A safe and effective method for treating ulcerative colitis with anti-IL12 / IL23 antibodies.

Abstract

To provide a clinically proven, safe, and clinically proven effective treatment for ulcerative colitis, particularly moderate to severe active ulcerative colitis. [Solution] To provide a method and composition for the clinically proven safe and effective treatment, as per the product label, of ulcerative colitis, particularly moderate to severe active ulcerative colitis, in patients who have had an insufficient response to or are intolerant of conventional or existing therapies involving intravenous and / or subcutaneous administration of anti-IL-12 / IL-23p40 antibodies.

Description

[Technical Field]

[0001] (Reference to electronically submitted sequence listings) This application was created on October 15, 2020, and the file name is "JBI6165WO As the ASCII format sequence list in "PCT1SequenceListing.txt", E Includes a sequence listing of 15kb size, submitted electronically via FS-Web. The sequence listings submitted via FS-Web are part of this specification and are available by reference in their entirety. This is incorporated herein.

[0002] (Field of invention) This invention relates to the intravenous and / or subcutaneous administration of anti-IL-12 / IL-23p40 antibodies. Have you had an inadequate response to previous or existing therapies, or are you intolerant to them? Clinical evidence of ulcerative colitis in patients, particularly moderate to severe active ulcerative colitis. Regarding methods for providing safe, clinically proven, and effective treatments. [Background technology]

[0003] Inflammatory bowel disease (IBD), including ulcerative colitis (UC) IBD (Inflammatory Bowel Disease) is a destructive inflammation and epithelial damage of the gastrointestinal (GI) tract. It is a chronic relapsing disease characterized by (Baumgart and Sandb) orn,J Clin Invest.98:1010-1020 (1996);Da nese and Fiocchi,N Engl J Med.365:1715-1 725 (2011). The incidence of UC in the United States is 205 per 100,000 people. With a prevalence of approximately 240 people, it is estimated to be 9-12 people per 100,000 (Tal ly et al.,Am J Gastroenterol.106 Suppl 1 :S2-S25 (2011). The estimated prevalence of UC in Europe is approximately 1,000,000. The number is 0 (Loftus, Gastroenterology. 126(6):150) 4-1517 (2004);Loftus,Gastoenterol Clin N Am.31:1-20(2002)). The etiology of UC is unknown. However, intestinal Abnormal immune responses to intestinal contents, including bacteria, occur in genetically predisposed individuals. It is thought to cause disease (Geremia et al., Autoimum n Rev.13:3-10(2014)). Dysregulation of congenital and adaptive immune pathways, It contributes to abnormal enteritis in IBD, and interleukin (IL)-12 and interfero Cytokines, including IFNγ and IL-23, are involved in the pathogenesis of UC. Geremia et al.,Autoimmune Rev.2014;13:3- 10;Neurath, Nat Rev Immunol.14(5):329-42( 2014).

[0004] The involvement of the IL-12 / 23 pathway in the pathogenesis of IBD is well established, and in intestinal inflammation... The important role of the IL-12 / IL-23 pathway in colitis has been elucidated (Ah ern et al.,Immunity.33(2):279-288(2010); Investigator's Brochure: STELARA (Registered Trademark) (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 - 1 290(1995)). Genome - wide association studies have implicated several loci in the human 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 G astroenterol Hepatol. 11(1):22 - 26(2013)). Subjects with active UC have been shown to 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 biological therapies currently approved for the treatment of UC include tumor necrosis factor (TMF). (Colombel et al.) are either tor, TNF, or integrin inhibitors. l.,Gastroenterology.132:52-65 (2007);Han auer et al., Lancet.359:1541-1549 (2002); Sandborn et al.,N Engl J Med.369:711-721 (2013); Sandborn et al., Gastroenterology .142:257-265 (2012)). However, all currently approved Of the treatments available, only vedolizumab is effective against TNF. Have you ever had a sufficient response (i.e., primary non-response or secondary non-response)? The efficacy of anti-TNF has been demonstrated in patients who are intolerant to it (Feagan et al.). al., N Engl J Med. 369:699710 (2013). Anti-TNF is ...and there are safety risks associated with immunosuppression, and all subjects respond appropriately to such treatment. That is not the case. Furthermore, as observed with anti-TNF, insufficient response and intolerance are also present. These have been identified in patients receiving vedolizumab for the treatment of UC. Therefore, there is still an unmet need for novel therapies with alternative mechanisms of action. It remains.

[0006] Upon investigation, it appears that the biological therapies currently approved for the treatment of UC are also used for Crohn's disease. This has shown effectiveness (Sandborn et al., Gastroentero logy.135(4):1130-1141(2008)). Numerous pieces of evidence suggest inflammatory bowel syndrome. Diseases (UC and Crohn's disease) are caused by inflammatory cytokines, IL-12, and IL-23. This suggests that it is mediated by Th1 or Th17 cells, which have a strong contribution. Tekinumab (STELARA®) is a complete agent for human IL-12 / 23p40 This is a whole human immunoglobulin G1 mAb, which is used in the bioactivity of IL-12 and IL-23. This inhibits them from interacting with the IL-12Rβ1 receptor protein on their cell surface. Prevent by causing harm (Investigator's Brochure: ST ELARA (registered trademark) (ustekinumab), edition 18. Jans sen Research & Development, LLC (2017). This Due to its mechanism of action, ustekinumab acts on IL-12(Th1)- and IL-23(Th17) )-Effectively neutralizes cellular responses. Ustekinumab effectively neutralizes moderate to severe active clamyotropin. Treatment for adults with Crohn's disease (the first approval for Crohn's disease was received on November 11, 2016) Treatment for adults with moderate to severe plaque psoriasis or active psoriatic arthritis. , as well as for the treatment of children (12-17 years old) with moderate to severe psoriasis vulgaris, North America It has received marketing approval worldwide, including in countries in Europe, South America, and the Asia-Pacific region. ru.

[0007] Efficacy and safety of intravenous (IV) ustekinumab as induction therapy in Crohn's disease Sex has been evaluated in clinical trials CRD3001 and CRD3002. In 3001, subjects who had previously shown failure or intolerance to one or more TNF antagonists were included. The evaluation revealed that CRD3002 showed an insufficient response to corticosteroids or immunomodulators. A history of response or intolerance to TNF antagonists, or a history of insufficient response or intolerance to TNF antagonists. The study evaluated subjects with no prior history of the drug. These trials evaluated two IV doses: 130mg. A fixed IV dose of g (approximately 2 mg / kg in mg / kg units) was selected for the low-dose group, while body Dosage based on severity 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: ustekinumab Ustekinumab (520 mg) was selected as the high-dose group in both trials. It showed clinically significant efficacy compared to placebo and had a good safety profile. It was tolerated. [Overview of the project] [Problems that the invention aims to solve]

[0008] Prior to this invention, no studies using ustekinumab for UC had been conducted, and the organism If you have previously failed or are intolerant of medical or other conventional therapies In subjects who have had or have shown corticosteroid dependence, treating UC In particular, improved methods for treating moderate to severe active UC are available in the art. It is needed. [Means for solving the problem]

[0009] This application describes how administering an anti-IL-12 / IL-23p40 antibody to a target can, in particular, improve performance compared to conventional methods. Or have you had an insufficient response to existing therapies, or are you intolerant of them? Clinically proven for the treatment of moderate to severe active ulcerative colitis (UC) in the target population. With regard to the disclosed safe and clinically proven effective methods and compositions, thereby this Addressing clearly unmet medical needs within elephant populations.

[0010] In one embodiment of the present invention, the pharmaceutical composition includes (i) the complementarity-determining heavy chain 1 of Sequence ID No. 1 ( CDRH1) amino acid sequence, CDRH2 amino acid sequence of SEQ ID NO: 2, and C of SEQ ID NO: 3 The heavy chain variable region containing the DRH3 amino acid sequence and the complementarity-determining region of Sequence ID No. 4, light chain 1 (CD RL1) amino acid sequence, CDRL2 amino acid sequence of SEQ ID NO: 5, and CDR of SEQ ID NO: 6 (ii) Light chain variable region containing the L3 amino acid sequence, (ii) Heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 (iii) the amino acid sequence of (iii) the light chain variable region of (iii) the amino acid sequence of (iii) 10 An antibody containing a heavy chain of acid sequence and a light chain of amino acid sequence of SEQ ID NO: 11, and moderate to severe A randomized, double-blind, pneumoconiometric study of adult men and women with active ulcerative colitis (UC). Includes one or more formulation label elements disclosed in Appendix I, including data from a racebo-controlled clinical trial. Including packaging.

[0011] In one general aspect, this application relates to the treatment of moderate to severe active ulcerative colitis (UC). To provide treatment to those who need it, clinically proven safe and clinically proven Regarding the effective method described, this method provides a safe and effective amount of anti-IL-12 / IL- Administer a pharmaceutical composition containing the 23p40 antibody (where the antibody is (i) the antibody of SEQ ID NO: 1 Complementarity-determining region heavy chain 1 (CDRH1) amino acid sequence, CDRH2 amino acid sequence of SEQ ID NO: 2 The column, and the heavy chain variable region including the CDRH3 amino acid sequence of SEQ ID NO: 3, and the complementary region of SEQ ID NO: 4 Sex-determining region light chain 1 (CDRL1) amino acid sequence, CDRL2 amino acid sequence of Sequence ID No. 5, and the light chain variable region including the CDRL3 amino acid sequence of SEQ ID NO: 6, (ii) the a of SEQ ID NO: 7 The heavy chain variable region of the amino acid sequence and the light chain variable region of the amino acid sequence of SEQ ID NO: 8, or (iii It includes the heavy chain of the amino acid sequence of SEQ ID NO: 10 and the light chain of the amino acid sequence of SEQ ID NO: 11. ) and in adult men and women with moderate to severe active ulcerative colitis (UC) One or more of the data disclosed in Appendix I, including data from randomized, double-blind, placebo-controlled clinical trials. Includes packaging containing formulation label elements. In certain embodiments, anti-IL-12 and / or The anti-IL-23 antibody is administered intravenously to the subject, preferably at week 0, per kg of the subject's body weight. It is administered in doses of approximately 6.0 mg, or 130 mg per administration.

[0012] In a particular embodiment, anti-IL-12 and / or anti-IL-23 antibodies are administered intravenously to the target. Alternatively, subcutaneously, preferably at 8 weeks, approximately 6.0 mg per kg of body weight of the subject, or administered It is administered at a dose of 90 mg per administration.

[0013] Preferably, the subject treated by the method according to the embodiments of this application is conventional or existing They have had an inadequate response to therapy in the past, or are intolerant of it. In this embodiment, the subject has previously received biological therapies such as anti-TNF and / or vedolizumab. They have failed or have been intolerant of these failures. In some embodiments, the subject is corticosteroids, azathioprine (AZA), and / or 6 mercaptopurine (6 Have you previously experienced failure with non-biological therapies such as MP treatment, or have you had a negative experience with these? It was well tolerated. In some embodiments, the subjects showed corticosteroid dependence. There is.

[0014] In another general aspect, the present invention relates to the treatment of moderate to severe active ulcerative colitis (UC). , performed in the area where it is needed, clinically proven safe and clinically proven Regarding effective methods, this method is The target group received approximately 6.0 mg per kg of body weight, or 130 mg per dose, during week 0 of treatment. A pharmaceutical composition containing anti-IL-12 / IL-23p40 antibody is administered intravenously at a dose of mg of the antibody. Administering the drug, The target group received an antibody dose of 90 mg per administration at the 8th week of treatment, anti-IL-12 / IL- This includes subcutaneous administration of a pharmaceutical composition containing a 23p40 antibody. The antibody has the amino acid sequence of the complementarity-determining region heavy chain 1 (CDRH1) of SEQ ID NO: 1, and SEQ ID NO: 2 The heavy chain variable region containing the CDRH2 amino acid sequence of SEQ ID NO: 3 and the CDRH3 amino acid sequence of SEQ ID NO: 3 The complementarity-determining region of SEQ ID NO: 4, the amino acid sequence of light chain 1 (CDRL1), and the C of SEQ ID NO: 5 The light chain variable region includes the DRL2 amino acid sequence and the CDRL3 amino acid sequence of SEQ ID NO: 6. Includes, The target is anti-TNF, vedolizumab, corticosteroids, azathioprine. At least one of the group consisting of phosphorus (AZA) and 6-mercaptopurine (6MP) Another treatment has failed or been intolerant of these treatments in the past, or Elephants have shown signs of corticosteroid dependence.

[0015] In a particular embodiment, the method of this application targets (i) the heavy chain variable region of Sequence ID No. 7. (ii) an amino acid sequence and the light chain variable region amino acid sequence of SEQ ID NO: 8, which are anti-IL-1 2 and / or a pharmaceutical composition containing an anti-IL-23 antibody or antigen-binding fragment is administered intravenously. (IV) and / or subcutaneous administration (SC).

[0016] In a particular embodiment, the method of this application applies to (i) the heavy chain amino of SEQ ID NO: 10 to the subject. (ii) containing the acid sequence and the light chain amino acid sequence of SEQ ID NO: 11, anti-IL-12 / 23p4 A pharmaceutical composition containing the antibody ustekinumab is administered intravenously (IV) and / or subcutaneously (SC). This includes doing so.

[0017] In a particular embodiment, the IV dose at week 0 is approximately 6.0 mg / kg. For example, the IV dose is 260 mg for subjects weighing between 35 kg and 55 kg. For subjects weighing over 55 kg but 85 kg or less, the dosage is 390 mg, and for subjects weighing 85 kg or less... For subjects exceeding g, the dose is 520 mg.

[0018] In a particular embodiment, the subject is a response to the treatment of the method according to one embodiment of this application. It is identified as a transponder having at least one of the following: (1) Clinical remission based on at least one of the World application and / or the U.S. application, (2) (3) Endoscopic healing, (4) Clinical response, (5) Inflammatory Bowel Disease Questionnaire Change from baseline in the se Questionnaire (IBDQ) score, (5) Mucosal healing (6) a decrease from baseline in the Mayo score, and (7) C-reactive protein One or more selected from the group consisting of chlorine, fecal lactoferrin, and fecal calprotectin. Normalization of the biomarker. Preferably, at least one of (1) to (7) above. This is done by the 16th week of treatment, more preferably by the 8th or 4th week, most preferably by the 2nd week. The target will be identified by the end of the week.

[0019] In certain embodiments, the present invention treats moderate to severe active UC in a subject. It provides a clinically proven safe and clinically proven effective method, and the target is anti- Responders to treatment by the body and have a Mayo endoscopic subscore of 0 or 1. A statistically significant improvement in disease activity, as determined by endoscopic healing, It is identified as being present by the 8th week of physical treatment.

[0020] In other embodiments, the present invention treats moderate to severe active UC in a subject. It provides a clinically proven safe and clinically proven effective method, and the subject is an antibody It is a responder to treatment and is an endoscopic severity assessment index (Ul) for ulcerative colitis with a score of ≤4. The cerative Colitis Endoscopic Index of Severity (UCEIS) score is determined by this score. A statistically significant improvement in disease activity, as observed by the 8th week of antibody treatment, is observed. It is identified as something that does.

[0021] In a particular embodiment, the subject is ≥30% from the baseline in the Mayo score. And a decrease of ≥3 points and a decrease of ≥1 point from baseline in the rectal bleeding subscore, The clinical response, determined by a rectal bleeding subscore of 0 or 1, is considered 8% of antibody treatment. This will be shown by the week.

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

[0023] In certain embodiments, the present invention treats moderate to severe active UC in a subject. It provides a clinically proven safe and clinically proven effective method for initial treatment. For subjects identified as non-responders, preferably a different administration regimen than the initial treatment. A second treatment is administered via the route. For example, the first treatment involves intravenous administration of an antibody or antibody-binding fragment. Subjects identified as non-responders to treatment are those with antibodies according to embodiments of the present invention. Alternatively, treatment can be performed by subsequent subcutaneous administration of an antibody-conjugated fragment.

[0024] In certain embodiments, this application treats moderate to severe active UC in the subject. A method of treatment is provided for use in IV administration of anti-IL-12 and / or anti-IL-23 The body contains 10 mM L-histidine, 8.5% (w / v) sucrose, and 0.04% (w / v) v) Polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL E It is present in a pharmaceutical composition containing a solution of DTA disodium salt, dehydrated form, at pH 6.0.

[0025] In certain embodiments, this application relates to the treatment of moderate to severe active UC in a subject. It provides a clinically proven safe and clinically proven effective method for subcutaneous administration. The anti-IL-12 and / or anti-IL-23 antibody to be used is 6.7 mM L-histidine N, 7.6% (w / v) sucrose, 0.004% (w / v) polysorbate 80 It is present in a pharmaceutical composition containing a solution with a pH of 6.0.

[0026] In a particular embodiment, this application relates to one or more additional The present invention provides a method further comprising administering a drug to a target. In a preferred embodiment, additional The drugs include oral 5-aminosalicylate (5-ASA) compounds, oral corticosteroids, Immunomodulators, 6-mercaptopurine (6-MP), azathioprine (AZA), or methotrexate The group is selected from the trexate (MTX) group.

[0027] Other aspects of this application relate to the treatment of moderate to severe active UC in subjects, clinically For use in proven safe and clinically proven effective ways, anti-IL-12 and / or a pharmaceutical composition containing an anti-IL-23 antibody, and a method for preparing the composition and the pharmaceutical composition. Includes a kit.

[0028] In a particular embodiment, a kit useful for the method of the present invention is a medical device for intravenous administration of the present invention. The invention comprises at least one of the drug composition and the subcutaneous pharmaceutical composition of the present invention. In terms of application, the kit contains both the intravenous and subcutaneous pharmaceutical compositions of the present invention. This includes the person. [Brief explanation of the drawing]

[0029] The above-mentioned "Outline of the Invention" and the following "Modes for Carrying Out the Invention" should be read in conjunction with the attached drawings. The present invention will be better understood by reading it in this way. The exact embodiments shown in the drawings It is important to understand that this is not limited to this. [Figure 1] The diagrammatic representation of the trial design is shown. Abbreviations: W8 = Week 8, W16 = Week 16, LTE = Long-term continuous administration. [Modes for carrying out the invention]

[0030] In the "Background Technology" section, and throughout this specification, various publications, papers, and patents are cited. Or, they may be listed, and each of these references is incorporated herein by reference in its entirety. The discussion of documents, operations, materials, devices, articles, etc. included in this specification is in the context of the present invention. This is to give a hint. Such considerations are based on the fact that any or all of these things are disclosed. or to allow it to constitute part of the prior art to any of the claimed inventions. No.

[0031] Unless otherwise specified, all technical and scientific terms used herein are defined in accordance with the present invention. It has the same meaning as generally understood by those skilled in the art to which it belongs. Otherwise, Certain terms used herein have the meanings set forth herein. All patents, published patent applications, and publications referenced in this specification are, by reference, as if they were true. The entire structure is incorporated as described herein.

[0032] When used in this specification and the appended claims, the singular forms "a", "an", and "t It is important to note that "he" can refer to multiple objects unless it is particularly clear from the context. be.

[0033] Unless otherwise stated, the term “at least” preceding a set of elements means all of the set. It should be understood that this refers to the elements of the subject. Those skilled in the art will know that using only ordinary experimental procedures... By doing so, one can recognize many equivalents to the specific embodiments of the present invention described herein. Or, it may be confirmed. Such equivalents are intended to be included by the present invention. It is illustrated.

[0034] Throughout this specification and the following claims, unless otherwise required by context, the term "including (comp The term "rise" and variations such as "comprises" and "comprising" The form includes a specified integer or process, or a group of integers or processes, but any other integer or It is understood that this does not mean that a process, an integer, or a group of processes is excluded. It is likely that, as used herein, the term "comprising" means "containing The terms "(contains)" or "includes" can be used instead, Sometimes, when used in this specification, it may be replaced with the term "having". Cut.

[0035] As used herein, "consisting of" means that the elements of the claims Any element, process, or component not specified herein is excluded. "Consisting essentially of" is the fundamental aspect of the patent claims. Furthermore, materials or processes that do not substantially affect the novel features are not excluded. When used herein in relation to embodiments, "includes" in order to change the scope of this disclosure. "comprising", "containing", "including", and "y The above terms, "having," are used to mean "consisting of" or "essentially from" the term It can be replaced with "ru".

[0036] When used herein, the connecting expression "and / or" between multiple enumerated elements is used The word is understood to encompass both individual and combined options. For example. When two elements are connected by "and / or", the first option is the second element. This refers to the applicability of the first element. The second option is that the second element is applicable without the first element. This refers to being able to do something. The third option is that the first and second elements can be applied together. This refers to. Any one of these options is included in the meaning, and therefore, in this specification When used in this context, it is understood that the requirements of the term "and / or" are met. The simultaneous applicability of two or more of these is also included in the meaning, and therefore, "and / or" It is understood that the terminology requirements are met.

[0037] As used herein, “subject” means a person treated by the method according to the embodiments of the present invention. This means any animal that has been treated or treated, preferably a mammal, most preferably a human. As used herein, the term “mammal” encompasses all mammals. Examples of mammals that exhibit this behavior are not limited to these, but include cows, horses, sheep, and pigs. non-human primates such as cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, or apes. Examples include non-human primates (NHPs), humans, and more preferably humans.

[0038] As used herein, the term “combined use” means two or more therapeutic agents applied to a subject. In relation to administration, it refers to the use of multiple therapeutic drugs. The term "combination therapy" is used in relation to treatment. The order in which drugs are administered is not limited. For example, the first therapeutic agent (for example, as specified herein) The composition described is placed before administering the second therapeutic agent to the subject (for example, at 5, 15, or 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, also (12 weeks prior), simultaneously, or afterward (for example, 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 (After 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks) It is possible to grant.

[0039] When used herein, "anti-IL-12 antibody," "anti-IL-23 antibody," and "anti-IL- "IL-12 / 23p40 antibody" or "IL-12 / 23p40 antibody" is a cytokine inhibitor. Tahleukin-12 and interleukin-23 (IL-12 / 23p40) Monoclonal antibodies (mAbs) that bind to the 40kDa (p40) subunit or This refers to the antigen-binding fragment. This antibody is RNA, DNA, or protein. Synthesis, IL-12 / 23 release, IL-12 / 23 receptor signaling, membrane IL-12 / 2 3. These include cleavage, IL-12 / 23 activity, IL-12 / 23 production and / or synthesis, but This includes, but does not limit, any effect on at least one of the IL-12 / 23 activity or function. It can be done.

[0040] The term "antibody" includes antibody mimetic drugs, or single-chain antibodies and their fragments. A portion of an antibody that mimics the structure and / or function of such an antibody, or its specified fraction Antibodies, digestion fragments thereof, identified parts, and mutations, including the compound or a portion thereof. Further intended to include heterologous organisms. Functional fragments include mammalian IL-12 / Examples include antigen-binding fragments that bind to 23. For example, Fab (e.g., papain). (by digestion), Fab' (e.g., by pepsin digestion and partial reduction) and F(ab' )2 (for example, by pepsin digestion), facb (for example, by plasmin digestion), p Fc' (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, (By partial reduction and reassembly), Fv or scFv (e.g., by molecular biological techniques) Fragments include, but are not limited to, those connected to IL-12 / 23 or parts thereof. Antibody fragments that can be combined are included in the present invention (for example, the above-mentioned Coll (See Igan, Immunology).

[0041] Such fragments are known in the art and / or described herein. Antibodies can be produced by enzymatic cleavage, synthesis, or recombination techniques. Using antibody genes in which one or more stop codons are introduced upstream of the natural stop site, It can also be generated in various cleavage forms. For example, a gene encoding the F(ab') double-stranded region. The combination of children is the heavy chain C H DNA encoding a single domain and / or hinge region It can be designed to include columns. Various parts of the antibody can be chemically bound using conventional techniques. It is possible to use genetic engineering techniques to combine contiguous proteins with It can be prepared in this way.

[0042] As used herein, the term "human antibody" refers to substantially all parts of a protein. minutes (for example, CDR, framework, C L , C H Domain (for example, C H 1, C H 2. C H 3) Hinge (V L , V H )) can be substantially altered or mutated in humans by only minor sequence changes or mutations. This refers to antibodies that are specifically non-immunogenic. "Human antibodies" also refer to human germline immunoglobulins. The antibody may be derived from the brin sequence, or it may be an antibody that is a very similar sequence. Human antibodies are biological Amino acid residues not encoded in the progenitor cell lineage immunoglobulin sequence (e.g., invincible By introducing random or site-specific mutations in Toro, or in vivo This may include mutations introduced by somatic mutations. In many cases, this is because human antibodies are In this context, it means that it is substantially non-immunogenic. Human antibodies are composed of their amino acids. The data is categorized into groups based on the similarity of the columns. Therefore, we use sequence similarity search. Therefore, antibodies with similar linear sequences are selected as templates for producing human antibodies. It is possible. Similarly, the names include primates (monkeys, baboons, chimpanzees, etc.) and rodents ( Antibodies including those from mice, rats, rabbits, guinea pigs, hamsters, etc., and other mammals are available. This specifies specific antibodies for certain species, subgenuses, genera, subfamilies, and families. Furthermore, chimeric antibodies are specified as described above. This may include any combination. Such changes or variations may, and preferably, be modified. Compared to antibodies that have not been treated, they retain or reduce immunogenicity in humans or other species. Therefore, human antibodies are different from chimeric antibodies or humanized antibodies.

[0043] Human antibodies are functionally reconstituted human immunoglobulins (e.g., heavy chains and / or light chains). ) A non-human animal capable of expressing the gene, or produced by prokaryotic or eukaryotic cells. It has been pointed out that this can occur. Furthermore, if the human antibody is a single-chain antibody, then natural human antibodies It may contain linkapeptides that are not found. For example, Fv is a variable region of the heavy chain and a variable region of the light chain. It contains a linkapeptide, such as 2 to approximately 8 glycine or other amino acid residues, that connects the regions. It is possible. Such linkapeptides are considered to be of human origin.

[0044] Anti-IL-12 / 23p40 antibody (IL-1) useful in the methods and compositions of the present invention The 2 / 23p40 antibody (also known as the antibody against IL-23) is used selectively. It has high affinity binding to IL-12 / 23p40 and optionally, and preferably, low toxicity. This can be characterized by the following: Specifically, the variable domain, the constant domain, and the framework, etc. The components of this material, individually and / or collectively, are selectively and preferably have low immunogenicity. The antibody of the present invention, a specified fragment thereof, or a variant thereof having the above characteristics is useful in the present invention. The antibodies that can be used in this invention are optionally selected to provide measurable relief and low levels of symptoms. Characterized by the ability to treat a subject for a long period of time with and / or tolerable toxicity. Low youth Alternatively, acceptable immunogenicity and / or high affinity, as well as other desirable properties, may be obtained. It can contribute to treatment outcomes. "Low immunogenicity" in this specification refers to the target of treatment. Less than approximately 75%, or preferably less than approximately 50%, were significantly HAHA, HACA, or Increased HAMA response and / or low titer (biantigen enzyme) in the subject being treated. An increase in approximately 300 (preferably less than 100) as measured by an immunoassay. Defined (Elliott et al., Lancet 344:1125-112) 7 (1994, the whole is incorporated herein by reference). "Low immunogenicity" also Preferably, less than 25% of patients treated with the recommended dose during the recommended therapeutic course of treatment. When it occurs in less than 10% of those being treated, it occurs in those being treated with anti-IL-12 antibodies. It can also be defined as the rate of antibody development at the titration level against an anti-IL-12 antibody. .

[0045] The terms "clinically proven efficacy" and "clinically proven effective" refer to dosage. When used herein in the context of an administration regimen, treatment or method, a specific dose, This refers to the effectiveness of the treatment regimen. Effectiveness refers to the course of the disease in response to the drug of the present invention. It can be measured based on the changes in the internal environment. For example, the anti-IL12 / 23p40 of the present invention (for example, Ustekinumab is used to measure the severity of the disability being treated by at least one indicator. The drug is administered to the subject in an amount and time sufficient to cause improvement, preferably a sustained improvement. To determine whether the amount and duration of treatment are sufficient, the target disease, illness, Alternatively, various indicators reflecting the severity of the disease may be evaluated. Such indicators include, for example, disease severity. This includes clinically recognized indicators of the degree, symptoms, or signs of the disorder. The degree of improvement is determined by the physician overall, and the physician makes this determination based on signs, symptoms, biopsy, or other factors. This can be done based on the test results, and also by questionnaires given to the subjects, for example, given disease Questionnaires on quality of life developed for patients can also be used. For example, this The anti-IL12 / 23p40 or anti-IL23 antibody of the invention is used to treat symptoms associated with ulcerative colitis. It may be administered to achieve improvement in condition.

[0046] This improvement may result in an improvement in the disease activity index, remission of clinical symptoms, or any other measure of disease activity. This can be indicated by the Mayo score for ulcerative colitis. Yes, the Mayo score is based on bowel movement frequency, rectal bleeding, endoscopic findings, and a comprehensive assessment by a physician. Mild, moderate, and severe ulcers are calculated as the sum of the four subscores of (PGA). For ulcerative colitis (UC), the disease activity index is an established and validated disease activity index, ranging from 0 to 0. The range is 12. A score of 3-5 indicates mild active illness, and a score of 6-10 indicates mild active illness. A score of 11-12 indicates moderately active disease, while a score of 11-12 indicates severe disease. Endoscopy subs The partial Mayo score, which is a Mayo score without a core, includes bowel movement frequency, rectal bleeding, and medical It is calculated as the sum of the comprehensive evaluation subscores by the instructor, ranging from 0 to 9. PGA Sub The modified Mayo score, which is a Mayo score without a score, is used for bowel movement frequency, rectal bleeding, and internal It is calculated as the sum of the endoscopic subscores and ranges from 0 to 9. Other disease activities related to UC Examples of dynamic indicators include the endoscopic severity assessment index for ulcerative colitis. This refers to the Endoscopic Index of Severity (UCEIS) score and the Bristol Stool Texture Scale. The Bristol Stoolform Scale (BSFS) score is one example. The UCEIS score is for mucosa. This system provides a comprehensive endoscopic assessment of UC severity based on vascular patterns, bleeding, and ulceration. (Travis et al., Gut. 61:535-542 (2012)). The core score ranges from 3 to 11, with higher scores indicating more severe disease as detected by endoscopy. The BSFS score classifies the characteristics (or viscosity) of human feces into seven categories. Used (Lewis and Heaton, Scand J Gastroen) terol.32(9):920:924-1997).

[0047] As used herein, the term “clinical response” refers to the subject’s response to drug administration. If relevant, a decrease from baseline or zero in the rectal bleeding subscore of ≥1. This is a Mayo score of ≥30% and ≥3 points accompanied by any of the rectal bleeding subscores. This refers to the decrease from the baseline during the initial phase.

[0048] The term "clinically proven safety" refers to the anti-IL-12 / IL-23p4 of the present invention. Regarding the dosage, administration regimen, treatment, or method of antibody (e.g., ustekinumab): In combination, compared to standard treatment or another comparator drug, adverse events (adverse e) that occurred during treatment. vent, AE, or treatment-emergent adverse even Good Risk: Refers to the benefit ratio. When used herein, "adverse event" refers to an adverse event that occurred during treatment. "Adverse events" and "adverse reactions" are related to the administration of a pharmaceutical composition or therapeutic agent, or to other related matters. Any harmful, undesirable, unintended, or unwanted consequences caused by these This refers to an unpleasant symptom or result. This is a troublesome medical condition in a subject who has been administered the drug. This is the event. However, any abnormal values ​​or observations should be considered clinically by the principal investigator. Unless deemed statistically significant, it will not be reported as an adverse event. When referring to adverse events, "clinically evident" means using a standard acceptable to those skilled in the art. This means that it is clinically significant, as determined by the physician or principal investigator. When the adverse or undesirable consequences of an adverse event reach such a severity, the regulatory authority may take action against the medical professional. A drug composition or therapeutic agent may be deemed unacceptable for the proposed use. Specifically, this Dosage, administration regimen, or treatment with the anti-IL12 / 23p40 or anti-IL23 antibody of the invention In relation to this, "safe" means that the adverse event is not caused by an anti-IL12 / 23p40 or anti-IL23 antibody. If it is considered likely, highly probable, or very likely that the use of [the substance] is the cause, then antibody administration This refers to the acceptable frequency and / or acceptable severity of adverse events associated with the administration.

