IFN-gamma secretion reflects TL1A production driven by the immune complexes of PBMC. The ability of a219 to inhibit IFN- γ release under these conditions was assessed in vitro in freshly collected monkey whole blood.
IFN-gamma levels in whole blood were measured after stimulation with immunocomplexes in combination with IL-12 and IL-18 in vitro and at increased A219 concentrations (concentration range 0.05nM to 100 nM). In monkey whole blood, IFN-gamma release was inhibited by A219 in a dose-dependent manner. The average IC50 and IC90 values for inhibition of IFN-gamma responses were 1.54nM (289 ng/mL) and 17.7nM (3321 ng/mL), respectively.
Example 14: in vivo pharmacology
In a single dose PK/PD study with monkeys for a 11 day follow-up period, a219 was administered to 3 animals/group (mixed sex) by IV bolus at doses of 0 (i.e., 0.56mg/kg human IgG1 isotype control), 0.0056, 0.056, and 0.56 mg/kg. Based on the results from the in vitro monkey whole blood IFN- γ assay, the a219 dose tested in the study was selected to produce a219 serum concentration of about 1, 10 or 100 fold IC 50. Blood was collected to assess PK, sTL1A concentration and whole blood IFN-release in vitro. Because of the insufficient increase in IFN-gamma release at the pre-dose baseline, the effect of A219 on inhibition of TL 1A-mediated IFN-gamma release at 0.0056mg/kg could not be evaluated. Administration of 0.056mg/kg or 0.56mg/kg of A219 resulted in almost complete inhibition of IFN-gamma release 1 hour after administration relative to isotype control. At 264 hours (11 days) post-dose, inhibition of IFN-gamma release was less than 1 hour post-dose, but persisted in the A219 group at 0.56 mg/kg. Inhibition of TL 1A-mediated IFN-gamma release is dose dependent at a dose of ≡0.056mg/kg, where the observed exposure at 0.056mg/kg is ≡6.8 times higher than the IC50 of 1.54nM (289 ng/mL) in vitro whole blood assay.
After administration of 0.0056, 0.056 or 0.56mg/kg of a219, the average concentration of sTL1A was increased 3.6-fold, 10.4-fold and 14.4-fold, respectively, in a dose-dependent manner relative to isotype control antibody 6 hours after administration (fig. 7B). In all a219 dose groups, an increase in TL1A concentration was observed at the earliest time point of the test (6 hours after dosing) and maintained to the last time point (264 hours after dosing).
Safe pharmacology
Cardiovascular, CNS and respiratory safety pharmacological endpoints were incorporated into 6 week repeat IV toxicity studies in monkeys.
There was no functional impact on the cardiovascular system as assessed by ECG measurements during the pre-dosing phase and between weeks 1 and 6 of the dosing phase, and by microscopic examination of the heart and main blood vessels at 300 mg/kg/week. There were no changes in heart rate associated with a219 administration, no arrhythmia or qualitative or quantitative ECG changes, and no mention was made of microscopic findings in the heart that could affect heart function.
There was no functional impact on the CNS based on daily clinical observations and detailed weekly checks comprising: changes in animal behavior and locomotion, autonomic activity (e.g., tear, erectile hair, pupil size), posture and responsiveness to treatment, as well as the presence of clonic or tonic movements, behavioral/psychological abnormalities, loops and self-disability at 300 mg/kg/week were observed as the cage was approached. There are no microscopic findings in the brain or nervous system that could affect CNS function.
There was no impact on the respiratory system based on daily clinical observations of animal respiration and detailed weekly checks comprising monitoring of abnormal breathing patterns at 300 mg/kg/week.
In summary, no functional cardiovascular, CNS or respiratory findings were observed in monkeys during 6 weeks of IV administration of a219 at 300 mg/kg/week once per week.
Systemic pharmacokinetics in animals
Serum PK and Toxicology (TK) of a219 were studied in monkeys to support dose selection for the key 6 week toxicity study and to help predict the appropriate starting dose in humans. IV administration was used for all in vivo studies.
A single IV dose PK/PD study was performed in monkeys to characterize the PK profile and associated PD effects of a219 at dose levels associated with predicting initial human body dose. PD results were summarized previously. The PK of a219 was nonlinear over the 0.0056, 0.056 and 0.56mg/kg dose ranges, consistent with the intended target-mediated drug Treatment (TMDD) of monoclonal antibodies against membrane-bound targets. AUC values increased more than dose scale and where estimated, t1/2 increased with increasing dose (table 20).
Table 20: average (SD) PK parameters following a single IV dose to cynomolgus monkey
Cmax = maximum observed concentration; AUC0-t = area under the concentration-time curve from time 0 to the time point of last measurable concentration; t1/2=terminal half-life
Unless otherwise stated, n=3
a N=1 (end of concentration-time curveCharacterization of the phase is insufficient to estimate this parameter in the other two animals
b N=2 (characterization of the final phase of the concentration-time curve is insufficient to estimate this parameter in the third animal)
TK and immunogenicity were evaluated in cynomolgus monkeys as part of a2 dose non-GLP PK/tolerance study and a GLP 6 week repeat toxicity study.
In A2 dose PK study, monkeys (n=1/sex/group) received 2 doses of a219 by IV bolus administration at dose level intervals of 30, 100 and 243mg/kg for one week. After the first (day 1) or second (day 8) dose, exposure based on the mean Cmax increased in a roughly proportional manner to the dose. The average AUC0-t value increases in a dose-dependent manner, but does not necessarily increase in a dose-proportional manner after the first and second doses.
In GLP 6 week repeat dosing toxicity studies, monkeys (n=3-5/sex/group) were administered once a week by IV bolus at dose levels of 0, 30, 100, or 300mg/kg to receive 7 doses of a219. Exposure to a219 was comparable in male and female monkeys after single and repeated dosing (the difference in mean Cmax and AUC values was less than 2-fold). After single and repeated dosing, a219 exposure increased in a roughly dose-proportional manner. At all dose levels, cumulative (approximately 1.5 to 2.3 times higher serum exposure after the last dose (day 42) than that observed after the first dose) was observed after repeated weekly dosing (table 21).
Table 21: average (SD) TK parameter after repeated weekly IV dosing to cynomolgus monkeys
The average was calculated based on the male and female pool.
Cmax = maximum observed concentration; AUC0-24hr = area under concentration-time curve from time 0 to 24 hours post-dose; AUC0-168hr = area under the concentration-time curve from time 0 to 168 hours post-administration; AUC0-t = area under the concentration-time curve from time 0 to the time point of last measurable concentration; ARCmax = accumulation ratio based on Cmax; ARAUC0-24hr = accumulation ratio based on AUC0-24 hr; t1/2=terminal half-life
N=3 males and 3 females in the 30 and 100mg/kg dose group, and 5 males and 5 females in the 300mg/kg dose group.
a Only in recovery animals (n=2/sex).
Example 15: toxicology of
A219 was evaluated in a series of in vitro and in vivo toxicity studies outlined in table 22. The IV exposure route was chosen for in vivo studies. The weekly dosing regimen used in the deterministic 6 week repeat dose monkey toxicity study was selected based on the half-life of a219 in monkeys and was designed to have a dosing regimen similar to or denser than the clinical dosing regimen.
Table 22: overview of toxicology projects
PBMC = peripheral blood mononuclear cells
Monkeys were selected as pharmacologically relevant non-clinical species due to similar TL1A protein sequence homology and almost equivalent binding affinity of a219 to monkey TL1A as compared to human TL1A. In an in vitro cell-based assay, a219 also has a pharmacological activity similar to IC50 values after binding to monkey or human soluble TL1A. In an in vitro assay using monkey whole blood, stimulation to express TL1A with subsequent IFN- γ release, addition of a219 inhibited release of IFN- γ in a dose-dependent manner. Similar inhibition of IFN- γ release was observed when blood from monkeys administered a219 was used in the assay. Binding of a219 to mouse or rat TL1A was also assessed, and a219 did not bind to rat or mouse TL1A.
2 dose PK and tolerability studies in monkeys
Tolerance was assessed in PK and tolerance studies over 2 weeks. A219 was administered at 30, 100 or 243 mg/kg/peripheral monkey (1/sex/group) IV on day 1 and day 8. A219 had good tolerability up to the highest dose tested, and the only clinical sign observed in a 219-treated animals was loose stool in all dose groups at multiple observation time points. Based on the small number of animals and the absence of control animals, the relationship of runny stool to a219 administration could not be determined. No a 219-related changes occurred in body weight, clinical chemistry or hematology parameters.
Study with 6 weeks of repeated dosing and 6 weeks recovery in monkeys
GLP repeat dosing toxicity studies with A219 were performed in monkeys for a 6 week duration (weekly dosing). A219 was administered to male and female monkeys (3/sex/group) by IV bolus at doses of 0 (vehicle control), 30, 100, or 300 mg/kg/week (total 7 doses). After a 6 week recovery period, additional animals (2 animals/sex/group) at 0 and 300 mg/kg/week were evaluated for reversibility of any a219 related effect.
A219 was well tolerated after 6 weeks of administration at doses up to 300 mg/kg/week. Based on these studies, NOAEL was 100 mg/kg/week for males and 30 mg/kg/week for females.
Human cytokine release assay
PBMC assay
The potential ability of a219 to trigger cytokine release in primary human PBMC derived from 10 normal healthy donors was evaluated in soluble and wet coated form. A range of A219 concentrations from 0.00002 to 2mg/mL was evaluated. Human IgG4 antibodies and untreated samples were used as negative controls; an anti-CD 3 (OKT 3) antibody was used as a positive control. IL-2, IL-6, IL-10, TNF and INF-levels were measured after PBMC or incubated with A219 for 24 hours. PBMC from all donors induced IL-2, IL-6, IL-10, TNF and IFN-gamma release in response to OKT3 treatment (positive control). Donor 9 had a lower IL-2 response but was present. IgG4 negative control antibodies did not induce or induce low IL-2, IL-10, TNF and IFN-gamma cytokine release under any of the test conditions. IgG4 negative control antibodies induced IL-6 production in several donors, although not as robust as positive control treatments. Cytokine release was not observed or was observed only at very low levels in untreated samples from all donors.
A219 did not induce IL-2 and IFN-release under any of the test conditions. A219 induced low levels of IL-10 and TNF release in some donors but not exceeding levels induced by IgG4 negative control antibodies and/or in untreated samples. A219 induced IL-6 release in several donors in two stimulated forms with the same induction range as observed with IgG4 negative controls and/or in untreated samples, but the response was not concentration dependent. Based on historical test facility data for IL-6 induction, a variable range of magnitudes of responses for isotype and other negative control antibodies, as well as other test items in a subset of donors that are generally not concentration dependent, has been observed. The a219, igG4 treatment-related and untreated PBMC responses were lower than those associated with the anti-CD 3 positive control treatment. Thus, induction of IL-6 in this assay may not be A219 specific, but rather is associated with changes that have also been historically observed in the assay for this cytokine.
In summary, a219 did not induce specific release of IL-2, IL-6, IL-10, TNF, IFN against PBMCs from 10 different donors observed with the above wet coated plates or soluble forms of IgG4 negative control antibodies and/or untreated samples.
Whole blood assay
The potential ability of a219 to trigger cytokine release in human whole blood from 10 normal healthy donors was evaluated in soluble and wet coated form. A range of A219 concentrations from 0.00002 to 2mg/mL was evaluated. Human IgG4 antibodies and untreated samples were used as negative controls; staphylococcal enterotoxin B (Staphylococcal enterotoxin B, SEB) was used as a positive control. IL-2, IL-6, IL-10, TNF and INF levels were measured 24 hours after culturing whole blood with A219.
Whole blood from all donors induced IL-2, IL-6, IL-10, TNF and IFN-gamma release in response to SEB treatment (soluble stimulated form). The IFN-responses of donors 1, 3 and 8 were lower but present. In whole blood from most donors, the human IgG4 negative antibody control did not induce or induce low cytokine production under all test conditions. No cytokine release was observed in untreated whole blood samples of most donors. Whole blood from one donor (donor 7) produced IL-6, IL-10 and TNF- α in response to several concentrations of soluble IgG4 negative antibody controls. However, cytokine levels are typically at or below levels observed for the same donor in untreated samples.
Of the nine donors, a219 did not induce any cytokine release under any of the test conditions. Stimulation with 0.02mg/mL of soluble a219 induced low levels of IL-6, IL-10 and TNF release in whole blood from donor 7. For this donor, no dose-response relationship between a219 concentration and cytokine levels was observed, and cytokine levels were lower than those observed in IgG4 negative control and/or untreated samples from this donor. Thus, induction of IL-6, IL-10 and TNF in donor 7 samples may be non-A219 specific.
In summary, A219 did not induce IL-2, IL-6, IL-10, TNF, IFN-gamma specific release in whole blood from 10 different donors observed with the above wet coated plates or soluble forms of the negative control antibodies against IgG4 and/or untreated samples.
Fc effector function assay
The likelihood that a219 triggers CDC or ADCC was evaluated in vitro. A219 is not expected to elicit CDC or ADCC, as antibodies are designed to eliminate effector functions.
The ability of a219 to elicit CDC or ADCC on recombinant human HEK293 TL1A cells expressing the target and on HEK293 parental cell lines (negative control cell lines) was evaluated. CDC was assessed by post-treatment culture of cells with a219 concentration ranging from 0.0031 to 30,000ng/mL in the presence of human complement, and analysis of the viability of target cells by flow cytometry. ADCC was assessed by culturing labeled target cells after treatment with human PBMCs (3 donors) at a concentration ranging from 0.0031 to 30,000ng/mL of a 219. Human IgG4 antibodies were used as negative controls in both assays.
Rituximab (anti-CD 20 antibody) was used as a positive control in CDC assays with Raji cells expressing CD20, while Darzalex (Darzalex) was used in ADCC assays with Daudi target cells.
The a219 treatment did not cause an increase in CDC mediated cell killing in HEK293 TL1A cells or in HEK293 cells compared to the negative control antibody. Rituximab treatment resulted in the expected increase in complement-mediated lysis of CD 20-expressing Raj i cells.
The a219 treatment did not cause an increase in ADCC mediated cell killing in HEK293 TL1A cells or in HEK293 cells compared to the negative control antibody. Treatment with darabine resulted in the expected increase in ADCC cytotoxicity of Daudi target cells.
In summary, and as expected, a219 did not elicit CDC or ADCC, respectively, of TL1A expressing cells in the presence of human complement or PBMC.
Finding a relationship with pharmacokinetics
As defined by Cmax and AUC, a219 exposure in monkeys increased with increasing dose over the tested dose range in 6-week repeat dosing toxicity studies, and exposure increased in a roughly proportional manner to dose. There were no significant gender-related differences in exposure. There was no clear correlation of ADA changes in exposure to a 219. However, at a later time point observed in some animals, ADA may result in a faster decrease in a219 concentration. Accumulation of a219 in monkeys was observed after repeated weekly administration.
The serum exposure thresholds associated with findings associated with a219 from the 6 week repeat drug administration monkey toxicity study are shown in table 23. Based on a comparison of a219AUC values from 6 week repeat drug administration monkey toxicity studies with predicted human AUC values at 5mg of the proposed clinical starting dose, safety margin at each dose level was presented.
Table 23: exposure to anti-TL 1A associated with findings in 6 week repeat dosing toxicity studies in monkeys.
AUC = area under concentration-time curve; RBC = red blood cells; cmax = maximum observed concentration
The exposure margin (i.e., safety margin) was calculated by dividing the AUC value in the repeat study with the estimated human AUC value at the estimated 5mg human starting dose of 143.5 μg hour/ml.
A219 preclinical study summary
A219 has a sub-nanomolar binding affinity for soluble TL1A and nanomolar affinity for membrane-associated TL 1A. In vitro studies, a219 blocked the ability of TL1A to bind and activate its receptor DR 3. In whole blood, A219 inhibited TL 1A-dependent IFN- γ responses after ex vivo exposure to immune complexes and combination of IL-12 and IL-18. In addition, a219 was observed to be highly selective for TL1A with no detectable binding to the relevant TNF superfamily member FAS, LIGHT or TRAIL.
The potential toxicity of a219 was evaluated in a series of non-clinical in vitro assays and in vivo studies in cynomolgus monkeys. Monkeys were selected as pharmacologically relevant non-clinical species due to similar TL1A protein sequence homology and almost equivalent binding affinity of a219 to monkey TL1A compared to humans. A219 has similar activity in monkey and human in vitro cell-based assays.
A219 has been engineered to remove the potential of mabs to induce immune responses. In an in vitro assay, a219 treatment did not result in antibody or cell mediated cytotoxicity or cytokine release from peripheral blood cells, thus indicating that this did not elicit an undesirable immune response.
In tolerability and Pharmacokinetic (PK) studies, cynomolgus monkeys (1/sex/group) were Intravenously (IV) administered a219 at 30, 100 and 243 mg/kg/week on days 1 and 8, and followed by a follow-up for about 11 weeks to assess systemic exposure of a219. No a 219-related clinical observations or changes occurred in body weight, clinical chemistry or hematology parameters. PK measurements showed a219 to have a long half-life of 5 to 11 days, consistent with human IgG1 in monkeys.
GLP studies were performed to assess potential toxicity (including immunotoxicity) of a219 after six weeks (7 total doses) of weekly administration in cynomolgus monkeys, and related systemic exposure. A219 was administered to male and female monkeys (3/sex/group) at a dose IV (bolus) of 0 (vehicle control), 30, 100, or 300 mg/kg/week. Animals recovered (2/sex/group) were administered 0 or 300 mg/kg/week of A219. In this study, the clinically relevant level of no visible adverse effects (NOAEL) was determined to be 300 mg/kg/week (highest dose tested). It was found that this was observed to be secondary to the production of anti-drug antibodies (ADA) in response to the administration of humanized monoclonal antibodies, comprising single deaths and minimal vascular inflammation in the 30mg/kg group, which was the only finding considered adverse. Except for perivascular infiltrates, all were found to be fully reversible after a 6 week recovery period, which persisted only marginally in some tissues at 300 mg/kg/week, and minimal glomerulopathy was noted in one recovery female at 300 mg/kg/week. ADA-related findings observed in non-clinical animal toxicity studies with human monoclonal antibodies are generally considered to be unrelated to humans.
Six month repeat dose monkey toxicity studies were performed to assess the likelihood of chronic dosing in UC and CD.
Example 16: phase 1 clinical trial
Phase 1a clinical trials have been initiated in normal healthy volunteers.
