Methods of treating inflammatory diseases

Abstract

The present invention relates to methods of treating inflammatory diseases, including methods of treating IL-23 associated diseases, in particular inflammatory diseases such as psoriasis, psoriatic arthritis or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radiographic negative ax-SpA, using anti-IL-23A antibodies.

Description

[0001] This application is a divisional application of Chinese invention patent application filed on February 2, 2016, with Chinese application number 201680008402.3 and invention title "Method for Treating Inflammatory Diseases". Technical Field

[0002] This invention generally relates to methods for treating inflammatory diseases using anti-IL-23A antibodies, such as psoriasis, psoriatic arthritis, or axial (vertebral) spondyloarthritis (ax-SpA), including ankylosing spondylitis (AS, also known as radiographic ax-SpA) and non-radiographic ax-SpA. Background Technology

[0003] Psoriasis is a chronic, immune-mediated inflammatory skin disease with a global prevalence of approximately 2%. It is associated with a significant prevalence and can have a substantial psychosocial impact on patients' quality of life and well-being. Plaque psoriasis is the most common form, affecting approximately 80–90% of patients, and manifests as raised patches on the skin; the disease often begins in late adolescence and early adulthood and can persist throughout adulthood. The extent of the 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. About one-third of patients with psoriasis also have associated arthritis (psoriatic arthritis (PsA), which causes pain and disability. Axial (vertebral) spondylitis (ax-SpA), including ankylosing spondylitis (AS, also known as radiographic axial spondylitis (ax-SpA)) and radionegative axial spondylitis (ax-SpA), is an inflammatory disease primarily involving the axial skeleton and sacroiliac joints.

[0004] Psoriasis, psoriatic arthritis, and axial (spinal) spondylitis (ax-SpA) (including ankylosing spondylitis and radionegative ax-SpA) are multifactorial autoimmune diseases whose exact etiology remains unknown. Multiple genome-wide association studies have linked variants in the IL-23 receptor gene to psoriasis susceptibility. Human IL-23 is primarily produced by antigen-presenting cells and induces T helper 17 (Th17) cell differentiation. This leads to the production of IL-17 and IL-22, which can mediate the development of epidermal hyperplasia and tissue inflammation observed in psoriasis.

[0005] Treatment options for inflammatory diseases that require a favorable prognosis for the patient, such as in terms of efficacy, safety, and / or tolerability, specifically psoriasis, psoriatic arthritis, and axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA. Summary of the Invention

[0006] The present invention satisfies the above-mentioned needs and provides a method for treating inflammatory diseases, specifically comprising administering an anti-IL-23A antibody to a patient in a measured amount and / or at intervals. In one aspect, the method of the present invention is used to treat psoriasis or psoriatic arthritis. In one aspect, the method of the present invention is used to treat axial (spinal) spondylitis (ax-SpA), including ankylosing spondylitis (AS) and radionegative ax-SpA. Therefore, in one aspect, the method of the present invention is used to treat ankylosing spondylitis (AS), and in another aspect, the method of the present invention is used to treat radionegative ax-SpA.

[0007] The method of the present invention provides the following benefits: enabling patients to experience clinical improvement while receiving less anti-IL-23A antibody administration.

[0008] In one embodiment, the present invention provides a method for treating an inflammatory disease, comprising administering an anti-IL-23A antibody to a patient, the method being used in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA, the method comprising:

[0009] a) Administer an initial dose of anti-IL-23A antibody to the patient;

[0010] b) Administering a first maintenance dose of anti-IL-23A antibody to the patient 4 to 24 weeks after the initial dose, for example 4 to 16 weeks, for example 4 to 12 weeks; and

[0011] c) At least one additional maintenance dose is administered to the patient 4 to 24 weeks after the administration of the first maintenance dose, for example 4 to 16 weeks, for example 4 to 12 weeks.

[0012] In one embodiment, the present invention provides a method for treating an inflammatory disease, comprising administering an anti-IL-23A antibody to a patient, the method being used in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA, the method comprising:

[0013] a) Administer an initial dose of anti-IL-23A antibody to the patient;

[0014] b) Administering a first maintenance dose of anti-IL-23A antibody to the patient 8 to 24 weeks after the initial dose, for example 8 to 16 weeks, for example 8 to 12 weeks, for example 6 to 24 weeks, for example 6 to 16 weeks, for example 6 to 12 weeks; and

[0015] c) At least one additional maintenance dose is administered to the patient 8 to 24 weeks after the administration of the first maintenance dose, for example 8 to 16 weeks, for example 8 to 12 weeks, for example 6 to 24 weeks, for example 6 to 16 weeks, for example 6 to 12 weeks.

[0016] In one implementation, the first maintenance dose is administered to the patient at 4, 6, 8, 12, 16, 20, or 24 weeks after the initial dose.

[0017] In one implementation, the patient is given at least one additional maintenance dose 4, 6, 8, 12, 16, 20 or 24 weeks after the administration of the first maintenance dose.

[0018] In one implementation, a first maintenance dose is administered to the patient 4, 6, 8, 12, 16, 20, or 24 weeks after the initial dose, and the patient is given the at least one additional maintenance dose 4, 6, 8, 12, 16, 20, or 24 weeks after the first maintenance dose.

[0019] In other implementation schemes:

[0020] The patient is given a first maintenance dose 4 weeks after the initial dose, and at least one additional maintenance dose is given 4 weeks after the first maintenance dose; or

[0021] The patient is given a first maintenance dose 6 weeks after the initial dose, and at least one additional maintenance dose is given 6 weeks after the first maintenance dose; or

[0022] Eight weeks after administering the initial dose, the patient is given a first maintenance dose, and eight weeks after administering the first maintenance dose, the patient is given at least one additional maintenance dose; or

[0023] The patient is given a first maintenance dose 12 weeks after the initial dose, and at least one additional maintenance dose is given 12 weeks after the first maintenance dose; or

[0024] The patient is given a first maintenance dose 16 weeks after the initial dose, and at least one additional maintenance dose is given 16 weeks after the first maintenance dose; or

[0025] The patient is given a first maintenance dose 20 weeks after the initial dose, and at least one additional maintenance dose is given 20 weeks after the first maintenance dose; or

[0026] The patient was given a first maintenance dose 24 weeks after the initial dose, and at least one additional maintenance dose was given 24 weeks after the first maintenance dose.

[0027] In one embodiment, in any of the methods described above, the initial dose comprises 15 to 300 mg, for example 15 to 250 mg, or for example 90 to 180 mg of anti-IL-23A antibody.

[0028] In one embodiment, in any of the above methods, the first maintenance dose and at least one additional maintenance dose comprise 15 to 300 mg, for example 15 to 250 mg, for example 90 to 180 mg of anti-IL-23A antibody.

[0029] In one embodiment, in any 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.

[0030] In one embodiment, in any 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.

[0031] In one embodiment, in any 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 of the above methods, the initial dose comprises 75 mg of anti-IL-23A antibody.

[0032] In one embodiment, in any 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 of the above methods, the first maintenance dose and at least one additional maintenance dose comprise 75 mg of anti-IL-23A antibody.

[0033] In one embodiment, in any 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 of the above methods, the initial dose, the first maintenance dose, and the at least one additional maintenance dose comprise 75 mg of anti-IL-23A antibody.

[0034] In one embodiment, the present invention provides a method for treating an inflammatory disease, comprising administering an anti-IL-23A antibody to a patient, the method being used in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA, the method comprising:

[0035] a) Administer an initial dose of anti-IL-23A antibody to the patient;

[0036] b) Administer the first maintenance dose of anti-IL-23A antibody to the patient 12 weeks after the initial dose; and

[0037] c) Administer at least one additional maintenance dose to the patient 12 weeks after the first maintenance dose.

[0038] In one embodiment, the initial and maintenance doses of the method comprise 150 mg of the anti-IL-23A antibody. In another embodiment, the initial and maintenance doses of the method comprise 75 mg of the anti-IL-23A antibody.

[0039] In one embodiment, the present invention provides a method for treating an inflammatory disease, comprising administering an anti-IL-23A antibody to a patient, the method being used in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA, the method comprising:

[0040] a) Administer an initial dose of anti-IL-23A antibody to the patient;

[0041] b) Administer the first maintenance dose of anti-IL-23A antibody to the patient 8 weeks after the initial dose; and

[0042] c) Administer at least one additional maintenance dose to the patient 8 weeks after the administration of the first maintenance dose.

[0043] In one embodiment, the initial and maintenance doses of the method comprise 90 mg of the anti-IL-23A antibody. In another embodiment, the initial and maintenance doses of the method comprise 150 mg of the anti-IL-23A antibody.

[0044] In one embodiment, the present invention provides a method for treating an inflammatory disease, comprising administering an anti-IL-23A antibody to a patient, the method being used in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA, the method comprising:

[0045] a) Administer an initial dose of anti-IL-23A antibody to the patient;

[0046] b) Administer the first maintenance dose of anti-IL-23A antibody to the patient 16 weeks after the initial dose; and

[0047] c) Administer at least one additional maintenance dose to the patient 16 weeks after the administration of the first maintenance dose.

[0048] In one embodiment, the initial dose and maintenance dose in the method comprise 150 mg of anti-IL-23A antibody.

[0049] In one embodiment, the present invention provides a method for treating an inflammatory disease, comprising administering an anti-IL-23A antibody to a patient, the method being used in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA, the method comprising:

[0050] a) Administer an initial dose of anti-IL-23A antibody to the patient;

[0051] b) Administer the first maintenance dose of anti-IL-23A antibody to the patient 6 weeks after the initial dose; and

[0052] c) Administer at least one additional maintenance dose to the patient 6 weeks after the first maintenance dose.

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

[0054] In one embodiment, the present invention provides a method for treating an inflammatory disease, comprising administering an anti-IL-23A antibody to a patient, the method being used in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA, the method comprising:

[0055] a) Administer an initial dose of anti-IL-23A antibody to the patient;

[0056] b) Administer the first maintenance dose of anti-IL-23A antibody to the patient 4 weeks after the initial dose; and

[0057] c) Administer at least one additional maintenance dose to the patient 4 weeks after the first maintenance dose.

[0058] In one embodiment, the initial dose and maintenance dose in the method comprise 150 mg of the anti-IL-23A antibody.

[0059] In one embodiment, the present invention further provides a method for treating inflammatory diseases, comprising administering an anti-IL-23A antibody to a patient, said method being used in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA, said method comprising:

[0060] a) Administer an initial dose of the anti-IL-23A antibody to the patient;

[0061] b) Administer the anti-IL-23A antibody loaded with the dose to the patient 1 to 6 weeks after the initial dose;

[0062] c) Administering a first maintenance dose of anti-IL-23A antibody to the patient 8 to 24 weeks, for example 8 to 16 weeks, for example 8 to 12 weeks, for example 6 to 24 weeks, for example 6 to 16 weeks, for example 6 to 12 weeks after administration of the loaded dose; and

[0063] d) Administer at least one additional maintenance dose to the patient 8 to 24 weeks after the administration of the first maintenance dose, for example 8 to 16 weeks, for example 8 to 12 weeks, for example 6 to 24 weeks, for example 6 to 16 weeks, for example 6 to 12 weeks.

[0064] In one implementation, the loaded dose is administered to the patient 1, 2, 3, 4, 5, or 6 weeks after the initial dose is administered.

[0065] In one implementation, a first maintenance dose is administered to the patient at 6, 8, 12, 16, 20, or 24 weeks after the administration of the loaded dose.

[0066] In one implementation, at least one additional maintenance dose is administered to the patient 6, 8, 12, 16, 20, or 24 weeks after the administration of the first maintenance dose.

[0067] In one implementation, a first maintenance dose is administered to the patient 6, 8, 12, 16, 20, or 24 weeks after the initial dose, 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.

[0068] In one implementation, a first maintenance dose is administered to the patient 6, 8, 12, 16, 20, or 24 weeks after the administration of the loaded dose, and at least one additional maintenance dose is administered to the patient 6, 8, 12, 16, 20, or 24 weeks after the administration of the first maintenance dose.

[0069] In other implementation schemes:

[0070] The patient is given a first maintenance dose 6 weeks after the initial dose, and at least one additional maintenance dose is given 6 weeks after the first maintenance dose; or

[0071] Eight weeks after administering the initial dose, the patient is given a first maintenance dose, and eight weeks after administering the first maintenance dose, the patient is given at least one additional maintenance dose; or

[0072] The patient is given a first maintenance dose 12 weeks after the initial dose, and at least one additional maintenance dose is given 12 weeks after the first maintenance dose; or

[0073] The patient is given a first maintenance dose 16 weeks after the initial dose, and at least one additional maintenance dose is given 16 weeks after the first maintenance dose; or

[0074] The patient is given a first maintenance dose 20 weeks after the initial dose, and at least one additional maintenance dose is given 20 weeks after the first maintenance dose; or

[0075] The patient was given a first maintenance dose 24 weeks after the initial dose, and at least one additional maintenance dose was given 24 weeks after the first maintenance dose.

[0076] In other implementation schemes:

[0077] The patient is given a first maintenance dose 6 weeks after administration of the loaded dose, and at least one additional maintenance dose is administered 6 weeks after administration of the first maintenance dose; or

[0078] The patient is given a first maintenance dose 8 weeks after administration of the loaded dose, and at least one additional maintenance dose is administered 8 weeks after administration of the first maintenance dose; or

[0079] The patient is given a first maintenance dose 12 weeks after administration of the loaded dose, and at least one additional maintenance dose is administered 12 weeks after administration of the first maintenance dose; or

[0080] The patient is given a first maintenance dose 16 weeks after administration of the loading dose, and at least one additional maintenance dose is administered 16 weeks after administration of the first maintenance dose; or

[0081] The patient is given a first maintenance dose 20 weeks after administration of the loaded dose, and at least one additional maintenance dose is administered 20 weeks after administration of the first maintenance dose; or

[0082] The patient was given a first maintenance dose 24 weeks after the administration of the loading dose, and at least one additional maintenance dose was administered 24 weeks after the administration of the first maintenance dose.

[0083] In one embodiment, in any of the methods described above, the initial dose comprises 15 to 300 mg, for example 15 to 250 mg, or for example 90 to 180 mg of anti-IL-23A antibody.

[0084] In one embodiment, in any of the above methods, the loading dose comprises 15 to 300 mg, for example 15 to 250 mg, or for example 90 to 180 mg of anti-IL-23A antibody.

[0085] In one embodiment, in any of the above methods, the first maintenance dose and at least one additional maintenance dose comprise 15 to 300 mg, for example 15 to 250 mg, for example 90 to 180 mg of anti-IL-23A antibody.

[0086] In one embodiment, in any 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.

[0087] In one embodiment, in any 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.

[0088] In one embodiment, in any 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.

[0089] In one embodiment, in any 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 of the above methods, the initial dose comprises 75 mg of anti-IL-23A antibody.

[0090] In one embodiment, in any 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 of the above methods, the first maintenance dose and at least one additional maintenance dose comprise 75 mg of anti-IL-23A antibody.

[0091] In one embodiment, in any of the above methods, the initial dose and 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, 250, 260, 270, 280, 290, or 300 mg of anti-IL-23A antibody. In one embodiment, in any of the above methods, the initial dose and loading dose comprise 75 mg of anti-IL-23A antibody.

[0092] In one embodiment, in any of the above methods, the initial dose, loading dose, 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 of the above methods, the initial dose, loading dose, first maintenance dose, and at least one additional maintenance dose comprise 75 mg of anti-IL-23A antibody.

[0093] In one embodiment, the present invention further provides a method for treating inflammatory diseases, comprising administering an anti-IL-23A antibody to a patient, said method being used in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA, said method comprising:

[0094] a) Administer an initial dose of the anti-IL-23A antibody to the patient;

[0095] b) Administer the anti-IL-23A antibody loaded with the stated dose to the patient 4 weeks after the administration of the initial dose;

[0096] c) Administer the first maintenance dose of the anti-IL-23A antibody to the patient 12 weeks after the administration of the loaded dose; and

[0097] d) Administer at least one additional maintenance dose to the patient 12 weeks after the administration of the first maintenance dose.

[0098] In one embodiment, the initial dose, loading dose, and maintenance dose comprise 150 mg of the anti-IL-23A antibody. In one embodiment, the initial dose and 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, the initial dose and 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, the initial dose, loading dose, and maintenance dose comprise 75 mg of the anti-IL-23A antibody.

[0099] In one embodiment, the present invention further provides a method for treating inflammatory diseases, including administering an anti-IL-23A antibody to a patient, in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA, said method comprising:

[0100] a) Administer an initial dose of the anti-IL-23A antibody to the patient;

[0101] b) Administer the anti-IL-23A antibody loaded with a dose to the patient 4 weeks after the initial dose;

[0102] c) Administer the first maintenance dose of the anti-IL-23A antibody to the patient 8 weeks after administration of the loaded dose; and

[0103] d) Administer at least one additional maintenance dose to the patient 8 weeks after the administration of the first maintenance dose.

