Methods of treating inflammatory diseases

Abstract

To provide methods for the treatment of inflammatory diseases utilizing anti-IL-23A antibodies.SOLUTION: A method for treating psoriasis or psoriatic arthritis comprises administering to a patient an anti-IL-23A antibody. The method comprises: a) administering an initial dose of the anti-IL-23A antibody to the patient; b) administering a first maintenance dose of the anti-IL-23A antibody to the patient 4 to 24 weeks, e.g., 4 to 12 weeks, e.g., 6 to 24 weeks, e.g., 6 to 12 weeks, after the initial dose is administered; and c) administering at least one additional maintenance dose to the patient 4 to 24 weeks, e.g., 4 to 12 weeks, e.g., 6 to 24 weeks, e.g., 6 to 12 weeks, after the first maintenance dose is administered.SELECTED DRAWING: None

Description

[Technical field]

[0001] TECHNICAL FIELD OF THEINVENTION The present invention relates generally to methods of treating inflammatory diseases, such as psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis (AS, also called radiographic ax-SpA) and non-radiographic ax-SpA, using anti-IL-23A antibodies.

[0002] 2. Background of the Invention Psoriasis is a chronic, immune-mediated, inflammatory skin disease with a worldwide incidence of 2%, associated with significant morbidity and can have a considerable psychosocial impact on the quality of life and health of patients. Plaque psoriasis is the most common form, affecting approximately 80-90% of patients and manifesting as plaques on the skin; the disease usually begins in late adolescence and early adulthood and can persist throughout adulthood. The extent of affected body surface area (BSA) and the degree of skin manifestations (including erythema, induration, and scaling) define the severity of psoriasis, with approximately 20-30% of patients having moderate to severe disease. Approximately one-third of psoriasis patients also suffer from joint inflammation (psoriatic arthritis (PsA)), resulting in pain and disability. Axial (spinal) spondyloarthritis (ax-SpA), which includes ankylosing spondylitis (AS, also called radiographic axial spondyloarthritis (ax-SpA) and non-radiographic axial spondyloarthritis (ax-SpA), is an inflammatory disease that primarily affects the axial skeleton and sacroiliac joints.

[0003] Psoriasis, psoriatic arthritis, and axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA) are multifactorial autoimmune diseases whose exact causes are unknown. Multiple genome-wide association studies have linked variants in the IL-23 receptor gene to susceptibility to psoriasis. Human IL-23 is produced primarily by antigen-presenting cells and induces the differentiation of T helper 17 (Th17) cells, which in turn produce IL-17 and IL-22, which may mediate the development of epidermal hyperplasia and tissue inflammation observed in psoriasis.

[0004] There is a need for treatment options for inflammatory diseases, particularly psoriasis, psoriatic arthritis, axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), that result in favorable patient outcomes, for example in terms of efficacy, safety, and / or tolerability of the treatment.

[0005] Summary of the Invention The present invention addresses the above needs and provides a method for treating inflammatory diseases, in particular a method comprising administering an anti-IL-23A antibody to a patient in a specific amount and / or at a specific interval. In one embodiment, the method of the invention is for treating psoriasis or psoriatic arthritis. In one embodiment, the method of the invention is for treating axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis (AS) and non-radiographic ax-SpA. Thus, in one embodiment, the method of the invention is for treating ankylosing spondylitis (AS), and in one embodiment, the method of the invention is for treating non-radiographic ax-SpA.

[0006] The methods of the present invention provide the advantage of allowing patients to receive fewer doses of anti-IL-23A antibody while experiencing clinical improvement.

[0007] In one embodiment, the invention provides a method for treating an inflammatory disease, in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), comprising administering to a patient an anti-IL-23A antibody, the method comprising: a) administering to the patient an initial dose of an anti-IL-23A antibody; b) administering to the patient a first maintenance dose of an anti-IL-23A antibody 4 to 24 weeks, e.g., 4 to 16 weeks, e.g., 4 to 12 weeks, after the initial dose; and c) administering to the patient at least one additional maintenance dose 4 to 24 weeks, e.g., 4 to 16 weeks, e.g., 4 to 12 weeks, after said first maintenance dose. Includes.

[0008] In one embodiment, the invention provides a method for treating an inflammatory disease, in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), comprising administering to a patient an anti-IL-23A antibody, the method comprising: a) administering to the patient an initial dose of an anti-IL-23A antibody; b) administering a first maintenance dose of an anti-IL-23A antibody to the patient 8 to 24 weeks, such as 8 to 16 weeks, such as 8 to 12 weeks, such as 6 to 24 weeks, such as 6 to 16 weeks, such as 6 to 12 weeks, after the initial dose; and c) administering to the patient at least one additional maintenance dose 8 to 24 weeks, such as 8 to 16 weeks, such as 8 to 12 weeks, such as 6 to 24 weeks, such as 6 to 16 weeks, such as 6 to 12 weeks, after said first maintenance dose. Includes.

[0009] In one embodiment, the first maintenance dose is administered to the patient 4, 6, 8, 12, 16, 20, or 24 weeks after the initial dose is administered.

[0010] In one embodiment, at least one additional maintenance dose is administered to the patient 4, 6, 8, 12, 16, 20, or 24 weeks after the first maintenance dose is administered.

[0011] In one embodiment, a first maintenance dose is administered to the patient 4, 6, 8, 12, 16, 20, or 24 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 4, 6, 8, 12, 16, 20, or 24 weeks after the first maintenance dose is administered.

[0012] In an additional embodiment, a first maintenance dose is administered to the patient four weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient four weeks after the first maintenance dose is administered; or a first maintenance dose is administered to the patient 6 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 6 weeks after the first maintenance dose is administered; or a first maintenance dose is administered to the patient 8 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 8 weeks after the first maintenance dose is administered; or a first maintenance dose is administered to the patient 12 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 12 weeks after the first maintenance dose is administered; or a first maintenance dose is administered to the patient 16 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 16 weeks after the first maintenance dose is administered; or a first maintenance dose is administered to the patient 20 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 20 weeks after the first maintenance dose is administered; or A first maintenance dose is administered to the patient 24 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 24 weeks after the first maintenance dose is administered.

[0013] In one embodiment, in any one of the above methods, the initial dose comprises 15-300 mg, such as 15-250 mg, for example 90-180 mg, of anti-IL-23A antibody.

[0014] In one embodiment, in any one of the above methods, the first maintenance dose and at least one additional maintenance dose comprises 15-300 mg, such as 15-250 mg, for example 90-180 mg, of anti-IL-23A antibody.

[0015] In one embodiment, in any one of the above methods, the initial dose comprises 70 to 90 mg, 80 to 100 mg, 90 to 110 mg, 100 to 120 mg, 110 to 130 mg, 120 to 140 mg, 130 to 150 mg, 140 to 160 mg, 150 to 170 mg, 160 to 180 mg, 170 to 190 mg, 180 to 200 mg, 190 to 210 mg, 200 to 220 mg, 210 to 230 mg, 220 to 240 mg, 230 to 250 mg, 240 to 260 mg, 250 to 270 mg, 260 to 280 mg, 270 to 290 mg, or 280 to 300 mg of anti-IL-23A antibody.

[0016] In one embodiment, in any one of the above methods, the first maintenance dose and at least one additional maintenance dose comprise 70 to 90 mg, 80 to 100 mg, 90 to 110 mg, 100 to 120 mg, 110 to 130 mg, 120 to 140 mg, 130 to 150 mg, 140 to 160 mg, 150 to 170 mg, 160 to 180 mg, 170 to 190 mg, 180 to 200 mg, 190 to 210 mg, 200 to 220 mg, 210 to 230 mg, 220 to 240 mg, 230 to 250 mg, 240 to 260 mg, 250 to 270 mg, 260 to 280 mg, 270 to 290 mg, or 280 to 300 mg of anti-IL-23A antibody.

[0017] In one embodiment, in any one of the above methods, the initial dose comprises 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg of anti-IL-23A antibody. In one embodiment, in any one of the above methods, the initial dose comprises 75 mg of anti-IL-23A antibody.

[0018] In one embodiment, in any one of the above methods, the first maintenance dose and at least one additional maintenance dose comprise 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg of anti-IL-23A antibody. In one embodiment, in any one of the above methods, the first maintenance dose and at least one additional maintenance dose comprise 75 mg of anti-IL-23A antibody.

[0019] In one embodiment, in any one of the above methods, the initial dose, the first maintenance dose, and at least one additional maintenance dose comprise 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg of anti-IL-23A antibody. In one embodiment, in any one of the above methods, the initial dose, the first maintenance dose, and at least one additional maintenance dose comprise 75 mg of anti-IL-23A antibody.

[0020] In one embodiment, the invention provides a method for treating an inflammatory disease, in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), comprising administering to a patient an anti-IL-23A antibody, the method comprising: a) administering to the patient an initial dose of an anti-IL-23A antibody; b) administering to the patient a first maintenance dose of an anti-IL-23A antibody 12 weeks after said initial dose is administered; and c) administering to the patient at least one additional maintenance dose 12 weeks after said first maintenance dose is administered. Includes.

[0021] In one embodiment, the method includes an initial dose and a maintenance dose of 150 mg of the anti-IL-23A antibody. In one embodiment, the method includes an initial dose and a maintenance dose of 75 mg of the anti-IL-23A antibody.

[0022] In one embodiment, the invention provides a method for treating an inflammatory disease, in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), comprising administering to a patient an anti-IL-23A antibody, the method comprising: a) administering to the patient an initial dose of an anti-IL-23A antibody; b) administering to the patient a first maintenance dose of an anti-IL-23A antibody 8 weeks after said initial dose is administered; and c) administering to the patient at least one additional maintenance dose 8 weeks after said first maintenance dose is administered. Includes.

[0023] In one embodiment, the method includes an initial dose and a maintenance dose of 90 mg of the anti-IL-23A antibody. In one embodiment, the method includes an initial dose and a maintenance dose of 150 mg of the anti-IL-23A antibody.

[0024] In one embodiment, the invention provides a method for treating an inflammatory disease, in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), comprising administering to a patient an anti-IL-23A antibody, the method comprising: a) administering to the patient an initial dose of an anti-IL-23A antibody; b) administering to the patient a first maintenance dose of an anti-IL-23A antibody 16 weeks after said initial dose is administered; and c) administering to the patient at least one additional maintenance dose 16 weeks after said first maintenance dose is administered. Includes.

[0025] In one embodiment, in the method, the initial dose and the maintenance dose comprise 150 mg of said anti-IL-23A antibody.

[0026] In one embodiment, the invention provides a method for treating an inflammatory disease, in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), comprising administering to a patient an anti-IL-23A antibody, the method comprising: a) administering to the patient an initial dose of an anti-IL-23A antibody; b) administering to the patient a first maintenance dose of an anti-IL-23A antibody six weeks after said initial dose is administered; and c) administering to the patient at least one additional maintenance dose six weeks after said first maintenance dose is administered. Includes.

[0027] In one embodiment, in the method, the initial dose and the maintenance dose comprise 150 mg of said anti-IL-23A antibody.

[0028] In one embodiment, the invention provides a method for treating an inflammatory disease, in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), comprising administering to a patient an anti-IL-23A antibody, the method comprising: a) administering to the patient an initial dose of an anti-IL-23A antibody; b) administering to the patient a first maintenance dose of an anti-IL-23A antibody four weeks after said initial dose is administered; and c) administering to the patient at least one additional maintenance dose four weeks after said first maintenance dose is administered. Includes.

[0029] In one embodiment, in the method, the initial dose and the maintenance dose comprise 150 mg of said anti-IL-23A antibody.

[0030] In one embodiment, the invention provides a method for treating an inflammatory disease, in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), comprising administering to a patient an anti-IL-23A antibody, the method comprising: a) administering to the patient an initial dose of said anti-IL-23A antibody; b) administering to the patient a loading dose of the anti-IL-23A antibody 1 to 6 weeks after administration of the initial dose; c) administering to the patient a first maintenance dose of an anti-IL-23A antibody 8 to 24 weeks, such as 8 to 16 weeks, such as 8 to 12 weeks, such as 6 to 24 weeks, such as 6 to 16 weeks, such as 6 to 12 weeks, after the loading dose; and d) administering at least one additional maintenance dose to the patient 8 to 24 weeks, such as 8 to 16 weeks, such as 8 to 12 weeks, such as 6 to 24 weeks, such as 6 to 16 weeks, such as 6 to 12 weeks, after the first maintenance dose. Includes.

[0031] In one embodiment, the loading dose is administered to the patient 1, 2, 3, 4, 5, or 6 weeks after the initial dose is administered.

[0032] In one embodiment, the first maintenance dose is administered to the patient 6, 8, 12, 16, 20, or 24 weeks after the loading dose is administered.

[0033] In one embodiment, at least one additional maintenance dose is administered to the patient 6, 8, 12, 16, 20, or 24 weeks after the first maintenance dose is administered.

[0034] In one embodiment, a first maintenance dose is administered to the patient 6, 8, 12, 16, 20, or 24 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 6, 8, 12, 16, 20, or 24 weeks after the first maintenance dose is administered.

[0035] In one embodiment, a first maintenance dose is administered to the patient 6, 8, 12, 16, 20, or 24 weeks after the loading dose is administered, and at least one additional maintenance dose is administered to the patient 6, 8, 12, 16, 20, or 24 weeks after the first maintenance dose is administered.

[0036] In an additional embodiment, a first maintenance dose is administered to the patient 6 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 6 weeks after the first maintenance dose is administered; or a first maintenance dose is administered to the patient 8 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 8 weeks after the first maintenance dose is administered; or a first maintenance dose is administered to the patient 12 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 12 weeks after the first maintenance dose is administered; or a first maintenance dose is administered to the patient 16 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 16 weeks after the first maintenance dose is administered; or a first maintenance dose is administered to the patient 20 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 20 weeks after the first maintenance dose is administered; or A first maintenance dose is administered to the patient 24 weeks after the initial dose is administered, and at least one additional maintenance dose is administered to the patient 24 weeks after the first maintenance dose is administered.

[0037] In an additional embodiment, a first maintenance dose is administered to the patient 6 weeks after the loading dose is administered, and at least one additional maintenance dose is administered to the patient 6 weeks after the first maintenance dose is administered; or a first maintenance dose is administered to the patient 8 weeks after the loading dose is administered, and at least one additional maintenance dose is administered to the patient 8 weeks after the first maintenance dose is administered; or a first maintenance dose is administered to the patient 12 weeks after the loading dose is administered, and at least one additional maintenance dose is administered to the patient 12 weeks after the first maintenance dose is administered; or a first maintenance dose is administered to the patient 16 weeks after the loading dose is administered, and at least one additional maintenance dose is administered to the patient 16 weeks after the first maintenance dose is administered; or a first maintenance dose is administered to the patient 20 weeks after the loading dose is administered, and at least one additional maintenance dose is administered to the patient 20 weeks after the first maintenance dose is administered; or A first maintenance dose is administered to the patient 24 weeks after the loading dose is administered, and at least one additional maintenance dose is administered to the patient 24 weeks after the first maintenance dose is administered.

[0038] In one embodiment, in any one of the above methods, the initial dose comprises 15-300 mg, such as 15-250 mg, for example 90-180 mg, of anti-IL-23A antibody.

[0039] In one embodiment, in any one of the above methods, the loading dose comprises 15-300 mg, such as 15-250 mg, such as 90-180 mg, of anti-IL-23A antibody.

[0040] In one embodiment, in any one of the above methods, the first maintenance dose and at least one additional maintenance dose comprises 15-300 mg, such as 15-250 mg, for example 90-180 mg, of anti-IL-23A antibody.

[0041] In one embodiment, in any one of the above methods, the initial dose comprises 70 to 90 mg, 80 to 100 mg, 90 to 110 mg, 100 to 120 mg, 110 to 130 mg, 120 to 140 mg, 130 to 150 mg, 140 to 160 mg, 150 to 170 mg, 160 to 180 mg, 170 to 190 mg, 180 to 200 mg, 190 to 210 mg, 200 to 220 mg, 210 to 230 mg, 220 to 240 mg, 230 to 250 mg, 240 to 260 mg, 250 to 270 mg, 260 to 280 mg, 270 to 290 mg, or 280 to 300 mg of anti-IL-23A antibody.

[0042] In one embodiment, in any one of the above methods, the loading dose comprises 70 to 90 mg, 80 to 100 mg, 90 to 110 mg, 100 to 120 mg, 110 to 130 mg, 120 to 140 mg, 130 to 150 mg, 140 to 160 mg, 150 to 170 mg, 160 to 180 mg, 170 to 190 mg, 180 to 200 mg, 190 to 210 mg, 200 to 220 mg, 210 to 230 mg, 220 to 240 mg, 230 to 250 mg, 240 to 260 mg, 250 to 270 mg, 260 to 280 mg, 270 to 290 mg, or 280 to 300 mg of anti-IL-23A antibody.

[0043] In one embodiment, in any one of the above methods, the first maintenance dose and at least one additional maintenance dose comprise 70 to 90 mg, 80 to 100 mg, 90 to 110 mg, 100 to 120 mg, 110 to 130 mg, 120 to 140 mg, 130 to 150 mg, 140 to 160 mg, 150 to 170 mg, 160 to 180 mg, 170 to 190 mg, 180 to 200 mg, 190 to 210 mg, 200 to 220 mg, 210 to 230 mg, 220 to 240 mg, 230 to 250 mg, 240 to 260 mg, 250 to 270 mg, 260 to 280 mg, 270 to 290 mg, or 280 to 300 mg of anti-IL-23A antibody.

[0044] In one embodiment, in any one of the above methods, the initial dose comprises 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg of anti-IL-23A antibody. In one embodiment, in any one of the above methods, the initial dose comprises 75 mg of anti-IL-23A antibody.

