Methods for treating Crohn's disease using anti-IL23 specific antibodies

Abstract

A method of treating Crohn's disease in a patient comprises administering an initial subcutaneous dose and subsequent subcutaneous doses of an IL-23 specific antibody, e.g., guselkumab, such that the patient responds to the antibody and meets one or more clinical endpoints.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention is directed to a method for treating Crohn's disease using an antibody that binds to human IL23. Specifically, the present invention provides a method for administering anti-IL23 specific antibodies and specific pharmaceutical compositions of the antibodies. This document relates to a dosing regimen for the treatment of rheumatoid arthritis.

[0002] (Reference to electronically submitted sequence listing) This application is submitted electronically through the U.S. Patent and Trademark Office Patent Center as a Sequence Listing in XML format. The file name "JBI6635WOPCT1 Sequence Listing g.xml", created on October 24, 2022, containing a sequence listing of 11kb in size. The sequence listing submitted through the Patent Center is incorporated herein by reference. No. 6,299,499, filed on Dec. 1, 2003, which is hereby incorporated in its entirety.

[0003] BACKGROUND OF THE INVENTION Interleukin (IL)-12 is a glycosaminoglycan consisting of two disulfide-linked glycosaminoglycans. The purified protein subunits (designated p35 and p40 for their approximate molecular weight) IL-12 is a secreted heterodimeric cytokine composed of IL-12 and IL-13. It is produced by T cells or natural killer (NK) cells. Promotes cell-mediated immunity by binding to a surface-expressed two-chain receptor complex The IL-12 receptor beta-1 (IL-12Rβ1) chain is Binds to the p40 subunit of IL-12, the primary interaction between IL-12 and its receptor However, intracellular signaling (e.g., STAT4 phosphorylation) and receptor The second receptor chain, IL-12Rβ2, mediates the activation of receptor-carrying cells. 12p35 ligation (Presky et al, 1996). Antigen presentation and Concomitant IL-12 signaling specifically induces interferon gamma (IFNγ) production. It is thought to induce T cell differentiation into the T helper 1 (Th1) phenotype, which is characteristic of Th1 cells are known to mediate the proliferation of several intracellular pathogens (Trinchieri, 2003). It is believed to promote immunity to the body, generate complementary antibody isotypes, and contribute to tumor immunosurveillance. Therefore, IL-12 is considered to be an important component of the host defense immune system. It is possible.

[0004] The p40 protein subunit of IL-12 is a separate protein designated p19 It can also associate with other subunits to form the novel cytokine IL-23. IL-23 also has a two-chain receptor complex. Signaling occurs through the p40 subunit, which is covalently linked to IL-12 and IL-23. Therefore, the IL-12Rβ1 chain is also shared between IL-12 and IL-23. However, IL-23-specific intracellular signaling (e.g., STAT3 phosphorylation) The IL-23 receptor complex mediates activation of IL-17 and subsequent IL-17 production by T cells. The second component of IL-23R is IL-23p19 ligation (Par Ham et al., 2002, Aggarwal et al., 2003). The study found that the biological functions of IL-23 and IL-12 are mediated by these two sites. Despite the structural similarities between the kinases, they are distinct (Langrish et al. al,2005).

[0005] Neutralization of IL-12 by antibodies has been shown to be effective in treating psoriasis, multiple sclerosis (MS), Rheumatoid arthritis, inflammatory bowel disease, insulin-dependent (type 1) diabetes mellitus, and uveitis Abnormal regulation of IL-12 and Th1 cell populations for efficacy in treating animal models has been implicated in many immune-mediated diseases (Leonard et al., 1995, H ong et al, 1999, Malfait et al, 1998, Davids However, these studies did not identify a common p40 subunit. Because it targets the IL-12 receptor, it neutralizes both IL-12 and IL-23 in vivo. Therefore, whether IL-12 or IL-23 mediated the disease or suppressed the disease remains unclear. It is unclear whether both cytokines need to be inhibited to achieve this. Studies have shown that IL-23 inhibition may offer benefits comparable to anti-IL-12p40 strategies. This was confirmed by IL-23p19-deficient mice or specific antibody neutralization of IL-23 (Cua et al. al,2003,Murphy et al,2003,Benson et al 2004). Thus, evidence for a specific role of IL-23 in immune-mediated diseases is emerging. There is increasing evidence that neutralizing IL-23 without inhibiting the IL-12 pathway is important. To provide an effective treatment for immune-mediated diseases with limited impact on essential host defense immune mechanisms. This would represent a significant improvement over other treatment options.

[0006] There are currently three classes of biologics approved for the treatment of moderately to severely active Crohn's disease. Drug: Tumor necrosis factor (TNF) antagonist therapy (infliximab) , adalimumab, certolizumab), integrin inhibitors (natalizumab and vedolizumab Introduction of biologic agents significantly improved the clinical management of patients with moderate to severe active Crohn's disease, but A significant proportion of the patient population will not respond or will lose response over time. A review of the available data for biologic agents is provided, particularly for patients with previous biologic failures. highlights the unmet need in achieving and maintaining long-term remission among patients with All treated patients (i.e., all randomized at week 0 of the study) were evaluated. In the biologics-failed or -intolerant (BIO-failed) population, clinical outcomes at 1 year were The estimated rate of remission is approximately 20%, and in the conventional therapy failure or intolerance (CON failure) population, it is 2. The range is 0% to 50%.

[0007] In summary, new treatment options, especially those that raise the efficacy bar and advance clinical practice, are essential. Has a novel mechanism of action that has the potential to maximize the proportion of patients who achieve and maintain remission There remains a significant unmet medical need for therapy.

[0008] (Summary of the Invention) In a first aspect, the present invention provides a method of treating a subject suffering from Crohn's disease, comprising: Anti-IL23 specific antibody (also known as IL23p19 or IL23p19 subunit antibody) For example, guselkumab was administered as an initial subcutaneous induction dose from the start of treatment until the fourth week of treatment. The patient is administered a single dose at 0, 4, 8, 12 or 14 weeks, followed by one dose every 4 or 8 weeks thereafter, e.g., at 0, 4, 8, 12 or 14 weeks. 16, 20 or 24, 28 or 32, 36 or 40, 44 or 48 weeks In yet another embodiment, the method comprises administering a specific antibody subcutaneously. Treatment will continue for at least 96 weeks after initiation of treatment.

[0009] In one embodiment, the subject receives an anti-IL23 specific antibody at the initial dose, 4 weeks after the initial dose, and 400 mg subcutaneously administered 8 weeks after the initial treatment, with 4 doses administered throughout the 24 weeks after initial treatment. Subcutaneous treatment with anti-IL23 specific antibody was continued at 100 or 200 mg every week or every 8 weeks. Continues for periods exceeding 24 weeks up to 48 weeks, 96 weeks and beyond, in some cases. Continue.

[0010] In another embodiment, the composition used in the methods of the present invention is a pharmaceutical composition comprising an anti-IL23 specific antibody. In a preferred embodiment, the anti-IL-23 specific antibody comprises 7.9% of the pharmaceutical composition. % (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monosodium salt Polysorbate 80 monohydrate; 0.053% (w / v) of the polysorbate 80 present in the composition The diluent is water at standard conditions.

[0011] In one embodiment, the anti-IL23 specific antibody is administered in a single dose with an YpsoMate autoinjector. It is provided in a 200 mg / mL formulation in a prefilled syringe (PFS-Y) and is available as an alternative. In embodiments, the anti-IL23 specific antibody is UltraSafe Plus™ Pas Single-dose prefilled syringe with sive Needle Guard (PFS- It is provided at 100 mg / mL in 100 mg / mL cereals containing 100 mg / mL

[0012] In one embodiment, patients with Crohn's disease are evaluated for a clinical endpoint selected from: Achieve significant improvements: (i) Crohn's Disease Activity Index (CDAI) score The CDAI score was calculated based on 8 different Crohn's disease-related variables. It is assessed by collecting information about the patient's condition, and the score ranges from 0 to approximately 600. A change in which a decrease over time indicates an improvement in disease activity; (ii) total number of liquid or very loose stools and weight of abdominal pain (AP) score Patient-Reported Outcomes (PRAs) defined by unlabeled CDAI components Ported Outcome, PRO)-2; (iii) Presence or absence of mucosal ulcers and Simple Endoscopic Score for Crohn's Disease Endoscopic evaluation of the intestinal mucosa based on the Standards for Crohn's Disease (SES-CD); (iv) histological evaluation; (v) C-reactive protein (CRP) or fecal calprotectin Inflammatory pharmacodynamic (PD) markers, including: (vi) fistula assessment; (vii) Inflammatory Bowel Disease Questionnaire (IBD) Q) and Patient-reported Outcomes Measurement Information System Health-related quality of life outcomes, including PROMIS (Progression, Response, and Inequality of Life Information System)-29 PRO scales to assess; (viii) Bristol Stool Form Scale (BSFS) and AP - Patient-reported symptom scales including the Numerical Rating Scale (NRS); (ix) Clinical outcome at week 12, defined as a CDAI of <150 points Bed remission. (x) A decrease of ≥ 100 points from baseline in the CDAI score or Clinical response at week 12, defined as a CDAI score <150. (xi) Week 12, as measured by Simplified Endoscopic Score for Crohn's Disease (SES-CD) SES-CD was performed using four endoscopic procedures across five ileocolonic segments. The total score is based on raw ratings and ranges from 0 to 56. (xii) 12 weeks, as measured by Simplified Endoscopic Score for Crohn's Disease (SES-CD) Endoscopic remission in eyes; SES-CD ≤ 2. (xiii) clinical remission at week 48, defined as a CDAI score <150; (xiv) CDAI < 150 for the majority of all visits between Weeks 12 and 48 Sustained clinical remission at 48 weeks, defined as (xv) CDAI score <150 at week 48 and corticosteroid activity at week 48 Corticosteroid-free at week 48, defined as not receiving corticosteroids Clinical remission. (xvi) Average daily stool frequency (SF) and average daily abdominal pain (AP) scores PRO-2 remission at week 48, defined based on the core. Patient-reported outcome measurement information system STEM (Patient-Reported Outcomes Measurement Information System, PROMIS) Fatigue response at week 12 based on the Fatigue Short Form 7a, which includes the severity of fatigue It contains seven items assessing fatigue, with higher scores indicating greater fatigue.