[0104] In one embodiment, the initial dose, loading dose, and maintenance dose comprise 90 mg of the anti-IL-23A antibody. In another embodiment, the initial dose, loading dose, and maintenance dose comprise 150 mg of the anti-IL-23A antibody.

[0105] In one embodiment, the present invention further provides a method for treating inflammatory diseases, comprising administering an anti-IL-23A antibody to a patient, said method being used in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA, said method comprising:

[0106] a) Administer an initial dose of the anti-IL-23A antibody to the patient;

[0107] b) Administer the anti-IL-23A antibody loaded with the stated dose to the patient 4 weeks after the administration of the initial dose;

[0108] c) Administer the first maintenance dose of the anti-IL-23A antibody to the patient 16 weeks after administration of the loaded dose; and

[0109] d) Administer at least one additional maintenance dose to the patient 16 weeks after the administration of the first maintenance dose.

[0110] In one embodiment, the initial dose, loading dose, and maintenance dose in the method comprise 150 mg of the anti-IL-23A antibody.

[0111] In one embodiment, the present invention further provides a method for treating inflammatory diseases, comprising administering an anti-IL-23A antibody to a patient, said method being used in one aspect for treating psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA, said method comprising:

[0112] a) Administer an initial dose of the anti-IL-23A antibody to the patient;

[0113] b) Administer the anti-IL-23A antibody loaded with the dose to the patient 4 weeks after the administration of the initial dose;

[0114] c) Administer the first maintenance dose of the anti-IL-23A antibody to the patient 6 weeks after administration of the loaded dose; and

[0115] d) Administer at least one additional maintenance dose to the patient 6 weeks after the administration of the first maintenance dose.

[0116] In one embodiment, the initial dose, loading dose, and maintenance dose in the method comprise 150 mg of the anti-IL-23A antibody.

[0117] In one embodiment, the invention further provides a method for treating an inflammatory disease, comprising administering to a patient 15 to 300 mg, for example 15 to 250 mg, or for example 90 to 180 mg, of an anti-IL-23A antibody. In one embodiment, the inflammatory disease is psoriasis, psoriatic arthritis, or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA.

[0118] In one embodiment, the method includes administering to a patient 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.

[0119] In one embodiment, the method includes 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 a patient. In one embodiment, the method includes administering 75 mg of anti-IL-23A antibody to a patient.

[0120] In one embodiment, the anti-IL-23A antibody is administered at an initial dose, a loading dose, or a maintenance dose.

[0121] In one embodiment, the present invention further provides a method for treating an inflammatory disease, comprising administering an anti-IL-23A antibody to a patient, the method being used in one aspect for treating psoriasis or psoriatic arthritis, the method comprising:

[0122] a) Administer an initial dose of the anti-IL-23A antibody to the patient; and

[0123] b) When a patient no longer maintains a certain PASI score, such as PASI 90, PASI 75, PASI 100 or PASI 50, administer a second dose of the anti-IL-23A antibody to the patient.

[0124] In one respect, the initial dose and the second dose are doses as described herein.

[0125] In one embodiment, the present invention further provides a method for treating an inflammatory disease, comprising administering an anti-IL-23A antibody to a patient, the method being used in one aspect for treating psoriasis or psoriatic arthritis, the method comprising:

[0126] a) Administer an initial dose of the anti-IL-23A antibody to the patient;

[0127] b) Administering the anti-IL-23A antibody loaded with the dose to the patient 1 to 6 weeks after the initial dose, for example, 4 weeks; and

[0128] c) When the patient no longer maintains a certain PASI score, such as PASI 90, PASI 75, PASI 100 or PASI 50, administer a third dose of the anti-IL-23A antibody to the patient.

[0129] In one respect, the initial dose, the loading dose, and the third dose are doses as described herein.

[0130] In one embodiment, in any of the above methods, the anti-IL-23A antibody is antibody A, antibody B, antibody C, or antibody D.

[0131] In one embodiment, the method described in any of the above methods is used to treat plaque psoriasis, such as chronic plaque psoriasis.

[0132] In one embodiment, the method described in any of the above methods is used to treat moderate to severe chronic plaque psoriasis in a patient, for example, as a candidate for systemic therapy or phototherapy.

[0133] In one embodiment, the method described in any of the above methods is used to treat a patient with moderate to severe chronic plaque psoriasis, such as a patient who has failed to respond to other systemic treatments (including cyclosporine, methotrexate, psoralen, or ultraviolet A light (PUVA)) or who has contraindications to or intolerance to said other systemic treatments.

[0134] In one embodiment, the method described in any of the above methods is used to treat pustular psoriasis.

[0135] In one embodiment, the method described in any of the above methods is used to treat erythrodermic psoriasis (also known as psoriatic erythroderma).

[0136] In one embodiment, the method described in any of the above methods is used to treat psoriatic arthritis, such as active psoriatic arthritis.

[0137] In one embodiment, the anti-IL-23A antibody is used alone or in combination with one or more non-biological DMARDs (disease-modifying antirheumatic drugs), for example, to treat psoriatic arthritis, such as active psoriatic arthritis, for example, to reduce signs and symptoms. In one embodiment, the anti-IL-23A antibody is used or indicated to inhibit the progression of structural damage and / or improve bodily function.

[0138] In one embodiment, the anti-IL-23A antibody is used alone or in combination with methotrexate (MTX), for example, to treat psoriatic arthritis, such as active psoriatic arthritis, for example, when the response to previous non-biological DMARD treatment has been insufficient. In one aspect, the anti-IL-23A antibody is used to reduce the rate of progression of peripheral joint damage as measured by X-ray, and / or to improve bodily function.

[0139] In one embodiment, in any of the above methods, the anti-IL-23A antibody is administered subcutaneously.

[0140] In one aspect, in the method of the present invention, 90-180 mg of anti-IL-23 antibody is administered to the patient every 6-12 weeks, for example every 8-12 weeks, with or without a loading dose.

[0141] In one implementation scheme, in any of the above methods, the patient is an adult patient.

[0142] In one aspect, the present invention provides an anti-IL-23A antibody for use in treating diseases as described herein.

[0143] In one aspect, the present invention provides an anti-IL-23A antibody for use in treating diseases by administration in a measured amount and / or at intervals as described herein, said diseases being, for example, inflammatory diseases such as psoriasis, psoriatic arthritis, or axial (vertebral) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA.

[0144] In one aspect, the present invention provides the use of an anti-IL-23A antibody in the preparation of a medicament for treating diseases as described herein.

[0145] In one aspect, the present invention provides the use of an anti-IL-23A antibody for the preparation of a medicament for the treatment of said disease, said treatment being performed by administration in an amount and / or at intervals as described herein, said disease being, for example, an inflammatory disease such as psoriasis, psoriatic arthritis, or axial (vertebral) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA.

[0146] In one embodiment, in any of the methods or uses described above, the anti-IL-23A antibody is disclosed as follows.

[0147] 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).

[0148] 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).

[0149] 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).

[0150] 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).

[0151] 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).

[0152] In one embodiment, the anti-IL-23A antibody comprises: a light chain variable region comprising an amino acid sequence comprising any one of SEQ ID NO: 10, 11, 12 or 13; and a heavy chain variable region comprising an amino acid sequence comprising any one of SEQ ID NO: 14, 15, 16 or 17.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] In one embodiment, the anti-IL-23A antibody comprises an amino acid sequence SEQ ID NO: 14 or 15 linked to the constant region of the heavy chain of human IgG1, IgG2, IgG3, IgG4, IgM, IgA, or IgE. In one embodiment, the anti-IL-23A antibody comprises an amino acid sequence SEQ ID NO: 14 or 15 linked to the constant region of the heavy chain of human IgG1. In one embodiment, the anti-IL-23A antibody comprises an amino acid sequence SEQ ID NO: 10 or 11 linked to the constant region of the light chain of human κ or λ.

[0158] In one embodiment, the anti-IL-23A antibody comprises an amino acid sequence SEQ ID NO: 14 or 15 linked to the constant region of the human IgG1 heavy chain; and an amino acid sequence SEQ ID NO: 10 or 11 linked to the constant region of the human κ light chain.

[0159] 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 any one of SEQ ID NO: 10, 11, 12 and 13, and a heavy chain variable region comprising an amino acid sequence selected from any one of SEQ ID NO: 14, 15, 16 and 17.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] In one embodiment, the anti-IL-23A antibody comprises: a light chain containing the amino acid sequence of SEQ ID NO: 18 or 21, and a heavy chain containing the amino acid sequence of SEQ ID NO: 19 or 20.

[0165] In one embodiment, the anti-IL-23A antibody comprises: a light chain containing the amino acid sequence of SEQ ID NO: 18, and a heavy chain containing the amino acid sequence of SEQ ID NO: 19.

[0166] 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.

[0167] In one embodiment, the anti-IL-23A antibody comprises: a light chain containing the amino acid sequence of SEQ ID NO: 21, and a heavy chain containing the amino acid sequence of SEQ ID NO: 19.

[0168] 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.

[0169] In one embodiment, the anti-IL-23A antibody is antibody A, antibody B, antibody C, or antibody D.

[0170] In one embodiment, the anti-IL-23A antibody is disclosed in WO2007 / 005955, WO2007 / 024846, WO2007 / 027714, WO2007 / 076524, WO2008 / 103432 or WO2012 / 061448. Attached Figure Description

[0171] Figure 1 The percentage (%) of patients with a pain-VAS reduction of >50% from baseline.

[0172] Figure 2 (Observed) PASI 50 was reached over time.

[0173] Figure 3 (Observed) PASI 75 was reached over time.

[0174] Figure 4 (Observed) PASI 90 was reached over time.

[0175] Figure 5 (Observed) PASI 100 was reached over time.

[0176] exist Figures 2 to 5 In this context, antibody A is also known as "BI". Detailed Implementation

[0177] 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 molecule’s biological activity is only detected when it synergizes with the IL-12p40 subunit to form IL-23. IL-23 is primarily expressed by activated dendritic cells (DCs) and phagocytes. The receptor for IL-23 has been 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)). This receptor was detected to be primarily expressed on memory T cells and NK cells. Therefore, the expression of this cytokine:receptor pair appears to be limited to specific immune cell populations. Although IL-12 and IL-23 were initially thought to share many functions, data show this is not the case. IL-12 plays a major role in the production of Th1 cells, while IL-23 has been found to be crucially involved in the production and maintenance of a newly identified 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 pro-inflammatory cytokines such as IL-6 and TNF-α. As described below, animal model studies on the role of these Th17 cells demonstrate their importance as a driver of chronic inflammation and autoimmunity.

[0178] SEQ ID NO: 22:

[0179]

[0180] In one aspect, the present invention provides a method for treating IL-23A-related diseases. In another aspect, the present invention provides a method for treating diseases, such as inflammatory diseases, specifically comprising administering an anti-IL-23A antibody to a patient in an amount and / or at intervals. In one aspect, the method of the present invention is used to treat psoriasis or psoriatic arthritis. In one aspect, the method of the present invention is used to treat ankylosing spondylitis (AS). In one aspect, the method of the present invention is used to treat axial (spinal) spondyloarthritis (ax-SpA), such as radionegative ax-SpA.

[0181] In one aspect, the present invention provides an anti-IL-23A antibody for use in treating diseases by administration in a measured amount and / or at intervals as described herein, said diseases being, for example, inflammatory diseases such as psoriasis, psoriatic arthritis, or axial (vertebral) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA.

[0182] In one aspect, the present invention provides the use of an anti-IL-23A antibody in the preparation of a medicament for treating said diseases by administration in a certain amount and / or at certain intervals as described herein, said diseases being, for example, inflammatory diseases such as psoriasis, psoriatic arthritis, or axial (vertebral) spondyloarthritis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA.

[0183] In one aspect, the method of the present invention includes administering an initial dose of anti-IL-23A antibody to a patient, followed by administering one or more maintenance doses of anti-IL-23A antibody. Optionally, between administering the initial dose and administering the first maintenance dose, a loaded dose of anti-IL-23A antibody is administered to the patient.

[0184] In one aspect, in one method of the invention, the interval between administering the initial dose and the first maintenance dose is 4 to 24 weeks, for example 4 to 16 weeks, for example 4 to 12 weeks, for example 4, 6, 8, 12, 16, 20, or 24 weeks. In another aspect, the interval between administering the first maintenance dose and subsequent maintenance doses is 4 to 24 weeks, for example 4 to 16 weeks, for example 4 to 12 weeks, for example 4, 6, 8, 12, 16, 20, or 24 weeks.

[0185] In one aspect, in a method of the invention, the interval between administering the initial dose and the first maintenance dose is 8 to 24 weeks, for example 8 to 16 weeks, for example 8 to 12 weeks, for example 6 to 24 weeks, for example 6 to 16 weeks, for example 6 to 12 weeks, for example 6, 8, 12, 16, 20, or 24 weeks. In another aspect, the interval between administering the first maintenance dose and subsequent maintenance doses is 8 to 24 weeks, for example 8 to 16 weeks, for example 8 to 12 weeks, for example 6 to 24 weeks, for example 6 to 16 weeks, for example 6 to 12 weeks, for example 6, 8, 12, 16, 20, or 24 weeks.

[0186] In one aspect, in one method of the invention, the interval between administering the initial dose and the first maintenance dose is the same as the interval between administering the first maintenance dose and the subsequent maintenance dose, for example, 4 to 24 weeks, for example, 4 to 16 weeks, for example, 4 to 12 weeks, for example, 4, 6, 8, 12, 16, 20 or 24 weeks.

[0187] In one aspect, in one method of the invention, the interval between administering the initial dose and the first maintenance dose is the same as the interval between administering the first maintenance dose and the subsequent maintenance dose, for example, 8 to 24 weeks, for example, 8 to 16 weeks, for example, 8 to 12 weeks, for example, 6 to 24 weeks, for example, 6 to 16 weeks, for example, 6 to 12 weeks, for example, 6, 8, 12, 16, 20 or 24 weeks.

[0188] In one aspect, in one method of the invention, the patient is given a loaded dose of anti-IL-23A antibody between the administration of an initial dose and the administration of a first maintenance dose.

[0189] In one aspect, the loaded dose is administered to the patient 1, 2, 3, 4, 5, or 6 weeks after the initial dose. In another aspect, in a method of the invention, the interval between administering the loaded dose and the first maintenance dose is 8 to 24 weeks, for example 8 to 16 weeks, for example 8 to 12 weeks, for example 6 to 24 weeks, for example 6 to 16 weeks, for example 6 to 12 weeks, for example 6, 8, 12, 16, 20, or 24 weeks. In another aspect, the interval between administering the first maintenance dose and subsequent maintenance doses is 8 to 24 weeks, for example 8 to 16 weeks, for example 8 to 12 weeks, for example 6 to 24 weeks, for example 6 to 16 weeks, for example 6 to 12 weeks, for example 6, 8, 12, 16, 20, or 24 weeks.

[0190] In one aspect, in one method of the invention, the interval between administering the loading dose and the first maintenance dose is the same as the interval between administering the first maintenance dose and the subsequent maintenance dose, for example, 8 to 24 weeks, for example, 8 to 16 weeks, for example, 8 to 12 weeks, for example, 6 to 24 weeks, for example, 6 to 16 weeks, for example, 6 to 12 weeks, for example, 6, 8, 12, 16, 20 or 24 weeks.

[0191] In one aspect, the amount of anti-IL-23A antibody in the initial dose and the maintenance dose is the same. In another aspect, the amount of anti-IL-23A antibody in the initial dose and the loading dose is the same. In another aspect, the amount of anti-IL-23A antibody in the loading dose and the maintenance dose is the same. In another aspect, the amount of anti-IL-23A antibody in the initial dose, the loading dose, and the maintenance dose is the same.

[0192] In one aspect, the amount of anti-IL-23A antibody in the maintenance dose is lower than the amount of anti-IL-23A antibody in the initial dose and / or the loading dose. In another aspect, the amount of anti-IL-23A antibody in the initial dose is twice the amount of anti-IL-23A antibody in the maintenance dose, for example, in the absence of a loading dose. In yet another aspect, 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.

[0193] In one aspect, in the method of the present invention, the initial dose comprises 15 to 300 mg, for example 15 to 250 mg, of anti-IL-23A antibody. In another aspect, the maintenance dose comprises 15 to 300 mg, for example 15 to 250 mg, of anti-IL-23A antibody. In yet another aspect, if a loading dose is administered, the loading dose comprises 15 to 300 mg, for example 15 to 250 mg, of anti-IL-23A antibody.

[0194] In another aspect, the initial dose, loading dose, or maintenance dose according to the invention 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.

[0195] In another aspect, the 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 another aspect, the initial dose, loading dose, or maintenance dose according to the invention comprises 75 mg of anti-IL-23A antibody.

