Safe and effective method of treating ulcerative colitis with Anti-il12 / il23 antibody

Abstract

To provide methods and compositions for clinically proven safe and effective treatment of ulcerative colitis, particularly moderately to severely active ulcerative colitis in patients who have had an inadequate response to or are intolerant of a conventional or existing therapy by intravenous and / or subcutaneous administration of an anti-IL-12 / IL-23p40 antibody.SOLUTION: The present invention provides a method for treating ulcerative colitis (UC) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a clinically proven safe and clinically proven effective amount of an anti-IL-12 / IL-23p40 antibody, wherein the antibody comprises a heavy chain variable region and a light chain variable region.SELECTED DRAWING: None

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application is an ASCII - formatted sequence listing named "JBI6010WOPCT1Seq uence Listing.txt" created on September 23, 2019, and was submitted electronically via EFS - Web and includes a sequence listing having a size of 14,801 bytes. The sequence listing submitted via EFS - Web is part of this specification and is hereby incorporated by reference in its entirety into this specification.

[0002] (Field of the Invention) The present invention relates to a method for providing a clinically proven safe and clinically proven effective treatment for ulcerative colitis, particularly in patients with moderate - to - severe active ulcerative colitis who show an inadequate response or poor tolerance to conventional or existing therapies by intravenous and / or subcutaneous administration of an anti - IL - 12 / IL - 23p40 antibody.

[0003] (Background of the Invention) Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC), are chronic relapsing diseases characterized by destructive inflammation of the gastrointestinal (GI) tract and epithelial injury (Baumgart and Sandborn, J Clin Invest. 98:1010 - 1020 (199 6), Danese and Fiocchi, N Engl J Med. 365:1 715 - 1725 (2011)). The incidence of UC in the United States is estimated to be 205 - 240 cases per 100,000 population and 9 - 12 cases per 100,000 population (Tally et al., Am J Gastroenterol. 106 Sup (Tally et al., Am J Gastroenterol. 106 Suppl 1:S3 - 4 (2011)). ​​​​​pl 1: S2 - S25(2011)). The estimated number of patients with UC in Europe is approximately 1,0 00,000 people (Loftus, Gastroenterology. 126(6 ): 1504 - 1517(2004), Loftus, Gastoenterol Cl in N Am. 31: 1 - 20(2002)). The etiology of UC is unknown. However, an abnormal immune response to intestinal contents, including gut bacteria, is thought to cause the disease in genetically susceptible individuals (Geremia et al., Auto immun Rev. 13: 3 - 10(2014)). Dysregulated innate and adaptive immune pathways contribute to abnormal intestinal inflammation in IBD, and cytokines including interleukin (IL)-12, inter feron γ (IFNγ), and IL-23 are involved in the etiology of UC (Geremia et al., Autoimmune Rev. 2014; 1 3: 3 - 10; Neurath, Nat Rev Immunol. 14(5): 329 - 42(2014)).

[0004] The involvement of the IL-12 / 23 pathway in the etiology of IBD is well established, and the important role of the IL-12 / IL-23 pathway in intestinal inflammation has been elucidated in colitis (Ah ern et al., Immunity. 33(2): 279 - 288(2010); Investigator’s Brochure: STELARA®(us tekinumab), edition 18. Janssen Research & Development, LLC(2017), Uhlig et al., Immu nity. 25: 309 318(2006), Yen et al., J Clin ​Invest. 116(5): 1310 - 1316(2006)). Initial studies have shown that treatment with anti - IFNγ (Berg et al., J Clin Invest. 98: 10 10 - 1020(1996), Davidson et al., J Immunol. 161: 3143 - 3149(1998)) or anti - IL - 12p40 monoclonal antibody (mAb) prevents disease in experimental models of colitis and suggests an important role for type 1 helper T (Th - 1) cells that promote intestinal inflammation (Neurath et al., J Exp Med. 182(5): 1281 - 12 90(1995)). Genome - wide association studies have implicated several loci in the IL - 12 / 23 pathway that are associated with increased susceptibility to UC, including IL - 23R and IL - 12B (Anderson et al., Nat Genet. 43(3): 246 - 252(2011), Brant et al., Clin Ga stroenterol Hepatol. 11(1): 22 - 26(2013)). Subjects with active UC have significantly more IL - 23, IL - 22, IL - 22R1, and p - STAT3 - positive cells than subjects with inactive UC and normal controls (Yu et al., World J Gastroenterol. 19( 17): 2638 - 2649(2013)).

[0005] The currently approved biological therapies for UC are either tumor necrosis factor (TNF) or integrin inhibitors (Colombel et al., Gastroenterology. 132: 52 - 65(2007), Hanauer et al., L erology. 132: 52 - 65(2007), Hanauer et al., L Lancet. 359:1541 - 1549(2002), Sandborn et al . N Engl J Med. 369:711 - 721(2013), Sandbor n et al., Gastroenterology. 142:257 - 265(2 012)). However, among all currently approved therapies, only one therapy, vedolizumab , has shown efficacy in subjects who show an inadequate response to anti - TNF (i.e., primary non - responsiveness or secondary non - responsiveness) or intolerance to anti - TNF (Feagan et al., N Engl J Med. 369:699 710(2013)). Anti - TNF has safety risks associated with immunosuppression, and not all subjects respond appropriately to such treatment. Furthermore, as observed with anti - TNF, inadequate responses and intolerance have been identified in subjects receiving vedolizumab for the treatment of their UC. Therefore, there remains an unmet need for novel therapies with alternative mechanisms of action. Looking into it, the currently approved biological therapies for the treatment of UC also show efficacy in Crohn's disease (Sandborn et al., Gastroenterology. 135(4):1130 - 1141(2008)). A number of

[0006] lines of evidence suggest that inflammatory bowel diseases (UC and Crohn's disease) are mediated by Th1 or Th17 cells that have a strong contribution from inflammatory cytokines, IL - 12, and IL - 23. Ustekinumab (STELARA®) is a fully human anti - IL - 12 / 23p40 monoclonal antibody. monoclonal antibody. A fully human immunoglobulin G1 mAb that inhibits the bioactivity of IL-12 and IL-23. by preventing them from interacting with the cell surface IL-12Rβ1 receptor protein. Preventing by Harming (Investigator's Brochure:STEL ARA® (ustekinumab), edition 18. Jansse n Research & Development, LLC (2017)). This effect By mechanism, ustekinumab inhibits IL-12 (Th1)- and IL-23 (Th17)- Ustekinumab effectively neutralizes the cellular response of HIV-1 mediated clonal antibodies. Treatment of adults with Crohn's disease (the first approval for Crohn's disease was received on November 11, 2016); Adult subjects with moderate to severe plaque psoriasis or active psoriatic arthritis For the treatment of elephants and children (ages 12-17) with moderate to severe plaque psoriasis It has marketing approvals worldwide, including in North America, Europe, South America, and countries in the Asia-Pacific region. is receiving.

[0007] Efficacy and safety of intravenous (IV) ustekinumab as induction therapy in Crohn's disease The efficacy and safety of serotonin-dependent agonists has been evaluated in clinical trials CRD3001 and CRD3002. 3001 is intended to treat patients who have previously failed or shown poor tolerance to one or more TNF antagonists. CRD3002 was evaluated in patients with inadequate response to corticosteroids or immunomodulatory agents. or have a history of poor tolerance, but have had an inadequate response or poor tolerance to TNF antagonists Subjects without a history were evaluated. Two IV doses were evaluated in these studies: 130 mg A fixed IV dose of 10 mg / kg (approximately 2 mg / kg) was selected for the low dose group, while a fixed IV dose of 10 mg / kg (approximately 2 mg / kg) was selected for the low dose group. Dose based on range: approximately 6 mg / kg IV (body weight ≤ 55 kg: ustekinumab 260 mg, body weight > 55 and ≤ 85 kg: ustekinumab 390 mg, body weight > 85 kg: ustekinuma b: 520 mg) was selected as the high-dose group. In both trials, ustekinumab showed clinically significant efficacy compared to placebo and was well tolerated with a favorable safety profile.

[0008] Prior to the present invention, no studies using ustekinumab for UC had been conducted, and there was a need in the art for an improved method of treating UC in subjects in whom either biological therapies or both other conventional therapies had previously been unsuccessful or poorly tolerated, or who had shown corticosteroid dependence, particularly for moderate to severe active UC.

[0009] (Summary of the Invention) This application relates to a clinically proven safe and clinically proven effective method and composition for the treatment of moderate to severe active ulcerative colitis (UC) by administration of an anti-IL-12 / IL-23p40 antibody to a subject, particularly in a subject who has shown an inadequate response or poor tolerance to conventional or existing

[0010] In one general aspect, this application relates to a clinically proven safe and clinically proven effective method of treating moderate to severe active ulcerative colitis (UC) in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising a - 23p40 antibody, the antibody comprising a heavy - chain variable region and a light - chain variable region, the heavy - chain variable region comprising the complementarity - determining region heavy - chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, and the light - chain variable region comprising the complementarity - determining region light - chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6. In certain embodiments, the anti - IL - 12 and / or anti - IL - 23 antibody is administered intravenously to the subject, preferably at week 0, at a dose of about 6.0 mg per 1 kg of the subject's body weight or 130 mg per administration. In certain embodiments, the anti - IL - 12 and / or anti - IL - 23 antibody is administered intravenously or subcutaneously to the subject, preferably at week 8, at a dose of about 6.0 mg per 1 kg of the subject's body weight or 90 mg per administration, respectively. Preferably, a subject treated by the method according to the embodiments of the present application has had an insufficient response to conventional or existing therapies or has been intolerant to them. In some embodiments, the subject has previously been unsuccessful or intolerant to biological therapies such as anti - TNF and / or vedolizumab. In some embodiments, the subject has previously been unsuccessful or intolerant to non - biological therapies such as treatment with corticosteroids, azathioprine (AZA), and / or 6 - mercaptopurine (6MP). In some embodiments, the subject has shown corticosteroid dependence.

[0011]

[0012]

[0013] ​​​​​​​​​​​​​​​

[0014] In another general aspect, the present application relates to the treatment of moderately to severely active ulcerative colitis (UC) in a subject in need thereof, by a clinically proven safe and clinically proven effective method, the method comprising: administering to the subject a pharmaceutical composition comprising an anti-IL-12 / IL-23p40 antibody at a dose of about 6.0 mg / kg of the subject's body weight or 130 mg of the antibody per administration, by intravenous administration at week 0 of treatment and administering to the subject a pharmaceutical composition comprising an anti-IL-12 / IL-23p40 antibody at a dose of 90 mg of the antibody per administration, by subcutaneous administration at week 8 of treatment, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the amino acid sequence of complementarity determining region heavy chain 1 (CDRH1) of SEQ ID NO: 1, the amino acid sequence of CDRH2 of SEQ ID NO: 2, and the amino acid sequence of CDRH3 of SEQ ID NO: 3, and the light chain variable region comprising the amino acid sequence of complementarity determining region light chain 1 (CDRL1) of SEQ ID NO: 4, the amino acid sequence of CDRL2 of SEQ ID NO: 5, and the amino acid sequence of CDRL3 of SEQ ID NO: 6, wherein the subject has previously failed or is intolerant to at least one therapy selected from the group consisting of anti-TNF, vedolizumab, corticosteroids, azathioprine (AZA), and 6-mercaptopurine (6MP), or the subject has shown corticosteroid dependence.

[0015] In certain embodiments, the method of the present application comprises administering to the subject a pharmaceutical composition comprising an anti-IL-12 and / or an anti-IL-23 antibody or antigen-binding fragment comprising the amino acid sequence of the heavy chain variable region of SEQ ID NO: 7 and (ii) the amino acid sequence of the light chain variable region of SEQ ID NO: 8, by intravenous administration. Comprises intravenous (IV) and / or subcutaneous (SC) administration.

[0016] In certain embodiments, the method of the present application comprises an anti-IL-12 / 23p40 antibody comprising (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and , (ii) the light chain amino acid sequence of SEQ ID NO: 11, and administering a pharmaceutical composition comprising ustekinumab to a subject by intravenous (IV) and / or subcutaneous (SC) administration. Comprises.

[0017] In certain embodiments, the IV dose at week 0 is about 6.0 mg / kg. For example, the IV dose is 260 mg for a subject weighing 35 kg or more up to 55 kg or less, 390 mg for a subject weighing more than 55 kg up to 85 kg or less, and 520 mg for a subject weighing more than 85 kg.

[0018] In certain embodiments, the subject is identified as a responder to treatment by the method according to an embodiment of the present application and has at least one of the following: (1) clinical remission based on at least one of the international application and the US application, (2) endoscopic healing, ( 3) clinical response, (4) change from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ) score, (5) mucosal healing, (6) decrease from baseline in the Mayo score, and (7) normalization of one or more biomarkers selected from the group consisting of C-reactive protein, fecal lactoferrin, and fecal calprotectin. Preferably, at least one of (1)-(7) above is identified by week 16 of treatment, more preferably by week 8 or week 4, and most preferably by week 2 of treatment. ​

[0019] In certain embodiments, the present invention provides a clinically proven safe and clinically proven effective method of treating moderately to severely active UC in a subject, wherein the subject is a responder to antibody therapy and has a statistically significant improvement in disease activity as determined by endoscopic healing with a Mayo endoscopic subscore of 0 or 1 by week 8 of antibody therapy. In certain embodiments, the present invention provides a clinically proven safe and clinically proven effective method of treating moderately to severely active UC in a subject, wherein the subject is a responder to antibody therapy and has a statistically significant improvement in disease activity as determined by ulcerative colitis endoscopic index of severity (UCEIS) score ≤ 4 by week 8 of antibody therapy. In certain embodiments, the subject demonstrates a clinical response as determined by a ≥ 30% and ≥ 3 point decrease from baseline in the Mayo score and a ≥ 1 point decrease from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1 by week 8 of antibody therapy. In other embodiments, a maintenance dose of the anti-IL-12 / IL-23p40 antibody is administered every 8 weeks or every 12 weeks after treatment at week 8, and the clinical response is maintained by the subject for at least 44 weeks. In certain embodiments, the present invention provides a clinically proven safe and clinically proven effective method of treating moderately to severely active UC in a subject, wherein the subject is a responder to antibody therapy and has a statistically significant improvement in disease activity as determined by endoscopic healing with a Mayo endoscopic subscore of 0 or 1 by week 8 of antibody therapy.

[0020] In other embodiments, the present invention provides a clinically proven safe and clinically proven effective method of treating moderately to severely active UC in a subject, wherein the subject is a responder to antibody therapy and has a statistically significant improvement in disease activity as determined by ulcerative colitis endoscopic index of severity (UCEIS) score ≤ 4 by week 8 of antibody therapy. In other embodiments, a maintenance dose of the anti-IL-12 / IL-23p40 antibody is administered every 8 weeks or every 12 weeks after treatment at week 8, and the clinical response is maintained by the subject for at least 44 weeks. In certain embodiments, the subject demonstrates a clinical response as determined by a ≥ 30% and ≥ 3 point decrease from baseline in the Mayo score and a ≥ 1 point decrease from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1 by week 8 of antibody therapy. In other embodiments, a maintenance dose of the anti-IL-12 / IL-23p40 antibody is administered every 8 weeks or every 12 weeks after treatment at week 8, and the clinical response is maintained by the subject for at least 44 weeks. In certain embodiments, the present invention provides a clinically proven safe and clinically proven effective method of treating moderately to severely active UC in a subject, wherein the subject is a responder to antibody therapy and has a statistically significant improvement in disease activity as determined by endoscopic healing with a Mayo endoscopic subscore of 0 or 1 by week 8 of antibody therapy. In other embodiments, a maintenance dose of the anti-IL-12 / IL-23p40 antibody is administered every 8 weeks or every 12 weeks after treatment at week 8, and the clinical response is maintained by the subject for at least 44 weeks.

[0021] In certain embodiments, the subject demonstrates a clinical response as determined by a ≥ 30% and ≥ 3 point decrease from baseline in the Mayo score and a ≥ 1 point decrease from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1 by week 8 of antibody therapy. In other embodiments, a maintenance dose of the anti-IL-12 / IL-23p40 antibody is administered every 8 weeks or every 12 weeks after treatment at week 8, and the clinical response is maintained by the subject for at least 44 weeks. In certain embodiments, the subject demonstrates a clinical response as determined by a ≥ 30% and ≥ 3 point decrease from baseline in the Mayo score and a ≥ 1 point decrease from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1 by week 8 of antibody therapy. In other embodiments, a maintenance dose of the anti-IL-12 / IL-23p40 antibody is administered every 8 weeks or every 12 weeks after treatment at week 8, and the clinical response is maintained by the subject for at least 44 weeks.

[0022] In other embodiments, a maintenance dose of the anti-IL-12 / IL-23p40 antibody is administered every 8 weeks or every 12 weeks after treatment at week 8, and the clinical response is maintained by the subject for at least 44 weeks. In other embodiments, a maintenance dose of the anti-IL-12 / IL-23p40 antibody is administered every 8 weeks or every 12 weeks after treatment at week 8, and the clinical response is maintained by the subject for at least 44 weeks. In other embodiments, a maintenance dose of the anti-IL-12 / IL-23p40 antibody is administered every 8 weeks or every 12 weeks after treatment at week 8, and the clinical response is maintained by the subject for at least 44 weeks.

[0023] In certain embodiments, the present invention provides a clinically proven safe and clinically proven effective method of treating moderately to severely active UC in a subject, and subjects identified as non-responders to initial treatment are preferably treated with a second treatment via a different route of administration than the initial treatment. For example, a subject identified as a non-responder to initial treatment by IV administration of an antibody or antibody-binding fragment can be treated with subsequent subcutaneous administration of an antibody or antibody-binding fragment according to embodiments of the present invention.

[0024] In certain embodiments, the present application provides a method of treating moderately to severely active UC in a subject, and the anti-IL-12 and / or anti-IL-23 antibodies for use in IV administration are in a pharmaceutical composition comprising a solution containing 10 mM L-histidine, 8.5% (w / v) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL disodium EDTA dihydrate at pH 6.0.

[0025] In certain embodiments, the present application provides a clinically proven safe and clinically proven effective method of treating moderately to severely active UC in a subject, and the anti-IL-12 and / or anti-IL-23 antibodies for use in subcutaneous administration are in a pharmaceutical composition comprising a solution containing 6.7 mM L-histidine, 7.6% (w / v) sucrose, 0.004% (w / v) polysorbate 80 at pH 6.0.

[0026] In certain embodiments, the present application provides one or more additional ​​​​​​​​​​​​Provided is a method further comprising administering to a subject a drug. In a preferred embodiment, the additional drug is selected from the group consisting of an oral 5-aminosalicylate (5-ASA) compound, an oral corticosteroid, an immunomodulatory agent, 6-mercaptopurine (6-MP), azathioprine (AZA), or methotrexate (MTX).

[0027] Another aspect of the present application is for use in a clinically proven safe and clinically proven effective method of treating moderately to severely active UC in a subject, an anti-IL-12 and / or anti-IL-23 antibody-containing pharmaceutical composition, as well as a method for preparing the composition and a kit containing the pharmaceutical composition.

[0028] In certain embodiments, a kit useful in the methods of the invention comprises at least one of the intravenous pharmaceutical composition of the invention and the subcutaneous pharmaceutical composition of the invention. In other embodiments, the kit comprises both the intravenous pharmaceutical composition and the subcutaneous pharmaceutical composition of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The above "Means for Solving the Problems" and the following "Modes for Carrying Out the Invention" will be better understood when read in conjunction with the accompanying drawings. It should be understood that the present invention is not limited to the embodiments shown in the drawings themselves.

Figure 1

[0030] (DETAILED DESCRIPTION OF THE INVENTION) In the background art, various publications, papers and patents are also cited or ​​​​​​​will be described. Each of these references is hereby incorporated by reference in its entirety into this specification. The discussions of documents, operations, materials, devices, articles, etc. contained in this specification are for the purpose of providing context for the present invention. Such discussions are not to be construed as admitting that any or all of these things constitute part of the prior art with respect to any invention disclosed or claimed herein.

[0031] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If not, the specific terms used in this specification have the meanings as set forth herein. All patents, published patent applications, and publications cited in this specification are incorporated by reference as if fully set forth herein.

[0032] It should be noted that the singular forms "a", "an", and "the" as used in this specification and the appended claims include plural referents unless the context clearly dictates otherwise. Unless otherwise stated, the term "at least" preceding a series of elements is to be understood as referring to all of the elements in the series. One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimental procedures, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

[0033] Throughout this specification and the following claims, unless the context requires otherwise, the term "comprising" the variations such as "comprise", "comprises", and "comprising" mean that it includes a specified integer or step or group of integers or steps, but does not exclude any other integer or step or group of integers or steps. As used herein, the term "comprising" can be replaced with the term "containing" or "including", or, when used herein at times, it can also be replaced with the term "having".

[0034] As used herein, "consisting of" excludes any element, step, or component not specified in the claim elements. As used herein, "consisting essentially of" does not exclude materials or steps that do not substantially affect the basic and novel features of the claim. When used herein in connection with an aspect or embodiment of the present invention, any of the above terms "comprising", "containing", "including", and "having" can be replaced with the term "consisting of" or "consisting essentially of" to vary the scope

[0035] As used herein, the conjunctive term "and / or" between a plurality of enumerated elements is understood to encompass both the individual and combined options. For example, if two elements are connected by "and / or", the first option refers to the applicability of the first element without the second element. The second option refers to the applicability of the second Any one of these alternatives is within the meaning and therefore is used herein. It is understood that the use of the term "and / or" as used herein satisfies the requirement of the term "and / or" when referring to two or more of the alternatives. It is understood that co-applicability is also included within the meaning, and thus the term "and / or" Meet the requirements.

[0036] As used herein, a "subject" refers to a subject to be treated by a method according to an embodiment of the present invention. The term "animal" refers to any animal, preferably a mammal, most preferably a human, that is administered or treated in a mammalian animal. As used herein, the term "mammal" includes any mammal. Examples of animals include, but are not limited to, cows, horses, sheep, pigs, rats, etc. Non-human primates such as dogs, mice, rats, rabbits, guinea pigs, monkeys, or apes ( NHP), humans, etc., more preferably humans.

[0037] As used herein, the term "combined" refers to the administration of two or more therapeutic agents to a subject. In the context of the present invention, the term "combined" refers to the use of more than one therapeutic agent. There is no limitation on the order in which the first therapeutic agent (e.g., a therapeutic agent described herein) is administered to the elephant. The composition to be administered may be administered at least 5 minutes, 15 minutes, 30 minutes, or 60 minutes prior to administration of the second therapeutic agent to the subject. 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 16 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior), at the same time, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 Hours, 4 hours, 6 hours, 12 hours, 16 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours , 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks later) can be performed.

[0038] As used herein, "anti-IL-12 antibody", "anti-IL-23 antibody", "anti-IL- 12 / 23p40 antibody", or "IL-12 / 23p40 antibody" refers to a monoclonal antibody (mAb) that binds to the 40 kDa (p40) subunit shared by cytokines interleukin-12 and interleukin-23 (IL-12 / 23p40), or its antigen-binding fragment. This antibody can affect at least one of IL-12 / 23 activities or functions, such as RNA, DNA, or protein synthesis, IL-12 / 23 release, IL-12 / 23 receptor signaling, membrane IL-12 / 2 3 cleavage, IL-12 / 23 activity, IL-12 / 23 production, and / or synthesis, but is not limited thereto. The term "antibody" is further intended to include antibody mimetics, or portions of antibodies that mimic the structure and / or function of antibodies, such as single-chain antibodies and their fragments, or specific fragments or portions thereof, including antibody digestion fragments, specific portions, and variants. Functional fragments include antigen-binding fragments that bind to mammalian IL-12 / 23. For example, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab') (e.g., by pepsin digestion), facb (e.g., by plasmin digestion), pFc'( e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction ).

[0039] The term "antibody" further includes antibody mimetics, or portions of antibodies that mimic the structure and / or function of antibodies, such as single-chain antibodies and their fragments, or specific fragments or portions thereof, including antibody digestion fragments, specific portions, and variants. Functional fragments include antigen-binding fragments that bind to mammalian IL-12 / 23. For example, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab') (e.g., by pepsin digestion), facb (e.g., by plasmin digestion), pFc'( e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction ). 2 For example, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab') (e.g., by pepsin digestion), facb (e.g., by plasmin digestion), pFc'( Fv or scFv (e.g., by molecular biological techniques), fragments of which are included in the present invention and which can bind to IL-12 / 23 or a portion thereof, include, but are not limited to, those obtainable by cleavage, synthesis, or recombinant techniques as known in the art and / or as described herein (see, e.g., Colligan, Immunology). Such fragments can be generated by enzymatic cleavage, synthesis, or recombinant techniques as known in the art and / or as described herein. Antibodies can also be generated in various truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, combinations of genes encoding the F(ab’) heavy chain portion can be designed to include DNA sequences encoding the C1 domain and / or hinge region of the heavy chain. Various portions of the antibody can be chemically linked by conventional techniques or prepared as contiguous proteins using genetic engineering techniques. As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type , Immunology for reference).

[0040] Such fragments can be generated by enzymatic cleavage, synthesis, or recombinant techniques as known in the art and / or as described herein. Antibodies can also be generated in various truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, combinations of genes encoding the F(ab’) heavy chain portion can be designed to include DNA sequences encoding the C1 domain and / or hinge region of the heavy chain. Various portions of the antibody can be chemically linked by conventional techniques or prepared as contiguous proteins using genetic engineering techniques. As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type 2 As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type H As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type

[0041] As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type L As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type H As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type H As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type H As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type H As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type L As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type H As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type As used herein, the term “human antibody” refers to an antibody in which substantially all portions of the protein (e.g., CDRs, frameworks, C, C domains (e.g., C1, C2, C3), hinge (V, V)) have minor sequence variations or mutations and are substantially non-immunogenic in humans. “Human antibody” also refers to immunoglobulin of human germline type It can be an antibody derived from an array or an exactly matching antibody. A human antibody is a germ cell Amino acid residues not encoded by the germline immunoglobulin sequence (e.g., introduced by random or site-specific mutagenesis in vitro, or by somatic mutations in vivo Mutations introduced by mutations). In many cases, this means that human antibodies are substantially non-immunogenic in humans Human antibodies are classified into groups based on the similarity of their amino acid sequences. Therefore, sequence similarity searches can be used to select antibodies with similar Linear sequences as templates for generating human antibodies Similarly, antibodies including primates (such as monkeys, baboons, chimpanzees, etc.), rodents (such as mice, Rats, rabbits, guinea pigs, hamsters, etc.) and other mammals in their names indicate that they are specific antibodies of such species, Subgenera, genera, subfamilies, and families. Furthermore, chimeric antibodies can include any of the above Combinations. Such changes or mutations may, and preferably, retain or reduce immunogenicity in humans or other species compared to unmodified antibodies . Therefore, human antibodies are different from chimeric or humanized antibodies. Human antibodies can be produced by non-human animals, or prokaryotic or eukaryotic cells that can express functionally reconstituted human immunoglobulins (e.g., heavy chains and / or light chains ) genes. In addition, when a human antibody is a single-chain antibody, it may contain a linker peptide not found in natural human antibodies . For example, Fv is a linker peptide such as 2 to about 8 glycine or other amino acid residues that connect the variable region of the heavy chain and the variable region of the light chain

[0042] ​​​​​It may include a linker peptide. Such a linker peptide is considered to be of human origin.

[0043] Anti-IL-12 / 23p40 antibodies (also referred to as IL-1 2 / 23p40 antibodies) (or antibodies against IL-23) that are useful in the methods and compositions of the present invention may, if desired, have high affinity binding to IL-12 / 23p40 and optionally and preferably low toxicity. Specifically, individual components such as variable regions, constant regions, and frameworks may individually and / or collectively, optionally and preferably, have low immunogenicity. The antibodies, specifically identified fragments, or variants of the present invention are useful in the present invention. The antibodies that can be used in the present invention may, if desired, be characterized by the ability to measurably alleviate symptoms and have low and / or acceptable toxicity over a long period of time to treat the subject. Low or acceptable immunogenicity, and / or high affinity, and other suitable properties can contribute to the treatment results obtained. "Low immunogenicity" as used herein means that in less than about 75%, or preferably less than about 50%, of the subjects being treated, there is a significant increase in HAHA, HACA, or preferably HAMA responses, and / or a low titer (less than about 300, preferably less than about 100, as measured by a double antigen enzyme immunoassay) increases in the subjects being treated. This is defined as (Elliott et al., Lancet 344:112 5-1127 (1994), which is incorporated herein by reference in its entirety). "Low immunogenicity" means that when it occurs in less than 25%, preferably less than 10%, of the subjects being treated with an anti-IL-12 antibody during the course of the recommended therapy during the treatment period at the recommended dose. When treated with an anti-IL-12 antibody, "low immunogenicity" means that when it occurs in less than 25%, preferably less than 10%, of the subjects being treated with an anti-IL-12 antibody during the course of the recommended therapy during the treatment period at the recommended dose. When treated with an anti-IL-12 antibody, "low immunogenicity" means that when it occurs in less than 25%, preferably less than 10%, of the subjects being treated with an anti-IL-12 antibody during the course of the recommended therapy during the treatment period at the recommended dose. When treated with an anti-IL-12 antibody, "low immunogenicity" means that when it occurs in less than 25%, preferably less than 10%, of the subjects being treated with an anti-IL-12 antibody during the course of the recommended therapy during the treatment period at the recommended dose. When treated with an anti-IL-12 antibody, "low immunogenicity" means that when it occurs in less than 25%, preferably less than 10%, of the subjects being treated with an anti-IL-12 antibody during the course of the recommended therapy during the treatment period at the recommended dose. This is defined as (Elliott et al., Lancet 344:112 5-1127 (1994), which is incorporated herein by reference in its entirety). "Low immunogenicity" means that when it occurs in less than 25%, preferably less than 10%, of the subjects being treated with an anti-IL-12 antibody during the course of the recommended therapy during the treatment period at the recommended dose. "Low immunogenicity" means that when it occurs in less than 25%, preferably less than 10%, of the subjects being treated with an anti-IL-12 antibody during the course of the recommended therapy during the treatment period at the recommended dose. When treated with an anti-IL-12 antibody, "low immunogenicity" means that when it occurs in less than 25%, preferably less than 10%, of the subjects being treated with an anti-IL-12 antibody during the course of the recommended therapy during the treatment period at the recommended dose. It can also be defined as the incidence rate of antibodies at the titration level against the anti-IL-12 antibody in question.