[0013] In another aspect of the invention, the pharmaceutical composition optionally comprises 7.9% (w / v) of the pharmaceutical composition. Sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, 0 (i) SEQ ID NO: 1, present in a composition of 0.053% (w / v) polysorbate 80; SEQ ID NO: 2 and the heavy chain CDR amino acid sequence of SEQ ID NO: 3, and (ii) SEQ ID NO: 4, SEQ ID NO: 5, and the light chain CDR amino acid sequence of SEQ ID NO: 6. It contains 23 specific antibodies and the diluent is standard water.

[0014] Another aspect of the method of the present invention is to optionally add 7.9% (w / v) sucrose to the pharmaceutical composition. , 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, 0.053% Heavy chain variable region amino acid sequence of SEQ ID NO: 7 present in a composition of (w / v) polysorbate 80 and a light chain variable region amino acid sequence of SEQ ID NO: 8. The method comprises administering the pharmaceutical composition containing the compound, wherein the diluent is standard water.

[0015] A further aspect of the method of the present invention is to optionally add 7.9% (w / v) sucrose to the pharmaceutical composition. 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, 0.053 Heavy chain amino acid sequence of SEQ ID NO: 9 present in a composition of % (w / v) Polysorbate 80 and a light chain amino acid sequence of SEQ ID NO: 10. The pharmaceutical composition is administered, and the diluent is standard water.

[0016] In yet a further embodiment, the method of the present invention optionally comprises administering to the patient 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate 0.053% (w / v) polysorbate 80. (marketed by Janssen Biotech, Inc. as Tremfya®) The method includes administering the pharmaceutical composition containing the compound (sold under the trade name "Campaigner"), wherein the diluent is standard water. is.

[0017] The details of one or more embodiments of the invention are set forth in the description below. Features and advantages will become apparent from the following detailed description, drawings, and appended claims. [Brief explanation of the drawings]

[0018] [Figure 1] 1 shows a schematic diagram of the study described herein. [Figure 2] The dosing regimen for the treatment phase and how the study intervention will be administered are shown.

[0019] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS As used herein, the method of treating a subject suffering from Crohn's disease includes administering an isolated , recombinant, and / or synthetic anti-IL-23 specific human antibodies; and Includes diagnostic and therapeutic compositions, methods, and devices.

[0020] As used herein, "anti-IL-23 specific antibody," "anti-IL-23 antibody," "Antibody portion," or "antibody fragment," and / or "antibody variant," etc., are used to describe antibodies of the present invention. At least one complementarity determining region of the heavy or light chain may be incorporated. CDR) or its ligand-binding portion, heavy or light chain chain variable region, heavy or light chain constant region, framework region, or any portion thereof or at least a portion of an IL-23 receptor or binding protein, Any protein or peptide containing at least a portion of an immunoglobulin molecule, including but not limited to Such antibodies may optionally be further directed to specific ligands. For example, but not by way of limitation, such antibodies may be used in vitro, in situ, and / or at least one IL-23 activity or binding, or IL-2 3. To regulate, reduce, increase, antagonize, stimulate, alleviate, mitigate, block, or inhibit receptor activity or binding. , inhibit and / or prevent. Non-limiting examples of suitable anti-IL-23 antibodies of the present invention include: The specified portion or variant is at least one IL-23 molecule or a specified portion or variant thereof. Suitable anti-IL-23 antibodies, specific portions, or domains thereof may be used. The variant optionally also affects at least one IL-23 activity or function. Such activities or functions can include RNA, DNA, or protein. Synthesis, release of IL-23, IL-23 receptor signaling, cleavage of membrane IL-23, IL These include, but are not limited to, IL-23 activity, IL-23 production and / or synthesis, and the like. stomach.

[0021] The term "antibody" includes antibody mimetics, or antibodies including single chain antibodies and fragments thereof. or portions of antibodies that mimic the structure and / or function of specific fragments or portions thereof It is further intended to encompass antibodies, digest fragments, specified portions, and variants thereof. Functional fragments include antigen-binding fragments that bind to mammalian IL-23. For example, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and F(ab')2 (e.g., by pepsin digestion), facb (e.g., by partial reduction) and F(ab')2 (e.g., by pepsin digestion), pFc' (e.g., by pepsin or plasmin digestion) , Fd (e.g., by pepsin digestion, partial reduction, and reassembly), Fv, or scFv (e.g., IL-23 fragments, including but not limited to those fragments obtained by molecular biology techniques. or a portion thereof are encompassed by the present invention (e.g., as described above). (See Colligan, Immunology).

[0022] Such fragments include those known in the art and / or described herein. Antibodies can be produced by enzymatic cleavage, synthetically, or recombinantly. or using an antibody gene in which two or more stop codons have been introduced upstream of the natural stop site. For example, the gene encoding the F(ab')2 heavy chain portion can be produced in various truncated forms. The gene combination is H DNA sequence encoding the 1 domain and / or hinge region The various portions of the antibody can be chemically linked by conventional techniques. can be combined or prepared as a contiguous protein using genetic engineering techniques can.

[0023] As used herein, the term "human antibody" refers to a human antibody in which substantially all portions of the protein are humanized. minutes (e.g., CDR, framework, C L , C H Domain (e.g., C H1. C H 2. C H 3), Hinge (V L , V H )) can be detected in humans with only slight sequence changes or mutations. A "human antibody" refers to an antibody that is substantially non-immunogenic to humans. Human antibodies may be antibodies derived from or closely related to globin sequences. , amino acid residues not encoded in the germline immunoglobulin sequence (e.g., By introducing random or site-specific mutations in vitro or by in vivo In many cases, this is because human antibodies are Human antibodies are essentially non-immunogenic in humans. They are grouped into groups based on sequence similarity. Therefore, sequence similarity searches can be used to An antibody with a similar linear sequence is selected as a template for generating a human antibody. Similarly, names can include primates (monkeys, baboons, chimpanzees, etc.), rodents (mammals, etc.), and antibodies, including those from mice, rats, rabbits, guinea pigs, hamsters, etc., and other mammals , designates antibodies specific to such species, subgenus, genus, subfamily, and family. Any combination of the above may be included. Such changes or mutations are optional and preferred. Preferably, the antibody retains immunogenicity in humans or other species relative to the unmodified antibody. Thus, a human antibody is distinct from a chimeric antibody or a humanized antibody.

[0024] Human antibodies are functionally rearranged human immunoglobulins (e.g., heavy and / or light chains). ) can be produced by a non-human animal or prokaryotic or eukaryotic cell capable of expressing the gene Furthermore, when a human antibody is a single-chain antibody, it is pointed out that there are some For example, Fv can be composed of a heavy chain variable region and a light chain variable region. A linker peptide of 2 to about 8 glycine or other amino acid residues connecting the regions Such linker peptides are considered to be of human origin.

[0025] Also, preferred monoclonal antibodies have binding specificities for at least two different antigens. Preferably, the antibody is a human or humanized antibody, and is bispecific, heterospecific, heterobinding, or similar. Similar antibodies may also be used, in which one of the binding specificities is for at least one IL- 23 protein and the other against any other antigen. Methods for producing heterospecific antibodies are known in the art. The production of antibodies is based on the co-expression of two immunoglobulin heavy-light chain pairs, where the two heavy chains are have different specificities (Milstein and Cuello, Nature 30 5:537(1983)). For random assortment of immunoglobulin heavy and light chains These hybridomas (quadromas) produce a possible mixture of 10 different antibody molecules. Only one of these has the correct bispecific structure. The purification of the product (usually performed by an affinity chromatography step) is quite laborious and The yield is low. Similar procedures are described, for example, in WO 93 / 08829, U.S. Pat. No. 210,668, No. 6,193,967, No. 6,132,992, No. 6,1 No. 06,833, No. 6,060,285, No. 6,037,453, No. 6,01 No. 0,902, No. 5,989,530, No. 5,959,084, No. 5,959 ,083, 5,932,448, 5,833,985, 5,821, No. 333, No. 5,807,706, No. 5,643,759, No. 5,601,8 No. 19, No. 5,582,996, No. 5,496,549, No. 4,676,98 0, International Publication Nos. 91 / 00360 and 92 / 00373, European Patent No. 03089 No., Traunecker et al., EMBO J.10:3655(1991) ,Suresh et al.,Methods in Enzymology 121 :210 (1986), each of which is incorporated herein by reference in its entirety. To be incorporated.

[0026] Anti-IL-23 specific antibodies (IL-23 specific) useful in the methods and compositions of the invention Antibodies against IL-23 (also called specific antibodies) have high affinity binding to IL-23. , and optionally and preferably, having low toxicity. Specifically, individual components such as variable regions, constant regions, and frameworks are individually and / or collectively, the antibodies of the present invention, optionally and preferably, having low immunogenicity. , specific fragments, or variants thereof are useful in the present invention. Antibodies that can be administered to patients with atopic dermatitis, optionally with measurable alleviation of symptoms and low and / or acceptable toxicity. , characterized by the ability to treat patients for long periods of time. Low or acceptable immunogenicity and / or high affinity, as well as other favorable properties, may contribute to the therapeutic results obtained. "Low immunogenicity" as used herein means immunogenicity in less than about 75% of treated patients, or Preferably, less than about 50% of patients have a significant HAHA, HACA, or HAMA response. elevated and / or low titers (measured by double antigen enzyme immunoassay) in treated patients is defined as an increase in the β-glucan concentration (βg) of less than about 300, preferably less than about 100, when the β-glucan concentration is increased (see reference Elliott et al., Lancet 344, which is incorporated herein in its entirety. :1125-1127(1994)). "Low immunogenicity" is the recommended course of treatment during the treatment period. less than 25% of patients treated at the recommended dose over the course of the study, preferably 10% of patients treated When the incidence of anti-IL-23 antibodies in patients treated with anti-IL-23 antibodies was less than It can also be defined as the incidence of titratable levels of antibodies that

[0027] The term "safety" refers to the use of an anti-IL-23 antibody of the invention (e.g., an anti-IL-23 antibody-based When referring to the administration, administration regimen, treatment, or method of Compared to the baseline, the treatment results from clinical trials conducted, e.g., phase 2 and earlier clinical trials, The frequency of adverse events (called AEs or TEAEs) occurring during treatment is relatively low or reduced. Adverse events are those that occur after the administration of a drug and / or are mild or reduced in severity. In particular, the anti-IL-23 antibodies of the present invention are Clinically proven safety is essential when it comes to administering a drug, dosing regimen, or treatment to a patient. are possibly, probably, or very likely to be due to the use of anti-IL-23 antibodies If possible, a relatively low or reduced frequency of adverse events associated with the administration of the antibody. and / or low or reduced severity.