Phase 1a clinical trial was a single-center, double-blind, placebo-controlled safety, tolerability and PK study in normal healthy volunteers receiving IV administration of a 219. The single incremental dose (SAD) phase of the trial consisted of 8 subjects (6 active and 2 placebo) per group with up to 6 dose levels. Multiple incremental dose (MAD) phases of the trial begin after equal or higher SAD doses have been studied and acceptable safety and tolerability have been observed. The MAD phase consisted of 8 subjects (6 active and 2 placebo) per group with up to 5 dose levels. The trial evaluated the safety, tolerability and pharmacokinetics of single and multi-dose a219 administration by IV in healthy, walking, smokeless, male or female volunteers from 18 to 60 years old, and PK of a219 after single and multi-dose. Furthermore, the assay determines the effect of a219 on the Pharmacodynamic (PD) marker and the exposure-response relationship of a219 on the PD marker. The summary of this study is shown in table 14.
Randomized placebo-controlled clinical trials of stage 1b/2a were conducted in patients with moderate to severe UC and open-label stage 1b clinical trials were conducted in patients with moderate to severe CD.
Table 14: summary of phase 1, single-center, double-blind, placebo-controlled, safety and pharmacokinetic studies of anti-TL 1A antibodies in healthy volunteers
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Based on clinical data from SAD groups 5, 25, 100, 300 and 600mg and MAD group 50mg, a219 PK showed target-mediated drug distribution (TMDD) at lower doses and linear PK at higher dose levels after saturation of the target-mediated clearance pathway.
After a single IV dose of a219, the median time to maximum concentration (T max ) The values range from 1.02 to 1.50 hours after administration. Based on average C max And AUC 0-t Is increased in a greater than dose-proportional manner between 5, 25 and 100mg dose levels, and is increased in a substantially dose-proportional manner between 100, 300 and 600mg dose levels. After repeated dosing of 50mg of a219 once every other week, exposure was increased relative to day 1. Average C on day 15 and day 29 compared to day 1 max And AUC 0-336hr About 1.3 times higher.
Example 17: human dosing range and safety margin
A219 is a humanized monoclonal antibody that binds human TL 1A. It is expected that the ultimate goal of a219 treatment in humans will be to saturate the TL1A target in the disease patient for optimal efficacy. The minimal expected biological effect level (MABEL) approach is considered unsuitable because a219 is an antagonist rather than an agonist antibody and the safety of antagonizing the TL1A pathway has been confirmed clinically. The maximum recommended starting dose for a219 is selected based on the predicted Pharmacologically Active Dose (PAD). A219 did not cross-react with murine TL1A, but bound cynomolgus monkey TL1A with approximately equivalent potency. Thus, cynomolgus monkeys are considered to be relevant species for scaling non-clinical a219 Pharmacokinetics (PK) to humans. In addition, PK data in monkeys suggests that a219 exhibits target-mediated drug profile, which results in nonlinear PK over a dose range of target unsaturation and linear PK over a dose range of target saturation.
Non-clinical PK and TK of a219 were characterized in monkeys and supported a planned once every other week dosing regimen in humans. The estimated safety margin of 1000mg for the initial dose of 5mg and the highest proposed dose studied relative to GLP safety data from monkeys is shown in table 24. This table compares safety margins derived from various methods.
Table 24: predicted safety margin for initial and maximum dose
C = maximum observed concentration; AUC = area under the concentration-time curve from time 0 to 168 hours post-dose; the predicted human C values for doses of 5 and 1000mg are about 1.78 and 382 μg/mL, respectively; the predicted human AUC values for doses of 5 and 1000mg are approximately 143.5 and 50700 hours, micrograms/milliliter, respectively. The human exposure parameter values are based on a hypothetical body weight of 70 kg.
Example 18: treatment of IBD with anti-TL 1A
Subjects with inflammatory bowel disease were treated with anti-TL 1A antibody a219 using one of two induction methods of this example:
induction method 1: 800mg of anti-TL 1A was administered subcutaneously on day 1 and then 175-200mg of anti-TL 1A was administered weekly for a total of 12 weeks.
Induction method 2: 500mg of anti-TL 1A was administered intravenously every other week for 12 weeks.
After the induction period, if the subject is responsive to the treatment, the subject is further treated in the maintenance period. The maintenance period includes administration of 175-200mg of anti-TL 1A every 2 or 4 weeks.
Example 19: animal model for idiopathic pulmonary fibrosis
Efficacy of anti-TL 1A antibodies in rodent models of idiopathic pulmonary fibrosis. Induction is performed by administration of bleomycin, silica, asbestos fiber or fluorescent isothiocyanate. In the prophylactic model, antibody treatment is initiated at the beginning of administration of the inducer. In the therapeutic model, antibody treatment was started several days after induction was started. The effect of treatment on pulmonary fibrosis, collagen deposition, alveolar septal thickening, intra-alveolar fibrosis, alveolar macrophage increase, bronchioles and alveolar catheter expansion, and in vivo pulmonary function measurements (e.g., elasticity and compliance) was determined. In other examples, transgenic mouse models were used to evaluate the efficacy of anti-TL 1A on idiopathic pulmonary fibrosis.
Example 20: animal model of virus-induced fibrosis
Efficacy of anti-TL 1A antibodies in rodent models of virus-induced fibrosis. Induction was performed by H5N1 infection. In the prophylactic model, antibody treatment was initiated at the time of infection. In the therapeutic model, antibody treatment was started several days after induction was started. The effect of treatment on pulmonary fibrosis, collagen deposition, alveolar septal thickening, intra-alveolar fibrosis, alveolar macrophage increase, bronchioles and alveolar catheter expansion, and in vivo pulmonary function measurements (e.g., elasticity and compliance) was determined. In other examples, transgenic mouse models were used to evaluate the efficacy of anti-TL 1A on virus-induced fibrosis.
Example 21: animal model of asthma
Efficacy of anti-TL 1A antibodies in rodent animal models of asthma were performed. Induction is performed by administering ovalbumin, house Dust Mites (HDM), such as house dust mites (Dermatophagoides pteronyssinus, der p) or dust mites (d.farinae, der f), mite allergens (Der p1, der f1, derp 23, etc.), fungi (aspergillus fumigatus (Aspergillus fumigatus), alternaria alternata (Alternaria alternata)), cockroach extracts, i antigens, cotton dust, ragweed, or latex (brazil rubber tree (Hevea brasiliensis)). In the prophylactic model, antibody treatment is initiated at the beginning of administration of the inducer. In the therapeutic model, antibody treatment was started several days after induction was started. The effect of treatment on pulmonary fibrosis, collagen deposition, alveolar septal thickening, intra-alveolar fibrosis, and cell counts of eosinophils, lymphocytes, macrophages and neutrophils in bronchoalveolar fluid was determined. In other examples, transgenic mouse models were used to evaluate efficacy against TL1A against asthma.
Example 22: animal model of COPD
Efficacy of anti-TL 1A antibodies in rodent animal models of COPD. Induction is by administration of Cigarette Smoke (CS), intratracheal Lipopolysaccharide (LPS) or intranasal elastase. In the prophylactic model, antibody treatment is initiated at the beginning of administration of the inducer. In the therapeutic model, antibody treatment was started several days after induction was started. The effect of treatment on airflow obstruction, chronic inflammation, increased cellular infiltration in the lung parenchyma, increased numbers of goblet cells secreted by mucus, airway epithelial thickening, and alveolar enlargement was determined. In vivo measurements of airway hyperresponsiveness assessed by systemic plethysmography following a methine challenge were also measured. In other examples, transgenic mouse models were used to evaluate efficacy against TL1A on COPD.
Example 23: clinical trial to test efficacy of anti-TL 1A in idiopathic pulmonary fibrosis
Phase 1b clinical trials were conducted to assess the efficacy of anti-TL 1A antibodies in patients with idiopathic pulmonary fibrosis.
Group: 10 patients were administered antibodies and 10 patients were administered placebo. The patient is monitored in real time.
Inclusion criteria: diagnosing patients with idiopathic pulmonary fibrosis
Primary outcome measure: the number of patients with treatment-related adverse effects; inflammatory markers comprising IL-1 beta, IL-2, IL-6, IL-17, IL-21, IL-22, IL-23, IFN-gamma and TGF-beta, C-reactive proteins; the number of patients with pulse oximetry abnormalities; mean change in volume of rigid breathing as measured by spirometry from baseline; average change in forced vital capacity from baseline as measured by a spirometry; average change in forced expiratory flow over the middle half of FVC as measured by spirometry from baseline; and a lung test to evaluate the diffusion capacity.
Example 24: clinical trial to test efficacy of anti-TL 1A in virus-induced fibrosis
Phase 1b clinical trials were conducted to assess the efficacy of anti-TL 1A antibodies in patients with virus-induced fibrosis.
Group: 10 patients were administered antibodies and 10 patients were administered placebo. The patient is monitored in real time.
Inclusion criteria: patients with virus-induced fibrosis are diagnosed.
Primary outcome measure: the number of patients with treatment-related adverse effects; inflammatory markers comprising IL-1 beta, IL-2, IL-6, IL-17, IL-21, IL-22, IL-23, IFN-gamma and TGF-beta, C-reactive proteins; the number of patients with pulse oximetry abnormalities; mean change in volume of rigid breathing as measured by spirometry from baseline; average change in forced vital capacity from baseline as measured by a spirometry; mean change in forced expiratory flow over the middle half of FVC from baseline as measured by spirometry.
Example 25: clinical trial to test efficacy of anti-TL 1A in asthma
Phase 1b clinical trials were conducted to assess the efficacy of anti-TL 1A antibodies in patients with asthma.
Group: 10 patients were administered antibodies and 10 patients were administered placebo. The patient is monitored in real time.
Inclusion criteria: patients diagnosed with asthma.
Primary outcome measure: the number of patients with treatment-related adverse effects; inflammatory markers comprising IL-1 beta, IL-2, IL-6, IL-17, IL-21, IL-22, IL-23, IFN-gamma and TGF-beta, C-reactive proteins; the number of patients with pulse oximetry abnormalities; mean change in volume of rigid breathing as measured by spirometry from baseline; average change in forced vital capacity from baseline as measured by a spirometry; mean change in forced expiratory flow over the middle half of FVC from baseline as measured by spirometry.
Example 26: clinical trial to test efficacy of anti-TL 1A in COPD
Phase 1b clinical trials were performed to assess the efficacy of anti-TL 1A antibodies in patients with COPD.
Group: 10 patients were administered antibodies and 10 patients were administered placebo. The patient is monitored in real time.
Inclusion criteria: patients diagnosed with COPD.
Primary outcome measure: the number of patients with treatment-related adverse effects; inflammatory markers comprising IL-1 beta, IL-2, IL-6, IL-17, IL-21, IL-22, IL-23, IFN-gamma and TGF-beta, C-reactive proteins; the number of patients with pulse oximetry abnormalities; mean change in volume of rigid breathing as measured by spirometry from baseline; average change in forced vital capacity from baseline as measured by a spirometry; average change in forced expiratory flow over the middle half of FVC as measured by spirometry from baseline; use of auxiliary muscles during breathing; and respiratory rate
Example 27: clinical trial to test efficacy of anti-TL 1A in systemic sclerosis-associated interstitial lung disease
Phase 1b clinical trials were conducted to assess the efficacy of anti-TL 1A antibodies in patients with systemic sclerosis-associated interstitial lung disease.
Group: 10 patients were administered antibodies and 10 patients were administered placebo. The patient is monitored in real time.
Inclusion criteria: a patient diagnosed with systemic sclerosis-related interstitial lung disease.
Primary outcome measure: efficacy was assessed by high resolution computer tomography (primary), pulmonary Function Test (PFT), combined response index for systemic sclerosis (crisp), and modified Rodnan skin score (mdss). The number of patients with treatment-related adverse effects; skin fibrosis, P1NP, BAFF, CD in serum 40L, CRP levels; evaluation of pain in patients.
Example 28: anti-TL 1A antibodies that bind to both TL1A monomers and TL1A trimers
To confirm that exemplary anti-TL 1A antibody a219 binds to both TL1A monomer and TL1A trimer, a peak shift assay with size exclusion chromatography was performed. Briefly, recombinantly produced human TL1A (rhTL 1A) was labeled with Alexa fluor 488 (AF 488) and added to Normal Human Serum (NHS). Labeled rhTL1A in serum was then injected into the size exclusion column and eluted by monitoring AF488 fluorescence signal.
RhTL1A was observed in at least two peaks of two different quaternary structures, one being a non-covalent trimer and one being a monomer (fig. 9A). The results show that the control reference antibody binds only to trimer TL1A (FIG. 9B) because in the presence of the control reference antibody, only the trimer TL1A peak is shifted (control reference antibody sequences, light chain SEQ ID NO:382 and heavy chain SEQ ID NO: 383). In contrast, a219 binds both TL1A trimer and monomer (fig. 9C), as both monomer and trimer TL1A peaks are shifted in the presence of a 219. The results demonstrate that exemplary anti-TL 1A antibody a219 binds to both TL1A monomer and TL1A trimer.
Example 29: PK/PD models for determining effective dosages
To confirm the use of the PK/PD model to determine effective doses, a pharmacokinetic (PBPK) based on the physiologically integrated whole body was established, as shown in fig. 10A. The integrated systemic PBPK contained a tissue level map, as shown in fig. 10B, to characterize the PK of mAb, ligand, and complex between mAb and ligand. The integrated systemic PBPK model contained the following drug specific parameters and/or inputs: (i) Soluble TL1A (sTL 1A) is synthesized by immune cells (e.g., dendritic cells) throughout the body; (ii) The half-life of monomer sTL1A was 20 minutes and the half-life of trimer sTL1A was 1 hour; (iii) Fixing affinity parameters (including start rate and end rate) between the antibody and sTL1A to values measured by SPR (e.g., as determined in example 12); (iv) Adjusting the synthesis rate of sTL1A to match the observed baseline and PK data; (v) In diseased individuals, the rate of sTL1A production increased 50-fold in the interstitial space of the intestine. Parameters and inputs may vary as described herein, including in section 4.
The systemic PBPK model summarizes PK observations for a219 and for TL1A in Normal Healthy Volunteers (NHVs). As shown in fig. 11A, the a219 concentration predicted by the systemic PBPK model matches the PK for a219 observed in NHV. Furthermore, as shown in fig. 11B, the TL1A concentration predicted by the whole-body PBPK model matches the TL1A concentration observed in NHV during the observed time course (assuming that TL1A production rate is constant).
When anti-TL 1A antibody A219, which binds to both monomer and trimeric TL1A, was injected, the observed serum concentration of TL1A was almost 10-fold higher (FIG. 12A) compared to the serum concentration when a control reference antibody that binds only to trimeric TL1A antibody was injected into the subject (control reference antibody sequences, light chain SEQ ID NO:382 and heavy chain SEQ ID NO: 383). This higher serum TL1A concentration is summarized in the systemic PBPK, as shown by the curve in fig. 12A. In addition, the model predicts about 40% monomer TL1A and 60% trimer TL1A, consistent with observations (fig. 12B). Fig. 12A thus confirms that patients treated with anti-TL 1A antibodies that bind to both monomeric and trimeric TL1A will sequester TL1A into serum 10-fold higher, thus reducing TL1A concentration in diseased tissue more than anti-TL 1A antibodies that bind to trimeric TL1A alone. Such isolation of more total TL1A in serum (both monomer and trimer) provides unexpected advantages for patients in need of reduced TL1A concentration in diseased tissue, both in the magnitude and rate of such TL1A reduction.
The baseline concentration of TL1A in serum from NHV was averaged to about 220ng/mL (162 to 414ng/mL,54 subjects, about 110 samples). The baseline concentration of TL1A in serum from CD subjects was averaged to about 273 (158 to 479ng/mL,17 CD subjects). Thus, the difference in serum TL1A concentration between NHV and CD patients was only modest, confirming the importance of targeting and reducing the concentration of soluble TL1A in diseased tissues. Assuming that all TL1A production is from the colon, the model determines that a 50-fold overproduction in the colon would replicate serum concentrations of 290ng/mL of TL1A, approaching observations in UC patients (fig. 12C). This large difference in TL1A in diseased tissue and the moderately corresponding difference in serum between NHV and UC patients again underscores the importance of targeting and reducing the concentration of soluble TL1A in diseased tissue.
To further verify and confirm the applicability of the systemic PBPK model, the predictive profile of TL1A concentration in serum of NHV and UC patients was compared to observations from clinical trials. As shown in FIGS. 13A-13B, the systemic PBPK model consistently predicts observations of total TL1A serum concentrations in NHV and UC patients from the reported phase I and phase II clinical trials (Banfield C. Et al, (J Clin Pharmacol.) (U.K. J) J.Pharmacol.) (4 months 2020; 86 (4): 812-824; and Danese S et al, (Clin Gastroenterol hepatology) 2021, 6 months 11; S1542-3565 (21) 00614-5). As shown in fig. 13C, the systemic PBPK model also predicts tissue interstitial space TL1A levels in NHV (normal tissue production) and UC patients (50-fold increase in local tissue production) in the absence of any administration of anti-TL 1A antibodies. Thus, the suitability of the systemic PBPK model has been verified by clinical observations.
After the systemic PBPK model has been established, the systemic PBPK model was used to model the concentration of TL1A in diseased tissue and serum with or without various doses of anti-TL 1A A219, with various conditions of overproduction of TL1A in diseased tissue. As shown in fig. 14A-14B, the systemic PBPK model mimics TL1A concentrations in the gut, for various levels of TL1A overproduction in the gut (fig. 14A) and corresponding serum (plasma) concentrations of TL1A at these levels of gut TL1A overproduction, each in the absence of any administration of any anti-TL 1A antibody.