[0044] The terms "clinically proven efficacy" and "clinically proven effective" as used herein in the context of a dose, administration regimen, treatment or method mean the efficacy of a particular dose, administration, treatment regimen. Efficacy can be measured based on changes in the course of a disease in response to the agent of the present invention. For example, the anti-IL12 / 23p40 of the present invention (e.g., ustekinumab) is administered to a subject in an amount and for a time sufficient to cause improvement, preferably sustained improvement, in at least one indicator reflecting the severity of the disorder being treated. To determine whether the amount and time of such treatment are sufficient, various indicators reflecting the degree of the subject's illness, disease or condition can be evaluated. Such indicators include, for example, clinically recognized indicators of disease severity, symptoms, or manifestation of the disorder being targeted. The degree of improvement is generally determined by a physician, who can make this determination based on signs, symptoms, biopsy results, or other test results, and can also employ questionnaires administered to the subject, such as quality of life questionnaires developed for a given disease. For example, the anti-IL12 / 23p40 or anti-IL23 antibody of the present invention can be administered to achieve improvement in the condition of a subject associated with ulcerative colitis. This improvement can be demonstrated by improvement in disease activity indicators, remission of clinical symptoms, or any other measure of disease activity. Such disease indicators include the Mayo score for ulcerative colitis. The Mayo score includes the number of bowel movements, rectal bleeding, endoscopic findings, and the physician's overall assessment (PG For example, the anti-IL12 / 23p40 or anti-IL23 antibody of the present invention can be administered to achieve improvement in the condition of a subject associated with ulcerative colitis. This improvement can be demonstrated by improvement in disease activity indicators, remission of clinical symptoms, or any other measure

[0045] of disease activity. Such disease indicators include the Mayo score for ulcerative colitis. The Mayo score includes the number of bowel movements, rectal bleeding, endoscopic findings, and the physician's overall assessment (PG Mayo score includes the number of bowel movements, rectal bleeding, endoscopic findings, and the physician's overall assessment (PG A calculated as the sum of four subscores, for mild, moderate, and severe ulcerative colitis (UC), is an established and validated disease activity index, ranging from 0 to 12. Scores from 3 to 5 indicate mild active disease, scores from 6 to 10 indicate moderate active disease, and scores from 11 to 12 indicate severe disease. The partial Mayo score, which is the Mayo score without the endoscopic subscore, is calculated as the sum of bowel movement frequency, rectal bleeding, and the physician's overall assessment subscore, and ranges from 0 to 9. The modified Mayo score, which is the Mayo score without the PGA subscore, is calculated as the sum of bowel movement frequency, rectal bleeding, and the endoscopic subscore, and ranges from 0 to 9. Other disease activity indicators for UC include, for example, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score and the Bristol Stool Form Scale (BSFS) score. The UCEIS score provides an overall assessment of the endoscopic severity of UC based on mucosal vascular pattern, bleeding, and ulceration (Travis et al., Gut. 61:535-542 (2012)). The score ranges from 3 to 11, and higher scores indicate more severe disease by endoscopy. The BSFS score is used to classify the consistency of human feces into seven categories (Lewis and Heaton, Scand J Gastroenterol .32(9):920-924(1997)).

[0046] As used herein, the term "clinical response" refers to the response of a subject to When relevant, a decrease from baseline in the rectal bleeding subscore of ≥ 1 or a decrease from the induction period baseline in the Mayo score of ≥ 30% and ≥ 3 points, with any of a rectal bleeding subscore of 0 or 1. is meant.

[0047] The term "clinically demonstrated safety" relates to the dose, administration regimen, treatment or method with the anti-IL-12 / IL-23p4 0 antibody (e.g., ustekinumab) of the present invention, and refers to a favorable risk:benefit ratio with an acceptable frequency and / or acceptable severity of adverse events (referred to as adverse event, AE or treatment-emergent adverse event, TEAE) expressed under treatment, compared to standard treatment or another comparator. As used herein, "adverse event", "adverse event occurring during treatment", and "adverse reaction" mean any harmful, undesirable, unintended or unwanted sign or consequence related to or caused by the administration of a pharmaceutical composition or therapeutic agent. This is an undesirable medical event in a subject administered the pharmaceutical. However, abnormal values or observations are not reported as adverse events unless clinically significant as determined by the treating physician. As used herein, when referring to an adverse event, "clinically apparent" means clinically significant as determined by a physician or treating physician using criteria acceptable to those skilled in the art. When the harmful or unwanted consequences of an adverse event reach such severity, the regulatory authority may consider the pharmaceutical composition or therapeutic agent unacceptable for the proposed use. In particular, with the anti-IL12 / 23p40 or anti-IL23 antibody of the present invention "Safe" as related to dosage, dosing regimen or treatment means that the adverse events are considered possible, likely or very likely to be due to the use of anti-IL12 / 23p4 0 or anti-IL23 antibodies, and refers to the acceptable frequency and / or acceptable severity of adverse events associated with the administration of the antibody when such is the case.

[0048] As used herein, unless otherwise indicated, the term "clinically proven" (used alone or to modify the terms "safety" and / or "effective") means proven by clinical trials that meet the approval criteria of the US Food and Drug Administration, the EMEA, or the corresponding national regulatory agency. For example, the clinical trial may be a randomized double-blind trial of appropriate size used to clinically prove the effect of the drug agent.

[0049] As used herein, the dosage of the anti-IL-12 / IL-23p40 antibody in "mg / kg" units refers to the amount of anti-IL-12 / IL- 23p40 antibody in milligrams per kilogram of body weight of the subject to whom the antibody is administered.

[0050] Antibody-production and preparation of the present invention At least one anti-IL-12 / 23p40 (or anti- IL-23) used in the method of the present invention can optionally be produced by cell lines, mixed cell lines, immortalized cells, or clonal populations of immortalized cells well-known in the art. For example, Aus ubel, et al., ed., Current Protocols in Mol ecular Biology, John Wiley & Sons, Inc., NY , NY (1987 - 2001), Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2nd Edition , Cold Spring Harbor, NY (1989), Harlow and Lane, antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989), Colligan, et al., eds., Current Protocols in Immunology, Joh n Wiley & Sons, Inc., NY (1994 - 2001), Colligan et al., Current Protocols in Protein Sci ence, John Wiley & Sons, NY, NY, (1997 - 2001) are incorporated herein by reference in their entirety, each being incorporated herein by reference in its entirety.

[0051] Human IL - 12 / 23p40 or IL - 23 protein or fragments thereof can be generated against specific immunogenic antigens such as isolated IL - 12 / 23p40 protein, IL - 23 protein, and / or portions thereof (including synthetic molecules such as synthetic peptides). Other specific or general mammalian antibodies can also be generated. The preparation of immunogenic antigens and the production of monoclonal antibodies can be carried out using any suitable techniques in view of the present disclosure. In one approach, suitable immortal cell lines (e.g., but not limited to, Sp2 / 0, S p2 / 0 - AG14, NSO, NS1, NS2, AE - 1, L.5, L243, P3X6 can be used.

[0052] p2 / 0 - AG14, NSO, NS1, NS2, AE - 1, L.5, L243, P3X6 p2 / 0 - AG14, NSO, NS1, NS2, AE - 1, L.5, L243, P3X6 3Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5 , U937, MLA144, ACT IV, MOLT4, DA-1, JURKAT, WE HI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA144, N Myeloma cell lines such as AMALWA, NEURO 2A, or heteromyelomas, their fusions products, or any cells or fused cells derived therefrom, or any other suitable cell lines known in the art (see, for example, www.atcc.org, www.lifet ech.com, etc.) are used, including but not limited to, isolated or cloned antibody-producing cells such as spleen, peripheral blood, lymph, tonsils, or other immune or B cell-containing cells , or as recombinant or endogenous, viral, bacterial, algal, prokaryotic, amphibian, insect, reptilian, fish, mammalian, rodent, horse, sheep, goat, pig, primate, eukaryotic, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single, double or triple-stranded, hybridized, etc., or any combination thereof, as any of the constant or variable, or framework or CDR sequences of the heavy or light chains to produce hybridomas by fusing with any other cells expressing them. For example, see Ausubel and Colligan, Immunology chapter 2 which is hereby incorporated by reference in its entirety. for reference, which is hereby incorporated by reference in its entirety. Antibody-producing cells can also be from the peripheral blood of humans or other suitable animals immunized with the antigen of interest, or

[0053] from the spleen, peripheral blood, lymph, tonsils, or other immune or B cell-containing cells It can preferably be obtained from the spleen or lymph nodes. Any other suitable host cells can be used to express the heterologous nucleic acid or endogenous nucleic acid encoding the antibody, the identified fragment or its variant of the present invention. The fusion cells (hybridomas) or recombinant cells can be isolated using selective culture conditions or other suitable known methods and cloned by limiting dilution or cell sorting or other known methods. Cells producing antibodies having the desired specificity can be selected by suitable assays (e.g., ELISA). It can also be obtained from the spleen or lymph nodes if desired. Any other suitable host cells can be used to express the heterologous nucleic acid or endogenous nucleic acid encoding the antibody, the identified fragment or its variant of the present invention. The fusion cells (hybridomas) or recombinant cells can be isolated using selective culture conditions or other suitable known methods and cloned by limiting dilution or cell sorting or other known methods. Cells producing antibodies having the desired specificity can be selected by suitable assays (e.g., ELISA). Recombinant antibodies can be selected from peptide or protein libraries (e.g., display libraries such as bacteriophage, ribosome, oligonucleotide, RNA, cDNA, etc., but not limited thereto), e.g., Cambridge antibody T Technologies, Cambridge, UK, MorphoSys, Martinsreid / Planegg, DE, Biovation, Aberdeen

[0054] Scotland, UK, BioInvent, Lund, Sweden, Dyax Corp., Enzon, Affymax / Biosite, Xoma, Berkeley CA, Ixsys. For example, European Patent No. 368,684, International Application PCT / GB 91 / 01134, International Application PCT / GB92 / 01755, International Application PCT / GB 92 / 002240, International Application PCT / GB92 / 00883, International Application PCT / G B93 / 00605, US Patent Application No. 08 / 350260 (5 / 12 / 94), International Application PCT / GB94 / 01422, International Application PCT / GB94 / 02662, International Application PCT / GB94 / 02662, International Application PCT / GB 91 / 01134, International Application PCT / GB92 / 01755, International Application PCT / GB 92 / 002240, International Application PCT / GB92 / 00883, International Application PCT / G B93 / 00605, US Patent Application No. 08 / 350260 (5 / 12 / 94), International Application PCT / GB94 / 01422, International Application PCT / GB94 / 02662, International Application PCT / GB97 / 01835, (CAT / MRC), International Publication No. 90 / 1444 International Publication No. 90 / 14424, International Publication No. 90 / 14430, International Application PCT / US 94 / 1234, International Publication No. 92 / 18619, International Publication No. 96 / 07754 (Sc ripps), International Publication No. 96 / 13583, International Publication No. 97 / 08320 (Mor phoSys), International Publication No. 95 / 16027 (BioInvent), International Publication No. 8 8 / 06630, International Publication No. 90 / 3809 (Dyax), US Patent No. 4,704,6 92 (Enzon), International Application PCT / US91 / 02989 (Affymax), International Publication No. 89 / 06283, European Patent No. 371998, European Patent No. 550400 , (Xoma), European Patent No. 229046, International Application PCT / US91 / 07149 (Ixsys), or a stochastically generated peptide or protein - US Patent No. 5 723323, No. 5763192, No. 5814476, No. 5817483 , No. 5824514, No. 5976862, International Publication No. 86 / 05803, European Patent No. 590 689 (Ixsys, predecessor of Applied Molecular Evolution (AME), each of which is hereby incorporated by reference in its entirety herein ), or known in the art and / or described herein , transgenic animals capable of producing a repertoire of human antibodies that depend on immunization of (e.g., SCID mice, Nguyen et al., Microbiol ol.Immunol.41:901 - 907(1997), Sandhu et al ., Crit.Rev.Biotechnol.16:95 - 118(1996), Er .,Crit.Rev.Biotechnol.16:95 - 118(1996), Er .,Crit.Rev.Biotechnol.16:95 - 118(1996), Er en et al., Immunol. 93:154-161(1998) (each is incorporated by reference in its entirety), and related patents and applications), and other suitable methods for generating or isolating antibodies of the required specificity, including but not limited to such, may be used. Such techniques include ribosome display (Hanes et al., Proc . Natl. Acad. Sci. USA, 94:4937-4942 (Can 1997 ), Hanes et al., Proc. Natl. Acad. Sci. USA, 95 :14130-14135 (Nov. 1998)), single cell antibody generation techniques (e.g., selected lymphocyte antibody method ("SLAM") (U.S. Patent No. 5,627,052, Wen et al., J. Immunol. 17:887-892(1987), Babcook et al., Proc. Natl. Acad. Sci. USA 93:7843-78 48(1996)), gel microdroplet, and flow cytometry (Powell et al., Biotechnol. 8:333-33 7(1990), One Cell Systems, Cambridge, MA, Gr ay et al., J. Imm. Meth. 182:155-163(1995), K enny et al., Bio / Technol. 13:787-790(1995) ), B cell selections (Steenbakkers et al., Molec. Biol. Reports 19:125-134(1994), Jonak et al., Pr ogress Biotech, Vol. 5, In Vitro Immunizati on), and the like), may be used. on in Hybridoma Technology,Borrebaeck,ed .,Elsevier Science Publishers B.V.,Amste rdam,Netherlands(1988)) can be mentioned, but not limited to these .

[0055] Methods for engineering or humanizing non - human antibodies or human antibodies can be used similarly and are well - known in the relevant technical field. Generally, humanized antibodies or modified antibodies have one or more amino acid residues derived from non - human sources, such as , but not limited to, mice, rats, rabbits, non - human primates, or other mammals. These non - human amino acid residues are often replaced by residues called " import" residues. Such "import" residues are typically obtained from the "import" variable domains, constant domains, or other domains of known human sequences . from

[0056] Known human Ig sequences are disclosed, for example, at www.ncbi.nlm.nih.gov / entrez / query.fcgi, www.ncbi.nih.gov / igbl ast, www.atcc.org / phage / hdb.html, www.mrc - cpe.cam.ac.uk / ALIGNMENTS.php, www.kabatda tabase.com / top.html, ftp.ncbi.nih.gov / rep ository / kabat, www.sciquest.com / , www.abca m.com / , www.antibodyresource.com / onlineco mp.html, www.public.iastate.edu / ~pedro / re search_tools.html, www.whfreeman.com / immu nology / CH05 / kuby05.htm, www.hhmi.org / gran ts / lectures / 1996 / vlab / , www.path.cam.ac.u k / ~mrc7 / mikeimages.html, mcb.harvard.edu / BioLinks / Immunology.html, www.immunologyl ink.com, pathbox.wustl.edu / ~hcenter / index .html, www.appliedbiosystems.com, www.nal. usda.gov / awic / pubs / antibody, www.m.ehime- u.ac.jp / ~yasuhito / Elisa.html, www.biodesi gn.com, www.cancerresearchuk.org, www.biot ech.ufl.edu, www.isac-net.org, baserv.uci. kun.nl / ~jraats / links1.html, www.recab.uni -hd.de / immuno.bme.nwu.edu, www.mrc-cpe.ca m.ac.uk, www.ibt.unam.mx / vir / V_mice.html, http: / / www.bioinf.org.uk / abs, antibody.ba th.ac.uk, www.unizh.ch, www.cryst.bbk.ac.u k / ~ubcg07s, www.nimr.mrc.ac.uk / CC / ccaewg / ccaewg.html, www.path.cam.ac.uk / ~mrc7 / hum anisation / TAHHP.html, www.ibt.unam.mx / vir / structure / stat_aim.html, www.biosci.miss ouri.edu / smithgp / index.html, www.jerini.d e, Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Dept. Health (1 983), each of which is hereby incorporated by reference in its entirety into this specification.

[0057] Such imported sequences can be used to reduce immunogenicity or to reduce, enhance or modify binding, affinity, association rate constant, dissociation rate constant, binding activity, specificity , half-life, or any other suitable property, as is known in the art. Generally, CDR residues directly and substantially affect antigen binding. Thus, while maintaining a non-human CDR sequence or part or all of a human CDR sequence, non-human sequences in the variable region and the constant region can be replaced with human amino acids or other amino acids. Antibodies can optionally be humanized, or human antibodies can be modified while retaining high affinity for the antigen and other advantageous biological properties. To achieve this purpose, optionally, a three-dimensional model of the parental and humanized sequences is used to analyze the parental sequence and various theoretical humanized products, and humanized (or human) antibodies can be prepared. Three-dimensional immunoglobulin models are generally available and well known to those skilled in the art. A likely three-dimensional conformation of the selected immunoglobulin sequence candidate is illustrated

[0058] for the selected immunoglobulin sequence candidates. ​​​​​​​and a computer program for display are available. By examining these displays, it is possible to analyze the likely functions indicated by the residues in the function of the immunoglobulin sequence candidates, that is, it is possible to analyze the residues that affect the antigen-binding ability of the immunoglobulin candidates. In this way, desirable antibody properties such as enhanced affinity for the target antigen(s) are achieved. Thus, framework (FR) residues can be selected and combined from the consensus sequence and the import sequence.

[0059] In addition, the human anti-IL-12 / 23p40 (or anti-IL -23) specific antibody used in the method of the present invention may include a human germline light chain framework. In certain embodiments, the light chain germline sequences are A1, A10, A11, A14, A17, A18, A19, A 2, A20, A23, A26, A27, A3, A30, A5, A7, B2, B3, L1, L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L 22, L23, L24, L25, L4 / 18a, L5, L6, L8, L9, O1, O11 including, but not limited to, O12, O14, O18, O2, O4, and O8, and are selected from human VK sequences. In certain embodiments, the light chain human germline framework is , V1-11, V1-13, V1-16, V1-17, V1-18, V1-19, V1- 2, V1-20, V1-22, V1-3, V1-4, V1-5, V1-7, V1-9, V 2-1, V2-11, V2-13, V2-14, V2-15, V2-17, V2-19, V2-6, V2-7, V2-8, V3-2, V3-3, V3-4, V4-1, V4-2, V4-3, V4-4, V4-6, V5-1, V5-2, V5-4, and V5-6 and are selected from is effected.

[0060] In other embodiments, the human anti-IL-12 / 23p40 ( or anti-IL-23) specific antibody used in the method of the invention may comprise a human germline heavy chain framework. In certain embodiments, this heavy chain human germline framework is VH1-18, VH1-2, V H1-24, VH1-3, VH1-45, VH1-46, VH1-58, VH1-69, VH1-8, VH2-26, VH2-5, VH2-70, VH3-11, VH3-13, VH3-15, VH3-16, VH3-20, VH3-21, VH3-23, VH3-3 0, VH3-33, VH3-35, VH3-38, VH3-43, VH3-48, VH3 -49, VH3-53, VH3-64, VH3-66, VH3-7, VH3-72, VH 3-73, VH3-74, VH3-9, VH4-28, VH4-31, VH4-34, V H4-39, VH4-4, VH4-59, VH4-61, VH5-51, VH6-1, and VH7-81.

[0061] In certain embodiments, the light chain variable region and / or the heavy chain variable region comprises a framework region, or at least a portion of a framework region (e.g., including two or three small regions such as FR2 and FR3). In certain embodiments, at least FRL1, FRL2, F RL3, or FRL4 is fully human. In other embodiments, at least FRH1, F RH2, FRH3, or FRH4 is fully human. In some embodiments, at least FRL1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., human germ line), or a human consensus sequence for a particular framework (known as described above is readily available from sources of human Ig sequences). In other embodiments, at least one of FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., a human germline sequence) or includes a human consensus sequence for a particular framework. Preferably in embodiments, the framework region is a complete human framework region.

[0062] Humanization or engineering of the antibodies of the invention is described in Winter (Jones et al., Nature 321:522(1986), Riechmann et al., Na ture 332:323(1988), Verhoeyen et al., Scie nce 239:1534(1988)), Sims et al., J.Immuno l.151:2296(1993), Chothia and Lesk, J.Mol. Biol.196:901(1987), Carter et al., Proc.Na tl.Acad.SCi.U.S.A.89:4285(1992), Presta e t al., J.Immunol.151-2623(1993), U.S. Patent No. 5723 323, No. 5976862, No. 5824514, No. 5817483, No. 5814476, No. 5763192, No. 5723323, No. 5,76688 6, No. 5714352, No. 6204023, No. 6180370, No. 56 93762, No. 5530101, No. 5585089, No. 5225539, No. 4816567, International Application PCT / :US98 / 16280, US96 / 189 78, US91 / 09630, US91 / 05939, US94 / 01234, GB 89 / 01334, GB 91 / 01134, GB 92 / 01755, International Publication No. 90 / 14443, International Publication No. 90 / 14424, International Publication No. 90 / 14430 , European Patent No. 229246 (each incorporated by reference in its entirety and including the documents cited therein), etc., but not limited thereto, and can be carried out using any known method.

[0063] In certain embodiments, the antibody comprises a modified (e.g., mutated) Fc region . For example, in some embodiments, the Fc region is modified to reduce or enhance the effector function of the antibody. In some embodiments, the Fc region is an isotype selected from IgM, IgA, IgG, IgE, or other isotypes . Alternatively, or in addition, it may be useful to combine amino acid modifications with one or more additional amino acid modifications that alter the C1q binding and / or complement-dependent cytotoxicity function of the Fc region of the IL-23 binding molecule. The starting polypeptide for a particular purpose can be one that binds to C1q and exhibits complement-dependent cytotoxicity (CDC). Polypeptides having existing C1q binding activity and optionally further the ability to mediate CDC can be modified such that one or both of these activities are enhanced. Amino acid modifications that modify C1q and / or its complement-dependent cytotoxic function are described, for example, in International Publication No. 004207 2 and incorporated herein by reference. As disclosed above, for example, modifying C1q binding and / or FcγR binding, and

[0064] so on. Thereby, the complement-dependent cytotoxicity (CDC) activity and / or the antibody-dependent cell-mediated cytotoxicity ( antibody-dependent cell-mediated cytotoxicity, ADCC) activity is changed, and thus, the Fc region of the human anti-IL-12 / 23p40 ( or anti-IL-23) specific antibody of the present invention having an altered effector function can be designed. "Effector function" plays a role in activating or reducing biological activity (e.g., in a subject). Examples of effector functions include, but are not limited to, C1q binding, CDC, Fc receptor binding, ADCC, phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptor, BCR), etc. Such effector functions may require the Fc region to bind to a binding domain (e.g., an antibody variable domain), and can be evaluated using a variety of assays (e.g., Fc binding assays, ADCC assays, CDC assays, etc.). )

[0065] For example, a mutant Fc region of a human anti-IL-12 / 23p40 (or anti-IL-23) antibody having improved C1q binding and improved FcγRIII binding (e.g., having both improved ADCC activity and improved CDC activity) can be generated. Alternatively, if it is desired to reduce or eliminate the effector function, the variant of the Fc region can be modified to reduce the CDC activity and / or to reduce the ADCC activity. In other embodiments, only one of these activities may be enhanced, and optionally, simultaneously, the other activity may be reduced (e.g., improved ADCC activity and reduced Fc region variants with CDC activity and methods for generating the reverse Fc region variants .

[0066] Fc mutations can also be engineered and introduced to alter their interaction with the neonatal Fc receptor (FcRn) and improve their pharmacokinetic properties. The collection of human Fc mutants with improved binding to FcRn has been described (Shields et al., (2 001). High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FCγR, J . Biol.Chem.276:6591-6604). FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FCγR, J . Biol.Chem.276:6591-6604). FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FCγR, J . Biol.Chem.276:6591-6604).

[0067] Another type of amino acid substitution can help to alter the glycosylation pattern of the Fc region of human anti-IL-12 / 23p40 (or anti-IL-23) specific antibodies. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the addition of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used. The recognition sequences for the enzymatic addition of carbohydrate moieties to asparagine side chain peptide sequences are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid other than proline. Thus, within the polypeptide Another type of amino acid substitution can help to alter the glycosylation pattern of the Fc region of human anti-IL-12 / 23p40 (or anti-IL-23) specific antibodies. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the addition of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used. The recognition sequences for the enzymatic addition of carbohydrate moieties to asparagine side chain peptide sequences are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid other than proline. Thus, within the polypeptide Another type of amino acid substitution can help to alter the glycosylation pattern of the Fc region of human anti-IL-12 / 23p40 (or anti-IL-23) specific antibodies. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the addition of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used. The recognition sequences for the enzymatic addition of carbohydrate moieties to asparagine side chain peptide sequences are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid other than proline. Thus, within the polypeptide Another type of amino acid substitution can help to alter the glycosylation pattern of the Fc region of human anti-IL-12 / 23p40 (or anti-IL-23) specific antibodies. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the addition of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used. The recognition sequences for the enzymatic addition of carbohydrate moieties to asparagine side chain peptide sequences are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid other than proline. Thus, within the polypeptide Another type of amino acid substitution can help to alter the glycosylation pattern of the Fc region of human anti-IL-12 / 23p40 (or anti-IL-23) specific antibodies. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the addition of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used. The recognition sequences for the enzymatic addition of carbohydrate moieties to asparagine side chain peptide sequences are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid other than proline. Thus, within the polypeptide Another type of amino acid substitution can help to alter the glycosylation pattern of the Fc region of human anti-IL-12 / 23p40 (or anti-IL-23) specific antibodies. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the addition of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used. The recognition sequences for the enzymatic addition of carbohydrate moieties to asparagine side chain peptide sequences are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid other than proline. Thus, within the polypeptide Another type of amino acid substitution can help to alter the glycosylation pattern of the Fc region of human anti-IL-12 / 23p40 (or anti-IL-23) specific antibodies. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the addition of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used. The recognition sequences for the enzymatic addition of carbohydrate moieties to asparagine side chain peptide sequences are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid other than proline. Thus, within the polypeptide Another type of amino acid substitution can help to alter the glycosylation pattern of the Fc region of human anti-IL-12 / 23p40 (or anti-IL-23) specific antibodies. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the addition of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used. The recognition sequences for the enzymatic addition of carbohydrate moieties to asparagine side chain peptide sequences are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid other than proline. Thus, within the polypeptide Another type of amino acid substitution can help to alter the glycosylation pattern of the Fc region of human anti-IL-12 / 23p40 (or anti-IL-23) specific antibodies. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the addition of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used. The recognition sequences for the enzymatic addition of carbohydrate moieties to asparagine side chain peptide sequences are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid other than proline. Thus, within the polypeptide The presence of any of these peptide sequences results in a site where glycosylation can occur .

[0068] The glycosylation pattern can be altered, for example, by deleting one or more glycosylation site(s) found in the polypeptide and / or adding one or more glycosylation sites that are not present in the polypeptide. Addition of glycosylation sites to the Fc region of a human IL-23 specific antibody is successfully achieved by modifying the amino acid sequence to include one or more of the above tripeptide sequences (in the case of N-linked glycosylation sites ). Exemplary glycosylation variants have an amino acid substitution at residue Asn297 of the heavy chain. This change can also be made by addition of one or more serine or threonine residues to or substitution by these in the original polypeptide sequence (in the case of O- linked glycosylation sites). Additionally, changing Asn 297 to Ala can remove one of the glycosylation sites.

[0069] In certain embodiments, the human anti-IL-12 / 23p40 (or anti-IL-23 ) specific antibody of the invention is expressed in cells that express beta(1,4)-N- acetylglucosaminyl transferase III (GnT III) such that GnT III adds GlcNAc to the human anti-IL-12 / 23p40 (or anti-IL-23) antibody. Methods for producing antibodies in such a manner are described in International Publication No. WO 99 / 54342, International Publication No. WO 03 / 011878, Japanese Patent Publication 20030003097A1, and Umana et al., Nature Biotechnology, 17:176-180, Feb. 1999 are provided, all of which are hereby incorporated by reference in their entirety. Hereby.

[0070] Human anti-IL-12 / 23p40 (or anti-IL-23) antibodies can also optionally be generated by immunizing transgenic animals (e.g., mice, rats, hamsters, non-human primates, etc.) capable of producing a repertoire of human antibodies, as described herein and / or known in the art. Cells producing human anti-IL-12 / 23p40 (or anti-IL-23) antibodies can be isolated from such animals and immortalized using suitable methods such as those

[0071] described herein. Transgenic mice capable of producing a repertoire of human antibodies that bind to human antigens can be generated by known methods (e.g., but not limited to, U.S. Patent Nos. 5,770,428; 5,569, 825; 5,545,806; 5,625,126; 5,625,825; 5,633,425; 5,661,016; and 5,789,650 issued to Lonberg et al., International Publication Nos. 98 / 50433; 98 / 24893; 98 / 24884; 97 / 13852; 94 / 25585; 96 / 34096 issued to Jakobovits et al., International Publication Nos. 98 / 24884; 98 / 24884; 97 / 13852; 94 / 25585; 96 / 34096 issued to Lonberg et al., European Patent No. 0463 151 B1; European Patent No. 0710 719 A1 issued to Kucherlapate et al., European Patent No. 0710 719 A1 issued to Kucherlapate et al., U.S. Patent No. 5,5 No. 45,807, International Publication No. WO 90 / 04036 by Bruggemann et al., European Patent No. 0438 474 B1 by Brugg emann et al., European Patent No. 0 814 259 A2 by Lonberg et al., British Patent No. 2 272 440 A by Lonberg et al., L onberg et al., Nature 368:856-859 (1994), Taylor et al of Int. Immunol. 6(4):579-591 (1994), Green et al. of Na ture Genetics 7:13-21 (1994), Mendez et al. of Natu re Genetics 15:146-156 (1997), Taylor et al. of Nuc leic Acids Research 20(23):6287-6295 (199 2), Tuaillon et al. of Proc Natl Acad Sci USA 90(8 )3720-3724 (1993), Lonberg et al. of Int Rev Immuno l 13(1):65-93 (1995) and Fishwald et al. of Nat Biote chnol 14(7):845-851 (1996), which are hereby incorporated by reference in their entireties into this specification). Generally, these mice are derived from at least one human immunoglobulin locus that has been functionally reconstituted or is capable of undergoing functional reconstitution and contain at least one transgene comprising DNA. The endogenous immunoglobulin loci of such mice can be disrupted or deleted to eliminate the ability of the mice to produce antibodies encoded by the endogenous genes . Screening for antibodies specific for similar proteins or fragments can be .

[0072] performed ​, can be successfully achieved using a peptide display library. This method involves screening a large collection of peptides for individual components with desirable functions or structures . Antibody screening of peptide display libraries is well known in the art . The length of the displayed peptide sequences is from 3 to 5000 or more amino acids, frequently 5 to 100 amino acids in length, and often about 8 to 25 amino acids in length. In addition to direct chemical synthesis methods for creating peptide libraries, several recombinant DNA methods have also been described. One type involves the display of peptide sequences on the surface of bacteriophages or cells . Each bacteriophage or cell contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. WO 91 / 17271, WO 91 / 18980, WO 91 / 1981 8, and WO 93 / 08278 .