[0196] In another aspect, the present invention provides a method for treating an inflammatory disease, the method comprising administering 15 to 250 mg of an anti-IL-23A antibody to a patient. In one aspect, the anti-IL-23A antibody is administered to the patient in doses of 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. In one aspect, the patient is given 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 aspect, the patient is given 75 mg of anti-IL-23A antibody. In one aspect, the disease is psoriasis or psoriatic arthritis. In one aspect, the disease is axial (spinal) spondylitis (ax-SpA), including ankylosing spondylitis and radionegative ax-SpA.

[0197] In one aspect, in the method of the present invention, 90-180 mg of anti-IL-23 antibody is administered to the patient every 6-12 weeks, for example every 8-12 weeks, with or without a loading dose.

[0198] Representative examples of dosages and dosing regimens according to the present invention are disclosed in Table A.

[0199] Table A: Dosage and Dosing Regimen

[0200]

[0201]

[0202] x: No loaded dose was administered.

[0203] In Table A, when the loaded dose is administered, it indicates that the dose is administered 4 weeks after the initial dose.

[0204] The following is also within the scope of this invention: One week after the initial dose, the loaded dose is administered at each dose and frequency of the maintenance dose determined in the table above.

[0205] The following is also within the scope of this invention: Two weeks after the initial dose, the loaded dose is administered at each dose and frequency of the maintenance dose determined in the table above.

[0206] The following is also within the scope of this invention: 3 weeks after the initial dose, the loaded dose is administered at each dose and frequency of the maintenance dose determined in the table above.

[0207] The following is also within the scope of this invention: Five weeks after the initial dose, the loaded dose is administered at each dose and frequency of the maintenance dose determined in the table above.

[0208] The following is also within the scope of this invention: 6 weeks after the initial dose, the loaded dose is administered at each dose and frequency of the maintenance dose determined in the table above.

[0209] For example, in the context of this invention, if the loaded dose is not administered to the patient and the maintenance dose is administered at 12-week intervals, the 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), and so on at 12-week dosing intervals. In one aspect, the initial and maintenance doses comprise 150 mg of anti-IL-23A antibody. In another aspect, the initial and maintenance doses comprise 75 mg of anti-IL-23A antibody.

[0210] For example, in the context of this invention, if the patient is given a loading dose and a maintenance dose is administered at 12-week intervals, the initial dose is administered at week 0, followed by a loading dose at week 4, a first maintenance dose at week 16, a second maintenance dose at week 28, and so on at 12-week intervals. In one aspect, the initial dose, loading dose, and maintenance dose comprise 150 mg of anti-IL-23A antibody. In another aspect, 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 another aspect, 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 yet another aspect, the initial dose, loading dose, and maintenance dose comprise 75 mg of anti-IL-23A antibody.

[0211] For example, in the context of this invention, if the loaded dose is not administered to the patient and the maintenance dose is administered at 8-week intervals, the 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), and so on at 8-week dosing intervals. In one aspect, the initial and maintenance doses comprise 90 mg of anti-IL-23A antibody. In another aspect, the initial and maintenance doses comprise 150 mg of anti-IL-23A antibody.

[0212] For example, in the context of this invention, if the patient is given a loading dose and a maintenance dose is administered at 8-week intervals, the initial dose is administered to the patient at week 0, followed by a loading dose at week 4, a first maintenance dose at week 12, a second maintenance dose at week 20, and so on at 8-week intervals. In one aspect, the initial dose, loading dose, and maintenance dose comprise 90 mg of anti-IL-23A antibody. In another aspect, the initial dose, loading dose, and maintenance dose comprise 150 mg of anti-IL-23A antibody.

[0213] For example, in the context of this invention, if the loaded dose has not been administered to the patient and the maintenance dose is administered at 16-week intervals, the 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), and so on at 16-week dosing intervals. In one aspect, the initial and maintenance doses comprise 150 mg of anti-IL-23A antibody.

[0214] For example, in the context of this invention, if the patient is given a loading dose and a maintenance dose is administered at 16-week intervals, the initial dose is administered at week 0, followed by a loading dose at week 4, a first maintenance dose at week 20, a second maintenance dose at week 36, and so on at 16-week intervals. In one aspect, the initial dose, loading dose, and maintenance dose comprise 150 mg of anti-IL-23A antibody.

[0215] For example, in the context of this invention, if the loaded dose is not administered to the patient and the maintenance dose is administered at a frequency of 6 weeks, the initial dose is administered to the patient at week 0, followed by administration at week 6 (first maintenance dose), then administration at week 12 (second maintenance dose), and so on at 6-week dosing intervals. In one aspect, the initial and maintenance doses comprise 150 mg of anti-IL-23A antibody.

[0216] For example, in the context of this invention, if the patient is given a loading dose and a maintenance dose is administered at 6-week intervals, the initial dose is administered at week 0, followed by a loading dose at week 4, a first maintenance dose at week 10, a second maintenance dose at week 16, and so on at 6-week intervals. In one aspect, the initial dose, loading dose, and maintenance dose comprise 150 mg of anti-IL-23A antibody.

[0217] For example, in the context of this invention, if the maintenance dose is administered at a frequency of 4 weeks, the initial dose is administered to the patient at week 0, followed by a further administration at week 4 (first maintenance dose), then at week 8 (second maintenance dose), then at week 12 (third maintenance dose), and so on at 4-week dosing intervals. In one aspect, the initial and maintenance doses comprise 150 mg of anti-IL-23A antibody.

[0218] In another aspect, in the method according to the invention, an initial dose of anti-IL-23 antibody is administered to the patient. A second dose of anti-IL-23 antibody is not administered to the patient as long as the therapeutic effect of the initial dose is maintained, for example, as assessed by PASI scores (e.g., PASI 90, PASI 75, PASI 100, or PASI 50). However, when the disease severity exceeds a certain level, for example, when the patient no longer maintains a certain PASI score, such as PASI 90, PASI 75, PASI 100, or PASI 50, the second dose is administered to the patient. The initial and second doses of the anti-IL-23 antibody are, for example, the doses described herein. In one aspect, after administering the initial dose, the patient is monitored, for example, by assessing the patient's PASI score. In one aspect, when the patient no longer maintains a certain PASI score, such as PASI 90, PASI 75, PASI 100, or PASI 50, a third dose of anti-IL-23 antibody is administered to the patient after administering the second dose. The third dose of anti-IL-23 antibody is, for example, the dose described herein, such as the same dose as the second dose. In one aspect, the patient is monitored after the second dose administration, for example, by assessing the patient's PASI score. In another aspect, at least one additional dose is administered to the patient in such a manner.

[0219] In another aspect, in the method according to the invention, a loaded dose of anti-IL-23 antibody is administered to the patient after the initial dose, for example, after the time period described herein. A third dose of anti-IL-23 antibody is not administered to the patient as long as the therapeutic effect of the initial dose is maintained, for example, by a PASI score (e.g., PASI 90, PASI 75, PASI 100, or PASI 50), but a third dose is administered to the patient when the disease severity exceeds a certain level, for example, when the patient no longer maintains a certain PASI score (e.g., PASI 90, PASI 75, PASI 100, or PASI 50). In one aspect, the loaded dose of the anti-IL-23 antibody is the dose described herein. In one aspect, a fourth dose of anti-IL-23 antibody is administered to the patient after the third dose when the patient no longer maintains a certain PASI score (e.g., PASI 90, PASI 75, PASI 100, or PASI 50). The fourth dose of anti-IL-23 antibody is, for example, the dose described herein, such as the same dose as the third dose. In one aspect, the patient is monitored after the third dose administration, for example, by assessing the patient's PASI score. In another aspect, at least one additional dose is administered to the patient in such a manner.

[0220] Therefore, in one embodiment, the present invention further provides a method for treating inflammatory diseases, which in one aspect is used to treat psoriasis or psoriatic arthritis, the method comprising administering an anti-IL-23A antibody to a patient, the method comprising:

[0221] a) Administer an initial dose of the anti-IL-23A antibody to the patient; and

[0222] b) When the patient no longer maintains PASI 90, PASI 75, PASI 100 or PASI 50, administer a second dose of the anti-IL-23A antibody to the patient.

[0223] In one respect, the amount of anti-IL-23A antibody in the second and subsequent doses is lower than the amount of anti-IL-23A antibody in the initial dose. In another respect, the amount of anti-IL-23A antibody in the initial dose is twice the amount of anti-IL-23A antibody in the second and subsequent doses.

[0224] In one embodiment, the present invention further provides a method for treating an inflammatory disease, comprising administering an anti-IL-23A antibody to a patient, the method being used in one aspect for treating psoriasis or psoriatic arthritis, the method comprising:

[0225] a) Administer an initial dose of the anti-IL-23A antibody to the patient;

[0226] b) Administer the anti-IL-23A antibody loaded with the dose to the patient 1 to 6 weeks after the initial dose, for example, 4 weeks; and

[0227] c) When the patient no longer maintains PASI 90, PASI 75, PASI 100 or PASI 50, administer a third dose of the anti-IL-23A antibody to the patient.

[0228] In one aspect, the amount of anti-IL-23A antibody in the third and subsequent doses is lower than the amount of anti-IL-23A antibody in the initial dose and / or loading dose. In another aspect, the amount of anti-IL-23A antibody in the initial dose is twice the amount of anti-IL-23A antibody in the third and subsequent doses. In yet another aspect, the amount of anti-IL-23A antibody in the initial and loading doses is twice the amount of anti-IL-23A antibody in the third and subsequent doses.

[0229] In one embodiment, the anti-IL-23A antibody in any of the above methods is disclosed herein.

[0230] In one aspect, in any of the above methods, a pharmaceutical composition comprising an anti-IL-23A antibody is administered to the patient. In one aspect, the patient is administered formulation 2 disclosed in Example 4, which comprises an anti-IL-23A antibody, such as antibody A, antibody B, antibody C, or antibody D. In one aspect, the patient is administered formulation 3 disclosed in Example 4, which comprises an anti-IL-23A antibody, such as antibody A, antibody B, antibody C, or antibody D.

[0231] In one aspect, the anti-IL-23A antibody is a humanized antibody. In another aspect, the anti-IL-23A antibody is a monoclonal antibody. In another aspect, the anti-IL-23A antibody is a full-length antibody. In yet another aspect, the anti-IL-23A antibody is a humanized monoclonal antibody, such as a full-length humanized monoclonal antibody.

[0232] The antibodies described herein recognize specific "IL-23A antigenic epitopes" or "IL-23A epitopes". As used herein, these terms refer to molecules (e.g., peptides) or molecular fragments capable of generating an immune response to anti-IL-23A antibodies, and include, for example, the IL-23A antigenic determinant, which is recognized by any antibody having the following light chain / heavy chain sequence combinations: SEQ ID NO: 11 / 14, 11 / 15, 10 / 14, or 10 / 15.

[0233] The generalized structures of antibodies or immunoglobulins are well known to those skilled in the art. These molecules are typically heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains, and are commonly referred to as full-length antibodies. Each light chain is covalently linked to the heavy chain by a disulfide bond to form a heterodimer, and the heterotetrameric molecule is formed by covalent disulfide bonds between the two identical heavy chains of the heterodimer. Although the light and heavy chains are linked together by a single disulfide bond, the number of disulfide bonds between the two heavy chains varies with immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (V) at its amino terminus. H ), followed by three or four constant fields (C H1 C H2 C H3 and C H4 ) and between C H1 With C H2 The hinge region between them. Each light chain has two domains, namely the amino-terminal variable domain (V... L ) and the carboxyl terminus constant domain (C L V L Domain and V H Domain non-covalent association, while C L Domains are typically connected to C via disulfide bonds. H1 Domain covalent linkage. It is believed that specific amino acid residues form interfaces between the variable domains of the light and heavy chains (Chothia et al., 1985, J. Mol. Biol. 186: 651-663). Variable domains are also referred to as variable regions in this paper.

[0234] Some domains within the variable domain differ significantly between different antibodies; these are termed "hypervariable." These hypervariable domains contain residues directly involved in the binding and specificity of each antibody to its specific antigenic determinant. The hypervariability of both the light and heavy chain variable domains is concentrated in three segments, termed complementarity-determining regions (CDRs) or hypervariable loops (HVLs). CDRs are defined by sequence comparisons in Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md., while HVLs (also referred to as CDRs in this paper) are determined based on the three-dimensional structure of the variable domain, as described by Chothia and Lesk, 1987, J. Mol. Biol. 196: 901-917. These two methods lead to slightly different identifications of CDRs. As determined by Kabat, CDR-L1 is located at approximately residues 24-34 in the variable domain of the light chain, CDR-L2 at approximately residues 50-56, and CDR-L3 at approximately residues 89-97; CDR-H1 is located at approximately residues 31-35 in the variable domain of the heavy chain, CDR-H2 at approximately residues 50-65, and CDR-H3 at approximately residues 95-102. The exact number of residues covering a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can conventionally determine which residues constitute a particular CDR based on the amino acid sequence of the variable region of the antibody. Therefore, CDR1, CDR2, and CDR3 of the heavy and light chains define unique functional properties specific to a given antibody.

[0235] The three CDRs within each heavy and light chain are separated by a framework region (FR), which contains sequences with generally low variability. From the amino terminus to the carboxyl terminus of the variable domain in both the heavy and light chains, the FRs and CDRs are arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The larger β-sheet configuration of the FRs ensures that the CDRs within each chain are adjacent to each other and to CDRs in another chain. This conformation facilitates antigen binding sites (see Kabat et al., 1991, NIH Publ. 91-3242, Vol. I, pp. 647-669), but not all CDR residues must directly participate in antigen binding.

[0236] FR residues and Ig constant domains do not directly participate in antigen binding, but they contribute to antigen binding and / or mediate antibody effector functions. It is believed that some FR residues significantly affect antigen binding in at least three ways: direct non-covalent binding to epitopes, interaction with one or more CDR residues, and influencing the interface between heavy and light chains. Constant domains do not directly participate in antigen binding, but mediate various Ig effector functions, such as mediating antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent phagocytosis (ADCP).

[0237] The light chains of vertebrate immunoglobulins can be assigned to one of two distinct classes (κ and λ) based on the amino acid sequence of their constant domains. By comparison, the heavy chains of mammalian immunoglobulins are classified into five main categories based on the sequence of their constant domains: IgA, IgD, IgE, IgG, and IgM. IgG and IgA are further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The constant domains of the heavy chains corresponding to different immunoglobulin species are designated as α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional conformations of each type of natural immunoglobulin are well known.

[0238] 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-23p19 epitope antibody," "variant humanized anti-IL-23A epitope antibody," and "variant humanized anti-IL-23p19 epitope antibody" specifically encompass monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and antibody fragments (e.g., variable domains and other parts of the antibody) that exhibit the desired biological activity (e.g., IL-23A binding). The term "monoclonal antibody" (mAb) refers to an antibody with high specificity, meaning it is highly specific against a single antigenic determinant (i.e., "epitope"). Therefore, the modifier "monoclonal" refers to an antibody targeting the same epitope and should not be construed as requiring any specific method to produce the antibody. It should be understood that monoclonal antibodies can be prepared by any technique or method known in the art; including, for example, hybridoma methods (Kohler et al., 1975, Nature 256:495), or recombinant DNA methods known in the art (see, for example, U.S. Patent No. 4,816,567), or methods for isolating monoclonal antibodies generated in a recombinant manner using a phage antibody library by techniques described in the following documents: Clackson et al., 1991, Nature 352:624-628; and Marks et al., 1991, J. Mol. Biol. 222:581-597.

[0239] The term "monomer" refers to the homogeneous form of an antibody. For example, for a full-length antibody, a monomer is a monomeric antibody having two identical heavy chains and two identical light chains.

[0240] Chimeric antibodies consist of variable regions of the heavy and light chains of an antibody from one species (e.g., a non-human mammal, such as a mouse) and 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 the first species (e.g., a mouse) with a DNA sequence encoding the constant region of an antibody from the second species (e.g., a human), and transforming a host with an expression vector containing the linked sequence, thereby enabling the host to produce chimeric antibodies. Alternatively, a chimeric antibody may also be one in which one or more regions or domains of the heavy chain and / or light chain are identical, homologous, or variants of corresponding sequences in a monoclonal antibody from another immunoglobulin species or isotype, or derived from a shared sequence or germline sequence. Chimeric antibodies may include fragments of such antibodies, provided that the antibody fragment exhibits the desired biological activity of its parent antibody, such as binding to the same epitope (see, for example, U.S. Patent No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81:6851-6855).

[0241] The terms "antibody fragment," "anti-IL-23A antibody fragment," "anti-IL-23A epitope antibody fragment," and "humanized anti-IL-23A antibody fragment" refer to a portion of a full-length anti-IL-23A antibody that retains variable domains or functional capabilities, such as specific IL-23A epitope binding. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fd, Fv, scFv, and scFv-Fc fragments.