The systemic PBPK model mimics the variation of TL1A concentration in diseased tissue over time when anti-TL 1A antibody a219 was injected at various doses (fig. 15A-15U). Such simulations may be plotted against TL1A concentration in the corresponding tissue or reference tissue of the NHV to determine if the dose is sufficient to reduce the TL1A concentration in the diseased tissue to below the TL1A concentration in the corresponding tissue or reference tissue of the NHV (fig. 15A-15U). Fig. 15A-15U also depict this simulation, as well as various parameters of TL1A overproduction (10×, 25×, 50×, or 100× overproduction or fold increase) in diseased intestinal tissue. As shown in fig. 15A-15U, the higher the fold of overproduction, the more dose or more of the administered anti-TL 1A antibody a219 is needed to reduce and maintain the TL1A concentration in diseased intestinal tissue below that shown in the concentration figure for the duration of time of NHV. More specifically, as shown in fig. 15R, administration of anti-TL 1A antibody a219 at 500mg every other week can cover up to about 125-fold overproduction (fold increase) of TL1A in the intestinal tract of a patient. As shown in fig. 15S, administration of anti-TL 1A antibody a219 at doses of 1000mg D1, 500mg W2, W6, W10 (i.e., 100mg at day 1, 500mg at week 2, 500mg at week 6, and 500mg at week 10) can cover up to about 60-fold overproduction (fold increase) of TL1A in the patient' S intestinal tract. As shown in fig. 15T, administration of anti-TL 1A antibody a219 at a dose of 1000mg D1, 500mg W4, W8, W12 (i.e., 1000mg at day 1, 500mg at week 4, 500mg at week 8, and 500mg at week 12) can cover up to about 55-fold overproduction (fold increase) of TL1A in the patient's intestinal tract. As shown in fig. 15U, administration of anti-TL 1A antibody a219 at doses of 1000mg D1, 500mg W2, W4, W8, W12 (i.e., 1000mg at day 1, 500mg at week 2, 500mg at week 4, 500mg at week 8, and 500mg at week 12) can cover up to about 60-fold overproduction (fold increase) of TL1A in the patient's intestinal tract. As shown in fig. 15V, administration of anti-TL 1A antibody a219 at doses of 1000mg D1, 500mg W2, W4, W6, W10 (i.e., 1000mg at day 1, 500mg at week 2, 500mg at week 4, 500mg at week 6, and 500mg at week 10) can cover up to about 75-fold overproduction (fold increase) of TL1A in the patient's intestinal tract.
For comparison, reference antibodies (reference antibody sequences, light chain SEQ ID NO:382 and heavy chain SEQ ID NO: 383) that bind only to trimeric TL1A were tested in a whole-body PBPK model. As shown in fig. 15W, such reference antibodies failed to consistently reduce or consistently maintain free TL1A concentrations in diseased tissue of patients below free TL1A concentrations in corresponding tissue of normal healthy volunteers when the diseased tissue overproduced TL1A by a factor of 50 or more than TL1A in corresponding tissue of normal healthy volunteers. This is in sharp contrast to fig. 15A, where anti-TL 1A antibody a219 that binds to both monomeric TL1A and trimeric TL1A consistently reduced the free TL1A concentration in diseased tissue and remained lower than the free TL1A concentration in the corresponding tissue of normal healthy volunteers, even though diseased tissue overproduces TL1A by a factor of 100 compared to TL1A in the corresponding tissue of normal healthy volunteers. As described above and shown in fig. 12C, 13C and 14A-14B, UC patients were determined to have 50-fold overproduction of TL1A in diseased tissue to summarize the observed modest increase in serum TL1A concentration. Thus, anti-TL 1A antibodies that bind to both monomeric and trimeric TL1A reduce the free TL1A concentration in diseased tissue of a patient to a lower concentration than the free TL1A concentration in corresponding tissue of normal healthy volunteers.
To further demonstrate the advantage of anti-TL 1A antibodies that bind to both monomeric and trimeric TL1A in treating patients and reducing free TL1A concentration in diseased tissues, such antibodies were directly compared to reference antibodies that bind to trimeric TL1A only. As shown in FIGS. 15X-15Z, anti-TL 1A antibody A219, which binds to both monomer and trimer TL1A, consistently and significantly reduced the free TL1A concentration in diseased tissue to a lower level than the free TL1A concentration in diseased tissue treated with reference anti-TL 1A antibodies that bind only to trimer TL1A (reference antibody sequences, light chain SEQ ID NO:382 and heavy chain SEQ ID NO: 383).
Example 30: population PK (popPK) model for determining effective doses
In addition, a population PK model was constructed to accurately model and predict a219PK in a population of normal healthy volunteers based on the available PK data available from example 16. PK data can be best described by a 2-chamber model with linear elimination. Demographic variables (including gender, age, race, and physique related variables) and laboratory clinical variables (including hematology, urine, and chemistry variables) were tested for the effect of clearance and distribution volume in the central chamber contained in the model. None of these variables were identified as important covariates for evaluation of 2 PK parameters. Population PK parameter estimates and Standard Error (SE) are described in table 27. Residual variability of a219 concentration associated with the population PK model was 11.9%. The goodness-of-fit plots are presented in fig. 16A-16H. These figures indicate good correlations between population predicted a219 concentrations ("predicted DV") and observed a219 concentrations ("observed DV") and between individual predicted a219 concentrations ("IPRED DV") and observed DV. No deviation of the normalized weighted residual from the predicted concentration or from time was observed. Evaluation of visual predictive examination (fig. 17A) indicated that the population PK model was able to adequately predict observed a219 concentration and was suitable for use in modeling a219 concentration.
Table 27: PK parameter estimates for the population PK model of A219
After the popPK model has been established, the popPK is used to select the induction dose to rapidly achieve steady state concentrations. As shown in fig. 17B, the loading dose of the induction regimen of 1000mg at day 1, 500mg at week 2, 500mg at week 6, and 500mg at week 10 ensured that the induced steady state concentration was reached from day 1. Furthermore, as shown in the systemic PBPK above, such induction regimen can address TL1A overproduction of more than 100 x in the colon over the first 5 weeks of induction and overproduction of more than 60 x over the 12 week period.
Example 31: formulation validation study
The exemplary formulations provided herein were placed in a long-term stability study (up to six months). The results of these storage stability studies are summarized in this example.
The materials used in this study contained a219 at different concentrations, as shown.
Method and program
UV analysis: sample absorbance and sample concentration were measured by standard UV absorbance instruments using an extinction coefficient of 1.41ml.mg-1cm-1 and correcting for background scatter.
pH analysis: the pH probes were calibrated with three pH standards ordered from fisher prior to starting the analysis. By inserting a pH probe into the sample and waiting until the measured value stabilizes, the pH of the formulation will be measured, which may take up to 1 to 2 minutes.
Permeability analysis: permeability analysis was performed using Osmo1 from andesite instruments (Advanced Instruments). At the beginning of the analysis, a reference standard at 290mOsm was analyzed to ensure that the instrument was working properly. After the reference standard is passed, the sample is then analyzed. 20uL of sample material was removed and analyzed by Osmo 1.
Viscosity: the viscosity of the samples was measured using m-Vroc from russen (San Ramon, CA, USA) at San-Ramon Meng Shi. The dynamic viscosity of the sample was calculated by flowing the sample through three differential pressure sensors. Then, linear regression of the pressure drop from the three sensors was used to calculate the dynamic viscosity of the sample. The instrument was calibrated and the dynamic viscosity of the samples measured according to manufacturer's instructions and industry standards. Analytical parameters for sample concentrations ranging from 60 to about 230mg/mL are listed in table 28:
table 28: viscosity parameters for evaluating protein samples
A219 concentration (mg/mL) Shear rate, 1/s Measuring time s Waiting time, s
60 1000 1.9 3
150 1000 1.9 3
175 1000 1.9 3
200 1000 1.9 3
Size Exclusion Chromatography (SEC): the SEC method was used to measure the stability of protein samples.
Cation exchange Chromatography (CEX): CEX is also used to measure the stability of protein samples.
Flow imaging (FlowCam): measurement of particle count in samples was prepared using a model VS-1FlowCAM flow imaging system (SN 551) with a Sony (Sony) SX90 camera and a C70 pump with a 1mL syringe (fluid imaging technologies company (Fluid Imaging Technologies)). System qualification consists of obtaining acceptable bead counts and acceptable program blanks (water) using NIST authentication count criteria (PharmTrol, siemens Fedder (Thermo), catalog number CS3800-15, or the like). The reception standard for the count standard was 3800±15% and the water blank was not more than 1 count/mL of 10 μm or more. The samples were visually evaluated during the sample runs and adjusted as necessary to optimize the results of each run. An x-y flowgram was recorded for each sample run.
Study design: validation studies examined formulations with a concentration of a219 ranging from 60 to 200mg/mL as shown in table 29 (formulations 1-9 are formulations 1-9 in the table, or F01-F08 in the present example). Table 30 shows the storage stability study schedule.
Table 29: formulations tested in this study
Table 30 study design
Annotation of table 30: initial time point (T0): pH, osmotic pressure, viscosity; at the end of each storage condition: SEC and CEX, etc., were visually inspected as described in this example.
Each time point (1M, 2M, 3M, 6M): visual inspection, SEC and CEX, etc., as described in this example
Results
The control (T0) samples listed in table 29 are characterized by visual inspection, osmolarity (osmo), pH, protein concentration, viscosity, SEC, CEX, and Flow Cam. The rest of the time was analyzed by SEC and CEX, except that the last time point of each temperature in table 30 was characterized by the same measurement in T0.
Visual characterization
The bulk material used in these studies had a pale yellow color, otherwise clear, with no visible particles observed. The formulation at T0 was visually inspected and was clear with no visible particles observed. At 60mg/mL, formulations 1 and 2 had a pale yellow color, with the color becoming stronger as the concentration increased from 60mg/mL to 200 mg/mL. A summary of visual observations can be found in table 31. No visible particles were observed throughout the study, and the sample remained clear under all conditions.
Table 31: visual characterization of stability samples
C=clear, np=no particles, nc=no color
Osmotic pressure
Osmotic pressure of the stability samples was measured at T0, 3 and 6 months (table 32). In addition, the theoretical osmotic pressure of all formulations except formulation 1 was calculated. For the highest protein concentration, the osmolarity of the sample ranged from 223 to 487mOsmol/kgH 2 O (Table 32). As the protein concentration increases from 60 to 200mg/ml, the difference between the theoretical and measured osmotic pressures becomes greater, reflecting the increased contribution of the protein. Over time, the osmotic values of some formulations did increase slightly (fig. 18), but the differences were relatively small.
Table 32: osmotic pressure was measured at T0, 3 and 6 months
Formulations Theoretical osmotic pressure mOsmoT0 mOsmo3M5℃ mOsmo3M25℃ mOsmo6M5℃
1 n.a 223 232 227 235
2 369 385 374 371 370
3 412 436 414 425 434
4 426 463 431 450 431
5 441 466 494 472 480
6 415 414 412 416 417
7 429 438 436 429 445
8 445 487 460 472 477
Protein concentration
Protein a219 concentration was measured to assess the stability of the samples at T0, 3 and 6 months, as shown in table 33. Most of the values appeared to be constant within the estimation error of the protein concentration method, indicating that a219 was stable in these formulations (table 33 and fig. 19). 0. Plots of the a219 protein concentration measured in each sample after 3 and 6 months showed that the concentration was fairly constant and may not reflect any substantial change in protein content (fig. 19). In addition, the protein concentration is within 5% of the target concentration of the formulation.
Table 33: protein concentration was measured at T0, 3 and 6 months
pH measurement results
The pH was measured to evaluate the stability of the samples at the time points of 0, 3 and 6 months (table 34). The measured pH values are all within less than 0.1 of the target pH of the formulation. The pH constancy is shown in FIG. 20.
Table 34: pH measured at T0, 3 and 6 months.
Viscosity measurement
Viscosity was measured to evaluate the stability of a219 samples of the various formulations at T0 and after 3 and 6 months, as shown in table 35. Figures 21A and 21B show graphical displays of viscosity data at T0 versus protein concentration consistent with exponential responses and viscosity of mAb as a function of concentration.
For formulations 6-8, the viscosity data ranged from about 5.3 to 13.4 mpa-s as the protein increased from about 150 to about 200 mg/mL. In contrast, formulation 3-5 had a slightly higher viscosity ranging from about 6.3 to 16.0mpa x s over the same protein concentration range. Some formulations did exhibit slightly higher viscosity values upon storage, possibly due to a slight increase in aggregate levels (see below).
Table 35: the viscosities at T0, 3 and 6 months were measured.
Stability measurement by Size Exclusion Chromatography (SEC)
The stability of the a219 sample is characterized by Size Exclusion Chromatography (SEC). At T0, the monomer content of these samples was > 98% (Table 36). After two months at 25 ℃, the monomer content was only slightly reduced, and all formulations retained > 97% of the monomer. The monomer content remained close to 97% even after three months at 25 ℃. Monomer losses (mainly due to the formation of Higher Molecular Weight (HMW) species) were only about 0.2-0.4% on average when stored at 5 ℃ (table 37).
Table 36A 219 samples T0, 1 and 2 month SEC results
The small loss of monomer is shown in the graph in fig. 22A. For high concentration formulations 3-8, aggregate (HMW species) formation appears to increase slightly at higher concentrations. The total monthly monomer loss for samples stored at 5 ℃ was only about 0.04 to 0.06% figure 22B. The monomer level of the 25 ℃ sample is provided in figure 22C. The average monthly loss for these samples was about 0.3 to 0.4% per month as shown in fig. 22D. Based on these data, the monomer loss will be less than 1% over two years at 5 ℃ and less than 5% when stored at 25 ℃.
Table 37: summary of 3 and 6 month SEC results for a219 samples
Stability as measured by cation exchange Chromatography (CEX)
The stability of the a219 sample was characterized by cation exchange Chromatography (CEX). CEX data for time points of 0, 1 and 2 months are summarized in table 38. The relative area of the main peak starts to approach 65%. Over time, this decrease is mainly due to an increase in acidic species, indicating that some hydrolytic changes, such as deamidation, are occurring. Formulation 1 (F01) shows the greatest variation.
Table 38: a219 samples characterized by cation exchange chromatography at T0, 1 and 2 months
Table 39: a219 samples characterized by cation exchange chromatography at T0, 3 and 6 months
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After three months at 25 ℃, the main peak averaged approximately 51%, while F01 continued to show a greater decrease, only about 46% of the main peak relative area (table 39). In contrast, samples stored at 5 ℃ showed very little decrease in CEX measurements. The relative area of the CEX main peak of formulations 2-8 remained close to 63% even after six months. The change in the relative area of the CEX main peak is shown in fig. 23A. At the same time, all high concentration (at or above 150mg/ml of A219) formulations showed comparable stability by CEX. The loss rate at 5C is provided in fig. 23B, and formulations 2-8 have very good stability, as determined by CEX.
CEX stability curves at 25℃are shown in FIG. 23C. The reduction in the main peak that may occur by hydrolytic modification is more pronounced at 25 ℃ than at 5 ℃. The rate of decrease per month was about 20 times greater at 25℃than at 5℃FIG. 23D.
Water stability measurements by FlowCAM Flow imaging analysis
The stability of these samples was characterized by FlowCAM, which calculates the number of microscopic visible particles (SVP) in boxes of different sizes. The level of SVP is reported in terms of particles per mL. At T0, F01 had a higher particle count than the other formulations (table 40). However, at one month/5C, the particle level of F01 was not comparable to other formulations. The results of the FlowCAM analysis of the samples after one and two months of retention at 25 ℃ are shown in table 41. After two months (table 41) and three months (table 42) at 25 ℃, the levels in all formulations remained relatively low. The SVP levels of the samples maintained at 5℃for three months appeared to be even slightly lower than the corresponding 25℃samples (Table 42). Finally, samples were analyzed for six months at 5 ℃ and the level of SVP remained low as shown (table 43).
Table 40: flowCAM analysis of T0 and 1 month stability samples
Table 41: flowCAM analysis of 1 and 2 month stability samples
Table 42: flowCAM analysis of 3 month stability samples
Table 43: flowCAM analysis of 6 month stability samples
PLS analysis of 2 month samples
Data at 25℃for 2 months were used to construct PLS models. The first PLS model with loss of MP was used as endpoint by SEC after two months at 25 ℃ (fig. 24A). The correlation coefficient for the calibration set was 0.975, while the r value for the validation set was 0.776, indicating a model of reasonable quality. PLS model indicates that significant factors affecting the stability of a219 include protein concentration, sucrose, etc.
This model indicated that monomer loss (e.g., aggregation) was greater at higher protein concentrations (fig. 24B). This effect is much more pronounced than the pH effect. This model predicts that lower pH and addition of acetate buffer reduced monomer loss when stored at 25 ℃ (figure 24C). Sucrose and Lys were both found to be effective stabilizers against aggregation (fig. 24D), while NaCl and Gly had little effect (fig. 24E).
Eight different formulations were stored for long periods at 5 ℃ and 25 ℃ and evaluated. The pH of each acetate formulation remained essentially unchanged after storage using the acetate buffer system. For the high concentration A219 samples, the viscosity of the formulation with sucrose/NaCl was significantly reduced relative to the sucrose/Lys formulation, corresponding to about 3cP at 200 mg/ml. The rate of monomer loss for samples in formulations 2-8 stored at 5 ℃ was very small and the total loss of monomer after two years was predicted to be < 1% for all high concentration formulations.
These compositions appear to have little tendency to form particles. Even after six months of storage, no evidence of particle formation was visible and the level of SVP was still low. Overall, these high concentration formulations appear to be very stable, and the formulations appear to support the use of 200mg/ml formulations.
Example 31: additional formulation validation studies
Exemplary A219 formulations (20 mM sodium phosphate, 5% (w/v) sucrose, 85mM glycine, 0.01% (w/v) polysorbate 20, pH 6.5) containing 60mg/mLA219 were placed in a long-term stability study. This example summarizes the results of the storage stability study of such exemplary formulations.
The long term stability conditions tested against anti-TL 1A (e.g. a 219) are 5±3 ℃ (upright). Accelerated stability conditions at 25 ℃/60% rh (upright) were also performed. The test was performed according to the stability protocol shown in tables 44 and 45 below. Methods for stability testing and acceptance criteria are presented in tables 46 and 47. In addition, comprehensive ICH stability studies were also performed on the A219 formulations listed in this example (ICH refers to International human pharmaceutical technology requirement coordination Condition).
Table 44: a219 formulation storage conditions and sampling time
Table 45: additional a219 formulation storage conditions and sampling time
Table 46: method for stability test in table 44
Table 47: method for stability test in table 45
The results from the stability study are shown in tables 48, 49 and 50. In short, no significant change in the amount of a219 protein was observed during storage at-20 ℃ or 2-8 ℃ for up to 12 months, and no overstandard findings or changes in key analytical parameters were observed. Antigen binding affinity and bioactivity preserved well at the 6 month, 25 ℃ time point. The biophysical changes seen indicate that the formulation is suitable for a219 monoclonal antibody for a longer period of time at high storage temperatures.
The results from the ICH stability study are shown in tables 51 and 52. In short, no significant change in the amount of a219 protein was observed during storage at 2-8 ℃ for up to 6 months, and no out-of-standard findings or changes in key analysis parameters were observed. Antigen binding affinity preserved well at the 6 month, 25 ℃ time point. The biophysical changes seen indicate that the formulation is suitable for a219 monoclonal antibody for a longer period of time at high storage temperatures.