[0073] Other systems for creating peptide libraries have aspects of both in vitro chemical synthesis methods and recombinant methods. See International Publication Nos. WO 92 / 05258, WO 92 / 14 843, and WO 96 / 19256. Also see U.S. Patent Nos. 5,658, 754 and 5,643,768. Peptide display libraries, vectors, and screening kits are commercially available from suppliers such as Invitrogen (Carlsbad , CA) and Cambridge Antibody Technologies (Ca mbridgeshire, UK). For example, Enz U.S. Patent Nos. 4,704,692, 4,939,666, 4,946,7 78, 5,260,203, 5,455,030, 5,518,889, 5 534,621, 5,656,730, 5,763,733, 5,767,260 , 5,856,456, U.S. Patent Nos. 5,223,409, 5,403,4 84, 5,571,698, 5,837,500, assigned to Affymax, U.S. Patent No. 5,427,908, 5,580,717, assigned to Cambridge antibody Technologies, U.S. Patent No. 5,885,793, assigned to Genentech, U.S. Patent No. 5,750,373, assigned to Xoma, U.S. Patent Nos. 5,618,920, 55 95,898, 5,576,195, 5,698,435, 5,693,493, 5,698,417, Colligan (supra), Ausubel (supra), or Sambrook (supra), each of the above patents and publications is hereby incorporated by reference in its entirety into this specification.

[0074] The antibodies used in the methods of the present invention may also be prepared using at least one anti-IL-12 / 23p40 (or anti-IL-23) antibody encoding nucleic acid to provide transgenic animals or mammals such as goats, cows, horses, sheep, rabbits, etc. that produce such antibodies in milk. Such animals can be prepared using known methods, for example, but not limited to, see U.S. Patent Nos. 5,827,690, 5,84 9,992, 4,873,316, 5,849,992, 5,994 ,616, 5,565,362, 5,304,489, etc. (Each of them is hereby incorporated by reference in its entirety).

[0075] The antibodies used in the method of the present invention can be further prepared using at least one anti-IL-12 / 23p40 (or anti-IL-23) antibody-encoding nucleic acid in plant parts or cells cultured therefrom. Transgenic plants and cultured plant cells (such as, but not limited to, tobacco and maize) that produce such antibodies, the identified parts, or variants are provided. For example, transgenic tobacco leaves expressing recombinant proteins using an inducible promoter have been successfully used to provide large amounts of recombinant proteins. See, for example, Cramer et al., Curr. Top. Microbiol. Immunol. 240:95-118 (1999) and the references cited therein. Also, transgenic maize has been used to express mammalian proteins with biological activities equivalent to those of proteins produced in other recombinant systems or purified from natural resources at commercial production levels. See, for example, Hood et al., Adv. Exp. Med. Biol. 464:127-147 (1999) and the references cited therein. Antibodies have also been produced in large quantities from seeds of transgenic plants such as tobacco seeds and potato tubers, including antibody fragments such as single-chain antibodies (scFv). See, for example, Conrad et al., Plant Mol. Biol. 38:101-109 (1998) and the references cited therein. Therefore, the antibodies of the present invention Alternatively, it can also be produced using transgenic plants according to known methods. For example, Fischer et al., Biotechnol. Appl. Biochem. 30:99 - 108 (Oct., 1999), Ma et al., Trends Biotechnol. 13:522 - 7 (1995), Ma et al., Plant Physiol. 109:341 - 6 (1995), Whitelam et al. ., Biochem. Soc. Trans. 22:940 - 944 (1994), and also see the references cited therein. Each of the above - mentioned references is incorporated herein by reference in its entirety.

[0076] The antibodies used in the method of the present invention can bind to human IL - 12 / IL - 23p40 or IL - 23 with a wide range of affinities (KD). In a preferred embodiment the human mAb can optionally bind to human IL - 12 / IL - 23p40 or IL - 23 with high affinity. For example, the human mAb can bind to human IL - 12 / IL - 23 p40 or IL - 23 with a KD of about 10 - 7M or less, for example, but not limited to, 0.1 - 9.9 ( or any range or value therein)×10 - 7, 10 - 8, 10 - 9, 10 - 10, 1 0 - 11, 10 - 12, 10 - 13, or any range or value therein, etc.

[0077] The affinity or binding activity of the antibody for the antigen can be determined experimentally using any suitable method. (For example, Berzofsky, et al., “Antibody - Antigen Interactions,” In Fundamental Imm unology, Unology, Paul, W.E., Ed., Raven Press: New Yo rk, NY(1984), Kuby, Janis Immunology, W.H.Fr eeman and Company: New York, NY(1992), and the methods described in this specification. (See.) The affinity measured for a particular antibody-antigen interaction can vary when measured under different conditions (e.g., salt concentration, pH). Therefore, the measurement of affinity and other antigen-binding parameters (e.g., KD, Ka, Kd) is preferably carried out using a standardized solution of the antibody and antigen, and a standardized buffer such as the buffer described in this specification. For a particular antibody-antigen interaction, the measured affinity can vary when measured under different conditions (e.g., salt concentration, pH). Thus, the measurement of affinity and other antigen-binding parameters (e.g., KD, Ka, Kd) is preferably carried out using a standardized solution of the antibody and antigen, and a standardized buffer such as the buffer described in this specification. For a particular antibody-antigen interaction, the measured affinity can vary when measured under different conditions (e.g., salt concentration, pH). Thus, the measurement of affinity and other antigen-binding parameters (e.g., KD, Ka, Kd) is preferably carried out using a standardized solution of the antibody and antigen, and a standardized buffer such as the buffer described in this specification. For a particular antibody-antigen interaction, the measured affinity can vary when measured under different conditions (e.g., salt concentration, pH). Thus, the measurement of affinity and other antigen-binding parameters (e.g., KD, Ka, Kd) is preferably carried out using a standardized solution of the antibody and antigen, and a standardized buffer such as the buffer described in this specification. For a particular antibody-antigen interaction, the measured affinity can vary when measured under different conditions (e.g., salt concentration, pH). Thus, the measurement of affinity and other antigen-binding parameters (e.g., KD, Ka, Kd) is preferably carried out using a standardized solution of the antibody and antigen, and a standardized buffer such as the buffer described in this specification. For a particular antibody-antigen interaction, the measured affinity can vary when measured under different conditions (e.g., salt concentration, pH). Thus, the measurement of affinity and other antigen-binding parameters (e.g., KD, Ka, Kd) is preferably carried out using a standardized solution of the antibody and antigen, and a standardized buffer such as the buffer described in this specification.

[0078] Vectors and Host Cells The present invention also relates to vectors containing isolated nucleic acid molecules, host cells genetically engineered with recombinant vectors, and the production of at least one anti-IL-12 / IL-23p40 antibody by recombinant techniques well known in the art. For example, reference is made to Sambrook et al. and Ausubel et al. supra, each of which is incorporated herein by reference in its entirety. The present invention also relates to vectors containing isolated nucleic acid molecules, host cells genetically engineered with recombinant vectors, and the production of at least one anti-IL-12 / IL-23p40 antibody by recombinant techniques well known in the art. For example, reference is made to Sambrook et al. and Ausubel et al. supra, each of which is incorporated herein by reference in its entirety. The present invention also relates to vectors containing isolated nucleic acid molecules, host cells genetically engineered with recombinant vectors, and the production of at least one anti-IL-12 / IL-23p40 antibody by recombinant techniques well known in the art. For example, reference is made to Sambrook et al. and Ausubel et al. supra, each of which is incorporated herein by reference in its entirety. The present invention also relates to vectors containing isolated nucleic acid molecules, host cells genetically engineered with recombinant vectors, and the production of at least one anti-IL-12 / IL-23p40 antibody by recombinant techniques well known in the art. For example, reference is made to Sambrook et al. and Ausubel et al. supra, each of which is incorporated herein by reference in its entirety. The present invention also relates to vectors containing isolated nucleic acid molecules, host cells genetically engineered with recombinant vectors, and the production of at least one anti-IL-12 / IL-23p40 antibody by recombinant techniques well known in the art. For example, reference is made to Sambrook et al. and Ausubel et al. supra, each of which is incorporated herein by reference in its entirety.

[0079] The polynucleotide can optionally be ligated to a vector containing a selectable marker for host cell growth. Generally, plasmid vectors are introduced into a precipitate such as a calcium phosphate precipitate or into a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into the host cell. The polynucleotide can optionally be ligated to a vector containing a selectable marker for host cell growth. Generally, plasmid vectors are introduced into a precipitate such as a calcium phosphate precipitate or into a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into the host cell. The polynucleotide can optionally be ligated to a vector containing a selectable marker for host cell growth. Generally, plasmid vectors are introduced into a precipitate such as a calcium phosphate precipitate or into a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into the host cell. The polynucleotide can optionally be ligated to a vector containing a selectable marker for host cell growth. Generally, plasmid vectors are introduced into a precipitate such as a calcium phosphate precipitate or into a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into the host cell. The polynucleotide can optionally be ligated to a vector containing a selectable marker for host cell growth. Generally, plasmid vectors are introduced into a precipitate such as a calcium phosphate precipitate or into a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into the host cell.

[0080] It should be noted that there are some unclear or potentially incorrect parts in the original text, such as incomplete words and inconsistent references, which may affect the accuracy of the overall understanding and translation. But the translation is carried out according to the requirements.The DNA insert should be operably linked to a suitable promoter. The expression construct should further include a ribosome binding site for translation within the transcription start site, transcription termination site, and transcribed region. The coding portion of the mature transcript expressed by the construct preferably includes start and stop codons (e.g., UAA, UGA, or UAG) appropriately positioned at the end of the mRNA to be translated, with UAA and UAG being preferred for mammalian or eukaryotic cell expression.

[0081] The expression vector preferably includes at least one selectable marker, although this is optional. Such markers include, for example, methotrexate (MTX) for eukaryotic cell culture, dihydrofolate reductase (DHFR, U.S. Pat. Nos. 4,399,216, 4,634,665, 4,656,134, 4,956,288, 5,149,636, 5,179,017), ampicillin, neomycin (G418), mycophenolic acid, or glutamine synthetase (GS, U.S. Pat. Nos. 5,122,464, 5,770,359, 5,827,739) resistance genes, as well as tetracycline or ampicillin resistance genes for culture in Escherichia coli (E. coli) and other bacteria or prokaryotes, but are not limited thereto (the above patents are hereby incorporated by reference in their entirety). Suitable culture media and conditions for the above host cells are known in the art. Suitable vectors will be readily apparent to the person of skill in the art. Suitable vectors will be readily apparent to the person of skill in the art. Introduction of the vector construct into the host cell can be achieved by calcium phosphate transfection , transfection mediated by DEAE-dextran, transfection mediated by cationic lipids , electroporation, transduction, infection or other known methods. Such methods are described in Sambrook, supra, Chapters 1-4 and Chapters 16-18, Ausubel, supra, Chapters 1, 9, 13, 15, 16, etc., in the art .

[0082] At least one antibody used in the method of the present invention can be expressed in a modified form such as a fusion protein and can contain not only a secretion signal but also an additional heterologous functional region. For example, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of the antibody to improve stability and persistence in the host cell during purification or subsequent processing and storage. Also, a peptide moiety can be added to the antibody of the present invention to facilitate purification. Such regions can be removed before the final preparation of the antibody or at least one fragment thereof. Such methods are described in many standard laboratory manuals such as Sambrook, supra, Chapters 17.29-17.42 and 18.1-18. 74, Ausubel, supra, Chapters 16, 17 and 18, etc.

[0083] Those skilled in the art are familiar with a number of available expression systems for the expression of nucleic acids encoding the proteins used in the method of the present invention. Alternatively, the nucleic acid can be expressed in a host cell containing the endogenous DNA encoding the antibody by (operationally) switching it on in the host cell. Such methods are described in U.S. Patent No. 5,580,734, the same ​​​​​​​​ As described in U.S. Patent Nos. 5,641,670, 5,733,746, and 5,733,761, which are well known in the art and are hereby incorporated by reference in their entirety into this specification. An example of a cell culture useful for the production of antibodies, specified portions or variants thereof is mammalian cells. Mammalian cell lines often take the form of a monolayer of cells, but suspensions or bioreactors of mammalian cells can also be used. Several suitable host cell lines capable of expressing intact glycosylated proteins have been developed in the art, including COS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-1651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., ATCC CRL1610) and BSC-1 (e.g., ATCC CRL-26) cell lines, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2 / 0-Ag14, 293 cells, HeLa cells, etc., which are readily available, for example, from the American Type Culture Collection, Manassas, Va (www.atcc.org). Preferred host cells include cells derived from lymphoid systems such as myelomas and lymphoma cells. Particularly preferred host cells are P3X63Ag8.653 cells (ATCC accession number CRL-1580) and SP2 / 0-Ag14 cells (ATCC accession number CRL-1851). In a particularly preferred embodiment, the recombinant cells are P3X63Ab8.653 or SP2 / 0-Ag14 cells.

[0084] An example of a cell culture useful for the production of antibodies, specified portions or variants thereof is mammalian cells. Mammalian cell lines often take the form of a monolayer of cells, but suspensions or bioreactors of mammalian cells can also be used. Several suitable host cell lines capable of expressing intact glycosylated proteins have been developed in the art, including COS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-1651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., ATCC CRL1610) and BSC-1 (e.g., ATCC CRL-26) cell lines, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2 / 0-Ag14, 293 cells, HeLa cells, etc., which are readily available, for example, from the American Type Culture Collection, Manassas, Va (www.atcc.org). Preferred host cells include cells derived from lymphoid systems such as myelomas and lymphoma cells. Particularly preferred host cells are P3X63Ag8.653 cells (ATCC accession number CRL-1580) and SP2 / 0-Ag14 cells (ATCC accession number CRL-1851). In a particularly preferred embodiment, the recombinant cells are P3X63Ab8.653 or SP2 / 0-Ag14 cells. American Type Culture Collection, Manassas, Va(www.atcc.org) from which they can be easily obtained. Preferred host cells include cells derived from lymphoid systems such as myelomas and lymphoma cells. Particularly preferred host cells are P3X63Ag8.653 cells (ATCC accession number CRL-1580) and SP2 / 0-Ag14 cells (ATCC accession number CRL-1851). In a particularly preferred embodiment, the recombinant cells are P3X63Ab8.653 or SP2 / 0-Ag14 cells.

[0085] ​​​​​​Expression vectors for these cells include an origin of replication, a promoter (e.g., late or early SV 40 promoter, CMV promoter (U.S. Patent Nos. 5,168,062, 5,3 85,839), HSV tk promoter, pgk (phosphoglycerate kinase) promoter, EF-1α promoter (U.S. Patent No. 5,266,491), at least one human immunoglobulin promoter, enhancer, and / or ribosome binding site, RNA splice site, polyadenylation site (e.g., SV40 large T Ag poly addition site), and processing information sites such as transcription termination sequences, etc., but are not limited thereto, and may include one or more of the expression control sequences. For example, see Ausubel et al. and Sambrook et al. above. Other cells useful for the production of the nucleic acids or proteins of the present invention are known and / or are available, for example, from cell lines and hybridoma catalogs of the American Type Culture Collection (www .atcc.org) or other known or commercial sources. .atcc.org) or other known or commercial sources.

[0086] When eukaryotic host cells are used, typically, a polyadenylation or transcription termination sequence is incorporated into the vector. An example of a termination sequence is the polyadenylation sequence from the bovine growth hormone gene. Sequences for accurate splicing of transcription can likewise be included. An example of a splicing sequence is the VP1 intron from SV40 (Sprague , et al., J. Virol. 45:773-781 (1983)). In addition, as is known in the art, gene sequences for controlling replication in the host cell can be incorporated into the vector. incorporated into the vector.

[0087] Purification of Antibodies Anti-IL-12 / IL-23p40 or IL-23 antibodies can be recovered from recombinant cell cultures by well-known methods including, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, hydroxyapatite chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, and lectin chromatography and purified. High performance liquid chromatography (HPLC) can also be used for purification. For example, see Colligan, Current Protocols in Immunology or Current Protocols in Protein Science, John Wiley & Sons, NY, NY (1997-2001), for example, Sections 1, 4, 6, 8, 9 and 10, each of which is incorporated herein by reference in its entirety. Current Protocols in Immunology or Current Protocols in Protein Science, John Wiley & Sons, NY, NY (1997-2001), for example, Sections 1, 4, 6, 8, 9 and 10, each of which is incorporated herein by reference in its entirety.

[0088] Antibodies used in the methods of the invention include naturally purified products, products of chemical synthetic procedures, and products produced by recombinant methods from eukaryotic hosts including, for example, yeast, higher plants, insects, and mammalian cells. Depending on the host used in the recombinant production procedure, the antibody may or may not be glycosylated, but glycosylation is preferred. Such methods are described in Sambrook, supra, Sections 17.37-17.42 and Ausubel, supra, Chapters 10, 12, 13, 16, 18, and 20, and Col supra, Sections 1, 4, 6, 8, 9 and 10, each of which is incorporated herein by reference in its entirety. Antibodies may or may not be glycosylated, but glycosylation is preferred. Such methods are described in Sambrook, supra, Sections 17.37-17.42 and Ausubel, supra, Chapters 10, 12, 13, 16, 18, and 20, and Col supra, Sections 1, 4, 6, 8, 9 and 10, each of which is incorporated herein by reference in its entirety. ligan, which is described in many standard laboratory manuals such as Chapters 12 to 14 of Protein Science, and all are incorporated herein by reference in their entirety. It is described in the laboratory manual and is hereby incorporated by reference in its entirety.

[0089] Anti-IL-12 / IL-23p40 or IL-23 antibody The anti-IL-12 / IL-23p40 or IL-23 antibody according to the present invention can be incorporated into an antibody and is at least a part of an immunoglobulin molecule, for example, but not limited to, at least one ligand binding portion (LBP), for example, but not limited to, a complementarity determining region (CDR) of a heavy chain or a light chain or a ligand binding portion thereof, a heavy chain or a light chain variable region, a framework region (for example, FR1, FR2, FR3, FR4, or fragments thereof, and further optionally including at least one substitution, insertion, or deletion), a heavy chain or a light chain constant region (for example, at least one CH1, hinge 1, hinge 2, hinge 3, hinge 4, CH2, or CH3, or fragments thereof, and further optionally including at least one substitution, insertion, or deletion), or any arbitrary portion thereof, and includes any protein or peptide-containing molecule. The antibody includes, but is not limited to, any mammal such as human, mouse, rabbit, rat, rodent, primate, or any combination thereof, and can include or be derived from any mammal. Preferably, a human antibody or antigen-binding fragment binds to human IL-12 / IL-23p4 0 or IL-23, thereby partially or substantially neutralizing at least one biological activity of the protein. At least one IL-12 / IL-23p40 or IL ... ... ...

[0090] Preferably, a human antibody or antigen-binding fragment binds to human IL-12 / IL-23p4 0 or IL-23, thereby partially or substantially neutralizing at least one biological activity of the protein. At least one IL-12 / IL-23p40 or IL ... - At least one biological activity of the -23 protein or fragment is partially or preferably or substantially neutralizing antibodies or identified portions or variants thereof bind to the protein or fragment, thereby inhibiting the activity of IL-12 / IL-23p40 or IL-23 mediated through binding to the IL-12 and / or IL-23 receptor, or through other IL-12 / IL-2 3p40 or IL-23-dependent or mediated mechanisms. As used herein, the term "neutralizing antibody" refers to an antibody that can inhibit IL-12 / IL-23p40 or IL-23-dependent activity by about 20 to 120% depending on the assay, preferably at least about 10, 20, 30, 40, 50, 55, 60, 65 , 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, , 99, 100% or more. The ability of an anti-IL-12 / IL-23p40 or IL-23 antibody to inhibit IL- 12 / IL-23p40 or IL-23-dependent activity is preferably evaluated by at least one suitable IL-1 2 / IL-23p40 or IL-23 protein or receptor assay described herein and / or known in the art. Human antibodies can be of any class (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and can include kappa or lambda light chains. In one embodiment, the human antibody includes at least one isotype of an IgG heavy chain or defined fragment, such as IgG1, IgG2, IgG 3 or IgG4 (e.g., γ1, γ2, γ3, γ4). This type of antibody is described herein and / or known in the art. At least one human light chain (e.g., IgG, IgA, and IgM) transgene can include. For example, Among them, at least one isotype of ip is included. ​ It can be prepared by utilizing transgenic mice or other transgenic mammals other than humans that contain . In another embodiment, the anti-IL-23 human antibody comprises an IgG1 heavy chain and an IgG1 light chain.

[0091] The antibody binds to at least one specified epitope specific to at least one IL-12 / IL-23p40 or IL-23 protein, subunit, fragment, portion, or any combination thereof. This at least one epitope can comprise at least one antibody-binding region that includes at least a portion of the protein, and this epitope preferably consists of at least one extracellular portion, soluble portion, hydrophilic portion, outer portion, or cytoplasmic portion of the protein. In general, a human antibody or antigen-binding fragment comprises an antigen-binding region that includes at least one human complementarity-determining region (CDR1, CDR2, and CDR3) or a variant of at least one heavy-chain variable region, and also at least one human complementarity-determining region (CDR1, CDR2, and CDR3) or a variant of at least one light-chain variable region. The CDR sequences may be derived from human germline-type sequences or may be exactly identical to germline-type sequences. For example, CDRs derived from synthetic libraries derived from original non-human CDRs can be used. These CDRs can be formed by incorporating conservative substitutions derived from the original non-human sequences. In another specific embodiment, the antibody or antigen-binding portion or variant

[0092] has at least one light-chain C with the amino acid sequences of the corresponding CDR1, 2, and / or 3 (CDR1, CDR2, and CDR3) or a variant of at least one heavy-chain variable region, and also at least one human complementarity-determining region (CDR1, CDR2, and CDR3) or a variant of at least one light-chain variable region. The CDR sequences may be derived from human germline-type sequences or may be exactly identical to germline-type sequences. For example, CDRs derived from synthetic libraries derived from original non-human CDRs can be used. These CDRs can be formed by incorporating conservative substitutions derived from the original non-human sequences. In another specific embodiment, the antibody or antigen-binding portion or variant comprises an antigen-binding region that includes at least one human complementarity-determining region (CDR1, CDR2, and CDR3) or a variant of at least one heavy-chain variable region, and also at least one human complementarity-determining region (CDR1, CDR2, and CDR3) or a variant of at least one light-chain variable region. The CDR sequences may be derived from human germline-type sequences or may be exactly identical to germline-type sequences. For example, CDRs derived from synthetic libraries derived from original non-human CDRs can be used. These CDRs can be formed by incorporating conservative substitutions derived from the original non-human sequences. In another specific embodiment, the antibody or antigen-binding portion or variant can have CDRs derived from a synthetic library derived from the original non-human CDRs. These CDRs can be formed by incorporating conservative substitutions derived from the original non-human sequences. In another specific embodiment, the antibody or antigen-binding portion or variant has at least one light-chain C with the amino acid sequences of the corresponding CDR1, 2, and / or 3 formed by incorporating conservative substitutions derived from the original non-human sequences. In another specific embodiment, the antibody or antigen-binding portion or variant has at least one light-chain C with the amino acid sequences of the corresponding CDR1, 2, and / or 3 comprising at least a portion of a DR (i.e., CDR1, CDR2, and / or CDR3) can have an antigen-binding region.

[0093] Such antibodies can be prepared and expressed by using conventional techniques related to recombinant DNA technology to prepare (i.e., one or more) nucleic acid molecules encoding the antibody, or by chemically bonding various portions of the antibody (e.g., CDRs, frameworks) together by using any other suitable method, and can be prepared by using conventional techniques. CDR, framework) together chemically.

[0094] In one embodiment, the anti-IL-12 / 23p40 antibodies useful in the present invention are monoclonal antibodies, preferably human mAbs, each comprising heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR 3 of SEQ ID NOs: 1, 2, and 3, respectively, and light chain CDRs LCDR1, LCDR2, and L CDR3 of SEQ ID NOs: 4, 5, and 6, respectively. CDR3, preferably a human mAb.

[0095] Anti-IL-12 / IL-23p40 or IL-23 specific antibodies can comprise at least one of a heavy or light chain variable region having a defined amino acid sequence. For example, in a preferred embodiment, the anti-IL-12 / IL-23p40 or IL-23 antibody has a heavy chain variable region comprising an amino acid sequence that is at least 85%, preferably at least 90%, more preferably at least 95 %, and most preferably 100% identical to SEQ ID NO: 7, and a light chain variable region comprising an amino acid sequence that is at least 85%, preferably at least 90%, more preferably at least 95% identical to SEQ ID NO: 8, and an anti-IL -12 / IL-23p40 antibody. %, and most preferably 100% identical to SEQ ID NO: 8, and an anti-IL -12 / IL-23p40 antibody having the same. -12 / IL-23p40 antibody containing.

[0096] Anti-IL-12 / IL-23p40 or IL-23 specific antibodies can comprise at least one of a heavy chain or a light chain having a defined amino acid sequence. In another preferred embodiment, the anti-IL-12 / IL-23p40 or IL-23 antibody has a heavy chain comprising an amino acid sequence that is at least 85%, preferably at least 90%, more preferably at least 95%, and most preferably 100% identical to SEQ ID NO: 10, and a light chain variable region comprising an amino acid sequence that is at least 85%, preferably at least 90%, more preferably at least 95%, and most preferably 100% identical to SEQ ID NO: 11. Included are anti-IL-12 / IL-23p40 antibodies. Preferably, the anti-IL-12 / 23p40 antibody is ustekinumab (Stelara®) comprising a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO: 11. Other examples of anti-IL-12 / 23p40 antibodies useful in the present invention include briakinumab (ABT-874, Abbott) and other antibodies described in U.S. Patent Nos. 6,914,128, 7,247,711, 7,700,739 (the entire contents of which are incorporated herein by reference), but are not limited thereto. The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains, and CDRs comprising amino acids in sequences that are substantially the same as the amino acid sequences described herein. Preferably, such antibodies or antigen-binding fragments and antibodies comprising such chains or CDRs have high affinity (e.g., KD of about 10 ). ). ). ). ).

[0097] ). ). ). ). ). ). ).

[0098] ). ). ). ). -9M or less), human IL-12 / IL-23p4 0 or can bind to IL-23. Substantially the same as the sequences described herein Amino acid sequences that are the same include conservative amino acid substitutions and amino acid deletions and / or insertions Sequences containing are included. Conservative amino acid substitutions are chemical Similar and / or physical properties (e.g., charge, structure, polarity, hydrophobicity / hydrophilicity) of the first amino acid Refers to substituting the first amino acid with a second amino acid. Conservative substitutions include, but are not limited to, one Amino acid is replaced with another amino acid within the following groups: lysine (K), arginine (R), and histidine (H); aspartate (D) and glutamate (E ); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D, and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W) , methionine (M), cysteine (C), and glycine (G); F, W, and Y; C, S , and T.

[0099] Antibodies that bind to human IL-12 / IL-23p40 or IL-23 and contain defined heavy or light chain Variable regions are known in the art and / or described herein, phage display (Katsube, Y., et al., Int J Mol. Med, 1(5 ):863-868(1998)) or methods employing transgenic animals, etc., preferably Appropriate methods can be used for preparation. For example, a functionally reconstituted human immunoglobulin Heavy chain transgene and a human immunoglobulin light chain capable of undergoing functional rearrangement and a transgenic mouse comprising a transgene comprising DNA from the human I locus. Immunization with IL-12 / IL-23p40 or IL-23 or a fragment thereof If desired, antibody-producing cells can be isolated and the present invention can be used to As described herein and / or known in the art, hybrid Alternatively, antibodies, The identified portion or variant can be expressed by using the encoding nucleic acid or a portion thereof in a suitable host cell. It can be expressed using

[0100] The anti-IL-12 / IL-23p40 or IL-23 antibody used in the method of the present invention is As specified in the specification, one or more It may include the above amino acid substitutions, deletions, or additions.

[0101] The number of amino acid substitutions a skilled artisan would make depends on many factors, including those described above. In other words, a given anti-IL-12 / IL-23p40 or IL-23 antibody, fragment or The number of amino acid substitutions, insertions or deletions of the variants may be, as specified herein, 40, 30, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 0, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7 , 6, 5, 4, 3, 2, 1, for example, 1 to 30 or any range or value therein do not have.

[0102] Functionally essential anti-IL-12 / IL-23p40 or IL-23 specific antibodies The amino acid may be modified by any suitable method, such as site-directed mutagenesis or alanine scanning mutagenesis. This can be determined by methods known in the art (e.g., Ausube, supra). l, Chapters 8, 15; Cunningham and Wells, Sci ence 244: 1081 - 1085 (1989)). In the latter procedure, a mutation with a single alanine is introduced for each residue within the molecule. The resulting mutant molecules are then tested for biological activities such as, but not limited to, at least one IL-12 / IL-23p40 or IL-23 neutralizing activity. Sites that are extremely important for antibody binding can also be identified by structural analysis such as crystallization, nuclear magnetic resonance, or photoaffinity labeling ([[]] Smith, et al., J. Mol. Biol. 224: 899 - 904 (1992 and de Vos, et al., Science 255: 306 - 312 (199 2)).

[0103] Anti-IL-12 / IL-23p40 or IL-23 antibodies can include at least one moiety, sequence, or combination selected from 5 to all of at least one of the adjacent amino acids of SEQ ID NOs: 1, 2, 3, 4, 5 , 6, 7, 8, 10, or 11, but are not limited thereto.

[0104] As IL-12 / IL-23p40 or IL-23 antibodies or specific moieties or variants, there can be mentioned at least one moiety, sequence, or combination selected from at least 3 - 5 adjacent amino acids of the above SEQ ID NOs, 5 - 17 adjacent amino acids of the above SEQ ID NOs, 5 - 10 adjacent amino acids of the above SEQ ID NOs, 5 - 11 adjacent amino acids of the above SEQ ID NOs, 5 - 7 adjacent amino acids of the above SEQ ID NOs, 5 - 9 adjacent amino acids of the above SEQ ID NOs, but are not limited thereto. amino acids of the above SEQ ID NOs, but are not limited thereto.

[0105] ​​​​​​​​An anti-IL-12 / IL-23p40 or IL-23 antibody can further optionally comprise at least one polypeptide of 70-100% of the above sequences number 5, 17, 10, 11, 7, 9, 119, 108, 449, or 214 adjacent ami no acids. In one embodiment the amino acid sequence of an immunoglobulin chain, or a portion thereof (e.g., variable region, CDR) is about 70-10 0% identical (e.g., 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 , 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or any range or value therein) with the amino acid sequence of at least one corresponding chain of the above sequence numbers. For example, the amino acid sequence of the light chain variable region can be compared with the sequences of the above sequence numbers or the amino acid sequence of the heavy chain CDR3 can be compared with the above sequence numbers . Preferably, 70-100% amino acid identity (i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or any range or value therein) is , as known in the art, determined using suitable computer algorithms .