[0242] Full-length antibodies can be treated with enzymes such as papain or pepsin to generate useful antibody fragments. Papain digestion produces two identical antigen-binding antibody fragments called "Fab" fragments (each with a single antigen-binding site) and the remaining "Fc" fragment. The Fab fragment also contains a light chain constant domain and a heavy chain C-terminal domain. H1 Domain. Pepsin treatment produces the F(ab')2 fragment, which has two antigen-binding sites and can still cross-link antigens.

[0243] The difference between Fab' fragments and Fab fragments lies in the C H1 The C-terminus of the domain contains additional residues, including one or more cysteine ​​residues from the antibody hinge region. The F(ab')2 antibody fragment is a Fab' fragment pair linked by cysteine ​​residues in the hinge region. Other chemical conjugations of antibody fragments are also known.

[0244] The “Fv” fragment contains a complete antigen recognition and binding site, which is a dimer composed of a heavy chain variable domain and a light chain variable domain tightly linked nonvalently. In this configuration, the three CDRs of each variable domain interact, thereby enabling the antigen to recognize and bind to the V. H -V L The surface of the dimer defines the antigen-binding site. These six CDRs collectively confer antigen-binding specificity to the antibody.

[0245] "Single-chain Fv" or "scFv" antibody fragments contain antibody V H and V L A single-chain Fv variant containing a domain, wherein the domain is present within a single polypeptide chain. The single-chain Fv can recognize and bind to antigens. The scFv polypeptide may also optionally contain a domain located at V... H Domain and V L Peptide linkers between domains facilitate the formation of desired three-dimensional structures for antigen binding of scFv (see, for example, Pluckthun, 1994, In The Pharmacology of monoclonal Antibodies, Vol. 113, edited by Rosenburg and Moore, Springer-Verlag, New York, pp. 269-315).

[0246] "Humanized antibodies" or "humanized antibody fragments" are specific types of chimeric antibodies that comprise immunoglobulin amino acid sequence variants or fragments thereof, capable of binding a predetermined antigen, and comprising one or more FRs having substantially human immunoglobulin amino acid sequences and one or more CDRs having substantially non-human immunoglobulin amino acid sequences. This non-human amino acid sequence is often referred to as the "import" sequence and is typically derived from the "import" antibody domain, particularly the variable domain. Typically, humanized antibodies comprise at least a non-human antibody CDR or HVL inserted between FRs of human heavy or light chain variable domains. This invention describes specific humanized anti-IL-23A antibodies containing CDRs or humanized CDRs of mouse-derived monoclonal antibodies as shown in Tables 1 and 2, inserted between FRs of human germline heavy and light chain variable domains. It should be understood that certain mouse FR residues may be important for the function of the humanized antibody, and therefore some human germline heavy and light chain variable domain residues are modified to be identical to their corresponding mouse counterparts.

[0247] In another aspect, humanized anti-IL-23A antibodies substantially contain all at least one (usually two) variable domains (e.g., those contained in fragments such as Fab, Fab', F(ab')2, Fac, and Fv), wherein all or substantially all CDRs correspond to those of non-human immunoglobulins, and in particular all CDRs are the mouse or humanized sequences detailed in Tables 1 and 2 below, and all or substantially all FRs are FRs of human immunoglobulin common sequences or germline sequences. In another aspect, humanized anti-IL-23A antibodies also include at least a portion of the Fc region of an immunoglobulin (usually a human immunoglobulin). Typically, the antibody contains at least both a light chain and a heavy chain variable domain. Where applicable, the antibody may also include a heavy chain C... H1 Hinges, C H2 C H3 and / or C H4 One or more of the districts.

[0248] Humanized anti-IL-23A antibodies can be selected from any type 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 can be a complement-fixed constant domain, where the desired humanized antibody exhibits cytotoxic activity, and the isotype is typically IgG1. If this cytotoxic activity is not desired, the constant domain can be another isotype, such as IgG2. Alternative humanized anti-IL-23A antibodies can contain sequences from more than one immunoglobulin species or isotype, and those skilled in the art can skillfully select specific constant domains to optimize the desired effector function. In a specific embodiment, the antibody provided by this invention is an IgG1 antibody, and more specifically, an IgG1 antibody that knocks out the effector function.

[0249] The FR and CDR or HVL of a humanized anti-IL-23A antibody do not need to correspond precisely to the parental sequence. For example, one or more residues in the input CDR or HVL, or the common FR or germline FR sequence, can be altered (e.g., through substitution, insertion, or deletion, mutagenesis) so that the resulting amino acid residues are no longer identical to the original residues at the corresponding positions in either parental sequence, but the antibody retains its IL-23A binding function. This alteration is usually not a broad change but a conserved one. Typically, at least 75% of the humanized antibody residues correspond to those residues in the parental common FR or germline FR and the input CDR sequence, more often at least 90%, and most commonly more than 95%, more than 98%, or more than 99%.

[0250] The interface (“V”) between the variable regions of heavy and light chains affects the interface between them. L -V HImmunoglobulin residues at the interface are those residues that affect the proximity or orientation of two chains relative to each other. Some residues that may be involved in interchain interactions include V... L Residues 34, 36, 38, 44, 46, 87, 89, 91, 96, and 98, and V H Residues 35, 37, 39, 45, 47, 91, 93, 95, 100, and 103 (using the numbering system described in Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987)). Also discussed in U.S. Patent No. 6,407,213, for example, V L Residues 43 and 85 and V H Residues such as 43 and 60 may also be involved in this interaction. Although these residues are described only for human IgG, they are applicable to other species as well. Important antibody residues that are reasonably expected to participate in interchain interactions are selected for substitution in the common sequence.

[0251] The terms "shared sequence" and "shared antibody" refer to the amino acid sequence containing the most frequently occurring amino acid residues at each position in all immunoglobulins (e.g., human immunoglobulin variable domains) of any particular species, isotype, or subunit structure. Shared sequences may be based on immunoglobulins of a specific species or multiple species. A "shared" sequence, structure, or antibody is understood to encompass shared human sequences as described in some embodiments, and refers to the amino acid sequence containing the most frequently occurring amino acid residues at each position in all human immunoglobulins of any particular species, isotype, or subunit structure. Therefore, the amino acid sequence contained in a shared sequence has amino acids present at each position in one or more known immunoglobulins, but it may not precisely replicate the entire amino acid sequence of any single immunoglobulin. Variable region shared sequences are not available from any naturally occurring antibody or immunoglobulin (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, Md.) or its variants. The FR sequences of the heavy and light chain common sequences and their variants provide useful sequences for the preparation of humanized anti-IL-23P19 antibodies. See, for example, U.S. Patents 6,037,454 and 6,054,297.

[0252] Germline sequences are naturally found in human populations. The combination of these germline genes produces antibody diversity. Germline antibody sequences of the antibody light chain originate from conserved human germline κ or λ v- and j- genes. Similarly, heavy chain sequences originate from germline v-, d-, and j- genes (LeFranc, MP and LeFranc, G, “The Immunoglobulin Facts Book”, Academic Press, 2001).

[0253] As used herein, “variant,” “anti-IL-23A variant,” “humanized anti-IL-23A variant,” or “variant humanized anti-IL-23A” each refers to a humanized anti-IL-23A antibody having at least a light chain variable mouse CDR sequence derived from any of the sequences shown in Table 1, or at least a heavy chain mouse CDR sequence derived from a mouse monoclonal antibody as shown in Table 2. Variants include those having one or more amino acid changes in one or both light chain or heavy chain variable domains, provided that the amino acid changes do not materially impair the binding of the antibody to IL-23A. Exemplary antibodies generated herein include antibodies referred to as antibody A, antibody B, antibody C, and antibody D, and the various light and heavy chains of said antibodies are shown in SEQ ID NO: 18 and 21, and SEQ ID NO: 19 and 20, respectively.

[0254] "Isolated" antibodies are those that have been identified and isolated and / or recovered from their natural environmental components. Contaminant components in the antibody's natural environment are substances that can interfere with the diagnostic or therapeutic application of the antibody, and can be enzymes, hormones, or other proteinaceous or non-proteinaceous solutes. In one aspect, antibodies can be purified to a point where they are at least 95% isolated by weight.

[0255] Since at least one component of the antibody is absent in its natural environment, isolated antibodies include in situ antibodies from the recombinant cells that produced them. However, isolated antibodies are typically prepared via at least one purification step, in which the recombinant cellular material is removed.

[0256] The term "antibody performance" refers to factors that contribute to antibody recognition of antigens or antibody potency in vivo. Changes in the antibody's amino acid sequence can affect antibody properties such as folding, and can also influence physical factors such as the initial rate of antibody-antigen binding (kb). a ), the dissociation constant of antibody from antigen (k) d ), antibody affinity constant (Kd) to antigen, antibody conformation, protein stability, and antibody half-life.

[0257] As used herein, the term "epitope-tagged" refers to the fusion of an anti-IL-23A antibody with an "epitope tag." An "epitope tag" is a polypeptide containing sufficient amino acids to provide an epitope for antibody production, but designed so as not to interfere with the desired activity of the anti-IL-23A antibody. Epitope tags are typically sufficiently unique so that antibodies generated against that epitope tag do not substantially cross-react with other epitopes. Suitable tagged polypeptides generally contain at least six amino acid residues and typically contain approximately 8 to 50 amino acid residues or approximately 9 to 30 residues. Examples of epitope tags and antibodies binding to epitopes include influenza HA-tagged peptides and their antibody 12CA5 (Field et al., 1988 Mol. Cell. Biol. 8: 2159-2165); c-myc tags and their 8F9, 3C7, 6E10, G4, B7, and 9E10 antibodies (Evan et al., 1985, Mol. Cell. Biol. 5(12): 3610-3616); and herpes simplex virus glycoprotein D (gD) tags and their antibodies (Paborsky et al., 1990, Protein Engineering 3(6): 547-553). In some embodiments, the epitope tag is a “salvage receptor binding epitope.” As used herein, a “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 increasing the in vivo serum half-life of the IgG molecule.

[0258] For diagnostic and therapeutic monitoring purposes, the antibodies of the present invention can also be conjugated to labels (labels alone or labels with an additional second agent (prodrug, chemotherapeutic agent, etc.)). The label, unlike other second agents, refers to a drug as a detectable compound or composition, and can be conjugated directly or indirectly to the antibodies of the present invention. The label itself is detectable (e.g., radioisotope labeling or fluorescent labeling), or, in the case of enzyme labeling, can catalyze a chemical change in a detectable substrate compound or composition. Labeled anti-IL-23A antibodies can be prepared and used in a variety of applications, including in vitro and in vivo diagnostics.

[0259] In various aspects of this invention, one or more domains of the antibody are recombinantly expressed. This recombinant expression may employ one or more control sequences, i.e., polynucleotide sequences required to express an operable linked coding sequence in a specific host organism. Control sequences suitable for prokaryotic cells include, for example, promoters, operons, and ribosome-binding site sequences. Eukaryotic control sequences include, but are not limited to, promoters, polyadenylation signals, and enhancers. These control sequences can be used to express and generate anti-IL-23A antibodies in prokaryotic and eukaryotic host cells.

[0260] When a nucleic acid sequence is placed in a position to functionally link with another nucleic acid sequence, the nucleic acid sequence is "operably linked." For example, if a pre-sequence or secretory leader sequence expresses a pre-protein involved in polypeptide secretion, then the pre-sequence or secretory leader sequence is operably linked to the nucleic acid encoding the polypeptide; if a promoter or enhancer affects the transcription of the sequence, then the promoter or enhancer is operably linked to the sequence; or if the localization of the ribosome binding site promotes translation, then the ribosome binding site is operably linked to the coding sequence. Generally, "operably linked" means that the linked DNA sequence is a continuous sequence, and in the case of a secretory leader sequence, it is a continuous sequence located within the reading frame. However, enhancers are optionally continuous. Ligation can be accomplished by joining at a convenient restriction site. If such a site is not available, synthetic oligonucleotide adapters or linkers can be used.

[0261] The terms “cell,” “cell line,” and “cell culture” used herein are used interchangeably, and all such names include their progeny. Therefore, “transformation” and “transformed cells” include primary test cells and their derived cultures regardless of the number of transfers.

[0262] For therapeutic purposes, the term "mammal" means any animal classified as a mammal, including humans, livestock and farm animals, as well as zoo animals, sporting animals, or pets, such as dogs, horses, cats, cattle, etc. Preferably, the mammal is a human.

[0263] As used herein, “condition” refers to any condition that can benefit from treatment with the anti-IL-23A antibody described herein. This term includes both chronic and acute conditions or diseases, including pathological conditions that predispose mammals to these conditions.

[0264] As used herein, the term "IL-23-related condition" or "IL-23-related disease" refers to a condition characterized by IL-23 activity and abnormal expression of IL-23. IL-23-related conditions include immune system disorders and conditions, such as autoimmune disorders and inflammatory diseases. These conditions include psoriasis, inflammatory bowel diseases such as ulcerative colitis or Crohn's disease, and spondyloarthritis such as ankylosing spondylitis, radionegative axial spondyloarthritis, peripheral spondyloarthritis, or psoriatic arthritis.

[0265] The term "intravenous infusion" refers to the administration of a drug into a vein in an animal or human patient over a period of time greater than approximately 15 minutes, typically between 30 and 90 minutes.

[0266] The term "intravenous bolus" or "intravenous push" refers to the administration of a drug into a vein in an animal or human, so that the body receives the drug in about 15 minutes or less, typically 5 minutes or less.

[0267] The term "subcutaneous administration" refers to the introduction of a drug under the skin of an animal or human patient, preferably within a pocket between the skin and the basal tissue, via a relatively slow and continuous delivery from the drug reservoir. A pocket is created by pinching or pulling the skin upwards away from the basal tissue.

[0268] The term "subcutaneous infusion" refers to the introduction of a drug under the skin of an animal or human patient, preferably within a capsule between the skin and the underlying tissue, over a period of time (including but not limited to 30 minutes or less, or 90 minutes or less) via a relatively slow, continuous delivery from a drug reservoir. Optionally, the infusion may be performed via a subcutaneously implanted drug delivery pump (implanted under the skin of an animal or human patient), wherein the pump delivers a predetermined amount of drug over a predetermined period of time (e.g., 30 minutes, 90 minutes, or a period spanning the entire treatment regimen).

[0269] The term "subcutaneous injection" refers to the administration of a drug under the skin of an animal or human patient, wherein the drug is delivered in less than about 15 minutes; in another respect, less than 5 minutes; and in yet another respect, less than 60 seconds. Alternatively, it may be administered within a sac between the skin and the underlying tissue, wherein the sac is created by pinching or pulling the skin upwards away from the underlying tissue.

[0270] The term "therapeutic effective dose" refers to the amount of an active medicine that relieves or improves one or more symptoms of the condition being treated. In another sense, a therapeutic effective dose refers to a target serum concentration that has been shown to be effective, for example, in slowing disease progression. Efficacy may be measured in a commonly used manner depending on the condition to be treated.

[0271] As used herein, the terms “treatment” and “therapeutic approach” and similar terms are intended to include therapeutic and preventative or inhibitory measures against a disease or condition that result in any clinically desired or beneficial effect, including but not limited to reducing or alleviating one or more symptoms of the disease or condition, or causing the progression of the disease or condition to subside, slow, or cease. Thus, for example, the term “treatment” includes administering a drug before or after the onset of symptoms of a disease or condition, thereby preventing or eliminating one or more signs of the disease or condition. As another example, the term includes administering a drug after the clinical manifestation of a disease, thereby combating the symptoms of that disease. Furthermore, administering a drug after an onset and after the appearance of clinical symptoms includes the use of “treatment” or “therapeutic approach” herein, wherein, regardless of whether the treatment results in disease improvement, the administration affects clinical parameters of the disease or condition, such as the degree of tissue damage or the amount or extent of metastasis. Additionally, any reduction or improvement in at least one symptom of the treated condition by the composition of the present invention, alone or in combination with another therapeutic agent, compared to the absence of the anti-IL-23A antibody composition, whether or not all symptoms of the condition are reduced, shall be considered an effective treatment for the underlying condition.

[0272] The term "instructions for use" as used refers to the instructions for use typically included in the commercial packaging of a therapeutic product, which contains information about the indications, usage, application, contraindications, and / or warnings for using the therapeutic product.

[0273] Antibody

[0274] The CDRs of the selected antibodies used in the context of this invention are shown in Tables 1 and 2. The variable regions of the selected antibodies used in the context of this invention are shown in Tables 3 and 4.

