Method of treating psoriasis in pediatric subjects with Anti-il12 / il23 antibody

Abstract

To provide methods for safe and effective treatment of psoriasis, specifically moderate to severe chronic plaque psoriasis, in pediatric patients.SOLUTION: A method of treating psoriasis in a pediatric patient in need thereof includes administering to the pediatric patient a pharmaceutical composition comprising a safe and effective amount of an anti-IL-12 / IL-23p40 antibody, such as Ustekinumab.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] (Reference to electronically submitted sequence listing) This application is filed under the name "Sequence Li sting_688097.0601" as an ASCII sequence table on EFS-Web The sequence listing was submitted electronically via the EFS-Western Centre for Evidence-Based Physics and has a size of 14.1 kb. The sequence listing submitted via http: / / www.ncbi.nlm.nih.gov / sequence_listing / is incorporated herein by reference in its entirety. is incorporated into.

[0002] FIELD OF THEINVENTION The present invention relates to a method for treating psoriasis, specifically, the treatment of psoriasis in patients aged 6 to 18 years by administration of an anti-IL-12 / IL-23 antibody. A safe and effective method for the treatment of moderate to severe chronic plaque psoriasis in pediatric patients under the age of 2 Regarding.

[0003] BACKGROUND OF THEINVENTION Psoriasis is associated with a number of health problems, including psoriatic arthritis (PsA), depression, cardiovascular disease, and hypertension. Common chronic conditions with significant comorbidities such as hypertension, obesity, diabetes, metabolic syndrome, and Crohn's disease It is an immune-mediated skin disease whose etiology is induced by different intrinsic and extrinsic factors. Psoriasis is an autoimmune condition caused by inflammation of the skin. There are various forms of psoriasis, including guttate psoriasis and pustular psoriasis. Among them, plaque psoriasis is the most common disease and usually appears on the knees and elbows. It is characterized by the appearance of reddish, sharply demarcated patches with colored scales. It is pruritic, painful, often disfiguring and disabling, and most people with psoriasis Psoriasis is therefore a major health-related disorder in people with psoriasis. These adverse effects include physical, mental, and emotional health. Beyond the skin symptoms, it can impose physical and psychosocial burdens that can even interfere with daily activities. Some examples include:

[0004] Histological characterization of psoriatic lesions reveals psoriasis caused by abnormal keratinocyte proliferation and differentiation. Skin thickening and dermal infiltration and colocalization of CD3+ T lymphocytes and dendritic cells were evident. The pathogenesis of psoriasis is not fully understood, but genetic and protein analysis has revealed Interleukin (IL)-12, IL-23, and their downstream molecules were analyzed by dry precipitation. It has been shown that psoriasis-related proteins are overexpressed in psoriatic lesions and may in part correlate with the severity of psoriatic disease. Several therapies used to treat psoriasis have IL-1 receptors that may contribute to their efficacy. Th1 and Th17 cells regulate the levels of IL-12 and IL-23. Effectors that induce the production of dilation factors, chemoattractants, and expression of adhesion molecules on endothelial cells These in turn promote the recruitment of monocytes and neutrophils, T cell infiltration, and proliferation. Promotes proliferation, angiogenesis, and activation and hyperplasia of keratinocytes. The cytoplasmic endothelial cells produce chemoattractant factors that promote the trafficking of neutrophils, monocytes, T cells, and dendritic cells. Thus, a cycle of inflammation and keratinocyte hyperproliferation is established.

[0005] Psoriasis can develop at any age, with about one-third of patients developing symptoms before age 20. (Farber and Nall, Dermatologica. 1974, 148:1-18). Treatment of pediatric patients is limited by the limited number of approved therapies and limited availability for this population. This is complicated by the relative paucity of data from available randomized controlled trials (Mente r et al.,J.Am.Acad.Dermatol.,2011,65:137 -1742;Fotiadou et al.,Adolesc.Health Med .Ther.,2014,5:25-34).

[0006] A human monoclonal antibody that targets the p40 subunit of IL-12 / 23. Ustekinumab is safe and effective for moderate to severe plaque psoriasis in adult patients In the PHOENIX trial, ustekinumab was shown to be an effective treatment for It effectively reduced the signs and symptoms of psoriasis in patients (Leonardi et al. ,Lancet,2008,371:1665-1674;Papp et al.,L ancet, 2008 371:1675-1684). Furthermore, in the clinical trial CADMUS The study evaluated subcutaneous administration of ustekinumab in adolescent patients aged 12 to 17 years with active psoriasis. The efficacy and safety of this treatment are being evaluated.

[0007] Since 2008, ustekinumab has been approved for the treatment of patients aged 12 years or older with moderate to severe plaque psoriasis. It is approved in Canada, Europe and the United States for the treatment of adults and children with On April 24, the FDA approved ustekinumab for the treatment of psoriatic arthritis. .

[0008] Prior to this invention, no studies of ustekinumab had been conducted for psoriasis in pediatric patients under the age of 12. The art has not yet established a method for the treatment of psoriasis, specifically moderate to severe psoriasis, in pediatric patients under the age of 12. There is a need for improved methods of treating chronic plaque psoriasis.

[0009] BRIEF SUMMARY OF THEINVENTION The present application provides a method for treating pediatric patients with IL-12 / IL-23p40 by administering an anti-IL-12 / IL-23p40 antibody to the patient. The present invention relates to methods and compositions for treating moderate to severe chronic plaque psoriasis in individuals, This addresses an unmet medical need in this patient population.

[0010] In one general aspect, the present application relates to a method for treating psoriasis, preferably moderate to severe chronic plaque psoriasis. A method for treating mycosis in a pediatric patient in need thereof, comprising administering a safe and effective amount of an anti-inflammatory drug to a pediatric patient. administering to a pediatric patient a pharmaceutical composition comprising an IL-12 / IL-23p40 antibody, The antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising a complementarity determining sequence of SEQ ID NO:1. The CDRH1 amino acid sequence of SEQ ID NO:2, the CDRH2 amino acid sequence of SEQ ID NO:3, and the The light chain variable region comprises the CDRH3 amino acid sequence of SEQ ID NO: 3, and the light chain variable region comprises the complementarity determining region of SEQ ID NO: 4. The CDRL1 amino acid sequence of SEQ ID NO:5, the CDRL2 amino acid sequence of SEQ ID NO:6, and the sequence The method further relates to a method comprising the CDRL3 amino acid sequence of number 6.

[0011] In some embodiments, the pediatric patient is a pediatric patient aged 6 years or older with moderate to severe chronic plaque psoriasis. ~Under 12 years of age.

[0012] In some embodiments, the pediatric patient has a Physician Global Assessment (PGA) score of at least 3. , a Psoriasis Area and Severity Index (PASI) score of at least 12, and at least 10% Moderate to severe chronic plaque dryness, defined by affected body surface area (BSA) Has psoriasis.

[0013] In some embodiments, the duration of moderate to severe chronic plaque psoriasis in pediatric patients The period is at least six months, preferably at least one year.

[0014] In certain embodiments, the anti-IL-12 and / or anti-IL-23 antibodies have the following safe and effective It is administered subcutaneously (SC) to pediatric patients in effective doses. (i) If the pediatric patient weighs less than 60 kg at the time of administration, Approximately 0.5 mg / kg to 1.0 mg / kg, preferably 0.75 mg / kg, of body weight. (ii) If the pediatric patient weighs between 60 kg and 100 kg at the time of administration, approximately 35 mg to 55 mg, preferably about 45 mg, or (iii) If the pediatric patient weighs more than 100 kg at the time of dosing, about 80mg to 100mg, preferably 90mg.

[0015] In certain embodiments, the anti-IL-12 and / or anti-IL-23 antibodies are administered at weeks 0 and 4. It is administered subcutaneously to pediatric patients.

[0016] In certain embodiments, the anti-IL-12 and / or anti-IL-23 antibodies are administered every 12 weeks (q 12w), preferably at weeks 0 and 4, followed by administration at weeks 16, 28, 40, and / or thereafter, administered subcutaneously to pediatric patients.

[0017] In certain embodiments, anti-IL-12 and / or anti-IL-23 antibodies are used in the methods of the invention. The antibody comprises (i) a heavy chain variable domain having the amino acid sequence of SEQ ID NO: 7, and (ii) a heavy chain variable domain having the sequence It comprises a light chain variable domain having the amino acid sequence number 8.

[0018] In certain embodiments, anti-IL-12 and / or anti-IL-23 antibodies are used in the methods of the invention. The antibody comprises (i) a heavy chain having the amino acid sequence of SEQ ID NO: 10, and (ii) a heavy chain having the amino acid sequence of SEQ ID NO: 11. The anti-IL-12 and / or anti-IL-12 antibodies used in the methods of the present invention include a light chain having an amino acid sequence. The IL-23 antibody can be ustekinumab.

[0019] In certain embodiments, the pediatric elephant patient is evaluated for response to treatment of the methods according to embodiments of the present application. (1) A physician who is a physician with a total score of 0 or 1 and is identified as having at least one of the following: (2) reduction in Psoriasis Area and Severity Index score (PASI), and and (3) Change from baseline in the Pediatric Dermatology Life Quality Index (CDLQI) after treatment. Preferably, at least one of the above (1) to (3) is achieved by the 52nd week of treatment. , preferably by 40 weeks, more preferably by 28 weeks or 16 weeks, and most preferably Most cases are identified in pediatric patients by 12 weeks of age.

[0020] In certain embodiments, the pediatric patient is a responder to treatment of the methods according to the present application. and had a Physician Global Assessment (PGA) score of 0 or 1 by the 12th week of treatment. and are identified as such.

[0021] In another embodiment, the pediatric patient is a responder to treatment of the methods according to the present application. Yes, PASI 75, PASI 90, or PASI 100, etc. at week 8 of treatment are identified as having a reduction in Psoriasis Area and Severity Index score (PASI).

[0022] In another embodiment, the pediatric patient is a responder to treatment of the methods according to the present application. There was a significant improvement in the Pediatric Dermatology Life Quality Index (CDLQ) from baseline by the 12th week of treatment. I) change is identified as having

[0023] In certain embodiments, the pediatric patient is treated with anti-IL-12 and / or anti-IL-23 antibody steady-state therapy. and a mean serum concentration at 52 weeks, preferably at 40 weeks, more preferably at 28 weeks of treatment. In a further embodiment, steady state trough serum concentrations are achieved by the 52nd week of treatment. This is maintained for up to a week.

[0024] In certain embodiments, a safe and effective amount of an anti-IL-12 antibody and / or an anti-IL-23 antibody is administered. The subject antibody comprises: (i) the heavy chain CDR amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3; and (ii) having the light chain CDR amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6. The isolated antibody is administered at about 77 mg to about 104 mg per mL of pharmaceutical composition, About 0.27 to about 0.80 mg of L-histidine is contained per mL of the pharmaceutical composition. About 0.69 to about 2.1 mg of thymine monohydrochloride monohydrate per mL of pharmaceutical composition, and about 0.5 to about 1.0 mg of polysol per mL of pharmaceutical composition. About 0.02 to about 0.06 mg of bait 80 and about 0.02 to about 0.06 mg of sucrose per mL of pharmaceutical composition The pharmaceutical composition is administered subcutaneously at about 65 to about 87 mg of the drug, and the diluent is water under standard conditions. Preferably, the pharmaceutical composition has a pH of about 5.5 to about 6.5. binds to a peptide chain comprising residues 1-88 of SEQ ID NO:9.

[0025] Another aspect of the present application includes the use of a pediatric patient under 12 years of age, preferably between 6 and 12 years of age. Anti-IL-1 for use in a safe and effective method for treating moderate to severe chronic plaque psoriasis Pharmaceutical compositions containing anti-IL-23 antibodies and / or anti-IL-23 antibodies, as well as methods for preparing the compositions and methods for use in medical treatments Kits containing pharmaceutical compositions are included.

[0026] In certain embodiments, the kit useful for the method of the invention includes the pharmaceutical composition for subcutaneous administration of the invention. Includes at least one of the following. [Brief description of the drawings]

[0027] The above Summary of the Invention and the following Detailed Description of the Invention should be read in conjunction with the accompanying drawings. The invention will be better understood by reading the following detailed description of the preferred embodiment shown in the drawings. It should be understood that the present invention is not limited to the above. [Figure 1] A diagrammatic representation of the study design is shown. [Diagram 2] Median and interquartile (IQ) ranges of serum ustekinumab concentrations from week 0 to week 52 are shown. [Figure 3A] The percentage of subjects achieving a clear (0) or minimal (1) PGA score (Figure 3A), PASI75 response (Figure 3B), PASI90 response (Figure 3C), and PASI100 (Figure 3D) response over time from Week 4 to Week 52 are shown. [Figure 3B] The percentage of subjects achieving a clear (0) or minimal (1) PGA score (Figure 3A), PASI75 response (Figure 3B), PASI90 response (Figure 3C), and PASI100 (Figure 3D) response over time from Week 4 to Week 52 are shown. [Figure 3C] The percentage of subjects achieving a clear (0) or minimal (1) PGA score (Figure 3A), PASI75 response (Figure 3B), PASI90 response (Figure 3C), and PASI100 (Figure 3D) response over time from Week 4 to Week 52 are shown. [Figure 3D] The percentage of subjects achieving a clear (0) or minimal (1) PGA score (Figure 3A), PASI75 response (Figure 3B), PASI90 response (Figure 3C), and PASI100 (Figure 3D) response over time from Week 4 to Week 52 are shown.

[0028] DETAILED DESCRIPTION OF THE PRESENT EMBODIMENT Various publications, articles and patents are cited or referenced in the Background and throughout this specification. Each of these references is incorporated herein by reference in its entirety. Any discussion of documents, operations, materials, devices, articles or the like which has been included in the specification is in accordance with the context of the present invention. Such discussion is intended to provide an overview of the present invention. or admitted to constitute part of the prior art to any claimed invention. It is not.

[0029] Unless otherwise defined, all technical and scientific terms used herein refer to the It has the same meaning as commonly understood by one of ordinary skill in the art to which it pertains. Certain terms used herein have the meanings set forth herein. All patents, published patent applications and publications cited herein are hereby incorporated by reference. No. 6,393,633, filed on Oct. 23, 2003, and is incorporated in its entirety as if set forth herein.

[0030] As used in this specification and the appended claims, the singular forms "a," "an," and " It should be noted that "the" includes plural referents unless the context clearly indicates otherwise. There is a need.

[0031] Unless otherwise noted, the term "at least" preceding a series of elements refers to every element in the series. It should be understood that the present invention refers to elements of the It will be appreciated that the present invention is not limited to the above embodiment, and that many equivalents to the specific embodiments described herein may be recognized. Such equivalents are intended to be encompassed by this invention. can be.

[0032] Throughout this specification and the following claims, unless the context otherwise requires, the term "comprises" or "includes" will be used interchangeably. "comprises" and variations such as "comprises" and "comprising" are used herein as examples. Including the specified integer or step or group of integers or steps, but including any other integer or step number. is not meant to exclude any whole number or step or group of steps. It will be understood that, as used herein, the term "comprising" includes but is not limited to the term " "containing" or "including" may be substituted or When used herein, the term "having" may be substituted.

[0033] As used herein, "consisting of" refers to a claim element. The term "compound" as used herein excludes any element, step, or ingredient not specified in the specification. In this case, "consisting essentially of" is the basis of the claim. The present invention does not exclude materials or steps that do not materially affect the present invention's novel characteristics. When used herein in connection with an aspect or embodiment, to vary the scope of the disclosure "comprising," "containing," "including," and and "having" may be replaced with the terms "consisting of" or "consisting essentially of." can be replaced with.

[0034] As used herein, the conjunctive term "and / or" between multiple listed elements means Both individual and combined options are understood to be encompassing. For example, When elements are connected by "and / or," the first option can be selected from the first option without the second option. The second option refers to the applicability of the first element. The second option refers to the applicability of the second element without the first element. The third option indicates that the first and second elements are applicable together. Any one of these alternatives is within the meaning and therefore is used herein. It is understood that when two of the options are used, the requirement of the term "and / or" is met. The above simultaneous applicability is also included in the meaning and therefore meets the requirement of the term "and / or". It is understood that.

[0035] As used herein, a "subject" refers to a subject to be treated by the methods according to embodiments of the present invention. The term "animal" refers to any animal, preferably a mammal, and most preferably a human, that is administered or treated. As used herein, the term "mammal" includes all mammals. Examples of dairy animals include, but are not limited to, cows, horses, sheep, pigs, Non-human primates such as cats, dogs, mice, rats, rabbits, guinea pigs, monkeys or apes (NHP), humans, etc., more preferably humans.

[0036] As used herein, "pediatric patient" refers to a human subject between the ages of 6 months and less than 12 years. For example, a pediatric patient may be approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 years of age. The human subject may be of any age between 11 and 18 years of age. The human subject may be 2 years of age. Preferably, the pediatric patient is between 6 and 12 years of age. More preferably, the pediatric patient has not responded to other treatments for psoriasis, such as topical treatments for psoriasis. Or the response is poor.

[0037] As used herein, the term "concomitantly" refers to the administration of two or more therapeutic agents to a subject. The use of the term "combined" refers to the use of multiple therapeutic agents in the context of There is no limitation on the order in which the therapeutic agent is administered to the subject. For example, the first therapeutic agent (e.g., The compositions described herein may be administered within 5 minutes, 15 minutes, 3 hours, or 6 minutes prior to administration of a second therapeutic agent to the subject. 0 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 16 hours, 24 hours, 48 Hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks , or 12 weeks prior), at the same time, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour 2 hours, 4 hours, 6 hours, 12 hours, 16 hours, 24 hours, 48 ​​hours, 72 hours, 9 6 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks later) can be administered.

[0038] As used herein, "anti-IL-12 antibody," "anti-IL-23 antibody," "anti-IL- "IL-12 / 23p40 antibody" or "IL-12 / 23p40 antibody" is a cytokine that inhibits Co-regulated by interleukin-12 and interleukin-23 (IL-12 / 23p40) Monoclonal antibodies (mAbs) that bind to the 40 kDa (p40) subunit of the IL-1 receptor refers to an antigen-binding fragment thereof. The antibody may be an RNA, DNA, or protein synthesis, IL-12 / 23 release, IL-12 / 23 receptor signaling, membrane IL-12 / 2 3 cleavage, IL-12 / 23 activity, IL-12 / 23 production and / or synthesis, etc. In particular, the present invention relates to a method for the treatment of IL-12 / 23 infections, the method comprising administering to the patient a therapeutically effective amount of the ... It can be done.

[0039] The term "antibody" includes antibody mimetics, such as single chain antibodies and fragments thereof. A portion of an antibody or a specific fragment or fragments thereof that mimics the structure and / or function of the antibody. The present invention includes antibodies, digested fragments, specified portions, and variants thereof, including any portion thereof. It is further contemplated that the functional fragments include those that bind to mammalian IL-12 / 23. For example, Fab (e.g., by papain digestion) , Fab' (e.g., by pepsin digestion and partial reduction) and F(ab')2 (e.g. , by pepsin digestion), facb (e.g., by plasmin digestion), pFc' (e.g. (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction and and reassembly), Fv or scFv (e.g., by molecular biology techniques) fragments. and the like, which are capable of binding to IL-12 / 23 or a portion thereof. Antibody fragments that can be used to generate antibodies are encompassed by the present invention (see, e.g., Colligan, I, supra). (see immunology).

[0040] Such fragments may be used as known in the art and / or as described herein. The antibody can be produced by enzymatic cleavage, synthetic or recombinant techniques, as described in The present invention relates to an antibody gene that uses an antibody gene in which one or more stop codons have been introduced upstream of the natural stop site. For example, a nucleotide sequence encoding a F(ab')2 double chain portion may be used to generate a variety of truncated forms. The combination of genes encoding the CH1 domain and / or hinge region of the heavy chain. The various portions of the antibody can be chemically engineered using conventional techniques to contain the DNA sequence. or as contiguous proteins using genetic engineering techniques. It can be prepared as follows.

[0041] As used herein, the term "human antibody" refers to an antibody in which substantially all portions of the protein (e.g., For example, CDR, framework, CL, CH domains (e.g., CH1, CH2, CH3 ), hinge (VL, VH)) are substantially non-human with only minor sequence changes or mutations. "Human antibody" refers to an antibody that is immunogenic. "Human antibody" also refers to a human germline immunoglobulin. Human antibodies can be either sequence-derived or exactly matched. Amino acid residues not encoded by the sequence-type immunoglobulin sequence (e.g., by the introduction of random or site-specific mutations in vivo or in somatic cells In many cases, this is because a human antibody can contain mutations that are specific to the human antibody. Human antibodies are essentially non-immunogenic in nature, meaning that they are similar in their amino acid sequence to human antibodies. Therefore, sequence similarity searches can be used to identify similar An antibody with a similar linear sequence can be selected as a template for generating a human antibody. Similarly, names can include primates (monkeys, baboons, chimpanzees, etc.), rodents (mouse Antibodies from such species include those from mammals such as rabbits, rats, rabbits, guinea pigs, hamsters, etc., and other mammals. In addition, chimeric antibodies may be used to designate specific antibodies of any of the above. Such changes or mutations may optionally and preferably include modifications. The antibody retains or reduces immunogenicity in humans or other species compared to the antibody without the antibody. Thus, a human antibody is distinct from a chimeric antibody or a humanized antibody.