[0106] As known in the art, "identity" is determined by comparing sequences and is a relationship between two or more polypeptide sequences or two or more polynucleotide sequences . In the art, "identity" also means the degree of sequence relatedness between polypeptide or polynucleotide sequences, as determined by the match between such linear sequences . "Identity" and "similarity" are defined in Computational Molecular B . iology, Lesk, A.M., ed., Oxford University P ress, New York, 1988. Biocomputing: Informat ics and Genome Projects, Smith, D.W., ed., A cademic Press, New York, 1993. Computer Ana lysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H.G., eds., Humana Press, Ne w Jersey, 1994. Sequence Analysis in Molec ular Biology, von Heinje, G., Academic Pres s, 1987. And Sequence Analysis Primer, Gribsk ov, M. and Devereux, J., eds., M Stockton Pre ss, New York, 1991. And Carillo, H., and Lipma n, D., Siam J. Applied Math., 48:1073(1988)に described, but not limited to these, can be easily calculated by known methods. In addition, the value regarding the percentage of identity can be obtained from amino acid and nucleotide sequence alignments created using the default settings of

[0107] AlignX, a component of Vector NTI Suite 8.0 (Informax, Frederick, MD). The preferred method It is codified in the RAM. Preferred computer program methods for determining identity and similarity between two arrays include, but are not limited to, the GCG program package (Devereux, J., et al., Nucleic Acids Research 12(1 ):387(1984)), BLASTP, BLASTN, and FASTA (Atsch ul, S.F. et al., J. Molec. Biol. 215:403-410(1 990)). The BLAST X program is available publicly from NCBI and other sources (BLAST Manual, Altschul, S., et al., N CBINLM NIH Bethesda, Md. 20894: Altschul, S. , et al., J. Mol. Biol. 215:403-410(1990)). The well-known Smith Waterman algorithm can also be used to determine identity. Exemplary heavy and light chain variable region sequences, and portions thereof, are shown in the above sequence numbers. The antibodies of the present invention, or their identified variants, can include any number of adjacent amino acid residues from the antibodies of the present invention, and the number is selected from the group of integers consisting of 10 to 100% of the number of adjacent residues in the anti-IL-12 / IL-23p40 or IL-23 antibody. Optionally, this subsequence of adjacent amino acids is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170

[0108] 180, 190, 200, 210, 220, 230, 240, 250, or more amino acids. The antibodies of the present invention, or their identified variants, can include any number of adjacent amino acid residues from the antibodies of the present invention, and the number is selected from the group of integers consisting of 10 to 100% of the number of adjacent residues in the anti-IL-12 / IL-23p40 or IL-23 antibody. Optionally, this subsequence of adjacent amino acids is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170 180, 190, 200, 210, 220, 230, 240, 250, or more The length of the amino acid, or any range or value therein. Further, the number of such subsequences is at least Any integer selected from the group consisting of 1 to 20, such as at least 2, 3, 4, or 5 is possible.

[0109] As will be apparent to those skilled in the art, the present invention includes at least one biologically active antibody of the present invention. The biologically active antibody is natural (non-synthetic), endogenous, or related, and has a specific activity of at least 20%, 30%, or 40%, and preferably at least 50%, 60%, or 70%, and most preferably at least 80%, 90%, or 9 5% to 100% or more (including, but not limited to, up to 10 times the maximum specific activity) of that of known antibodies. Methods for the assay and quantitative measurement of enzyme activity and substrate specificity are well known to those skilled in the art.

[0110] In another aspect, the present invention relates to human antibodies and antigen-binding fragments described herein that are modified by covalent attachment of an organic moiety. Such modifications can produce antibodies or antigen-binding fragments with improved pharmacokinetic properties (e.g., increased serum half-life in vivo). The organic moiety can be a linear or branched hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. In certain embodiments, the hydrophilic polymer group has a molecular weight of about 800 to about 120,000 daltons and is a polyalkane glycol (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)), a carbohydrate polymer, an amino acid polymer, or polyvinyl pyrrolidone, and the fatty acid group or fatty acid ester group can contain about 8 to about 40 carbon atoms. (polypropylene glycol, PPG)), a carbohydrate polymer, an amino acid polymer, or polyvinyl pyrrolidone, and the fatty acid group or fatty acid ester group can contain about 8 to about 40 carbon atoms.

[0111] The modified antibodies and antigen-binding fragments may contain one or more organic moieties that are covalently attached directly or indirectly to the antibody. Each organic moiety attached to the antibody or antigen-binding fragment of the present invention is independently a hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. As used herein, the term "fatty acid" includes monocarboxylic acids and dicarboxylic acids. As used herein, the term "hydrophilic polymer group" means an organic polymer that has a higher solubility in water than octane. For example, polylysine has a higher solubility in water than octane. Thus, an antibody modified by covalent attachment of polylysine is included in the present invention. Suitable hydrophilic polymers for modifying the antibodies of the present invention may be linear or branched, and include, for example, polyalkylene glycols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG, etc.), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides, etc.), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, polyaspartic acid, etc.), polyalkylene oxides (e.g., polyethylene oxide, polypropylene oxide, etc.), and polyvinylpyrrolidone. Preferably, the hydrophilic polymer for modifying the antibodies of the present invention has a molecular weight of about 800 to about 150,000 daltons as an individual molecular entity. For example, PEG5000 and PEG20,000 can be used. The subscript indicates the average molecular weight (daltons) of the polymer. The hydrophilic polymer group can be substituted with 1 to about 6 alkyl groups, fatty acid groups, or fatty acid ester groups. Substituted with a fatty acid or fatty acid ester group is included in the present invention. The preferred hydrophilic polymers for modifying the antibodies of the present invention are branched or linear, and include, for example, polyalkylene glycols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG, etc.), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides, etc.), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, polyaspartic acid, etc.), polyalkylene oxides (e.g., polyethylene oxide, polypropylene oxide, etc.), and polyvinylpyrrolidone. Preferably, the hydrophilic polymer for modifying the antibodies of the present invention has a molecular weight of about 800 to about 150,000 daltons as an individual molecular entity. For example, PEG5000 and PEG20,000 can be used. The subscript indicates the average molecular weight (daltons) of the polymer. The hydrophilic polymer group can be substituted with 1 to about 6 alkyl groups, fatty acid groups, or fatty acid ester groups. As used herein, the term "fatty acid" includes monocarboxylic acids and dicarboxylic acids. As used herein, the term "hydrophilic polymer group" means an organic polymer that has a higher solubility in water than octane. For example, polylysine has a higher solubility in water than octane. Thus, an antibody modified by covalent attachment of polylysine is included in the present invention. Suitable hydrophilic polymers for modifying the antibodies of the present invention may be linear or branched, and include, for example, polyalkylene glycols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG, etc.), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides, etc.), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, polyaspartic acid, etc.), polyalkylene oxides (e.g., polyethylene oxide, polypropylene oxide, etc.), and polyvinylpyrrolidone. Preferably, the hydrophilic polymer for modifying the antibodies of the present invention has a molecular weight of about 800 to about 150,000 daltons as an individual molecular entity. For example, PEG5000 and PEG20,000 can be used. The subscript indicates the average molecular weight (daltons) of the polymer. The hydrophilic polymer group can be substituted with 1 to about 6 alkyl groups, fatty acid groups, or fatty acid ester groups. Substituted with a fatty acid or fatty acid ester group can be substituted with 1 to about 6 alkyl groups, fatty acid groups, or fatty acid ester groups. The hydrophilic polymers to be substituted can be prepared by using suitable methods. For example, a polymer containing an amine group can be linked to a carboxylate of a fatty acid or a fatty acid ester. The activated carboxylate on the fatty acid or fatty acid ester (e.g., activated by N,N-carbonyl diimidazole) can be linked to the hydroxyl group on the polymer.

[0112] The fatty acids and fatty acid esters suitable for modifying the antibodies of the present invention may be saturated or may contain one or more unsaturated units. Suitable fatty acids for modifying the antibodies of the present invention include, for example, n-dodecanoic acid (C12, lauric acid), n-tetradecanoic acid (C14, myristic acid), n-octadecanoic acid (C18, stearic acid), n-eicosanoic acid (C20, arachidic acid), n-docosanoic acid (C22, behenic acid), n-triacontanoic acid (C30), n-tetracosanoic acid (C40), cis-Δ9-octadecenoic acid (C 18, oleic acid), all cis-Δ5,8,11,14-eicosatetraenoic acid (C2 0, arachidonic acid), octanedioic acid, tetradecanedioic acid, octadecanedioic acid and docosanedioic acid. Suitable fatty acid esters include mono-esters of dicarboxylic acids containing a straight-chain or branched-chain lower alkyl group. The lower alkyl group may contain from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms.

[0113] Modified human antibodies and antigen-binding fragments can be prepared using suitable methods, such as reacting with one or more modifying agents. As used herein, the term "modifying agent" ​​, a suitable organic group containing an activating group (e.g., a hydrophilic polymer, a fatty acid, a fatty acid ester) means. An "activating group" is a chemical moiety or functional group that can react with a second chemical group under appropriate conditions to form a covalent bond between the modifier and the second chemical group. For example, amine-reactive activating groups include electrophilic groups such as tosylate, mesylate, halo (chloro, bromo, fluoro, iodo), and N-hydroxysuccinimidyl esters (N-hydrox ysuccinimidyl esters, NHS), etc. Activating groups capable of reacting with thiols include, for example, maleimide, iodoacetyl, acryloyl, pyridyldisulfide, 5-thiol-2-nitrobenzoic acid thiol (TNB-thiol), etc. An aldehyde functional group can be linked to an amine- or hydrazide-containing molecule, and an azide group can react with a trivalent phosphorus group to form a phosphoramidate or phosphorimide bond . Suitable methods for introducing an active group into a molecule are known in the art (see, for example, Hermanson, G.T., Bioconjugate Tec hniques, Academic Press: San Diego, CA (1996 ). The activating group can be bonded directly to an organic group (e.g., a hydrophilic polymer, a fatty acid, a fatty acid ester) or via a linker moiety (e.g., a divalent C1-C12 group, where one or more carbon atoms can be replaced by a heteroatom such as oxygen, nitrogen, or sulfur). Suitable linker moieties include, for example, tetraethylene glycol, -(CH2)3- , -NH-(CH2)6-NH-, -(CH2)2-NH-, and -CH2-O-CH2- . Examples include CH2-O-CH2-CH2-O-CH-NH-. Modifications containing a linker moiety The agent can be, for example, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (ethyl- 3-(3-dimethylaminopropyl)carbodiimide, EDC) in the presence of mono-Boc-alkyl diamine (e.g., mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid to form an amide bond between the free amine and the fatty acid carboxylate, thereby being generated. The Boc protecting group can be removed from the product by treatment with trifluoroacetic acid (TFA) to expose a primary amine that can be coupled to another carboxylate as described, or it can be reacted with maleic anhydride and the resulting product cyclized to generate an activated maleimide derivative of the fatty acid. (See, for example, International Publication No. 92 / 16221 (Thompson et al.), which is hereby incorporated herein by reference in its entirety).

[0114] The modified antibody can be produced by reacting a human antibody or antigen-binding fragment with the modifying agent. For example, the organic moiety can be attached to the antibody in a non-site-specific manner using an amine-reactive modifying agent such as the NHS ester of PEG. The modified human antibody or antigen-binding fragment can also be prepared by reducing the disulfide bonds (e.g., intra-chain disulfide bonds) of the antibody or antigen-binding fragment. At this time, the reduced antibody or antigen-binding fragment can be reacted with a thiol-reactive modifying Modified human antibodies and antigen-binding fragments containing organic moieties that bind to specific sites are prepared using suitable methods such as those described in reverse proteolysis (Fisch et al., Bioconjugate Che m., 3:147-153 (1992), Werlen et al., Bioconj ugate Chem., 5:411-417 (1994), Kumaran et a l., Protein Sci. 6(10):2233-2241 (1997), Ito h et al., Bioorg.Chem., 24(1):59-68 (1996), Capellas et al., Biotechnol.Bioeng., 56(4) :456-463 (1997)), and Hermanson, G.T., Bioconj ugate Techniques, Academic Press: San Dieg o, CA(1996). It can be done.

[0115] The methods of the present invention also provide at least one, at least two, at least three, at least four, at least five, at least six or more of those anti IL-12 / IL-23p40 or IL-23 antibodies, in unnatural-occurring compositions, mixtures, or forms, as described herein and / or known in the art Anti-IL-12 / IL-23p 40 or IL-23 antibody compositions are also used. Such compositions are at least 70-100% of the adjacent amino acids of the above sequence numbers, or a specified fragment, domain, or variant thereof Selected from the group consisting of amino acid sequences of anti-IL-12 / IL-23p40 or IL-23 antibodies At least one or two full-length, C- and / or N-terminal deletion mutants, domains , a non-naturally occurring composition comprising a fragment, or a specified variant. Preferred anti-IL -12 / IL-23p40 or IL-23 antibody compositions are, for example, 70 to 100% of the anti-IL-12 / IL-23p40 or IL-23 antibody sequences described herein, or a specified fragment, domain, or variant thereof, comprising at least one of the CDRs or LBP-containing portions as at least one or two full-lengths, fragments, domains, or variants. Even more preferred compositions are, for example, 70 to 100% of those described above, such as SEQ ID NOs, or at least one of a specified fragment, domain, or variant thereof, containing at least 40 to 99%. The percentages of such compositions are known in the art as such, or as described herein, by weight, volume, concentration, molarity, or molarity as a liquid or dry solution, mixture, suspension, emulsion, particle, powder , or colloid.

[0116] Antibody compositions containing additional therapeutic active ingredients The antibody compositions used in the methods of the present invention may optionally further contain at least one compound or protein selected from at least one of anti-infective agents, cardiovascular (CV) system acting agents, central nervous system (CNS) agents, autonomic nervous system (ANS) agents, respiratory agents, gastrointestinal (GI ) tract acting agents, hormonal agents, body fluid or electrolyte balance agents, blood acting agents, anti-tumor agents, immunomodulatory agents, ophthalmic, otic or nasal agents, topical agents, nutritional agents, etc., in an effective amount. Such agents are described in the present specification ) tract acting agents, hormonal agents, body fluid or electrolyte balance agents, blood acting agents, anti-tumor agents, immunomodulatory agents, ophthalmic, otic or nasal agents, topical agents, nutritional agents, etc., in an effective amount. Such agents are described in the present specification and can contain an effective amount of at least one compound or protein selected from at least one of them. Such agents are described in the present specification Well-known in the art, including each formulation, indication, dosage, and administration shown in the book (e.g., Nursing 2001 Handbook of Drug s, 21st edition, Springhouse Corp., Springh ouse, PA, 2001, Health Professional’s Drug Guide 2001, ed., Shannon, Wilson, Stang, Pren tice-Hall, Inc, Upper Saddle River, NJ, Phar mcotherapy Handbook, Wells et al., Appleto n&Lange, Stamford, CT are referred to, each of which is incorporated herein by reference ).

[0117] Examples of drugs that can be combined with the antibodies of the method of the present invention include, as anti-infective drugs, amoebicidal drugs or at least one antiprotozoal drug, anthelmintics, antifungal drugs, antimalarial drugs, antituberculosis drugs, or at least one antibacterial drug, aminoglycosides, penicillins, cephalosporins, tet racyclines, sulfonamides, fluoroquinolones, antiviral drugs, macrolide anti-infective drugs, and at least one selected from various anti-infective drugs. Hormonal drugs include corticosteroids, androgens, or at least one anabolic steroid, est rogens, or at least one progestin, gonadotropins, antidiabetic drugs, or at least one glucagon, thyroid hormones, thyroid hormone antagonists, pituitary hormones, and at least one selected from parathyroid-like drugs. At least one cephalospor lin includes cefaclor, cephradroxil, cefazolin sodium, cefdinir, hydrochloric acid (e.g., Nursing 2001 Handbook of Drug Cefepime, cefixime, cefmetazole sodium, cefonicid sodium, cef operazone sodium, cefotaxime sodium, cefotetan disodium, cef xitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime, cef tibuten, ceftezoxime sodium, ceftriaxone sodium, cefroxime ax etyl, cefroxime sodium, cefalexin hydrochloride, cefalexin monohydrate, cef radine, and loracarbef, and may be at least one selected therefrom.

[0118] At least one corticosteroid may be betamethasone, betamethasone acetate or betamethasone sodium phosphate, betamethasone sodium phosphate, cortisone acetate dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, acetate fluorocortisone, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate tizone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, me thylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate um, prednisolone, prednisolone acetate, prednisolone sodium phosphate, tebut onic acid prednisolone, prednisone, triamcinolone, triamcinolone acetonide, and and may be at least one selected from triamcinolone diacetate. At least one androgen or anabolic steroid drug is danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate, nandrolone phenpropionate, test osterone, testosterone cypionate, testosterone enanthate, testosterone propionate It may be at least one selected from testosterone and testosterone transdermal preparations.

[0119] At least one immunosuppressant may be at least one selected from azathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immunoglobulin, muromonab-CD3, mycophenolic acid mofetil, mycophenolate mofetil hydrochloride, sirolimus, 6-mercaptopurine, methotrexate, mizoribine, and tacrolimus.

[0120] At least one topical anti-infective agent is at least one selected from acyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole, econazole nitrate, erythromycin, gentamicin sulfate, ketoconazole, acetic acid mafenide, metronidazole (topical), miconazole nitrate, mupirocin, naftifine hydrochloride, neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, terbinafine hydrochloride, tetracycline hydrochloride, tioconazole, and tolnaftate. At least one scabies insecticide or lice-killing agent may be at least one selected from crothiamide, lindane, permethrin, and pyrethrin. At least one topical corticosteroid is betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate, fluocinonide acetonide, fluocinonide, flurandrenolide, fluocortolone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, butyric acid cortisone, etc. At least one selected from hydrocortisone acid, hydrocortisone valerate, mometasone furoate, and triamcinolone acetonide may be used. (For example, see pages 1098 to 1136 of Nursing 2001 Drug Handbook.)

[0121] The anti-IL-12 / IL-23p40 or IL-23 antibody composition is contacted with or administered to at least one cell, tissue, organ, animal, or subject in need of such regulation, treatment, or therapy, and contains at least one anti-IL-12 / 23p40 or IL-23 antibody, and optionally further contains at least one TNF antagonist (for example, but not limited to, a TNF chemical or protein antagonist, a TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (for example, p55, p70, or p85) or fragment, a fusion polypeptide thereof, or a small molecule TNF antagonist, such as TNF binding protein I or II (TBP-1 or TBP-II), nerelimonmab, infliximab, etanercept, CDP-571, CDP-870, afelimomab, renesept, etc.), an anti-rheumatic drug (for example, methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, sodium aurothiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), an immunization, an immunoglobulin, an immunosuppressive drug (for example, azathioprine, basiliximab, cyclosporine, daclizumab), a cytokine, or a cytokine antagonist, and can further contain at least one of any suitable and effective amount of a composition or a pharmaceutical composition. ​​​​​​​​​​​​​​​​Non-limiting examples of such cytokines include, but are not limited to, IL-1 to IL-23 (e.g., IL -1, IL-2, etc.). Suitable dosages are well known in the art. For example, see Wells et al., eds., P harmacotherapy Handbook, 2nd Edition, Appl eton and Lange, Stamford, CT (2000), PDR Pha rmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing , Loma Linda, CA (2000), each of which is hereby incorporated by reference in its entirety into this specification.

[0122] The anti-IL-12 / IL-23p40 or IL-23 antibody compounds, compositions, or mixtures used in the methods of the present invention may further comprise at least one of any suitable adjuvants such as, but not limited to, diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc. Pharmaceutically acceptable adjuvants are preferred. Methods for preparing such sterile solutions and non-limiting examples thereof are well known in the art and include, for example, Gennaro, Ed., Remington’s Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (Easton, P A), 1990, but are not limited thereto. Well known in the art or as described herein, pharmaceutically acceptable carriers suitable for the administration methods, solubility, and / or stability of anti-IL-12 / IL-23p40, fragments, The body can be selected on a daily basis.

[0123] Pharmaceutical excipients and additives useful in the present composition include, but are not limited to, tampa proteins, peptides, amino acids, lipids, and carbohydrates (e.g., saccharides including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides, alditols, aldonic acids, derivatized sugars such as esterified sugars, and polysaccharides or sugar polymers), which may be present alone or in combination and are included in an amount of 1 to 99.99% by weight or volume, either alone or in combination. Exemplary protein excipients include serum albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, case in, etc. Representative amino acid / antibody components that can also function in buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenyl alanine, aspartame, etc. One of the preferred amino acids is glycine . .

[0124] Suitable carbohydrate excipients for use in the present invention include, for example, monosaccharides such as fructose, maltose , galactose, glucose, D-mannose, sorbose, etc., disaccharides such as lactose , sucrose, trehalose, cellobiose, etc., polysaccharides such as raffinose, melezitose , maltodextrin, dextran, starches, etc., and alditols such as mannitol, xylitol , maltitol, lactitol, xylitol, sorbitol (glucitol), mi Alditols such as myo-inositol can be mentioned. The carbohydrate excipients preferably used in the present invention are mannitol, trehalose, and raffinose.

[0125] The anti-IL-12 / IL-23p40 or IL-23 antibody composition may also contain a buffer or a pH adjuster and typically, the buffer is a salt prepared from an organic acid or a base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid , or phthalic acid, tris, tromethamine hydrochloride, or phosphate buffers. Preferred buffers for use in the present composition are organic acid salts such as citric acid.

[0126] In addition, the anti-IL-12 / IL-23p40 or IL-23 antibody composition may contain polymer excipients / additives such as polyvinylpyrrolidone, ficoll (polymer sugar), dextrates (such as cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin), polyethylene glycol, flavoring agents, antibacterial agents, sweeteners, antioxidants, antistatic agents, surfactants (such as polysorbates such as "TWEEN20" and "TWEEN80"), lipids (such as phospholipids, fatty acids) , steroids (such as cholesterol), and chelating agents (such as EDTA).

[0127] These and additional known pharmaceutical excipients and / or additives suitable for use in the anti-IL-12 / IL-23p40 or IL-23 antibody, fragment or variant composition according to the present invention are known in the art and are described, for example, in "Remington: The Science & Practice of Pharmacy", 19th ed., William & Wilkins, Philadelphia, PA (1995). s&Williams, (1995), and "Physician’s Desk Re ference", 52nd ed, Medical Economics, Montv ale, NJ (1998), and these disclosures are incorpor ated herein by reference in their entirety. Prefe rred carrier or excipient materials are carbohydr ates (e.g., monosaccharides and alditols) and buff

[0128] Formulations As described above, the present invention pref erably provides a stable formulation comprisin g physiological saline or a phosphate buffer c ontaining a selected salt, as well as a preservat ion solution and formulation containing a preser vative, and a multi-purpose preservative formu lation suitable for pharmaceutical or veterina ry use containing at least one anti-IL-12 / IL-23p4 0 or IL-23 antibody. The preservative formula lation contains, in an aqueous diluent, at least one known preservative, i.e., at least one of p henol, m-cresol, p-cresol, o-cresol, chlorocresol 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, or any range or value therein etc., but not limited thereto, any suitable concentration or mixture of any range or value therein can be used. As non-limiting examples, preservative-free, 0.1 - 2% m- cresol (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1 - 3% benzyl alcohol (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0 , 2.5%), 0.001 - 0.5% thimerosal (e.g., 0.005, 0.01) , 0.001 - 2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5 , 0.9, 1.0%), 0.0005 - 1.0% alkyl parabens (plural available) (e.g., , 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075 , 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2 , 0.3, 0.5, 0.75, 0.9, 1.0%) etc. can be mentioned.

[0129] As described above, the method of the present invention uses a product comprising at least one vial containing a packaging material and a solution of at least one anti-IL-12 / IL-23p40 or IL-2 3 antibody, optionally with a buffer and / or a preservative formulated in an aqueous diluent, and the packaging material Such a solution can be retained for 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40 , 48, 54, 60, 66, 72 hours or more, and includes a label The present invention further uses a product comprising a packaging material, a first vial containing a lyophilized anti-IL-12 / IL-23p40 or IL-23 antibody, and a second vial containing an aqueous diluent of a formulated buffer or preservative, wherein the packaging material includes a label instructing the subject to reconstitute the anti-IL-12 / IL-23 p40 or IL-23 antibody with an aqueous diluent to form a solution that can be retained for 24 hours or more.

[0130] The anti-IL-12 / IL-23p40 or IL-23 antibody used according to the present invention can be produced by recombinant means including being produced from mammalian cells or transgenic preparations as described in the present specification or known in the art, or can be purified from other biological sources.

[0131] The range of the anti-IL-12 / IL-23p40 or IL-23 antibody, in the case of a wet / dry system, is included in an amount that provides a concentration of about 1.0 μg / ml to about 1000 mg / ml when reconstituted, but can also be operative at lower and higher concentrations and depends on the intended delivery vehicle, for example, in a solution formulation, it is different from a transdermal patch, lung, transmucosal, or osmotic or micropump method.

[0132] Preferably, the aqueous diluent optionally further includes a pharmaceutically acceptable preservative. Preferred preservatives include phenol, m-cresol, p-cresol, o-cresol, chloro cresol, benzyl alcohol, alkyl parabens (methyl, ethyl, propyl, butyl ​​​​​ benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal or mixtures thereof. The concentration of preservatives used in the formulation is a concentration sufficient to produce an antibacterial effect. Such concentration varies depending on the preservative selected and can be readily

[0133] determined by those skilled in the art. Other excipients, such as isotonic agents, buffering agents, antioxidants, and preservative enhancers, can be optionally and preferably added to the diluent. Isotonic agents such as glycerin are commonly used at known concentrations. Preferably, a physiologically tolerated buffering agent is added to provide improved pH control. The formulation can be targeted to a wide range of pH ranges, such as from about pH 4 to about pH 10, and preferably from about pH 5 to about pH 9, and most preferably from about 6.0 to about 8.0. Preferably, the formulation of the present invention has a pH of

[0134] about 6.8 to about 7.8. Suitable buffering agents include phosphate buffering agents, and most preferably, sodium phosphate, especially phosphate buffered saline (PBS). Other additives, such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 Registered trademark) Nonionic surfactants such as polyls, other block copolymers, and Chelating agents such as EDTA and EGTA can be optionally added to the formulation or composition to reduce aggregation. These additives are particularly useful when pumps or plastic containers are used for administering the formulation. The presence of pharmaceutically acceptable surfactants reduces the tendency of proteins to aggregate.

[0135] The formulation comprises at least one anti-IL-12 / IL-23p40 or IL-23 antibody and phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal or a preservative selected from the group consisting of these mixtures, and is prepared by a process comprising mixing in an aqueous diluent. Mixing of at least one anti-IL-12 / IL-23p 40 or IL-23 specific antibody with the preservative in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a fixed amount of at least one anti-IL-12 / IL-23p40 or IL-23 antibody in a buffer solution is combined with the desired preservative in a buffer solution in an amount sufficient to provide the desired concentration of protein and preservative. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, the presence or absence of additional additives, the temperature and pH during formulation preparation are

[0136] The formulation is provided to the subject as a dual vial containing a lyophilized anti-IL-12 / IL-23p40 or IL-23 specific antibody vial that is reconstituted in a second vial containing water, a preservative and / or excipient, preferably a phosphate salt buffer and / or saline, and a selected salt in an aqueous diluent. Single solution vials or dual vials that require reconstitution can both be reused multiple times and can satisfy single or multiple subject treatment cycles, thus providing a more convenient treatment regimen than is currently available. The product is useful for administration over a period ranging from immediately up to 24 hours or more. Thus, the product claimed by the present invention provides a great benefit to the subject. The formulation of the present invention can be safely stored at a temperature of about 2°C to about 40°C as desired and retain the biological activity of the protein for a long time, and thus the packaging label can indicate that the solution can be stored and / or used for 6, 12, 18, 24, 36, 48, 72, or 96 hours or more. When using a stored diluent, such a label can include use up to 1 to 12 months, half a year, one and a half years and / or up to 2 years. A solution of an anti-IL-12 / IL-23p40 or IL-23 specific antibody can be prepared by a process that includes mixing at least one

[0137] antibody in an aqueous diluent. Mixing is carried out using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, a certain amount of at least one antibody in water or a buffer is brought to the desired concentration of protein, and The claimed product of the present invention provides a great benefit to the subject. The formulation of the present invention can be safely stored at a temperature of about 2°C to about 40°C as desired and retain the biological activity of the protein for a long time, and thus the packaging label can indicate that the solution can be stored and / or used for 6, 12, 18, 24, 36, about 2°C to about 40°C as desired and retain the biological activity of the protein for a long time, and thus the packaging label can indicate that the solution can be stored and / or used for 6, 12, 18, 24, 36, 48, 72, or 96 hours or more. When using a stored diluent, such a label can include use up to 1 to 12 months, half a year, one and a half years and / or up to 2 years. When using a stored diluent, such a label can include use up to 1 to 12 months, half a year, one and a half years and / or up to 2 years.

[0138] A solution of an anti-IL-12 / IL-23p40 or IL-23 specific antibody can be prepared by a process that includes mixing at least one antibody in an aqueous diluent. Mixing is carried out using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, a certain amount of at least one antibody in water or a buffer is brought to the desired concentration of protein, and is carried out using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, a certain amount of at least one antibody in water or a buffer is brought to the desired concentration of protein, and for example, a certain amount of at least one antibody in water or a buffer is brought to the desired concentration of protein, and and optionally combine in an amount sufficient to provide a preservative or buffer. This process variations will be recognized by those skilled in the art. For example, the order of addition of components, the addition of additional additives, the temperature and pH during formulation preparation are all factors that can be optimized with respect to the dosage concentration and administration regimen to be used.

[0139] The claimed product can be provided to a subject as a clear solution or as a dual vial containing a second vial containing an aqueous diluent, which is returned to a lyophilized vial of at least one anti-IL-12 / IL-23p40 or IL-23 specific antibody. A single solution vial or a dual vial requiring reconstitution can both be reused multiple times and can fulfill one or more subject treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0140] The claimed product can be indirectly provided to a subject by providing a dual vial containing a lyophilized vial of at least one anti-IL-12 / IL-23p40 or IL-2 3 specific antibody, which is returned to a clear solution or a second vial containing an aqueous diluent, to a pharmacy, clinic, or other such institution and facility. The clear solution in this case can have a volume of up to 1 liter or even more, and a smaller amount of at least one antibody solution can be removed from this large container one or more times and transferred to a smaller vial and provided to customers and / or subjects by a pharmacy or clinic.