[0275] Table 1: Light Chain CDR Sequences

[0276]

[0277] Table 2: Heavy Chain CDR Sequences

[0278]

[0279] Table 3: Humanized 6B8-VK sequence

[0280]

[0281] Table 4: Humanized 6B8-VH sequence

[0282]

[0283] Selected combinations of humanized light and heavy chain variable regions derived from mouse antibody 6B8 produced antibodies A, B, C, and D:

[0284] Antibody A: 6B8-IgG1KO-2 with IgK-66 (heavy chain variable region 6B8CVH-02 and light chain variable region 6B8CVK-66);

[0285] Antibody B: 6B8-IgG1KO-5 with IgK-66 (heavy chain variable region 6B8CVH-05 and light chain variable region 6B8CVK-66);

[0286] Antibody C: 6B8-IgG1KO-2 with IgK-65 (heavy chain variable region 6B8CVH-02 and light chain variable region 6B8CVK-65);

[0287] Antibody D: 6B8-IgG1KO-5 with IgK-65 (heavy chain variable region 6B8CVH-05 and light chain variable region 6B8CVK-65).

[0288] Antibodies A, B, C, and D have the heavy and light chain sequences shown in Table 5.

[0289] Table 5: Heavy and light chain DNA and amino acid sequences of antibodies A, B, C, and D

[0290]

[0291]

[0292] In Table 5 above, the variable regions of the light and heavy chains of antibodies A, B, C, and D are underlined.

[0293] In another 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 another 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 another 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 another 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.

[0294] In another 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 another 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 another 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 another 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.

[0295] In a further embodiment, the anti-IL-23A antibody binds to human IL-23A at an epitope consisting of amino acid residues 108 to 126 and amino acid residues 137 to 151 of SEQ ID NO:22.

[0296] In a further embodiment, the anti-IL23A antibody competitively binds to human IL-23A with antibodies of the present invention (e.g., antibody A, antibody B, antibody C, and antibody D described herein). The ability of the antibody to competitively bind to IL23A can be measured using competitive binding assays known in the art.

[0297] In some embodiments, the anti-IL-23A antibody comprises a light chain variable region sequence having the amino acid sequence shown 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 shown 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 a combination of a light chain variable region and a heavy chain variable region having SEQ ID NO: 11 / 14, 11 / 15, 10 / 14, or 10 / 15. Such variable regions can be combined with human constant regions.

[0298] Polynucleotides, vectors, host cells and recombination methods

[0299] Other embodiments encompass isolated polynucleotides containing sequences encoding anti-IL-23A antibodies, and vectors, host cells, and recombinant technologies for producing the humanized antibodies, containing said polynucleotides. The isolated polynucleotides can encode any desired form of the anti-IL-23A antibody, including, for example, full-length monoclonal antibodies, Fab, Fab', F(ab')2, and Fv fragments.

[0300] A polynucleotide containing a sequence encoding an anti-IL-23A antibody may be fused with one or more regulatory or control sequences known in the art and may be contained in a suitable expression vector or host cell known in the art. Each polynucleotide molecule encoding a heavy or light chain variable domain may be independently fused with a polynucleotide sequence encoding a constant domain (e.g., a human constant domain) to generate a complete antibody. Alternatively, polynucleotides or portions thereof may be fused together to provide a template for generating a single-chain antibody.

[0301] For recombinant production, a polynucleotide encoding an antibody is inserted into a reproducible vector for cloning (DNA amplification) or expression. A variety of vectors suitable for expressing recombinant antibodies are available. Vector components typically include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer component, a promoter, and a transcription termination sequence.

[0302] Anti-IL-23A antibodies can also be produced in fusion peptide form, where the antibody is fused to a heterologous peptide, such as a signal sequence or another peptide having a specific cleavage site at the N-terminus of a mature protein or peptide. The selected heterologous signal sequence is typically a sequence that can be recognized and processed by the host cell (i.e., cleaved by a signal peptidase). For prokaryotic host cells that cannot recognize and process the anti-IL-23A antibody signal sequence, the signal sequence can be replaced by a prokaryotic signal sequence. The signal sequence can be, for example, alkaline phosphatase, penicillinase, lipoprotein, thermostable enterotoxin II leader sequence, etc. For yeast secretion, the natural signal sequence can be replaced by, for example, leader sequences derived from yeast convertase α-factors (including Saccharomyces and Kluyveromyces α-factor leader sequences), acid phosphatase, Candida albicans glucoamylase, or signals described in WO90 / 13646. In mammalian cells, mammalian signal sequences and viral secretion leader sequences (e.g., herpes simplex virus gD signal) can be used. The DNA in the precursor region binds to the DNA encoding the anti-IL-23A antibody within the reading frame.

[0303] Expression and cloning vectors contain nucleic acid sequences that enable the vector to replicate in one or more selected host cells. Typically, in cloning vectors, this sequence is the one that enables the vector to replicate independently of the host chromosomal DNA, and it includes an origin of replication or an autonomous replication sequence. Such sequences are well known in the art for use in a variety of bacteria, yeasts, and viruses. Origin of replication from plasmid pBR322 is suitable for most Gram-negative bacteria, 2-υ plasmid origins are suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV, and BPV) can be used for cloning vectors in mammalian cells. Typically, mammalian expression vectors do not require an origin of replication component (the SV40 origin may often be used, simply because it contains an early promoter).

[0304] Expression and cloning vectors may contain genes encoding selectable markers to aid in the identification of expression. Typical selectable marker genes encode proteins that confer resistance to antibiotics or other toxins (e.g., ampicillin, neomycin, methotrexate, or tetracycline); proteins that are complement auxotrophs; or proteins that supply specific nutrients not present in the complex culture medium in other alternatives, such as genes encoding D-alanine racemic enzymes in Bacilli.

[0305] One example of a selection strategy utilizes drugs to inhibit the growth of host cells. Cells successfully transformed with the heterologous gene produce drugs-conferring proteins and thus survive in this selection process. Examples of this dominant selection use drugs such as neomycin, mycophenolic acid, and hygromycin. Common selectable markers for mammalian cells are those that allow identification of cells occupying nucleic acids encoding anti-IL-23A antibodies, 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 medium containing methotrexate (Mtx) (a competitive antagonist of DHFR). When using wild-type DHFR, suitable host cells are DHFR-deficient Chinese hamster ovary (CHO) cell lines (e.g., DG44).

[0306] Alternatively, host cells transformed or co-transformed with a DNA sequence encoding an anti-IL-23A antibody, wild-type DHFR protein, and another selectable marker (e.g., glucosinolate 3'-phosphotransferase (APH)) (especially wild-type hosts containing endogenous DHFR) can be selected by growing the cells in a medium containing a selector targeting the selectable marker (e.g., an aminoglycoside antibiotic, such as kanamycin, neomycin, or G418). See, for example, U.S. Patent No. 4,965,199.

[0307] When using yeast cells as host cells for recombinant production, the TRP1 gene, present in the yeast plasmid YRp7 (Stinchcomb et al., 1979, Nature 282:39), can be used as a selectable marker. The TRP1 gene provides a selectable marker for yeast mutant strains lacking the ability to grow in tryptophan (e.g., ATCC 44076 or PEP4-1) (Jones, 1977, Genetics 85:12). The presence of trp1 damage in the yeast host cell genome then provides an effective environment for detecting transformation by growth in the absence of tryptophan. Similarly, Leu2p-deficient yeast strains (e.g., ATCC20,622 or 38,626) are supplemented using known plasmids containing the LEU2 gene.

[0308] Alternatively, a vector derived from the 1.6 μm circular plasmid pKD1 can be used to transform Kluyveromyces. Or, an expression system reported for the large-scale production of recombinant bovine chymotrypsin can be used in Kluyveromyces lactis (K. lactis.) (Van den Berg, 1990, Bio / Technology 8:135). Stable multi-copy expression vectors for the secretion of mature recombinant human serum albumin by industrial strains of Kluyveromyces have also been disclosed (Fleer et al., 1991, Bio / Technology 9:968-975).

[0309] Expression and cloning vectors typically contain a promoter that is recognized by the host organism and operatively linked to a nucleic acid molecule encoding an anti-IL-23P19 antibody or its polypeptide chain. Promoters suitable for prokaryotic hosts include the phoA promoter, β-lactamase and lactose promoter systems, alkaline phosphatase, tryptophan (trp) promoter systems, and hybrid promoters (e.g., the tac promoter). Other known bacterial promoters are also suitable. Promoters for bacterial systems may also contain a Shine-Dalgamo (SD) sequence operatively linked to DNA encoding an anti-IL-23A antibody.

[0310] A variety of eukaryotic promoter sequences are known. In fact, all eukaryotic genes possess an AT-rich region, located approximately 25 to 30 bases upstream of the transcription start site. Another sequence, the CNCAAT region, is found 70 to 80 bases upstream of the transcription start site in many genes, where N can be any nucleotide. The AATAAA sequence is located at the 3' end of most eukaryotic genes, which may be a signal to add a poly-A tail to the 3' end of the coding sequence. All these sequences are inserted appropriately into eukaryotic expression vectors.

[0311] Examples of suitable promoter sequences for yeast hosts include promoters of the following enzymes: 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, triose phosphate isomerase, glucose phosphate isomerase, and glucoskinase.

[0312] Another advantage of inducible promoters is the ability to control transcription through growth conditions. These include yeast promoter regions for enzymes such as alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, nitrogen metabolism-related derivative enzymes, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization. Suitable vectors and promoters for yeast expression are further described in EP 73,657. Yeast enhancers can also be advantageously used in conjunction with yeast promoters.

[0313] Transcription of anti-IL-23A antibody self-vectors in mammalian host cells is controlled by promoters derived from, for example, viral genomes such as polyomavirus, fowlpox virus, adenovirus (e.g., adenovirus 2), bovine papillomavirus, avian sarcoma virus, cytomegalovirus, retrovirus, hepatitis B virus, and simian virus 40 (SV40); heterologous mammalian promoters such as actin promoters or immunoglobulin promoters; or heat shock promoters, provided that the promoters are compatible with the host cell system.

[0314] Early and late promoters of SV40 virus are conveniently obtained in the form of SV40 restriction fragments, which also contain the SV40 virus origin of replication. The immediate early promoter of human cytomegalovirus is conveniently obtained in the form of HindIII E restriction fragments. A system for expressing DNA in a mammalian host using bovine papillomavirus as a vector is disclosed in U.S. Patent No. 4,419,446. Modifications to this system are described in U.S. Patent No. 4,601,978. See also Reyes et al., 1982, Nature 297:598-601, which discloses the expression of human p-interferon cDNA in mouse cells under the control of a thymidine kinase promoter derived from herpes simplex virus. Alternatively, a long terminal repeat sequence of Rous sarcoma virus can be used as a promoter.

[0315] Another available element for recombinant expression vectors is the enhancer sequence, which is used to enhance the transcription of DNA encoding anti-IL-23A antibodies in higher eukaryotes. Several enhancer sequences are known from mammalian genes (e.g., globin, elastase, albumin, alpha-fetoprotein, and insulin). However, enhancers from eukaryotic viruses are commonly used. Examples include the SV40 enhancer located on the late side (bp 100-270) of the origin of replication, the cytomegalovirus early promoter enhancer, the polyoma enhancer located on the late side of the origin of replication, and the adenovirus enhancer. A description of enhancer elements that activate eukaryotic promoters can also be found in Yaniv, 1982, Nature 297:17-18. The enhancer can be spliced ​​to the 5' or 3' position of the anti-IL-23A antibody coding sequence in the vector, but preferably at the 5' site of the promoter.

[0316] Expression vectors intended for use in eukaryotic host cells (yeast, fungi, insects, plants, animals, human cells, or nucleated cells from other multicellular organisms) may also contain sequences required to terminate transcription and stabilize the mRNA. These sequences are generally derived from the 5' untranslated region of eukaryotic or viral DNA or cDNA, and sometimes from its 3' untranslated region. These regions contain nucleotide segments that are transcribed into polyadenylated fragments in the untranslated portion of the mRNA encoding the anti-IL-23A antibody. One available transcription termination component is the bovine growth hormone polyadenylated region. See WO94 / 11026 and the expression vectors disclosed therein. In some embodiments, humanized anti-IL-23p19 antibodies may be expressed using the CHEF system. (See, for example, U.S. Patent No. 5,888,809, the disclosure of which is incorporated herein by reference.)

[0317] Suitable host cells for cloning or expressing DNA in the vector described above are prokaryotic cells, yeast cells, or higher eukaryotic cells. Suitable prokaryotes for this purpose include eubacteria, such as Gram-negative or Gram-positive organisms, such as: Enterobacteriaceae such as Escherichia (e.g., *Escherichia coli*), Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella (e.g., *Salmonella typhimurium*), Serratia (e.g., *Serratia marcescans*), and Shigella; and Bacillus (e.g., *Bacillus subtilis* and *Bacillus licheniformis*, as described in DD, published on April 12, 1989). The *Bacillus licheniformis* 41P, *Pseudomonas* (e.g., *Pseudomonas aeruginosa*), and *Streptomyces* disclosed in 266,710 are examples. A preferred *Escherichia coli* cloning host is *Escherichia coli* 294 (ATCC 31,446), but other strains (e.g., *Escherichia coli* B, *Escherichia coli* X1776 (ATCC 31,537), and *Escherichia coli* W3110 (ATCC 27,325)) are also suitable. The examples described are illustrative and not limiting.

[0318] Besides prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeasts are also suitable cloning or expression hosts for vectors encoding anti-IL-23A antibodies. Saccharomyces cerevisiae or common baker's yeast are the most commonly used lower eukaryotic host microorganisms. However, many other genera, species, and strains are generally available and can be used in this paper, such as *Schizosaccharomyces pombe*; hosts of the genus *Kluyveromyces*, such as *Kluyveromyces lactis*, *Kluyveromyces fragilis* (ATCC 12,424), *Kluyveromyces bulgaricus* (ATCC 16,045), *Kluyveromyces wickeramii* (ATCC 24,178), *Kluyveromyces waltii* (ATCC 56,500), *Kluyveromyces drosophilarum* (ATCC 36,906), *Kluyveromyces thermotolerans*, and *Kluyveromyces marxianus*; the genus *Yarrowia* (EP 402,226); and *Pichiapastoris* (EP 402,226). 183,070); Candida; Trichoderma reesia (EP244,234); Neurospora crassa; Schwanniomyces, such as Schwanniomyces occidentalis; and filamentous fungi, such as hosts of Neurospora, Penicillium, Tolypocladium and Aspergillus (e.g. Aspergillus nidulans and Aspergillus niger).

[0319] Suitable host cells for expressing glycosylated anti-IL-23A antibodies are derived from multicellular organisms. Examples of invertebrate cells include plant and insect cells, including, for example, various baculovirus strains and variants, and corresponding licensed insect host cells from, for example, the fall armyworm (Spodoptera frugiperda), the mosquito (Aedes aegypti), the mosquito (Aedes albopictus), the fruit fly (Drosophila melanogaster), and the silkworm (Bombyx mori). Various transfection virus strains are available from publicly available sources, such as the L-1 variant of the alfalfa silver-striped armyworm (Autographa californica) NPV and the Bm-5 strain of the silkworm NPV, and these viruses are particularly useful for transfecting fall armyworm cells.

[0320] Plant cell cultures of cotton, corn, potato, soybean, petunia, tomato, and tobacco can also be used as hosts.

[0321] On another front, the expression of anti-IL-23A antibodies occurs in vertebrate cells. The propagation of vertebrate cells in culture (tissue culture) has become routine and the techniques are widely available. Examples of usable mammalian host cell lines include monkey kidney CV1 line (COS-7, ATCC CRL 1651) transformed with SV40, human embryonic kidney line (293 line or 293 cells subcloned for growth in suspension culture, Graham et al., 1977, J. Gen Virol. 36:59), juvenile hamster kidney cells (BHK, ATCCCCL 10), Chinese hamster ovary cells / -DHFR1 (CHO, Urlaub et al., 1980, Proc. Natl. Acad. Sci. USA77:4216; e.g. DG44), mouse testicular 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), and human cervical cancer cells (HELA, ATCC CCL). 2) Canine kidney cells (MDCK, ATCC CCL 34), buffalo rat hepatocytes (BRL 3A, ATCC CRL 1442), human lung cells (W138, ATCC CCL 75), human hepatocytes (Hep G2, HB 8065), mouse mammary tumors (MMT 060562, ATCC CCL51), TR1 cells (Mather et al., 1982, Annals NYAcad. Sci. 383: 44-68), MRC 5 cells, FS4 cells, and human hepatocellular carcinoma lineage (Hep G2).

[0322] The host cells were transformed using the expression or cloning vector described above for generating anti-IL-23A antibodies and cultured in a conventional nutrient medium modified to induce promoters, select transformants, or amplify genes encoding desired sequences.

