Treatment methods for inflammatory diseases

Abstract

The present invention provides a pharmaceutical composition used to induce and maintain remission of inflammatory bowel disease. [Solution] A pharmaceutical composition comprising an anti-IL-23A antibody, wherein the anti-IL-23A antibody is a full-length IL-23A antibody and has two light chains having a specific amino acid sequence and two heavy chains having a specific amino acid sequence.

Description

[Technical Field]

[0001] Technical field of inventions The present invention generally relates to a method for treating inflammatory diseases, such as Crohn's disease (CD), using anti-IL-23A antibodies.

[0002] Background of the Invention Crohn's disease (CD) is a relapsing-remitting chronic inflammatory disease of the gastrointestinal tract characterized by abdominal pain, fever, and bloody or mucous diarrhea. The disease occurs discontinuously throughout the gastrointestinal tract from mouth to anus, but most frequently in the ileum and colon (40%), followed by the small intestine only (30%), and the colon only (25%). It occurs in a relatively young population and there is no significant difference between sexes.

[0003] The incidence of C. difficile (CD) appears to be increasing, with more recent estimates in North America and Europe showing a shift from 7.9 to 20.2 cases per 100,000 people, and a rise in prevalence from 161 to 319 cases per 100,000 people. Mucosal lesions can be complicated by perforation and fistula formation, which may require hospitalization for medical or surgical management. For example, there is a need for treatment options for inflammatory diseases, particularly Crohn's disease, that lead to favorable outcomes for patients in terms of treatment efficacy, safety, and / or tolerability.

[0004] Summary of the Invention The present invention addresses the above needs and provides a method for treating inflammatory diseases, particularly a method comprising the step of administering an anti-IL-23A antibody to a patient in a specific amount and / or at specific intervals. In one embodiment, the method of the present invention is for the treatment of Crohn's disease. In one embodiment, the method of the present invention is for the treatment of ulcerative colitis.

[0005] The method of the present invention offers the advantage of enabling patients to experience clinical improvement while receiving fewer doses of anti-IL-23A antibody.

[0006] In one embodiment, the present invention provides a method for treating an inflammatory disease, in one aspect for treating Crohn's disease, comprising the step of (a) administering a single dose of anti-IL-23A antibody to a patient by intravenous infusion at weeks 0, 4, and 8, wherein the dose of anti-IL-23A antibody comprises 200 mg or 600 mg of antibody. In one embodiment, the method further comprises (b) administering three doses of anti-IL-23A antibody to a patient by intravenous infusion, for example at weeks 14, 18, and 22, wherein the dose of anti-IL-23A antibody comprises 600 mg of antibody. In one embodiment, the method further comprises (c) administering to a patient by subcutaneous injection one or more doses of anti-IL-23A antibody at 8-week intervals, for example, four doses of anti-IL-23A antibody at 8-week intervals, for example, at weeks 26, 34, 42, and 50, wherein one or more doses of anti-IL-23A antibody comprise 180 mg of antibody.

[0007] In one embodiment, at week 12, the patient is evaluated for complete remission, defined, for example, by achieving clinical remission (CDAI score < 150) and endoscopic remission (CDEIS ≤ 4). In one embodiment, in patients with early isolated ileitis, endoscopic remission is defined by CDEI ≤ 2.

[0008] In one embodiment, the present invention provides a method for treating an inflammatory disease, in one aspect for treating Crohn's disease, comprising the step of (a) administering a single dose of anti-IL-23A antibody to a patient by intravenous infusion at weeks 0, 4, and 8, wherein the dose of anti-IL-23A antibody comprises 200 mg or 600 mg of antibody. In one embodiment, the method further comprises (b) administering one or more doses of anti-IL-23A antibody to a patient by subcutaneous injection at 8-week intervals, for example, four doses of anti-IL-23A antibody by subcutaneous injection at 8-week intervals, for example, at weeks 26, 34, 42, and 50, wherein the one or more doses of anti-IL-23A antibody comprises 180 mg of antibody.

[0009] In one embodiment, at week 12, the patient is evaluated for complete remission, defined, for example, by achieving clinical remission (CDAI score < 150) and endoscopic remission (CDEIS ≤ 4). In one embodiment, in patients with early isolated ileitis, endoscopic remission is defined by CDEI ≤ 2.

[0010] In one embodiment, the present invention provides a method for treating an inflammatory disease, in one aspect for treating Crohn's disease, comprising the step of administering 180 mg of anti-IL-23A antibody to a patient by subcutaneous injection at 8-week intervals.

[0011] In one embodiment, the present invention provides a method for treating an inflammatory disease, in one embodiment for treating Crohn's disease, comprising the step of administering an anti-IL-23A antibody to a patient, the method comprising the step of administering at least one induction dose of anti-IL-23A antibody to the patient, the induction dose comprising 200 to 1,200 mg of anti-IL-23A antibody, for example, 450 to 1,200 mg of anti-IL-23A antibody. In one embodiment, the induction dose comprises 200 mg, 450 mg, 600 mg, 900 mg, or 1,200 mg of anti-IL-23A antibody. In one embodiment, one, two, or three induction doses are administered to the patient. In one embodiment, two or three induction doses are administered, for example, at 4-week intervals. In one embodiment, the induction dose(s) are administered by intravenous infusion.

[0012] In one embodiment, the induction dose contains 200 mg of anti-IL-23A antibody, and three induction doses are administered to the patient at 4-week intervals.

[0013] In one embodiment, the induction dose contains 450 mg of anti-IL-23A antibody, and three induction doses are administered to the patient at 4-week intervals.

[0014] In one embodiment, the induction dose contains 600 mg of anti-IL-23A antibody, and three induction doses are administered to the patient at 4-week intervals.

[0015] In one embodiment, the induction dose comprises 900 mg of an anti-IL-23A antibody, and three induction doses are administered to a patient at 4-week intervals.

[0016] In one embodiment, the induction dose comprises 1,200 mg of an anti-IL-23A antibody, and three induction doses are administered to a patient at 4-week intervals.

[0017] In one embodiment, at least one additional induction dose of an anti-IL-23A antibody is administered to the patient after the last induction dose described above. In one aspect, the additional induction dose comprises from 200 to 1,200 mg of an anti-IL-23A antibody, such as from 450 to 1,200 mg of an anti-IL-23A antibody. In one aspect, the additional induction dose comprises 200 mg, 450 mg, 600 mg, 900 mg or 1,200 mg of an anti-IL-23A antibody. In one aspect, one, two or three additional induction doses are administered to the patient. In one aspect, two or three additional induction doses are administered, for example, at 4-week intervals. In one aspect, the additional induction dose(s) is administered by intravenous infusion.

[0018] In one embodiment, the patient has a CDAI score of 220 - 450 before administration of the first induction dose.

[0019] In one embodiment, the patient achieves clinical remission after administration of one or more induction doses. In one embodiment, the patient achieves a CDAI score of less than 150 after administration of one or more induction doses. In one embodiment, the patient achieves a PRO-2 score of 75 or less after administration of one or more induction doses. In one embodiment, the patient achieves a CDAI score of less than 150 and a PRO-2 score of 75 or less after administration of one or more induction doses.

[0020] In one embodiment, the present invention further provides a method for inducing clinical remission of Crohn's disease in a patient, comprising the step of administering to the patient an anti-IL-23 antibody as described above or herein.

[0021] In one embodiment, the present invention further provides a method for inducing a clinical response to Crohn's disease in a patient, comprising the step of administering an anti-IL-23 antibody, as described above or herein, to the patient.

[0022] In one embodiment, the method further includes administering an initial maintenance dose of anti-IL-23A antibody to the patient after the last induction dose has been administered, and administering at least one additional maintenance dose to the patient 4 to 12 weeks after the initial maintenance dose has been administered. In one embodiment, the initial maintenance dose is administered 2 to 8 weeks after the last induction dose has been administered, for example 4 to 6 weeks, for example 2 weeks, 4 weeks, 6 weeks, or 8 weeks later. In one embodiment, at least one additional maintenance dose is administered to the patient 4 weeks, 8 weeks, or 12 weeks after the initial maintenance dose has been administered.

[0023] In one embodiment, the initial maintenance dose contains 150-300 mg of anti-IL-23A antibody. In another embodiment, the initial maintenance dose contains 150 mg, 225 mg, or 300 mg of anti-IL-23A antibody. In yet another embodiment, the initial maintenance dose contains 180 mg or 270 mg of anti-IL-23A antibody.

[0024] In one embodiment, at least one additional maintenance dose comprises 150–300 mg of anti-IL-23A antibody. In one embodiment, at least one additional maintenance dose comprises 150 mg, 225 mg, or 300 mg of anti-IL-23A antibody. In one embodiment, at least one additional maintenance dose comprises 180 mg or 270 mg of anti-IL-23A antibody.

[0025] In one embodiment, the initial maintenance dose and at least one additional maintenance dose comprises 150 to 300 mg of anti-IL-23A antibody. In one embodiment, the initial maintenance dose and at least one additional maintenance dose comprises 150 mg, 225 mg, or 300 mg of the anti-IL-23A antibody. In one embodiment, the initial maintenance dose and at least one additional maintenance dose comprises 180 mg or 270 mg of the anti-IL-23A antibody.

[0026] In one embodiment, the maintenance dose is administered by subcutaneous injection.

[0027] In one embodiment, the maintenance dose contains 150 mg of anti-IL-23A antibody and is administered to the patient at 4-week intervals.

[0028] In one embodiment, the maintenance dose contains 150 mg of anti-IL-23A antibody and is administered to the patient at 8-week intervals.

[0029] In one embodiment, the maintenance dose contains 225 mg of anti-IL-23A antibody and is administered to the patient at 8-week intervals.

[0030] In one embodiment, the maintenance dose contains 225 mg of anti-IL-23A antibody and is administered to the patient at 12-week intervals.

[0031] In one embodiment, the maintenance dose contains 300 mg of anti-IL-23A antibody and is administered to the patient at 8-week intervals.

[0032] In one embodiment, the maintenance dose contains 300 mg of anti-IL-23A antibody and is administered to the patient at 12-week intervals.

[0033] In one embodiment, the patient maintains clinical remission after one or more maintenance doses. In one embodiment, the patient maintains a CDAI score of less than 150 after one or more maintenance doses. In one embodiment, the patient maintains a PRO-2 score of 75 or less after one or more maintenance doses. In one embodiment, the patient maintains a CDAI score of less than 150 and a PRO-2 score of 75 or less after one or more maintenance doses.

[0034] In one embodiment, the present invention further provides a method for maintaining clinical remission of Crohn's disease in a patient, comprising the step of administering an anti-IL-23 antibody, as described above or herein, to the patient.

[0035] In one embodiment, the present invention further provides a method for maintaining a clinical response to Crohn's disease in a patient, comprising the step of administering an anti-IL-23 antibody, as described above or herein, to the patient.

[0036] In one embodiment, the present invention further provides a method for treating Crohn's disease by inducing and maintaining clinical remission in a patient, comprising the step of administering an anti-IL-23 antibody, as described above or herein, to the patient.

[0037] In one embodiment, the present invention further provides a method for maintaining endoscopic remission of Crohn's disease in a patient, comprising the step of administering an anti-IL-23 antibody, as described above or herein, to the patient.

[0038] In one embodiment, the present invention provides a method for inducing clinical remission of Crohn's disease, comprising the step of administering an anti-IL-23A antibody to a patient, the method comprising the step of administering at least one induction dose of the anti-IL-23A antibody to the patient, the induction dose comprising 200 to 1,200 mg of the anti-IL-23A antibody. In one embodiment, the induction dose comprises 450 to 1,200 mg of the anti-IL-23A antibody. In one embodiment, the induction dose comprises 200 mg, 450 mg, 600 mg, 900 mg, or 1,200 mg of the anti-IL-23A antibody. In one embodiment, one, two, or three induction doses are administered to the patient. In one embodiment, two or three induction doses are administered at 4-week intervals. In one embodiment, the induction dose(s) are administered by intravenous infusion. In one embodiment, the patient has a CDAI score of 220-450 prior to administration. In one embodiment, the patient achieves a CDAI score of less than 150. In one embodiment, the patient achieves a PRO-2 score of 75 or less.

[0039] In one embodiment, the method further comprises the steps of maintaining clinical remission of Crohn's disease, the method further comprising the steps of administering an initial maintenance dose of the anti-IL-23A antibody to the patient after the last induction dose has been administered, and administering at least one additional maintenance dose to the patient 4 to 12 weeks after the initial maintenance dose has been administered. In one embodiment, the initial maintenance dose is administered 2 to 8 weeks after the last induction dose has been administered, for example 4 to 6 weeks, for example 2 weeks, 4 weeks, 6 weeks, or 8 weeks later. In one embodiment, at least one additional maintenance dose is administered to the patient 4 weeks, 8 weeks, or 12 weeks after the initial maintenance dose has been administered. In one embodiment, the initial maintenance dose comprises 150 to 300 mg of the anti-IL-23A antibody. In one embodiment, the initial maintenance dose comprises 150 mg, 225 mg, or 300 mg of the anti-IL-23A antibody. In one embodiment, the initial maintenance dose comprises 180 mg or 270 mg of the anti-IL-23A antibody. In one embodiment, at least one additional maintenance dose comprises 150 to 300 mg of the anti-IL-23A antibody. In one embodiment, at least one additional maintenance dose comprises 150 mg, 225 mg, or 300 mg of the anti-IL-23A antibody. In one embodiment, at least one additional maintenance dose comprises 180 mg or 270 mg of the anti-IL-23A antibody. In one embodiment, the initial maintenance dose and the aforementioned at least one additional maintenance dose comprises 150 to 300 mg of the anti-IL-23A antibody. In one embodiment, the initial maintenance dose and the aforementioned at least one additional maintenance dose comprises 150 mg, 225 mg, or 300 mg of the anti-IL-23A antibody. In one embodiment, the initial maintenance dose and the aforementioned at least one additional maintenance dose comprise 180 mg or 270 mg of the anti-IL-23A antibody. In one embodiment, the maintenance dose is administered by subcutaneous injection. In one embodiment, the patient maintains a CDAI score of less than 150. In one embodiment, the patient maintains a PRO-2 score of 75 or less.

[0040] In one embodiment, the present invention provides a method for treating an inflammatory disease, in one aspect for treating Crohn's disease, comprising the step of administering 150 to 1,200 mg of anti-IL-23A antibody to a patient. In one aspect, the method comprises the step of administering 200 to 1,200 mg of anti-IL-23A antibody, for example, 450 to 1,200 mg of anti-IL-23A antibody to a patient. In one aspect, the method comprises the step of administering 200 mg, 450 mg, 600 mg, 900 mg, or 1,200 mg of anti-IL-23A antibody to a patient. In one aspect, the method comprises the step of administering 150 to 300 mg of anti-IL-23A antibody to a patient. In one aspect, the method comprises the step of administering 150 mg, 225 mg, or 300 mg of anti-IL-23A antibody to a patient. In one embodiment, the method includes the step of administering 180 mg or 270 mg of an anti-IL-23A antibody to a patient.

[0041] In one embodiment, in any one of the methods described above, the anti-IL-23A antibody is antibody A, antibody B, antibody C, or antibody D.

[0042] In one embodiment, in any one of the methods described above, the method is for the treatment of Crohn's disease, for example, moderate to severe active Crohn's disease. In one embodiment, in the context of the method of the present invention, the patient is untreated or has been previously treated with anti-TNF therapy. In one embodiment, in the context of the method of the present invention, the patient has been previously treated with one, two, three or more TNF antagonists(s). In one embodiment, the patient is a patient who has shown an inadequate response, intolerance, or dependence on corticosteroids. In one embodiment, the patient is a patient who has shown an inadequate response, no response, or intolerance to immunomodulators, TNFα inhibitors (or TNF antagonists) or integrin inhibitors. In one embodiment, the treatment is by inducing and maintaining clinical remission, corticosteroid-free remission, endoscopic remission, and mucosal healing.

[0043] In one embodiment, a patient treated by the method of the present invention has a CDAI score of 220 to 450.