[0042] A human antibody is a functionally rearranged human immunoglobulin (e.g., a heavy and / or light chain ) produced by a non-human animal, or a prokaryotic or eukaryotic cell, capable of expressing a gene Moreover, when the human antibody is a single chain antibody, it is possible to obtain a single chain antibody that is similar to a natural human antibody. For example, Fv can include a linker peptide not found in the heavy chain variable region and the light chain variable region. A linker peptide of 2 to about 8 glycine or other amino acid residues that connects the variable region Such linker peptides are considered to be of human origin.

[0043] Anti-IL-12 / 23p40 antibodies (IL-1 IL-23p40 antibody (or antibody against IL-23) is optionally High affinity binding to L-12 / 23p40, optionally and preferably with low toxicity Specifically, the individual structures such as the variable region, the constant region, and the framework region can be characterized as The components, individually and / or collectively, optionally and preferably have low immunogenicity. The antibody of the present invention, or a specified fragment or variant thereof, is useful in the present invention. The antibodies that can be used in the present invention can be used to, if desired, provide a measurable alleviation of symptoms, as well as and the ability to treat subjects for extended periods with low and / or tolerable toxicity. Low or acceptable immunogenicity and / or high affinity, as well as other favorable properties, "Low immunogenicity" as used herein can contribute to the therapeutic results obtained. Less than about 75% of subjects, or preferably less than about 50% of subjects, show significant HAHA or HAC. A or HAMA responses are increased and / or low titers ( less than about 300, preferably less than about 100, as measured by double antigen enzyme immunoassay. (Elliott et al., Lancet 344: 1125-1127 (1994), which is incorporated herein by reference in its entirety. Immunogenicity is defined as a response rate of 25% in subjects treated at the recommended dose for the recommended course of therapy during the treatment period. and preferably occurs in less than 10% of treated subjects. It is also defined as the incidence of titer levels of antibodies to anti-IL-12 antibodies in treated subjects. It can be defined as:

[0044] The terms "efficacious" and "effective" in the context of a dosage, dosing regimen, treatment or method As used herein, the term refers to the efficacy of a particular dosage, administration, or treatment regimen. Efficacy can be measured based on changes in the course of a disease in response to an agent of the invention. For example, the anti-IL12 / 23p40 of the invention (e.g., ustekinumab) may be used to treat the disorder being treated. Elicit an improvement, preferably a sustained improvement, in at least one indicator that reflects the severity of the injury. The treatment is administered to the subject in an amount and for a duration sufficient to cause To determine whether a subject has a disease, illness, or condition, various indicators that reflect the severity of the disease or condition are used. Such indicators may include, for example, disease severity, symptoms, or the subject's These include clinically recognized indicators of the manifestations of the disorder. The diagnosis is made by a physician based on signs, symptoms, biopsy, or other test results. It is also possible to administer questionnaires to subjects, e.g. For example, a quality of life questionnaire may be used. 23p40 or anti-IL23 antibodies may be used to achieve improvement in a subject's condition related to psoriasis. It can be administered.

[0045] This improvement may be an improvement in a disease activity index, remission of clinical symptoms, or any other measure of disease activity. One such disease index is the most useful for measuring the severity of psoriasis. A widely used tool is the Psoriasis Area and Severity Index (PASI). The Patient Acute and Prognostic Severity Index (PASI) assesses the severity of psoriasis lesions and their response to treatment. The PASI is a system used to rate people with mental retardation, anxiety, and anxiety disorders. The PASI is a numerical score ranging from 0 to 72. The severity of the disease is calculated as follows in the PASI system: The body is divided into four regions: head, torso, upper limbs, and lower limbs, each of which is approximately 100% of the total body surface area. Each of these areas represents 10%, 30%, 20%, and 40% of the total area. Skin irritation and scaling were assessed separately and each was rated on a scale of 0 to 4 (0 = none, 1 = severe). PASI is a grading system that measures lesion severity and morbidity (1 = slight, 2 = moderate, 3 = severe, and 4 = very severe). Area ratings were combined into a single score ranging from 0 (no disease) to 72 (maximal disease). The reduction in PASI score may be used to evaluate the effectiveness of treatment for psoriasis. For example, a 75% reduction in Psoriasis Area and Severity Index (PASI) score ( 75) is the current benchmark for the primary endpoint of most clinical trials in psoriasis. .

[0046] Other disease activity indices for psoriasis include, for example, the psoriasis body surface area (BSA) score and physician-reported psoriasis score. The Psoriasis Global Assessment (PGA) score is the percentage of the total body surface area affected by psoriasis. PGA is a commonly used measure of the severity of skin disease, defined as the percentage of skin The data will be used to determine the participant's overall psoriasis lesions at time point 1. Overall lesions are scored as 0 (plaques) or 1 (no psoriasis). The induration scale ranged from 0 (no evidence of erythema, color) to 5 (severe raised spots), 0 (no evidence of erythema, color) The erythema scale ranges from 0 (maybe pigmentation) to 5 (dull to deep red color), with 0 (no scales) on a scaling scale ranging from 5 (no evidence of scale) to 6 (severe, very thick, highly adhesive scale predominates) The sum of the three scales is then divided by 3 to give a final PGA score on a scale of 0 to 5. The scale is calculated as follows: 0=clear, 1=minimal, 2=mild, 3=moderate, 4=marked, 5=severe.

[0047] In addition, a pediatric dermatology study was conducted designed to assess the impact of the disease on children's quality of life. The Clinical Dermatology Quality of Life Index (CDLQI) is a dermatology-specific quality of life instrument. I is a 10-item questionnaire with four response options and a one-week recall period. In addition to assessing overall quality of life, the CDLQI also assesses factors that may affect quality of life. There are six different aspects: symptoms and emotions, leisure, school or holidays, personal relationships, sleep, and The CDLQI can be used to evaluate the outcome of a treatment or treatment. It is calculated by: The decline in quality of life will be significant.

[0048] In some embodiments, prior to receiving a treatment according to embodiments of the present application, the pediatric patient may Physician Global Assessment (PGA) score of at least 3 and Psoriasis Area and Severity Index score of at least 12 Core (PASI), and percent of body surface area (BSA) affected of at least 10% Moderate to severe chronic plaque dryness as defined by at least one, and preferably all, of the following: In some embodiments, the pediatric patient has a PGA score of at least 3, Moderate-severe, defined as at least 12 PASIs and at least 10% BSA In some embodiments, the pediatric patient has chronic plaque psoriasis of at least 6 months. , 1 year, 1.5 years, 2 years, 2.5 years, 3 years or more, etc. Moderate to severe for at least 6 months Patients with chronic plaque psoriasis.

[0049] The subject's responsiveness to treatment can be evaluated by measures of disease activity, clinical symptoms, or any other indication of disease activity. As used herein, "non-response to treatment" can be measured by a scale of "or poor responder" refers to patients with no improvement or minimal improvement following treatment.

[0050] Administration of anti-IL-12 / IL-23p40 antibodies of the present invention (e.g., ustekinumab) When referring to a dose, administration regimen, treatment, or method, the term "safe" means a dose that is safer than the standard of care or another Tolerable treatment-emergent adverse events (called AEs or TEAEs) compared with comparator subjects As used herein, a favorable risk:benefit ratio is defined as a disease that has a reasonable frequency and / or acceptable severity. When used, "adverse event", "treatment-emergent adverse event" and "adverse reaction" refer to Any adverse medical events occurring in clinical trial subjects administered an investigational drug or non-investigational drug An AE does not necessarily have a causal relationship to treatment. Therefore, an AE is Any undesirable side effects that are temporally related to the use of a medicinal product (investigational or non-investigational medicinal product) It may also refer to an unintended sign (e.g., abnormal laboratory test), symptom, or disease that is not Regardless of whether there is a causal relationship with a drug (investigational or non-investigational drug), International Conference on Harm An adverse event is a harmful or undesirable consequence of When such a severity is reached, a regulatory agency may deem the pharmaceutical composition or treatment to be unacceptable for the proposed use. Specifically, the anti-IL12 / 23p40 or anti-IL23 of the present invention may be considered unacceptable. "Safety" associated with the dose, dosing regimen, or treatment with an antibody is determined based on whether adverse events were associated with anti-IL12 Possibly, likely, or very likely to be due to the use of IL23p40 or anti-IL23 antibodies If deemed high, the acceptable frequency and / or tolerability of adverse events associated with administration of the antibody This refers to the severity of the condition.

[0051] As used herein, anti-IL-12 / IL-23p40 antibodies in "mg / kg" units. The dosage of the antibody is 100 mg of anti-IL-12 / IL-13 per kilogram of body weight of the subject receiving the antibody. Refers to the milligram amount of 23p40 antibody.

[0052] Psoriasis Treatment Psoriasis treatments reduce inflammation and clear the skin. Treatments include topical agents, phototherapy, and total Physical drugs can be divided into three main types.

[0053] Topicals are creams and ointments that can treat mild to moderate psoriasis. Treatments for psoriasis include topical corticosteroids, vitamin D analogs, anthralin, and topical These include retinoids, calcineurin inhibitors, salicylic acid, coal tar, and moisturizers. These include, but are not limited to:

[0054] Phototherapy involves exposing the skin to controlled amounts of ultraviolet light, which can be natural sunlight or artificial ultraviolet light. This is also called phototherapy, which is a method of applying light to the skin. The simplest and easiest form of phototherapy is: It involves exposing the skin to controlled amounts of natural sunlight. Other forms of phototherapy include artificial The use of effective ultraviolet A (UVA) or ultraviolet B (UVB) light alone or in combination with drugs There is a way to do this.

[0055] Systemic drugs are oral or injectable drugs that are classified as non-biologic and biologic. Biologic systemic agents include retinoids, methotrexate, cyclosporine, and acridil. These include, but are not limited to, tretinoin, apimist, and tofacitinib. Biological drugs include etanercept (Enbrel) and infliximab (Remicade). , adalimumab (Humira), golimumab (Simponi), secukinumab (Cosentiq) s), ixekizumab (Taltz), alefacept, efalizumab, briakinumab, These include biological drugs that alter the immune system, such as brodalumab. Darimumab (Humira), etanercept (Enbrel), infliximab (Remicake) (D) is an anti-TNFα agent.

[0056] Antibodies of the invention - production and purification At least one anti-IL-12 / 23p40 (or anti-IL-12 / 23p40) antibody used in the methods of the present invention IL-23) can optionally be administered from cell lines, mixed cell lines, immortalized cells, or other cell lines known in the art. The antibodies can be produced by clonal populations of immortalized cells, or immortalized cells. ubel,et al.,ed.,Current Protocols in Mol. ecular Biology, John Wiley & Sons, Inc., NY ,NY(1987-2001),Sambrook,et al.,Molecular Cloning:A Laboratory Manual,2nd Edition , Cold Spring Harbor, NY (1989), Harlow and Lane,antibodies,a Laboratory Manual,Cold Spring Harbor, NY (1989), Colligan, et al. eds.,Current Protocols in Immunology,Joh n Wiley & Sons, Inc., NY (1994-2001), Collig an et al.,Current Protocols in Protein S science,John Wiley & Sons,NY,NY,(1997-200 1), each of which is incorporated herein by reference in its entirety.

[0057] Human IL-12 / 23p40 or IL-23 protein or a fragment thereof The heterologous human antibody is an isolated IL-12 / 23p40 protein, an IL-23 protein, and / or portions thereof (including synthetic molecules such as synthetic peptides). Other specific or general mammalian antibodies may be raised against the native antigen. Preparation of immunogenic antigens and production of monoclonal antibodies can be performed in any suitable manner in light of the present disclosure. The present invention can be implemented using various techniques.

[0058] In one approach, a suitable immortal cell line (e.g., but not limited to, Sp2 / 0, S 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, NEURO 2A, or heteromyelomas, The fusion product, or any cell or fusion cell derived therefrom, or any cell or fusion cell derived therefrom, Any other suitable cell line known in the art) (see, for example, www.atcc.org, www.lif etech.com), including, but not limited to, isolated or cloned Antibody cells such as cultured spleen, peripheral blood, lymph, tonsils, or other immune or B cell-containing cells. The nucleic acid may be derived from recombinant or endogenous, viral, cellular, or endogenous cells, or from endogenous or heterologous nucleic acids. 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, single As single-, double- or triple-stranded, hybridized, etc., or any combination thereof Either the heavy or light chain constant or variable, or framework or CDR sequences Hybridomas are produced by fusing the cells with any other cells expressing the above vector. See Ausubel, supra, and Colligan, Immunology, chapter 2, supra. No. 6,393,945, both of which are incorporated herein by reference in their entireties.

[0059] Antibody producing cells can also be isolated from the peripheral blood of humans or other suitable animals immunized with an antigen of interest, or can also be obtained preferably from the spleen or lymph nodes. The antibody, specified fragment, or variant thereof may be encoded by a different nucleic acid sequence. It is also possible to express seed or endogenous nucleic acid. The recombinant cells are isolated using selective culture conditions or other suitable known methods and cultured by limiting dilution or Alternatively, the desired specificity can be determined by cell sorting or other known methods. Cells producing antibodies having the following structure are selected by a suitable assay (e.g., ELISA). It is possible.

[0060] Any other suitable method for producing or isolating antibodies with the required specificity can be used. This includes peptide or protein libraries (e.g., bacteriophage, ribosomal Display libraries of genomic DNA, oligonucleotides, RNA, cDNA, etc., e.g., C ambridge antibody technologies,Cambridge shire, UK, MorphoSys, Martinsreid / Planegg, D E, Biovation, Aberdeen, Scotland, UK, BioInve nt, Lund, Sweden, Dyax Corp., Enzon, Affymax / Available from Biosite, Xoma, Berkeley, CA, and Ixsys. These include, but are not limited to, methods for selecting recombinant antibodies from Non-limiting examples include European Patent No. 368,684 and International Application No. PCT / GB91 / 01. 134, International Application No. PCT / GB92 / 01755, International Application No. PCT / GB92 / 00 2240, International Application No. PCT / GB92 / 00883, International Application No. PCT / GB93 / 0 No. 0605, U.S. Patent Application No. 08 / 350260 (5 / 12 / 94), International Application PCT / GB94 / 01422, International Application PCT / GB94 / 02662, International Application PCT / GB97 / 01835, (CAT / MRC), International Publication No. 90 / 14443, International Publication No. 90 / 14424, International Publication No. 90 / 14430, International Application PCT / US94 / 1234, International Publication No. 92 / 18619, International Publication No. 96 / 07754 (Scr ipps), WO 96 / 13583, WO 97 / 08320 (Morp hoSys), International Publication No. 95 / 16027 (BioInvent), International Publication No. 88 / 06630, WO 90 / 3809 (Dyax), U.S. Pat. No. 92 (Enzon), International Application No. PCT / US91 / 02989 (Affymax), WO 89 / 06283, EP 371 998, EP 550 400 No., (Xoma), European Patent No. 229 046, International Application PCT / US91 / 0714 No. 9 (Ixsys), or stochastically generated peptides or proteins - U.S. Pat. No. 23323, No. 5763192, No. 5814476, No. 5817483, International Publication Nos. 5824514, 5976862, WO 86 / 05803, European Patent Application Nos. No. 590 689 (Ixsys, Applied Molecular Evolu tion (AME), each of which is incorporated herein by reference in its entirety) or Tra It relies on immunization of transgenic animals (e.g., SCID mice, Nguyen et al. al.,Microbiol.Immunol.41:901-907(1997), Sandhu et al.,Crit.Rev.Biotechnol.16:95- 118(1996), Eren et al., Immunol.93:154-161 (1998), each of which may be used as known in the art and / or as described herein. As described in the related patents and applications, , which are also incorporated by reference in their entireties. Such techniques include ribosome display ( Hanes et al.,Proc.Natl.Acad.Sci.USA,94:4 937-4942 (Can 1997), Hanes et al., Proc. Nat. l.Acad.Sci.USA,95:14130-14135(Nov.1998)) , single cell antibody generation techniques (e.g., Selected Lymphocyte Antibody Method ("SLAM") (U.S. Pat. No. 6,313,623); No. 5,627,052, Wen et al., J. Immunol. 17:887-8 92(1987), Babcook et al., Proc. Natl. Acad.S ci.USA 93:7843-7848(1996)), gel microdrop let and flow cytometry(Powell et al.,Bio technol.8:333-337(1990), One Cell Systems ,Cambridge,MA,Gray et al.,J.Imm.Meth.182 :155-163(1995), Kenny et al.,Bio / Technol. 13:787-790(1995), B-cell selection(Steenb akkers et al.,Molec.Biol.Reports 19:125- 134 (1994), Jonak et al., Progress Biotech, Vol.5, In Vitro Immunization in Hybridoma Technology,Borrebaeck,ed.,Elsevier Scie nce Publishers BV,Amsterdam,Netherland s(1988)) but are not limited to these.

[0061] Methods for engineering or humanizing non-human or human antibodies can be used as well. Generally, humanized or engineered antibodies are antibodies that are produced by a non-human, e.g. Including, but not limited to, mice, rats, rabbits, non-human primates, or other mammals. These non-human amino acid residues are These residues are often replaced by residues called "import" residues. The "import" variable domain, constant domain, and or from other domains.

[0062] Known human Ig sequences are disclosed, for example, at: www.ncbi.nlm.nih.gov / IgSequences. ih.gov / entrez / query.fcgi, www.ncbi.nih.go v / igblast;www.atcc.org / phage / hdb.html;ww w.mrc-cpe.cam.ac.uk / ALIGNMENTS.php;www.k abatdatabase.com / top.html;ftp.ncbi.nih.g ov / repository / kabat, www.sciquest.com;www .abcam.com;www.antibodyresource.com / onli necomp.html;www.public.iastate.edu / ~pedr o / research_tools.html;www.whfreeman.com / immunology / CH05 / kuby05.htm;www.hhmi.org / grants / lectures / 1996 / vlab;www.path.cam.a c.uk / ~mrc7 / mikeimages.html;mcb.harvard.e du / BioLinks / Immunology.html、www.immunolo gylink.com;pathbox.wustl.edu / ~hcenter / in dex.html、www.appliedbiosystems.com;www.n al.usda.gov / awic / pubs / antibody;www.m.ehi me-u.ac.jp / ~yasuhito / Elisa.html;www.biod esign.com;www.cancerresearchuk.org;www.b iotech.ufl.edu;www.isac-net.org;baserv.u ci.kun.nl / ~jraats / links1.html、www.recab. uni-hd.de / immuno.bme.nwu.edu;www.mrc-cpe .cam.ac.uk;www.ibt.unam.mx / vir / V_mice.ht ml;http: / / www.bioinf.org.uk / abs;antibody .bath.ac.uk、www.unizh.ch;www.cryst.bbk.a c.uk / ~ubcg07s、www.nimr.mrc.ac.uk / CC / ccae wg / ccaewg.html;www.path.cam.ac.uk / ~mrc7 / humanisation / TAHHP.html;www.ibt.unam.mx / vir / structure / stat_aim.html;www.biosci.m issouri.edu / smithgp / index.html;www.jerin i.de;Kabat et al.,Sequences of Proteins of Immunological Interest,USDept.Healt h (1983), each of which is incorporated herein by reference in its entirety.

[0063] Such imported sequences may be used to reduce immunogenicity or to enhance the expression of polypeptides, as described in the art. As known in the art, the term "binding," "affinity," "association rate constant," "dissociation rate constant," "binding activity," "specificity," The compounds may be used to reduce, enhance or modify the half-life, half-life, or any other suitable property. Generally, the CDR residues directly and most substantially influence antigen binding. Thus, it is possible to maintain some or all of the non-human or human CDR sequences while modifying the CDRs with variable The non-human sequences in the regions and constant regions can be replaced with human amino acids or other amino acids. It is also possible.

[0064] Antibodies may optionally be humanized, or human antibodies have high affinity for the antigen. To this end, the genetic material may be modified while retaining its sex and other advantageous biological properties. Optionally, a three-dimensional model of the parental and humanized sequences is used to identify the parental and various Humanized (or human) antibodies can be prepared by a process of analyzing theoretical humanized products. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. The most likely three-dimensional structures of selected immunoglobulin sequence candidates have been determined. Computer programs are available for illustrating and displaying the images. The analysis of the likely role of residues in the function of the candidate immunoglobulin sequence. In other words, it is possible to analyze residues that affect the antigen-binding ability of immunoglobulin candidates. As a result, desirable antibody properties such as enhanced affinity for the target antigen(s) are achieved. Framework (FR) residues were selected from the consensus and import sequences so that You can choose and combine them.

[0065] In addition, human anti-IL-12 / 23p40 (or anti-IL -23) The specific antibody may comprise 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 , O12, O14, O18, O2, O4, and O8, In certain embodiments, the light chain human germline framework VK sequences are selected from the group consisting of 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. It is selected.