[0323] Host cells used to produce the anti-IL-23A antibody described herein can be cultured in a variety of media. Commercially available media suitable for culturing host cells include Ham's F10 (Sigma-Aldrich, St. Louis, Mo.), Minimal Essential Medium (MEM, Sigma-Aldrich), RPMI-1640 (Sigma-Aldrich), and Dulbecco's Modified Eagle's Medium (DMEM, Sigma-Aldrich). Alternatively, any culture medium described in one or more of the following documents may be used as the culture medium for host cells: Ham et al., 1979, Meth. Enz. 58:44; Barnes et al., 1980, Anal. Biochem. 102:255; U.S. Patent Nos. 4,767,704, 4,657,866, 4,927,762, 4,560,655, 5,122,469, WO 90 / 103430, and WO 87 / 00195. Any of the culture media may be supplemented as needed with hormones and / or other growth factors (e.g., insulin, transferrin, or epidermal growth factor), salts (e.g., sodium chloride, calcium, magnesium, and phosphate), buffers (e.g., HEPES), nucleotides (e.g., adenosine and thymidine), antibiotics (e.g., gentamicin), trace elements (defined as inorganic compounds typically present in micromolar final concentrations), and glucose or an equivalent energy source. Other supplements may also be included at appropriate concentrations known to those skilled in the art. Culture conditions, such as temperature, pH, etc., are those previously used for expression in the selected host cells and are obvious to those skilled in the art.

[0324] When using recombinant technology, antibodies can be produced intracellularly, in the periplasmic space, or secreted directly into the culture medium. If antibodies are produced intracellularly, the first step is to rupture the cells to release the proteins. Microparticle debris, i.e., host cells or lysed fragments, can be removed by centrifugation or ultrafiltration. Carter et al., 1992, Bio / Technology 10: 163-167, describe the steps for isolating antibodies secreted into the intermembrane space of *E. coli*. Briefly, the cell paste is thawed for approximately 30 minutes in the presence of sodium acetate (pH 3.5), EDTA, and benzoyl sulfonyl fluoride (PMSF). Cell debris can be removed by centrifugation. If antibodies are secreted into the culture medium, the supernatant from the expression system is typically concentrated first using a commercially available protein concentrater (e.g., an Amicon or Millipore Pellicon ultrafiltration unit). Protease inhibitors, such as PMSF, may be included in any of the aforementioned steps to inhibit proteolysis, and antibiotics may be included to prevent the growth of foreign contaminants. Various methods can be used to isolate antibodies from host cells.

[0325] Cell-derived antibody compositions can be purified using, for example, hydroxyapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being a commonly used 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 γ1, γ2, or γ4 heavy chains (see, for example, Lindmark et al., 1983 J. Immunol. Meth. 62: 1-13). Protein G is recommended for all mouse isotypes and human γ3 (see, for example, Guss et al., 1986 EMBO J. 5: 1567-1575). The most frequently used matrix for affinity ligand attachment is agarose, but other matrices can also be used. Mechanically stable matrices (e.g., controlled porous glass or poly(divinyl)styrene) allow for faster flow rates and shorter processing times compared to agarose. If the antibody contains C... H3 For this purpose, Bakerbond ABX™ resin (JT Baker, Phillipsburg, NJ) can be used for purification. Depending on the antibody to be recovered, other protein purification techniques may also be used, such as ion exchange column fractionation, ethanol precipitation, reversed-phase HPLC, silica gel chromatography, heparin SEPHAROSE™ chromatography on anion or cation exchange resins (e.g., polyaspartic acid columns), chromatographic focusing, SDS-PAGE, and ammonium sulfate precipitation.

[0326] After any initial purification step, the mixture containing the target antibody and contaminants can be subjected to low-pH hydrophobic interaction chromatography using an elution buffer with a pH of about 2.5 to 4.5, typically at low salt concentrations (e.g., about 0–0.25 M salt).

[0327] Therapeutic uses

[0328] In another embodiment, the anti-IL-23A antibody disclosed herein can be used to treat various conditions related to IL-23p19 expression as described herein. In one aspect, a method for treating IL-23-related conditions includes administering a therapeutically effective amount of the anti-IL-23A antibody to a subject in need.

[0329] Anti-IL-23A antibodies or drugs may be administered by any suitable method, including parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal administration, and, if local immunosuppressive therapy is required, intralesional administration (including perfusion or other methods of contacting the graft with the antibody prior to transplantation). Anti-IL-23A antibodies or drugs may be administered, for example, by infusion or bolus. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Additionally, anti-IL-23A antibodies are suitable for appropriate administration by pulsatile infusion, particularly by decreasing doses of the antibody. In one aspect, administration may be by injection, preferably intravenous or subcutaneous, depending in part on whether the administration is for short-term or long-term use. In another aspect, administration of anti-IL-23 antibodies may be performed by subcutaneous injection.

[0330] When preventing or treating disease, the appropriate dosage of antibodies can depend on a variety of factors, such as the type of disease to be treated as defined above, the severity and course of the disease, whether the antibody is administered for prevention or treatment, prior treatment, the patient's clinical history and response to the antibody, and the judgment of the attending physician. Antibodies may be administered to the patient in a single dose or as part of a series of appropriate treatments.

[0331] The term “suppression” as used in this article refers to the reduction of one or more features of a disease in the same context as “improvement” and “relief”.

[0332] Antibodies can be formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this context include the specific disease being treated, the specific mammal being treated, the individual patient's clinical condition, etiology, drug delivery site, method of administration, timing of administration, and other factors known to the practitioner. The "therapeutic effective amount" of antibody to be administered may depend on the aforementioned factors and is the minimum amount required to prevent, improve, or treat conditions associated with IL-23 expression.

[0333] The antibody may optionally be formulated with one or more drugs currently used for the prevention or treatment of the condition in question. The effective amount of the other drugs depends on the amount of anti-IL-23A antibody present in the formulation, the type of condition or treatment, and the other factors mentioned above.

[0334] IL-23 related diseases

[0335] Anti-IL-23p19 antibodies or agents can be used to treat or prevent immune disorders characterized by abnormal IL-23 expression, for example, due to inappropriate activation of immune cells (e.g., lymphocytes or dendritic cells). This abnormal expression of IL-23 can be attributed to, for example, increased IL-23 protein levels.

[0336] Immune diseases characterized by inappropriate activation of immune cells and which can be treated or prevented by the methods described herein can be classified according to, for example, the type of hypersensitivity response to the condition. These responses are generally classified into four categories: anaphylactic reactions, cytotoxic (cell lysis) reactions, immune complex reactions, or cell-mediated immune (CMI) reactions (also known as delayed-type hypersensitivity (DTH) reactions). (See, for example, Fundamental Immunology (edited by William E. Paul, Raven Press, NY, 3rd ed., 1993)). Immune diseases include inflammatory diseases and autoimmune diseases.

[0337] Examples of immune disorders include psoriasis, inflammatory bowel diseases such as ulcerative colitis or Crohn's disease, and vertebral arthritis such as ankylosing spondylitis, radionegative axial vertebral arthritis, peripheral vertebral arthritis, or psoriatic arthritis.

[0338] In one aspect, within the context of this invention, the immune disease is psoriasis. Psoriasis is a chronic inflammatory disease of the skin characterized by dysfunction and excessive proliferation of keratinocyte differentiation, and a significant accumulation of inflammatory T cells and dendritic cells. For example, the immune disease includes plaque psoriasis, such as chronic plaque psoriasis, such as moderate to severe chronic plaque psoriasis, for example, in patients who are candidates for systemic therapy or phototherapy. In one aspect, the immune disease is moderate to severe plaque psoriasis, and the patient is a patient who has no response to, or has contraindications to, or is intolerant to, other systemic therapies, including cyclosporine, methotrexate, psoralen, or ultraviolet-A light (PUVA)).

[0339] For example, the immune diseases mentioned include palmar pustular psoriasis, guttate psoriasis, skinfold psoriasis, pustular psoriasis, or erythrodermic psoriasis (also known as psoriatic erythroderma).

[0340] For psoriasis, disease severity can be characterized as follows: a body surface area (BSA) of <5% is considered mild, 5-10% is considered moderate, and >10% is considered severe. In some cases, the Psoriasis Area and Severity Index (PASI) is used to measure the disease status. The PASI is a composite measure of erythema, induration, scaling, and BSA affected by psoriasis, scored from 0 to 72. In one aspect, achieving a PASI score... 75 The percentage of patients with a PASI score of 75% (i.e., a 75% reduction from baseline at a given time (e.g., 12 or 16 weeks)) is used as the primary endpoint in psoriasis treatment (e.g., in psoriasis treatment trials). In one aspect, achieving the PASI score... 90 The percentage of patients whose PASI 90 score (i.e., a 90% decrease from baseline at a certain time (e.g., week 12 or 16) is used as the primary endpoint in psoriasis treatment (e.g., in psoriasis treatment trials).

[0341] In one aspect, the method according to the invention, for example using antibody A, achieves PASI at week 12. 90 The percentage of patients is at least 60%, at least 65%, or at least 70%.

[0342] In one aspect, the percentage of patients who achieve sPGA score clearance (score 0) or essential clearance (score 1) at a certain time (e.g., week 12 or 16) will be used as the primary endpoint in psoriasis treatment (e.g., in psoriasis treatment trials).

[0343] In one aspect, patients treated in the context of this invention are those with stable moderate to severe chronic plaque psoriasis, with or without psoriatic arthritis involving 10% or more of the body surface area, a disease severity PASI of 12 or greater, and / or a moderate or higher sPGA score (at least 3). In another aspect, patients treated with the content of this invention are those with a psoriasis duration of at least 6 months prior to the start of treatment.

[0344] In one aspect, within the context of this invention, the immune disease is psoriatic arthritis. For psoriatic arthritis, it refers to a patient with a history of psoriatic skin lesions or psoriasis combined with nail dystrophy, inflammation (dactylitis), and characteristic radiographic appearance (ill-defined ossification near joint margins) accompanied by a negative serological test for rheumatoid factor. The efficacy of treatment for psoriatic arthritis in clinical trials is often measured by the percentage of patients achieving the American College of Rheumatology (ACR) composite measure of efficacy, as used significantly in trials for rheumatoid arthritis. ACR20 refers to at least a 20% improvement in the number of swollen joints and the number of tender joints compared to baseline at some time point after the start of treatment (e.g., at 24 weeks), and a 20% improvement in 3 out of 5 ACR core suite measurements.

[0345] In one aspect, the percentage of ACR20 responders (20% improvement in the American College of Rheumatology response criteria) is used as the primary endpoint for the treatment of psoriatic arthritis (e.g., the Psoriatic Arthritis Treatment Trial) at 24 weeks.

[0346] In one aspect, the immune disease is psoriatic arthritis, such as active psoriatic arthritis, and the anti-IL-23A antibody is used alone or in combination with one or more non-biological DMARDs (disease-modifying antirheumatic drugs), for example, to reduce signs and symptoms. In another aspect, the anti-IL-23A antibody is used or indicated for inhibiting the progression of structural damage and / or improving bodily function.

[0347] In one aspect, the anti-IL-23A antibody, alone or in combination with methotrexate (MTX), is used for the treatment of psoriatic arthritis (e.g., active psoriatic arthritis), for example, when prior non-biological DMARD treatment has been insufficient. In another aspect, the anti-IL-23A antibody is used to reduce the rate of progression of peripheral joint damage as measured by X-ray, and / or improve physical function.

[0348] In one aspect, within the context of this invention, the immune disease is axial (vertebral) spondylitis (ax-SpA), including ankylosing spondylitis (AS, also known as radiographic ax-SpA) and radionegative ax-SpA.

[0349] In one aspect, within the context of this invention, the immune disease is ankylosing spondylitis. Ankylosing spondylitis (AS) is an inflammatory disease primarily involving the axial skeleton and sacroiliac joints. Other musculoskeletal manifestations of the disease include peripheral arthritis and enthesitis. Extra-articular manifestations include uveitis, osteoporosis, heart disease primarily involving the valves, kidney disease, lung disease, gastrointestinal disease, and skin disease. AS is predominantly male, with a male-to-female ratio of 3:1. The peak age of onset is typically between twenty and thirty years of age. The worldwide prevalence of AS is estimated to be between 0.5% and 0.07%. Patients with AS may lose their physical function and ability to work, which can significantly impact their quality of life without appropriate treatment.

[0350] For ankylosing spondylitis, patients present with inflammatory back pain, asymmetric peripheral arthritis, tendinitis (origin-insertion inflammation), and extra-articular features such as uveitis, as well as a strong genetic association with human leukocyte antigen B27. In one aspect, the percentage of responders (e.g., at 24 weeks) of the ankylosing spondylitis disease activity score 40 (ASDAS 40) is used as the primary endpoint for ankylosing spondylitis treatment (e.g., the Ankylosing Spondylitis Treatment Trial).

[0351] In one aspect, within the context of this invention, the immune disease is radionuclide-negative axial spondylitis (ax-SpA). Radionuclide-negative axial spondylitis (a more recently defined entity than AS) is considered to be an earlier manifestation representing the same pathological process as AS, although it is increasingly recognized that some patients (especially women) may not progress to radiographic disease and can therefore be considered as having a different subtype of this disease.

[0352] Pharmaceutical Compositions and Their Administration

[0353] Compositions containing anti-IL-23A antibodies can be administered to subjects at risk of developing an immune disorder. As used herein, the term "subject" means any mammalian patient to whom anti-IL-23A antibodies may be administered, including, for example, humans and non-human mammals such as primates, rodents, and dogs. Subjects who explicitly intend to be treated using the methods described herein include humans. In the prevention or treatment of an immune disorder, the antibody may be administered alone or in combination with other compositions.

[0354] Anti-IL-23A antibodies used in these pharmaceutical compositions are, as described herein, such as antibody A, antibody B, antibody C, or antibody D.

[0355] Various delivery systems are known and can be used to administer anti-IL-23A antibodies. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The anti-IL-23A antibody can be administered, for example, by infusion, bolus, or injection, and can be administered in combination with other bioactive agents, such as chemotherapeutic agents. Administration can be systemic or local. In one embodiment, administration is performed via subcutaneous injection. A formulation for injection can be prepared, for example, in a pre-filled syringe, which can be administered once weekly.

[0356] In specific embodiments, the anti-IL-23A antibody is administered by injection, via catheter, via suppository, or via implant, said implant being a porous, non-porous, or gel-like material, including membranes (e.g., silicone rubber membranes) or fibers. Typically, materials that do not absorb the anti-IL-23A antibody or the drug are used when administering the composition.

[0357] In other embodiments, the anti-IL-23A antibody is delivered using a controlled-release system. In one embodiment, a pump may be used (see, for example, 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 may be used. (See, for example, 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 controlled release systems are discussed, for example, in Ranger (as above).

[0358] Anti-IL-23p19 antibodies are typically administered as pharmaceutical compositions containing a therapeutically effective amount of the antibody and one or more pharmaceutically compatible ingredients.

[0359] In a typical implementation, the pharmaceutical composition is formulated according to standard procedures for intravenous or subcutaneous administration to humans. Typically, compositions intended for injection are solutions in a sterile isotonic buffer solution. If desired, the drug may also contain a solubilizer and a local anesthetic (e.g., lignocaine) to reduce pain at the injection site. Typically, the components are supplied individually or in combination in unit dosage forms, such as as lyophilized powders or anhydrous concentrates in sealed containers, such as ampoules or capsules, indicating the amount of active agent. If the drug is to be administered by infusion, it may be dispensed into infusion bottles containing sterile pharmaceutical-grade water or saline. If the drug is to be administered by injection, ampoules containing sterile water or saline for injection may be provided so that the components can be mixed prior to administration.

[0360] In addition, the pharmaceutical composition can be provided in the form of a pharmaceutical kit comprising: (a) a container containing an anti-IL-23A antibody in lyophilized form, and (b) a second container containing a pharmaceutically acceptable injectable diluent (e.g., sterile water). The pharmaceutically acceptable diluent can be used to reconstitute or dilute the lyophilized anti-IL-23A antibody. Optionally, the container may be accompanied by a notification in the form prescribed by a government agency regulating the manufacture, use, or sale of the pharmaceutical or biological product, indicating that the agency has approved its manufacture, use, or sale for human administration.

[0361] Examples of pharmaceutical compositions used in the context of this invention are disclosed in Example 4 below.

[0362] The present invention is further described in the following embodiments, which are not intended to limit the scope of the invention.

[0363] Example

[0364] Example 1: Clinical Study

[0365] The results shown in Examples 1a, 1b and 1c are derived from the same clinical study.

[0366] Example 1a: Research

[0367] This study evaluated the efficacy and safety of antibody A compared to ustekinumab in patients with moderate to severe plaque psoriasis.

[0368] 166 patients were randomized to one of three dosing regimens: antibody A (18 mg single injection; 90 or 180 mg at weeks 0 and 4) or ustecumab (45 or 90 mg). PASI (Psoriasis Area and Severity Index), sPGA (Static Physician Global Assessment), and safety parameters were assessed. The primary endpoint was achieving a PASI 90 at week 12 (≥90% reduction in PASI score from baseline), and a preliminary analysis comparing the two highest doses of antibody A (pooled) with ustecumab.