[0141] Approved devices containing a single vial system include BD Pens, BD Autoj ​​​​ector (Registered Trademark), Humaject (Registered Trademark), NovoPen (Registered Trademark) , B-D (Registered Trademark) Pen, AutoPen (Registered Trademark), and OptiPen (Registered Trademark), GenotropinPen (Registered Trademark), Genotronorm Pen( Registered Trademark), Humatro Pen (Registered Trademark), Reco-Pen (Registered Trademark), R oferon Pen (Registered Trademark), Biojector (Registered Trademark), Iject (Registered Trademark), J-tip Needle-Free Injector (Registered Trademark), In traject (Registered Trademark), Medi-Ject (Registered Trademark), Smartject( Registered Trademark), etc., pen-type injector devices for solution delivery (e.g., Becton D ickensen (Franklin Lakes, NJ, www.bectondic kenson.com), Disetronic (Burgdorf, Switzerl and, www.disetronic.com), Bioject, Portland , Oregon (www.bioject.com), National Medica l Products, Weston Medical (Peterborough, U K, www.weston-medical.com), Medi-Ject Corp (Minneapolis, MN, www.mediject.com) manufactured or developed by), and similar suitable devices. Approved devices including combination vial systems include pen-type injection systems for dissolving freeze-dried drugs in a cartridge for delivering a dissolved solution, such as HumatroPen (Registered Trademark). Examples of other suitable devices include pre-filled syringes, self ​​ Examples include autoinjectors, needleless syringes, and needleless IV infusion sets.

[0142] The product may include a packaging material. The packaging material provides the conditions under which the product can be used, in addition to the information required by the regulatory authorities. The packaging material of the present invention, where applicable, returns at least one anti-IL-12 / IL-23p40 or IL-23 antibody to an aqueous diluent to form a solution and provides instructions for using this solution in wet / dry two-vial products over a period of 2 to 24 hours or more. For single-vial solution products, pre-filled syringes, or autoinjectors, the label indicates that such a solution can be used over a period of 2 to 24 hours or more. The product is useful for pharmaceutical product applications in humans .

[0143] The formulation used in the method of the present invention can be prepared by a process that includes mixing an anti-IL-12 / IL-23p40 and a selected buffer, preferably phosphate buffer containing saline or a selected salt. Mixing of the anti-IL-12 / IL-23p40 antibody and the buffer in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a certain amount of at least one antibody in water or buffer is combined with the desired buffer in water in an amount sufficient to provide the desired concentration of protein and buffer. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, the presence or absence of additional additives, the temperature and pH during formulation preparation are all factors that can be optimized with respect to the administration concentration and means of administration to be used.

[0144] ​​​​​​​​​The method of the present invention provides a pharmaceutical composition useful and acceptable for administration to human or animal subjects, which comprises. Such pharmaceutical compositions are prepared using water in "standard state" as a diluent and routine methods well known to those skilled in the art. For example, buffer components such as histidine and histidine monohydrochloride monohydrate are first provided, followed by the addition of a suitable non-final volume of "standard state" water diluent, sucrose, and polysorbate 80. Then, the isolated antibody can be added. Finally, the volume of the pharmaceutical composition is adjusted to the desired final volume under the "standard state" conditions using water as the diluent. Those skilled in the art will recognize several other methods suitable for the preparation of pharmaceutical compositions.

[0145] The pharmaceutical composition can contain each component in the indicated mass per volume unit of water, or can be an aqueous solution or suspension having the indicated pH in "standard state". As used herein , the term "standard state" means a temperature of 25 °C ± 2 °C and a pressure of 1 atmosphere. " Standard state" is not used in the art to refer to a set of temperatures or pressures recognized by a single art, but rather is a reference state that specifies the temperature and pressure used to describe a solution or suspension containing a particular composition under reference "standard state" conditions. This is because the volume of the solution is a function of temperature and pressure in part. Those skilled in the art will recognize that pharmaceutical compositions equivalent to those disclosed herein can be manufactured at other temperatures and pressures. Whether such pharmaceutical compositions are equivalent to those disclosed herein should be determined under the "standard state" conditions defined above (e.g., 25 °C ± 2 °C and a pressure of 1 atmosphere).

[0146] Importantly, such pharmaceutical compositions contain a component mass of "about" a certain value (e.g., "about 0.53 mg of L - histidine") per unit volume of the pharmaceutical composition, or may have a pH value of about a certain value. The component mass or pH value present in the pharmaceutical composition is such that, whether the isolated antibody is present in the pharmaceutical composition or after the isolated antibody has been removed from the pharmaceutical composition (e.g., by dilution), the isolated antibody present in the pharmaceutical composition can bind to the peptide chain when it can bind to the peptide chain. That is, the mass value of the component or a value such as the pH value is "about" a given numerical value when the binding activity of the isolated antibody is maintained and detectable after the isolated antibody is placed in the pharmaceutical composition. That is, the mass value of the component or a value such as the pH value is "about" a given numerical value when the binding activity of the isolated antibody is maintained and detectable after the isolated antibody is placed in the pharmaceutical composition. Perform competitive binding assays to determine whether the IL - 12 / IL - 23p40 or IL - 23 - specific mAb binds to similar or different epitopes and / or competes with each other. E Individually coat the Ab on the ELISA plate. Add competing mAbs, followed by

[0147] biotinylated hrIL - 12 or IL - 23. For the positive control, the same mAb used for coating can be used as the competing mAb ("self - competition"). IL - 12 / IL - 23p 40 or IL - 23 binding is detected using streptavidin. These results indicate whether the mAb recognizes similar or partially overlapping epitopes on IL - 12 / IL - 23p40 or IL - 23. whether the mAb recognizes similar or partially overlapping epitopes on IL - 12 / IL - 23p40 or IL - 23. whether the mAb recognizes similar or partially overlapping epitopes on IL - 12 / IL - 23p40 or IL - 23.

[0148] In one embodiment of the pharmaceutical composition, the isolated antibody concentration is about 7 7 to about 104 mg per 1 mL of the pharmaceutical composition. In another embodiment of the pharmaceutical composition, the pH is about 5.5 to about 6.5 is.

[0149] The stable or preservable formulation can be provided to a patient as a combined vial containing a lyophilized at least one anti-IL-12 / IL-23p40 vial, which is returned to a second vial containing a preservative or buffer and / or an excipient as a transparent solution or in an aqueous diluent. Both single-solution vials or dual vials requiring reconstitution can be reused multiple times and can fulfill single or multiple treatment cycles, thus providing a more convenient treatment regimen than currently available.

[0150] Other formulations or methods for stabilizing anti-IL-12 / IL-23p40 antibodies may be other than a transparent solution of a lyophilized powder containing the antibody. Non-transparent solutions include formulations containing microparticle suspensions, such microparticles being compositions containing anti-IL-12 / IL-23p40 antibodies within variously sized structures variously known as microspheres, microparticles, nanoparticles, nanospheres, or liposomes. Such relatively homogeneous, essentially spherical microparticle formulations containing the active agent can be formed, as taught in U.S. Patent No. 4,589,330, by contacting an aqueous phase and a non-aqueous phase containing the active agent and a polymer, and then evaporating the non-aqueous phase to cause coalescence of the particles from the aqueous phase. Porous microparticles can be prepared, as taught in U.S. Patent No. 4,818,542, using a first phase containing the active agent and a polymer dispersed in a continuous solvent and removing the solvent from the suspension by lyophilization or dilution-extraction-precipitation. Polymers preferred for such preparations are gelatin, agar, starch, arabinogalactan, albumin, collagen, polyglycol Acids, polylactic acid, glycolide-L(-)lactide poly(epsilon-caprolactone), poly (epsilon-caprolactone-CO-lactic acid), poly(epsilon-caprolactone-C O-glycolic acid), poly(beta-hydroxybutyric acid), polyethylene oxide, polyethyl ene, poly(alkyl-2-cyanoacrylate), poly(hydroxyethyl methacrylate to), polyamide, poly(amino acid), poly(2-hydroxyethyl DL-aspartoic a mid), poly(ester urea), poly(L-phenylalanine / ethylene glycol / 1 ,6-diisocyanatohexane) and poly(methyl methacrylate) selected from the group consisting of natural or synthetic copolymers or polymers. Particularly preferred polymers are poly glycolic acid, polylactic acid, glycolide-L(-)lactide poly(epsilon-caprolact one), poly(epsilon-caprolactone-CO-lactic acid), and poly(epsilon-capro lactone-CO-glycolic acid) and other polyesters. Solvents useful for dissolving the polymer and / or the active substance include water, hexafluoroisopropanol, methylene chloride, tetrahydrofuran, hexane, benzene, or hexafluoroacetone sesqui hydrate. The process of dispersing the active substance-containing phase into the second phase can include a step of forcing the above-mentioned first phase through the orifices in the nozzle under pressure to act on droplet formation . Dry powder formulations can be obtained as a result of processes other than freeze-drying, such as spray drying, solvent extraction by evaporation, or solvent extraction by precipitation of a crystalline composition followed by one or more steps for removing aqueous or non-aqueous solvents. Spray-dried antibody formulations .

[0151] For example, spray drying, solvent extraction by evaporation, or solvent extraction by precipitation of a crystalline composition followed by one or more steps for removing aqueous or non-aqueous solvents. Spray-dried antibody formulations can be obtained as a result of processes other than freeze-drying. The preparation is taught in U.S. Patent No. 6,019,968. Antibody-based dry powder compositions can be produced by spray drying a solution or slurry of the antibody and, optionally, an excipient in a solvent under conditions to provide a respirable dry powder. Solvents can include polar compounds that are readily driable, such as water and ethanol. The stability of the antibody can be enhanced by performing the spray drying procedure in the absence of oxygen, such as under a nitrogen blanket, or by using nitrogen as the drying gas. Another relatively dry formulation is a dispersion of a plurality of porous microstructures dispersed in a suspension medium, typically containing a hydrofluoroalkane propellant, as taught in International Publication No. WO 99 / 16419. The stabilized dispersion can be administered to the lungs of a subject using a metered dose inhaler. Equipment useful in the commercial manufacture of spray dried pharmaceuticals is manufactured by Buchi Ltd. or Niro Corp. Any of the stable or preservative formulations or solutions described herein of anti-IL-12 / IL -23p40 can be administered to a subject according to the present invention via a variety of delivery methods such as SC or IM injection, transdermal, transpulmonary, transmucosal, implantation, osmotic pump, cartridge, micropump, or other means well known in the art and understood by one of ordinary skill in the art.

[0152]

[0153] Therapeutic Applications The present invention also provides for administering or contacting a therapeutically effective amount of IL-12 / IL-23p40 or an IL-23 specific antibody to a cell, tissue, organ, animal, or subject, for example, using at least one IL-23 antibody of the present invention as known in the art or as described herein. ​​​​​​​​​​ for regulating or treating ulcerative colitis in cells, tissues, organs, animals, or subjects also provides a method of

[0154] Any method of the present invention involves administering a composition or pharmaceutical composition containing IL-12 / IL-23p40 to cells, tissues, organs, animals, or subjects in need of such regulation, treatment, or therapy in an effective amount. Such methods may further include, if desired, co-administration or combination therapy for the treatment of such diseases or disorders, where administration of at least one IL-12 / IL-23p40, specific moiety, or variant thereof is at least one TNF antagonist (e.g., but not limited to, a chemical or proteinaceous TNF antagonist, a TNF monoclonal or polyclonal antibody or fragment thereof, a soluble TNF receptor (e.g., p55, p70, or p85) or fragment thereof, a fusion polypeptide thereof, or a small molecule TNF antagonist, such as TNF binding protein I or II (TBP-1 or TBP-II), neralimomab, infliximab, etanercept (Enbrel™), adalimumab (Humira™), CDP-5 71, CDP-870, afelimomab, renercept, etc.), antirheumatic drugs (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, sodium aurothiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxants, anesthetics, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., 5-aminosalicylic acid ), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blocking agents, antibacterial agents (e.g., aminogly ycosides, antifungal agents, antiparasitic agents, antiviral agents, carbapenems, cephalosporins, f or example, methotrexate, auranofin, aurothioglucose, azathioprine, sodium aurothiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxants, anesthetics, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., 5-aminosalicylic acid ), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blocking agents, antibacterial agents (e.g., aminogly ycosides, antifungal agents, antiparasitic agents, antiviral agents, carbapenems, cephalosporins, f or example, aminoglycosides, antifungal agents, antiparasitic agents, antiviral agents, carbapenems, cephalosporins, f Luloxynolone, macrolide, penicillin, sulfonamide, tetracycline, and the like (other antibacterial agents), psoriasis treatment agents, corticosteroids, anabolic steroids, diabetes-related drugs , minerals, nutritional agents, thyroid agents, vitamins, calcium-related hormones, antidiarrheal agents, antitussive agents , antiemetic agents, antitumor agents, laxatives, anticoagulants, erythropoietin (e.g., epoetin alfa ), filgrastim (e.g., G-CSF, Neupogen), sargramostim (GM-CSF, Leukine), immunopotentiators, immunoglobulins, immunosuppressants (e.g., basiliximab, cyclosporine, daclizumab), growth hormones, hormone replacement agents, e strogen receptor modulators, mydriatics, cycloplegics, alkylating agents, antimetabolites, mitotic inhibitors , radiopharmaceuticals, antidepressants, antimanic agents, antipsychotics, anxiolytics, hypnotics, sympathomimetics , stimulants, donepezil, tacrine, asthma treatment agents, beta-agonists, inhaled steroids , leukotriene inhibitors, methylxanthines, cromolyn, epinephrine or analogs , dornase alfa (Pulmozyme), cytokines or cytokine antagonists administer at least one selected from the group consisting of before, simultaneously with, and / or after . Suitable dosages are well known in the art. For example, Wells et al., eds., Pharmacotherapy Handbook, 2nd Ed ition, Appleton and Lange, Stamford, CT (200 0), PDR Pharmacopoeia, Tarascon Pocket Pha rmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), Nursing 2 001 Handbook of Drugs, 21st edition, Sprin ghouse Corp., Springhouse, PA, 2001, Health Professional’s Drug Guide 2001, ed., Shann on, Wilson, Stang, Prentice - Hall, Inc, Upper Saddle River, NJ, are referred to, and each of these references is hereby incorporated by reference in its entirety into this specification.

[0155] Treatment The treatment of ulcerative colitis is affected by administering an effective amount or dosage of an anti - IL - 12 / 23p40 composition to a subject in need thereof. The dosage administered will vary depending on known factors such as the pharmacodynamic characteristics of the particular agent as well as its method and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms the type of concurrent treatment, the frequency of treatment, and the desired effect. In some cases, repeated administration, i.e., providing repeated individual administrations of a specific monitored or measured amount, may be necessary to reach the desired therapeutic amount and in this case, the individual administrations are repeated until the desired daily dose or effect is obtained.

[0156] In one exemplary regimen for providing a safe and effective treatment of severe active UC in a subject in need thereof about 130 mg of the total dose of an anti - IL - 12 / IL - 23p40 antibody is administered intravenously to the subject per administration. For example, the total volume of the composition administered is 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 14 mg, etc. per administration. ​Target doses of the antibody are 0 mg, 150 mg, 160 mg, 170 mg or 180 mg are appropriately adjusted to be provided to a subject.

[0157] Provide safe and effective treatment of severe active UC to subjects in need thereof In one exemplary regimen, a total dose of anti-IL-12 / IL-23 p40 antibody of about 6.0 ± 1.5 mg / kg is intravenously administered to a subject per administration. For example, the composition to be administered total amount is 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, 6.5 mg / k g, 7.0 mg / kg, 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, or 9.0 mg per 1 kg of subject body weight, and is appropriately adjusted to provide the target dose of the antibody to the subject. regulated.

[0158] The total dose of anti-IL-12 / IL-23 p40 antibody administered to a subject per administration is about administered by intravenous infusion over a period of 30 minutes to 180 minutes, preferably 60 minutes to 120 minutes, for example, 30 minutes, 6 0 minutes, 90 minutes, 120 minutes, 150 minutes, or 180 minutes. can be.

[0159] Provide safe and effective treatment of severe active UC to subjects in need thereof In another exemplary regimen, a total dose of about 90 mg of anti-IL-12 / IL-23 p40 antibody is subcutaneously administered to a subject per administration. For example, the total amount of the composition to be administered is per administration 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 m g, 120 mg, 130 mg, or 140 mg, and the target dose of the antibody is provided to the subject. It is appropriately adjusted as described above. The target dose per administration can be administered by a single subcutaneous injection or multiple subcutaneous injections, for example, 1, 2, 3, 4, 5 or more subcutaneous injections. It can be done.

[0160] The total dose of the anti-IL-12 / IL-23p40 antibody can be administered once a day, once a week, once a month, once every 6 months, etc., over a period of 1 day, 1 week, 1 month, 6 months, 1 year, 2 years or more. Multiple administrations of the anti-IL-12 / IL-23p40 antibody at the total dose described herein can be administered to a subject in need thereof. It can be administered.

[0161] Dosage forms (compositions) suitable for parenteral administration generally contain from about 0.001 milligrams to about 500 milligrams of the active ingredient per unit or container.

[0162] For parenteral administration, the antibody can be formulated as a solution, suspension, emulsion, particles, powder, or lyophilized powder, provided together with or separately from a pharmaceutically acceptable parenteral vehicle. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and 1-10% human serum albumin. Non-aqueous vehicles such as liposomes and non-volatile oils can also be used. The vehicle or lyophilized powder can contain additives (e.g., sodium chloride, mannitol for isotonicity; buffers and preservatives for chemical stability) to maintain isotonicity and chemical stability. The formulation is sterilized by known or suitable techniques. It can be sterilized.

[0163] Suitable pharmaceutical carriers are described in Remington’s, a standard reference text in this field. Described in the latest edition of Pharmaceutical Sciences, A. Osol It is described.

[0164] To administer a pharmaceutically effective amount of an IL-12 / IL-23p40 antibody, according to the present invention many known and developed methods can be used. The IL-12 / IL-23p40 or IL-23 antibody of the present invention can be delivered in a carrier, as a solution, emulsion, colloid or suspension, or as a dry powder, by inhalation, or by any of a variety of devices and methods suitable for administration by other means described herein or known in the art. It can be delivered using any of the methods.

[0165] Formulations for parenteral administration may contain sterile water or physiological saline as common excipients, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydrogenated naphthalene, etc. It may also contain. Aqueous or oily suspensions for injection can be prepared by using appropriate emulsifiers or wetting agents and suspending agents according to known methods. Injectables may be, for example, non-toxic parenterally administrable diluents such as aqueous solutions, sterile injectable solutions or suspensions in solvents. Possible vehicles or solvents that can be used include water, Ringer's solution, isotonic physiological saline, etc., and for ordinary solvents or suspending solvents, sterile non-volatile oils can be used. For these purposes all kinds of non-volatile oils and fatty acids, including natural or synthetic or semi-synthetic, fatty oils or fatty acids, natural or synthetic or semi-synthetic, monoglycerides or diglycerides or triglycerides can be used. Parenteral administration is known in the art and conventional injection means, gas pressurized needleless as described in U.S. Patent No. 5,851,198 natural or synthetic or semi-synthetic, including monoglycerides or diglycerides or triglycerides, can be used. Parenteral administration is known in the art and conventional injection means, gas pressurized needleless as described in U.S. Patent No. 5,851,198 Injectable devices, and laser drilling devices such as those described in U.S. Patent No. 5,839,446 are included, but are not limited thereto, and these are incorporated herein by reference in their entirety.

[0166] Alternative delivery The present invention further relates to the administration of anti-IL-12 / IL-23p40 or IL-23 antibodies by parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intra-bronchial, intra-abdominal, intra-capsular, intra-cartilaginous, intra-cavity, intra-cerebellar, intra-ventricular, intra-colonic, intra-cervical, intra-gastric, intra-hepatic, intra-myocardial, intra-osseous, intra-pelvic, intra-pericardial, intra-abdominal, intra-pleural, intra-prostatic, intra-pulmonary, intra-rectal, intra-renal, intra-retinal, intra-spinal cord, intra-synovial sac, intra-thoracic, intra-uterine, intra-bladder, intra-lesion, bolus, intra-vaginal, rectal, intra-oral, sublingual, intra-nasal, or transdermal means. The anti-IL-12 / IL-23p40 or IL-23 antibody composition is for parenteral (subcutaneous, intramuscular, or intravenous) or any other administration, particularly for use in the form of a liquid solution or suspension, particularly in a semi-solid form such as creams and suppositories but not limited thereto, for vaginal or rectal administration, in a form such as tablets or capsules but not limited thereto, for oral or sublingual administration, or in a form such as powders, nasal drops or aerosols, or certain agents but not limited thereto, for intra-nasal administration, or for either modifying the skin structure or increasing the drug concentration in a transdermal patch, using a chemical enhancer such as dimethyl sulfoxide (Junginger, et al. In “Drug Permeation Enhancement;” Hsieh, D. S., Eds., pp.59 - 90 (Marcel Dekker, Inc. New Y In “Drug Permeation Enhancement;” Hsieh, D. S., Eds., pp.59 - 90 (Marcel Dekker, Inc. New Y ork 1994, which is incorporated herein by reference in its entirety), or the application of a formulation containing proteins and peptides to the skin (International Publication No. 98 / 53847), or for creating transient transport pathways such as electroporation, or the application of an electric field to increase the mobility of charged drugs through the skin such as iontophoresis, or the application of ultrasound such as ultrasonic introduction (U.S. Patent Nos. 4,309,989 and 4,767,402). It can be prepared transdermally in forms such as, but not limited to, gels, ointments, lotions, suspensions or patch delivery systems using oxidizing agents that enable this (the above publications and patents are incorporated herein by reference in their entirety). or the application of a formulation containing proteins and peptides to the skin (International Publication No. 98 / 53847), or for creating transient transport pathways such as electroporation, or the application of an electric field to increase the mobility of charged drugs through the skin such as iontophoresis, or the application of ultrasound such as ultrasonic introduction (U.S. Patent Nos. 4,309,989 and 4,767,402). It can be prepared transdermally in forms such as, but not limited to, gels, ointments, lotions, suspensions or patch delivery systems using oxidizing agents that enable this (the above publications and patents are incorporated herein by reference in their entirety). or for creating transient transport pathways such as electroporation, or the application of an electric field to increase the mobility of charged drugs through the skin such as iontophoresis, or the application of ultrasound such as ultrasonic introduction (U.S. Patent Nos. 4,309,989 and 4,767,402). It can be prepared transdermally in forms such as, but not limited to, gels, ointments, lotions, suspensions or patch delivery systems using oxidizing agents that enable this (the above publications and patents are incorporated herein by reference in their entirety). or the application of an electric field to increase the mobility of charged drugs through the skin such as iontophoresis, or the application of ultrasound such as ultrasonic introduction (U.S. Patent Nos. 4,309,989 and 4,767,402). It can be prepared transdermally in forms such as, but not limited to, gels, ointments, lotions, suspensions or patch delivery systems using oxidizing agents that enable this (the above publications and patents are incorporated herein by reference in their entirety). or the application of ultrasound such as ultrasonic introduction (U.S. Patent Nos. 4,309,989 and 4,767,402). It can be prepared transdermally in forms such as, but not limited to, gels, ointments, lotions, suspensions or patch delivery systems using oxidizing agents that enable this (the above publications and patents are incorporated herein by reference in their entirety). using oxidizing agents that enable this, in forms such as, but not limited to, gels, ointments, lotions, suspensions or patch delivery systems, it can be prepared transdermally (the above publications and patents are incorporated herein by reference in their entirety). using oxidizing agents that enable this, in forms such as, but not limited to, gels, ointments, lotions, suspensions or patch delivery systems, it can be prepared transdermally (the above publications and patents are incorporated herein by reference in their entirety). using oxidizing agents that enable this, in forms such as, but not limited to, gels, ointments, lotions, suspensions or patch delivery systems, it can be prepared transdermally (the above publications and patents are incorporated herein by reference in their entirety).

[0167] Embodiments The present invention also provides the following non-limiting embodiments.

[0168] 1. A method for treating moderately to severely active ulcerative colitis (UC) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a clinically proven safe and clinically proven effective amount of an anti-IL-12 / IL- 23p40 antibody, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, and the light chain variable region comprises the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6. and the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, and the light chain variable region comprises the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRH3 amino acid sequence of SEQ ID NO: 3, and the light chain variable region comprises the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6. and the CDRL3 amino acid sequence of SEQ ID NO: 6.

[0169] 2. The antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and an amino acid sequence of SEQ ID NO: 8 The method according to Embodiment 1, comprising the light chain variable region of

[0170] 3. The method according to Embodiment 1, wherein the antibody comprises a heavy chain of the amino acid sequence of SEQ ID NO: 10 and a light chain of the amino acid sequence of SEQ ID NO: 11.

[0171] 4. The method according to any one of Embodiments 1 to 3, wherein the antibody is intravenously administered to the subject, preferably at week 0 of treatment, at a dose of about 6.0 mg per 1 kg of the subject's body weight or 130 mg per administration.

[0172] 5. The method according to any one of Embodiments 1 to 4, wherein the antibody is further subcutaneously administered to the subject, preferably at week 8 of treatment, at a dose of about 90 mg per administration.

[0173] 6. The method according to any one of Embodiments 1 to 5, wherein the subject has previously failed or had poor tolerance to at least one therapy selected from the group consisting of anti-TNF, vedolizumab, corticosteroids, azathioprine (AZA), and 6-mercaptopurine (6MP), or the subject has shown corticosteroid dependence.

[0174] 7. The method according to Embodiment 5, wherein the antibody is administered every 8 weeks or every 12 weeks at a maintenance dose after treatment at week 8.

[0175] 8. The subject is identified as a responder to treatment with the antibody and has a clinical remission based on at least one of the World Definition and the US Definition, preferably by week 16 of treatment, more preferably by week 8 of treatment, even more preferably by week 2 of treatment. The clinical remission is at least The method according to embodiment 7, which continues at least until the 44th week.

[0176] 9. The method according to embodiment 8, wherein the subject is in corticosteroid-free clinical remission at least until the 44th week after week 0. The method according to embodiment 8, wherein the subject is in corticosteroid-free clinical remission at least until the 44th week after week 0.

[0177] 10. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as having endoscopic healing that continues at least until the 44th week after week 0. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as having endoscopic healing that continues at least until the 44th week after week 0. .

[0178] 11. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as achieving a clinical response based on the Mayo endoscopic subscore that continues at least until the 44th week after week 0. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as achieving a clinical response based on the Mayo endoscopic subscore that continues at least until the 44th week after week 0. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as achieving a clinical response based on the Mayo endoscopic subscore that continues at least until the 44th week after week 0.

[0179] 12. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as having a change from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ) score that continues at least until the 44th week after week 0. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as having a change from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ) score that continues at least until the 44th week after week 0. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as having a change from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ) score that continues at least until the 44th week after week 0. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as having a change from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ) score that continues at least until the 44th week after week 0.

[0180] 13. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as having mucosal healing that continues at least until the 44th week after week 0. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as having mucosal healing that continues at least until the 44th week after week 0.

[0181] 14. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as having a decrease from baseline in the Mayo score that continues at least until the 44th week after week 0. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as having a decrease from baseline in the Mayo score that continues at least until the 44th week after week 0. The method according to embodiment 7, wherein the subject is a responder to treatment with an antibody and is identified as having a decrease from baseline in the Mayo score that continues at least until the 44th week after week 0.

[0182] 15. The subject is a responder to antibody treatment, and at least 44 weeks after week 0 continuing, normalization of one or more biomarkers selected from the group consisting of C-reactive protein, fecal lactoferrin, and fecal calprotectin is identified as having, the method according to embodiment 7.

[0183] 16. The subject is continuing at least until week 44 after week 0, a decrease of ≧ 30% and ≧ 3 points from the baseline in the Mayo score and a decrease of ≧ 1 point from the baseline in the rectal bleeding subscore, or a clinical response determined by a rectal bleeding subscore of 0 or 1, the method according to embodiment 7.

[0184] 17. A method of treating moderately to severely active ulcerative colitis (UC) in a subject in need thereof, comprising: a. administering to the subject an anti-IL-12 / IL-23p40 antibody in a first pharmaceutical composition at a dose of about 6. 0 mg per kg of the subject's body weight or 130 mg per administration, by intravenous administration at week 0 of treatment; b. administering to the subject an anti-IL-12 / IL-23p40 antibody in a second pharmaceutical composition at a dose of 90 mg per administration, preferably by subcutaneous administration at week 8 of treatment, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises the amino acid sequence of complementarity-determining region heavy chain 1 (CDRH1) of SEQ ID NO: 1, the amino acid sequence of CDRH2 of SEQ ID NO: 2, and the amino acid sequence of CDRH3 of SEQ ID NO: 3, and the light chain variable region comprises the amino acid sequence of complementarity-determining region light chain 1 (CDRL1) of SEQ ID NO: 4, the amino acid sequence of CDRL2 of SEQ ID NO: 5, and the amino acid sequence of CDRL3 of SEQ ID NO: 6. ​​​​​​​​​​The subject has previously failed at least one therapy selected from the group consisting of anti-TNF, vedolizumab, corticosteroids, azathioprine (AZA), and 6-mercaptopurine (6MP), or has been intolerant to these, or the subject has shown corticosteroid dependence, method.

[0185] 18. The method according to embodiment 17, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8.

[0186] 19. The method according to embodiment 17, wherein the antibody comprises a heavy chain of the amino acid sequence of SEQ ID NO: 10 and a light chain of the amino acid sequence of SEQ ID NO: 11.

[0187] 20. The method according to any one of embodiments 1 to 19, wherein the pharmaceutical composition for intravenous administration further comprises a solution containing 10 mM L-histidine, 8.5% (w / v) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL disodium EDTA dihydrate at pH 6.0.

[0188] 21. The method according to any one of embodiments 1 to 20, wherein the pharmaceutical composition for subcutaneous administration further comprises a solution containing 6.7 mM L-histidine, 7.6% (w / v) sucrose, and 0.004% (w / v) polysorbate 80 at pH 6.0.

[0189] 22. The subject is a responder to treatment with the antibody and has a clinical remission based on at least one of the World Definition and the US Definition by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment, as specified for any one of embodiments 1 to 21. ​​​​​​​​​​ The method according to any one of claims 1.

[0190] 23. The method according to any one of embodiments 1-22, wherein the subject is a responder to treatment with an antibody and has endoscopic healing by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment. being identified as

[0191] 24. The method according to any one of embodiments 1-23, wherein the subject is a responder to treatment with an antibody and achieves a clinical response based on the Mayo endoscopic subscore by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment. .