[0066] In another embodiment, the human anti-IL-12 / 23p40 ( Or anti-IL-23) specific antibodies may comprise a human germline heavy chain framework. In embodiments, the heavy chain human germline framework is selected from the group consisting of VH1-18, VH1-2, VH1-3, VH1-4, VH1-5, VH1-6, VH1-7, VH1-8, VH1-9, VH1-10, VH1-11, VH1-12, VH1-13, VH1-14, VH1-15, VH1-16, VH1-17 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 and VH7-81.

[0067] In certain embodiments, the light chain variable region and / or the heavy chain variable region comprises a framework region: or at least a portion of a framework region (e.g., 2 or 3, such as FR2 and FR3) In certain embodiments, the FRL1, FRL2, and FRL3 subregions are included. In another embodiment, at least FRH1, FRL2, or FRL3 is fully human. FRH2, FRH3, or FRH4 is fully human. At least FRL1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., a sequence that is identical to that of a human The human consensus sequence for a particular framework (see above) is used. In another embodiment, the antibody comprises at least one of the following: Each of FRH1, FRH2, FRH3, and FRH4 is a germline sequence (e.g., a human germline sequence). or comprises a human consensus sequence for a particular framework. In a preferred embodiment, the framework regions are completely human framework regions.

[0068] The humanization or engineering of the antibodies of the present invention can be carried out according to the methods described in Winter (Jones et al., Nature 321:522(1986), Riechmann et al.,Na ture 332:323 (1988), Verhoeyen et al. nce 239:1534(1988)), Sims et al., J. Immuno l.151:2296(1993);Chothia and Lesk, J. Mol. Biol.196:901(1987), Carter et al., Proc.89 :4285(1992);Presta et al.,J.Immunol.151: 2623 (1993), U.S. Patent Nos. 5,723,323, 5,976,862, and 58 No. 24514, No. 5817483, No. 5814476, No. 5763192, Same No. 5723323, Same No. 5,766886, Same No. 5714352, Same No. 6204 No. 023, No. 6180370, No. 5693762, No. 5530101, No. No. 5585089, No. 5225539, No. 4816567, International Application PCT / : US98 / 16280, US96 / 18978, US91 / 09630, US91 / 05939, US94 / 01234, GB89 / 01334, GB91 / 011 34, GB92 / 01755, International Publication No. 90 / 14443, International Publication No. 90 / 1442 No. 4, No. 90 / 14430, and European Patent No. 229246 (each of which is expressly incorporated by reference in its entirety). (including the references incorporated herein and cited therein) This can be done using any known method, including but not limited to.

[0069] In some embodiments, the antibody comprises an altered (e.g., mutated) Fc region. For example, in some embodiments, the Fc region comprises a polypeptide that reduces the effector functions of the antibody. In some embodiments, the Fc region is altered to reduce or enhance the Ig The isotype is selected from M, IgA, IgG, IgE, or other isotypes. Alternatively or additionally, amino acid modifications and C1q binding of the Fc region of the IL-23 binding molecule. and / or one or more additional amino acid modifications that alter complement-dependent cytotoxicity function. It may be useful to combine the starting polypeptides of particular interest with those that bind C1q. and exhibits complement-dependent cytotoxicity (CDC). Among these activities, the polypeptides having the ability to mediate CDC may be The antibody may be modified to enhance one or both of the following: Amino acid modifications that modify the somatic cell-dependent cytotoxicity function are described, for example, in WO 0042072. and is incorporated herein by reference.

[0070] As disclosed above, for example, C1q binding and / or FcγR binding may be modified, Complement-dependent cytotoxicity (CDC) activity and / or antibody-dependent cell-mediated cytotoxicity ( By altering antibody-dependent cell-mediated cytotoxicity (ADCC) activity, Thus, the human anti-IL-12 / 23p40 (or human anti-IL-23p40) of the present invention with altered effector function is It is possible to design the Fc region of an anti-IL-23 specific antibody. , which act to activate or reduce biological activity (e.g., in a subject). Examples of functions include, but are not limited to, C1q binding, CDC, Fc receptor Adenosine cytokinin binding, ADCC, phagocytosis, downregulation of cell surface receptors (e.g., B cell receptor, BCR) Such effector functions include upregulation of the Fc region, which is a binding domain. In some cases, the antibody may need to bind to a wide variety of target domains (e.g., antibody variable domains). Use various assays (e.g., Fc binding assays, ADCC assays, CDC assays, etc.) It can be evaluated using

[0071] For example, having improved C1q binding and improved FcγRIII binding (e.g., Human anti-IL-12 / IL-13 antibody (having both improved ADCC activity and improved CDC activity) A variant Fc region of an IL-23 antibody can be generated. In cases where it is desired to reduce or eliminate effector function, the mutant Fc region may be The antibody can be modified to reduce C activity and / or to reduce ADCC activity. In other embodiments, only one of these activities may be enhanced, optionally including: At the same time, other activities may be reduced (e.g., improved ADCC activity and reduced CDC activity). (to generate Fc region variants that have the same or similar properties, and vice versa).

[0072] Fc mutations alter interactions with fetal Fc receptors (FcRn) and their pharmacokinetics Genes can also be engineered and introduced to improve properties. A collection of improved human Fc variants has been described (Shields et al., (2001). High resolution mapping of the binding s ite on human IgG1 for FcγRI,FcγRII, FcγRI II, and FcRn and design of IgG1 variants with improved binding to the FcγR, J.Biol .Chem.276:6591-6604).

[0073] Another type of amino acid substitution is human anti-IL-12 / 23p40 (or anti-IL-23) specific The glycosylation pattern of the Fc region of the target antibody is modified. The cleavage is typically either N-linked or O-linked. N-linked refers to the attachment of an asparagine It refers to the addition of a carbohydrate moiety to the side chain of a glycosylation residue. O-linked glycosylation is the addition of a 5-hydroxyproline Hydroxyamino acids, most commonly lysine or 5-hydroxylysine, may also be used. Sugars attached to serine or threonine, N-acetylgalactosamine, galactose, or xylose The enzyme attachment of a carbohydrate moiety to an asparagine side chain peptide sequence. The recognition sequences for selective addition are asparagine-X-serine and asparagine-X-threo. where X is any amino acid other than proline. The presence of any of these peptide sequences provides a potential glycosylation site. do.

[0074] A glycosylation pattern can refer to, for example, one or more glycosylations found on a polypeptide. Deleting a site(s) and / or removing one or more groups that are not present in the polypeptide The Fc of the human IL-23 specific antibody can be modified by adding glycosylation sites. The addition of glycosylation sites to the region can be accomplished by modifying the region to include one or more of the above tripeptide sequences. This is successfully achieved by modifying the amino acid sequence (in the case of N-linked glycosylation sites). An exemplary glycosylation variant has an amino acid substitution at residue Asn 297 of the heavy chain. The alteration may involve the addition of one or more serine or threonine residues to the original polypeptide sequence. For O-linked glycosylation sites, this can also be achieved by addition, or substitution with, In addition, changing Asn 297 to Ala removes one of the glycosylation sites. can be done.

[0075] In certain embodiments, the human anti-IL-12 / 23p40 (or anti-IL-23 ) specific antibody binds GlcNAc to human anti-IL-12 / 23p40 (or beta(1,4)-N-acetylglucosaminyl esters of anti-IL-23 antibodies It is expressed in cells that express guanidine dehydrogenase III (GnT III). Methods for producing antibodies in this manner are described in WO 9954342 and WO 030118. 78, Patent Publication No. 20030003097(A1), and Umana et al. ,Nature Biotechnology,17:176-180,Feb.199 9, all of which are specifically incorporated herein by reference in their entireties. Can be enjoyed.

[0076] Human anti-IL-12 / 23p40 (or anti-IL-23) antibodies are also optionally disclosed herein. As described herein and / or known in the art, a repertoire of human antibodies may be used. Transgenic animals capable of producing ribosomal proteins (e.g., mice, rats, hamsters, etc.) Human anti-IL-12 / 23 antibodies can also be generated by immunization of mammalian animals (human or non-human primates, etc.). Cells producing p40 (or anti-IL-23) antibodies can be isolated from such animals and used to treat the diseases described herein. The cells may be immortalized using any suitable method, such as those described herein.

[0077] Transgenics capable of producing a repertoire of human antibodies that bind to human antigens Mice can be generated by known methods, including but not limited to, U.S. Patent Nos. 5,770,428 and 5,569,828 issued to Lonberg et al. No. 25, No. 5,545,806, No. 5,625,126, No. 5,625,82 No. 5, No. 5,633,425, No. 5,661,016, and No. 5,789,6 50, WO 98 / 50433 by Jakobovits et al. s et al., International Publication No. 98 / 24893; Lonberg et al., International Publication No. 98 / 24884 No. 97 / 13852 to Lonberg et al., and International Publication No. 94 / 25585, Kucherlapate et al., International Publication No. 96 / 34096, K European Patent No. 0463 151(B1) to Kucherlapate et al. Pate et al., European Patent No. 0710 719(A1), Surani et al., U.S. Pat. 545,807, Bruggemann et al., International Publication No. WO 90 / 04036, Brug Gemann et al., European Patent No. 0438 474(B1), Lonberg et al., European Patent No. 0814 259(A2), Lonberg et al., UK Patent No. 2 272 440(A No. 10, Lonberg et al., Nature 368:856-859 (1994), Tay lor et al., Int. Immunol. 6(4)579-591(1994), Green Nature Genetics 7:13-21 (1994); Mendez et al. Nature Genetics 15:146-156(1997), Taylor et al. Nucleic Acids Research 20(23):6287-6295 (1992), Tuaillon et al., Proc Natl Acad Sci USA 90(8)3720-3724(1993), Lonberg et al., Int Rev Im munol 13(1):65-93 (1995) and Fishwald et al., Nat B iotechnol 14(7):845-851(1996), which are incorporated by reference. (Each of which is incorporated herein in its entirety.) In general, these mice contain functionally reconstituted or at least one human immunoglobulin gene capable of undergoing functional rearrangement. The mouse comprises at least one transgene comprising DNA derived from an endogenous locus. The immunoglobulin locus is disrupted or deleted to allow the mouse to be coded for by its endogenous genes. The ability to produce antibodies that have been cloned can be eliminated.

[0078] Screening antibodies for specific binding to similar proteins or fragments This can be successfully achieved using peptide display libraries. A large collection of peptides with individual members having a desired function or structure. Antibody screening of peptide display libraries. The length of the displayed peptide sequence is 3 to 100 μg / s. More than 5000 amino acids, frequently 5-100 amino acids long, most often about 8-2 In addition to direct chemical synthesis methods for generating peptide libraries, Several recombinant DNA methods have also been described. One type uses bacteriophages. Each bacteriophage or cell includes displaying a peptide sequence on its surface. The cells contain nucleotide sequences that encode the particular displayed peptide sequence. Such methods are described in International Patent Application Publication Nos. 91 / 17271, 91 / 18980 and 91 / 18981. This is described in US Pat. Nos. 91 / 19818 and 93 / 08278.

[0079] Other systems for generating peptide libraries include in vitro chemical synthesis and recombinant The present invention has both aspects of the above-mentioned method. See U.S. Pat. Nos. 5,658,754 and 96 / 19256. See also U.S. Pat. Nos. 5,643,768 and 5,643,768. The assay and screening kit were purchased from Invitrogen (Carlsbad, CA). and Cambridge Antibody Technologies (Cambridge These are commercially available from sources such as Enzon (Edgeshire, UK). Passed U.S. Patent Nos. 4,704,692, 4,939,666, and 4,946,778; Same No. 5260203, Same No. 5455030, Same No. 5518889, Same No. 55346 No. 21, No. 5656730, No. 5763733, No. 5767260, No. 5 No. 856456, U.S. Patent Nos. 5,223,409 and 540,348 assigned to Dyax Nos. 4, 5571698, and 5837500, assigned to Affymax, U.S. Patent No. 5427908, No. 5580717, Cambridge antibod U.S. Patent No. 5,885,793, assigned to Gent Technologies; No. 5,750,373, assigned to Ech, and Xoma, supra, to Colligan Assigned U.S. Patent Nos. 5,618,920, 5,595,898, and 5,576,195 , Nos. 5698435, 5693493, 5698417, and the above-mentioned Aus See, e.g., Ubel, or Sambrook, supra; each of the above patents and publications is incorporated herein by reference. The entire contents of which are incorporated herein by reference.

[0080] The antibodies used in the methods of the present invention may be derived from goats, cows, horses, sheep, etc., which produce such antibodies in their milk. To provide a transgenic animal or mammal, such as a Japanese rhododendron or rabbit, a nucleic acid is encoded. At least one anti-IL-12 / 23p40 (or anti-IL-23) antibody is used to Such animals can be prepared using known methods. See, for example, but not limited to, U.S. Pat. Nos. 5,827,690, 5,849, No. 992, No. 4,873,316, No. 5,849,992, No. 5,994,6 See, for example, US Patent No. 16, US Patent No. 5,565,362, and US Patent No. 5,304,489 (see, each of which is incorporated herein by reference in its entirety.

[0081] The antibodies used in the method of the present invention may be used in plant parts or cells cultured therefrom. Transgenic plants and cultured plants that produce such antibodies, specified portions, or variants. providing plant cells (e.g., but not limited to, tobacco and corn) To achieve this, a nucleic acid encoding at least one anti-IL-12 / 23p40 (or anti-IL-12 / 23p40) is provided. L-23) antibodies can be used to further prepare. Using the induced promoter, transgenic tobacco leaves expressing recombinant proteins were successfully generated. For example, Cramer et al., Curr. r.Top.Microbol.Immunol.240:95-118(1999) and See, for example, the US Pat. No. 6,333,625 and the references cited therein. Transgenic maize is also Other proteins produced in recombinant systems or purified from natural sources, etc. Used to express mammalian proteins with novel biological activity at commercial production levels. For example, Hood et al., Adv. Exp. Med. Biol. 464:127 See, e.g., J. Am. Soc. 1999, 147, and references cited therein. The antibody may be a single chain antibody ( Antibody fragments such as antibody fragments (e.g., scFv) have been isolated from tobacco seeds and potato tubers. It has also been produced in large quantities from the seeds of transgenic plants. ant Mol. Biol. 38:101-109 (1998) and references cited therein. Thus, the antibodies of the present invention can also be transfected according to known methods. Alternatively, the gene can be produced using transgenic plants. See, for example, Fischer et al. .,Biotechnol.Appl.Biochem.30:99-108(Oct. , 1999), Ma et al., Trends Biotechnol. 13:52 2-7(1995), Ma et al., Plant Physiol.109:341-6(19 95) Whitelam et al., Biochem. Soc. Trans. 22:940-9 44 (1994), and the references cited therein. , which is incorporated herein by reference in its entirety.

[0082] The antibodies used in the methods of the present invention bind to human IL-1 with a wide range of affinities (KD). In a preferred embodiment, the antibody can bind to IL-12 / IL-23p40 or IL-23. The human mAb optionally binds human IL-12 / IL-23p40 or IL-12 with high affinity. For example, a human mAb can bind to human IL-12 / IL-23. p40 or IL-23 is about 10 M or less, for example, but not limited to, 0.1 to 9.9 ( or any range or value therein) x 10-7, 10-8, 10-9, 10-10, With a KD of 10-11, 10-12, 10-13, or any range or value therein can be combined.

[0083] The affinity or avidity of an antibody for an antigen can be determined experimentally using any suitable method. (See, for example, Berzofsky et al., "Antibody-Antibody en Interactions,” In Fundamental Immunolo gy, Paul, WE, Ed., Raven Press: New York, NY. (1984), Kuby, Janis Immunology, WH Freeman. and Company: New York, NY (1992), and as described herein. (See methods described in the literature.) The affinity measured for a particular antibody-antigen interaction may vary depending on the The affinity may differ when measured under different conditions (e.g., salt concentration, pH). Measurement of the affinity and other antigen binding parameters (e.g., KD, Ka, Kd) is preferably performed using an antibody The assay is performed using standardized solutions of antibodies and antigens, and standardized buffers, such as those described herein. It can be done.

[0084] Vectors and host cells The present invention relates to vectors containing isolated nucleic acid molecules, host cells that can be genetically engineered with recombinant vectors, and The host cell and at least one anti-IL-1 produced by recombinant techniques well known in the art. The present invention also relates to the production of IL-12 / IL-23p40 antibodies. See Ausubel et al., supra, each of which is incorporated herein by reference in its entirety. can be.

[0085] The polynucleotide may optionally be expressed in a vector containing a selectable marker for propagation in a host. Generally, plasmid vectors are prepared by precipitating them in a calcium phosphate precipitate. In the case of a virus, the vector is introduced into the host in a precipitate or in a complex with a charged lipid. This can be packaged in vitro using an appropriate packaging cell line and then transduced into host cells. This can be done.

[0086] The DNA insert should be operably linked to an appropriate promoter. The cleavage site contains the transcription initiation site, transcription termination site, and, within the transcribed region, the ribosome for translation. The coding portion of the mature transcript expressed by the construct preferably further comprises a is a start and stop codon (e.g., UA A, UGA, or UAG) for translation, whereas UA for expression in mammalian or eukaryotic cells. A and UAG are preferred.

[0087] The expression vector preferably contains at least one selectable marker, although this is optional. Such markers include, for example, methotrexate for eukaryotic cell culture. (MTX), dihydrofolate reductase (DHFR, US Permit No. 4,399,216, No. 4,634,665, No. 4,656,134, Same No. 4,956,288, No. 5,149,636, No. 5,179,017, Anne Picillin, neomycin (G418), mycophenolic acid or glutamine synthetase (GS, U.S. Patent Nos. 5,122,464, 5,770,359, and 5,82 No. 7,739) resistance genes and their expression in E. coli and other bacteria or prokaryotes including, but not limited to, tetracycline or ampicillin resistance genes for culture in (The above patents are incorporated herein by reference in their entireties.) Appropriate culture media and conditions for this are known in the art. It will be readily apparent to those skilled in the art that the introduction of a vector construct into a host cell can be accomplished by , calcium phosphate transfection, DEAE-dextran mediated transfection ation, cationic lipid-mediated transfection, electroporation, transduction The cells may be affected by infection, or other known methods, as described in Sam. brook, chapters 1-4 and 16-18; Ausubel, supra, chapters 1, 9, 13; These are described in the art, such as in Chapters 15 and 16.

[0088] At least one antibody used in the methods of the invention may be a modified antibody, such as a fusion protein. The vector may be expressed in a form that includes not only a secretion signal but also additional heterologous functional regions. For example, A region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the antibody to enhance its affinity for ribozyme during purification or subsequent processing. It can improve the stability and persistence in the host cell during processing and storage. Peptide moieties can also be added to the antibodies of the invention to facilitate purification. Such regions can be removed prior to final preparation of the fragment. The method is described in Sambrook, supra, Chapters 17.29-17.42 and 18.1-18. Many standard laboratory manuals, such as Chapter 74, Ausubel, supra, Chapters 16, 17 and 18, It's stated in the manual.

[0089] Those skilled in the art will appreciate that various methods are available to express nucleic acids encoding proteins for use in the methods of the present invention. Alternatively, the nucleic acid may be expressed intracellularly as a nucleic acid encoding an antibody. By switching on (by engineering) the gene in a host cell that contains the gene for the gene, the host cell Such methods can be expressed in cells. Nos. 5,641,670, 5,733,746, and 5,733,761. These methods are well known in the art, as described in the above publications, and are incorporated herein by reference in their entirety. will be incorporated into the subsection.

[0090] One example of a cell culture useful for the production of an antibody, specified portion, or variant thereof is a mammalian cell line. Mammalian cell lines often take the form of a monolayer of cells, but mammalian cells Suspension or bioreactors can also be used. Intact glycosylated proteins can be expressed. Several suitable host cell lines capable of producing S-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL- 1651), HEK293, BHK21 (e.g. ATCC CRL-10), CHO (e.g. ATCC CRL1610) and BSC-1 (e.g., ATCC CRL-26) cells strain, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP 2 / 0-Ag14, 293 cells, HeLa cells, etc., which are, for example, rican Type Culture Collection,Manassas,V The preferred host cells are bone marrow cells, Particularly preferred host cells include cells derived from the lymphatic system, such as myeloma and lymphoma cells. The cells were P3X63Ag8.653 cells (ATCC accession no. CRL-1580) and SP2 1 / 0-Ag14 cells (ATCC Accession No. CRL-1851). In one embodiment, the recombinant cell is a P3X63Ab8.653 or SP2 / 0-Ag14 cell. .

[0091] Expression vectors for these cells include an origin of replication, a promoter (e.g., the late or early SV40 Promoter, CMV promoter (U.S. Patent Nos. 5,168,062 and 5,385,8 No. 39), HSV tk promoter, pgk (phosphoglycerate kinase) promoter , EF-1α promoter (U.S. Patent No. 5,266,491), at least one human immune Immunoglobulin promoter, enhancer, and / or ribosome binding site, RNA splice a polyadenylation site (e.g., the SV40 large T Ag polyaddition site), and Expression control sequences, such as, but not limited to, processing information sites, such as transcription termination sequences The sequences may include one or more of the sequences described in, for example, Ausubel et al., supra; Sambr. See Oook et al. Other cells useful for producing the nucleic acids or proteins of the invention have been previously described. knowledge and / or, for example, American Type Culture C Collection of cell lines and hybridomas cataloged (www.atcc.org ) or other known or commercial sources.