Table 48 stability study: data for storage conditions-20 ℃
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Table 49 stability study: data for storage conditions 2-8deg.C
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NP = unexecuted; picIEF
Table 50 stability study: data for storage conditions 25 ℃/60% RH
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icIEF = imaging capillary isoelectric focusing
Table 51ICH stability study: storage conditions 2-8deg.C, data on erection
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Table 52ICH stability study: storage conditions 25 ℃/60% RH, upright data
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Example 32: double blind, randomized, placebo-controlled studies to evaluate the efficacy and safety of a219 in subjects with systemic sclerosis-related interstitial lung disease (SSc-ILD).
SSc is a rare connective tissue disease affecting approximately 120,000 patients in the united states and 80,000 patients in europe, mainly middle-aged women (bergamaasco, clinical epidemiology (Clinical Epidemiology) 2019, 11257-273). The etiology of SSc is largely unknown, but may involve genetic and environmental factors. Primary events in the pathogenesis of SSc are thought to be damage to endothelial cells; followed by abnormal vascular and immune responses that lead to excessive deposition and accumulation of extracellular matrix. The resulting progressive tissue remodeling may disrupt tissue architecture and lead to loss of organ function (bergamaasco, clinical epidemiology 2019, 11257-273).
SSc disease affects the skin, blood vessels, heart, lung, kidney, GI tract, and skeletal muscle system and causes a variable combination of symptoms, including Raynaud's phenomenon, arthritis, painful ulcers on the fingers and toes, skin thickening, shortness of breath, hypertension, and severe fatigue.
Quality of life (Qol) of SSc patients decreases and severe disability, fibrosis-related organ failure and premature death often occur (management of systemic sclerosis from various angles (Tackling systemic sclerosis from all angles) & Lancet rheumatology (Lancet Rheumatoid) & 2020, 2:e121). In the European sclerosant test and study (EUSTAR) database, pulmonary fibrosis accounts for 35% of disease-specific mortality and approximately 20% of total mortality (Tyndall, annual. Rheumatology (Ann RheumDis) 2010, 69:1809-15). Recent data indicate that ILD is currently the most common cause of death in SSc patients, with prevalence of up to 30% and mortality of up to 40% in 10 years (Perelas, medical science of lancet breathing (Lancet Respir Med) 2020, 8:304-20).
Corticosteroids and immunosuppressive therapy (MMF, methotrexate, cyclosporin) are suitable for SSc-ILD patients, but this indication is not specifically approved, indicating an unmet need.
Both drugs (nintedanib and tobalizumab) have recently been approved for SSc, both for SSc-ILD; however, there is still a significant unmet need. Although able to slow down the rate of lung function decline in SSc-ILD patients, neither therapy brings practical benefit to mRSS, dyspnea, and QoL or survival (Khanna, J.Sclerosis and related diseases (J Scleroderma RelDis) 2017,2 (1) 11-18; distler, new Engl J Med) 2019, 380:2518-28; roofeh, arthritis and rheumatic diseases (Arthritis Rheumatol) 2021, 73:1301-1310).
The present disclosure suggests that systemic sclerosis is accompanied by diffuse skin sclerosis and interstitial lung disease (SSc-ILD) characterized by fibrosis and extensive inflammatory features (a combination of both interstitial inflammatory changes and fibrosis). This profile is consistent with the role of TL1A and its receptor DR3, which promotes inflammation and fibrosis in Inflammatory Bowel Disease (IBD). The present disclosure suggests that the multidirectional effect of TL1A encompasses many effects of pathogenesis directly related to the direct impact of SSc on fibroblasts of Th2 and Th17 immune responses. In addition to its role in driving inflammation, TL1A and DR3 can drive fibrosis by direct stimulation of fibroblasts, independent of inflammatory mechanisms. TL1A also drives fibrosis by direct activation of fibroblasts and up-regulation of cytokines, such as transforming growth factor- β (TGF- β), leading to collagen distribution and fibrosis. Expression of TGF-beta regulated genes is associated with disease activity in fibrotic skin and lung in patients with SSc, indicating that this cytokine is a mediator of pathogenesis. Higher serum values of TGF- β were also observed in SSc patients compared to serum values in healthy subjects with positive correlation to disease severity (e.g., digital ulcers, broader skin fibrosis).
The present disclosure particularly suggests that TL1A-DR3 signaling promotes the occurrence of pulmonary fibrosis in SSc patients, and that therapeutic intervention with anti-TL 1A blocking antibodies such as a219 would produce clinical benefit for such patients. Consistent with TL1A as a therapeutic target for SSc as provided herein, serum TL1A levels in patients with SSc were higher than in healthy controls (p=0.001), and TL1AmRNA expression in Peripheral Blood Mononuclear Cells (PBMCs) in SSc patients was significantly higher (p < 0.001) compared to healthy controls. The causal relationship between TL1A-DR3 axis and fibrosis has been demonstrated in a mouse model of pulmonary fibrosis. In the mouse model, DR3 deficiency or blockage is sufficient to significantly ameliorate fibrotic disease in the lung. In addition, direct administration of recombinant TL1A into the lungs of mice triggered rapid onset of fibrosis in a DR 3-dependent manner. Primary human lung fibroblasts and bronchial epithelial cells express TL1A receptor DR3 and respond to recombinant TL1A in vitro by proliferating, expressing smooth muscle actin, and secreting extracellular matrix proteins, collagen, and periostin. Agents that disrupt TL1A interactions with DR3 then have the potential to prevent deregulated tissue cell activity in lung diseases involving fibrosis and remodeling.
To verify the efficacy of anti-TL 1A antibody a219 in SSc-ILD, A2-phase clinical trial was performed. The clinical trial included an induction period, as shown in fig. 25, and an open label extension (maintenance) period, as shown in fig. 25. The detailed design of the clinical trial protocol is shown in the protocol outline of table 53 below.
Table 53: summary of clinical trial protocol
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Example 33: results of phase I clinical studies on safety, PK, PD and immunogenicity.
Phase I clinical studies were completed to assess safety, PK, PD, and other parameters of anti-TL 1A antibodies (e.g., a 219). Phase I clinical study tested double blind, randomized, placebo controlled, single dose followed by multiple doses. In a Single Ascending Dose (SAD) group, anti-TL 1A antibodies (e.g. a 219) were tested in a total of 46 subjects randomized at 3 to 1 (35 to 11) in each dosing cohort. 6 cohorts (e.g., 6 dose levels) were tested for SAD, 5mg, 25mg, 100mg, 300mg, 600mg, and 1000mg, and the follow-up period was 14 weeks. In multiple escalated dose (MAD) studies, anti-TL 1A antibodies (e.g., a 219) were tested in 23 subjects randomized at 3 to 1 (17 to 6) in each dosing cohort. In the MAD study, all subjects received 3 doses on days 1, 15 and 29. 3 cohorts (dose levels) were tested for MAD study, 50mg, 200mg, 500mg, and the follow-up period was 18 weeks. Phase I clinical studies evaluate safety and tolerability of anti-TL 1A antibodies (e.g., a 219), pharmacokinetics (PK), immunogenicity (e.g., by evaluating anti-drug antibody ADA), and Pharmacodynamic (PD) labeling.
68 out of 69 subjects (98.5%) completed the study and follow-up period, with one patient completed up to week 8 in 200mg MAD, but failed to follow-up. No Serious Adverse Events (SAE) were observed in the clinical study. During the study period (30 min infusion up to 1000 mg), there was no drug-related infusion reaction or drug-related infusion time extension. No clinically significant changes were reported by physical examination, laboratory values, electrocardiography, or vital signs.
All Adverse Events (AEs) assessed as related to study drug were mild. Exemplary mild AEs reported in the SAD study included 1 somnolence report in 35 subjects tested with a219 (at a dose of 600 mg) and 1 headache report in the placebo group of 11 subjects. Exemplary mild AEs reported in MAD studies contained: 1 diarrhea report in 17 subjects tested with a 219; diarrhea report in placebo group of 6 subjects; 1 of 17 subjects tested with a219 were reported to sleep drowsiness; dizziness report in 1 out of 17 subjects tested with a 219; headache report in 1 case of placebo group of 11 subjects was studied.
Thus, anti-TL 1A antibodies (e.g., a 219) have advantageous safety and tolerability.
Various PK parameters were determined and are shown in fig. 26A and 26B, as well as tables 54-58.
Table 54: summary of serum a219 pharmacokinetic parameters following single dose of a219 as IV infusion administration (SAD)
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Table 55: summary of serum a219 pharmacokinetic parameters after multiple doses of a219Q2W were administered as IV infusion-day 1 (MAD)
Table 56: summary of serum a219 pharmacokinetic parameters after multiple doses of a219Q2W were administered as IV infusion-day 15 (MAD)
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Table 57: summary of serum a219 pharmacokinetic parameters after multiple doses of a219Q2W were administered as IV infusion-day 29 (MAD)
Table 58: serum A219C after multiple doses of A219Q2W were administered as IV infusion (MAD) trough Steady state evaluation of values
The results are shown in fig. 26A and 26B, and tables 54-58 demonstrate that the PK of an anti-TL 1A antibody (e.g., a 219) meets the PK performance criteria of a therapeutic antibody and supports the 2-phase dosing regimen discussed in section 5 (example). Half-life after 500mg dose every other week was about 19 days. Dose-proportional exposure at doses greater than or equal to 100mg was observed in the PK profile.
Furthermore, target engagement was assessed by determining the concentration of soluble TL1A in the serum of subjects in the clinical study. The anti-TL 1A antibody a219 provided herein demonstrates dose-dependent, robust, sustained target engagement, as shown in fig. 27A and 27B. Target engagement, as determined by an increase in soluble TL1A in serum, was maximized at about 45,000pg/mL sTL1A at 200mg a219q2w (fig. 27B). This target binding was more than 4-fold higher than that observed in the control reference anti-TL 1A antibody binding to trimer TL1A alone (control reference antibody sequence, light chain SEQ ID NO:382 and heavy chain SEQ ID NO: 383) (see Banfield C et al J Clin Pharmacol 2020;86:812-824; danese S et al J gastroenterology and liver disease (Clin Gastroenterol hepatol.)) (2021, 6 months 11 days; S1542-3565 (21) 00614-5; danese S et al J gastroenterology and liver disease (2021, 11 months; 19 (11): 2324-2332.e6). Thus, the anti-TL 1A antibodies provided herein that bind to monomeric and trimeric TL1A provide better target engagement than anti-TL 1A antibodies that bind to trimeric TL1A alone.
In addition, immunogenicity of anti-TL 1A antibodies was assessed by determining anti-drug antibodies (ADA). At clinically relevant doses (1000 mg SAD, 200mg and 500mg MAD), the immunogenicity rate was no more than 20%. In contrast, the reported immunogenicity (e.g., ADA positive) rates (light chain SEQ ID NO:382 and heavy chain SEQ ID NO: 383) of the control reference anti-TL 1A antibodies were within 80% at similar doses in both normal healthy volunteers and UC patients (see Banfield C et al, J. England Pharmacol 2020;86:812-824; danese S et al, clinical gastroenterology and liver disease 2021, month 6, 11 days; S1542-3565 (21) 00614-5; danese S et al, clinical gastroenterology and liver disease 2021, month 11; 19 (11): 2324-2332.e6). ADA titers observed in clinical trials were inversely proportional to a219 exposure, and ADA positivity occurred only at low a219 concentrations.
To further evaluate the potential impact of ADA, neutralizing antibodies were also determined in phase I trials. Neutralizing antibody rates at clinically relevant doses are unusual and were observed in only 1 (6%) of 17 subjects in the clinically relevant dose group (1000 mg SAD, 200mg and 500mg MAD). The immunogenicity observed in phase I trials was not clinically relevant because (1) ADA did not affect safety, as no infusion reactions were reported throughout the study; (2) ADA did not affect clearance of a219 in the population PK model, and (3) ADA did not affect target engagement, as there was no significant effect on sTL1A levels, as shown in fig. 27A and 27B.
In summary, the anti-TL 1A antibodies provided herein have advantageous safety and tolerability; the PK of the anti-TL 1A antibodies provided herein meet performance criteria and support a 2-phase dosing regimen; the anti-TL 1A antibodies provided herein neutralize both active trimer TL1A and inactive monomer TL1A, resulting in increased and sustained target engagement, and potentially resulting in more effective reduction of active TL1A in tissue; the anti-TL 1A antibodies provided herein do not trigger immunogenicity that may adversely affect their therapeutic efficacy.
Example 34: physiological Based Pharmacokinetic (PBPK) modeling and population pharmacokinetic modeling (popPK) were further validated with phase I clinical trial results.
Further PBPK modeling, popPK modeling and model validation were performed based on PK, PD and TL1A concentration data from subjects in phase I clinical trials. As further described above (e.g., in section 5 (example)), the key mechanisms involved in the PBPK model include: central, peripheral, and diseased tissue (e.g., bowel) compartments; TL1A synthesis and clearance, exchange between trimer and monomer states; up-regulated TL1A synthesis in diseased intestinal tissue of IBD patients; a219 binds to both monomer and trimer TL1A, and the control reference antibody binds only to trimer TL 1A; administration, distribution, non-specific elimination, and membrane TL1A mediated targeting-mediated drug distribution of anti-TL 1A antibodies; distribution and clearance of bound complexes. Inputs to the PBPK model include: (1) The anti-TL 1A antibodies provided herein bind to both TL1A monomers and trimers, while the control reference antibodies (light chain SEQ ID NO:382 and heavy chain SEQ ID NO: 383) bind only to TL1A trimers; (2) TL1A is synthesized systemically in the peripheral compartment and inflamed intestinal tissue in healthy subjects, and elevated tissue expression of TL1A results from increased synthesis of TL1A within the diseased tissue; (3) Trimer TL1A and monomer TL1A interchange at a rapid equilibrium, resulting in a fixed steady state ratio of monomer to trimer; (4) Drug-binding TL1A trimer/monomer does not change form; (5) The anti-TL 1A antibody binds to a trimer or monomer with the same effective Kd in a single binding event; (6) free TL1A monomers and trimers are cleared at different rates; (7) Antibodies that bind TL1A monomers and antibodies that bind TL1A trimers are cleared at the same rate; (8) Antibodies that bind TL1A monomers and antibodies that bind TL1A trimers are assigned identically to antibodies; antibodies that bind to membrane TL1A internalize at the same rate as membrane TL 1A. Exemplary values for various parameters of anti-TL 1A antibodies are described in table 59.
Table 59: parameters used in modeling (drug = anti-TL 1A antibody)
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To validate the model, the model was fitted to the SAD data and normalized to the Q2W data of the phase I clinical trial with a 219. As shown in fig. 28A and 28B, the model was fitted to the single incremental dose data of a219 with reasonable consistency. Further, as shown in fig. 28C and 28D, the model was able to capture multiple incremental dose data of a219 without additional fitting, indicating the consistency and robustness of the model. Likewise, and without additional fitting, the model captured data for control reference antibodies that bound only to TL1A trimer (light chain SEQ ID NO:382 and heavy chain SEQ ID NO: 383), versus (1) phase I single incremental dose data (FIGS. 28E and 28F); (2) multiple incremental dose data at stage I (fig. 28G and 28H); and (3) phase II data (FIGS. 28I and 28J) on PK and total sTL1A levels (Banfield C et al, J.UK. J.Clin.Clin.Chem.Pharmacol.2020; 86:812-824.Danese S et al, J.Clin.G.CHEMICAL & liver disease 2021, month 11; 19 (11): 2324-2332.e6; hassan-Zahraee M et al, inflammatory bowel disease (Inflammatory Bowel Diseases), 2021, XX, 1-13). The IBD-specific parameters were then calibrated to capture free tissue TL1A levels in the intestine (FIG. 28K), as observed in clinical trials with control reference antibodies (light chain SEQ ID NO:382 and heavy chain SEQ ID NO: 383). Thus, the model was validated with clinical trial data.
This validation model can be used to determine the dose to reduce the free TL1A concentration in the diseased tissue of the patient below the TL1A concentration of the corresponding tissue in a healthy subject, similar to that described in examples 29 and 30 above. Fig. 29A and 29B show examples of such doses determined from validated models, which can result in free TL1A concentrations in diseased tissue of a patient that are lower than TL1A concentrations in corresponding tissue in healthy subjects (iv_4×=1000 mg loading dose, 3×500mg at day 14, 42, 70; sc administration 240mg Q1W or Q2W).
The validated model also demonstrates that anti-TL 1A antibodies that bind to both TL1A monomers and trimers can bind more TL1A in the circulation than anti-TL 1A antibodies that bind only to TL1A trimers, and result in greater reduction of TL1A in diseased tissue. In face-to-face comparisons in the validated model, anti-TL 1A antibodies that bound to both TL1A monomers and trimers bound more TL1A in circulation than anti-TL 1A antibodies that bound only to TL1A trimers, as shown in fig. 29C, where circulating TL1A accumulation rate was determined to be 3.5 fold. In face-to-face comparisons in the validated model, anti-TL 1A antibodies that bound to both TL1A monomers and trimers also resulted in a higher percentage of TL1A reduction (about 100% reduction relative to day 0) in diseased tissue when compared to anti-TL 1A antibodies that bound to only TL1A trimers, as shown in fig. 29D. Since diseased tissue of an IBD patient typically produces 20, 30, 40, 50, 60, 70, or even 100 times more TL1A, as shown in examples 29 and 30 above, a few percent of the residual TL1A production in the patient's diseased tissue may still be pathological TL1A concentrations.
Similarly, the popPK model was further fitted and validated with phase I clinical trial data. Briefly, A2-chamber popPK model for a219 with linear and nonlinear elimination (targeted mediated drug treatment) was established as shown in fig. 30A and described above. Covariates were not found to have clinically relevant effects on PK parameters. The popPK model fits phase I clinical trial data well and reliably predicts a219 and TL1A concentration data in the test population, as shown in fig. 30B-30E. In addition, there was no significant deviation between the predicted and observed a219 and TL1A concentrations (fig. 30B-30E).
After validation of the popPK model, the popPK model was used to determine a219 and TL1A concentrations under various dosing regimens. The validated popPK model confirmed the dose to achieve anti-TL 1A antibody concentration levels in serum and binding of TL1A (total soluble TL1A concentration in circulation) in order to reduce TL1A concentration in diseased tissue below that of healthy subjects, as shown in fig. 31A-31H.
Example 35: verification of SSe-ILD treatment with anti-TL 1A antibodies
The present disclosure suggests that SSc-ILD is characterized by fibrosis and a broad range of inflammatory characteristics. The inventors recognized that the pathogenesis of SSc-ILD involves cellular damage, thereby initiating infiltration and activation of innate and adaptive immunoinflammatory cells, followed by recruitment, activation and differentiation of fibroblasts into myofibroblasts, resulting in accumulation of extracellular matrix, particularly collagen, and ultimately destruction of tissue structure and function. In view of the increasing evidence that the TL1A-DR3 pathway is involved as a driver of downstream inflammatory pathways observed in SSc as well as in fibrotic responses, the inventors recognized that inhibition of TL1A by antibodies that block TL1A, as provided herein, may be effective for SSc-ILD.