[0049] When used in this specification, unless otherwise specified, the term "clinically proven" ( Used independently or to modify the terms “safety” and / or “effectiveness” (To be used) must meet the approval standards of the U.S. Food and Drug Administration, EMEA, or the corresponding national regulatory agency. This means that it has been proven by clinical trials. The trial is a randomized, dual-encompassing study of an appropriate size, used to clinically demonstrate the effects of a drug. A blinded trial is acceptable.

[0050] When used in this specification, the anti-IL-12 / IL-23p40 antibody in "mg / kg" is The dosage is calculated as anti-IL-12 / IL-23 per kilogram of body weight of the person receiving the antibody. This refers to the amount of p40 antibody in milligrams.

[0051] Antibody production and generation according to the present invention At least one anti-IL-12 / 23p40 (or anti-IL-12 / 23p40) used in the method of the present invention IL-23) is selectively used with cell lines, mixed cell lines, and immortal cell lines known in the art. It can be produced by a clonal population of immortalized or fused cells. 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 Lan e,antibodies,a Laboratory Manual,Cold Sp ring Harbor, NY (1989), Colligan, et al., ed. ,Current Protocols in Immunology,John Wi ley & Sons, Inc., NY (1994~2001), Colligan, et al. al.,Current Protocols in Protein Science See John Wiley & Sons, NY, NY, (1997-2001). Each of these is incorporated herein by reference in its entirety.

[0052] Specifically for human IL-12 / 23p40 or IL-23 protein or its fragments. Different human antibodies are isolated from IL-12 / 23p40 protein and IL-23 protein. The quality and / or parts thereof (including synthetic molecules such as synthetic peptides) of proper immunity This can occur in response to the geniculating antigen. Similar reactions can occur with other specific or common mammalian antibodies. The preparation of immunogenic antigens and the production of monoclonal antibodies may be carried out in any suitable manner, taking into consideration the present disclosure. It can be implemented using various technologies.

[0053] One approach involves using a suitable immortal cell line (e.g., Sp2 / 0, S, etc., but not limited to Sp2 / 0). p2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, L243, P3X6 3Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5 , U937, MLA 144, ACT IV, MOLT4, DA-1, JURKAT, W EHI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA 144 Myeloma cell lines such as NAMALWA and NEURO 2A, or heteromylomas, A fusion product, or any cell or fusion cell derived therefrom, or in the art Any other known suitable cell lines) (e.g., www.atcc.org, www.lif) (See etech.com, etc.) but not limited to isolated or cloned Anti-inflammatory cells such as the spleen, peripheral blood, lymph, tonsils, or other immune or B-cell-containing cells. Somatically produced cells, or endogenous or heterologous nucleic acids, recombinant or endogenous, viruses, cells Fungi, algae, prokaryotes, amphibians, insects, reptiles, fish, mammals, rodents, horses, sheep, goats Sheep, primates, eukaryotes, genomic DNA, cDNA, rDNA, mitochondrial DNA A or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, mono 1. Double or triple hemispheres, hybrids, etc., or any combination thereof In either case, the heavy chain or light chain is constant or variable, or the framework or CDR sequence is used. Hybridomas are produced by fusing with any other cell that expresses it. For example, See Ausubel and Chapter 2 of Colligan, Immunology mentioned above. Please refer to the above. Both documents are incorporated herein in their entirety by reference.

[0054] Antibody-producing cells are also obtained from the peripheral blood of a human or other suitable animal immunized with the antigen of interest, It can preferably be obtained from the spleen or lymph nodes. Any other suitable host cell Using the antibodies of the present invention, heterogeneous nucleic acids encoding identified fragments or variants thereof, or Endogenous nucleic acids can also be expressed. Fusion cells (hybridomas) or recombinant cells are selected. Isolate using selective culture conditions or other suitable known methods, and then perform limiting dilution or cell sorting. It can be cloned by other known methods. An antibody with the desired specificity can be obtained. The cells to be produced can be selected by a suitable assay (e.g., ELISA). .

[0055] One method is to select recombinant antibodies from a peptide or protein library. Suitable for producing or isolating antibodies having the required specificity, not limited to those mentioned above. Other methods can be used (e.g., bacteriophages, ribosomes, oligonucleotides) These are display libraries for creotides, RNA, cDNA, etc., but are not limited to these. For example, Cambridge Bold Technologies, Ca mbridgeshire, UK, MorphoSys, Martinsreid / Pl anegg, DE, Biovation, Aberdeen, Scotland, UK, BioInvent, Lund, Sweden, Dyax Corp., Enzon, A From ffymax / Biosite, Xoma, Berkeley, CA, and Ixsys. (Available for purchase). For example, European Patent No. 368,684, International Application PCT / GB91 / Application No. 01134, International Application PCT / GB92 / 01755, International Application PCT / GB92 / Application No. 002240, International Application PCT / GB92 / 00883, International Application PCT / GB93 Patent No. / 00605, U.S. Patent Application No. 08 / 350260 (5 / 12 / 94), International Application P International application No. CT / GB94 / 01422, International application PCT / GB94 / 02662, International application P CT / GB97 / 01835, (CAT / MRC), International Publication No. 90 / 14443, International Publication No. 90 / 14424, International Publication No. 90 / 14430, International Application PCT / US International Publication No. 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 Publication No. 8 / 06630, International Publication No. 90 / 3809 (Dyax), U.S. 4,704, Patent No. 692 (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 probabilistically generated peptides or proteins - United States No. 5723323, No. 5763192, No. 5814476, No. 5817483 Publication No. 5824514, Publication No. 5976862, International Publication No. 86 / 05803, European Publication No. State Patent No. 590689 (Ixsys, Applied Molecular Evolution) (ution)(AME) predecessors, each of which is incorporated into this specification by reference) or there are or are known in the art and / or described herein, human antibodies It depends on the immunization of transgenic animals that can produce partley (for example) , SCID mouse, Nguyen et al., Microbiol. Immunol .41:901-907 (1997);Sandhuet al.,Crit.Rev .Biotechnol.16:95-118(1996), Erenet al.,I mmunol.93:154-161(1998), each is incorporated in its entirety by reference. (This technology includes ribosome display (Haneset al., Proc). .Natl.Acad.Sci.USA,94:4937-4942(Can 1997 ), Haneset al.,Proc.Natl.Acad.Sci.USA,95: 14130-14135 (November 1998), single-cell antibody production technology (e.g., selection) Lymphocyte Antibody Method ("SLAM") (U.S. Patent No. 5,627,052, Wenet a l.,J.Immunol.17:887-892 (1987);Babcooket al.,Proc.Natl.Acad.Sci.USA 937843-7848( 1996)), Gel microdroplets and flow cytometry (Powellet al.,Biotechnol.8:333-337(1990), One Cell Systems (Cambridge, MA), Grayet al., J. Imm. Meth.182:155-163(1995), Kenny et al.,Bio / T echnol.13:787-790 (1995), B cell selection (Steenbakk erset al.,Molec.Biol.Reports 19:125-134( 1994), Jonaket al., Progress Biotech, Vol.5 ,In Vitro Immunization in Hybridoma Tech nology,Borrebaeck,ed.,Elsevier Science P publishers BV,Amsterdam,Netherlands(198 8)) are examples, but are not limited to these.

[0056] Methods for processing or humanizing non-human antibodies or human antibodies through engineering can also be used. This is well known in the technical field. Generally, humanized antibodies or modified antibodies are used for non-human purposes, for example, The supply of mice, rats, rabbits, non-human primates, or other mammals is not limited to these. It has one or more amino acid residues from its source. These non-human amino acid residues are often These are replaced by residues called "import" residues. These typically involve "imported" variable domains, constant domains, or other known human sequences. It is obtained from the domain.

[0057] Known human Ig sequences are disclosed below: for example, www.ncbi.nlm. nih.gov / entrez / query.fcgi, www.ncbi.nih.g ov / igblast, www.atcc.org / phage / hdb.html, w www.mrc-cpe.cam.ac.uk / ALIGNMENTS.php, www. kabatdatabase.com / top.html, ftp.ncbi.nih. gov / repository / kabat, www.sciquest.com, ww w.abcam.com, www.antibodyresource.com / onl inecomp.html, www.public.iastate.edu / ~ped ro / research_tools.html、www.whfreeman.com / immunology / CH05 / kuby05.htm、www.hhmi.org / grants / lectures / 1996 / vlab、www.path.cam. ac.uk / ~mrc7 / mikeimages.html、mcb.harvard. edu / BioLinks / Immunology.html、www.immunol ogylink.com、pathbox.wustl.edu / ~hcenter / i ndex.html、www.appliedbiosystems.com、www. nal.usda.gov / awic / pubs / antibody、www.m.eh ime-u.ac.jp / ~yasuhito / Elisa.html、www.bio design.com、www.cancerresearchuk.org、www. biotech.ufl.edu、www.isac-net.org、baserv. uci.kun.nl / ~jraats / links1.html、www.recab .uni-hd.de / immuno.bme.nwu.edu、www.mrc-cp e.cam.ac.uk、www.ibt.unam.mx / vir / V_mice.h tml、http: / / www.bioinf.org.uk / abs、antibod y.bath.ac.uk、www.unizh.ch、www.cryst.bbk. ac.uk / ~ubcg07s、www.nimr.mrc.ac.uk / CC / cca ewg / ccaewg.html、www.path.cam.ac.uk / ~mrc7 / humanisation / TAHHP.html、www.ibt.unam.mx / vir / structure / stat_aim.html, www.biosci. missouri.edu / smithgp / index.html, www.jeri ni.de, Kabat et al., Sequences of Proteins of Immunological Interest,USDept.Heal th (1983), each of which is incorporated herein by reference in whole.

[0058] Such imported sequences are used to reduce immunogenicity, or in the field of technology. As is well known, binding, affinity, binding rate constant, dissociation rate constant, binding activity, specificity, semi-binding It can be used to reduce, enhance, or modify the lifespan, or any other suitable characteristic. Generally, CDR residues directly and almost substantially affect antigen binding. This means maintaining a non-human CDR sequence or part or all of a human CDR sequence, while maintaining the variable region Furthermore, the non-human sequence in the constant region may be replaced with human amino acids or other amino acids. can.

[0059] Antibodies may be optionally humanized, or human antibodies may have high affinity for antigens. It may be modified while retaining sex and other advantageous biological characteristics. To achieve this objective This involves optionally using three-dimensional models of the parent sequence and the humanized sequence to analyze the parent sequence and various other aspects. Humanized (or human) antibodies are prepared through a process that analyzes theoretical humanized products. This is possible. Three-dimensional immunoglobulin models are generally available and are well known to those skilled in the art. The three-dimensional structures with a high probability of success for the selected immunoglobulin sequence candidates are shown. Computer programs that display and show information are available. Therefore, we analyze the likely functions of residues in candidate immunoglobulin sequences, that is, This makes it possible to analyze the residues that affect the antigen-binding ability of candidate immunoglobulins. Then, desirable antibody characteristics such as enhanced affinity for target antigens (multiple antigens are possible) are achieved. To do this, select framework (FR) residues from the consensus sequence and import sequence. They can be combined.

[0060] In addition, the human anti-IL-12 / 23p40 (or anti-IL) used in the method of the present invention -23) Specific antibodies 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 This includes, but is not limited to, O12, O14, O18, O2, O4, and O8. Selected from the VK sequence. In certain embodiments, this light chain human germline frame The models are 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, V2-1, 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 They are selected.

[0061] In other embodiments, the human anti-IL-12 / 23p40 used in the method of the present invention ( Alternatively, an anti-IL-23) specific antibody may include a human germline heavy chain framework. In this embodiment, this heavy chain human germline framework includes 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 Select from VH7-81.

[0062] In certain embodiments, the light chain variable region and / or heavy chain variable region are framework regions. or at least a portion of the framework area (for example, 2 or 3 such as FR2 and FR3) (including two subregions). In a particular embodiment, at least FRL1, FRL2, FRL3, or FRL4, is fully human. In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 are fully human. In some embodiments, less However, FRL1, FRL2, FRL3, or FRL4 are germline sequences (for example, human germline sequences). (A breeding series) or a human consensus sequence for a specific framework (as described above) Includes (which is readily available from a source of human Ig sequences). In other embodiments, less FRH1, FRH2, FRH3, or FRH4 are germline sequences (e.g., human germline sequences). (A series) or containing a human consensus sequence for a specific framework. In a particular embodiment, the framework domain is a complete human framework domain.

[0063] The humanization or engineering treatment of the antibody of the present invention is performed by Winter (Joneset al., N ature 321:522(1986), Riechmannet al., Natu re 332:323 (1988), Verhoeyenet al., Science 2391534(1988)), Simset al., J. Immunol.151 :2296(1993), Chothia and Lesk, J.Mol.Biol.196 :901(1987), Carteret al.,Proc.Natl.Acad.S Ci.USA89:4285(1992), Presta et al., J.Im. munol.151:2623(1993), U.S. Patent No. 5723323, and No. 597 6862, 5824514, 5817483, 5814476, No. 5763192, No. 5723323, No. 5,766886, No. 57143 No. 52, No. 6204023, No. 6180370, No. 5693762, No. 5 No. 530101, No. 5585089, No. 5225539, No. 4816567 International applications US98 / 16280, US96 / 18978, and US91 / 0 9630, US91 / 05939, US94 / 01234, British Patent No.8 Issues 9 / 01334, 91 / 01134, 92 / 01755, and International Publication No. 90 Patent No. / 14443, No. 90 / 14424, No. 90 / 14430, European Patent No. 229 No. 246 (each incorporated in its entirety by reference, including the references cited therein) This includes, but is not limited to, those described in ), and can be performed using any known method. It is possible.

[0064] In a particular embodiment, the antibody is a modified (e.g., mutated) Fc Includes a region. For example, in some embodiments, the Fc region is an effector of the antibody. It has been modified to reduce or enhance. In some embodiments, the Fc region is IgM, IgA, IgG, IgE, or an isotype selected from other isotypes Yes. Or, in addition, amino acid modification and the C1q region of the Fc domain of the IL-23 binding molecule. Combined with one or more further amino acid modifications that alter binding and / or complement-dependent cytotoxicity function Combining them may be useful. A starting polypeptide for a specific purpose binds to C1q. It can be, and complement-dependent cytotoxicity (C) It exhibits DC) activity. It has existing C1q binding activity and the ability to optionally further mediate CDC. Polypeptides possessing these can be modified to enhance one or both of these activities. Amino acid modifications that alter C1q and / or modify its complement-dependent cytotoxic function. For example, this is described in International Publication No. 0042072, which is incorporated herein by reference. put in.

[0065] As disclosed above, for example, modify the C1q bond and / or FcγR bond, Therefore, complement-dependent cytotoxicity (CDC) activity and / or antibody-dependent cell-mediated cytotoxicity ( By altering antibody-dependent cell-mediated cytotoxicity (ADCC) activity... Therefore, the present invention provides a modified effector function for human anti-IL-12 / 23p40 (or It can design the Fc region of an anti-IL-23) specific antibody. The "effector function" is It plays a role in activating or reducing biological activity (for example, in a target). Examples of functions, though not limited to these, include C1q binding, CDC, and Fc reception. Body binding, ADCC, phagocytosis, and Dow of cell surface receptors (e.g., B cell receptor, BCR) Examples include regulation. Such effector functions are linked domains in the Fc area. It may be necessary to bind to a (for example, an antibody variable domain), and there are many different types. Use an assay (e.g., Fc binding assay, ADCC assay, CDC assay, etc.) It can be used to evaluate.

[0066] For example, having improved C1q bonds and improved FcγRIII bonds (for example, Human anti-IL-12 (possessing both improved ADCC activity and improved CDC activity) It is possible to generate mutant Fc regions of 23p40 (or anti-IL-23) antibodies. If it is desired to reduce or remove the effector function, the mutant Fc region is CD The modification can be made to reduce C activity and / or ADCC activity. In other embodiments, only one of these activities may be enhanced, optionally, At the same time, other activities may be reduced (for example, improved ADCC activity and reduced CDC activity). (To generate Fc region variants that have the property, and vice versa).

[0067] Fc mutations alter the interaction with the fetal Fc receptor (FcRn) and their pharmacokinetics. It is also possible to modify genes to improve traits and introduce them. The collection of improved human Fc variants is described (Shields et al., (20 01).High resolution mapping of the bindi ng site on human IgG1 for FcγRI,FcγRII, F cγRIII, and FcRn and design of IgG1 varia nts with improved binding to the FCγR, J. Biol.Chem.276:6591-6604).

[0068] Another type of amino acid substitution is specific to human anti-IL-12 / 23p40 (or anti-IL-23). It helps to alter the glycosylation pattern of the Fc region of the target antibody. The chemical structure is typically either N-linked or O-linked. The N-linked form is asparagine. This refers to the addition of a carbohydrate moiety to the side chain of a residue. O-linked glycosylation refers to 5-hydroxy Proline or 5-hydroxylysine may also be used, but hydroxy amino acids are the most common. This includes sugars converted to serine or threonine, N-acetylgalactosamine, galactose, or This refers to the attachment of one of the xylose molecules to the asparagine side chain peptide sequence. The recognition sequences for enzymatic addition are asparagine-X-serine and asparagine-X-serine. It is rheonine, and X is any amino acid other than proline. Therefore, polypeptide The presence of any of these peptide sequences therein results in potential glycosylation sites being provided

[0069] 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 not present in the polypeptide. Addition of glycosylation sites to the Fc region of a human IL-23-specific antibody is successfully achieved by altering 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 effected 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). In addition, changing Asn 297 to Ala can remove one of the glycosylation sites

[0070] In certain embodiments, the human anti-IL-12 / 23p40 (or anti-IL-23 )-specific antibodies of the invention are 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 WO 9954342, WO 03011878, JP 20030003097(A1), and Umana et al. , Nature Biotechnology, 17:176-180, Feb. 199 9 are provided in 9, all of which are hereby specifically incorporated by reference in their entirety herein

[0071] 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.) that are 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 described herein

[0072] 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; 5,625,8 25; 5,633,425; 5,661,016; and 5,789, 650 issued to Lonberg et al., International Publication Nos. 98 / 50433; 98 / 24893; 98 / 2488 4; 97 / 13852; 94 / 25585; 96 / 34096 issued to Lonberg et al., International Publication Nos. 98 / 24884; 97 / 13852; 94 / 25585; 96 / 34096 issued to Lonberg et al., International Publication Nos. 98 / 24884; 97 / 13852; 94 / 25585; 96 / 34096 issued to Lonberg et al., International Publication Nos. 98 / 24884; 97 / 13852; 94 / 25585; 96 / 34096 issued to Lonberg et al., International Publication Nos. 98 / 24884; 97 / 13852; 94 / 25585; 96 / 34096 issued to Lonberg et al., International Publication Nos. 98 / 24884; 97 / 13852; 94 / 25585; 96 / 34096 issued to Lonberg et al., International Publication Nos. 98 / 24884; 97 / 13852; 94 / 25585; 96 / 34096 issued to Lonberg et al., apate et al., European Patent No. 0463 151 (B1); 0710 719 (A1) issued to Kucherlapate et al., U.S. Patent No. 5 , No. 545,807, International Publication No. 90 / 04036 by Bruggemann et al., Bru European Patent No. 0438 474(B1) by ggemann et al., European Patent No. 0438 474(B1) by Lonberg et al. Patent No. 0814 259(A2), Lonberg et al., British Patent No. 2 272 440( A) No. 368, Lonberg et al., Nature 368 856-859 (1994), Ta Ylor et al., Int.Immunol.6(4)579-591(1994), Gree n et al. Nature Genetics 7:13-21 (1994), Mendez et al. ,Nature Genetics 15:146-156(1997), Taylor et al. Nucleic Acids Research 20(23):6287-629 5 (1992), Tuaillon et al., Proc Natl Acad Sci USA 90(8)3720-3724(1993), Lonberg et al., Int Rev I mmunol 13(1):65-93(1995) and Fishwald et al., Nat Biotechnol 14(7):845-851(1996), these are references. (Each of these is incorporated herein.) Generally, these mice are functionally reconfigured. or at least one human immunoglobulin gene that can undergo functional reconstitution The mouse contains at least one transgene that includes DNA derived from the zodiac. By disrupting or deleting the sex immunoglobulin gene locus, the endogenous genes of mice encode... It is possible to eliminate the ability of animals to produce antibodies that have been identified.

[0073] Screening antibodies for specific binding to similar proteins or fragments is done using peptides. This can be successfully achieved using the display library. This method is desired. A large collection of peptides for each member with a unique function or structure This includes screening. Antibody screening of peptide display libraries is relevant. This is well known in the technical field. The length of the displayed peptide sequence is 3 to 5000. It consists of more than one amino acid, frequently with a length of 5 to 100 amino acids, and most often with about 8 to 25 amino acids. It may be a amino acid length. In addition to direct chemical synthesis methods for creating peptide libraries, several The recombinant DNA method is also described. One type involves bacteriophages or cells. This includes the display of peptide sequences on the surface. Each bacteriophage or cell is particularly It contains a nucleotide sequence that encodes a specific displayed peptide sequence. The method is described in International Publication Nos. 91 / 17271, 91 / 18980, and 91 / 19 It is described in issue 818 and issue 93 / 08278.

[0074] Other systems for creating peptide libraries include in vitro chemical synthesis and It has both aspects of the recombinant method. International Patent Publication No. 92 / 05258, 92 / 148 See Patent No. 43 and No. 96 / 19256. U.S. Patent No. 5,658,754 See also No. 5,643,768. Peptide display library, vec The TA and screening kit contain Invitrogen (Carlsbad, CA) and and Cambridge antibody Technologies(Cambrid It is sold commercially by suppliers such as Geshire, UK. For example, it was transferred to Enzon. U.S. Patent Nos. 4,704,692, 4,939,666, 4,946,778, 5,260,203, 5,455,030, 5,518,889, 5,534,62 1, 5,656,730, 5,763,733, 5,767,260, 5,8 56,456, U.S. Patent No. 5,223,409 assigned to Dyax, 5,403,484 assigned to Affymax, 5,571,698, 5,837,500, U.S. Patent No. 5,427,908 assigned to Affymax, 5,580,717, Cambridge antibody Technologies, U.S. Patent No. 5,885,793 assigned to Genente ch, U.S. Patent No. 5,750,373 assigned to Xoma, U.S. Patent No. 5,61 8,920, 5,595,898, 5,576,195, 5,698,435, 5,693,493, 5,698,417, reference is made to the above Colligan, the above Ausu bel, or the above Sambrook, and each of the above patents and publications is incorporated herein by reference in its entirety.

[0075] The antibodies used in the method of the present invention can also be prepared using at least one anti-IL-12 / 23p40 (or anti-IL-23) antibody that encodes nucleic acids to provide transgenic animals or mammals such as goats, cows, horses, pigs, 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, 5,849,99 2, 4,873,316, 5,849,992, 5,994,616, 5,5 65,362, 5,304,489, etc. (each of which is incorporated by reference in its entirety). in its entirety). (The whole is incorporated into this specification.)

[0076] The antibodies used in the method of the present invention are found in plant parts or cells cultured therefrom. Transgenic plants that produce antibodies, specific parts, or mutants, and cultured Provides plant cells (e.g., tobacco and corn, but not limited to these). To do this, at least one anti-IL-12 / 23p40 (or anti-IL-12) encoding nucleic acid is required. It can be further prepared using L-23 antibodies. As a non-limiting example, for example, Using a guide promoter, we successfully produced transgenic tobacco leaves that express recombinant proteins. Large quantities of recombinant proteins have been provided using this method. For example, Cramer et al. .,Curr.Top.Microbol.Immunol.240:95-118(1 See 999) and the references cited therein. Also, Transgenic Tomo Rokoshi is a protein produced in other recombinant systems or refined from natural resources. Expressing mammalian proteins with biological activity equivalent to that of other proteins at a commercially viable level. It has been used for this purpose. For example, Hoodet al., Adv.Exp.Med.Bi Please refer to ol.464:127-147(1999) and the literature cited therein. The antibodies include antibody fragments such as single-chain antibodies (scFv), found in tobacco seeds and potato tubers, etc. They have also been produced in large quantities from the seeds of transgenic plants such as Conr adr, Plant Mol. Biol. 38:101-109 (1998) and within Please refer to the literature cited. Therefore, the antibody of the present invention is also produced according to known methods. Furthermore, it can also be produced using transgenic plants. For example, Fischer et al.,Biotechnol.Appl.Biochem.30:99-108 (October 1999), Maet al.,Trends Biotechnol.13 :522-7(1995), Maet al., Plant Physiol.109: 341-6(1995), Whitelamet al.,Biochem.Soc.T See rans.22:940-944(1994) and the literature cited therein. Please do so. Each of the above references is incorporated herein in its entirety by reference.

[0077] The antibody used in the method of the present invention has a wide affinity (KD) for human IL- It can be coupled to 12 / IL-23p40 or IL-23. In a preferred embodiment, Human mAbs are selectively targeted to human IL-12 / IL-23p40 or I with high affinity. It can bind to L-23. For example, human mAbs can bind to human IL-12 / IL-23. p40 or IL-23 is approximately 10⁻⁷M or less, for example, not limited to 0.1~9.9( (or any range or value within that range) X 10⁻⁷, 10⁻⁸, 10⁻⁹, 10⁻¹⁰ KD such as 10⁻¹¹, 10⁻¹², 10⁻¹³, ​​or any range or value within those ranges. They can be combined.

[0078] The affinity or binding activity of an antibody to an antigen can be determined experimentally using any suitable method. It is possible. (For example, Berzofsky, et al., "Antibody- Antigen Interactions,” In Fundamental Imm. unology, Paul, WE, Ed., Raven Press: New Yo rk, NY (1984), Kuby, Janis Immunology, WHFr eeman and Company: New York, NY (1992), and Honmei (See the method described in the detailed document.) Parents who are measured for specific antibody-antigen interactions. The compatibility may differ 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 preferred. Alternatively, standardized solutions of antibodies and antigens, and standardized buffers such as buffers described herein. It is done using an agent.

[0079] Vector and host cell This invention relates to a vector containing isolated nucleic acid molecules, which are genetically engineered using a recombinant vector. Chief cells and at least one anti-IL cell by recombinant technology known in the art It is also related to the production of -12 / IL-23p40 antibodies. For example, Sambrook et al. mentioned above, Please refer to Ausubel et al. above, each of which is incorporated herein by reference in whole. It can be done.

[0080] Polynucleotides are vectors that optionally contain a selection marker for host proliferation. It can bind to the phosphate. Generally, plasmid vectors are made of calcium phosphate precipitate. It is introduced into the precipitate or into a complex with charged lipids. If the vector is a virus These cells are then packaged in vitro using an appropriate packaging cell line, and subsequently transduced into host cells. It is possible.

[0081] DNA insertions should be functionally linked to the appropriate promoter. The kut is a ribosomal cell that is used for translation within the transcription start site, transcription termination site, and the transcribed region. It further includes a binding site. The coding portion of the mature transcript expressed by the construction is preferably These are the start and stop codons (e.g., UA) that are appropriately located at the end of the mRNA to be translated. Translations beginning with A, UGA, or UAG are expressed in mammalian or eukaryotic cells as UA A and UAG are preferred.

[0082] The expression vector preferably contains at least one selection marker, but this is optional. Yes, such markers include, for example, methotrexate for eukaryotic cell culture. MTX), dihydrofolate reductase (DHFR), US special Permit No. 4,399,216, No. 4,634,665, No. 4,656,134, Same Nos. 4,956,288, 5,149,636, 5,179,017, and Ann Picillin, neomycin (G418), mycophenolic acid, or glutamine synthetase (GS, U.S. Patent No. 5,122,464, No. 5,770,359, No. 5,827) (No. 739) Resistance genes, and in Escherichia coli (E. coli) and other bacteria or prokaryotes It contains tetracycline or ampicillin resistance genes for culture in, but these Not limited to (the above patents are incorporated herein by reference in their entirety). The above host molecules Appropriate culture media and conditions for the cells are known in the art. Suitable vectors This will become readily apparent to those involved. The introduction method involved calcium phosphate transfection, mediated by DEAE-dextran. Transfection, transfection mediated by cationic lipids, electro This can be achieved by electroporation, transduction, infection, or other known methods. In addition, Sambrook, Chapters 1-4 and 16-18, and Ausube, mentioned above. It is described in Chapters 1, 9, 13, 15, and 16, among others, within the relevant technical field.

[0083] At least one antibody used in the method of the present invention is a modified antibody such as a fusion protein. It can be expressed morphologically and may include not only secretory signals but also additional heterologous functional regions. For example, The region of additional amino acids, particularly charged amino acids, is added to the N-terminus of the antibody during or after purification. During processing and storage, stability and persistence in host cells can be improved. The ptide portion can also be added to the antibody of the present invention to promote purification. Another region can be removed before the final preparation of that fragment. Such a method is, The above Sambrook, Chapters 17.29-17.42 and 18.1-18.74, Many standard laboratory manuals, such as Ausubel, Chapters 16, 17, and 18 mentioned above. It is described there.

[0084] Those skilled in the art will be able to use the nucleic acid encoding the protein used in the method of the present invention for expression. They are familiar with a large number of possible expression systems. Alternatively, nucleic acids are endogenous, encoding antibodies. In a host cell containing DNA, by switching it on (through manipulation), in the host cell This can be expressed by, for example, U.S. Patent No. 5,580,734. Nos. 5,641,670, 5,733,746, and 5,733,761 As described above, these are well known in the technical field, and by reference they are entirely obvious. It will be included in the detailed specifications.

[0085] Examples of cell cultures useful for producing antibodies, their specific parts, or variants include mammalian cells. It is a cell. Mammalian cell lines often take the form of a single layer of cells, but a suspension of mammalian cells. Alternatively, a bioreactor can also be used. Several suitable host cell lines have been developed in the field, including COS-1( For example, ATCC CRL 1650), COS-7 (for example, ATCC CRL-1651) ), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., AT CC CRL1610) and BSC-1 (e.g., ATCC CRL-26) cell lines, Co s-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2 / 0- Examples include Ag14, 293 cells, and HeLa cells, which are used in, for example, America. n Type Culture Collection,Manassas,Va(ww It is readily available from w.atcc.org. Preferred host cells include myeloma cells. Examples include lymphocytes and other lymphoid cells. Particularly preferred host cells are P3X63Ag8.653 cells (ATCC registration number CRL-1580) and SP2 / 0 -Ag14 cells (ATCC registration number CRL-1851). In a particularly preferred embodiment... The recombinant cells are P3X63Ab8.653 or SP2 / 0-Ag14 cells.

[0086] These cell expression vectors are used as origins of replication, promoters (e.g., late or early SV40) Promoter, CMV Promoter (U.S. Patent No. 5,168,062, and No. 5,385,8) (No. 39), HSV tk promoter, pgk (phosphoglycerate kinase) promoter EF-1α Promotor (U.S. Patent No. 5,266,491), at least one human-powered motor Epidemic globulin promoter, enhancer, and / or ribosome binding site, RNA spra Chair portion, polyadenylation portion (e.g., SV40 large T Ag poly addition portion), and This includes, but is not limited to, processing information sites such as transcription termination sequences, and expression levels. It may include one or more of the above sequences. For example, Ausubel et al. above, Samb above See Rook et al. Other cells useful for the production of nucleic acids or proteins of the present invention are Known and / or, for example, American Type Culture Catalog of cell lines and hybridomas in the Collection (www.atcc.or g) Available from other known or commercial sources.

[0087] When eukaryotic host cells are used, typically polyadenylation or transcription termination occurs within the vector. The sequence is incorporated. An example of a termination sequence is polyadenylation from the bovine growth hormone gene. It is a sequence. Sequences for accurate splicing of transcription can also be included. An example of a pricing sequence is the VP1 intron derived from SV40 (Sprague, et al., J. Virol. 45:773-781 (1983). In addition, the technique As is well known in the field of science, gene sequences that control replication within host cells are vectors It can be incorporated into the device.

[0088] Antibody purification Anti-IL-12 / IL-23p40 or IL-23 antibody is purified protein A, sulfate ammonium Monium or ethanol precipitation, acid extraction, anion or cation exchange chromatography, Sulfocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography Chromatography, hydroxyl apatite chromatography, and lectin chromatography Examples include, but are not limited to, well-known methods for recovering recombinant cell cultures. It can be purified using high-performance liquid chromatography. Matography (HPLC) can also be used for purification. For example, Colligan Current Protocols in Immunology or Current Protocols in Protein Science,John Wiley For example, tracks 1, 4, 6, 8, and 9 of & Sons, NY, NY (1997-2001). Please refer to Chapter 10, each of which is incorporated into this specification by reference.