[0044] In one embodiment, the patient is an adult patient in any of the methods described above.

[0045] In one embodiment, the method described above is for the treatment of ulcerative colitis.

[0046] In one embodiment, the present invention provides an anti-IL-23A antibody for use in the treatment of a disease, such as an inflammatory disease, such as Crohn's disease, administered in a specific amount and / or at specific intervals as described herein. In one embodiment, the inflammatory disease is ulcerative colitis.

[0047] In one embodiment, the present invention provides the use of an anti-IL-23A antibody for the preparation of a pharmaceutical for the treatment of a disease, such as an inflammatory disease, such as Crohn's disease, by administration in a specific amount and / or at specific intervals as described herein. In one embodiment, the inflammatory disease is ulcerative colitis.

[0048] In one embodiment, in any of the above methods or uses, an anti-IL-23A antibody is disclosed below.

[0049] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region including the amino acid sequence of SEQ ID NO: 1 (CDR1-L); the amino acid sequence of SEQ ID NO: 2 (CDR2-L); and the amino acid sequence of SEQ ID NO: 3 (CDR3-L); and a heavy chain variable region including the amino acid sequence of SEQ ID NO: 4, 7, 8, or 9 (CDR1-H); the amino acid sequence of SEQ ID NO: 5 (CDR2-H); and the amino acid sequence of SEQ ID NO: 6 (CDR3-H).

[0050] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region including the amino acid sequence of SEQ ID NO: 1 (CDR1-L); the amino acid sequence of SEQ ID NO: 2 (CDR2-L); and the amino acid sequence of SEQ ID NO: 3 (CDR3-L); and a heavy chain variable region including the amino acid sequence of SEQ ID NO: 4 (CDR1-H); the amino acid sequence of SEQ ID NO: 5 (CDR2-H); and the amino acid sequence of SEQ ID NO: 6 (CDR3-H).

[0051] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region including the amino acid sequence of SEQ ID NO: 1 (CDR1-L); the amino acid sequence of SEQ ID NO: 2 (CDR2-L); and the amino acid sequence of SEQ ID NO: 3 (CDR3-L); and a heavy chain variable region including the amino acid sequence of SEQ ID NO: 7 (CDR1-H); the amino acid sequence of SEQ ID NO: 5 (CDR2-H); and the amino acid sequence of SEQ ID NO: 6 (CDR3-H).

[0052] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region including the amino acid sequence of SEQ ID NO: 1 (CDR1-L); the amino acid sequence of SEQ ID NO: 2 (CDR2-L); and the amino acid sequence of SEQ ID NO: 3 (CDR3-L); and a heavy chain variable region including the amino acid sequence of SEQ ID NO: 8 (CDR1-H); the amino acid sequence of SEQ ID NO: 5 (CDR2-H); and the amino acid sequence of SEQ ID NO: 6 (CDR3-H).

[0053] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region including the amino acid sequence of SEQ ID NO: 1 (CDR1-L); the amino acid sequence of SEQ ID NO: 2 (CDR2-L); and the amino acid sequence of SEQ ID NO: 3 (CDR3-L); and a heavy chain variable region including the amino acid sequence of SEQ ID NO: 9 (CDR1-H); the amino acid sequence of SEQ ID NO: 5 (CDR2-H); and the amino acid sequence of SEQ ID NO: 6 (CDR3-H).

[0054] In one embodiment, the anti-IL-23A antibody comprises a light chain variable region containing any one amino acid sequence of SEQ ID NOs: 10, 11, 12, or 13; and a heavy chain variable region containing any one amino acid sequence of SEQ ID NOs: 14, 15, 16, or 17.

[0055] In one embodiment, the anti-IL-23A antibody comprises 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.

[0056] In one embodiment, the anti-IL-23A antibody comprises 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.

[0057] In one embodiment, the anti-IL-23A antibody comprises 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.

[0058] In one embodiment, the anti-IL-23A antibody comprises 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.

[0059] In one embodiment, the anti-IL-23A antibody comprises the amino acid sequence of SEQ ID NO: 14 or 15 linked to the constant region of human IgG1, human IgG2, human IgG3, human IgG4, IgM, IgA, or IgE heavy chain. In one embodiment, the anti-IL-23A antibody comprises the amino acid sequence of SEQ ID NO: 14 or 15 linked to the constant region of human IgG1 heavy chain.

[0060] In one embodiment, the anti-IL-23A antibody comprises the amino acid sequence of SEQ ID NO: 10 or 11 linked to the constant region of a human κ or λ light chain.

[0061] In one embodiment, the anti-IL-23A antibody comprises the amino acid sequence of SEQ ID NO: 14 or 15 linked to the human IgG1 heavy chain constant region; and the amino acid sequence of SEQ ID NO: 10 or 11 linked to the human κ light chain constant region.

[0062] In one embodiment, the anti-IL-23A antibody is a humanized monoclonal antibody comprising a light chain variable region containing an amino acid sequence selected from the group consisting 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 SEQ ID NOs: 14, 15, 16, and 17.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] In one embodiment, the anti-IL-23A antibody comprises a light chain containing the amino acid sequence of SEQ ID NO: 18 or 21 and a heavy chain containing the amino acid sequence of SEQ ID NO: 19 or 20.

[0068] In one embodiment, the anti-IL-23A antibody comprises a light chain containing the amino acid sequence of SEQ ID NO: 18 and a heavy chain containing the amino acid sequence of SEQ ID NO: 19.

[0069] In one embodiment, the anti-IL-23A antibody comprises a light chain containing the amino acid sequence of SEQ ID NO: 18 and a heavy chain containing the amino acid sequence of SEQ ID NO: 20.

[0070] In one embodiment, the anti-IL-23A antibody comprises a light chain containing the amino acid sequence of SEQ ID NO: 21 and a heavy chain containing the amino acid sequence of SEQ ID NO: 19.

[0071] In one embodiment, the anti-IL-23A antibody comprises a light chain containing the amino acid sequence of SEQ ID NO: 21 and a heavy chain containing the amino acid sequence of SEQ ID NO: 20.

[0072] In one embodiment, the anti-IL-23A antibody is antibody A, antibody B, antibody C, or antibody D.

[0073] In one embodiment, the anti-IL-23A antibody is such as those disclosed in International Publication No. 2007 / 005955, International Publication No. 2007 / 024846, International Publication No. 2007 / 027714, International Publication No. 2007 / 076524, International Publication No. 2008 / 103432, or International Publication No. 2012 / 061448.

[0074] In one embodiment, the present invention provides a method for detecting whether or not there is a beneficial response in a patient after administration of an IL-23A antagonist, comprising the steps of: a) obtaining a biological sample from a patient; b) measuring the expression level of one or more genes in the sample; c) comparing the level in b) with the expression level of one or more genes of a control; and d) determining whether the difference in levels between the sample and the control affects the biological response in the patient, wherein one or more genes are one or more genes described herein. In one embodiment, the patient suffers from Crohn's disease. In one embodiment, the biological sample is colonic or ileal tissue. In one embodiment, the biological sample is taken from the upper gastrointestinal tract (GI), e.g., the stomach or esophagus. In one embodiment, the IL-23A antagonist is an anti-IL-23A antibody or its antigen-binding fragment, e.g., antibody A, antibody B, antibody C, or antibody D. [Brief explanation of the drawing]

[0075] [Figure 1]Study design. Complete remission was defined as reaching clinical remission (CDAI score <150) and CDEIS remission (CDEIS score ≤4, or ≤2 in patients with early sporadic ileitis). [Figure 2A] Figures 2A and 2B: Percentage of patients showing clinical remission (A) or clinical response (B) at weeks 4, 8, and 12. Clinical remission is defined as a CDAI score < 150. Clinical response is either a CDAI score < 150 or a decrease of 100 points or more from baseline in the CDAI. Patients who received a drug contraindicated for concomitant use in Crohn's disease treatment before week 12 were judged to have treatment failure. The largest analysis population was used for these analyses. *p<0.05 compared to placebo. **p<0.005 compared to placebo. ***p<0.001 compared to placebo. [Figure 2B] Figures 2A and 2B: Percentage of patients showing clinical remission (A) or clinical response (B) at weeks 4, 8, and 12. Clinical remission is defined as a CDAI score < 150. Clinical response is either a CDAI score < 150 or a decrease of 100 points or more from baseline in the CDAI. Patients who received a drug contraindicated for concomitant use in Crohn's disease treatment before week 12 were judged to have treatment failure. The largest analysis population was used for these analyses. *p<0.05 compared to placebo. **p<0.005 compared to placebo. ***p<0.001 compared to placebo. [Figure 3A] Figures 3A-D: Median CDAI score over time (A), median CRP over time (B), median percentage change from baseline in FCP (C), and median percentage change from baseline in IL-22 (D). *p<0.001, Bonferroni-corrected p-value for 600 mg of antibody A compared to placebo. *p<0.05, Bonferroni-corrected p-value for 600 mg of antibody A compared to placebo. CDAI (Crohn's disease activity index); CRP (C-reactive protein); FCP (fecal calprotectin). [Figure 3B]Figures 3A-D: Median CDAI score over time (A), median CRP over time (B), median percentage change from baseline in FCP (C), and median percentage change from baseline in IL-22 (D). *p<0.001, Bonferroni-corrected p-value for 600 mg of antibody A compared to placebo. *p<0.05, Bonferroni-corrected p-value for 600 mg of antibody A compared to placebo. CDAI (Crohn's disease activity index); CRP (C-reactive protein); FCP (fecal calprotectin). [Figure 3C] Figures 3A-D: Median CDAI score over time (A), median CRP over time (B), median percentage change from baseline in FCP (C), and median percentage change from baseline in IL-22 (D). *p<0.001, Bonferroni-corrected p-value for 600 mg of antibody A compared to placebo. *p<0.05, Bonferroni-corrected p-value for 600 mg of antibody A compared to placebo. CDAI (Crohn's disease activity index); CRP (C-reactive protein); FCP (fecal calprotectin). [Figure 3D] Figures 3A-D: Median CDAI score over time (A), median CRP over time (B), median percentage change from baseline in FCP (C), and median percentage change from baseline in IL-22 (D). *p<0.001, Bonferroni-corrected p-value for 600 mg of antibody A compared to placebo. *p<0.05, Bonferroni-corrected p-value for 600 mg of antibody A compared to placebo. CDAI (Crohn's disease activity index); CRP (C-reactive protein); FCP (fecal calprotectin).

[0076] Detailed explanation 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-amino acid leader sequence (Oppmann et al. Immunity 13:715 (2000), SEQ ID NO: 22). The biological activity of this molecule is detected only when it pairs with the IL-12p40 subunit to form IL-23. IL-23 is primarily expressed by activated dendritic cells (DCs) and phagocytic cells. The IL-23 receptor has been found to consist of the IL-12Rβ1 subunit of the IL-12 receptor paired with a unique subunit called IL-23R (Parham et al. J. Immunol. 168:5699 (2002)). Expression of this receptor is primarily detected on memory T cells and NK cells. Therefore, the expression of this cytokine:receptor pair appears to be limited to specific populations of immune cells. While it was initially thought that IL-12 and IL-23 would share many functions, data have shown the situation to be different. IL-12 plays a primary role in Th1 cell generation, while IL-23 has been found to be critically involved in the generation and maintenance of a recently recognized Th cell subset called Th17 (Kikly et al. Curr. Opin. Immunol. 18:670 (2006), Kastelein et al. Ann. Rev. Immunol. 25:221 (2007)). These cells produce IL-17A, IL-17F, IL-22, and other pro-inflammatory cytokines, such as IL-6 and TNF-α. As described below, animal model studies on the role of these Th17 cells demonstrate their importance as a driving force in chronic inflammation and autoimmunity.

[0077] [ka]

[0078] In one aspect, the present invention provides a method for treating IL-23A-related diseases. In one aspect, the present invention provides a method for treating a disease, such as an inflammatory disease, in particular a method comprising the step of administering an anti-IL-23A antibody to a patient in a specific amount and / or at specific intervals. In one aspect, the method of the present invention is for the treatment of Crohn's disease.

[0079] In one embodiment, the present invention provides an anti-IL-23A antibody for use in the treatment of a disease, such as an inflammatory disease, such as Crohn's disease, administered in a specific amount and / or at specific intervals as described herein.

[0080] In one embodiment, the present invention provides the use of an anti-IL-23A antibody for the preparation of pharmaceuticals for the treatment of diseases, such as inflammatory diseases, such as Crohn's disease, by administration in a specific amount and / or at specific intervals as described herein.

[0081] In one embodiment, in the context of the present invention, patient treatment includes an induction phase and a maintenance phase. During the induction phase, one or more doses of anti-IL-23 antibody, for example as the induction dose as referred herein, are administered to the patient, for example, by intravenous infusion. During the maintenance phase, an initial dose of anti-IL-23 antibody, for example as the maintenance dose as referred herein, is administered to the patient, followed by at least one additional dose of anti-IL-23 antibody, for example as the maintenance dose as referred herein. The maintenance dose is administered, for example, by subcutaneous injection. Examples of the induction and maintenance phases are described herein.

[0082] In one embodiment, a specific treatment outcome, such as clinical remission, is achieved by the patient during or at the end of the induction period. In one embodiment, the patient achieves a CDAI score of less than 150 during or at the end of the induction period. In one embodiment, the patient achieves a PRO-2 score of 75 or less during or at the end of the induction period. In one embodiment, the patient achieves a CDAI score of less than 150 and a PRO-2 score of 75 or less during or at the end of the induction period.

[0083] Therefore, in one embodiment, in the method of the present invention, the patient is evaluated for clinical remission during or at the end of the induction period.

[0084] In one embodiment, if the patient is not responsive during the induction phase, the induction phase is repeated before initiating the maintenance phase (also referred to herein as the re-induction phase). In one embodiment, in the method of the present invention, the patient is re-evaluated for clinical remission during or at the end of the re-induction phase, for example, during or after the induction phase.

[0085] In one embodiment, a specific treatment outcome, such as clinical remission, is maintained by the patient during the maintenance phase. In one embodiment, the patient maintains a CDAI score of less than 150 during the maintenance phase. In one embodiment, the patient maintains a PRO-2 score of 75 or less during the maintenance phase. In one embodiment, the patient maintains a CDAI score of less than 150 and a PRO-2 score of 75 or less during the maintenance phase.

[0086] Therefore, in one embodiment, in the method of the present invention, the patient is evaluated for clinical remission during the maintenance phase.

[0087] In one embodiment, the present invention provides a method for treating an inflammatory disease, in one aspect for treating Crohn's disease, comprising the step of (a) administering a single dose of anti-IL-23A antibody to a patient by intravenous infusion at weeks 0, 4, and 8, wherein the dose of anti-IL-23A antibody comprises 200 mg or 600 mg of antibody. In one embodiment, the method further comprises (b) administering three doses of anti-IL-23A antibody to a patient by intravenous infusion, for example at weeks 14, 18, and 22, wherein the dose of anti-IL-23A antibody comprises 600 mg of antibody. In one embodiment, the method further comprises (c) administering to a patient by subcutaneous injection one or more doses of anti-IL-23A antibody at 8-week intervals, for example, four doses of anti-IL-23A antibody at 8-week intervals, for example, at weeks 26, 34, 42, and 50, wherein one or more doses of anti-IL-23A antibody comprise 180 mg of antibody.

[0088] In one embodiment, at week 12, the patient is evaluated for complete remission, defined, for example, by achieving clinical remission (CDAI score < 150) and endoscopic remission (CDEIS ≤ 4). In one embodiment, in patients with early isolated ileitis, endoscopic remission is defined by CDEI ≤ 2.

[0089] In one embodiment, the present invention provides a method for treating an inflammatory disease, in one aspect for treating Crohn's disease, comprising the step of (a) administering a single dose of anti-IL-23A antibody to a patient by intravenous infusion at weeks 0, 4, and 8, wherein the dose of anti-IL-23A antibody comprises 200 mg or 600 mg of antibody. In one embodiment, the method further comprises (b) administering one or more doses of anti-IL-23A antibody to a patient by subcutaneous injection at 8-week intervals, for example, four doses of anti-IL-23A antibody by subcutaneous injection at 8-week intervals, for example, at weeks 26, 34, 42, and 50, wherein the one or more doses of anti-IL-23A antibody comprises 180 mg of antibody.