The present disclosure suggests that TL1A is a cytokine produced primarily by antigen presenting cells and endothelial cells, and that TL1A is expressed as a type II transmembrane protein that can be subsequently cleaved by extracellular proteases and converted into active soluble trimers. Whether membrane-bound or in soluble form, TL1A signals through its only known receptor DR3 and members of the TNF receptor superfamily, which are widely found on T cells, natural Killer (NK) and NK-T cells, congenital lymphocytes (ILC), fibroblasts and epithelial cells. DR3 has no known ligand other than TL1A and is effective in driving inflammation through the enhancement of effector T cells (including Th1, th2 and Th17 lineage cells). In addition, the inventors realized that TL1A was induced in antigen presenting cells by toll-like receptor (TLR) ligand and FcR cross-linking, and in T cells by T Cell Receptor (TCR) stimulation.
The inventors realized that the multidirectional effect of TL1A encompasses activation of cellular pathways directly involved in SSc pathogenesis, ranging from activation of Th2 and Th17 responses to direct effects on fibroblasts. The present disclosure suggests that Th17 cells may be specifically enhanced by TL1A-DR3 signaling. To demonstrate the central role of TL1A in driving differential gene expression profiles between SSc patients and healthy subjects, a set of TL1A signature genes were identified that respond to TL1A stimulation. Briefly, cultured Th17 cells were induced with TL1A, and gene expression in stimulated Th17 cells was analyzed 24, 48, or 72 hours after TL1A stimulation. The overexpression genes in TH17 cells in response to TL1A treatment were identified as TL1A signature genes. TL1A signature genes in cultured cd4+ T cells were also identified by evaluating genes induced and responsive to TL1A stimulation of cd4+ T cells in culture. The expression of these TL1A signature genes in SSc patients and healthy control subjects was then analyzed using the bulk RNA sequence expression data and compared to determine if TL1A signature genes were expressed differently in SSc patients compared to healthy subjects (fig. 32). FIG. 32 shows that both sets of TL1A signature genes, namely TL1A response signature genes in TH17 cells and TL1A response signature genes in CD4+ cells, are elevated in RNAseq data set from tissues of SSc patients compared to healthy control tissues (FIG. 32).
Thus, the expression of TL1A response genes was elevated in SSc patients compared to healthy subjects.
In addition, the present disclosure suggests that chronic inflammation may promote altered extracellular matrix deposition and eventual fibrosis in SSc, and that a biased balance between Th1 and Th2 cytokines is a characteristic of fibrosis, where the number of Th2 cells producing IL-13, IL-4 and IL-5 exceeds Th1 interferon gamma (IFNg) producing cells in inflamed fibrotic tissue. In addition to its pleiotropic pro-inflammatory activity, the present disclosure also suggests that the TL1A-DR3 pathway has the ability to drive fibrosis by direct stimulation of fibroblasts, irrespective of T cell inflammatory mechanisms (e.g., fig. 8). Similarly, the inventors realized that human primary lung fibroblasts and bronchial epithelial cells express DR3 and respond in vitro to recombinant TL1A by proliferating, expressing smooth muscle actin, and secreting extracellular matrix proteins, collagen, and periostin. TL1A drives fibrosis by direct activation of fibroblasts, leading to collagen distribution and fibrosis.
In summary, the inventors recognize through the present disclosure that TL1A-DR3 signaling can promote fibrosis, which is a marker of SSc, pulmonary fibrosis in patients comprising SSc-ILD, and blocking TL1A with an anti-TL 1A antibody (as provided herein) can provide therapeutic benefit. By targeting both inflammation and fibrosis of the lung, anti-TL 1A antibodies (as provided herein) can significantly improve the effects of SSc patients, and more particularly SSc-ILD patients.
To further support that pathogenesis of SSc is driven by TL1A-DR3 signaling pathway, and thus can be treated by inhibiting the TL1A-DR3 pathway with anti-TL 1A (as provided herein), molecular data is generated from biopsies of human skin of SSc patients and analyzed (fig. 33). As shown in fig. 33, expression of TNFSF15 (TL 1A) was increased in bone marrow cells from SSc patients, while expression of TNFRSF25 (DR 3) was increased in T cells as well as fibroblasts and keratinocytes from SSc patients (n=4 patients). Expression of DR3 supports the role of TL 1A-mediated signaling in activation of inflammatory T cells, while expression of DR3 in fibroblasts and keratinocytes is consistent with activation of fibroblasts in the skin and supports the contribution of TL1A-DR3 signaling to fibrosis.
The chromatin availability data generated by ATAC-seq (an assay of chromatin accessible using sequenced transposases) was also analyzed for gene expression at the single cell level, and the results further supported the role of TL1A-DR3 signaling pathway in SSc and the treatment of SSc by inhibition of the TL1A-DR3 pathway with anti-TL 1A. Briefly, ATAC-seq is a technique in molecular biology for studying chromatin availability and helps identify regions with stable transcriptional activity. As shown in fig. 34A, the increased chromatin availability of the TNFSF15 (TL 1A) gene seen in dendritic cells as well as monocytes/macrophages further confirmed the expression of the TNFSF15 gene at the single cell level, which can be seen in fig. 33, which is shown on the panel on the right side of fig. 34A. Similarly, ATAC sequence data was generated for DR3 (TNFRSF 25) gene at single cell level (fig. 34B). As shown in fig. 34A-34B, TL1A is expressed in bone marrow cells; DR3 is expressed in T cells and bone marrow cells, both of which are important cells of inflammation seen in SSc patients.
Thus, the role of TL1A in the pathogenesis of SSc and the therapeutic mechanism of treating SSc by blocking TL1A with anti-TL 1A provided herein has been validated by: (1) Increased expression of TL1A response signature genes in SSc patients compared to healthy subjects; (2) TL1A and DR3 are themselves elevated in SSc patients, and in particular in pro-inflammatory cells; (3) The high chromatin availability of TL1A and DR3 genes in cell types promotes pathogenesis in SSc patients.
Table 9B: fc and constant region
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The foregoing description of various embodiments known to the applicant at the time of filing the application has been presented and is intended for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and many modifications and variations are possible in light of the above teaching. The embodiments described are presented to explain the principles and practical application and to enable others skilled in the art to utilize various embodiments and with various modifications as are suited to the particular use contemplated. Therefore, it is intended that the disclosure not be limited to the particular embodiments disclosed.
Sequence listing
<110> Promendes bioscience Co (PROMETHUS BIOSCIENCES, INC.)
Sida-Saanese medical center (CEDARS-SINAI MEDICAL CENTER)
<120> anti-TL 1A antibody compositions and methods for treating lung
<130> 56884-788.601
<140>
<141>
<150> 63/285,785
<151> 2021-12-03
<150> 63/226,041
<151> 2021-07-27
<150> 63/180,896
<151> 2021-04-28
<150> 63/150,832
<151> 2021-02-18
<160> 455
<170> patent In version 3.5
<210> 1
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Gly Phe Asp Ile Gln Asp Thr Tyr Met His
1 5 10
<210> 2
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<400> 2
Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe Gln
1 5 10 15
Val
<210> 3
<211> 17
<212> PRT
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<400> 3
Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe Gln
1 5 10 15
Gly
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<211> 17
<212> PRT
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Arg Ile Asp Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe Gln
1 5 10 15
Gly
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<400> 5
Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe Gln
1 5 10 15
Val
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<212> PRT
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<400> 6
Ser Gly Gly Leu Pro Asp Val
1 5
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<211> 9
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<400> 7
Ala Arg Ser Gly Gly Leu Pro Asp Val
1 5
<210> 8
<211> 7
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<400> 8
Ser Gly Gly Leu Pro Asp Trp
1 5
<210> 9
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<400> 9
Ala Arg Ser Gly Gly Leu Pro Asp Trp
1 5
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<400> 10
Arg Ala Ser Ser Ser Val Ser Tyr Met Tyr
1 5 10
<210> 11
<211> 7
<212> PRT
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<400> 11
Ala Thr Ser Asn Leu Ala Ser
1 5
<210> 12
<211> 9
<212> PRT
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<400> 12
Gln Gln Trp Glu Gly Asn Pro Arg Thr
1 5
<210> 13
<211> 9
<212> PRT
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<400> 13
Gln Gln Trp Lys Gly Asn Pro Arg Thr
1 5
<210> 14
<211> 9
<212> PRT
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<220>
<223> description of artificial sequence: synthetic peptides
<400> 14
Gln Gln Trp Ser Gly Asn Pro Arg Thr
1 5
<210> 15
<211> 9
<212> PRT
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<220>
<223> description of artificial sequence: synthetic peptides
<400> 15
Gln Gln Trp Ser Arg Asn Pro Arg Thr
1 5
<210> 16
<400> 16
000
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<400> 98
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<400> 99
000
<210> 100
<400> 100
000
<210> 101
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 101
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 102
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 102
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 103
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 103
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 104
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 104
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 105
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 105
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 106
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 106
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 107
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 107
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 108
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 108
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 109
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 109
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 110
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 110
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 111
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 111
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 112
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 112
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 113
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 113
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 114
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 114
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 115
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 115
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 116
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 116
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 117
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 117
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 118
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 118
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 119
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 119
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 120
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 120
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 121
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 121
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 122
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 122
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 123
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 123
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 124
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 124
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 125
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 125
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 126
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 126
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 127
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 127
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 128
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 128
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 129
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 129
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 130
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 130
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 131
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 131
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 132
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 132
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 133
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 133
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 134
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 134
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 135
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 135
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 136
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 136
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 137
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 137
Asp Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 138
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 138
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 139
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 139
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 140
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 140
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 141
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 141
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 142
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 142
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 143
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 143
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 144
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 144
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 145
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 145
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 146
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 146
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 147
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 147
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 148
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 148
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 149
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 149
Asp Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 150
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 150
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 151
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 151
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 152
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 152
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 153
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 153
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 154
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 154
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Val Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 155
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 155
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 156
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 156
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 157
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 157
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 158
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 158
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 159
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 159
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 160
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 160
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 161
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 161
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 162
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 162
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 163
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 163
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 164
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 164
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 165
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 165
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 166
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 166
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 167
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 167
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 168
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 168
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 169
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 169
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Glu Pro Ala Ser Gly His Ile Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Trp Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 170
<400> 170
000
<210> 171
<400> 171
000
<210> 172
<400> 172
000
<210> 173
<400> 173
000
<210> 174
<400> 174
000
<210> 175
<400> 175
000
<210> 176
<400> 176
000
<210> 177
<400> 177
000
<210> 178
<400> 178
000
<210> 179
<400> 179
000
<210> 180
<400> 180
000
<210> 181
<400> 181
000
<210> 182
<400> 182
000
<210> 183
<400> 183
000
<210> 184
<400> 184
000
<210> 185
<400> 185
000
<210> 186
<400> 186
000
<210> 187
<400> 187
000
<210> 188
<400> 188
000
<210> 189
<400> 189
000
<210> 190
<400> 190
000
<210> 191
<400> 191
000
<210> 192
<400> 192
000
<210> 193
<400> 193
000
<210> 194
<400> 194
000
<210> 195
<400> 195
000
<210> 196
<400> 196
000
<210> 197
<400> 197
000
<210> 198
<400> 198
000
<210> 199
<400> 199
000
<210> 200
<400> 200
000
<210> 201
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 201
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Glu Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 202
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 202
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Glu Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 203
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 203
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 204
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 204
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Lys Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 205
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 205
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Glu Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 206
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 206
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Lys Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 207
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 207
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 208
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 208
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Val Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 209
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 209
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Glu Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 210
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 210
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Val Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 211
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 211
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Val Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 212
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 212
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Val Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 213
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 213
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 214
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 214
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 215
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 215
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Val Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 216
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 216
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Glu Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 217
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 217
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Val Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Glu Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 218
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 218
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Val Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Glu Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 219
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 219
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Glu Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 220
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 220
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Met Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Glu Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 221
<400> 221
000
<210> 222
<400> 222
000
<210> 223
<400> 223
000
<210> 224
<400> 224
000
<210> 225
<400> 225
000
<210> 226
<400> 226
000
<210> 227
<400> 227
000
<210> 228
<400> 228
000
<210> 229
<400> 229
000
<210> 230
<400> 230
000
<210> 231
<400> 231
000
<210> 232
<400> 232
000
<210> 233
<400> 233
000
<210> 234
<400> 234
000
<210> 235
<400> 235
000
<210> 236
<400> 236
000
<210> 237
<400> 237
000
<210> 238
<400> 238
000
<210> 239
<400> 239
000
<210> 240
<400> 240
000
<210> 241
<400> 241
000
<210> 242
<400> 242
000
<210> 243
<400> 243
000
<210> 244
<400> 244
000
<210> 245
<400> 245
000
<210> 246
<400> 246
000
<210> 247
<400> 247
000
<210> 248
<400> 248
000
<210> 249
<400> 249
000
<210> 250
<400> 250
000
<210> 251
<400> 251
000
<210> 252
<400> 252
000
<210> 253
<400> 253
000
<210> 254
<400> 254
000
<210> 255
<400> 255
000
<210> 256
<400> 256
000
<210> 257
<400> 257
000
<210> 258
<400> 258
000
<210> 259
<400> 259
000
<210> 260
<400> 260
000
<210> 261
<400> 261
000
<210> 262
<400> 262
000
<210> 263
<400> 263
000
<210> 264
<400> 264
000
<210> 265
<400> 265
000
<210> 266
<400> 266
000
<210> 267
<400> 267
000
<210> 268
<400> 268
000
<210> 269
<400> 269
000
<210> 270
<400> 270
000
<210> 271
<400> 271
000
<210> 272
<400> 272
000
<210> 273
<400> 273
000
<210> 274
<400> 274
000
<210> 275
<400> 275
000
<210> 276
<400> 276
000
<210> 277
<400> 277
000
<210> 278
<400> 278
000
<210> 279
<400> 279
000
<210> 280
<400> 280
000
<210> 281
<400> 281
000
<210> 282
<400> 282
000
<210> 283
<400> 283
000
<210> 284
<400> 284
000
<210> 285
<400> 285
000
<210> 286
<400> 286
000
<210> 287
<400> 287
000
<210> 288
<400> 288
000
<210> 289
<400> 289
000
<210> 290
<400> 290
000
<210> 291
<400> 291
000
<210> 292
<400> 292
000
<210> 293
<400> 293
000
<210> 294
<400> 294
000
<210> 295
<400> 295
000
<210> 296
<400> 296
000
<210> 297
<400> 297
000
<210> 298
<400> 298
000
<210> 299
<400> 299
000
<210> 300
<400> 300
000
<210> 301
<211> 118
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<220>
<221> MOD_RES
<222> (1)..(1)
<223> any amino acid
<220>
<221> MOD_RES
<222> (38)..(38)
<223> any amino acid
<220>
<221> MOD_RES
<222> (40)..(40)
<223> any amino acid
<220>
<221> MOD_RES
<222> (48)..(48)
<223> any amino acid
<220>
<221> MOD_RES
<222> (50)..(66)
<223> this region may encompass one of the following sequences:
"RIDPASGHTKYDPKFQV" or "RIEPASGHIKYDPKFQG" or
"RIDPASGHIKYDPKFQG" or "RIEPASGHIKYDPKFQV"
<220>
<221> MOD_RES
<222> (68)..(68)
<223> any amino acid
<220>
<221> MOD_RES
<222> (70)..(70)
<223> any amino acid
<220>
<221> MOD_RES
<222> (72)..(72)
<223> any amino acid
<220>
<221> MOD_RES
<222> (79)..(79)
<223> any amino acid
<220>
<221> MOD_RES
<222> (81)..(81)
<223> any amino acid
<220>
<221> MOD_RES
<222> (99)..(107)
<223> this region may encompass one of the following sequences:
"SGGLPDV" or "ARSGGLPDV" or "SGGLPDW" or "ARSGGLPDW"
<220>
<223> refer to the specification filed for a detailed description of alternative and preferred embodiments
<400> 301
Xaa Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Xaa Gln Xaa Pro Gly Gln Gly Leu Glu Trp Xaa
35 40 45
Gly Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
50 55 60
Xaa Xaa Arg Xaa Thr Xaa Thr Xaa Asp Thr Ser Thr Ser Thr Xaa Tyr
65 70 75 80
Xaa Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 302
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<220>
<221> MOD_RES
<222> (1)..(1)
<223> any amino acid
<220>
<221> MOD_RES
<222> (38)..(38)
<223> any amino acid
<220>
<221> MOD_RES
<222> (40)..(40)
<223> any amino acid
<220>
<221> MOD_RES
<222> (48)..(48)
<223> any amino acid
<220>
<221> MOD_RES
<222> (50)..(66)
<223> this region may encompass one of the following sequences:
"RIDPASGHTKYDPKFQV" or "RIEPASGHIKYDPKFQG" or
"RIDPASGHIKYDPKFQG" or "RIEPASGHIKYDPKFQV"
<220>
<221> MOD_RES
<222> (68)..(68)
<223> any amino acid
<220>
<221> MOD_RES
<222> (70)..(70)
<223> any amino acid
<220>
<221> MOD_RES
<222> (72)..(72)
<223> any amino acid
<220>
<221> MOD_RES
<222> (79)..(79)
<223> any amino acid
<220>
<221> MOD_RES
<222> (81)..(81)
<223> any amino acid
<220>
<221> MOD_RES
<222> (97)..(105)
<223> this region may encompass one of the following sequences:
"SGGLPDV" or "ARSGGLPDV" or "SGGLPDW" or "ARSGGLPDW"
<220>
<223> refer to the specification filed for a detailed description of alternative and preferred embodiments
<400> 302
Xaa Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Xaa Gln Xaa Pro Gly Gln Gly Leu Glu Trp Xaa
35 40 45
Gly Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
50 55 60
Xaa Xaa Arg Xaa Thr Xaa Thr Xaa Asp Thr Ser Thr Ser Thr Xaa Tyr
65 70 75 80
Xaa Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 303
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<220>
<221> MOD_RES
<222> (45)..(46)
<223> any amino acid
<220>
<221> MOD_RES
<222> (88)..(96)
<223> this region may encompass one of the following sequences:
"QQWEGNPRT" or "QQWKGNPRT" or "QQWSGNPRT" or "QQWSRNPRT"
<220>
<223> refer to the specification filed for a detailed description of alternative and preferred embodiments
<400> 303
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Xaa Xaa Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 304
<211> 25
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 304
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser
20 25
<210> 305
<211> 14
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 305
Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 306
<211> 32
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 306
Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Leu Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 307
<211> 30
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 307
Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Leu Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
20 25 30
<210> 308
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 308
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 309
<211> 23
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 309
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys
20
<210> 310
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 310
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile Tyr
1 5 10 15
<210> 311
<211> 32
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 311
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
20 25 30
<210> 312
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 312
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 313