[0089] The antibodies used in the method of the present invention include naturally purified products and products produced by chemical synthesis methods. Recombination from eukaryotic hosts, including, for example, yeast, higher plants, insects, and mammalian cells. It contains products produced by the recombinant method. Depending on the host used in the recombinant product procedure, The body can be glycosylated or not, but glycosylation is preferable. This is preferable. Such a method is described above in Sambrook, sections 17.37–17.42. , Ausubel, Chapters 10, 12, 13, 16, 18, and 20, Col Many standard practices, such as those described in chapters 12-14 of Ligan, Protein Science, etc. This is described in the laboratory manual, and the entirety is incorporated herein by reference.

[0090] Anti-IL-12 / IL-23p40 or IL-23 antibody The anti-IL-12 / IL-23p40 or IL-23 antibody according to the present invention incorporates into the antibody It is possible to remove at least a portion of an immunoglobulin molecule, for example, but not limited to a small portion. at least one ligand-binding portion (LBP), for example, limited to However, the complementarity-determining region (CDR) of the heavy chain or light chain, or its ligand-binding portion, heavy chain Alternatively, the light chain variable region, the framework region (for example, FR1, FR2, FR3, FR4) , or those fragments, and optionally, at least one substitution, insertion, or deletion. (including loss), heavy chain or light chain steady region (for example, at least one CH1, hinge 1, Hinge 2, Hinge 3, Hinge 4, CH2, or CH3, or their fragments, Furthermore, optionally, including at least one substitution, insertion, or deletion, or any of them It contains any protein or peptide-containing molecule that includes the portion. Antibodies are human, mouse, and Herons, rats, rodents, primates, or any combination thereof, etc. It includes, or may be derived from, any mammal, without limitation.

[0091] Preferably, the human antibody or antigen-binding fragment is human IL-12 / IL-23p4 It binds to 0 or IL-23, thereby affecting at least one biological activity of the protein. Partially or substantially neutralize at least one IL-12 / IL-23p40 or IL -23 The biological activity of at least one protein or fragment is partially or preferably Alternatively, an antibody that substantially neutralizes the protein or a specific part or variant thereof may be a protein or It binds to the fragment, thereby forming IL-12 / IL-23p40 or IL-23, I Through binding to L-12 and / or IL-23 receptors, or other IL-12 / IL -23p40 or IL-23-dependent or mediated activity is inhibited. It can be harmful. When used herein, the term "neutralizing antibody" is used in an assay. Depending on the amount, approximately 20-120%, preferably at least 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, IL-12 / IL-23p40 or IL-23 dependent activity This refers to antibodies that can inhibit sexual activity. Specifically, anti-IL-12 / IL-23p40 or IL-23 The ability of an antibody to inhibit IL-12 / IL-23p40 or IL-23-dependent activity is preferred. or at least one good which is described herein and / or known in the art By appropriate IL-12 / IL-23p40 or IL-23 protein or receptor assays Human antibodies are evaluated based on their class (IgG, IgA, IgM, IgE, IgD, etc.). ) or isotype, and may include kappa or lambda light chains. One implementation form In this state, human antibodies are composed of IgG heavy chains or defined fragments, for example, IgG1, IgG2 , at least one of IgG3 or IgG4 (e.g., γ1, γ2, γ3, γ4) This includes isotypes. Antibodies of this type are described herein and / or in the art. In which known derivatives of at least one human light chain (e.g., IgG, IgA, and IgM) Transgenic mice or other non-human transgenic milk-feeding mice containing entered genes. It can be prepared by utilizing animals. In another embodiment, anti-IL-2 3. Human antibodies contain both IgG1 heavy chain and IgG1 light chain.

[0092] The antibody contains at least one IL-12 / IL-23p40 or IL-23 protein. At least one specific to a subunit, fragment, part, or any combination thereof It also binds to one identified epitope. This at least one epitope is a protein It may include at least one antibody-binding region that includes at least a portion of the substance, This epitope is preferably at least one extracellular portion of the protein, a soluble portion. It is composed of a hydrophilic portion, an outer portion, or a cytoplasmic portion.

[0093] Generally, human antibodies or antigen-binding fragments contain at least one human complementarity-determining region (CDR). 1, CDR2, and CDR3) or variants of at least one heavy chain variable region, and less Each has one human complementarity-determining region (CDR1, CDR2, and CDR3) or at least one The CDR sequence contains an antigen-binding region that includes a variant of one of the light chain variable regions. It may be derived from a type sequence, or it may be a sequence that strictly matches a germline type sequence. For example, using a CDR from a synthetic library derived from a non-human CDR. Yes, these CDRs can be created by incorporating conserved substitutions derived from the original non-human sequence. It may be formed. In another specific embodiment, the antibody or antigen-binding moiety or variant is the corresponding At least one light chain CDR having the amino acid sequence of CDR1, 2 and / or 3 an antigen-binding region including at least a portion of CDR1, CDR2, and / or CDR3) It can have.

[0094] Such antibodies encode antibodies using conventional techniques of recombinant DNA technology (i.e., By preparing and expressing one or more nucleic acid molecules, or by any other suitable method By using this method, various parts of the antibody (e.g., CDR, Fray) can be extracted using conventional techniques. It can be prepared by chemically bonding the following together:

[0095] In one embodiment, the anti-IL-12 / 23p40 antibodies useful in the present invention are, respectively, SEQ ID NOs. 1, 2, and 3 Heavy Chain Complementarity Determining Regions (CDRs) HCDR1, HCDR2, and HCDR 3 and the light chain CDRs LCDR1, LCDR2, and L of sequence numbers 4, 5, and 6, respectively. A monoclonal antibody containing CDR3, preferably a human mAb, is used.

[0096] Anti-IL-12 / IL-23p40 or IL-23 specific antibodies are formulated according to a defined amino acid composition. It may include at least one of the heavy chain variable region or light chain variable region having columns. For example, in a preferred embodiment, an anti-IL-12 / IL-23p40 or IL-23 antibody is , in SEQ ID NO: 7, at least 85%, preferably at least 90%, more preferably less A heavy chain variable region containing 95%, and preferably 100%, identical amino acid sequences, and sequence Number 8 should be at least 85%, preferably at least 90%, more preferably at least 9 Anti-IL- Contains 12 / IL-23p40 antibody.

[0097] Anti-IL-12 / IL-23p40 or IL-23 specific antibodies are also defined amino acids. It can include at least one of a heavy chain or a light chain having an acid sequence. Another preferred In an embodiment, the anti-IL-12 / IL-23p40 or IL-23 antibody is set forth in SEQ ID NO: 10 at least 85%, preferably at least 90%, more preferably at least 95%, most preferably 100% identical amino acid sequence of the heavy chain, and at least 85 in SEQ ID NO: 11 %, preferably at least 90%, more preferably at least 95%, most preferably 1 00% identical amino acid sequence of the light chain variable region, and the anti-IL-12 / IL-23p40 antibody.

[0098] Preferably, the anti-IL-12 / 23p40 antibody comprises 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, and ustekinumab (Stelar a (registered trademark)). Other examples of anti-IL12 / 23p40 antibodies useful in the present invention include , briakinumab (ABT-874, Abbott), and U.S. Patent Nos. 6,914,128, 7,247,711, 7700739 ( the entire contents of which are incorporated herein by reference), and other antibodies described therein are included, but are not limited thereto.

[0099] The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains, and CDRs that contain 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 containing such chains or CDRs have high affinity (e.g., KD is about 10 -9 M or less) and can bind to human IL-12 / IL-23p40 or IL-23. Substantially the same as the sequences described herein A certain amino acid sequence includes conservative amino acid substitutions and amino acid deletions and / or insertions. Examples of sequences include: Conservative amino acid substitutions are chemically similar to those of the first amino acid. A second mesh having physical properties (e.g., charge, structure, polarity, hydrophobic / hydrophilic) This refers to the substitution of the first amino acid with an acid. Conservative substitutions are not limited to certain types of substitutions. This includes substituting amino acids with other amino acids from the following groups: lysine (K), arginine (R), and histidine (H); aspartate (D) and glutamate (E); a Sparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y) ), K, R, H, D, and E; alanine (A), valine (V), leucine (L), isol Icin (I), proline (P), phenylalanine (F), tryptophan (W), methicone Onine (M), cysteine ​​(C), and glycine (G); F, W, and Y; C, S, and T.

[0100] A defined heavy or light chain bound to human IL-12 / IL-23p40 or IL-23. Antibodies containing a variable region are known in the art and / or described herein as phagedies. Spray (Katsube, Y., et al., Int J Mol. Med, 1(5 Methods such as employing transgenic animals (863-868 (1998)) or other preferred methods. It can be prepared using an appropriate method. For example, functionally reconstituted human immunoglobulins A brin heavy chain transgene and a human immunoglobulin light chain capable of functional rearrangement. Transgenic mice containing a transgene with DNA from a gene locus, human IL -12 / IL-23p40 or IL-23 or its fragments are used to immunize and produce antibodies. Production can be induced. If desired, antibody-producing cells can be isolated. As described in the details and / or as known in the art, hybrid M or other immortalized antibody-producing cells can be prepared. Alternatively, antibodies, specific The modified portion or mutant is expressed in a suitable host cell using the coding nucleic acid or a portion thereof. It can be made to happen.

[0101] 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 of the following are caused by either spontaneous mutation or human manipulation. This may include substitutions, deletions, or additions of the above amino acids.

[0102] The number of amino acid substitutions that a person skilled in the art can perform depends on many factors, including those mentioned above. In other words, any given anti-IL-12 / IL-23p40 or IL-23 antibody, flag The number of amino acid substitutions, insertions, or deletions in the ment or variant is as specified herein. 40, 30, 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 within this range Do not exceed the value.

[0103] Functionally essential anti-IL-12 / IL-23p40 or IL-23 specific antibodies Mino acids are used in site-directed mutagenesis or alanine scanning mutagenesis, etc. It can be identified by methods known in the technical field (for example, the above Ausube l, Chapters 8,15; Cunningham and Wells, Science e 244:1081-1085(1989)). In the latter procedure, one residue per molecule A mutation is introduced using alanine. The resulting mutant molecule is then, for example, limited However, it does not necessarily mean that it has at least one IL-12 / IL-23p40 or IL-23 neutralizing activity, etc. Its biological activity is tested. The site that is extremely important for antibody binding is also crystallized. It can be identified by structural analysis such as nuclear magnetic resonance or photoaffinity labeling (Smit h,.et al., J.Mol.Biol.224:899-904(1992) and de Vos, et al., Science 255:306-312(1992)) .

[0104] Anti-IL-12 / IL-23p40 or IL-23 antibodies are available under Sequence IDs 1, 2, 3, 4, and 5. , 5 to 11 of at least one adjacent amino acid It may include at least one part, array, or combination selected from there. , but not limited to these.

[0105] IL-12 / IL-23p40 or IL-23 antibody or specific part or variant thereof Therefore, at least 3 to 5 adjacent amino acids of the above sequence number, and 5 to 17 of the above sequence number Adjacent amino acids, 5 to 10 adjacent amino acids of the above sequence number, 5 to 11 adjacent amino acids of the above sequence number Adjacent amino acids, 5 to 7 adjacent amino acids of the above sequence number, 5 to 9 adjacent amino acids of the above sequence number This could include at least one part, sequence, or combination selected from amino acids. , but not limited to these.

[0106] Anti-IL-12 / IL-23p40 or IL-23 antibodies may be further optionally selected from the above sequence. The numbers 5, 17, 10, 11, 7, 9, 119, 108, 449, or 214 adjacent A It may contain at least one polypeptide making up 70-100% of the amino acids. In this state, the amino acid distribution of immunoglobulin chains, or a portion thereof (e.g., variable region, CDR) The column contains the amino acid sequence of at least one corresponding chain from the above sequence numbers, and approximately 70-1 00% identity (for example, 70, 71, 72, 73, 74, 75, 76, 77, 78, 7 9, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92 , 93, 94, 95, 96, 97, 98, 99, 100, or any range within these numbers (is a value). For example, the amino acid sequence of the light chain variable region is compared with the sequence of the above sequence number. It is possible to compare the amino acid sequence of heavy chain CDR3 with the above sequence number. Preferably, 70-100% amino acid identity (i.e., 90, 91, 92, 93) , 94, 95, 96, 97, 98, 99, 100, or any range or value within these numbers. This involves using a suitable computer algorithm, as is known in the art. It will be decided.

[0107] As is well known in the art, "identity" is determined by comparing sequences. This refers to the relationship between two or more polypeptide sequences or two or more polynucleotide sequences. In the art, "identity" is also determined by the agreement between such linear arrangements. This refers to the degree of sequence relevance between polypeptide or polynucleotide sequences. "Identity" and "similarity" are defined in Computational Molecular B. iology,Lesk,AM,ed.,Oxford University P ress, New York, 1988, Biocomputing:Informat. ics and Genome Projects, Smith, DW, ed., A Academic Press, New York, 1993, Computer Ana Analysis of Sequence Data,Part I,Griffin,A. M.,and Griffin,HG,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). The methods listed are, but are not limited to, easily known methods It can be calculated. In addition, the value related to the percentage of identity is Vector NTI S A is a component of uite 8.0 (Informax, Frederick, MD). Amino acid and nucleotide sequence allies created using the default settings of lignX. It can be obtained from the munition.

[0108] The preferred method for determining identity is to obtain the greatest degree of agreement between the sequences being tested. The method for determining identity and similarity is based on publicly available computer programs. It is codified in Lamb. It determines the identity and similarity between two sequences. A preferred computer program method for this purpose is the GCG program packaging (Devere ux, J. et al., Nucleic Acids Research 12(1) :387(1984)), BLASTP, BLASTN, and FASTA (Atschu l,SFet al.,J. Molec.Biol.215:403-410(19 This includes, but is not limited to, 90)). The BLAST X program is operated by NCBI and Other sources (BLAST Manual, Altschul, S., et al., NC) BINLM NIH Bethesda,Md.20894:Altschul,S., Officially published from et al., J.Mol.Biol.215:403-410(1990) It is available. The well-known Smith-Waterman algorithm also determines identity. It can be used for that purpose.

[0109] Exemplary arrangements of heavy and light chain variable regions, and their portions, are shown in the above sequence number. The antibody of the present invention, or its identified variant, is derived from any number of adjacent antibodies of the present invention. It may contain no acid residues, and the number of these residues depends on whether it is anti-IL-12 / IL-23p40 or IL-23 The antibody is selected from an integer group consisting of 10-100% of the number of adjacent residues. (Arbitrary selection) In this subsequence of adjacent amino acids, there are at least approximately 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170 , amino acid lengths of 180, 190, 200, 210, 220, 230, 240, 250 or more , or any range or value within them. Furthermore, the number of such subsequences is at least 2 It could be any integer selected from the group consisting of 1 to 20, such as 3, 4, or 5.

[0110] As will be apparent to those skilled in the art, the present invention includes at least one biologically active antibody of the present invention. It contains. Bioactive antibodies are natural (non-synthetic), endogenous, or related, and known Of the antibody, at least 20%, 30%, or 40%, preferably at least 50%, 60%, or 70%, most preferably at least 80%, 90%, or 95%-100% It has a specific activity of the above (but is not limited to, up to 10 times the specific activity). Enzyme activity and group Methods for assaying and quantitatively measuring qualitative specificity are well known to those skilled in the art.

[0111] In another aspect, the present invention is modified by covalent bonding of organic parts as described herein. This relates to human antibodies and antigen-binding fragments. Such modifications result in improved pharmacokinetic properties. (For example, an antibody or antigen-binding fragment with an increased in vivo serum half-life) It can be produced. The organic part consists of linear or branched hydrophilic polymer groups, fatty acid groups, or This can be a fatty acid ester group. In certain embodiments, the hydrophilic polymer group is about It may have a molecular weight of 800 to approximately 120,000 daltons, and is a polyalkane glycol (for example) Polyethylene glycol (PEG), polypropylene glycol (PPG), carbohydrate It may be a polymer, amino acid polymer, or polyvinylpyrrolidone, and may have a fatty acid group or fatty acid An ester group can contain approximately 8 to 40 carbon atoms.

[0112] Modified antibodies and antigen-binding fragments are covalently bound to the antibody, either directly or indirectly. It may contain one or more organic moieties. It is bound to the antibody or antigen-binding fragment of the present invention. Each organic part is independently a hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. Obtain. As used herein, the term "fatty acid" refers to monocarboxylic acids and dicarbic acid. Contains octane acid. When used herein, the term "hydrophilic polymer group" means octane acid. It also refers to organic polymers with high solubility in water. For example, polylysine is an octane polymer. It has higher solubility in water than [another antibody]. Therefore, antibodies modified by covalent bonding of polylysine are , encompassed in the present invention. Suitable hydrophilic polymers for modifying the antibodies of the present invention are linear or fractional. They can be branched, for example, polyalkane glycols (e.g., PEG, monomethoxy-poly Ethylene glycol (mPEG), PPG, etc.), carbohydrates (e.g., dextran, ce Coulose, oligosaccharides, polysaccharides, etc., hydrophilic amino acid polymers (e.g., polylysine, poly Real ginine, polyaspartic acid, etc.), polyalkane oxides (e.g., polyethylene It contains (such as polypropylene oxide and polyvinylpyrrolidone). Furthermore, the hydrophilic polymer that modifies the antibody of the present invention is expressed as individual molecules in a quantity of approximately 800 to approximately 1 It has a molecular weight of 50,000 daltons. For example, PEG5000 and PEG2000. The value 0 can be used. The subscript represents the average molecular weight (in Daltons) of the polymer. The hydrophilic polymer group is substituted with 1 to approximately 6 alkyl groups, fatty acid groups, or fatty acid ester groups. Hydrophilic polymers substituted with fatty acids or fatty acid ester groups are preferred. It can be prepared by utilizing the method. For example, a polymer containing an amine group, It can be linked to a carboxylate salt of a fatty acid or fatty acid ester, and fatty acid or fatty acid Activated carboxylate salts on ster (e.g., activated with N,N-carbonyldiimidazole) The (which is present) can be linked to the hydroxyl group on the polymer.

[0113] 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 for modifying the antibody of the present invention. Examples of fatty acids include n-dodecanoic acid (C12, lauric acid) and n-tetradecanoic acid. (C14, myristic acid), n-octadecanoic acid (C18, stearic acid), n-eiko sanic acid (C20, arachidic acid), n-docosanoic acid (C22, behenic acid), n-triacin tanoic acid (C30), n-tetracontanoic acid (C40), cis-Δ9-octadecanoic acid ( C18, oleic acid), all cis-Δ5,8,11,14-eicosatetraenoic acid (C18, oleic acid), all cis-Δ5,8,11,14-eicosatetraenoic acid (C18, oleic acid), C18,oleic acid (C18, oleic acid 20. Arachidonic acid, octanedionic acid, tetradecanedionic acid, octadecanedione Examples include acids and docosanedionic acid. Preferred fatty acid esters are linear or branched low-chain fatty acids. It contains monoesters of dicarboxylic acids, including lower alkyl groups. The lower alkyl groups are 1 to approximately 1 It may contain 2, preferably 1 to about 6, carbon atoms.

[0114] Modified human antibodies and antigen-binding fragments are preferably reacted with one or more modifying agents. It can be prepared using the following methods. When used herein, the term "modifier" is used. The term refers to a suitable organic group containing an activating group (e.g., hydrophilic polymers, fatty acids, fatty acid esters). This refers to a "activating group." An "activating group" is a group that reacts with a second chemical group under appropriate conditions and thereby modifies the chemical group. A chemical moiety or functional group that can form a covalent bond between the agent and the second chemical group. For example, amine-reactive activating groups include tosylic acid, mesylic acid, halo(chloro, bromo) Electrophilic groups such as fluorocarbons and iodine, N-hydroxysuccinimidyl esters (N-hydr Examples include oxysuccinimidyl esters (NHS). These are activated groups that can react with thiols. For example, maleimide, iodoacetyl, acryloryl, pyridyl disulfide, Examples include 5-thiol-2-nitrobenzoic acid thiol (TNB-thiol). The aldehyde functional group can be linked to amine- or hydrazide-containing molecules, and The zide group reacts with the trivalent phosphorus group to form a phosphoramidate or phosphorimide bond. This is possible. A suitable method for introducing an active group into a molecule has been established in the art. Knowledge (for example, Hermanson, GT, Bioconjugate Tec hniques, Academic Press: San Diego, CA (1996 (See reference). The activating group is attached to an organic group (e.g., hydrophilic polymers, fatty acids, fatty acid esters). Directly, or in the linker portion (e.g., divalent C1-C12 groups, where one or more carbon atoms) The child can be bonded via (substitution of heteroatoms such as oxygen, nitrogen, or sulfur). Suitable linker components 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 including the linker portion. The agent is, for example, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC In the presence of ( ), mono-Boc-alkyldiamine (e.g., mono-Boc-ethylenediamine) A amine (mono-Boc-diaminohexane) is reacted with a fatty acid to produce a free amine and fatty acid carboxylate. It can be produced by forming an amide bond with a boxylate. Boc protection The group is removed from the product by treatment with trifluoroacetic acid (TFA). As described, it is possible to expose a primary amine that can be linked to another carboxylate salt. Alternatively, reacting this with maleic anhydride and cyclizing the resulting product activates the fatty acid. Maleimide derivatives can be produced. (For example, International Publication No. 92 / 16221) See Thompson et al., by which reference the entirety of this instruction is incorporated herein. (to be able to).

[0115] Modified antibodies are produced by reacting human antibodies or antigen-binding fragments with a modifying agent. It can be produced in this way. For example, the organic part is an amine-reactive modifier, such as PEG. By utilizing NHS esters, it is possible to bind antibodies in a non-site-specific manner. Yes, it is possible. Disulfide bonds of antibodies or antigen-binding fragments (e.g., intrachain disulfide) By reducing the binding, modified human antibodies or antigen-binding fragments are prepared. It is also possible to do this. At this time, the reduced antibody or antigen-binding fragment is thiol-reactive. It is possible to produce the modified antibody of the present invention by reacting it with a modifying agent. Modified human antibodies and antigen-binding fragments containing organic parts that bind to specific parts of the body. The reverse proteolysis, etc. (Fisch et al., Bioconjugate) Chem.,3:147-153(1992), Werlenet al.,Bioco njugate Chem.,5:411-417(1994), Kumaran et al. al.,Protein Sci.6(10):2233-2241 (1997); Itoh et al.,Bioorg.Chem.,24(1):59-68(199 6), Capellas et al.,Biotechnol.Bioeng.,56 Appropriate methods of (4):456-463(1997)), and Hermanson, GT. .,Bioconjugate Techniques,Academic Press It can be prepared using the method described in San Diego, CA (1996). Cut.

[0116] The methods of the present invention are also described herein and / or known in the art. Thus, at least one, provided in the form of a non-naturally occurring composition, mixture, or other form. Two, at least three, at least four, at least five, at least six or more of its resistance Anti-IL-12 / IL-23p40 or IL-23 antibody A 40 or IL-23 antibody composition may also be used. Such a composition may contain the adjacent amino acids of the above sequence number. 70-100% of the acid, or its identified fragments, domains, or variants The amino acid composition of an anti-IL-12 / IL-23p40 or IL-23 antibody selected from the group. At least one or two full-length, C and / or N-terminal deletion variants of a column, domain The composition includes non-naturally occurring compositions containing fragments or identified variants. Preferred anti-IL -12 / IL-23p40 or IL-23 antibody composition, for example, 70~ of the above SEQ ID NO: 100% of the anti-IL-12 / IL-23p40 or IL-23 antibody described herein. At least one of the sequence, or an identified fragment, domain, or variant thereof. The CDR or LBP containing portion of the CDR or LBP contains at least one or two full-length fragments, Includes domains or variants. More preferred compositions include, for example, 70 such as the above sequence number. ~100%, or a small percentage of the identified fragment, domain, or variant. It contains at least one of the following in an amount of 40-99%. The percentage of such composition is known in the art. As is or as described herein, weight, volume, concentration, molar concentration, or Liquid or dry solution, mixture, suspension, emulsion, particles, powder, Alternatively, it depends on the molar concentration as a colloid.

[0117] Antibody composition containing further therapeutic active ingredients The antibody composition used in the method of the present invention optionally contains an anti-infective agent, a cardiovascular agent, etc. Vascular (CV) system agonists, central nervous system (CNS) drugs, autonomic nervous system Autonomic nervous system (ANS) drugs, respiratory drugs, gastrointestinal drugs (G) I) Vascular agents, hormone agents, fluid or electrolyte balance agents, hematological agents, antitumor agents, immunomodulatory agents , selected from at least one of the following: eye, ear or nose medications, topical medications, nutritional supplements, etc. The drug may further contain an effective amount of at least one compound or protein. This includes the respective formulations, indications, dosages, and administrations shown herein, as well as the technical aspects of the technology. It is well known in the field (for example, Nursing 2001 Handbook of Drugs,21st edition,Springhouse Corp.,Sp ringhouse, PA, 2001, Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang ,Prentice-Hall,Inc,Upper Saddle River,NJ ,Pharmcotherapy Handbook,Wells et al.,Ap. Please refer to Pleton & Lange, Stamford, CT, and each of them is referenced accordingly. (This is incorporated herein.)

[0118] Examples of drugs that can be combined with the antibody of the present invention include anti-infective drugs, such as anti-cancer agents. - A drug or at least one antiparasitic drug, anthelmintic drug, antifungal drug, antimalarial drug, antituberculosis drug or At least one antifungal drug, aminoglycoside, penicillin, cephalosporin, tetra Lacycline, sulfonamides, fluoroquinolones, antiviral drugs, macrolide antiinfectives It may be a drug, and at least one selected from various anti-infective drugs. Hormone drugs are corticosteroids. Thycosteroids, androgens, or at least one anabolic steroid, est Rogen, or at least one progestin, gonadotropin, antidiabetic drug, or less Both include one type of glucagon, thyroid hormones, thyroid hormone antagonists, pituitary hormones, and It may be at least one selected from parathyroid-like drugs. Phosphorus is found in cefaclor, cefadroxyl, cefazolin sodium, cefdinir, and hydrochloride. Cefepime, cefixime, cefmetazole sodium, cefonisid sodium, cef Operazone sodium, cefotaxime sodium, cefotetan disodium, cefo Sodium xytin, cefpodoxime proxetil, cefprodil, ceftazidime, cef Tibuten, ceftizoxime sodium, ceftriaxone sodium, cefuroxime axine Cetyl, cefuroxime sodium, cephalexin hydrochloride, cephalexin monohydrate, cef It may be at least one selected from radin and lorakalbev.

[0119] At least one type of corticosteroid, betamethasone, betamethasone acetate Methasone or betamethasone sodium phosphate, betamethasone sodium phosphate, col acetate Thizone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, acetate Fludrocortisone, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate Dizone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, Me Chilprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate Um, prednisolone, prednisolone acetate, prednisolone sodium phosphate, tebut Prednisolone acid, prednisone, triamcinolone, triamcinolone acetonide, and It may be at least one selected from triamcinolone diacetate. Androgens or anabolic steroids include danazol, fluoxymesterone, and melanin. Chiltestosterone, Nandrolone decanoate, Nandrolone fenpropionate, Test Testosterone, testosterone cypionic acid, testosterone enanthate, testosterone propionic acid It may be at least one selected from sterone and the testosterone transdermal system.

[0120] At least one immunosuppressant is azathioprine, basiliximab, cyclosporine, Daclizumab, lymphocyte immunoglobulin, muromonab-CD3, mycophenolate mophe Chil, mycophenolate mofetil hydrochloride, sirolimus, 6-mercaptopurine, methotrexate It may be at least one selected from xant, mizoribine, and tacrolimus.

[0121] At least one topical anti-infective agent is acyclovir, amphotericin B, or azelaic acid. Ream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole Econazole nitrate, erythromycin, gentamicin sulfate, ketoconazole, acetate Mafenide, metronidazole (topical), miconazole nitrate, mupirocin, naphthifol hydrochloride Neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, tetrahydrochloride Rubinafine, terconazole, tetracycline hydrochloride, thioconazole, and tolnaf It may be at least one selected from tate. At least one scabies insecticide or scabies insecticide. Lami drugs are selected from a small number of crotamiton, lindane, permethrin, and pyrethrin. It can be at least one type. At least one type of topical corticosteroid is dipropionate vesicle Tametasone, betamethasone valerate, clobetasol propionate, desonide, desoxi Metazone, dexamethasone, dexamethasone sodium phosphate, diflorazone diacetate, f Luocinolone acetonide, fluocinonide, flurandrenolide, flutica propionate Hydrocortisone, halcionide, hydrocortisone acetate, hydrocortisone butyrate Hydrocortisone, hydrocortisone valerate, mometasone fluate, and triamcinolone It may be at least one selected from cetonides. (e.g., Nursing 200) (Please refer to pages 1098-1136 of the Drug Handbook.)

[0122] Anti-IL-12 / IL-23p40 or IL-23 antibody compositions are used for such adjustments, treatments, and This refers to a small amount of cells, tissues, organs, animals, or subjects that are in contact with or administered to cells, tissues, organs, animals, or subjects that require treatment. It contains at least one anti-IL-12 / 23p40 or IL-23 antibody, and optionally, a small amount. At least one TNF antagonist (for example, but not limited to, TNF chemical or protein) Antagonists, TNF monoclonal or polyclonal antibodies or fragments, soluble T NF receptors (e.g., p55, p70, or p85) or fragments thereof, and their fusion polyps Butide, or small molecule TNF antagonist, for example, TNF-binding protein I or II (TB) P-1 or TBP-II), nerelimonmab, infliximab, eta Nacept (eternacept), CDP-571, CDP-870, afelimomab, renerce (e.g., ptometra), anti-rheumatic drugs (e.g., methotrexate, auranofin, aurothiogone) Lucose, azathioprine, etanercept, sodium aurothiomalate, hydroxychloro Roroquin sulfate, leflunomide, sulfasalazine), immunization, immunoglobulin, immunosuppression Antidotes (e.g., azathioprine, basiliximab, cyclosporine, daclizumab), Any preferred further comprising at least one selected from itokines or cytokine antagonists. It may further contain at least one of the compositions or pharmaceutical compositions in an appropriate and effective amount. Non-restrictive examples of such cytokines include IL-1 to IL-23 (for example, I Examples include, but are not limited to, L-1, IL-2, etc. Suitable dosage This is well known in the relevant technical field. For example, Wells et al., eds. Pharmacotherapy Handbook,2nd Edition,App leton and Lange, Stamford, CT (2000), PDR Ph. armacopoeia, Tarascon Pocket Pharmacopoei a 2000, Deluxe Edition, Tarascon Publishing See g, Loma Linda, CA (2000), each of which is a reference. The whole is incorporated herein by reference.

[0123] Anti-IL-12 / IL-23p40 or IL-23 antibody compounds used in the method of the present invention The composition or mixture contains diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, Adjuvants, but not limited to these, include at least one of any suitable adjuvants. It may further contain one more. Pharmaceutically acceptable adjuvants are preferred. How to prepare such a sterile solution. The law and its non-limiting examples are well known in the art, for example, Gennaro, E. d.,Remington's Pharmaceutical Sciences,1 8th Edition,Mack Publishing Co.(Easton,P A) 1990 is an example, but is not limited to this. , or as described herein, anti-IL-12 / IL-23p40, fragment, Alternatively, a pharmaceutically acceptable carrier suitable for the administration method, solubility, and / or stability of the mutant composition. You can choose your body on a daily basis.

[0124] Useful pharmaceutical excipients and additives in this composition are not limited to those listed above, but include protein Proteins, peptides, amino acids, lipids and carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and Sugars containing oligosaccharides, algitol, aldonic acid, esterified sugars and other derivatives, It also contains polysaccharides or sugar polymers, which may exist individually or in combination. , present in 1 to 99.99% by weight or volume, either alone or in combination. Exemplary protein Excipients include serum albumin such as human serum albumin (HSA). Min, recombinant human albumin (rHA), gelatin, cold Examples include amino acids such as 1, 2, and 3. Representative amino acids / antibody components that can also function in buffering capacity. It contains alanine, glycine, arginine, betaine, histidine, glutamic acid, and asparagus. Ginic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenyl Examples include alanine and aspartame. One preferred amino acid is glycine. .