[0090] In one embodiment, at week 12, the patient is evaluated for complete remission, defined, for example, by achieving clinical remission (CDAI score < 150) and endoscopic remission (CDEIS ≤ 4). In one embodiment, in patients with early isolated ileitis, endoscopic remission is defined by CDEI ≤ 2.

[0091] In one embodiment, the present invention provides a method for treating an inflammatory disease, in one aspect for treating Crohn's disease, comprising the step of administering 180 mg of anti-IL-23A antibody to a patient by subcutaneous injection at 8-week intervals.

[0092] In one embodiment, the administration of the anti-IL-23A antibody of the present invention is further described in the following examples or in Figure 1.

[0093] In one embodiment, the present invention provides a method for treating an inflammatory disease, in one aspect for treating Crohn's disease, comprising the step of administering an anti-IL-23A antibody to a patient, the method comprising the step of administering at least one induction dose of the anti-IL-23A antibody to the patient, the induction dose comprising 200 to 1,200 mg of the anti-IL-23A antibody, for example, 450 to 1,200 mg of the IL-23A antibody. In one aspect, the induction dose comprises 200 mg, 450 mg, 600 mg, 900 mg, or 1,200 mg of the anti-IL-23A antibody. In one aspect, one, two, or three induction doses are administered to the patient. In one aspect, two or three induction doses are administered, for example, at 4-week intervals. In one aspect, the induction dose(s) are administered by intravenous infusion.

[0094] In one embodiment, the induction dose contains 200 mg of anti-IL-23A antibody, and three induction doses are administered to the patient at 4-week intervals.

[0095] In one embodiment, the induction dose contains 450 mg of anti-IL-23A antibody, and three induction doses are administered to the patient at 4-week intervals.

[0096] In one embodiment, the induction dose contains 600 mg of anti-IL-23A antibody, and three induction doses are administered to the patient at 4-week intervals.

[0097] In one embodiment, the induction dose contains 900 mg of anti-IL-23A antibody, and three induction doses are administered to the patient at 4-week intervals.

[0098] In one embodiment, the induction dose contains 1,200 mg of anti-IL-23A antibody, and three induction doses are administered to the patient at 4-week intervals.

[0099] In one embodiment, if the patient is unresponsive during the induction phase, the induction phase is repeated before the maintenance phase begins. For example, if the initial induction phase includes three induction doses, three additional induction doses are administered to the patient (re-induction phase), resulting in a total of six induction doses. The additional induction doses (groups) include, for example, the amount of anti-IL-23 antibody described herein. The additional induction doses are administered, for example, at intervals described herein.

[0100] In one embodiment, the method further comprises the steps of administering an initial maintenance dose of anti-IL-23A antibody to the patient after the last induction dose has been administered; and administering at least one additional maintenance dose to the patient 4 to 12 weeks after the initial maintenance dose has been administered. In one embodiment, the initial maintenance dose is administered 2 to 8 weeks after the last induction dose has been administered, for example 4 to 6 weeks, for example 2 weeks, 4 weeks, 6 weeks, or 8 weeks later. In one embodiment, at least one additional maintenance dose is administered to the patient 4, 8, or 12 weeks after the initial maintenance dose has been administered.

[0101] In one embodiment, the initial maintenance dose contains 150-300 mg of anti-IL-23A antibody. In another embodiment, the initial maintenance dose contains 150 mg, 225 mg, or 300 mg of anti-IL-23A antibody. In yet another embodiment, the initial maintenance dose contains 180 mg or 270 mg of anti-IL-23A antibody.

[0102] In one embodiment, at least one additional maintenance dose comprises 150–300 mg of anti-IL-23A antibody. In one embodiment, at least one additional maintenance dose comprises 150 mg, 225 mg, or 300 mg of anti-IL-23A antibody. In one embodiment, at least one additional maintenance dose comprises 180 mg or 270 mg of anti-IL-23A antibody.

[0103] In one embodiment, the initial maintenance dose and at least one additional maintenance dose comprises 150 to 300 mg of anti-IL-23A antibody. In one embodiment, the initial maintenance dose and at least one additional maintenance dose comprises 150 mg, 225 mg, or 300 mg of the anti-IL-23A antibody. In one embodiment, the initial maintenance dose and at least one additional maintenance dose comprises 180 mg or 270 mg of the anti-IL-23A antibody.

[0104] In one embodiment, the maintenance dose is administered by subcutaneous injection.

[0105] In one embodiment, the maintenance dose consists of 150 mg of anti-IL-23A antibody, administered to the patient at 4-week intervals.

[0106] In one embodiment, the maintenance dose consists of 150 mg of anti-IL-23A antibody and is administered to the patient at 8-week intervals.

[0107] In one embodiment, the maintenance dose consists of 225 mg of anti-IL-23A antibody and is administered to the patient at 8-week intervals.

[0108] In one embodiment, the maintenance dose consists of 225 mg of anti-IL-23A antibody and is administered to the patient at 12-week intervals.

[0109] In one embodiment, the maintenance dose consists of 300 mg of anti-IL-23A antibody and is administered to the patient at 8-week intervals.

[0110] In one embodiment, the maintenance dose consists of 300 mg of anti-IL-23A antibody and is administered to the patient at 12-week intervals.

[0111] In one embodiment, the present invention provides a method for treating an inflammatory disease, in one aspect for treating Crohn's disease, comprising the step of administering 150 to 1,200 mg of anti-IL-23A antibody to a patient. In one aspect, the method comprises the step of administering 200 to 1,200 mg of anti-IL-23A antibody, for example, 450 to 1,200 mg of anti-IL-23A antibody to a patient. In one aspect, the method comprises the step of administering 200 mg, 450 mg, 600 mg, 900 mg, or 1,200 mg of anti-IL-23A antibody to a patient. In one aspect, the method comprises the step of administering 150 to 300 mg of anti-IL-23A antibody to a patient. In one aspect, the method comprises the step of administering 150 mg, 225 mg, or 300 mg of anti-IL-23A antibody to a patient. In one embodiment, the method includes the step of administering 180 mg or 270 mg of an anti-IL-23A antibody to a patient.

[0112] In one embodiment, the present invention further provides a method for inducing clinical remission of Crohn's disease in a patient, the method comprising administering to the patient at least one induction dose of anti-IL-23 antibody as described above or herein. In one embodiment, the method further comprises a step of maintaining clinical remission of Crohn's disease, the method further comprising a step of administering to the patient an initial maintenance dose of anti-IL-23A antibody after the last induction dose has been administered, and a step of administering to the patient at least one additional maintenance dose as described above or herein.

[0113] In one embodiment, the present invention further provides a method for inducing a clinical response to Crohn's disease in a patient, the method comprising administering to the patient at least one induction dose of anti-IL-23 antibody as described above or herein. In one embodiment, the method further comprises a step of maintaining a clinical response to Crohn's disease, the method further comprising a step of administering to the patient an initial maintenance dose of anti-IL-23A antibody after the last induction dose has been administered, and a step of administering to the patient at least one additional maintenance dose as described above or herein.

[0114] Representative examples of dosages and formulation plans for the present invention are disclosed in Table A.

[0115] [Table 1] TIFF2026108768000003.tif173165

[0116] In one embodiment, one, two, or three induction doses (groups) are administered to the patient according to the prescription plan described in Table A.

[0117] The following are representative additional examples of dosage and prescription plans of the present invention. In these examples, the initial maintenance dose is administered to the patient 4 weeks after the last induction dose. In addition, in the present invention, the initial maintenance dose may be administered 2 weeks, 6 weeks, or 8 weeks after the last induction dose.

[0118] For example, in the context of the present invention, the induction dose is administered to the patient at weeks 0, 4, and 8, followed by the initial maintenance dose at week 12, the second maintenance dose at week 16, the third maintenance dose at week 20, and so on, with maintenance doses administered at 4-week intervals. In one embodiment, the induction dose contains 200 mg, 450 mg, 600 mg, 900 mg, or 1,200 mg of anti-IL-23A antibody. In one embodiment, the maintenance dose contains 150 mg of anti-IL-23A antibody.

[0119] For example, in the context of the present invention, the induction dose is administered to the patient at weeks 0, 4, and 8, followed by the initial maintenance dose at week 12, the second maintenance dose at week 20, the third maintenance dose at week 28, and so on, with maintenance doses administered at intervals of 8 weeks. In one embodiment, the induction dose comprises 200 mg, 450 mg, 600 mg, 900 mg, or 1,200 mg of anti-IL-23A antibody. In another embodiment, the induction dose comprises 150 mg, 225 mg, or 300 mg of anti-IL-23A antibody.

[0120] For example, in the context of the present invention, the induction dose is administered to the patient at weeks 0, 4, and 8, followed by the initial maintenance dose at week 12, the second maintenance dose at week 24, the third maintenance dose at week 36, and so on, with maintenance doses administered at 12-week intervals. In one embodiment, the induction dose comprises 200 mg, 450 mg, 600 mg, 900 mg, or 1,200 mg of anti-IL-23A antibody. In one embodiment, the maintenance dose comprises 225 mg or 300 mg of anti-IL-23A antibody.

[0121] In one embodiment, the method of the present invention evaluates patients for complete remission, defined, for example, by achieving clinical remission (CDAI score < 150) and endoscopic remission (CDEIS ≤ 4). In one embodiment, in patients with early isolated ileitis, endoscopic remission is defined by CDEI ≤ 2. In one embodiment, the patient's PRO response is evaluated, for example, by either a PRO-2 score less than 8 or a decrease of at least 8 points from baseline (PRO-2: patient-reported outcome-2).

[0122] In one embodiment, the method of the present invention evaluates the patient for clinical remission, clinical response, endoscopic remission, endoscopic response, or mucosal healing, as defined herein, for example.

[0123] In one embodiment, the anti-IL-23A antibody in any one of the above methods is disclosed herein. In one embodiment, the anti-IL-23A antibody in any one of the above methods is antibody A. In one embodiment, the anti-IL-23A antibody in any one of the above methods is antibody B. In one embodiment, the anti-IL-23A antibody in any one of the above methods is antibody C. In one embodiment, the anti-IL-23A antibody in any one of the above methods is antibody D.

[0124] In one embodiment, a pharmaceutical composition containing an anti-IL-23A antibody is administered to a patient by any one of the methods described above. In one embodiment, formulation 2 disclosed in Example 2, which contains an anti-IL-23A antibody, for example antibody A, antibody B, antibody C, or antibody D, is administered to a patient. In one embodiment, formulation 3 disclosed in Example 2, which contains an anti-IL-23A antibody, for example antibody A, antibody B, antibody C, or antibody D, is administered to a patient. In one embodiment, formulation 1 disclosed in Example 2, which contains an anti-IL-23A antibody, for example antibody A, antibody B, antibody C, or antibody D, is administered to a patient.

[0125] In one embodiment, the anti-IL-23A antibody is a humanized antibody. In one embodiment, the anti-IL-23A antibody is a monoclonal antibody. In one embodiment, the anti-IL-23A antibody is a full-length antibody. In one embodiment, the anti-IL-23A antibody is a humanized monoclonal antibody, for example, a full-length humanized monoclonal antibody.

[0126] The antibodies described herein recognize specific "IL-23A antigenic epitopes" or "IL-23A epitopes." As used herein, these terms refer to molecules (e.g., peptides) or molecular fragments that can undergo immunoreactivity with anti-IL-23A antibodies, including, for example, IL-23A antigenic determinants recognized by any of the antibodies having the light chain / heavy chain sequence combinations of SEQ ID NOs. 11 / 14, 11 / 15, 10 / 14, or 10 / 15.

[0127] The general structure of antibodies or immunoglobulins is well-known to those skilled in the art. These molecules are typically about 150,000 dalton heterotetrameric glycoproteins composed of two identical light chains (L) and two identical heavy chains (H), which are typically called full-length antibodies. Each light chain is covalently linked to the heavy chain by one disulfide bond to form a heterodimer, and a heterotetrameric molecule is formed through disulfide covalent bonds between the two identical heavy chains of the heterodimer. The light chain and the heavy chain are linked to each other by one disulfide bond, but the number of disulfide bonds between the two heavy chains varies depending on the immunoglobulin isotype. Each heavy chain and light chain also has regularly arranged intra-chain disulfide bridges. Each heavy chain has a variable domain (V H ) at the amino terminus, followed by three or four constant domains (C H1 , C H2 , C H3 and C H4 ), and a hinge region between CH1 and CH2. Each light chain has two domains, an amino-terminal variable domain (V L ) and a carboxy-terminal constant domain (C L ). The V L domain associates non-covalently with the V H domain, while the C L domain is generally covalently linked to the C H1 domain via a disulfide bond. Certain amino acid residues are thought to form the interface between the light chain variable domain and the heavy chain variable domain (Chothia et al., 1985, J. Mol. Biol. 186:651-663). The variable domains are also referred to herein as variable regions.

[0128] Certain domains within the variable domain differ significantly among various antibodies, i.e., they are "hypervariable." These hypervariable domains contain residues directly involved in the binding and specificity of each particular antibody to 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 described in Kabat et al., 1991, In: Sequences of Proteins of Immunological Interest, 5 th The HVL (also referred to herein as CDR) is defined by sequence comparison in Ed. Public Health Service, National Institutes of Health, Bethesda, Md., while the HVL is structurally defined according to the three-dimensional structure of the variable domain, as described in Chothia and Lesk, 1987, J. Mol. Biol. 196: 901-917. The identification of CDRs differs slightly between these two methods. As defined by Kabat, CDR-L1 is located approximately 24-34 residues within the light chain variable domain, CDR-L2 approximately 50-56 residues, and CDR-L3 approximately 89-97 residues; CDR-H1 is located approximately 31-35 residues within the heavy chain variable domain, CDR-H2 approximately 50-65 residues, and CDR-H3 approximately 95-102 residues. The exact residue numbers encompassing a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can conventionally determine which residues contain specific CDRs, given the amino acid sequence of the variable region of an antibody. Therefore, the CDR1, CDR2, and CDR3 of the heavy and light chains define unique and functional properties specific to a given antibody.

[0129] The three CDRs within each of the heavy and light chains are separated by a framework region (FR), which contains sequences that tend to be less variable. From the amino terminus to the carboxyl terminus of the variable domains of the heavy and light chains, the FRs and CDRs are aligned in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Due to the stereochemistry of the FRs, primarily the β-sheets, the CDRs within each chain are in close proximity to each other and to CDRs in other chains. The resulting conformation contributes to the antigen-binding site (see Kabat et al., 1991, NIH Publ. No. 91-3242, Vol. I, pages 647-669), but not all CDR residues are directly involved in antigen binding.

[0130] FR residues and Ig constant domains are not directly involved in antigen binding, but contribute to antigen binding and / or mediate antibody effector functions. Several FR residues are thought to exert a significant effect on antigen binding in at least three ways: by non-covalent direct binding to the epitope, by interacting 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 the involvement of antibodies in antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cytophagocytosis (ADCP).

[0131] The light chains of vertebrate immunoglobulins are assigned to one of two distinct classes, kappa (κ) and lambda (λ), based on the amino acid sequence of the constant domain. In contrast, the heavy chains of mammalian immunoglobulins are assigned to one of five major classes according to the sequence of the constant domain: IgA, IgD, IgE, IgG, and IgM. IgG and IgA are further classified into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the various classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of the classes of innate immunoglobulins are well known.