[0028] usefulness The isolated nucleic acids of the present invention may be used to identify at least one anti-IL-23 antibody or its specific barrier. The antibodies or variants can be used to generate antibodies for diagnosing Crohn's disease symptoms. to monitor, regulate, treat, mitigate, assist in preventing the occurrence of, or reduce the symptoms of, For measuring or otherwise using cells, tissues, organs, or animals (including mammals and humans) It can be used to act on these.

[0029] Such methods include those that modulate, treat, alleviate, prevent, or reduce symptoms, effects, or mechanisms. a cell, tissue, organ, animal, or patient in need thereof, administered at least one anti-IL- The effective amount may comprise administering an effective amount of a composition or pharmaceutical composition comprising antibody 23. The method may be performed and determined using known methods, such as those described herein or known in the relevant art. Approximately 0.001 to 100 mg / kg of a single (e.g., bolus), multiple, or continuous dose, as determined by the 500 mg / kg or 0.01 to 5000 per single, multiple, or continuous dose 100 μg / ml serum concentration, or any effective range or value therein. It can be done.

[0030] References All publications or patents cited herein, whether specifically designated or not, are hereby incorporated by reference. which are incorporated herein in their entirety by reference to represent prior art at the time of the present invention; and / or The publications provide a description and enablement of the invention. Any scientific or patent publication available in any media format, including all The following documents are incorporated herein by reference in their entirety: :Ausubel,et al.,ed.,Current Protocols in Molecular Biology,John Wiley & Sons,Inc .,NY,NY(1987-2001),Sambrook,et al.,Molec ular Cloning:A Laboratory Manual,2 nd Edi tion, Cold Spring Harbor, NY (1989), Harlow and Lane, antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989), Colligan, et al. al.,eds.,Current Protocols in Immunology , John Wiley & Sons, Inc., NY (1994-2001), Co. lligan et al.,Current Protocols in Prote in Science,John Wiley & Sons,NY,NY,(1997 -2001).

[0031] Antibodies of the invention - production and generation The at least one anti-IL-23 antibody used in the methods of the present invention is optionally a compound known in the art. Cell lines, mixed cell lines, immortalized cells, or clonal populations of immortalized cells are well known in the field. For example, the A. usubel,et al.,ed.,Current Protocols in M Olecular Biology,John Wiley & Sons,Inc. NY, NY (1987-2001), Sambrook, et al., Molecule ar Cloning:A Laboratory Manual,2 nd Editi on, Cold Spring Harbor, NY (1989), Harlow an d Lane,antibodies,a Laboratory Manual,Co ld Spring Harbor, NY (1989), Colligan, et al. .,eds.,Current Protocols in Immunology,J ohn Wiley & Sons, Inc., NY (1994-2001), Coll. igan et al.,Current Protocols in Protein Science,John Wiley & Sons,NY,NY,(1997-2 Please refer to 001).

[0032] A preferred anti-IL-23 antibody has the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 8 and the heavy chain variable region amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3. CDR amino acid sequences and light chain CDR amino acids of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6 Other anti-IL-23 drugs include guselkumab (also known as CNTO1959), which has the sequence The antibodies have the sequences listed herein, the entire contents of which are incorporated herein by reference. This is described in US Patent No. 7,935,344.

[0033] Human antibodies specific for human IL-23 protein or fragments thereof include isolated IL-23 Suitable immunosuppressants such as proteins and / or portions thereof (including synthetic molecules such as synthetic peptides) Other specific or general mammalian antibodies may be produced as well. The preparation of immunogenic antigens and the production of monoclonal antibodies can be carried out in any suitable manner. This can be done using technology.

[0034] In one approach, a suitable immortal cell line (such as, but not limited to, Sp 2 / 0, Sp2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, L243 , P3X63Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp 2 SA5, U937, MLA 144, ACT IV, MOLT4, DA-1, JUR KAT, WEHI, K-562, COS, RAJI, NIH 3T3, HL-60, ML Myeloma cell lines such as A144, NAMALWA, and NEURO 2A, or heteromyeloma Heteromylomas, their fusion products, or any cells or fused cells derived therefrom. or any other suitable cell line known in the art) (see, for example, www.at cc.org, www.lifetech.com. isolated or cloned spleen, peripheral blood, lymph, tonsils, or Other immune or antibody-producing cells, such as B-cell containing cells, or endogenous or heterologous nucleic acids recombinant or endogenous viruses, bacteria, algae, prokaryotes, amphibians, insects, reptiles, fish, mammals Mammal, rodent, horse, sheep, goat, ovine, primate, eukaryote, genomic DNA, c DNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA hnRNA, mRNA, tRNA, single, double or triple stranded, hybridized, etc. or any combination thereof, or any other cell that expresses the variable, framework, or CDR sequences. and producing hybridomas. See, for example, the methods described herein, which are incorporated by reference in their entirety. See Ausubel, supra, and Colligan, supra, in Immunology, Vol. 2 See Chapter.

[0035] Antibody-producing cells can be isolated from the peripheral blood of humans or other suitable animals immunized with the antigen of interest, or can also be obtained preferably from the spleen or lymph nodes. can be used to express heterologous nucleic acids encoding antibodies of the invention, specified fragments or variants thereof, or Endogenous nucleic acids can also be expressed. Hybridomas or recombinant cells can be Isolate using selective culture conditions or other suitable known methods, such as limiting dilution or cell sorting. or by other known methods. Cells producing the antibody can be selected by a suitable assay (e.g., ELISA). do.

[0036] Examples include methods for selecting recombinant antibodies from peptide or protein libraries. Other suitable methods for producing or isolating antibodies with the required specificity include, but are not limited to: methods can be used (e.g., bacteriophage, ribosomes, oligonucleotides, Display libraries include, but are not limited to, nucleic acids, RNA, and cDNA. For example, Cambridge Antibody Technologies, mbridgeshire, UK, MorphoSys, Martinsreid / Pl anegg, DE, Biovation, Aberdeen, Scotland, UK, BioInvent, Lund, Sweden, Dyax Corp., Enzon, A ffymax / Biosite, Xoma, Berkeley, CA, from Ixsys. (See, for example, European Patent No. 368,684, International Application No. GB91 / 011.) 34, International Application No. PCT / GB92 / 01755, International Application No. PCT / GB92 / 0 02240, International Application No. PCT / GB92 / 00883, International Application No. PCT / GB9 3 / 00605, U.S. Patent Application Publication No. 08 / 350260 (5 / 12 / 94), International Application No. PCT / GB94 / 01422, International Application No. PCT / GB94 / 02662, International Application No. PCT / GB97 / 01835, (CAT / MRC), International Publication No. 90 / 1 4443, International Publication No. 90 / 14424, International Publication No. 90 / 14430, International Application US94 / 1234, WO92 / 18619, WO96 / 07754 (S cripps), WO 96 / 13583, WO 97 / 08320 (Mo rphoSys), International Publication No. 95 / 16027 (BioInvent), International Publication No. 88 / 06630, WO 90 / 3809 (Dyax), U.S. Pat. No. 4,704 ,692 (Enzon), International Application No. US91 / 02989 (Affymax), International Publication No. 89 / 06283, European Patent No. 371998, European Patent No. 550400, (Xoma), European Patent No. 229046, International Application No. US91 / 07149 (Ixs ys), or stochastically generated peptides or proteins - U.S. Patent No. 57233 No. 23, No. 5763192, No. 5814476, No. 5817483, No. 5 Nos. 824514, 5976862, WO 86 / 05803, EP 5 No. 90689 (Ixsys, Applied Molecular Evolution) Evolution (AME), each of which is incorporated herein by reference in its entirety. ), or other known in the art and / or described herein. The method relies on immunization of transgenic animals capable of producing a repertoire of human antibodies. (e.g., SCID mice, see Nguyen et al., each of which is incorporated by reference in its entirety.) 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), and related patents and applications. Such techniques include ribosome display Hanes et al., Proc. Natl. Acad. Sci. USA, 94 :4937-4942(May 1997), Hanes et al., Proc.N atl.Acad.Sci.USA,95:14130-14135(Nov.1998 )), single cell antibody production techniques (e.g., selected lymphocyte antibody methods spherocyte antibody method, "SLAM") (U.S. Patent No. 5, No. 627,052, Wen et al., J. Immunol. 17:887-892 (1987);Babcook et al.,Proc.Natl.Acad.Sci USA 93:7843-7848(1996)), gel microdroplets and Flow cytometry (Powell et al., Biotechnol. 8:33 3-337(1990);One Cell Systems,Cambridge,M A, Gray et al., J. Imm. Meth. 182:155-163 (199 5);Kenny et al.,Bio / Technol.13:787-790(1 995)), B cell selection (Steenbakkers et al., Molec.B iol.Reports 19:125-134(1994), Jonak et al. .,Progress Biotech,Vol.5,In Vitro Immuni zation in Hybridoma Technology,Borrebaec k,ed.,Elsevier Science Publishers BV,A Amsterdam, Netherlands (1988), but not limited to these. Not determined.

[0037] Methods for engineering or humanizing non-human or human antibodies can also be used, Generally, humanized or modified antibodies are antibodies that are derived from non-human, e.g., including, but not limited to, mouse, rat, rabbit, non-human primate, or other mammalian source These non-human amino acid residues have one or more amino acid residues derived from the The residue is often replaced by a residue called an "import" residue. Residues are typically found in "import" variable domains, constant domains, or Obtained from other domains.