[0125] Suitable carbohydrate excipients for use in the present invention include, for example, fructose and maltose. Monosaccharides such as sucrose, galactose, glucose, D-mannose, and sorbose, lactose Disaccharides such as sucrose, trehalose, cellobiose, raffinose, merezito Polysaccharides such as maltodextrin, dextran, and starch, as well as mannitol, ki Silitol, maltitol, lactitol, xylitol, sorbitol (glucitol) Examples include algitols such as myo-inositol. Preferred carbon for use in the present invention The aqueous excipients are mannitol, trehalose, and raffinose.

[0126] Anti-IL-12 / IL-23p40 or IL-23 antibody composition, buffer or pH adjuster It may also include, and typically, the buffer is a salt prepared from an organic acid or base. The amphetamines include citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, and acetic acid. , or organic acid salts such as phthalic acid salts, Tris, tromethamine hydrochloride, or phosphate buffers For example, a preferred buffering agent for use in this composition is an organic salt such as citric acid. .

[0127] In addition, anti-IL-12 / IL-23p40 or IL-23 antibody composition, polyvinyl acetate Loridone, Ficol (polymer sugar), Dextrate (e.g., 2-hydroxypropyl Cyclodextrins such as β-cyclodextrin, polyethylene glycol, Fragrances, antibacterial agents, sweeteners, antioxidants, antistatic agents, surfactants (for example, "TWEEN20 Polysorbates such as "TWEEN80" and lipids (e.g., phospholipids, fatty acids) , steroids (e.g., cholesterol), and chelating agents (e.g., EDTA), etc. May contain polymer excipients / additives.

[0128] Anti-IL-12 / IL-23p40 or IL-23 antibody, partial or mutant according to the present invention These and additional known pharmaceutically acceptable excipients and / or additives suitable for use in compositions are: This is known in the field of the art, for example, "Remington: The Science ce&Practice of Pharmacy”, 19th ed., Willia ms&Williams, (1995), and "Physician's Desk R eference”, 52nd ed., Medical Economics, Mont. These are listed in Vale, NJ (1998), and these disclosures are fully revealed by reference. It is incorporated into the details. Preferred carrier or excipient material is carbohydrates (e.g., monosaccharides and a Luditol) and a buffering agent (e.g., citric acid) or polymer agent. Exemplary carrier molecules These are mucopolysaccharides and hyaluronic acid, which may be useful for intra-articular delivery.

[0129] formulation As described above, the present invention preferably provides a phosphate buffer containing physiological saline or a selected salt. Stable formulations containing the agent, as well as preservative solutions and formulations containing the preservative, and pharmaceutically acceptable The formulation contains at least one anti-IL-12 / IL-23p40 or IL-23 antibody. The present invention provides a versatile preservative formulation suitable for various pharmaceutical or veterinary uses. The preservative formulation is aqueous dilution. The agent contains at least one known preservative, namely at least one phenol, m-c Resol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, Phenylmercury nitrate, phenoxyethanol, formaldehyde, chlorobutanol, chloride Magnesium (e.g., hexahydrate), alkylparabens (methyl, ethyl, propyl, b) (e.g., tyl), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and Contains a preservative optionally selected from the group consisting of thimerosal or mixtures thereof. It possesses. As is known in the art, 0.001 to 5%, or 0.001, 0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0. 09, 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 within those ranges This includes values, but is not limited to these; it includes any range or value within them, any preference. Appropriate concentrations or mixtures may be used. Non-limiting examples include no preservatives added, 0.1-2 %m-cresol (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 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% alkylparabens (for example, 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 Examples include 0.3%, 0.5%, 0.75%, 0.9%, and 1.0%.

[0130] As described above, the method of the present invention involves a packaging material and a saturating agent optionally formulated in an aqueous diluent. At least one anti-IL-12 / IL-23p40 or I having a buffer and / or preservative Using a product comprising at least one vial containing a solution of L-23 antibody, and the packaging material The solution is divided into 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, It must be able to be retained for a period of 40, 48, 54, 60, 66, or 72 hours or more. The present invention includes a label indicating the following. The present invention relates to a packaging material and freeze-dried anti-IL-12 / IL-23p A first vial containing 40 or IL-23 antibody, and an aqueous dilute of the prescribed buffer or preservative. The product further includes a second vial containing a release agent, and the packaging material is anti-IL-12 / I Reconstitute L-23p40 or IL-23 antibody with an aqueous diluent and store for 24 hours or more. Includes a label that instructs the subject to form a solution that can be held.

[0131] The anti-IL-12 / IL-23p40 or IL-23 antibody used in accordance with this invention is As described in the specification or known in the art, mammalian cells or trans It can be produced by recombinant means such as from genetic formulations, or purified from other biological sources. It is possible.

[0132] The range of anti-IL-12 / IL-23p40 or IL-23 antibodies is as follows, in the case of wet / dry systems: It is included in an amount that yields a concentration of approximately 1.0 μg / mL to approximately 1000 mg / mL when reconstituted. However, it can be used at both lower and higher concentrations, depending on the intended delivery vehicle. For example, in solution formulations, these can be administered via transdermal patch, lung, transmucosa, or osmotically or microponges. This is different from the method used.

[0133] Preferably, the aqueous diluent further optionally comprises a pharmaceutically acceptable preservative. Common preservatives include phenol, m-cresol, p-cresol, o-cresol, and chloroform. Locresol, benzyl alcohol, alkylparabens (methyl, ethyl, propyl, b) (e.g., tyl), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and This includes thimerosal or a mixture thereof, selected from the group. The concentration of the preservative used is sufficient to produce an antibacterial effect. Such a concentration is selected. This varies depending on the preservative used and can be easily determined by those skilled in the art.

[0134] Other excipients, such as isotonic agents, buffers, antioxidants, and preservative enhancers, are optional. It can be added to the diluent, preferably a known isotonic agent such as glycerin. It is commonly used at various concentrations. Preferably, a physiologically tolerable buffer is added for improved performance. It provides pH control. The formulation has a pH of approximately 4 to approximately 10, preferably approximately 5 to approximately 9. The range covers a wide pH range, most preferably a range of about 6.0 to about 8.0. This is possible. Preferably, the formulation of the present invention has a pH of about 6.8 to about 7.8. Suitable buffering agents include phosphate buffering agents, most preferably sodium phosphate, and especially phosphate buffering agents. It contains saline solution (phosphate-buffered saline, PBS).

[0135] Other additives, for example, Tween20 (polyoxyethylene (20) sorbitan monolauan). (Rate), Tween40 (Polyoxyethylene (20) Sorbitan Monopalmitate) Tween80 (polyoxyethylene (20) sorbitan monooleate), Plur onic F68 (polyoxyethylene polyoxypropylene block copolymer), and A pharmaceutically acceptable solubilizer such as PEG (polyethylene glycol), or polysorbate Rubate 20 or 80 or Poloxamer 184 or 188, Pluronic Nonionic surfactants such as (registered trademark) polyl, and other block copolymers Mer, as well as chelating agents such as EDTA and EGTA, optionally in a formulation or composition. These additives can be added to reduce aggregation. Particularly useful when pumps or plastic containers are used. Pharmacochemically acceptable. The presence of surfactants reduces the tendency for proteins to aggregate.

[0136] The formulation contains at least one anti-IL-12 / IL-23p40 or IL-23 antibody, and Enol, m-cresol, p-cresol, o-cresol, chlorocresol, ben Dioxide alcohol, alkylparabens (methyl, ethyl, propyl, butyl, etc.), methyl chloride Inzalkonium, benzethonium chloride, sodium dehydroacetate, and thimerosal or This includes mixing a preservative selected from the group consisting of these mixtures in an aqueous diluent. It can be prepared by the following process. At least one anti-IL-12 / IL-23p Mixing of 40 or IL-23 specific antibody with preservative in an aqueous diluent is conventional dissolution and mixing. This is carried out using a standard procedure. To prepare a suitable formulation, for example, a certain amount of buffer solution is used. A certain amount of at least one anti-IL-12 / IL-23p40 or IL-23 antibody, concentrated to the desired concentration. Combine the desired preservative with a buffer solution in a sufficient amount to provide the desired protein and preservative. To combine. Variations of this process will be recognized by those skilled in the art. For example, configuration The order of ingredient addition, whether or not additional additives are used, and the temperature and pH during preparation of the formulation are all specified for use. These are factors that can be optimized regarding the dosage concentration and means of administration.

[0137] The formulation may be in the form of a clear solution, or with water, a preservative and / or an excipient, preferably phosphoric acid. A second solution containing a salt buffer and / or physiological saline, and a selected salt in an aqueous diluent. Freeze-dried anti-IL-12 / IL-23p40 or IL-2 in vials. 3. Provided to the target group as a dual vial containing a vial of a specific antibody. Yes, it is possible. Single-solution vials or combination vials requiring reconstitution can both be reused multiple times. It can meet one or more target treatment cycles, and therefore, This allows us to provide more convenient treatment regimens than those currently available.

[0138] This product is useful for administration over a period ranging from immediate to 24 hours or more. The product claimed by this invention provides significant benefits to the target. The formulation of this invention is Selectively, safely store the protein at a temperature of approximately 2°C to 40°C to maintain its biological activity for extended periods. It can maintain its properties, and therefore the packaging label indicates that the solution is 6, 12, 18, 24, 3 Indicates that it can be stored and / or used for 6, 48, 72, or 96 hours or longer. This is possible. When using stored diluents, write up to 1 to 12 on such labels. This may include use for months, half a year, one and a half years, and / or up to two years.

[0139] A solution of anti-IL-12 / IL-23p40 or IL-23 specific antibody is required. The antibody can be prepared by a process that includes mixing the antibody in an aqueous diluent. This is carried out using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, For example, a certain amount of at least one antibody in water or a buffer, and a desired concentration of protein, Combine in amounts sufficient to optionally provide a preservative or buffer. The variations will be recognizable to those skilled in the art. For example, the order of adding the constituent components, addition The presence or absence of additives, the temperature and pH during preparation of the formulation, the dosage concentration used, and the administration method are all considered. This is a factor that can be optimized with respect to the stage.

[0140] The claimed product is a clear solution or a second vial containing an aqueous diluent. But it is returned, freeze-dried, at least one anti-IL-12 / IL-23p40 or I It can be provided to the target audience as a combination vial containing a vial of L-23-specific antibody. Single-solution vials or combination vials requiring reconstitution are both reused multiple times. It can meet one or more target treatment cycles, and therefore, currently used To provide a more convenient treatment regimen than what is currently available.

[0141] The claimed product is a clear solution, or a second vial containing an aqueous diluent. This involves freeze-dried anti-IL-12 / IL-23p40 or IL-2 3. Distribute the combination vial containing the specific antibody to a pharmacy, clinic, or other such institution and By providing it to a facility, it can be provided indirectly to the target. The light solution may be up to 1 liter or even more, and this large container or Take out a smaller amount of at least one antibody solution once or multiple times and put it into a smaller vial. It can be transferred and provided to customers and / or subjects by a pharmacy or clinic.

[0142] Recognized devices including a single vial system include those for delivering solutions. Pen-type injector devices, e.g., BD Pens, BD Autojector (Registered) (Registered Trademark), Humaject (Registered Trademark), NovoPen (Registered Trademark), BD (Registered Trademark) Trademarks) Pen, AutoPen (registered trademark), and OptiPen (registered trademark), Gen otropinPen (registered trademark), Genotronorm Pen (registered trademark), H umatro Pen (registered trademark), Reco-Pen (registered trademark), Roferon Pen (registered trademark), Biojector (registered trademark), Iject (registered trademark), J- tip Needle-Free Injector (registered trademark), Intraject (Registered Trademark), Medi-Ject (Registered Trademark), Smartject (Registered Trademark) (Example) For example, Becton Dickensen (Franklin Lakes, NJ, WW w.bectondickenson.com), Disetronic (Burgd orf, Switzerland, www.disetronic.com, Bioje ct,Portland,Oregon(www.bioject.com),Nati onal Medical Products,Weston Medical(Pet erborough, UK, www.weston-medical.com), Med i-Ject Corp (Minneapolis, MN, www.mediject. Examples of suitable devices include those manufactured or developed by (com), and similar devices. Recognized devices that include combined vial systems include HumatroPen( Lyophilized chemicals in cartridges for delivering dissolved solutions (such as registered trademarks) A pen-type syringe system for dissolving the substance is one example. Other suitable devices include Examples include pre-filled syringes, auto-injectors, needleless syringes, and needleless IV infusion kits. It can be done.

[0143] The product may include packaging materials. The packaging materials may contain information required by regulatory authorities, The present invention provides conditions under which the product can be used. The packaging material of the present invention, where applicable, is less Rehydrate one anti-IL-12 / IL-23p40 or IL-23 antibody with an aqueous diluent. Form a solution and leave it in two wet / dry conditions for a period of 2 to 24 hours or more. This product is intended for use with Al products. It is a single vial of solution product, pre-filled. For syringes or auto-injectors, the label indicates that the solution will be used for a period of 2 to 24 hours or more. This indicates that it can be used over a wide range of applications. The product is useful for human pharmaceutical product applications. .

[0144] The formulation used in the method of the present invention is an anti-IL-12 / IL-23p40 and selected stimulant. Mix in a buffering agent, preferably physiological saline or a phosphate buffering agent containing a selected salt. It can be prepared by a process that includes anti-IL-12 / IL-23p40 antibody and Mixing with the amphetamine in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare such a formulation, for example, a certain amount of at least one antibody in water or a buffer, Combine the desired buffer with a sufficient amount of water to provide the desired concentration of protein and buffer. To combine. Variations of this process will be recognized by those skilled in the art. For example, The order of addition of ingredients, whether or not additional additives are used, and the temperature and pH during preparation of the formulation are all subject to change. These are factors that can be optimized regarding the administered concentration and method of administration.

[0145] The method of the present invention provides a variety of formulations that are useful and acceptable for administration to human or animal subjects. A pharmaceutical composition is provided which contains water at "standard conditions" as a diluent, It is prepared using routine methods well known to those skilled in the art. For example, histidine and histidine Buffering components such as monohydrochloride hydrate are provided first, followed by an appropriate non-final volume of "standard" A water diluent, sucrose, and polysorbate 80 may be added to the "state". Then, isolation The antibodies can be added. Finally, use water as a diluent under the "standard conditions" rule. Under these conditions, the volume of the pharmaceutical composition is adjusted to the desired final volume. Those skilled in the art will know how to prepare the pharmaceutical composition. You will recognize several other methods that are suitable for this purpose.

[0146] The pharmaceutical composition contains each component in the indicated mass per unit volume of water, or "standard It may be an aqueous solution or suspension having the pH indicated by "state". When used in this specification, The term "standard conditions" refers to a temperature of 25°C ± 2°C and a pressure of 1 atmosphere. In the art, the term "state" refers to a single temperature or pressure as recognized by the art. It is not used to refer to a set, but instead refers to a specific composition under "standard conditions". This is a reference state that specifies the temperature and pressure used to describe a solution or suspension. This is because the volume of the solution is partly a function of temperature and pressure. Those skilled in the art will see this specification. It is recognized that pharmaceutical compositions equivalent to those disclosed can be manufactured at other temperatures and pressures. It is likely that such pharmaceutical compositions are equivalent to those disclosed herein, as defined above. It should be determined under the specified "standard conditions" (e.g., 25°C ± 2°C and 1 atmosphere of pressure). That is the case.

[0147] Importantly, such pharmaceutical compositions contain "approximately" a certain value per unit volume of the pharmaceutical composition. It contains the constituent mass of (for example, "approximately 0.53 mg of L-histidine") or approximately It may have a pH value of a certain value. The mass or pH value of the constituent elements present in the pharmaceutical composition is The isolated antibody is present in the pharmaceutical composition, or the isolated antibody is removed from the pharmaceutical composition. After being diluted (for example, by dilution), the isolated antibody present in the pharmaceutical composition becomes a peptide chain. It is "approximately" a given number when it can be combined with the mass value of the constituent elements. The pH value and other values ​​are determined after the isolated antibody is added to the pharmaceutical composition. This is an approximate value given when the combined activity is maintained and detectable.

[0148] Competitive binding analysis was performed to determine whether IL-12 / IL-23p40 or IL-23-specific mAbs were found to be effective. Determine whether they bind to similar or different epitopes and / or compete with each other. Individual mAbs are coated onto a LISA plate. Competing mAbs are added, followed by... Biotinylated hrIL-12 or IL-23 is added. For a positive control, the same coating is used. The mAb can be used as a competing mAb ("self-competitive"). IL-12 / IL-23p 40 or IL-23 binding is detected using streptavidin. These results , mAb is similar or partially overlapping on IL-12 / IL-23p40 or IL-23 This indicates whether or not the epitope is recognized.

[0149] In one embodiment of the pharmaceutical composition, the isolated antibody concentration is approximately 7 per 1 mL of the pharmaceutical composition. The amount is approximately 7 to 104 mg. In another embodiment of the pharmaceutical composition, the pH is approximately 5.5 to 6.5. be.

[0150] Stabilized or preservative formulations are available as clear solutions or in aqueous diluents containing preservatives or buffers. A lyophilized at least one anti-I compound is returned in a second vial containing an excipient. To be provided to the target audience as a combination vial containing L-12 / IL-23p40 vials. This is possible. Single-solution vials or combination vials requiring reconstitution can both be reconstituted multiple times. It can be used and can satisfy one or more target treatment cycles, therefore This provides a more convenient treatment regimen than those currently available.

[0151] Other formulations or methods for stabilizing anti-IL-12 / IL-23p40 include frozen antibodies. This may result in something other than a clear solution of the dried powder. For example, a non-transparent solution may be obtained from finely spun powder. Some formulations contain turbidity, and such fine particles are microspheres, fine particles, nanoparticles, and Within structures of various sizes, known by various names such as nospheres or liposomes, anti-IL-1 This is a composition containing the 2 / IL-23p40 antibody. A high-quality, essentially spherical particulate formulation is as taught in U.S. Patent No. 4,589,330. The aqueous phase containing the active agent and polymer is brought into contact with the non-aqueous phase, and then the non-aqueous phase is evaporated. These can be formed by causing the accretion of particles from the aqueous phase. Porous microparticles This is an active compound dispersed in a continuous solvent, as taught in U.S. Patent No. 4,818,542. The first phase, containing the drug and polymer, is used for suspension by lyophilization or dilution-extraction-precipitation. This can be prepared by removing the solvent from the liquid. A polymer preferred for this preparation is - contains gelatin agar, starch, arabinogalactan, albumin, collagen, polyglycerides Licolic acid, polylactic acid, glycolide-L(-)lactide poly(epsilon-caprolact) N, poly(epsilon-caprolactone-CO-lactic acid), poly(epsilon-caprolactone) (Ton-CO-glycolic acid), poly(β-hydroxybutyric acid), polyethylene oxide, PO Polyethylene, poly(alkyl-2-cyanoacrylate), poly(hydroxyethylmeth acrylate), polyamide, poly(amino acid), poly(2-hydroxyethyl DL-asphalt) (palmamide), poly(ester urea), poly(L-phenylalanine / ethylene glyco) A group consisting of 1,6-diisocyanatohexane and poly(methyl methacrylate). A natural or synthetic copolymer or polymer selected from the following. Particularly preferred polymer This includes polyglycolic acid, polylactic acid, glycolydo-L(-)lactide poly(epsilon-ca Prolactone), poly(epsilon-caprolactone-CO-lactic acid), and poly(epsilon-caprolactone-CO-lactic acid), Polyesters such as lon-caprolactone-CO-glycolic acid. Polymers and / or, useful solvents for dissolving the active substance include water, hexafluoroisopropanol ethanol, methylene chloride, tetrahydrofuran, hexane, benzene, or hexafluorocarbon Seton sesquihydrate is one example. The process of dispersing the active substance-containing phase into the second phase is as follows: The first phase described above is forced through the orifice inside the sulphur by pressure to induce droplet formation. It can include.

[0152] The dried powder formulation can be obtained, for example, by spray drying, solvent extraction by evaporation, or aqueous solution. Or dissolution by precipitation of the crystalline composition, followed by one or more steps to remove the non-aqueous solvent. Spray-dried antibodies can be obtained as a result of processes other than freeze-drying, such as fluid extraction. Preparation of the formulation is taught in U.S. Patent No. 6,019,968. Antibody-based dry powder The final composition provides an antibody solution or slurry, and optionally, a respiration-free dry powder. It can be produced by spray-drying the excipient in a solvent under the specified conditions. Examples of easily driesable polar compounds include water and ethanol. Stability is ensured by performing the spray drying procedure in the absence of oxygen, for example, under a nitrogen blanket. Alternatively, it can be enhanced by using nitrogen as a drying gas. The dried formulation is typically hydro, as taught in International Publication No. 9916419. A dispersion of multiple porous microstructures dispersed in a suspension medium containing a fluoroalkane propellant. The stabilized dispersion can be administered to the target lungs using a metered-dose inhaler. Equipment useful in the commercial manufacture of dried drugs is available from Buchi Ltd. or Niro Manufactured by Corp.

[0153] Any of the stable or preserved formulations or solutions described herein that contain anti-IL-12 / IL -23p40 can be administered via SC or IM injection, percutaneous, transpulmonary, transmucosal, implantation, or osmotic pump. , cartridges, micropumps, or are well known in the art and can be handled by those skilled in the art The present invention can be administered to the subject via various delivery methods, such as other means that can be interpreted. Cut.

[0154] therapeutic application The present invention also includes at least one known in the art or as described herein. Using one of the IL-23 antibodies of the present invention, for example, cells, tissues, organs, animals, or subjects, A therapeutically effective dose of IL-12 / IL-23p40 or IL-23 specific antibody is administered or applied. To regulate or treat ulcerative colitis in cells, tissues, organs, animals, or subjects. It also provides a method for this.

[0155] Any method of the present invention relates to cells, tissues, etc. that require such regulation, treatment, or therapy. A composition or pharmaceutical composition containing IL-12 / IL-23p40 is administered to an organ, animal, or subject. This may include administering an effective dose. Such methods may be optional for such diseases or illnesses. This may further include concurrent administration or combination therapy for the treatment of the patient, wherein at least Administering a single IL-12 / IL-23p40, a specific part, or a variant thereof is less likely to be effective. at least one TNF antagonist (e.g., but not limited to the following, chemical or protein-based) TNF antagonists, TNF monoclonal or polyclonal antibodies or flag Menthol, soluble TNF receptors (e.g., p55, p70, or p85) or fragments T, its fusion polypeptide, or a small molecule TNF antagonist, for example, TNF-binding protein I Or II (TBP-1 or TBP-II), nererimonmab, infliximab, etane Lucept (Enbrel®), Adalimumab (Humira®), CDP- 571, CDP-870, afelimomab, renercept, etc.), antirheumatic drugs (for example) Methotrexate, auranofin, aurothioglucose, azathiopurine, gold thio Sodium malate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), Muscle relaxants, narcotics, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., 5-aminosalicylates) (e.g., amino acids), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blocking agents, antibacterial agents (e.g., amino acids) Glycosides, antifungal drugs, antiparasitic drugs, antiviral drugs, carbapenams, cephalosporins, Fluoroquinolones, macrolides, penicillins, sulfonamides, tetracyclines, etc. Antibiotics, psoriasis medications, corticosteroids, anabolic steroids, diabetes-related medications Minerals, nutritional supplements, thyroid medications, vitamins, calcium-related hormones, antidiarrheals, cough suppressants, Antiemetics, antitumor drugs, laxatives, anticoagulants, erythropoietin (e.g., epoetin alfa) ), filgrastim (e.g., G-CSF, Neupogen), salgramostim ( GM-CSF, Leukine), immunoconjugates, immunoglobulins, immunosuppressants (for example, Basiliximab, cyclosporine, daclizumab, growth hormone, hormone replacement therapy, etc. Strogen receptor modulators, mydriatics, ciliary muscle paralyzers, alkylating agents, antimetabolites, mitotic inhibitors Harmful drugs, radiopharmaceuticals, antidepressants, antimanic drugs, antipsychotics, anxiolytics, sleeping pills, sympathetic nerve stimulants Drugs, stimulants, donepezil, tacrine, asthma medications, beta-agonists, inhaled steroids, Leukotriene inhibitors, methylxanthines, cromolyn, epinephrine or its analogues, Select from dorneza alfa (Pulmozyme), cytokines, or cytokine antagonists. The further part includes administering at least one of the following before, simultaneously, and / or after. Appropriate dosages are well known in the art. For example, Wells et al. eds.,Pharmacotherapy Handbook,2nd Editorial n, Appleton and Lange, Stamford, CT (2000), P DR Pharmacopoeia, Tarascon Pocket Pharmac opoeia 2000,Deluxe Edition,Tarascon Publ nursing, Loma Linda, CA (2000), Nursing 2001 Handbook of Drugs,21st edition,Springhou se Corp., Springhouse, PA, 2001, Health Prof. essional's Drug Guide 2001, ed., Shannon, W. ilson,Stang,Prentice-Hall,Inc,Upper Sadd Please refer to le River, NJ, and each of these references is referenced to the whole. This specification is incorporated herein.

[0156] Treatment The treatment of ulcerative colitis involves administering an effective amount or dose of an anti-IL-12 / 23p40 composition. It is affected by administering it to those who need it. The amount administered depends on the specific drug. The pharmacodynamic characteristics of the drug, its method and route of administration, the recipient's age, health condition, and weight. Known factors such as the nature and severity of symptoms, the type of simultaneous treatment, the frequency of treatment, and the desired effect. This may vary. In some cases, repeated administration may be necessary to reach the desired therapeutic dose, i.e. When it is necessary to provide repeated individual doses of a specific monitored or measured amount. In this case, individual doses are repeated until the desired daily dose or effect is achieved. ru.

[0157] To provide safe and effective treatment for severely active ulcerative colitis to those who need it. One example regimen involves a total dose of approximately 130 mg of anti-IL-12 / IL-23p40 antibody. The dosage is administered intravenously to the subject with each administration. For example, the total amount of the composition administered is per administration. 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg The target dose of antibody is administered in the following amounts: g, 150 mg, 160 mg, 170 mg, or 180 mg. It is appropriately adjusted to be served to elephants.

[0158] To provide safe and effective treatment for severely active ulcerative colitis to those who need it. One exemplary regimen involves approximately 6.0 ± 1.5 mg / kg of anti-IL-12 / IL-23p. The total dose of 40 antibodies is administered intravenously to the subject with each dose. For example, the composition to be administered The total doses per administration are 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, and 4.5 mg / kg. g / kg, 5.0mg / kg, 5.5mg / kg, 6.0mg / kg, 6.5mg / kg 7.0 mg / kg, 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, or 9 The antibody is administered appropriately at a dose of 0.0 mg / kg of body weight per subject, targeting the desired dosage. It will be adjusted.

[0159] The total dose of anti-IL-12 / IL-23p40 antibody administered to a target per dose is approximately Over a period of 30 to 180 minutes, preferably 60 to 120 minutes, for example, 30 minutes, 6 It can be administered by intravenous infusion at 0, 90, 120, 150, or 180 minutes. can.

[0160] To provide safe and effective treatment for severely active UC to those who need it. In this example regimen, the total dose of anti-IL-12 / IL-23p40 antibody is approximately 90 mg. However, it is administered subcutaneously to the target each time a dose is given. For example, the total amount of the composition administered per dose is 4 0mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg The product is offered in doses of 120 mg, 130 mg, or 140 mg, targeting the desired antibody dosage. It is appropriately adjusted so as to be. The target dose per administration is a single subcutaneous injection or multiple injections. It can be administered by subcutaneous injection, for example, by 1, 2, 3, 4, 5 or more subcutaneous injections. Cut.

[0161] The total dose of anti-IL-12 / IL-23p40 antibody is once daily, once weekly, for one month. Once a week, once every six months, or every day, every week, every month, every six months, every year, every two years. It can be administered over a period of time longer than that. Multiple administrations of anti-IL-12 / IL-23p40 antibody in dosed amounts are appropriate for those who require it. It can be administered to [the patient].

[0162] A dosage form (composition) suitable for internal administration is generally about 0.001 mg per unit or container. Each gram contains approximately 500 milligrams of active ingredients.

[0163] For parenteral administration, the antibody is administered either together with or separately from a pharmaceutically acceptable parenteral vehicle. Provided as a solution, suspension, emulsion, particles, powder, or lyophilized powder, It can be formulated into a drug. Examples of such vehicles include water, physiological saline, Ringer's solution, and dextrose. The solution is 1-10% human serum albumin. It is a non-aqueous solution such as liposomes and non-volatile oils. A suitable vehicle can also be used. The vehicle or freeze-dried powder is isotonic and chemically stable. Additives that maintain properties (for example, sodium chloride, mannitol, chemical ammonium compounds for isotonicity) Qualitatively, it may contain buffering agents and preservatives. The formulation may contain known or preferred ingredients. It is sterilized by technology.

[0164] Suitable pharmaceutical carriers are described in Remington's, a standard reference text in this field. This information is included in the latest edition of Pharmaceutical Sciences, by A. Osol. It is being done.

[0165] In order to administer a pharmaceutically effective amount of IL-12 / IL-23p40 antibody, according to the present invention Therefore, many known and developed methods can be used. IL-12 / IL-23p40 or IL-23 antibody is used in a carrier, solution, emulsion, colloid, or Dispensing may be done by inhalation or by means of a suspension or dry powder, or by the method described herein. Alternatively, various devices suitable for administration by other methods known in the relevant art, and It can be delivered using either of the following methods.

[0166] Parenteral formulations typically use sterile water or physiological saline, polyethylene glycol as excipients. Even if it contains polyalkylene glycols such as kohl, vegetable oils, naphthalene hydrogenates, etc. Good. Aqueous or oily suspensions for injection may be prepared according to known methods, with appropriate emulsifiers or humectants and It can be prepared by using a suspension. For example, the injectable solution can be an aqueous solution or a sterile injection solution. Alternatively, a non-toxic, parenterally administered diluent such as a suspension in a solvent may be used. Suitable solvents include water, Ringer's solution, and isotonic saline. As the medium or suspension solvent, a sterile, non-volatile oil can be used. , natural, synthetic or semi-synthetic, fatty oils or fatty acids, natural, synthetic or semi-synthetic, Non-volatile oils of any kind, including monoglycerides, diglycerides, or triglycerides. And fatty acids can be used. Parenteral administration is known in the art, and Conventional injection methods include gas-pressurized needleless injection methods, such as those described in U.S. Patent No. 5,851,198. Injection devices, and laser perforation as described in U.S. Patent No. 5,839,446. Examples of such devices include, but are not limited to, those which are referred to herein in their entirety by reference. It will be incorporated into it.

[0167] alternative delivery This invention relates to parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intra-bronchial, intra-abdominal, intracapsular, intra-cartilage, Intrasinus, intracavitary, cerebellar, ventricle, colon, cervical canal, stomach, liver, myocardium, bone, pelvis, heart Intramembranous, intraperitoneal, intrapleural, intraprostate, intrapulmonary, intrarectal, intraneural, intraretinal, intraspinal cord, intrasynovial bursa, Intrathoracic cavity, intrauterine cavity, intrabladder, intralesional lesion, bolus, intravaginal cavity, rectum, oral cavity, sublingual cavity, intranasal cavity, or Further information regarding the administration of anti-IL-12 / IL-23p40 or IL-23 antibodies via transdermal means. Anti-IL-12 / IL-23p40 or IL-23 antibody composition, parenteral (subcutaneous, intramuscular) , or intravenously) or any other administration, in particular when used in the form of a liquid solution or suspension. In particular, semi-solid forms such as creams and suppositories, but not limited to these, for use in the vagina or For use in rectal administration, the form may be tablets or capsules, but is not limited to these. In a form that is not used for oral or sublingual administration, or as a powder, nasal spray, or aerosol. , or in the form of certain drugs, but not limited to these, administered into the nasal cavity or on the skin To either modify the skin structure or increase the drug concentration in the transdermal patch, Using chemical accelerators such as dimethyl sulfoxide (Junginger, et al.) In “Drug Permeation Enhancement”;Hsieh,D .S.,Eds.,pp.59-90(Marcel Dekker,Inc.New York 1994 (the whole is incorporated herein by reference), or protein and Application of peptide-containing formulations to the skin (International Publication No. 98 / 53847), or Elec To create transient transport pathways such as troporation, or iontophoresis Application of an electric field or introduction of ultrasound to increase the mobility of charged drugs through the skin, such as by swabs. Applications of ultrasound such as (U.S. Patent Nos. 4,309,989 and 4,767,402) Using an oxidizing agent that enables this, gels, ointments, lotions, suspensions, or patch delivery systems are available. However, it can be prepared transdermally in forms that are not limited to these (see above publication). The works and patents are incorporated herein by reference in their entirety.

