EA046375B1 - METHOD FOR TREATING INFLAMMATORY DISEASES - Google Patents

Description

Field of technology to which the invention relates

The invention generally relates to a method of treating inflammatory diseases, for example psoriasis, psoriatic arthritis or axial spondyloarthritis (ax-SpA), including ankylosing spondylitis (AS, also called radiographic ax-SpA) and non-radiographic ax-SpA using anti-IL-23A antibodies.

Background of invention creations

Psoriasis is a chronic immune system-mediated inflammatory skin disease with a worldwide prevalence of approximately 2%, associated with significant complications, and can have a significant psychosocial impact on patients' quality of life and well-being. Plaque psoriasis is the most common form and affects approximately 80-90% of patients, appearing as raised plaques on the skin; the disease usually begins in late adolescence and early adulthood and may persist into adulthood. The extent of body surface area (BSA) involvement and the distribution of skin manifestations, including erythema, induration, and scaliness, determine the severity of psoriasis, with approximately 20-30% of patients having moderate to severe disease. Approximately one third of patients with psoriasis are associated with inflammation of the joints (psoriatic arthritis (PsA)), which leads to pain and disability. Axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis (AS, also called radiographic axial spondyloarthritis (ax-SpA)) and non-radiographic axial spondyloarthritis (ax-SpA), is an inflammatory disease primarily involving the axial skeleton and sacral -iliac joints.

Psoriasis, psoriatic arthritis, and axial spondyloarthritis (ax-SpA), which includes ankylosing spondylitis and non-radiographic ax-SpA, are multifactorial autoimmune diseases whose exact etiology is unknown. Multiple whole-genome studies have linked variants in genes for the IL-23 receptor to psoriasis susceptibility. Human IL-23 is initially produced by antigen-presenting cells and induces the differentiation of T helper 17 (Th17) cells. This leads to the production of IL-17 and IL-22, which may mediate the development of epidermal hyperplasia and tissue inflammation observed in psoriasis.

There is a need for treatment options for inflammatory diseases, particularly psoriasis, psoriatic arthritis, axial spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA, that lead to favorable patient outcomes, e.g. safety and/or tolerability of treatment.

The essence of the invention

The present invention solves the above problems and provides methods for treating inflammatory diseases, particularly methods comprising administering an anti-IL-23A antibody to a patient in specified amounts and/or at specified intervals. In one aspect, the method of the present invention is for the treatment of psoriasis or psoriatic arthritis. In one aspect, the method of the present invention is for the treatment of axial spondyloarthritis (ax-SpA), including ankylosing spondylitis (AS) and non-radiographic ax-SpA. Therefore, in one aspect, the method of the present invention is for the treatment of ankylosing spondylitis (AS) and in one aspect, the method of the present invention is for the treatment of non-radiographic ax-SpA.

The methods of the present invention provide the advantage of providing patients with the opportunity for clinical improvement while receiving fewer administrations of anti-IL-23A antibody.

In one embodiment, the present invention provides a method of treating an inflammatory disease, in one aspect treating psoriasis, psoriatic arthritis or axial spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA, comprising administering anti-HL to the patient -23A antibodies, where said method includes:

A. administering an initial dose of anti-IL-23A antibody to the patient;

b. administering a first maintenance dose of anti-IL-23A antibody to the patient 4-24 weeks, eg 4-16 weeks, eg 4-12 weeks, after administration of said initial dose; And

V. administering at least one maintenance dose to the patient 4-24 weeks, such as 4-16 weeks, such as 4-12 weeks, after administration of said first maintenance dose.

In one embodiment, the present invention provides a method of treating an inflammatory disease, in one aspect treating psoriasis, psoriatic arthritis or axial spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA, comprising administering anti-HL to the patient -23A antibodies, where said method includes:

A. administering an initial dose of anti-IL-23A antibody to the patient;

b. administration of the first maintenance dose of anti-L-23A antibody to the patient after 8-24 weeks, for example, 8-16 weeks, for example, 8-12 weeks, for example, 6-24 weeks, for example, 6-16 weeks, for example, 612 weeks, after administration of the specified initial dose; And

V. administration of at least one maintenance dose to the patient after 8-24 weeks, e.g. 8-16 weeks, e.g. 8-12 weeks, e.g. 6-24 weeks, e.g. 6-16 weeks, e.g. 6-12 not

- 1 046375 del, after administration of the indicated first maintenance dose.

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

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

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

In additional embodiments:

the first maintenance dose is administered to the patient 4 weeks after the initial maintenance dose and at least one additional maintenance dose is administered to the patient 4 weeks after the first maintenance dose; or the first maintenance dose is administered to the patient 6 weeks after the initial maintenance dose and at least one additional maintenance dose is administered to the patient 6 weeks after the first maintenance dose; or the first maintenance dose is administered to the patient 8 weeks after the initial maintenance dose and at least one additional maintenance dose is administered to the patient 8 weeks after the first maintenance dose; or the first maintenance dose is administered to the patient 12 weeks after the initial maintenance dose and at least one additional maintenance dose is administered to the patient 12 weeks after the first maintenance dose; or the first maintenance dose is administered to the patient 16 weeks after the initial maintenance dose and at least one additional maintenance dose is administered to the patient 16 weeks after the first maintenance dose; or the first maintenance dose is administered to the patient 20 weeks after the initial maintenance dose and at least one additional maintenance dose is administered to the patient 20 weeks after the first maintenance dose; or the first maintenance dose is administered to the patient 24 weeks after the initial maintenance dose and at least one additional maintenance dose is administered to the patient 24 weeks after the first maintenance dose.

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

In one embodiment, in any of the methods described above, the first maintenance dose and at least one additional maintenance dose comprises 15-300 mg, for example 15250 mg, for example 90-180 mg, anti-IL-23A antibody.

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

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

In one embodiment, in any of the methods described above, the initial dose includes 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 anti-IL-23A antibody. In one embodiment, in any of the methods described above, the initial dose includes 75 mg of anti-IL-23A antibody.

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

In one embodiment, in any of the methods described above, the initial dose, the first maintenance dose, and at least one additional maintenance dose includes 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 anti-IL-23A antibody. In one embodiment, in any of the methods described above, the initial dose, the first maintenance dose, and at least one additional maintenance dose comprises 75 mg of anti-IL-23A antibody.

In one embodiment, the present invention provides a method of treating inflammation

- 2 046375 body disease, in one aspect of the treatment of psoriasis, psoriatic arthritis or axial (spinal) spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA, comprising administering to the patient an anti-IL-23A antibody, wherein said method includes:

A. administering an initial dose of anti-IL-23A antibody to the patient;

b. administering a first maintenance dose of anti-IL-23A antibody to the patient 12 weeks after administration of said initial dose; And

V. administering at least one maintenance dose to the patient 12 weeks after administration of said first maintenance dose.

In one embodiment, in this method, the initial dose and maintenance dose include 150 mg of the specified anti-IL-23A antibody. In one embodiment, in this method, the initial dose and maintenance dose include 75 mg of the specified anti-IL-23A antibody.

In one embodiment, the present invention provides a method of treating an inflammatory disease, in one aspect treating psoriasis, psoriatic arthritis or axial spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA, comprising administering anti-HL to the patient -23A antibodies, where said method includes:

A. administering an initial dose of anti-IL-23A antibody to the patient;

b. administering the first maintenance dose of anti-IL-23A antibody to the patient 8 weeks after administration of said initial dose; And

V. administering at least one maintenance dose to the patient 8 weeks after administration of said first maintenance dose.

In one embodiment, in this method, the initial dose and maintenance dose include 90 mg of the specified anti-IL-23A antibody. In one embodiment, in this method, the initial dose and maintenance dose include 150 mg of the specified anti-IL-23A antibody.

In one embodiment, the present invention provides a method of treating an inflammatory disease, in one aspect treating psoriasis, psoriatic arthritis or axial spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA, comprising administering anti-HL to the patient -23A antibodies, where said method includes:

A. administering an initial dose of anti-IL-23A antibody to the patient;

b. administering a first maintenance dose of anti-IL-23A antibody to the patient 16 weeks after administration of said initial dose; And

V. administering at least one maintenance dose to the patient 16 weeks after administration of said first maintenance dose.

In one embodiment, in this method, the initial dose and maintenance dose include 150 mg of the specified anti-IL-23A antibody.

In one embodiment, the present invention provides a method of treating an inflammatory disease, in one aspect treating psoriasis, psoriatic arthritis or axial spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA, comprising administering anti-HL to the patient -23A antibodies, where said method includes:

A. administering an initial dose of anti-IL-23A antibody to the patient;

b. administering the first maintenance dose of anti-IL-23A antibody to the patient 6 weeks after administration of said initial dose; And

V. administering at least one maintenance dose to the patient 6 weeks after administration of said first maintenance dose.

In one embodiment, in this method, the initial dose and maintenance dose include 150 mg of the specified anti-IL-23A antibody.

In one embodiment, the present invention provides a method of treating an inflammatory disease, in one aspect treating psoriasis, psoriatic arthritis or axial spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA, comprising administering anti-HL to the patient -23A antibodies, where said method includes:

A. administering an initial dose of anti-IL-23A antibody to the patient;

b. administering the first maintenance dose of anti-IL-23A antibody to the patient 4 weeks after administration of said initial dose; And

V. administering at least one maintenance dose to the patient 4 weeks after administration of said first maintenance dose.

In one embodiment, in this method, the initial dose and maintenance dose include 150 mg of the specified anti-IL-23A antibody.

In one embodiment, the present invention further provides a method of treating an inflammatory disease, in one aspect treating psoriasis, psoriatic arthritis or axial spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA, comprising administering to the patient anti-Lb- 23A antibodies, where said method includes:

A. administering an initial dose of said anti-IL-23A antibody to the patient;

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b. administering a loading dose of said anti-IL-23A antibody to the patient 1-6 weeks after administration of said initial dose;

V. administration of the first maintenance dose of said anti-IL-23A antibody to the patient after 8-24 weeks, e.g. 8-16 weeks, e.g. 8-12 weeks, e.g. 6-24 weeks, e.g. 6-16 weeks, e.g. 12 weeks, after administration of the specified loading dose; And

d. administering at least one maintenance dose to the patient after 8-24 weeks, e.g. 8-16 weeks, e.g. 8-12 weeks, e.g. 6-24 weeks, e.g. 6-16 weeks, e.g. 6-12 weeks , after administration of the indicated first maintenance dose.

In one embodiment, the loading dose is administered to the patient 1, 2, 3, 4, 5 or 6 weeks after administration of the specified initial dose.

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

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

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

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

In additional embodiments:

the first maintenance dose is administered to the patient 6 weeks after the initial maintenance dose and at least one additional maintenance dose is administered to the patient 6 weeks after the first maintenance dose; or the first maintenance dose is administered to the patient 8 weeks after the initial maintenance dose and at least one additional maintenance dose is administered to the patient 8 weeks after the first maintenance dose; or the first maintenance dose is administered to the patient 12 weeks after the initial maintenance dose and at least one additional maintenance dose is administered to the patient 12 weeks after the first maintenance dose; or the first maintenance dose is administered to the patient 16 weeks after the initial maintenance dose and at least one additional maintenance dose is administered to the patient 16 weeks after the first maintenance dose; or the first maintenance dose is administered to the patient 20 weeks after the initial maintenance dose and at least one additional maintenance dose is administered to the patient 20 weeks after the first maintenance dose; or the first maintenance dose is administered to the patient 24 weeks after the initial maintenance dose and at least one additional maintenance dose is administered to the patient 24 weeks after the first maintenance dose.

In additional embodiments:

the first maintenance dose is administered to the patient 6 weeks after administration of the loading dose and at least one additional maintenance dose is administered to the patient 6 weeks after administration of the first maintenance dose; or the first maintenance dose is administered to the patient 8 weeks after administration of the loading dose and at least one additional maintenance dose is administered to the patient 8 weeks after administration of the first maintenance dose; or the first maintenance dose is administered to the patient 12 weeks after administration of the loading dose and at least one additional maintenance dose is administered to the patient 12 weeks after administration of the first maintenance dose; or the first maintenance dose is administered to the patient 16 weeks after administration of the loading dose and at least one additional maintenance dose is administered to the patient 16 weeks after administration of the first maintenance dose; or the first maintenance dose is administered to the patient 20 weeks after administration of the loading dose and at least one additional maintenance dose is administered to the patient 20 weeks after administration of the first maintenance dose; or the first maintenance dose is administered to the patient 24 weeks after administration of the loading dose and at least one additional maintenance dose is administered to the patient 24 weeks after administration of the first maintenance dose.

In one embodiment, in any of the methods described above, the initial dose includes 15-300 mg, such as 15-250 mg, such as 90-180 mg, anti-IL-23A antibody.

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In one embodiment, in any of the methods described above, the loading dose includes 15-300 mg, eg 15-250 mg, eg 90-180 mg, anti-IL-23A antibody.

In one embodiment, in any of the methods described above, the first maintenance dose and at least one additional maintenance dose comprises 15-300 mg, for example 15250 mg, for example 90-180 mg, anti-IL-23A antibody.

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

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

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

In one embodiment, in any of the methods described above, the initial dose includes 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 anti-IL-23A antibody. In one embodiment, in any of the methods described above, the initial dose includes 75 mg of anti-IL-23A antibody.

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

In one embodiment, in any of the methods described above, the initial dose and loading dose include 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-III-23A antibody. In one embodiment, in any of the methods described above, the initial dose and loading dose include 75 mg of anti-IL-23A antibody.

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

In one embodiment, the present invention further provides a method of treating an inflammatory disease, in one aspect treating psoriasis, psoriatic arthritis or axial spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA, comprising administering to the patient anti-Lb- 23A antibodies, where said method includes:

A. administering an initial dose of said anti-IL-23A antibody to the patient;

b. administering a loading dose of said anti-IL-23A antibody to the patient 4 weeks after administration of said initial dose;

V. administering a first maintenance dose of said anti-L-23A antibody to the patient 12 weeks after administration of said loading dose; And

d. administering at least one maintenance dose to the patient 12 weeks after the administration of said first maintenance dose.

In one embodiment, in this method, the initial dose, loading dose and maintenance dose include 150 mg of the specified anti-IL-23A antibody. In one embodiment, in this method, the initial dose and loading dose includes 300 mg of the specified anti-IL-23A antibody and the maintenance dose includes 150 mg of the specified anti-IL-23A antibody. In one embodiment, in this method, the initial dose and loading dose includes 180 mg of the specified anti-III-23A antibody and the maintenance dose includes 90 mg of the specified anti-III-23A antibody. In one embodiment, in this method, the initial dose, loading dose and maintenance dose include 75 mg of the specified anti-IL-23A antibody.

In one embodiment, the present invention further provides a method of treating an inflammatory disease, in one aspect treating psoriasis, psoriatic arthritis or axial spondylitis (ax-SpA), including ankylosing spondylitis and non-radiation

- 5 046375 graphic ax-SpA, including the administration of an anti-IL-23A antibody to the patient, where the specified method includes:

A. administering an initial dose of said anti-IL-23A antibody to the patient;

b. administering a loading dose of said anti-IL-23A antibody to the patient 4 weeks after administration of said initial dose;

V. administering a first maintenance dose of said anti-L-23A antibody to the patient 8 weeks after administration of said loading dose; And

d. administering at least one maintenance dose to the patient 8 weeks after the administration of said first maintenance dose.