[0045] In one embodiment, in any one of the above methods, the first maintenance dose and at least one additional maintenance dose comprise 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg of anti-IL-23A antibody. In one embodiment, in any one of the above methods, the first maintenance dose and at least one additional maintenance dose comprise 75 mg of anti-IL-23A antibody.

[0046] In one embodiment, in any one of the above methods, the loading dose comprises 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg of anti-IL-23A antibody. In one embodiment, in any one of the above methods, the loading dose comprises 75 mg of anti-IL-23A antibody.

[0047] In one embodiment, in any one of the above methods, the initial dose, the loading dose, the first maintenance dose, and at least one additional maintenance dose comprise 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg of anti-IL-23A antibody. In one embodiment, in any one of the above methods, the initial dose, the loading dose, the first maintenance dose, and at least one additional maintenance dose comprise 75 mg of anti-IL-23A antibody.

[0048] In one embodiment, the invention further provides a method for treating an inflammatory disease, in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), comprising administering an anti-IL-23A antibody to a patient, the method comprising: a) administering to the patient an initial dose of said anti-IL-23A antibody; b) administering to the patient a loading dose of said anti-IL-23A antibody four weeks after said initial dose is administered; c) administering to the patient a first maintenance dose of the anti-IL-23A antibody 12 weeks after the loading dose is administered; and d) administering to the patient at least one additional maintenance dose 12 weeks after said first maintenance dose is administered. Includes.

[0049] In one embodiment, in the method, the loading dose, the loading dose, and the maintenance dose comprise 150 mg of the anti-IL-23A antibody. In one embodiment, in the method, the loading dose and the loading dose comprise 300 mg of the anti-IL-23A antibody and the maintenance dose comprises 150 mg of the anti-IL-23A antibody. In one embodiment, in the method, the loading dose and the loading dose comprise 180 mg of the anti-IL-23A antibody and the maintenance dose comprises 90 mg of the anti-IL-23A antibody. In one embodiment, in the method, the loading dose, the loading dose, and the maintenance dose comprise 75 mg of the anti-IL-23A antibody.

[0050] In one embodiment, the invention further provides a method for treating an inflammatory disease, in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), comprising administering an anti-IL-23A antibody to a patient, the method comprising: a) administering to the patient an initial dose of said anti-IL-23A antibody; b) administering to the patient a loading dose of said anti-IL-23A antibody four weeks after said initial dose is administered; c) administering to the patient a first maintenance dose of the anti-IL-23A antibody 8 weeks after the loading dose is administered; and d) administering to the patient at least one additional maintenance dose 8 weeks after said first maintenance dose is administered. Includes.

[0051] In one embodiment, the initial dose, loading dose, and maintenance dose in the method include 90 mg of the anti-IL-23A antibody. In one embodiment, the initial dose, loading dose, and maintenance dose in the method include 150 mg of the anti-IL-23A antibody.

[0052] In one embodiment, the invention further provides a method for treating an inflammatory disease, in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), comprising administering an anti-IL-23A antibody to a patient, the method comprising: a) administering to the patient an initial dose of said anti-IL-23A antibody; b) administering to the patient a loading dose of said anti-IL-23A antibody four weeks after said initial dose is administered; c) administering to the patient a first maintenance dose of the anti-IL-23A antibody 16 weeks after the loading dose is administered; and d) administering to the patient at least one additional maintenance dose 16 weeks after said first maintenance dose is administered. Includes.

[0053] In one embodiment, in the method, the loading dose, and the maintenance dose comprise 150 mg of the anti-IL-23A antibody.

[0054] In one embodiment, the invention further provides a method for treating an inflammatory disease, in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), comprising administering an anti-IL-23A antibody to a patient, the method comprising: a) administering to the patient an initial dose of said anti-IL-23A antibody; b) administering to the patient a loading dose of said anti-IL-23A antibody four weeks after said initial dose is administered; c) administering to the patient a first maintenance dose of the anti-IL-23A antibody six weeks after the loading dose is administered; and d) administering to the patient at least one additional maintenance dose six weeks after said first maintenance dose is administered. Includes.

[0055] In one embodiment, in the method, the loading dose, and the maintenance dose comprise 150 mg of the anti-IL-23A antibody.

[0056] In one embodiment, the present invention further provides a method for treating an inflammatory disease, comprising administering 15 to 300 mg, for example 15 to 250 mg, for example 90 to 180 mg, of an anti-IL-23A antibody to a patient. In one embodiment, the inflammatory disease is psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA).

[0057] In one embodiment, the method includes the step of administering 70 to 90 mg, 80 to 100 mg, 90 to 110 mg, 100 to 120 mg, 110 to 130 mg, 120 to 140 mg, 130 to 150 mg, 140 to 160 mg, 150 to 170 mg, 160 to 180 mg, 170 to 190 mg, 180 to 200 mg, 190 to 210 mg, 200 to 220 mg, 210 to 230 mg, 220 to 240 mg, 230 to 250 mg, 240 to 260 mg, 250 to 270 mg, 260 to 280 mg, 270 to 290 mg, or 280 to 300 mg of an anti-IL-23A antibody to a patient.

[0058] In one embodiment, the method comprises administering 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg of anti-IL-23A antibody to the patient. In one embodiment, the method comprises administering 75 mg of anti-IL-23A antibody to the patient.

[0059] In one embodiment, the anti-IL-23A antibody is administered as an initial dose, a loading dose, or a maintenance dose.

[0060] In one embodiment, the invention further provides a method for treating an inflammatory disease, in one aspect for treating psoriasis or psoriatic arthritis, comprising administering an anti-IL-23A antibody to a patient, the method comprising: a) administering to the patient an initial dose of the anti-IL-23A antibody; and b) administering a second dose of said anti-IL-23A antibody to the patient if the patient no longer maintains a particular PASI score, e.g., PASI 90, PASI 75, PASI 100, or PASI 50. Includes.

[0061] In one embodiment, the first dose and the second dose are as described herein.

[0062] In one embodiment, the invention further provides a method for treating an inflammatory disease, in one aspect for treating psoriasis or psoriatic arthritis, comprising administering an anti-IL-23A antibody to a patient, the method comprising: a) administering to the patient an initial dose of the anti-IL-23A antibody; and b) administering to the patient a loading dose of the anti-IL-23A antibody 1 to 6 weeks, e.g., 4 weeks, after administration of the initial dose; and c) administering a third dose of said anti-IL-23A antibody to the patient if the patient no longer maintains a particular PASI score, e.g., PASI 90, PASI 75, PASI 100, or PASI 50. Includes.

[0063] In one embodiment, the initial dose, the loading dose, and the third dose are as described herein.

[0064] In one embodiment, in any one of the above methods, the anti-IL-23A antibody is Antibody A, Antibody B, Antibody C, or Antibody D.

[0065] In one embodiment, in any one of the above methods, the method is for treating psoriasis vulgaris, such as chronic plaque psoriasis.

[0066] In one embodiment, in any one of the above methods, the method is for treating moderate to severe chronic plaque psoriasis, e.g., in a patient who is a candidate for systemic therapy or phototherapy.

[0067] In one embodiment, in any one of the methods above, the method is for treating moderate to severe chronic plaque psoriasis in patients who have not responded to, are contraindicated to, or are intolerant to other systemic therapies, including, for example, cyclosporine, methotrexate, psoralen, or ultraviolet A (psoralen ultraviolet B therapy).

[0068] In one embodiment, in any one of the above methods, said method is for treating pustular psoriasis.

[0069] In one embodiment, in any one of the above methods, said method is for treating erythodermic psoriasis (also called psoriatic erythroderma).

[0070] In one embodiment, in any one of the above methods, the method is for treating psoriatic arthritis, such as active psoriatic arthritis.

[0071] In one embodiment, anti-IL-23A antibodies are used, e.g., to treat psoriatic arthritis, e.g., active psoriatic arthritis, e.g., to reduce signs and symptoms, alone or in combination with one or more non-biologic DMARDs (disease-modifying antirheumatic drugs). In one embodiment, anti-IL-23A antibodies are used or indicated to inhibit progression of structural damage and / or improve physical function.

[0072] In one embodiment, anti-IL-23A antibodies are used, e.g., to treat psoriatic arthritis, e.g., active psoriatic arthritis, e.g., when there has been an inadequate response to prior non-biologic DMARD therapy, alone or in combination with methotrexate (MTX). In one aspect, anti-IL-23A antibodies are used to reduce the rate of progression of peripheral joint damage as measured by x-ray and / or to improve physical function.

[0073] In one embodiment, in any one of the above methods, the anti-IL-23A antibody is administered by subcutaneous administration.

[0074] In one embodiment, in the methods of the invention, 90-180 mg of anti-IL-23A antibody is administered to a patient every 6-12 weeks, for example, every 8-12 weeks, with or without a loading dose.

[0075] In one embodiment, in any one of the above methods, the patient is an adult patient.

[0076] In one aspect, the invention provides an anti-IL-23A antibody for use in the treatment of a disease as described herein.

[0077] In one aspect, the invention provides an anti-IL-23A antibody for use in treating a disease, e.g., an inflammatory disease, e.g., psoriasis, psoriatic arthritis or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), by administration in specific amounts and / or at specific intervals as described herein.

[0078] In one embodiment, the invention provides the use of an anti-IL-23A antibody for the preparation of a medicament for the treatment of a disease as described herein.

[0079] In one aspect, the invention provides the use of an anti-IL-23A antibody for the preparation of a medicament for treating a disease, e.g., an inflammatory disease, e.g., psoriasis, psoriatic arthritis or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), by administration in specific amounts and / or at specific intervals as described herein.

[0080] In one embodiment, in any one of the above methods or uses, the anti-IL-23A antibody is disclosed below.

[0081] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:1 (CDR1-L); the amino acid sequence of SEQ ID NO:2 (CDR2-L); and the amino acid sequence of SEQ ID NO:3 (CDR3-L); and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4, 7, 8, or 9 (CDR1-H); the amino acid sequence of SEQ ID NO:5 (CDR2-H); and the amino acid sequence of SEQ ID NO:6 (CDR3-H).

[0082] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:1 (CDR1-L); the amino acid sequence of SEQ ID NO:2 (CDR2-L); and the amino acid sequence of SEQ ID NO:3 (CDR3-L); and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 (CDR1-H); the amino acid sequence of SEQ ID NO:5 (CDR2-H); and the amino acid sequence of SEQ ID NO:6 (CDR3-H).

[0083] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:1 (CDR1-L); the amino acid sequence of SEQ ID NO:2 (CDR2-L); and the amino acid sequence of SEQ ID NO:3 (CDR3-L); and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 (CDR1-H); the amino acid sequence of SEQ ID NO:5 (CDR2-H); and the amino acid sequence of SEQ ID NO:6 (CDR3-H).

[0084] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:1 (CDR1-L); the amino acid sequence of SEQ ID NO:2 (CDR2-L); and the amino acid sequence of SEQ ID NO:3 (CDR3-L); and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8 (CDR1-H); the amino acid sequence of SEQ ID NO:5 (CDR2-H); and the amino acid sequence of SEQ ID NO:6 (CDR3-H).

[0085] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:1 (CDR1-L); the amino acid sequence of SEQ ID NO:2 (CDR2-L); and the amino acid sequence of SEQ ID NO:3 (CDR3-L); and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9 (CDR1-H); the amino acid sequence of SEQ ID NO:5 (CDR2-H); and the amino acid sequence of SEQ ID NO:6 (CDR3-H).

[0086] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 10, 11, 12, or 13; and a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 14, 15, 16, or 17.

[0087] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:11 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:14.

[0088] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:11 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:15.

[0089] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:10 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:14.

[0090] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:10 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:15.

[0091] In one embodiment, the anti-IL-23A antibody comprises the amino acid sequence of SEQ ID NO: 14 or 15 linked to a human IgG1, IgG2, IgG3, IgG4, IgM, IgA, or IgE heavy chain constant region. In one embodiment, the anti-IL-23A antibody comprises the amino acid sequence of SEQ ID NO: 14 or 15 linked to a human IgG1 heavy chain constant region. In one embodiment, the anti-IL-23A antibody comprises the amino acid sequence of SEQ ID NO: 10 or 11 linked to a human kappa or lambda light chain constant region.

[0092] In one embodiment, the anti-IL-23A antibody comprises the amino acid sequence of SEQ ID NO: 14 or 15 linked to a human IgG1 heavy chain constant region; and the amino acid sequence of SEQ ID NO: 10 or 11 linked to a human kappa light chain constant region.

[0093] In one embodiment, the anti-IL-23A antibody is a humanized monoclonal antibody comprising a light chain variable region comprising an amino acid sequence selected from the group consisting of any one of SEQ ID NOs: 10, 11, 12, and 13, and a heavy chain variable region comprising an amino acid sequence selected from the group consisting of any one of SEQ ID NOs: 14, 15, 16, and 17.

[0094] In one embodiment, the anti-IL-23A antibody is a humanized monoclonal antibody comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO:11 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:14.

[0095] In one embodiment, the anti-IL-23A antibody is a humanized monoclonal antibody comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO:11 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:15.

[0096] In one embodiment, the anti-IL-23A antibody is a humanized monoclonal antibody comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO:10 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:14.

[0097] In one embodiment, the anti-IL-23A antibody is a humanized monoclonal antibody comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO:10 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:15.

[0098] In one embodiment, the anti-IL-23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:18 or 21 and a heavy chain comprising the amino acid sequence of SEQ ID NO:19 or 20.

[0099] In one embodiment, the anti-IL-23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:18 and a heavy chain comprising the amino acid sequence of SEQ ID NO:19.

[0100] In one embodiment, the anti-IL-23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:18 and a heavy chain comprising the amino acid sequence of SEQ ID NO:20.

[0101] In one embodiment, the anti-IL-23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:21 and a heavy chain comprising the amino acid sequence of SEQ ID NO:19.

[0102] In one embodiment, the anti-IL-23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:21 and a heavy chain comprising the amino acid sequence of SEQ ID NO:20.

[0103] In one embodiment, the anti-IL-23A antibody is Antibody A, Antibody B, Antibody C, or Antibody D.

[0104] In one embodiment, the anti-IL-23A antibody is as disclosed in WO 2007 / 005955, WO 2007 / 024846, WO 2007 / 027714, WO 2007 / 076524, WO 2008 / 103432, or WO 2012 / 061448. [Brief description of the drawings]

[0105] [Figure 1]Percentage of patients showing >50% reduction from baseline on Pain-VAS. [Diagram 2] Achievement of PASI 50 over (observed) time. [Diagram 3] Achievement of PASI 75 over (observed) time. [Figure 4] Achievement of PASI 90 over (observed) time. [Diagram 5] Achievement of PASI 100 over time (observed). Antibody A is also referred to as "BI" in Figures 2-5.

[0106] Detailed Description The p19 subunit of IL-23 (also referred to herein as "IL-23A", "IL-23p19" and "p19 subunit") is a 189 amino acid polypeptide containing a 21 amino acid leader sequence (Oppmann et al. Immunity 13:715 (2000), SEQ ID NO: 22). The biological activity of the molecule is only detected when it pairs with the IL-12p40 subunit to form IL-23. IL-23 is expressed primarily by activated dendritic cells (DCs) and phagocytes. The receptor for IL-23 was found to consist of the IL-12Rβ1 subunit of the IL-12 receptor paired with a unique subunit called IL-23R (Parham et al. J. Immunol. 168:5699 (2002)). Expression of the receptor is primarily detected on memory T cells and NK cells. Thus, expression of this cytokine:receptor pair appears to be restricted to specific populations of immune cells. Initially, IL-12 and IL-23 were thought to share many functions, but data suggest a different picture. While IL-12 has a key role in the generation of Th1 cells, IL-23 has been shown to be critically involved in the generation and maintenance of a recently recognized Th cell subset called Th17 (Kikly et al. Curr. Opin. Immunol. 18:670 (2006), Kastelein et al. Ann. Rev. Immunol. 25:221 (2007)). These cells produce IL-17A, IL-17F, IL-22, and other proinflammatory cytokines such as IL-6 and TNF-α. As described below, animal model studies of the role of these Th17 cells demonstrate their importance as a driving force in chronic inflammation and autoimmunity.

[0107] SEQ ID NO:22: [ka]

[0108] In one embodiment, the present invention provides a method for treating an IL-23A-related disease. In one embodiment, the present invention provides a method for treating a disease, e.g., an inflammatory disease, in particular a method comprising administering an anti-IL-23A antibody to a patient in a specific amount and / or at a specific interval. In one embodiment, the method of the present invention is for treating psoriasis or psoriatic arthritis. In one embodiment, the method of the present invention is for treating ankylosing spondylitis (AS). In one embodiment, the method of the present invention is for treating axial (spinal) spondyloarthritis (ax-SpA), e.g., ax-SpA without radiological findings.

[0109] In one aspect, the invention provides an anti-IL-23A antibody for use in treating a disease, e.g., an inflammatory disease, e.g., psoriasis, psoriatic arthritis or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), by administration in specific amounts and / or at specific intervals as described herein.

[0110] In one aspect, the invention provides the use of an anti-IL-23A antibody for the preparation of a medicament for treating a disease, e.g., an inflammatory disease, e.g., psoriasis, psoriatic arthritis or axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis and non-radiographic ax-SpA), by administration in specific amounts and / or at specific intervals as described herein.

[0111] In one embodiment, the method of the invention comprises administering to the patient an initial dose of an anti-IL-23A antibody, followed by one or more maintenance doses of an anti-IL-23A antibody. Optionally, a loading dose of an anti-IL-23A antibody is administered to the patient between the administration of the initial dose and the first maintenance dose.

[0112] In one embodiment, in the method of the invention, the administration interval between the initial dose and the first maintenance dose is 4 to 24 weeks, such as 4 to 16 weeks, such as 4 to 12 weeks, such as 4, 6, 8, 12, 16, 20, or 24 weeks. In another embodiment, the administration interval between the first maintenance dose and the subsequent maintenance dose is 4 to 24 weeks, such as 4 to 16 weeks, such as 4 to 12 weeks, such as 4, 6, 8, 12, 16, 20, or 24 weeks.