[0168] Embodiment The present invention also provides the following non-limiting embodiments. 1. Treatment of moderate to severe active ulcerative colitis (UC) for those who require it. A method performed in which a clinically proven safe and clinically proven effective amount The treatment involves administering a pharmaceutical composition containing an anti-IL-12 / IL-23p40 antibody to the target, The body includes a heavy chain variable region and a light chain variable region, and the heavy chain variable region is the complementary determination of Sequence ID No. 1. The amino acid sequence of the constant region heavy chain 1 (CDRH1), the amino acid sequence of CDRH2 in SEQ ID NO: 2, and The CDRH3 amino acid sequence of SEQ ID NO: 3 is included, and the light chain variable region determines the complementarity of SEQ ID NO: 4. The amino acid sequence of region light chain 1 (CDRL1), the amino acid sequence of CDRL2 in SEQ ID NO: 5, and the Includes the CDRL3 amino acid sequence at column number 6.

[0169] 2. The antibody has a heavy chain variable region in 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, including a variable region of the column's light chain.

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

[0171] 4. The antibody is administered at a dose of approximately 6.0 mg per kg of body weight of the subject, or 130 mg per dose. The drug is administered intravenously to the subject in the prescribed dose, preferably during week 0 of treatment, in any of embodiments 1 to 3. One method.

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

[0173] 6. The target is anti-TNF, vedolizumab, corticosteroid, azathioprine (AZ) A) and at least one treatment selected from the group consisting of 6 mercaptopurine (6MP) The law has failed before or has been intolerant of these, or the subject is col The method according to any one of Embodiments 1 to 5, which has shown tycosteroid dependence. .

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

[0175] 8. The subjects are responders to antibody therapy and meet the global and US definitions. Clinical remission based on at least one of these, by week 16 of treatment, preferably week 8. It is identified as having clinical remission by, more preferably by the second week, and by week 0. The method according to Embodiment 7, which is continued for at least 44 weeks thereafter.

[0176] 9. The subjects were clinically remission, having not received corticosteroids for at least 44 weeks from week 0 onwards. The method described in Embodiment 8 of the solution.

[0177] 10. The subject is a responder to antibody treatment and has been at least since week 0. The method of Embodiment 7, which is identified as having an endoscopic healing that lasts for 44 weeks. .

[0178] 11. The subject is a responder to antibody treatment and has been at least since week 0. Achieving a clinical response based on Mayo endoscopic subscores, which is sustained for 44 weeks, is particularly important. The method according to Embodiment 7.

[0179] 12. The subject is a responder to antibody therapy and has been at least since week 0. A 44-week continuous assessment of the Inflammatory Bowel Disease Questionnaire (IBDQ) score from baseline. The method of Embodiment 7, which is identified as having a change.

[0180] 13. The subject is a responder to antibody treatment and has been at least since week 0. The method according to Embodiment 7, which is identified as having mucosal healing that lasts for 44 weeks.

[0181] 14. The subject is a responder to antibody therapy and has been at least since week 0. As a result of a decrease from baseline in the Mayo score that continues for 44 weeks. The method described in Embodiment 7.

[0182] 15. The subject is a responder to antibody treatment and has been at least since week 0. A 44-week course of C-reactive protein, fecal lactoferrin, and fecal calprotectin Identified as having normalization of one or more biomarkers selected from the group consisting of the following: The method according to embodiment 7.

[0183] 16. The subject has maintained a Mayo score of 0 for at least 44 weeks from week 0 onwards. A decrease of ≥30% and ≥3 points from the baseline rectal bleeding subscore and baseline rectal bleeding subscore Clinical response determined by a decrease of ≥1 point from the rectal bleeding subscore, or a score of 0 or 1. The method according to Embodiment 7, which demonstrates the present invention.

[0184] 17. Treatment of moderate to severe active ulcerative colitis (UC) is necessary for those who require it. A method used with elephants, a. In week 0 of treatment, administer approximately 6.0 mg per kg of body weight or 1 dose to the subject. The anti-IL-12 / IL-23p40 antibody in the first pharmaceutical composition is administered intravenously at a dose of 30 mg. Administering the drug, b. The subject receives a dose of 90 mg per administration, preferably the second drug at the 8th week of treatment. The method includes subcutaneous administration of the anti-IL-12 / IL-23p40 antibody contained in the composition. The antibody contains a heavy chain variable region and a light chain variable region, and the heavy chain variable region is complementary to SEQ ID NO: 1. Sex-determining region heavy chain 1 (CDRH1) amino acid sequence, CDRH2 amino acid sequence of SEQ ID NO: 2, and includes the CDRH3 amino acid sequence of SEQ ID NO: 3, and the light chain variable region is complementary to SEQ ID NO: 4. The amino acid sequence of the determinant region light chain 1 (CDRL1), the amino acid sequence of CDRL2 in SEQ ID NO: 5, and It includes a light chain variable region containing the CDRL3 amino acid sequence of sequence number 6, The target drugs are anti-TNF, vedolizumab, corticosteroids, azathioprine (AZA), and at least one therapy selected from the group consisting of 6-mercaptopurine (6MP) Have you failed before, or have you been unable to tolerate these, or is the subject of Cortico? A method that has shown signs of steroid dependence.

[0185] 18. The antibody has a heavy chain variable region in the amino acid sequence of SEQ ID NO: 7 and the amino acids in SEQ ID NO: 8. The method according to Embodiment 17, comprising a light chain variable region of the array.

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

[0187] 20. A pharmaceutical composition for intravenous administration contains 10 mM L-histidine, 8.5% (w Sucrose (w / v), 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine and 20 μg / mL of EDTA disodium salt, dehydrated, at pH 6. The method according to any one of Embodiments 1 to 19, further comprising a solution containing 0.

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

[0189] 22. The subject is a responder to antibody therapy, and meets both the global and US definitions. Clinical remission based on at least one of the following, by the 16th week of treatment, preferably 8 weeks. Embodiments 1 to 21 are identified as having, more more precisely, by the second week. The method described in any one of the following ways.

[0190] 23. The subjects are responders to antibody-based treatment, and endoscopic healing is considered a treatment. By the 16th week, preferably by the 8th week, more preferably by the 2nd week, The method according to any one of Embodiments 1 to 22, as specified by [the specified method].

[0191] 24. The subjects are responders to antibody therapy and Mayo Endoscopy Subscription A core-based clinical response is expected by week 16 of treatment, preferably by week 8, more preferably The following is identified as something to be achieved by the second week, as described in any one of Embodiments 1 to 23. Method of loading.

[0192] 25. The subjects are responders to antibody therapy and have completed the Inflammatory Bowel Disease Questionnaire ( Changes from baseline in the Infla (IBDQ) score up to week 16 of treatment. They are identified as having, preferably by the 8th week, more preferably by the 2nd week. or the method according to any one of Embodiments 1 to 24.

[0193] 26. The target is a responder to antibody treatment, and mucosal healing is one of the treatments. Having by the 6th week, preferably by the 8th week, more preferably by the 2nd week The method according to any one of Embodiments 1 to 25.

[0194] 27. The subjects are responders to antibody treatment and have a Mayo score. The reduction from baseline should be achieved by week 16 of treatment, preferably by week 8, more preferably. Mashiku is identified as having one of Embodiments 1 to 26 by the second week. Method of description.

[0195] 28. The target is a responder to antibody therapy, and C-reactive protein, One or more vials selected from the group consisting of fecal lactoferrin and fecal calprotectin Normalization of omarkers should occur by the 16th week of treatment, preferably by the 8th week, more preferably. This is identified as having by the second week, as described in any one of Embodiments 1 to 27. method.

[0196] 29. The subject has a decrease of ≥30% and ≥3 points from baseline in their Mayo score. and a decrease of ≥1 point from baseline in the rectal bleeding subscore, or a score of 0 or 1. The clinical response determined by the intestinal bleeding subscore is preferably measured by the 16th week of treatment. By week 2, one of the embodiments 1 to 28 shown in the civilization by week 2 The method.

[0197] 30. The subject is not a responder to antibody treatment by the 8th week of treatment. Responders who are in treatment by week 16, according to any one of embodiments 17-21 method.

[0198] 31. Treatment of moderate to severe active ulcerative colitis (UC) is necessary for the treatment of patients who require it. A method used with elephants, a. In week 0 of treatment, administer approximately 6.0 mg per kg of body weight or 1 dose to the subject. The anti-IL-12 / IL-23p40 antibody in the first pharmaceutical composition is administered intravenously at a dose of 30 mg. Administering the drug, b. The subject receives a dose of 90 mg per administration, preferably the second drug at the 8th week of treatment. The method includes subcutaneous administration of the anti-IL-12 / IL-23p40 antibody contained in the composition. The antibody contains a heavy chain variable region and a light chain variable region, and the heavy chain variable region is complementary to SEQ ID NO: 1. Sex-determining region heavy chain 1 (CDRH1) amino acid sequence, CDRH2 amino acid sequence of SEQ ID NO: 2, and the heavy chain variable region containing the CDRH3 amino acid sequence of SEQ ID NO: 3, and the complementary determination of SEQ ID NO: 4 The amino acid sequence of the constant region light chain 1 (CDRL1), the amino acid sequence of CDRL2 of SEQ ID NO: 5, and The CDRL3 amino acid sequence of sequence number 6 is included, followed by maintenance therapy. Maintenance therapy involves administering 90 mg of the drug once every 8 weeks or once every 12 weeks to the target patient. Maintenance therapy includes subcutaneous administration of anti-IL-12 / IL-23p40 antibody in prescribed doses, and 4 A method provided over four weeks.

[0199] 32. A pharmaceutical composition of an anti-IL-12 / IL-23p40 antibody, comprising an antibody and moderate From a randomized study of adult men and women with severe active ulcerative colitis (UC), One or more formulations disclosed in Appendix I, including data from double-blind, placebo-controlled clinical trials. The packaging includes a Bell element and the antibody contains (i) the complementarity-determining heavy chain 1 (CD) of SEQ ID NO: 1. RH1) amino acid sequence, CDRH2 amino acid sequence of SEQ ID NO: 2, and CDR of SEQ ID NO: 3 The heavy chain variable region containing the H3 amino acid sequence and the complementarity-determining region of Sequence ID No. 4, light chain 1 (CDRL) 1) Amino acid sequence, CDRL2 amino acid sequence of SEQ ID NO: 5, and CDRL3 amino acid sequence of SEQ ID NO: 6 (ii) Light chain variable region containing amino acid sequence, and (iii) the light chain variable region of the amino acid sequence of SEQ ID NO: 8, or (iii) the amino acid sequence of SEQ ID NO: 10 A pharmaceutical composition comprising a heavy chain of a sequence and a light chain of the amino acid sequence of SEQ ID NO: 11.

[0200] 33. A method for selling a preparation containing ustekinumab, wherein the ustekinumab is manufactured Furthermore, therapies including ustekinumab are safe and effective in treating patients with ulcerative colitis. To promote effectiveness, by carrying out steps a) and b), medical professionals This brings about and promotes the purchase of the formulation by the medical professional (HCP), and thereby the formulation Methods, including selling.

[0201] The present invention has been described in general terms, and similar examples are provided, but are not limited to the above. This can be more easily understood by referring to the following examples which are not intended to do so. There may be. Furthermore, details of the present invention are illustrated by the following non-limiting embodiments. All disclosures of quotations are expressly incorporated herein by reference. [Examples]

[0202] Example 1: Study on the introduction of ustekinumab in the treatment of ulcerative colitis in humans In adult men and women with moderate to severe active ulcerative colitis (UC) as described below: A multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted: moderate to severe active In patients with ulcerative colitis, the safety of ustekinumab induction and maintenance therapy, and A phase 3, randomized, double-blind, placebo-controlled, parallel-group comparison study to evaluate efficacy. , a multicenter trial.

[0203] Overall theoretical basis Conventional therapy (corticosteroids or 6-mercaptopurine / azathioprine [6- MP / AZA) or biological therapy (TNF antagonists and / or integrin antagonists, vedo) Moderate to severe active ulcers that show an inadequate response to or poor tolerance of lizumab. This study evaluates the efficacy of intravenous (IV) administration of ustekinumab in patients with ileocolitis. To that end, a trial was conducted. The subjects received a single dose of 130 mg and a single dose of 6 mg / kg in week 0. IV doses of either the drug or placebo were administered. Subjects who did not show a clinical response at week 8 received 8 An additional IV or subcutaneous (SC) dose was administered in the second week.

[0204] the purpose The primary objectives of this study include (1) clinical assessment of patients with moderate to severe active UC. To evaluate the efficacy of ustekinumab in inducing bedside remission, and (2) moderate to severe This includes evaluating the safety of IV ustekinumab in patients with active ulcerative colitis (UC). Ta.

[0205] A secondary objective of this study is to (1) in subjects with moderate to severe active UC IV ustequinone in the induction of endoscopic healing (i.e., improvement in endoscopic observation of the mucosa) (2) To evaluate the effectiveness of mab and in subjects with moderate to severe active UC To evaluate the efficacy of IV ustekinumab in inducing clinical responses to (3) diseases To evaluate the effects of IV ustekinumab on specific health-related quality of life, and (4 ) Ustekinumab treatment for mucosal healing (i.e., endoscopic healing and histological healing) To evaluate efficacy and (5) the efficacy of IV ustekinumab in biologically impaired states To evaluate the effectiveness of the infusion therapy, and (6) C-reactive protein (CRP), fecal carpro Moderate changes, including alterations in tectin, fecal lactoferrin, and other PD biomarkers. Pharmacokinetics of ustekinumab induction therapy in patients with moderate to severe active UC (P This included evaluating K), immunogenicity, and pharmacodynamics (PD).

[0206] The exploratory purpose of this study is to (1) May without physician-led comprehensive assessment (PGA) subscores. (1) Evaluate the response using the o score, and (2) Bristol Stool Scale (BSFS) This included evaluating the performance of the scores.

[0207] Experimental Design The Phase 3 development program for ustekinumab consists of two separate trials, namely, This included entrance and maintenance trials. In the introductory trial, subjects were divided into three treatment groups at week 0: placebo, Patients were randomized to receive either a low dose of ustekinumab or a high dose of ustekinumab. 8 In the first week, all subjects were evaluated for the primary endpoints of clinical remission and clinical response. Participants who achieved a clinical response at week 8 were eligible to enter the maintenance trial. In subjects who did not achieve the desired response, a second dose of ustekinumab was administered at week 8 of treatment. .

[0208] At week 16, subjects who had not achieved a clinical response at week 8 were re-evaluated for their clinical response. Individuals who achieved a clinical response at week 16 were eligible to enter the maintenance trial. Subjects that did not achieve a clinical response were not eligible to enter the maintenance study and were the last subjects to receive the investigational drug. The patient visited the hospital approximately 20 weeks after administration (8 weeks) for a follow-up check on safety.

[0209] The group that clinically responded to IV ustekinumab during induction was the primary population in the maintenance trial. The following was constructed. The maintenance trial was designed to evaluate maintenance therapy using SC ustekinumab. This is a randomized treatment discontinuation trial, and it is currently ongoing.

[0210] Dosage and administration The subjects received either a single IV dose of ustekinumab or a placebo at week 0 of the study. The induction antibody levels based on the administered dose are as follows: ● Low fixed dose of ustekinumab at 130 mg ● Ustekinumab doses based on a high weight range of approximately 6 mg / kg: ○ Ustekinumab 260 mg (body weight ≤ 55 kg) ○ Ustakinumab 390mg (body weight > 55kg, but ≤ 85kg) ○ Ustekinumab 520 mg (body weight > 85 kg).

[0211] In subjects who did not show a clinical response, a second dose of ustekinumab was administered at week 8. The test antibodies for the second dose administered are as follows: ● In the first week, participants randomized to placebo received approximately 6 mg of ustekinumab at week 8. One dose of IV at / kg plus placebo SC (to maintain blindness) was administered. ● In subjects randomized to ustekinumab at week 0, at week 8, One dose of 90 mg SC plus placebo IV (to maintain blindness) was administered.

[0212] Safety evaluation Safety is assessed based on AE and clinical laboratory test results (i.e., hematology and serology). It was deemed worthwhile. Adverse events were either spontaneously reported by the subjects or reported at the time of the trial visit. This was obtained by conducting interviews with the subjects using a non-inducing method. Safety evaluation This included the following clinical laboratory tests. ● Hematology: Hemoglobin (Hb), hematocrit, red blood cell count, white blood cell (WBC) count , and platelets. ● Serum chemistry: sodium, potassium, chloride, blood urea nitrogen (BUN), creatine Nin, aspartate aminotransferase (AST), alanine aminotransferase Bilirubin (ALT), total bilirubin and direct bilirubin, alkaline phosphatase, Cylium, phosphates, albumin, total protein. ● Screening: Serological testing for human immunodeficiency virus antibodies, hepatitis C virus (H) CV) Serological tests for antibodies, hepatitis B virus (HBV) antibody, hepatitis B surface antigen, HBV Serological testing of the total of surface antibodies (anti-HB) and HBV core (anti-HB) antibodies, quantitative FERON-TB Gold (QuantiFERON-TB Gold) test, pregnancy test (β-human chorionic gonadotropin) Pin [β-HCG]).

[0213] Pharmacokinetics Blood samples for measuring serum ustekinumab concentration should be collected at week 0 (before and after infusion). Samples were collected at weeks 2, 4, and 8. Serum ustekinumab concentration analysis was performed using a mesoscale. Discovery (MSD®) platform (Gaithersburg, On MD, USA, the electrochemiluminescence immunoassay (ECLIA) method, whose effectiveness has been confirmed, The lowest sample size of the ECLIA method using the MSD platform. The quantifiable concentration was 0.1688 μg / mL.

[0214] immunogenicity Antibodies to ustekinumab were evaluated using serum samples collected from all subjects. The analysis of antibodies against ustekinumab confirmed efficacy, drug resistance, and electrochemistry. The analysis was performed using luminescence immunoassay (ECLIA), and in this analysis, ustekinumab was used. We used this method to capture and detect the immune response induced by ustekinumab. For all subjects possessing antibodies against the drug, the antibody titer was determined, and the anti-drug antibody-positive samples were identified. The neutralizing antibody (Nab) status was determined.

[0215] Evaluation of effectiveness Effectiveness assessments were collected throughout the entire trial. Mayo scores and partial Mayo scores were collected. a. Endoscopic Severity Assessment Index for Ulcerative Colitis (UCEIS), Bristol Stool Texture Scale (BSFS) score, C-reactive protein (CRP), fecal lactoferrin, fecal calcium Protectin, Inflammatory Bowel Disease Questionnaire (IBDQ), 36-item short-form health survey The (SF-36) and EuroQoL-5D health questionnaires were all evaluated, and their effectiveness was determined. The effectiveness criteria were defined as follows: ● Clinical remission (world application) is a Mayo with no individual subscores >1 and ≤2. Score. ● Clinical remission (US application): ≤3 absolute bowel movements, 0 rectal bleeding score, and 0 or This is a Mayo endoscopy subscore of 1. ● Clinical response: Decrease from baseline or 0 in the rectal bleeding subscore ≥1 A Mayo score of ≥30% and ≥3 points accompanied by any of the rectal bleeding subscores. Decrease from baseline during the initial phase. ● Endoscopic healing (i.e., improvement in endoscopic observation of the mucosa): 0 or 1 Mayo endoscopic examination Mirror subscore. ● Histological healing: Based on the Geboes score, neutrophils from 0 to <5% of the epithelium, and It is defined as being without crypt destruction, erosion, ulceration, or granulation tissue. ● Mucosal healing: Both endoscopic 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 / kJ g. ● Modified Mayo score response: ○ Definition 1: A decrease in the modified Mayo score of ≥2 points and ≥35%, and a rectal level of ≥1. A decrease in the bleeding subscore or a rectal bleeding subscore of 0 or 1. ○ Definition 2: A decrease in the modified Mayo score of ≥2 points and ≥30% and a rectal of ≥1. A decrease in bleeding or a rectal bleeding score of 0 or 1.

[0216] Safety results Both intravenous ustekinumab doses of approximately 6 mg / kg and 130 mg were administered over 8 weeks. It showed generally good tolerability, accompanied by a safety profile comparable to placebo. Of the 960 subjects in the safety analysis set, over the course of 8 weeks, 1 AEs that occurred under one or more treatments were compared in the approximately 6 mg / kg, 130 mg, and placebo groups. Reports were given for 50.0%, 41.4%, and 48.0% of the subjects, respectively. Throughout the study, serious adverse events (SAEs) were observed in groups of approximately 6 mg / kg, 130 mg, and placebo. Reports were received from 3.1%, 3.7%, and 6.6% of the subjects, respectively.

[0217] The adverse event (AE) within one hour of infusion was approximately 6 mg / kg, 130 mg, and in the placebo group. The percentages were 0.9%, 2.2%, and 1.9%, respectively.

[0218] The proportion of subjects with one or more infectious diseases was approximately 6 mg / kg, 130 mg, and placebo. The percentages in the groups were 15.3%, 15.9%, and 15.0%, respectively. Infections occurred in approximately 6 mg / kg, 130 mg, and 0 mg of the target population in the placebo group, respectively. We reported on 3%, 0.6%, and 1.3%.

[0219] Pharmacokinetic results Serum samples were taken at week 0 (before administration), week 0 (1 hour after administration), week 2, week 4, and Samples were collected in week 8. For subjects randomized to ustekinumab treatment, ustekinumab A single IV infusion is an adjusted dose based on body weight of approximately 6 mg / kg (i.e., ≤ 55 kg). For those weighing g, the dosage is 260 mg; for those weighing >55 kg and ≤85 kg, the dosage is 390 mg. (or 520 mg for those weighing >85 kg), or a fixed dose of 130 mg. It was given. Considering that the median body weight of the subjects in the 130 mg group was 72 kg, A 130 mg dose of kinumab was equivalent to approximately 2 mg / kg per kg. Therefore, On average, the ustekinumab exposure in the approximately 6 mg / kg group was about three times that of the 130 mg group. Consistent with the prediction, after a single IV dose of ustekinumab approximately 6 mg / kg or 130 mg, The median serum ustekinumab concentration was approximately the dose at all sampling points throughout the 8-week period. The results were proportional. The median serum ustekinumab concentration observed 1 hour after the end of the infusion in week 0 was P. For the approximately 6 mg / kg group and the 130 mg group, the values ​​were 127.0 μg / mL and 137.0 μg / mL, respectively. The level was 43.16 μg / mL. At week 8, at the time of evaluation of the primary efficacy endpoint, The median serum ustekinumab concentration was approximately 6 mg / kg for the 6 mg / kg group and 130 mg for the 130 mg group, respectively. The concentrations were 8.59 μg / mL and 2.51 μg / mL, respectively.

[0220] In subjects who received placebo IV at week 0 and did not show a clinical response at week 8, In week 1, approximately 6 mg / kg of ustekinumab was administered intravenously, while in week 0, ustekinumab For subjects who did not show a clinical response at week 8 after receiving B IV, Ustekin was administered at week 8. Numab 90mg was administered via SC. Placebo IV was administered in week 0, followed by Usui in week 8. Among those who received tekinumab IV at approximately 6 mg / kg, at week 16 (ustekinumab IV administration) The median serum ustekinumab concentration at 8 weeks post-administration was slightly lower than that observed at 8 weeks. (Among those who received approximately 6 mg / kg of ustekinumab intravenously in week 0, [they had a high rate.) [10.51 μg / mL vs. 8.59 μg / mL]). (First IV IV infusion at week 0) Among those who received ustekinumab 90 mg via SC at week 8 (after numab administration), at week 16 The median serum ustekinumab concentration was for subjects who received 130 mg of ustekinumab at week 0. In comparison, in subjects who received approximately 6 mg / kg of ustekinumab intravenously at week 0, there was a slight decrease. The levels were high (1.92 μg / mL vs. 1.59 μg / mL, respectively).

[0221] Immunogenic results In the ustekinumab group, where there are samples suitable for evaluating antibodies against ustekinumab Of the 635 subjects, 4 (0.6%) received ustekinumab throughout the 8-week period. The antibody test for the NAb was positive. Of these four subjects, two (50%) tested positive for the NAb. The result was positive.

[0222] Ustekinumab was administered at any point throughout the 16-week period, and anti-drug antibody (ADA) levels were evaluated. Of the 822 subjects with suitable samples, 18 (2.2%) were final Up until the visit for safety evaluation, the patients were positive for antibodies against ustekinumab. Of the 15 subjects, 4 (26.7%) had a NA (Natural Aptitude) until their final safety evaluation visit. Among those that could be evaluated as b, the NAb test was positive. Ustekinumab 90 mg was administered at week 8. Among those who received SC administration, the incidence of antibodies against ustekinumab over 16 weeks was: The values ​​were higher in the 130 mg IV → 90 mg SC group compared to the approximately 6 mg / kg IV → 90 mg SC group. The percentage was high (4.5% [6 out of 132 people] vs. 1.0% [out of 101 people]). [1 person].

[0223] Results of effectiveness Clinical remission at 8 weeks - World definition At week 8, there was a significantly larger proportion of subjects in the groups of approximately 6 mg / kg and 130 mg (each 15.5% and 15.6% achieved clinical remission compared to the placebo group. 5.3%; p<0.001 for both comparisons; Table 1).

[0224] [Table 1] N = number of subjects, CI = confidence interval

[0225] Clinical remission at 8 weeks - US definition At week 8, there was a significantly larger proportion of subjects in the groups of approximately 6 mg / kg and 130 mg (each 18.9% and 16.6% achieved clinical remission compared to the placebo group. 6.3%; p<0.001 for both comparisons; Table 2).

[0226] [Table 2] N = number of subjects, CI = confidence interval

[0227] Endoscopic healing at 8 weeks At week 8, there was a significantly larger proportion of subjects in the groups of approximately 6 mg / kg and 130 mg (each 27.0% and 26.3% achieved endoscopic healing compared to the placebo group. (13.8%; p<0.001 for both comparisons; Table 3).

[0228] [Table 3] N = number of subjects, CI = confidence interval

[0229] Clinical response at week 8 At week 8, there was a significantly larger proportion of subjects in the groups of approximately 6 mg / kg and 130 mg (each 61.8% and 51.3% achieved a clinical response compared to the placebo group (3 1.3%; p<0.001 for both comparisons; Table 4).

[0230] [Table 4] N = number of subjects, CI = confidence interval

[0231] 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 approximately 6 mg / kJ. In the g and 130 mg groups (31.0 and 31.5, respectively), compared to the placebo group... The difference was significantly larger (10.0; p<0.001 for both comparisons).

[0232] Clinical remission at 8 weeks Remission is assessed as clinical remission (world definition) by a rectal bleeding score of 0 at 8 weeks. In that case, the proportion of subjects who achieved this endpoint is based on the primary efficacy analysis (world definition). The observed proportions were almost identical to those of the groups receiving approximately 6 mg / kg and 130 mg. A significantly larger proportion (15.2% and 15.3%, respectively) reached this endpoint. This was achieved compared to the placebo group (5.3%; p<0.001 for both comparisons).

[0233] Symptomatic remission in the 8th week At week 8, there was a significantly larger proportion of subjects in the groups of approximately 6 mg / kg and 130 mg (each 44.7% and 41.3% achieved symptomatic remission compared to the placebo group. 22.6% (p<0.001 for both comparisons).

[0234] Histological healing at 8 weeks Histological healing involves 0-<5% neutrophils in the epithelium, and crypt destruction, erosions, ulcers, or tissue. It was defined as not having buds. At week 8, the subjects in the groups of approximately 6 mg / kg and 130 mg had A surprisingly large percentage (35.6% and 37.9%, respectively) experienced histological healing compared to the placebo group. This was achieved compared to the control group (21.9%; p<0.001 for both comparisons).

[0235] Change from baseline in the Mayo score at week 8. At baseline, the mean Mayo score was the same across all treatment groups. For the group 8.9). At week 8, the mean from baseline in the Mayo score The decrease in values ​​was observed in the groups of approximately 6 mg / kg and 130 mg (3.5 and 3.2, respectively). ), was significantly larger compared to 1.8 in the placebo group (p<0.00 for both comparisons). 1).

[0236] Change from baseline in 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). This continued as early as the second week, and throughout the eighth week until the next hospital visit. The mean reduction in partial Mayo scores was approximately 6 mg / kg and 13 mg / kg compared to the placebo group. The 0 mg group showed a significantly larger result. At week 2, the mean of the partial Mayo score was The reduction from the baseline was approximately 6 mg / kg and 130 mg compared to the placebo group (1.0). In the group, the values ​​were 1.6 and 1.5, respectively (p<0.001 for both comparisons). ). At week 8, the mean partial Mayo score decreased from baseline compared to the placebo group. Compared to group 1.5, the groups of approximately 6 mg / kg and 130 mg had values ​​of 2.9 and 2.9, respectively. The value was 2.6 (p<0.001 for both comparisons).

[0237] UCEIS score in week 8 The UCEIS score is based on mucosal vascular patterns, bleeding, and ulceration, and is used in endoscopy for UC. It provides an overall assessment of the severity of the condition. The score ranges from 3 to 11, with higher scores indicating a higher severity. It indicates a more severe disease as seen by endoscopic examination. The UCEIS score is the central part of the endoscopic video. Evaluated only during reading.

[0238] At baseline, mean UCEIS scores were similar across all treatment groups. The efficacy rates were 7.6, 7.5, and 7.5 in the approximately 6 mg / kg, 130 mg, and placebo groups, respectively. At week 8, the mean decrease from baseline in the UCEIS score was approximately 6m. In the g / kg and 130 mg groups (1.3 and 1.1, respectively), the placebo group was 0 It was significantly larger compared to 0.5 (p<0.001 for both comparisons).

[0239] At week 8, there was a significantly larger proportion of subjects in the groups of approximately 6 mg / kg and 130 mg (each 20.2% and 19.1% of the patient group had a UCE of ≤4 compared to the placebo group (11.0%). They had IS scores (p<0.001 and p=0.004, respectively). UC ≤ 4 The EIS score was 0 or 1, which defined endoscopic cure as defined in this study. It is assumed that this will be associated with the endoscopic subscore.

[0240] Bristol Stool Consistency Scale Score The BSFS score at the time of visit was the average of the daily averages of the BSFS scores over three days prior to the visit. The same 3 days used to calculate the number of bowel movements and rectal bleeding score for the Mayo score. The average BSFS score at the time of visit was calculated using the interval.

[0241] Approximately 40% (370 / 961 people) of the randomized subjects were B, which was collected at baseline. They had an SFS score. At baseline, 99.2% (367 / 370 people) of the group had an SFS score. The group had an average BSFS score of ≥3, and the majority of the group (54.3%) showed diarrhea ≥6. They had an average BSFS score. As early as the second week, and continued throughout the eighth week until their next visit. The proportion of individuals experiencing diarrhea (average BSFS score of ≥6) was approximately 6 mg higher in the group compared to the placebo group. The levels were lower in the / kg and 130mg groups. At week 8, the levels were approximately 6mg / kg and 130mg. In the g and placebo groups, the percentages were 22.8%, 21.1%, and 32.0%, respectively. % had diarrhea (average BSFS score of ≥6). Furthermore, at week 8, normal stools were observed. The proportion of subjects with (≧3 and <5) was approximately 6 mg / kg and 130 compared to placebo. The levels were higher in the mg group (48.3%, 48.9%, and 29.3%, respectively).

[0242] Normalization of C-reactive proteins C-reactive protein (CRP) is used as a marker of inflammation in subjects with IBD. In UC, high CRP is used in cases of severe clinical activity, high sedimentation rate, and colonoscopy. It is associated with active disease detected by microscopy. C-reactive protein is a validated high-sensitivity protein. The test was performed using a CRP assay.

[0243] At baseline, the proportion of subjects with abnormal CRP (>3 mg / L) was among all treatments. Similar across groups, overall, 59.2% of randomized subjects were baseline. The patient had abnormally high CRP levels. They visited the hospital again as early as the second week, and again throughout the eighth week. In the subsequent study, among subjects with abnormal values ​​at baseline, the results were approximately 6m higher compared to the placebo group. A significantly larger proportion of subjects in the g / kg and 130mg groups showed normalization of CRP (≤3mg / L) was achieved. At week 8, the target group was determined in the approximately 6 mg / kg and 130 mg groups, respectively. 38.7% and 34.1% of the group had higher CRP levels compared to 21.1% of the group in the placebo group. Normalization was achieved (p<0.001 for both comparisons).