[0038] Known human Ig sequences are available, for example, at: www.ncbi.nlm.nih.gov / en trez / query.fcgi, www.ncbi.nih.gov / igblast , www.atcc.org / phage / hdb.html, www.mrc-cpe .cam.ac.uk / ALIGNMENTS.php;www.kabatdatab ase.com / top.html、ftp.ncbi.nih.gov / reposi tory / kabat;www.sciquest.com、www.abcam.co m、www.antibodyresource.com / onlinecomp.ht ml、www.public.iastate.edu / ~pedro / researc h_tools.html、www.whfreeman.com / immunolog y / CH05 / kuby05.htm、www.hhmi.org / grants / le ctures / 1996 / vlab、www.path.cam.ac.uk / ~mrc 7 / mikeimages.html、mcb.harvard.edu / BioLin ks / Immunology.html;www.immunologylink.co m、pathbox.wustl.edu / ~hcenter / index.html; www.appliedbiosystems.com、www.nal.usda.g ov / awic / pubs / antibody、www.m.ehime-u.ac.j p / ~yasuhito / Elisa.html、www.biodesign.com 、www.cancerresearchuk.org、www.biotech.uf l.edu、www.isac-net.org、baserv.uci.kun.nl / ~jraats / links1.html;www.recab.uni-hd.de / immuno.bme.nwu.edu、www.mrc-cpe.cam.ac.u k、www.ibt.unam.mx / vir / V_mice.html、http: / / www.bioinf.org.uk / abs, antibody.bath.ac. uk;www.unizh.ch, www.cryst.bbk.ac.uk / ~ubc g07s, www.nimr.mrc.ac.uk / CC / ccaewg / ccaewg .html, www.path.cam.ac.uk / ~mrc7 / humanisat ion / TAHHP.html, www.ibt.unam.mx / vir / struc ture / stat_aim.html, www.biosci.missouri.e du / smithgp / index.html, www.jerini.de, Kaba t et al.,Sequences of Proteins of Immuno Logical Interest, USDept. Health (1983) is shown.

[0039] Such imported sequences can be used to reduce immunogenicity or to enhance the ability of the present technology to As known in the art, binding, affinity, association rate constant, dissociation rate constant, avidity, Reducing, enhancing, or modulating the specificity, half-life, or any other suitable characteristic In general, the CDR residues are directly and most substantially involved in influencing antigen binding. Thus, it is possible to modify the variable region while maintaining some or all of the non-human or human CDR sequences. Non-human sequences in the ribozyme and constant regions can also be replaced with human amino acids or other amino acids. .

[0040] The antibody optionally retains high affinity for the antigen and other favorable biological properties. The antibody may be a humanized or human antibody that has been genetically engineered as is. Optionally, three-dimensional models of the parental and humanized sequences are used to compare the parental and various theoretical sequences. Humanized (or human) antibodies can be prepared by a process of analyzing the humanized product. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Illustrate and display the most probable three-dimensional conformations of selected immunoglobulin sequence candidates Computer programs are available. By examining these displays, immunoglobulins can be identified. Analysis of the likely role of residues in the function of candidate purine sequences, i.e., immunoglobulin This allows for the analysis of residues that affect the antigen-binding ability of candidate phospholipases. Consensus sequences are used to achieve desired antibody properties, such as increased affinity for and framework (FR) residues can be selected and combined from the import sequence. .

[0041] In addition, the human IL-23 specific antibodies used in the methods of the present invention contain human germline light chain fragments. In certain embodiments, the light chain germline sequence may comprise the sequences A1, A10, A 11, A14, A17, A18, A19, A2, A20, A23, A26, A27, A3 , A30, A5, A7, B2, B3, L1, L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23, L24, L25, L4 / 18 a, L5, L6, L8, L9, O1, O11, O12, O14, O18, O2, O4, and The VK sequences are selected from human VK sequences, including, but not limited to, O8 and O9. In form, the light chain human germline framework is V1-11, V1-13, V1-16 , V1-17, V1-18, V1-19, V1-2, V1-20, V1-22, V1-3 , V1-4, V1-5, V1-7, V1-9, 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.

[0042] In another embodiment, the human IL-23 specific antibody used in the methods of the invention is human genital IL-23 specific. In certain embodiments, the heavy chain may comprise a human germline heavy chain framework. The teamwork is VH1-18, VH1-2, VH1-24, 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, VH3-2 0, VH3-21, VH3-23, VH3-30, VH3-33, VH3-35, VH3 -38, VH3-43, VH3-48, VH3-49, VH3-53, VH3-64, V H3-66, VH3-7, VH3-72, VH3-73, VH3-74, VH3-9, V H4-28, VH4-31, VH4-34, VH4-39, VH4-4, VH4-59, Selected from VH4-61, VH5-51, VH6-1, and VH7-81.

[0043] In certain embodiments, the light chain variable region and / or the heavy chain variable region comprises framework regions: or at least a portion of a framework region (e.g., 2 or 3, such as FR2 and FR3) In certain embodiments, the FRL1 gene comprises at least one subregion (FRL1, FRL2, and FRL3). In another embodiment, at least FRH1, FRL2, FRL3, or FRL4 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 of a human the human consensus sequence for a particular framework (see above). In other embodiments, the antibody comprises at least Each of FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., a human germline sequence). sequence) or contains a human consensus sequence for a particular framework. In a preferred embodiment, the framework regions are completely human framework regions.

[0044] Humanization or genetic engineering of the antibodies of the present invention can be carried out using methods such as those described by 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.Na tl.Acad.Sci.USA89:4285(1992), Presta e t al., J. Immunol. 151:2623 (1993), U.S. Patent No. 5723 No. 323, No. 5976862, No. 5824514, No. 5817483, No. No. 5814476, No. 5763192, No. 5723323, No. 5,76688 No. 6, No. 5714352, No. 6204023, No. 6180370, No. 56 No. 93762, No. 5530101, No. 5585089, No. 5225539, No. 4,816,567, International Application Nos. US98 / 16280 and US96 / 18978 No. US91 / 09630, US91 / 05939, US94 / 012 34, International Application Nos. GB89 / 01334, GB91 / 01134, GB9 2 / 01755, WO 90 / 14443, WO 90 / 14424, WO 90 / 14430, European Patent No. 229246 (each of which is incorporated by reference in its entirety). and the references cited therein). This can be done using any known method.

[0045] In certain 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 function of the antibody. In some embodiments, the Fc region is modified to enhance or enhance the binding of IgM, ... The isotype is selected from IgA, IgG, IgE, or other isotypes. Alternatively or additionally, amino acid modifications and C1q binding and / or C1q cleavage in the Fc region of the IL-23 binding molecule may be used. or in combination with one or more additional amino acid modifications that alter complement-dependent cytotoxicity function. It may be useful to combine these starting polypeptides. It may also be a compound that induces complement dependent cytotoxicity (CD) C) have pre-existing C1q binding activity and, optionally, the ability to mediate CDC. Polypeptides having further activity may be modified to enhance one or both of these activities. may be modified to alter C1q and / or modify its complement-dependent cytotoxicity function. Amino acid modifications can be made, for example, as described in WO 0042072, which is incorporated herein by reference. It is listed in the number.

[0046] As disclosed above, for example, C1q binding and / or FcγR binding may be modified, By this, complement-dependent cytotoxicity (CDC) activity and / or antibody-dependent cell-mediated cytotoxicity ( By altering antibody-dependent cell-mediated cytotoxicity (ADCC) activity, Thus, the Fc of the human IL-23 specific antibody of the present invention with altered effector functions An "effector function" can be designed to have a biological effect (e.g., in a subject). They play a role in activating or reducing biological activity. Examples of effector functions include C 1q binding, CDC, Fc receptor binding, ADCC, phagocytosis, cell surface receptors (e.g., B These include, but are not limited to, downregulation of the BCR (bone-cell receptor). Such effector functions are not achieved by the Fc region, which is a binding domain (e.g., an antibody variable domain). This may require binding to a variety of assays (e.g., Fc binding assays). The antibody can be evaluated using a variety of assays, including ELISA, ADCC assay, and CDC assay.

[0047] For example, having improved C1q binding and improved FcγRIII binding (e.g., Human IL-23 (also known as IL-23) with both improved ADCC and improved CDC activity Alternatively, the Fc region of an anti-IL-23 antibody can be generated. When it is desired to reduce or eliminate receptor function, the mutant Fc region may have CDC activity. The antibody can be modified to reduce its activity and / or to reduce its ADCC activity. In embodiments, only one of these activities may be enhanced, optionally simultaneously with the other. The activity of the antibody may be reduced (e.g., improved ADCC activity and reduced CDC activity). (To generate Fc region variants with and without ...

[0048] It alters the interaction with neonatal Fc receptor (FcRn) and Fc mutations may be introduced during genetic engineering to improve their pharmacokinetic properties. A collection of human Fc variants with improved binding to cRn has been described (Shields et al.,(2001).High resolution mapping of the binding site on human IgG1 for FcγR I, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to t he FCγR, J.Biol.Chem.276:6591-6604).

[0049] Another type of amino acid substitution is the glycosylation paclitaxel of the Fc region of a human IL-23-specific antibody. Glycosylation of the Fc region is typically N-linked or O-linked. N-linked carbohydrate moieties are attached to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of hydroxyamino acids, most commonly serine or threo. one of the following sugars: N-acetylgalactosamine, galactose, or xylose refers to one bond, but when 5-hydroxyproline or 5-hydroxylysine is used Recognition sequence for enzymatic attachment of carbohydrate moieties to asparagine side chain peptide sequences. are asparagine-X-serine and asparagine-X-threonine, where X is , any amino acid other than proline. The presence of this peptide sequence provides a potential glycosylation site.

[0050] A glycosylation pattern can refer to, for example, one or more glycosylation sites found on a polypeptide. Deleting a glycosylation site and / or one or more glycosylation sites not present in the polypeptide The glycosylation of the Fc region of the human IL-23-specific antibody can be modified by adding The addition of sylation sites can be achieved by arranging the peptide 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). A representative glycosylation variant has an amino acid substitution at residue Asn297 of the heavy chain. The modification may involve the addition of one or more serine or threonine residues to the original polypeptide sequence. This may be achieved by the addition of, or substitution with, (in the case of O-linked glycosylation sites, In addition, changing Asn 297 to Ala removes one of the glycosylation sites. It is possible.