[0192] 25. The method according to any one of embodiments 1-24, wherein the subject is a responder to treatment with an antibody and has a change from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ) score by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment. being identified as

[0193] 26. The method according to any one of embodiments 1-25, wherein the subject is a responder to treatment with an antibody and has mucosal healing by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment. being identified as

[0194] 27. The method according to any one of embodiments 1-26, wherein the subject is a responder to treatment with an antibody and has a decrease from baseline in the Mayo score by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment. being identified as​​​​​​​ Method

[0195] 28. The method according to any one of embodiments 1 to 27, wherein the subject is a responder to treatment with an antibody and has normalization of one or more biomarkers selected from the group consisting of C-reactive protein, fecal lactoferrin, and fecal calprotectin by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment. ferrin and fecal calprotectin by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment. ferrin and fecal calprotectin by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment. ferrin and fecal calprotectin by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment.

[0196] 29. The method according to any one of embodiments 1 to 28, wherein the subject shows a decrease of ≧30% and ≧3 points from baseline in the Mayo score and a decrease of ≧1 point from baseline in the rectal bleeding subscore, or a clinical response determined by a rectal bleeding subscore of 0 or 1, by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment. ferrin and fecal calprotectin by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment. ferrin and fecal calprotectin by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment. ferrin and fecal calprotectin by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment. ferrin and fecal calprotectin by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment.

[0197] 30. The method according to any one of embodiments 17 to 21, wherein the subject is not a responder to treatment with an antibody by week 8 of treatment but is a responder by week 16 of treatment. ferrin and fecal calprotectin by week 16 of treatment, preferably by week 8 of treatment, more preferably by week 2 of treatment.

[0198] 31. A method for treating moderately to severely active ulcerative colitis (UC) in a subject in need thereof, comprising: a. administering to the subject an anti-IL-12 / IL-23p40 antibody in a first pharmaceutical composition at a dose of about 6.0 mg / kg of the subject's body weight or 130 mg per administration by intravenous administration at week 0 of treatment; a. administering to the subject an anti-IL-12 / IL-23p40 antibody in a first pharmaceutical composition at a dose of about 6.0 mg / kg of the subject's body weight or 130 mg per administration by intravenous administration at week 0 of treatment; a. administering to the subject an anti-IL-12 / IL-23p40 antibody in a first pharmaceutical composition at a dose of about 6.0 mg / kg of the subject's body weight or 130 mg per administration by intravenous administration at week 0 of treatment; a. administering to the subject an anti-IL-12 / IL-23p40 antibody in a first pharmaceutical composition at a dose of about 6.0 mg / kg of the subject's body weight or 130 mg per administration by intravenous administration at week 0 of treatment; b. administering to the subject an anti-IL-12 / IL-23p40 antibody in a second pharmaceutical composition at a dose of 90 mg per administration, preferably by subcutaneous administration at week 8 of treatment. b. administering to the subject an anti-IL-12 / IL-23p40 antibody in a second pharmaceutical composition at a dose of 90 mg per administration, preferably by subcutaneous administration at week 8 of treatment. The antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region being a sequence corresponding to SEQ ID NO:1. Complementary determining region heavy chain 1 (CDRH1) amino acid sequence and CDRH2 amino acid sequence of SEQ ID NO:2 and the CDRH3 amino acid sequence of SEQ ID NO:3, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:4. Complementarity determining region light chain 1 (CDRL1) amino acid sequence and CDRL2 amino acid sequence of SEQ ID NO:5 and the CDRL3 amino acid sequence of SEQ ID NO:6, followed by maintenance therapy; Maintenance therapy consisted of administering anti-IL-12 / IL-23p40 antibody to subjects at a dose of 90 mg per dose. Maintenance therapy includes administration subcutaneously once every 8 weeks or once every 12 weeks at a dose of ,Method ,provided ,for ,44 ,weeks.

[0199] 32. A pharmaceutical composition of an anti-IL-12 / IL-23p40 antibody, comprising the antibody and a combination of ... Randomized study of adult men and women with severe, active ulcerative colitis (UC) One or more of the drugs disclosed in Appendix I, including data from a double-blind, placebo-controlled clinical trial and packaging including a product label element, the antibody comprising: (i) a heavy chain variable region and a light chain variable region; wherein the heavy chain variable region comprises the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO:1. sequence, the CDRH2 amino acid sequence of SEQ ID NO:2, and the CDRH3 amino acid sequence of SEQ ID NO:3. and wherein the light chain variable region comprises the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:4. the CDRL2 amino acid sequence of SEQ ID NO:5 and the CDRL3 amino acid sequence of SEQ ID NO:6. and (ii) a heavy chain variable region and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7. a light chain variable region having the amino acid sequence of SEQ ID NO: 8; or (iii) a light chain variable region having the amino acid sequence of SEQ ID NO: 10. and a light chain having the amino acid sequence of SEQ ID NO: 11.

[0200] A method of selling a drug product comprising ustekinumab, comprising manufacturing ustekinumab and promoting that a therapy comprising ustekinumab is safe and effective for treating a subject having ulcerative colitis, by performing steps a) and b) to cause a healthcare professional (HCP) to purchase the drug product, thereby selling the drug product. A method comprising:

[0201] Having described the invention generally, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and not of limitation. By referring to the following examples, which are not intended to be limiting, the invention will be more readily understood. Furthermore, the details of the invention are illustrated by the following non-limiting examples. All cited disclosures herein are incorporated herein by reference expressly.

Example

[0202] Example 1: Introduction study of ustekinumab in the treatment of ulcerative colitis in humans A multi-center, randomized, double-blind, placebo-controlled clinical trial was conducted in adult men and women with moderate to severe active ulcerative colitis (UC) as follows: A phase 3, randomized, double-blind, placebo-controlled, parallel-group comparison, multi-center trial to evaluate the safety and efficacy of ustekinumab induction and maintenance therapy in subjects with moderate to severe active ulcerative colitis.

[0203] Overall rationale Conventional therapies (corticosteroids or 6-mercaptopurine / azathioprine [6- MP / AZA]) or biological therapies (TNF antagonists and / or integrin antagonists, ved Subjects with moderately to severely active ulcerative colitis who showed an inadequate response or poor tolerance to adalimumab were enrolled in a study to evaluate the efficacy of intravenous (IV) ustekinumab. Subjects were randomized to receive a single 130-mg dose, a single 6-mg / kg IV dose, or placebo at week 0. Subjects who did not show a clinical response at week 8 received an additional IV or subcutaneous (SC) dose at week 8.

[0204] Objectives The primary objectives of this study were to (1) evaluate the efficacy of ustekinumab in inducing clinical remission in subjects with moderately to severely active UC, and (2) evaluate the safety of IV ustekinumab in subjects with moderately to severely active UC.

[0205] The secondary objectives of this study were to (1) evaluate the efficacy of IV ustekinumab in inducing endoscopic healing (ie, improvement on endoscopic examination of the mucosa) in subjects with moderately to severely active UC, (2) evaluate the efficacy of IV ustekinumab in inducing clinical response in subjects with moderately to severely active UC, (3) evaluate the effect of IV ustekinumab on disease-specific health-related quality of life, (4) evaluate the efficacy of ustekinumab treatment on mucosal healing (ie, endoscopic and histological healing), (5) evaluate the efficacy of induction therapy with IV ustekinumab for biologic inefficacy, and (6) evaluate changes in C-reactive protein (CRP), fecal calprotectin, fecal lactoferrin, and other PD biomarkers. The drug of the induction therapy of ustekinumab in subjects with moderately to severely active UC included the evaluation of pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD).

[0206] The exploratory objectives of the study included (1) evaluating the response using the Mayo score without the physician global assessment (PGA) subscore, and (2) evaluating the performance of the Bristol Stool Form Scale (BSFS) score.

[0207] Study design The Phase 3 development program for ustekinumab included two separate trials, namely, an induction trial and a maintenance trial. In the induction trial, subjects were randomized at Week 0 to one of three treatment groups: placebo, low-dose ustekinumab, or high-dose ustekinumab. At Week 8, all subjects were evaluated for the primary endpoints of clinical remission and clinical response. Subjects who achieved a clinical response at Week 8 were eligible to enter the maintenance trial. Subjects who did not achieve a clinical response at Week 8 were administered a second dose of ustekinumab at Week 8 of treatment.

[0208] At Week 16, subjects who did not achieve a clinical response at Week 8 were re-evaluated for clinical response. Subjects who achieved a clinical response at Week 16 were eligible to enter the maintenance trial. Subjects who did not achieve a clinical response at Week 16 were not eligible to enter the maintenance study and returned for safety follow-up approximately 20 weeks after the last dose of the study drug (Week 8).

[0209] Subjects who responded clinically to IV ustekinumab during induction were the main cohort in the maintenance trial ​​​A group was formed. The maintenance trial is a randomized treatment discontinuation trial designed to evaluate maintenance therapy using secukinumab and is currently ongoing.

[0210] Dose and Administration Subjects were administered a single IV dose of ustekinumab or placebo at week 0 of the trial. The induction trial antibodies by the administered dose are as follows. ● Ustekinumab at a low fixed dose of 130 mg ● Ustekinumab at a dose based on a high body weight range of approximately 6 mg / kg, ○ Ustekinumab 260 mg (body weight ≤ 55 kg) ○ Ustekinumab 390 mg (body weight > 55 kg but ≤ 85 kg) ○ Ustekinumab 520 mg (body weight > 85 kg).

[0211] Subjects who did not have a clinical response were administered a second dose of ustekinumab at week 8. The trial antibodies by the administered second dose are as follows. ● Subjects randomized to placebo at week 0 were administered a single IV dose of ustekinumab approximately 6 mg / kg + placebo SC (to maintain blinding) at week 8. ● Subjects randomized to ustekinumab at week 0 were administered a single SC dose of ustekinumab 90 mg + placebo IV (to maintain blinding) at week 8.

[0212] Safety Assessment Safety was evaluated based on AEs and clinical laboratory test results (i.e., hematology and serum chemistry). Adverse events were either reported spontaneously by the subjects or obtained by interviewing the subjects in a non-leading manner at the time of trial hospitalization. Safety assessment included the following clinical laboratory tests.

[0213] ● Hematology: Hemoglobin (Hb), hematocrit, red blood cell count, white blood cell (WBC) count, and platelets.

[0214] ● Serum chemistry: Sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin and direct bilirubin, alkaline phosphatase, calcium, phosphate, albumin, total protein. ● Screening: Serological tests for human immunodeficiency virus antibodies, serological tests for hepatitis C virus (HCV) antibodies, hepatitis B virus (HBV) antibodies, hepatitis B surface antigen, total serological tests for hepatitis B surface antibody (anti-HB) and HBV core (anti-HB) antibodies, QuantiFERON-TB Gold test, pregnancy test (β-human chorionic gonadotropin [β-HCG]).

[0215] ● Pharmacokinetics Blood samples for the measurement of serum ustekinumab concentration were collected at week 0 (before and after injection) and at weeks 2, 4, and 8. Analysis of serum ustekinumab concentration was performed using an electrochemiluminescence immunoassay (ECLIA) method with confirmed effectiveness on the Meso Scale Discovery (MSD®) platform (Gaithersburg, MD, USA). The lowest quantifiable concentration in samples of the ECLIA method using the MSD platform was 0.1688 μg / mL. ● Immunogenicity

[0216] Serum samples collected from all subjects were used to evaluate antibodies against ustekinumab. and at weeks 2, 4, and 8. Analysis of serum ustekinumab concentration was performed using an electrochemiluminescence immunoassay (ECLIA) method with confirmed effectiveness on the Meso Scale Discovery (MSD®) platform (Gaithersburg, MD, USA). The lowest quantifiable concentration in samples of the ECLIA method using the MSD platform was 0.1688 μg / mL. MD, USA) using an electrochemiluminescence immunoassay (ECLIA) method with confirmed effectiveness on the Meso Scale Discovery (MSD®) platform (Gaithersburg, MD, USA). The lowest quantifiable concentration in samples of the ECLIA method using the MSD platform was 0.1688 μg / mL. using an electrochemiluminescence immunoassay (ECLIA) method with confirmed effectiveness on the Meso Scale Discovery (MSD®) platform (Gaithersburg, MD, USA). The lowest quantifiable concentration in samples of the ECLIA method using the MSD platform was 0.1688 μg / mL.

[0217] ● Immunogenicity Serum samples collected from all subjects were used to evaluate antibodies against ustekinumab. Valued. Analysis of antibodies against ustekinumab was performed using electrochemiluminescence immunoassay (ECLIA), which has been confirmed to be effective, for drug resistance and electrification Performed using electrochemiluminescence immunoassay (ECLIA), in which ustekinumab Was used to capture and detect the immune response induced against ustekinumab. Antibody titers were determined for all subjects with antibodies against ustekinumab, and the neutralizing antibody (Nab) status of anti-drug antibody-positive Samples was determined.

[0218] Evaluation of efficacy Evaluations of efficacy were collected throughout the study. The Mayo score, as well as the partial Mayo Core, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), the Bristol Stool Form Scale (BSFS) score, C-reactive protein (CRP), fecal lactoferrin, fecal cal protectin, the Inflammatory Bowel Disease Questionnaire (IBDQ), the 36-item Short Form Health Survey (SF-36), and the EuroQo L-5D health questionnaire were all evaluated to determine efficacy. The efficacy criteria were defined as follows Defined. ● Clinical remission (World application): No individual subscore > 1, Mayo score ≤ 2 ● Clinical remission (US application): ≤ 3 absolute number of bowel movements, rectal bleeding score of 0, and Mayo endoscopic subscore of 0 or 1. ● Clinical response: Decrease from baseline in rectal bleeding subscore ≥ 1 or either a rectal bleeding subscore of 0 or 1, with a ≥ 30% and ≥ 3-point decrease in Mayo score Decrease from the baseline during the induction period. ● Endoscopic healing (i.e., improvement in endoscopic observation of the mucosa): Mayo endoscopic subscore of 0 or 1. ● Histological healing: Based on the Geboes score, defined as 0 to <5% neutrophils in the epithelium and no crypt destruction, erosion, ulcer, or granulation. ● Mucosal healing: Both endoscopic healing and histological healing. ● Normal or inactive mucosal disease: Mayo endoscopic subscore of 0. ● Symptomatic remission: Mayo bowel movement frequency subscore of 0 or 1 and rectal bleeding subscore of 0. ● Normalization of CRP concentration: CRP concentration ≤ 3 mg / L. ● Normalization of fecal lactoferrin concentration: Fecal lactoferrin concentration ≤ 7.24 μg / g. ● Normalization of fecal calprotectin concentration: Fecal calprotectin concentration ≤ 250 mg / kg. ● Modified Mayo score response: ○ Definition 1: Decrease of ≥ 2 points and ≥ 35% in the modified Mayo score and decrease in the rectal bleeding subscore of ≥ 1 or either a rectal bleeding subscore of 0 or 1. ○ Definition 2: Decrease of ≥ 2 points and ≥ 30% in the modified Mayo score and decrease in the rectal bleeding subscore of ≥ 1 or either a rectal bleeding score of 0 or 1.

[0219] Results of safety Both intravenous ustekinumab doses of approximately 6 mg / kg and 130 mg were generally associated with a safety profile comparable to placebo over 8 weeks and showed generally good tolerability. Among the 960 subjects in the safety analysis set, over 8 weeks, AEs that developed under one or more treatments were observed in the approximately 6 mg / kg, 130 mg, and placebo groups. The results were reported in 50.0%, 41.4%, and 48.0% of subjects, respectively. Overall, serious adverse events (SAEs) occurred in approximately the 6 mg / kg, 130 mg, and placebo groups. reported in 3.1%, 3.7%, and 6.6% of subjects, respectively.

[0220] AEs within 1 hour of infusion were approximately 10% in the 6 mg / kg, 130 mg, and placebo groups. The rates were 0.9%, 2.2%, and 1.9%, respectively.

[0221] The proportion of subjects with one or more infections was approximately 10% at 6 mg / kg, 130 mg, and placebo. The incidence rates in subjects in the 15.3%, 15.9%, and 15.0% groups, respectively, were Serious infections occurred in approximately 100 subjects in the 6 mg / kg, 130 mg, and placebo groups, respectively. The authors reported rates of 0.3%, 0.6%, and 1.3%.

[0222] Pharmacokinetic results Serum samples were collected at week 0 (pre-dose), week 0 (1 hour post-dose), week 2, week 4, and week 5. For subjects randomized to ustekinumab treatment, A single IV infusion of mab was administered as a titrated dose of approximately 6 mg / kg body weight (i.e., ≤5 260 mg for subjects weighing 5 kg, 3 mg for subjects weighing >55 kg and ≤85 kg 90 mg, or 520 mg for subjects weighing >85 kg), or a fixed dose of 130 mg Considering that the median weight of subjects in the 130 mg group was 72 kg, and a 130 mg dose of ustekinumab is equivalent to approximately 2 mg / kg on a per kg basis. Therefore, on average, the exposure to ustekinumab in the 6 mg / kg group was approximately 10% higher than that in the 130 mg group. Consistent with this expectation, the mean mean of 6 mg / kg ustekinumab or 130 mg After a single intravenous (IV) dose, the median serum ustekinumab concentration was approximately dose-proportional at all sampling time points throughout 8 weeks. The median peak serum ustekinumab concentration observed 1 hour after the end of infusion at week 0 was 127.0 μg / mL and 43.16 μg / mL for the approximately 6 mg / kg group and the 130 mg group, respectively. At the evaluation time point of the primary efficacy endpoint at week 8, the median serum ustekinumab concentration was 8.59 μg / mL and 2.51 μg / mL for the approximately 6 mg / kg group and the 130 mg group, respectively. Subjects who did not have a clinical response at week 8 after receiving placebo IV at week 0 were administered approximately 6 mg / kg of ustekinumab IV at week 8, while subjects who did not have a clinical response at week 8 after receiving ustekinumab IV at week 0 were administered 90 mg of ustekinumab subcutaneously (SC) at week 8. Among the subjects who received placebo IV at week 0 and subsequently approximately 6 mg / kg of ustekinumab IV at week 8, the median serum ustekinumab concentration at week 16 (8 weeks after the ustekinumab IV administration) was slightly higher than that observed at week 8 (among the subjects who received approximately 6 mg / kg of ustekinumab IV at week 0, 10.51 μg / mL vs. 8.59 μg / mL, respectively). Among the subjects who received 90 mg of ustekinumab SC at week 8 (after the first IV ustekinumab administration at week 0), the median serum ustekinumab concentration at week 16 was slightly higher than that of the subjects who received 130 mg of ustekinumab at week 0 and slightly higher than that of the subjects who received approximately 6 mg / kg of ustekinumab IV at week 0 (1.92 μg / mL vs. 1.59 μg / mL, respectively).

[0223] After receiving placebo IV at week 0, subjects who did not have a clinical response at week 8 were administered approximately 6 mg / kg of ustekinumab IV at week 8, while subjects who did not have a clinical response at week 8 after receiving ustekinumab IV at week 0 were administered 90 mg of ustekinumab SC at week 8. Among the subjects who received placebo IV at week 0 and subsequently approximately 6 mg / kg of ustekinumab IV at week 8, the median serum ustekinumab concentration at week 16 (8 weeks after the ustekinumab IV administration) was slightly higher than that observed at week 8 (among the subjects who received approximately 6 mg / kg of ustekinumab IV at week 0, 10.51 μg / mL vs. 8.59 μg / mL, respectively). Among the subjects who received 90 mg of ustekinumab SC at week 8 (after the first IV ustekinumab administration at week 0), the median serum ustekinumab concentration at week 16 was slightly higher than that of the subjects who received 130 mg of ustekinumab at week 0 and slightly higher than that of the subjects who received approximately 6 mg / kg of ustekinumab IV at week 0 (1.92 μg / mL vs. 1.59 μg / mL, respectively). After receiving placebo IV at week 0, subjects who did not have a clinical response at week 8 were administered approximately 6 mg / kg of ustekinumab IV at week 8, while subjects who did not have a clinical response at week 8 after receiving ustekinumab IV at week 0 were administered 90 mg of ustekinumab SC at week 8. Among the subjects who received placebo IV at week 0 and subsequently approximately 6 mg / kg of ustekinumab IV at week 8, the median serum ustekinumab concentration at week 16 (8 weeks after the ustekinumab IV administration) was slightly higher than that observed at week 8 (among the subjects who received approximately 6 mg / kg of ustekinumab IV at week 0, 10.51 μg / mL vs. 8.59 μg / mL, respectively). Among the subjects who received 90 mg of ustekinumab SC at week 8 (after the first IV ustekinumab administration at week 0), the median serum ustekinumab concentration at week 16 was slightly higher than that of the subjects who received 130 mg of ustekinumab at week 0 and slightly higher than that of the subjects who received approximately 6 mg / kg of ustekinumab IV at week 0 (1.92 μg / mL vs. 1.59 μg / mL, respectively). After a single intravenous (IV) dose, the median serum ustekinumab concentration was approximately dose-proportional at all sampling time points throughout 8 weeks. The median peak serum ustekinumab concentration observed 1 hour after the end of infusion at week 0 was 127.0 μg / mL and 43.16 μg / mL for the approximately 6 mg / kg group and the 130 mg group, respectively. At the evaluation time point of the primary efficacy endpoint at week 8, the median serum ustekinumab concentration was 8.59 μg / mL and 2.51 μg / mL for the approximately 6 mg / kg group and the 130 mg group, respectively. Subjects who did not have a clinical response at week 8 after receiving placebo IV at week 0 were administered approximately 6 mg / kg of ustekinumab IV at week 8, while subjects who did not have a clinical response at week 8 after receiving ustekinumab IV at week 0 were administered 90 mg of ustekinumab subcutaneously (SC) at week 8. Among the subjects who received placebo IV at week 0 and subsequently approximately 6 mg / kg of ustekinumab IV at week 8, the median serum ustekinumab concentration at week 16 (8 weeks after the ustekinumab IV administration) was slightly higher than that observed at week 8 (among the subjects who received approximately 6 mg / kg of ustekinumab IV at week 0, 10.51 μg / mL vs. 8.59 μg / mL, respectively). Among the subjects who received 90 mg of ustekinumab SC at week 8 (after the first IV ustekinumab administration at week 0), the median serum ustekinumab concentration at week 16 was slightly higher than that of the subjects who received 130 mg of ustekinumab at week 0 and slightly higher than that of the subjects who received approximately 6 mg / kg of ustekinumab IV at week 0 (1.92 μg / mL vs. 1.59 μg / mL, respectively).

[0224] ​ Immunogenicity results Among 635 subjects in the ustekinumab group with samples appropriate for the evaluation of antibodies against ustekinumab Of these, 4 subjects (0.6%) were positive for antibodies against ustekinumab throughout 8 weeks Of these 4 subjects, 2 (50%) were positive for NAb

[0225] Ustekinumab was administered at any time throughout 16 weeks, and among 822 subjects with samples appropriate for the evaluation of anti-drug antibodies (ADA) 18 subjects (2.2%) were positive for antibodies against ustekinumab until the visit for the final safety assessment Of these, 4 (26.7%) of 15 subjects were positive for NAb among those evaluable as NAb until the visit for the final safety assessment Among the subjects who received 90 mg of ustekinumab by SC injection at week 8 The incidence of antibodies against ustekinumab throughout 16 weeks was numerically higher in the 130 mg IV→90 mg SC group than in the approximately 6 mg / kg IV→90 mg SC group (4.5% [6 out of 132 subjects] vs. 1.0% [1 out of 101 subjects])

[0226] Efficacy results Clinical remission - World definition at week 8 At week 8, a significantly greater proportion of subjects in the approximately 6 mg / kg and 130 mg groups (15.5% and 15.6% respectively) Achieved clinical remission compared to subjects in the placebo group (5.3%; p < 0.001 for both comparisons; Table 1)

[0227] [Table 1] ​​​​N = Number of subjects, CI = Confidence interval.

[0228] Clinical remission at week 8 - US definition At week 8, a significantly larger proportion of subjects in the groups of approximately 6 mg / kg and 130 mg (18.9% and 16.6% respectively) achieved clinical remission compared to the subjects in the placebo group (6.3%; p < 0.001 for both comparisons; Table 2).

[0229]

Table 2

[0230] Endoscopic response of endoscopic healing at week 8 At week 8, a significantly larger proportion of subjects in the groups of approximately 6 mg / kg and 130 mg (27.0% and 26.3% respectively) achieved endoscopic healing compared to the subjects in the placebo group (13.8%; p < 0.001 for both comparisons; Table 3).

[0231]

Table 3

[0232] Clinical response at week 8 At week 8, a significantly larger proportion of subjects in the groups of approximately 6 mg / kg and 130 mg (61.8% and 51.3% respectively) achieved clinical response compared to the subjects in the placebo group (31.3%; p < 0.001 for both comparisons; Table 4).

[0233]

Table 4

[0234] Change from baseline in total IBDQ score at week 8. At baseline, the median IBDQ score was similar across all treatment groups. At week 8, the median improvement from baseline in the IBDQ score was about 6 mg / k g and in the 130 mg groups (31.0 and 31.5, respectively), significantly greater than in the placebo group (10.0; p < 0.001 for both comparisons).

[0235] Clinical remission at week 8 Remission was evaluated as clinical remission (world definition) by a rectal bleeding score of 0 at week 8. When this endpoint was achieved, the proportion of subjects who achieved it was almost identical to the proportion observed based on the primary efficacy analysis (world definition). A significantly greater proportion of subjects in the about 6 mg / kg and 130 mg groups (15.2% and 15.3%, respectively) achieved this endpoint compared to subjects in the placebo group (5.3%; p < 0.001 for both comparisons). )

[0236] Symptomatic remission at week 8 At week 8, a significantly greater proportion of subjects in the about 6 mg / kg and 130 mg groups (44.7% and 41.3%, respectively) achieved symptomatic remission compared to subjects in the placebo group (22.6%; p < 0.001 for both comparisons). )

[0237] Histological healing at week 8 Histological healing was defined as 0 - <5% neutrophils in the epithelium and no crypt destruction, erosion, ulcer, or granulation. At week 8, a significantly greater proportion of subjects in the about 6 mg / kg and 130 mg groups (35.6% and 37.9%, respectively) achieved histological healing compared to subjects in the placebo group. Achieved compared to the placebo group (21.9%; p < 0.001 for both comparisons).

[0238] Change from baseline in the Mayo score at week 8. At baseline, the mean Mayo score was the same across all treatment groups (8.9 for all groups). At week 8, the mean decrease from baseline in the Mayo score was significantly greater in the groups of approximately 6 mg / kg and 130 mg (3.5 and 3.2, respectively) compared to 1.8 in the placebo group (p < 0.00 1 for both comparisons).

[0239] Change from baseline in the partial Mayo score over 8 weeks. At baseline, the mean partial Mayo score was the same across all treatment groups (6.2 for all groups). As early as week 2, and continuing through week 8 until the clinic visit, the decrease in the mean value of the partial Mayo score was significantly greater in the groups of approximately 6 mg / kg and 130 mg compared to the placebo group. At week 2, the decrease from baseline in the mean value of the partial Mayo score was 1.6 and 1.5 in the groups of approximately 6 mg / kg and 130 mg, respectively, compared to 1.0 in the placebo group (p < 0.001 for both comparisons). At week 8, the decrease from baseline in the mean value of the partial Mayo score was 2.9 and 2.6 in the groups of approximately 6 mg / kg

[0240] UCEIS score at week 8 The UCEIS score is based on mucosal vascular pattern, bleeding, and ulceration Provides a comprehensive assessment of severity. The score ranges from 3 to 11, and a higher score indicates a more severe disease by endoscopy. The UCEIS score was evaluated only during the central reading of the endoscopy video.

[0241] At baseline, the mean UCEIS score was similar across all treatment groups ( about 6 mg / kg, 130 mg, and placebo groups, respectively, 7.6, 7.5, 7.5 ). At week 8, the mean decrease from baseline in the UCEIS score was about 6 m g / kg and in the 130 mg groups (1.3 and 1.1, respectively), significantly greater than the 0 .5 in the placebo group (p < 0.001 for both comparisons).

[0242] At week 8, a significantly greater proportion of subjects in the about 6 mg / kg and 130 mg groups ( 20.2% and 19.1%, respectively) had a UCEIS score ≤ 4 compared to 11.0% of subjects in the placebo group ( p < 0.001 and p = 0.004, respectively). A UCEIS score ≤ 4 was assumed to be associated with a Mayo endoscopic subscore of 0 or 1, which defined endoscopic healing as defined in this trial.

[0243] Bristol Stool Form Scale Score The BSFS score at presentation was the mean of the 1-day average over 3 days of the pre-presentation BSFS score. The same 3 days used to calculate the number of bowel movements and rectal bleeding scores of the Mayo score were used to calculate the mean BSFS score at presentation.

[0244] Approximately 40% (370 / 961) of the randomized subjects had stool samples collected at baseline ​​had a BSFS score. At baseline, 99.2% (367 / 370) of the subjects had an average BSFS score of ≥3, and the majority (54.3%) of the subjects had an average BSFS score of ≥6, indicating diarrhea. As early as week 2, and continuing through week 8, the proportion of subjects with diarrhea (average BSFS score of ≥6) was lower in the groups of about 6 mg / kg and 130 mg compared to the placebo group. At week 8, in the groups of about 6 mg / kg, 130 mg, and placebo, 22.8%, 21.1%, and 32.0% of the subjects, respectively, had diarrhea (average BSFS score of ≥6). Furthermore, at week 8, the proportion of subjects with normal stools (≥3 and <5) was higher in the groups of about 6 mg / kg and 130 mg compared to placebo (48.3%, 48.9%, and 29.3%, respectively).

[0245] Normalization of C-reactive protein C-reactive protein (CRP) is used as a marker of inflammation in subjects with IBD. In UC, high CRP is associated with severe clinical activity, high sedimentation rate, and active disease detected by colonoscopy. C-reactive protein is assayed using a validated high-sensitivity CRP assay.

[0246] At baseline, the proportion of subjects with abnormal CRP (>3 mg / L) was similar across all treatment groups, and overall, 59.2% of the randomized subjects had abnormal CRP concentrations at baseline. As early as week 2, and continuing through week 8, among the subjects with abnormal baseline values, a significantly higher proportion of subjects in the groups of about 6 mg / kg and 130 mg compared to the placebo group had normalization of CRP (≤3) mg / L) was achieved. At week 8, in the groups of approximately 6 mg / kg and 130 mg, 38.7% and 34.1% of the subjects respectively achieved normalization of CRP compared to 21.1% of the subjects in the placebo group (p < 0.001 for both comparisons).