[0113] In one embodiment, in the method of the invention, the administration interval between the initial dose and the first maintenance dose is 8 to 24 weeks, such as 8 to 16 weeks, for example 8 to 12 weeks, such as 6 to 24 weeks, for example 6 to 16 weeks, for example 6 to 12 weeks, such as 6, 8, 12, 16, 20, or 24 weeks. In another embodiment, the administration interval between the first maintenance dose and the subsequent maintenance dose is 8 to 24 weeks, such as 8 to 16 weeks, for example 8 to 12 weeks, for example 6 to 24 weeks, such as 6 to 16 weeks, for example 6 to 12 weeks, for example 6, 8, 12, 16, 20, or 24 weeks.

[0114] In one embodiment, in the methods of the invention, the administration interval between the initial dose and the first maintenance dose, and the administration interval between the first maintenance dose and any subsequent maintenance doses, is the same, e.g., 4 to 24 weeks, e.g., 4 to 16 weeks, e.g., 4 to 12 weeks, e.g., 4, 6, 8, 12, 16, 20, or 24 weeks.

[0115] In one embodiment, in the methods of the invention, the administration interval between the initial dose and the first maintenance dose, and the administration interval between the first maintenance dose and any subsequent maintenance doses, are the same, for example 8 to 24 weeks, such as 8 to 16 weeks, for example 8 to 12 weeks, for example 6 to 24 weeks, such as 6 to 16 weeks, for example 6 to 12 weeks, for example 6, 8, 12, 16, 20, or 24 weeks.

[0116] In one embodiment, in the methods of the invention, a loading dose of an anti-IL-23A antibody is administered to the patient between the administration of the initial dose and the administration of the first maintenance dose.

[0117] In one embodiment, the loading dose is administered 1, 2, 3, 4, 5, or 6 weeks after the initial dose is administered. In one embodiment, in the method of the present invention, the administration interval between the loading dose and the first maintenance dose is 8 to 24 weeks, such as 8 to 16 weeks, for example 8 to 12 weeks, such as 6 to 24 weeks, for example 6 to 16 weeks, for example 6 to 12 weeks, such as 6, 8, 12, 16, 20, or 24 weeks. In another embodiment, the administration interval between the first maintenance dose and the subsequent maintenance dose is 8 to 24 weeks, such as 8 to 16 weeks, for example 8 to 12 weeks, for example 6 to 24 weeks, such as 6 to 16 weeks, for example 6 to 12 weeks, for example 6, 8, 12, 16, 20, or 24 weeks.

[0118] In one embodiment, in the methods of the invention, the administration interval between the loading dose and the first maintenance dose, and the administration interval between the first maintenance dose and any subsequent maintenance doses, is the same, such as 8 to 24 weeks, such as 8 to 16 weeks, for example 8 to 12 weeks, such as 6 to 24 weeks, for example 6 to 16 weeks, for example 6 to 12 weeks, such as 6, 8, 12, 16, 20, or 24 weeks.

[0119] In one embodiment, the amount of anti-IL-23A antibody in the initial dose and the maintenance dose is the same. In one embodiment, the amount of anti-IL-23A antibody in the initial dose and the loading dose is the same. In one embodiment, the amount of anti-IL-23A antibody in the loading dose and the maintenance dose is the same. In one embodiment, the amount of anti-IL-23A antibody in the initial dose, loading dose, and maintenance dose is the same.

[0120] In one embodiment, the amount of anti-IL-23A antibody in the maintenance dose is less than the amount of anti-IL-23A antibody in the initial dose and / or the loading dose. In one embodiment, the amount of anti-IL-23A antibody in the initial dose is twice the amount of anti-IL-23A antibody in the maintenance dose, e.g., in the absence of a loading dose. In one embodiment, the amount of anti-IL-23A antibody in the initial dose and the loading dose is twice the amount of anti-IL-23A antibody in the maintenance dose.

[0121] In one embodiment, in the method of the present invention, the initial dose comprises 15-300 mg, e.g., 15-250 mg, of anti-IL-23A antibody. In another embodiment, the maintenance dose comprises 15-300 mg, e.g., 15-250 mg, of anti-IL-23A antibody. In another embodiment, if a loading dose is administered, such loading dose comprises 15-300 mg, e.g., 15-250 mg, of anti-IL-23A antibody.

[0122] In a further aspect, an initial dose, loading dose, or maintenance dose according to the present invention comprises 70-90 mg, 80-100 mg, 90-110 mg, 100-120 mg, 110-130 mg, 120-140 mg, 130-150 mg, 140-160 mg, 150-170 mg, 160-180 mg, 170-190 mg, 180-200 mg, 190-210 mg, 200-220 mg, 210-230 mg, 220-240 mg, 230-250 mg, 240-260 mg, 250-270 mg, 260-280 mg, 270-290 mg, or 280-300 mg of anti-IL-23A antibody.

[0123] In a further aspect, an initial dose, loading dose, or maintenance dose according to the invention comprises 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg of anti-IL-23A antibody. In a further aspect, an initial dose, loading dose, or maintenance dose according to the invention comprises 75 mg of anti-IL-23A antibody.

[0124] In a further aspect, the present invention provides a method for treating an inflammatory disease, the method comprising administering to a patient between 15 and 250 mg of an anti-IL-23A antibody. In one embodiment, 70 to 90 mg, 80 to 100 mg, 90 to 110 mg, 100 to 120 mg, 110 to 130 mg, 120 to 140 mg, 130 to 150 mg, 140 to 160 mg, 150 to 170 mg, 160 to 180 mg, 170 to 190 mg, 180 to 200 mg, 190 to 210 mg, 200 to 220 mg, 210 to 230 mg, 220 to 240 mg, 230 to 250 mg, 240 to 260 mg, 250 to 270 mg, 260 to 280 mg, 270 to 290 mg, or 280 to 300 mg of an anti-IL-23A antibody is administered to a patient. In one embodiment, 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg of anti-IL-23A antibody is administered to the patient. In one embodiment, 75 mg of anti-IL-23A antibody is administered to the patient. In one embodiment, the disease is psoriasis or psoriatic arthritis. In one embodiment, the disease is axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA.

[0125] In one embodiment, in the methods of the invention, 90-180 mg of anti-IL-23A antibody is administered to a patient every 6-12 weeks, for example, every 8-12 weeks, with or without a loading dose.

[0126] Representative examples of doses and dosing regimens according to the present invention are disclosed in Table A.

[0127] [Table 1] TIFF2025060797000003.tif220168TIFF2025060797000004.tif183168

[0128] In Table A it is shown that if a loading dose is administered, it is administered 4 weeks after the first dose.

[0129] For each of the doses and maintenance dose frequencies identified in the table above, it is also within the scope of the invention to administer a loading dose one week after the initial dose.

[0130] For each of the doses and maintenance dose frequencies identified in the table above, it is also within the scope of the invention to administer a loading dose two weeks after the initial dose.

[0131] For each of the doses and maintenance dose frequencies identified in the table above, it is also within the scope of the invention to administer a loading dose three weeks after the initial dose.

[0132] For each of the doses and maintenance dose frequencies identified in the table above, it is also within the scope of the invention to administer a loading dose 5 weeks after the initial dose.

[0133] For each of the doses and maintenance dose frequencies identified in the table above, it is also within the scope of the invention to administer a loading dose six weeks after the initial dose.

[0134] For example, in the context of the present invention, if no loading dose is administered to the patient and the administration frequency of the maintenance dose is 12 weeks, an initial dose is administered to the patient at week 0, followed by a further administration at week 12 (first maintenance dose), then at week 24 (second maintenance dose), etc., with an administration interval of 12 weeks. In one embodiment, the initial dose and the maintenance dose comprise 150 mg of anti-IL-23A antibody. In one embodiment, the initial dose and the maintenance dose comprise 75 mg of anti-IL-23A antibody.

[0135] For example, in the context of the present invention, if a loading dose is administered to a patient and the administration frequency of the maintenance dose is 12 weeks, an initial dose is administered to the patient at week 0, followed by further administrations at week 4 (loading dose), then at week 16 (first maintenance dose), at week 28 (second maintenance dose), etc., with an administration interval of 12 weeks. In one embodiment, the initial dose, loading dose, and maintenance dose comprise 150 mg of anti-IL-23A antibody. In one embodiment, the initial dose and loading dose comprise 300 mg of anti-IL-23A antibody, and the maintenance dose comprises 150 mg of anti-IL-23A antibody. In one embodiment, the initial dose and loading dose comprise 180 mg of anti-IL-23A antibody, and the maintenance dose comprises 90 mg of anti-IL-23A antibody. In one embodiment, the initial dose, loading dose, and maintenance dose comprise 75 mg of anti-IL-23A antibody.

[0136] For example, in the context of the present invention, if no loading dose is administered to the patient and the administration frequency of the maintenance dose is 8 weeks, an initial dose is administered to the patient at week 0, followed by a further administration at week 8 (first maintenance dose), then at week 16 (second maintenance dose), etc., with an 8-week interval between doses. In one embodiment, the initial dose and the maintenance dose comprise 90 mg of anti-IL-23A antibody. In one embodiment, the initial dose and the maintenance dose comprise 150 mg of anti-IL-23A antibody.

[0137] For example, in the context of the present invention, where a loading dose is administered to a patient and the administration frequency of the maintenance doses is 8 weeks, an initial dose is administered to the patient at week 0, followed by further administrations at week 4 (loading dose), then at week 12 (first maintenance dose), at week 20 (second maintenance dose), etc., with an 8 week interval between doses. In one embodiment, the initial dose, loading dose, and maintenance dose comprise 90 mg of anti-IL-23A antibody. In one embodiment, the initial dose, loading dose, and maintenance dose comprise 150 mg of anti-IL-23A antibody.

[0138] For example, in the context of the present invention, if no loading dose is administered to a patient and the administration frequency of the maintenance doses is 16 weeks, then an initial dose is administered to the patient at week 0, followed by a further administration at week 16 (first maintenance dose), then at week 32 (second maintenance dose), etc., with an interval of 16 weeks between doses. In one embodiment, the initial dose and the maintenance dose comprise 150 mg of anti-IL-23A antibody.

[0139] For example, in the context of the present invention, where a loading dose is administered to a patient and the administration frequency of the maintenance doses is 16 weeks, an initial dose is administered to the patient at week 0, followed by additional administrations at week 4 (loading dose), then at week 20 (first maintenance dose), then at week 36 (second maintenance dose), etc., with an interval of 16 weeks between administrations. In one embodiment, the loading dose and maintenance dose comprise 150 mg of anti-IL-23A antibody.

[0140] For example, in the context of the present invention, if no loading dose is administered to the patient and the administration frequency of the maintenance dose is 6 weeks, then an initial dose is administered to the patient at week 0, followed by a further administration at week 6 (first maintenance dose), then at week 12 (second maintenance dose), etc., with an interval of 6 weeks between doses. In one embodiment, the initial dose and the maintenance dose comprise 150 mg of anti-IL-23A antibody.

[0141] For example, in the context of the present invention, where a loading dose is administered to a patient and the administration frequency of the maintenance doses is 6 weeks, an initial dose is administered to the patient at week 0, followed by additional administrations at week 4 (loading dose), then at week 10 (first maintenance dose), then at week 16 (second maintenance dose), etc., with an interval of 6 weeks between administrations. In one embodiment, the initial dose, loading dose and maintenance dose comprise 150 mg of anti-IL-23A antibody.

[0142] For example, in the context of the present invention, where the administration frequency of the maintenance dose is 4 weeks, an initial dose is administered to the patient at week 0, followed by further administrations at week 4 (first maintenance dose), then at week 8 (second maintenance dose), at week 12 (third maintenance dose), etc., with an interval of 4 weeks between administrations. In one embodiment, the initial and maintenance doses comprise 150 mg of anti-IL-23A antibody.

[0143] In a further embodiment, in the method according to the invention, a first dose of anti-IL-23 antibody is administered to the patient. As long as the therapeutic benefit of the first dose is maintained, e.g., as assessed by PASI score, e.g., PASI 90, PASI 75, PASI 100, or PASI 50, a second dose of anti-IL-23 antibody is not administered, but if the severity of the disease increases above a certain level, e.g., if the patient no longer maintains a certain PASI score, e.g., PASI 90, PASI 75, PASI 100, or PASI 50, a second dose is administered to the patient. The first and second doses of anti-IL-23 antibody are, e.g., as described herein. In one embodiment, the patient is monitored after the first dose is administered, e.g., by assessing the patient's PASI score. In one embodiment, if after administration of the second dose, the patient no longer maintains a particular PASI score, e.g., PASI 90, PASI 75, PASI 100, or PASI 50, a third dose of anti-IL-23 antibody is administered. The third dose of anti-IL-23 antibody is at a dose, e.g., as described herein, e.g., the same dose as the second dose. In one embodiment, after administration of the second dose, the patient is monitored, e.g., by assessing the patient's PASI score. In a further embodiment, at least one additional dose is administered to the patient in this manner.

[0144] In a further embodiment, in the method according to the invention, after administration of the first dose, e.g., after a period of time as described herein, a loading dose of anti-IL-23 antibody is administered to the patient. As long as the therapeutic benefit of the first dose is maintained, e.g., as assessed by PASI score, e.g., PASI 90, PASI 75, PASI 100, or PASI 50, a third dose of anti-IL-23 antibody is not administered to the patient, but if the severity of the disease increases above a certain level, e.g., if the patient no longer maintains a certain PASI score, e.g., PASI 90, PASI 75, PASI 100, or PASI 50, a third dose is administered to the patient. In one embodiment, the loading dose of anti-IL-23 antibody is as described herein. In one embodiment, if after administration of the third dose the patient no longer maintains a particular PASI score, e.g., PASI 90, PASI 75, PASI 100, or PASI 50, a fourth dose of anti-IL-23 antibody is administered to the patient. The fourth dose of anti-IL-23 antibody is, e.g., at a dose as described herein, e.g., the same dose as the third dose. In one embodiment, after administration of the third dose the patient is monitored, e.g., by assessing the patient's PASI score. In a further embodiment, at least one additional dose is administered to the patient in this manner.

[0145] Thus, in one embodiment, the invention further provides a method for treating an inflammatory disease, in one aspect for treating psoriasis or psoriatic arthritis, comprising administering to a patient an anti-IL-23A antibody, the method comprising: a) administering to the patient an initial dose of the anti-IL-23A antibody; and b) if the patient is no longer maintaining PASI 90, PASI 75, PASI 100, or PASI 50, administering a second dose of said anti-IL-23A antibody to the patient. Includes.

[0146] In one embodiment, the amount of anti-IL-23A antibody in the second and subsequent doses is less than the amount of anti-IL-23A antibody in the first dose, hi one embodiment, the amount of anti-IL-23A antibody in the first dose is twice the amount of anti-IL-23A antibody in the second and subsequent doses.

[0147] In one embodiment, the invention further provides a method for treating an inflammatory disease, in one aspect for treating psoriasis or psoriatic arthritis, comprising administering an anti-IL-23A antibody to a patient, the method comprising: a) administering to the patient an initial dose of said anti-IL-23A antibody; b) administering to the patient a loading dose of the anti-IL-23A antibody 1 to 6 weeks, e.g., 4 weeks, after administration of the initial dose; and c) if the patient is no longer maintaining PASI 90, PASI 75, PASI 100, or PASI 50, administering a third dose of said anti-IL-23A antibody to the patient. Includes.

[0148] In one embodiment, the amount of anti-IL-23A antibody in the third dose and subsequent doses is less than the amount of anti-IL-23A antibody in the initial dose and / or the loading dose. In one embodiment, the amount of anti-IL-23A antibody in the initial dose is twice the amount of anti-IL-23A antibody in the third dose and subsequent doses. In one embodiment, the amount of anti-IL-23A antibody in the initial dose and loading dose is twice the amount of anti-IL-23A antibody in the third dose and subsequent doses.

[0149] In one embodiment, the anti-IL-23A antibody in any one of the above methods is disclosed herein.

[0150] In one embodiment, in any one of the above methods, a pharmaceutical composition comprising an anti-IL-23A antibody is administered to the patient. In one embodiment, Formulation 2 disclosed in Example 4 comprising an anti-IL-23A antibody, e.g., Antibody A, Antibody B, Antibody C, or Antibody D, is administered to the patient. In one embodiment, Formulation 3 disclosed in Example 4 comprising an anti-IL-23A antibody, e.g., Antibody A, Antibody B, Antibody C, or Antibody D, is administered to the patient.

[0151] In one embodiment, the anti-IL-23A antibody is a humanized antibody. In one embodiment, the anti-IL-23A antibody is a monoclonal antibody. In one embodiment, the anti-IL-23A antibody is a full-length antibody. In one embodiment, the anti-IL-23A antibody is a humanized monoclonal antibody, e.g., a full-length humanized monoclonal antibody.

[0152] The antibodies described herein recognize a specific "IL-23A antigenic epitope" or "IL-23A epitope." As used herein, these terms refer to a molecule (e.g., a peptide) or a fragment of a molecule that is capable of immunoreacting with an anti-IL-23A antibody and that contains an IL-23A antigenic determinant recognized by any of the antibodies having, for example, the light chain / heavy chain sequence combinations of SEQ ID NOs: 11 / 14, 11 / 15, 10 / 14, or 10 / 15.