[0244] Normalization of fecal lactoferrin levels At baseline, subjects with abnormal fecal lactoferrin levels (>7.24 μg / g) were included. The proportions were similar across all treatment groups, and overall, 90% of the randomized subjects 0% had abnormal fecal lactoferrin concentrations at baseline. At week 8, among subjects with abnormal values ​​at baseline, compared to the placebo group, A significantly larger proportion of subjects in the groups receiving approximately 6 mg / kg and 130 mg of fecal lactoferrin were found to have high levels of fecal lactoferrin. Normalization (≤7.24 μg / g) was achieved. At week 8, the levels were approximately 6 mg / kg and 130 mg. 14.6% and 17.2% of the subjects in the group that developed the drug were compared to 9.3% of the subjects in the placebo group. All achieved normalization of fecal lactoferrin levels (for the ustekinumab group, p (=0.042, p=0.006).

[0245] Normalization of fecal calprotectin At baseline, subjects had abnormal fecal calprotectin levels (>250 mg / kg). The proportion was approximately 85.1% in the 6 mg / kg group compared to the placebo group (78.4%). The average size was slightly larger, and 82.5% of the subjects in the 130 mg group had abnormalities at baseline. The fecal calprotectin levels were abnormal at baseline during weeks 2 and 4. Among those with certain values, the proportion of subjects in the approximately 6 mg / kg and 130 mg groups was significantly larger. However, normalization of fecal caprotectin (≤250 mg / kg) was achieved. At week 8, Among subjects with abnormal fecal calprotectin levels in Sline, normalized fecal calprotectin The proportion of subjects with lotectin was significantly higher compared to the placebo group (20.4%). However, in the groups receiving approximately 6 mg / kg and 130 mg of ustekinumab (25, respectively). The figures were numerically larger (5% and 24.2%) (p=0.14 for both comparisons). 8. p=0.301).

[0246] Example 2: Maintenance study of ustekinumab in the treatment of human ulcerative colitis methodology In this randomized treatment discontinuation maintenance trial, all enrolled subjects received the same treatment as in the induction trial. Responders to the investigational drug. Primary (randomized) population: IV vasoconstrictor after induction. The subjects who showed a clinical response to numab constituted the main population in the maintenance trial. The population included: ustekinumab (i.e., 130 mg) at week 0 of the introductory trial. Patients were randomized to receive either V or approximately 6 mg / kg IV, and a clinical response was observed at week 8 of the induction period. The subjects indicated were randomized to receive a placebo at week 0 of the induction trial, and for the induction period 8. Although there was no clinical response in week 1, the dose of IV ustekinumab (approximately 6 mg / ) was administered at week 8 of the induction phase. After administration of (kg), a clinical response was observed at week 16 of the induction phase (placebo → ustekinumab approximately 6m (g / kg IV) is the target group. These subjects were administered ustekinumab 90 mg SC at week 0 of the maintenance phase. This is administered every 8 weeks (q8w), and ustekinumab 90mg SC every 12 weeks (q12w), and also Participants were randomized in a 1:1:1 ratio to receive placebo SC. Non-randomized group: The additional subjects entering this study were not randomized in the primary population, and in this study, as follows: Maintenance treatment was received by: ustekinumab delayed responseers (i.e., at week 8 of the induction phase). Although there was no clinical response to V ustekinumab, at week 8 of the induction phase, ustekinumab 9 In subjects who showed a clinical response at week 16 of the induction phase after 0 mg of SC administration, ustekinumab was used. 90 mg was administered via SC at q8w, and placebo induction responders (i.e., placebo IV induction) Subjects who showed a clinical response to the initial treatment received placebo via SC. Non-randomized subjects were evaluated for efficacy. We tracked both efficacy and safety, but these were not included in important efficacy analyses.

[0247] All subjects will receive their assigned dose of the SC test drug at their visit during week 0 of the maintenance phase. The drug was administered. Subsequently, in order to maintain blinding, all subjects received all planned study drugs. The study drug was administered at each visit for administration. Clinical flare was evaluated for each participant at each visit. If a decline in clinical response was observed, the patient was considered for rescue medication. The main part of the maintenance study was: The trial will continue until week 44, and the long-term trial will be extended to week 220.

[0248] Number of subjects (planned and analyzed): The 783 subjects who completed the introduction trial and showed a clinical response to the introduction trial drug were selected for this maintenance Participants were enrolled in the ongoing trial. The number of subjects in each treatment group at week 0 of the maintenance phase was as follows: It was. ● Randomized (primary) population (523 participants [327 participants were planned]) ): - 176 participants were randomized to receive ustekinumab 90 mg, SC, or q8w. - 172 participants were randomized to receive ustekinumab 90 mg, SC, or q12w. - 175 participants were randomized to either a placebo or a single-component study (SC). ● Non-randomized population (260 participants): - 157 subjects who were delayed responders to ustekinumab induction (i.e., during the first 8 weeks of induction) (Although there was no clinical response to ustekinumab initially, a clinical response was observed at 16 weeks into the induction phase.) For this patient, ustekinumab 90 mg was administered via SC at q8w. - Among the 103 subjects who clinically responded to the introduction of IV placebo (placebo responders): A placebo was administered via SC.

[0249] Diagnostic and Key Criteria for Inclusion All subjects enrolled in this randomized treatment discontinuation maintenance trial received conventional therapy (i.e., co Luticosteroids or immunomodulators) or biological therapies (i.e., TNF antagonists and The patient showed an insufficient response to / or vedolizumab, or was intolerant of it, and the induction trial was initiated. Patients with moderate to severe active ulcerative colitis who showed a clinical response to the study drug during the trial. This was due to the clinical response to IV ustekinumab compared to IV placebo. The subjects are those with a clinical response, or a delayed clinical response to ustekinumab, and the introduction trial The study included subjects who did not undergo any drug changes prohibited by the protocol during the trial.

[0250] Evaluation criteria: ● Pharmacokinetics (PK): Serum ustekinumab concentration ● Immunogenicity: Antibodies against ustekinumab ● Pharmacodynamics (PD) / Biomarkers: Serum biomarkers; Fecal microbiome; RNA expression and histological evaluation of disease activity and healing in mucosal biopsy ● Genetics and Epigenetics: Whole blood deoxyribonucleic acid (DNA) ● Effectiveness: Mayo score and partial Mayo score, UC Endoscopic Index of Severity (UCEIS) (Classification based on endoscopic findings), CRP , fecal lactoferrin, and fecal calprotectin ● Health-related quality of life: Inflammatory Bowel Disease Questionnaire (IBDQ), 36 short-form questionnaire Home Health Survey (SF-36), EuroQoL-5D Health Questionnaire (EQ-5D) ● Health Economics: Hospitalizations and surgeries related to UC disease; Visual analog scale of productivity (Visual Analog Scale, VAS), and questionnaires regarding work productivity and activity impairments - Work Productivity and Activity Impairment Questionnaire - General Health (WPAI-GH) ● Safety: Adverse events (AEs), serious adverse events (SAEs), infections, injection site reactions, Allergic reactions, hematological and chemical parameters, vital signs, physical examination, and tuberculosis Early detection

[0251] endpoint ● The primary endpoint was clinical remission at week 44. Definition of clinical remission (and The trial procedure is adapted to the preferred definition of clinical remission worldwide and in the United States. The definitions differ between the application form and applications submitted outside the U.S. Each definition of clinical remission is applied to the primary efficacy analysis population. It was applied to all targets. - The global definition of the primary endpoint of clinical remission is having individual subscores >1. It was defined as a Mayo score of ≤2 points. - The US definition of clinical remission is an absolute fecal count of ≤3 and a Mayo rectal bleeding subscore of 0. These were defined as Mayo endoscopic subscores of 0 or 1. ● The primary secondary endpoints, listed in the order in which they were tested, are as follows: It was: - Maintaining clinical response up to week 44 - Endoscopic healing at 44 weeks - Clinical remission at 44 weeks without concomitant corticosteroid administration (corticosteroids) (Clinical remission without teroid administration) - Among subjects who achieved clinical remission at baseline during the maintenance phase, up to week 44. Maintenance of clinical remission For the third and fourth primary secondary endpoints, we used the global definition of clinical remission. Therefore, we support applications from countries outside the United States and use the U.S. definition of clinical remission in the United States. I provided support for the application.

[0252] Demographic and baseline disease characteristics were analyzed for 961 individuals in the primary efficacy analysis population. It was compiled based on the target audience.

[0253] Except for the fourth major secondary endpoint related to the maintenance of clinical remission, multiplicity control was the only endpoint. The analysis of the endpoints was performed to determine the clinical remission (world definition) status at the maintenance baseline. Yes / No as determined by IWRS and induction treatment (placebo IV [I-0 ] → Ustekinumab approximately 6 mg / kg IV [I-8], Ustekinumab 130 mg IV [I Stratified richness by [-0] or ustekinumab approximately 6 mg / kg IV [I-0]) Cochran-Mantel-Haenszel (CM H) The test was performed using the chi-square test. The fourth major secondary endpoint (clinical remission) For maintenance of the condition, a CMH chi-squared test stratified by induction treatment was used.

[0254] Multiple test procedures specific to the world and the United States are used in this test, which involves redundancy and controlled endpoints. To control the overall Type 1 error rate at the 0.05 level across the entire dataset. As specified in advance (Section 3.11.2.7.3), all statistical tests were performed two-tailed. The analysis was performed at a significance level of 0.05. The nominal p-value is presented.

[0255] Safety is assessed by adverse events (AEs) that occur during treatment and laboratory parameters (hematology and chemistry). The frequency and type of vital sign parameters were evaluated together. The safety summary is Provided separately to randomized subjects, non-randomized subjects, and all treated subjects. The presentation of safety data will focus on randomized populations.

[0256] result: Test population The pilot study was completed, and a total of 783 subjects who showed a clinical response to the pilot drug were selected. They were enrolled in this maintenance study. Of these, 523 subjects were targeted for the maintenance study. Belonging to the targeted primary population, SC received either ustekinumab or placebo at week 0 of the maintenance phase. Randomized to receive the treatment (ustekinumab 90mgSC q8w group, ustekinumab In the numab 90mgSC q12w group and the placebo group, there were 176 patients, 172 patients, and (175 subjects). The remaining 250 subjects were 157 ustekinumab initiation delay response. The group (ustekinumab 90 mg administered via SC at q8w) and 103 placebo-initiated patients. They belonged to a non-randomized group, including responders (who received a placebo). Maintenance phase base All registered subjects assigned treatment via SLINE will receive those investigational drugs at that time. It was administered.

[0257] Before week 40 (visit for the final dose of the maintenance trial), 85 people (16) in the primary population 0.3% of participants discontinued the study drug. The percentage of participants who discontinued the study drug was higher in the placebo group. (24.6%), the ustekinumab q8w and q12W groups (10, respectively) The percentages were higher than 2% and 14.0%. The most common reason for discontinuation was worsening of UC. The lack of efficacy and adverse events were due to the following: prior to 44 weeks, the 29 subjects in the main population. (5.5%) discontinued participation in the study, and the most common reason for discontinuing participation in the study was consent. It was a retraction.

[0258] Baseline clinical disease characteristics include moderate to severe activity, refractory to available therapies. Representing the target population with sexual UC, and generally balanced across the three treatment groups. The median duration of the disease was 6.05 years, and the median baseline Mayo score was... The value was 9.0, with 86.9% and 13.1% having moderate and severe UC, respectively. At baseline during the introductory phase, 52.2% of subjects in the main population of the maintenance study were colitis. They are taking tycosteroids, 26.6% are taking immunomodulatory drugs, and 70.7% are They were taking aminosalicylates. The majority of the subjects (93.5%) were in the baseline phase. In patients with an insufficient response to corticosteroids and / or 6-MP / AZA They either tolerated it, or it was unbearable, or they showed corticosteroid dependence. Overall In the main population, 47.6% of subjects had a documented history of biological therapy failure. 52.4% of the subjects did not have this condition. Also, 47.2% had at least one anti-TNF agent. Although unsuccessful, 13.4% were unsuccessful with both anti-TNF and vedolizumab, and 4 9.3% were prior to biological therapy, and two subjects were vedolizumab alone. It was a biological failure.

[0259] Results of effectiveness Ustekinumab maintenance therapy is a conventional treatment including TNF antagonists and / or vedolizumab. They have previously failed biological treatments or are intolerant to them, and Ustekin After receiving a single dose of mab IV induction therapy, patients with moderate to severe symptoms showed a clinical response at 8 weeks. The study demonstrated efficacy in a population of subjects with active UC.

[0260] Based on pre-specified global and US-specific test procedures, statistical significance was 4 The primary endpoint was clinical remission at week 4 and maintenance of clinical response throughout week 44. Endoscopic healing at week 7, and clinical remission without corticosteroid administration at week 44. For one of the primary secondary endpoints, the ustekinumab administration regimen (90 mg q It is possible to claim both 8 weeks and 90 mg (12 weeks). In addition, in the United States only ustekinumab dose based on standard clinical procedures, and ustekinumab q based on global clinical procedures. Maintenance of clinical remission throughout 44 weeks for both 12-week regimens (maintenance baseline) (Among subjects who achieved clinical remission) statistical significance can be claimed. ●Clinical efficacy in the main population (i.e., those who received IV induction therapy with ustekinumab) (Subjects showing a clinical response for the next 8 weeks) - Primary endpoint: Clinical remission ○ The proportion of subjects in clinical remission (based on the world definition) at 44 weeks was compared to the placebo group. Compared to the control group (24.0%), the ustekinumab q8w group and the ustekinumab q12w group showed a significant difference. The difference was significantly larger in the groups (43.8% and 38.4%, respectively) (p<0.0 for both groups). (01 and p = 0.002). ○ The proportion of subjects in clinical remission (based on the definition limited to the United States) at week 44 was: Compared to the cebo group (24.6%), the ustekinumab q8w group and ustekinumab group The q12w group (42.6% and 39.5%, respectively) showed significantly larger values ​​(p, respectively). (<0.001 and p=0.002). ○ Towards achieving clinical remission (based on both the global and limited US definitions) The effect of ustekinumab is (in subjects who were unsuccessful with biological treatment and in subjects who were unsuccessful with biological treatment Subjects that did not benefit, and those who were concomitant immunomodulatory agents or corticosteroids at baseline during the induction phase. (Including subjects who received steroids and subjects who did not) It is generally consistent and robust to predetermined changes in data processing rules. That's it. - Primary secondary endpoints: maintenance of clinical response, endoscopic cure, corticosteroids Clinical remission without idoids, and maintenance of clinical remission. ○ Maintained clinical response throughout 44 weeks, achieved endoscopic healing, and corticosterone Achieved non-administered remission (applying both the global and US-specific definitions of clinical remission). The proportion of subjects was different in the ustekinumab q8w and q12w groups compared to the placebo group. It was significantly larger (p<0.01). ○ Among subjects who achieved clinical remission at baseline during the maintenance phase, those who maintained clinical remission. The proportion of subjects was compared to the placebo group in the ustekinumab q8w and q12w For both groups, the numerical values ​​were large (the global definition of clinical remission and the definition limited to the United States). (Apply both). Statistical significance (p<0.01) is defined using a US-specific definition of clinical remission. Using this method, we were able to achieve a comparison between both the q8w group and the q12w group relative to placebo. Statistical significance, using the world definition of clinical remission, was observed in the q12w group compared to placebo. This was achieved only in this respect (p<0.01). - Other histological, mucosal, clinical, and endoscopic endpoints The analysis summarized below was not controlled for multiplicity. The description of statistical significance is as follows: Based on nominal p-values. ○ Histological healing was achieved at 44 weeks (i.e., <5% of neutrophils in the crypts). The proportion of subjects (without infiltration, crypt destruction, erosion, ulceration, or granulation tissue) was compared to the placebo group. In comparison, the values ​​were significantly larger in the ustekinumab q8w and q12w groups (p<0.0). 01). ○ Mucosal healing (a combination of endoscopic and histological healing) was achieved at 44 weeks. The proportion of subjects was higher in the ustekinumab q8w and q12w groups compared to the placebo group. The impact was significant (p<0.01). ○ Applying both the global definition and the US-specific definition of clinical remission, a small number of people were found to have remission 44 weeks prior. At least 90 days without corticosteroid administration, the proportion of subjects achieving remission was higher with placebo. Compared to the group, the ustekinumab q8w and q12w groups showed significantly larger values. p<0.01). Furthermore, subjects receiving corticosteroids at maintenance baseline. In particular, compared to the placebo group, the ustekinumab q8w and q12w groups showed better results. A significantly larger proportion of subjects (p<0.05) were clinically remitted, and the small number of patients 44 weeks prior to the first 44 weeks was lower. At the very least, the patient had not been administered any concomitant corticosteroids for 90 days. ○ The efficacy of ustekinumab maintenance therapy is demonstrated by sustained improvement in partial Mayo scores. Clinical outcomes, as measured by the maintenance of symptomatic remission and endoscopic healing, It has been demonstrated. Further evidence of the efficacy of ustekinumab maintenance therapy is available over time in partial Mayo This was observed in remission, symptomatic remission, and symptom control (bowel movement frequency and rectal bleeding). - Inflammatory biomarkers ○ The ustekinumab treatment group was observed at maintenance baseline levels over time up to week 44. The CRP, fecal lactoferrin, and fecal calprotectin levels were maintained. On the other hand, in the placebo group, median CRP, fecal lactoferrin, and fecal calprotectin were higher. The concentration worsened (increased). ○ At 44 weeks, CRP, fecal calprotectin, and fecal lactoferrin were normalized. The proportion of subjects with ferrin was higher in the ustekinumab group compared to the placebo group, specifically in q8w and q12. The values ​​were generally significantly larger in the w group. - Clinical endpoints due to failure of biological treatment ○ For subjects with a history of unsuccessful biological treatment and those without: The primary endpoint, major secondary endpoints, and mucosal healing were achieved. The proportion of subjects who underwent this treatment was generally higher in the ustekinumab q8w and q compared to the placebo group. The results were larger in the 12-week group. ○ In some cases, the treatment effect was not unsuccessful in the biological treatment and in the population. If similar in the target population, the therapeutic effect of ustekinumab on the q8w group is Consistency across endpoints, which is greater than that of the tekinumab q12w group. This tendency was observed in subjects who were unsuccessful with biological treatment. This was not observed in groups where treatment was successful. - Efficacy based on inflammatory biomarker subgroups ○ Higher inflammatory load (CR) at either the induction phase or the maintenance phase baseline. Among subjects with elevated P and / or elevated fecal inflammation markers, both doses were generally Although it showed efficacy compared to placebo, the efficacy of ustekinumab q8w was... The numab q12w group appeared to be superior across the range of clinical endpoints. However, in subjects with low baseline inflammatory load, the ustekinumab q8w group The q12w group and the q12w group showed similar efficacy against the endpoint. - Health-related quality of life ○ By week 44, the subjects of the ustekinumab q8w and q12w groups are generally Compared to the placebo group, the participants were evaluated using the IBDQ, SF36, and EQ5D assessment methods. When this was achieved, improvements in health-related quality of life were maintained. - Ustekinumab 90 mg, q8w dose and ustekinumab 90 mg, q12w dose Prognosis of the quantity ○ Both the q8w and q12w groups of ustekinumab generally show signs of major endopoietic activity. While it showed similar efficacy for the primary and primary secondary endpoints, q8w showed further efficacy. Based on the more objective and rigorous effectiveness scale below, it was slightly better than q12w. Ta. ◆ Endoscopic and mucosal healing at 44 weeks ◆ Sustained partial Mayo remission at 44 weeks ◆ Among subjects receiving corticosteroids at baseline during the maintenance phase And, at least 90 days prior to 44 weeks, clinical remission and corticosteroid-free treatment. Elimination of tycosteroids ○ Furthermore, if efficacy is tested over time (for the following endpoints), The q8w group showed greater efficacy than the q12w group. ◆ May indicate inactivity or mild illness (i.e., subscore of 0 or 1) oFrequency of bowel movements and rectal bleeding subscore, as well as absolute stool counts of ≤3 over time up to week 44. ◆ Partial Mayo remission and symptomatic remission over time up to week 44 ◆ Time course of fecal lactoferrin and calprotectin concentrations up to 44 weeks The median change from the baseline. ● Efficacy in delayed responders to ustekinumab induction therapy The subjects who were delayed responders to ustekinumab induction therapy were those who received ustekinumab 9 During administration of 0 mg over 8 weeks, the clinical response was maintained, clinical remission, endoscopic cure, and tissue Achieving both endoscopic and histological healing. It was done. ● Efficacy and pharmacokinetics / immunogenicity - Generally, during maintenance, serum ustekinumab concentrations and clinical remission and endoscopic cure are observed. A clear correlation was observed between the results and the effectiveness of the treatment. In addition, measurements were taken using CRP. In some cases, lower levels of inflammation were observed in subjects with higher serum ustekinumab concentrations. . - Among patients receiving maintenance ustekinumab, antibodies against ustekinumab The occurrence of [the condition] is associated with clinical remission, endoscopic cure, clinical response, and maintenance of the Mayo score. Clinical efficacy, measured by multiple endpoints such as changes from the line, is undermined. Although it didn't seem to have an impact, the interpretation of the data was limited by the small sample size. It is limited.

[0261] Pharmacokinetic and immunogenicity results ● Following maintenance therapy with ustekinumab 90 mg via SC administration at q8w or q12w The subjects will receive ustekinumab 90 mg via SC administration over 8 weeks, or ustekinumab 90 mg After initiating a maintenance regimen in which g is administered via SC at q12w, approximately 8 weeks or 12 weeks In week [number], a steady state was reached. The median steady-state value of trough serum ustekinumab concentration over time. This is because, compared to the q12w group (0.92 μg / mL ~ 1.19 μg / mL), Uste In the numab q8w group (2.69 μg / mL to 3.09 μg / mL), the concentration was approximately three times higher. That's it. ● Maintenance regimen of ustekinumab 90 mg administered via SC at q8w or q12w Subsequently, serum ustekinumab concentrations persisted until week 44 in almost all subjects and were undetectable. The proportion of subjects with a viable trough concentration over time was 4.9% in the 90 mg q12w group. The incidence rate was lower in the 90mg q8w group (0.7%~2.4%) than in the placebo group (~7.1%). The median ustekinumab concentration in the group was at a detectable level by week 16. It fell below that. ● The impact of different ustekinumab IV induction doses on maintenance serum ustekinumab concentrations As expected, Hibiki continued to decrease over time. ● The median trough serum ustekinumab concentration tends to be lower in high-body-weight subjects. there were. ● Non-randomized subjects in the ustekinumab delayed response group were 90m After SC administration of the same ustekinumab administration regimen of q8w in g, ustekinumab q8w Compared to the randomized subjects in the group, those with lower serum ustekinumab concentrations over time. There was a tendency for this to happen. ● 680 people with suitable samples to evaluate antibodies against ustekinumab Of those treated, 39 (5.7%) developed anti-ustekinumab antibodies over 52 weeks of treatment. The body tested positive, and most had antibody titers of ≤1:800. Of the 39 patients who tested positive for ustekinumab antibodies, 11 (2 8.2% were positive for neutralizing antibodies. ● In all randomized treatment groups, the median serum ustekinumab concentration was Compared to the levels of the control group that were negative for numab antibodies, the levels of ustekinumab antibodies In subjects who tested positive, the levels decreased over time.

[0262] Safety results Subcutaneous maintenance regimen of ustekinumab 90 mg administered at q12W or q8W up to week 44 Men generally showed good tolerability, consistent with the known safety profile of ustekinumab. Ta. ● AEs were observed in the ustekinumab q8w group, the ustekinumab q12w group, and the placebo group. The issue was reported in 77.3%, 69.2%, and 78.9% of the subjects in the group, respectively. - The AEs with a rational causal relationship are the ustekinumab q8w group and the ustekinumab q In the 12-week group and the placebo group, 26.1%, 17.4%, and 28.6% of the subjects were respectively It was reported. ●Infections (identified by the clinical trial physician) were observed in the ustekinumab q8w group. 48.9%, 33.7%, and 46.3% of the subjects in the numab q12w group and the placebo group, respectively. These were reported separately. - Infections requiring oral or parenteral antibiotic treatment were treated in the ustekinumab q8w group. 22.7%, 15.7%, and 1% of the subjects in the ustekinumab q12w group and the placebo group, respectively. Each was reported in 9.4% of cases. ● Serious infections were infrequent among the randomized subjects, and ustekinumab q8w In the group receiving ustekinumab q12w and the placebo group, the rates were 1.7%, 3.5%, respectively. And reported in 2.3%. Opportunistic infections were observed in 3 subjects (all in randomized populations). ) was identified. Cytomegalovirus colitis was identified in two patients in the ustekinumab q12w group. In an elephant, one subject was diagnosed with simultaneous moderate AEs of ocular and oral herpes. No cases of active TB were reported among those treated with ustekinumab throughout the 44-week period. It was. ● The proportion of randomized subjects who experienced adverse events (AEs) leading to discontinuation of the study drug was higher in the placebo group. In this group, the rate was higher than in the q12w and q8w groups, and was the most common cause of discontinuation in the placebo group. Frequent adverse events (AEs) worsened the ulcerative colitis (UC). ● Overall safety among all treatment subjects, including ustekinumab delayed responseers. Sexual profiles were consistent with those observed in the randomized population. ● This patient is a delayed responder to ustekinumab induction and was administered ustekinumab at q8w. One of the subjects has been reported dead. The cause of death was thyroiditis due to multinodular goiter. It was caused by acute respiratory failure that occurred during surgery. ● Of all the treatment candidates, two were selected (one of whom had a delayed response to ustekinumab induction). In the patient group [ustekinumab administered at q8w], one subject experienced ustekinumab during induction. Patients who received IV doses of β1 (a placebo group) reported serious major adverse cardiovascular events. The report indicated that both events were associated with perioperative complications. ● Among all patients treated, there were 6 patients in whom malignant disease was reported (5 Ustek (Numab treatment subjects and one placebo subject only). - Three patients treated with ustekinumab reported non-melanoma skin cancer (NMSC), and three of them All had a prior history of either azathioprine or 6-MP treatment, and two were diagnosed At times, she received concomitant immunomodulatory therapy. - Two patients treated with ustekinumab reported having solid tumors, and one patient... One patient had papillary renal cell carcinoma (q12w), and one patient had colon cancer (q8w). Tumors in both individuals were detected early during the subjects' participation in the maintenance study. ● Cases of anaphylaxis or delayed hypersensitivity reactions identified in patients treated with ustekinumab are: It wasn't there. ● Having chemical and hematological laboratory values ​​of the maximum toxicity grade after baseline of ≥1 There was no significant difference in the proportion of participants between the placebo group and each ustekinumab group. Grade 3 and Grade 4 chemical and hematological laboratory values ​​are infrequent.

[0263] Results of healthcare economics and utilization of medical resources ● By week 44, the group receiving ustekinumab in combination showed a higher percentage of patients compared to the placebo group. There were very few hospitalizations or surgeries related to disease C. ● At week 44, the maintenance baseline in the Visual Analog Score (VAS) for productivity The changes from the previous group were improvements in the ustekinumab treatment group and improvements in the placebo group. This demonstrated a worsening of the condition. ● At week 44, the percentages within each of the four WPAI-GH domains were: In the ustekinumab treatment group, maintenance was maintained from baseline, and ustekinumab q8 In the group w, the rate of work-related impairment due to health, and the overall work-related impairment due to health. Further improvements were observed in the rate and the rate of activity impairment due to health reasons compared to the placebo group. Regarding elephants, the percentages for all four WPAI-GH domains worsened. (That is, it increased.)

[0264] conclusion ● The ustekinumab maintenance study involved administering ustekinumab 90 mg at q12w and q8w in a sustained scalding (SC) regimen. The administration regimen is for moderate to severe symptoms that respond to a single IV ustekinumab induction dose. In adults with active UC, both treatments were consistently and definitively effective. I presented the evidence. - The efficacy of ustekinumab is evident in patients who have failed with biological therapies, as well as in conventional treatments. Subjects who were unsuccessful with therapeutic intervention but not with biological therapy (i.e., biological therapy (Observed in a legal context) - Notably, both doses of ustekinumab were effective, but the q8w administration was effective. The regimen includes several objective and / or more stringent endpoints (e.g., endoscopic Cure and long-term partial Mayo remission, as well as the temporal progression of symptomatic and partial Mayo remission. The analysis showed slightly better effectiveness. ● Ustekinumab 90 mg for q12w and 90 mg for q8w SC administration regimens The maintenance dose is 4 in a population of adults with moderate to severe ulcerative colitis. The drug was generally well-tolerated over a four-week period. ● The safety and efficacy data from this study are for ustekinumab SC maintenance therapy. Supports a favorable profit / risk profile.

[0265] The U.S. Food and Drug Administration (FDA) announced that as of October 18, 2019, ulcerative colitis (UC) is prevalent in the United States. They have approved STELARA® (ustekinumab) for the treatment of ). The labels are shown in Appendix I below.

[0266] The present invention further includes a pharmaceutical composition of an anti-IL-12 / IL-23p40 antibody, and Appendix I, II. and packaging comprising one or more label elements disclosed in III, wherein the antibody is (i) sequence The amino acid sequence of the complementarity-determining region heavy chain 1 (CDRH1) of sequence number 1, and the amino acid sequence of CDRH2 of sequence number 2. The heavy chain variable region includes the amino acid sequence and the CDRH3 amino acid sequence of SEQ ID NO: 3, and SEQ ID NO: The complementarity-determining region of 4, light chain 1 (CDRL1) amino acid sequence, and the CDRL2 amino acid sequence of SEQ ID NO: 5. (ii) Acid sequence, and the light chain variable region including the CDRL3 amino acid sequence of SEQ ID NO: 6, The heavy chain variable region of the amino acid sequence of sequence number 7 and the light chain variable region of the amino acid sequence of sequence number 8, or (iii) The heavy chain of the amino acid sequence of SEQ ID NO: 10 and the light chain of the amino acid sequence of SEQ ID NO: 11, Includes.

[0267] Appendix I Main part of prescription information These key components are necessary for the safe and effective use of STELARA®. This does not include all information. Please refer to the full prescription information for STELARA®. sea ​​bream.

[0268] STELARA® (ustekinumab) injection for subcutaneous or intravenous use. First domestic approval in the U.S.: 2009

[0269] ---------------Recent Major Changes--------------- Indications and Dosage, Ulcerative Colitis (1.4) October 2019 Dosage and administration (2.3) October 2019 Warnings and Precautions for Use (5.1) October 2019

[0270] ----------------Indications and Dosage---------------- STELARA® is a human interleukin-12 indicated for the following treatments. - and -23 are antagonists. Adult patients with the following: ● Moderate to severe psoriasis vulgaris (Ps) that is a candidate for phototherapy or systemic therapy. (1. 1) ● Used alone or in combination with methotrexate for active psoriatic arthritis (PsA). (1 .2) ● Moderate to severe active Crohn's disease (CD). (1.3) ● Moderate to severe active ulcerative colitis. (1.4) Adolescent patients (12 years of age or older) with the following conditions: ● Moderate to severe psoriasis vulgaris (Ps) that is a candidate for phototherapy or systemic therapy. (1. 1)

[0271] ----------------Dosage and Administration---------------- Recommended subcutaneous dose for adults with psoriasis (2.1):

[0272] [Table 5]

[0273] Recommended subcutaneous dose for young adult patients (12 years and older) with psoriasis (2.1): Weight-based administration is The initial dose is recommended, followed by doses after 4 weeks, and then every 12 weeks thereafter.

[0274] [Table 6]

[0275] Recommended subcutaneous dose for adults with psoriatic arthritis (2.2): ● The recommended dosage is 45 mg subcutaneously initially and after 4 weeks, followed by 4 mg every 12 weeks thereafter. Administer 5 mg subcutaneously. ● In patients weighing over 100 kg with coexisting moderate to moderate psoriasis vulgaris, The recommended dosage is 90 mg subcutaneously initially and after 4 weeks, followed by 90 mg every 12 weeks thereafter. It is administered subcutaneously.