<211> 14
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 313
Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 314
<211> 32
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 314
Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Leu Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 315
<211> 30
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 315
Arg Ala Thr Ile Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Leu Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
20 25 30
<210> 316
<211> 98
<212> PRT
<213> Homo sapiens (Homo sapiens)
<400> 316
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Asn Ser Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg
<210> 317
<211> 96
<212> PRT
<213> Homo sapiens (Homo sapiens)
<400> 317
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
<210> 318
<400> 318
000
<210> 319
<211> 107
<212> PRT
<213> Homo sapiens (Homo sapiens)
<400> 319
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 320
<211> 330
<212> PRT
<213> Homo sapiens (Homo sapiens)
<400> 320
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 321
<211> 330
<212> PRT
<213> Homo sapiens (Homo sapiens)
<400> 321
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 322
<211> 330
<212> PRT
<213> Homo sapiens (Homo sapiens)
<400> 322
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 323
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 323
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 324
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 324
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 325
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 325
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 326
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 326
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 327
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 327
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 328
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 328
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 329
<211> 329
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 329
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 330
<211> 329
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 330
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 331
<211> 329
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 331
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 332
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 332
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 333
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 333
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 334
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 334
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 335
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 335
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 336
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 336
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 337
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 337
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 338
<211> 329
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 338
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Glu Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 339
<211> 329
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 339
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Glu Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 340
<211> 329
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 340
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Glu Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 341
<211> 329
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 341
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Glu Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 342
<211> 329
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 342
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Glu Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 343
<211> 329
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 343
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Glu Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 344
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 344
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Ala Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 345
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 345
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Ala Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 346
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 346
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Ala Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 347
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 347
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 348
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 348
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 349
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 349
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 350
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 350
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 351
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 351
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 352
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 352
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 353
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 353
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 354
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 354
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 355
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 355
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 356
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 356
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 357
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 357
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 358
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 358
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 359
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 359
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 360
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 360
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 361
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 361
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 362
<211> 327
<212> PRT
<213> Homo sapiens (Homo sapiens)
<400> 362
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 363
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 363
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Ala Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 364
<211> 330
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 364
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Glu Phe Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 365
<211> 327
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 365
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 366
<211> 327
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 366
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 367
<211> 327
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 367
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 368
<211> 446
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 368
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 369
<211> 446
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 369
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Glu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 370
<211> 446
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 370
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 371
<211> 446
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 371
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Ala Glu Gly Ala Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 372
<211> 446
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 372
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Ala Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 373
<211> 446
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 373
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 374
<211> 446
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 374
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Ala Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 375
<211> 446
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 375
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Glu Phe Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 376
<211> 446
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 376
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 377
<211> 446
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 377
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 378
<211> 443
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 378
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 379
<211> 443
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 379
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 380
<211> 443
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 380
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Gln Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Ala Ser Gly His Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Val Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Gly Leu Pro Asp Val Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 381
<211> 213
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 381
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Glu Gly Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 382
<211> 214
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 382
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 383
<211> 453
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 383
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Asp Phe Thr Tyr Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Thr Tyr Asn Gly Asn Thr His Tyr Ala Arg Met Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Asn Tyr Tyr Gly Ser Gly Ala Tyr Arg Gly Gly Met Asp
100 105 110
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
355 360 365
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly
450
<210> 384
<400> 384
000
<210> 385
<400> 385
000
<210> 386
<400> 386
000
<210> 387
<400> 387
000
<210> 388
<400> 388
000
<210> 389
<400> 389
000
<210> 390
<400> 390
000
<210> 391
<211> 6
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 391
His His His His His His
1 5
<210> 392
<400> 392
000
<210> 393
<400> 393
000
<210> 394
<400> 394
000
<210> 395
<400> 395
000
<210> 396
<400> 396
000
<210> 397
<400> 397
000
<210> 398
<400> 398
000
<210> 399
<400> 399
000
<210> 400
<400> 400
000
<210> 401
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 401
Gly Tyr Asp Phe Thr Tyr Tyr Gly Ile Ser
1 5 10
<210> 402
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 402
Trp Ile Ser Thr Tyr Asn Gly Asn Thr His Tyr Ala Arg Met Leu Gln
1 5 10 15
Gly
<210> 403
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 403
Glu Asn Tyr Tyr Gly Ser Gly Ala Tyr Arg Gly Gly Met Asp Val
1 5 10 15
<210> 404
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 404
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 405
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 405
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 406
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 406
Gln Gln Arg Ser Asn Trp Pro Trp Thr
1 5
<210> 407
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 407
Gly Tyr Thr Phe Thr Ser Tyr Asp Ile Asn
1 5 10
<210> 408
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 408
Trp Leu Asn Pro Asn Ser Gly Tyr Thr Gly
1 5 10
<210> 409
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 409
Glu Val Pro Glu Thr Ala Ala Phe Glu Tyr
1 5 10
<210> 410
<211> 14
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 410
Thr Ser Ser Ser Ser Asp Ile Gly Ala Gly Leu Gly Val His
1 5 10
<210> 411
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 411
Gly Tyr Tyr Asn Arg Pro Ser
1 5
<210> 412
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 412
Gln Ser Trp Asp Gly Thr Leu Ser Ala Leu
1 5 10
<210> 413
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 413
Thr Ser Asn Met Gly Val Val
1 5
<210> 414
<211> 16
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 414
His Ile Leu Trp Asp Asp Arg Glu Tyr Ser Asn Pro Ala Leu Lys Ser
1 5 10 15
<210> 415
<211> 14
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 415
Met Ser Arg Asn Tyr Tyr Gly Ser Ser Tyr Val Met Asp Tyr
1 5 10
<210> 416
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 416
Ser Ala Ser Ser Ser Val Asn Tyr Met His
1 5 10
<210> 417
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 417
Ser Thr Ser Asn Leu Ala Ser
1 5
<210> 418
<211> 8
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 418
His Gln Trp Asn Asn Tyr Gly Thr
1 5
<210> 419
<400> 419
000
<210> 420
<211> 124
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 420
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Asp Phe Thr Tyr Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Thr Tyr Asn Gly Asn Thr His Tyr Ala Arg Met Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Asn Tyr Tyr Gly Ser Gly Ala Tyr Arg Gly Gly Met Asp
100 105 110
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 421
<211> 119
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 421
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Leu Asn Pro Asn Ser Gly Tyr Thr Gly Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Ala Asp Arg Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Val Pro Glu Thr Ala Ala Phe Glu Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 422
<211> 114
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 422
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Tyr Ile Ser Cys Lys Ser Ser Gln Asn Ile Val His
20 25 30
Ser Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys
65 70 75 80
Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln
85 90 95
Gly Ser His Val Pro Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg
<210> 423
<211> 453
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 423
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Asp Phe Thr Tyr Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Thr Tyr Asn Gly Asn Thr His Tyr Ala Arg Met Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Asn Tyr Tyr Gly Ser Gly Ala Tyr Arg Gly Gly Met Asp
100 105 110
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
355 360 365
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly
450
<210> 424
<211> 448
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 424
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Leu Asn Pro Asn Ser Gly Tyr Thr Gly Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Ala Asp Arg Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Val Pro Glu Thr Ala Ala Phe Glu Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 425
<211> 124
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 425
Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Asn Met Gly Val Val Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu
35 40 45
Trp Leu Ala His Ile Leu Trp Asp Asp Arg Glu Tyr Ser Asn Pro Ala
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Met Ser Arg Asn Tyr Tyr Gly Ser Ser Tyr Val Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 426
<211> 122
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 426
Gln Val Thr Leu Lys Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Asn Met Gly Val Val Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu
35 40 45
Trp Leu Ala His Ile Leu Trp Asp Asp Arg Glu Tyr Ser Asn Pro Ala
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Met Ser Arg Asn Tyr Tyr Gly Ser Ser Tyr Val Met Asp
100 105 110
Tyr Trp Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 427
<211> 119
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 427
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Leu Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Ala Asp Arg Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Val Pro Glu Thr Ala Ala Phe Glu Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 428
<400> 428
000
<210> 429
<400> 429
000
<210> 430
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 430
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 431
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 431
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Ser Ser Ser Ser Asp Ile Gly Ala Gly
20 25 30
Leu Gly Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Glu Gly Tyr Tyr Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Thr Ile Thr Gly Leu
65 70 75 80
Leu Pro Glu Asp Glu Gly Asp Tyr Tyr Cys Gln Ser Trp Asp Gly Thr
85 90 95
Leu Ser Ala Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 432
<211> 113
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 432
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Phe Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Leu Lys Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 433
<211> 214
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 433
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 434
<211> 216
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 434
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Ser Ser Ser Ser Asp Ile Gly Ala Gly
20 25 30
Leu Gly Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Glu Gly Tyr Tyr Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Thr Ile Thr Gly Leu
65 70 75 80
Leu Pro Glu Asp Glu Gly Asp Tyr Tyr Cys Gln Ser Trp Asp Gly Thr
85 90 95
Leu Ser Ala Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210> 435
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 435
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys His Gln Trp Asn Asn Tyr Gly Thr Phe
85 90 95
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 436
<211> 106
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 436
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys His Gln Trp Asn Asn Tyr Gly Thr Phe
85 90 95
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 437
<211> 111
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic polypeptides
<400> 437
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Ser Ser Ser Ser Asp Ile Gly Ala Gly
20 25 30
Leu Gly Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Glu Gly Tyr Tyr Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Thr Ile Thr Gly Leu
65 70 75 80
Leu Pro Glu Asp Glu Gly Asp Tyr Tyr Cys Gln Ser Tyr Asp Gly Thr
85 90 95
Leu Ser Ala Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 438
<400> 438
000
<210> 439
<400> 439
000
<210> 440
<400> 440
000
<210> 441
<400> 441
000
<210> 442
<400> 442
000
<210> 443
<400> 443
000
<210> 444
<400> 444
000
<210> 445
<400> 445
000
<210> 446
<400> 446
000
<210> 447
<400> 447
000
<210> 448
<400> 448
000
<210> 449
<400> 449
000
<210> 450
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 450
Gly Tyr Thr Phe Thr Ser Tyr Asp Ile Asn
1 5 10
<210> 451
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 451
Trp Leu Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 452
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 452
Glu Val Pro Glu Thr Ala Ala Phe Glu Tyr
1 5 10
<210> 453
<211> 14
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 453
Thr Ser Ser Ser Ser Asp Ile Gly Ala Gly Leu Gly Val His
1 5 10
<210> 454
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 454
Gly Tyr Tyr Asn Arg Pro Ser
1 5
<210> 455
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> description of artificial sequence: synthetic peptides
<400> 455
Gln Ser Tyr Asp Gly Thr Leu Ser Ala Leu
1 5 10

Claims (203)

1. A method of treating inflammation in a subject in need thereof, the method comprising administering to the subject an antibody that binds to tumor necrosis factor-like protein 1A (an anti-TL 1A antibody).
2. The method of claim 1, wherein the lung of the subject has inflammation.
3. A method of treating fibrosis in a subject in need thereof, the method comprising administering to the subject an antibody that binds to tumor necrosis factor-like protein 1A (an anti-TL 1A antibody).
4. The method of claim 3, wherein the subject's lungs are fibrotic.
5. A method of treating a disease and/or condition of the lung of a subject in need thereof, the method comprising administering to the subject an antibody that binds to tumor necrosis factor-like protein 1A (an anti-TL 1A antibody).
6. The method of any one of claims 1-5, wherein the subject has a systemic sclerosis-related interstitial lung disease.
7. The method of any one of claims 1-6, wherein the subject has idiopathic pulmonary fibrosis.
8. The method of any one of claims 1-6, wherein the subject has virus-induced pulmonary fibrosis.
9. The method of any one of claims 1 to 6, wherein the subject has asthma.
10. The method of any one of claims 1 to 6, wherein the subject has COPD.
11. The method of any one of claims 1-6, wherein the subject has pneumonia.
12. The method of any one of claims 1-6, wherein the subject has a chronic pulmonary disorder, idiopathic interstitial pneumonia, pulmonary sarcoidosis, interstitial lung disease, bronchiolitis, alveolitis, vasculitis, interstitial pneumonia, nonspecific interstitial pneumonia, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, acute interstitial pneumonia, allergic rhinitis, emphysema, chronic bronchitis, primary cholangitis, behcet's disease, systemic sclerosis-associated interstitial lung disease, or cystic fibrosis, or a combination thereof.
13. The method of any one of claims 1 to 12, wherein the anti-TL 1A antibody is administered in a pharmaceutical composition.
14. The method of claim 13, wherein the pharmaceutical composition comprises the anti-TL 1A antibody at a concentration of greater than about 150 mg/mL.
15. The method of claim 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 250mg/mL.
16. The method of claim 14, wherein the concentration is about 150mg/mL to about 250mg/mL.
17. The method of claim 14, wherein the concentration is about 175mg/mL to about 225mg/mL.
18. The method of any one of claims 13 to 17, wherein the pharmaceutical composition is administered subcutaneously.
19. The method of any one of claims 13 to 18, wherein about 150mg to about 500mg of the anti-TL 1A antibody is present in the composition.
20. The method of any one of claims 13-19, wherein the total volume of the composition is less than or equal to about 2mL.
21. The method of any one of claims 13 to 20, wherein the pharmaceutical composition comprises a therapeutically effective dose of the anti-TL 1A antibody.
22. The method of any one of claims 13-21, wherein the total volume of the composition is less than or equal to about 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, or 0.8mL.
23. The method of any one of claims 13 to 22, wherein the total volume of the composition is from about 0.5mL to about 1.5mL.
24. The method of any one of claims 13-23, wherein the viscosity of the composition is less than about 20cP.
25. The method of claim 24, wherein the viscosity of the composition is less than about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5cP.
26. The method of any one of claims 13-25, wherein the viscosity of the composition is from about 1cP to about 20cP.
27. The method of any of claims 13-26, wherein the percentage of aggregation of anti-TL 1A antibodies in the pharmaceutical composition is less than about 5% of the total anti-TL 1A antibodies in the composition as measured by size exclusion chromatography.
28. The method of claim 27, wherein aggregation is less than about 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5%.
29. The method of any one of claims 13 to 27, wherein the composition comprises a surfactant.
30. The method of claim 29, wherein the surfactant comprises a nonionic surfactant.
31. The method of claim 30, wherein the non-ionic surfactant comprises polysorbate-20.
32. The method of any one of claims 29 to 31, wherein the surfactant is present at a concentration of about 0.005% to about 0.05% of the composition.
33. The method of claim 32, wherein the surfactant is present at a concentration of about 0.01% to about 0.02% of the composition.
34. The method of any one of claims 13 to 33, wherein the composition comprises a salt.
35. The method of claim 34, wherein the salt comprises sodium chloride, glycine, lysine-hydrochloride, arginine glutamate, potassium chloride, magnesium chloride, or calcium chloride, or a combination thereof.
36. The method of claim 35, wherein the salt comprises sodium chloride.
37. The method of claim 35, wherein the salt comprises lysine-HCl.
38. The method of any one of claims 34 to 37, wherein the salt is present in the composition at a concentration of about 10mM to about 100 mM.
39. The method of claim 38, wherein the salt is present in the composition at a concentration of about 25 mM.
40. The method of claim 38, wherein the salt is present in the composition at a concentration of about 40 mM.
41. The method of any one of claims 13 to 40, wherein the composition comprises a stabilizer.
42. The method of claim 41, wherein the stabilizing agent comprises a sugar, a polyol, an amino acid or polymer, a cyclodextrin (e.g., HP-b-CD), or a combination thereof.
43. The method of claim 42, wherein the stabilizing agent comprises the sugar.
44. The method of claim 43, wherein the sugar comprises sucrose, glucose, trehalose, maltose, or lactose, or a combination thereof.
45. The method of claim 44, wherein the sugar comprises sucrose.
46. The method of any one of claims 41-45, wherein the stabilizing agent is present in the composition at a concentration of about 50mM to about 300 mM.
47. The method of claim 46, wherein the stabilizing agent is present at a concentration of about 200mM to about 280 mM.
48. The method of claim 47, wherein the stabilizing agent is present at a concentration of about 220 to about 240 mM.
49. The method of any one of claims 13 to 48, wherein the composition comprises a buffer.
50. The method of claim 49, wherein the buffer comprises acetate, phosphate, citrate, glutamate, succinate, gluconate, histidine, glycylglycine, citric acid, tris (hydroxymethyl) aminomethane) or diethanolamine or a combination thereof.
51. The method of claim 50, wherein the buffer comprises an acetate buffer.
52. The method of any one of claims 49-51, wherein the buffer is present in the composition at a concentration of about 10mM to about 50 mM.
53. The method of claim 52, wherein the composition comprises about 20mM buffer.
54. The method of any one of claims 13 to 53, wherein the pH of the composition is from about 4.5 to about 8.0.
55. The method of claim 54, wherein the pH of the composition is about 4.5 to about 7.5.
56. The method of claim 55, wherein the pH of the composition is from about 5 to about 5.5.
57. The method of claim 56, wherein the pH of said composition is about 5.3.
58. The method of any one of claims 1-57, wherein the anti-TL 1A antibody is administered to the subject at a first dose of up to about 1000mg.
59. The method of any one of claims 1-57, wherein the anti-TL 1A antibody is administered to the subject at a first dose of about 150mg to about 1000mg.
60. The method of claim 59, wherein the first dose is about 500mg to about 1000mg.
61. The method of claim 60, wherein the first dose is about 500mg or about 800mg.
62. The method of any one of claims 58 to 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.
63. The method of claim 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.
64. The method of claim 62, wherein the second time point is about 1, 2, 3, or 4 weeks after the first time point.
65. The method of any one of claims 62 to 64, wherein the second dose comprises up to about 1000mg of anti-TL 1A antibody.
66. The method of any one of claims 62 to 64, wherein the second dose comprises about 150mg to about 1000mg.
67. The method of claim 66, wherein the second dose comprises about 150mg to about 600mg of the anti-TL 1A antibody.
68. The method of any one of claims 62 to 67, wherein a third dose of anti-TL 1A antibody is administered to the subject at a third time point.
69. The method of claim 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.
70. The method of claim 68, wherein the third time point is about 1, 2, 3, or 4 weeks after the second time point.
71. The method of any one of claims 68-70, wherein the third dose comprises up to about 1000mg of anti-TL 1A antibody.
72. The method of any one of claims 68 to 70, wherein the third dose comprises about 150mg to about 1000mg of the anti-TL 1A antibody.