[0153] The general structure of an antibody or immunoglobulin is well known to those skilled in the art. These molecules are heterotetrameric glycoproteins, typically of about 150,000 daltons, composed of two identical light chains (L) and two identical heavy chains (H), which are typically referred to as full-length antibodies. Each light chain is covalently linked to a heavy chain by one disulfide bond to form a heterodimer, and the heterotetrameric molecule is formed through covalent disulfide bonds between the two identical heavy chains of the heterodimer. The light and heavy chains are linked to each other by one disulfide bond, while the number of disulfide bonds between the two heavy chains varies depending on the immunoglobulin isotype. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain contains a variable domain (V) at the amino terminus. H), followed by three or four constant domains (C H1 , C H2 , C H3 and C H4 ), and a hinge region between CH1 and CH2. Each light chain contains an amino-terminal variable domain (V L ) and the carboxy-terminal constant domain (C L ) has two domains. L The domain is non-covalently linked to V H domain, whereas C L The domain is generally C H1 The light chain variable domain and the heavy chain variable domain are covalently linked to each other via disulfide bonds. Certain amino acid residues are believed to form an interface between the light chain variable domain and the heavy chain variable domain (Chothia et al., 1985, J. Mol. Biol. 186:651-663). The variable domain is also referred to herein as the variable region.

[0154] Certain domains within the variable domains vary widely among different antibodies, i.e., are "hypervariable". These hypervariable domains contain the residues that are directly involved in the binding and specificity of each particular antibody to its specific antigenic determinant. The hypervariability in both the light and heavy variable domains is concentrated in three segments known as complementarity determining regions (CDRs) or hypervariable loops (HVLs). The CDRs are described in Kabat et al., 1991, In: Sequences of Proteins of Immunological Interest, 5 thThe light chain variable domain is defined by sequence comparison according to the Ed. Public Health Service, National Institutes of Health, Bethesda, Md., whereas the HVL (also referred to herein as CDR) is structurally defined according to the three-dimensional structure of the variable domain as described in Chothia and Lesk, 1987, J. Mol. Biol. 196: 901-917. The identification of the CDRs in these two methods is slightly different. As defined by Kabat, CDR-L1 is located at approximately 24-34 residues in the light chain variable domain, CDR-L2 is located at approximately 50-56 residues, and CDR-L3 is located at approximately 89-97 residues; CDR-H1 is located at approximately 31-35 residues in the heavy chain variable domain, CDR-H2 is located at approximately 50-65 residues, and CDR-H3 is located at approximately 95-102 residues. The exact residue numbers encompassing a particular CDR will vary depending on the sequence and size of the CDR. One of skill in the art can routinely determine which residues comprise a particular CDR, given the amino acid sequence of the variable region of an antibody. Thus, the CDR1, CDR2, and CDR3 of the heavy and light chains define the unique and functional properties specific to a given antibody.

[0155] The three CDRs in each of the heavy and light chains are separated by framework regions (FRs), which contain sequences that tend to be less variable. From the amino terminus to the carboxy terminus of the heavy and light chain variable domains, the FRs and CDRs are arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The predominantly β-sheet conformation of the FRs brings the CDRs in each chain into close proximity with each other and with the CDRs of the other chain. The resulting conformation contributes to the antigen-binding site (see Kabat et al., 1991, NIH Publ. No. 91-3242, Vol. I, pages 647-669), although not all CDR residues are directly involved in binding to the antigen.

[0156] FR residues and Ig constant domains are not directly involved in antigen binding, but contribute to antigen binding and / or mediate antibody effector functions. Some FR residues are thought to have a significant effect on antigen binding in at least three ways: by directly binding non-covalently to the epitope, by interacting with one or more CDR residues, and by affecting the interface between the heavy and light chains. The constant domains are not directly involved in antigen binding, but mediate various Ig effector functions, such as antibody participation in antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP).

[0157] The light chains of vertebrate immunoglobulins are assigned to one of two clearly distinct classes, kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domains. In contrast, the heavy chains of mammalian immunoglobulins are assigned to one of five major classes according to the sequence of their constant domains: IgA, IgD, IgE, IgG, and IgM. IgG and IgA are further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the various classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of the classes of native immunoglobulins are well known.

[0158] The terms "antibody," "anti-IL-23A antibody," "anti-IL-23p19 antibody," "humanized anti-IL-23A antibody," "humanized anti-IL-23p19 antibody," "humanized anti-IL-23A epitope antibody," "humanized anti-IL-2319 epitope antibody," "mutated humanized anti-IL-23A epitope antibody," and "mutated humanized anti-IL-23p19 epitope antibody" specifically encompass monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and antibody fragments, such as variable domains and other portions of antibodies, that exhibit the desired biological activity, e.g., binding to IL-23A. The term "monoclonal antibody" (mAb) refers to an antibody that is highly specific and directed against a single antigenic determinant or "epitope." Thus, the modifier "monoclonal" refers to antibodies that are directed against the same epitope and is not to be construed as requiring production of the antibody by any particular method. It should be understood that the monoclonal antibodies may be made by any technique or method known in the art, including, for example, the hybridoma method (Kohler et al., 1975, Nature 256:495) or recombinant DNA methods known in the art (see, e.g., U.S. Pat. No. 4,816,567), or isolation of recombinantly produced monoclonal antibodies using phage antibody libraries using the techniques described in Clackson et al., 1991, Nature 352: 624-628, and Marks et al., 1991, J. Mol. Biol. 222: 581-597.

[0159] The term "monomeric" refers to an antibody of homogeneous form, e.g., for a full-length antibody, monomer means a monomeric antibody having two identical heavy chains and two identical light chains.

[0160] A chimeric antibody consists of the variable regions of the heavy and light chains of an antibody from one species (e.g., a non-human mammal, e.g., a mouse) and the constant regions of the heavy and light chains of an antibody from another species (e.g., a human), and can be obtained by linking a DNA sequence encoding the variable region of an antibody from a first species (e.g., a mouse) to a DNA sequence of the constant region of an antibody from a second species (e.g., a human) and transforming a host with an expression vector containing the linked sequences to enable it to produce the chimeric antibody. Alternatively, a chimeric antibody can also be one in which one or more regions or domains of the heavy and / or light chains are identical to, homologous to, or variants of corresponding sequences in a monoclonal antibody from another immunoglobulin class or isotype, or from a consensus or germline sequence. A chimeric antibody can also include fragments of such antibodies. However, the antibody fragment retains the desired biological activity of the parent antibody, e.g., binding to the same epitope (see, e.g., U.S. Pat. No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81: 6851-6855).

[0161] The terms "antibody fragment", "anti-IL-23A antibody fragment", "anti-IL-23A epitope antibody fragment", "humanized anti-IL-23A antibody fragment", "humanized anti-IL-23A epitope antibody fragment", "mutated humanized anti-IL-23A epitope antibody fragment" refer to a portion of a full-length anti-IL-23A antibody, which retains the variable region or functional capability, e.g., binding to a specific IL-23A epitope. Examples of antibody fragments include Fab, Fab', F(ab')2, Fd, Fv, scFv, and scFv-Fc fragments.

[0162] Useful antibody fragments can be generated by treating full-length antibodies with enzymes such as papain or pepsin. Papain digestion is used to generate two identical antigen-binding antibody fragments, called "Fab" fragments (each with one antigen-binding site), and a residual "Fc" fragment. The Fab fragment also contains the constant domains of the light chain and the C domain of the heavy chain. H1 Treatment with pepsin yields an F(ab')2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen.

[0163] Fab' fragments are H1 They differ from Fab fragments by the presence of additional residues at the C-terminus of the domain, including one or more cysteines from the antibody hinge region. F(ab')2 antibody fragments are pairs of Fab' fragments linked by cysteine ​​residues in the hinge region. Other chemical linkages of antibody fragments are also known.

[0164] An "Fv" fragment contains a complete antigen recognition and binding site consisting of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association. In this configuration, the three CDRs of each variable domain interact to form the V H -V L Together, the six CDRs define an antigen-binding site on the surface of the dimer and confer antigen-binding specificity to the antibody.

[0165] "Single-chain Fv" or "scFv" antibody fragments are fragments of the V H Domain and V L and a single chain Fv variant comprising a V domain, wherein the domains are present in a single polypeptide chain. The single chain Fv is capable of recognizing and binding to an antigen. The scFv polypeptide also optionally comprises a V H Domain and V LThey may contain a polypeptide linker located between the domains, which promotes the formation of the desired three-dimensional structure for binding of the scFv to the antigen (see, e.g., Pluckthun, 1994, In The Pharmacology of monoclonal Antibodies, Vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315).

[0166] A "humanized antibody" or "humanized antibody fragment" is a special type of chimeric antibody that can bind to a predetermined antigen and includes an immunoglobulin amino acid sequence variant or fragment thereof that includes one or more FRs that have substantially the amino acid sequence of a human immunoglobulin and one or more CDRs that have substantially the amino acid sequence of a non-human immunoglobulin. This non-human amino acid sequence, often referred to as an "import" sequence, is typically taken from an "import" antibody domain, particularly the variable domain. In general, a humanized antibody includes at least the CDRs or HVLs of a non-human antibody inserted between the FRs of a human heavy or light chain variable domain. The present invention describes certain humanized anti-IL-23A antibodies that contain CDRs derived from a mouse monoclonal antibody or humanized CDRs shown in Tables 1 and 2 inserted between the FRs of the heavy and light chain variable domains of human germline sequences. It will be appreciated that certain murine FR residues may be important for the function of the humanized antibody and therefore certain human germline sequence heavy and light chain variable domain residues will be altered to be identical to the corresponding murine sequences.

[0167] In another embodiment, the humanized anti-IL-23A antibody comprises substantially all of at least one, typically two, variable domains (e.g., as contained in Fab, Fab', F(ab')2, Fabc, and Fv fragments), in which all or substantially all of the CDRs correspond to the CDRs of a non-human immunoglobulin, specifically, in this specification, all of the CDRs are murine or humanized sequences as detailed in Tables 1 and 2 herein below, and all or substantially all of the FRs are human immunoglobulin consensus or germline sequence FRs. In another embodiment, the humanized anti-IL-23A antibody also comprises at least a portion of an immunoglobulin Fc region, typically that of a human immunoglobulin. Usually, the antibody will contain both light chains, as well as at least the variable domains of the heavy chain. The antibody may also optionally comprise the C of the heavy chain. H1 Area, hinge area, C H2 area, C H3 Area and / or C H4 It may include one or more of the regions.

[0168] The humanized anti-IL-23A antibody may be selected from any class of immunoglobulin, including IgM, IgG, IgD, IgA, and IgE, and any isotype, including IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. For example, the constant domain may be a constant domain that binds complement, in which case it is desired that the humanized antibody exhibit cytotoxic activity, and the isotype is typically IgG1. If such cytotoxic activity is not desired, the constant domain may be another isotype, for example IgG2. Alternative humanized anti-IL-23A antibodies may contain sequences from more than one immunoglobulin class or isotype, and it is within the skill of the art to select a particular constant domain to optimize the desired effector function. In a specific embodiment, the invention provides an antibody that is an IgG1 antibody, more particularly an IgG1 antibody in which the effector function has been knocked out.

[0169] The FR and CDR or HVL of the humanized anti-IL-23A antibody need not correspond exactly to the parent sequence. For example, one or more residues in the import CDR or HVL or the FR sequence of the consensus or germline sequence may be modified (e.g., mutagenized) by substitution, insertion, or deletion, so that the resulting amino acid residue is no longer identical to the original residue at the corresponding position of either parent sequence, but the antibody nevertheless retains the function of binding to IL-23A. Such modifications will typically not be extensive, but conservative modifications. Usually, at least 75%, more frequently at least 90%, and most frequently more than 95%, or more than 98%, or more than 99% of the humanized antibody residues will correspond to the residues of the FR and import CDR sequences of the parent consensus or germline sequence.

[0170] The interface between the heavy and light chain variable regions ("V L -V H Immunoglobulin residues that affect the "interface" are those that affect the proximity or orientation of the two chains with respect to each other. Specific residues that may be involved in interchain interactions include the V L Residues 34, 36, 38, 44, 46, 87, 89, 91, 96 and 98, and V H These include residues 35, 37, 39, 45, 47, 91, 93, 95, 100, and 103 (using the numbering system set out in Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987)). U.S. Patent No. 6,407,213 also discloses that V L Residues 43 and 85, and V H Residues such as residues 43 and 60 are also considered to be potentially involved in this interaction. Although these residues are shown only for human IgG, they are applicable across species. Key antibody residues that are reasonably expected to be involved in interchain interactions are selected for substitution in the consensus sequence.

[0171] The terms "consensus sequence" and "consensus antibody" refer to an amino acid sequence that includes the most frequently occurring amino acid residue at each position in all immunoglobulins of any particular class, isotype, or subunit structure, such as human immunoglobulin variable domains. A consensus sequence may be based on immunoglobulins of a particular species or of many species. A "consensus" sequence, structure, or antibody is understood to include a consensus human sequence as described in certain embodiments, and refers to an amino acid sequence that includes the most frequently occurring amino acid residue at each position in all human immunoglobulins of any particular class, isotype, or subunit structure. Thus, a consensus sequence contains an amino acid sequence that has an amino acid at each position that is present in one or more known immunoglobulins, but may not exactly duplicate the complete amino acid sequence of any single immunoglobulin. The consensus sequence of the variable region is not derived from any naturally occurring antibody or immunoglobulin (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.) and variants thereof. The FRs of the heavy and light chain consensus sequences, and variants thereof, provide useful sequences for the preparation of humanized anti-IL-23p19 antibodies, see, e.g., U.S. Patent Nos. 6,037,454 and 6,054,297.

[0172] Human germline sequences are naturally found in the human population. The combination of such germline genes generates antibody diversity. Germline antibody sequences for antibody light chains are derived from conserved human germline kappa or lambda v-genes and j-genes. Similarly, heavy chain sequences are derived from germline v-, d-, and j-genes (LeFranc, MP, and LeFranc, G, "The Immunoglobulin Facts Book" Academic Press, 2001).

[0173] As used herein, "variant," "anti-IL-23A variant," "humanized anti-IL-23A variant," or "variant humanized anti-IL-23A" each refer to a humanized anti-IL-23A antibody having at least one light chain variable mouse CDR derived from any of the sequences as shown in Table 1, or one heavy chain mouse CDR sequence derived from a mouse monoclonal antibody as shown in Table 2. Variants include variants with one or more amino acid changes in the variable domains of one or both light or heavy chains, provided that the amino acid changes do not substantially impair binding of the antibody to IL-23A. Exemplary antibodies generated herein include those designated as Antibody A, Antibody B, Antibody C, and Antibody D, whose various light and heavy chains are shown in SEQ ID NOs: 18 and 21, and SEQ ID NOs: 19 and 20, respectively.

[0174] An "isolated" antibody is one that has been identified and separated and / or recovered from a component of its natural environment. Contaminant components of the antibody's natural environment are materials that may interfere with diagnostic or therapeutic uses of the antibody, such as enzymes, hormones, or other proteinaceous or nonproteinaceous solutes. In one embodiment, the antibody will be isolated and purified to at least 95% by weight of the antibody.

[0175] Isolated antibody includes the antibody in situ within a recombinant cell in which it is produced, since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step in which recombinant cellular material is removed.

[0176] The term "antibody performance" refers to factors that contribute to the recognition of an antigen by an antibody or the in vivo efficacy of an antibody. Changes in the amino acid sequence of an antibody can affect antibody properties such as folding and the initial rate of binding of the antibody to the antigen (k a ), the dissociation constant of the antibody from the antigen (k d ), the affinity constant of the antibody for the antigen (K d), can affect physical factors such as antibody conformation, protein stability, and antibody half-life.

[0177] As used herein, the term "epitope tagged" refers to an anti-IL-23A antibody fused to an "epitope tag." An "epitope tag" is a polypeptide having a sufficient number of amino acids to provide an epitope for antibody production, but designed so that it does not interfere with the desired activity of the anti-IL-23A antibody. The epitope tag is usually sufficiently unique so that antibodies raised against the epitope tag do not substantially cross-react with other epitopes. Suitable tag polypeptides generally contain at least six amino acid residues, and usually contain about 8-50 amino acid residues, or about 9-30 residues. Examples of epitope tags and antibodies that bind to the epitope include the flu HA tag polypeptide and its antibody 12CA5 (Field et al., 1988 Mol. Cell. Biol. 8: 2159-2165); the c-myc tag and its 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies (Evan et al., 1985, Mol. Cell. Biol. 5(12):3610-3616); and the herpes simplex virus glycoprotein D (gD) tag and its antibodies (Paborsky et al. 1990, Protein Engineering 3(6): 547-553). In certain embodiments, the epitope tag is a "salvage receptor-binding epitope." As used herein, the term "salvage receptor-binding epitope" refers to an epitope in the Fc region of an IgG molecule (e.g., IgG1, IgG2, IgG3, or IgG4) that is responsible for extending the serum half-life of the IgG molecule in vivo.

[0178] For diagnostic and therapeutic monitoring purposes, the antibodies of the present invention may also be conjugated to a label, either alone or with an additional second agent (prodrug, chemotherapeutic agent, etc.). A label, as distinguished from other second agents, refers to a substance that is a detectable compound or composition, which may be directly or indirectly conjugated to the humanized antibody of the present invention. The label may be detectable itself (e.g., a radioisotope label or a fluorescent label) or, in the case of an enzymatic label, may catalyze a chemical alteration of a substrate compound or composition that is detectable. Labeled anti-IL-23A antibodies can be prepared and used for a variety of applications, including in vitro and in vivo diagnosis.

[0179] In various embodiments of the present invention, one or more domains of the antibody will be recombinantly expressed. Such recombinant expression may use one or more control sequences, i.e., polynucleotide sequences required for the expression of an operably linked coding sequence in a particular host organism. Control sequences suitable for use in prokaryotic cells include, for example, promoter, operator, and ribosome binding site sequences. Control sequences for eukaryotic cells include, but are not limited to, promoters, polyadenylation signals, and enhancers. These control sequences may be used for the expression and production of anti-IL-23A antibodies in prokaryotic and eukaryotic host cells.

[0180] A nucleic acid sequence is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, a nucleic acid presequence or secretory leader is operably linked to a nucleic acid encoding a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, "operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers are optionally contiguous. Linking can be accomplished by ligation at convenient restriction enzyme sites. If such sites do not exist, synthetic oligonucleotide adaptors or linkers may be used.