[0132] The terms “antibody,” “anti-IL-23A antibody,” “anti-IL-23p19 antibody,” “humanized anti-IL-23A antibody,” “humanized anti-IL-23p19 antibody,” “humanized anti-IL-23A epitope antibody,” “humanized anti-IL-2319 epitope antibody,” “mutant humanized anti-IL-23A epitope antibody,” and “mutant humanized anti-IL-23p19 epitope antibody” specifically encompass monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and antibody fragments, such as variable domains, and other parts of the antibody that exhibit the desired biological activity, e.g., binding to IL-23A. The term “monoclonal antibody” (mAb) refers to an antibody that is highly specific and directed to a single antigenic determinant, i.e., “epitope.” Therefore, the modifier “monoclonal” indicates an antibody directed to the same epitope and should not be interpreted as requiring antibody production by any particular method. It should be understood that monoclonal antibodies can be produced by any known technique or method 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, U.S. Patent No. 4,816,567), or the isolation of monoclonal antibodies recombinantly produced using a phage antibody library using the techniques described in Clackson et al., 1991, Nature 352: 624-628 and Marks et al., 1991, J. Mol. Biol. 222: 581-597.

[0133] The term "monomer" refers to an antibody with a uniform morphology. For example, in the case of a full-length antibody, a monomer refers to an antibody that has two identical heavy chains and two identical light chains.

[0134] A chimeric antibody consists of variable regions of the heavy and light chains of an antibody derived from one species (e.g., a non-human mammal, e.g., mouse) and constant regions of the heavy and light chains of an antibody derived from another species (e.g., human). This can be obtained by ligating the DNA sequence encoding the variable region of the antibody from the first species (e.g., mouse) to the DNA sequence of the constant region of the antibody from the second species (e.g., human), and transforming the host using an expression vector containing the ligated sequence, thereby enabling the host to produce a chimeric antibody. Alternatively, a chimeric antibody may also have one or more regions or domains of the heavy and / or light chains that are identical, homologous, or variant thereof to a corresponding sequence in a monoclonal antibody derived from another immunoglobulin class or isotype, or from a common sequence or germline sequence. A chimeric antibody may contain such antibody fragments. However, the antibody fragment exhibits the desired biological activity of its parent antibody, for example, binding to the same epitope (see, for example, U.S. Patent No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81: 6851-6855).

[0135] The terms "antibody fragment," "anti-IL-23A antibody fragment," "anti-IL-23A epitope antibody fragment," "humanized anti-IL-23A antibody fragment," "humanized anti-IL-23A epitope antibody fragment," and "mutant humanized anti-IL-23A epitope antibody fragment" refer to a portion of a full-length anti-IL-23A antibody, while retaining its variable region or functional capabilities, such as binding to a specific IL-23A epitope. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fd, Fv, scFv, and scFv-Fc fragments.

[0136] Useful antibody fragments can be produced by treating full-length antibodies with enzymes such as papain or pepsin. Using papain digestion, two identical antigen-binding antibody fragments (each with one antigen-binding site), called "Fab" fragments, and the remaining "Fc" fragment are produced. The Fab fragments also contain the constant domain of the light chain and the C of the heavy chain. H1 It also contains a domain. Treatment with pepsin produces an F(ab')2 fragment with two antigen-binding sites, which can still crosslink with the antigen.

[0137] Fab' fragment is C H1 It differs from the Fab fragment by the presence of additional residues, including one or more cysteines derived from the antibody hinge region at the C-terminus of the domain. The F(ab')2 antibody fragment is a pair of Fab' fragments linked by cysteine ​​residues within the hinge region. Other chemical bindings of antibody fragments are also known.

[0138] The "Fv" fragment contains a complete antigen recognition binding site consisting of a dimer of one heavy chain variable domain and one light chain variable domain that are tightly and noncovalently associated. In this configuration, the three CDRs of each variable domain interact to form V H -V L It defines the antigen-binding sites on the surface of the dimer. In short, the six CDRs confer antigen-binding specificity to the antibody.

[0139] "Single-stranded Fv," or "scFv," antibody fragments are the V of the antibody. H Domain and V L This is a single-stranded Fv variant containing a domain, where the domain resides within a single polypeptide chain. The single-stranded Fv can recognize and bind to antigens. The scFv polypeptide can also, in some cases, contain V H Domain and V LThe scFv may contain polypeptide linkers located between the domains, which facilitate the formation of a desirable three-dimensional structure for binding between the scFv and the antigen (see, for example, Pluckthun, 1994, In The Pharmacology of monoclonal Antibodies, Vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315).

[0140] A “humanized antibody” or “humanized antibody fragment” is a special type of chimeric antibody comprising an immunoglobulin amino acid sequence variant or fragment thereof, which can bind to a predetermined antigen and comprises one or more FRs substantially having the amino acid sequence of a human immunoglobulin and one or more CDRs substantially having the amino acid sequence of a non-human immunoglobulin. This non-human amino acid sequence, often referred to as the “import” sequence, is typically adopted from the “import” antibody domain, particularly the variable domain. Generally, a humanized antibody comprises at least a CDR or HVL of a non-human antibody inserted between the FRs of a human heavy chain variable domain or light chain variable domain. The present invention describes a specific humanized anti-IL-23A antibody containing a CDR derived from a mouse monoclonal antibody, or a humanized CDR shown in Tables 1 and 2 inserted between the FRs of the heavy chain variable domain and light chain variable domain of a human germline sequence. Certain mouse FR residues may be important for the function of humanized antibodies, and therefore, it is understandable that variable domain residues in the heavy and light chains of specific human germline sequences may be modified to be the same as the residues in the corresponding mouse sequences.

[0141] In another embodiment, the humanized anti-IL-23A antibody comprises substantially all of at least one, typically two, variable domains (e.g., those contained in the Fab, Fab', F(ab')2, Fabc, and Fv fragments), where all or substantially all of the CDRs correspond to the CDRs of non-human immunoglobulins, specifically, in this specification, all of the CDRs are mouse sequences or humanized sequences as detailed in Tables 1 and 2 below, and all or substantially all of the FRs are human immunoglobulin common sequences or germline sequences. In another embodiment, the humanized anti-IL-23A antibody also comprises at least a portion of the immunoglobulin Fc region, typically that of a human immunoglobulin. Typically, the antibody will contain both light chains, as well as at least the variable domains of the heavy chain. The antibody also, as appropriate, the C of the heavy chain. H1 Region, hinge region, C H2 area, C H3 Area, and / or C H4 It may include one or more regions.

[0142] Humanized anti-IL-23A antibodies can be selected from any class of immunoglobulin, including IgM, IgG, IgD, IgA, and IgE, and from any isotype, including IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. For example, the constant domain may be a complement-binding constant domain, in which case the humanized antibody is desired to exhibit cytotoxic activity, and the isotype is typically IgG1. If such cytotoxic activity is undesirable, the constant domain may be another isotype, such as IgG2. Alternative humanized anti-IL-23A antibodies may contain sequences derived from one or more classes or isotypes of immunoglobulin, and selecting a specific constant domain to optimize the desired effector function is within the scope of the art. In specific embodiments, the present invention provides an antibody that is an IgG1 antibody, more specifically an IgG1 antibody in which the effector function is knocked out.

[0143] The FR and CDR or HVL of a humanized anti-IL-23A antibody do not need to correspond precisely to the parent sequence. For example, one or more residues in the import CDR or HVL, or in the FR sequence of the common or germline sequence, may be modified (e.g., mutagenesized) by substitution, insertion, or deletion, and the resulting amino acid residues will no longer be identical to the original residues at the corresponding positions in either parent sequence, yet the antibody will still retain its function of binding to IL-23A. Such modifications are typically not large-scale and will be conservative modifications. Usually, at least 75%, more frequently at least 90%, and most frequently more than 95%, 98%, or 99% of the humanized antibody residues will correspond to residues in the FR sequence of the parent common or germline sequence and the import CDR sequence.

[0144] The interface between the heavy chain variable region and the light chain variable region ("V L -V H Immunoglobulin residues that affect the "interface" are residues that affect the proximity or orientation of the two chains to each other. Specific residues that may be involved in interchain interactions include V L Residues 34, 36, 38, 44, 46, 87, 89, 91, 96 and 98, and V H Examples include residues 35, 37, 39, 45, 47, 91, 93, 95, 100, and 103 (using the numbering system shown in Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987)). U.S. Patent No. 6,407,213 also states V L Residues 43 and 85, and V H We consider that residues such as 43 and 60 may also be involved in this interaction. Although these residues have only been shown for human IgG, they are applicable across species. Key antibody residues that are reasonably expected to be involved in interchain interactions are selected for common sequence substitutions.

[0145] The terms “common sequence” and “common antibody” refer to an amino acid sequence containing the most frequently present amino acid residues at each position in all immunoglobulins of any particular class, isotype, or subunit structure, such as human immunoglobulin variable domains. A common sequence may be based on immunoglobulins of a particular species or many species. A “common” sequence, structure, or antibody is understood to encompass a common human sequence, such as those described in a particular embodiment, and refers to an amino acid sequence containing the most frequently present amino acid residues at each position in all human immunoglobulins of any particular class, isotype, or subunit structure. Therefore, a common sequence contains an amino acid sequence having amino acids present in one or more known immunoglobulins at each position, but does not necessarily have to be an exact replica of the complete amino acid sequence of any single immunoglobulin. A common sequence of the variable region cannot be obtained 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.) or its variants. The common heavy and light chain sequences (FR) and their variants provide useful sequences for the preparation of humanized anti-IL-23p19 antibodies. See, for example, U.S. Patents 6,037,454 and 6,054,297.

[0146] Human germline sequences are naturally occurring in human populations. These germline gene combinations give rise to antibody diversity. The germline antibody sequences for the light chain of an antibody are derived from conserved human germline κ or λv- and j- genes. Similarly, the heavy chain sequences are derived from germline v-, d-, and j- genes (LeFranc, MP, and LeFranc, G, “The Immunoglobulin Facts Book” Academic Press, 2001).

[0147] In this specification, the terms "mutant," "anti-IL-23A mutant," "humanized anti-IL-23A mutant," or "mutant humanized anti-IL-23A" refer to a humanized anti-IL-23A antibody having a light chain variable mouse CDR sequence derived from at least one of the sequences shown in Table 1, or a heavy chain mouse CDR sequence derived from a mouse monoclonal antibody as shown in Table 2. Examples of mutants include those having one or more amino acid changes in the variable domain of one or both light chains or heavy chains, provided that the amino acid changes do not substantially impair the binding of the antibody to IL-23A. Examples of antibodies produced in this specification include those referred to as antibody A, antibody B, antibody C, and antibody D, with various light and heavy chains shown in SEQ ID NOs: 18 and 21, and SEQ ID NOs: 19 and 20, respectively.

[0148] "Isolated" antibodies are those identified, separated, and / or recovered from components of their natural environment. Contaminants in the antibody's natural environment are materials that may interfere with the antibody's diagnostic or therapeutic use, and these may be enzymes, hormones, or other proteinaceous or non-proteinaceous solutes. In one embodiment, the antibody would be isolated and purified to at least 95% or more of its weight.

[0149] Isolated antibodies include those found in situ within the recombinant cells in which they were produced, because at least one component of the antibody's natural environment would likely be absent. However, isolated antibodies are typically prepared through at least one purification step that removes recombinant cellular material.

[0150] The term "antibody performance" refers to factors that contribute to the recognition of antigens by antibodies or the in vivo efficacy of antibodies. Changes in the amino acid sequence of an antibody can affect antibody properties such as folding, and the initial rate (k) at which the antibody binds to the antigen. a ), the dissociation constant (k) of the antibody from the antigen. dThis can affect physical factors such as the antibody's affinity constant (Kd) for the antigen, antibody conformation, protein stability, and antibody half-life.

[0151] As used herein, the term “epitope-tagged” refers to an anti-IL-23A antibody fused to an “epitope tag.” An “epitope tag” is a polypeptide having a sufficient number of amino acids to provide an epitope for antibody production, but is designed not to interfere with the desired activity of the anti-IL-23A antibody. Epitope tags are usually sufficiently unique that antibodies produced against an epitope tag do not substantially cross-react with other epitopes. A suitable tag polypeptide generally contains at least six amino acid residues, and typically contains about 8 to 50 amino acid residues, or about 9 to 30 residues. Examples of epitope tags and antibodies that bind to said epitopes include the flu HA tag polypeptide and its antibody 12CA5 (Field et al., 1988 Mol. Cell. Biol. 8: 2159-2165); the c-myc tag and its antibodies 8F9, 3C7, 6E10, G4, B7, and 9E10 (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 "an epitope that binds to a salvage receptor." As used herein, the term “epitope that binds to a salvage receptor” refers to an epitope in the Fc region of an IgG molecule (e.g., IgG1, IgG2, IgG3, or IgG4) that is involved in prolonging the in vivo serum half-life of the IgG molecule.

[0152] For diagnostic and therapeutic monitoring, the antibody of the present invention may also be conjugated with a label, i.e., the label alone or the label and an additional second agent (such as a prodrug or chemotherapeutic agent). A label that distinguishes it from other second agents refers to a substance that is a detectable compound or composition, which may be directly or indirectly conjugated to the antibody of the present invention. The label may be detectable in itself (e.g., radioisotope labeling or fluorescent labeling), or, in the case of enzyme labeling, may catalyze a chemical change in a detectable substrate compound or composition. Labeled anti-IL-23A antibodies can be prepared and used in a variety of applications, including in vitro and in vivo diagnostics.

[0153] In various embodiments of the present invention, one or more domains of an antibody will be recombinantly expressed. Such recombinant expression may utilize one or more regulatory sequences, i.e., polynucleotide sequences required for the expression of an operablely linked coding sequence in a particular host organism. Suitable regulatory sequences for use in prokaryotic cells include, for example, promoters, operators, and ribosome binding site sequences. Suitable regulatory sequences for eukaryotic cells include, but are not limited to, promoters, polyadenylation signals, and enhancers. These regulatory sequences can be used for the expression and production of anti-IL-23A antibodies in prokaryotic and eukaryotic host cells.

[0154] A nucleic acid sequence is "operably linked" if it is positioned in a functional relationship with another nucleic acid sequence. For example, a nucleic acid presequence or secretion leader is operably linked to the nucleic acid encoding a polypeptide if it is expressed as a preprotein involved in polypeptide secretion; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned to facilitate translation. Generally, "operably linked" means that the linked DNA sequences are contiguous, and in the case of a secretion leader, contiguous and within the reading frame. Enhancers, however, may be in proximity. Linking can be achieved by ligation at a convenient restriction enzyme site. If such a site is not present, synthetic oligonucleotide adapters or linkers may be used.

[0155] In this specification, the terms “cell,” “cell line,” and “cell culture medium” are used synonymously, and all such names include their offspring. Therefore, “transformed organism” and “transformed cell” include the original target cell and the culture medium obtained therefrom, regardless of the passage number.

[0156] For the purposes of this procedure, the term “mammal” refers to humans, domesticated animals and livestock, and any animals classified as mammals, including zoo animals, sports animals, or pet animals such as dogs, horses, cats, and cows. Preferably, the mammal is human.

[0157] As used herein, “disorder” refers to any condition that would benefit from treatment with the anti-IL-23A antibodies described herein. This includes chronic and acute disorders or diseases, such as medical conditions that make mammals susceptible to the disorder in question.

[0158] As used herein, the terms “IL-23-related disorder” or “IL-23-related disease” refer to a condition in which IL-23 activity is the cause of a disease, typically characterized by abnormal expression of IL-23. IL-23-related disorders include diseases and disorders of the immune system, such as autoimmune disorders and inflammatory disorders. Such conditions include psoriasis, inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, and spondyloarthritis, such as ankylosing spondylitis, axial spondyloarthritis without radiographic findings, peripheral spondyloarthritis, or psoriatic arthritis.

[0159] The term "intravenous infusion" refers to the delivery of a drug into the veins of an animal or human patient over a period of time exceeding approximately 15 minutes, typically ranging from 30 to 90 minutes.

[0160] The terms "intravenous bolus" or "intravenous push" refer to the administration of a drug intravenously to an animal or human, in which the body receives the drug within approximately 15 minutes, and typically within 5 minutes.

[0161] The term "subcutaneous administration" refers to the delivery of a drug from a drug storage device to the subcutaneous tissue of an animal or human patient, preferably into a pocket between the skin and the underlying tissue, by relatively slow and continuous delivery. A pocket can be created by pinching the skin or pulling the skin up and separating it from the underlying tissue.