[0051] In certain embodiments, the human IL-23-specific antibodies of the invention are characterized by the ability of GnT III to bind to G A beta(1,4)-N-acetylglucosamine derivative was synthesized to add lcNAc to the human IL-23 antibody. Expressed in cells expressing glucosaminyltransferase III (GnT III) Methods for producing antibodies in such a manner are described in WO 99 / 54342, No. 03 / 011878, JP 2003 / 0003097(A1), and Umana et al.,Nature Biotechnology,17:176-180, Feb. 1999, all of which are incorporated herein by reference in their entirety. is explicitly incorporated into

[0052] Anti-IL-23 antibodies are also optionally prepared as described herein and / or in the art. As is known in the field, transgenic mice capable of generating a repertoire of human antibodies have For immunization of transgenic animals (e.g., mice, rats, hamsters, non-human primates, etc.) Human anti-IL-23 antibody-producing cells can also be produced by the methods described herein. They may be isolated from such animals and immortalized using suitable methods such as those described in.

[0053] Transgenic mice capable of producing a repertoire of human antibodies that bind to human antigens The mice can be cultured using known methods, including, but not limited to, those described herein, each of which is incorporated by reference in its entirety. U.S. Patent No. 5,770,428 issued to Lonberg et al., which is incorporated herein by reference; Same No. 5,569,825, Same No. 5,545,806, Same No. 5,625,126, Same No. Nos. 5,625,825, 5,633,425, 5,661,016, and No. 5,789,650, Jakobovits et al., International Publication No. 98 / 50433, WO 98 / 24893 to Jakobovits et al., WO 98 / 24893 to Lonberg et al. WO 98 / 24884, Lonberg et al., WO 97 / 13852, Lonbe International Publication No. 94 / 25585 by rg et al., International Publication No. 96 by Kucherlapate et al. / 34096, European Patent No. 0463151(B1) to Kucherlapate et al., European Patent No. 0710719(A1) by Kucherlapate et al., US Patent No. Surani et al. Patent No. 5,545,807, and International Publication No. 90 / 04036 by Bruggemann et al. No. 0438474(B1) by Bruggemann et al., European Patent No. 0438474(B1) by Lonberg et al. European Patent No. 0814259(A2) to Lonberg et al., and UK Patent No. 2272440 to Lonberg et al. (A), Lonberg et al.Nature 368:856-859(19 94),Taylor et al.,Int.Immunol.6(4)579-59 1(1994), Green et al, Nature Genetics 7:13 -21(1994),Mendez et al.,Nature Genetics 15:146-156(1997), Taylor et al., Nucleic A cids Research 20(23):6287-6295(1992),Tua illon et al., Proc Natl Acad Sci USA 90(8 )3720-3724(1993), Lonberg et al., Int Rev. Immunol 13(1):65-93(1995), and Fishwald et al. al., Nat Biotechnol 14(7):845-851(1996)) Generally, these mice can be generated by functionally reconstituted or derived from at least one human immunoglobulin locus capable of undergoing functional rearrangement. The mouse contains at least one transgene containing DNA that is derived from the endogenous immune system. The globin locus was disrupted or deleted to remove endogenously encoded globin genes in mice. The ability to produce antibodies against the virus can be eliminated.

[0054] Screening of antibodies for specific binding to similar proteins or fragments can be performed using peptide This can be successfully achieved using a display library. Screening large collections of peptides for individual members with function or structure Antibody screening of peptide display libraries is a method known in the art. The displayed peptide sequences may be 3,000 to 5,000 or more. amino acid length, frequently 5-100 amino acids, often about 8-25 amino acids In addition to direct chemical synthesis methods for creating peptide libraries, several Recombinant DNA methods have also been described. One type involves the expression of bacteriophages or cells. Each bacteriophage or cell contains a specific peptide sequence displayed on its surface. The method comprises the step of: are disclosed in International Publication Nos. 91 / 17271, 91 / 18980, and 91 / 19818. and 93 / 08278.

[0055] Other systems for generating peptide libraries include in vitro chemical synthesis and Both aspects of the recombinant method are included. See U.S. Patent Nos. 5,658,754 and 96 / 19256. See also US Pat. No. 5,643,768. Peptide display libraries, vectors and screening kits were purchased from Invitrogen (Carlsbad, CA) and Cambridge antibody Technologies These are commercially available from suppliers such as Enzon (East End, Dublin, UK). U.S. Patent Nos. 4,704,692, 4,939,666, 4,946,778, and No. 5260203, No. 5455030, No. 5518889, No. 5534621 No. 5656730, No. 5763733, No. 5767260, No. 585 No. 6456, U.S. Patent Nos. 5,223,409 and 5,403,484 assigned to Dyax , 5571698, 5837500, U.S. Patents assigned to Affymax No. 5427908, No. 5580717, Cambridge antibody U.S. Patent No. 5,885,793, assigned to Genentec Technologies, U.S. Patent No. 5,750,373 assigned to H.U.S. Patent No. 5,618 assigned to Xoma 920, 5595898, 5576195, 5698435, 5698435, 5595898, 5576195, 5698435, Nos. 5693493, 5698417, Colligan supra, Ausub supra el, or Sambrook, supra. Each of the above patents and publications is incorporated herein by reference. and is incorporated herein in its entirety.

[0056] The antibodies used in the methods of the present invention are derived from goats, cows, horses, and other animals that produce such antibodies in their milk. The nucleic acid can be used to provide a transgenic animal or mammal, such as a mouse, sheep, rabbit, etc. The present invention can also be prepared using at least one anti-IL23 antibody encoding such an antibody. The product can be provided using known methods, for example but not limited to: , U.S. Patent No. 5,827,690, each of which is incorporated herein by reference in its entirety. No. 5,849,992, No. 4,873,316, No. 5,849,992, No. See Nos. 5,994,616, 5,565,362, and 5,304,489. I want to be illuminated.

[0057] The antibodies used in the methods of the present invention are capable of detecting the activity of the antibodies in plant parts or cells cultured therefrom. Transgenic plants and cultured cells that produce antibodies, specific portions, or variants such as providing plant cells (e.g., but not limited to, tobacco and corn) The method further comprises preparing a nucleic acid encoding at least one anti-IL23 antibody. As a non-limiting example, for example, an inducible promoter can be used to express a recombinant protein. Transgenic tobacco leaves expressing proteins have been successfully used to produce large amounts of recombinant proteins. For example, Cramer et al., Curr. Top. Micro bol. Immunol. 240:95-118 (1999) and the texts cited therein See the references. Transgenic maize has also been produced in other recombinant systems. have biological activity equivalent to that of the protein as produced or purified from a natural source It has been used to express mammalian proteins at commercial production levels. ood et al.,Adv.Exp.Med.Biol.464:127-147( 1999) and the references cited therein. The antibodies were prepared from tobacco seeds and potato. antibody fragments, such as single chain antibodies (scFv), including tubers. It is also produced in large quantities from the seeds of transgenic plants. For example, Conrad et al. al., Plant Mol. Biol. 38:101-109 (1998) and Therefore, the antibodies of the present invention can be prepared by known methods, for example, It can also be produced using transgenic plants. For example, Fischer e t al.,Biotechnol.Appl.Biochem.30:99-108( Oct.,1999), Ma et al.,Trends Biotechnol.1 3:522-7(1995), Ma et al., Plant Physiol.10 9:341-6(1995);Whitelam et al.,Biochem.So c. Trans. 22:940-944(1994); and references cited therein. See also, U.S. Pat. No. 6,229,139, each of which is incorporated herein by reference in its entirety.

[0058] The antibodies used in the methods of the present invention have a wide range of affinities (K D ) to human IL-23 In a preferred embodiment, the human mAb is optionally capable of binding to a high affinity For example, a human mAb can bind human IL-23 at approximately 10 -7 M or less, for example, but not limited to, 0.1 to 9.9 (or any range therein) (or value) x 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 1 0 -13 K, such as, or any range or value therein D can be combined with

[0059] 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- Antigen Interactions,”Fundamental Immuno logy, Paul, WE, Ed., Raven Press: New York, NY (1984), Kuby, Janis Immunology, WHFreem an and Company: New York, NY (1992), and herein (See methods described therein.) The affinity measured for a particular antibody-antigen interaction is may differ when measured under different conditions (e.g., salt concentration, pH). Therefore, affinity and other antigen binding parameters (e.g., K D , K. a , K. d ) measurement is preferred Preferably, standardized solutions of antibodies and antigens, and standardized buffers such as those described herein. This is done using a buffer.

[0060] nucleic acid molecule Among the sequences disclosed herein, for example, the light chain or or at least 70 of at least one contiguous amino acid in the variable or CDR region of the heavy chain. Nucleotide sequences encoding ~100%, specific fragments, variants thereof, or Consensus sequences, or deposited vectors containing at least one of these sequences, Using the information provided herein, a nucleic acid sequence encoding at least one anti-IL-23 antibody can be generated. The nucleic acid molecules of the invention can be synthesized using methods described herein or known in the art. can be obtained by doing so.

[0061] The nucleic acid molecules of the present invention may be in the form of mRNA, hnRNA, tRNA, or any other form. in the form of RNA, or cDNA obtained by cloning or produced synthetically and forms of DNA, including but not limited to genomic DNA, or any combination thereof. The DNA may be triple-stranded, double-stranded, or single-stranded, or any combination thereof. Any portion of at least one strand of DNA or RNA may be a sensor. The coding strand, also known as the antisense strand, may be the non-coding strand, called the antisense strand. It may also be a code chain.

[0062] The isolated nucleic acid molecules used in the methods of the invention optionally contain one or more a polypeptide, such as, but not limited to, at least one heavy or light chain CDR at least one characteristic of at least one CDR, such as CDR1, CDR2, and / or CDR3 Contains an open reading frame (ORF) with a specific portion Nucleic acid molecules, nucleic acid molecules comprising coding sequences for anti-IL-23 antibodies or variable regions, and the above Although the nucleotide sequence of the present invention may differ substantially from that of the at least one anti-IL-23 antibody described herein and / or known in the art It will be appreciated that the genetic code may still include nucleic acid molecules that encode the Therefore, the specific anti-IL- 23 It is routine for one of skill in the art to generate such degenerate nucleic acid variants encoding antibodies. See, e.g., Ausubel et al., supra. Such nucleic acid variants may be used in the present invention. Non-limiting examples of isolated nucleic acid molecules include those having HC CDRs 1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC C Nucleic acids encoding DR3 are included.