[0092] When a eukaryotic host cell is used, typically a polyadenylation or transcription termination site is included in the vector. An example of a termination sequence is the polyadenylation sequence from the bovine growth hormone gene. Sequences for accurate splicing of the transcript may also be included. One example of a splicing sequence is the VP1 intron from SV40 (Sprague, (E. et al., J. Virol. 45:773-781 (1983)). As is well known in the art, gene sequences for controlling replication in a host cell are incorporated into the vector. It can be incorporated.

[0093] Antibody purification Anti-IL-12 / IL-23p40 or IL-23 antibodies were purified using protein A and sulfate amide. ammonium or ethanol precipitation, acid extraction, anion or cation exchange chromatography, cellulose chromatography, hydrophobic interaction chromatography, affinity chromatography Chromatography, Hydroxyapatite Chromatography and Lectin Chromatography , or recovered from recombinant cell culture by well-known methods, including, but not limited to, , and can be purified by high performance liquid chromatography. By using HPLC (high performance liquid chromatography) for purification, For example, Colligan, Current Protocols in Immunology or Current Protocols in Protein Science,John Wiley & Sons,NY,NY(1997-20 01), e.g., Chapters 1, 4, 6, 8, 9, and 10, each of which is incorporated herein by reference in its entirety. The body is incorporated herein.

[0094] The antibodies used in the method of the present invention may be naturally purified products, products produced by chemical synthesis techniques, or the like. and recombinantly produced from eukaryotic hosts, including, for example, yeast, higher plants, insects, and mammalian cells. Depending on the host utilized in the recombinant production procedure, The body may be glycosylated or non-glycosylated, but glycosylation is preferred. Such a method is described in Sambrook, supra, Sections 17.37-17.42. , Ausubel, supra, chapters 10, 12, 13, 16, 18, and 20, Col, supra Many standard studies, such as Ligan, Protein Science, Chapters 12-14, Laboratory manuals, all of which are incorporated herein by reference in their entireties.

[0095] Anti-IL-12 / IL-23p40 or IL-23 antibody The anti-IL-12 / IL-23p40 or IL-23 antibodies of the present invention incorporate At least a portion of an immunoglobulin molecule, such as, but not limited to, At least one ligand binding portion (LBP), e.g., a limited However, the heavy or light chain complementarity determining regions (CDRs) or ligand-binding portions thereof, the heavy chain or a light chain variable region, a framework region (e.g., FR1, FR2, FR3, FR4, or or fragments thereof, and optionally, at least one substitution, insertion, or deletion. ), heavy or light chain constant region (e.g., at least one of CH1, hinge 1, hinge 2, Hinge 3, hinge 4, CH2, or CH3, or a fragment thereof, and optionally containing at least one substitution, insertion, or deletion, or any portion thereof. Any protein or peptide-containing molecule. Antibodies may be human, mouse, rabbit, rat, , rodents, primates, or any combination thereof, etc. , may include or be derived from any mammal.

[0096] Preferably, the human antibody or antigen-binding fragment is human IL-12 / IL-23p4. 0 or IL-23, thereby inhibiting at least one biological activity of the protein. Partially or substantially neutralizes at least one of IL-12 / IL-23p40 or IL 5. Partial or preferential retention of at least one biological activity of the 23 protein or fragment thereof. or substantially neutralizing antibodies, or specified portions or variants thereof, may be used to detect the presence or absence of a protein or fragment, thereby inhibiting the I Through binding to the IL-12 and / or IL-23 receptors, or through other IL-12 / IL -Inhibits activity mediated through IL-23p40 or IL-23-dependent or -mediated mechanisms As used herein, the term "neutralizing antibody" refers to an antibody that is capable of inhibiting the activity of a given antibody in an assay. Depending on the amount, about 20 to 120%, preferably at least about 10, 20, 30, 40, 50, 55 , 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% or more, IL-12 / IL-23p40 or IL-23 dependent activity Anti-IL-12 / IL-23p40 or IL-23 The ability of the antibody to inhibit IL-12 / IL-23p40 or IL-23 dependent activity is preferred. or at least one preferred method described herein and / or known in the art. by suitable IL-12 / IL-23p40 or IL-23 protein or receptor assays. Human antibodies are evaluated based on their class. ) or isotype and may include kappa or lambda light chains. In some embodiments, the human antibody comprises an IgG heavy chain or a defined fragment thereof, e.g., IgG1, IgG2, IgA, IgB, IgC, IgD, IgE ... At least one of the following antibodies: IgG3 or IgG4 (e.g., γ1, γ2, γ3, γ4) Antibodies of this type include those of the following types: At least one human light chain (e.g., IgG, IgA, IgM) transfectant known in the art. Using transgenic mice or other transgenic non-human mammals containing the gene In another embodiment, the anti-IL-23 human antibody can be prepared by comprises an IgG1 heavy chain and an IgG1 light chain.

[0097] The antibody comprises at least one of an IL-12 / IL-23p40 or IL-23 protein, At least one specific subunit, fragment, portion, or any combination thereof The at least one epitope binds to the protein. and at least one antibody binding region comprising at least a portion of a protein, The epitope is preferably located in at least one extracellular portion of the protein, in a soluble portion, It is composed of a hydrophilic portion, an outer portion, or a cytoplasmic portion.

[0098] Generally, a human antibody or antigen-binding fragment contains at least one human complementarity determining region. (CDR1, CDR2, and CDR3) or at least one heavy chain variable region variant, and at least one human complementarity determining region (CDR1, CDR2, and CDR3) or at least The CDR sequences are derived from human germline antigen-binding domains that contain at least one variant of the light chain variable region. May be derived from a germline sequence or may be an exact match to a germline sequence. For example, CDRs from a synthetic library derived from original non-human CDRs may be used. These CDRs can be modified by incorporating conservative substitutions from the original non-human sequence. In another particular embodiment, the antibody or antigen-binding portion or variant may be formed by: At least one light chain CDR having a corresponding CDR1, 2 and / or 3 amino acid sequence (i.e., CDR1, CDR2, and / or CDR3) It may have a binding region.

[0099] Such antibodies can be produced using conventional techniques involving recombinant DNA technology to encode the antibodies (such as i.e., by preparing and expressing one or more) nucleic acid molecules, or by any other suitable method. By using such methods, various portions of the antibody (e.g., CDRs) can be isolated using conventional techniques. , framework) together chemically.

[0100] In one embodiment, the anti-IL-12 / 23p40 antibodies useful in the present invention are each represented by SEQ ID NO: Heavy chain complementarity determining regions (CDRs) 1, 2, and 3 HCDR1, HCDR2, and HCDR3 3 and the light chain CDRs LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively. The antibody is a monoclonal antibody, preferably a human mAb, that contains the CDR3.

[0101] Anti-IL-12 / IL-23p40 or IL-23 specific antibodies have a defined amino acid sequence. For example, the variable region may include at least one of a heavy or light chain having the following sequence: In a preferred embodiment, the anti-IL-12 / IL-23p40 or IL-23 antibody has the sequence No. 7 is at least 85%, preferably at least 90%, more preferably at least 95%. %, and most preferably 100% identical amino acid sequence to SEQ ID NO:8. at least 85%, preferably at least 90%, more preferably at least 95%, and most preferably, a light chain variable region that comprises 100% identical amino acid sequence. -12 / IL-23p40 antibody.

[0102] Anti-IL-12 / IL-23p40 or IL-23 specific antibodies also include those having defined amino acids. The nucleic acid sequence of the present invention may include at least one of a heavy chain or a light chain having an amino acid sequence. In embodiments, the anti-IL-12 / IL-23p40 or IL-23 antibody is selected from the group consisting of SEQ ID NO:10. At least 85%, preferably at least 90%, more preferably at least 95%, and and most preferably 100% identical amino acid sequence to SEQ ID NO: 11. 85%, preferably at least 90%, more preferably at least 95%, and most preferably or an anti-IL-12 / IL-13 antibody having a light chain variable region that contains 100% identical amino acid sequence to the antibody. - Includes 23p40 antibodies.

[0103] Preferably, the anti-IL-12 / 23p40 antibody has the amino acid sequence of SEQ ID NO: 10. Ustekinumab (Stela) comprising a heavy chain and a light chain comprising the amino acid sequence of SEQ ID NO:11. Other examples of anti-IL12 / 23p40 antibodies useful in the present invention include Briakinumab (ABT-874, Abbott) and U.S. Patent No. Nos. 6,914,128, 7,247,711, and 7,700,739 (among which (the entire contents of which are incorporated herein by reference) But not limited to these.

[0104] The present invention also relates to amino acids in sequences which are substantially the same as the amino acid sequences described herein. The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs comprising the amino acid. or such antibodies or antigen-binding fragments and antibodies comprising such chains or CDRs. , high affinity (e.g., KD of about 10 -9 M or less) and human IL-12 / IL-23p4 0 or IL-23. The amino acid sequence may include conservative amino acid substitutions and amino acid deletions and / or insertions. Conservative amino acid substitutions include sequences containing a chemically similar to that of the first amino acid. a second one having electrical and / or physical properties (e.g., charge, structure, polarity, hydrophobicity / hydrophilicity) Conservative substitutions refer to the substitution of a first amino acid with a second amino acid. Conservative substitutions include, but are not limited to, This includes replacing one amino acid with another amino acid within the following group: lysine (K), alanine (A), arginine (R), and histidine (H); aspartate (D) and glutamate ( E); Asparagine (N), Glutamine (Q), Serine (S), Threonine (T), Tyridine (C), Cysine (Y), K, R, H, D, and E; Alanine (A), Valine (V), Leucine (L) , isoleucine (I), proline (P), phenylalanine (F), tryptophan (W ), methionine (M), cysteine ​​(C), and glycine (G); F, W, and Y; C, S, and T.

[0105] Defined heavy or light chains that bind to human IL-12 / IL-23p40 or IL-23 Antibodies containing the variable regions can be prepared using phage vectors known in the art and / or described herein. Spray (Katsube, Y., et al., Int J Mol. Med, 1(5):863 1998), or methods employing transgenic animals. For example, functionally rearranged human immunoglobulin heavy chains can be used to prepare A transgene and a human immunoglobulin light chain locus capable of undergoing functional rearrangement Transgenic mice containing a transgene containing DNA from these vectors were then cultured to express human IL-12 / I Immunization with IL-23p40 or IL-23 or a fragment thereof to induce antibody production If desired, antibody-producing cells can be isolated and cultured as described herein. As described herein and / or known in the art, hybridomas or Other immortalized antibody-producing cells can be prepared. Alternatively, antibodies, specific moieties can be produced. The fragment or variant can be expressed in a suitable host cell using an encoding nucleic acid or a portion thereof. It can be done.

[0106] The anti-IL-12 / IL-23p40 or IL-23 antibody used in the method of the present invention is As specified in the specification, one or more It may include the above amino acid substitutions, deletions, or additions.

[0107] The number of amino acid substitutions a skilled artisan would make depends on many factors, including those described above. Specifically, a given anti-IL-12 / IL-23p40 or IL-23 antibody, fragment or the number of amino acid substitutions, insertions or deletions of the variant, as specified herein, is 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 or value therein I can't.

[0108] Functionally essential anti-IL-12 / IL-23p40 or IL-23 specific antibodies The amino acid may be modified by any suitable method, such as site-directed mutagenesis or alanine scanning mutagenesis. This can be determined by methods known in the art (e.g., Ausube, supra). l, Chapters 8,15; Cunningham and Wells, Sci. ence 244:1081-1085 (1989)). In the latter procedure, each residue in the molecule is A single alanine mutation is introduced at each base. The resulting mutant molecules are then , including but not limited to, at least one of IL-12 / IL-23p40 or IL-23 neutralization The sites critical for antibody binding are also tested for biological activity, such as cytotoxicity. The identification can be achieved by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling ( Smith, et al., J. Mol. Biol. 224:899-904 (1992) and e Vos, et al., Science 255:306-312 (1992)).

[0109] Anti-IL-12 / IL-23p40 or IL-23 antibodies are represented by SEQ ID NOs: 1, 2, 3, 4, 5 5 to all of at least one of the following contiguous amino acids: The present invention may include at least one portion, sequence, or combination selected from the following: , but not limited to these.

[0110] IL-12 / IL-23p40 or IL-23 antibodies or specific portions or variants thereof At least 3 to 5 adjacent amino acids of the above SEQ ID NO., 5 to 17 adjacent amino acids of the above SEQ ID NO. 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 At least one portion, sequence, or combination selected from the group consisting of amino acids, , but not limited to these.

[0111] The anti-IL-12 / IL-23p40 or IL-23 antibody further optionally comprises the sequence Numbers 5, 17, 10, 11, 7, 9, 119, 108, 449, or 214 adjacent lattices In one embodiment, the polypeptide may comprise at least one polypeptide that is 70 to 100% of the amino acid. The amino acid sequence of an immunoglobulin chain, or a portion thereof (e.g., a variable region, CDR) is a sequence of about 70 to 10 amino acids corresponding to at least one of the above sequence numbers. 0% identity (e.g., 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 , 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or any range therein For example, the amino acid sequence of the light chain variable region is compared with the sequence of the above SEQ ID NO. or the amino acid sequence of the heavy chain CDR3 can be compared to the above SEQ ID NOs. Preferably, the amino acid identity is between 70 and 100% (i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or any range or value therein) using suitable computer algorithms, as known in the art. It is decided.

[0112] As known in the art, "identity" is determined by comparing sequences. The relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by the In the art, "identity" is also determined by the match between such linear sequences. "Sequence relatedness" refers to the degree of sequence relatedness between polypeptide or polynucleotide sequences, as determined by the "Identity" and "similarity" are defined as 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 can be readily performed by known methods, including but not limited to those described herein. In addition, the percent identity value can be calculated using the Vector NTI S A component of Suite 8.0 (Informax, Frederick, MD) Amino acid and nucleotide sequence alignments generated using the default settings of lignX. can be obtained from the

[0113] Preferred methods to determine identity are those that give the largest match between the sequences tested. Methods to determine identity and similarity are designed using publicly available computer programs. The method for determining identity and similarity between two sequences is codified in the NIH Standards Track [Page 11] RFC 2411 Sequence Identification and Similarity Index (SIGMA). A preferred computer program method for doing this is the GCG program package (Devere ux, J. et al., Nucleic Acids Research 12(1):387( 1984), BLASTP, BLASTN, and FASTA (Atschul, SF , et al., J. Molec. Biol. 215:403-410 (1990)), The BLAST X program uses BLAST queries from NCBI and other sources (BLAS T Manual, Altschul, S. et al., NCBINLM NIH Bethes da,Md.20894:Altschul,S. et al.,J.Mol.Biol.215: 403-410 (1990). The man algorithm may also be used to determine identity.

[0114] Exemplary heavy and light chain variable region sequences, and portions thereof, are set forth in the SEQ ID NOs. The antibodies of the invention, or specified variants thereof, may be derived from an antibody of the invention by combining any number of adjacent amino acids. The number of amino acid residues in the anti-IL-12 / IL-23p40 or anti-IL-23p40 peptide can be is selected from the group of integers consisting of 10 to 100% of the number of adjacent residues in the antibody. In addition, the subsequence of adjacent amino acids may be at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170 , 180, 190, 200, 210, 220, 230, 240, 250 or more The amino acid sequence may be any number of subsequences, or any range or value therein. Any integer selected from the group consisting of 1 to 20, such as at least 2, 3, 4, or 5. It is possible.

[0115] As will be apparent to one of skill in the art, the present invention includes at least one biologically active compound of the present invention. Biologically active antibodies include antibodies that are naturally occurring (non-synthetic), endogenous, or related, and At least 20%, 30%, or 40%, preferably at least 5%, of that of a known antibody. 0%, 60%, or 70%, and most preferably at least 80%, 90%, or 95% to 1 00% or greater (including but not limited to up to 10 times the specific activity). Methods for assaying and quantitatively determining substrate specificity are well known to those of skill in the art.

[0116] In another aspect, the present invention provides a method for the preparation of a compound according to any one of the preceding claims, wherein the compound is modified by the covalent attachment of an organic moiety. The present invention relates to human antibodies and antigen-binding fragments that have been modified to have improved pharmacokinetic properties. (e.g., increased serum half-life in vivo) The organic moiety can be a linear or branched hydrophilic polymeric group, a fatty acid group, or In certain embodiments, the hydrophilic polymeric group can be a fatty acid ester group. The polyalkane may have a molecular weight of about 800 to about 120,000 daltons, and glycols (e.g., polyethylene glycol (PEG), polypropylene glycol) (PPG), carbohydrate polymers, amino acid polymers or polyvinylpyrrolidone. and the fatty acid group or fatty acid ester group can contain from about 8 to about 40 carbon atoms. do.

[0117] The modified antibodies and antigen-binding fragments are directly or indirectly covalently attached to the antibody. The antibody or antigen-binding fragment of the present invention may contain one or more organic moieties that are attached to the antibody or antigen-binding fragment of the present invention. Each organic moiety is independently a hydrophilic polymeric group, a fatty acid group, or a fatty acid ester group. As used herein, the term "fatty acid" refers to mono- and di-carboxylic acids. As used herein, the term "hydrophilic polymeric group" includes octane, It refers to an organic polymer that is more soluble in water than in water. For example, polylysine is Therefore, antibodies modified with covalent polylysine have a higher solubility in water than Suitable hydrophilic polymers for modifying the antibodies of the invention include linear or branched hydrophilic polymers. They may be branched, for example polyalkane glycols (e.g., PEG, monomethoxy-poly ethylene glycol (mPEG, PPG, etc.), carbohydrates (e.g., dextran, sugars, oligosaccharides, polysaccharides, etc.), polymers of hydrophilic amino acids (e.g., polylysine, poly realginine, polyaspartic acid, etc.), polyalkane oxide (e.g., polyethylene Polyvinylpyrrolidone, polyvinyl oxide, polypropylene oxide, etc. For example, the hydrophilic polymer that modifies the antibody of the present invention has about 800 to about 1000 individual molecular entities. 50,000 daltons. For example, PEG 5000 and PEG 20,000 0 can be used. The subscript is the average molecular weight of the polymer in Daltons. The hydrophilic polymer group is substituted with 1 to about 6 alkyl groups, fatty acid groups, or fatty acid ester groups. Hydrophilic polymers substituted with fatty acid or fatty acid ester groups are suitable For example, a polymer containing amine groups can be prepared by , can be linked to a carboxylate of a fatty acid or a fatty acid ester, Activated carboxylates on esters (e.g., activated with N,N-carbonyldiimidazole) The hydroxyl groups on the polymer can be linked to the hydroxyl groups on the polymer.

[0118] The fatty acids and fatty acid esters suitable for modifying the antibodies of the invention may be saturated. Suitable for modifying the antibodies of the invention may contain one or more unsaturated units. Examples of fatty acids include n-dodecanoic acid (C12, lauric acid), n-tetradecanoic acid, (C14, myristic acid), n-octadecanoic acid (C18, stearic acid), n-eicosanoic acid Arachidic acid (C20, arachidic acid), n-docosanoic acid (C22, behenic acid), n-triacyl n-tetradecanoic acid (C30), n-tetradecanoic acid (C40), cis-Δ9-octadecanoic acid ( C18, oleic acid), all cis-Δ5,8,11,14-eicosatetraenoic acid (C 20, Arachidonic acid), Octanedionic acid, Tetradecanedionic acid, Octadecanedione Suitable fatty acid esters include linear or branched low molecular weight fatty acid esters. The monoesters of dicarboxylic acids contain a lower alkyl group. The lower alkyl group has 1 to about 1 It may contain 2, preferably 1 to about 6 carbon atoms.