[0162] The term "subcutaneous injection" refers to the introduction of a drug by relatively slow and continuous delivery from a drug storage device into the subcutaneous tissue of an animal or human patient, preferably into a pocket between the skin and the underlying tissue, over a period of time including but not limited to 30 minutes or 90 minutes. In some cases, the injection may be performed by subcutaneous implantation of a drug delivery pump embedded under the skin of an animal or human patient, where the pump delivers a predetermined amount of drug over a predetermined period of time, for example, 30 minutes, 90 minutes, or the length of the treatment plan.

[0163] The term "subcutaneous bolus" refers to the administration of a drug under the skin of an animal or human patient, where the bolus drug delivery is within approximately 15 minutes; in another embodiment, within 5 minutes; and in yet another embodiment, within 60 seconds. In yet another embodiment, the administration is within a pocket between the skin and the underlying tissue, where the pocket may be created by pinching or lifting the skin to separate it from the underlying tissue.

[0164] The term “therapeutic dose” is used to refer to the amount of an active substance that alleviates or relieves one or more symptoms of the disorder being treated. In another embodiment, the therapeutic dose refers to the serum concentration of a target substance that has been shown to be effective in slowing the progression of the disease. Potency may be measured by conventional methods, depending on the condition being treated.

[0165] As used herein, the terms “treatment” and “therapy” include therapeutic and preventive or inhibitory measures for any disease or disorder that produce any clinically desirable or beneficial effect, including but not limited to the reduction or alleviation of one or more symptoms, or the regression, slowing, or cessation of a disease or disorder. Therefore, for example, the term “treatment” includes the administration of a drug before or after the onset of symptoms of a disease or disorder, thereby preventing or eliminating one or more signs of the disease or disorder. Another example includes combating symptoms of a disease by administering a drug after the clinical signs of the disease. Furthermore, the administration of a drug after the onset and after the occurrence of clinical symptoms (where the administration affects clinical parameters of the disease or disorder, such as the degree of tissue damage or the amount or extent of metastasis, regardless of whether the treatment results in remission of the disease) includes “treatment” or “therapy” as used herein. Furthermore, the composition of the present invention, either alone or in combination with another therapeutic agent, should be judged as an effective treatment of the underlying disorder, insofar as it reduces or remits at least one symptom of the disorder being treated compared to the symptoms without the use of the anti-IL-23A antibody composition, regardless of whether all symptoms of the disorder are reduced.

[0166] The term "package insert" is used to refer to instructions that are customarily included on the commercial packaging of a therapeutic product, containing information regarding indications, usage, administration, contraindications, and / or warnings relating to the use of such therapeutic product.

[0167] antibody Tables 1 and 2 show the CDRs of the selected antibodies used in the context of the present invention. Tables 3 and 4 show the variable regions of the selected antibodies used in the context of the present invention.

[0168] [Table 2]

[0169] [Table 3]

[0170] [Table 4]

[0171] [Table 5]

[0172] Antibodies A, B, C, and D were obtained from selected combinations of humanized light chain variable regions and heavy chain variable regions obtained from mouse antibody 6B8: 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); 6B8-IgG1KO-2 (heavy chain variable region 6B8CVH-02 and light chain variable region 6B8CVK-65) possessing antibody C:IgK-65; 6B8-IgG1KO-5 possessing antibody D:IgK-65 (heavy chain variable region 6B8CVH-05 and light chain variable region 6B8CVK-65).

[0173] Antibodies A, B, C, and D have the heavy and light chain sequences shown in Table 5.

[0174] [Table 6] TIFF2026108768000009.tif240169

[0175] In Table 5 above, the variable regions of the light and heavy chains of antibodies A, B, C, and D are underlined.

[0176] In one embodiment, the anti-IL-23A antibody includes the light chain sequence of SEQ ID NO: 18 and the heavy chain sequence of SEQ ID NO: 19. In one embodiment, the anti-IL-23A antibody includes the light chain sequence of SEQ ID NO: 18 and the heavy chain sequence of SEQ ID NO: 20. In one embodiment, the anti-IL-23A antibody includes the light chain sequence of SEQ ID NO: 21 and the heavy chain sequence of SEQ ID NO: 19. In one embodiment, the anti-IL-23A antibody includes the light chain sequence of SEQ ID NO: 21 and the heavy chain sequence of SEQ ID NO: 20.

[0177] In one embodiment, the anti-IL-23A antibody consists of the light chain sequence of SEQ ID NO: 18 and the heavy chain sequence of SEQ ID NO: 19. In one embodiment, the anti-IL-23A antibody consists of the light chain sequence of SEQ ID NO: 18 and the heavy chain sequence of SEQ ID NO: 20. In one embodiment, the anti-IL-23A antibody consists of the light chain sequence of SEQ ID NO: 21 and the heavy chain sequence of SEQ ID NO: 19. In one embodiment, the anti-IL-23A antibody consists of the light chain sequence of SEQ ID NO: 21 and the heavy chain sequence of SEQ ID NO: 20.

[0178] In a further embodiment, the anti-IL-23A antibody binds to an epitope of human IL-23A consisting of amino acid residues 108-126 and 137-151 of SEQ ID NO: 22.

[0179] In further embodiments, an anti-IL-23A antibody binds to human IL-23A competitively with the antibodies of the present invention, such as antibody A, antibody B, antibody C, or antibody D described herein. The competitive binding ability of an antibody to IL-23A can be measured using competitive binding assays known in the art.

[0180] In some embodiments, the anti-IL-23A antibody includes a light chain variable region sequence having the amino acid sequence shown in SEQ ID NOs: 10, 11, 12, or 13. In some embodiments, the anti-IL-23A antibody includes a heavy chain variable region sequence having the amino acid sequence shown in SEQ ID NOs: 14, 15, 16, or 17 (see Tables 3 and 4 above). The CDR sequences of these antibodies are shown in Tables 1 and 2. For example, the anti-IL-23A antibody is a monoclonal antibody having a combination of the light chain variable region and the heavy chain variable region of SEQ ID NOs: 11 / 14, 11 / 15, 10 / 14, or 10 / 15. Such variable regions may be combined with human constant regions.

[0181] Polynucleotides, vectors, host cells, and recombinant methods Other embodiments include isolated polynucleotides containing sequences encoding an anti-IL-23A antibody, vectors, and host cells containing the polynucleotides, as well as recombinant techniques for the production of humanized antibodies. The isolated polynucleotides can encode any desired form of anti-IL-23A antibody, including, for example, full-length monoclonal antibodies, Fab, Fab', F(ab')2, and Fv fragments.

[0182] A polynucleotide(s) containing a sequence encoding an anti-IL-23A antibody can be fused to one or more regulatory sequences known in the art, and this can be incorporated into a suitable expression vector or host cell known in the art. Each polynucleotide molecule encoding a heavy chain variable domain or a light chain variable domain can be independently fused to a polynucleotide sequence encoding a constant domain, such as a human constant domain, thereby enabling the production of intact antibodies. Alternatively, polynucleotides or parts thereof can be fused to each other, thereby providing a template for the production of single-chain antibodies.

[0183] For recombinant production, the polynucleotide encoding the antibody is inserted into a replicable vector for cloning (DNA amplification) or expression. Many suitable vectors for expressing recombinant antibodies are available. Vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer sequence, a promoter, and a transcription termination sequence.

[0184] Anti-IL-23A antibodies may also be generated as fusion polypeptides, in which the antibody is fused with a heterologous polypeptide such as a signal sequence, or another polypeptide having a cleavage site specific to the amino terminus of a mature protein or polypeptide. The selected heterologous signal sequence is typically recognized and processed (i.e., cleaved by a signal peptidase) by the host cell. In prokaryotic host cells that do not recognize and process the anti-IL-23A antibody signal sequence, the signal sequence may be replaced with a prokaryotic signal sequence. The signal sequence may be, for example, alkaline phosphatase, penicillinase, lipoprotein, or a thermostable enterotoxin II reader. For secretion in yeast, the native signal sequence may be replaced with, for example, a leader sequence obtained from the yeast invertase α factor (including Saccharomyces and Kluyveromyces α factor leaders), acid phosphatase, C. albicans glucoamylase, or the signals described in International Publication No. 90 / 13646. In mammalian cells, mammalian signal sequences, as well as viral secretion leaders, such as the herpes simplex gD signal, may be used. The DNA for such a precursor region is ligated within the reading frame to the DNA encoding the anti-IL-23A antibody.

[0185] Expression vectors and cloning vectors contain nucleic acid sequences that enable the vector to replicate in one or more selected host cells. Generally, these sequences within a cloning vector enable the vector to replicate independently of host chromosomal DNA and include origins of replication or autonomous replication sequences. Such sequences are well known for various bacteria, yeasts, and viruses. Origins of replication derived from plasmid pBR322 are suitable for most Gram-negative bacteria, 2-upsilon plasmid origins are suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV, and BPV) are useful for cloning vectors in mammalian cells. Generally, components of the origin of replication are not required for mammalian expression vectors (the SV40 origin is typically used because it contains the initial promoter).

[0186] Expression vectors and cloning vectors may contain genes encoding selection markers to facilitate the identification of expression. Typical selection marker genes are those encoding proteins that confer resistance to antibiotics or other toxins, such as ampicillin, neomycin, methotrexate, or tetracycline, or alternatively, complementary nutritional deficiencies, or, as another alternative option, genes that supply specific nutrients not present in the complex medium, such as D-alanine racemase for bacilli.

[0187] One example of a selection scheme involves using drugs that halt the growth of host cells. Cells successfully transformed using heterologous genes produce proteins that confer drug resistance, thus surviving the selection scheme. Examples of such dominant selection use the drugs neomycin, mycophenolate, and hygromycin. Common selection markers for mammalian cells include those that allow for the identification of cells capable of incorporating nucleic acids encoding anti-IL-23A antibodies, such as DHFR (dihydrofolate reductase), thymidine kinase, metallothionein-I and -II (e.g., primate metallothionein genes), adenosine deaminase, and ornithine decarboxylase. Cells transformed using DHFR selection genes are first identified by culturing all transformants in a culture medium containing methotrexate (Mtx), a competitive antagonist of DHFR. A suitable host cell when using wild-type DHFR is a Chinese hamster ovary (CHO) cell line lacking DHFR activity (e.g., DG44).

[0188] Alternatively, host cells transformed or co-transformed with an anti-IL-23A antibody, wild-type DHFR protein, and another selection marker, such as a DNA sequence encoding aminoglycoside 3'-phosphotransferase (APH), (particularly wild-type hosts containing endogenous DHFR) can be selected by cell growth in a medium containing a selection substance for the selection marker, such as an aminoglycoside antibiotic, such as kanamycin, neomycin, or G418. See, for example, U.S. Patent No. 4,965,199.

[0189] When recombinant production is carried out in yeast cells as the host cell, the TRP1 gene present in the yeast plasmid YRp7 (Stinchcomb et al., 1979, Nature 282: 39) can be used as a selection marker. The TRP1 gene provides a selection marker for yeast mutants lacking the ability to grow in tryptophan, such as ATCC number 44076 or PEP4-1 (Jones, 1977, Genetics 85:12). Therefore, the presence of trp1 deletion in the yeast host cell genome provides an effective environment for detecting transformation by growth in the absence of tryptophan. Similarly, Leu2p-deficient yeast strains, such as ATCC20,622 and 38,626, can be complemented by known plasmids containing the LEU2 gene.

[0190] Furthermore, a vector derived from the 1.6 μm circular plasmid pKD1 can be used for the transformation of Kluyveromyces yeast. Alternatively, an expression system for the large-scale production of recombinant bovine chymosin has been reported in K. lactis (Van den Berg, 1990, Bio / Technology 8:135). A stable multi-copy expression vector for the secretion of mature recombinant human serum albumin by industrially produced Kluyveromyces strains has also been disclosed (Fleer et al., 1991, Bio / Technology 9:968-975).

[0191] Expression vectors and cloning vectors typically contain a promoter that is recognized by the host organism and operably ligated to a nucleic acid molecule encoding an anti-IL-23p19 antibody or its polypeptide chain. Suitable promoters for use with prokaryotic hosts include the phoA promoter, β-lactamase and lactose promoter systems, alkaline phosphatase, tryptophan (trp) promoter systems, and hybrid promoters, such as the tac promoter. Other known bacterial promoters are also suitable. Promoters for use in bacterial systems will also likely contain a Shine-Dalgarno (SD) sequence operably ligated to the DNA encoding the anti-IL-23A antibody.

[0192] Many eukaryotic promoter sequences are known. Almost all eukaryotic genes have an AT-rich region located approximately 25–30 base pairs upstream from the transcription initiation site. Another sequence found 70–80 base pairs upstream from the transcription initiation site in many genes is the CNCAAT region, where N can be any nucleotide. The 3' end of most eukaryotic genes contains an AATAAA sequence, which may be a signal for the addition of a polyA tail to the 3' end of the coding sequence. All of these sequences are appropriately inserted into eukaryotic expression vectors.

[0193] Examples of promoter sequences suitable for use with a yeast host include promoters for 3-phosphoglycerate kinase or other glycolytic enzymes, such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triose phosphate isomerase, phosphoglucose isomerase, and glucokinase.

[0194] Inducible promoters have the additional advantage of transcription controlled by growth conditions. These include yeast promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatases, derivative enzymes related to nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes involved in the utilization of maltose and galactose. Vectors and promoters suitable for expression in yeast are further described in European Patent No. 73,657. Yeast enhancers are also advantageously used in conjunction with yeast promoters.

[0195] The transcription of anti-IL-23A antibodies from vectors within mammalian host cells is controlled by heterogeneous mammalian promoters, such as actin promoters or immunoglobulin promoters, or by heat shock promoters, using promoters derived from the genomes of viruses such as polyomavirus, fowlpox virus, adenovirus (e.g., adenovirus type 2), bovine papillomavirus, aerosarcoma virus, cytomegalovirus, retrovirus, hepatitis B virus, and Simian virus 40 (SV40). However, such promoters must be compatible with the host cell line.

[0196] Early and late promoters of the SV40 virus can be conveniently obtained as SV40 restriction enzyme fragments that also contain the SV40 virus origin of replication. The very early promoter of human cytomegalovirus can be conveniently obtained as a HindIII E restriction enzyme fragment. A system for expressing DNA in a mammalian host using bovine papillomavirus as a vector is disclosed in U.S. Patent No. 4,419,446. Modifications of this system are described in U.S. Patent No. 4,601,978. See also Reyes et al., 1982, Nature 297:598-601, which discloses the expression of human p-interferon cDNA in mouse cells under the control of a herpes simplex virus-derived thymidine kinase promoter. Alternatively, a long terminal repeat sequence of Roussarcoma virus may be used as a promoter.

[0197] Another useful sequence that can be used in recombinant expression vectors is the enhancer sequence, which is used by higher eukaryotes to increase the transcription of DNA encoding anti-IL-23A antibodies. Many enhancer sequences derived from mammalian genes (e.g., globin, elastase, albumin, α-fetoprotein, and insulin) are currently known. However, typically, enhancers derived from eukaryotic viruses are used. Examples include the SV40 enhancer (bp100-270) on the late side of the origin of replication, the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the origin of replication, and the adenovirus enhancer. See also Yaniv, 1982, Nature 297:17-18 for a description of enhancer sequences for eukaryotic promoter activation. The enhancer can be spliced ​​into the vector at the 5' or 3' position of the sequence encoding the anti-IL-23A antibody, but is preferably located at the 5' position relative to the promoter.

[0198] Expression vectors used in eukaryotic host cells (nucleated cells derived from yeast, fungi, insects, plants, animals, humans, or other multicellular organisms) may also contain sequences required for transcription termination and mRNA stabilization. Such sequences are generally obtained from the 5' and optionally 3' untranslated regions of eukaryotic or viral DNA or cDNA. These regions contain nucleotide segments that are transcribed as polyadenylated fragments within the untranslated portion of mRNA encoding an anti-IL-23A antibody. One useful transcription termination component is the bovine growth hormone polyadenylated region. See International Publication No. 94 / 11026 and the expression vectors disclosed therein. In some embodiments, humanized anti-IL-23p19 antibodies can be expressed using a CHEF system (see, e.g., U.S. Patent No. 5,888,809; its disclosure is incorporated herein by reference).