[0247] Normalization of fecal lactoferrin At baseline, the proportion of subjects with abnormal fecal lactoferrin (> 7.24 μg / g) was similar across all treatment groups, and overall, 90.0% of the randomized subjects had abnormal fecal lactoferrin concentrations at baseline. At week 4 and week 8, among the subjects with abnormal values at baseline, a significantly greater proportion of the subjects in the groups of approximately 6 mg / kg and 130 mg achieved normalization of fecal lactoferrin (≤ 7.24 μg / g) compared to the placebo group. At week 8, 14.6% and 17.2% of the subjects in the groups of approximately 6 mg / kg and 13 0 mg respectively achieved normalization of fecal lactoferrin compared to 9 .3% of the subjects in the placebo group (for the ustekinumab group, p = 0.042 and p = 0.006 respectively).

[0248] Normalization of fecal calprotectin At baseline, the proportion of subjects with abnormal fecal calprotectin (> 250 mg / kg) was slightly greater in the group of approximately 6 mg / kg (85.1%) compared to the placebo group (78.4%), and 82.5% of the subjects in the 130 mg group had abnormal fecal calprotectin at baseline. At week 2 and week 4, among the subjects with abnormal values at baseline, a significantly greater proportion of the subjects in the groups of approximately 6 mg / kg and 130 mg The proportion achieved normalization (≤250 mg / kg) of fecal calprotectin at week 8. Among subjects with abnormal fecal calprotectin at baseline, the proportion of subjects with normalized fecal calprotectin was not significant compared to subjects in the placebo group (20.4%), but numerically larger in the ustekinumab groups of approximately 6 mg / kg and 130 mg (25.5% and 24.2%, respectively) (p = 0.148, p = 0.301 for both comparisons).

[0249] Example 2: Maintenance trial of ustekinumab in the treatment of human ulcerative colitis Methodology In this randomized treatment discontinuation maintenance trial, all enrolled subjects were responders to the investigational drug administered in the induction trial. Primary (randomized) population: Subjects who showed a clinical response to IV ustekinumab after induction constituted the primary population in the maintenance trial. This population included the following: Subjects randomized to receive ustekinumab (i.e., 130 mg IV or approximately 6 mg / kg IV) at week 0 of the induction trial and who showed a clinical response at week 8 of induction, and subjects randomized to receive placebo at week 0 of the induction trial, who did not show a clinical response at week 8 of induction, but showed a clinical response at week 16 of induction after administration of the IV ustekinumab dose (approximately 6 mg / kg) at week 8 of induction (placebo → ustekinumab approximately 6 mg / kg IV). These subjects were randomized at week 0 of the maintenance period in a 1:1:1 ratio to receive ustekinumab 90 mg SC every 8 weeks (q8w), ustekinumab 90 mg SC every 12 weeks (q12w), or placebo SC. Non-randomized population Additional subjects entering the maintenance trial were not randomized in the main population and received maintenance treatment in this trial as follows : Subjects who had a delayed response to ustekinumab introduction (i.e., those who did not have a clinical response to IV ustekinumab at week 8 of the induction period but had a clinical response at week 16 of the induction period after SC administration of 90 mg of ustekinumab at week 8 of the induction period) were administered 90 mg of ustekinumab SC q8w, and subjects who had a placebo induction response (i.e., those who had a clinical response to placebo IV induction were administered placebo SC. Non-randomized subjects were followed for both efficacy and safety but were not included in the key efficacy analyses. All subjects were administered the assigned dose of the SC study drug at the visit at week 0 of the maintenance period. Thereafter, to maintain blinding, all subjects were administered the study drug at the visit for all scheduled study drug administrations. Subjects were evaluated for clinical flares at each visit, and if a decrease in clinical response was confirmed, they were eligible for rescue medication. The main part of the maintenance trial was conducted until week 44, and the extension of the long-term trial continued until week 220. The number of subjects (planned and analyzed): Seven hundred and eighty-three subjects who completed the induction trial and had a clinical response to the induction study drug were enrolled in this

[0250] maintenance trial. The number of subjects in each treatment group at week 0 of the maintenance period was as follows : ● Randomized (main) population (523 subjects [327 subjects were planned]): - One hundred and seventy-six subjects were randomized to receive 90 mg of ustekinumab SC q8w - One hundred and seventy-two subjects were randomized to receive 90 mg of ustekinumab SC q12w

[0251] maintenance trial. The number of subjects in each treatment group at week 0 of the maintenance period was as follows : ● Randomized (main) population (523 subjects [327 subjects were planned]): - One hundred and seventy-six subjects were randomized to receive 90 mg of ustekinumab SC q8w - One hundred and seventy-two subjects were randomized to receive 90 mg of ustekinumab SC q12w ​​​Completed. - 175 subjects were randomized to placebo SC administration. ● Non-randomized group (260 subjects): - 157 subjects who were ustekinumab-introduction delayed responders (i.e., did not have a clinical response to ustekinumab at week 8 of the introduction period but had a clinical response at week 16 of the introduction period) were administered ustekinumab 90 mg SC q8w. - 103 subjects who had a clinical response to placebo IV introduction (placebo-introduction responders) were administered placebo SC.

[0252] Diagnosis and main criteria for inclusion All subjects enrolled in this randomized treatment discontinuation maintenance trial had an inadequate response to conventional therapy (i.e., corticosteroids or immunomodulators) or poor tolerance and showed a clinical response to the investigational drug during the introduction trial, and had moderate to severe active UC. This included subjects with a clinical response to IV ustekinumab, a clinical response to IV placebo, or a delayed clinical response to ustekinumab, who did not receive a drug change prohibited by the protocol during the introduction trial.

[0253] Evaluation criteria: ● Pharmacokinetics (PK): Serum ustekinumab concentration ● Immunogenicity: Antibodies against ustekinumab ● Pharmacodynamics (PD) / biomarkers: Serum biomarkers; fecal microbiota; RNA expression and histological evaluation of disease activity and healing in mucosal biopsies ● Genetics and epigenetics: Whole blood deoxyribonucleic acid (DNA) ●Efficacy: Mayo score, partial Mayo score, endoscopic severity assessment index for UC (UCEIS), CRP, fecal lactoferrin, and fecal calprotectin ●Health-related quality of life: Inflammatory Bowel Disease Questionnaire (IBDQ), 36-item Short Form Health Survey (SF-36), and EuroQoL-5D health questionnaire (EQ-5D) ●Healthcare economics: Hospitalization and surgery related to UC disease; Visual Analogue Scale for productivity (VAS), and Work Productivity and Activity Impairment Questionnaire-General Health (WPAI-GH) ●Safety: Adverse events (AE), serious adverse events (SAE), infections, injection site reactions, allergic reactions, hematological and chemical parameters, vital signs, physical examinations, and early detection of tuberculosis Endpoints ●The primary endpoint was clinical remission at week 44. The definition of clinical remission (along with the test procedure) differed between the US applications and non-US applications in order to conform to the preferred worldwide and US definitions of clinical remission. Each definition of clinical remission was applied to all subjects in the primary efficacy analysis population. - The worldwide definition of the primary endpoint of clinical remission was defined as a Mayo score of ≤2 with no individual subscore >1. - The US definition of clinical remission was defined as an absolute stool count of ≤3, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopic subscore of 0 or 1. ●The major secondary endpoints, listed in the order in which they were tested, were as follows​​​​​​​​​​​ There were: - Maintenance of clinical response up to week 44 - Endoscopic healing at week 44 - Clinical remission at week 44 and no administration of concomitant corticosteroids (corticosteroid-free clinical remission) - Maintenance of clinical remission up to week 44 among subjects who achieved clinical remission at maintenance baseline For the third and fourth major secondary endpoints, the world definition of clinical remission was used to support applications in countries outside the United States, and the US definition of clinical remission was used to support applications in the United States. Demographics and baseline disease characteristics were summarized based on 961 subjects in the primary efficacy analysis population. Except for the fourth major secondary endpoint related to maintenance of clinical remission, the analysis of multiplicity-controlled endpoints was stratified by the state of clinical remission (yes / no as determined by IWRS) at maintenance baseline and induction treatment (placebo IV [I-0] → ustekinumab ~6 mg / kg IV [I-8], ustekinumab 130 mg IV [I-0], or ustekinumab ~6 mg / kg IV [I-0]) and performed using the Cochran-Mantel-Haenszel (CMH) chi-square test. For the fourth major secondary endpoint (maintenance of clinical remission), the CMH chi-square test stratified by induction treatment was used. Multiple test procedures specific to the world and the United States were used for multiplicity-controlled endpoints in this trial.

[0254]

[0255] → ustekinumab ~6 mg / kg IV [I-8], ustekinumab 130 mg IV [I-0], or ustekinumab ~6 mg / kg IV [I-0]) and performed using the Cochran-Mantel-Haenszel (CMH ​​​​​​​​​​​To control the overall Type 1 error rate at the 0.05 level across the board as pre-specified (Section 3.11.2.7.3). All statistical tests were two-sided at the 0.05 significance level. Nominal p-values are presented.

[0256] Safety was evaluated comprehensively by the frequency and type of adverse events (AEs) that occurred under treatment, laboratory parameters (hematology and chemistry) , and vital sign parameters. Safety summaries are provided separately for randomized subjects, non-randomized subjects, and all treated subjects.

[0257] Results Study Population A total of 783 subjects who completed the lead-in trial and had a clinical response to the lead-in trial drug were enrolled in this maintenance trial. Of these, 523 subjects belonged to the targeted primary population for the maintenance trial and were randomized to receive either ustekinumab or placebo SC at Week 0 of the maintenance period (176 subjects in the ustekinumab 90 mg SC q8w group, 172 subjects in the ustekinumab 90 mg SC q12w, and 175 subjects in the placebo group). The remaining 250 subjects belonged to the non-randomized population including 157 late responders to ustekinumab induction (who received ustekinumab 90 mg SC q8w) and 103 responders to placebo induction (who received placebo). All registered subjects assigned treatment at the baseline of the maintenance period received their study drug at that time.

[0258] Before 40 weeks (visit for the last dose of the maintenance trial), 85 subjects (16 .3%) in the main population discontinued the study drug. The proportion of subjects who discontinued the study drug was higher than that in the placebo group (24.6%), and higher than those in the ustekinumab q8w and q12W groups (1 0.2% and 14.0% respectively). The most common reasons for discontinuation were lack of efficacy and adverse events due to worsening of UC. Before 44 weeks, 29 subjects (5.5%) in the main population terminated their participation in the trial, and the most common reason for termination of participation in the trial was withdrawal of consent.

[0259] Baseline clinical disease characteristics represented a population of subjects with moderate to severe active phase UC refractory to available therapies, and were generally balanced across the three treatment groups. The median disease duration was 6.05 years, the median baseline Mayo score was 9.0, and 86.9% and 13.1% had moderate and severe UC respectively. At baseline in the induction period, 52.2% of the subjects in the main population of the maintenance trial were taking corticosteroids, 26.6% were taking immunomodulators, and 70.7% were taking aminosalicylates. Most subjects (93.5%) had an inadequate response to corticosteroids and / or 6-MP / AZA, or intolerance, or corticosteroid dependence at the induction baseline. Overall in the main population, 47.6% of the subjects had a documented history of failure of biological therapies, and 52.4% did not. Also, 47.2% had failed at least one anti-TNF, while 13.4% had failed both anti-TNF and vedolizumab. Overall in the main population, 47.6% of the subjects had a documented history of failure of biological therapies, and 52.4% did not. Also, 47.2% had failed at least one anti-TNF, while 13.4% had failed both anti-TNF and vedolizumab. was effective, 49.3% were naive to biological therapies, and 2 subjects had biological inadequacy to vedolizumab alone.

[0260] Results of Efficacy USTEKINUMA B maintenance therapy was effective in a population of subjects with moderate to severe active UC who had previously been unsuccessful or intolerant to conventional therapies including TNF antagonists and / or vedolizumab or biological therapies and who were in clinical response at week 8 after receiving an induction dose of a single administration of Ustekinumab IV. Statistical significance was claimed for both Ustekinumab dosing regimens (90 mg q8w and 90 mg q12w) for the primary endpoint of clinical remission at week 44 and maintenance of clinical response through week 44, endoscopic healing at week 44, and the 3 key secondary endpoints of corticosteroid-free clinical remission at week 44, based on a plurality of pre-specified trial procedures limited to the world and the United States. In addition, statistical significance was claimed for maintenance of clinical remission through week 44 (among subjects who achieved clinical remission at baseline during the maintenance period) for both the Ustekinumab

[0261] dose based on US-specified trial procedures and the Ustekinumab q12w regimen ● Clinical Efficacy in the Primary Population (i.e., subjects who were in clinical response for 8 weeks after receiving an IV induction dose of Ustekinumab) - Primary Endpoint: Clinical Remission ○ The proportion of subjects in clinical remission (based on the world definition) at week 44 was higher in the Ustekinumab q8w group and the The w-group (43.8% and 38.4%, respectively) was significantly larger (p < 0. 001 and p = 0.002), respectively). ○ The proportion of subjects in clinical remission (based on the US-limited definition) at week 44 was significantly larger in the ustekinumab q8w group and the ustekinumab q12w group (42.6% and 39.5%, respectively) compared to the placebo group (24.6%) (p < 0.001 and p = 0.002, respectively). ○ The effect of ustekinumab on achieving clinical remission (based on both the worldwide definition and the US-limited definition) was generally consistent across the overall subgroup (including subjects who were unsuccessful with biological therapy and those who were not, as well as subjects who were administered concomitant immunomodulatory drugs or corticosteroids at baseline during the induction period and those who were not) and was robust to predefined changes in the data handling rules. - Major secondary endpoints: maintenance of clinical response, endoscopic healing, corticosteroid-free clinical remission, and maintenance of clinical remission ○ The proportion of subjects who maintained a clinical response, achieved endoscopic healing, and achieved corticosteroid-free remission (applying both the worldwide definition and the US-limited definition of clinical remission) over 44 weeks was significantly larger in the ustekinumab q8w and q12w groups compared to the placebo group (p < 0.01). ○ The proportion of subjects who maintained clinical remission among those who achieved clinical remission at baseline during the maintenance period was numerically larger for both the ustekinumab q8w and q1 2w groups compared to the placebo group (for the worldwide definition and US-limited definition of clinical remission). definition of clinical remission). Statistical significance (p<0.01) was observed for the US definition of clinical remission. was achieved for both the q8w and q12w comparisons against placebo using However, statistical significance was not achieved using the global definition of clinical remission in q12w patients compared with placebo. This was achieved only for the group (p<0.01). - Other histologic, mucosal, clinical, and endoscopic endpoints The analyses summarized below were not controlled for multiplicity. Statements of statistical significance are Based on nominal p-values. Achieved histological cure at 44 weeks (i.e., neutrophil infiltration in <5% of crypts) The proportion of subjects with no cysts, crypt destruction, erosions, ulcers, or granulation tissue was 100% higher than in the placebo group. In comparison, the difference was significantly greater in the ustekinumab q8w and q12w groups (p<0.0 01). Patients who achieved mucosal healing (combination of endoscopic and histological healing) at 44 weeks The proportion of patients who underwent q8w and q12w ustekinumab therapy was significantly higher than that of patients who underwent q12w ustekinumab therapy compared with placebo. The difference was significantly larger (p<0.01). Applying both the global and US-specific definitions of clinical remission, The proportion of subjects who achieved corticosteroid-free remission for at least 90 days was significantly higher than that of the placebo group. The mean mean mean 14.4% of patients receiving ustekinumab q8w and q12w were significantly greater than those receiving q12w (p <0.01). In addition, subjects receiving corticosteroids at baseline in the maintenance phase In the ustekinumab q8w and q12w groups compared with the placebo group, A significantly greater proportion of subjects (p<0.05) were in clinical remission and had They had been off concomitant corticosteroids for at least 90 days. ○ The effectiveness of ustekinumab maintenance therapy was also demonstrated in clinical outcomes measured by maintained improvement in the partial Mayo score, maintenance of symptomatic remission, and maintenance of endoscopic healing. Further evidence of the effectiveness of ustekinumab maintenance therapy was observed in partial Mayo remission and symptomatic remission over time, and symptom control (number of bowel movements and rectal bleeding). - Inflammatory biomarkers

[0262] ○ Through week 44, the ustekinumab treatment group maintained the CRP, fecal lactoferrin, and fecal calprotectin concentration levels observed at maintenance-phase baseline, whereas in the placebo group, the median CRP, fecal lactoferrin, and fecal calprotectin concentrations worsened (increased). ○ At week 44, the proportion of subjects with normalized CRP, fecal calprotectin, and fecal lactoferrin was generally significantly greater in the q8w and q12w groups of ustekinumab compared to the placebo group. - Clinical endpoints due to failure of biologic therapy ○ For subjects with and without a history of failure of biologic therapy, the proportion of subjects who achieved the primary endpoint and each of the key secondary endpoints and mucosal healing was generally greater in the q8w and q12w groups of ustekinumab compared to subjects in the placebo group. ○ In some cases, when the treatment effect was similar in populations where biologic therapy was not a failure and in populations where it was a failure, there was a consistent trend across endpoints for the treatment effect of the q8w group of ustekinumab to be greater than that of the q12w group of ustekinumab in subjects in whom biologic therapy had failed. This trend was seen in subjects in whom biologic therapy had failed. This trend was seen in subjects in whom biologic therapy had failed. ○ In some cases, when the treatment effect was similar in populations where biologic therapy was not a failure and in populations where it was a failure, there was a consistent trend across endpoints for the treatment effect of the q8w group of ustekinumab to be greater than that of the q12w group of ustekinumab in subjects in whom biologic therapy had failed. This trend was seen in subjects in whom biologic therapy had failed. It was not observed in the group that was not unsuccessful in treatment. - Efficacy based on inflammatory biomarker subgroups ○ Among subjects with a higher inflammatory burden (increase in CRP and / or increase in fecal inflammatory markers) at either baseline in the induction or maintenance phase, both doses generally showed efficacy compared to placebo, but the efficacy of ustekinumab q8w was thought to be better across the range of clinical endpoints than the ustekinumab q12w group. However, in subjects with a low inflammatory burden at baseline, the ustekinumab q8w group and the q12w group showed similar efficacy for the endpoint.

[0263] - Health-related quality of life ○ By week 44, subjects in the ustekinumab q8w group and q12w group generally were able to maintain an improvement in health-related quality of life as evaluated using the IBDQ, SF36, and EQ5D assessment methods compared to subjects in the placebo group. - Outcomes of ustekinumab 90 mg q8w dose and ustekinumab 90 mg q12w dose ○ Both the ustekinumab q8w group and q12w group generally showed similar efficacy for the primary endpoint and major secondary endpoints, but q8w was slightly better than q12w based on the following more objective and stringent measures of efficacy. . ◆ Endoscopic healing and mucosal healing at week 44 ◆ Long-term partial Mayo remission at week 44 ◆ Among subjects receiving corticosteroids at baseline in the maintenance phase, clinical remission without corticosteroids and ​Exclusion of Ruticosteroids ○ Furthermore, when the effectiveness was tested over time (for the following endpoints), q The 8w group showed greater effectiveness than the q12w group. ◆ Mayo showing inactive or mild disease (i.e., subscore of 0 or 1) Number of bowel movements and rectal bleeding subscores, and absolute number of stools ≤ 3 over time up to week 44. ◆ Partial Mayo remission and symptomatic remission over time up to week 44 ◆ Median change from baseline in fecal lactoferrin and calprotectin concentrations over time up to week 44 ● Effectiveness in ustekinumab introduction delayed responders Subjects who were delayed responders to ustekinumab introduction therapy maintained a clinical response while receiving 90mg of ustekinumab q8w and achieved clinical remission, endoscopic healing, histological healing, and mucosal healing (combination of endoscopic and histological healing). was able to. ● Effectiveness and pharmacokinetics / immunogenicity - Generally, during maintenance, an obvious correlation was observed between serum ustekinumab concentration and the clinical outcomes of effectiveness of clinical remission and endoscopic healing. In addition, when measured by CRP lower levels of inflammation were observed in subjects with higher serum ustekinumab concentrations. - Among subjects receiving maintenance ustekinumab, the occurrence of antibodies against ustekinumab did not seem to affect the clinical effectiveness measured by multiple endpoints such as changes from the maintenance baseline in clinical remission, endoscopic healing, clinical response, and Mayo score. However, the interpretation of the data is limited by the small sample size.

[0264] ​​​​​Pharmacokinetic and immunogenicity results ● Following maintenance treatment by subcutaneous administration of ustekinumab 90 mg q8w or q12w, subjects initiated maintenance dosing regimens of subcutaneous administration of ustekinumab 90 mg q8w or ustekinumab 90 m g q12w, respectively. At about week 8 or 12 weeks, steady state was reached. The steady state geometric mean value of trough-type serum ustekinumab concentration over time was approximately 3-fold higher in the ustekinumab q8w group (2.69 μg / mL - 3.09 μg / mL) than in the q12w group (0.92 μg / mL - 1.19 μg / mL). . ● After maintenance dosing regimens of subcutaneous administration of ustekinumab 90 mg q8w or q12w, serum ustekinumab concentration was maintained in almost all subjects until week 44, and the proportion of subjects with undetectable trough-type concentrations over time was lower in the 90 mg q8w group (0.7% - 2.4%) than in the 90 mg q12w group (4. 9% - 7.1%). The median ustekinumab concentration in subjects of the placebo group was below the detectable level by week 16. ● The influence of different ustekinumab IV induction doses on the maintained serum ustekinumab concentration continued to decrease over time as expected. ● The geometric mean of trough-type serum ustekinumab concentration tended to be lower in subjects with higher body weight. ● Non-randomized subjects in the ustekinumab late-onset responder group had a tendency to have lower serum ustekinumab concentrations over time compared to randomized subjects in the ustekinumab q8w group after subcutaneous administration of the same ustekinumab dosing regimen of 90 mg q8w. ● Among 680 treated subjects with appropriate samples for evaluating antibodies against ustekinumab, 39 subjects (5.7%) were positive for antibodies against ustekinumab throughout 52 weeks of treatment, and most had an antibody titer of ≤1:800. In this maintenance study, among the 39 treated subjects who were positive for antibodies against ustekinumab, 11 subjects (28.2%) were positive for neutralizing antibodies. ● In all randomized treatment groups, the median serum ustekinumab concentration was lower over time in subjects who were positive for antibodies against ustekinumab compared to the level in subjects who were negative for antibodies against ustekinumab. Safety Results The subcutaneous maintenance regimen of 90 mg of ustekinumab administered q12W or q8W until week 44 generally showed good tolerability, consistent with the known safety profile of ustekinumab. ● AEs were reported in 77.3%, 69.2%, and 78.9% of the subjects in the ustekinumab q8W group, ustekinumab q12W group, and placebo group, respectively. - AEs with a reasonable causal relationship were reported in 26.1%, 17.4%, and 28.6% of the subjects in the ustekinumab q8W group, ustekinumab q12W group, and placebo group, respectively. ● Infections (identified by the treating physician) were reported in 48.9%, 33.7%, and 46.3% of the subjects in the ustekinumab q8W group, ustekinumab q12W group, and placebo group, respectively.

[0265] ● Infections requiring oral or parenteral antibiotic treatment were reported in the ustekinumab q8W group, ​​​​​​​​​​​​​In the ustekinumab q12w group and the placebo group, 22.7%, 15.7 %, and 19.4% were reported, respectively. ● Serious infections were infrequent among the randomized subjects, and occurred in 1.7%, 3.5% of the ustekinumab q8w group, the ustekinumab q12w group, and the placebo group, respectively. Opportunistic infections were identified in 3 subjects (all in the randomized cohort). Cytomegalovirus colitis was diagnosed in 2 subjects in the ustekinumab q12w group, and 1 subject was diagnosed with concurrent moderate AE of eye and lip herpes. No cases of active TB were reported among the ustekinumab-treated subjects over 44 weeks. ● The proportion of randomized subjects with AEs leading to discontinuation of the study drug was higher in the placebo group than in the q12w and q8w groups, and the most frequent AE leading to discontinuation in the placebo group was worsening of UC. ● Among all treated subjects, including ustekinumab late responders, the overall safety profile was consistent with that observed in the randomized cohort. ● Death was reported in 1 subject who was a ustekinumab late responder and was receiving ustekinumab q8w. The cause of death was attributed to acute respiratory failure that occurred during thyroid surgery for multinodular goiter. ● Among all treated subjects, 2 subjects (1 subject belonged to the ustekinumab late responder group [receiving ustekinumab q8w], and 1 subject was randomized to the placebo group that received IV ustekinumab I during induction) reported serious major adverse cardiovascular events, and both events were associated with perioperative complications. ● Among all the treatment subjects, there were 6 subjects in whom a malignant disease was reported (5 ustekinumab treatment subjects and 1 placebo-only subject). ● Three ustekinumab treatment subjects reported non-melanoma skin cancer (NMSC), and all three had a previous history of either azathioprine or 6-MP treatment, and 2 were receiving concomitant immunomodulatory therapy at the time of diagnosis. ● Two ustekinumab treatment subjects reported having solid tumors. One subject had papillary renal cell carcinoma (q12w), and one subject had colon cancer (q8w), and during the subjects' participation in this maintenance study, both tumors were detected early. ● Cases of anaphylaxis or delayed hypersensitivity reactions were not identified among subjects treated with ustekinumab. ● The proportion of subjects with ≥1 maximum toxicity grade chemical and hematological laboratory values after baseline was not significantly different between the placebo group and each ustekinumab group. Grade 3 and grade 4 chemical and hematological laboratory values were of low frequency.

[0266] Results of Healthcare Economics and Medical Resource Utilization ● By week 44, subjects in the combined ustekinumab group had few UC disease-related hospitalizations or surgeries compared to the placebo group. ● At week 44, the change from maintenance baseline in the productivity visual analog score demonstrated improvement in subjects in the ustekinumab treatment group and worsening in subjects in the placebo group. ● At week 44, the percentage in each of the four WPAI-GH domains was maintained from maintenance baseline for the ustekinumab treatment group, and for the q8 In the w-group of subjects, additional improvements were observed in the work impairment rate due to health, the overall work impairment rate due to health, and the activity impairment rate due to health. For the subjects in the placebo group, the percentages for all four WPAI-GH domains worsened (i.e., increased).

[0267] Conclusion ● The ustekinumab maintenance trials showed consistent and definitive evidence that both dosing regimens of subcutaneous ustekinumab at 90 mg q12w and q8w were effective in adult subjects with moderate to severe active ulcerative colitis who responded to a single intravenous ustekinumab induction dose. - The efficacy of ustekinumab was observed in subjects who were unsuccessful with biological therapies, as well as in subjects who were unsuccessful with conventional therapies but not with biological therapies (i.e., naive to biological therapies). - Notably, both doses of ustekinumab were effective, but the q8w dosing regimen showed slightly better efficacy for some objective and / or more stringent endpoints (e.g., endoscopic healing and long-term partial Mayo remission), as well as for the analysis of symptomatic and partial Mayo remission over time. ● The maintenance doses of subcutaneous ustekinumab at 90 mg q12w and 90 mg q8w showed generally good tolerability over 44 weeks in a population of adult subjects with moderate to severe ulcerative colitis. ● The safety and efficacy data from this trial support a favorable benefit / risk profile for subcutaneous ustekinumab maintenance therapy.

[0268] ​​​​​​​​​​​​​​As of September 4, 2019, the European Commission has established the following standards in Europe: STELARA® (registered trademark) for the treatment of ulcerative colitis (UC) The approved labeling is for the intravenous formulation (section The compositions are shown in Appendix I, which describes the formulations for intravenous administration (sections 1-10) and subcutaneous administration (sections 1-10).

[0269] The present invention relates to pharmaceutical compositions of anti-IL-12 / IL-23p40 antibodies and the compositions disclosed in Appendix I. and packaging comprising one or more label elements, the antibody comprising: (i) a heavy chain variable region and a light chain variable region; A variable region, wherein the heavy chain variable region is a complementarity determining region heavy chain 1 (CDRH1) of SEQ ID NO: 1. The amino acid sequence of CDRH2 is shown in SEQ ID NO:2, and the amino acid sequence of CDRH3 is shown in SEQ ID NO:3. and a light chain variable region comprising the complementarity determining region light chain 1 (CDRL1) of SEQ ID NO:4. ) amino acid sequence of SEQ ID NO:5, and CDRL3 amino acid sequence of SEQ ID NO:6. (ii) a heavy chain variable region and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and a light chain variable region of the amino acid sequence of SEQ ID NO: 8; or (iii) the sequence 10 and a light chain having the amino acid sequence of SEQ ID NO:11.

[0270] Appendix I Product Characteristics Overview 1. Name of medical product STELARA 130 mg concentrate for solution for injection

[0271] 2. Qualitative and quantitative composition Each vial contains 130 mg of ustekinumab in 26 mL (5 mg / mL) .

[0272] USTEKINUMAB is produced in a murine myeloma cell line using recombinant DNA technology and is a fully human IgG1κ monoclonal antibody against interleukin (IL)-12 / 23. It is as follows.

[0273] For a complete list of excipients, see Section 6.1.

[0274] 3. Pharmaceutical Form Concentrate for infusion.

[0275] The solution is clear and ranges from colorless to pale yellow.

[0276] 4. Clinical Characteristics 4.1 Therapeutic Indications Crohn's disease STELARA is indicated for the treatment of adult patients with moderate to severe active Crohn's disease who have had an inadequate response to, lost response to, or are intolerant to either conventional therapy or TNFα antagonists, or who have a medical contraindication to such therapy.

[0277] Ulcerative colitis STELARA is indicated for the treatment of adult patients with moderate to severe active ulcerative colitis who have had an inadequate response to, lost response to, or are intolerant to either conventional therapy or biological therapy, or who have a medical contraindication to such therapy (see Section 5.1).

[0278] 4.2 Dosage and Administration The STELARA concentrate for infusion is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of Crohn's disease or ulcerative colitis. The STELARA concentrate for infusion should be used only for intravenous infusion. ​

[0279] Dosage Crohn's disease and ulcerative colitis STELARA treatment is initiated with a single intravenous dose based on body weight. The infusion consists of the number of vials of STELARA 130 mg specified in Table 1 in the label (see section 6.6 for the preparation).

[0280]

Table 5

[0281] The first subcutaneous dose should be administered 8 weeks after the intravenous dose. For subsequent subcutaneous dosing regimens, for the dosage of the injection (vial) of STELARA solution and prefilled syringe, please refer to section 4.2 of the injection solution in the SmPC.

[0282] Elderly (≥ 65 years old) No dosage adjustment is required for elderly patients (see section 4.4).

[0283] Renal and hepatic impairmentSTELARA has not been tested in these patient populations. No dosing recommendations can be made.

[0284]

[0285]

[0286] Route of administration STELARA 130 mg is used only for intravenous administration. This drug should be administered over at least 1 hour.

[0286] For instructions on the dilution of the medicinal product before administration, refer to Section 6.6.