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

In one embodiment, the present invention further provides a method of treating an inflammatory disease, in one aspect treating psoriasis, psoriatic arthritis or axial spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA, comprising administering to the patient anti-Lb- 23A antibodies, where said method includes:

A. administering an initial dose of said anti-IL-23A antibody to the patient;

b. administering a loading dose of said anti-L-23A antibody to the patient 4 weeks after administration of said initial dose;

V. administering the first maintenance dose of said anti-L-23A antibody to the patient 16 weeks after administration of said loading dose; And

d. administering at least one maintenance dose to the patient 16 weeks after the administration of said first maintenance dose.

In one embodiment, in this method, the initial dose, loading dose and maintenance dose include 150 mg of the specified anti-IL-23A antibody.

In one embodiment, the present invention further provides a method of treating an inflammatory disease, in one aspect treating psoriasis, psoriatic arthritis or axial spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA, comprising administering to the patient anti-Lb- 23A antibodies, where said method includes:

A. administering an initial dose of said anti-IL-23A antibody to the patient;

b. administering a loading dose of said anti-L-23A antibody to the patient 4 weeks after administration of said initial dose;

V. administering the first maintenance dose of said anti-IL-23A antibody to the patient 6 weeks after administration of said loading dose; And

d. administering at least one maintenance dose to the patient 6 weeks after the administration of said first maintenance dose.

In one embodiment, in this method, the initial dose, loading dose and maintenance dose include 150 mg of the specified anti-IL-23A antibody.

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

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

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

In one embodiment, the anti-IL-23A antibody is administered as a starting dose, a loading dose, or a maintenance dose.

In one embodiment, the present invention further provides a method of treating an inflammatory disease, in one aspect treating psoriasis or psoriatic arthritis, comprising administering an anti-IL-23A antibody to a patient, wherein the method comprises:

A. administering an initial dose of said anti-IL-23A antibody to the patient; And

b. administering a second dose of said anti-L-23A antibody to the patient if the patient no longer maintains a particular PASI score, such as PASI 90, PASI 75, PASI 100, or PASI 50.

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In one aspect, the initial dose and the second dose are the doses described herein.

In one embodiment, the present invention further provides a method of treating an inflammatory disease, in one aspect treating psoriasis or psoriatic arthritis, comprising administering an anti-Ib-23A antibody to a patient, wherein the method comprises:

A. administering an initial dose of said anti-!B-23A antibody to the patient;

b. administering a loading dose of said anti-III-23A antibody to the patient 1-6 weeks, for example 4 weeks, after administration of said initial dose; And

V. administering a third dose of the specified anti-Ib-23A antibody to the patient if the patient no longer maintains a particular PASI score, such as PASI 90, PASI 75, PASI 100, or PASI 50.

In one aspect, the initial dose, loading dose, and third dose are the doses described herein.

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

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

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

In one embodiment, in any of the methods described above, the method is for the treatment of moderate to severe chronic plaque psoriasis, for example, in a patient who is unresponsive to treatment or who has contraindications or is refractory to other systemic therapy, including cyclosporine, methotrexate, psoralen or ultraviolet-A light (PUVA)

In one embodiment, in any of the methods described above, the method is for treating pustular psoriasis.

In one embodiment, in any of the methods described above, the method is for treating erythrodermal psoriasis (also known as psoriatic erythroderma).

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

In one embodiment, the anti-IL-23A antibody is used alone or in combination with one or more non-biological DMARDs (disease-modifying antirheumatic agent), for example, to treat psoriatic arthritis, for example, active psoriatic arthritis, for example, to reduce signs and symptoms. In one embodiment, the anti-IL-23A antibody is used or intended to inhibit the progression of structural damage, and/or improve physical functioning.

In one embodiment, the anti-IL-23A antibody is used alone or in combination with methotrexate (MTX), for example, to treat psoriatic arthritis, for example, active psoriatic arthritis, for example, if the response to prior non-biologic DMARD therapy has been inadequate. In one aspect, an anti-IL-23A antibody is used to reduce the progression of peripheral joint disease, as measured by x-ray, and/or to improve physical functioning.

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

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.

In one embodiment, in any of the methods described above, the patient is an adult patient.

In one aspect, the present invention provides an anti-IL-23A antibody for use in treating a disease as described herein.

In one aspect, the present invention provides an anti-IL-23A antibody for use in treating a disease, such as an inflammatory disease, such as psoriasis, psoriatic arthritis, or axial spondyloarthritis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA , by administration in certain quantities and/or at certain intervals, as described in this application.

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

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 a disease, such as an inflammatory disease, such as psoriasis, psoriatic arthritis or axial spondylitis (ax-SpA), including ankylosing spondylitis and non-inflammatory diseases. -radiographic ax-SpA, by administration in certain quantities and/or at certain intervals, as described in this application.

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

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); amino acid sequence SEQ ID NO: 2 (CDR2-L); and amino acid sequence SEQ ID NO: 3 (CDR3L); and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4, 7, 8 or 9 (CDR1-H); amino acid sequence SEQ ID NO: 5 (CDR2-H); and the amino acid sequence of SEQ ID NO: 6 (CDR3-H).

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); amino acid sequence SEQ ID NO: 2 (CDR2-L); and amino acid sequence SEQ ID NO: 3 (CDR3L); and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4 (CDR1-H); amino acid sequence SEQ ID NO: 5 (CDR2-H); and the amino acid sequence of SEQ ID NO: 6 (CDR3-H).

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); amino acid sequence SEQ ID NO: 2 (CDR2-L); and amino acid sequence SEQ ID NO: 3 (CDR3L); and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 (CDR1-H); amino acid sequence SEQ ID NO: 5 (CDR2-H); and the amino acid sequence of SEQ ID NO: 6 (CDR3-H).

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); amino acid sequence SEQ ID NO: 2 (CDR2-L); and amino acid sequence SEQ ID NO: 3 (CDR3L); and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8 (CDR1-H); amino acid sequence SEQ ID NO: 5 (CDR2-H); and the amino acid sequence of SEQ ID NO: 6 (CDR3-H).

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); amino acid sequence SEQ ID NO: 2 (CDR2-L); and amino acid sequence SEQ ID NO: 3 (CDR3L); and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 (CDR1-H); amino acid sequence SEQ ID NO: 5 (CDR2-H); and the amino acid sequence of SEQ ID NO: 6 (CDR3-H).

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

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 containing the amino acid sequence of SEQ ID NO: 14.

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

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

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

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

In one embodiment, In one embodiment, the anti-IL-23A antibody comprises the amino acid sequence of SEQ ID NO: 14 or 155 associated with the human IgG1 heavy chain constant region; and the amino acid sequence of SEQ ID NO: 10 or 11 associated with the human kappa light chain constant region.

In one embodiment, the anti-IL-23A antibody is a humanized monoclonal antibody comprising a light chain variable region containing the amino acid

- 8 046375 a sequence selected from the group consisting of any of SEQ ID NOs: 10, 11, 12 and 13 and a heavy chain variable region containing an amino acid sequence selected from the group consisting of any of SEQ ID NOs: 14, 15, 16 and 17.

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

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

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

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

In one embodiment, the anti-IL-23A antibody includes 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.

In one embodiment, the anti-IL-23A antibody includes 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.

In one embodiment, the anti-IL-23A antibody includes 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: 20.

In one embodiment, the anti-IL-23A antibody includes 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.

In one embodiment, the anti-IL-23A antibody includes 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: 20.

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

In one embodiment, the anti-IL-23A antibody is an antibody as described in WO2007/005955, WO2007/024846, WO2007/027714, WO2007/076524, WO2008/103432 or WO2012/061448.

Brief description of the figures

Fig. 1: Number of patients with >50% reduction from baseline in pain -VAS (%).

Fig. 2: Reaching PASI 50 over time (observed).

Fig. 3: Achievement of PASI 75 over time (observed).

Fig. 4: Achievement of PASI 90 as a function of time (observed).

Fig. 5: Reaching PASI 100 over time (observed).

Antibody A is also referred to as BI in FIG. 2-5.

Detailed Description The IL-23 p19 subunit (also referred to herein as IL-23A, IL-23p19 and p19 subunit) is a 189 amino acid polypeptide containing a 21 aa leader sequence (Oppmann et al., Immunity 13:715 (2000), SEQ ID NO: 22). The biological activity of the molecule is only detected when it is coupled with the IL-12p40 subunit to form IL-23. IL-23 is mainly expressed by activated dendritic cells (DCs) and phagocytes. The receptor for IL-23 was found to consist of the IL-12Re1 subunit of the IL-12 receptor paired with a single subunit called IL-23R (Parham et al., J. Immunol. 168:5699 (2002)). Receptor expression is found primarily on memory T cells and NK cells. Thus, it is believed that the expression of the cytokine:receptor pair is limited to a specific population of immune cells. Although it was initially thought that IL-12 and IL-23 may share many functions, the data suggest a different situation. While IL-12 has a major role in the generation of Th1 cells, IL-23 has been found to be critically involved in the acquisition and maintenance of a newly recognized subset of Th cells termed Th17 (Kikly et al., Curr. Opin. Immunol. 18 :670 (2006), Kastelein et al., Ann. Rev. Immunol. 25:221 (2007)). These cells produce IL

- 9 046375

17A, IL-17F, IL-22 and other pro-inflammatory cytokines such as IL-6 and TNF-α. As described below, studies in animal models regarding the role of these Th17 cells have demonstrated their importance as a driver of chronic inflammation and autoimmune processes.

SEQ ID NO: 22:

mlgsravmll lllpwtaqgr deettndvph iqcgdgcdpq vgqlhasllg Isqllqpegh ahgaatlsp avpggsspaw tqcqqlsqkl glrdnsqfcl qrihqglify hwetqqipsl spsqpwqrll ctlawsahpl vghmdlreeg ekllgsdift gepsllpdsp Ir fkilrslq afvavaarvf

In one aspect, the present invention provides methods for treating diseases associated with IL-23A. In one aspect, the present invention provides methods for treating a disease, such as an inflammatory disease, particularly methods comprising administering an anti-anti-23A antibody to a patient in specified amounts and/or at specified intervals. In one aspect, the method of the present invention is for the treatment of psoriasis or psoriatic arthritis. In one aspect, the method of the present invention is for the treatment of ankylosing spondylitis (AS). In one aspect, the method of the present invention is for the treatment of axial spondyloarthritis (ax-SpA), for example, non-radiographic ax-SpA.

In one aspect, the present invention provides an anti-!k-23A antibody for use in the treatment of a disease, such as an inflammatory disease, such as psoriasis, psoriatic arthritis, or axial spondylitis (ax-SpA), including ankylosing spondylitis and non-radiographic axial arthritis. SpA, by administration in certain quantities and/or at certain intervals, as described in this application.

In one aspect, the present invention provides the use of an anti-III-23A antibody for the preparation of a medicament for the treatment of a disease, such as an inflammatory disease, such as psoriasis, psoriatic arthritis or axial spondylitis (ax-SpA), including ankylosing spondylitis and non-inflammatory diseases. -radiographic ax-SpA, by administration in certain quantities and/or at certain intervals, as described in this application.

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

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

In one aspect, in the method of the present invention, the interval between administration of the initial dose and the first maintenance dose is 8-24 weeks, for example 8-16 weeks, for example 8-12 weeks, for example 6-24 weeks, for example 6-16 weeks, for example 6-12 weeks, for example 6, 8, 12, 16, 20 or 24 weeks. In another aspect, the interval between administration of the first maintenance dose and subsequent maintenance doses is 8-24 weeks, e.g., 8-16 weeks, e.g., 8-12 weeks, e.g., 6-24 weeks, e.g., 6-16 weeks, e.g. 6-12 weeks, for example 6, 8, 12, 16, 20 or 24 weeks.

In one aspect, in the method of the present invention, the interval between the administration of the initial dose and the first maintenance dose and the interval between the administration of the first maintenance dose and subsequent maintenance doses are the same, for example, 4-24 weeks, for example, 4-16 weeks, for example, 4 -12 weeks, for example 4, 6, 8, 12, 16, 20 or 24 weeks.

In one aspect, in the method of the present invention, the interval between the administration of the initial dose and the first maintenance dose and the interval between the administration of the first maintenance dose and subsequent maintenance doses are the same, for example, 8-24 weeks, for example, 8-16 weeks, for example, 8 -12 weeks, for example, 6-24 weeks, for example, 6-16 weeks, for example, 6-12 weeks, for example, 6, 8, 12, 16, 20 or 24 weeks.

In one aspect, in the method of the present invention, a loading dose of anti-III-23A antibody is administered to the patient between the administration of the initial dose and the administration of the first maintenance doses.

In one aspect, the loading dose is administered to the patient 1, 2, 3, 4, 5, or 6 weeks after administration of the initial dose. In one aspect, in the method of the present invention, the interval between administration of the loading dose and the first maintenance dose is 8-24 weeks, for example 8-16 weeks, for example 8-12 weeks, for example 6-24 weeks, for example 6-16 weeks, for example 6-12 weeks, for example 6, 8, 12, 16, 20 or 24 weeks. In another aspect, the interval between administration of the first maintenance dose and subsequent maintenance doses is 8-24 weeks, e.g., 8-16 weeks, e.g., 8-12 weeks, e.g., 6-24 weeks, e.g., 6-16 weeks, e.g. 6-12 weeks, for example 6, 8, 12, 16, 20 or 24

- 10 046375 weeks.

In one aspect, in the method of the present invention, the interval between the administration of the loading dose and the first maintenance dose and the interval between the administration of the first maintenance dose and subsequent maintenance doses are the same, for example, 8-24 weeks, for example, 8-16 weeks, for example, 8 -12 weeks, for example, 6-24 weeks, for example, 6-16 weeks, for example, 6-12 weeks, for example, 6, 8, 12, 16, 20 or 24 weeks.

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

In one aspect, the amount of anti-L-23A antibody in the maintenance doses is less than the amount of anti-L-23A antibody in the initial dose and/or loading dose. In one aspect, the amount of anti-IL23A antibody in the initial dose is twice the amount of anti-IL23A antibody in the maintenance dose, for example, in the absence of a loading dose. In one aspect, the amount of anti-III-23A antibody in the initial dose and loading dose is twice the amount of anti-III-23A antibody in the maintenance dose.

In one aspect, in the method according to the present invention, the initial dose includes 15-300 mg, for example, 15-250 mg of anti-III-23A antibody. In another aspect, maintenance doses include 15-300 mg, for example, 15-250 mg of anti-III-23A antibody. In another aspect, if a loading dose is administered, the loading dose includes 15-300 mg, for example, 15-250 mg of anti-IL-23A antibody.

In a further aspect, the initial dose, loading dose or maintenance dose in accordance with the present invention includes 70-90 mg, 80-100 mg, 90-110 mg, 100-120 mg, 110-130 mg, 120-140 mg, 130- 150 mg, 140-160 mg, 150-170 mg, 160-180 mg, 170-190 mg, 180-200 mg, 190-210 mg, 200-220 mg, 210-230 mg, 220-240 mg, 230- 250 mg, 240-260 mg, 250-270 mg, 260-280 mg, 270-290 mg or 280-300 mg anti-III-23A antibody.

In a further aspect, the initial dose, loading dose or maintenance dose in accordance with the present invention includes 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 anti-III-23A antibody. In a further aspect, the initial dose, loading dose or maintenance dose in accordance with the present invention includes 75 mg of anti-IL-23A antibody.