[0199] Suitable host cells for cloning or expressing DNA in a vector, as described herein, are the prokaryotic cells, yeast cells, or higher eukaryotic cells. Suitable prokaryotic cells for this purpose include bacteria, such as Gram-negative or Gram-positive bacteria, such as Enterobacteriaceae, such as Escherichia coli, such as E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, such as Salmonella typhimurium, Serratia, such as Serratia marcescans, and Shigella, as well as bacilli, such as Bacillus subtilis and Bacillus licheniformis (e.g., B. licheniformis 41P disclosed in DD266,710 published April 12, 1989), Pseudomonas, such as Pseudomonas aeruginosa, and Streptomyces. One preferred E. coli cloning host is E. coli 294 (ATCC 31,446), but 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 not limiting, but rather illustrative.

[0200] In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeast are also suitable cloning or expression hosts for vectors encoding anti-IL-23A antibodies. Saccharomyces cerevisiae or common baker's yeast are among the most commonly used lower eukaryotic host microorganisms. However, many other genera, species, and strains are commonly available and useful herein, for example, fission yeast (Schizosaccharomyces pombe); Kluyveromyces hosts, such as K. lactis, K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906), K. thermotolerans, and K. marxianus (K. marxianus); yarrowia (European Patent No. 402,226); Pichia pastors (European Patent No. 183,070); Candida; Trichoderma reesia (European Patent No. 244,234); Neurospora crassa; Schwanniomyces, e.g., Schwanniomyces occidentalis; and filamentous fungi, e.g., Neurospora, Penicillium, Tolypocladium, and Aspergillus hosts, e.g., A. nidulans and A. niger.

[0201] Host cells suitable for the expression of glycosylated anti-IL-23A antibodies can be obtained from multicellular organisms. Examples of invertebrate cells include plant cells and insect cells, such as numerous baculovirus strains and mutants, as well as corresponding acceptable insect host cells from hosts such as the armyworm (Spodoptera frugiperda), Aedes aegypti, Aedes albopictus, Drosophila melanogaster, and Bombyx mori (silkworm). Various virus strains for transfection are publicly available, such as the L-1 mutant of Autographa californica NPV and the Bm-5 strain of Bombyx mori NPV, and such viruses can be used, in particular, for the transfection of armyworm cells.

[0202] Plant cell culture solutions from cotton, corn, potatoes, soybeans, petunias, tomatoes, and tobacco can also be used as hosts.

[0203] In another embodiment, the expression of anti-IL-23A antibodies occurs within vertebrate cells. The proliferation of vertebrate cells in culture medium (tissue culture medium) is a conventional procedure, and the technique is widely available. Examples of useful mammalian host cell lines include SV40-transformed monkey kidney CV1 cell line (COS-7, ATCC CRL 1651), human embryonic kidney cell line (293 or 293 cells subcloned for growth in suspension culture (Graham et al., 1977, J. Gen Virol. 36: 59)), baby hamster kidney cells (BHK, ATCC CCL10), Chinese hamster ovary cells / -DHFR1 (CHO, Urlaub et al., 1980, Proc. Natl. Acad. Sci. USA 77: 4216; e.g., DG44), mouse Sertoli cells (TM4, Mather, 1980, Biol. Reprod. 23:243-251), monkey kidney cells (CV1 ATCC CCL 70), and African green monkey kidney cells (VERO-76, ATCC These include CRL-1587, human cervical cancer cells (HELA, ATCC CCL 2), canine kidney cells (MDCK, ATCC CCL 34), buffalo rat liver cells (BRL 3A, ATCC CRL 1442), human lung cells (W138, ATCC CCL 75), human liver cells (HepG2, HB8065), mouse mammary tumor cells (MMT 060562, ATCC CCL 51), TR1 cells (Mather et al., 1982, Annals NY Acad. Sci. 383: 44-68), MRC5 cells, FS4 cells, and human hepatocellular carcinoma cell line (HepG2).

[0204] Host cells are transformed using the above-mentioned expression vector or cloning vector for anti-IL-23A antibody production, and then cultured in a conventional nutrient medium that has been appropriately modified to induce a promoter, select transformants, or amplify a gene encoding a desired sequence.

[0205] The host cells used to produce the anti-IL-23A antibodies described herein can be cultured in a variety of media. Commercial media, such as Ham's F10 (Sigma-Aldrich Co., St. Louis, Missouri), Minimum Essential Medium ((MEM), (Sigma-Aldrich Co.), RPMI-1640 (Sigma-Aldrich Co.), and Dulbecco's Modified Eagle Medium ((DMEM), Sigma-Aldrich Co.), are suitable for culturing host cells. Furthermore, Ham et al., 1979, Meth. Enz. 58: 44, Barnes et al., 1980, Anal. Biochem. 102: Any of the media described in one or more of the following publications may be used as culture media for host cells: 255, U.S. Patent No. 4,767,704, U.S. Patent No. 4,657,866, U.S. Patent No. 4,927,762, U.S. Patent No. 4,560,655, U.S. Patent No. 5,122,469, International Publication No. 90 / 103430, and International Publication No. 87 / 00195. These media may, if necessary, be mixed with hormones and / or other growth factors (e.g., insulin, transferrin, or epidermal growth factor), salts (e.g., sodium chloride). The cells may be supplemented with calcium, magnesium, and phosphates, buffers (e.g., HEPES), nucleotides (e.g., adenosine and thymidine), antibiotics (e.g., gentamicin), trace elements (defined as inorganic compounds that are normally present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Other auxiliary substances may also be included in appropriate concentrations that would be known to those skilled in the art. Culture conditions, such as temperature and pH, are those previously used with the host cells selected for expression and would be obvious to those skilled in the art.

[0206] When using recombinant technology, antibodies may be produced in the perimembranous space within cells or secreted directly into the culture medium. If antibodies are produced intracellularly, the first step may be to disrupt the cells to release the proteins. Particulate debris, either from the host cells or the lysed fragments, can be removed, for example, by centrifugation or ultrafiltration. Carter et al., 1992, Bio / Technology 10:163-167 describes a procedure for isolating antibodies secreted into the perimembranous space of E. coli.

[0207] In short, the cell paste is thawed for approximately 30 minutes in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonyl fluoride (PMSF). Cell debris can be removed by centrifugation. If antibodies are secreted into the culture medium, the supernatant from such an expression system is generally first concentrated using a commercially available protein concentration filter, such as an Amicon or Milliporepericon ultrafiltration system. Protein degradation can be suppressed by including a protease inhibitor such as PMSF in one of the above steps, and the proliferation of foreign contaminants can be prevented by including an antibiotic. Antibodies can be isolated from host cells using various methods.

[0208] Antibody compositions prepared from cells can be purified using, for example, hydroxyapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being the typical purification technique. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain present in the antibody. Protein A can be used to purify antibodies based on human γ1, γ2, or γ4 heavy chains (see, e.g., Lindmark et al., 1983 J. Immunol. Meth. 62:1-13). Protein G is recommended for all mouse isotypes and human γ3 (see, e.g., Guss et al., 1986 EMBO J. 5:1567-1575). The matrix to which the affinity ligand attaches is most often agarose, but other matrices are also available. Mechanically stable matrices, such as controlled-pore glass or poly(styrenedivinyl)benzene, allow for faster flow rates and shorter processing times that can be achieved with agarose. H3 If the antibody contains domains, Bakerbond ABX® resin (JT Baker, Philipsburg, New Jersey) is useful for purification. Other techniques for protein purification, such as fractionation on ion-exchange columns, precipitation with ethanol, reverse-phase HPLC, silica chromatography, chromatography on anion or cation exchange resins (e.g., polyaspartate columns), chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation, are also available depending on the antibody to be recovered.

[0209] After any preliminary purification steps, the mixture containing the antibody of interest and any contaminants can be subjected to hydrophobic interaction chromatography at a low pH, typically using a low salt concentration (e.g., about 0–0.25 M salt) and an elution buffer with a pH of about 2.5–4.5.

[0210] therapeutic use In another embodiment, the anti-IL-23A antibody disclosed herein is useful for treating various disorders associated with IL-23p19 expression, as described herein. In one embodiment, a method for treating an IL-23-related disorder comprises the step of administering a therapeutically effective dose of anti-IL-23A antibody to a subject in need.

[0211] Anti-IL-23A antibodies are administered by any appropriate means, including parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, as well as intrafocal administration (including perfusion or otherwise contact of the graft with the antibody before transplantation) if local immunosuppressive treatment is desired. Anti-IL-23A antibodies or drugs may be administered, for example, as infusion or as a bolus. Parenteral infusion includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. Furthermore, anti-IL-23A antibodies are appropriately administered by pulse infusion, particularly with decreasing doses of antibody. In one embodiment, the administration is carried out by injection, most preferably intravenous or subcutaneous injection, depending in part whether the administration is short-term or chronic. In one embodiment, the administration of anti-IL-23 antibodies is carried out by subcutaneous injection.

[0212] For the prevention or treatment of a disease, the appropriate dosage of an antibody will depend on various factors, including the type of disease being treated as defined above, the severity and progression of the disease, whether the antibody is administered for prophylactic or therapeutic purposes, previous therapies, the patient's clinical history, and the patient's response to the antibody, as well as the physician's discretion. The antibody should be administered appropriately to the patient, either as a single dose or over a series of treatments.

[0213] The term "suppression" is used herein in the same sense as "remission" and "reduction," and means a reduction in one or more characteristics of a disease.

[0214] The aforementioned antibody is formulated, weighed, and administered in a manner consistent with good medical practice. Factors to consider in this context include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disorder, the site of drug delivery, the method of administration, the administration plan, and other factors known to healthcare professionals. The "therapeutic dose" of the antibody to be administered will depend on these considerations.

[0215] The antibody may optionally be formulated together with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of anti-IL-23A antibody present in the formulation, the type of disorder or treatment, and other factors considered above.

[0216] IL-23 related issues Anti-IL-23p19 antibodies or drugs are useful for treating or preventing immunological disorders characterized by, for example, inappropriate activation of immune cells (e.g., lymphocytes or dendritic cells) due to abnormal expression of IL-23. Such abnormal IL-23 expression may be caused, for example, by elevated IL-23 protein levels.

[0217] Immunological disorders characterized by inappropriate activation of immune cells and treatable or preventable by the methods described herein can be classified, for example, by the type(s) of hypersensitivity reactions(s) underlying the disorder. These reactions are typically classified into four types: anaphylactic reactions, cytotoxic (cytolytic) reactions, immune complex reactions, or cellular immunity (CMI) reactions (also known as delayed-type hypersensitivity (DTH) reactions). (See, for example, Fundamental Immunology (William E. Paul ed., Raven Press, NY, 3rd ed. 1993)). Immunological disorders include inflammatory diseases and autoimmune diseases.

[0218] Examples of immunological disorders include: psoriasis, inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, and spondyloarthritis, such as ankylosing arthritis, axial spondyloarthritis without radiographic findings, peripheral spondyloarthritis, or psoriatic arthritis.

[0219] In one embodiment, in the context of the present invention, the immunological disorder is Crohn's disease, for example, moderate to severe active Crohn's disease. In one embodiment, in the context of the present invention, the patient is untreated or has been previously treated with anti-TNF therapy. In one embodiment, in the context of the method of the present invention, the patient has been previously treated with one, two, three or more TNF antagonists(s). In one embodiment, the patient is a patient who has shown an inadequate response to, had no response to, or was intolerant of TNF antagonists. In one embodiment, the patient treated by the method of the present invention has a CDAI score of 220 to 450.

[0220] The severity of Crohn's disease is measured, for example, using the Crohn's Disease Activity Index (CDAI). The CDAI is a comprehensive score used to quantify the symptoms of patients with Crohn's disease. In one embodiment, the index consists of the sum of eight coefficients, after being adjusted for predetermined weighting coefficients (see Table B below). The CDAI score ranges from 0 to 600. Index values ​​of 150 or less are associated with inactive disease; values ​​above 150 are associated with active disease; and values ​​above 450 are seen in very severe disease.

[0221] [Table 7]

[0222] At the mucosal level, the severity of the disease is graded, for example, by the Endoscopic Severity Index (CDEIS) for Crohn's Disease after colonoscopy. In one aspect, the CDEIS is a validated scoring system in which six endoscopic variables (presence of deep ulcers, presence of superficial ulcers, presence of non-ulcerated strictures, presence of ulcerated strictures, ulcerated surface ratio, and diseased surface ratio) are evaluated in each of five sites (rectum, sigmoid left colon, transverse colon, right colon, and ileum). For these sites, the ratio of ulcerated colonic surface and the ratio of surface affected by any Crohn's disease lesions are shown on a 10 cm visual analog scale. The CDEIS score ranges from 0 to 44, with higher scores indicating a more severe disease.

[0223] Other evaluations of the disease are described, for example, in the following examples herein. In one embodiment, the efficacy of anti-IL-23A antibodies, such as antibody A, antibody B, antibody C, or antibody D, in the treatment of Crohn's disease, such as moderate to severe active Crohn's disease, is evaluated using CDAI or CDEIS, or both, or any one of the evaluations described in the following examples herein.

[0224] For example, patients are evaluated for clinical remission, which is defined as a CDAI score of less than 150.

[0225] For example, patients are evaluated for their clinical response, which is defined by either a CDAI score of less than 150 or a decrease of at least 100 points from baseline in their CDAI score.

[0226] For example, a patient is evaluated for endoscopic remission, which is defined, for example, as a CDEIS of 4 or less. In patients with early isolated ileitis, endoscopic remission is defined, for example, as a CDEIS of 2 or less.

[0227] For example, patients are evaluated for endoscopic response, defined as, for example, a reduction of more than 50% from baseline in CDEIS.

[0228] For example, a patient is evaluated for complete remission, which is defined as achieving, for example, clinical remission (CDAI score < 150) and / or endoscopic remission (CDEIS ≤ 4). In one embodiment, for patients with early isolated ileitis, endoscopic remission is defined as a CDEI of 2 or less. For example, complete remission is defined as achieving both clinical and endoscopic remission.

[0229] In one embodiment, a patient's patient-reported outcome (PRO) is assessed, for example, using a PRO-2 score. In another embodiment, PRO-2 remission is assessed, for example, defined as a PRO-2 score of 75 or less. In yet another embodiment, PRO-2 response is assessed, for example, defined as a reduction of 50 points or more from baseline.

[0230] In one embodiment, PRO-2 includes only two CDAI items: stool frequency and abdominal pain. In another embodiment, PRO-2 is calculated based on the sum of weighted CDAI subscores reported by patients for the frequency of liquid or loose stools and abdominal pain during the seven days prior to the hospital visit. PRO-2 is calculated by adding a value obtained by multiplying the total stool frequency score by 2 and a value obtained by multiplying the total abdominal pain score by 5.

[0231] In one aspect, health-related quality of life (HRQoL) is assessed by asking patients to complete 32 questions on the Inflammatory Bowel Disease Questionnaire (IBDQ), a tool for measuring the impact of bowel-related symptoms, systemic complaints, social functioning, and emotional state on HRQoL; higher scores indicate better HRQoL. A mean change of 16 points is considered clinically meaningful.

[0232] In one embodiment, in the context of the present invention, the immunological disease is ulcerative colitis. In one embodiment, an anti-IL-23A antibody, such as antibody A, antibody B, antibody C, or antibody D, is used to treat patients with moderate to severe active ulcerative colitis, for example, patients who have shown an inadequate response, no response, or intolerance to conventional therapy or tumor necrosis factor alpha (TNFα) antagonists. For example, the treatment may be by inducing and maintaining clinical remission, by inducing and maintaining a clinical response, by improving the appearance of the mucosa on endoscopic examination, or by achieving remission without corticosteroids.