[0287] 4.3 Contraindications Hypersensitivity to any of the active substances or excipients listed in Section 6.1.

[0288] Clinically significant active infections (e.g., active tuberculosis; refer to Section 4.4).

[0289] 4.4 Special Warnings and Precautions Traceability To improve the traceability of biological medicinal products, it is necessary to clearly record the trade name and batch number of the product administered.

[0290] Infections USTEKINUMAB has the potential to increase the risk of infection and reactivate latent infections. In clinical trials, serious bacterial, fungal, and viral infections have been observed in patients administered STELARA (refer to Section 4.8).

[0291] Caution should be exercised when considering the use of STELARA in patients with a history of chronic or recurrent infections (refer to Section 4.3).

[0292] Before starting treatment with STELARA, patients should be evaluated for tuberculosis infection. STELARA must not be administered to patients with active tuberculosis (refer to Section 4.3). Treatment of latent tuberculosis infection should be initiated before administering STELARA. Antituberculosis treatment should also be considered before starting STELARA in patients with a history of potential or active tuberculosis where an appropriate treatment course cannot be confirmed. Patients being administered STELARA should be closely monitored for signs and symptoms of active tuberculosis during and after treatment.

[0293] If signs or symptoms of an infection occur, the patient should be instructed to seek medical advice. If the patient develops a serious infection, the patient should be closely monitored and STELARA should not be administered until the

[0294] Malignant tumors Immunosuppressive agents such as ustekinumab may have the potential to increase the risk of malignancies. Some patients administered STELARA in clinical trials developed cutaneous and non-cutaneous malignancies (see

[0295] Section 4.8). Trials have not been conducted to continue treatment in patients with a history of malignancy or who develop a malignancy while being administered

[0296] STELARA. Therefore, caution should be exercised when considering the use of STELARA in these patients. All patients, particularly those over 60 years of age, those with a history

[0297] of long-term immunosuppressive therapy, or those with a history of PUVA Systemic Severe hypersensitivity reactions have been reported in the post-marketing medical setting, and in some cases have been reported within days after treatment. Anaphylaxis and angioedema have occurred. If anaphylaxis It is necessary to discontinue the administration of ARA (see Section 4.8).

[0298] Respiratory Cases of allergic alveolitis and eosinophilic pneumonia have been reported during post-approval use of ustekinumab. Clinical symptoms included cough, dysphagia, and interstitial infiltrates after 1 to 3 doses . Severe outcomes included respiratory failure and prolonged hospitalization. Improvement has been reported after interruption of ustekinumab , and in some cases after administration of corticosteroids. If an infectious disease is excluded and the diagnosis is confirmed, discontinue ustekinumab and initiate appropriate treatment (see Section 4.8). 4.8).

[0299] Vaccination Live virus vaccines or live bacterial vaccines (such as Bacillus Calmette-Guérin (BCG)) are not recommended to be administered concomitantly with STELARA. Specific studies have not been conducted in patients who have recently received live virus vaccines or live bacterial vaccines. There is no data on secondary transmission of infection by live vaccines in patients receiving STELARA ARA. Treatment with STELARA should be withheld for at least 15 weeks after the last dose before live virus vaccination or live bacterial vaccination and can be resumed at least 2 weeks after vaccination. Prescribers should consult the summary of product characteristics of the specific vaccine for additional information and guidance regarding co-administration of immunosuppressive agents after vaccination . 2 weeks after vaccination. Prescribers should consult the summary of product characteristics of the specific vaccine for additional information and guidance regarding co-administration of immunosuppressive agents after vaccination . .

[0300] Patients receiving STELARA may receive concomitant inactivated or non-live vaccinations .

[0301] ​Long-term treatment with STELARA does not suppress the humoral immune response to pneumococcal polysaccharide or tetanus vaccine (see Section 5.1).

[0302] Combined immunosuppressive therapy In psoriasis trials, the safety and efficacy of STELARA in combination with immunosuppressive agents, including biologics or phototherapy, have not been evaluated. In psoriatic arthritis trials, the use of concomitant MTX did not appear to affect the safety or efficacy of STELARA. In Crohn's disease and ulcerative colitis trials, the combination of immunosuppressive agents or corticosteroids did not appear to affect the safety or efficacy of STELARA. When considering co-administration of STELARA with other immunosuppressive agents or switching from other immunosuppressive biologics, care should be taken (see Section 4.5). ARA. When considering co-administration of STELARA with other immunosuppressive agents or switching from other immunosuppressive biologics, care should be taken (see Section 4.5). ELARA, or when switching from other immunosuppressive biologics, care should be taken (see Section 4.5). (see Section 4.5).

[0303] Immunotherapy STELARA has not been evaluated in patients receiving allergy immunotherapy. It is not known whether STELARA can affect allergy immunotherapy. ELARA can affect allergy immunotherapy.

[0304] Severe skin conditions In psoriasis patients, exfoliative dermatitis has been reported after ustekinumab treatment (see Section 4.8). Patients with plaque psoriasis may develop psoriatic erythroderma with symptoms that cannot be clinically distinguished from exfoliative dermatitis as part of the natural course of the disease. As part of the monitoring of the patient's psoriasis, the physician should not overlook the symptoms of psoriatic erythroderma or exfoliative dermatitis. If these symptoms occur, appropriate treatment should be initiated. If a drug reaction is suspected, STELARA should be discontinued. (see Section 4.8). Patients with plaque psoriasis may develop psoriatic erythroderma with symptoms that cannot be clinically distinguished from exfoliative dermatitis as part of the natural course of the disease. As part of the monitoring of the patient's psoriasis, the physician should not overlook the symptoms of psoriatic erythroderma or exfoliative dermatitis. If these symptoms occur, appropriate treatment should be initiated. If a drug reaction is suspected, STELARA should be discontinued. from exfoliative dermatitis. As part of the monitoring of the patient's psoriasis, the physician should not overlook the symptoms of psoriatic erythroderma or exfoliative dermatitis. If these symptoms occur, appropriate treatment should be initiated. If a drug reaction is suspected, STELARA should be discontinued. As part of the monitoring of the patient's psoriasis, the physician should not overlook the symptoms of psoriatic erythroderma or exfoliative dermatitis. If these symptoms occur, appropriate treatment should be initiated. If a drug reaction is suspected, STELARA should be discontinued. If these symptoms occur, appropriate treatment should be initiated. If a drug reaction is suspected, STELARA should be discontinued. STELARA should be discontinued.

[0305] Special population Elderly (≥ 65 years old) Patients 65 years of age and older who received STELARA in clinical trials for approved indications No overall differences in effectiveness or safety were observed compared to younger patients, but the number of patients 65 years of age and older was not sufficient to determine whether they exhibit a different response than younger patients. In general, because the incidence of infectious diseases is high in the elderly population, care should be exercised in treating the elderly.

[0306] Sodium content STELARA contains less than 1 millimole (23 mg) of sodium per dose and is thus essentially "sodium-free". However, STELARA is diluted with a 9 mg / ml (0.9%) sodium chloride solution for injection. This should be considered in patients on a low-sodium diet (see Section 6.6).

[0307] 4.5 Interactions with other medicinal products and other forms of interaction Live vaccines should not be administered concomitantly with STELARA (see Section 4.4).

[0308] Interaction studies have not been conducted in humans. In a population pharmacokinetic analysis of Phase III trials, the effect of concomitant medicinal products most frequently used in patients with psoriasis (including paracetamol, ibuprofen, acetylsalicylic acid, metformin, atorvastatin, levothyroxine) on the pharmacokinetics of ustekinumab was investigated. No signs of interaction with these concomitantly administered medicinal products were found. This analysis was based on at least 100 patients (> 5% of the population studied) being treated concomitantly with these medicinal products for at least 90% of the study period. ​​​​​​​​​Tezepelumab pharmacokinetics were not affected by concomitant MTX, NSAIDs, 6-mercaptopurine, azathioprine, and oral corticosteroids in patients with psoriatic arthritis, Crohn's disease, or ulcerative colitis, or by prior exposure to anti-TNFα agents in patients with psoriatic arthritis or Crohn's disease, or by prior exposure to biological agents (i.e., anti-TNFα agents and / or vedolizumab) in patients with ulcerative colitis. The results of in vitro studies do not suggest the need for dose adjustment in patients receiving concomitant CYP450 substrates (see Section 5.2). In psoriasis trials, the safety and efficacy of STELARA in combination with biological agents or immunosuppressants, including phototherapy, have not been evaluated. In psoriatic arthritis trials, the use of concomitant MTX did not appear to affect the safety or efficacy of STELARA. In Crohn's disease and ulcerative colitis trials, the use of concomitant immunosuppressants or corticosteroids did not appear to affect the safety or efficacy of STELARA (see Section 4.4). 4.6 Fertility, Pregnancy, and Lactation Women of Childbearing Potential Women of childbearing potential should use effective contraception during treatment and for at least 15 weeks after treatment.

[0309] Pregnancy There are no adequate data on the use of tezepelumab in pregnant women. Animal studies have shown adverse effects on pregnancy, embryo-fetal development, and postnatal development at maternally toxic doses.

[0310] Therefore, tezepelumab should not be used in pregnant women unless the potential benefit to the mother outweighs the potential risk to the fetus. Lactation It is not known whether tezepelumab is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from tezepelumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

[0311]

[0312] ​​​​​​​​​Does not show direct or indirect harmful effects on fetal development, childbirth or postnatal development (see section 5.3). As a preventive measure, it is preferable to avoid the use of STELARA during pregnancy. See section 5.3. It is preferable to avoid the use of STELARA during pregnancy.

[0313] Breastfeeding It is not known whether ustekinumab is excreted in human breast milk. Animal studies have shown excretion of ustekinumab at low levels in breast milk. It is not known whether ustekinumab is systemically absorbed after ingestion. Due to the potential for adverse reactions in infants from ustekinumab, the decision whether to interrupt breastfeeding during and up to 15 weeks after treatment, or to interrupt treatment with STELARA, must be made taking into account the benefits of breastfeeding for the child and the benefits of STELARA therapy for the woman. Animal studies have shown excretion of ustekinumab at low levels in breast milk. It is not known whether ustekinumab is systemically absorbed after ingestion. Due to the potential for adverse reactions in infants from ustekinumab, the decision whether to interrupt breastfeeding during and up to 15 weeks after treatment, or to interrupt treatment with STELARA, must be made taking into account the benefits of breastfeeding for the child and the benefits of STELARA therapy for the woman. It is not known whether ustekinumab is systemically absorbed after ingestion. Due to the potential for adverse reactions in infants from ustekinumab, the decision whether to interrupt breastfeeding during and up to 15 weeks after treatment, or to interrupt treatment with STELARA, must be made taking into account the benefits of breastfeeding for the child and the benefits of STELARA therapy for the woman. Due to the potential for adverse reactions in infants from ustekinumab, the decision whether to interrupt breastfeeding during and up to 15 weeks after treatment, or to interrupt treatment with STELARA, must be made taking into account the benefits of breastfeeding for the child and the benefits of STELARA therapy for the woman. Due to the potential for adverse reactions in infants from ustekinumab, the decision whether to interrupt breastfeeding during and up to 15 weeks after treatment, or to interrupt treatment with STELARA, must be made taking into account the benefits of breastfeeding for the child and the benefits of STELARA therapy for the woman. Due to the potential for adverse reactions in infants from ustekinumab, the decision whether to interrupt breastfeeding during and up to 15 weeks after treatment, or to interrupt treatment with STELARA, must be made taking into account the benefits of breastfeeding for the child and the benefits of STELARA therapy for the woman.

[0314] Fertility The effect of ustekinumab on human fertility has not been evaluated (see section 5.3). See section 5.3.

[0315] 4.7 Effects on driving and ability to operate machinery STELARA does not affect or has a negligible effect on the ability to drive and operate machinery. STELARA does not affect or has a negligible effect on the ability to drive and operate machinery.

[0316] 4.8 Side effects Summary of safety profile The most common adverse reactions (>5%) during the comparative control period of clinical trials of ustekinumab in adults with psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis were nasopharyngitis and headache. Most were considered mild and did not require interruption of the test treatment. The most serious adverse reactions reported for STELARA include severe reactions including anaphylaxis. The most common adverse reactions (>5%) during the comparative control period of clinical trials of ustekinumab in adults with psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis were nasopharyngitis and headache. Most were considered mild and did not require interruption of the test treatment. The most serious adverse reactions reported for STELARA include severe reactions including anaphylaxis. Most were considered mild and did not require interruption of the test treatment. The most serious adverse reactions reported for STELARA include severe reactions including anaphylaxis. The most serious adverse reactions reported for STELARA include severe reactions including anaphylaxis. is a non - allergic reaction (see Section 4.4). The overall safety profile was similar to that of patients with psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis.

[0317] List of Adverse Reactions The safety data described below reflect the exposure to ustekinumab in 6,709 patients (4,135 patients with psoriasis and / or psoriatic arthritis, 1,749 patients with Crohn's disease, and 825 patients with ulcerative colitis) in 14 Phase II and Phase III trials, in adults. This includes exposure to STELARA during the comparative and non - comparative control periods of clinical trials of at least 6 months or 1 year (4,577 patients and 3,253 patients with psoriasis, psoriatic arthritis, Crohn's disease or ulcerative colitis respectively), and exposure of at least 4 years or 5 years (1,482 patients and 838 patients with psoriasis respectively).

[0318] Table 2 of the label provides a list of adverse reactions from clinical studies in adults with psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, as well as a list of adverse reactions reported from post - marketing experience. Adverse reactions are classified by organ - based major classification (System Organ Class) and frequency using the following conventions: Very Common (≥1 / 10), Common (≥1 / 100 to <1 / 10), Uncommon (≥1 / 1,000 to <1 / 100), Rare (≥1 / 10,000 to <1 / 1,000), Very Rare (<1 / 10,000), not known (estimated from available data) (not possible). Within each frequency grouping, adverse reactions are presented in descending order of severity. are presented.

[0319] [Table 6]

[0320] Description of selected adverse reactions Infectious diseases In placebo-controlled trials of patients with psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis the rate of infectious or serious infectious diseases was similar between ustekinumab-treated patients and placebo-treated patients. During the placebo control periods of these clinical trials, the infection rate was 1.36 per patient-year of follow-up in ustekinumab-treated patients and 1.34 in placebo-treated patients. Serious infectious diseases occurred at a rate of 0.03 per patient-year of follow-up in ustekinumab-treated patients (30 serious infectious diseases in 930 patient-years of follow-up) and at a rate of 0.03 in placebo-treated patients (15 serious infectious diseases in 434 patient-years of follow-up) (see Section 4.4).

[0321] In the comparative and non-comparative control periods of clinical trials of psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, representing 11,581 patient-years of exposure in 6,709 patients, the median follow-up was 1.0 year, 1.1 years in psoriasis disease trials, 0.6 years in Crohn's disease trials, and 1.0 year in ulcerative colitis trials. The infection rate was 0.91 per patient-year of follow-up in ustekinumab-treated patients, and the rate of severe infections was 0.02 per patient-year of follow-up in ustekinumab-treated patients (11,581 patient-years of follow-up in 11,581 patients). In the observation, 199 severe infectious diseases were reported, including pneumonia, perianal abscess, cellulitis, diverticulitis, gastroenteritis, and viral infections. In clinical trials, patients with latent tuberculosis treated with isoniazid did not develop tuberculosis.

[0322] In clinical trials, patients with latent tuberculosis treated with isoniazid did not develop tuberculosis. In the placebo-controlled periods of clinical trials for psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, the incidence of malignancies excluding non-melanoma skin cancer was 0.23 per 100 patient-years of follow-up (1 patient in 434 patients followed for 1 year) in placebo-treated patients, compared with 0.11 per 100 patient-years of follow-up (1 patient in 929 patients followed for 1 year) in ustekinumab-treated patients. The incidence of non-melanoma skin cancer was 0.46 per 100 patient-years of follow-up (2 patients in 433 patients followed for 1 year) in placebo-treated patients, compared with 0.43 per 100 patient-years of follow-up (4 patients in 929 patients followed for 1 year) in ustekinumab-treated patients.

[0323] Malignant tumors In the placebo-controlled periods of clinical trials for psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, the incidence of malignancies excluding non-melanoma skin cancer was 0.23 per 100 patient-years of follow-up (1 patient in 434 patients followed for 1 year) in placebo-treated patients, compared with 0.11 per 100 patient-years of follow-up (1 patient in 929 patients followed for 1 year) in ustekinumab-treated patients. The incidence of non-melanoma skin cancer was 0.46 per 100 patient-years of follow-up (2 patients in 433 patients followed for 1 year) in placebo-treated patients, compared with 0.43 per 100 patient-years of follow-up (4 patients in 929 patients followed for 1 year) in ustekinumab-treated patients. In the placebo-controlled periods of clinical trials for psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, the incidence of malignancies excluding non-melanoma skin cancer was 0.23 per 100 patient-years of follow-up (1 patient in 434 patients followed for 1 year) in placebo-treated patients, compared with 0.11 per 100 patient-years of follow-up (1 patient in 929 patients followed for 1 year) in ustekinumab-treated patients. The incidence of non-melanoma skin cancer was 0.46 per 100 patient-years of follow-up (2 patients in 433 patients followed for 1 year) in placebo-treated patients, compared with 0.43 per 100 patient-years of follow-up (4 patients in 929 patients followed for 1 year) in ustekinumab-treated patients. In the placebo-controlled periods of clinical trials for psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, the incidence of malignancies excluding non-melanoma skin cancer was 0.23 per 100 patient-years of follow-up (1 patient in 434 patients followed for 1 year) in placebo-treated patients, compared with 0.11 per 100 patient-years of follow-up (1 patient in 929 patients followed for 1 year) in ustekinumab-treated patients. The incidence of non-melanoma skin cancer was 0.46 per 100 patient-years of follow-up (2 patients in 433 patients followed for 1 year) in placebo-treated patients, compared with 0.43 per 100 patient-years of follow-up (4 patients in 929 patients followed for 1 year) in ustekinumab-treated patients. In the placebo-controlled periods of clinical trials for psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, the incidence of malignancies excluding non-melanoma skin cancer was 0.23 per 100 patient-years of follow-up (1 patient in 434 patients followed for 1 year) in placebo-treated patients, compared with 0.11 per 100 patient-years of follow-up (1 patient in 929 patients followed for 1 year) in ustekinumab-treated patients. The incidence of non-melanoma skin cancer was 0.46 per 100 patient-years of follow-up (2 patients in 433 patients followed for 1 year) in placebo-treated patients, compared with 0.43 per 100 patient-years of follow-up (4 patients in 929 patients followed for 1 year) in ustekinumab-treated patients. In the placebo-controlled periods of clinical trials for psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, the incidence of malignancies excluding non-melanoma skin cancer was 0.23 per 100 patient-years of follow-up (1 patient in 434 patients followed for 1 year) in placebo-treated patients, compared with 0.11 per 100 patient-years of follow-up (1 patient in 929 patients followed for 1 year) in ustekinumab-treated patients. The incidence of non-melanoma skin cancer was 0.46 per 100 patient-years of follow-up (2 patients in 433 patients followed for 1 year) in placebo-treated patients, compared with 0.43 per 100 patient-years of follow-up (4 patients in 929 patients followed for 1 year) in ustekinumab-treated patients. In the placebo-controlled periods of clinical trials for psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, the incidence of malignancies excluding non-melanoma skin cancer was 0.23 per 100 patient-years of follow-up (1 patient in 434 patients followed for 1 year) in placebo-treated patients, compared with 0.11 per 100 patient-years of follow-up (1 patient in 929 patients followed for 1 year) in ustekinumab-treated patients. The incidence of non-melanoma skin cancer was 0.46 per 100 patient-years of follow-up (2 patients in 433 patients followed for 1 year) in placebo-treated patients, compared with 0.43 per 100 patient-years of follow-up (4 patients in 929 patients followed for 1 year) in ustekinumab-treated patients. In the placebo-controlled periods of clinical trials for psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, the incidence of malignancies excluding non-melanoma skin cancer was 0.23 per 100 patient-years of follow-up (1 patient in 434 patients followed for 1 year) in placebo-treated patients, compared with 0.11 per 100 patient-years of follow-up (1 patient in 929 patients followed for 1 year) in ustekinumab-treated patients. The incidence of non-melanoma skin cancer was 0.46 per 100 patient-years of follow-up (2 patients in 433 patients followed for 1 year) in placebo-treated patients, compared with 0.43 per 100 patient-years of follow-up (4 patients in 929 patients followed for 1 year) in ustekinumab-treated patients. In the placebo-controlled periods of clinical trials for psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, the incidence of malignancies excluding non-melanoma skin cancer was 0.23 pe...

Claims

1. Clinically proven safe and clinically proven effective amounts of anti-IL-12 / IL-23 The present invention relates to a method for treating moderate to severe active inflammatory bowel disease, comprising administering to a subject a pharmaceutical composition comprising a p40 antibody. A method of treating ulcerative colitis (UC) in a subject in need thereof, comprising administering to said subject an anti-UC antibody. The antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region being a polypeptide of SEQ ID NO:

1. Complementary determining region heavy chain 1 (CDRH1) amino acid sequence and CDRH2 amino acid sequence of SEQ ID NO:2 and a CDRH3 amino acid sequence of SEQ ID NO:3, wherein the light chain variable region comprises The complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4 and the CDRL2 amino acid sequence of SEQ ID NO:

5. and a CDRL3 amino acid sequence of SEQ ID NO:6, and after treatment with said antibody, The method, wherein the subject is a responder to the treatment.

2. The antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO:7 and a heavy chain variable region of the amino acid sequence of SEQ ID NO:

8. and the light chain variable region of sequence:

3. The antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO:

11. and a chain.

4. The pharmaceutical composition for intravenous administration contains 10 mM L-histidine, 8.5% (w / v ) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L- Methionine, and 20 μg / mL of EDTA disodium salt dihydrate at pH 6.

0. The method of any one of claims 1 to 3, further comprising a solution containing

5. The pharmaceutical composition for subcutaneous administration contains 6.7 mM L-histidine, 7.6% (w / v 0.004% (w / v) sucrose, 0.004% (w / v) polysorbate 80, pH 6.0 The method of claim 4 further comprising a liquid.

6. The antibody is administered at a dose of about 6.0 mg / kg of the subject's body weight or 130 mg per administration. The method of claim 4, wherein the subject is administered intravenously, preferably at week 0 of the treatment. Law.

7. The antibody is administered to the subject at a dose of about 90 mg per administration, preferably within 8 days of the treatment. The method of claim 6 , further administered subcutaneously weekly.

8. The subject is receiving anti-TNF, vedolizumab, corticosteroids, azathioprine (AZA ), and 6-mercaptopurine (6MP). or the subject has previously failed or is intolerant to corticosteroids. The method of claim 7, which exhibits steroid dependency.

9. the antibody is administered every 8 weeks at a maintenance dose following the treatment at week 8, or 8. The method of claim 7, wherein said treatment in week 1 is followed by a maintenance dose every 12 weeks.

10. The subject has achieved clinical remission according to at least one of the global and US definitions. By the 16th week of the treatment, preferably by the 8th week, more preferably by the 2nd week. and the clinical remission continues for at least 44 weeks after week 0. The method of claim 9 .

11. The subject achieves corticosteroid-free clinical remission at least 44 weeks after week 0. The method of claim 9 in the solution.

12. The subject has endoscopic healing that continues for at least 44 weeks after week 0. The method of claim 8, wherein the method is specified as follows:

13. The subject is a patient receiving Mayo endoscopic substudy that continues for at least 44 weeks after week 0.

10. The method of claim 9, which is identified as achieving a core-based clinical response.

14. The subject completes the Inflammatory Bowel Disease Questionnaire (IBDQ) for at least 44 weeks after week 0.

1. Identify patients as having a change from baseline in IBDQ score. Item 9. The method according to item 9.

15. The subject has mucosal healing that continues for at least 44 weeks after week 0. The method of claim 9 , wherein the

16. The subject is a patient with a decreased mean mean score on the Mayo scale that continues from week 0 through at least week 44.

10. The method of claim 9, wherein the subject is identified as having a decrease from baseline in

17. C-reactive protein, wherein the subject continues at least 44 weeks after week 0; One or more biosynthetic proteins selected from the group consisting of fecal lactoferrin and fecal calprotectin. The method of claim 9, wherein the patient is identified as having normalization of omarkers.

18. The subject is a patient with a decreased mean mean score on the Mayo scale that continues from week 0 through at least week 44. ≥ 30% and ≥ 3 point reduction from baseline in rectal bleeding subscore and Clinical outcome as determined by a ≥1 point decrease from baseline or a rectal bleeding subscore of 0 or 1. The method of claim 9 , further comprising indicating a response.

19. To provide treatment for moderate to severe active ulcerative colitis (UC) in subjects who need it. A method for carrying out the method, comprising the steps of: a. administering to the subject an anti-IL-12 / IL-23p40 antibody in a first pharmaceutical composition for about 6 0 mg / kg of the subject's body weight or 130 mg per dose, at week 0 of the treatment Intravenous administration to the eye; b. administering to the subject the anti-IL-12 / IL-23p40 antibody in a second pharmaceutical composition; subcutaneous administration at a dose of 90 mg per dose, preferably at week 8 of said treatment; Including, The antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region being represented by SEQ ID NO: The complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO:1 and the CDRH2 amino acid sequence of SEQ ID NO:2 and a CDRH3 amino acid sequence of SEQ ID NO:3, wherein the light chain variable region comprises: The complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4 and the CDR of SEQ ID NO: 5 and a CDRL3 amino acid sequence of SEQ ID NO:6, The subject is a responder to treatment, and is administered anti-TNF, vedolizumab, or corticosteroids. selected from the group consisting of 6-mercaptopurine (6MP), azathioprine (AZA), and 6-mercaptopurine (6MP); have previously failed or been intolerant to at least one of the therapies available; or wherein the subject exhibits corticosteroid dependence.

20. The antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO:7 and a heavy chain variable region of the amino acid sequence of SEQ ID NO:

8. and the light chain variable region of sequence:

21. The antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 10 and a light chain having the amino acid sequence of SEQ ID NO:

11. and a chain.

22. The pharmaceutical composition for intravenous administration contains 10 mM L-histidine, 8.5% (w / v ) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L- Methionine, and 20 μg / mL of EDTA disodium salt dihydrate at pH 6.

0. The method of any one of claims 19 to 21, further comprising a solution containing

23. The pharmaceutical composition for subcutaneous administration contains 6.7 mM L-histidine, 7.6% (w / v 0.004% (w / v) sucrose, 0.004% (w / v) polysorbate 80, pH 6.0 23. The method of claim 22 further comprising a liquid.

24. The subject has achieved clinical remission according to at least one of the global and US definitions. By the 16th week of the treatment, preferably by the 8th week, more preferably by the 2nd week. The method according to any one of claims 19 to 21, characterized in that

25. The subject achieves endoscopic healing by week 16 of the treatment, preferably by week 8. More preferably, any of claims 19 to 21 is specified as having by the second week.

13. The method according to claim 1.

26. The subject has a clinical response based on Mayo endoscopic subscores through week 16 of the treatment. Preferably, the patient is at least 18 weeks old, more preferably at least 2 weeks old. The method according to any one of claims 19 to 21,

27. The subject is administered a 20 mg / kg / day diet supplement or a 20 mg / kg / day diet supplement. by the 16th week of said treatment, preferably by the 8th week, more preferably by the 2nd week. The method of any one of claims 19 to 21, characterized in that it comprises

28. The subject achieves mucosal healing by week 16 of the treatment, preferably by week 8, more preferably by week 9. Any one of claims 19 to 21, preferably identified as having by the second week The method described above.

29. The subject has a reduction from baseline in Mayo score at 16 weeks of treatment. by week 8, preferably by week 2 The method according to any one of claims 19 to 21,

30. The subject is further characterized by the presence of C-reactive protein, fecal lactoferrin, and fecal calprotectin. normalization of one or more biomarkers selected from the group consisting of by week 16 of said treatment. , preferably by week 8, more preferably by week 2, The method according to any one of claims 19 to 21.

31. The subject has a ≥ 30% and ≥ 3 point reduction from baseline in Mayo score, and A reduction of ≥ 1 point from baseline in the rectal bleeding subscore, or a reduction of 0 or 1 rectal bleeding Clinical response as determined by blood subscore was monitored for up to 16 weeks of treatment, preferably after 8 weeks. The method according to any one of claims 19 to 21, wherein the method is performed within 2 weeks, more preferably within 2 weeks. Law.

32. The subject is not a responder to treatment with the antibody by week 8 of the treatment, The method of any one of claims 19 to 21, wherein the patient is a responder by week 16 of said treatment.

33. To provide treatment for moderate to severe active ulcerative colitis (UC) in subjects who need it. A method for carrying out the method, comprising the steps of: a. administering to the subject an anti-IL-12 / IL-23p40 antibody in a first pharmaceutical composition for about 6 0 mg / kg of the subject's body weight or 130 mg per dose, at week 0 of the treatment Intravenous administration to the eye; b. administering to the subject the anti-IL-12 / IL-23p40 antibody in a second pharmaceutical composition; subcutaneous administration at a dose of 90 mg per dose, preferably at week 8 of said treatment; Including, The antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region being represented by SEQ ID NO: The complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO:1 and the CDRH2 amino acid sequence of SEQ ID NO:2 and a CDRH3 amino acid sequence of SEQ ID NO:3, wherein the light chain variable region comprises: The complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4 and the CDR of SEQ ID NO: 5 and the CDRL3 amino acid sequence of SEQ ID NO:6, followed by The therapy continues, The maintenance therapy comprises administering to the subject the anti-IL-12 / IL-23p40 antibody. The study included administering 90 mg subcutaneously once every 8 weeks or once every 12 weeks. wherein said maintenance therapy is provided for 44 weeks.

34. 1. A pharmaceutical composition of an anti-IL-12 / IL-23p40 antibody, comprising: (i) an antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising: The complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1 and the CDR of SEQ ID NO: 2 and a CDRH3 amino acid sequence of SEQ ID NO: 3, The region is a complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4 and a complementarity determining region light chain 2 (CDRL3) amino acid sequence of SEQ ID NO:

5. An antibody comprising the CDRL2 amino acid sequence of SEQ ID NO: 6 and the CDRL3 amino acid sequence of SEQ ID NO:

7. ii) a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8; or (iii) an antibody comprising a heavy chain of the amino acid sequence of SEQ ID NO: 10 and a variable region thereof; an antibody comprising a light chain of amino acid sequence 11; b. In adult men and women with moderate to severe active ulcerative colitis (UC) The data disclosed in Appendix I include data from a randomized, double-blind, placebo-controlled clinical trial. and packaging comprising one or more drug product label elements.

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