In a further aspect, the present invention provides a method of treating an inflammatory disease, wherein the method comprises administering 15-250 mg of anti-III-23A antibody to a patient. In one aspect, 70-90 mg, 80-100 mg, 90-110 mg, 100-120 mg, 110-130 mg, 120-140 mg, 130-150 mg, 140-160 mg, 150-170 mg, 160-180 mg, 170-190 mg, 180-200 mg, 190-210 mg, 200-220 mg, 210-230 mg, 220-240 mg, 230-250 mg, 240-260 mg, 250-270 mg, 260-280 mg, 270-290 mg or 280-300 mg of anti-III-23A antibodies are administered to the patient. In one aspect, 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-III-23A antibody is administered to the patient. In one aspect, 75 mg of anti-[L-23A antibody is administered to a patient. In one aspect, the disease is psoriasis or psoriatic arthritis. In one aspect, the disease is axial spondylitis (ax-SpA), including ankylosing spondylitis and non-radiographic ax-SpA.

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

Representative examples of doses and dosage regimens in accordance with the present invention are presented in table. A.

- 11 046375

Table A

Doses and dosage regimens

Initial dose (mg) Loading dose (mg, 4 weeks after initial dose) Maintenance dose (mg) Maintenance dose frequency Alternative frequency of maintenance doses 90 X 90 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 90 90 90 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 180 X 180 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 180 180 180 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 150 X 150 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 150 150 150 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 140 X 140 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 140 140 140 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 130 X 130 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 130 130 130 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 120 X 120 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 120 120 120 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks BY X BY Every 12 weeks Every 6, 8, 16, 20 or 24 weeks BY By BY Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 100 X 100 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 100 100 100 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 160 X 160 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 160 160 160 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 170 X 170 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 170 170 170 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 190 X 190 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 190 190 190 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 200 X 200 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 200 200 200 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 210 210 210 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 220 220 220 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 230 230 230 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 240 240 240 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 250 250 250 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 260 260 260 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 270 270 270 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 280 280 280 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 290 290 290 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks 300 300 300 Every 12 weeks Every 6, 8, 16, 20 or 24 weeks

- 12 046375 x: loading dose is not administered.

In table And if a loading dose is administered, then it is indicated that it is administered 4 weeks after the initial dose.

It is also within the scope of the present invention to administer a loading dose 1 week after the initial dose for each of the doses and maintenance dose frequencies indicated in the table above.

It is also within the scope of the present invention to administer a loading dose 2 weeks after the initial dose for each of the doses and maintenance dose frequencies indicated in the table above.

It is also within the scope of the present invention to administer a loading dose 3 weeks after the initial dose for each of the doses and maintenance dose frequencies indicated in the table above.

It is also within the scope of the present invention to administer a loading dose 5 weeks after the initial dose for each of the doses and maintenance dose frequencies indicated in the table above.

It is also within the scope of the present invention to administer a loading dose 6 weeks after the initial dose for each of the doses and maintenance dose frequencies indicated in the table above.

For example, in the context of the present invention, if a loading dose is not administered to a patient, and with a maintenance dosing frequency of 12 weeks, then an initial dose is administered to the patient at week 0, followed by an additional dose at week 12 (first maintenance dose), then at week 24 ( second maintenance dose) and so on, with a dosing interval of 12 weeks. In one aspect, the initial dose and maintenance doses include 150 mg of anti-IL-23A antibody. In one aspect, the initial dose and maintenance doses include 75 mg of anti-IL-23A antibody.

For example, in the context of the present invention, if a loading dose is administered to a patient, and with a maintenance dosing frequency of 12 weeks, then the initial dose is administered to the patient at week 0, followed by an additional dose at week 4 (loading dose), then at week 16 (first maintenance dose). dose), at week 28 (second maintenance dose) and so on, with a dosing interval of 12 weeks. In one aspect, the initial dose, loading dose, and maintenance doses include 150 mg of anti-III-23A antibody. In one aspect, the initial dose and loading dose include 300 mg of anti-IL-23A antibody and maintenance doses include 150 mg of anti-IL-23A antibody. In one aspect, the initial dose and loading dose include 180 mg of anti-IL-23A antibody and maintenance doses include 90 mg of anti-IL-23A antibody. In one aspect, the initial dose, loading dose, and maintenance doses include 75 mg of anti-IL23A antibody.

For example, in the context of the present invention, if a loading dose is not administered to a patient, and with a maintenance dosing frequency of 8 weeks, then an initial dose is administered to the patient at week 0, followed by an additional dose at week 8 (first maintenance dose), then at week 16 ( second maintenance dose) and so on, with a dosing interval of 8 weeks. In one aspect, the initial dose and maintenance doses include 90 mg of anti-IL-23A antibody. In one aspect, the initial dose and maintenance doses include 150 mg of anti-IL-23A antibody.

For example, in the context of the present invention, if a loading dose is administered to a patient, and with a maintenance dosing frequency of 8 weeks, then an initial dose is administered to the patient at week 0, followed by an additional dose at week 4 (loading dose), then at week 12 (first maintenance dose). dose), at week 20 (second maintenance dose) and so on, with a dosing interval of 8 weeks. In one aspect, the initial dose, loading dose, and maintenance doses include 90 mg of anti-[k-23A antibody. In one aspect, the initial dose, loading dose, and maintenance doses include 150 mg of anti-IL-23A antibody.

For example, in the context of the present invention, if a loading dose is not administered to a patient, and with a maintenance dosing frequency of 16 weeks, then an initial dose is administered to the patient at week 0, followed by an additional dose at week 16 (first maintenance dose), then at week 32 ( second maintenance dose) and so on, with a dosing interval of 16 weeks. In one aspect, the initial dose and maintenance doses include 150 mg of anti-IL-23A antibody.

For example, in the context of the present invention, if a loading dose is administered to a patient, and with a maintenance dosing frequency of 16 weeks, then an initial dose is administered to the patient at week 0, followed by an additional dose at week 4 (loading dose), then at week 20 (first maintenance dose). dose), at week 36 (second maintenance dose) and so on, with a dosing interval of 16 weeks. In one aspect, the initial dose, loading dose, and maintenance doses include 150 mg of anti-III-23A antibody.

For example, in the context of the present invention, if a loading dose is not administered to the patient, and with a maintenance dosing frequency of 6 weeks, then the initial dose is administered to the patient at week 0, followed by an additional dose at week 6 (first maintenance dose), then at week 12 ( second maintenance dose) and so on, with a dosing interval of 6 weeks. In one aspect, initial

- 13 046375 dose and maintenance doses include 150 mg of anti-III-33A antibody.

For example, in the context of the present invention, if a loading dose is administered to a patient, and with a maintenance dosing frequency of 6 weeks, then an initial dose is administered to the patient at week 0, followed by an additional dose at week 4 (loading dose), then at week 10 (first maintenance dose). dose), at week 16 (second maintenance dose) and so on, with a dosing interval of 6 weeks. In one aspect, the initial dose, loading dose, and maintenance doses include 150 mg of anti-1G-23A antibody.

For example, in the context of the present invention, if the frequency of administration of maintenance doses is 4 weeks, then the initial dose is administered to the patient at week 0, followed by additional administration at week 4 (first maintenance dose), then at week 8 (second maintenance dose), per week 12 (third maintenance dose) and so on, with a dosing interval of 4 weeks. In one aspect, the initial dose and maintenance doses include 150 mg of anti-!E-23A antibody.

In a further aspect, in the method in accordance with the present invention, an initial dose of anti-IL-23 antibody is administered to the patient. A second dose of anti-[G-2.3 antibody is not administered to the patient until the therapeutic effect of the initial dose is maintained, for example, as assessed by a PASI scale, for example, PASI 90, PASI 75, PASI 100 or PASI 50, but a second dose is administered to the patient if the severity of the disease increases above a certain level, for example, if the patient no longer maintains a certain PASI score, for example PASI 90, PASI 75, PASI 100 or PASI 50. The initial dose and second dose of anti-III-23 antibodies are e.g. , doses as described in this application. In one aspect, the patient is monitored after administration of the initial dose, for example, using the patient's PASI score. In one aspect, a third dose of anti-HELD3 antibody is administered to the patient if the patient no longer maintains a particular PASI score, such as PASI 90, PASI 75, PASI 100, or PASI 50, after administration of the second dose. The third dose of anti-III3 antibody is, for example, a dose as described herein, for example, the same dose as the second dose. In one aspect, the patient is monitored after administration of the second dose, for example, using the patient's PASI score. In a further aspect, at least one additional dose is administered to the patient in the same manner.

In a further aspect, in the method in accordance with the present invention, a loading dose of anti-IL23 antibody is administered to the patient after administration of the initial dose, for example, after a period of time as described herein. The third dose of anti-TE-23 antibody is not administered to the patient until the therapeutic effect of the initial dose is maintained, for example, as assessed by a PASI scale, for example, PASI 90, PASI 75, PASI 100 or PASI 50, but the third dose is administered to the patient if the severity of the disease increases above a certain level, for example, if the patient no longer maintains a particular PASI score, for example, PASI 90, PASI 75, PASI 100 or PASI 50. In one aspect, the loading dose of 8^^^-23 antibody is a dose , as described in this application. In one aspect, a fourth dose of anti-TE-23 antibody is administered to a patient if the patient no longer maintains a particular PASI score, such as PASI 90, PASI 75, PASI 100, or PASI 50, after administration of the third dose. The fourth dose of anti-IL-23 antibody is, for example, a dose as described herein, for example, the same dose as the third dose. In one aspect, the patient is monitored after administration of the third dose, for example, using the patient's PASI score. In a further aspect, at least one additional dose is administered to the patient in the same manner.

Therefore, in one embodiment, the present invention further provides a method of treating an inflammatory disease, in one aspect of treating psoriasis or psoriatic arthritis, comprising administering an anti-IL-23A antibody to a patient, wherein the method comprises:

A. administering an initial dose of said anti-IL-23A antibody to the patient; And

b. administering a second dose of the specified anti-IL-23A antibody to the patient if the patient no longer maintains PASI 90, PASI 75, PASI 100, or PASI 50.

In one aspect, the amount of anti-IL-23A antibody in the second and subsequent doses is less than the amount of anti-IL-23A antibody in the initial dose. In one aspect, 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.

In one embodiment, the present invention further provides a method of treating an inflammatory disease, in one aspect treating psoriasis or psoriatic arthritis, comprising administering an anti-IL-23A antibody to a patient, wherein the method comprises:

A. administering an initial dose of said anti-IL-23A antibody to the patient;

b. administering a loading dose of said anti-IL-23A antibody to the patient 1-6 weeks, for example 4 weeks, after administration of said initial dose; And

V. administering a third dose of the specified anti-IL-23A antibody to the patient if the patient no longer maintains PASI 90, PASI 75, PASI 100, or PASI 50.

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

- 14 046375

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

In one aspect, in any of the methods described above, the patient is administered a pharmaceutical composition containing an anti-IL-23A antibody. In one aspect, the patient is administered drug 2 described in example 4, containing an anti-IL-23A antibody, for example, antibody A, antibody B, antibody C or antibody D. In one aspect, the patient is administered drug 3 described in example 4, containing an anti-IL23A antibody, for example, antibody A, antibody B, antibody C or antibody D.

In one aspect, the anti-IL-23A antibody is a humanized antibody. In one aspect, the anti-III-23A antibody is a monoclonal antibody. In one aspect, the anti-IL23A antibody is a full-length antibody. In one aspect, the anti-III-23A antibody is a humanized monoclonal antibody, such as a full-length humanized monoclonal antibody.

The antibody described herein recognizes a specific IL-23A antigen epitope or IL-23A epitope. As used herein, these terms refer to a molecule (eg, peptide) or fragment of a molecule capable of reacting immunologically with an anti-IL-23A antibody and, for example, includes an IL-23A antigenic determinant that recognizes any of the antibodies having light chain/heavy chain sequence combination SEQ ID NO: 11/14, 11/15, 10/14 or 10/15.

The general structure of an antibody or immunoglobulin is well known to those skilled in the art. These molecules are heterotetrameric glycoproteins, typically with a molecular weight of 150 kDa, consisting of two identical light (L) chains and two identical heavy (H) chains and are typically referred to as full-length antibodies. Each light chain is covalently linked to a heavy chain via a single disulfide bond to form a heterodimer, and a heterotetrameric molecule is formed via a covalent disulfide bond between two identical heterodimer heavy chains. Although the light and heavy chains are linked by a single disulfide bond, the number of disulfide bonds between the two heavy chains varies depending on the type of immunoglobulin. Each heavy and light chain is also regularly separated by intrachain disulfide bridges. Each heavy chain has a variable domain (VH) at the amino terminus, followed by three or four constant domains ( _CH1 , _CH2 , _CH3 , and _CH4 ), and a hinge region between _CH1 and _CH2 . Each light chain has two domains, an amino-terminal variable domain (VL) and a carboxy-terminal constant domain ( _CL ). The V _L domain is linked non-covalently to the VH domain, while the C _L domain is usually covalently linked to the C _H1 domain via a disulfide bond. Preferred amino acid residues are believed to form the interface between the light and heavy chain variable domains (Chothia et al., 1985, J. Mol. Biol. 186:651-663). Variable domains are also referred to as variable regions in the present invention.

Certain domains within the variable domains differ significantly between different antibodies, that is, they are hypervariable. These hypervariable domains contain residues that are directly involved in the binding and specificity of each particular antibody for its specific antigenic determinant. Hypervariability, in both the light chain and heavy chain variable domains, is concentrated in three segments known as complementarity determining regions (CDRs) or hypervariable loops (HVLs). CDRs are determined by sequence comparison according to Kabat et al., 1991, in: Sequences of Proteins of Immunological Interest, ^5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., while HVLs (also referred to herein as CDRs) are structurally defined according to the three-dimensional variable domain structure as described by Chothia and Lesk, 1987, J. Mol. Biol. 196:901-917. The two methods result in slightly different CDR identifications. As defined by Kabat, CDRL1 is located at approximately residues 24-34, CDR-L2 at approximately residues 50-56, and CDRL3 at approximately residues 89-97 in the light chain variable domain; CDR-H1 is located at approximately residues 31-35, CDR-H2 at approximately residues 50-65, and CDR-H3 at approximately residues 95-102 in the heavy chain variable domain.

The exact number of residues covered by a particular CDR will depend significantly on the sequence and size of the CDR. Those skilled in the art can, using conventional methods, determine which residue contains a particular CDR of a given amino acid sequence of an antibody variable region. Therefore, CDR1, CDR2, CDR3 of the heavy and light chains determine the unique and functional properties specific to a given antibody.

The three CDRs within each of the heavy and light chains are separated by framework regions (FRs) that contain sequences that have less variability. From the amino terminus to the carboxy terminus of the heavy and light chain variable domains, the FRs and CDRs are arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The primarily β-sheet configuration of the FR brings the CDRs within each of the chains into close proximity to each other, as well as to the CDRs from the other

- 15 046375 chains. The resulting conformation contributes to the antigen-binding site (see Kabat et al., 1991, NIH Publ. No. 91-3242, vol. I, pp. 647-669), although not all CDR residues are necessarily directly involved in antigen binding.

FR residues and Ig constant domains are not directly involved in antigen binding, but facilitate antigen binding and/or mediate antibody effector functions. Some FR residues are believed to have a significant influence on antigen binding in at least three ways: by noncovalent binding directly to the epitope, by interaction with one or more CDR residues, and by influencing the interface between the heavy and light chains. Constant domains are not directly involved in antigen binding but mediate various Ig effector functions, such as antibody involvement in antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP).