[0181] As used herein, the expressions "cell," "cell line," and "cell culture" are used synonymously and all such designations include the progeny thereof. Thus, "transformants" and "transformed cells" include the primary subject cell and cultures derived therefrom without regard for the number of transfers.

[0182] The term "mammal" for purposes of treatment refers to any animal classified as a mammal, including humans, domesticated and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal is a human.

[0183] As used herein, a "disorder" is any condition that would benefit from treatment with an anti-IL-23A antibody described herein, including chronic and acute disorders or diseases, such as medical conditions that predispose a mammal to the disorder in question.

[0184] As used herein, the term "IL-23-associated disorder" or "IL-23-associated disease" refers to conditions in which IL-23 activity is a cause of the disease and typically IL-23 is abnormally expressed. IL-23-associated disorders include diseases and disorders of the immune system, such as autoimmune disorders and inflammatory disorders. Such conditions include psoriasis, inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, and spondyloarthritis, such as ankylosing spondylitis, non-radiographic axial spondyloarthritis, peripheral spondyloarthritis, or psoriatic arthritis.

[0185] The term "intravenous infusion" refers to the introduction of a drug into a vein of an animal or human patient over a period of more than about 15 minutes, generally from about 30 to 90 minutes.

[0186] The term "intravenous bolus" or "intravenous push" refers to the administration of a drug into a vein of an animal or human such that the organism receives the drug within about 15 minutes, typically within 5 minutes.

[0187] The term "subcutaneous administration" refers to the introduction of an agent by relatively slow and sustained delivery from a drug reservoir under the skin of an animal or human patient, preferably into a pocket between the skin and the underlying tissue. The pocket can be created by pinching the skin or by pulling the skin up and away from the underlying tissue.

[0188] The term "subcutaneous infusion" refers to the introduction of a drug under the skin of an animal or human patient, preferably into a pocket between the skin and the underlying tissue, by relatively slow and sustained delivery from a drug reservoir, over a period of time, including but not limited to, 30 minutes or less, or 90 minutes or less. Optionally, the infusion can be performed by subcutaneous implantation of a drug delivery pump implanted under the skin of the animal or human patient, where the pump delivers a predetermined amount of drug over a predetermined period of time, for example, 30 minutes, 90 minutes, or over the length of the treatment regimen.

[0189] The term "subcutaneous bolus" refers to administration of a drug under the skin of an animal or human patient, where the bolus drug delivery is within about 15 minutes; in another embodiment, within 5 minutes, and in yet another embodiment, within 60 seconds. In still yet another embodiment, administration is within a pocket between the skin and the underlying tissue, where the pocket can be created by pinching or pulling the skin up and away from the underlying tissue.

[0190] The term "therapeutically effective amount" is used to refer to an amount of an active agent that relieves or ameliorates one or more symptoms of the disorder being treated. In another embodiment, a therapeutically effective amount refers to a serum concentration of a target that has been shown to be effective in slowing the progression of the disease. Efficacy can be measured by conventional methods, depending on the condition to be treated.

[0191] As used herein, the terms "treatment" and "therapy" and the like are meant to include therapeutic measures as well as preventive or suppressive measures for a disease or disorder that produce any clinically desirable or beneficial effect, including, but not limited to, alleviation or mitigation of one or more symptoms, regression, slowing, or cessation of a disease or disorder. Thus, for example, the term treatment includes administration of an agent before or after the onset of a disease or disorder symptom, thereby preventing or eliminating one or more signs of a disease or disorder. As another example, the term includes combating a disease symptom by administering an agent after clinical signs of the disease. In addition, administration of an agent after onset and after clinical signs have occurred (where administration affects a clinical parameter of a disease or disorder, such as the degree of tissue damage, or the amount or extent of metastasis, regardless of whether the treatment results in disease remission) includes "treatment" or "therapy" as used herein. Furthermore, so long as a composition of the invention, alone or in combination with another therapeutic agent, reduces or ameliorates at least one symptom of the disorder being treated compared to the symptom in the absence of the anti-IL-23A antibody composition, the result should be deemed to be an effective treatment of the underlying disorder, regardless of whether all symptoms of the disorder are alleviated.

[0192] The term "package insert" is used to refer to instructions customarily included in the commercial packaging of therapeutic products that contain information regarding the indications, uses, administration, contraindications, and / or warnings concerning the use of such therapeutic products.

[0193] antibody The CDRs of selected antibodies used in the context of the present invention are shown in Tables 1 and 2. The variable regions of selected antibodies used in the context of the present invention are shown in Tables 3 and 4.

[0194] [Table 2]

[0195] [Table 3]

[0196] [Table 4]

[0197] [Table 5]

[0198] Selected combinations of humanized light and heavy chain variable regions derived from murine antibody 6B8 resulted in antibodies A, B, C and D: Antibody A: 6B8-IgG1KO-2 with IgK-66 (heavy chain variable region 6B8CVH-02 and light chain variable region 6B8CVK-66); Antibody B; 6B8-IgG1KO-5 with IgK-66 (heavy chain variable region 6B8CVH-05 and light chain variable region 6B8CVK-66); Antibody C: 6B8-IgG1KO-2 with IgK-65 (heavy chain variable region 6B8CVH-02 and light chain variable region 6B8CVK-65); Antibody D: 6B8-IgG1KO-5 with IgK-65 (heavy chain variable region 6B8CVH-05 and light chain variable region 6B8CVK-65).

[0199] Antibodies A, B, C and D have the heavy and light chain sequences shown in Table 5.

[0200] [Table 6] TIFF2025060797000010.tif238168

[0201] The light and heavy chain variable regions of antibodies A, B, C and D in Table 5 above are underlined.

[0202] In one embodiment, the anti-IL-23A antibody comprises the light chain sequence of SEQ ID NO: 18 and the heavy chain sequence of SEQ ID NO: 19. In one embodiment, the anti-IL-23A antibody comprises the light chain sequence of SEQ ID NO: 18 and the heavy chain sequence of SEQ ID NO: 20. In one embodiment, the anti-IL-23A antibody comprises the light chain sequence of SEQ ID NO: 21 and the heavy chain sequence of SEQ ID NO: 19. In one embodiment, the anti-IL-23A antibody comprises the light chain sequence of SEQ ID NO: 21 and the heavy chain sequence of SEQ ID NO: 20.

[0203] In one embodiment, the anti-IL-23A antibody consists of the light chain sequence of SEQ ID NO: 18 and the heavy chain sequence of SEQ ID NO: 19. In one embodiment, the anti-IL-23A antibody consists of the light chain sequence of SEQ ID NO: 18 and the heavy chain sequence of SEQ ID NO: 20. In one embodiment, the anti-IL-23A antibody consists of the light chain sequence of SEQ ID NO: 21 and the heavy chain sequence of SEQ ID NO: 19. In one embodiment, the anti-IL-23A antibody consists of the light chain sequence of SEQ ID NO: 21 and the heavy chain sequence of SEQ ID NO: 20.

[0204] In a further embodiment, the anti-IL-23A antibody binds to human IL-23A at an epitope consisting of amino acid residues 108-126 and amino acid residues 137-151 of SEQ ID NO:22.

[0205] In a further embodiment, the anti-IL-23A antibody binds to human IL-23A competitively with an antibody of the invention, e.g., Antibody A, Antibody B, Antibody C, or Antibody D described herein. The competitive binding ability of an antibody to IL-23A can be measured using competitive binding assays known in the art.

[0206] In some embodiments, the anti-IL-23A antibody comprises a light chain variable region sequence having the amino acid sequence set forth in SEQ ID NO: 10, 11, 12 or 13. In some embodiments, the anti-IL-23A antibody comprises a heavy chain variable region sequence having the amino acid sequence set forth in SEQ ID NO: 14, 15, 16 or 17 (see Tables 3 and 4 above). The CDR sequences of these antibodies are shown in Tables 1 and 2. For example, the anti-IL-23A antibody is a monoclonal antibody having the combination of light chain variable region and heavy chain variable region of SEQ ID NO: 11 / 14, 11 / 15, 10 / 14 or 10 / 15. Such variable regions may be combined with human constant regions.

[0207] Polynucleotides, Vectors, Host Cells, and Recombinant Methods Other embodiments include isolated polynucleotides comprising sequences encoding anti-IL-23A antibodies, vectors, and host cells comprising the polynucleotides, as well as recombinant techniques for the production of humanized antibodies. The isolated polynucleotides can encode any desired form of anti-IL-23A antibody, including, for example, full-length monoclonal antibodies, Fab, Fab', F(ab')2, and Fv fragments.

[0208] The polynucleotide(s) containing the sequence encoding the anti-IL-23A antibody can be fused to one or more regulatory or control sequences as known in the art and can be contained in a suitable expression vector or host cell as known in the art. Each polynucleotide molecule encoding a heavy or light chain variable domain can be independently fused to a polynucleotide sequence encoding a constant domain, such as a human constant domain, allowing for the production of an intact antibody. Alternatively, the polynucleotides or portions thereof can be fused to each other, providing a template for the production of a single chain antibody.

[0209] For recombinant production, a polynucleotide encoding the antibody is inserted into a replicable vector for cloning (amplification of the DNA) or expression. Many suitable vectors are available for expressing recombinant antibodies. The vector components generally include one or more of the following, but are not limited to: a signal sequence, an origin of replication, one or more marker genes, an enhancer sequence, a promoter, and a transcription termination sequence.

[0210] Anti-IL-23A antibodies may also be produced as fusion polypeptides, in which the antibodies are fused to a heterologous polypeptide, such as a signal sequence, or other polypeptide that has a specific cleavage site at the amino terminus of the mature protein or polypeptide. The heterologous signal sequence selected is typically one that is recognized and processed (i.e., cleaved by a signal peptidase) by the host cell. In prokaryotic host cells that do not recognize and process the anti-IL-23A antibody signal sequence, the signal sequence may be replaced by a prokaryotic signal sequence. The signal sequence may be, for example, an alkaline phosphatase, penicillinase, lipoprotein, heat-stable enterotoxin II leader, or the like. For secretion in yeast, the native signal sequence may be substituted with leader sequences derived, for example, from yeast invertase alpha-factor (including the Saccharomyces and Kluyveromyces alpha-factor leaders), acid phosphatase, C. albicans glucoamylase, or the signals described in WO 90 / 13646. In mammalian cells, mammalian signal sequences may be used as well as viral secretory leaders, such as the herpes simplex gD signal. DNA for such a precursor region is ligated in reading frame to DNA encoding the anti-IL-23A antibody.

[0211] Expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Generally, in cloning vectors, this sequence enables the vector to replicate independently of the host chromosomal DNA and includes an origin of replication or autonomously replicating sequences. Such sequences are well known for a variety of bacteria, yeast, and viruses. The origin of replication from the plasmid pBR322 is suitable for most gram-negative bacteria, the 2-ν. plasmid origin is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV, and BPV) are useful for cloning vectors in mammalian cells. Generally, the origin of replication component is not needed for mammalian expression vectors (the SV40 origin may typically be used because it contains the early promoter).

[0212] Expression and cloning vectors may contain genes encoding selectable markers to facilitate identification of expression. Typical selectable marker genes are those encoding proteins that confer resistance to antibiotics or other toxins, such as ampicillin, neomycin, methotrexate, or tetracycline, or alternatively complementary auxotrophic deficiencies, or in other alternatives, genes encoding proteins that supply specific nutrients not present in complex media, such as D-alanine racemase for Bacillus.

[0213] One example of a selection scheme utilizes drugs to stop the growth of host cells. Cells successfully transformed with a heterologous gene produce a protein that confers drug resistance and thus survive the selection regime. Examples of such dominant selection use the drugs neomycin, mycophenolic acid, and hygromycin. Common selection markers for mammalian cells are those that allow the identification of cells that are capable of incorporating nucleic acid encoding an anti-IL-23A antibody, such as DHFR (dihydrofolate reductase), thymidine kinase, metallothionein-I and -II (e.g., primate metallothionein genes), adenosine deaminase, ornithine decarboxylase, etc. Cells transformed with the DHFR selection gene are first identified by culturing all transformants in a culture medium containing methotrexate (Mtx), a competitive antagonist of DHFR. An appropriate host cell when wild-type DHFR is used is a Chinese hamster ovary (CHO) cell line deficient in DHFR activity (eg DG44).

[0214] Alternatively, host cells transformed or co-transformed with an anti-IL-23A antibody, a wild-type DHFR protein, and a DNA sequence encoding another selectable marker, such as an aminoglycoside 3'-phosphotransferase (APH), (particularly wild-type hosts containing endogenous DHFR), can be selected by growing the cells in medium containing a selection agent for the selectable marker, such as an aminoglycoside antibiotic, such as kanamycin, neomycin, or G418. See, e.g., U.S. Patent No. 4,965,199.

[0215] When recombinant production is carried out in yeast cells as host cells, the TRP1 gene present in the yeast plasmid YRp7 (Stinchcomb et al., 1979, Nature 282: 39) can be used as a selection marker. The TRP1 gene provides a selection marker for mutant strains of yeast lacking the ability to grow in tryptophan, such as ATCC No. 44076 or PEP4-1 (Jones, 1977, Genetics 85:12). Thus, the presence of the trp1 lesion in the yeast host cell genome provides an effective environment for detecting transformation by growth in the absence of tryptophan. Similarly, Leu2p-deficient yeast strains, such as ATCC 20,622 and 38,626, are complemented by known plasmids carrying the LEU2 gene.

[0216] Furthermore, vectors derived from the 1.6 μm circular plasmid pKD1 can be used for transformation of Kluyveromyces yeast. Alternatively, an expression system for large-scale production of recombinant calf chymosin was reported in K. lactis (Van den Berg, 1990, Bio / Technology 8:135). A stable multicopy expression vector for secretion of mature recombinant human serum albumin by industrial strains of Kluyveromyces has also been disclosed (Fleer et al., 1991, Bio / Technology 9:968-975).

[0217] Expression and cloning vectors usually contain a promoter that is recognized by the host organism and is operably linked to the nucleic acid molecule encoding the anti-IL-23p19 antibody or its polypeptide chain. Suitable promoters for use with prokaryotic hosts include the phoA promoter, β-lactamase and lactose promoter systems, alkaline phosphatase, tryptophan (trp) promoter system, and hybrid promoters such as the tac promoter. Other known bacterial promoters are also suitable. Promoters for use in bacterial systems will also contain a Shine-Dalgarno (SD) sequence operably linked to the DNA encoding the anti-IL-23A antibody.

[0218] Many eukaryotic promoter sequences are known. Virtually all eukaryotic genes have an AT-rich region located approximately 25-30 bases upstream from the site where transcription is initiated. Another sequence found 70-80 bases upstream from the start of transcription of many genes is a CNCAAT region, where N can be any nucleotide. At the 3' end of most eukaryotic genes is an AATAAA sequence that may be a signal for addition of a poly A tail to the 3' end of the coding sequence. All of these sequences are appropriately inserted into eukaryotic expression vectors.

[0219] Examples of promoter sequences suitable for use with yeast hosts include the promoters of 3-phosphoglycerate kinase or other glycolytic enzymes, such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase.

[0220] Inducible promoters have the added advantage of transcription being controlled by growth conditions. These include yeast promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, inducible enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes involved in maltose and galactose utilization. Vectors and promoters suitable for use in expression in yeast are further described in EP 73,657. Yeast enhancers are also advantageously used with yeast promoters.

[0221] Transcription of the anti-IL-23A antibody from the vector in mammalian host cells is controlled by promoters derived from the genomes of viruses such as polyoma virus, cockscomb virus, adenovirus (e.g., adenovirus type 2), bovine papilloma virus, simian sarcoma virus, cytomegalovirus, retroviruses, hepatitis B virus, and simian virus 40 (SV40), from heterologous mammalian promoters such as the actin promoter or immunoglobulin promoter, or from a heat shock promoter, provided that such promoters are compatible with the host cell system.

[0222] The early and late promoters of the SV40 virus are conveniently obtained as an SV40 restriction fragment which also contains the SV40 viral origin of replication. The immediate early promoter of the human cytomegalovirus is conveniently obtained as a HindIII E restriction fragment. A system for expressing DNA in mammalian hosts using the bovine papilloma virus as a vector is disclosed in U.S. Pat. No. 4,419,446. A modification of this system is described in U.S. Pat. No. 4,601,978. See also Reyes et al., 1982, Nature 297:598-601, which discloses expression of human p-interferon cDNA in mouse cells under the control of a thymidine kinase promoter from herpes simplex virus. Alternatively, the Rous sarcoma virus long terminal repeat may be used as a promoter.

[0223] Another useful sequence that can be used in a recombinant expression vector is an enhancer sequence, which is used to increase the transcription of DNA encoding an anti-IL-23A antibody by higher eukaryotes. Many enhancer sequences are now known from mammalian genes (e.g., globin, elastase, albumin, α-fetoprotein, and insulin). Typically, however, enhancers from eukaryotic cell viruses are used. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. See also Yaniv, 1982, Nature 297:17-18 for a description of enhancer sequences for the activation of eukaryotic promoters. The enhancer can be spliced ​​into the vector at a 5' or 3' position of the anti-IL-23A antibody-encoding sequence, but is preferably located at a site 5' to the promoter.

[0224] Expression vectors used in eukaryotic host cells (yeast, fungi, insects, plants, animals, humans, or nucleated cells from other multicellular organisms) may also contain sequences required for transcription termination and for stabilizing the mRNA. Such sequences are generally available from the 5' and sometimes 3' untranslated regions of eukaryotic or viral DNA or cDNA. These regions contain nucleotide segments that are transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding the anti-IL-23A antibody. One useful transcription termination component is the bovine growth hormone polyadenylation region. See WO 94 / 11026 and the expression vectors disclosed therein. In some embodiments, humanized anti-IL-23p19 antibodies may be expressed using the CHEF system (see, e.g., U.S. Pat. No. 5,888,809; the disclosure of which is incorporated herein by reference).