[0369] Preliminary analysis showed that antibody A was superior to ustecumab (PASI 90 response rate of 77.1% for antibody A compared to 40% for ustecumab [p<0.0001]). 90.4% of antibody A patients achieved an sPGA score of 0 (clearance) or 1 (basic clearance), compared to 67.5% for ustecumab patients. Complete clearance of damage (PASI 100) was achieved in 45.8% of antibody A patients and 17.5% of ustecumab patients. AEs were similar between treatment groups, with no drug-related severe or serious AEs (adverse events).

[0370] In patients with moderate to severe plaque psoriasis, selective blockade of IL-23p19 by antibody A was associated with a superior clinical response compared to uteroclosporine.

[0371] Example 1b: Research

[0372] Objective: To evaluate the efficacy and safety of antibody A as a selective IL-23p19 antagonist monoclonal antibody and to compare it with uteroclobeta in patients with moderate to severe plaque psoriasis (including those with and without concurrent psoriatic arthritis (PsA)).

[0373] Methods: In this phase 2 study, 166 patients were randomized (1:1:1:1) to receive one of three subcutaneous dosing regimens: antibody A (18 mg single dose at week 0; 90 or 180 mg at weeks 0, 4, and 16) or utecumab (45 or 90 mg at weeks 0, 4, and 16). Skin lesions were assessed using the Psoriasis Area and Severity Index (PASI), with the primary endpoint being a PASI 90 at week 12 (90% improvement from baseline). In patients with concurrent PsA (diagnosed or suspected by a rheumatologist), pain was assessed using the Visual Analogue Scale (VAS) at baseline and at weeks 4, 12, and 24. In this interim analysis, all patients completed the week 12 visit; incomplete data are available after week 12.

[0374] Results: In the 18, 90, and 180 mg groups, 32.6% (14 / 43), 73.2% (30 / 41), and 81.0% (34 / 42) of antibody A patients, respectively, achieved the primary endpoint of PASI 90 response at week 12, compared to 40.0% (16 / 40) of ustecimab patients. Two-sided Cochran-Mantel-Haenszel (stratified chi-square) tests for PASI 90 response at week 12 between the antibody A 18, 90, and 180 mg groups and ustecimab yielded p-values ​​of 0.4337, 0.0013, and <0.0001, respectively. 46 (27.7%) of the 166 patients also had PsA. In patients receiving antibody A at doses of 18, 90, and 180 mg, the median percentages of pain-VAS reduction from baseline at week 12 were 31.9%, 70.2%, and 58.4%, respectively, compared to 57.3% in patients treated with utecumab. In the antibody A at doses of 18, 90, and 180 mg, 29% (2 / 7), 73% (8 / 11), and 50% (6 / 12), respectively, achieved a reduction of more than 50% in pain-VAS (as defined above) at week 12, compared to 54% (7 / 13) in patients treated with utecumab. Figure 1 This indicates that a reduction in pain-VAS scores was observed as early as 4 weeks and maintained throughout 24 weeks (data incomplete). Adverse events (AEs) were similar between treatment groups, with no drug-related severe or serious AEs.

[0375] Conclusion: In patients with moderate to severe plaque psoriasis, selective blockade of IL-23p19 by antibody A was associated with a superior clinical response compared to utecumab for skin lesions. Improvements in pain-VAS values ​​compared to utecumab were also observed in patients with PsA.

[0376] In the above study, PASI 50, PASI 75, and PASI 100 responses at week 12 were also determined. The results showed that in antibody A patients in the 18, 90, and 180 mg groups, the proportions achieving PASI 50 at week 12 were 93%, 95%, and 100%, respectively, while the proportion was 87% in patients receiving uteroclobeta antibody. The PASI 50 achievement over time was shown in... Figure 2 middle.

[0377] It also showed that among antibody A patients in the 18, 90, and 180 mg groups, the proportions achieving PASI 75 at week 12 were 76%, 90%, and 98%, respectively, while the proportion for uteroclosab patients was 68%. The PASI 75 achievement over time was shown in... Figure 3 middle.

[0378] It also showed that among antibody A patients in the 18, 90, and 180 mg groups, the proportions achieving PASI 100 at week 12 were 18%, 41%, and 49%, respectively, while the proportion was 15% for patients with utecumab. The PASI 100 achievement over time is shown in... Figure 5 middle.

[0379] PASI 90 is reached over time. Figure 4 middle.

[0380] Example 1c: Research

[0381] This study evaluated the flare-ups and duration of clinical response after treatment with a selective IL-23p19 inhibitor (antibody A) compared to untecumbumab in patients with moderate to severe chronic plaque psoriasis.

[0382] Materials & Methods: In this multicenter, randomized, double-blind (within the antibody A dose group) phase II study, 166 patients with moderate to severe chronic plaque psoriasis were assigned to receive either three different dosing regimens of antibody A (a single 18 mg injection; 90 or 180 mg at weeks 0, 4, and 16) or utecumab (45 or 90 mg at weeks 0, 4, and 16, based on body weight). PASI was assessed at weeks 0, 1, 2, 4, 6, and 8, then every 4 weeks for a total of 48 weeks. Safety was assessed by recording adverse events (AEs) at all visits.

[0383] Results: In the 90 mg and 180 mg antibody A groups (arm), 66% (27 / 41) and 86% (36 / 42) of patients, respectively, achieved PASI 90 at week 24, compared to 55% (22 / 40) of patients receiving ustecumab. In the 90 and 180 mg antibody A groups, 41% (17 / 41) and 57% (24 / 42) of patients, respectively, achieved complete clearance of damage (PASI 100), compared to 28% of patients receiving ustecumab. The time to PASI 90 was approximately twice as fast in the 90 and 180 mg antibody A groups (median days to PASI 90 = 57 days [~8 weeks in both antibody A dose groups] vs. 113 days [~16 weeks], p = 0.0016 [90 mg] and p < 0.0001 [180 mg]). In the 90 and 180 mg antibody A groups, patients who achieved PASI 90 maintained this response for longer than those receiving ustecumab (the number of days to 50% of patients with the first PASI 90 loss = 337 days [~48 weeks in both antibody A dose groups] vs. 253 days [~36 weeks]). AEs were similar between treatment groups, and there was no dose-response relationship 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 ustecumab group); all were considered unrelated to the study drug.

[0384] The same study showed that antibody A had a rapid onset of efficacy, with 69% and 66% of patients achieving PASI 50 (180 mg and 90 mg, respectively) at week 4, compared to 45% for patients receiving ustecumab. At week 8, 83% and 80% of antibody A patients (180 mg and 90 mg, respectively) achieved PASI 75, compared to 60% for ustecumab patients. At week 12, the proportion of patients achieving PASI 90 (the primary endpoint) was 81% and 73% in the 180 mg and 90 mg antibody A groups, respectively, compared to 40% for ustecumab. Body weight had little effect on the efficacy of antibody A. At week 20, 90% and 76% of antibody A patients (180 mg and 90 mg, respectively) achieved PASI 90, compared to 55% with ustecumab; and 62% and 51% of antibody A patients had complete damage clearance (PASI 100), compared to 25% with ustecumab. Clinical response remained high after week 36 in both the 180 mg and 90 mg antibody A dose groups. In patients with PsA, a greater reduction in pain was observed at week 12 with antibody A (180 mg and 90 mg, pooled) compared to ustecumab (68% vs. 57%). In patients with psoriatic arthritis, pain was assessed using the visual analog scale and expressed as a percentage change from baseline median.

[0385] Conclusion: Compared with blocking IL-12 and IL-23 with uteroclosporine, selective blocking of IL-23 with antibody A demonstrated superior efficacy, faster onset, and longer duration of response.

[0386] In the same study, the Dermatological Quality of Life Index (DLQI) and EuroQol-5D (EQ-5D) were completed at weeks 0, 12, 24, and 48. At weeks 12 and 24, the median percentage change from baseline in the total DLQI score (descriptive analysis, via the van Elteren trial) was compared with that of uteroclosab. The proportion of patients achieving a DLQI score of 0 or 1 was also assessed. EQ-5D index scores were descriptively analyzed. Results for antibody A in the combined 90 mg and 180 mg groups are reported.

[0387] At baseline, the median DLQI score of patients randomized to receive antibody A was 13.0, compared to 16.0 in patients randomized to receive ustecumab. The mean EQ-5D score was 0.7 in both treatment groups. At week 12, the median percentage improvement in DLQI score was greater in patients receiving antibody A than in those receiving ustecumab (100% vs. 90.6%; p = 0.0304). At week 24, 80% of antibody A patients had a DLQI score of 0 or 1, compared to 61% in ustecumab patients. At week 12, a 50% greater mean improvement in EQ-5D score was observed in antibody A patients than in ustecumab patients (0.3 vs. 0.2). This continued into week 24.

[0388] In patients with moderate to severe plaque psoriasis, selective blocking of IL-23 with antibody A demonstrated superior efficacy compared to uterotumab, and provided a significant improvement in QoL outcomes.

[0389] The efficacy of antibody A in treating scalp, palmar-plantar, and nail psoriasis was evaluated in the same study.

[0390] The Psoriasis Scalp Severity Index (PSSI) and Palmoplantar Psoriasis Area and Severity Index (PPASI) were used to evaluate scalp and palmoplantar psoriasis, respectively. The Nail Psoriasis Severity Index (NAPSI) was assessed only on the hands. Assessments were performed at baseline (for patients with symptoms at baseline) and at weeks 1, 2, 4, 6, 8, and 12, and every 4 weeks until week 48. Patients who were reported as having no signs or symptoms were assigned a total score of 0 at that visit. The median percentage improvement from baseline with antibody A (90 mg and 180 mg, pooled) was compared with that with uteroclosporine.

[0391] Of the 154 (92.8%) patients with scalp psoriasis, 42 (25.3%) with palmoplantar psoriasis, and 96 (57.8%) with nail psoriasis, the response to scalp and palmoplantar diseases was rapid; at week 2, patients treated with antibody A showed improvements in PSSI and PPASI of 50% and 51% from baseline, respectively, compared to 37% and 30% in patients treated with ustecumab. At week 6, complete clearance of scalp psoriasis was observed in both the antibody A and ustecumab groups, and this effect was maintained throughout the study. For PPASI, complete clearance was observed in the antibody A group at week 6 and in the ustecumab group at week 16, and was maintained throughout the study. Nail disease resolved more slowly; at week 6, there was a 30% improvement in NAPSI in the antibody A group, compared to 0% in the ustecumab group. At week 12, antibody A and uteroclosporine improved NAPSI by 41% and 36%, respectively, and at week 24, the improvements were 61% and 67%, respectively.

[0392] Selective blocking of AIL-23 with antibodies has demonstrated promising efficacy in treating scalp, palmar-plantar, and nail psoriasis, and suggests that antibody A can achieve faster improvement compared to utectumab.

[0393] Example 2: Evaluation of Efficacy

[0394] Antibody A was administered to the patient at the dosage and dosing regimen described herein. The efficacy of antibody A was assessed by one or more of the following endpoints, determined using known methods. For example, endpoints were measured at one or more of the following times following administration: weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, or 104, or endpoints as described below.

[0395] psoriasis :

[0396] For example, in week 12, a PASI score reduction of ≥90% from baseline was achieved. 90 ).

[0397] For example, at weeks 12 and 24, a PASI score reduction of ≥75% from baseline was achieved. 75 ).

[0398] For example, in week 12, a 100% reduction in PASI score from baseline was achieved. 100 ).

[0399] For example, in week 12, a PASI score reduction of ≥50% from baseline was achieved. 50 ).

[0400] For example, reaching PASI in week 24 90 .

[0401] For example, sPGA clearance or near-clearance is achieved in week 12.

[0402] For example, the percentage decrease in PASI from baseline at week 12.

[0403] To PASI 50 The time lost in response. This endpoint is calculated as follows: from the first treatment until the first PASI score after achieving this response is reduced by <50% compared to baseline.

[0404] Other endpoints are as follows:

[0405] For example, PASI is achieved in weeks 4, 6, 8, 16, 20, 28, 32, 36, 40, 44, and 48. 90 and PASI 75 .

[0406] For example, PASI is achieved in weeks 4, 6, 8, 16, 20, 24, 28, 32, 36, 40, 44, and 48. 100 PASI 50 And the percentage decrease in PASI from baseline.

[0407] For example, sPGA clearance or near-clearance is achieved in weeks 4, 6, 8, 16, 20, 24, 28, 32, 36, 40, 44, and 48.

[0408] To PASI 50 Response onset (time from the first treatment to the first PASI score reduction of ≥50% compared to baseline).

[0409] For example, the percentage changes from baseline in NAPSI (Nail Psoriasis Severity Index), PSSI (Psoriasis Scalp Severity Index), and PPASI (Palm and Plantar Psoriasis Area Severity Index) at weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48.

[0410] For example, changes from baseline in PGAR (Patient Overall Assessment Rating) and PAI (Patient Itch Assessment) at weeks 4, 12, 24, 36, and 48.

[0411] For example, the change in pain-VAS from baseline at week 12 (in a subgroup of patients with only psoriatic arthritis).

[0412] For example, the change in the Dermatological Quality of Life Index (DLQI) from baseline at weeks 4, 6, 8, 12, 16, 20, 24, and 48.

[0413] For example, the change in VAS score (Visual Analog Scale) from baseline in the EQ-5D (EuroQoL Group Questionnaire) at week 12.

[0414] For example, the change in the EQ-5D index score from baseline in week 12.

[0415] For example, the proportion of patients who achieved a Dermatological Quality of Life Index (DLQI) score of 0 or 1 at week 12.

[0416] For example, at week 16, changes in psoriasis symptoms from baseline were assessed using the total score in the PSS (Psoriasis Symptom Scale).

[0417] For example, achieving a PSS total score of 0 in week 16.

[0418] Psoriatic arthritis (For example, responses assessed at one or more of weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, and 104):

[0419] For example, the Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire is administered at weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48.

[0420] For example, at weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, there was a 20% improvement in the American College of Rheumatology response criteria (ACR 20).

[0421] 50% and 70% improvement in the American College of Rheumatology response criteria (ACR 50 and ACR 70).

[0422] Clinical Disease Activity Index (CDAI).

[0423] Disease activity score based on 28-joint count (DAS28).

[0424] Assess dactylitis (swelling of the entire finger) by the number of infected fingers out of all 20 fingers (range 0 to 20 fingers (fingers and toes), with or without infection on each finger).

[0425] Origin and insertion inflammation (inflammation of tendon and ligament insertions, assessed by the presence of tenderness at six sites on the Leeds Origin and Insertion Inflammation Index (LEI)).

[0426] Individual ACR components include the number of tender or painful joints and the number of swollen joints.

[0427] Patient's overall assessment of disease activity and joint pain.

[0428] The doctor's overall assessment of the disease activity.

[0429] Response to the Health Assessment Questionnaire – Disability Index (HAQ-DI).

[0430] C-reactive protein levels.

[0431] Erythrocyte sedimentation rate.

[0432] Patient-reported outcome measures included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score is also included.

[0433] Medical Outcomes Study: 36 Simplified Format Database Construction Survey, Second Edition (SF-36).

[0434] Detailed table of psoriasis symptoms.

[0435] For example, the improved total Sharp score (mTSS) in weeks 24, 52, and 104.

[0436] Number of tender joints.

[0437] Number of swollen joints.

[0438] Patient's evaluation of pain,

[0439] Patient's assessment of their level of disability.

[0440] Acute phase reactants (C-reactive protein or erythrocyte sedimentation rate),

[0441] The patient's overall evaluation of the disease.

[0442] The doctor's overall assessment of the disease.

[0443] Minimal disease activity (MDA).

[0444] Composite Psoriasis Disease Activity Index (CPDAI).

[0445] Percentage change from baseline in Psoriasis Area and Severity Index (PASI) (PASI 75 / 90 / 100).

[0446] Modified Nail Psoriasis Severity Index (mNAPSI).

[0447] Quality of life in psoriatic arthritis (PsAQOL).

[0448] Functional assessment of fatigue in chronic disease treatment (FACIT-F).

[0449] For example, the Psoriatic Arthritis Magnetic Resonance Imaging Scoring System (PsAMRIS) at weeks 24, 52, and 104.

[0450] For ankylosing spondylitis and radionegative ax-SpA (For example, responses assessed at one or more of weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 104):

[0451] Patient-reported inflammatory symptoms.

[0452] Acute phase response (ESR or CRP).

[0453] Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Change in BASDAI score compared to baseline.

[0454] Ankylosing spondylitis Disease Activity Score (ASDAS). Change in ASDAS score compared to baseline.

[0455] Bath Ankylosing Spondylitis Functional Index (BASFI). Change in BASFI score compared to baseline.