Vertebrate immunoglobulin light chains belong to one of two distinct classes, kappa (k) and lambda (λ), based on the amino acid sequence of the constant domain. By comparison, mammalian immunoglobulin heavy chains belong to one of five major classes, according to the sequence of constant domains: IgA, IgD, IgE, IgG, and IgM. IgG and IgA are further divided into subclasses (isotypes), for example, IgGi, IgG ₂ , IgG ₃ , IgG ₄ , IgAi, and IgA ₂ . The heavy chain constant domains that correspond to the various classes of immunoglobulins are designated α, δ, ε, γ, and μ, respectively. The subunit structure and three-dimensional configurations of native immunoglobulin classes are well known.

Terms, antibody, anti-IL-23A antibody, anti-IL-23p19 antibody, humanized anti-IL-23A antibody, humanized anti-IL-23p19 antibody, humanized anti-IL-23A antibody epitope, humanized anti-IL-2319 antibody epitope, The humanized anti-IL-23A antibody epitope variant and the humanized anti-IL-23p19 antibody epitope variant specifically cover monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and antibody fragments, such as variable domains and other portions of antibodies, that exhibit a desired biological activity, eg IL-23A binding. The term monoclonal antibody (mAb) refers to an antibody that is extremely specifically directed against a single antigenic determinant, an epitope. Thus, the monoclonal modifier is an indicator of antibody targeting to an identical epitope and should not be considered to require production of the antibody by any particular route. It is understood that monoclonal antibodies can be produced using any techniques or techniques known in the art; including, for example, the hybridoma method (Kohler et al., 1975, Nature 256:495), or recombinant DNA methods known in the art (see, for example, US Pat. No. 4,816,567), or methods for isolating recombinantly produced monoclonals using phage antibody libraries using techniques described in Clackson et al., 1991, Nature 352: 624-628, and Marks et al., 1991, J. Mol. Biol. 222:581-597.

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

Chimeric antibodies consist of the heavy and light chain variable regions of an antibody from one species (eg, non-human mammal, such as mouse) and the heavy and light chain constant regions of another species (eg, human) antibody and can be produced by linking DNA sequences encoding antibody variable regions from a first species (eg, mouse) with DNA sequences for antibody constant regions from a second species (eg, human) and transforming the host with an expression vector containing the linked sequences, allowing the production of a chimeric antibody. Alternatively, a chimeric antibody may also be an antibody in which one or more heavy and/or light chain regions or domains are identical to, homologous to, or a variant of the corresponding sequence in a monoclonal antibody from an immunoglobulin of a different class or isotype, or from a consensus sequence or germline sequences. A chimeric antibody may include fragments of such antibodies, provided that the antibody fragments exhibit the desired biological activity of its parent antibody, such as binding to the same epitope (see, for example, US Pat. No. 4,816,567; and Morrison et al., 1984, Proc. Natl Acad Sci USA 81: 6851-6855).

Terms, antibody fragment, anti-IL-23A antibody fragment, anti-IL-23A antibody epitope fragment, humanized anti-IL-23A antibody fragment, humanized anti-IL-23A antibody epitope fragment, humanized anti-IL-23A epitope variant fragment antibody refers to the portion of a full-length anti-IL-23A antibody that retains the variable region or functional ability, such as specific binding of the IL-23A epitope. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab') ₂ , Fd, Fv, scFv and scFv-Fc fragment

- 16 046375 ment.

Full length antibodies can be processed with enzymes such as papain or pepsin to produce useful antibody fragments. Papain digestion is used to produce 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 _H1 domain. Treatment with pepsin results in an F(ab')2 fragment that has two antigen-binding sites and is still able to cross-link antigen.

Fab' fragments differ from Fab fragments by the presence of additional residues, including one or more cysteines from the antibody hinge region at the C-terminus of the C _H1 domain. F(ab')2 antibody fragments are pairs of Fab' fragments linked by cysteine residues in the hinge region. Also known. Other chemical compounds of antibody fragments are also known.

The Fv fragment contains a complete antigen recognition and binding site consisting of a dimer of one heavy and one light chain variable domain in tight, non-covalent association. In this configuration, the three CDRs of each variable domain interact to define an antigen binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody.

A single chain Fv or scFv antibody fragment is a single chain Fv variant containing a variant containing the V _H and V _L domains of an antibody, where the domains are present on a single polypeptide chain. Single-chain Fv recognizes in binding antigen. The scFv polypeptide may also optionally contain a polypeptide linker located between the VH and VL domains to facilitate formation of the desired three-dimensional structure for antigen binding by the scFv (see, for example, Pluckthun, 1994, In The Pharmacology of monoclonal Antibodies, volume 113, Rosenburg and Moore ed., Springer-Verlag, New York, pp. 269-315).

A humanized antibody or humanized antibody fragment is a specific type of chimeric antibody that includes a variant of an immunoglobulin amino acid sequence, or fragment thereof, that is capable of binding a predetermined antigen and that includes one or more FRs having essentially the amino acid sequence of a human immunoglobulin and one or more CDRs, having essentially the amino acid sequence of a non-human immunoglobulin. This non-human amino acid sequence, often referred to as an imported sequence, typically borrows from the imported domain of an antibody, especially the variable domain. In general, a humanized antibody includes at least a CDR or HVL of a non-human antibody inserted between the FRs of a human heavy or light chain variable domain. The present invention describes specific humanized anti-III-23A antibodies that contain CDRs derived from murine monoclonal antibodies or the humanized CDRs shown in Tables 1 and 2 inserted between the FR variable domains of human heavy and light chain germline sequences. It is understood that certain murine FR residues may be important for the function of the humanized antibody and, therefore, certain residues of the germline heavy and light chain sequence variable domains are modified to be the same as the corresponding murine sequence.

In another aspect, a humanized anti-III-23A antibody includes substantially all of at least one, and typically two, variable domains (such as, for example, those contained in Fab, Fab', F(ab')2, Fabc, and Fv fragments) in which all, or substantially all, of the CDRs correspond to those of non-human immunoglobulin, and specifically in this application, all of the CDRs are murine or humanized sequences, as detailed in Tables 1 and 2 herein below, and all, or substantially all, of the FRs are those of a consensus or germline human immunoglobulin sequence. In another aspect, the humanized anti-IL-23A antibody also includes at least a portion of an immunoglobulin Fc, typically such a human immunoglobulin. Typically, an antibody will contain both a light chain and a heavy chain variable domain. The antibody may also include one or more _CH1 loop, _CH2 , _CH3 , and/or _CH4 heavy chain regions, as appropriate.

The humanized anti-III-23A antibody may be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including IgG1, _IgG2 , _IgG3 , IgG4, IgA1 and _IgA2 . For example, the constant domain may be a complement fixing constant domain if it is desired that the humanized antibody exhibit cytotoxic activity, and the isotype is typically IgG|. If such cytotoxic activity is not desired, then the constant domain may be of a different isotype, for example IgG2. The alternative humanized anti-III-23A antibody may contain sequences from more than one class or isotype of immunoglobulin, and the selection of preferred constant domains to optimize the desired effector functions is within the skill of one skilled in the art. In specific embodiments, the present invention provides antibodies that

- 17 046375 These are IgG1 antibodies and, more preferably, are IgG1 antibodies in which effector functions are disabled.

The FR and CDR, or HVL, of a humanized anti-IL-23A antibody do not need to correspond exactly to the original sequences. For example, one or more residues in an imported CDR, or HVL, or consensus or germline FR sequence may be altered (eg, mutagenized) by substitution, insertion, or deletion such that the resulting amino acid residues are no longer identical to the original residue at the corresponding position in any original sequence, but, nevertheless, the antibody retains the function of binding IL-23A. Such changes are usually not extensive and will be conservative changes. Typically, at least 75% of the residues of the humanized antibody will correspond to such residues of the original consensus or germline FR and imported CDR sequences, most often at least 90%, and most often greater than 95%, or greater than 98%, or greater than 99%.

Immunoglobulin residues that relate to the region of interaction between the variable regions of the heavy and light chains (V _L -V _H interface) are those residues that relate to the spatial proximity or orientation of the two chains with respect to each other. Specific residues that may be involved in intrachain interactions include VL residues 34, 36, 38, 44, 46, 87, 89, 91, 96, and 98 and VH residues 35, 37, 39, 45, 47, 91, 93 , 95, 100, and 103 (using the numbering system proposed by Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987)). US Pat. No. 6,407,213 also discusses that residues such as _VL residues 43 and 85, and VH residues 43 and 60 may also be involved in this interaction. Although these residues are specified only for human IgG, they are applicable to other species. Important antibody residues that are reasonably expected to be involved in intrachain interactions are selected for replacement in the consensus sequence.

The terms consensus sequence and consensus antibody refer to an amino acid sequence that includes the most frequently occurring amino acid residue at each location in all immunoglobulins of any particular class, isotype, or subunit structure, for example, a human immunoglobulin variable domain. The consensus sequence may be based on immunoglobulins from a specific species or from many species. A consensus sequence, structure, or antibody encompasses a human consensus sequence, as described in certain embodiments of the invention, and refers to an amino acid sequence that includes the most commonly occurring amino acid residues at each location in all human immunoglobulins of any particular class, isotype, or subunit structure. Thus, the consensus sequence contains an amino acid sequence having at each position an amino acid that is present in one or more known immunoglobulins, but which may not be exactly copied in the entire amino acid sequence of any single immunoglobulin. The variable region consensus sequence is not derived from any naturally occurring antibody or immunoglobulin. Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., and variations thereof. The heavy and light chain FR consensus sequences, and variants thereof, provide useful sequences for the production of humanized anti-III-23p19 antibodies. See, for example, US Patent Nos. 6,037,454 and 6,054,297.

Human germline sequences have been found naturally in human populations. The combination of such germline genes creates antibody diversity. The antibody germline sequences for the antibody light chain are derived from the conserved human germline kappa or lambda v genes and j genes. Likewise, the heavy chain sequences are derived from the v-, d-, and j-gene germlines (LeFranc, M-P, and LeFranc, G, The Immunoglobulin Facts Book Academic Press, 2001).

As used herein, a variant, an anti-IL-23A variant, a humanized anti-IL-23A variant, or a humanized anti-IL-23A variant each refers to a humanized anti-IL-23A antibody having at least a variable murine mild CDR chains from any of the sequences, as shown in table. 1, or a murine heavy chain CDR sequence derived from a murine monoclonal antibody, as shown in Table. 2. Variants include those that have one or more amino acid changes in one or both of the light chain or heavy chain variable domains, provided that the amino acid changes should not significantly affect the binding of the antibody to IL-23A. Exemplary antibodies produced herein include those antibodies designated Antibody A, Antibody B, Antibody C, and Antibody D, and their various light chains and heavy chains are set forth in SEQ ID Nos: 18 and 21, and SEQ ID Nos: 19 and 20, respectively.

An isolated antibody is an antibody that has been identified and isolated and/or separated from components of its natural environment. Contaminants in the natural environment of an antibody are those materials that may interfere with diagnostic or therapeutic applications of the antibody, and may be enzymes, hormones, or other

- 18 046375 some protein-like or non-protein-like solutes. In one aspect, the antibody will be purified to at least greater than 95% recovery by weight of the antibody.

An isolated antibody includes the antibody in situ within the recombinant cells that produce it, since at least one component of the antibody's natural environment will not be present. However, typically, the isolated antibody will be prepared by at least one purification step in which the recombinant cellular material is removed.

The term antibody performance refers to factors that contribute to the recognition of an antigen by an antibody or the effectiveness of an antibody in vivo. Changes in the amino acid sequence of an antibody can affect properties of the antibody, such as folding, and can be influenced by physical factors such as the initial rate of binding of the antibody to the antigen ( _ka ), the dissociation constant of the antibody from the antigen (kd), the affinity constant of the antibody for the antigen (Kd ), antibody conformation, protein stability, and antibody half-life.

The term epitope tagged, as used herein, refers to an anti-IL-23A antibody fused to an epitope tag. An epitope tag is a polypeptide having a sufficient number of amino acids to provide an epitope for antibody production, while being designed so that it does not interfere with the desired activity of the anti-IL-23A antibody. The epitope tag is typically sufficiently unique such that an antibody constructed against the epitope tag does not substantially cross-react with other epitopes. Suitable tagging polypeptides typically contain at least 6 amino acid residues and typically contain about 8-50 amino acid residues, or about 9-30 residues. Examples of epitope tags and antibodies that bind the epitope include flu HA tagged polypeptide and its antibody 12CA5 (Field et al., 1988 Mol. Cell. Biol. 8: 2159-2165; c-myc tag and 8F9, 3C7, 6E10, G4 , B7 and 9E10 antibodies to it (Evan et al., 1985, Mol. Cell. Biol. 5(12):3610-3616; and the herpes simplex virus glycoprotein D (gD) tag and its antibody (Paborsky et al., 1990 , Protein Engineering 3(6): 547-553).In certain embodiments, the epitope tag is a salvage receptor binding epitope. As used herein, the term salvage receptor binding epitope refers to an epitope of the Fc region of an IgG molecule (such as IgGi, IgG ₂ , IgG ₃ , or IgG ₄ ), which is responsible for increasing the serum half-life of the IgG molecule in vivo.

For diagnostic as well as therapeutic monitoring, antibodies according to the invention can be conjugated to a label, either to one label or to a label and an additional second agent (prodrug, chemotherapeutic agent, etc.). A label, which is different from other second agents, refers to an agent that is a detectable compound or composition and can conjugate directly or indirectly to an antibody of the present invention. The label itself may be detectable (eg, radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze a chemical change in the substrate compound or composition that is detectable. Labeled anti-IL23A antibody can be prepared and used for a variety of indications, including in vitro and in vivo diagnostics.

In various aspects of the present invention, one or more antibody domains are recombinantly expressed. Such recombinant expression may use one or more control sequences, that is, polynucleotide sequences necessary for expression of an operably linked coding sequence in the preferred host organism. Control sequences suitable for use in prokaryotic cells include, for example, promoter, operator, and ribosomal site binding sequences. Eukaryotic control sequences include, but are not limited to, promoters, polyadenylation signals, and enhancers. These control sequences can be used for the expression and production of anti-IL-23A antibodies in prokaryotic and eukaryotic host cells.

A nucleotide sequence is operably linked if it is placed in a functional relationship with another nucleotide sequence. For example, a nucleotide presequence or secretory leader sequence is operably linked to a nucleic acid encoding a polypeptide if it is expressed as a precursor protein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects transcription of the sequence; or the ribosome binding site is operably linked to the coding sequence if it is located in such a way that it facilitates translation. In general, operably linked means that the DNA sequences are linked contiguously, and, in the case of a secretory leader sequence, contiguously and in frame. However, enhancers are not necessarily continuous. Linking can be accomplished by ligation at convenient restriction sites. If such sites do not exist, then synthetic oligonucleotide adapters or linkers can be used.

As used herein, the expressions cell, cell line, and cell culture are used interchangeably and all such designations include their progeny. Thus,

- 19 046375 transformants and transformed cells include the primary cell used and cultures derived from it, regardless of the number of transfers.

The term mammal for medical purposes refers to any animal classified as a mammal, including humans, domesticated and farm animals, and zoo animals, sporting animals, or pets such as dogs, horses, cats, cows and others. Preferably, the animal is a human.