73. The method of claim 72, wherein the third dose comprises about 150mg to about 600mg of the anti-TL 1A antibody.
74. The method of any one of claims 68 to 73, wherein a fourth dose of anti-TL 1A antibody is administered to the subject at a fourth point in time.
75. The method of claim 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.
76. The method of claim 74, wherein the fourth time point is about 1, 2, 3, or 4 weeks after the third time point.
77. The method of any one of claims 74-76, wherein the fourth dose comprises up to about 1000mg of anti-TL 1A antibody.
78. The method of any one of claims 74-76, wherein the fourth dose comprises about 150mg to about 1000mg of the anti-TL 1A antibody.
79. The method of claim 78, wherein the fourth dose comprises about 150mg to about 600mg of the anti-TL 1A antibody.
80. The method of any one of claims 74-79, wherein a fifth dose of anti-TL 1A is administered to the subject at a fifth time point.
81. The method of claim 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.
82. The method of claim 80, wherein the fifth time point is about 1, 2, 3, or 4 weeks after the fourth time point.
83. The method of any one of claims 80-82, wherein the fifth dose comprises up to about 1000mg of anti-TL 1A antibody.
84. The method of any one of claims 80-82, wherein the fifth dose comprises about 150mg to about 1000mg of the anti-TL 1A antibody.
85. The method of claim 84, wherein the fifth dose comprises about 150mg to about 600mg of the anti-TL 1A antibody.
86. The method of any one of claims 80-85, wherein a sixth dose of anti-TL 1A is administered to the subject at a sixth time point.
87. The method of claim 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.
88. The method of claim 86, wherein the sixth time point is about 1, 2, 3, or 4 weeks after the fifth time point.
89. The method of any one of claims 86-88, wherein the sixth dose comprises up to about 1000mg of anti-TL 1A antibody.
90. The method of any of claims 86-88, wherein the sixth dose comprises about 150mg to about 1000mg of the anti-TL 1A antibody.
91. The method of claim 90, wherein the sixth dose comprises about 150mg to about 600mg of the anti-TL 1A antibody.
92. The method of any one of claims 58 to 91, wherein an additional dose of the anti-TL 1A antibody is administered to the subject at one or more additional time points.
93. The method of claim 92, wherein the one or more additional points in time comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 additional points in time.
94. The method of claim 92, wherein the composition is administered to the subject at about 12 additional time points.
95. The method of any one of claims 92 to 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 the previous time point.
96. The method of any one of claims 92 to 94, wherein each additional time point is independently about 1, 2, 3 or 4 weeks after the previous time point.
97. The method of claim 96, wherein at least one of the additional time points is about 2 weeks after the previous time point.
98. The method of any one of claims 92 to 97, wherein the additional dose comprises up to about 1000mg of anti-TL 1A antibody.
99. The method of any one of claims 92 to 97, wherein the additional dose comprises about 150mg to about 1000mg of the anti-TL 1A antibody.
100. The method of claim 99, wherein the additional dose is about 175mg to about 300mg of the anti-TL 1A antibody.
101. A method of neutralizing monomeric TL1A and trimeric TL1A in a subject suffering from pulmonary inflammation and/or pulmonary fibrosis, the method comprising (a) administering to the subject an effective dose of an anti-TL 1A antibody or antigen-binding fragment,
wherein the antibody or antigen-binding fragment binds to both monomer TL1A and trimer TL1A,
wherein the antibody or antigen binding fragment blocks the interaction of TL1A with DR3,
wherein the concentration of TL1A in diseased tissue in the subject is reduced to a lower concentration than the concentration of TL1A in corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis,
And wherein the diseased tissue comprises any one or more selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis.
102. The method of claim 101, wherein the subject has one or more inflammatory conditions selected from the group consisting of: systemic sclerosis-related interstitial lung disease, idiopathic pulmonary fibrosis, virus-induced pulmonary fibrosis, asthma, chronic Obstructive Pulmonary Disease (COPD) and pneumonia.
103. The method of claim 101 or 102, wherein the subject has a chronic pulmonary disorder, idiopathic interstitial pneumonia, pulmonary sarcoidosis, interstitial pulmonary disease, bronchiolitis, alveolitis, vasculitis, interstitial pneumonia, nonspecific interstitial pneumonia, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, acute interstitial pneumonia, allergic rhinitis, emphysema, chronic bronchitis, primary cholangitis, behcet's disease, systemic sclerosis-associated interstitial pulmonary disease, or cystic fibrosis, or a combination thereof.
104. A method of reducing the concentration of TL1A in diseased tissue in a subject having pulmonary inflammation and/or pulmonary fibrosis, the method comprising (a) administering to the subject an effective amount of an anti-TL 1A antibody or antigen-binding fragment,
thereby reducing the concentration of TL1A in said diseased tissue in said subject to a lower concentration than the concentration of TL1A in corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis,
wherein the diseased tissue comprises any one or more selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis.
105. A method of treating pulmonary inflammation and/or pulmonary fibrosis in a subject in need thereof, the method comprising (a) administering to the subject an anti-TL 1A antibody or antigen-binding fragment,
wherein the anti-TL 1A antibody or antigen-binding fragment is administered in an effective dose such that after step (a) the concentration of TL1A in diseased tissue in the subject is lower than the concentration of TL1A in corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis,
And wherein the diseased tissue comprises any one or more selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis.
106. A method of treating pulmonary inflammation and/or pulmonary fibrosis in a subject in need thereof, the method comprising:
(a) Administering to the subject an anti-TL 1A antibody or antigen-binding fragment in an effective dose, and
(b) Bringing the concentration of TL1A in the diseased tissue in the subject to be lower than the concentration of TL1A in the corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis,
wherein the diseased tissue comprises any one or more selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis.
107. The method of any one of claims 101 to 106, wherein the effective dose comprises an induction regimen.
108. The method of any one of claims 101-107, further comprising
(c) Maintaining a concentration of TL1A in diseased tissue in the subject below a concentration of TL1A in the corresponding tissue in the control subject.
109. The method of claim 108, wherein the TL1A in the diseased tissue in the subject is maintained with a maintenance regimen of the anti-TL 1A antibody or antigen binding fragment.
110. The method of claim 109, wherein the induction regimen and the maintenance regimen are the same.
111. The method of claim 109, wherein the induction regimen and the maintenance regimen are different.
112. The method of any one of claims 109-111, wherein the maintenance regimen is administered after the induction regimen.
113. The method of any one of claims 102-112, wherein during the induction regimen, the diseased tissue in the subject produces TL1A that is at most 50, 60, 70, 80, 90, 100, or more times greater than TL1A produced by the corresponding tissue in the control subject.
114. The method of any one of claims 102-112, wherein TL1A produced by the diseased tissue in the subject is at most 50, 60, 70, 80, 90, 100 or more times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5 or 6 weeks of the initiation of the induction regimen.
115. The method of any one of claims 102-112, wherein the diseased tissue in the subject produces TL1A that is at most 50, 60, 70, 80, 90, 100 or more times greater than TL1A produced by the corresponding tissue in the control subject.
116. The method of any one of claims 107-115, wherein the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment.
117. The method of claim 116, wherein the anti-TL 1A 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.
118. The method of any one of claims 107-115, wherein the induction regimen comprises multiple administrations of the anti-TL 1A antibody or antigen binding fragment.
119. The method of any one of claims 107-115 and 118, wherein the induction regimen comprises:
(i) 1000 mg/dose at week 0, 1000 mg/dose at week 2, 1000 mg/dose at week 6, and 1000 mg/dose at week 10;
(ii) 500 mg/dose at week 0, 500 mg/dose at week 2, 500 mg/dose at week 6, and 500 mg/dose at week 10;
(iii) 1000 mg/dose at week 0, 1000 mg/dose at week 2, 1000 mg/dose at week 6, and 500 mg/dose at week 10;
(iv) 1000 mg/dose at week 0, 1000 mg/dose at week 2, 500 mg/dose at week 6 and 500 mg/dose at week 10; or alternatively
(v) 1000 mg/dose at week 0, 500 mg/dose at week 2, 500 mg/dose at week 6 and 500 mg/dose at week 10.
120. The method of any one of claims 107-115 or 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.
121. The method of any one of claims 107-115, 118, or 120, wherein the induction regimen comprises administration every 2, 4, 6, or 8 weeks.
122. The method of any one of claims 107-115, 118, or 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.
123. The method of any one of claims 108-122, wherein TL1A produced by the diseased tissue in the subject is at most 10, 15, 20, 25, 30, 35, 40, 45, 50 or more times greater than TL1A produced by the corresponding tissue in the control subject.
124. The method of any one of claims 108-119, wherein during the maintenance regimen, the diseased tissue in the subject produces TL1A that is at most 10, 15, 20, 25, 30, 35, 40, 45, 50 or more times greater than TL1A produced by the corresponding tissue in the control subject.
125. The method of any one of claims 108-119, wherein TL1A produced by the diseased tissue in the subject is at most 10, 15, 20, 25, 30, 35, 40, 45, 50 or more times greater than TL1A produced by the corresponding tissue in the control subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks or more at the beginning of the maintenance regimen.
126. The method of any one of claims 109-125, wherein the maintenance regimen comprises multiple administrations of the anti-TL 1A antibody or antigen binding fragment.
127. The method of any one of claims 109-126, wherein the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment as follows:
(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) Every 2 weeks 100 mg/dose v
(viii) 50 mg/dose every 2 weeks;
(ix) 500 mg/dose every 4 weeks;
(x) 400 mg/dose every 4 weeks;
(xi) 300 mg/dose every 4 weeks;
(xii) 250 mg/dose every 4 weeks;
(xiii) 200 mg/dose every 4 weeks;
(xiv) 150 mg/dose every 4 weeks;
(xv) 100 mg/dose every 4 weeks;
(xvi) 50 mg/dose every 4 weeks;
(xvii) 500 mg/dose every 6 weeks;
(xviii) 400 mg/dose every 6 weeks;
(xix) 300 mg/dose every 6 weeks;
(xx) 250 mg/dose every 6 weeks;
(xxi) 200 mg/dose every 6 weeks;
(xxii) 150 mg/dose every 6 weeks;
(xxiii) 100 mg/dose every 6 weeks;
(xxiv) 50 mg/dose every 6 weeks;
(xxv) 500 mg/dose every 8 weeks;
(xxvi) 400 mg/dose every 8 weeks;
(xxvii) 300 mg/dose every 8 weeks;
(xxviii) 250 mg/dose every 8 weeks;
(xxix) 200 mg/dose every 8 weeks;
(xxx) 150 mg/dose every 8 weeks;
(xxxi) 100 mg/dose every 8 weeks; or alternatively
(xxxii) 50 mg/dose every 8 weeks.
128. The method of any one of claims 109-126, wherein the maintenance regimen comprises administering the anti-TL 1A 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.
129. The method of any one of claims 109-126 or 128, wherein the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment once every 2, 4, 6, 8, 10, or 12 weeks.
130. The method of any one of claims 109-129, wherein the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at a dose of 250 mg/dose every 4 weeks.
131. The method of any one of claims 109-129, wherein the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at a dose of 100 mg/dose every 4 weeks.
132. The method of any one of claims 109-131, 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.
133. The method of any one of claims 104-132, wherein the antibody or antigen-binding fragment binds to both monomeric TL1A and trimeric TL1A, and wherein the antibody or antigen-binding fragment blocks binding of TL1A to DR 3.
134. The method of any one of claims 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 TL1A in the blood of the subject is occupied by the anti-TL 1A antibody or antigen binding fragment.
135. The method of any one of claims 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 TL1A in the blood of the subject is occupied by the anti-TL 1A antibody or antigen binding fragment.
136. The method according to any one of claims 101 to 135, wherein the method is performed by dissociating the equilibrium constant (K D-monomer ) The binding affinity of the antibody or antigen binding fragment to monomeric TL1A is measured, e.g. by dissociation equilibrium constant (K D-trimer ) The binding affinity of the antibody or antigen binding fragment measured was comparable to that of trimeric TL 1A.
137. The method of claim 136, wherein the K D-monomer At said K D-trimer 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times.
138. The method of claim 136 or 137, wherein the K D-monomer No more than 0.06nM.
139. The method of any one of claims 136-138, wherein the K D-trimer No more than 0.06nM.
140. The method of any one of claims 103-139, wherein the subject has one or more inflammatory conditions selected from the group consisting of: systemic sclerosis-related interstitial lung disease, idiopathic pulmonary fibrosis, virus-induced pulmonary fibrosis, asthma, chronic Obstructive Pulmonary Disease (COPD) and pneumonia.
141. The method of any one of claims 102-140, wherein the subject has a chronic pulmonary disorder, idiopathic interstitial pneumonia, pulmonary sarcoidosis, interstitial lung disease, bronchiolitis, alveolitis, vasculitis, interstitial pneumonia, non-specific interstitial pneumonia, hypersensitivity pneumonitis, cryptogenic mechanized pneumonia, acute interstitial pneumonia, allergic rhinitis, emphysema, chronic bronchitis, primary cholangitis, behcet's disease, systemic sclerosis-associated interstitial lung disease, or cystic fibrosis, or a combination thereof.
142. The method of any one of claims 101-141, wherein the effective dose or the induction regimen is determined by a dose determination method, wherein the dose determination method comprises:
(i) Receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in the normal reference tissue;
(ii) Integrating the parameters received in (a) into a physiologically integrated whole-body based pharmacokinetic (PBPK) model or population pharmacokinetic model (popPK); and
(iii) Determining an effective dose or induction regimen such that after step (a) the concentration of TL1A in the diseased tissue in the subject is lower than the concentration of TL1A in the corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis.
143. The method of claim 142, wherein the overproduction of TL1A over-produces 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 times greater than TL1A production in the normal reference tissue.
144. The method of any one of claims 109-143, wherein the maintenance regimen is determined by a dose determination method, wherein the dose determination method comprises:
(i) Receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in the normal reference tissue;
(ii) Integrating the parameters received in (i) into a physiologically integrated whole-body based pharmacokinetic (PBPK) model or population pharmacokinetic model (popPK); and
(iii) Determining the maintenance regimen such that after step (c) the concentration of TL1A in the diseased tissue in the subject is lower than the concentration of TL1A in the corresponding tissue in a control subject not suffering from pulmonary inflammation and/or pulmonary fibrosis.
145. The method of claim 144, wherein the overproduction of TL1A over-produces 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more times greater than TL1A production in the normal reference tissue.
146. The method of any one of claims 142-145, wherein step (i) in the dosing method further comprises receiving a rate of association (k on-mAb ) The dissociation rate of the antibody from TL1A (k off-mAb ) Rate of synthesis of TL1A in Normal tissue (k syn-normal ) Rate of synthesis of TL1A in diseased tissue (k syn-disease ) And/or the degradation rate (k) of TL1A deg-Total-TL 1A )。
147. The method of claim 146, wherein the rate of association (k on-mAb ) Including the rate of association (k) of the antibody with monomer TL1A on-monomer ) And antibodies and trimersAssociation rate of TL1A (k on-trimer ) Wherein the dissociation rate (k off-mAb ) Comprising the dissociation rate (k off-monomers ) And the dissociation rate (k) of the antibody from trimeric TL1A off-trimer ) And/or wherein the degradation rate (k deg-Total-TL 1A ) Degradation rate (k) including monomer TL1A deg-TL 1A-monomer ) And rate of degradation (k) of trimer TL1A deg-TL 1A-trimer )。
148. The method of any one of claims 142-147, wherein step (i) of the method of determining the dose further comprises receiving a rate of association (k on-mAb-FcRn ) The dissociation rate of the antibody from FcRn (k off-mAb-FcRn ) Rate of association of antibody-TL 1A complex with FcRn receptor (k on-(mAb-TL1A)-FcRn ) And/or the dissociation rate (k) of the antibody-TL 1A complex from FcRn off-(mAb-TL1A)-FcRn )。
149. The method of claim 148, wherein the rate of association (k on-(mAb-TL1A)-FcRn ) Comprising the rate of association (k) of the antibody-monomer TL1A complex with the FcRn receptor on-(mAb-monoTL1A)-FcRn ) And the rate of association of the antibody-trimeric TL1A complex with FcRn receptor (k on-(mAb-triTL1A)-FcRn ) And/or wherein the dissociation rate (k) of the antibody-TL 1A complex from FcRn off-(mAb-TL1A)-FcRn ) Comprising the dissociation rate (k) of the antibody-monomer TL1A complex from FcRn off-(mAb-monoTL1A)-FcRn ) And dissociation rate of antibody-trimeric TL1A complex from FcRn (k off-(mAb-triTL1A)-FcRn )。
150. The method of any one of claims 142-149, wherein step (i) of the method of dose determination further comprises receiving the clearance (k deg-mAb-FcRn )。
151. The device according to claim 150The method, wherein the clearance (k) of the FcRn receptor bound by the antibody deg-mAb-FcRn ) Comprising the clearance (k) of the antibody to FcRn bound by the antibody-monomer TL1A complex deg-(mAb-monoTL1A)-FcRn ) And FcRn receptor clearance bound by the antibody-trimeric TL1A complex (k deg-(mAb-triTL1A)-FcRn )。
152. The method of any one of claims 146-151, wherein in the dose determination method:
(1)k on-monomer And k on-trimer The same or different;
(2)k off-monomers And k off-trimer The same or different;
(3)k deg-monomer And k deg-trimer The same or different;
(4)k on-(mAb-monoTL1A)-FcRn and k on-(mAb-triTL1A)-FcRn The same or different;
(5)k on-mAb-FcRn and k on-(mAb-monoTL1A)-FcRn The same or different;
(6)k on-mAb-FcRn and k on-(mAb-triTL1A)-FcRn The same or different;
(7)k off-(mAb-monoTL1A)-FcRn and k off-(mAb-triTL1A)-FcRn The same or different;
(8)k koff-mAb-FcRn and k off-(mAb-monoTL1A)-FcRn The same or different;
(9)k off-mAb-FcRn and k off-(mAb-triTL1A)-FcRn The same or different;
(10)k deg-(mAb-monoTL1A)-FcRn and k kdeg-(mAb-triTL1A)-FcR n is the same or different;
(11)k deg-mAb-FcRn and k -(mAb-triTL1A)-FcRn The same or different;
(12)k deg-mAb-FcRn and k deg-(mAb-monoTL1A)-FcRn The same or different; or (b)
(13) Any combination of (1) to (12).