[0276] Recommended intravenous dose for adults with Crohn's disease and ulcerative colitis in the early stages (2.3): weight-based dose Single intravenous infusion using a prescribed volume:

[0277] [Table 7]

[0278] Recommended subcutaneous dose for adults with Crohn's disease and ulcerative colitis (2.3): Initial intravenous administration Eight weeks later, and then every eight weeks thereafter, a subcutaneous dose of 90 mg.

[0279] ----------------Dosage Form and Strength---------------- Subcutaneous injection (3) ● Injection: 45 mg / 0.5 mL or 90 mg / m² in a single-dose pre-filled syringe. L ● Injection: 45 mg / 0.5 mL in a single-dose vial. ---------------------------------------- Intravenous infusion (3) ● Injection: 130 mg / 26 mL (5 mg / mL) per single-dose vial (3)

[0280] ------------------Contraindications------------------- Clinically significant hypersensitivity to ustekinumab or any of its excipients. (4)

[0281] --------------Warnings and Precautions for Use--------------- ● Infections: A serious infection has occurred. Among all clinically significant active infections Do not initiate STELARA®. If a serious or clinically significant infection occurs... If this occurs, consider discontinuing STELARA® until the infection disappears. (5 .1) ● Theoretical risk of specific infections: Mycobacteria, Salmonella, and Bacillus. Severe infections caused by Calmette-Guérin (BCG) vaccination include IL-12 / IL-2 It has been reported in patients with a genetic deficiency of gene 3. Diagnostic tests for these infections are based on clinical symptoms. It should be considered that the decision will depend on the circumstances. (5.2) ● Tuberculosis (TB): Before starting treatment with STELARA®, please note the following about TB. Evaluate the patient. Begin treatment for latent TB before administering STELARA®. (5.3) ● Malignant tumors: STELARA® may increase the risk of malignant tumors. The safety of STELARA in patients with known malignancies or a history thereof has been evaluated. None. (5.4) ● High sensitivity reaction: There is a risk of anaphylaxis or other clinically significant hypersensitivity reactions. Yes. (5.5) ● Reversible posterior leukoencephalopathy (RPLS): One case has been reported. If suspected, rapid Treat and discontinue STELARA®. (5.6) ● Non-infectious pneumonia: Interstitial pneumonia observed when using STELARA (registered trademark) after approval. Cases of eosinophilic pneumonia and latent organized pneumonia have been reported. If a diagnosis is confirmed... Discontinue STELARA and initiate appropriate treatment. (5.9)

[0282] -----------------Adverse Reactions----------------- The most common adverse reactions are as follows: ● Psoriasis (≧3%): Nasopharyngitis, upper respiratory tract infections, headache, and fatigue. (6.1) ● Crohn's disease, induction (≧3%): vomiting. (6.1) ● Crohn's disease, maintenance (≧3%): nasopharyngitis, injection site erythema, vulvovaginal candidiasis / fungal Infections, bronchitis, itching, urinary tract infections, and sinusitis. (6.1) ● Ulcerative colitis, induction (≧3%): nasopharyngitis (6.1) ● Ulcerative colitis, maintenance (≧3%): nasopharyngitis, headache, abdominal pain, influenza, fever, Diarrhea, sinusitis, fatigue, and nausea (6.1)

[0283] To report a suspected adverse reaction, refer to Janssen Biotech, Inc. 1-8. 00-JANSSEN (1-800-526-7736), or FDA (1-800-F Contact DA-1088 or www.fda.gov / medwatch.

[0284] For patient counseling information and medication guidelines, please refer to section 17. Revised: October 2019

[0285] Full prescription information: Contents * 1. Indications and Dosage 1.1 Psoriasis (Ps) 1.2 Psoriatic arthritis (PsA) 1.3 Crohn's disease (CD) 1.4 Ulcerative colitis 2. Dosage and Administration 2.1 Psoriasis 2.2 Psoriatic arthritis 2.3 Crohn's disease and ulcerative colitis 2.4 General Considerations for Administration 2.5 Instructions for administering STELARA® Pre-emptive needle with safety guard Filled syringe 2.6 Preparation and Administration of STELARA® 130 mg / 26 ml for intravenous infusion L (5 mg / mL) vial (Crohn's disease and ulcerative colitis) 3. Dosage Form and Strength 4 Contraindications 5. Warnings and Precautions for Use 5.1 Infectious diseases 5.2 Theoretical risks of vulnerability to specific infectious diseases 5.3 Pre-treatment evaluation of tuberculosis 5.4 Malignant Tumors 5.5 Hypersensitivity reactions 5.6 Reversible occipital lobe leukoencephalopathy 5.7 Immunization 5.8 Combination Therapy 5.9 Non-infectious pneumonia 6. Adverse reactions 6.1 Experience in clinical trials 6.2 Immunogenicity 6.3 Post-market experience 7. Drug Interactions 7.1 Live vaccines 7.2 Combination Therapy 7.3 CYP450 Substrates 7.4 Allergen Immunotherapy 8. Use in a specific population 8.1 Pregnancy 8.2 Breastfeeding 8.4 Use in children 8.5 Use in the elderly 10. Overdose 11 Properties 12. Clinical Pharmacology 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 Non-clinical toxicity 13.1 Carcinogenicity, mutagenicity, and reproductive dysfunction 13.2 Animal Toxicology and / or Pharmacology 14 Clinical Trials 14.1 Psoriasis 14.2 Target population of young adults with psoriasis vulgaris 14.3 Psoriatic arthritis 14.4 Crohn's disease 14.5 Ulcerative colitis 15 References 16. Supply / Storage / Handling Methods 17. Patient consultation information * Sections or subsections omitted from the complete prescription information are not included.

[0286] Full prescription information 1. Indications and Dosage 1.1 Psoriasis (P) STELARA® is a registered trademark for moderate to severe cases that are candidates for phototherapy or systemic therapy. It is indicated for the treatment of patients aged 12 years or older with psoriasis vulgaris.

[0287] 1.2 Psoriatic arthritis (PsA) STELARA® is indicated for the treatment of adult patients with active psoriatic arthritis. STELARA (registered trademark) can be used alone or in combination with methotrexate (MTX). ) can be used in conjunction with this.

[0288] 1.3 Crohn's disease (CD) STELARA® is a registered trademark for adult patients with moderate to severe active Crohn's disease. It is suitable for the treatment of [condition].

[0289] 1.4 Ulcerative colitis STELARA® is a registered trademark for adult patients with moderate to severe active ulcerative colitis. It is suitable for the treatment of [unclear / unclear].

[0290] 2. Dosage and Administration 2.1 Psoriasis Subcutaneous administration adult dosage regimen ● For patients weighing 100 kg or less, the recommended dose is 45 mg initially and again after 4 weeks. After that, 45 mg every 12 weeks. ● For patients weighing over 100 kg, the recommended dose is 90 mg initially and again after 4 weeks. The next dose is 90 mg every 12 weeks.

[0291] In subjects weighing over 100 kg, 45 mg has been shown to be effective. However, In these subjects, 90 mg demonstrated high efficacy [see clinical trial (14)].

[0292] Subcutaneous administration dosage regimen for young adults STELARA® is administered subcutaneously at week 0 and week 4, and then every 12 weeks thereafter. thing.

[0293] STELARA®'s weight-based recommendations for young adults (ages 12-17) The dosage is shown below (Table 1 on the label).

[0294] [Table 8]

[0295] Recommended dose (0.75 mg / kg) for young adult patients weighing less than 60 kg. The volume is shown in Table 2 on the label. Take the appropriate volume from the single-dose vial.

[0296] [Table 9]

[0297] 2.2 Psoriatic arthritis Subcutaneous administration adult dosage regimen ● The recommended dosage is 45 mg initially and after 4 weeks, and then 45 mg every 12 weeks thereafter. ru. ● In patients weighing over 100 kg with coexisting moderate to severe psoriasis vulgaris, The recommended dosage is 90 mg initially and after 4 weeks, followed by 90 mg every 12 weeks thereafter.

[0298] 2.3 Crohn's disease and ulcerative colitis Adult dosage regimens for induction therapy via intravenous administration STELARA (registered trademark) uses a dosage regimen based on body weight as specified in Table 3 of the label. Single intravenous infusion dose (standard) [STELARA® 130mg vial for intravenous infusion] See instructions regarding the dilution of the solution (2.6).

[0299] [Table 10]

[0300] Adult dosage regimens for maintenance therapy administered subcutaneously The recommended maintenance dose is 90 mg subcutaneously 8 weeks after the initial intravenous administration, and thereafter... It is administered every 8 weeks.

[0301] 2.4 General Considerations for Administration ● STELARA® is intended for use under the guidance and supervision of a physician. STELARA (registered trademark) is closely monitored and regularly followed up by a physician. It should only be administered to patients who come to the clinic. The appropriate dose is determined based on the patient's current condition at the time of administration. It must be determined by the healthcare provider using body weight. In young adult patients, STE LARA® is recommended to be administered by a healthcare provider. Subcutaneous injection. After receiving appropriate training on the method, if the physician deems it appropriate, the patient may undergo STE. LARA® can be administered by the patient themselves or by a caregiver. You must be instructed to follow the instructions outlined in the drug guide. [See Drug Guide] . ● The needle cover on the pre-filled syringe contains dried natural rubber (a latex derivative). It is present. Those with latex sensitivity should not handle the needle cover. ● Each injection will be administered in a different anatomical location than the previous injection (upper arm, buttocks, thigh, or abdomen). Administer to any quarter of the body, etc., and treat if the skin is soft, bruised, erythematous, or indurated. It is recommended not to administer to areas where this is observed. When using a single-dose vial, 27 A 1 mL syringe with a gauge and a 1 / 2-inch needle is recommended. ● Prior to administration, visually inspect STELARA® for particulate matter and discoloration. To test. STELARA® is a colorless to pale yellow solution, with a small number of translucent or It may contain white particles. STELARA® may be discolored or cloudy. If this is the case, or if other particulate matter is present, use STELARA®. Do not use. STELARA® does not contain preservatives, therefore vials and Discard any unused product remaining in the syringe.

[0302] 2.5 Dispensing of STELARA® pre-filled syringes equipped with needle safety guards Instructions for use Please refer to the following instruction manual.

[0303] To prevent accidental activation of the needle safety guard, the needle guard activation click can be activated at any point during use. Do not touch the pu.

[0304] JPEG2026068731000011.jpg50161● Hold the main body and remove the needle cover. When removing the needle cover, the plunger or plunger Do not hold the head. The plunger may move. Do not drop it with the needle cover removed. If this occurs, do not use a pre-filled syringe. ● Subcutaneously inject STELARA® as recommended [Dosage and administration ( See sections 2.1, 2.2, and 2.3). ● Push the plunger until the plunger head is fully seated between the needle guard wings. Inject all of the medication solution using the syringe. To activate the needle guard, use a pre-filled syringe. It is necessary to inject all of its contents.

[0305] JPEG2026068731000012.jpg55128● After injection, keep pressing the plunger head while withdrawing the needle from the skin. See diagram below. As you slowly release your thumb from the plunger head, the entire needle is covered by the needle guard. The empty syringe will move upwards until it is filled.

[0306] JPEG2026068731000013.jpg55128● Place used syringes in a container that cannot be punctured.

[0307] 2.6 STELARA® (registered trademark) for intravenous infusion (Crohn's disease and ulcerative colitis) Preparation and administration of 30 mg / 26 mL (5 mg / mL) vials STELARA® concentrate for intravenous infusion is administered by healthcare professionals using sterile techniques. It must be diluted, prepared, and injected by a qualified professional. 1. Based on the patient's weight, determine the required dosage of STELARA® and Calculate the number of vials (Label Table 3). Each 26mL vial of STELARA® This product contains 130 mg of ustekinumab. 2. From a 250 mL infusion bag, add an amount equal to the volume of STELARA® to be added. Remove and discard a certain volume of the 0.9% sodium chloride injection solution USP standard (as needed). Each vial of STELARA® contains 26 mL of sodium chloride, and two bottles Discard 52 mL in one vial, 78 mL in three vials, and 104 mL in four vials. (Teru). 3. Remove 26 mL of STELARA® from each required vial. Add to a 250 mL infusion bag. The final volume in the infusion bag must be 250 mL. No. Mix gently. 4. Visually inspect the diluted solution before injection. Check for any opaque particles, discoloration, or foreign matter. Do not use if it is likely to be misunderstood. 5. Inject the diluted solution over a period of at least one hour. After dilution, the injection solution should be used before injection. It can be stored for up to 4 hours. 6. In-line, sterile, non-pyrogenic, low-protein-binding filter (pore size 0.2mm) Use only injection sets that have an chromate. 7. Do not inject STELARA® simultaneously with other medications through the same intravenous line. 8. STELARA® does not contain preservatives. Each vial is for single use only. This is for use only. Discard all remaining solution. Unused in accordance with local requirements. Dispose of medicines intended for use.

[0308] keep If necessary, the diluted injection solution can be stored at room temperature for up to 4 hours up to 25°C (77°F). It can be stored. Do not freeze. Discard any unused portion of the injected solution.

[0309] 3. Dosage Form and Strength STELARA® (ustekinumab) is a colorless to pale yellow solution, and a small number of people It may contain translucent or white particles.

[0310] subcutaneous injection ● Injection: 45 mg / 0.5 mL or 90 mg / m² in a single-dose pre-filled syringe. L solution ● Injection: 45 mg / 0.5 mL solution in a single-dose vial.

[0311] Intravenous infusion ● Injection: 130 mg / 26 mL (5 mg / mL) solution in a single-dose vial.

[0312] 4 Contraindications STELARA® is a registered trademark for clinical use against either ustekinumab or its excipients. It is contraindicated in patients with significant hypersensitivity to it [see Warnings and Precautions for Use (5.5)]. light].

[0313] 5. Warnings and Precautions for Use 5.1 Infectious diseases STELARA® increases the risk of infection and the reactivation of latent infections. There is a risk of serious bacterial infections in subjects who have been administered STELARA (registered trademark). Bacterial and viral infections have been observed (see Adverse Reactions (6.1)).

[0314] Severe infections requiring hospitalization, or other clinically significant infections, as reported in clinical trials. This includes the following: ● Psoriasis: Diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infection Symptoms include gastroenteritis and urinary tract infections. ● Psoriatic arthritis: Cholecystitis. ● Crohn's disease: Anal abscess, gastroenteritis, herpes zoster of the eye, pneumonia, and listeriosis. ● Ulcerative colitis: gastroenteritis, herpes zoster ocularis, pneumonia, and listeriosis.

[0315] Treatment with STELARA® will continue until the infection is cleared or adequately treated. It should not be initiated in patients with clinically significant active infections. (Chronic infections) Alternatively, in patients with a history of recurrent infections, the use of STELARA® should be initiated. Before proceeding, consider the risks and benefits of treatment.

[0316] If you experience any signs or symptoms suggestive of an infection during treatment with STELARA® Seek medical advice, and in the case of a serious or clinically significant infection, wait until the infection disappears or is properly treated. Instruct the patient to consider discontinuing STELARA® until treatment is complete.

[0317] 5.2 Theoretical risks of vulnerability to specific infectious diseases Individuals with IL-12 / IL-23 gene deficiencies are susceptible to mycobacteria (non-tuberculous, Environmental mycobacteria (including), Salmonella (including non-typhus strains), and Bacillus sulphureus It is particularly vulnerable to disseminated infections caused by Mett-Guérin (BCG) vaccination. In such patients, severe infections and fatal prognoses have been reported.

[0318] Pharmacological blockade of IL-12 / IL-23 from treatment with STELARA® Whether patients with this condition are more susceptible to these types of infections is a matter of judgment. It is not disclosed. It is determined by the clinical situation, for example, by appropriate diagnostic methods such as tissue culture and stool culture. Testing should be considered.

[0319] 5.3 Pre-treatment evaluation of tuberculosis Evaluate patients for tuberculosis infection before initiating treatment with STELARA®. do.

[0320] STELARA® should not be administered to patients with active tuberculosis infection. Treatment for latent tuberculosis should be initiated before administering LARA®. Ensure that the appropriate treatment process is confirmed. In patients with a history of undiagnosed latent or active tuberculosis, STELARA (registered trademark) Before initiating the standard treatment, consider anti-tuberculosis therapy. Patients who have received STELARA® should Closely monitor for signs and symptoms of active tuberculosis during and after treatment.

[0321] 5.4 Malignant Tumors STELARA® is an immunosuppressant and may increase the risk of malignant tumors. In clinical trials, malignant tumors were reported among subjects who received STELARA®. Adverse reactions have been reported [see Adverse reactions (6.1)]. In rodent models, IL-12 / I Inhibition of L-23p40 increased the risk of malignant tumors [see Nonclinical Toxicity (13)]. ).

[0322] STELAR in patients with a history of malignant tumors or patients with known malignant tumors The safety of A (registered trademark) has not been evaluated.

[0323] STELARA® is used by individuals with pre-existing risk factors for developing non-melanoma skin cancer. There have been post-marketing reports of the rapid onset of multiple cutaneous squamous cell carcinomas in patients who received the drug. All patients treated with ARA® must be monitored for the development of non-melanoma skin cancer. Patients older than 60 years of age, with a history of long-term immunosuppressive therapy and PUVA treatment. Patients with a history of adverse reactions must be carefully followed up [see Adverse reactions (6.1)]. .

[0324] 5.5 Hypersensitivity reactions STELARA® is known to cause hypersensitivity reactions, including anaphylaxis and angioedema. Reported adverse reactions (see 6.1, 6.3). Anaphylaxis or other clinical reactions. If a significant hypersensitivity reaction occurs, appropriate therapy should be initiated, and STELARA (registered trademark) ) will be cancelled.

[0325] 5.6 Reversible occipital lobe leukoencephalopathy In clinical trials for psoriasis and psoriatic arthritis, one case of reversible occipital lobeleukoencephalopathy (RPLS) was detected. Cases have been observed. This subject received 12 doses of STELARA over approximately 2 years (registered He was administered STELARA (registered trademark) and experienced headaches, seizures, and confusion. Additional STELARA (registered trademark) (Target) No injection was administered, and the subject recovered completely with appropriate treatment. Crohn's disease or ulcerative colon No cases of RPLS were observed in the clinical trials for inflammation.

[0326] RPLS is a neurological disorder not caused by demyelination or known infectious agents. LS can present with headache, seizures, confusion, and visual disturbances. RPLS is associated with the following conditions. These include pre-eclampsia, eclampsia, acute hypertension, cytotoxic drugs, and immunosuppressive therapy. A fatal prognosis has been reported.

[0327] If RPLS is suspected, administer appropriate medication and discontinue STELARA®. do.

[0328] 5.7 Immunization Patients should review their current immunotherapy guidelines before starting treatment with STELARA®. Immunization must be carried out according to the recommended regimen for all age groups. Patients being treated for ARA (registered trademark) should not be given live vaccines. During ARA (registered trademark) treatment, or for one year prior to the start of treatment, or for one year after discontinuation of treatment, BCG vaccine should not be administered. (Home of a patient who received STELARA®) When administering live vaccines to contacts within the yard, there is a risk of latent infection from viruses released by household contacts into the patient. There is a real risk, so exercise caution.

[0329] Non-live vaccines administered during treatment with STELARA® prevent disease. It may not elicit a sufficient immune response.

[0330] 5.8 Combination Therapy In clinical trials for psoriasis, STELARA was used in combination with other immunosuppressants or phototherapy. The safety of (registered trademark) has not been evaluated. UV-induced skin cancer is associated with IL-12 and IL- In mice genetically engineered to lack both of IL-12 or IL-12 alone, earlier It occurs more frequently and infrequently [see nonclinical toxicity (13.1)].

[0331] 5.9 Non-infectious pneumonia Interstitial pneumonia, eosinophilic pneumonia, and Cases of latent organized pneumonia have been reported. Clinical symptoms include cough and swallowing after 1-3 doses. , and interstitial infiltration were included. Severe prognoses included respiratory failure and prolonged hospitalization. The condition improved upon discontinuation of treatment, and in certain cases, it improved with the administration of corticosteroids. If a diagnosis is confirmed, discontinue STELARA® and begin appropriate treatment. See 6.3 Post-market experience.

[0332] 6. Adverse reactions The following serious adverse reactions are discussed elsewhere on the label. ● Infectious diseases [See Warnings and Precautions for Use (5.1)] ● Malignant tumors [See Warnings and Precautions for Use (5.4)] ● Hypersensitivity reactions [See Warnings and Precautions for Use (5.5)] ● Reversible occipital lobe leukoencephalopathy [See warnings and precautions for use (5.6)]

[0333] 6.1 Experience in clinical trials Clinical trials are conducted under a wide range of changing conditions, so in clinical trials of drugs, The adverse reaction rates observed cannot be directly compared to rates in clinical trials of other drugs, and in reality... This may not reflect the observed rate.

[0334] For adults with psoriasis vulgaris. Safety data includes 2414 people exposed for at least 6 months, and 2414 people exposed for at least 1 year. 1,855 people were exposed, 1,653 were exposed for at least two years, and 1,653 were exposed for at least three years. 1,569 people, 1,482 people exposed for at least 4 years, and 1,569 people exposed for at least 5 years Exposure to STELARA® in 3,117 adult psoriasis subjects, including 838 individuals. It reflects the dew.

[0335] Label Table 4 indicates that this occurs in at least 1% of the STELARA® group. Furthermore, the incidence rate was higher than that of the placebo group during the placebo-controlled period of Ps Trial 1 and Ps Trial 2. Summarize any adverse reactions that occurred [see Clinical Trials (14)].

[0336] [Table 11]

[0337] Adverse reactions that occurred in less than 1% of cases during the control period up to week 12 of the Ps trials 1 and 2. These include cellulitis, herpes zoster, diverticulitis, and certain injection site reactions (pain, swelling, itching, hardening). There was lumps, bleeding, subcutaneous bleeding, and irritation.

[0338] One case of RPLS occurred during clinical trials [see Warnings and Precautions (5.6)]. .

[0339] ● Infectious disease Placebo-controlled period in clinical trials for psoriasis (12.6 weeks and STE in the placebo treatment group) In a 13.4-week average follow-up study of LARA® treatment subjects, placebo treatment Compared to 24% of the target group (1.21 per follow-up group per year), STELARA (Registered Trademark) Infections were reported in 27% of those treated (1.39 per follow-up subject per year). Severe infections account for 0.3% of patients treated with STELARA® (follow-up study 1 subject per year). (0.01%) and 0.4% of those receiving placebo (0.02% per year per follow-up group) [See Warnings and Precautions for Use (5.1)] as a result of the above.

[0340] 8998 Target / exposure years, control and non-control periods of psoriasis clinical trials (within follow-up period) At a median of 3.2 years, infections were reported in 72.3% of patients treated with STELARA®. (0.87 per year per group in follow-up study). Severe infections were reported in 2.8% of the group. (Follow-up survey 1 target, 0.01 per year).

[0341] ● Malignant tumor In the control and uncontrollable portions of the psoriasis clinical trial, (8998 subjects and years of exposure are represented, followed up) At a median of 3.2 years, 1.7% of patients treated with STELARA® had non-melanoma. Infections other than skin cancer were reported (0.60 per follow-up subject per year). Non-melanoma skin Cancer was reported in 1.5% of patients treated with STELARA® (follow-up study 1). (0.52% per year) [See Warnings and Precautions for Use (5.4)]. Non-melanoma in clinical trials. The most frequently observed malignant tumors other than skin cancer were prostate cancer, melanoma, colorectal cancer, and The patient had breast cancer. In the control and non-control portions of the trial, patients treated with STELARA® were also included. Malignant tumors other than non-melanoma skin cancer that occur in the following cases are recorded in the SEER database (age, sex and race). Based on adjustments made to the above, the expected types and number of malignancies in the general American population. The same was true in [location]. 1 .

[0342] Targeting young adults with psoriasis vulgaris The safety of STELARA® is confirmed for patients aged 12-2 years with moderate to severe psoriasis vulgaris. The study evaluated 110 participants aged 17. These participants were evaluated up to week 60. The safety profile is based on the safety profile from a study in adults with psoriasis vulgaris. It was similar to that.

[0343] Psoriatic arthritis The safety of STELARA® is confirmed in adults with active psoriatic arthritis (PsA). In two randomized, double-blind, placebo-controlled trials involving 927 patients, The overall safety of STELARA® in patients with PsA was evaluated. The profile is consistent with the safety profile observed in clinical trials for adult psoriasis. In the placebo-controlled portion of the clinical trial for PsA, compared to patients treated with placebo, A high incidence of joint pain, nausea, and dental infections was observed in patients treated with STELARA®. It was observed (3% for joint pain compared to 1%, 3% for nausea compared to 1%, and 0% for dental psoriasis). 0.6% versus 1%.

[0344] Crohn's disease The safety of STELARA® was evaluated in a randomized, double-blind, placebo-controlled, parallel-group study. In a multicenter trial (3 trials), moderate to severe active Crohn's disease (Crohn's disease activity) In 1407 patients with a dynamics index [CDAI] of 220 or higher and 450 or lower The evaluation included 1407 patients who had previously received the investigational intravenous ustekinumab formulation. This included 40 patients who were administered the drug but were not included in the efficacy analysis. CD-1 and In the CD-2 trial, 470 patients received a single intravenous dose of 6 mg / kg based on body weight. STELARA (registered trademark) was administered to 466 people, and a placebo was administered to 466 people. [Dosage and See administration (2.3). Responders in either the CD-1 or CD-2 trial In the CD-3 trial, patients received 90 mg of STELA every 8 weeks for 44 weeks. In either the subcutaneous maintenance regimen administering RA(registered trademark) or the group receiving placebo, there was no It was manipulated. Patients in these three trials received aminosalicylic acid for Crohn's disease, immunotherapy Medication reduction [azathioprine (AZA), 6-mercaptopurine (6-MP), MTX], oral Corticosteroids (prednisone or budesonide), and / V include other concomitant medications including antibiotics. Oral therapy may be administered [see clinical trials (14.4)].

[0345] The overall safety profile of STELARA® is for adult psoriasis and psoriatic-related conditions. The safety profile was consistent with that observed in clinical trials for arthritis. (CD-1 and CD-2 trials) Furthermore, common adverse reactions in the CD-3 test are listed in Label Tables 5 and 6, respectively. It is.

[0346] [Table 12]

[0347] Other low-frequency adverse reactions reported in patients in the CD-1 and CD-2 trials include: These included asthenia (1% vs. 0.4%), acne (1% vs. 0.4%), and pruritus (2% vs. 0.4%). That was the case.

[0348] [Table 13]

[0349] ● Infectious disease In patients with Crohn's disease, serious or other clinically significant infections include anal abscesses. There were cases of gastroenteritis and pneumonia. In addition, there were cases of Listeria meningitis and herpes eye infections. This was reported in one patient. (See Warnings and Precautions for Use (5.1)).

[0350] ● Malignant tumor In clinical trials for Crohn's disease, STELARA® is used for treatment lasting up to one year. 0.2% of treated patients (0.36 cases per 100 patients / year) and 0.2% of placebo-treated patients % (0.58 cases per 100 patients / year) developed non-melanoma skin cancer. External malignancies account for 0.2% (per 100 patients / year) of patients treated with STELARA®. It occurred in 0.27 cases, but was not observed in placebo-treated patients.

[0351] ● Hypersensitivity reactions, including anaphylaxis In the CD trial, hypersensitivity reactions were reported in two patients after STELARA®. In one patient, signs and symptoms consistent with anaphylaxis after a single subcutaneous administration (throat constriction). (Past patients who received subcutaneous STELARA®) experienced symptoms such as shortness of breath and flushing. 0.1%). Furthermore, one patient (a patient who received intravenous STELARA®) In 0.08% of cases, hypersensitivity reactions (chest discomfort) occurred after the first intravenous administration of STELARA®. Signs and symptoms consistent with or related to (a feeling of fever, flushing, hives, and elevated body temperature) occurred. These patients are treated with oral antihistamines or corticosteroids, in either case However, the symptoms disappeared within an hour.

[0352] ulcerative colitis The safety of STELARA (registered trademark) is confirmed for patients with moderate to severe active ulcerative colitis. Randomized, double-blind, placebo-controlled clinical trials (2 trials) involving 960 adult patients. [Clinical trials (14.5) evaluated in UC-1 [IV induction] and UC-2 [SC maintenance]] [Reference] Overall safety of STELARA® in patients with ulcerative colitis. The sex profile is consistent with the safety profile observed for all approved indications. In at least 3% of patients treated with STELARA®, and compared to placebo, The following adverse reactions were reported at a high rate: ● Introduction (UC-1): Nasopharyngitis (7% vs. 4%). ● Maintenance (UC-2): Nasopharyngitis (24% vs. 20%), headache (10% vs. 4%), abdominal pain (7% vs 3%), influenza (6% vs 5%), fever (5% vs 4%), diarrhea (4% vs 1%) %, sinusitis (4% vs 1%), fatigue (4% vs 2%), and nausea (3% vs 2%).

[0353] ● Infectious disease In patients with ulcerative colitis, serious or other clinically significant infections include gastroenteritis. In addition, pneumonia was present. Furthermore, listeriosis and herpes zoster of the eye were reported in one patient each. [See Warnings and Precautions for Use (5.1)].

[0354] ● Malignant tumor In clinical trials for ulcerative colitis, STELARA (registered trademark) was used for treatment for up to one year. ) 0.4% of treated patients (0.48 cases per 100 patients / year) and 0.0% of placebo-treated patients. 0% (0.00 cases per 100 patients / year) developed non-melanoma skin cancer. Other malignant tumors account for 0.5% (100 patients / year) of patients treated with STELARA®. (0.64 cases) and 0.2% of placebo-treated patients (0.40 cases per 100 patients / year) It manifested in [location].

[0355] 6.2 Immunogenicity Like all therapeutic proteins, it has the potential to be immunogenic. Detection of antibody production is... It is highly dependent on the sensitivity and specificity of the assay. Furthermore, the antibody in the assay (including neutralizing antibodies) The observed incidence of positive results depends on the assay method, sample handling, timing of sample collection, and other factors. It can be influenced by several factors, including medications and underlying medical conditions. Therefore, the incidence of antibodies against ustekinumab in the tests described below is compared to other formulations. Comparing this to the incidence of antibodies against [the substance] could be misleading.

[0356] Subjects treated with STELARA® in clinical trials for psoriasis and psoriatic arthritis Approximately 6-12.4% expressed antibodies against ustekinumab, but generally at low titers. In clinical trials for psoriasis, antibodies against ustekinumab were low or undetectable in blood. In trials for psoriasis, ustekinumab concentration was associated with low efficacy. Neutralizing antibodies were found in the majority of patients who tested positive for antibodies against numab.

[0357] In clinical trials for Crohn's disease and ulcerative colitis, 2.9% and 4% of patients, respectively, developed the condition. 0.6% of patients who were treated with STELARA (registered trademark) for approximately one year were compared to ustekinumab. The antibody was expressed. Between the expression of antibody against ustekinumab and the expression of injection site reaction, No clear correlation was found.

[0358] 6.3 Post-market experience The following adverse reactions have been reported since the approval of STELARA®. Since responses are spontaneously reported from populations of uncertain size, it is difficult to reliably estimate their frequencies. Establishing a causal relationship with STELARA® exposure levels is not necessarily required. It's not necessarily possible.

[0359] Immune system disorders: Severe hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity Reactions (including rash and hives) [See Warnings and Precautions for Use (5.5)].

[0360] Respiratory, thoracic, and mediastinal diseases: interstitial pneumonia, eosinophilic pneumonia, and latent organized pneumonia [Warning] See also the precautions for use (5.9).

[0361] Skin reactions: pustular psoriasis, psoriatic erythroderma.

[0362] 7. Drug Interactions 7.1 Live vaccines Avoid using STELARA® (registered trademark) in combination with live vaccines [Warning and Precautions for Use] (See 5.7)

[0363] 7.2 Combination Therapy In trials for psoriasis, STELARA® was used in combination with immunosuppressants or phototherapy. The safety of using this method has not been evaluated [see Warnings and Precautions for Use (5.8)]. In trials concerning psoriatic arthritis, the use of concomitant MTX was found to be associated with STELARA®. No impact on safety or efficacy was observed in the induction trials for Crohn's disease and ulcerative colitis. In addition, immunomodulatory agents (6-MP, AZA, MTX) were used in combination in approximately 30% of patients, and corticosteroids Ido was used in combination with Crohn's disease and ulcerative colitis in approximately 40% and 50% of patients, respectively. The use of these combination therapies does not affect the overall safety or efficacy of STELARA®. They did not acknowledge it.