A disorder, as used herein, is any condition that will benefit from treatment with the anti-IL-23A antibody described herein. It includes chronic and acute disorders or diseases, including those pathological conditions that predispose the mammal to the disorder.

As used herein, the term IL-23-related disorder or IL-23-related disease refers to a condition in which IL-23 activity contributes to the disease and typically where IL-23 is atypically expressed. IL-23-related disorder includes diseases and disorders of the immune system, such as autoimmune disorders and inflammatory diseases. Such conditions include psoriasis, inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, and spondyloarthritis, such as ankylosing spondylitis, non-radiographic axial spondyloarthritis, peripheral spondyloarthritis, or psoriatic arthritis.

The term intravenous infusion refers to the administration of an agent into a vein into an animal or human patient over a period of time greater than about 15 minutes, typically in the range of about 30-90 minutes.

The term intravenous bolus or intravenous bolus refers to the administration of a drug into a vein of an animal or person such that the body receives the drug in approximately 15 minutes or less, generally 5 minutes or less.

The term subcutaneous administration refers to the administration of an agent under the skin of an animal or human patient, preferably in a pocket between the skin and underlying tissue, through a relatively slow, sustained delivery from a drug reservoir. Piercing or pulling the skin upward and away from the underlying tissue can create a pocket.

The term subcutaneous infusion refers to the administration of a drug under the skin of an animal or human patient, preferably into a pocket between the skin and underlying tissue, by relatively slow, sustained delivery from a drug reservoir over a period of time including, but not limited to, 30 minutes or less, or 90 minutes or less. Optionally, infusion can be accomplished by subcutaneously implanting a drug delivery pump implanted under the skin of an animal or human patient, where the pump delivers a predetermined amount of drug over a predetermined period of time, such as 30 minutes, 90 minutes, or a period of time, covering the duration of the treatment protocol.

The term subcutaneous bolus refers to the administration of a drug under the skin of an animal or human patient, where the bolus delivery of the drug lasts less than about 15 minutes; in another aspect, less than 5 minutes, and in still another aspect, less than 60 seconds. In yet another aspect, insertion into a pocket between the skin and underlying tissue, where the pocket can be created by piercing or pulling the skin upward and away from the underlying tissue.

The term therapeutically effective amount is used to refer to an amount of active agent that alleviates or ameliorates one or more symptoms of the disorder being treated. In another aspect, a therapeutically effective amount refers to a target serum concentration that has been shown to be effective, for example, in slowing the progression of a disease. Efficacy may be measured using conventional methods, depending on the condition being treated.

The terms treatment and therapy and the like as used herein include therapeutic as well as prophylactic or suppressive measures for a disease or disorder resulting in any clinically desirable or beneficial effect, including, but not limited to, alleviation or attenuation of one or more several symptoms, regression, slowing or stopping the progression of a disease or disorder. Thus, for example, the term treatment includes administering an agent before or after the onset of a symptom of a disease or disorder, thereby preventing or removing one or more symptoms of the disease or disorder. As another example, the term includes the administration of an agent after the clinical manifestation of a disease to combat symptoms of the disease. Additionally, administration of the agent after the onset of manifestation and after clinical symptoms is carried out if the administration has an effect on the clinical parameters of the disease or disorder, such as the extent of tissue damage or the number or distribution of metastases, regardless of whether the treatment will or will not ameliorate the disease, includes treating or treating as used herein. In addition, since the compositions in accordance with the invention, either alone or in combination with another therapeutic agent, weaken or

- 20 046375 alleviate at least one symptom of the disorder being treated compared with that symptom in the absence of application of the anti-!X-23A antibody composition, the result should be considered as an effective treatment of the underlying disorder, regardless of whether all symptoms of the disorder are alleviated or No.

The term package insert refers to instructions commonly included in commercial packaging of therapeutic products that contain information regarding the indications, uses, administration, contraindications and/or warnings relevant to the use of such therapeutic products.

Antibodies

The CDRs of selected antibodies used in the context of the present invention are presented in table.

and 2. The variable regions of selected antibodies used in the context of the present invention are presented in table. 3 and 4.

Table 1 LIGHT CHAIN CDR sequences

L-CDR1 L-CDR2 L-CDR3 6B8 KASRDVAIAVA (SEQ ID NO:1) WASTRHT (SEQ ID NO:2) HQYSSYPFT (SEQ ID NO:3)

table 2

HEAVY CHAIN CDR Sequences

H-CDR1 H-CDR2 H-CDR3 6B8 GNTFTDQTIH (SEQ ID NO:4) YIYPRDDSPKYNENFKG (SEQ ID NO:5) PDRSGYAWFIY (SEQ ID NO:6) Hu_6B82 GYTFTDQTIH (SEQ ID NO:7) YIYPRDDSPKYNENFKG (SEQ ID NO:5) PDRSGYAWFIY (SEQ ID NO:6) Hu_6B85 GFTFTDQTIH (SEQ ID NO:8) YIYPRDDSPKYNENFKG (SEQ ID NO:5) PDRSGYAWFIY (SEQ ID NO:6) Hu_6B836/65 GGTFTDQTIH (SEQ ID NO:9) YIYPRDDSPKYNENFKG (SEQ ID NO:5) PDRSGYAWFIY (SEQ ID NO:6)

Table 3

Humanized 6B8-VK sequences

6B8CVK-65 DIQMTQSPSSLSASVGDRVTITCKASRDVAIAVAWYQQKPGKVP KLLLFWASTRHTGVPDRFSGSGSGTDFTLTISSLQPEDLADYYC HQYSSYPFTFGQGTKLEIK (SEQ ID NO :10) 6B8CVK-66 DIQMTQSPSSLSASVGDRVTITCKASRDVAIAVAWYQQKPGKVP KLLIYWASTRHTGVPSRFSGSGSRTDFTLTISSLQPEDVADYFC HQYSSYPFTFGSGTKLEIK (SEQ ID NO :11) 6B8CVK-67 DIQMTQSPSSLSASVGDRVTITCKASRDVAIAVAWYQQKPGKVP KLLLYWASTRHTGVPSRFSGSGSRTDFTLTISSLQPEDVATYYC HQYSSYPFTFGSGTKLEIK (SEQ ID NO:12) 6B8CVK-78 DIQMTQSPSSLSASVGDRVTITCKASRDVAIAVAWYQQKPGKVP KLLLFWASTRHTGVPDRFSGSGSRTDFTLTISSLQPEDLADYYC HQYSSYPFTFGSGTKLEIK (SEQ ID NO :13)

- 21 046375

Table 4

Humanized 6B8-VH sequences

6B8CVH-02 QVQLVQSGAEVKKPGSSVKVSCKASGYTFTDQTIHWMRQAPGQG LEWIGYIYPRDDSPKYNENFKGKVTITADKSTSTAYMELSSLRS EDTAVYYCAIPDRSGYAWFIYWGQGTLVTVSS (SEQ ID NO:14 ) 6B8CVH-05 QVQLVQSGAEVKKPGSSVKVSCKASGFTFTDQTIHWVRQAPGQG LEWMGYIY PRDDS PKYNENFKGKV TL TADKS T S TAYME LS S LRS EDTAVYYCAIPDRSGYAWFIYWGQGTLVTVSS (SEQ ID NO :15) 6B8CVH-36 QVQLVQSGAEVKKPGSSVKTSCKASGGTFTDQTIHWVRQRPGQG LEWMGYIYPRDDSPKYNENFKGRVTITADKSTSTAYMELSSLRS EDTAVYYCAIPDRSGYAWFIYWGQGTLVTVSS (SEQ ID NO :16) 6B8CVH-65 QVQLVQSGAEVKKPGSSVKVSCKASGGTFTDQTIHWVRQAPGQG LEWMGYIY PRDDS PKYNENFKGRV TL TADKS T S TAYME LS S LRS EDTAVYFCARPDRSGYAWFIYWGQGTLVTVSS (SEQ ID NO :17)

The selected combination of humanized light chain and heavy chain variable regions derived from the murine 6B8 antibody results in Antibodies A, B, C and D:

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

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

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

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

Antibodies A, B, C and D have the heavy and light chain sequences presented in table. 5.

Table 5

DNA and amino acid sequences for Antibodies A, B, C, and D

Antibody A Light chain IgG #66 DIQMTQSPSSLSSASVGDRVTITCKASRDVAIAVAW YQQKPGKVPKLLIYWASTRHTGVPSRFSGSGSRTD FTLTISSLQPEDVADYFCHQYSSYPFTFGSGTKLE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC (SEQ ID NO :18) Heavy chain IgGl KO #2 QVQLVQSGAEVKKPGSSVKVSCKASGYTFTDQTIH WMRQAPGQGLEWIGYIYPRDDS PKYNENFKGKVTI TADKSTSTAYMELSSLRSEDTAVYYCAIPDRSGYA WFIYWGQGTLVTVSSASTKGPSVFPLAPS SKS T SG GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKP (SEQ ID NO:19)

- 22 046375

Antibody B Light chain IgG #66 (SEQ ID NO:18) Heavy chain IgGlKO #5 QVQLVQSGAEVKKPGSSVKVSCKASGFTFTDQTIH WVRQAPGQGLEWMGYIYPRDDS PKYNENFKGKVTL TADKSTSTAYMELSSLRSEDTAVYYCAIPDRSGYA WFIYWGQGTLVTVSSASTKGPSVFPLAPSSKS TSG G TAALGCLVKDY F PE PV TVS WNS GAL T S GVH ΤΕΡΑ VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO :20) Antibody C Light chain IgG #65 DIQMTQSPSSLSSASVGDRVTITCKASRDVAIAVAW YQQKPGKVPKLLLFWASTRHTGVPDRFSSGSGTD FTLTISSLQPEDLADYYCHQYSSYPFTFGQGTKLE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC (SEQ ID NO:21) Heavy chain IgGlKO #2 (SEQ ID NO:19) Antibody D Light chain IgG #65 (SEQ ID NO:21) Heavy chain IgGlKO #5 (SEQ ID NO:20)

The variable regions of the light chains and heavy chains of Antibodies A, B, C, and D are underlined in the table. 5 above.

In one embodiment, the β11pi-P.-23L antibody comprises the light chain sequence set forth in SEQ ID NO: 18 and the heavy chain sequence set forth in SEQ ID NO: 19. In one embodiment, the α11pi-P.- The 23A antibody comprises the light chain sequence set forth in SEQ ID NO: 18 and the heavy chain sequence set forth in SEQ ID NO: 20. In one embodiment, the anti-IL-23A antibody includes the light chain sequence set forth in SEQ ID NO: 20. 21, and the heavy chain sequence set forth in SEQ ID NO: 19. In one embodiment, the anti-Ib-23A antibody comprises the light chain sequence set forth in SEQ ID NO: 21 and the heavy chain sequence set forth in SEQ ID NO: : 20. In one embodiment, the anti-!b-23A antibody consists of the light chain sequence set forth in SEQ ID NO: 18 and the heavy chain sequence set forth in SEQ ID NO: 19. In one embodiment, the anti-!b The -23A antibody consists of the light chain sequence set forth in SEQ ID NO: 18 and the heavy chain sequence set forth in SEQ ID NO: 20. In one embodiment, the anti-IL-23A antibody consists of the light chain sequence set forth in SEQ ID NO: 21, and the heavy chain sequence presented in SEQ ID NO: 19. In one embodiment, the anti-III-23A antibody consists of the light chain sequence presented in SEQ ID NO: 21 and the heavy chain sequence presented in SEQ ID NO: 20. In a further embodiment, the anti-!X-23A antibody binds to human IL-23A at the epitope consisting of amino acid residues 108-126 and amino acid residues 137-151 of SEQ ID NO: 22.

In a further embodiment, the IL-2.3L antibody competitively binds human IL-23A with an antibody of the present invention, eg, Antibody A, Antibody B, Antibody C, or Antibody D, as described herein. The ability of an antibody to competitively bind IL-23A can be measured using a competitive binding assay known in the art.

- 23 046375 field of technology.

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

Polynucleotides, vectors, host cells and recombinant methods

Other embodiments include isolated polynucleotides, which include the anti-IL-23A antibody coding sequence, vectors, and host cells containing the polynucleotides, and recombinant techniques for producing a humanized antibody. The isolated polynucleotides may encode any desired form of anti-IL-23A antibody, including, for example, full-length monoclonal antibodies, Fab, Fab', F(ab') ₂ and Fv fragments.

The polynucleotide(s) that contain(s) a sequence encoding an anti-IL-23A antibody may be coupled to one or more regulatory or control sequences as known in the art and may be contained in suitable expression vectors or host cells, as is known in the art. Each of the polynucleotide molecules encoding the heavy or light chain variable domains can be independently paired with a polynucleotide sequence encoding a constant domain, such as a human constant domain, enabling the production of intact antibodies. Alternatively, the polynucleotides, or portions thereof, may be conjugated together to provide a template for the production of a single chain antibody.

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

Ahtu-IL-23A antibodies can also be prepared as fusion polypeptides in which the antibody is fused to a heterologous polypeptide, such as a signal sequence or other polypeptide having a specific cleavage site at the amino terminus of the mature protein or polypeptide. The heterologous signal sequence is typically selected from a sequence that is recognized and processed (ie, cleaved by a signal peptidase) by the host cell. For prokaryotic host cells that do not recognize or process the anti-IL-23A antibody signal sequence, the signal sequence can be replaced with a prokaryotic signal sequence. The signal sequence may be, for example, alkaline phosphatase, penicillinase, lipoprotein, thermostable enterotoxin II leader sequences, and the like. For secretion by yeast, the native signal sequence can be replaced, for example, by a leader sequence derived from yeast alpha-factor invertase (including the Saccharomyces and Kluyveromyces alpha-factor leader sequences), acid phosphatase, C. albicans glucoamylase, or the signal sequence described in WO90/ 13646. In mammalian cells, mammalian signal sequences as well as viral secretory leader sequences, for example the herpes simplex gD signal sequence, can be used. The DNA for such a precursor region is ligated in frame to the DNA encoding the anti-IL-23A antibody.

Expression and cloning vectors contain a nucleotide sequence that enables the vector to replicate in one or more selected host cells. In general, in cloning vectors, this sequence is the sequence that enables the vector to replicate independently of the host chromosomal DNA, and includes origins of replication or autonomously replicating sequences. Such sequences are well known for various bacteria, yeasts and viruses. The origin of replication from plasmid pBR322 is suitable for most gram-negative bacteria, the origin of replication is 2-υ. Plasmids are suitable for yeast, and various viral origins of replication (SV40, polyoma, adenovirus, VSV, and BPV) are suitable as cloning vectors in mammalian cells. In general, the origin of replication component is not necessary for mammalian expression vectors (the SV40 origin of replication can typically be used only because it contains an early promoter).

Expression and cloning vectors may contain a gene that encodes a selectable

- 24 046375 marker to facilitate expression identification. Typical selectable marker genes encode proteins that confer resistance to antibiotics or other toxins, such as ampicillin, neomycin, methotrexate or tetracycline, or alternatively, complement axotrophic deficiencies, or in other alternatives, supplement specific nutrients that are not present in complex nutrient media, for example, the gene encoding Dalanine racemate for Bacilli.