[0233] Pharmaceutical composition and administration thereof A composition containing an anti-IL-23A antibody may be administered to subjects who have or are at risk of having an immunological disorder. As used herein, the term “subject” means any mammalian patient to whom an anti-IL-23A antibody can be administered, e.g., humans and non-human mammals, e.g., primates, rodents, and dogs. Humans are particularly intended subjects for treatment using the methods described herein. The antibody may be administered alone or in combination with other compositions for the prevention or treatment of an immunological disorder.

[0234] Anti-IL-23A antibodies for use in such pharmaceutical compositions are described herein and are, for example, antibody A, antibody B, antibody C, or antibody D.

[0235] Various delivery systems are known and can be used to administer anti-IL-23A antibodies. Methods of delivery include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. Anti-IL-23A antibodies may be administered, for example, by infusion, bolus, or injection, and may be administered together with other bioactive agents, such as chemotherapeutic agents. Administration may be systemic or topical. In one embodiment, administration is by subcutaneous injection. Such injectable formulations may be prepared, for example, in pre-filled syringes, which can be administered once every two weeks.

[0236] In specific embodiments, the anti-IL-23A antibody is administered by injection, via a catheter, via a suppository, or via an implant, the implant being a porous material, a non-porous material, a gel material (including a membrane such as a thyrustic membrane), or a fiber. Typically, when the composition is administered, a material is used that does not absorb the anti-IL-23A antibody or the drug.

[0237] In other embodiments, the anti-IL-23A antibody is delivered using a sustained-release system. In one embodiment, a pump may be used (see, e.g., Langer, 1990, Science 249:1527-1533; Sefton, 1989, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321:574). In another embodiment, a polymer material may be used. (See, for example, Medical Applications of Controlled Release (Langer and Wise eds., CRC Press, Boca Raton, Fla., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., Wiley, New York, 1984); Ranger and Peppas, 1983, Macromol. Sci. Rev. Macromol. Chem. 23:61; Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105). Other sustained-release systems are also discussed, for example, in Langer's work mentioned above.

[0238] Anti-IL-23p19 antibodies are typically administered as a pharmaceutical composition containing a therapeutically effective dose of the antibody and one or more pharmaceutically compatible components.

[0239] In a typical embodiment, the pharmaceutical composition is formulated according to conventional procedures as a pharmaceutical composition suitable for intravenous or subcutaneous administration to humans. Typically, a composition for administration by injection is a solution in sterile isotonic aqueous buffer. If necessary, the pharmaceutical may also contain a solubilizer and a local anesthetic, such as lignocaine, to alleviate pain at the injection site. Generally, the components are supplied either separately or mixed together in a unit dosage form, for example, as a lyophilized powder or a water-free concentrate, in sealed containers such as ampoules or sachets indicating the amount of active substance. When the pharmaceutical is to be administered by injection, it can be administered using an injection bottle containing sterile pharmaceutical-grade water or saline. When the pharmaceutical is to be administered by injection, ampoules of sterile water or saline for injection may be provided so that the components can be mixed before administration.

[0240] Furthermore, the pharmaceutical composition may be provided as a pharmaceutical kit comprising (a) a container containing lyophilized anti-IL-23A antibody and (b) a second container containing a pharmaceutically acceptable diluent for injection (e.g., sterile water). The pharmaceutically acceptable diluent may be used to restore or dilute the lyophilized anti-IL-23A antibody. Optionally accompanying such containers(s) may be a notice in the form prescribed by the governmental authority regulating the manufacture, use, or sale of pharmaceuticals or biological products, which reflects the authority's approval for manufacture, use, or sale for human administration.

[0241] Examples of pharmaceutical compositions used in the context of the present invention are disclosed in Example 2 below.

[0242] The present invention is further described in the following embodiments, which do not limit the scope of the invention.

[0243] Examples Example 1: Clinical Trial This study is a proof-of-concept, multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase II dose-range study of antibody A in patients with moderate to severe active Crohn's disease.

[0244] The trial consists of a screening period of up to 4 weeks, a 12-week blinded intravenous therapy period (Phase 1), a 14-week open-label intravenous therapy / disease period (Phase 2), a 26-week subcutaneous therapy period (Phase 3), and a 15-week follow-up period.

[0245] Approximately 240 patients will be screened, and about 120 patients with moderate to severe Crohn's disease and mucosal ulcers detected by colonoscopy will be randomized in a 1:1:1 ratio to one of three treatment groups for the following period: • Group 1: Placebo (intravenous) (n=40) • Group 2: 200 mg of antibody A (intravenous) (n=40) • Group 3: 600 mg antibody A (intravenous) (n=40)

[0246] Randomization will be stratified according to prior experience with anti-TNF therapy (untreated vs. experienced). Safety and efficacy will be evaluated until the end of the trial. The end of the trial will be defined as the day the last patient completes their final follow-up visit.

[0247] Each treatment group receives the corresponding dose of antibody A or placebo via intravenous infusion at weeks 0, 4, and 8. At week 12, patients are evaluated for complete remission, defined as reaching clinical remission (CDAI score < 150) and endoscopic remission (CDEIS ≤ 4), as confirmed by a central independent re-evaluator(s). In patients with early isolated ileitis, endoscopic remission is defined by CDEI ≤ 2.

[0248] The treatment for period 2 will be determined by the outcome at week 12.

[0249] Patients in complete remission at week 12 discontinue medication and enter a drug-free period until week 26.

[0250] If disease relapse occurs during this period (including the E1 visit), defined as an increase of 70 points or more in the CDAI score compared to week 12, or a CDAI score of 220 or higher, the investigator will perform a colonoscopy within two weeks; If the CDEIS score is 4 or less (2 or less in patients with early-stage ileitis), the patient should continue medication-free until week 26. If the CDEIS score is greater than 4 (greater than 2 in patients with early-stage ileitis), the patient receives open-label intravenous induction therapy with 600 mg of antibody A (three doses administered at 4-week intervals), as shown in Figure 1.

[0251] Patients who do not achieve complete remission by week 12 receive open-label intravenous induction therapy with 600 mg of antibody A (three doses administered at 4-week intervals), as shown in Figure 1.

[0252] Patients in clinical remission at the time of their E1 visit, regardless of their 12-week outcome and treatment during period 2, will enter period 3 (open-label subcutaneous period) and receive four injections of antibody A (180 mg subcutaneously) at 8-week intervals.

[0253] Colonoscopy will be performed on all patients at screening, at 12 weeks, and at 52 weeks to assess endoscopic response / remission and to prepare mucosal biopsy specimens for pre- and post-treatment molecular pharmacokinetic evaluation. Patients who experience a relapse after achieving complete remission at 12 weeks will also be required to undergo colonoscopy and will receive open-label re-induction therapy only if their CDEIS score is greater than 4 (greater than 2 in patients with early ileitis), as confirmed by a central independent re-evaluator(s). All colonoscopies will be videotaped using a standard protocol and interpreted by independent re-evaluators(s) who are not informed of the study group assignment or procedure timing. Patients participating in the study have agreed to undergo up to four colonoscopies.

[0254] The criteria for effectiveness are as follows:

[0255] The primary efficacy endpoint is clinical remission, defined, for example, a CDAI score of less than 150 at week 12.

[0256] The secondary efficacy endpoints are as follows: Clinical response, defined, for example, by a CDAI score of less than 150 at week 12 or a decrease of at least 100 points from baseline in CDAI. • PRO response (PRO-2: Patient-Reported Outcome-2), defined, for example, by a PRO-2 score of less than 8 or a decrease of at least 8 points from baseline at week 12. CDEIS remission is defined, for example, as a score of 4 or less at week 12 (a score of 2 or less in patients with early isolated ileitis). • CDEIS response, defined as a score of 7 or less at week 12 (a decrease of more than 50% from baseline in patients with early isolated ileitis). For example, the change in the SES-CD score during week 12. Mucosal healing is defined, for example, as the absence of mucosal ulcers at 12 weeks. · Complete remission defined by clinical remission and endoscopic remission (CDEIS) at, for example, week 12. Change from baseline of the CDAI score at clinic visit.

[0257] Other efficacy evaluation items are as follows: · Change from baseline of the CDAI score at clinic visit. · Change from baseline of the PRO-2 score at clinic visit. · 75% decrease from baseline of the CDEIS score at, for example, week 12. · 75% decrease from baseline of the SES-CD score at, for example, week 12. · Time to re-heat for patients who achieved complete remission and discontinued drug therapy at, for example, week 12. · Time to re-heat for patients who achieved clinical remission at, for example, week 26. · Change from baseline of the bowel frequency at clinic visit based on the patient's diary. · Viscosity of stools at clinic visit based on the patient's diary. · Change from baseline of the abdominal pain score at clinic visit scored based on a numerical rating scale from 0 (no pain) to 10 (worst possible pain) based on the patient's diary. · Change from baseline of the IBDQ score at clinic visit. · Change from baseline of the profiles of CRP (C-reactive protein), calprotectin and lactoferrin at clinic visit. · Sustained clinical remission (from week 12) after withdrawal of corticosteroids. · Decrease in the number of draining fistulas in patients with draining fistulas at baseline. · RPO-2 remission at, for example, weeks 204 / 206 / 216 defined by a PRO-2 score of less than 75. · RPO-2 response at, for example, weeks 204 / 206 / 216 defined as a decrease of 50 points or more from baseline. · Change in CDEIS at clinic visit. · Change in SES-CD at clinic visit. · Change in the CDEIS rate from baseline at the time of visit. · Change in the SES-CD rate from baseline at the time of visit.

[0258] Methods The trial included three treatment periods: a 12-week double-blind intravenous (iv) induction period, a 14-week open-label intravenous re-induction / drug holiday period (i.e., re-induction at weeks 14–26 or drug holiday at weeks 12–26 for patients not receiving re-induction), and a 26-week subcutaneous maintenance period. During the induction period, patients (N = 121) with endoscopically confirmed (index of endoscopic severity of Crohn's disease [CDEIS] score ≥ 7; ≥ 4 for isolated ileitis patients), clinically active disease (Crohn's disease activity index [CDAI] score ≥ 220) who had failed either a TNF antagonist or conventional Crohn's disease therapy were randomized to receive either antibody A (200 mg or 600 mg) or placebo at weeks 0, 4, and 8. The primary endpoint was clinical remission (CDAI < 150) at week 12. Secondary endpoints at week 12 included clinical response, endoscopic remission / response, and complete remission.

[0259] Eligible patients were 18–75 years of age. They had received a diagnosis of Crohn's disease for at least 3 months and, at screening, had moderate to severe Crohn's disease defined as a Crohn's disease activity index (CDAI) of 220–450, along with mucosal ulcers in the ileum and / or colon, and an index of endoscopic severity of Crohn's disease (CDEIS) of ≥ 7 (≥ 4 for isolated ileitis patients) on colonoscopy scored by a blinded central reader. Patients who were untreated or had experienced one or more tumor necrosis factor (TNF) antagonists were included (Table C). Some patients had shown an inadequate response, no response, or intolerance to TNF antagonists (Table C). Patients previously treated with ustekinumab were excluded, as were patients who had received any biologic agent within 8 weeks prior to randomization, i.e., prior to the first dose of study drug, or within a period equal to 5 times the half-life of the biologic agent.

[0260] The difference between antibody A and placebo was analyzed using appropriate tests for pairwise comparison of binary data. The results for the induction period are reported.

[0261] [Table 8]

[0262] result Baseline demographics and disease characteristics were similar across the study groups. In total, there were 47 males and 74 females, with a mean age of 38.1 years, and mean CDAI and CDEIS scores of 306.8 and 13.4, respectively; 94.2% of patients had previously been exposed to one or more TNF antagonists. At week 12, clinical remission was achieved in 24.4% and 36.6% of patients with 200 mg and 600 mg of antibody A, respectively, compared to 15.4% of patients with placebo (p=0.308 and p=0.025) (Table 6); the clinical response rates were 36.6% and 41.5% in the 200 mg and 600 mg antibody A groups, respectively, compared to 20.5% in the placebo group (p=0.103 and p=0.037). Endoscopic remission was achieved in 14.6% and 19.5% of patients using 200 mg and 600 mg of antibody A, respectively, compared to 2.6% of patients using placebo (p=0.056 and p=0.017); endoscopic response was achieved in 26.8% and 36.6% of patients using 200 mg and 600 mg of antibody A, respectively, compared to 12.8% of patients using placebo (p=0.117 and p=0.014). Complete remission was achieved in 2.4% and 12.2% of patients using 200 mg and 600 mg of antibody A, respectively, compared to 0.0% with placebo (p=1.0 and p=0.062). Mucosal healing was detected in 3.0%, 2.9%, and 7.5% of patients using placebo, 200 mg, and 600 mg of antibody A, respectively. Adverse events (AEs) were similar between antibody A and placebo, with no dose-related increase in adverse events. A small number of severe and serious adverse events were reported in the 600 mg antibody A group. The results are shown in Tables 6 and 7. Tables 6 and 7 include combined figures for antibody A.

[0263] Clinical remission and clinical response to antibody A over 12 weeks are also shown in Figure 2. In Figure 2, from left to right, placebo, 200 mg of antibody A, 600 mg of antibody A, and combined antibody A are shown at weeks 4, 8, and 12.

[0264] Figure 2A, Clinical remission over time: Week 4: Placebo (3 patients / 7.7% showing clinical remission), 200 mg of antibody A (4 patients / 9.8% showing clinical remission), 600 mg of antibody A (8 patients / 19.5% showing clinical remission), combined antibody A (12 patients / 14.6% showing clinical remission). Week 8: Placebo (1 patient / 2.6% showing clinical remission), 200 mg of antibody A (7 patients / 17.1% showing clinical remission), 600 mg of antibody A (10 patients / 24.4% showing clinical remission), combined antibody A (17 patients / 20.7% showing clinical remission). Week 12: Placebo (6 patients / 15.4% showing clinical remission), 200 mg of antibody A (10 patients / 24.4% showing clinical remission), 600 mg of antibody A (15 patients / 36.6% showing clinical remission), combined antibody A (25 patients / 30.5% showing clinical remission).

[0265] Figure 2B, Clinical response over time: Week 4: Placebo (6 patients showing a clinical response / 15.4%), 200 mg of antibody A (10 patients showing a clinical response / 24.4%), 600 mg of antibody A (13 patients showing a clinical response / 31.7%), combined antibody A (23 patients showing a clinical response / 28.0%). Week 8: Placebo (5 patients / 12.8% showing a clinical response), 200 mg of antibody A (13 patients / 31.7% showing a clinical response), 600 mg of antibody A (13 patients / 31.7% showing a clinical response), combined antibody A (26 patients / 31.7% showing a clinical response). Week 12: Placebo (8 patients showing a clinical response / 20.5%), 200 mg of antibody A (15 patients showing a clinical response / 36.6%), 600 mg of antibody A (17 patients showing a clinical response / 41.5%), combined antibody A (32 patients showing a clinical response / 39.0%).

[0266] The median CDAI values ​​over time are shown in Figure 3A and Table 8A. The PRO-2 response at week 12 is shown in Table 8B, and PRO-2 remission at week 12 is shown in Table 8C.

[0267] safety No dose-related increase was observed in any of the adverse events reported using antibody A (Table 11). The most frequent adverse events were gastrointestinal in nature. The incidence of severe adverse events was higher in the placebo group than in the antibody A group (23%, 15%, and 7%, respectively). Adverse events leading to discontinuation were reported in 15%, 12%, and 2% of patients in the placebo, 200 mg antibody A, and 600 mg antibody A groups, respectively (Table 11). Severe adverse events occurred in 31%, 22%, and 7% of patients in the placebo, 200 mg antibody A, and 600 mg antibody A groups, respectively. The most common severe adverse event was exacerbation of the underlying disease. No deaths occurred, but serious infections were reported in 3 patients (abdominal, anal, and rectal abscesses, and pneumonia), 1 patient (pneumonia), and 2 patients (osteomyelitis and anal abscess) in the placebo group, the 200 mg antibody A group, and the 600 mg antibody A group, respectively. Infusion-related reactions were mild to moderate and were reported in 5%, 2%, and 2% of patients in the placebo group, the 200 mg antibody A group, and the 600 mg antibody A group, respectively.