[0119] The modified human antibodies and antigen-binding fragments can be subjected to any suitable treatment, such as by reacting them with one or more modifying agents. As used herein, the term "modifying agent" means , a suitable organic group (e.g., a hydrophilic polymer, a fatty acid, a fatty acid ester) containing an activating group. An "activating group" means a group that, under appropriate conditions, reacts with a second chemical group, thereby forming a modifying agent. A chemical moiety or functional group capable of forming a covalent bond between a first chemical group and a second chemical group. For example, amine-reactive activating groups include tosylate, mesylate, halo (chloro, bromo, Electrophilic groups such as fluoro and iodo, N-hydroxysuccinimidyl esters (N-hydrox Activated groups that can react with thiols and Examples of suitable aryl groups include maleimide, iodoacetyl, acryloyl, and pyridyl disulfides. 5-thiol-2-nitrobenzoic acid thiol (TNB-thiol) and the like. The aldehyde functional group can be linked to an amine- or hydrazide-containing molecule, and The dido group reacts with a trivalent phosphorus group to form a phosphoramidate or phosphorimide bond. Suitable methods for introducing active groups into a molecule are known in the art. (e.g., Hermanson, GT, Bioconjugate Technology, hniques, Academic Press: San Diego, CA (1996 ) The activating group is attached to an organic group (e.g., a hydrophilic polymer, a fatty acid, a fatty acid ester). directly or via a linker moiety (e.g., a divalent C1-C12 group, where one or more carbon atoms The bond can be made via a heteroatom, such as oxygen, nitrogen, or sulfur. Suitable linker moieties include, for example, tetraethylene glycol, -(CH2)3- , -NH-(CH2)6-NH-, -(CH2)2-NH- and -CH2-O-CH2- CH2-O-CH2-CH2-O-CH-NH-. Modifications containing a linker moiety The agent may be, for example, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC ) in the presence of a mono-Boc-alkyldiamine (e.g., mono-Boc-ethylenediamine By reacting the diaminohexane (mono-Boc-diaminohexane) with fatty acids, the free amine and a fatty acid carboxylate. The Boc protecting group was removed from the product by treatment with trifluoroacetic acid (TFA). to expose a primary amine which can be coupled to another carboxylate as described. or it can be reacted with maleic anhydride and the resulting product cyclized to give fatty acids. Activated maleimide derivatives of the acids can be produced (see, for example, WO 92 / 16 221 (Thompson et al.), the entire teachings of which are incorporated herein by reference. (Incorporated into the

[0120] The modified antibodies can be prepared by reacting a human antibody or antigen-binding fragment with a modifying agent. For example, the organic moiety can be produced by an amine-reactive modifying agent, e.g., PEG. NHS esters of the compounds can be used to conjugate to antibodies in a non-site-specific manner. Disulfide bonds (e.g., intrachain disulfide bonds) of antibodies or antigen-binding fragments can be (a) preparing a modified human antibody or antigen-binding fragment thereof; In this case, the reduced antibody or antigen-binding fragment can be subjected to thiol-reactive modification. The antibody of the present invention can be reacted with a decorating agent to produce a modified antibody of the present invention. Modified human antibodies and antigen-binding fragments containing organic moieties attached to specific sites of , reverse proteolysis, etc. (Fisch et al., Bioconjugate Chem., 3 :147-153(1992), Werlen et al., Bioconjugate Chem. .,5:411-417(1994), Kumaran et al., Protein Sci. (10):2233-2241(1997);Itoh et al.,24(1):59-68(1 996), Capellas et al., Biotechnol. Bioeng., 56(4): 456-463 (1997)), and Hermanson, GT, Bi oconjugate Techniques,Academic Press:San Diego, CA (1996) or the like. .

[0121] The methods of the present invention also include those described herein and / or known in the art. At least one of the at least one non-naturally occurring compositions, mixtures, or forms is provided, such as 2, at least 3, at least 4, at least 5, at least 6 or more of the Anti-IL-12 / IL-23p, including IL-12 / IL-23p40 or IL-23 antibodies 40 or IL-23 antibody compositions are also used. Such compositions include those comprising adjacent amino acids of the above SEQ ID NOs. 70-100% of the acid, or a specified fragment, domain, or variant thereof The amino acid sequence of an anti-IL-12 / IL-23p40 or IL-23 antibody selected from the group consisting of At least one or two full-length, C- and / or N-terminal deletion mutants, domains of The present invention also includes non-naturally occurring compositions that contain the specified variants, fragments, or variants of the specified anti-IL-1. The IL-12 / IL-23p40 or IL-23 antibody composition may be, for example, any of SEQ ID NOs: 70 to 74. 100% of the anti-IL-12 / IL-23p40 or IL-23 antibodies described herein At least one of the sequences, or a specified fragment, domain, or variant thereof At least one or two full-length, fragment, or CDR- or LBP-containing portions of Further preferred compositions include the 70 domains, such as those of SEQ ID NO: ~100% or less of a specified fragment, domain, or variant thereof The percentages of such compositions are known in the art. As used herein, by weight, volume, concentration, molarity, or as described herein. Liquid or dry solutions, mixtures, suspensions, emulsions, particles, powders, Or by molar concentration as a colloid.

[0122] Antibody compositions containing further therapeutically active ingredients The antibody compositions used in the methods of the present invention may optionally further comprise an anti-infective agent, a cardiovascular scular (CV) acting drugs, central nervous system (CNS) drugs, autonomic nervous autonomic nervous system (ANS) drugs, respiratory drugs, gastrointestinal, GI ) Vascular activating agents, hormonal agents, fluid or electrolyte balancing agents, hemoactive agents, antitumor agents, immunomodulatory agents, A small amount of medicine selected from at least one of the following: eye, ear or nose medicines, topical medicines, nutritional medicines, etc. Such a medicament may comprise an effective amount of at least one compound or protein. The present invention is well known in the art, including the respective formulations, indications, dosages, and administration set forth in the literature. It is well known (e.g., Nursing 2001 Handbook of Dr gs,21st edition,Springhouse Corp.,Spring house, PA, 2001, Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Pre. ntice-Hall, Inc., Upper Saddle River, NJ, Pha rmacotherapy Handbook, Wells et al., Appleton & See Lange, Stamford, CT, each of which is incorporated herein by reference in its entirety. (Incorporated into the book).

[0123] Examples of drugs that can be combined with the antibodies of the present method include anti-infective drugs, ampicillinicide, or at least one antiprotozoal, anthelmintic, antifungal, antimalarial, antituberculous, or At least one antimycobacterial drug, aminoglycoside, penicillin, cephalosporin, tetracycline Lacyclines, sulfonamides, fluoroquinolones, antivirals, macrolides anti-infectives The hormonal drug may be at least one selected from the group consisting of steroids, anti-inflammatory drugs, and various anti-infective drugs. steroids, androgens, or at least one anabolic steroid, estrogens, or at least one progestin, gonadotropin, antidiabetic agent, or A type of glucagon, thyroid hormone, thyroid hormone antagonist, pituitary hormone, and At least one selected from the group consisting of parathyroid mimetics and at least one cephalosporin. Phosphorus is cefaclor, cefadroxil, cefazolin sodium, cefdinir, hydrochloride Cefepime, cefixime, cefmetazole sodium, cefonicid sodium, cef Operazon sodium, cefotaxime sodium, cefotetan disodium, cefo Cefpodoxime sodium, cefpodoxime proxetil, cefprozil, ceftazidime, cef Thibuten, ceftizoxime sodium, ceftriaxone sodium, cefuroxime aki Cetyl, Cefuroxime Sodium, Cephalexin Hydrochloride, Cephalexin Monohydrate, Cef The active ingredient may be at least one selected from the group consisting of azithromycin and loracarbef.

[0124] The at least one corticosteroid is betamethasone, betamethasone acetate or betamethasone phosphate. Betamethasone sodium, betamethasone sodium phosphate, cortisone acetate, dexamethasone dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisone acetate , hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone phosphate dihydrocortisone sodium, hydrocortisone sodium succinate, methylprednisolone , methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, Prednisone, triamcinolone, triamcinolone acetonide, and triamcinol acetate At least one selected from the group consisting of androgens and tannins. The anabolic steroids are Danazol, Fluoxymesterone, Methyltestosterone, Nandrolone Decanoate, Nandrolone Phenpropionate, Testosterone, Cypionate Testosterone, Testosterone Enanthate, Testosterone Propionate, and Test The therapeutic agent may be at least one selected from the group consisting of steroid transdermal systems.

[0125] At least one immunosuppressant is selected from the group consisting of azathioprine, basiliximab, cyclosporine, Daclizumab, lymphocyte immunoglobulin, muromonab-CD3, mycophenolate mofetil mycophenolate mofetil, sirolimus, 6-mercaptopurine, methotrexate The drug may be at least one selected from the group consisting of oxalate, mizoribine, and tacrolimus.

[0126] At least one topical anti-infective agent is selected from the group consisting of acyclovir, amphotericin B, azelaic acid cyclovir, and the like. Ream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole nitrate, econazole, erythromycin, gentamicin sulfate, ketoconazole, acetate Mafenide, metronidazole (topical), miconazole nitrate, mupirocin, naphthyl hydrochloride , neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, tetrahydrofuran Rubinafine, terconazole, tetracycline hydrochloride, tioconazole, and tolnaf At least one scabicide or at least one tate. The pediculicide is selected from crotamiton, lindane, permethrin, and pyrethrins. The at least one topical corticosteroid may be dipropionate. Betamethasone valerate, clobetasol propionate, desonide, desoxyglucose Ximethasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate , fluocinolone acetonide, fluocinonide, flurandrenolide, flupropionate Ticasonide, halcionide, hydrocortisone, hydrocortisone acetate, butyrate Hydrocortisone valerate, hydrocortisone valerate, mometasone furoate, and triamcinol The at least one selected from the group consisting of acetonides and acetonides (see, for example, Nursing 2 (See pages 1098-1136 of the 001 Drug Handbook.)

[0127] Specifically, the antibody compositions used in the methods of the present invention contain at least one effective amount of the antibody useful for treating psoriasis. The pharmaceutical composition may further comprise at least one drug. Drugs may include topical agents, non-biological systemic drugs, and and biological drugs. These include topical corticosteroids, vitamin D analogues, anthralin, and topical retinoids. , calcineurin inhibitors, salicylic acid, coal tar, and moisturizers. Non-biological systemic agents include, but are not limited to, retinoids, methotrexate, These include cyclosporine, acritretin, apimist, and tofacitinib. Biological agents include, but are not limited to, etanercept (Enbrel), infliximab (Influenza), and cefotaxime (Citroviral). Liximab (Remicade), adalimumab (Humira), golimumab (Sim poni), secukinumab (Cosentyx), and ixekizumab (Taltz). Examples include, but are not limited to:

[0128] Anti-IL-12 / IL-23p40 or IL-23 antibody compositions are useful for such modulation, treatment, or is contacted or administered to a cell, tissue, organ, animal, or subject in need of treatment. At least one anti-IL-12 / 23p40 or IL-23 antibody, and optionally further at least one TNF antagonist (e.g., but not limited to, a TNF chemoattractant or protein antagonist); TNF antagonists, TNF monoclonal or polyclonal antibodies or fragments, soluble TNF receptors (e.g., p55, p70, or p85) or fragments, fusion polypeptides thereof peptides, or small molecule TNF antagonists, such as TNF binding proteins I or II ( TBP-1 or TBP-II), nerelimonmab, infliximab, Eternacept, CDP-571, CDP-870, Afelimomab, Rene rucept, etc.), antirheumatic drugs (e.g., methotrexate, auranofin, aurotine Glucose, azathioprine, etanercept, sodium gold thiomalate, hydroxy chloroquine sulfate, leflunomide, sulfasalazine), immunization, immunoglobulin, immunotherapy Immunosuppressants (e.g., azathioprine, basiliximab, cyclosporine, daclizumab) any suitable compound including at least one selected from the group consisting of a cytokine and a cytokine antagonist; The composition may further comprise a suitable and effective amount of at least one of the following compositions or pharmaceutical compositions: Non-limiting examples of such cytokines include IL-1 to IL-23 (e.g., I Examples of suitable dosages include, but are not limited to, any of the following: IL-1, IL-2, etc. are well known in the art. See, for example, Wells et al., eds., Pharma Cotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, CT (2000), PDR Pharmaco. poeia, Tarascon Pocket Pharmacopoeia 2000 ,Deluxe Edition,Tarascon Publishing,Loma See Linda, CA (2000), each of which is incorporated herein by reference in its entirety. INCORPORATED INTO THE SPECIFICATION.

[0129] Anti-IL-12 / IL-23p40 or IL-23 Antibody Compounds for Use in the Methods of the Invention The composition or mixture may further comprise a diluent, binder, stabilizer, buffer, salt, lipophilic solvent, preservative, any suitable auxiliary agent, including, but not limited to, a pharmaceutical agent, an adjuvant, etc. Pharmaceutically acceptable excipients are preferred. Methods and non-limiting examples thereof are well known in the art and are described, for example, in Gennaro, E. d.,Remington's Pharmaceutical Sciences,1 8th Edition,Mack Publishing Co.(Easton,P A), 1990. or as described herein, anti-IL-12 / IL-23p40, fragments, or a pharma- ceutical acceptable carrier suitable for the mode of administration, solubility, and / or stability of the variant composition. You can choose your body on a daily basis.

[0130] Pharmaceutical excipients and additives useful in the present compositions include, but are not limited to, protein Proteins, peptides, amino acids, lipids and carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and Sugars including oligosaccharides, alditols, aldonic acids, esterified sugars, and other derivative sugars, and polysaccharides or sugar polymers), which may be present alone or in combination. , alone or in combination, at 1 to 99.99% by weight or volume. The excipients include serum albumin such as human serum albumin (HSA). Recombinant human albumin (rHA), gelatin, Representative amino acids / antibody components that can also function in buffering capacity include Alanine, glycine, arginine, betaine, histidine, glutamic acid, asparagus Glycine, Cysteine, Lysine, Leucine, Isoleucine, Valine, Methionine, Phenyl Alanine, aspartame, etc. One of the preferred amino acids is glycine. .

[0131] Carbohydrate excipients suitable for use in the present invention include, for example, fructose, maltose, and the like. Monosaccharides such as lactose, galactose, glucose, D-mannose, and sorbose; Disaccharides such as sucrose, trehalose, and cellobiose, raffinose, melezitol, and Polysaccharides such as maltodextrin, dextran, and starches, mannitol, xylitol, and glyceryl stearate. Litol, maltitol, lactitol, xylitol sorbitol (glucitol), Preferred carbohydrates for use in the present invention include alditols such as myo-inositol. The compound excipients are mannitol, trehalose, and raffinose.

[0132] The anti-IL-12 / IL-23p40 or IL-23 antibody composition may contain a buffer or pH adjuster. Typically, the buffering agent is a salt prepared from an organic acid or base. Buffers include citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, and acetic acid. or organic acid salts such as salts of phthalic acid, Tris, tromethamine hydrochloride, or phosphate buffers. Preferred buffers for use in the present compositions are organic acid salts such as citric acid. .

[0133] Furthermore, the anti-IL-12 / IL-23p40 or IL-23 antibody composition may comprise a polyvinylpyrrolidone (PVP)-based Lidone, Ficoll (polymeric sugar), Dextrates (e.g., 2-hydroxypropyl -β-cyclodextrin and other cyclodextrins), polyethylene glycol, flavoring agents, antibacterial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., "TWEEN 20") and polysorbates such as "TWEEN 80"); lipids (e.g., phospholipids, fatty acids); Polyamines such as steroids (e.g., cholesterol) and chelating agents (e.g., EDTA). It may contain polymer excipients / additives.

[0134] Anti-IL-12 / IL-23p40 or IL-23 Antibodies, Parts or Variants of the Invention These and additional known pharmaceutical excipients and / or additives suitable for use in the compositions include: The methods are well known in the art and are described in, for example, Remington: The Science ce & Practice of Pharmacy”, 19th ed.,Will iams & Williams, (1995) and “Physician's De sk Reference”, 52nd ed,Medical Economics, Montvale, NJ (1998), the disclosures of which are incorporated by reference in their entireties. Preferred carrier or excipient materials are carbohydrates (e.g., monosaccharides, and alditol) and buffering agents (e.g., citric acid) or polymeric agents. The molecule is a mucopolysaccharide, hyaluronic acid, which may be useful for intra-articular delivery.

[0135] formulation As mentioned above, the present invention preferably comprises a phosphate buffer containing saline or a selected salt. Stable formulations comprising the compound, as well as storage solutions and formulations containing a preservative, and pharma- ceutically acceptable The present invention relates to a pharmaceutical composition comprising at least one anti-IL-12 / IL-23p40 or IL-23 antibody. The present invention provides a multi-use preserved formulation suitable for pharmaceutical or veterinary use, including the preparation of a pharmaceutical or veterinary preparation comprising an aqueous diluent. At least one of the known compounds, namely, at least one of phenol, m-cresol, , p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenyl nitrate Mercury, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylparabens (methyl, ethyl, propyl, butyl, etc. ), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosin The composition further comprises a preservative, optionally selected from the group consisting of: sodium sarcoid, sodium lauryl phosphate, sodium lauryl sulfate, sodium phosphate ester, sodium lauryl sulfate ... As known in the art, 0.001 to 5%, or 0.001, 0.00 3, 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 or value therein Any suitable concentration, such as, but not limited to, any range or value therein. Or mixtures may be used. Non-limiting examples include no preservatives, 0.1-2% m-chlorine, Resole (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1-3 % benzyl alcohol (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (e.g., 0.005, 0.01), 0.001 to 2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005 to 1.0% of alkylparaben(s) (e.g., 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, Examples include 0.3, 0.5, 0.75, 0.9, and 1.0%).

[0136] As mentioned above, the method of the present invention comprises the steps of: and / or preservatives. and at least one vial containing a solution of the antibody, The solution is divided into 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, Capable of being retained for periods of 40, 48, 54, 60, 66, or 72 hours or more The present invention relates to a packaging material and a lyophilized anti-IL-12 / IL-23p A first vial containing the IL-40 or IL-23 antibody and an aqueous dilution of the formulated buffer or preservative. and a second vial containing an anti-IL-12 / IL-2 inhibitor. IL-23p40 or IL-23 antibody is reconstituted in an aqueous diluent and incubated for at least 24 hours. The solution contains a label instructing the subject to form a solution that can be retained.

[0137] The anti-IL-12 / IL-23p40 or IL-23 antibodies used in accordance with the present invention are As described herein or known in the art, mammalian cells or transgenic plants may be used. It can be produced by recombinant means, such as from a genic preparation, or purified from other biological sources. It can be done.

[0138] The range of anti-IL-12 / IL-23p40 or IL-23 antibodies is as follows for wet / dry systems: The amount is such that when reconstituted, a concentration of approximately 1.0 μg / mL to approximately 1000 mg / mL is obtained. However, lower and higher concentrations are workable, depending on the intended delivery vehicle. For example, solution formulations may be delivered by transdermal patches, pulmonary, transmucosal, or osmotic or micropump delivery systems. This is different from the method used.

[0139] Preferably, the aqueous diluent optionally further comprises a pharma- ceutically acceptable preservative. New preservatives include phenol, m-cresol, p-cresol, o-cresol, and chloroform. Croxysol, benzyl alcohol, alkylparaben (methyl, ethyl, propyl, butyl ethyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and Thimerosal or mixtures thereof. The concentration of preservative used is sufficient to produce an antimicrobial effect. The amount of preservative used will vary depending on the preservative used and can be readily determined by one of skill in the art.

[0140] Other excipients, such as isotonicity agents, buffers, antioxidants, and preservative enhancers, are optional. An isotonic agent such as glycerin may be optionally and preferably added to the diluent. Preferably, a physiologically tolerable buffer is added to improve Provides pH control. The formulations have a pH range of about pH 4 to about pH 10, and preferably about pH 5 to about pH 9, and most preferably in the range of about 6.0 to about 8.0. Preferably, the formulation of the present invention has a pH of about 5.5 to about 6.5. Exemplary buffers include phosphate buffers such as sodium phosphate, specifically phosphate buffers. Examples include phosphate buffered saline (PBS).

[0141] Other additives, such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate) rate), Tween 40 (Polyoxyethylene (20) Sorbitan Monopalmitate) , Tween 80 (Polyoxyethylene (20) Sorbitan Monooleate), Plur onic F68 (polyoxyethylene polyoxypropylene block copolymer), and and PEG (polyethylene glycol), or a pharma- ceutically acceptable solubilizer. Rubate 20 or 80 or Poloxamer 184 or 188, Pluronic ( Nonionic surfactants such as Polyls®, other block copolymers, and Optionally adding chelating agents such as EDTA and EGTA to the formulation or composition These additives can be used in conjunction with pumps or other devices to administer the formulation. This is particularly useful when plastic containers are used. Its presence reduces the tendency of the protein to aggregate.

[0142] The formulation comprises at least one anti-IL-12 / IL-23p40 or IL-23 antibody and a Enol, m-cresol, p-cresol, o-cresol, chlorocresol, benzoyl Diethyl alcohol, alkylparaben (methyl, ethyl, propyl, butyl, etc.), phenyl chloride Benzalkonium, benzethonium chloride, sodium dehydroacetate, and thimerosal or and a preservative selected from the group consisting of mixtures thereof in an aqueous diluent. The antibody can be prepared by a process including at least one anti-IL-12 / IL-23p antibody. The mixing of IL-40 or IL-23 specific antibodies with a preservative in an aqueous diluent is similar to conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a constant concentration of 10 ... A quantity of at least one anti-IL-12 / IL-23p40 or IL-23 antibody is added to the desired concentration. Combine with the desired preservative in a buffer solution sufficient to provide the desired protein and preservative concentrations. Variations on this process will be recognized by those skilled in the art. For example, The order of addition of the ingredients, whether or not additional excipients are used, and the temperature and pH at which the formulation is prepared can all be determined by the These are factors that can be optimized with respect to the dosage concentration and means of administration.

[0143] The formulation may be prepared as a clear solution or in the form of a mixture of water, preservatives and / or excipients, preferably phosphate. Salt buffer and / or saline, and a second solution containing the selected salt in an aqueous diluent. Lyophilized anti-IL-12 / IL-23p40 or IL-2, reconstituted in a vial Provide subjects with a dual vial containing vials of three specific antibodies Either the single solution vial or the combination vial requiring reconstitution can be reused multiple times. can be used to fulfill single or multiple subject treatment cycles, and thus , could provide a more convenient treatment regimen than is currently available.