One example of a selection scheme uses a drug to stop the growth of a host cell. Those cells that are successfully transformed with the heterologous gene produce the drug resistance protein and therefore survive the selection scheme. Examples of such dominant selection are the use of the drugs neomycin, mycophenolic acid and hygromycin. Common selectable markers for mammalian cells are those that provide the ability to identify cells competent to accept the nucleic acid encoding the anti-IL-23A antibody, such as DHFR (dihydrofolate reductase), thymidine kinase, metallothionein-I and -II (such as the primate metallothionein genes ), adenosine deaminase, ornithine decarboxylase, and others. Cells transformed by the DHFR selectable gene are first identified by culturing all transformants in a culture medium that contains methotrexate (Mtx), a competitive antagonist of DHFR. A suitable host cell used, if wild-type DHFR is used, is a Chinese hamster ovary (CHO) cell line deficient in DHFR activity (eg, DG44).

Alternatively, host cells (preferably wild-type hosts that contain endogenous DHFR) transformed or co-transformed with DNA sequences encoding an anti-GR-23A antibody, wild-type DHFR protein, and another selectable marker such as aminoglycoside 3'-phosphotransferase (ARN) can be selected by growing cells in a medium containing a selectable agent for the selectable marker, such as an aminoglycoside antibiotic, for example kanamycin, neomycin, or G418. see, for example, US patent 4,965,199.

When recombinant production is carried out in a yeast cell as a host cell, 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 selection marker for a mutant yeast strain that lacks the ability to grow on tryptophan, such as ATCC No. 44076 or PEP4-1 (Jones, 1977, Genetics 85:12). Subsequently, the presence of the trp1 lesion in the host yeast cell genome provides an efficient environment for detecting transformation by growth in the absence of tryptophan. Likewise, Leu2p-deficient yeast strains such as ATCC 20,622 and 38,626 are complemented with known plasmids carrying the LEU2 gene.

Additionally, vectors derived from the 1.6 μm circular plasmid pKD1 can be used to transform Kluyveromyces yeast. Alternatively, an expression system for the industrial production of recombinant bovine chymosin for K. lactis has been described (Van den Berg, 1990, Bio/Technology 8:135). Stable multicopy expression vectors for the secretion of mature recombinant human serum albumin using commercial Kluyveromyces strains have also been described (Fleer et al., 1991, Bio/Technology 9:968-975).

Expression and cloning vectors typically contain a promoter that is recognized by the host and is operably linked to a nucleic acid molecule encoding an anti-IL23p19 antibody or polypeptide chain thereof. Promoters suitable for use with prokaryotic hosts include the phoA promoter, β-lactamase and lactose promoter systems, alkaline phosphatase, tryptophan (trp) promoter system, and hybrid promoters such as the tac promoter. Other known bacterial promoters are also suitable. Promoters for use in bacterial systems will also contain a Shine-Dalgarno sequence (ShineDalgarno, S.D.) operably linked to the DNA encoding the anti-III-23A antibody.

Many eukaryotic promoter sequences are known. In fact, all eukaryotic genes have an AT-rich region located approximately 25-30 bp upstream of the transcription start site. Another sequence, 70-80 bases upstream from the start of transcription of many genes, is the CNCAAT region, where N can be any nucleotide. At the 3' end of most eukaryotic genes there is an AATAAAA sequence, which can be a signal for the addition of a poly-A tail to the 3' end of the coding sequence. All of these sequences are suitably inserted into expression vectors.

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

Inducible promoters have the added benefit of transcription under the control of growth conditions. These include the yeast promoter regions for alcohol dehydrogenase 2, isocyto

- 25 046375 chromium C, acid phosphatase, derivatives of enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for the utilization of maltose and galactose. Suitable vectors and promoters for use for expression in yeast are further described in EP 73,657. Yeast enhancers are also advantageously used with yeast promoters.

Transcription of anti-IL-23A antibody from vectors in mammalian host cells is controlled, for example, by promoters derived from the genomes of viruses such as polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus , cytomegalovirus, retrovirus, hepatitis B virus and simian virus 40 (SV40), from heterologous mammalian promoters, for example, actin promoter or immunoglobulin promoter, or from heat shock promoters, provided that such promoters are compatible with host cell systems.

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

Another useful element that can be used in a recombinant expression vector is an enhancer sequence, which is used to enhance transcription of DNA encoding the anti-HE-23A antibody by higher eukaryotes. Many enhancer sequences are now known from mammalian genes (eg, globin, elastase, albumin, afetoprotein, and insulin). However, typically an enhancer from a eukaryotic cell virus is used. Examples include the SV40 late origin enhancer (100-270), cytomegalovirus early promoter enhancer, late polyoma enhancer, and adenoviral enhancers. Also see Yaniv, 1982, Nature 297:17-18 for a description of enhancer elements for activation of eukaryotic promoters. The enhancer can be spliced into the vector at a position 5' or 3' to the anti-HE-23A antibody coding sequence, but is preferably located at a 5' site from the promoter.

Expression vectors used in eukaryotic host cells (yeast, fungi, insects, plants, animals, humans or nucleated cells from other multicellular organisms) may also contain sequences necessary for transcription termination and for mRNA stabilization. Such sequences are publicly available from the 5' and sometimes 3' untranslated regions of eukaryotic or viral DNA or cDNA. These regions contain nucleotide segments transcribed as polyadenylated fragments in the translated portion of the mRNA encoding the anti-GE-23A antibody. One useful transcription termination component is the bovine growth hormone polyadenylation site. See WO94/11026 and the expression vector described therein. In some embodiments, humanized anti-HE-23p19 antibodies can be expressed using the CHEF system. (See, for example, US Patent No. 5,888,809; the contents of which are incorporated herein by reference.)

Suitable host cells for cloning or expressing DNA in the vectors of the present invention are prokaryotic, yeast or higher eukaryotic cells as described above. Suitable prokaryotes for this purpose include eubacteria, such as gram-negative or gram-positive organisms, e.g. Enterobacteriaceae, such as Escherichia, e.g. E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g. Salmonella typhimurium, Serratia, for example, Serratia marcescans, and Shigella, as well as Bacilli, such as B. subtilis and B. licheniformis (for example, B. licheniformis 41 P, disclosed in DD 266,710, published April 12, 1989), Pseudomonas, such as P. aeruginosa, and Streptomyces. One of the preferred hosts for cloning E. coli is E. coli 294 (ATCC 31,446), although other strains such as E. coli B, E. coli X1776 (ATCC 31,537), and E. coli W3110 (ATCC 27,325) are also suitable. . These examples are illustrative and not restrictive.

In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeast are suitable hosts for cloning or expression of vectors encoding anti-III-23A antibody. Saccharomyces cerevisiae, or the common baker's yeast, is the most commonly used lower eukaryotic microorganism host. However, various other genera, species and strains are publicly available and useful herein, such as Schizosaccharomyces pombe; Kluyveromyces hosts, such as, for example, K. lactis, K. fragilis (ATCC 12.424), K. bulgaricus (ATCC 16.045), K. wickeramii (ATCC 24.178), K. waltii (ATCC 56.500), K. drosophilarum (ATCC 36.906 ), K. thermotolerans, and K. marxianus; yarrowia (EP 402.226); Pichia pastors (EP 183.070); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa; Schwanniomyces such as Schwanniomyces occidentalis; and filamentous fungi, such as, for example, Neurospora, Penicillium, Tolypo

- 26 046375 cladium, and Aspergillus hosts such as A. nidulans and A. niger.

Suitable host cells for expression of glycosylated anti-HE-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 insect-permitted host cells from organisms such as Spodoptera frugiperda (caterpillar), Aedes aegypti (mosquito), Aedes albopictus (mosquito), Drosophila melanogaster (fruit fly), and Bombyx mori (silkworm). Various viral strains for transfection are publicly available, for example the L-1 variant of Autographa californica NPV and the Bm-5 strain of Bombyx mori NPV, and such viruses can be used particularly for transfection of Spodoptera frugiperda cells.

Plant cell cultures of cotton, corn, potatoes, soybeans, petunia, tomato and tobacco can also be used as hosts.

In another aspect, the expression of anti-HE-23A antibodies is carried out in vertebrate cells. Propagating vertebrate cells in culture (tissue culture) has become a common procedure and techniques are widely available. Examples of suitable mammalian host cell lines include the monkey kidney line CV1 transformed with SV40 (COS-7, ATCC CRL 1651), human embryonic kidney lines (293 or 293 cells subcloned for growth in suspension culture, (Graham et al., 1977, J. Gen Virol. 36: 59), newborn hamster kidney cells (BHK, ATCC CCL 10), Chinese hamster ovary cells/-E№1 and (CHO, Urlaub et al., 1980, Proc. Natl. Acad. Sci. USA 77: 4216; e.g. DG44), mouse Sertoli cells (TM4, Mather, 1980, Biol. Reprod. 23:243-251), monkey kidney cells (CV1 ATCC CCL 70), African green monkey kidney cells (VERO -76, ATCC CRL-1587), human cervical carcinoma cells (HELA, ATCC CCL 2), dog kidney cells (MDCK, ATCC CCL 34), Buffalo rat kidney cells (BRL 3A, ATCC CRL 1442), human lung cells (W138, ATCC CCL 75), human liver cells (Hep G2, HB 8065), mouse mammary tumor (MMT 060562, ATCC CCL51), TR1 cells (Mather et al., 1982, Annals N.Y. Acad. Sci. 383: 44 -68), MRC 5 cells, FS4 cells, and a human hepatoma line (Hep G2).

Host cells are transformed using the expression or cloning vectors described above to produce anti-HE-23A antibodies and cultured in a suitable growth medium modified, if appropriate, to induce promoters, select transformants, or amplify genes encoding the desired sequences.

The host cells used to produce the anti-HE-23A antibodies described herein can be cultured in a variety of culture media. Commercially available media such as Ham's F10 (Sigma-Aldrich Co., St. Louis, Mo.), minimal essential medium (MEM), (SigmaAldrich Co.), RPMI-1640 (Sigma-Aldrich Co.), and modified Dulbecco's Eagle's Medium ((DMEM), Sigma-Aldrich Co.) are suitable for culturing host cells. Additionally, any of the media described in one or more references: Ham et al., 1979, Meth. Enz. 58: 44, Barnes et al., 1980, Anal Biochem 102: 255, US Patent No. 4,767,704, US Patent No. 4,657,866, US Patent No. 4,927,762, US Patent No. 4,560,655, US Patent No. 5,122,469, WO 90/103430, and WO 87 /00195, can be used as a culture medium for host cells.Any of these media can be supplemented, if necessary, with hormones and/or other growth factors (such as insulin, transferrin or epidermal growth factor), salts (such as sodium chloride , calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics (such as gentamicin), trace elements (defined as inorganic compounds typically present in final concentrations in the micromolar range), and glucose or equivalent energy source. Other additives may also be included in suitable concentrations as will be apparent to one skilled in the art. Culture conditions, such as temperature, pH, and others, are conditions that have previously been used for the host cell selected for expression and will be understood by one skilled in the art.

Using recombinant techniques, the antibody can be produced intracellularly, into the periplasmic space, or directly secreted into the culture medium. If the antibody is produced intracellularly, the cells can be disrupted to release the protein as a first step. Particulate waste, either host cells or lysed fragments, can be removed, for example, by centrifugation or ultrafiltration. Carter et al., 1992, Bio/Technology 10:163-167 describes a procedure for isolating antibodies that are secreted into the periplasmic space of E. coli. Briefly, the cell mass is thawed in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonyl fluoride (PMSF) for approximately 30 minutes. Cellular debris can be removed by centrifugation. If the antibody is secreted into the culture medium, the supernatants from such expression systems are generally first concentrated using a commercially available protein concentration filter, such as an Amicon or Millipore Pellicon ultrafiltration unit. A protease inhibitor such as PMSF may be included in any of the above steps to inhibit proteolysis and antibiotics may be included to prevent the growth of incidental contaminants. To isolate an antibody from a host cell, you can use

- 27 046375 call various methods.

The antibody composition prepared from cells can be purified, for example, by hydroxyapatite chromatography, gel electrophoresis, dialysis and affinity chromatography, where a typical purification technique is affinity chromatography. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain that is present in the antibody. Protein A can be used to purify antibodies that are based on human gamma 1, gamma 2, or gamma 4 heavy chains (see, eg, Lindmark et al., 1983 J. Immunol. Meth. 62:1-13). Protein G is recommended for all murine isotypes and for human gamma 3 (see, eg, Guss et al., 1986 EMBO J. 5:1567-1575). The matrix to which the affinity ligand is attached is most often agarose, but other matrices are also available. Mechanically stable matrices such as controlled pore glass or poly(styrene divinyl)benzene offer the possibility of faster flow rates and shorter processing times, which can be achieved with agarose. If the antibody includes a C3 domain, then Bakerbond ABX™ resin (J. T. Baker, Phillipsburg, N.J.) is suitable for purification. Other technologies for protein purification are also available, such as ion exchange column fractionation, ethanol precipitation, reverse phase HPLC, silica chromatography, heparin chromatography SEPHAROSE™ chromatography on anion or cation exchange resin (such as a polyaspartic acid column ), chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation, depending on the antibody being recovered.

After any preparatory purification step(s), the mixture containing the antibody of interest and contaminants can be subjected to hydrophobic interaction chromatography at low pH using an elution buffer at a pH in the range of 2.5-4.5, typically carried out at low salt concentrations (eg, from about 0-0.25 M salt).

Therapeutic Applications

In another embodiment, the anti-Gk-23A antibody described herein is useful for treating various disorders associated with IL-23p19 expression as described herein. In one aspect, a method of treating a disorder associated with IL-23 includes administering a therapeutically effective amount of an anti-IL-23A antibody to a subject in need thereof.

The Ahtu-IL-23A antibody is administered by any suitable route, including parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and, if desired for local immunosuppressive treatment, intralesional administration (including perfusion or otherwise contacting the graft with the antibody prior to transplantation). The Ahtu-IL-23A antibody or agent can be administered, for example, as an infusion or bolus. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Additionally, the anti-Gk-23A antibody is suitably administered by pulsatile infusion, especially with tapering doses of the antibody. In one aspect, dosing is carried out by injection, most preferably intravenous or subcutaneous injection, depending in part on whether the administration will be short or chronic. In one aspect, dosing of the anti-Gk-23 antibody is accomplished by subcutaneous injection.

To prevent or treat a disease, the appropriate dosage of the antibody will depend on various factors, such as the type of disease being treated as defined above, the severity and course of the disease, whether the antibody is administered for prophylactic or therapeutic purposes, prior therapy, the patient's medical history, and response to antibodies, and the decisions of the attending physician. The antibody is suitably administered to the patient at one time or in a series of treatments.

The term suppression is used herein in the same context as improvement and alleviation to refer to the reduction of one or more characteristic features of a disease.

The antibody is formulated, dosed and administered in a manner consistent with good medical practice. Factors that are taken into account in this context include, but are not limited to, the disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the route of administration, the schedule of administration, and other factors known to those skilled in the art. doctors. The following considerations will be used to determine the therapeutically effective amount of antibody administered.

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

IL-23-associated disorders

Anti-Gk-23p19 antibodies or agents are useful for treating or preventing an immunological disorder that is characterized by abnormal expression of IL-23, for example, by inappropriate activation of immune cells (eg, lymphocytes or dendritic cells). Such abnormal expression of IL-23 may be due, for example, to increased levels of IL-23 protein.