[0364] 7.3 CYP450 Substrates Specific cytokines during chronic inflammation (e.g., IL-1, IL-6, IL-10, TNF) An increase in α,IFN levels may alter the production of CYP450 enzymes. Therefore, STELARA (inspector) is the antagonist of IL-12 and IL-23. (Registered trademark) is thought to normalize the production of CYP450 enzymes. CYP450 substrates, In particular, in patients receiving concomitant treatment with a narrow therapeutic index, we initiate STELARA®. When doing so, observe the therapeutic effect (e.g., warfarin) or drug concentration (e.g., cyclosporine). Consider the following and adjust the individual dosages of the drugs as needed [see Clinical Pharmacology (12.3)]. .

[0365] 7.4 Allergen Immunotherapy STELARA® has been evaluated in patients who have received allergy immunotherapy. No. STELARA (registered trademark) reduces the protective effect of allergen immunotherapy. This may reduce tolerability, and as a result, it may reduce tolerance to certain doses of allergen immunotherapy. The risk of allergic reactions may increase. Therefore, especially for anaphylaxis... Patients who are currently receiving or have previously received allergen immunotherapy need to be given special attention. ru.

[0366] 8. Use in a specific population 8.1 Pregnancy Pregnancy exposure registry Pregnancy exposure: Observing the pregnancy outcomes of women exposed to STELARA® during pregnancy. A registry exists. Patients should be encouraged to register (telephone number 1-877- 311-8972).

[0367] Risk Overview Limited data regarding the use of STELARA® in pregnant women is related to drug use. The information provided is insufficient to inform about the risks [see data]. Reproductive and developmental toxicity studies in animals. In the experiment, exposure exceeded 100 times the human exposure level at the maximum recommended human subcutaneous dose (MRHD). No adverse effects on development were observed after administration of ustekinumab to pregnant monkeys at the prescribed dose. That's it.

[0368] All pregnant women have a background risk of birth defects, miscarriage, or other adverse outcomes. The estimated background risk of major birth defects and miscarriages in adapted populations. The reason is unknown. In the general population of the United States, the major birth defects in clinically confirmed pregnant women are The estimated background risks for pregnancy and miscarriage are 2-4% and 15-20%, respectively.

[0369] data ● Human data Based on observational studies, previously reported case reports, and post-marketing surveillance, ST in pregnant women Limited data regarding the use of ELARA® is intended to inform about drug-related risks. This is insufficient.

[0370] ● Animal data Ustekinumab was tested in embryo-fetal development toxicity studies (2 studies) in cynomolgus monkeys. Fetuses of pregnant monkeys that received ustekinumab subcutaneously twice a week or intravenously once a week during organogenesis. No teratogenic or other adverse developmental effects were observed in the offspring. The serum concentration of ustekinumab was 4 after subcutaneous administration of 90 mg of ustekinumab once a week. The serum concentration was more than 100 times higher than that of patients who received treatment over a week.

[0371] In combined studies of toxicity to embryo-fetal development and prenatal and postnatal development, pregnancy In cynomolgus monkeys, from the onset of organogenesis to 33 days postpartum, they were exposed to 100 times the subcutaneous exposure level of humans. Ustekinumab was administered subcutaneously twice a week to achieve a higher exposure level. Neonatal mortality was 22.5%. One monkey was administered ustekinumab at mg / kg and another monkey was administered 45 mg / kg. It was observed in baby monkeys. In newborns from birth to 6 months of age, functional development and morphology No ustekinumab-related effects on development or immunological development were observed.

[0372] 8.2 Breastfeeding Risk Overview The presence of ustekinumab in human breast milk, its effects on breastfed infants, or its impact on breast milk production. No data has been obtained regarding the effects of this. In the milk of lactating monkeys administered ustekinumab... The presence of Ustekinumab has been confirmed. Due to species differences in lactation physiology, animal data It is not possible to reliably predict drug levels in human breast milk from this. Human breast milk contains maternal I It is known that gG exists. From the publicly available data, ustekinumab is large Because it is a small molecule and is broken down in the digestive tract, systemic exposure in breastfed infants is expected to be low. It has been suggested that if ustekinumab is transferred to human milk, The effects of local exposure in the gastrointestinal tract are unknown.

[0373] The developmental and health benefits of breastfeeding are based on the maternal assessment of STELARA®. Due to medical necessity and STELARA®, or due to the mother's underlying medical condition, breastfeeding This must be considered in conjunction with all potential adverse effects on infants.

[0374] 8.4 Use in children The safety and efficacy of STELARA® are demonstrated in the treatment of moderate to severe psoriasis vulgaris. This has been established in pediatric patients aged 12-17 years. STELAR in this age group The use of A (registered trademark) was studied in a 12-week double-blind study involving 110 children aged 12 years or older. Evidence from a 60-week multicenter randomized trial, including placebo-controlled, parallel-group comparisons. Supported by [see Adverse Reactions (6.1), Clinical Trials (14.2)]. Psoriasis The safety and efficacy of STELARA® in pediatric patients under 12 years of age are It is not established.

[0375] STELAR in pediatric patients with psoriatic arthritis, Crohn's disease, or ulcerative colitis The safety and effectiveness of A (registered trademark) have not been established.

[0376] 8.5 Use in the elderly Of the 6,709 patients exposed to STELARA®, a total of 340 had 6 Ages 5 and over (183 psoriasis patients, 65 psoriatic arthritis patients, 58 Crohn's disease patients, and ulcers) The group consisted of 34 patients with cerebral colitis, 40 of whom were 75 years of age or older. No overall difference in safety or efficacy was observed between the group and the group, however, the number of patients aged 65 and over This is not sufficient to determine whether they will show different responses compared to younger patients.

[0377] 10. Overdose In clinical trials, single doses up to 6 mg / kg were administered without dose-limiting toxicity and showed no adverse effects. It is administered intravenously. In case of overdose, the patient should not give any signs of adverse reaction or adverse effect. It is recommended that the symptoms be observed and appropriate symptomatic treatment be initiated immediately.

[0378] 11 Properties Ustekinumab targets the p40 subunit of IL-12 and IL-23 cytokines. It is a human IgG1κ monoclonal antibody. Ustekinumab is a DNA recombination technology. Produced using recombinant cell lines whose characteristics have been thoroughly studied and standard bioprocess technology It is purified using [method]. The manufacturing process includes a virus removal step. Ustekinumab It is composed of 1326 amino acids and has a range of 148,079 to 149,690 daltons. It has an estimated molecular weight of [molecular weight].

[0379] STELARA® (ustekinumab) injection is sterile and preservative-free. It is a colorless to pale yellow solution, may contain a few translucent or white particles, and has a pH of 5. It ranges from 0.7 to 6.3.

[0380] STELARA (registered trademark) (for subcutaneous administration) Ustekinumab 45 mg (0.5 mL) and ustekinumab 90 mg (1 mL) are 2 Sterile lysate in a single-dose pre-filled syringe with a fixed 7-gauge x 1 / 2-inch needle. The ustekinumab 45 mg (0.5 mL) is supplied as a liquid and comes in a coated stock. It is supplied as a 2 mL single-dose Type I glass vial with a bar. The needle is fitted with a passive needle guard and a needle cover containing dry natural rubber (latex derivative). ru.

[0381] Ustekinumab 45 mg per 0.5 mL pre-filled syringe or vial L-histidine, and L-histidine monohydrochloride monohydrate (0.5 mg), polysorbate Administer To80 (0.02 mg) and sucrose (38 mg).

[0382] Each 1 mL pre-filled syringe contains ustekinumab 90 mg and L-histidine. , and L-histidine monohydrochloride monohydrate (1 mg), polysorbate 80 (0.04 mg ), and sucrose (76 mg) are administered.

[0383] STELARA (registered trademark) (for intravenous infusion) Ustekinumab 130 mg (26 mL) has a coated stopper. It is supplied as a 0 mL single-dose Type I glass vial.

[0384] Each 26mL vial contains 130mg of ustekinumab and 2mg of EDTA disodium salt. Hydrate (0.52 mg), L-histidine (20 mg), L-histidine hydrochloride monohydrate (27mg), L-methionine (10.4mg), polysorbate 80 (10.4mg) Administer 2210 mg of sucrose.

[0385] 12. Clinical Pharmacology 12.1 Mechanism of Action Ustekinumab is used for both cytokines IL-12 and IL-23. This is a human IgG1κ monoclonal antibody that specifically binds to 40 protein subunits. IL-12 and IL-23 activate natural killer cells and CD4+ T cells. These are naturally occurring cytokines involved in inflammatory and immune responses, such as differentiation and activation. In in vitro models, ustekinumab shared with IL-12 and IL-23. By interfering with the interaction with IL-12Rβ1, a cell surface receptor chain, this Inhibiting cytokine-mediated signaling and cytokine cascades can It has been shown that cytokines IL-12 and IL-23 are involved in Crohn's disease and ulcerative colitis. It has been suggested that this is an important contributing factor to chronic inflammation, which is a characteristic of colitis. In the physical model, the p40 subgroups of IL-12 and IL-23, which are targets of ustekinumab, are It has been shown that the unit is genetically deficient or acts protectively when blocked by an antibody. It is being done.

[0386] 12.2 Pharmacodynamics psoriasis In a small exploratory trial, subjects with psoriasis showed results at baseline and up to 2 weeks after treatment. The mRNA levels of IL-12 and IL-23, molecular targets, measured in lesional skin biopsies. A decrease in expression was observed.

[0387] ulcerative colitis In both the UC-1 trial (induction) and the UC-2 trial (maintenance), exposure levels and the percentage of clinical remissions were observed. A positive correlation was observed between response, clinical response, and endoscopic improvement. The response rate was high for maintenance treatment. Ustekinumab exposure levels related to the recommended dosing regimen approached a plateau [clinical trial( See 14.5).

[0388] 12.3 Pharmacokinetics absorption In adult subjects with psoriasis, 45 mg (N=22) and 90 mg (N=24) of psoriasis were used. Maximum serum concentration (T) after a single subcutaneous administration of kinumab max The median time to reach ) is The durations were 13.5 days and 7 days, respectively. In healthy subjects (N=30), 90 mg of u T after a single subcutaneous administration of stekinumab max The median (8.5 days) for subjects with psoriasis It was equivalent to what was recognized.

[0389] In adults with psoriasis, repeated subcutaneous administration of STELARA® was followed by usequine. Mab serum concentrations reached a steady state by week 28. Steady-state trough serum ustekinumab The mean concentration (±SD) was 0.69± in patients weighing 100 kg or less who received a 45 mg dose. In patients weighing over 100 kg who received a dose of 0.69 mcg / mL or 90 mg, the result was 0.74 ± 0. The concentration was 78 mcg / mL. When administered subcutaneously every 12 weeks, serum ustekinumab concentration was No accumulation over time was observed.

[0390] After administration of the recommended intravenous induction dose, the mean ± SD of the peak serum ustekinumab concentration was In Crohn's disease patients, the level was 125.2 ± 33.6 mcg / mL, and in ulcerative colitis patients, it was 129 The level was 0.1 ± 27.6 mcg / mL. Recommended subcutaneous maintenance dose of ustekinumab: 90 mg. The treatment was started at week 8 and administered every 8 weeks. The steady state ustekinumab concentration was the second maintenance dose. This was achieved by initiating the dose. When administered subcutaneously every 8 weeks, the ustekinumab concentration was reached. No temporal accumulation was observed. The baseline results were obtained when 90 mg of ustekinumab was administered every 8 weeks. The mean ± SD of the normal trough concentration was 2.5 ± 2.1 mcg / mL in Crohn's disease patients. In patients with ulcerative colitis, the average dose was 3.3 ± 2.3 mcg / mL.

[0391] distribution In population pharmacokinetic analysis, the volume of distribution of ustekinumab in the central compartment was: In Crohn's disease patients, the intake was 2.7L (95% CI: 2.69, 2.78), and in ulcerative colitis patients... The volume was 3.0 L (95% CI: 2.96, 3.07). The total distributed volume in steady state was: The average intake was 4.6L for patients with Roon's disease and 4.4L for patients with ulcerative colitis.

[0392] Disappearance The mean half-life (±SD) after subcutaneous administration was 14.9±4.6 across all studies related to psoriasis. The range was ~45.6 ± 80.2 days. In population pharmacokinetic analysis, ustekinumab The clearance rate in Crohn's disease patients was 0.19 L / day (95% CI: 0.185, 0.1 97) In patients with ulcerative colitis, the intake was 0.19 L / day (95% CI: 0.179, 0.192). The median estimated terminal half-life is the same for both IBD (Crohn's disease and ulcerative colitis) populations. So, it was about 19 days.

[0393] These results indicate the pharmacokinetics of ustekinumab between patients with Crohn's disease and patients with ulcerative colitis. This indicates that the forms are similar.

[0394] metabolism The metabolic pathway of ustekinumab has not been elucidated. Ustekinumab is derived from human IgG1κ mononucleotide. As a clonal antibody, it undergoes catabolism similar to endogenous IgG, producing small peptides. It is thought to be broken down into amino acids.

[0395] A specific population ● Weight When the same dose is administered to subjects with psoriasis or psoriatic arthritis, serum ustekinumab concentration The median degree is higher for those weighing over 100kg compared to those weighing 100kg or less. The levels were low. Ustekinuma in heavier (over 100 kg) subjects in the 90 mg group. The median trough serum concentration was lower in the 45 mg group (subjects weighing 100 kg or less) compared to subjects with lower body weight. They were equivalent.

[0396] ● Age: Elderly group To evaluate the effect of age on the pharmacokinetics of ustekinumab, population pharmacokinetic analysis was performed. The study was conducted on psoriasis patients aged 65 and older (N=106 / 1937 cases). There were no significant changes in pharmacokinetic parameters (clearance and volume of distribution).

[0397] ● Age: Children Repeated use of STELARA® in young adults aged 12-17 years with psoriasis After administering the recommended dose, steady-state serum concentrations of ustekinumab were reached at week 28. At week 28, The mean ± SD of the steady-state trough serum ustekinumab concentration was 0.54 ± 0.43 mcg. It was / mL.

[0398] ● Drug interaction testing The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were investigated using human hepatocytes. In an in vitro study, it was evaluated that IL-12 and / or were present at a level of 10 ng / mL. IL-23 is related to human CYP450 enzyme activity (CYP1A2, 2B6, 2C9, 2C19, 2 It was shown that D6 (or 3A4I) did not change. However, the in vitro data Clinical relevance has not been established [see drug interactions (7.3)].

[0399] No in vivo drug interaction studies using STELARA® have been conducted. .

[0400] From population pharmacokinetic analysis, ustekinumab clearance in patients with psoriatic arthritis is , MTX, NSAIDs, and oral corticosteroids in combination or past use of TNF blockers It was shown that there were no effects from the exposure.

[0401] In patients with Crohn's disease and ulcerative colitis, population pharmacokinetic analysis shows that corticosteroids Alternatively, clearing of ustekinumab by concomitant use of immunomodulators (AZA, 6-MP, or MTX). No change in lance was observed. Furthermore, serum ustekinumab concentrations were observed in the combined use of these drugs. It was not affected by it.

[0402] 13 Non-clinical toxicity 13.1 Carcinogenicity, mutagenicity, and reproductive dysfunction Animal experiments to evaluate the potential carcinogenicity or mutagenicity of STELARA® No trials have been conducted. In published literature, administration of IL-12 to mice has been shown to be effective in treating tumor transplantation. It induces an antitumor effect in mice, resulting in IL-12 / IL-23p40 knockout mice or In mice treated with anti-IL-12 / IL-23p40 antibodies, the host's defense against tumors was reduced. It has been shown that both IL-12 and IL-23 or IL-12 alone are used. Mice genetically engineered to have the defect show earlier and higher frequency compared to wild-type mice. She developed UV-induced skin cancer at a certain temperature. This was observed in a mouse model regarding the risk of malignant tumors. The relevance of their experimental findings to humans is unknown.

[0403] Male crab-eating macaques were given Ustekinuma at a maximum dose of 45 mg / kg before and during the mating season. When the drug was administered subcutaneously twice a week (45 times the dose of MRHD based on mg / kg), fertility improved. No effect was observed in the reproductive function and pregnancy prognosis of females after mating. Therefore, I did not evaluate it.

[0404] Take up to 50 mg of the same IL-12 / IL-23p40 antibody before and during the first trimester of pregnancy. In female mice administered subcutaneously twice a week at a dose of / kg, no effect on reproductive function was observed. That's it.

[0405] 13.2 Animal Toxicology and / or Pharmacology In a 26-week toxicology trial, 45 mg / kg of ustekinumab was administered twice a week for 26 weeks. A bacterial infection was observed in one of the ten monkeys that received subcutaneous administration over a period of time.

[0406] 14 Clinical Trials 14.1 Psoriasis Multicenter, randomized, double-blind, placebo-controlled trials (2 trials, Ps trial 1 and Ps trial 1) In experiment 2), the lesions occupied at least 10% of the body surface area, and the psoriasis area and severity index (Psoriasis) was measured. Phototherapy or systemic therapy for those with an Area and Severity Index (PASI) score of 12 or higher. The study included a total of 1,996 candidates aged 18 and over. (Gutate psoriasis, erythrodermic psoriasis) Subjects with psoriasis or pustular psoriasis were excluded from these studies.

[0407] Ps Trial 1 enrolled 766 participants, and Ps Trial 2 enrolled 1230 participants. The same design was used in each trial until week 28. In both trials, the subjects were divided into a placebo group and an S group. Equally distributed to either the TELARA® 45mg group or the STELARA® 90mg group. Participants were randomized in a certain proportion. Among those randomized to STELARA®, there were 0, 4 In addition, at week 16, a dose of 45 mg or 90 mg was administered regardless of body weight. Randomized participants received a placebo at weeks 0 and 4, and a cross-observation test at weeks 12 and 16. The patient was then given STELARA® (either 45 mg or 90 mg). .

[0408] In both trials, the endpoint was the PASI score from baseline to week 12. The proportion of subjects who showed a reduction of at least 75% in PASI75 and comprehensive physician assessment This represents the percentage of subjects who showed a therapeutic effect (disappearance or minimal effect) based on evaluation (PGA). A is a comprehensive physician's assessment of psoriasis, focusing on plaque thickness / induration, erythema, and scaling. This scale, which indicates the value of a condition, consists of six categories ranging from 0 (absence) to 5 (severe).

[0409] In all trials, the median baseline PASI score for all treatment groups was approximately 17. The range was 18. The baseline PGA score was 44% of the subjects in Ps Test 1, and P In 40% of the subjects in trial s2, the condition was significant or severe. Approximately two-thirds of all subjects used it as a treatment for psoriasis. Of those who had previously received phototherapy, 69% had previously received conventional systemic therapy or biological therapy. They had received one of the following (of which 56% had previously received conventional systemic therapy) (43% had previously received biological therapy). A total of 28% of the subjects had psoriatic arthritis. He had a history.

[0410] Clinical response The results of Ps Test 1 and Ps Test 2 are shown in Table 7, labeled below.

[0411] [Table 14]

[0412] In examining subgroups by age, sex, and race, among these subgroups No difference was observed in responses to STELARA®.

[0413] In subjects weighing 100 kg or less, the response rate was the same in both the 45 mg and 90 mg dose groups. However, for subjects weighing over 100 kg, the dose was 90 mg compared to 45 mg. A higher response rate was observed at this dose (Table 8 in the label below).

[0414] [Table 15] * The study drug was administered to the patients at week 0 and week 4.

[0415] Participants in the Ps trial 1 who were PASI75 responders at both weeks 28 and 40 were selected. , in the 40th week STELARA(registered trademark) (in the 40th week STELARA(registered trademark)) Patients were randomized again to either continue treatment or discontinue treatment (placebo at week 40). Week 52 In the eyes, 63% (100%) of the subjects re-randomized to placebo (treatment discontinued after 28 weeks of administration) Compared to 89% of subjects re-randomized to STELARA® treatment (159) 144 / 162) were PASI75 responders. These were the subjects randomized to discontinue treatment. The median time to disappearance of the PASI75 response was 16 weeks.

[0416] 14.2 Target population of young adults with psoriasis vulgaris In a multicenter, randomized, double-blind, placebo-controlled trial (Ps Trial 3), body surface area (B In SA, lesions account for at least 10%, the PASI score is 12 or higher, and the PGA score is 3. Based on the above, phototherapy or systemic therapy is a candidate, and local therapy for the disease is inappropriate. The study included 110 young adults aged 12-17.

[0417] The target group will receive subcutaneous injections at weeks 0 and 4, followed by administration every 12 weeks thereafter (q12w). Placebo (n=37), recommended dose of STELARA® (n=36), or S Participants were randomized to receive half the recommended dose of TELARA® (n=37). The recommended dosage of ELARA® is 0.75 mg / kg for individuals weighing less than 60 kg. For subjects weighing 60kg to 100kg, the dosage is 45mg; for subjects weighing over 100kg, The dose was set at 90 mg. At week 12, the subjects who received placebo were given the recommended dose or 1 / 2 of the recommended dose. The treatment was crossed over to the administration of STELARA® (registered trademark) 2.

[0418] Of the young adults surveyed, approximately 63% had previously undergone phototherapy or conventional systemic therapy. Approximately 11% had a history of exposure to biological products.

[0419] The endpoint is when the PGA score disappears (0) or is minimized (1) at week 12, or PASI The percentage of patients who achieved PASI 75 and PASI 90 was used. The subjects were those who achieved the most [number] after the first dose of the study drug. The patient was followed up for 60 weeks.

[0420] Clinical response The efficacy results at week 12 of the Ps trial 3 are shown in Table 9...

Claims

1. A pharmaceutical composition containing an anti-IL-12 / IL-23p40 antibody, A. (i) Complementarity-determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, SEQ ID NO: Heavy chain variable containing the CDRH2 amino acid sequence of 2 and the CDRH3 amino acid sequence of SEQ ID NO: 3 The region, the complementarity-determining region of SEQ ID NO: 4, the light chain 1 (CDRL1) amino acid sequence, and SEQ ID NO: 5 Light chain variable region including the CDRL2 amino acid sequence and the CDRL3 amino acid sequence of SEQ ID NO: 6 (ii) The heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and the light chain variable region of the amino acid sequence of SEQ ID NO: 8 The chain variable region, or (iii) the heavy chain of the amino acid sequence of SEQ ID NO: 10 and the amino acid sequence of SEQ ID NO: 11 Antibodies containing light chains with no acid sequences, B. In adult men and women with moderate to severe active ulcerative colitis (UC) One or more of the data disclosed in Appendix I, including data from randomized, double-blind, placebo-controlled clinical trials. Packaging including the formulation label elements and The pharmaceutical composition comprising the above.

2. A pharmaceutical composition containing an anti-IL-12 / IL-23p40 antibody, (i) Complementarity-determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2 Heavy chain variable region including the CDRH2 amino acid sequence and the CDRH3 amino acid sequence of SEQ ID NO: 3 The amino acid sequence of the complementarity-determining region light chain 1 (CDRL1) of SEQ ID NO: 4, and the CD of SEQ ID NO: 5 Light chain variable region including the RL2 amino acid sequence and the CDRL3 amino acid sequence of SEQ ID NO: 6, ii) The heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and the light chain variable region of the amino acid sequence of SEQ ID NO: 8 The variant region, or (iii) the heavy chain of the amino acid sequence of SEQ ID NO: 10 and the amino acids of SEQ ID NO: 11 The present invention comprises an antibody containing a light chain of a sequence, wherein the antibody is effective in treating moderate to severe active ulcerative colitis (UC). Data from a randomized, double-blind, placebo-controlled clinical trial in adult men and women with ) Provided in packaging that includes one or more formulation label elements disclosed in Appendix I, including the following: The aforementioned pharmaceutical composition.

3. The aforementioned pharmaceutical composition is for intravenous administration and 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, dehydrated, at pH 6.0 The pharmaceutical composition according to claim 2, comprising a solution containing [a specific component].

4. The aforementioned pharmaceutical composition is for subcutaneous administration and contains 6.7 mM L-histidine and 7.6% (w / v A solution containing sucrose (0.004% w / v) polysorbate 80 at pH 6.

0. A pharmaceutical composition according to claim 2, comprising a liquid.

5. Treatment of moderate to severe active ulcerative colitis (UC) is provided to those who require it. A method that is performed by the subject, wherein the subject has been clinically proven safe and clinically proven effective The process involves administering the pharmaceutical composition according to claim 2 in an appropriate amount, and after treatment with the antibody, the The method wherein the elephant is the responder to treatment.

6. The antibody is administered at a dose of approximately 6.0 mg per kg of body weight of the subject, or 130 mg per dose. The method according to claim 5, wherein the dosage is administered intravenously to the subject in week 0 of the treatment.

7. The aforementioned antibody is administered subcutaneously to the subject at a dose of approximately 90 mg per administration during the 8th week of the treatment. The method according to claim 6, which is administered.

8. The aforementioned subjects include anti-TNF, vedolizumab, corticosteroids, and azathioprine (AZA At least one therapy selected from the group consisting of ), and 6-mercaptopurine (6MP). They have previously failed at or were intolerant of these, or the subject is The method according to claim 7, which has shown luticosteroid dependence.

9. The antibody is administered at a maintenance dose every 8 weeks after the treatment in week 8, or 8 The method according to claim 7, wherein a maintenance dose is administered every 12 weeks after the aforementioned treatment in week 7.

10. The subject has achieved clinical remission based on at least one of the world definition and the US definition. It is identified as having the following by the 16th week of treatment, preferably by the 8th week, and the clinical The method according to claim 9, wherein the remission is maintained for at least 44 weeks from week 0.

11. The aforementioned subjects have achieved clinical remission without corticosteroid administration for at least 44 weeks from week 0 onwards. The method according to claim 9.

12. The subject is defined as having endoscopic healing that continues for at least 44 weeks from week 0 onwards. The method according to claim 9, as specified.

13. The aforementioned subjects, based on the Mayo endoscopic subscore, continued for at least 44 weeks from week 0. The method according to claim 9, which is specified as achieving a clinical response.

14. The aforementioned subjects have been continuously using the Inflammatory Bowel Disease Questionnaire (IBDQ) for at least 44 weeks from week 0 onwards. ) identified as having a change from baseline in the score, as described in claim 9 Method of loading.

15. The aforementioned subjects are identified as having mucosal healing that continues for at least 44 weeks from week 0 onwards. The method according to claim 9.

16. The subject in question has a baseline Mayo score that continues for at least 44 weeks from week 0. The method according to claim 9, which is specified as having a reduction from the line.

17. The aforementioned subjects have been exhibiting C-reactive protein and fecal lacryma for at least 44 weeks from week 0 onwards. One or more biomarkers selected from the group consisting of toferin and fecal calprotectin The method according to claim 9, which is specified as having normalization.

18. The subject in question has a baseline Mayo score that continues for at least 44 weeks from week 0. A decrease of ≥30% and ≥3 points from the baseline in the rectal bleeding subscore and from baseline. A clinical response is indicated by a decrease of ≥1 point, or a rectal bleeding subscore of 0 or 1. The method according to claim 9.

19. Treatment of moderate to severe active ulcerative colitis (UC) is provided to those who require it. This is a method of doing so, A. In the first week of the treatment, the subject was given approximately 6.0 mg per kg of body weight, This involves intravenously administering the pharmaceutical composition at a dose of 130 mg per administration (where the pharmaceutical composition is administered intravenously). The composition includes (i) the amino acid sequence of the complementarity-determining region heavy chain 1 (CDRH1) of Sequence ID No. 1, and the sequence Heavy chain containing the CDRH2 amino acid sequence of number 2 and the CDRH3 amino acid sequence of sequence number 3 Variable region and complementarity-determining region of SEQ ID NO: 4, light chain 1 (CDRL1) amino acid sequence, SEQ ID NO: Light chain variable including the CDRL2 amino acid sequence of 5 and the CDRL3 amino acid sequence of SEQ ID NO: 6 (ii) The heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 8 The light chain variable region, or (iii) the heavy chain of the amino acid sequence of SEQ ID NO: 10 and SEQ ID NO: 11 A pharmaceutical composition of an antibody containing a light chain of amino acid sequence, wherein the pharmaceutical composition is moderate to severe A randomized, double-blind study in adult men and women with active ulcerative colitis (UC). Includes one or more formulation label elements disclosed in Appendix I, including data from placebo-controlled clinical trials. It is provided in its packaging. B. The subject is given the pharmaceutical composition at a dose of 90 mg per administration during the 8th week of the treatment. Subcutaneous administration and Includes, The aforementioned subjects are responders to treatment, and the treatment involves anti-TNF, vedolizumab, and cortisol. It consists of costeroids, azathioprine (AZA), and 6-mercaptopurine (6MP). At least one therapy selected from the group has failed in the past, or has had a similar experience with these therapies. It was intolerable, or the subject had previously shown corticosteroid dependence. The aforementioned method.

20. 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, dehydrated, at pH 6.0 The method according to claim 19, comprising a solution containing [the specified solution].

21. The pharmaceutical composition for subcutaneous administration contains 6.7 mM L-histidine, 7.6% (w / v A solution containing sucrose (0.004% w / v) polysorbate 80 at pH 6.

0. The method according to claim 19, further comprising a liquid.

22. The subject has achieved clinical remission based on at least one of the world definition and the US definition. The method according to claim 19, which is specified as having the condition by the 16th week of treatment.

23. The subject is identified as having achieved endoscopic healing by the 16th week of the treatment. The method according to claim 19.

24. The subject showed a clinical response based on the Mayo endoscopic subscore by the 16th week of the treatment. The method according to claim 19, as specified to be achieved.

25. The aforementioned subjects, by the 16th week of the aforementioned treatment, have an Inflammatory Bowel Disease Questionnaire (IBDQ) score of The method according to claim 19, which is identified as having a change from a baseline.

26. The subject is identified as having mucosal healing by the 16th week of the treatment, The method described in item 19.

27. The subject showed a reduction from baseline in the Mayo score by the 16th week of the treatment. The method according to claim 19, which is specified as having a small amount.

28. The subject, by the 16th week of the treatment, showed C-reactive protein, fecal lactoferrin and Normalization of one or more biomarkers selected from the group consisting of fecal calprotectins The method according to claim 19, which is specified as doing the following.

29. The subject, by the 16th week of the treatment, showed a Mayo score of ≥3 from baseline. 0% and a decrease of ≥3 points and a decrease of ≥1 point from baseline in the rectal bleeding subscore, Claim 19, which shows a clinical response determined by a rectal bleeding subscore of 0 or 1. Methods used.

30. The subject is a responder to the antibody-mediated treatment by the 8th week of the treatment. Claim 19 states that, by the 16th week of the treatment, the patient is a responder to the treatment. Method of description.

31. Treatment of moderate to severe active ulcerative colitis (UC) is provided to those who require it. This is a method of doing so, A. In the first week of the treatment, the subject was given approximately 6.0 mg per kg of body weight, This involves intravenously administering the pharmaceutical composition at a dose of 130 mg per administration, and the pharmaceutical The composition includes (i) the amino acid sequence of the complementarity-determining region heavy chain 1 (CDRH1) of Sequence ID No. 1, and the sequence Heavy chain containing the CDRH2 amino acid sequence of number 2 and the CDRH3 amino acid sequence of sequence number 3 Variable region and complementarity-determining region of SEQ ID NO: 4, light chain 1 (CDRL1) amino acid sequence, SEQ ID NO: Light chain variable including the CDRL2 amino acid sequence of 5 and the CDRL3 amino acid sequence of SEQ ID NO: 6 (ii) The heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 8 The light chain variable region, or (iii) the heavy chain of the amino acid sequence of SEQ ID NO: 10 and SEQ ID NO: 11 A pharmaceutical composition of an antibody containing an amino acid sequence light chain, wherein the pharmaceutical composition is moderate to heavy A randomized, double-blind study in adult men and women with active ulcerative colitis (UC). , one or more formulation label elements disclosed in Appendix I, including data from placebo-controlled clinical trials The packaging provided includes the aforementioned intravenous administration, B. The subjects mentioned above should receive the above treatment once every eight weeks thereafter, or every twelve weeks thereafter, at the eighth week of treatment. The maintenance therapy involves subcutaneously administering the pharmaceutical composition at a dose of 90 mg per administration, once per session. and The maintenance therapy is administered over a period of 44 weeks, and the subject responds to the treatment Dar is The aforementioned method.

Images