[0063] As described herein, nucleic acid molecules comprising nucleic acids encoding anti-IL-23 antibodies include The antibody fragment itself may encode the amino acid sequence of a full-length antibody or a fragment of a full-length antibody. The coding sequence for a portion of the antibody, fragment or portion, as well as additional sequences, e.g. with or without additional coding sequences as described above, e.g., at least one intron. In addition, non-coding 5' and 3' sequences, such as splicing and polyadenylation signals ( transcription, mRNA processing, including mRNA ribosome binding and stability Additional non-coding sequences, including but not limited to transcribed, non-translated sequences that play a role in a coding sequence for at least one signal leader or fusion peptide, together with a coding sequence for the other signal leader or fusion peptide; Additional coding sequences encoding additional amino acids, e.g., amino acids that provide additional functions Therefore, the antibody coding sequence can be It can be fused to a marker sequence, e.g., the marker sequence can be attached to an antibody to which it is fused. A sequence encoding a peptide that facilitates the purification of the antibody, including fragments or portions thereof.

[0064] Polynucleotides that selectively hybridize to the polynucleotides described herein The method of the present invention provides a method for selectively hybridizing to the polynucleotides disclosed herein. The present invention uses isolated nucleic acids that hybridize under hybridization conditions. Polynucleotides of the embodiments are useful for isolating, detecting, and analyzing nucleic acids comprising such polynucleotides. For example, the polynucleotides of the present invention can be used to quantify to identify, isolate, or amplify partial or full-length clones in the deposited library. In some embodiments, the polynucleotide can be isolated, or otherwise complementary to the cDNA of a human or mammalian nucleic acid library. It is a genome sequence or a cDNA sequence.

[0065] Preferably, the cDNA library contains at least 80% of the full-length sequences, preferably the full-length It contains at least 85% or 90% of the sequence, more preferably at least 95% of the full-length sequence. This cDNA library can be normalized to increase the representation of rare sequences. Low or medium stringency, using sequences with low sequence identity to the complementary sequence The hybridization conditions are typical, but not limited to, the following. For higher sequences, medium and high stringency conditions can optionally be used. Low stringency conditions allow selective hybridization of sequences with approximately 70% sequence identity. and can be used to identify orthologous or paralogous sequences. can.

[0066] Optionally, the polynucleotide encodes at least a portion of an antibody. The nucleotides are capable of selective hybridization to the polynucleotides encoding the antibodies of the present invention. For example, the present invention includes nucleic acid sequences that can be used in the preparation of nucleic acid sequences, each of which is incorporated herein by reference in its entirety. See Ausubel, supra; Colligan, supra, all of which are incorporated herein by reference.

[0067] Nucleic acid construction Isolated nucleic acids can be prepared by (a) recombinant methods, (b) recombinant DNA methods, as are well known in the art. (c) synthesis techniques, (d) purification techniques, and / or (e) combinations thereof. It is possible.

[0068] The nucleic acids can conveniently include sequences in addition to the polynucleotides of the present invention. For example, a multiple cloning sequence containing one or more endonuclease restriction sites may be used. The site can be inserted into a nucleic acid to aid in the isolation of the polynucleotide. A sequence capable of being inserted to aid in the isolation of the translated polynucleotide of the present invention can be used. For example, a hexa-histidine marker sequence may be useful for purifying the proteins of the present invention. The nucleic acids of the invention (excluding the coding sequence) can optionally be used to generate polynucleotides of the invention. Vectors, adapters, or linkers for cloning and / or expression of nucleotides is.

[0069] Additional sequences may be added to such cloning and / or expression sequences to facilitate cloning and expression. and / or optimizing their function in expression, aiding in the isolation of polynucleotides. This can improve the transfer of polynucleotides into cells. The use of vectors, expression vectors, adapters, and linkers is well known in the art. (See, for example, Ausubel, supra, or Sambrook, supra.)

[0070] Recombinant methods for constructing nucleic acids Isolated nuclei, such as RNA, cDNA, genomic DNA, or any combination thereof Acid compositions can be obtained from biological sources using any number of cloning methods known to those of skill in the art. In some embodiments, stringent PCR is performed on the polynucleotides of the present invention. Oligonucleotide probes that selectively hybridize under suitable conditions are used to prepare cDNA or Used for the identification of desired sequences in genome DNA libraries. The construction of A and genomic libraries is well known to those skilled in the art (see, e.g., Ausub, supra). el, or see Sambrook above.)

[0071] Nucleic Acid Screening and Isolation Methods Polynucleotide sequences for use in the methods of the invention, such as those disclosed herein, Screening a cDNA or genomic library using sequence-based probes Probes can be used to hybridize to genomic DNA or cDNA sequences. By combining these sequences, it is possible to isolate homologous genes from the same or different organisms. Various degrees of hybridization stringency can be used in It is understood that either the hybridization or the wash medium can be stringent. The more stringent the hybridization conditions, the more likely it is that duplex formation will occur. The degree of complementarity between the probe and target must be high for synthesis to occur. The degree of deactivation is influenced by temperature, ionic strength, pH, and partially denaturing agents such as formamide. The hybridization rate can be controlled by one or more of the following: The stringency of the reaction can be determined, for example, by the formamide concentration in the range of 0% to 50%. This can be successfully altered by changing the polarity of the reaction solution through the manipulation of The degree of complementarity (sequence identity) required can be determined by the hybridization medium and / or washing conditions. The degree of complementarity varies depending on the stringency of the purification medium. Optimally, it is 100% or 70-100%, or any range or value therein. Minor differences in the sequences in the primers and the hybridization and / or washing medium may affect the stability of the hybridization and / or washing medium. It should be understood that this can be compensated for by reducing truncation. .

[0072] Methods for amplifying RNA or DNA are well known in the art and are not limited to those presented herein. Based on the teachings and guidance provided herein, one can utilize the present invention in accordance with the present invention without undue experimentation.

[0073] Known methods for DNA or RNA amplification include the polymerase chain reaction (PCR). in reaction, PCR) and related amplification processes (see, e.g., U.S. Pat. No. 5,499,623 to Mullis et al., No. 4,683,195, No. 4,683,202, No. 4,800,159, No. No. 4,965,188 to Tabor et al., U.S. Pat. Nos. 4,795,699 and 4,9 No. 21,794, Innis U.S. Pat. No. 5,142,033, Wilson et al. Patent No. 5,122,464, Innis U.S. Patent No. 5,091,310, Gyll U.S. Patent No. 5,066,584 to Ensten et al., U.S. Patent No. 4, No. 889,818, Silver et al., U.S. Pat. No. 4,994,370, Biswas et al. U.S. Patent No. 4,766,067 and Ringold's U.S. Patent No. 4,656,134 (see, for example, nucleotide sequences) and act on the target sequence as a template for double-stranded DNA synthesis. RNA-mediated amplification using antisense RNA (Malek et al., U.S. Patent No. 5,130,200; 38, trademark NASBA), and the entire contents of these documents are not limited thereto. The contents of which are incorporated herein by reference (e.g., Ausubel, supra, or (See Sambrook in

[0074] For example, using polymerase chain reaction (PCR) techniques, genomic DNA or cDNA Polynucleotides and related genes used in the methods of the present invention can be isolated directly from the library. PCR and other in vitro amplification methods can also be used to amplify sequences, e.g., expression cloning a nucleic acid sequence encoding a protein of interest; Probes for detecting the presence of RNA, for nucleic acid sequencing, or for other purposes It may be useful for generating nucleic acids for use as a nucleic acid sequence by in vitro amplification methods. Examples of techniques sufficient to guide one skilled in the art are found in Berger, supra; Sambrook, supra; and and Ausubel, supra, as well as U.S. Pat. No. 4,683,202 to Mullis et al. 987), and Innis, et al., PCR Protocols A Guide e to Methods and Applications,Eds.,Acade MIC Press Inc., San Diego, CA (1990). Commercially available kits for general PCR amplification are known in the art. See ge-GC Genomic PCR Kit (Clontech). In addition, for example, T4 gene 32 protein (Boehringer Mannheim) can be used to improve the yield of long PCR products.

[0075] Synthetic methods for constructing nucleic acids The isolated nucleic acids used in the methods of the present invention can be prepared by direct chemical synthesis using known methods. They can also be prepared (see, for example, Ausubel et al., supra). , generally by hybridization with a complementary sequence or by separating a single strand from a template single strand that can be converted into double stranded DNA by polymerization with DNA polymerase used as Those skilled in the art will appreciate that chemical synthesis of DNA produces oligonucleotides in approximately 100 or so steps. Although sequences of 1 or more bases may be limited, longer sequences may be used for ligation of shorter sequences. So realize what you can achieve.

[0076] Recombinant Expression Cassette The present invention uses recombinant expression cassettes containing nucleic acids. The cDNA or genomic sequence encoding the antibody to be used is used to generate at least one desired A recombinant expression cassette can be constructed that can be introduced into a host cell. An expression cassette typically directs transcription of a polynucleotide in an intended host cell. It includes polynucleotides that are operably linked to transcription initiation regulatory sequences, rather than to a heterologous or non-heterologous sequence. Both species (ie, endogenous) promoters can be used to direct expression of the nucleic acid.

[0077] In some embodiments, isolated proteins that function as promoters, enhancers, or other elements. The nucleic acid thus obtained can be used in combination with a polynucleotide of the invention to up- or down-regulate expression of the polynucleotide. The non-heterologous form of the nucleotide can be introduced into the appropriate location (upstream, downstream, or within an intron). For example, mutations, deletions, and / or substitutions can be used to alter endogenous The promoter can be varied.

[0078] Vectors and host cells The present invention also relates to vectors containing the isolated nucleic acid molecules, recombinant vectors, and methods for genetic manipulation. and the production of at least one recombinant host cell by recombinant techniques well known in the art. For example, see U.S. Pat. No. 6,233,999, each of which is incorporated herein by reference in its entirety. See Sambrook et al., supra; Ausubel et al., supra, which are incorporated herein by reference.

[0079] The polynucleotide may optionally be incorporated into a vector containing a selectable marker for propagation in a host. Generally, the plasmid vector is prepared by precipitation with calcium phosphate precipitates. or in a complex with a charged lipid. If desired, package it in vitro using an appropriate packaging cell line and can then be transduced into host cells.