- 28 046375

Immunological diseases that are characterized by inappropriate activation of immune cells and can be treated or prevented using the methods described herein can be classified, for example, by the type(s) of hypersensitivity reaction(s) that underlie the disorder. These reactions are typically classified into four types: anaphylactic reactions, cytotoxic (cytolytic) reactions, immunological complex reactions, or cell-mediated immunological (CMI) reactions (also referred to as delayed-type hypersensitivity (DTH) reactions). (See, for example, Fundamental Immunology (William E. Paul ed., Raven Press, N.Y., 3rd ed. 1993).) Immunological diseases include inflammatory diseases and autoimmune diseases.

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

In one aspect, in the context of the present invention, the immunological disease is psoriasis. Psoriasis is a chronic inflammatory skin disease that is characterized by dysfunctional differentiation of keratinocytes and hyperproliferation and marked accumulation of inflammatory T cells and dendritic cells. For example, the immunological disease includes plaque psoriasis, such as chronic plaque psoriasis, such as moderate or severe chronic plaque psoriasis, such as in patients who are candidates for systemic therapy or phototherapy. In one aspect, the immunological disease is moderate or severe plaque psoriasis and the patient is a patient who has not responded to treatment, or has contraindications to, or is unresponsive to, other systemic therapy, including cyclosporine, methotrexate, psoralen, or ultraviolet A (PUVA) light ).

For example, the immunological disease includes palmar pustular psoriasis, guttate psoriasis, fold psoriasis, pustular psoriasis, or erythroderma psoriasis (also known as erythroderma psoriasis).

For psoriasis, disease severity can be characterized by body surface area (BSA) involved, with <5% considered mild, 5-10% moderate, and >10% severe. In some cases, disease status is measured using the Psoriasis Area and Severity Index (PASI), a composite measure of erythema, induration, scaling and BSA affected by psoriasis with a score of 0-72. In one aspect, the percentage of patients achieving PASI75 (PASI 75), a 75% reduction in score from baseline at a specific time point (eg, 12 or 16 weeks) is used as a primary endpoint in the treatment of psoriasis, for example, in psoriasis treatment trials. In one aspect, the percentage of patients achieving PASI90 (PASI 90), a 90% reduction in score from baseline at a specific time point (eg, week 12 or 16) is used as a primary endpoint in psoriasis treatment, for example, in psoriasis treatment trials .

In one aspect, the percentage of patients achieving PASI90 at week 12, in accordance with the method of the present invention, for example, using Antibody A, is at least 60%, at least 65%, or at least 70%.

In one aspect, the percentage of patients achieving an sPGA score of clear (score 0) or essentially clear (score 1) at a given time point (eg, week 12 or 16) is used as a primary endpoint in the treatment of psoriasis, for example, in trial treatments psoriasis.

In one aspect, the patient being treated in the context of the present invention is a patient with stable moderate to severe chronic plaque psoriasis with or without psoriatic arthritis affecting 10% or more of body surface area, with a PASI disease severity equal to or greater than 12 and/or sPGA score moderate or higher (score of at least 3). In one aspect, the patient being treated in the context of the present invention is a patient with psoriasis disease of at least 6 months' duration prior to treatment.

In one aspect, in the context of the present invention, the immunological disease is psoriatic arthritis. For psoriatic arthritis, the patient has a history of psoriatic skin lesions or psoriasis in combination with nail dystrophy, inflammation of the fingers (dactylitis), and a characteristic radiographic appearance (vague ossification around the edges of the joints) with a negative serum test for rheumatoid factor. Treatment effectiveness for psoriatic arthritis in clinical trials is often determined using the percentage of patients achieving the American College of Rheumatology (ACR) composite efficacy measure, as previously used prospectively in clinical trials for rheumatoid arthritis. ACR20 indicates achieving at least a 20% improvement in the number of swollen and tender joints, as well as a 20% improvement to 3 from 5 in the baseline ACR scores, compared with baseline values, by a specified time point after the start of treatment, for example, at 24 weeks.

In one aspect, the percentage of ACR20 respondents (20% improvement on the American response criterion

- 29 046375 of the College of Rheumatology), for example, at week 24, was used as a primary endpoint for the treatment of psoriatic arthritis, for example, for trial treatments of psoriatic arthritis.

In one aspect, the immunological 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 one aspect, the anti-IL-23A antibody is used or intended to inhibit the progression of structural damage, and/or improve physical functioning.

In one aspect, the anti-IL-23A antibody is used alone or in combination with methotrexate (MTX) to treat psoriatic arthritis, such as active psoriatic arthritis, for example, if the response to prior non-biologic DMARD therapy has been inadequate. In one aspect, the anti-IL-23A antibody is used to reduce the progression of peripheral joint disease, as measured by x-ray, and/or to improve physical functioning.

In one aspect, in the context of the present invention, the immunological disease is axial spondyloarthritis (ax-SpA), including ankylosing spondylitis (AS, also called radiographic ax-SpA) and non-radiographic ax-SpA.

In one aspect, in the context of the present invention, the immunological disease is ankylosing spondylitis. Ankylosing spondylitis (AS) is an inflammatory disease primarily involving the skeleton of the head and trunk and the sacroiliac joints. Other musculoskeletal manifestations of the disease include peripheral arthritis and enthesitis. Extra-articular disease includes anterior uveitis, osteoporosis, cardiac disease primarily involving valves, kidney disease, pulmonary disease, gastrointestinal disease, and skin disease. AS occurs predominantly in males with a male:female ratio of 3:1. The peak age for onset of the disease is typically in the second or third decade of life. Estimates of AS prevalence worldwide range from approximately 0.5% to 0.07%. Patients with AS are likely to lose their physical function and ability to work, which is likely to have a significant impact on quality of life if the patient does not receive appropriate treatment.

For ankylosing spondylitis, the patient has low back pain, asymmetric peripheral arthritis, tendon inflammation (enthesitis) and extra-articular features such as uveitis, and a strong genetic link to human leukocyte antigen B27. In one aspect, the percentage of Ankylosing Spondylitis Disease Activity Score 40 (ASDAS 40) responders, for example, at week 24, is used as a primary endpoint for treatment of ankylosing spondylitis, for example, for trial treatments for ankylosing spondylitis.

In one aspect, in the context of the present invention, the immunological disease is non-radiographic axial spondyloarthritis (ax-SpA). Non-radiographic axial spondyloarthritis, recently self-identified in relation to AS, represents an earlier manifestation of the same pathological processes as AS, despite the fact that it is widely recognized that some patients (mainly females) may do not progress to radiographic disease, and may therefore be considered to have a distinctive subtype of that disease.

Pharmaceutical compositions and their administration

A composition containing an anti-IL-23A antibody can be administered to a subject having or at risk of having an immunological disorder. The term subject, as used herein, refers to any mammalian patient to which an anti-IL-23A antibody can be administered, including, for example, humans and non-human mammals such as primates, rodents and dogs. Subjects specifically intended for treatment using the methods described herein include humans. Antibodies can be administered either alone or in combination with other compositions to prevent or treat an immunological disorder.

Ahtu-IL-23A antibodies for use in such pharmaceutical compositions are those described herein, for example, Antibody A, Antibody B, Antibody C, or Antibody D.

Various delivery systems are known and can be used to administer the anti-IL-23A antibody. Routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The Ahtu-IL-23A antibody may be administered, for example, by infusion, bolus, or injection, and may be administered in conjunction with other biologically active agents, such as chemotherapeutic agents.

Administration may be systemic or local. In one embodiment, administration is by subcutaneous injection. Preparations for such injections can be prepared, for example, in pre-filled syringes, so that they can be administered once every two weeks.

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In specific embodiments, the anti-IL-23A antibody is administered by injection, by catheter, by suppository, or by implant, the implant being a porous, non-porous or gelatinous material, including a membrane such as a sialastic membrane, or fiber. Typically, when administering the composition, materials are used to which the anti-IL-23A antibody or agent is not adsorbed.

In other embodiments, the anti-IL-23A antibody is delivered using a controlled release system. In one embodiment, a pump can 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, polymeric materials can 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 Langer, supra.

The Ahtu-IL-23p19 antibody is typically administered in the form of pharmaceutical compositions containing a therapeutically effective amount of the antibody and one or more pharmaceutically compatible components.

In typical embodiments, the pharmaceutical composition is prepared in accordance with conventional procedures in the form of a pharmaceutical composition adapted for intravenous or subcutaneous administration to humans. Typically, compositions for injection are solutions in sterile isotonic aqueous buffer. If necessary, pharmaceutical preparations may also include a solubilizing agent and a local anesthetic such as lidocaine to numb the injection site. Typically, the components are supplied either separately or mixed together in a unit dosage form, for example, as an anhydrous lyophilized powder or an anhydrous concentrate in a hermetically sealed container, such as an ampoule or sachet, indicating the amount of active ingredient. If the pharmaceutical drug is administered by infusion, it may be dispersed from an infusion bottle containing sterile pharmaceutical grade water or saline solution. If the pharmaceutical drug is administered by injection, then an ampoule of sterile water for injection or saline solution may be provided so that the components can be mixed before administration.

Additionally, the pharmaceutical composition may be presented in the form of a pharmaceutical kit containing (a) a container containing an anti-[k-2.3A antibody in lyophilized form, and (b) a second container containing a pharmaceutically acceptable diluent (eg, sterile water) for injection . A pharmaceutically acceptable diluent can be used to reconstitute or dilute the lyophilized anti-IL-23A antibody. Optionally associated with the container(s) may be an instruction in a form prescribed by a government agency that regulates the manufacture, use, or safety of pharmaceuticals or biological products, the instructions indicating the agency's approval of the manufacture, use, or safety for administration to humans.

Examples of pharmaceutical compositions used in the context of the present invention are disclosed in Example 4 presented later in the present description.

The invention is further described with reference to the following examples, which are not intended to limit the scope of the invention.

Examples

Example 1: Clinical Trials

The results presented in examples 1a, 1b and 1c originate from the same clinical study.

Example 1a: Research

This study assessed the efficacy and safety of Antibody A compared with ustekinumab in patients with moderate to severe plaque psoriasis.

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

The primary analysis showed Antibody A to be superior to ustekinumab (PASI 90 response rate of 77.1% for Antibody A versus 40% for ustekinumab [p<0.0001]). An sPGA score of 0 (pure) or 1 (almost pure) was achieved by 90.4% of antibody A patients compared to 67.5% in ustekinumab patients. Complete lesion clearance (PASI 100) was achieved with 45.8% of antibody A in patients and 17.5% in ustekinumab patients. AEs were similar between treatment groups

- 31 046375 without drug-related severe or serious AEs (side effects).

Selective blockade of IL-23p19 with antibody A is associated with better clinical response to ustekinumab in patients with moderate to severe plaque psoriasis.

Example 1b: Research

Objectives: The efficacy and safety of the selective IL-23p19 antagonist monoclonal antibody Antibody A was evaluated and compared with ustekinumab in patients with moderate to severe plaque psoriasis (including patients with or without concomitant psoriatic arthritis (PsA).

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

Results: The primary endpoint of PASI 90 response at week 12 was achieved by 32.6% (14/43), 73.2% (30/41) and 81.0% (34/42) of antibody A in patients in the groups with 18, 90 and 180 mg, respectively, and 40.0% (16/40) in ustekinumab patients. Using a two-sided Cochran-Mantel-Haenszel test, the PASI 90 response at week 12 between the 18, 90, and 180 mg antibody A and ustekinumab groups yielded p-values of 0.4337, 0.0013, and <0.0001, respectively. Of the 166 patients, 46 (27.7%) had concomitant PsA. The mean percentage reduction from baseline for pain-VAS at week 12 was 31.9%, 70.2%, and 58.4%, respectively, in patients receiving Antibody A in the 18, 90, and 180 mg dose groups, versus with 57.3% in patients treated with ustekinumab. Greater than 50% reduction in pain-VAS (determined post hoc) at week 12 was achieved by 29% (2/7), 73% (8/11) and 50% (6/12) of patients receiving Antibody A in the doses of 18, 90 and 180 mg s, respectively, compared with 54% (7/13) in patients treated with ustekinumab. In fig. Figure 1 shows that reductions in pain-VAS scores were observed at the earliest at 4 weeks and were maintained until week 24 (incomplete data). Adverse events (AEs) were similar across treatment groups with no drug-related severe or serious AEs.

Conclusions: Selective blockade of IL-23p19 with antibody A is associated with superior clinical response compared with ustekinumab in cutaneous lesions in patients with moderate to severe plaque psoriasis. Quantitative improvement compared with ustekinumab for pain-VAS was also observed in patients with PsA.

PASI 50, PASI 75 and PASI 100 responses at week 12 were also determined in the study described above. They showed the proportions of patients achieving PASI 50 at week 12 for 93%, 95% and 100% of patients receiving Antibody A in the 18, 90 and 180 mg groups, respectively, and 87% in patients with ustekinumab. The achievement of PASI 50 as a function of time is shown in FIG. 2.

They also showed the proportions of patients achieving PASI 75 at week 12 for 76%, 90% and 98% of patients receiving Antibody A in the 18, 90 and 180 mg groups, respectively, and 68% in patients with ustekinumab. The achievement of PASI 75 as a function of time is shown in FIG. 3.

They also showed the proportions of patients achieving PASI 100 at week 12 for 18%, 41% and 49% of patients receiving Antibody A in the 18, 90 and 180 mg groups, respectively, and 15% in patients with ustekinumab. The achievement of PASI 100 as a function of time is shown in FIG. 5.

The achievement of PASI 90 as a function of time is shown in FIG. 4.

Example 1c: Research

This study assessed the onset and duration of clinical response following treatment with a selective IL-23p19 inhibitor (Antibody A) compared with ustekinumab in patients with moderate-to-severe chronic plaque psoriasis.

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

Results: At week 24, PASI 90 was achieved in 66% (27/41) and 86% (36/42) of patients in the Antibody A 90 mg and 180 mg groups, respectively, compared to 55% (22/42). 40) patients treated with ustekinumab. Complete lesion clearance (PASI 100) was achieved in 41% (17/41) and 57% (24/42) of patients in the Antibody A 90 mg and 180 mg groups, compared with 28% of patients receiving ustekinumab. The time to initiation of PASI 90 was approximately two times faster in patients in the Antibody A 90 and 180 mg groups compared with patients in the Antibody A group.

- 32 046375 ustekinumab (median days to PASI 90=57 days [both antibody A dose groups; ~8 weeks] vs 113 days [~16 weeks], respectively, p=0.0016 [90 mg] and p<0.0001 [180 mg]). Patients in the 90 and 180 mg Antibody A groups who achieved PASI 90 maintained responses longer than patients receiving (days up to 50% of patients having first loss PASI 90=337 days [both groups , dosed with Antibody A; ~48 weeks] versus 253 days [~36 weeks], respectively). AEs were similar between treatment groups, and there was no dose-response relationship for any AEs. Severe AE was described in seven patients (four in the 18 mg dose group and two in the 90 mg dose group of Antibody A and one in the ustekinumab group); all were considered unrelated to the study drug.