[0225] Suitable host cells for cloning or expressing the DNA in the vector herein are the above-mentioned prokaryotic cells, yeast cells, or higher eukaryotic cells. Suitable prokaryotic cells for this purpose include eubacteria, such as gram-negative or gram-positive bacteria, such as Enterobacteriaceae, such as Escherichia coli, such as E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, such as Salmonella typhimurium, Serratia, such as Serratia marcescans, and Shigella, as well as bacilli, such as Bacillus subtilis and Bacillus licheniformis (e.g., B. licheniformis 41P, disclosed in DD 266,710 published April 12, 1989), Pseudomonas, such as Pseudomonas aeruginosa, and Streptomyces. One preferred E. coli cloning host is E. coli 294 (ATCC 31,446), although other strains such as E. coli B, E. coli X1776 (ATCC 31,537), and E. coli W3110 (ATCC 27,325) are also suitable. These examples are illustrative rather than limiting.

[0226] In addition to prokaryotes, eukaryotic microbes, such as filamentous fungi or yeast, are suitable cloning or expression hosts for anti-IL-23A antibody-encoding vectors. Saccharomyces cerevisiae, or common baker's yeast, is the most commonly used among lower eukaryotic host microorganisms. However, many other genera, species, and strains are commonly available and useful herein, such as Schizosaccharomyces pombe; Kluyveromyces hosts, such as K. lactis, K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906), K. thermotolerans, and K. marxianus (ATCC 36,906). marxianus; Yarrowia (EP 402,226); Pichia pastors (EP 183,070); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa; Schwanniomyces, such as Schwanniomyces occidentalis; and filamentous fungi, such as Neurospora, Penicillium, Tolypocladium, and Aspergillus hosts, such as A. nidulans and A. niger.

[0227] Suitable host cells for the expression of glycosylated anti-IL-23A antibodies are obtained from multicellular organisms. Examples of invertebrate cells include plant cells and insect cells, such as numerous baculovirus strains and mutants, as well as corresponding permissive insect host cells from hosts such as Spodoptera frugiperda (caterpillar), Aedes aegypti (mosquito), Aedes albopictus (mosquito), Drosophila melanogaster (fruit fly), and Bombyx mori (silkworm). Various virus strains for transfection are publicly available, such as the L-1 mutant of Autographa californica NPV and the Bm-5 strain of Bombyx mori NPV, and such viruses may be used, in particular, for transfection of Spodoptera frugiperda cells.

[0228] Plant cell cultures of cotton, corn, potato, soybean, petunia, tomato, and tobacco can also be used as hosts.

[0229] In another embodiment, expression of anti-IL-23A is in vertebrate cells. Propagation of vertebrate cells in culture (tissue culture) has become a routine procedure and the techniques are widely available. Examples of useful mammalian host cell lines are the SV40 transformed monkey kidney CV1 line (COS-7, ATCC CRL 1651), human embryonic kidney lines (293 or 293 cells subcloned for growth in suspension culture), (Graham et al., 1977, J. Gen Virol. 36: 59), baby hamster kidney cells (BHK, ATCC CCL10), Chinese hamster ovary cells / -DHFR1 (CHO, Urlaub et al., 1980, Proc. Natl. Acad. Sci. USA 77: 4216; e.g., DG44), mouse Sertoli cells (TM4, Mather, 1980, Biol. Reprod. 23:243-251), monkey kidney cells (CV1 ATCC CCL 70), African green monkey kidney cells (VERO-76, ATCC CRL-1587), human cervical carcinoma cells (HELA, ATCC CCL 2), canine kidney cells (MDCK, ATCC CCL 34), buffalo rat liver cells (BRL 3A, ATCC CRL 1442), human lung cells (W138, ATCC CCL 75), human liver cells (HepG2, HB8065), mouse mammary tumor (MMT 060562, ATCC CCL 51), TR1 cells (Mather et al., 1982, Annals NY Acad. Sci. 383: 44-68), MRC5 cells, FS4 cells, and a human hepatoma line (HepG2).

[0230] Host cells are transformed with the above-described expression vectors or cloning vectors for producing anti-IL-23A antibodies and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying genes encoding the desired sequences.

[0231] The host cells used to produce the anti-IL-23A antibodies described herein may be cultured in a variety of media. Commercially available media, such as Ham's F10 (Sigma-Aldrich Co., St. Louis, MO), Minimum Essential Medium (MEM), (Sigma-Aldrich Co.), RPMI-1640 (Sigma-Aldrich Co.), and Dulbecco's Modified Eagle's Medium (DMEM), Sigma-Aldrich Co., are suitable for culturing the host cells. In addition, media such as those described in Ham et al., 1979, Meth. Enz. 58: 44, Barnes et al., 1980, Anal. Biochem. 102: Any of the media described in one or more of U.S. Pat. Nos. 255, 4,767,704, 4,657,866, 4,927,762, 4,560,655, 5,122,469, WO 90 / 103430, and WO 87 / 00195 may be used as a culture medium for the host cells. Any of these media may contain, if necessary, hormones and / or other growth factors (e.g., insulin, transferrin, or epidermal growth factor), salts (e.g., sodium chloride), etc. The culture medium may be supplemented with nutrients such as calcium, magnesium, and phosphates, buffers (e.g., HEPES), nucleotides (e.g., adenosine and thymidine), antibiotics (e.g., gentamicin), trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Other supplementary substances may also be included at appropriate concentrations that would be known to one of skill in the art. Culture conditions, such as temperature, pH, etc., will be those previously used with the host cell selected for expression and will be apparent to one of skill in the art.

[0232] When using recombinant techniques, antibodies may be produced intracellularly in the periplasmic space or directly secreted into the medium. If the antibody is produced intracellularly, the cells may be disrupted to release the protein as a first step. Particulate debris, either host cells or lysed fragments, can be removed, for example, by centrifugation or ultrafiltration. Carter et al., 1992, Bio / Technology 10:163-167, describes a procedure for isolating antibodies secreted into the periplasmic space of E. coli.

[0233] Briefly, cell paste is thawed in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonyl fluoride (PMSF) for approximately 30 minutes. Cell debris can be removed by centrifugation. If the antibody is secreted into the medium, the supernatant from such expression systems is generally first concentrated using a commercially available protein concentration filter, such as an Amicon or Millipore Pellicon ultrafiltration device. Protease inhibitors such as PMSF can be included in any of the above steps to inhibit protein degradation, and antibiotics can be included to prevent the growth of adventitious contaminants. A variety of methods can be used to isolate the antibody from the host cells.

[0234] The antibody composition prepared from the cells can be purified using, for example, hydroxyapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being a typical purification technique. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain present in the antibody. Protein A can be used to purify antibodies based on human gamma 1, gamma 2, or gamma 4 heavy chains (see, e.g., Lindmark et al., 1983 J. Immunol. Meth. 62:1-13). Protein G is recommended for all mouse isotypes and human gamma 3 (see, e.g., Guss et al., 1986 EMBO J. 5:1567-1575). The matrix to which the affinity ligand is attached is most often agarose, although other matrices are available. Mechanically stable matrices such as controlled pore glass or poly(styrenedivinyl)benzene allow for faster flow rates and shorter processing times than can be achieved with agarose. H3 If the antibody contains a nucleotide sequence similar to that of the nucleotide sequence ...

[0235] After any preliminary purification step(s), the mixture containing the antibody of interest and contaminants may be subjected to hydrophobic interaction chromatography at low pH, typically performed with a low salt concentration (e.g., about 0-0.25 M salt) and using an elution buffer of about pH 2.5-4.5.

[0236] therapeutic use In another embodiment, the anti-IL-23A antibodies disclosed herein are useful for treating various disorders associated with expression of IL-23p19 as described herein. In one aspect, a method for treating an IL-23-associated disorder comprises administering a therapeutically effective amount of an anti-IL-23A antibody to a subject in need thereof.

[0237] The anti-IL-23A antibody is administered by any suitable means, including parenterally, subcutaneously, intraperitoneally, intrapulmonary, and intranasally, as well as intralesional administration (including perfusing or otherwise contacting the graft with the antibody prior to transplantation) if localized immunosuppressive treatment is desired. The anti-IL-23A antibody or agent may be administered, for example, as an infusion or as a bolus. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Additionally, the anti-IL-23A antibody is suitably administered by pulse infusion, particularly with tapering doses of the antibody. In one embodiment, dosing is by injection, most preferably intravenous or subcutaneous injection, depending in part on whether administration is brief or chronic. In one embodiment, administration of the anti-IL-23 antibody is by subcutaneous injection.

[0238] For the prevention or treatment of disease, the appropriate dosage of antibody will depend on a variety of factors, such as the type of disease being treated as defined above, the severity and history of the disease, whether the antibody is being administered for prophylactic or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician. The antibody is suitably administered to the patient at one time or over a series of treatments.

[0239] The term "suppression" is used interchangeably herein with "amelioration" and "relief" and refers to a decrease in one or more characteristics of a disease.

[0240] The antibody will be formulated, measured, and administered in a manner consistent with good medical practice. Factors to consider in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the dosing schedule, and other factors known to medical practitioners. The "therapeutically effective amount" of the antibody to be administered will be governed by such considerations.

[0241] The antibody may optionally be formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of anti-IL-23A antibody present in the formulation, the type of disorder or treatment, and other factors discussed above.

[0242] IL-23-Related Disorders Anti-IL-23p19 antibodies or agents are useful for treating or preventing immunological disorders characterized by aberrant expression of IL-23, e.g., by inappropriate activation of immune cells (e.g., lymphocytes or dendritic cells). Such aberrant expression of IL-23 can result, for example, from elevated IL-23 protein levels.

[0243] Immunological disorders characterized by inappropriate activation of immune cells and treatable or preventable by the methods described herein can be classified, for example, by the type(s) of hypersensitivity reaction(s) underlying the disorder. These reactions are typically classified into four types: anaphylactic reactions, cytotoxic (cytolytic) reactions, immune complex reactions, or cell-mediated immunity (CMI) reactions (also called delayed-type hypersensitivity (DTH) reactions). (See, for example, Fundamental Immunology (William E. Paul ed., Raven Press, NY, 3rd ed. 1993). Immunological disorders include inflammatory and autoimmune disorders.

[0244] Examples of immunological diseases include: psoriasis, inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, and spondyloarthritis, such as ankylosing arthritis, non-radiographic axial spondyloarthritis, peripheral spondyloarthritis, or psoriatic arthritis.

[0245] In one embodiment, in the context of the present invention, the immunological disease is psoriasis.Psoriasis is a chronic inflammatory disease of the skin, characterized by dysfunctional keratinocyte differentiation and hyperproliferation, and significant accumulation of inflammatory T cells and dendritic cells.For example, the immunological disease includes psoriasis vulgaris, such as chronic plaque psoriasis, such as moderate to severe chronic plaque psoriasis, in patients who are candidates for systemic therapy or phototherapy.In one embodiment, the immunological disease is moderate to severe plaque psoriasis, and the patient is one who has not responded to, or is contraindicated to, or intolerant to other systemic therapies, including cyclosporine, methotrexate, psoralen, or long-wave ultraviolet light (psoralen long-wave ultraviolet light therapy).

[0246] For example, immunological disorders include palmar pustular psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, or erythodermic psoriasis (also called psoriatic erythroderma).

[0247] For psoriasis, disease severity can be characterized by the body surface area (BSA) affected, with less than 5% considered mild, 5-10% considered moderate, and more than 10% considered severe. In some cases, disease status is measured using the Psoriasis Area and Severity Index (PASI), a composite measure of erythema, induration, scaling, and BSA affected by psoriasis, with scores ranging from 0 to 72. In one embodiment, the PASI score at a particular time point (e.g., at 12 or 16 weeks) is 75 (PASI 75), i.e., the proportion of patients achieving a 75% reduction in score from baseline, is used as a primary endpoint in psoriasis treatments, e.g., psoriasis treatment trials. In one embodiment, the PASI score at a particular time point (e.g., at 12 or 16 weeks) is 90(PASI 90), the proportion of patients achieving a 90% reduction in score from baseline, is used as a primary endpoint in psoriasis treatments, eg, psoriasis treatment trials.

[0248] In one embodiment, PASI is performed at 12 weeks according to the methods of the present invention, e.g., using Antibody A. 90 The proportion of patients achieving this is at least 60%, at least 65%, or at least 70%.

[0249] In one embodiment, the proportion of patients achieving a sPGA score of clear (score 0) or almost clear (score 1) at a particular time point (e.g., week 12 or 16) is used as a primary endpoint in a psoriasis treatment, e.g., a psoriasis treatment trial.

[0250] In one embodiment, patients treated within the context of the present invention are patients with stable moderate to severe chronic plaque psoriasis, with or without psoriatic arthritis affecting 10% or more of the body surface area, with a disease severity PASI of 12 or above, and / or with an sPGA score of moderate and above (score of at least 3). In one embodiment, patients treated within the context of the present invention are patients with a duration of psoriatic disease of at least 6 months prior to the start of treatment.

[0251] In one embodiment, in the context of the present invention, the immunological disease is psoriatic arthritis.In psoriatic arthritis, patients have psoriatic skin lesions or a history of psoriasis, combined with nail dysplasia, inflammation of the fingers (dactylitis), and characteristic radiographic findings (ill-defined ossification near the joint margins), and serum tests for rheumatoid factor are negative.The efficacy of treating psoriatic arthritis in clinical examinations is frequently measured using the proportion of patients who achieve the American College of Rheumatology (ACR) comprehensive efficacy scale, which has been used prominently in rheumatoid arthritis trials.ACR20 indicates at least a 20% improvement in swollen joint count and tender joint count, and a 20% improvement in 3 out of 5 ACR core set scales, when comparing baseline with some time point after the start of treatment, such as 24 weeks.

[0252] In one embodiment, ACR20 response rate (20% improvement in American College of Rheumatology response criteria), for example at 24 weeks, is used as a primary endpoint in treatment of psoriatic arthritis, eg, in psoriatic arthritis treatment trials.

[0253] In one embodiment, the immunological disease is psoriatic arthritis, e.g., active psoriatic arthritis, and the anti-IL-23A antibody is used, for example, alone or in combination with one or more non-biologic DMARDs (disease-modifying antirheumatic drugs) to reduce signs and symptoms. In one embodiment, the anti-IL-23A antibody is used or indicated to inhibit progression of structural damage and / or improve physical function.

[0254] In one embodiment, anti-IL-23A antibodies are used to treat psoriatic arthritis, e.g., active psoriatic arthritis, alone or in combination with methotrexate (MTX), e.g., when there has been an inadequate response to prior non-biologic DMARD therapy. In one embodiment, anti-IL-23A antibodies are used to reduce the rate of progression of peripheral joint damage as measured by x-ray and / or to improve physical function.

[0255] In one embodiment, within the context of the present invention, the immunological disease is axial (spinal) spondyloarthritis (ax-SpA) (including ankylosing spondylitis (AS, also called radiographic ax-SpA) and non-radiographic ax-SpA).

[0256] In one embodiment, in the context of the present invention, the immunological disease is ankylosing spondylitis. Ankylosing spondylitis (AS) is an inflammatory disease that mainly affects the axial skeleton and sacroiliac joints. Other musculoskeletal manifestations of the disease include peripheral arthritis and enthesitis. Extra-articular diseases include anterior uveitis, osteoporosis, cardiac disease mainly affecting the valves, renal disease, pulmonary disease, gastrointestinal disease, and skin disease. AS is more prevalent in men, with a male-female ratio of 3:1. The peak age of onset is typically in the 20s or 30s. The estimated prevalence of AS worldwide ranges from about 0.5% to 0.07%. AS patients appear to lose their physical functions and ability to work, which can have a significant impact on quality of life if appropriate treatment is not administered to the patient.

[0257] In ankylosing spondylitis, patients suffer from inflammatory back pain, asymmetric peripheral arthritis, inflammation of the tendons (enthesitis), and extra-articular manifestations such as uveitis, and there is a strong genetic association with human leukocyte antigen B27. In one embodiment, the Ankylosing Spondylitis Disease Activity Score 40 (ASDAS40) response rate, e.g., at week 24, is used as a primary endpoint in ankylosing spondylitis treatment, e.g., ankylosing spondylitis treatment trials.

[0258] In one embodiment, in the context of the present invention, the immunological disease is non-radiographic axial spondyloarthritis (ax-SpA). A more recently defined entity than AS, non-radiographic axial spondyloarthritis is believed to demonstrate an earlier manifestation of the same pathological process as AS, although it is increasingly recognized that some patients, particularly women, may not progress to radiographic disease and may therefore be considered to represent a distinct subtype of the disease.

[0259] Pharmaceutical Compositions and Their Administration Compositions comprising anti-IL-23A antibodies can be administered to subjects with or at risk of having immunological disorders. As used herein, the term "subject" refers to any mammalian patient to which anti-IL-23A antibodies can be administered, including humans and non-human mammals, such as primates, rodents, and dogs. Subjects specifically intended for treatment using the methods described herein include humans. The antibodies can be administered either alone or in combination with other compositions in the prevention or treatment of immunological disorders.

[0260] Described herein are anti-IL-23A antibodies, such as Antibody A, Antibody B, Antibody C, or Antibody D, for use in such pharmaceutical compositions.

[0261] Various delivery systems are known and can be used to administer anti-IL-23A antibodies. Introduction methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. Anti-IL-23A antibodies can be administered, for example, by infusion, bolus, or injection, and can be administered together with other biologically active agents, for example, chemotherapeutic agents. Administration can be systemic or local. In one embodiment, administration is by subcutaneous injection. Such formulations for injection can be prepared, for example, in prefilled syringes that can be administered once every two weeks.