[0144] The product is useful for administration over periods ranging from immediate to 24 hours or more. Thus, the products claimed in accordance with the present invention provide significant benefits to subjects. The protein can be safely stored at a temperature of about 2° C. to about 40° C. as desired to maintain its biological activity for a long period of time. The packaging label indicates that the solution is available in 6, 12, 18, 24, and 36 , 48, 72, or 96 hours or more of storage and / or usability. If a stored diluent is used, the label shall state that the diluent has a shelf life of 1 to 12 months. This may include up to six months, one and a half years, and / or two years of use.

[0145] The solution of anti-IL-12 / IL-23p40 or IL-23 specific antibody comprises at least one The antibody can be prepared by a process comprising mixing the antibody of the present invention in an aqueous diluent. The dissolution and mixing is carried out using conventional dissolution and mixing procedures. For example, a quantity of at least one antibody in water or buffer is added to a desired concentration of protein, and and optionally a preservative or buffering agent. Variations in the above will be recognized by those of skill in the art. For example, the order of addition of the components, The use of additives, the temperature and pH during preparation of the formulation, and the dosage concentration and administration method used It is a factor that can be optimized for a stage.

[0146] The products useful in the present invention are available as clear solutions or with a second vial containing an aqueous diluent. Lyophilized at least one anti-IL-12 / IL-23p40 or anti-IL-23p40 antibody reconstituted with or a combination vial containing a vial of an IL-23 specific antibody. Either the single solution vial or the combination vial requiring reconstitution can be reused multiple times. can be utilized to fulfill single or multiple subject treatment cycles, and therefore This provides a more convenient treatment regimen than is currently available.

[0147] The product may be distributed to pharmacies, clinics, or other such institutions and facilities in a second, Reconstituted with a vial, lyophilized at least one anti-IL-12 / IL- A clear solution or combination vial containing a vial of 23p40 or IL-23 specific antibody In this case, the clear solution can be indirectly provided to the subject by providing the clear solution The container may be up to 1 liter or even more in volume, and more can be extracted from this large container. Remove a small amount of at least one antibody solution one or more times and transfer it to a smaller vial. , and can be provided to customers and / or subjects by a pharmacy or clinic.

[0148] Approved devices that contain single vial systems include, for example, Becton Dicke nsen(Franklin Lakes, NJ, www.bectondickens on.com), Disetronic (Burgdorf, Switzerland, www.disetronic.com, Bioject, Portland, Oreg. on(www.bioject.com), National Medical Pro ducts,Weston Medical(Peterborough,UK,www .weston-medical.com), Medi-Ject Corp (Minn. Manufactured or developed by BD Medical Devices Inc. (Denver, MN, www.mediject.com). Pens, BD Autojector (registered trademark), Humaject (registered trademark) , NovoPen (registered trademark), BD (registered trademark) Pen, AutoPen (registered trademark) ), and OptiPen (registered trademark), GenotropinPen (registered trademark), Genotronorm Pen(registered trademark), Humatro Pen(registered trademark), Reco-Pen(registered trademark), Roferon Pen(registered trademark), Bioject or (registered trademark), Iject (registered trademark), J-tip Needle-Free I Injector (registered trademark), Intraject (registered trademark), Medi-Ject ( Pen-type injectors for delivering solutions, such as Smartject®, Smartject®, Approved devices, including combination vial systems, and similar suitable devices. Devices that deliver a dissolved solution, such as HumatroPen®, Patent application title: Pen-type syringe system for dissolving a lyophilized drug in a cartridge for administering the drug to a patient Examples of suitable other devices include pre-filled syringes, auto-injectors, These include needle-free syringes, and needle-free IV infusion sets.

[0149] The product may include packaging material that, in addition to any information required by regulatory authorities, The packaging material of the present invention, if applicable, provides at least Reconstitute one anti-IL-12 / IL-23p40 or IL-23 antibody in an aqueous diluent. A solution is formed and the solution is then subjected to a wet / dry biphasic treatment over a period of 2 to 24 hours. Provide subjects with instructions that the solution product is to be used in a single vial, pre-filled. In the case of a prefilled syringe or auto-injector, the label shall state that such solution is intended to be used for at least 2 to 24 hours. The product is useful for human pharmaceutical product applications. do.

[0150] The formulations used in the methods of the present invention include anti-IL-12 / IL-23p40 and a selected buffer. Mixing a buffer, preferably saline or a phosphate buffer containing the selected salt. The preparation can be carried out by a process comprising the steps of: Mixing in an aqueous diluent with a buffer is carried out using conventional dissolution and mixing procedures. To prepare such a formulation, for example, a quantity of at least one antibody in water or a buffer is Combine with the desired buffer in a sufficient amount of water to provide the desired concentrations of protein and buffer. Variations on this process will be recognized by those skilled in the art. For example, The order of addition of ingredients, whether or not additional excipients are used, and the temperature and pH during preparation of the formulation are all determined by the These are factors that can be optimized with respect to the dosage concentration and means of administration used.

[0151] The methods of the present invention include administering various formulations useful and acceptable for administration to human or animal subjects. The pharmaceutical composition uses a pharmaceutical composition comprising water at "normal" conditions as a diluent, and are prepared using routine methods well known to those of skill in the art. For example, histidine and histidine A buffer component, such as rifampicin monohydrochloride hydrate, is provided first, followed by an appropriate non-final volume of “standard Sub-normal water diluent, sucrose, and polysorbate 80 may then be added. Finally, a "standard" condition is used, using water as the diluent. The volume of the pharmaceutical composition is adjusted to the desired final volume under certain conditions. We recognize several other methods that may be suitable for fabrication.

[0152] The pharmaceutical compositions contain the indicated masses of each component per volume unit of water or are "standardized" in the As used herein, the term "aqueous solution" refers to a solution or suspension having a pH value indicated in the "state of the art." The term "standard conditions" means a temperature of 25°C ± 2°C and a pressure of 1 atmosphere. "Substate" is used to refer to a single temperature or pressure set as recognized in the art. Instead, they have a specific composition under standard "standard" conditions. Means a reference condition that specifies the temperature and pressure used to describe a solution or suspension This is because the volume of the solution is in part a function of temperature and pressure. It is recognized that pharmaceutical compositions equivalent to those disclosed in may be prepared at other temperatures and pressures. Such pharmaceutical compositions would be equivalent to those disclosed herein as defined above. should be determined under prescribed "standard state" conditions (e.g., 25°C ± 2°C and 1 atmosphere pressure). It is.

[0153] Importantly, such pharmaceutical compositions have a mass of "about" a certain value per unit volume of the pharmaceutical composition. (e.g., "about 0.53 mg L-histidine") or The pH value of the pharmaceutical composition may be a specific value. The isolated antibody may be present in a pharmaceutical composition or may be removed from a pharmaceutical composition. After being diluted (e.g., by dilution), the isolated antibody present in the pharmaceutical composition may be When the mass of a component or a part can be combined, the numerical value is "about" the mass of the component or part. The values, such as pH value, are determined based on the binding of the isolated antibody after the isolated antibody is placed in a pharmaceutical composition. When activity is maintained and detectable, it is "about" the value given.

[0154] Competitive binding analysis was performed to determine whether IL-12 / IL-23p40 or IL-23 specific mAbs Determine whether they bind to similar or different epitopes and / or compete with each other. Abs are individually coated onto LISA plates. Competing mAbs are added, followed by Add biotinylated hrIL-12 or IL-23. The same mAb can be used as a competing mAb ("self-competition"). IL-40 or IL-23 binding is detected using streptavidin. The mAbs target similar or overlapping sites on IL-12 / IL-23p40 or IL-23. This indicates whether the antibody recognizes a specific epitope.

[0155] In one embodiment of the pharmaceutical composition, the isolated antibody concentration is about 77 mL per mL of pharmaceutical composition. For example, the pharmaceutical composition useful in the present invention may contain a heavy chain variable region and Approximately 77mg / mL and 80mg of anti-IL-12 / IL-23p40 antibody containing the light chain variable region / mL, 85mg / mL, 90mg / mL, 95mg / mL, 100mg / mL, 104 The heavy chain variable region may comprise any one of the following: Complementarity determining region heavy chain 1 (CDRH1) amino acid sequence, CDRH2 amino acid sequence of SEQ ID NO:2 and the CDRH3 amino acid sequence of SEQ ID NO:3, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:4. Complementary determining region light chain 1 (CDRL1) amino acid sequence, CDRL2 amino acid sequence of SEQ ID NO:5 and the CDRL3 amino acid sequence of SEQ ID NO:6.

[0156] In another embodiment, the pharmaceutical composition has a molecular weight of about 5.5, 5.6, 5.7, 5.8, 5.9, 6. About 5. It has a pH of 5 to about 6.5.

[0157] Stable or preserved formulations may be formulated as clear solutions or in aqueous diluents without preservatives or buffers. and a second vial containing excipients. Provide patients with a combination vial containing a vial of L-12 / IL-23p40 Either the single solution vial or the combination vial requiring reconstitution can be reused multiple times. can be utilized to fulfill single or multiple patient treatment cycles, and therefore , providing a more convenient treatment regimen than is currently available.

[0158] Other formulations or methods for stabilizing anti-IL-12 / IL-23p40 antibodies include The liquid may be anything other than a clear solution of a freeze-dried powder, including a particulate suspension. Such particles are also known as microspheres, microparticles, nanoparticles, nanospheres, etc. Anti-IL-12 / IL-13 antibody was administered in structures of various sizes known variously as spheres or liposomes. The present invention relates to a composition containing an IL-23p40 antibody. Essentially spherical microparticle formulations can be used to prepare active The aqueous phase containing the drug and polymer is contacted with a non-aqueous phase, and the non-aqueous phase is then evaporated to form the aqueous phase. Porous microparticles can be formed by inducing the coalescence of particles from rice. As taught in U.S. Patent No. 4,818,542, an active agent and a polymer dispersed in a continuous solvent are The first phase, which contains the polymer, is used to extract the polymer from the suspension by lyophilization or dilution-extraction-precipitation. The preferred polymer for such preparation is a zeolite. Latin agar, starch, arabinogalactan, albumin, collagen, polyglycol Acid, Polylactic Acid, Glycolide-L(-) Lactide Poly(epsilon-caprolactone, Poly (epsilon-caprolactone-co-lactic acid), poly(epsilon-caprolactone-C O-glycolic acid), poly(β-hydroxybutyric acid), polyethylene oxide, polyethylene Poly(alkyl-2-cyanoacrylate), Poly(hydroxyethyl methacrylate) Poly(amino acids), poly(2-hydroxyethyl DL-aspartate), polyamides, poly(amino acids), poly(2-hydroxyethyl DL-aspartate) amide), poly(ester urea), poly(L-phenylalanine / ethylene glycol / 1 ,6-diisocyanatohexane) and poly(methyl methacrylate). Particularly preferred polymers are poly(N,N-dimethylformamide), poly( ... Glycolic acid, polylactic acid, glycolide-L(-) lactide poly(epsilon-caprolactone) ton), poly(epsilon-caprolactone-co-lactic acid), and poly(epsilon-caprolactone-co-lactic acid). Polyesters such as prolactone-co-glycolic acid. Solvents useful for dissolving soluble substances include water, hexafluoroisopropanol, salts, and the like. methylene chloride, tetrahydrofuran, hexane, benzene, or hexafluoroacetone The process of dispersing the active substance-containing phase in the second phase is carried out by dispersing the active substance-containing phase in the nozzle. forcing said first phase through an orifice under pressure to affect droplet formation. can be done.

[0159] Dry powder formulations can be prepared by processes other than freeze-drying, e.g., spray drying, solvent extraction by evaporation, or by precipitation of the crystalline composition followed by one or more steps of removing the aqueous or non-aqueous solvent. The preparation of spray-dried antibody formulations is described in U.S. Pat. No. 6,019,968. The antibody-based dry powder composition is prepared by mixing a solution or slurry of the antibody and, optionally, Alternatively, the excipients are spray dried in a solvent under conditions to provide a respirable dry powder. The solvent can be easily dried, for example, water and ethanol. Polar compounds may be included. Antibody stability is improved in the absence of oxygen, e.g., under a nitrogen blanket. This can be increased by performing a spray drying procedure in a drying gas such as nitrogen. Another relatively dry formulation is taught in WO 9916419. Dispersed in a suspension medium typically containing a hydrofluoroalkane propellant, such as those described in The stabilized dispersion was tested using a metered dose inhaler. Equipment useful in the commercial production of spray-dried drugs is available from the Buchmann Laboratory. Manufactured by i Ltd. or Niro Corp.

[0160] Anti-IL-12 / IL-13 compositions comprising any of the stable or preserved formulations or solutions described herein -23p40 can be administered by SC or IM injection, percutaneous, pulmonary, or mucosal administration, or by implantation or osmotic pump. , cartridges, micropumps or other devices known in the art and understood by those skilled in the art. The present invention can be administered to a subject via a variety of delivery methods, including other means such as those described herein. Cut.

[0161] therapeutic application The present invention relates to at least one method for producing a medicament for use in a method for treating a vascular endothelial disorder, the method comprising the steps of: The IL-23 antibodies of the invention can be used to administer, for example, therapeutically, to a cell, tissue, organ, animal, or subject. administering or contacting an effective amount of an IL-12 / IL-23p40 or IL-23 specific antibody Also provided are methods for modulating or treating psoriasis in a cell, tissue, organ, animal, or subject. Provide.

[0162] Any of the methods of the invention may be used to treat a cell, tissue, or organ in need of such modulation, treatment, or therapy. A composition or pharmaceutical composition comprising IL-12 / IL-23p40 in an organ, animal, or subject. Such methods may optionally include administering to a patient suffering from such a disease or disorder an effective amount of The present invention can further include a co-administration or combination therapy for the treatment of a disease, wherein at least Administration of a single IL-12 / IL-23p40, a specific portion or a variant thereof may be beneficial. At least one TNF antagonist (e.g., but not limited to, chemical or protein Catalytic TNF antagonists, TNF monoclonal or polyclonal antibodies or flagella ment, a soluble TNF receptor (e.g., p55, p70, or p85) or a fragment thereof or a fusion polypeptide thereof, or a small molecule TNF antagonist, e.g., TNF binding protein I. or II (TBP-1 or TBP-II), nerelimonumab, infliximab, etanercept Rucept (Enbrel™), Adalimumab (Humira™), CDP- 571, CDP-870, afelimomab, Lenercept, etc.), antirheumatic drugs (e.g. , methotrexate, auranofin, aurothioglucose, azathioprine, aurothioprine sodium malate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), Muscle relaxants, narcotics, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., 5-aminosalicylic acid analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blocking agents, antibacterial agents (e.g., amino Glycosides, antifungals, antiparasitics, antivirals, carbapenams, cephalosporins, Fluoroquinolones, macrolides, penicillins, sulfonamides, tetracyclines, and other antibacterial drugs), psoriasis medications, corticosteroids, anabolic steroids, diabetes-related Medicines, minerals, nutritional drugs, thyroid drugs, vitamins, calcium-related hormones, antidiarrheals, antitussives , antiemetics, antineoplastics, laxatives, anticoagulants, erythropoietin (e.g., epoetin alfa ), filgrastim (e.g., G-CSF, Neupogen), sargramostim (GM-CSF, Leukine), immunosuppressants, immunoglobulins, immunosuppressants (e.g. , basiliximab, cyclosporine, daclizumab), growth hormone, hormone replacement drugs, Estrogen receptor modulators, mydriatics, cycloplegics, alkylating agents, metabolic antagonists, mitotic agents Inhibitors, radiopharmaceuticals, antidepressants, antimanics, antipsychotics, anxiolytics, hypnotics, sympathetic stimulants Stimulants, stimulants, donepezil, tacrine, asthma medications, beta agonists, inhaled steroids , leukotriene inhibitors, methylxanthines, cromolyn, epinephrine or analogues , dornase alfa (Pulmozyme), cytokines or cytokine antagonists and administering, prior to, simultaneously with, and / or after the administration of at least one of the following drugs: Suitable dosages are well known in the art. See, for example, Wells et al., ds.,Pharmacotherapy Handbook,2nd Edition , Appleton and Lange, Stamford, CT (2000), P.D. R Pharmacopoeia, Tarascon Pocket Pharmaco poeia 2000, Deluxe Edition, Tarascon Publi shing, Loma Linda, CA (2000), Nursing 2001 H andbook of Drugs,21st edition,Springhouse e Corp., Springhouse, PA, 2001, Health Profe ssional's Drug Guide 2001, ed., Shannon, Wi. lson,Stang,Prentice-Hall,Inc,Upper Saddl See, e River, NJ, each of which is incorporated herein by reference in its entirety. INCORPORATED INTO THE SPECIFICATION.

[0163] Treatment Treatment of psoriasis involves administering an effective amount or dosage of an anti-IL-12 / 23p40 composition to a subject in need thereof. The effects of a particular drug are measured by administering it to a subject. Pharmacodynamic characteristics and the method and route of administration, age, health condition and weight of the recipient, The dosage will depend on known factors such as the nature and severity of the condition, type of concurrent treatment, frequency of treatment, and the desired effect. In some cases, repeated administration, i.e., multiple doses, may be required to reach a desired therapeutic dose. It may be necessary to provide repeated individual doses of fixed monitored or metered amounts. In this case, the individual doses are repeated until the desired daily dose or effect is achieved.

[0164] The subject under treatment is a pediatric patient aged between 6 months and less than 12 years. Preferably, the pediatric patient is Approximately 6, 7, 8, 9, 10, 11 years old, any age in between, or 11 to 1 More preferably, the pediatric patient is under 6 to 12 years of age, such as 2 years of age. The psoriasis does not respond or responds poorly to other treatments.

[0165] A safe and effective treatment for moderate to severe chronic plaque psoriasis in pediatric patients who need it. In one exemplary regimen for providing treatment, a weight-based dose of anti-IL-12 / IL- The 23p40 antibody is administered subcutaneously to the patient.

[0166] In one embodiment, the anti-IL-12 and / or anti-IL-23 antibody, about 0.5 mg / kg to 1.0 mg / kg per administration, preferably Preferably, the composition is administered subcutaneously to a patient at a dose of 0.75 mg / kg. The total amount of the substance per dose is approximately 0.50 mg / kg, 0.55 mg / kg, or 0.60 mg / kg. g, 0.70mg / kg, 0.75mg / kg, 0.80mg / kg, 0.90mg / k g, 0.95 mg / kg, 1.0 mg / kg, or any dose therebetween, and appropriately adjusted to provide a target dose of anti-IL-12 and / or anti-IL-23 antibody to the patient. do.

[0167] In another embodiment, the antibody is administered to a pediatric patient having a body weight of between 60 kg and 100 kg at the time of administration. The IL-12 and / or anti-IL-23 antibody is administered at a dose of about 35 mg to 55 mg, preferably The composition is administered subcutaneously to a patient in a dose of about 45 mg. For example, the total amount of the composition administered is Approximately 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or any value therebetween per dose The dosage is intended to provide a target dose of anti-IL-12 and / or anti-IL-23 antibody to the patient. The temperature is adjusted appropriately.

[0168] In another embodiment, the anti-IL-1 inhibitor is administered to a pediatric patient having a body weight of more than 100 kg at the time of administration. The anti-IL-12 and / or anti-IL-23 antibody is administered at a dose of about 80 mg to 100 mg, preferably A dose of 90 mg is administered subcutaneously to the patient. For example, the total amount of the composition administered is Approximately 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, or any value therebetween The dosage is designed to provide a target dose of anti-IL-12 and / or anti-IL-23 antibody to the patient. The temperature is adjusted appropriately.

[0169] The total dose of anti-IL-12 / IL-23p40 antibody was administered once daily, once weekly, or once every two weeks. once every four weeks or months, once every twelve weeks, once every six months, etc., or Any combination of 1 day, 1 week, 1 month, 6 months, 1 year, 2 years or longer The anti-IL-12 / Multiple doses of the IL-23p40 antibody can be administered to a subject in need thereof. Cut.

[0170] Dosage forms (compositions) suitable for internal administration generally contain about 0.001 milligrams per unit or container. Contains 100 mg to approximately 500 milligrams of active ingredient.

[0171] For parenteral administration, the antibody may be administered either together with a pharma- ceutically acceptable parenteral vehicle or separately. provided as a solution, suspension, emulsion, particle, powder, or lyophilized powder, Examples of such vehicles include water, saline, Ringer's solution, dextrose, etc. solutions, and 1-10% human serum albumin. Non-aqueous solutions such as liposomes and fixed oils. A liquid vehicle may also be used. The vehicle or lyophilized powder must be isotonic and chemically stable. Additives to maintain stability (e.g., sodium chloride for isotonicity, mannitol; chemical stabilizers) The formulation may contain any known or suitable additives (e.g., buffers and preservatives). Sterilized by technology.

[0172] Suitable pharmaceutical carriers are described in Remington's, a standard reference text in this field. Described in the latest edition of Pharmaceutical Sciences, A. Osol It has been done.