In a similar study, Antibody A was shown to have a rapid onset of effect in 69% and 66% of patients (180 mg and 90 mg, respectively), achieving PASI 50 at week 4, compared with 45% of patients with ustekinumab. At week 8, 83% and 80% of patients treated with Antibody A (180 mg and 90 mg, respectively) achieved a PASI 75 compared with 60% of patients treated with ustekinumab. At week 12, the proportion of patients achieving PASI 90 (the primary endpoint) was 81% and 73% for the Antibody A 180 mg and 90 mg groups, compared with 40% for ustekinumab. Body weight had little effect on the effectiveness of Antibody A. At week 20, 90%, and 76% of patients receiving Antibody A (180 mg and 90 mg, respectively) achieved a PASI 90 compared with 55% for ustekinumab; and 62% and 51% of patients treated with the antibody had complete lesion clearance (PASI 100) compared with 25% of patients with ustekinumab. Clinical responses were maintained at high levels through week 36 for the 180 mg and 90 mg Antibody A dose groups. In patients with PsA, there was a greater reduction in pain at week 12 observed with Antibody A (180 mg and 90 mg combined) compared with ustekinumab (68% vs. 57%). In patients with psoriatic arthritis, pain was assessed using a visual analogue scale and expressed as the mean percent change from baseline.

Conclusions: Selective blockade of IL-23 with antibody A shows higher efficacy, faster onset, and longer duration of response compared with blockade of IL-12 and IL-23 with ustekinumab.

In a similar study, the Skin Disease Life Quality Index (DLQI) and EuroQol-5D (EQ-5D) were assessed at weeks 0, 12, 24, and 48. Mean percentage changes from baseline in the DLQI total score (analyzed descriptively and with using the van Elteren test) was compared with ustekinumab at weeks 12 and 24. The proportion of patients achieving a DLQI score of 0 or 1 was also assessed. The EQ-5D performance scales were analyzed descriptively. Results for Antibody A are reported for the 90 mg and 180 mg groups combined.

At baseline, the mean DLQI score was 13.0 for patients randomized to antibody A compared with 16.0 for those randomized to ustekinumabp. The mean EQ-5D score was 0.7 in both treatment groups. At week 12, the mean percentage improvement for the DLQI score was greater for patients receiving Antibody A compared to patients receiving ustekinumab (100% vs. 90.6%, respectively; p=0.0304). The proportion of patients with a DLQI score of 0 or 1 at week 24 was 80% for patients receiving Antibody A compared with 61% for patients receiving ustekinumab. At week 12, patients receiving Antibody A had a 50% greater improvement in mean EQ-5D score compared with patients receiving ustekinumab (0.3 versus 0.2, respectively). This was maintained at week 24. In patients with moderate to severe plaque psoriasis, selective blockade of IL-23 with antibody A exhibits superior efficacy and significantly improved QoL outcomes compared with ustekinumab.

In a similar study, the effectiveness of Antibody A was assessed for the treatment of scalp, palmoplantar and nail psoriasis.

The Psoriasis Scalp Severity Index (PSSI) and Palmoplantar Psoriasis Area and Severity Index (PPASI) were used to evaluate scalp psoriasis and palmoplantar psoriasis, respectively. The Nail Psoriasis Severity Index (NAPSI) was assessed on the hands only. Assessments were completed at baseline and (for those with symptoms at baseline) at weeks 1, 2, 4, 6, 8, 12 and every 4 weeks until week 48. Patients with no documented signs or symptoms received an overall score of zero for this visit. The mean percentage improvements from baseline for Antibody A (90 mg and 180 mg combined) were comparable to those for ustekinumab.

One hundred fifty-four patients (92.8%) had scalp psoriasis, 42 patients (25.3%) had palmoplantar psoriasis, and 96 patients (57.8%) had nail psoriasis. Scalp and hand-foot disease spreads quickly; at week 2, patients treated with antibody A had improvements from baseline in PSSI and PPASI of 50% and 51%, compared with 37% and 30% for patients treated with ustekinumab. At week 6, patients in both antibody A and ustekinumab groups had complete resolution of scalp psoriasis that persisted for

- 33 046375 research. For PPASI, complete resolution was observed at week 6 for antibody A and week 16 for ustekinumab and was maintained throughout the study. Nail disease cleared more slowly, with a 30% improvement in NAPSI for antibody A at week 6 compared to 0% for ustekinumab. At week 12, improvements in NAPSI scores were 41% and 36% for antibody A and ustekinumab, respectively, and at week 24, improvements in NAPSI scores were 61% and 67%, respectively.

Selective blockade of IL-23 with Antibody A shows promising efficacy for the treatment of psoriasis of the scalp, palmoplantar and nail psoriasis, and confirms that faster improvements can be achieved with Antibody A compared with ustekinumab.

Example 2: Performance Evaluation

Antibody A is administered to the patient at the dose and dosage schedules described in this application. The effectiveness of Antibody A was assessed using one or more of the following endpoints, which were determined using known methods. Endpoints were measured, for example, at one or more of weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, or 104 after administration or as indicated below.

Psoriasis:

Achieving a >90% reduction from baseline values for the PASI scale (PASI90), for example, at week 12.

Achieving a >75% reduction from baseline for the PASI score (PASI ₇₅ ), for example, at weeks 12 and 24.

Achieving a 100% reduction from baseline for the PASI scale (PASI ₁₀₀ ), for example, in week 12.

Achieving >50% reduction from baseline for PASI score (PASI ₅₀ ), e.g. at week 12.

Achieving PASI ₉₀ , for example, in week 24.

Achieving sPGA clear or almost clear, for example, in week 12.

Percentage of PASI decrease from baseline, for example, at week 12.

Time to loss of PASI50 response. This endpoint was calculated from the first treatment until the first <50% decrease in PASI score from baseline after response was achieved.

Other endpoints were as follows:

Achieving PASI90 and PASI ₇₅ for example in weeks 4, 6, 8, 16, 20, 28, 32, 36, 40, 44, 48.

Achievement of PASI ₁₀₀ , PASI50 and PASI percentage reduction from baseline, for example, in weeks 4, 6, 8, 16, 20, 24, 28, 32, 36, 40, 44, 48.

Achieving sPGA clear or nearly clear, for example, in weeks 4, 6, 8, 16, 20, 24, 28, 32, 36, 40, 44, 48.

Time to PASI50 response (from first treatment to first >50% decrease in PASI score from baseline).

Percentage change from baseline for NAPSI (Nail Psoriasis Severity Index), PSSI (Scalp Psoriasis Severity Index), and PPASI (Palmoplantar Psoriasis Area Severity Index), e.g., at weeks 4, 6, 8, 12, 16, 20, 24 , 28, 32, 36, 40, 44, 48.

Change from baseline for PGAR (Patient Global Rating Scale) and PAI (Patient Pruritus Rating Scale), e.g., at weeks 4, 12, 24, 36, 48.

Change from baseline for Pain-VAS, for example, at week 12 (in the subgroup of patients with psoriatic arthritis only).

Change from baseline for Skin Disease Life Quality Index (DLQI), e.g., weeks 4, 6, 8, 12, 16, 20, 24, 48.

Change from baseline for EQ-5D (European Quality of Life Questionnaire) VAS (Visual Analogue Scale) scale, for example at week 12.

Change from baseline for the EQ-5D score, for example, at week 12.

Proportion of patients achieving a Skin Disease Life Quality Index (DLQI) score of 0 or 1, for example, at week 12.

Change from baseline for psoriasis symptoms assessed using the general scale for PSS (Psoriasis Symptom Scale), for example, at week 16.

Achieving an overall PSS score of 0, for example, in week 16.

Psoriatic arthritis (responses assessed, for example, after one or more weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 104):

Psoriatic Arthritis Screening and Evaluation Questionnaire (PASE), for example, at weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48.

20% improvement in American College of Rheumatology response criteria (ACR 20), e.g., at weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48.

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

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Clinical Disease Activity Index (CDAI).

Disease Activity Score 28 Joints (DAS28).

Dactylitis (swelling of the entire finger), with an estimate of the number of all 20 fingers that are affected (range 0-20 fingers (hands and toes), as present or absent for each finger).

Enthesitis (inflammation of the insertions of tendons and ligaments, assessed by the presence or absence of tenderness in six areas of the Leeds Enthesopathies Index (LEI)).

Individual ACR components, including number of painful or tender joints, number of swollen joints.

Overall patient assessment of disease activity and joint pain.

The attending physician's general assessment of disease activity.

Responses of the Health Assessment Questionnaire - Disability Index (HAQ-DI), Health Assessment Questionnaire - Disability Index (HAQ-DI).

C-reactive protein levels.

Erythrocyte sedimentation rate.

Patient-reported outcome measures including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score.

Version 2 of the 36-item Short Form Health Survey (SF-36).

Questionnaire on psoriasis symptoms.

Modified Total Sharpe Score (mTSS), e.g. week 24, 52, 104.

Number of painful joints.

Number of leaking joints.

Patient's assessment of pain

Patient's assessment of the level of disability.

Acute phase protein (C-reactive protein or erythrocyte sedimentation rate),

The patient's overall assessment of the disease.

The doctor's general assessment of the disease.

Minimum disease activity (MDA).

Composite Psoriatic Disease Activity Index (CPDAI).

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

Modified Nail Psoriasis Severity Index (mNAPSI).

Quality of life in psoriatic arthritis (PsAQOL).

Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F).

Psoriatic Arthritis Magnetic Resonance Imaging Scoring System (PsAMRIS), for example, at weeks 24, 52, and 104.

For ankylosing spondylitis and non-radiographic ax-SpA (responses assessed, for example, after one or more weeks 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 76, 104):

Inflammatory symptoms described by patients.

Acute phase reagents (erythrocyte sedimentation rate [ESR] or CRP).

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Changes in BASDAI score from baseline.

Ankylosing spondylitis disease activity score (ASDAS). Changes in ASDAS score from baseline.

Bath Ankylosing Spondylitis Functional Impairment Index (BASFI). Changes in BASFI scores from baseline.

Bath Ankylosing Spondylitis Metrology Index (BASMI). Changes in spinal mobility assessed using the BASMI score compared to baseline.

Magnetic resonance imaging (MRI), for example, at weeks 24, 52, 104.

ASAS 40 response.

ASAS 5/6 response.

ASAS criterion for partial remission.

ASAS 20 response

Changes in the number of peripheral joints (TJC and SJC) compared to baseline.

Changes in Enthesitis Score (MASES) from baseline.

Changes from baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS).

Time until loss of service.

Time until exacerbation after treatment.

Time until loss of service.

Ankylosing spondylitis quality of life scale (ASQoL).

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Example 3: Pharmacokinetic Endpoint(s)

To determine the pharmacokinetic parameters of an anti-III-23A antibody, such as Antibody A, the following parameters were assessed using methods known in the art:

maximum measured plasma concentration (Cmax) time for dosing maximum plasma concentration (t _max ), area under the plasma concentration-time curve for the treatment time interval (AUC _0-t ), area under the plasma concentration-time curve for time interval from zero to infinity (AUC _0-/ ), terminal half-life (t _1/2 ), population pharmacokinetics.

Example 4: Pharmaceutical Compositions

Examples of preparations suitable for the antibody of the present invention are presented below. The antibodies used in the preparations below are, for example, Antibody A, Antibody B, Antibody C or Antibody D.

Preparation 1:

Components Concentration [mmol/l] Concentration [g/l] Nominal quantity [mg/vial] V = 10.0 ml Antibody 10.0 100.0 succinic acid 0.7 0.083 0.8 Disodium succinate hexahydrate 24.3 6,564 65.6 Sodium chloride 125 7,305 73.1 Polysorbate 20 0.16 0.20 0.20 Water for injections - Up to 1 l Up to 1 ml

The pH of Formulation 1 is typically in the range of pH 6.0-7.0, for example pH 6.5. This drug is extremely suitable for intravenous administration.

Molecular weight (MB in g/mol) of excipients used: Disodium succinate hexahydrate = 270.14 g/mol; Succinic acid = 118.09 g/mol; Sodium chloride = 58.44 g/mol.

The osmolarity of the drug is 300 +/- 30 mOsmol/kg, as determined using Osmomat 030 (Gonotec GmbH, Berlin, Germany). The density at 20°C of the preparation is approximately 1.0089 g/cm ³ as determined using a DMA 4500 measuring device (Anton Paar GmbH, OstfildernScharnhausen, Germany).

Preparation 2:

Components Concentration [mmol/l] Concentration [g/l] Nominal quantity [mg/syringe] V = 1.0 ml Antibody 0.6 90.0 90.0 succinic acid 0.5 0.059 0.059 Disodium succinate hexahydrate 3.9 1.054 1.054 Sorbitol 225 41.00 41.00 Polysorbate 20 0.16 0.20 0.20 Water for injections - Up to 1 l Up to 1 ml

The pH of formulation 2 is typically in the pH range of 5.5-6.5, eg 5.5-6.1, eg pH 5.8. This preparation is extremely suitable for subcutaneous administration.

Molecular weight (MB in g/mol) of excipients used:

MB: Succinic acid (C ₄ H ₆ O ₄ ) = 118.09 g/mol

MB: Disodium succinate hexahydrate (C ₄ O ₄ Na ₂ H ₄ x 6H ₂ O) = 270.14 g/mol

MB: Sorbitol = 182.17 g/mol

MB: Polysorbate 20 = 1227.72 g/mol

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

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Claims (12)

Preparation 3: Components Concentration [mmol/l] Concentration [g/l] Nominal quantity [mg/syringe] V = 1.0 ml Antibody 0.6 90.0 90.0 Sorbitol 240 43,733 43,733 Polysorbate 20 0.16 0.20 0.20 Water for injections - Up to 1 l Up to 1 ml, the pH of preparation 3 is typically in the pH range of 5.5-6.5, for example 5.5-6.1, for example pH 5.8. This preparation is extremely suitable for subcutaneous administration. Molecular weight (MB in g/mol) of excipients used: MB: Sorbitol = 182.17 g/mol MB: Polysorbate 20 = 1227.72 g/mol. The osmolarity of the drug is 300 +/- 30 mOsmol/kg, as determined using Osmomat 030 (Gonotec GmbH, Berlin, Germany). CLAIM 1. A method of treating psoriasis, comprising administering to a patient an anti-IL-23A antibody containing 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, which involves: a) administering to the patient a first dose of 150 mg of said anti-IL-23A antibody; and b) administering to the patient a second dose of 150 mg of said anti-I.-23A antibody 4 weeks after the administration of said first dose. 2. The method of claim 1, wherein said method further comprises administering a first maintenance dose of 150 mg of said anti-IL-23A antibody to the patient 12 weeks after administration of said second dose. 3. The method of claim 2, wherein said method further comprises administering a maintenance dose of 150 mg of said anti-IL-23A antibody to the patient every 12 weeks after administration of said first maintenance dose. 4. The method according to any one of claims 1 to 3, wherein said method is for the treatment of moderate to severe chronic plaque psoriasis. 5. The method according to any one of claims 1 to 4, wherein said anti-IL-23A antibody is administered by subcutaneous administration. 6. Method according to any one of paragraphs. 1-5, where the patient reaches 50 points on the PASI scale (PASI 50). 7. Method according to any one of paragraphs. 1-6, where the patient reaches 75 points on the PASI scale (PASI 75). 8. The method according to any of paragraphs 1-7, where the patient reaches 90 points on the PASI scale (PASI 90). 9. Method according to any one of paragraphs. 1-8, where the patient reaches 100 points on the PASI scale (PASI 100). 10. The method according to any one of claims 1-3, where the specified method is intended for the treatment of plaque psoriasis. 11. The method according to any one of claims 1-3, where the specified method is intended for the treatment of erythrodermic psoriasis. 12. The method according to claim 10 or 11, wherein said anti-IL-23A antibody is administered by subcutaneous administration. -