[0262] In specific embodiments, the anti-IL-23A antibody is administered by injection, using a catheter, using a suppository, or using an implant, which is a porous, non-porous, or gelatinous material (including membranes such as silastic membranes), or a fiber. Typically, a material is used that the anti-IL-23A antibody or agent does not absorb when administering the composition.

[0263] In other embodiments, the anti-IL-23A antibody is delivered in a sustained release system. In one embodiment, a pump can be used (see, e.g., Langer, 1990, Science 249:1527-1533; Sefton, 1989, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321:574). In another embodiment, a polymeric material can be used. (See, e.g., Medical Applications of Controlled Release (Langer and Wise eds., CRC Press, Boca Raton, Fla., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., Wiley, New York, 1984); Ranger and Peppas, 1983, Macromol. Sci. Rev. Macromol. Chem. 23:61. See also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105.) Other sustained release systems are discussed, e.g., in Langer, supra.

[0264] Anti-IL-23p19 antibodies are typically administered as pharmaceutical compositions comprising a therapeutically effective amount of the antibody and one or more pharma- ceutically compatible ingredients.

[0265] In a typical embodiment, the pharmaceutical composition is formulated according to conventional procedures as a pharmaceutical composition adapted for intravenous or subcutaneous administration to humans. Typically, compositions for administration by injection are solutions in sterile isotonic aqueous buffer. If necessary, the medicament can also contain a solubilizing agent and a local anesthetic, such as lignocaine, to ease pain at the injection site. Generally, the ingredients are supplied in a sealed container, such as an ampoule or sachet, indicating the amount of active substance, either separately or mixed together in a unit dosage form, for example as a lyophilized powder or water-free concentrate. If the medicament is to be administered by injection, it can be dispensed using an infusion bottle containing sterile pharmaceutical grade water or saline. If the medicament is to be administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0266] Further, the pharmaceutical composition may be provided as a pharmaceutical kit comprising (a) a container containing the anti-IL-23A antibody in lyophilized form, and (b) a second container containing a pharma- ceutically acceptable diluent for injection (e.g., sterile water). The pharma- ceutically acceptable diluent may be used for reconstitution or dilution of the lyophilized anti-IL-23A antibody. Optionally associated with such container(s) may be a notice in the form prescribed by a governmental authority regulating the manufacture, use, or sale of pharmaceuticals or biological products, which notice reflects approval by the authority of the manufacture, use, or sale for administration to humans.

[0267] An example of a pharmaceutical composition for use in the context of the present invention is disclosed in Example 4 herein below.

[0268] The present invention is further described in the following examples, which do not limit the scope of the invention.

[0269] Working Example Example 1: Clinical Trials The results shown in Examples 1a, 1b, and 1c are derived from the same clinical trial.

[0270] Example 1a: Testing This study evaluated the efficacy and safety of Antibody A versus ustekinumab in patients with moderate-to-severe plaque psoriasis.

[0271] 166 patients were randomly assigned to one of three dose regimens of antibody A (18 mg single injection; 90 or 180 mg at weeks 0 and 4) or ustekinumab (45 or 90 mg). PASI (Psoriasis Area and Severity Index), sPGA (Static Physician Global Assessment) and safety parameters were assessed. The primary endpoint was achievement of PASI 90 at week 12 (achieving ≥90% reduction from baseline PASI score) and the primary analysis will compare the two highest doses of antibody A (pooled) with ustekinumab.

[0272] Primary analysis showed that Antibody A was superior to ustekinumab (PASI 90 response rate of 77.1% for Antibody A vs. 40% for ustekinumab [p<0.0001]). An sPGA score of 0 (clear) or 1 (almost clear) was achieved by 90.4% of Antibody A patients vs. 67.5% of ustekinumab patients. Complete disease clearance (PASI 100) was achieved in 45.8% of Antibody A patients and 17.5% of ustekinumab patients. AEs were similar between treatment groups, with no drug-related severe or serious AEs.

[0273] Selective blockade of IL-23p19 with Antibody A is associated with superior clinical responses to ustekinumab in patients with moderate to severe plaque psoriasis.

[0274] Example 1b: Testing Objective: To evaluate the efficacy and safety of Antibody A, a selective IL-23p19 antagonist monoclonal antibody, in patients with moderate to severe plaque psoriasis, with and without concomitant psoriatic arthritis (PsA), and compare it with ustekinumab.

[0275] Methods: In this phase 2 study, 166 patients were randomly assigned (1:1:1:1 ratio) to receive subcutaneous injections of antibody A (18 mg single dose at week 0; 90 or 180 mg at weeks 0, 4, and 16) or ustekinumab (45 or 90 mg at weeks 0, 4, and 16) in one of three dose regimens. Skin lesions were assessed using the Psoriasis Area and Severity Index (PASI) at week 12 with a primary endpoint of PASI 90 (90% improvement from baseline). In patients with concomitant psoriatic arthritis (either diagnosed or suspected by a rheumatologist), pain was assessed at baseline and at weeks 4, 12, and 24 using a visual analog scale (Pain-VAS). In this interim analysis, all patients completed the week 12 visit; data beyond week 12 are incomplete.

[0276] RESULTS:The primary endpoint of PASI 90 response rate at week 12 was achieved by 32.6% (14 / 43), 73.2% (30 / 41), and 81.0% (34 / 42) of antibody A patients in the 18, 90, and 180 mg groups, respectively, and by 40.0% (16 / 40) of ustekinumab patients. Two-sided Cochran-Mantel-Haenszel tests of PASI 90 response rates at week 12 between antibody A and ustekinumab in the 18, 90, and 180 mg groups gave p-values ​​of 0.4337, 0.0013, and <0.0001, respectively. Of the 166 patients, 46 (27.7%) had concurrent psoriatic arthritis. The median percent reduction from baseline in pain-VAS at week 12 was 31.9%, 70.2%, and 58.4% in antibody A patients in the 18, 90, and 180 mg dose groups, respectively, compared to 57.3% in ustekinumab-treated patients. A >50% reduction in pain-VAS (defined post hoc) at week 12 was achieved in 29% (2 / 7), 73% (8 / 11), and 50% (6 / 12) of antibody A patients in the 18, 90, and 180 mg dose groups, respectively, compared to 54% (7 / 13) of ustekinumab-treated patients. Figure 1 demonstrates that reductions in pain-VAS scores were observed as early as week 4 and were maintained through 24 weeks (incomplete data). Adverse events (AEs) were similar between treatment groups, with no drug-related severe or serious AEs.

[0277] Conclusions: Selective blockade of IL-23p19 with antibody A is associated with superior clinical responses to skin lesions compared with ustekinumab in patients with moderate-to-severe plaque psoriasis. Improvements in pain-VAS scores over ustekinumab were also observed in patients with psoriatic arthritis.

[0278] PASI 50, PASI 75 and PASI 100 response rates at Week 12 were also determined in the above study. They showed that the proportion of patients achieving PASI 50 was 93%, 95%, and 100% of Antibody A patients in the 18, 90 and 180 mg groups, respectively, and 87% of ustekinumab patients at Week 12. Achievement of PASI 50 over time is shown in Figure 2.

[0279] They also showed the proportion of patients achieving PASI 75: 76%, 90%, and 98% of antibody A patients in the 18, 90, and 180 mg groups, respectively, and 68% of ustekinumab patients at week 12. Achievement of PASI 75 over time is shown in Figure 3.

[0280] They also showed the proportion of patients who achieved PASI 100: 18%, 41%, and 49% of antibody A patients in the 18, 90, and 180 mg groups, respectively, and 15% of ustekinumab patients at week 12. Achievement of PASI 100 over time is shown in Figure 5 . Achievement of PASI 90 over time is shown in Figure 4 .

[0281] Example 1c: Testing This study evaluated the incidence and duration of clinical response following treatment with a selective IL-23p19 inhibitor (Antibody A) compared with ustekinumab in patients with moderate to severe chronic plaque psoriasis.

[0282] Materials and Methods: In this multicenter, randomized, double-blind (within antibody A dose group) Phase II study, 166 patients with moderate-to-severe chronic plaque psoriasis were assigned to receive subcutaneous injections of either antibody A (single injection of 18 mg; 90 or 180 mg at weeks 0, 4, and 16) or ustekinumab (45 or 90 mg based on weight at weeks 0, 4, and 16). PASI was assessed at weeks 0, 1, 2, 4, 6, and 8, and then every 4 weeks for a total of 48 weeks. Safety was assessed at every visit by recording adverse events (AEs).

[0283] RESULTS: At week 24, PASI 90 was achieved by 66% (27 / 41) and 86% (36 / 42) of patients in the 90 mg and 180 mg antibody A groups, respectively, compared with 55% (22 / 40) of patients receiving ustekinumab. Complete clearance of disease (PASI 100) was achieved in 41% (17 / 41) and 57% (24 / 42) of patients in the 90 and 180 mg antibody A groups, respectively, compared with 28% of patients receiving ustekinumab. The time to PASI 90 was approximately 2-fold faster in patients in the 90 and 180 mg Antibody A arms compared with the ustekinumab arm (median days to PASI 90=57 days [both Antibody A dose groups; ~8 weeks] vs. 113 days [~16 weeks], respectively, p=0.0016 [90 mg] and p<0.0001 [180 mg]). Patients in the 90 and 180 mg Antibody A arms who achieved PASI 90 maintained their response longer than patients receiving ustekinumab (days to 50% of patients experiencing first decrease in PASI 90=337 days [both Antibody A dose groups; ~48 weeks] vs. 253 days [~36 weeks], respectively). AEs were similar between treatment arms, and no dose-response relationship was observed for any AE. Seven patients reported serious AEs (4 in the 18 mg Antibody A group, 2 in the 90 mg Antibody A group, and 1 in the ustekinumab group); all were deemed unrelated to study drug.

[0284] The same study showed that Antibody A developed a rapid response, with 69% and 66% of patients (180 mg and 90 mg, respectively) achieving PASI 50 by week 4, compared with 45% of ustekinumab patients. By week 8, 83% and 80% of Antibody A patients (180 mg and 90 mg, respectively) achieved PASI 75, compared with 60% of ustekinumab patients. By week 12, the proportion of patients achieving PASI 90 (the primary endpoint) was 81% and 73% for the 180 mg and 90 mg Antibody A arms, compared with 40% for ustekinumab. Body weight had little effect on efficacy for Antibody A. At week 20, 90% and 76% of antibody A patients (180 mg and 90 mg, respectively) achieved PASI 90, compared with 55% with ustekinumab; 62% and 51% of antibody A patients showed complete clearance of lesions (PASI 100), compared with 25% with ustekinumab. Clinical responses were maintained at high levels beyond week 36 in the 180 mg and 90 mg antibody A dose groups. In patients with psoriatic arthritis, greater reductions in pain were observed with antibody A (180 mg and 90 mg, pooled) compared with ustekinumab (68% vs. 57%) at week 12. In patients with psoriatic arthritis, pain was assessed by visual analog scale and expressed as median percent change from baseline.

[0285] Conclusions: Selective blockade of IL-23 with Antibody A demonstrates superior potency, more rapid onset, and longer duration of response compared to blockade of IL-12 and IL-23 with ustekinumab.

[0286] In the same study, the Dermatology Quality of Life Index (DLQI) and EuroQol-5D (EQ-5D) were completed at weeks 0, 12, 24, and 48. The median percent change from baseline in DLQI total score (analyzed descriptively by van Elteren test) was compared with ustekinumab at weeks 12 and 24. The proportion of patients achieving a DLQI score of 0 or 1 was also evaluated. The EQ-5D index score was analyzed descriptively. Pooled antibody A results for the 90 mg and 180 mg groups are reported. At baseline, the median DLQI score for patients randomized to antibody A was 13.0 compared to 16.0 for patients randomized to ustekinumab. The mean EQ-5D index score was 0.7 in both treatment groups. At week 12, the median improvement in DLQI score was higher in patients receiving Antibody A than in patients receiving ustekinumab (100% vs. 90.6%, respectively; p=0.0304). At week 24, the proportion of patients with a DLQI score of 0 or 1 was 80% for Antibody A patients versus 61% for ustekinumab patients. At week 12, Antibody A patients were observed to show a greater than 50% improvement in the mean EQ-5D score compared to ustekinumab patients (0.3 vs. 0.2, respectively). This was maintained at week 24.

[0287] Selective blockade of IL-23 with Antibody A demonstrates superior efficacy and provides significantly improved quality of life outcomes compared with ustekinumab in patients with moderate-to-severe plaque psoriasis.

[0288] In the same study, the efficacy of Antibody A was evaluated for the treatment of scalp psoriasis, palmoplantar psoriasis, and nail psoriasis.

[0289] The Scalp Psoriasis Severity Index (PSSI) and Palmoplantar Psoriasis Area and Severity Index (PPASI) were used to assess scalp and palmoplantar psoriasis, respectively. The Nail Psoriasis Severity Index (NAPSI) was assessed on the hands only. Assessments were performed at baseline and (in patients who had symptoms at baseline) at weeks 1, 2, 4, 6, 8, 12, and every 4 weeks up to week 48. Patients described as having no signs or symptoms were assigned a total score of zero at that visit. Median improvement rates from baseline for Antibody A (90 mg and 180 mg, pooled) were compared to those for ustekinumab.

[0290] 154 (92.8%) patients had scalp psoriasis, 42 (25.3%) patients had palmoplantar psoriasis, and 96 (57.8%) patients had nail psoriasis. Scalp and palmoplantar disease responded rapidly; by week 2, patients treated with Antibody A showed a 50% and 51% improvement from baseline in PSSI and PPASI, compared with 37% and 30% in patients treated with ustekinumab. By week 6, patients in both the Antibody A and ustekinumab groups showed complete clearance of scalp psoriasis, which was maintained throughout the study. For PPASI, complete clearance was seen at week 6 for Antibody A and at week 16 for ustekinumab, which was maintained throughout the study. Nail disease resolved more slowly, with Antibody A showing a 30% improvement in NAPSI at week 6, compared with 0% for ustekinumab. By week 12, NAPSI improvements for Antibody A and ustekinumab were 41% and 36%, respectively, and by week 24, NAPSI improvements were 61% and 67%, respectively.

[0291] Selective blockade of IL-23 with Antibody A demonstrated promising efficacy in the treatment of scalp, palmoplantar, and nail psoriasis, and suggests that more rapid improvement may be achieved with Antibody A compared to ustekinumab.

[0292] Example 2: Efficacy assessment ANTIBODY A is administered to patients at doses and dosage regimens described herein. Efficacy of ANTIBODY A is assessed by one or more of the following endpoints, which are determined using known methods. Endpoints are measured, for example, at one or more of weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, or 104 after administration, or as indicated below.

[0293] psoriasis: Achieving a 90% or greater reduction in PASI score from baseline at week 12 (e.g., PASI 90 ). Achieving a 75% or greater reduction in PASI score from baseline, e.g., at weeks 12 and 24 (PASI 75 ). Achieving a 100% reduction in PASI score from baseline, e.g., at week 12 (PASI 100 ). Achieving a 50% or greater reduction in PASI score from baseline at week 12 (e.g., PASI 50 ). For example, at 24 weeks, PASI 90 Achievement of. Achievement of sPGA of clear or almost clear, for example at week 12. Percent reduction in PASI from baseline, e.g. at week 12. ·PASI 50 Time to loss of response rate. This endpoint is calculated from the first treatment to the first <50% reduction in PASI score compared to baseline after a response is achieved.

[0294] Other evaluation items were: For example, PASI at weeks 4, 6, 8, 16, 20, 28, 32, 36, 40, 44, and 48 90 and PASI 75 Achievement of. For example, PASI at weeks 4, 6, 8, 16, 20, 24, 28, 32, 36, 40, 44, and 48 100 , PASI 50 Achievement of PASI and percentage reduction in PASI from baseline. Achievement of clearance or near clearance of sPGA at, for example, weeks 4, 6, 8, 16, 20, 24, 28, 32, 36, 40, 44, and 48. ·PASI 50 Time to occurrence of response rate (time from first treatment to first ≥50% decrease in PASI score compared to baseline). For example, percent change from baseline in NAPSI (Nail Psoriasis Severity Index), PSSI (Scalp Psoriasis Severity Index), and PPASI (Palmoplantar Psoriasis Area and Severity Index) at weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. For example, change from baseline in Patient Global Assessment Rating (PGAR) and Patient Assessment of Itch (PAI) at weeks 4, 12, 24, 36, and 48. - Change from baseline in Pain-VAS, e.g. at week 12 (in the subgroup of patients with psoriatic arthritis only). For example, change from baseline in Dermatology Quality of Life Index (DLQI) at weeks 4, 6, 8, 12, 16, 20, 24, and 48. Change from baseline in EQ-5D (EuroQOL questionnaire) VAS score (visual analogue scale) at, for example, 12 weeks. Change from baseline in EQ-5D index score, for example at week 12. The proportion of patients achieving a Dermatology Quality of Life Index (DLQI) score of 0 or 1, e.g. at week 12. - Change from baseline in psoriasis symptoms assessed using the total score on the Psoriasis Symptom Scale (PSS), for example at week 16. Achieving a total score of 0 on the PSS, for example at week 16.