[0080] The DNA insert should be operably linked to an appropriate promoter. The target is a transcription start site, a transcription termination site, and, within the transcribed region, a ribosome for translation. The coding portion of the mature transcript expressed by the construct further contains a nucleotide sequence encoding the nucleotide sequence of the target gene. , preferably with initiation and termination codons appropriately positioned at the end of the mRNA to be translated (e.g. UAA, UGA, or UAG), and in mammalian or eukaryotic cells. UAA and UAG are preferred for expression.

[0081] It is preferred, but optional, that the expression vector include at least one selectable marker. Such markers include, for example, methotrexate for eukaryotic cell culture. , MTX), dihydrofolate reductase (DHFR, US Patent No. Permit No. 4,399,216, No. 4,634,665, No. 4,656,134, Same Nos. 4,956,288, 5,149,636, 5,179,017, and Picillin, neomycin (G418), mycophenolic acid, or glutamine synthetase (glutamine synthetase, GS, U.S. Patent Nos. 5,122,464 and 5,770,3 59, 5,827,739) resistance genes and E. coli and other bacteria or contains tetracycline or ampicillin resistance genes for cultivation in prokaryotes (The above patents are incorporated herein by reference in their entirety.) Appropriate culture media and conditions for the above host cells are known in the art. Suitable vectors will be readily apparent to those skilled in the art. Introduction of ATP can be achieved by calcium phosphate transfection, DEAE-dextran mediated transfection, and transfection, cationic lipid-mediated transfection, electroporation, The cells may be affected by transduction, infection, or other known methods, as described above. Sambrook, chapters 1-4 and 16-18; Ausubel, supra, chapters 1 and 9 , Chapters 13, 15, and 16 of the technical field.

[0082] At least one antibody used in the methods of the present 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, can be added to the N-terminus of the antibody to facilitate purification or This can improve stability and persistence in the host cell during subsequent 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 at least one of the fragments. The method is described in Sambrook, supra, Chapters 17.29-17.42 and 18.1-18. Many standard laboratories, such as Chapter 74, Ausubel, supra, Chapters 16, 17, and 18 It's written in the manual.

[0083] Those skilled in the art will appreciate that various methods are available for expressing nucleic acids encoding proteins used in the methods of the present invention. Numerous expression systems are available that are well known. Alternatively, the nucleic acid may be expressed as an endogenous antibody encoding nucleic acid. By switching it on (by manipulation) in the host cell containing the DNA, Such methods can be expressed in the methods described herein, which are incorporated by reference in their entirety. , U.S. Patent Nos. 5,580,734, 5,641,670, and 5,733,74 6 and 5,733,761, It is knowledge.

[0084] An example of a cell culture useful for producing antibodies, specified portions or variants thereof is mammalian cells. Mammalian cell lines often take the form of a monolayer of cells, but suspensions of mammalian cells A suspension or bioreactor can also be used. Several suitable host cell lines have been developed in the art, including: COS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CR L-1651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., ATCC CRL1610) and BSC-1 (e.g., ATCC CRL-26) Cell lines, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2 / 0-Ag14, 293 cells, HeLa cells, etc. American Type Culture Collection(Manassas) , Va) (www.atcc.org). Particularly preferred are cells derived from the lymphatic system, such as myeloma and lymphoma cells. The host cells were P3X63Ag8.653 cells (ATCC accession number CRL-1580) and Particularly preferred are SP2 / 0-Ag14 cells (ATCC deposit number CRL-1851). In embodiments, the recombinant cells are P3X63Ab8.653 or SP2 / 0-Ag14 cells. is.

[0085] Expression vectors for these cells include an origin of replication, a promoter (e.g., late or early SV4 0 promoter, CMV promoter (U.S. Patent Nos. 5,168,062, 5,385, No. 839), HSV tk promoter, pgk (phosphoglycerate kinase) promoter EF-1 alpha promoter (U.S. Patent No. 5,266,491), at least one Human immunoglobulin promoter, enhancer, and / or ribosome binding site, RNA Splice sites, polyadenylation sites (e.g., SV40 large T Ag polyaddition site) , as well as processing information sites such as transcription termination sequences, but are not limited to these. , and expression control sequences. For example, the above-mentioned Ausu See, e.g., bel et al., Sambrook et al., supra. Other cells useful for synthesis are known and / or are described, for example, in American T ype Culture Collection Catalog of Cell Lines and Hybridomas (www.atcc.org) or others These compounds are available from well-known or commercial sources.

[0086] When a eukaryotic host cell is used, a polyadenylation or transcription termination site is typically located within 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. An example of a splicing sequence is the VP1 intron from SV40 (Sprague , et al., J. Virol. 45:773-781(1983)). As is known in the art, genetic sequences for controlling replication within a host cell are used to It can be incorporated into the controller.

[0087] Antibody purification Anti-IL-23 antibodies were purified using protein A, ammonium sulfate or ethanol precipitation, and acid extraction. extraction, anion or cation exchange chromatography, phosphocellulose chromatography -, hydrophobic interaction chromatography, affinity chromatography, hydroxy Examples of such methods include luapatite chromatography and lectin chromatography. The protein can be recovered and purified from recombinant cell culture by well-known methods, including but not limited to, High performance liquid chromatography (HPL) C") can also be used for purification. For example, see the following: Colligan, Current Protocols in Immuno logy or Current Protocols in Protein Science ce,John Wiley & Sons,NY,NY(1997-2001), e.g. See, for example, Chapters 1, 4, 6, 8, 9, and 10.

[0088] Antibodies for use in the methods of the present invention include naturally occurring purified products, those derived from chemically synthesized procedures, and the like. and recombinant products from eukaryotic hosts, including, for example, yeast, higher plants, insects, and mammalian cells. The host used in the recombinant production process is Accordingly, the antibody may be glycosylated or non-glycosylated, but may also be glycosylated. Such methods are preferably carried out as described above, all of which are incorporated herein by reference in their entirety. Sambrook, verses 17.37-17.42; Ausubel, supra, chapter 10, 1 Chapters 2, 13, 16, 18, and 20, Colligan, Protein Sci, supra. ence, Chapters 12-14, and many other standard laboratory manuals.

[0089] Anti-IL-23 antibody. The anti-IL-23 antibodies of the present invention can be incorporated into immunoglobulin molecules, At least a portion of, for example, but not limited to, at least one ligand bond Ligand binding portion (LBP), for example, but not limited to, heavy chain or light chain complementarity determining regions (CDRs) or ligand-binding portions thereof, heavy or light chain potentials Variable regions, framework regions (e.g., FR1, FR2, FR3, FR4, or their fragment, and optionally containing at least one substitution, insertion, or deletion), heavy chain or The constant region of the light chain (e.g., at least one C H1, Hinge 1, Hinge 2, Hinge 3, Hinge Range 4, C H 2 or C H 3, or a fragment thereof, and optionally at least one any protein or protein containing a polypeptide (including substitutions, insertions, or deletions of a polypeptide or polypeptide chain) or any part thereof The antibodies include peptide-containing molecules. The antibodies may be human, mouse, rabbit, rat, rodent, or primate. any mammal, such as, but not limited to, a mammalian animal, It can comprise or be derived from

[0090] The isolated antibodies used in the methods of the present invention may be synthesized by any suitable polynucleotide. The amino acid sequence of the antibody disclosed herein that is encoded, or any isolated or prepared Preferably, the human antibody or antigen-binding fragment binds to human IL-23 and thereby partially or substantially neutralizing at least one biological activity of the protein. At least one biological activity of at least one IL-23 protein or fragment is retained. Partially or preferably substantially neutralizing antibodies, or specified portions or variants thereof, IL-23 receptor. or through other IL-23-dependent or -mediated mechanisms. As used herein, the term "neutralizing antibody" refers to a neutralizing antibody that, depending on the assay, , about 20 to 120%, preferably at least about 10, 20, 30, 40, 50, 55, 6 0, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97 , 98, 99, 100% or more. The ability of the anti-IL-23 antibody to inhibit IL-23-dependent activity is preferably determined by the methods described herein. at least one suitable IL-23 transcription factor, as described in and / or known in the art; Human antibodies can be evaluated by protein or receptor assays. IgA, IgM, IgE, IgD, etc.) or isotype, In one embodiment, the human antibody comprises an IgG heavy chain or a lambda light chain. Defined fragments, e.g., isotypes IgG1, IgG2, IgG3, or IgG4 (e.g., γ1, γ2, γ3, γ4). at least one of the compounds described herein and / or known in the art transgenic vectors containing human light chain (e.g., IgG, IgA, and IgM) transgenes; prepared by utilizing a transgenic mouse or other non-human mammal. In another embodiment, the anti-IL-23 human antibody has an IgG1 heavy chain and an IgG1 and a light chain.

[0091] The antibody is an antibody that binds to at least one IL-23 protein, subunit, fragment, portion, or It binds to at least one specific epitope specific to any combination of these. At least one epitope is at least one antigen that comprises at least a portion of a protein. The epitope may comprise a target binding region of the protein, and the epitope preferably comprises at least one It consists of an extracellular portion, a soluble portion, a hydrophilic portion, an outer portion, or a cytoplasmic portion. .

[0092] Generally, a human antibody or antigen-binding fragment contains at least one human complementarity-determining region (CDR variants of at least one heavy chain variable region, and at least Each of the complementarity determining regions (CDR1, CDR2, and CDR3) is human, or at least one The CDR sequences are derived from human germline variants of the antigen-binding region of the light chain variable region. It may be derived from a germline sequence or may be an exact match to a germline sequence. Alternatively, CDRs from a synthetic library derived from the original non-human CDRs can be used. These CDRs may be formed by incorporation of conservative substitutions from the original non-human sequence. In another particular embodiment, the antibody or antigen-binding portion or variant has corresponding CDRs 1, 2, and / or at least one light chain CDR (i.e., CDR1 , CDR2, and / or CDR3) can be done.

[0093] Such antibodies can be prepared using conventional techniques involving recombinant DNA technology to encode the antibodies (i.e., by preparing and expressing a nucleic acid molecule (i.e., one or more) or by any other method. By using suitable methods, various portions of antibodies (e.g., can be prepared by chemically linking together .