[0173] Alternative Administration In order to administer a pharma- ceutical effective amount of an IL-12 / IL-23p40 antibody, a method according to the present invention is Many known and developed methods can be used for this purpose. The IL-23p40 or IL-23 antibody may be in the form of a solution, emulsion, colloid or other suitable carrier. or as a suspension, or as a dry powder, by inhalation or any of the methods described herein. Various devices and methods suitable for administration by other modes known in the art are also available. The notice may be served using any of the methods described above.

[0174] Parenteral Formulation and Administration Preparations for parenteral administration are generally made up of sterile water or saline, polyethylene glycol, Even if it contains polyalkylene glycols such as ethanol, vegetable oils, hydrogenated naphthalene, etc. Aqueous or oily suspensions for injection may be prepared by adding suitable emulsifying agents or wetting agents and Injections can be prepared, for example, by using aqueous solutions, sterile injectable solutions, and suspensions. The diluent may be a non-toxic parenterally administrable diluent such as a suspension in a solvent. The vehicle or solvent may be water, Ringer's solution, isotonic saline, or the like. As a solvent or suspending medium, sterile, fixed oils can be used. , natural or synthetic or semi-synthetic, fatty oils or fatty acids, natural or synthetic or semi-synthetic, Any type of fixed oil, including monoglycerides, diglycerides, or triglycerides Parenteral administration is well known in the art and can be used in the art. A conventional injection device, such as a gas-pressurized needleless injection device as described in U.S. Pat. No. 5,851,198. injection devices, and laser perforation devices as described in U.S. Pat. No. 5,839,446. These include, but are not limited to, drilling devices, all of which are incorporated herein by reference in their entirety. is incorporated into the book.

[0175] alternative delivery The present invention further relates to parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraperitoneal, intracapsular, intrachondral, Intracavitary, intracavity, intracerebellum, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic , intrapericardium, intraperitoneum, intrapleura, intraprostate, intrapulmonary, intrarectum, intrakidney, intraretina, intraspinal cord, bursa Intrathoracic, intrauterine, intravesical, intralesional, bolus, intravaginal, rectal, oral, sublingual, intranasal, or for administering anti-IL-12 / IL-23p40 or IL-23 antibodies by transdermal means. Anti-IL-12 / IL-23p40 or IL-23 antibody compositions can be administered parenterally (subcutaneously, intramuscularly, or intravenously) or any other administration, particularly for use in the form of a liquid solution or suspension. For this purpose, the pharmaceutical composition may be administered vaginally or intravenously, particularly in semi-solid forms such as, but not limited to, creams and suppositories. For use in rectal administration, such as, but not limited to, tablets or capsules. for oral or sublingual administration, or as a powder, nasal spray or aerosol or certain drugs, but are not limited to, administered intranasally or dermally. To either modify skin structure or increase drug concentration in transdermal patches, Using chemical enhancers such as dimethyl sulfoxide (Junginger et al., In "Dr. ug Permeation Enhancement”;Hsieh,DS,Ed s.,pp.59-90(Marcel Dekker,Inc.New York 1 994, incorporated herein by reference in its entirety), or proteins and peptides. Application of a formulation having the same properties to the skin (WO 98 / 53847), or electroporation or to create a transient delivery pathway, such as iontophoresis, or to administer drugs to the skin, such as iontophoresis. Application of an electric field to increase the mobility of a charged drug through a membrane, or ultrasound, such as sonophoresis (U.S. Patents 4,309,989 and 4,767,402) The oxidizing agent may be used to create a gel, ointment, lotion, suspension, or patch delivery system. It can be prepared transdermally, including, but not limited to, the above publications and patents. (which is incorporated herein by reference in its entirety).

[0176] Embodiment The present invention also provides the following non-limiting embodiments.

[0177] Embodiment 1 is directed to the treatment of psoriasis, preferably moderate to severe chronic psoriasis, in a pediatric patient in need thereof. A method of treating psoriasis comprising administering to a subject a safe and effective amount of an anti-IL-12 / IL-23p4 0 antibody to the subject.

[0178] Embodiment 1a is the method of embodiment 1, wherein the antibody comprises a heavy chain variable region and a light chain variable region. the heavy chain variable region has the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO:1; The CDRH2 amino acid sequence of SEQ ID NO:2 and the CDRH3 amino acid sequence of SEQ ID NO:3. The light chain variable region has the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4. It includes the CDRL2 amino acid sequence of sequence number 5 and the CDRL3 amino acid sequence of sequence number 6.

[0179] Embodiment 2 is the method of any one of embodiments 1 and 1a, wherein the antibody is a heavy chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO:7; and a light chain variable region having an amino acid sequence at least 90% identical to that of SEQ ID NO:8.

[0180] Embodiment 2a is the method of embodiment 2, wherein the antibody is at least 95% identical to SEQ ID NO:7. a heavy chain variable region having an amino acid sequence identical to that of SEQ ID NO:8 and an amino acid sequence at least 95% identical to SEQ ID NO:8; and a light chain variable region having the sequence

[0181] Embodiment 2b is the method of embodiment 2, wherein the antibody has a heavy chain of the amino acid sequence of SEQ ID NO:7. and a light chain variable region of the amino acid sequence of SEQ ID NO:8.

[0182] Embodiment 3 is the method of any one of embodiments 1 and 1a, wherein the antibody is: A heavy chain having an amino acid sequence at least 90% identical to SEQ ID NO:10 and a heavy chain having an amino acid sequence at least 90% identical to SEQ ID NO:11. and a light chain having an amino acid sequence that is at least 90% identical to that of the human IgG1A.

[0183] Embodiment 3a is the method of embodiment 3, wherein the antibody has at least one sequence identical to SEQ ID NO: 10. A heavy chain having an amino acid sequence at least 95% identical to SEQ ID NO:11. and a light chain having the amino acid sequence of

[0184] Embodiment 3b is the method of embodiment 3, wherein the antibody has the amino acid sequence of SEQ ID NO: 10. and a light chain having the amino acid sequence of SEQ ID NO:11.

[0185] Embodiment 4 is a method according to any one of embodiments 1 to 3b, The children ranged in age from approximately 6 months to under 6 years old.

[0186] Embodiment 4a is the method of embodiment 4, wherein the pediatric patient is about 6 months, 1 year, 2 years, The age range is 2, 3, 4, 5, any age in between, or 5-6 years old.

[0187]

[0023] Embodiment 4b is a method according to any one of embodiments 1 to 3b, The patients are approximately 6 to under 12 years of age.

[0188] Embodiment 4c is the method of embodiment 4b, wherein the pediatric patient is about 6, 7, 8 years old. , 9, 10, 11, any age in between, or 11 to 12 years old.

[0189] Embodiment 4d is a method according to any one of embodiments 4 to 4c, comprising the steps of: Prior to this, pediatric patients were required to have a Physician Global Assessment (PGA) score of at least 3, a dry eye score of at least 12, and Psoriasis Area and Severity Index score (PASI) and the area of ​​at least 10% of the body surface area affected Moderate to severe chronic plaque as defined by at least one of the following: I have psoriasis.

[0190] Embodiment 4e is the method of embodiment 4d, wherein prior to treatment, the pediatric patient has at least Physician Global Assessment (PGA) score of at least 3 and Psoriasis Area and Severity Index score of at least 12 (PASI), and at least 10% of the affected body surface area (BSA) Both have moderate to severe chronic plaque psoriasis, as defined by two criteria.

[0191]

[0033] Embodiment 4f is the method of embodiment 4d, wherein prior to treatment, the pediatric patient has at least Physician Global Assessment (PGA) score of at least 3 and Psoriasis Area and Severity Index score of at least 12 (PASI), and at least 10% of the body surface area (BSA) affected. Patients with moderate to severe chronic plaque psoriasis.

[0192] Embodiment 4g is a method according to any one of embodiments 4 to 4f, have moderate to severe chronic plaque psoriasis for at least 6 months.

[0193] Embodiment 4h is the method of embodiment 4g, wherein the pediatric patient is at least 6 months, Have moderate to severe chronic plaque psoriasis for 1, 2, 3, 4, 5 years or more.

[0194] Embodiment 5 is the method according to any one of embodiments 1 to 4h, wherein the antibody is It is administered subcutaneously to pediatric patients.

[0195] Embodiment 5a is the method of embodiment 5, wherein the pediatric patient is less than 60 kg at the time of administration. and the anti-IL-12 and / or anti-IL-23 antibodies are administered to the pediatric patient at a weight A dose of about 0.5 mg / kg to 1.0 mg / kg, preferably 0.75 mg / kg, based on the weight of the patient. A total and effective amount is administered subcutaneously to the patient.

[0196] Embodiment 5a1 is a method according to embodiment 5a, comprising administering anti-IL-12 and / or anti-IL The dose of the -23 antibody is approximately 0.50 mg / kg and 0.55 mg / kg of body weight for pediatric patients. g / kg, 0.60mg / kg, 0.70mg / kg, 0.75mg / kg, 0.80m g / kg, 0.90mg / kg, 0.95mg / kg, or 1.0mg / kg of safe and An effective amount is administered subcutaneously to the patient.

[0197] Embodiment 5b is the method of embodiment 5, wherein the pediatric patient is between 60 kg and 1 and the anti-IL-12 and / or anti-IL-23 antibodies are administered at a dose of about 35 The drug is administered subcutaneously to a patient in a safe and effective amount ranging from about 45 mg to about 55 mg, preferably about 45 mg.

[0198] Embodiment 5b1 is a method according to embodiment 5b, comprising administering anti-IL-12 and / or anti-IL The -23 antibody is administered at approximately 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or is administered subcutaneously to a patient in any safe and effective amount therebetween.

[0199] Embodiment 5c is the method of embodiment 5, wherein the pediatric patient weighs 100 kg at the time of administration. and the anti-IL-12 and / or anti-IL-23 antibodies are administered at a dose of about 80 mg / dose. A safe and effective amount of up to 100 mg, preferably 90 mg, is administered subcutaneously to the patient.

[0200] Embodiment 5c1 is a method according to embodiment 5c, in which IL-12 and / or anti-IL- 23 Antibodies are available in doses of approximately 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, or is administered subcutaneously to a patient in any safe and effective amount therebetween.

[0201] Embodiment 6 is a method according to any one of embodiments 1 to 5c1, and administering an effective amount of anti-IL-12 and / or anti-IL-23 antibody to the pediatric patient two or more times. This includes:

[0202] Embodiment 6a is the method of embodiment 6, wherein the first dose is administered at week 0 or later, 4 weeks after the first dose. and administering subcutaneously a safe and effective amount of an anti-IL-12 and / or anti-IL-23 antibody. nothing.

[0203] Embodiment 7 is the method of embodiment 6, comprising administering to said patient a safe and effective amount of anti-IL-12 and and / or administering an anti-IL-23 antibody subcutaneously to a pediatric patient every 12 weeks (q12w). .

[0204]

[0023] Embodiment 7a is the method of embodiment 7, wherein after 4 weeks, the method further comprises administering the 0, 4, and 1 week Anti-IL-12 and / or anti-IL-23 antibodies are administered subcutaneously to pediatric patients every 2 weeks (q12w) This includes:

[0205]

[0023] Embodiment 7b is the method of embodiment 7, comprising administering to the subject at week 0, week 4, week 16, week 28, Safe and effective amounts of anti-IL-12 and / or anti-IL-23 in pediatric patients at week 30 and week 40. This involves administering the antibody subcutaneously.

[0206] Embodiment 7c is the method of embodiment 7b, wherein after 40 weeks, anti-IL-12 and / or anti-IL-12 are administered. Or further comprising subcutaneously administering the anti-IL-23 antibody to the pediatric patient.

[0207] Embodiment 8 is a method according to any one of embodiments 1 to 7c, The patient is naïve to psoriasis drugs or psoriasis treatments.

[0208] Embodiment 8a is a method according to any one of embodiments 1 to 7c, Patients were treated with a combination of topical agents, phototherapy, non-biologic systemic agents, and biologic agents. Patients had previously received at least one of the following therapies:

[0209] Embodiment 8b is the method of embodiment 8a, wherein the pediatric patient is treated with a topical agent. do.

[0210] Embodiment 8c is the method of embodiment 8a, wherein the pediatric patient is treated with phototherapy. There are.

[0211] Embodiment 8d is the method of embodiment 8a, wherein the pediatric patient is administered a non-biologic systemic agent. is being treated with

[0212] Embodiment 8e is the method of embodiment 8a, wherein the pediatric patient is treated with a biologic agent. It is being done.

[0213] Embodiment 8f is the method of embodiment 8e, wherein the pediatric patient is treated with an anti-TNFα agent. It is being done.

[0214] Embodiment 8g is the method of embodiment 8a, wherein the pediatric patient is administered at least one therapeutic Not responsive to the law or responsiveness is poor.

[0215] Embodiment 8h is the method of embodiment 8g, wherein the pediatric patient is administered at least one therapeutic Not responsive to the law or responsiveness is poor.

[0216] Embodiment 8i is the method of embodiment 8g, wherein the pediatric patient is non-responsive to phototherapy. Or the response is poor.

[0217] Embodiment 8j is the method of embodiment 8g, wherein the pediatric patient is administered a non-biologic systemic drug They do not respond to drugs or respond poorly to them.

[0218] Embodiment 8k is the method of embodiment 8g, wherein the pediatric patient is administered anti-IL-12 and / or anti-IL-12. No or poor response to biologic agents other than IL-23 antibodies.

[0219] Embodiment 8l is the method of embodiment 8k, wherein the pediatric patient is responsive to an anti-TNFα agent. No power supply or poor response.

[0220] Embodiment 9 is a method according to any one of embodiments 1 to 8, comprising administering the method subcutaneously. The pharmaceutical composition administered comprises the isolated antibody of embodiment 1a, about 0.27 mg / mL of pharmaceutical composition. about 0.80 mg of L-histidine, about 0.69 to about 2.1 mg per mL of pharmaceutical composition L-histidine monohydrochloride monohydrate, about 0.02 to about 0.06 mg per mL of pharmaceutical composition Polysorbate 80, and about 65 to about 87 mg of sucrose per mL of the pharmaceutical composition. The diluent is water at standard conditions.

[0221] Embodiment 9a is the method of embodiment 9, wherein the pharmaceutical composition for subcutaneous administration is About 77mg / ml, 80mg / ml, 85mg / ml, 90mg, including any concentration between / ml, 95mg / ml, 100mg / ml, 104mg / ml, or any value in between The anti-IL-12 / IL-23p40 antibody of embodiment 1a at a concentration of

[0222] Embodiment 9b is the method according to embodiment 9 or embodiment 9a, wherein the medicament is for subcutaneous administration. The composition is about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6. A pH of about 5.5 to about 6.5, such as a pH of 3, 6.4, 6.5, or any value therebetween has.

[0223] Embodiment 10 is a method according to any one of embodiments 1 to 9b, The patient is a responder to treatment with anti-IL-12 and / or anti-IL-23 antibodies and is cured. By the 52nd week of treatment, preferably by the 28th week, more preferably by the 12th week, of treatment, 0 or are identified as having a recipient (PGA) score of 1.

[0224] Embodiment 11 is a method according to any one of embodiments 1 to 10, The patient is a responder to treatment with anti-IL-12 and / or anti-IL-23 antibodies and is cured. By week 52, preferably by week 28, more preferably by week 12 of treatment, psoriasis A Pain Area and Severity Index score (PASI) of 75 is identified as a 75% reduction.

[0225] Embodiment 12 is the method of embodiment 11, wherein the pediatric patient is Preferably, by the 28th week, more preferably by the 12th week, the psoriasis area and severity index is A PASI score of 90 is identified as a 90% reduction.

[0226] Embodiment 13 is the method of embodiment 12, wherein the pediatric patient is Preferably, by the 28th week, more preferably by the 12th week, the psoriasis area and severity index is A PASI score of 100 is identified as a 100% reduction.

[0227] Embodiment 14 is the method according to any one of embodiments 1 to 10, The patient is a responder to treatment with anti-IL-12 and / or anti-IL-23 antibodies and is cured. By the 52nd week of treatment, preferably by the 40th week, more preferably by the 28th week, Pediatric mortality from baseline, preferably by Week 16, most preferably by Week 12 are identified as having a change in the Dermatological Life Quality Index (CDLQI).

[0228] Embodiment 15 is the method according to any one of embodiments 1 to 14, the patient has a steady state trough serum concentration of anti-IL-12 and / or anti-IL-23 antibodies; Steady-state trough serum concentrations should be achieved by week 52 of treatment, preferably by week 40. This is preferably achieved by 28 weeks.

[0229] Embodiment 15a is the method of embodiment 15, wherein the steady-state trough serum concentration is: This is maintained until week 52 of treatment.

[0230] Embodiment 16 provides a safe and effective amount of an anti-IL-12 / IL-23p40 antibody for use in pediatric patients. A method for treating moderate to severe chronic plaque psoriasis in a pediatric patient comprising subcutaneously administering and the antibody comprises (i) a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO:1. a heavy chain variable region comprising the CDRH2 amino acid sequence of SEQ ID NO: 2, and a CDRH 3 amino acid sequence, as well as the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:4 5, and the CDRL3 amino acid sequence of SEQ ID NO:6. (ii) a light chain variable region having the amino acid sequence of SEQ ID NO: 7, and (iii) a heavy chain variable region having the amino acid sequence of SEQ ID NO: or (iii) a light chain variable region having the amino acid sequence of SEQ ID NO: 10. and a light chain having the amino acid sequence of SEQ ID NO: 11, The amount of anti-IL-12 / IL-23p40 antibody 1) If the pediatric patient weighs less than 60 kg at the time of administration, Approximately 0.5 mg / kg to 1.0 mg / kg, preferably 0.75 mg / kg, based on body weight. 2) If the pediatric patient weighs 60kg to 100kg at the time of administration, approximately 35 mg / dose mg to 55 mg, preferably about 45 mg, or 3) If the pediatric patient weighs more than 100 kg at the time of administration, approximately 80 ml g to 100 mg, preferably 90 mg.

[0231] Embodiment 16a is the method of embodiment 16, wherein the pediatric patient is over 60 kg at the time of administration. and the anti-IL-12 and / or anti-IL-23 antibodies are administered to pediatric patients having a body weight of less than 0.55mg / kg, 0.60mg / kg, 0.70mg / kg, 0.7 5mg / kg, 0.80mg / kg, 0.90mg / kg, 0.95mg / kg, or about 0.50 mg / kg or 1.0 mg / kg, or any dose therebetween that is a safe and effective amount. g / kg is administered subcutaneously to patients.

[0232] Embodiment 16b is the method of embodiment 16, wherein the pediatric patient is over 60 kg at the time of administration. and the anti-IL-12 and / or anti-IL-23 antibodies are administered at approximately 35mg, 40mg, 45mg, 50mg, 55mg, or any dose in between A safe and effective amount is administered subcutaneously to the patient.

[0233] Embodiment 16c is the method of embodiment 16, wherein the pediatric patient receives 100k and the anti-IL-12 and / or anti-IL-23 antibodies are administered in an amount of about 80 mg / dose. mg, 85mg, 90mg, 95mg, 100mg, or any dose therebetween A total and effective amount is administered subcutaneously to the patient.

[0234] Embodiment 17 is a method according to any one of embodiments 16 to 16c, The antibody comprises a heavy chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO:7, and a sequence and a light chain variable region having an amino acid sequence at least 90% identical to sequence number 8.

[0235] Embodiment 17a is the method of embodiment 17, wherein the antibody has at least one sequence identical to SEQ ID NO:7. a heavy chain variable region having an amino acid sequence at least 95% identical to SEQ ID NO:8; and a light chain variable region having a single amino acid sequence.

[0236] Embodiment 17b is the method of embodiment 17, wherein the antibody comprises the amino acid sequence of SEQ ID NO:7. and a light chain variable region having the amino acid sequence of SEQ ID NO:8. nothing.

[0237] Embodiment 18 is a method according to any one of embodiments 16 to 16c, The antibody comprises a heavy chain having an amino acid sequence at least 90% identical to SEQ ID NO: 10 and a and a light chain having an amino acid sequence at least 90% identical to that of 11.

[0238] Embodiment 18a is the method of embodiment 18, wherein the antibody has at least one sequence selected from SEQ ID NO: 10. and a heavy chain having an amino acid sequence at least 95% identical to SEQ ID NO:11. and a light chain having an amino acid sequence.

[0239] Embodiment 18b is the method of embodiment 18, wherein the antibody has the amino acid sequence of SEQ ID NO: 10. and a light chain having the amino acid sequence of SEQ ID NO:11.

[0240] Embodiment 19 is a method according to any one of embodiments 16 to 18b, Pediatric patients range in age from approximately 6 months to less than 6 years.

[0241] Embodiment 19a is the method of embodiment 19, wherein the pediatric patient is about 6 months, 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, any age in between, or 5 to 6 years old.

[0242] Embodiment 19b is a method according to any one of embodiments 16 to 18b. Pediatric patients are approximately 6 to less than 12 years of age.

[0243] Embodiment 19c is the method of embodiment 19b, wherein the pediatric patient is about 6 years old, 7 years old, 8, 9, 10, 11, any age in between, or between 11 and 12 years old.