153. The method of any one of claims 142-152, wherein in the dose determination method:
k syn-disease Is k syn-normal At most 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 or more times.
154. The method of any one of claims 142-153, wherein step (i) in the dose determination method further comprises receiving a rate (k on-TL 1A-monomer to trimer ) And/or the rate of TL1A monomer (k off-TL 1A-trimer to monomer )。
155. A method of determining an effective dosage regimen for administering an anti-TL 1A antibody to a subject suffering from pulmonary inflammation and/or pulmonary fibrosis, wherein the method comprises:
(a) Receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in the normal reference tissue;
(b) Integrating the parameters received in (a) into a physiologically integrated whole-body based pharmacokinetic (PBPK) model; and
(c) Determining the effective dosage regimen of the anti-TL 1A antibody with the PBPK model from (b) such that, after administration of the effective dosage regimen, the concentration of TL1A in diseased tissue in said subject having pulmonary inflammation and/or pulmonary fibrosis is lower than the concentration of TL1A in corresponding tissue in a control subject not having pulmonary inflammation and/or pulmonary fibrosis,
wherein the diseased tissue comprises any one or more selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis.
156. A method of determining an effective dosage regimen for administering an anti-TL 1A antibody to a subject suffering from pulmonary inflammation and/or pulmonary fibrosis, wherein the method comprises:
(a) Receiving a parameter of TL1A overproduction in the diseased tissue compared to TL1A production in the normal reference tissue;
(b) Integrating the parameters received in (a) into a population pharmacokinetic (popPK) model; and
(c) Determining the effective dose regimen of the anti-TL 1A antibody with a popPK model from (b) such that, after administration of the effective dose regimen, the concentration of TL1A in diseased tissue in the subject having lung inflammation and/or lung fibrosis is lower than the concentration of TL1A in corresponding tissue in a control subject not having lung inflammation and/or lung fibrosis,
Wherein the diseased tissue comprises any one or more selected from the group consisting of: bronchi, bronchioles, alveolar ducts, alveoli, pleura, fibrotic tissue in the lungs, other tissue with pulmonary inflammation and/or pulmonary fibrosis, and other tissue with pathogenesis of the pulmonary inflammation and/or pulmonary fibrosis.
157. The method of claim 155 or 156, wherein the overproduction of the TL1A over-produced parameter 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 times greater than the TL1A production in the normal reference tissue.
158. The method of any one of claims 155-157, wherein step (a) further comprises receiving a rate of association (k on-mAb ) The dissociation rate of the antibody from TL1A (k off-mAb ) Rate of synthesis of TL1A in Normal tissue (k syn-normal ) Rate of synthesis of TL1A in diseased tissue (k syn-disease ) And/or the degradation rate (k) of TL1A deg-Total-TL 1A )。
159. The method of any one of claims 155-158, wherein the rate of association (k on-mAb ) Comprises the association rate (k on-monomer ) And the rate of association (k) of the antibody with trimeric TL1A on-trimer ) Wherein the dissociation rate (k off-mAb ) Comprising the dissociation rate (k off-monomers ) And the dissociation rate (k) of the antibody from trimeric TL1A off-trimer ) And/or wherein the degradation rate (k deg-Total-TL 1A ) Degradation rate (k) including monomer TL1A deg-TL 1A-monomer ) And rate of degradation (k) of trimer TL1A deg-TL 1A-trimer )。
160. The method of any one of claims 155-159, wherein step (a) comprises receiving a rate of association (k on-mAb-FcRn ) The dissociation rate of the antibody from FcRn (k off-mAb-FcRn ) Rate of association of antibody-TL 1A complex with FcRn receptor (k on-(mAb-TL1A)-FcRn ) And/or the dissociation rate (k) of the antibody-TL 1A complex from FcRn off-(mAb-TL1A)-FcRn )。
161. The method of claim 160, wherein the rate of association (k on-(mAb-TL1A)-FcRn ) Comprising the rate of association (k) of the antibody-monomer TL1A complex with the FcRn receptor on-(mAb-monoTL1A)-FcRn ) And the rate of association of the antibody-trimeric TL1A complex with FcRn receptor (k on-(mAb-triTL1A)-FcRn ) And/or wherein the dissociation rate (k) of the antibody-TL 1A complex from FcRn off-(mAb-TL1A)-FcRn ) Comprising the dissociation rate (k) of the antibody-monomer TL1A complex from FcRn off-(mAb-monoTL1A)-FcRn ) And dissociation rate of antibody-trimeric TL1A complex from FcRn (k off-(mAb-triTL1A)-FcRn )。
162. The method of any one of claims 155 to 161, wherein step (a) further comprises receiving a polypeptide bound by the antibodyClearance of the synthetic FcRn receptor (k deg-mAb-FcRn )。
163. The method of claim 162, wherein the clearance of FcRn receptor bound by the antibody (k deg-mAb-FcRn ) Further comprising clearance (k) of the antibody to FcRn bound by the antibody-monomer TL1A complex deg-(mAb-monoTL1A)-FcRn ) And FcRn receptor clearance bound by the antibody-trimeric TL1A complex (k deg-(mAb-triTL1A)-FcRn )。
164. The method of any one of claims 155 to 163, wherein the subject has one or more inflammatory conditions selected from the group consisting of: systemic sclerosis-related interstitial lung disease, idiopathic pulmonary fibrosis, virus-induced pulmonary fibrosis, asthma, chronic Obstructive Pulmonary Disease (COPD) and pneumonia.
165. The method of any one of claims 155-164, wherein the subject has a chronic pulmonary disorder, idiopathic interstitial pneumonia, pulmonary sarcoidosis, interstitial lung disease, bronchiolitis, alveolitis, vasculitis, interstitial pneumonia, non-specific interstitial pneumonia, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, acute interstitial pneumonia, allergic rhinitis, emphysema, chronic bronchitis, primary cholangitis, behcet's disease, systemic sclerosis-associated interstitial lung disease, or cystic fibrosis, or a combination thereof.
166. The method of any one of claims 155 to 165, wherein:
(1)k on-monomer And k on-trimer The same or different;
(2)k off-monomers And k off-trimer The same or different;
(3)k deg-monomer And k deg The trimers are identical or different;
(4)k on-(mAb-monoTLlA)-FcRn and k on-(mAb-triTL1A)-FcRn The same or different;
(5)k on-mAb-FcRn and k on-(mAb-monoTL1A)-FcRn The same or different;
(6)k on-mAb-FcRn and k on-(mAb-triTL1A)-FcRn The same or different;
(7)k off-(mAb-monoTL1A)-FcRn and k off-(mAb-triTL1A)-FcRn The same or different;
(8)k koff-mAb-FcRn and k off-(mAb-monoTL1A)-FcRn The same or different;
(9)k off-mAb-FcRn and k off-(mAb-triTL1A)-FcRn The same or different;
(10)k deg-(mAb-monoTL1A)-FcRn and k kdeg-(mAb-triTL1A)-FcRn The same or different;
(11)k deg-mAb-FcRn and k -(mAb-triTL1A)-FcRn The same or different;
(12)k deg-mAb-FcRn and k deg-(mAb-monoTL1A)-FcRn The same or different; or (b)
(13) Any combination of (1) to (12).
167. The method of any one of claims 155 to 166, wherein:
k syn-disease Is k syn-normal At most 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 or more times.
168. The method of any one of claims 155-167, wherein the effective dosage regimen comprises an induction regimen of the anti-TL 1A antibody or antigen binding fragment.
169. The method of any one of claims 155-168, wherein the effective dosage regimen comprises a maintenance regimen of the anti-TL 1A antibody or antigen binding fragment.
170. The method of claim 169, wherein the induction regimen and the maintenance regimen are the same.
171. The method of claim 169, wherein the induction regimen and the maintenance regimen are different.
172. The method of any one of claims 169-171, wherein the maintenance regimen is administered after the induction regimen.
173. The method of any one of claims 168 to 172, wherein during the induction regimen, the diseased tissue in the subject produces TL1A that is at most 50, 60, 70, 80, 90, 100, or more times greater than TL1A produced by the corresponding tissue in the control subject.
174. The method of any one of claims 168 to 173, wherein TL1A produced by the diseased tissue in the subject is at most 50, 60, 70, 80, 90, 100 or more times greater than TL1A produced by the corresponding tissue in the control subject within 1, 2, 3, 4, 5 or 6 weeks of the initiation of the induction regimen.
175. The method of any one of claims 155-172, wherein TL1A produced by the diseased tissue in the subject is at most 50, 60, 70, 80, 90, 100 or more times greater than TL1A produced by the corresponding tissue in the control subject.
176. The method of any one of claims 168 to 175, wherein the induction regimen comprises one administration of the anti-TL 1A antibody or antigen binding fragment.
177. The method of claim 176, wherein the anti-TL 1A 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.
178. The method of any one of claims 168 to 175, wherein the induction regimen comprises multiple administrations of the anti-TL 1A antibody or antigen binding fragment.
179. The method of any one of claims 168 to 175 or 178, wherein the induction regimen comprises:
(i) 1000 mg/dose at week 0, 1000 mg/dose at week 2, 1000 mg/dose at week 6, and 1000 mg/dose at week 10;
(ii) 500 mg/dose at week 0, 500 mg/dose at week 2, 500 mg/dose at week 6, and 500 mg/dose at week 10;
(iii) 1000 mg/dose at week 0, 1000 mg/dose at week 2, 1000 mg/dose at week 6, and 500 mg/dose at week 10;
(iv) 1000 mg/dose at week 0, 1000 mg/dose at week 2, 500 mg/dose at week 6 and 500 mg/dose at week 10; or alternatively
(v) 1000 mg/dose at week 0, 500 mg/dose at week 2, 500 mg/dose at week 6, and 500 mg/dose at week 10.
180. The method of any one of claims 168 to 175 or 178, 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.
181. The method of any one of claims 168 to 175, 178 or 180, wherein the induction regimen comprises administration every 2, 4, 6 or 8 weeks.
182. The method of any one of claims 168 to 175, 178 or 180, 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.
183. The method of any one of claims 155-172 and 176-182, wherein TL1A produced by the diseased tissue in the subject is at most 10, 15, 20, 25, 30, 35, 40, 45, 50 or more times greater than TL1A produced by the corresponding tissue in the control subject.
184. The method of any one of claims 169-183, wherein during the maintenance regimen, the diseased tissue in the subject produces TL1A that is at most 10, 15, 20, 25, 30, 35, 40, 45, 50 or more fold greater than TL1A produced by the corresponding tissue in the control subject.
185. The method of any one of claims 169-184, wherein TL1A produced by the diseased tissue in the subject is at most 10, 15, 20, 25, 30, 35, 40, 45, 50 or more times greater than TL1A produced by the corresponding tissue in the control subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 44, 48, or 52 weeks or more at the beginning of the maintenance regimen.
186. The method of any one of claims 169-185, wherein the maintenance regimen comprises multiple administrations of the anti-TL 1A antibody or antigen binding fragment.
187. The method of any one of claims 169-186, wherein the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment as follows:
(i) 500 mg/dose every 2 weeks;
(ii) 400 mg/dose every 2 weeks;
(iii) 300 mg/dose every 2 weeks;
(iv) 250 mg/dose every 2 weeks;
(v) 200 mg/dose every 2 weeks;
(vi) 150 mg/dose every 2 weeks;
(vii) 100 mg/dose every 2 weeks;
(viii) 50 mg/dose every 2 weeks;
(ix) 500 mg/dose every 4 weeks;
(x) 400 mg/dose every 4 weeks;
(xi) 300 mg/dose every 4 weeks;
(xii) 250 mg/dose every 4 weeks;
(xiii) 200 mg/dose every 4 weeks;
(xiv) 150 mg/dose every 4 weeks;
(xv) 100 mg/dose every 4 weeks;
(xvi) 50 mg/dose every 4 weeks;
(xvii) 500 mg/dose every 6 weeks;
(xviii) 400 mg/dose every 6 weeks;
(xix) 300 mg/dose every 6 weeks;
(xx) 250 mg/dose every 6 weeks;
(xxi) 200 mg/dose every 6 weeks;
(xxii) 150 mg/dose every 6 weeks;
(xxiii) 100 mg/dose every 6 weeks;
(xxiv) 50 mg/dose every 6 weeks;
(xxv) 500 mg/dose every 8 weeks;
(xxvi) 400 mg/dose every 8 weeks;
(xxvii) 300 mg/dose every 8 weeks;
(xxviii) 250 mg/dose every 8 weeks;
(xxix) 200 mg/dose every 8 weeks;
(xxx) 150 mg/dose every 8 weeks;
(xxxi) 100 mg/dose every 8 weeks; or alternatively
(xxxii) 50 mg/dose every 8 weeks.
188. The method of any one of claims 169-186, wherein the maintenance regimen comprises administering the anti-TL 1A 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.
189. The method of any one of claims 169-186 or 188, wherein the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment once every 2, 4, 6, 8, 10, or 12 weeks.
190. The method of any one of claims 169-189, wherein the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment every 4 weeks at a dose of 250 mg/dose.
191. The method of any one of claims 169-190, wherein the maintenance regimen comprises administering the anti-TL 1A antibody or antigen binding fragment at a dose of 100 mg/dose every 4 weeks.
192. The method of any one of claims 169-191, 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.
193. The method of any one of claims 155-192, wherein the effective dose regimen maintains a concentration of TL1A in diseased tissue in the subject that is lower than a concentration of TL1A in corresponding tissue in a control subject that does not have pulmonary inflammation and/or pulmonary 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.
194. The method of any of claims 155-193, wherein during the effective dose regimen, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the monomeric TL1A in the blood of the subject is occupied by the anti-TL 1A antibody or antigen binding fragment.
195. The method of any one of claims 155 to 194, wherein during the effective dose regimen, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the trimeric TL1A in the blood of the subject is occupied by the anti-TL 1A antibody or antigen binding fragment.
196. The method of any one of claims 155 to 195, wherein step (a) further comprises receiving a rate (k on-TL 1A-monomer to trimer ) And/or the rate of TL1A monomer (k off-TL 1A-trimer to monomer )。
197. The method of any one of claims 102-196, wherein the concentration of TL1A is the concentration of free TL 1A.
198. The method of any one of claims 1-197, wherein the anti-TL 1A antibody comprises: a heavy chain variable region comprising: HCDR1, said HCDR1 comprising a sequence consisting of SEQ ID NO:1, and a polypeptide sequence shown in the specification; HCDR2, said HCDR2 comprising a sequence consisting of SEQ ID NO:2-5, and a polypeptide comprising the amino acid sequence shown in any one of 2-5; and HCDR3, said HCDR3 comprising a sequence consisting of SEQ ID NO: 6-9; and a light chain variable region comprising: LCDR1, said LCDR1 comprising a sequence consisting of SEQ ID NO:10, and a polypeptide comprising the amino acid sequence shown in seq id no; LCDR2, said LCDR2 comprising a nucleotide sequence consisting of SEQ ID NO:11, and a polypeptide comprising the amino acid sequence shown in seq id no; LCDR3, said LCDR3 comprising a nucleotide sequence consisting of SEQ ID NO: 12-15.
199. The method of any one of claims 1-198, wherein the anti-TL 1A antibody comprises: a heavy chain variable framework region comprising a human IGHV1-46 x 02 framework or a modified human IGHV1-46 x 02 framework; and a light chain variable framework region comprising a human IGKV3-20 framework or a modified human IGKV3-20 framework; wherein said heavy chain variable framework region and said light chain variable framework region together comprise no or less than nine amino acid modifications from said IGHV1-46 x 02 framework and said human IGKV3-20 framework.
200. The method of any one of claims 1-199, wherein the anti-TL 1A antibody comprises: a heavy chain variable domain comprising a sequence identical to SEQ ID NO:101-169, at least 96% identical in amino acid sequence; and a light chain variable domain comprising a sequence identical to SEQ ID NO:201-220, at least 96% identical in amino acid sequence.
201. The method of any one of claims 1-200, wherein the anti-TL 1A antibody comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:301X1 VQLVQSQAGEVKKGASVKVACUSCHAS [ HCDR1] WVX2QX3PGQGLEWX4G [ HCDR2] RXR5 TX6 TXDSTX8 YX9 ELSSLRSEDTAVYCAR [ HCDR3] WGQGTTVTVSS; and a light chain variable region comprising the amino acid sequence of SEQ ID NO:303EIVLTQSPGTLSLSPGERATLSC [ LCDR1] WYQKPGQAPRX 10X11IY [ LCDR2] GIPDRFSGSGTDFTTYLCREPLDEFAVYC [ LCDR3] FGGGTKLEIK, wherein each of X1-X11 is independently selected from A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y or V, wherein HCDR1 comprises a polypeptide consisting of SEQ ID NO:1, and HCDR2 comprises an amino acid sequence represented by SEQ ID NO:2-5, HCDR3 comprises an amino acid sequence represented by any one of SEQ ID NOs: 6-9, LCDR1 comprises an amino acid sequence represented by any one of SEQ ID NOs: 10, LCDR2 comprises an amino acid sequence represented by SEQ ID NO:11, and LCDR3 comprises an amino acid sequence represented by SEQ ID NO:12 or 13.
202. The method of any one of claims 1-197, wherein the anti-TL 1A antibody comprises: a heavy chain variable region comprising: HCDR1, said HCDR1 comprising a sequence consisting of SEQ ID NO: 401. 407, 413 or 450; HCDR2, said HCDR2 comprising a sequence consisting of SEQ ID NO: 402. 408, 414 or 451; and HCDR3, said HCDR3 comprising a sequence consisting of SEQ ID NO: 403. 409, 415 or 452; and a light chain variable region comprising: LCDR1, said LCDR1 comprising a sequence consisting of SEQ ID NO: 404. 410, 416 or 453; LCDR2, said LCDR2 comprising a nucleotide sequence consisting of SEQ ID NO: 405. 411, 417 or 454; LCDR3, said LCDR3 comprising a nucleotide sequence consisting of SEQ ID NO: 406. 412, 418 or 455.
203. The method of any one of claims 1-197 or 202, wherein the anti-TL 1A antibody comprises: a heavy chain variable domain comprising a sequence identical to SEQ ID NO:420-427, at least 96% identical in amino acid sequence; and a light chain variable domain comprising a sequence identical to SEQ ID NO:430-437, at least 96% identical in amino acid sequence.
CN202280029342.9A 2021-02-18 2022-02-17 anti-TL 1A antibody compositions and methods for treating lung Pending CN117202932A (en)

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US63/285,785 2021-12-03
PCT/US2022/016840 WO2022178158A1 (en) 2021-02-18 2022-02-17 Anti-tl1a antibody compositions and methods of treatment in the lung

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