[0295] Psoriatic arthritis (response assessed at one or more of the following weeks: e.g., weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 104): · The Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire, e.g. at weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. - 20% improvement in American College of Rheumatology response criteria (ACR20) at weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. · 50% and 70% improvement in American College of Rheumatology response criteria (ACR50 and ACR70). ·Clinical Disease Activity Index (CDAI). Disease Activity Score for 28 joints (DAS28). Dactylitis (swelling of all digits), assessed as present or absent for each digit, and the number affected among all 20 digits (ranging from 0 to 20 digits (fingers and toes)). Enthesitis (inflammation of the attachments of tendons and ligaments, assessed by the presence or absence of tenderness on the Leeds Enthesitis Index (LEI) at six sites). Individual ACR components, including number of tender or painful joints and number of swollen joints. Patient's global assessment of disease activity and joint pain. -Physician's global assessment of disease activity. · Health Assessment Questionnaire Disability Index (HAQ-DI) responses, Health Assessment Questionnaire Disability Index (HAQ-DI). · C-reactive protein levels. -Erythrocyte sedimentation rate. Patient-reported outcomes included the Bath Ankylosing Spondylitis Activity Index (BASDAI). Medical Outcomes Study 36-Item Short-Form Health Survey (2nd edition) (SF-36). Psoriasis symptoms chart. Modified total Sharp score (mTSS), e.g., at weeks 24, 52, and 104. · Tender joint count. · Number of swollen joints. -Patient assessment of pain. Patient assessment of disability. · Acute phase reactants (C-reactive protein or erythrocyte sedimentation rate). - Patient's overall assessment of the disease. A doctor's overall assessment of the disease. ·Minimum disease activity (MDA). · Composite Psoriasis Disease Activity Index (CPDAI). Percent change in Psoriasis Area and Severity Index (PASI) from baseline (PASI 75 / 90 / 100). ·Modified Nail Psoriasis Severity Index (mNAPSI). · Psoriatic Arthritis Quality of Life (PsAQOL). · Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). For example, Psoriatic Arthritis Magnetic Resonance Imaging Scoring System (PsAMRIS) at weeks 24, 52, and 104.

[0296] For ankylosing spondylitis and non-radiographic ax-SpA (e.g., response assessed at one or more of weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 104): - Inflammatory symptoms reported by the patient. · Acute phase reactants (erythrocyte sedimentation rate [ESR] or CRP). Bath Ankylosing Spondylitis Activity Index (BASDAI). Change in BASDAI score compared to baseline. Ankylosing Spondylitis Activity Score (ASDAS). Change in ASDAS score compared to baseline. Bath Ankylosing Spondylitis Functional Index (BASFI). Change in BASFI score compared to baseline. Bath Ankylosing Spondylitis Measurement Index (BASMI). Change in spinal mobility assessed by the BASMI score compared to baseline. Magnetic resonance imaging (MRI), for example at 24, 52 and 104 weeks. ·ASAS 40 response rate. ·ASAS 5 / 6 response rate. -ASAS partial remission criteria. ·ASAS 20 response rate. Change in peripheral joint counts (TJC and SJC) compared to baseline. - Change in Enthesitis Score (MASES) compared to baseline. - Change in Ankylosing Spondylitis Disease Activity Score (ASDAS) score compared to baseline. Time until it is no longer maintained. -Time to redness after treatment. Time until it is no longer maintained. · Ankylosing Spondylitis Quality of Life Scale (ASQoL).

[0297] Example 3: Pharmacokinetic endpoint(s) To determine the pharmacokinetic parameters of an anti-IL-23A antibody, such as Antibody A, the following parameters are assessed using methods known in the art: Maximum plasma concentration measured (C max ). Time from administration to maximum plasma concentration (t max ). Area under the plasma concentration-time curve (AUC) versus treatment time interval 0~t ). Area under the plasma concentration-time curve (AUC) for the time interval extrapolated from time 0 to infinity 0~∞ ). Terminal half-life (t 1 / 2 ). Population pharmacokinetics.

[0298] Example 4: Pharmaceutical Composition Examples of suitable formulations for the antibodies of the invention are shown below. The antibodies used in the following formulations are, for example, Antibody A, Antibody B, Antibody C, or Antibody D.

[0299] [Table 7]

[0300] The pH of formulation 1 is typically in the range of pH 6.0 to 7.0, for example pH 6.5. This formulation is particularly suitable for intravenous administration.

[0301] Molecular weights of excipients used (molecular weight in g / mol): disodium succinate hexahydrate = 270.14 g / mol; succinic acid = 118.09 g / mol; sodium chloride = 58.44 g / mol.

[0302] The osmolarity of the formulation is 300 + / - 30 mOsmol / kg as determined using an Osmomat 030 (Gonotec GmbH, Berlin, Germany). The density of the formulation at 20 °C is approximately 1.0089 g / cm as determined using a DMA 4500 (Anton Paar GmbH, Ostfildern-Scharnhausen, Germany) measuring device. 3 It is.

[0303] [Table 8]

[0304] The pH of formulation 2 is typically in the range of pH 5.5 to 6.5, for example pH 5.5 to 6.1, for example the pH is 5.8. This formulation is particularly suitable for subcutaneous administration.

[0305] Molecular weight of excipients used (molecular weight in g / mol): Molecular weight: Succinic acid (C4H6O4) = 118.09g / mol Molecular weight: disodium succinate hexahydrate (C4O4Na2H4×6H2O) = 270.14 g / mol Molecular weight: sorbitol = 182.17 g / mol Molecular weight: Polysorbate 20 = 1227.72 g / mol.

[0306] The osmolarity of the formulation is 300 + / - 30 mOsmol / kg as determined using an Osmomat 030 (Gonotec GmbH, Berlin, Germany). The density of the formulation at 20 °C is approximately 1.040 g / cm as determined using a DMA 4500 (Anton Paar GmbH, Ostfildern-Scharnhausen, Germany) measuring device. 3 It is.

[0307] [Table 9]

[0308] The pH of formulation 3 is typically in the range of pH 5.5 to 6.5, for example 5.5 to 6.1, for example the pH is 5.8. This formulation is particularly suitable for subcutaneous administration.

[0309] Molecular weight of excipients used (molecular weight in g / mol): Molecular weight: sorbitol = 182.17 g / mol Molecular weight: Polysorbate 20 = 1227.72 g / mol.

[0310] The osmolarity of the formulation is 300+ / -30 mOsmol / kg as determined using an Osmomat 030 (Gonotec GmbH, Berlin, Germany).

Claims

1. 1. A method for treating psoriasis or psoriatic arthritis comprising administering to a patient an anti-IL-23A antibody, the method comprising: a) administering to a patient an initial dose of said anti-IL-23A antibody; b) administering to the patient a first maintenance dose of said anti-IL-23A antibody 4 to 24 weeks, such as 4 to 12 weeks, such as 6 to 24 weeks, such as 6 to 12 weeks, after said initial dose; and c) administering at least one additional maintenance dose to the patient 4 to 24 weeks, such as 4 to 12 weeks, such as 6 to 24 weeks, such as 6 to 12 weeks, after said first maintenance dose. The method comprises:

2. The method comprises: a) administering to a patient an initial dose of said anti-IL-23A antibody; b) administering to the patient a first maintenance dose of the anti-IL-23A antibody 8 to 24 weeks, e.g., 8 to 12 weeks, after the initial dose is administered; and c) administering to the patient at least one additional maintenance dose 8 to 24 weeks, e.g., 8 to 12 weeks, after said first maintenance dose is administered. The method of claim 1 , comprising:

3. 10. The method of claim 1, wherein said first maintenance dose is administered to the patient 8, 12, 16, 20, or 24 weeks after said initial dose is administered.

4. 10. The method of claim 1, wherein said at least one additional maintenance dose is administered to the patient 8, 12, 16, 20, or 24 weeks after said first maintenance dose is administered.

5. 2. The method of claim 1, wherein said first maintenance dose is administered to the patient 8, 12, 16, 20, or 24 weeks after said initial dose is administered, and said at least one additional maintenance dose is administered to the patient 8, 12, 16, 20, or 24 weeks after said first maintenance dose is administered.

6. i. said first maintenance dose is administered to the patient 8 weeks after said initial dose is administered, and said at least one additional maintenance dose is administered to the patient 8 weeks after said first maintenance dose is administered; or ii. the first maintenance dose is administered to the patient 12 weeks after the initial dose is administered, and the at least one additional maintenance dose is administered to the patient 12 weeks after the first maintenance dose is administered; or iii. the first maintenance dose is administered to the patient 16 weeks after the initial dose is administered, and the at least one additional maintenance dose is administered to the patient 16 weeks after the first maintenance dose is administered; or iv. said first maintenance dose is administered to the patient 20 weeks after said initial dose is administered, and said at least one additional maintenance dose is administered to the patient 20 weeks after said first maintenance dose is administered; or v. said first maintenance dose is administered to the patient 24 weeks after said initial dose is administered, and said at least one additional maintenance dose is administered to the patient 24 weeks after said first maintenance dose is administered. The method of claim 1.

7. i. said first maintenance dose is administered to the patient four weeks after said initial dose is administered, and said at least one additional maintenance dose is administered to the patient four weeks after said first maintenance dose is administered; or ii. the first maintenance dose is administered to the patient 6 weeks after the initial dose is administered, and the at least one additional maintenance dose is administered to the patient 6 weeks after the first maintenance dose is administered; The method of claim 1.

8. The method of any one of claims 1 to 7, wherein said initial dose comprises 15 to 300 mg of said anti-IL-23A antibody.

9. The method of any one of claims 1 to 7, wherein said first maintenance dose and said at least one additional maintenance dose comprises 15 to 300 mg of said anti-IL-23A antibody.

10. The method of any one of claims 1 to 7, wherein said initial dose comprises 15 to 250 mg, such as 90 to 180 mg, of said anti-IL-23A antibody.

11. The method of any one of claims 1 to 7, wherein said first maintenance dose and said at least one additional maintenance dose comprises 15 to 250 mg, such as 90 to 180 mg, of said anti-IL-23A antibody.

12. 8. The method of any one of claims 1-7, wherein the initial dose comprises 70-90 mg, 80-100 mg, 90-110 mg, 100-120 mg, 110-130 mg, 120-140 mg, 130-150 mg, 140-160 mg, 150-170 mg, 160-180 mg, 170-190 mg, 180-200 mg, 190-210 mg, 200-220 mg, 210-230 mg, 220-240 mg, or 230-250 mg of the anti-IL-23A antibody.

13. 8. The method of any one of claims 1-7, wherein said first maintenance dose and said at least one additional maintenance dose comprises 70-90 mg, 80-100 mg, 90-110 mg, 100-120 mg, 110-130 mg, 120-140 mg, 130-150 mg, 140-160 mg, 150-170 mg, 160-180 mg, 170-190 mg, 180-200 mg, 190-210 mg, 200-220 mg, 210-230 mg, 220-240 mg, or 230-250 mg of said anti-IL-23A antibody.

14. 8. The method of any one of claims 1 to 7, wherein said initial dose comprises 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 mg of said anti-IL-23A antibody.

15. 8. The method of any one of claims 1 to 7, wherein said first maintenance dose and said at least one additional maintenance dose comprises 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 mg of said anti-IL-23A antibody.

16. 8. The method of any one of claims 1-7, wherein said initial dose, said first maintenance dose and said at least one additional maintenance dose comprise 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 mg of anti-IL-23A antibody.

17. 1. A method for treating psoriasis or psoriatic arthritis comprising administering to a patient an anti-IL-23A antibody, the method comprising: a) administering to a patient an initial dose of said anti-IL-23A antibody; b) administering to the patient a loading dose of said anti-IL-23A antibody 1-6 weeks after said initial dose is administered; c) administering to the patient a first maintenance dose of the anti-IL-23A antibody 6 to 24 weeks, e.g., 6 to 12 weeks, after the loading dose; and d) administering to the patient at least one additional maintenance dose 6 to 24 weeks, e.g., 6 to 12 weeks, after said first maintenance dose. The method comprises:

18. The method further comprising: a) administering to a patient an initial dose of said anti-IL-23A antibody; b) administering to the patient a loading dose of said anti-IL-23A antibody 1-6 weeks after said initial dose is administered; c) administering to the patient a first maintenance dose of the anti-IL-23A antibody 8 to 24 weeks, e.g., 8 to 12 weeks, after the loading dose; and d) administering to the patient at least one additional maintenance dose 8 to 24 weeks, e.g., 8 to 12 weeks, after said first maintenance dose is administered.

20. The method of claim 17, comprising:

19. 20. The method of claim 17, wherein the loading dose is administered to the patient 1, 2, 3, 4, 5, or 6 weeks after the initial dose is administered.

20. 20. The method of claim 17 or 19, wherein said first maintenance dose is administered to the patient 8, 12, 16, 20, or 24 weeks after said loading dose is administered.

21. 20. The method of claim 17 or 19, wherein said at least one additional maintenance dose is administered to the patient 8, 12, 16, 20, or 24 weeks after said first maintenance dose is administered.

22. 20. The method of claim 17 or 19, wherein said first maintenance dose is administered to the patient 8, 12, 16, 20, or 24 weeks after said initial dose is administered, and said at least one additional maintenance dose is administered to the patient 8, 12, 16, 20, or 24 weeks after said first maintenance dose is administered.

23. i. said first maintenance dose is administered to the patient 8 weeks after said initial dose is administered, and said at least one additional maintenance dose is administered to the patient 8 weeks after said first maintenance dose is administered; or ii. the first maintenance dose is administered to the patient 12 weeks after the initial dose is administered, and the at least one additional maintenance dose is administered to the patient 12 weeks after the first maintenance dose is administered; or iii. the first maintenance dose is administered to the patient 16 weeks after the initial dose is administered, and the at least one additional maintenance dose is administered to the patient 16 weeks after the first maintenance dose is administered; or iv. said first maintenance dose is administered to the patient 20 weeks after said initial dose is administered, and said at least one additional maintenance dose is administered to the patient 20 weeks after said first maintenance dose is administered; or v. said first maintenance dose is administered to the patient 24 weeks after said initial dose is administered, and said at least one additional maintenance dose is administered to the patient 24 weeks after said first maintenance dose is administered.

20. The method of claim 17 or 19.

24. i. the first maintenance dose is administered to the patient 6 weeks after the initial dose is administered, and the at least one additional maintenance dose is administered to the patient 6 weeks after the first maintenance dose is administered; 20. The method of claim 17 or 19.

25. The method of any one of claims 17 to 24, wherein said initial dose comprises 15 to 300 mg of said anti-IL-23A antibody.

26. The method of any one of claims 17 to 24, wherein said loading dose comprises 15 to 300 mg of said anti-IL-23A antibody.

27. The method of any one of claims 17 to 24, wherein said first maintenance dose and said at least one additional maintenance dose comprises 15 to 300 mg of said anti-IL-23A antibody.

28. The method of any one of claims 17 to 24, wherein said initial dose comprises 15 to 250 mg, such as 90 to 180 mg, of said anti-IL-23A antibody.

29. The method of any one of claims 17 to 24, wherein said loading dose comprises 15 to 250 mg, such as 90 to 180 mg, of said anti-IL-23A antibody.

30. The method of any one of claims 17 to 24, wherein said first maintenance dose and said at least one additional maintenance dose comprises 15 to 250 mg, such as 90 to 180 mg, of said anti-IL-23A antibody.

31. 25. The method of any one of claims 17-24, wherein the initial dose comprises 70-90 mg, 80-100 mg, 90-110 mg, 100-120 mg, 110-130 mg, 120-140 mg, 130-150 mg, 140-160 mg, 150-170 mg, 160-180 mg, 170-190 mg, 180-200 mg, 190-210 mg, 200-220 mg, 210-230 mg, 220-240 mg, or 230-250 mg of the anti-IL-23A antibody.

32. 25. The method of any one of claims 17-24, wherein the loading dose comprises 70-90 mg, 80-100 mg, 90-110 mg, 100-120 mg, 110-130 mg, 120-140 mg, 130-150 mg, 140-160 mg, 150-170 mg, 160-180 mg, 170-190 mg, 180-200 mg, 190-210 mg, 200-220 mg, 210-230 mg, 220-240 mg, or 230-250 mg of the anti-IL-23A antibody.

33. 25. The method of any one of claims 17-24, wherein said first maintenance dose and said at least one additional maintenance dose comprises 70-90 mg, 80-100 mg, 90-110 mg, 100-120 mg, 110-130 mg, 120-140 mg, 130-150 mg, 140-160 mg, 150-170 mg, 160-180 mg, 170-190 mg, 180-200 mg, 190-210 mg, 200-220 mg, 210-230 mg, 220-240 mg, or 230-250 mg of said anti-IL-23A antibody.

34. 25. The method of any one of claims 17 to 24, wherein said initial dose comprises 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 mg of said anti-IL-23A antibody.

35. 25. The method of any one of claims 17-24, wherein said first maintenance dose and said at least one additional maintenance dose comprises 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 mg of said anti-IL-23A antibody.

36. 25. The method of any one of claims 17-24, wherein said initial dose and said loading dose comprise 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 mg of said anti-IL-23A antibody.

37. 25. The method of any one of claims 17-24, wherein the initial dose, the loading dose, the first maintenance dose and the at least one additional maintenance dose comprise 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 mg of the anti-IL-23A antibody.

38. A method for treating psoriasis or psoriatic arthritis comprising administering to a patient between 15 and 300 mg of an anti-IL-23A antibody.

39. 39. The method of claim 38, comprising administering to the patient 15 to 250 mg, such as 90 to 180 mg, of an anti-IL-23A antibody.

40. 40. The method of claim 39, comprising administering to the patient 70-90 mg, 80-100 mg, 90-110 mg, 100-120 mg, 110-130 mg, 120-140 mg, 130-150 mg, 140-160 mg, 150-170 mg, 160-180 mg, 170-190 mg, 180-200 mg, 190-210 mg, 200-220 mg, 210-230 mg, 220-240 mg, or 230-250 mg of the anti-IL-23A antibody.

41. 31. The method of claim 30, comprising administering 18, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, or 250 mg of anti-IL-23A antibody to the patient.

42. The method of any one of claims 38 to 41, wherein the anti-IL-23A antibody is administered as an initial dose, a loading dose, or a maintenance dose.

43. The method of any one of claims 1 to 42, wherein said IL-23A antibody is antibody A, antibody B, antibody C, or antibody D.

44. The method of any one of claims 1 to 43, wherein said method is for treating moderate to severe chronic plaque psoriasis.

45. The method of any one of claims 1 to 44, wherein said anti-IL-23A antibody is administered by subcutaneous administration.

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