[0268] Anti-drug antibodies (ADAs) that appeared in response to the treatment were detected in 4% of patients (3 out of 76 patients) receiving antibody A. ADA titers were low (8 or less), and no neutralizing antibodies were detected. Pre-existing ADAs were observed in 5 patients in the antibody A group and 3 patients in the placebo group.

[0269] conclusion In patients with active Crohn's disease, selective blockade of IL-23 using antibody A was more effective than placebo in inducing clinical and endoscopic remission at week 12 and was well-tolerated.

[0270] [Table 9]

[0271] Table 7. Evaluation items for effectiveness at week 12 Table 7 shows the evaluation items of efficacy at week 12 using improved statistical analysis (see also Table 6). Mucosal healing is also shown in Table 7.

[0272]

Table 10

[0273] Clinical remission is defined as a CDAI score of less than 150. Clinical response is either a CDAI score of less than 150 or a decrease of 100 or more from the CDAI baseline. Endoscopic remission is a CDEIS score of 4 or less at week 12 (2 or less in initial isolated ileitis patients). Endoscopic response is a decrease of more than 50% in the CDEIS score from baseline to week 12. Mucosal healing is defined as the absence of mucosal ulcers. Complete remission is clinical remission and endoscopic remission. The largest analysis population was used for this analysis, and non-respondent imputation and stratified Cochran-Mantel-Haenszel tests were used for missing values. CDAI, Crohn's disease activity index; CDEIS, endoscopic severity index of Crohn's disease; SD, standard deviation.

[0274] Biomarker The median CRP concentration decreased over time in both antibody A groups compared to placebo and was significantly decreased compared to placebo at week 12 (P < 0.001; Figure 3B). Treatment with 600 mg of antibody A significantly decreased the FCP level compared to placebo (from baseline to week 12) (P < 0.001; Figure 3C). Furthermore, a significantly greater decrease in plasma IL-22 levels (from baseline to week 12) was observed with 600 mg of antibody A compared to placebo (P = 0.018; Figure 3D). The plasma IL-22 levels in patients were measured using the Erenna (registered trademark) SMC (trademark) IL-22 immunoassay - a semi-quantitative fluorescence sandwich immunoassay technique. FCP in feces was measured using an enzyme immunoassay by Bühlmann Laboratories AG and tested by Covance Central Laboratories.

[0275] Table 8A also shows the median CRP (mg / L), median FCP (μg / g), and median % change in IL-22 over time (BL: baseline, IQR: interquartile range).

[0276] [Table 11]

[0277] [Table 12]

[0278] [Table 13]

[0279] [Table 14]

[0280] [Table 15]

[0281] [Table 16]

[0282] Molecular Profile Colon tissue was collected from a subset of patients at baseline and at 12 weeks (63% received 200 mg of antibody A, 66% received 600 mg of antibody A, and 67% received placebo). A significant decrease in the expression of selected genes related to the IL-23 immune pathway was observed in patients treated with antibody A compared to placebo (Table 9).

[0283] [Table 17]

[0284] Molecular profiles in colon and / or ileal tissue were investigated in a subset of Crohn's disease patients who had received either 200 mg of antibody A (n=26), 600 mg of antibody A (n=27), or placebo (n=26) anti-TNF agents. Six to nine biopsy samples from each patient were obtained from inflammatory lesions in the colon or ileum at baseline and 12 weeks after treatment. Ileal and colon biopsy samples were analyzed separately by whole-transcriptome RNA sequencing profiling. Univariate associations were assessed using linear regression. Effective size, p-value, and FDR were calculated for significant genes. CDEIS response (decrease of more than 50% from baseline) and CDEIS remission (≤4; ≤2 in patients with isolated ileitis) were assessed at 12 weeks by independent, blinded re-evaluators.

[0285] Treatment with antibody A significantly reduced the expression of 1146 genes in the colon tissue of Crohn's disease patients from baseline to week 12 compared to placebo (p<0.05). In particular, significant decreases in the expression of genes associated with the IL-23 pathway (IL-23A, IL-26, IL-21R, IL-17A, STAT3), innate immunity (IL6, IL7, IL7R, IL8, ICAM1, IL1, IL11, IL13RA2, IL15RA, IL18R1, TNF), tissue turnover (S-100A8, A9, A12, MMP1, MMP3, MMP9, MMP12, ADAM8, ADAM12, ADAM33), and solute transporter families (SLC11A1, SLC1A3, SLC2A3, SLC2A6, SLC6A14, SLC7A11, SLC7A5) were observed using antibody A treatment. The overall changes in the expression of these genes in the antibody A-treated population reflected the molecular changes observed in patients who achieved CDEIS response and remission at week 12. A comparison of significantly antibody A-regulated gene expression changes in the colon at week 12 with anti-TNF agent treatment at week 14 in the published patient population highlighted a greater reduction in the suppression of pathways related to epithelial biological function (intercellular adhesion, morphogenesis, intracellular signaling, and second messenger signaling) after antibody A treatment. In contrast, no significant changes were observed in the molecular profile of the ileum in patients treated with antibody A compared to placebo from baseline to week 12.

[0286] Pharmacokinetic / pharmacodynamic analysis The relationship between antibody A concentration at week 12 and CDAI or CDEI category response shows that the median CDAI and CDEI response rates (95% confidence interval) increase from 36% (23%, 51%) to 47% (33%, 62%) and from 33% (21%, 49%) to 36% (23%, 53%), respectively, relative to the median concentration of 200 mg to 600 mg at week 12 (Table 10A).

[0287] Plasma concentrations of antibody A were sampled before administration and at weeks 2, 4, 8, 12, 23, and 26, then every 8 weeks until week 50, and again at weeks 52 and 65 (last visit). Concentrations were determined by a validated enzyme-linked immunosolvent assay. Pharmacokinetics were assessed using a nonlinear mixed-effects population approach with NONMEM version 7.3. Logistic regression analysis was performed using R software (package glm) for statistical calculations to examine the relationship between CDEIS and CDEI responses as dependent categorical variables and antibody A concentration at week 12 as an independent variable.

[0288] [Table 18]

[0289] [Table 19] TIFF2026108768000023.tif110165

[0290] Clinical response is defined as either CDAI < 150 or a decrease of 100 or more from baseline CDAI at week 12. Clinical remission is defined as CDAI < 150 at week 12. Endoscopic response is defined as a decrease of more than 50% from baseline CDEIS. Endoscopic remission is defined as CDEIS ≤ 4 at week 12 (≤ 2 in patients with early isolated ileitis). The concentration quantiles correspond to the ranges of minimum ~25% (Q1), 25~50% (Q2), 50~75% (Q3), and 75%~maximum (Q4).

[0291] [Table 20]

[0292] Assessment using the Inflammatory Bowel Disease Questionnaire (IBDQ) at week 12. Assessment using the IBDQ demonstrated a reduction in HRQoL at baseline in the randomized trial population. Treatment with the study drug resulted in dose-dependent increases of 7.3, 21.7, and 34.7 points from baseline to week 12 in the placebo, 200 mg, and 600 mg dose groups, respectively.

[0293] [Table 21]

[0294] Re-guidance At week 12, patients entered period 2; at this point, patients in complete remission received drug discontinuation, while all other patients received open-label intravenous reinduction therapy (600 mg of antibody A at weeks 14, 18, and 22).

[0295] result: Baseline demographics and disease characteristics were similar across the study groups. The mean age was 38.1 years, and the median CDAI and CDEIS scores were 298 and 12, respectively; 94% of patients had previously received one or more TNF antagonists. At week 12, clinical remission was achieved in 24.4% and 36.6% of patients with 200 and 600 mg of antibody A, compared to 15.4% with placebo (p=0.31 and p=0.025), and complete remission was achieved in 2.4% and 12.2% of patients with 200 and 600 mg of antibody A, compared to 0% with placebo (p=0.31 and p=0.016). In patients who entered period 2 without clinical remission, open-label re-induction in placebo patients induced clinical remission rates similar to those in the 600 mg group during blinded period 1, dose escalation from 200 to 600 mg induced higher clinical remission rates, and re-induction in the 600 mg group further increased the clinical remission rate in this group at week 26 (Table 13). None of the patients with complete remission relapsed during the antibody A discontinuation period by week 26. Adverse events were similar between antibody A and placebo, and no dose-related increase in adverse events was observed in period 1. Antibody A showed good tolerability in period 2.

[0296] Conclusion: Re-induction therapy with 600 mg of antibody A was effective in achieving a higher clinical remission rate at week 26. Overall, antibody A was well-tolerated.

[0297] [Table 22]

[0298] Example 2: Pharmaceutical composition Examples of formulations suitable for the antibody of the present invention are shown below. The antibodies used in the following formulations are, for example, antibody A, antibody B, antibody C, or antibody D.

[0299] [Table 23]

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

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

[0302] The osmotic pressure of the formulation was determined to be 300 ± 30 mOsmol / kg using Osmomat 030 (Gonotec GmbH, Berlin, Germany). The density of the formulation at 20°C was determined to be approximately 1.0089 g / cm³ using a DMA 4500 (Anton Paar GmbH, Ostfildaan-Scharnhausen, Germany) measuring device. 3 That is the case.

[0303] [Table 24]

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

[0305] Molecular weight of the excipient used (molecular weight in g / mol): Molecular weight: succinic acid (C4H6O4) = 118.09 g / mol Molecular weight: Disodium succinate hexahydrate (C4O4Na2H4×6H2O) = 270.14 g / mol Molecular weight: Sorbitol = 182.17 g / mol Molecular weight: Polysorbate 20 = 1227.72 g / mol.

[0306] The osmotic pressure of the formulation was determined to be 300 ± 30 mOsmol / kg using Osmomat 030 (Gonotec GmbH, Berlin, Germany). The density of the formulation at 20°C was determined to be approximately 1.040 g / cm³ using a DMA 4500 (Anton Paar GmbH, Ostfildaan-Scharnhausen, Germany) measuring device. 3 That is the case.

[0307] [Table 25]

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

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

[0310] The osmotic pressure of the formulation was determined to be 300 ± 30 mOsmol / kg using Osmomat 030 (Gonotec GmbH, Berlin, Germany).

Claims

1. A method for inducing remission of Crohn's disease, comprising the step of administering an anti-IL-23A antibody to a patient, wherein the method is a) The step of administering at least one induction dose of the anti-IL-23A antibody to the patient (the induction dose includes 200 to 1,200 mg of the anti-IL-23A antibody). Methods that include...

2. The method according to claim 1, wherein the induction amount comprises 450 to 1,200 mg of the anti-IL-23A antibody.

3. The method according to claim 1, wherein the induction amount comprises 200 mg, 450 mg, 600 mg, 900 mg, or 1,200 mg of the anti-IL-23A antibody.

4. The method according to any one of claims 1 to 3, wherein one, two, or three induction doses are administered to the patient.

5. The method according to any one of claims 1 to 4, wherein two or three induction doses are administered at four-week intervals.

6. The method according to any one of claims 1 to 5, wherein the induction amount is administered by intravenous infusion.

7. The method according to any one of claims 1 to 6, wherein the CDAI score of the patient before administration of step a) is 220 to 450.

8. The method according to any one of claims 1 to 7, wherein the patient achieves a CDAI score of less than 150.

9. The method according to any one of claims 1 to 8, wherein the patient achieves a PRO-2 score of 75 or less.

10. A method further comprising a step of maintaining remission of Crohn's disease, the method further b) The step of administering the initial maintenance dose of the anti-IL-23A antibody to the patient after the final induction dose has been administered; and c) The process of administering at least one additional maintenance dose to the patient 4 to 12 weeks after the initial maintenance dose has been administered. A method according to any one of claims 1 to 9, including the method described in any one of claims 1 to 9.

11. The method according to any one of claims 10, wherein the initial maintenance dose is administered 2 to 8 weeks after the last induction dose was administered, for example 4 to 6 weeks, for example 2 weeks, 4 weeks, 6 weeks, or 8 weeks later.

12. The method according to any one of claims 10 or 11, wherein the at least one additional maintenance dose is administered to the patient 4, 8, or 12 weeks after the initial maintenance dose has been administered.

13. The method according to any one of claims 10 to 12, wherein the initial maintenance dose comprises 150 to 300 mg of the anti-IL-23A antibody.

14. The method according to any one of claims 10 to 13, wherein the initial maintenance dose comprises 150 mg, 225 mg, or 300 mg of the anti-IL-23A antibody.

15. The method according to any one of claims 10 to 14, wherein the initial maintenance dose comprises 180 mg or 270 mg of the anti-IL-23A antibody.

16. The method according to any one of claims 10 to 15, wherein the at least one additional maintenance dose comprises 150 to 300 mg of the anti-IL-23A antibody.

17. The method according to any one of claims 10 to 16, wherein the at least one additional maintenance dose comprises 150 mg, 225 mg, or 300 mg of the anti-IL-23A antibody.

18. The method according to any one of claims 10 to 17, wherein the at least one additional maintenance dose comprises 180 mg or 270 mg of the anti-IL-23A antibody.

19. The method according to any one of claims 10 to 18, wherein the initial maintenance dose and the at least one additional maintenance dose comprise 150 to 300 mg of the anti-IL-23A antibody.

20. The method according to any one of claims 10 to 19, wherein the initial maintenance dose and the at least one additional maintenance dose comprise 150 mg, 225 mg, or 300 mg of the anti-IL-23A antibody.

21. The method according to any one of claims 10 to 20, wherein the initial maintenance dose and the at least one additional maintenance dose comprise 180 mg or 270 mg of the anti-IL-23A antibody.

22. The method according to any one of claims 10 to 21, wherein the maintenance dose is administered by subcutaneous injection.

23. The method according to any one of claims 10 to 22, wherein the patient maintains a CDAI score of less than 150.

24. The method according to any one of claims 10 to 23, wherein the patient maintains a PRO-2 score of 75 or less.

25. A method for treating Crohn's disease, comprising the step of administering 150 to 1,200 mg of anti-IL-23A antibody to a patient.

26. The method according to claim 25, wherein the method comprises the step of administering 200 to 1,200 mg of anti-IL-23A antibody to a patient.

27. The method according to claim 25, wherein the method comprises the step of administering 450 to 1,200 mg of anti-IL-23A antibody to a patient.

28. The method according to claim 25, wherein the method comprises the step of administering 200 mg, 450 mg, 600 mg, 900 mg, or 1,200 mg of anti-IL-23A antibody to a patient.

29. The method according to claim 25, wherein the method comprises the step of administering 150 to 300 mg of anti-IL-23A antibody to a patient.

30. The method according to claim 25, wherein the method comprises the step of administering 150 mg, 225 mg, or 300 mg of an anti-IL-23A antibody to a patient.

31. The method according to claim 25, wherein the method comprises the step of administering 180 mg or 270 mg of anti-IL-23A antibody to a patient.

32. A method for treating Crohn's disease, comprising the step of administering an anti-IL-23A antibody to a patient, wherein the method is a) The step of administering at least one induction dose of the anti-IL-23A antibody to the patient (the induction dose includes 200 to 1,200 mg of the anti-IL-23A antibody). Methods that include...

33. moreover b) The step of administering the initial maintenance dose of the anti-IL-23A antibody to the patient after the final induction dose has been administered; and c) The process of administering at least one additional maintenance dose to the patient 4 to 12 weeks after the initial maintenance dose has been administered. The method according to claim 32, including the method described in claim 32.

34. The method according to claim 33, wherein the initial maintenance dose comprises 150 to 300 mg of the anti-IL-23A antibody.

35. The method according to claim 33 or 34, wherein the at least one additional maintenance dose comprises 150 to 300 mg of the anti-IL-23A antibody.

36. The method according to any one of claims 1 to 35, wherein the anti-IL-23A antibody is antibody A, antibody B, antibody C, or antibody D.

37. The method according to any one of claims 1 to 36, wherein the method is for the treatment of moderate to severe active Crohn's disease.

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