[0456] The Bath Ankylosing Spondylitis Index (BASMI). Changes in spinal mobility compared to baseline, assessed by BASMI score.

[0457] Magnetic resonance imaging (MRI), for example, at weeks 24, 52, and 104.

[0458] ASAS 40 response.

[0459] ASAS 5 / 6 response.

[0460] ASAS partial relief criteria.

[0461] ASAS 20 Response

[0462] Changes in peripheral joint counts (TJC and SJC) compared to baseline.

[0463] Change in entheseal score (MASES) compared to baseline.

[0464] Changes in Ankylosing Spondylitis Disease Activity Score (ASDAS) compared to baseline.

[0465] Until the time it takes to sustain the loss.

[0466] The time until the condition worsens after treatment.

[0467] Until the time it takes to sustain the loss.

[0468] Ankylosing spondylitis Quality of Life Scale (ASQoL).

[0469] Example 3: Pharmacokinetic endpoints

[0470] To determine the pharmacokinetic parameters of anti-IL-23A antibodies (such as antibody A), the following parameters were evaluated using methods known in the art:

[0471] Maximum measurable plasma concentration (C max )

[0472] Time from drug administration to the maximum plasma concentration (t) max )

[0473] Area under the plasma concentration-time curve (AUC) of the treatment interval 0-t )

[0474] The area under the plasma concentration-time curve extrapolated from 0 to infinity. )

[0475] terminal half-life (t) 1 / 2 )

[0476] Population pharmacokinetics.

[0477] Example 4: Pharmaceutical Composition

[0478] Examples of formulations suitable for the antibodies of the present invention are shown below. The antibodies used in the following formulations are, for example, antibody A, antibody B, antibody C, or antibody D.

[0479] Table 6 - Formulation 1:

[0480]

[0481] Formulation 1 typically has a pH in the range of 6.0 to 7.0, for example, pH 6.5. This formulation is particularly suitable for intravenous administration.

[0482] The molecular weight (MW in g / mol) of the excipients used is as follows: disodium succinate = 270.14 g / mol; succinic acid = 118.09 g / mol; sodium chloride = 58.44 g / mol.

[0483] The volumetric permeation molar concentration of the formulation is 300 ± 30 mOsmol / kg, as determined using Osmomat 030 (Gonotec GmbH, Berlin, Germany). The formulation is effective at 20... oThe density at point C is approximately 1.0089 g / cm³. 3 As determined using the measurement unit DMA 4500 (Anton Paar GmbH, Ostfildern-Scharnhausen, Germany).

[0484] Table 7 - Formulation 2:

[0485]

[0486] Formulation 2 typically has a pH range of 5.5 to 6.5, for example, 5.5 to 6.1, or even a pH of 5.8. This formulation is particularly suitable for subcutaneous application.

[0487] The molecular weight (MW, in g / mol) of the excipients used:

[0488] MW: Succinic acid (C4H6O4) = 118.09 g / mol

[0489] MW: Disodium succinate hexahydrate (C4O4Na2H4 x 6H2O) = 270.14 g / mol

[0490] MW: Sorbitol = 182.17 g / mol

[0491] MW: Polysorbate 20 = 1227.72 g / mol

[0492] The volumetric permeation molar concentration of the formulation is 300 ± 30 mOsmol / kg, as determined using Osmomat 030 (Gonotec GmbH, Berlin, Germany). The formulation is effective at 20... o The density at point C is approximately 1.040 g / cm³. 3 As determined using the measurement unit DMA 4500 (Anton Paar GmbH, Ostfildern-Scharnhausen, Germany).

[0493] Table 8 - Formulation 3:

[0494]

[0495] Formulation 3 typically has a pH range of 5.5 to 6.5, for example, 5.5 to 6.1, or even a pH of 5.8. This formulation is particularly suitable for subcutaneous application.

[0496] The molecular weight (MW, in g / mol) of the excipients used:

[0497] MW: Sorbitol = 182.17 g / mol

[0498] MW: Polysorbate 20 = 1227.72 g / mol.

[0499] The volumetric permeation molar concentration of the formulation is 300 + / - 30 mOsmol / kg, as determined using Osmomat 030 (Gonotec GmbH, Berlin, Germany).

[0500] In summary, the present invention includes, but is not limited to, the following technical items:

[0501] 1. A method for treating psoriasis or psoriatic arthritis, comprising administering an anti-IL-23A antibody to a patient, the method comprising:

[0502] a) Administer an initial dose of the anti-IL-23A antibody to the patient;

[0503] b) administering a first maintenance dose of the anti-IL-23A antibody to the patient 4 to 24 weeks, for example 4 to 12 weeks, for example 6 to 24 weeks, for example 6 to 12 weeks, following the administration of the initial dose; and

[0504] c) Four to 24 weeks after the administration of the first maintenance dose, for example, four to 12 weeks, for example, six to 24 weeks, for example, six to 12 weeks, the patient shall be given at least one additional maintenance dose.

[0505] 2. The method according to technical item 1, the method comprising:

[0506] a) Administer an initial dose of the anti-IL-23A antibody to the patient;

[0507] b) Eight to 24 weeks after the administration of the initial dose, for example, 8 to 12 weeks, the patient is given a first maintenance dose of the anti-IL-23A antibody; and

[0508] c) Eight to 24 weeks after the administration of the first maintenance dose, for example, eight to 12 weeks, the patient is given at least one additional maintenance dose.

[0509] 3. The method according to technical item 1, wherein the first maintenance dose is administered to the patient at 8, 12, 16, 20 or 24 weeks after the administration of the initial dose.

[0510] 4. The method according to technical item 1, wherein the at least one additional maintenance dose is administered to the patient 8, 12, 16, 20 or 24 weeks after the administration of the first maintenance dose.

[0511] 5. The method according to technical item 1, wherein the first maintenance dose is administered to the patient 8, 12, 16, 20 or 24 weeks after the administration of the initial dose, and the at least one additional maintenance dose is administered to the patient 8, 12, 16, 20 or 24 weeks after the administration of the first maintenance dose.

[0512] 6. According to the method of technical item 1, wherein:

[0513] i. Administer the first maintenance dose to the patient 8 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 8 weeks after administering the first maintenance dose; or

[0514] ii. Administer the first maintenance dose to the patient 12 weeks after the initial dose and administer the at least one additional maintenance dose to the patient 12 weeks after the first maintenance dose; or

[0515] iii. Administer the first maintenance dose to the patient 16 weeks after the initial dose and administer the at least one additional maintenance dose to the patient 16 weeks after the first maintenance dose; or

[0516] iv. Administer the first maintenance dose to the patient 20 weeks after the initial dose and administer the at least one additional maintenance dose to the patient 20 weeks after the first maintenance dose; or

[0517] v. Administer the first maintenance dose to the patient 24 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 24 weeks after administering the first maintenance dose.

[0518] 7. According to the method of technical item 1, wherein:

[0519] i. Administer the first maintenance dose to the patient 4 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 4 weeks after administering the first maintenance dose; or

[0520] ii. Administer the first maintenance dose to the patient 6 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 6 weeks after administering the first maintenance dose.

[0521] 8. The method according to any one of claims 1 to 7, wherein the initial dose comprises 15 to 300 mg of the anti-IL-23A antibody.

[0522] 9. The method according to any one of claims 1 to 7, wherein the first maintenance dose and the at least one additional maintenance dose comprise 15 to 300 mg of the anti-IL-23A antibody.

[0523] 10. The method according to any one of claims 1 to 7, wherein the initial dose comprises 15 to 250 mg, for example 90 to 180 mg of the anti-IL-23A antibody.

[0524] 11. The method according to any one of claims 1 to 7, wherein the first maintenance dose and the at least one additional maintenance dose comprise 15 to 250 mg, for example 90 to 180 mg of the anti-IL-23A antibody.

[0525] 12. The method according to any one of claims 1 to 7, wherein 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, or 230 to 250 mg of the anti-IL-23A antibody.

[0526] 13. The method according to any one of claims 1 to 7, wherein the first maintenance dose and the 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, or 230 to 250 mg of the anti-IL-23A antibody.

[0527] 14. The method according to any one of claims 1 to 7, wherein 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 or 250 mg of the anti-IL-23A antibody.

[0528] 15. The method according to any one of claims 1 to 7, wherein 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.

[0529] 16. The method according to any one of claims 1 to 7, wherein the initial 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.

[0530] 17. A method for treating psoriasis or psoriatic arthritis, comprising administering an anti-IL-23A antibody to a patient, the method comprising:

[0531] a) Administer an initial dose of the anti-IL-23A antibody to the patient;

[0532] b) Administer the anti-IL-23A antibody loaded with the dose to the patient 1 to 6 weeks after the administration of the initial dose;

[0533] c) Six to 24 weeks after administration of the loaded dose, for example, 6 to 12 weeks, administer a first maintenance dose of the anti-IL-23A antibody to the patient; and

[0534] d) Six to 24 weeks after the administration of the first maintenance dose, for example, six to 12 weeks, the patient shall be given at least one additional maintenance dose.

[0535] 18. The method according to technical item 17, the method comprising:

[0536] a) Administer an initial dose of the anti-IL-23A antibody to the patient;

[0537] b) Administer the anti-IL-23A antibody loaded with the dose to the patient 1 to 6 weeks after the administration of the initial dose;

[0538] c) Eight to 24 weeks after administration of the loaded dose, for example, 8 to 12 weeks, the patient is given a first maintenance dose of the anti-IL-23A antibody; and

[0539] d) Eight to 24 weeks after the administration of the first maintenance dose, for example, eight to 12 weeks, the patient is given at least one additional maintenance dose.

[0540] 19. The method according to technical item 17, wherein the loaded dose is administered to the patient 1, 2, 3, 4, 5 or 6 weeks after the administration of the initial dose.

[0541] 20. The method according to technical item 17 or 19, wherein the first maintenance dose is administered to the patient 8, 12, 16, 20 or 24 weeks after the administration of the loaded dose.

[0542] 21. The method according to technical item 17 or 19, wherein the at least one additional maintenance dose is administered to the patient 8, 12, 16, 20 or 24 weeks after the administration of the first maintenance dose.

[0543] 22. The method according to technical item 17 or 19, wherein the first maintenance dose is administered to the patient 8, 12, 16, 20 or 24 weeks after the administration of the initial dose, and the at least one additional maintenance dose is administered to the patient 8, 12, 16, 20 or 24 weeks after the administration of the first maintenance dose.

[0544] 23. The method according to technical item 17 or 19, wherein:

[0545] i. Administer the first maintenance dose to the patient 8 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 8 weeks after administering the first maintenance dose; or

[0546] ii. Administer the first maintenance dose to the patient 12 weeks after the initial dose and administer the at least one additional maintenance dose to the patient 12 weeks after the first maintenance dose; or

[0547] iii. Administer the first maintenance dose to the patient 16 weeks after the initial dose and administer the at least one additional maintenance dose to the patient 16 weeks after the first maintenance dose; or

[0548] iv. Administer the first maintenance dose to the patient 20 weeks after the initial dose and administer the at least one additional maintenance dose to the patient 20 weeks after the first maintenance dose; or

[0549] v. Administer the first maintenance dose to the patient 24 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 24 weeks after administering the first maintenance dose.

[0550] 24. The method according to technical item 17 or 19, wherein:

[0551] i. Administer the first maintenance dose to the patient 6 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 6 weeks after administering the first maintenance dose.

[0552] 25. The method according to any one of claims 17 to 24, wherein the initial dose comprises 15 to 300 mg of the anti-IL-23A antibody.

[0553] 26. The method according to any one of claims 17 to 24, wherein the loading dose comprises 15 to 300 mg of the anti-IL-23A antibody.

[0554] 27. The method according to any one of claims 17 to 24, wherein the first maintenance dose and the at least one additional maintenance dose comprise 15 to 300 mg of the anti-IL-23A antibody.

[0555] 28. The method according to any one of claims 17 to 24, wherein the initial dose comprises 15 to 250 mg, for example 90 to 180 mg of the anti-IL-23A antibody.

[0556] 29. The method according to any one of claims 17 to 24, wherein the loading dose comprises 15 to 250 mg, for example 90 to 180 mg, of the anti-IL-23A antibody.

[0557] 30. The method according to any one of claims 17 to 24, wherein the first maintenance dose and the at least one additional maintenance dose comprise 15 to 250 mg, for example 90 to 180 mg of the anti-IL-23A antibody.

[0558] 31. The method according to any one of claims 17 to 24, wherein 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, or 230 to 250 mg of the anti-IL-23A antibody.

[0559] 32. The method according to any one of claims 17 to 24, wherein 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, or 230 to 250 mg of the anti-IL-23A antibody.

[0560] 33. The method according to any one of claims 17 to 24, wherein the first maintenance dose and the 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, or 230 to 250 mg of the anti-IL-23A antibody.

[0561] 34. The method according to any one of claims 17 to 24, wherein 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 or 250 mg of the anti-IL-23A antibody.

[0562] 35. The method according to any one of claims 17 to 24, wherein 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.

[0563] 36. The method according to any one of claims 17 to 24, wherein the initial dose and the 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 the anti-IL-23A antibody.

[0564] 37. The method according to any one of claims 17 to 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.

[0565] 38. A method for treating psoriasis or psoriatic arthritis, comprising administering 15 to 300 mg of an anti-IL-23A antibody to a patient.

[0566] 39. The method according to technical item 38, which includes administering 15 to 250 mg, for example 90 to 180 mg, of an anti-IL-23A antibody to a patient.

[0567] 40. The method according to technical item 39, comprising administering to a patient 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, or 230 to 250 mg of anti-IL-23A antibody.

[0568] 41. The method according to technical item 30, which includes 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 a patient.

[0569] 42. The method according to any one of claims 38 to 41, wherein the anti-IL-23A antibody is administered at an initial dose, a loading dose, or a maintenance dose.

[0570] 43. The method according to any one of claims 1 to 42, wherein the anti-IL-23A antibody is antibody A, antibody B, antibody C or antibody D.

[0571] 44. The method according to any one of technical items 1 to 43, wherein the method is used to treat moderate to severe chronic plaque psoriasis.

[0572] 45. The method according to any one of claims 1 to 44, wherein the anti-IL-23A antibody is administered subcutaneously.

Claims

1. A method for treating psoriasis or psoriatic arthritis, comprising administering an anti-IL-23A antibody to a patient, the method comprising: a) Administer 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, for example 4 to 12 weeks, for example 6 to 24 weeks, for example 6 to 12 weeks, following the administration of the initial dose; and c) Four to 24 weeks after the administration of the first maintenance dose, for example, four to 12 weeks, for example, six to 24 weeks, for example, six to 12 weeks, the patient shall be given at least one additional maintenance dose.

2. A method for treating psoriasis or psoriatic arthritis, comprising administering an anti-IL-23A antibody to a patient, the method comprising: a) Administer an initial dose of the anti-IL-23A antibody to the patient; b) Administer the anti-IL-23A antibody loaded with the dose to the patient 1 to 6 weeks after the administration of the initial dose; c) Six to 24 weeks after administration of the loaded dose, for example, six to 12 weeks, the patient is given a first maintenance dose of the anti-IL-23A antibody; as well as d) Six to 24 weeks after the administration of the first maintenance dose, for example, six to 12 weeks, the patient shall be given at least one additional maintenance dose.

3. The method according to claim 1 or 2, wherein the method comprises: a) Administer an initial dose of the anti-IL-23A antibody to the patient; b) Eight to 24 weeks after the administration of the initial dose, for example, 8 to 12 weeks, the patient is given a first maintenance dose of the anti-IL-23A antibody; and c) Eight to 24 weeks after the administration of the first maintenance dose, for example, eight to 12 weeks, the patient is given at least one additional maintenance dose.

4. The method of claim 1 or 2, wherein the first maintenance dose is administered to the patient 8, 12, 16, 20 or 24 weeks after the administration of the initial dose.

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

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

7. The method according to claim 1 or 2, wherein: i. Administer the first maintenance dose to the patient 8 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 8 weeks after administering the first maintenance dose; or ii. Administer the first maintenance dose to the patient 12 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 12 weeks after administering the first maintenance dose; or iii. Administer the first maintenance dose to the patient 16 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 16 weeks after administering the first maintenance dose; or iv. Administer the first maintenance dose to the patient 20 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 20 weeks after administering the first maintenance dose; or v. Administer the first maintenance dose to the patient 24 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 24 weeks after administering the first maintenance dose.

8. The method according to claim 1 or 2, wherein: i. Administer the first maintenance dose to the patient 4 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 4 weeks after administering the first maintenance dose; or ii. Administer the first maintenance dose to the patient 6 weeks after administering the initial dose, and administer the at least one additional maintenance dose to the patient 6 weeks after administering the first maintenance dose.

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

10. The method of any one of claims 1 to 8, wherein the first maintenance dose and the at least one additional maintenance dose comprise 15 to 300 mg of the anti-IL-23A antibody.

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