[0244] Embodiment 19d is a method according to any one of embodiments 19 to 19c. Prior to treatment, pediatric patients were required to have a Physician Global Assessment (PGA) score of at least 3 and a Psoriasis Area and Severity Index (PASI) score of 2 and at least 10% affected Moderate to severe, as defined by at least one of the following: percent body surface area (BSA) I have some degree of chronic plaque psoriasis.

[0245] Embodiment 19e is the method of embodiment 19d, wherein prior to treatment, the pediatric patient is Physician Global Assessment (PGA) score of at least 3 and Psoriasis Area and Severity Index score of at least 12 Core (PASI), and percent of body surface area (BSA) affected of at least 10% Patients with moderate to severe chronic plaque psoriasis as defined by at least two of the following criteria: do.

[0246] Embodiment 19f is the method of embodiment 19d, wherein prior to treatment, the pediatric patient is Physician Global Assessment (PGA) score of at least 3 and Psoriasis Area and Severity Index score of at least 12 Core (PASI), percent of body surface area (BSA) affected of at least 10% Patients with chronic plaque psoriasis, as defined by the above criteria, have moderate to severe chronic plaque psoriasis.

[0247] Embodiment 19g is a method according to any one of embodiments 19 to 19f, Patients have moderate to severe chronic plaque psoriasis of at least 6 months duration.

[0248] Embodiment 19h is the method of embodiment 19g, wherein the pediatric patient is at least 6 months old. Have moderate to severe chronic plaque psoriasis for more than a month, 1 year, 2 years, 3 years, 4 years, or 5 years .

[0249] Embodiment 20 is the method according to any one of embodiments 16 to 19h, Pediatric patients are naïve to psoriasis drugs or psoriasis treatments.

[0250] Embodiment 20a is a method according to any one of embodiments 16 to 19h. Pediatric patients were randomized to receive treatment with a group consisting of topical agents, phototherapy, non-biologic systemic agents, and biologic agents. The patient had previously received at least one therapy selected from the following:

[0251] Embodiment 20b is the method of embodiment 20a, wherein the pediatric patient is treated with a topical agent. He is being treated.

[0252] Embodiment 20c is the method of embodiment 20a, wherein the pediatric patient is treated with phototherapy. He is being treated.

[0253] Embodiment 20d is the method of embodiment 20a, wherein the pediatric patient is a non-biologic systemic Being treated with medication.

[0254] Embodiment 20e is the method of embodiment 20a, wherein the pediatric patient is treated with a biologic agent. It is being treated.

[0255] Embodiment 20f is the method of embodiment 20e, wherein the pediatric patient is treated with an anti-TNFα agent. It is being treated.

[0256] Embodiment 20g is the method of embodiment 20a, wherein the pediatric patient is The patient does not respond or responds poorly to conventional therapy.

[0257] Embodiment 20h is the method of embodiment 20g, wherein the pediatric patient is responsive to a topical agent. No power supply or poor response.

[0258] Embodiment 20i is the method of embodiment 20g, wherein the pediatric patient is a pediatric patient that responds to phototherapy. Or the response is poor.

[0259] Embodiment 20j is the method of embodiment 20g, wherein the pediatric patient is a non-biological systemic The patient does not respond or responds poorly to anti-inflammatory drugs.

[0260] Embodiment 20k is the method of embodiment 20g, wherein the pediatric patient is administered anti-IL-12 and and / or non-responsive or poorly responsive to biologic agents other than anti-IL-23 antibodies.

[0261] Embodiment 20l is the method of embodiment 20k, wherein the pediatric patient is treated with an anti-TNFα agent. No response or poor response.

[0262] Embodiment 21 is the method according to any one of embodiments 16 to 20l, The method comprises administering a safe and effective amount of the pharmaceutical composition subcutaneously to a pediatric patient two or more times.

[0263] Embodiment 21a is the method of embodiment 21, wherein after the first dose at week 0, The method includes subcutaneously administering an effective amount of the pharmaceutical composition to a pediatric patient starting from the fourth week.

[0264] Embodiment 22 is the method of embodiment 21, wherein a safe and effective amount of the pharmaceutical composition is administered. administered subcutaneously every 12 weeks (q12w) to pediatric patients.

[0265]

[0036] Embodiment 22a is the method of embodiment 22, wherein after 4 weeks, the method further comprises: and every 12 weeks (q12w), a safe and effective amount of the pharmaceutical composition is administered subcutaneously to the pediatric patient. This includes:

[0266]

[0036] Embodiment 22b is the method of embodiment 22, comprising administering to the subject a therapeutically effective amount of the ... Administer a safe and effective amount of the pharmaceutical composition subcutaneously to pediatric patients at weeks 8 and 40. Includes.

[0267]

[0036] Embodiment 22c is the method of embodiment 22b, wherein after 40 weeks, the method is performed in a pediatric patient. and further comprising administering an effective amount of the pharmaceutical composition subcutaneously.

[0268] Embodiment 23 relates to the method according to any one of embodiments 1 to 22c, A safe and effective amount for use in the treatment of moderate to severe chronic plaque psoriasis in pediatric patients The present invention relates to a pharmaceutical composition comprising an anti-IL-12 and / or anti-IL-23 antibody of the present invention.

[0269] Embodiment 24 is a kit comprising the pharmaceutical composition of embodiment 23.

[0270] Having generally described the present invention, the same is provided by way of illustration and not limitation. This will be more readily understood by reference to the following examples, which are not intended to be exhaustive. Further details of the present invention are illustrated by the following non-limiting examples. The disclosures of all citations are expressly incorporated herein by reference. EXAMPLES

[0271] Example 1: Study of Ustekinumab in the Treatment of Plaque Psoriasis in Pediatric Patients Pediatric participants aged 6 to 12 years with moderate to severe chronic plaque psoriasis The following open-label, multicenter clinical trials were conducted: Phase 3, open-label, multicenter study To evaluate the efficacy and safety of ustekinumab-induced psoriasis in subjects with moderate to severe chronic plaque psoriasis. The efficacy and safety of initial and maintenance treatment were evaluated.

[0272] Overall Rationale Efficacy and Clinical Evaluation of Subcutaneous (SC) Administration in Subjects with Moderate to Severe Chronic Plaque Psoriasis Participants received weight-based doses of ustekinumab from 0 to 24 hours prior to the study to evaluate efficacy and safety. The drug was administered subcutaneously at weeks 1 and 4, then every 12 weeks (q12w) until week 40. .

[0273] Inclusion criteria Participants had psoriatic arthritis (PsA) for at least 6 months prior to receiving their first dose of study medication. Patients with a diagnosis of plaque psoriasis with or without a psoriasis area and severity of 12 or more (>= 12) Patient Acute Anomaly Index score (PASI) of ≥3, Physician Global Assessment (PGA) of ≥10, and Moderate to severe chronic plaque psoriasis defined by involved body surface area (BSA) in (%) Participants consisted of boys and girls with glaucoma, glaucoma, and glaucoma. Participants were candidates for phototherapy or systemic treatment. or was deemed by the investigators to be poorly controlled with local therapy.

[0274] Participants Overview A total of 52 subjects were screened, of which 44 were enrolled and at least Patients were also treated with a single injection of ustekinumab. The trial was conducted in Belgium, Canada, Germany and Hungary. The study was conducted at 20 locations across seven countries: Belgium, Belgium, the Netherlands, Poland, and the United States.

[0275] The majority of subjects were white (90.9%) and male (61.4%). The median age was 9.5 years and the median baseline weight was 33.3 kg. The median percentile of involved body surface area (BSA) at baseline was 2.9 years. The median PASI score was 16.1 and the mean mean score was 18.0. 10.4% of subjects had PGA=3 (moderate), 34.1% of subjects had PGA≧4, and 10.4% had significant or severe It was found to be a severe disease.

[0276] Overall, 34.1% had received prior phototherapy and 18.2% had received prior systemic therapy. 4.5% had previously received biologic therapy. Furthermore, 56.8% had previously received non-biologic systemic therapy. The subjects were naïve to previous non-biologic systemic therapy and phototherapy, and 77.3% of subjects had undergone all previous non-biologic systemic therapy. The patients were naïve to chemotherapy and biological therapy.

[0277] Legend: Baseline demographics, psoriasis disease characteristics, and prior psoriasis medications / therapies are shown in Table 1 To summarize:

[0278] [Table 1]

[0279] A total of 3 (6.8%) subjects discontinued study drug before week 40. Of these, two subjects discontinued the study drug because they did not meet the PASI acceptance criteria. One subject discontinued the study drug due to lack of efficacy.

[0280] Test Design The study included a screening phase (up to 10 weeks before administration of the study drug), a treatment period (week 0 to The study consisted of a follow-up period (week 52) and a safety follow-up period (week 56). Participants were randomized to receive a weight-based dose of Tekinumab was administered subcutaneously at weeks 0 and 4, then every 12 weeks (q12w) for 40 The final dose was administered in week 26. Eligible participants in the long-term extension study (LTE) were randomized from week 56 to week 26. In week 4, weight-based dosing of ustekinumab was continued q12w. Figure 1 shows the study data. The diagram of the design is shown below.

[0281] Dosage and Administration The standard dose of ustekinumab was administered at each visit based on body weight.

[0282] [Table 2]

[0283] the purpose The primary efficacy analysis was conducted in patients enrolled who received at least one injection of ustekinumab during the study. The analysis was based on all subjects who received treatment. This is also called the full analysis set. Analysis sets were used for all primary and key secondary efficacy endpoints.

[0284] The primary objective of this study is to evaluate patients aged ≥6 to <12 years with moderate to severe chronic plaque psoriasis. The objective of this study was to evaluate the efficacy and safety of ustekinumab in pediatric patients of any age. The outcome endpoint was a clear (0) or minimal (1) investigator's global assessment (P GA).

[0285] The PGA is used to assess a participant's overall psoriasis lesions at a given time point. Lesions were graded on a scale ranging from 0 = no evidence of macular elevation to 5 = severe macular elevation, with 0 = no evidence of erythema. 5 = no evidence, possible hyperpigmentation, erythema scale ranging from dull to deep red tones; Scaling scale ranging from 0 = no evidence of scaling to 5 = severe, dominated by very thick, highly adhesive scaling The sum of the three scales is divided by 3 and rounded to the nearest whole number to arrive at the final PGA score ( Obtain a total score (0-5).

[0286] The secondary objectives of this study were (1) to evaluate serum ustekinumab concentrations over time, (2 ) PASI 75 response rate (i.e., ≥ 75 percent (%)) at Week 12 To evaluate the proportion of participants achieving a Phase 3 Allergy Area and Severity Index (PASI) score, 3) to evaluate the PASI 90 response rate at week 12, and (4) to evaluate the baseline response rate at week 12. The study included assessing change in the Children's Dermatology Life Index (CDLQI) from the study.

[0287] Primary endpoint results Based on the full analysis set, achieving a PGA score of clear (0) or minimal (1) at Week 12 The proportion of subjects achieving the AE was 77.3% (34 / 44), with an exact 95% CI of (62.2%, 8 8.5%, Table 3).

[0288] [Table 3]

[0289] Primary secondary endpoint analysis Serum ustekinumab concentration Serum ustekinumab concentrations were summarized over time up to 52 weeks (Figure 2 and Table 4).

[0290] [Table 4]

[0291] The proportion of subjects who achieved a PASI 75 response at week 12 was 84.1% (37 / 44). , with exact 95% CI being (69.9%, 93.4%) (Table 5).

[0292] [Table 5]

[0293] The proportion of subjects who achieved a PASI 90 response at week 12 was 63.6% (28 / 44). , with exact 95% CI being (47.8%, 77.6%) (Table 6).

[0294] [Table 6]

[0295] At week 12, the mean (SD) change from baseline in CDLQI was -6.3 (6.43 ), with a 95% CI of (-8.29, -4.28) (Table 7).

[0296] [Table 7]

[0297] Results of other efficacy endpoints IGA and PASI responses over time During the period from 4 to 52 weeks, PGA score was clear (0) or minimal (1) and PASI 7 The percentage of subjects who achieved a PASI 5 response, a PASI 90 response, and a PASI 100 response are shown in Figure 3A-C. This is summarized in Figure 3D.

[0298] Other pharmacokinetics Serum ustekinumab concentrations were measured using a validated electrochemiluminescence immunoassay (ECLIA) method. The mean or median steady-state trough serum ustekinumab concentrations were measured at 0.75 mg / mL. Subjects with baseline weight <60 kg treated with a fixed dose of 45 mg The results were roughly comparable between subjects with baseline weights of ≥60kg and ≥100kg treated with However, only a limited number of subjects (N=4) had a baseline weight of ≥60kg to ≤100kg. (Table 8).

[0299] [Table 8]

[0300] immunogenicity Treated subjects with adequate specimens to measure antibodies to ustekinumab Antibodies against ustekinumab were measured (immunogenicity assay set). The incidence of was 9.5% (4 / 42) and was detected by a highly sensitive and drug-resistant assay. (Table 9).

[0301] [Table 9]

[0302] Two of the four subjects who tested positive for antibodies to ustekinumab in vitro had antibodies capable of neutralizing the biological activity of ustekinumab (Table 10).

[0303] [Table 10]

[0304] Safety Results Safety was assessed in all enrolled subjects who received at least one dose of ustekinumab. The safety analysis set was the same as the full analysis set. Legend Safety Event are summarized in Table 11.

[0305] [Table 11]

[0306] A total of three subjects reported serious adverse events (SAEs): one subject had mononucleosis; The patient was hospitalized for diagnosis and treatment for 4 days, made a full recovery, and continued receiving ustekinumab. Another subject was hospitalized for treatment of a traumatic eyelid injury, and a third subject had attention deficit hyperactivity disorder. He was electively admitted from the outpatient unit for further evaluation of harm (ADHD).

[0307] No significantly abnormal chemical blood test results occurred. Four subjects had lymphocytopenia (one One patient reported significant hematologic abnormalities, including neutrophilemia. Both were resolved and subsequently The events resolved without interruption of tekinumab treatment (Table 12).

[0308] [Table 12]

[0309] Those skilled in the art may make changes to the above-described embodiments without departing from the broad inventive concept. It will be understood that the invention is therefore not limited to the particular embodiments disclosed. However, the present invention is not limited to the above-mentioned specific embodiments, and covers modifications within the spirit and scope of the present invention as defined by the specific description. It is understood that it is intended to

Claims

1. A method of treating psoriasis in a pediatric patient in need thereof, comprising administering to a pediatric patient a safe and effective amount of an anti-IL-1 inhibitor. administering to said pediatric patient a pharmaceutical composition comprising an IL-12 / IL-23p40 antibody; The antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region being a sequence corresponding to SEQ ID NO:

1. Complementary determining region heavy chain 1 (CDRH1) amino acid sequence, CDRH2 amino acid sequence of SEQ ID NO:2 and a CDRH3 amino acid sequence of SEQ ID NO:3, wherein the light chain variable region comprises a Complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:5, CDRL2 amino acid sequence of SEQ ID NO:5 and a CDRL3 amino acid sequence of SEQ ID NO:6, wherein the pediatric patient is at least 6 years of age. and are under 12 years of age and have a Physician Global Assessment (PGA) score of 0 or 1 after treatment. and / or a Psoriasis Area and Severity Index (PASI) score of at least 75%, 9 The anti-IL-12 / IL-23p4 antibody is identified as having a 0% or 100% decrease. 0 antibody treatment.

2. The method of claim 1 , wherein the antibody is administered subcutaneously to the pediatric patient.

3. The pediatric patient has a body weight of less than 60 kg at the time of administration, and the anti-IL-12 / IL- The 23p40 antibody is administered at a dose of about 0.5 mg / kg to 1 mg / kg of the pediatric patient's body weight. 0.0 mg / kg, preferably 0.75 mg / kg, of said safe and effective amount.

3. The method of claim 2, wherein the administration is subcutaneous.

4. the pediatric patient has a body weight of 60 kg to 100 kg at the time of administration; / The IL-23p40 antibody is administered in a safe and effective amount of about 35 mg to 55 mg per dose.

3. The method of claim 2, wherein the patient is administered subcutaneously with

5. The anti-IL-12 / IL-23p40 antibody is administered at 45 mg per dose. The method according to claim 4.

6. The pediatric patient has a body weight of greater than 100 kg at the time of administration, and the anti-IL-12 / I The L-23p40 antibody is administered in a safe and effective amount of about 80 mg to 100 mg per dose. The method of claim 2, wherein the therapeutic agent is administered subcutaneously to the patient.

7. The anti-IL-12 / IL-23p40 antibody is administered at 90 mg per dose. The method according to claim 6.

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

8. and a light chain variable region having the sequence of

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

11. and a light chain having an array.

10. The safe and effective amount of the anti-IL-12 / IL-23p40 antibody is administered to the pediatric patient. The method of claim 1 , which is administered repeatedly.

11. The safe and effective amount of the anti-IL-12 / IL-23p40 antibody is administered at week 0 of the treatment.

10. The method of claim 1, wherein the pediatric patient is administered at the first and fourth weeks.

12. The safe and effective amount of the anti-IL-12 / IL-23p40 antibody is administered at week 4 and week 12. The method of claim 11 , further administered to the pediatric patient every 24 hours.

13. The method of claim 1 , wherein the pediatric patient is naïve to psoriasis medications or treatments.

14. The pediatric patient is treated with a combination of topical agents, phototherapy, non-biologic systemic agents, and biologic agents.

1. The patient of claim 1, who has received at least one psoriasis medication or treatment selected from the group consisting of: The method described above.

15. The pediatric patient is non-responsive or non-responsive to the at least one psoriasis medication or psoriasis treatment. The method of claim 14, wherein the response is poor.

16. The method of claim 15, wherein the pediatric patient is unresponsive or poorly responsive to topical agents. Law.

17. The pediatric patient responds to the treatment with the anti-IL-12 / IL-23p40 antibody. Respondents who received a physician global rating of 0 or 1 by week 52, 28, or 12 of treatment The method of claim 1, wherein the patient is identified as having a PGA score.

18. The pediatric patient responds to the treatment with the anti-IL-12 / IL-23p40 antibody. and determining whether said psoriasis area and severity is increased by 52 weeks, 28 weeks, or 12 weeks of said treatment. Patients were identified as having at least a 75%, 90%, or 100% reduction in their PASI score. The method of claim 1 , wherein

19. The pediatric patient responds to the treatment with the anti-IL-12 / IL-23p40 antibody. Respondents were assessed for improvement in the Pediatric Dermatology Life Quality Index (CDLQI) by 12 weeks of treatment. The method of claim 1 , wherein the first and second inputs are identified as having a variation from the baseline.

20. The pediatric patient has a steady-state trough serum concentration of the anti-IL-12 / IL-23p40 antibody. and the steady-state trough serum concentration is at 52 weeks, 40 weeks, or 28 weeks of the treatment. The method of claim 1, wherein the method is accomplished by 1 week.

21. 21. The method of claim 20, wherein the steady-state trough serum concentration is maintained through 52 weeks of the treatment. The method described.

22. 2. The method of claim 1, wherein the anti-IL-12 / 23p40 antibody is ustekinumab. 。

23. 2. The method of claim 1, wherein the psoriasis being treated is moderate to severe chronic plaque psoriasis. method.

24. The psoriasis being treated has a Physician Global Assessment (PGA) score of at least 3, A Psoriasis Area and Severity Index (PASI) score of 2, and / or at least 10% affected Severe chronic plaque psoriasis, defined as the percentage of affected body surface area (BSA) The method of claim 23 .

25. A method of treating severe chronic plaque psoriasis in a pediatric patient, comprising administering to said patient Psoriasis is characterized by a Physician Global Assessment (PGA) score of at least 3, a psoriasis area of ​​at least 12, and Patients with a history of cardiovascular disease (PASI) and / or at least 10% affected body surface area ( and wherein the method is safe and effective in the pediatric patient, the method being defined by a percentage of total BSA. The method comprises administering subcutaneously an amount of an anti-IL-12 / IL-23p40 antibody, the antibody comprising: 3.) a heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO:1; A CDRH2 amino acid sequence of SEQ ID NO:2 and a CDRH3 amino acid sequence of SEQ ID NO:3, and The complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDR a light chain variable region comprising the L2 amino acid sequence of SEQ ID NO: 6, and the CDRL3 amino acid sequence of SEQ ID NO: 7; i) a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7, and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 8 or (iii) a heavy chain having the amino acid sequence of SEQ ID NO: 10, and and a light chain having an amino acid sequence as set forth in SEQ ID NO:

11. an amount of the anti-IL-12 / IL-23p40 antibody, 1) if the pediatric patient weighs less than 60 kg at the time of administration, Approximately 0.5 mg / kg to 1.0 mg / kg, preferably 0.75 mg / kg of body weight for pediatric patients. g / kg, 2) When the pediatric patient has a body weight of 60 kg to 100 kg at the time of administration, about 35 mg to 55 mg, preferably about 45 mg, or 3) if the pediatric patient weighs more than 100 kg at the time of administration, About 80 mg to 100 mg, preferably 90 mg; method.

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