[0094] Anti-IL-23 specific antibodies have heavy or light chain variable regions with defined amino acid sequences. For example, in a preferred embodiment, the antibody may include at least one of anti-IL-2 3. The antibody optionally comprises at least one heavy chain variable region having the amino acid sequence of SEQ ID NO:7. and / or optionally a light chain variable region having the amino acid sequence of SEQ ID NO: 8. For example, in a preferred embodiment, the anti-IL-23 antibody comprises at least one of Optionally, at least one heavy chain variable region having the amino acid sequence of SEQ ID NO: 9; and and / or optionally at least one of a light chain variable region having the amino acid sequence of SEQ ID NO: 10. The present invention also includes a method for the preparation of a human IL-23 antibody having a defined heavy or light chain variable region. Antibodies can be generated using phage display (Ka Tsube, Y., et al., Int J Mol. Med, 1(5):863-8 68 (1998)) or methods employing transgenic animals. For example, functionally rearranged human immunoglobulin heavy chains can be introduced. genes from the human immunoglobulin light chain locus that are capable of undergoing functional rearrangement. and a transgenic mouse containing a transgene containing DNA encoding human IL-23 or its derivatives. If desired, antibody-producing cells can be immunized with a fragment of the can be isolated and are described herein and / or known in the art. Hybridomas or other immortalized antibody-producing cells can be prepared. The gene, particular part or variant can be produced by using the encoding nucleic acid or part thereof in a suitable host cell. It can be expressed by

[0095] The present invention also provides amino acids in sequences that are substantially the same as the amino acid sequences described herein. The present invention relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs comprising the amino acid. Such antibodies or antigen-binding fragments and antibodies comprising such chains or CDRs may be used with high affinity (e.g. If so, about 10 -9 K below M D) can bind to human IL-23. Amino acid sequences that are substantially the same as the sequences listed include those with conservative amino acid substitutions and Conservative amino acid substitutions include sequences containing amino acid deletions and / or insertions in the first Chemical and / or physical properties similar to those of amino acids (e.g., charge, structure, polarity, refers to the substitution of a first amino acid with a second amino acid that has hydrophilic (hydrophilic) properties. Substitutions include, but are not limited to, replacing one amino acid with another amino acid within the following group: Substituting: lysine (K), arginine (R), and histidine (H); Paragine (D) and glutamate (E); asparagine (N), glutamine (Q) , serine (S), threonine (T), tyrosine (Y), K, R, H, D, and E; Acetone (A), valine (V), leucine (L), isoleucine (I), proline (P), phenanthroline (P), thialanine (F), tryptophan (W), methionine (M), cysteine ​​(C), and and glycine (G); F, W, and Y; C, S, and T.

[0096] Amino acid code The amino acids constituting the anti-IL-23 antibodies of the present invention are often abbreviated. The acid notation can be its one-letter code, its three-letter code, its name, or the code of the three nucleotides. This can be shown by representing the amino acid by a symbol, which is well understood in the art. (Alberts, B. et al., "Molecular Biology of The Cell, 3rd Edition, Garland Publishing, Inc., New see York (1994).

[0097] [Table 1]

[0098] The IL-23 antibodies used in the methods of the present invention may be naturally occurring variants, as designated herein. Contains one or more amino acid substitutions, deletions, or additions, either by mutation or human manipulation. It can be seen.

[0099] The number of amino acid substitutions a skilled artisan would make depends on many factors, including those described above. Specifically, amino acid substitutions, insertions, or deletions of a given anti-IL-23 antibody, fragment, or variant. The number of losses is 40, 30, 20, 19, 18, 17, 16, as specified herein. 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 and below, e.g. For example, it is 1 to 30 or any range or value therein.

[0100] Amino acids within the anti-IL-23 specific antibody that are essential for function can be identified by site-directed mutagenesis or Identified by methods known in the art, such as alanine scanning mutagenesis (See, e.g., Ausubel, supra, Chapters 8, 15; Cunn Ingham and Wells, Science 244:1081-1085 (1989 The latter procedure involves the introduction of single alanine mutations at every residue in the molecule. and the resulting mutant molecule has biological activity, for example, but not limited to, at least one IL-1. The site critical for antibody binding is also tested for ATP-23 neutralizing activity. These can be identified by structural analysis such as crystallization, nuclear magnetic resonance, or photoaffinity labeling (Sm Ith et al., J. Mol. Biol. 224:899-904 (1992) and de Vo s et al., Science 255:306-312 (1992).

[0101] The anti-IL-23 antibody may be selected from the group consisting of at least one of SEQ ID NOs: 1, 2, 3, 4, 5, and 6. At least one portion, sequence, or combination selected from all five of the adjacent amino acids The present invention can include, but is not limited to, a combination of the above.

[0102] The IL-23 antibody or specific portion or variant thereof includes at least 3 of the above SEQ ID NOs. 5 to 17 adjacent amino acids of the above SEQ ID NO: 5 to 17 adjacent amino acids of the above SEQ ID NO: 10 adjacent amino acids, 5 to 11 adjacent amino acids of the above SEQ ID NO: 7 adjacent amino acids, at least 5 to 9 adjacent amino acids selected from the above SEQ ID NO: This may include, but is not limited to, a single portion, sequence, or combination.

[0103] The IL-23 antibody further optionally comprises any of SEQ ID NOs: 5, 17, 10, 11, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, At least one polynucleotide consisting of 70 to 100% of the 1, 119, or 108 adjacent amino acids In one embodiment, the immunoglobulin chain or a portion thereof (e.g., The amino acid sequence of each of the amino acid sequences (variable region, CDR) corresponds to at least one of the above SEQ ID NOs. The amino acid sequence of the corresponding chain has approximately 70 to 100% identity (e.g., 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 8 7, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 10 0, or any range or value therein). For example, The sequence can be compared to the sequence of the above SEQ ID NO: or the amino acid sequence of the heavy chain CDR3 can be It can be compared with the above SEQ ID NO. Preferably, it is 70 to 100% amino acid identity ( That is, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or (or any range or value therein) can be used in a suitable computer program known in the art. It is determined using an algorithm.

[0104] "Identity" is defined as the degree of identity found by comparing sequences, as known in the art. The relationship between two or more polypeptide sequences or two or more polynucleotide sequences that is to be determined. In the art, "identity" refers to the match between strings of such sequences. It also refers to the degree of sequence relatedness between polypeptide or polynucleotide sequences, as determined by "Identity" and "similarity" are defined in the Computational Molecular Biology,Lesk,AM,ed.,Oxford University Press, New York, 1988, Biocomputing:Inform tics and Genome Projects, Smith, DW, ed. ,Academic Press,New York,1993,Computer A analysis of Sequence Data,Part I,Griffin, AM, and Griffin, HG, eds., Humana Press, New Jersey,1994, Sequence Analysis in Mol ecular Biology, von Heinje, G., Academic Pr. ess, 1987, and Sequence Analysis Primer, Grib skov, M. and Devereux, J., eds., M Stockton P. Ress, New York, 1991, and Carillo, H., and Lip man, D., Siam J. Applied Math.,48:1073(1988 ) and the like. In addition, percent identity values ​​can be calculated using Vector NTI Suite 8.0 (Informax, Frederick, MD) The amino acid and nucleotide sequence alignments are generated using the default settings of AlignX. can be obtained from the alignment.

[0105] 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 10]. A preferred computer program method for this is the GCG program package (Dev Ereux, J. et al., Nucleic Acids Research 12(1):3 87 (1984)), BLASTP, BLASTN, and FASTA (Atschul, SF et al., J. Molec. Biol. 215:403-410 (1990) The BLAST X program is available from NCBI and other Source (BLAST Manual, Altschul, S. et al., NCBINLM NI H Bethesda, Md. 20894: Altschul, S. et al., J. Mol. B iol. 215:403-410 (1990). The Waterman algorithm may also be used to determine identity.

[0106] Preferred parameters for polypeptide sequence comparison include the following: (1) Algorithm Mu: Needleman and Wunsch, J. Mol Biol. 48:443 -453(1970)Comparison matrix:BLOSSUM62 fr om Hentikoff and Hentikoff,Proc.Natl.Aca d.Sci,USA.89:10915-10919(1992), Gap penalty: 12 Gap length penalty: 4 A useful program for these parameters is Genetics Computer G Publicly available as the "Gap" program from the Madison, Wis. group. The above parameters are the default parameters for peptide sequence comparison (terminal (Just as there is no penalty for caps.)

[0107] Preferred parameters for polynucleotide comparison include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Bi ol.48:443-453(1970) Comparison matrix: match = +10, mismatch = 0 Gap penalty: 50 Gap length penalty: 3 " from Genetics Computer Group, Madison Wis. These are available as programs with default parameters for nucleic acid sequence comparison. is.

[0108] For example, a polynucleotide sequence may be identical to another sequence, i.e., 100% identical. or contain a specific integer or less nucleotide alteration compared to the reference sequence. Such modifications may include deletions, substitutions (including transitions and transversions) of at least one nucleotide. or an insertion, the modification being 5' or 6' of the reference nucleotide sequence. It may occur at the 3'-terminal position or anywhere between these terminal positions and may be a nucleotide of the reference sequence. either individually between the peptides or dispersed among one or more adjacent groups within the reference sequence. The number of nucleotide alterations is determined by multiplying the total number of nucleotides in the sequence by the corresponding identity. Multiply the percentage by the percentage (divided by 100) and use the product to find the number of nucleotides in the sequence. Subtract from the total number of chids, or by n.sub.n.ltorsim.x.sub.n-(x.sub.ny) It is decided, where n.sub.n is the number of nucleotide alterations and x.sub.n is the number of nucleotides in the sequence. The total number of leucocytes, y is, for example, 0.70 for 70% and 0 for 80%. .80, 0.85 for 85%, 0.90 for 90%, and 0 for 95%. 95, and any non-integer product of x.sub.n and y is Round down to the nearest integer before subtracting.

[0109] The polynucleotide sequence encoding the above SEQ ID NOs may be modified to include a N-terminal fragment in the coding sequence. A sense, missense, or frameshift mutation occurs, which results in the formation of a polynucleotide that is The polypeptide encoded by the oligonucleotide can be modified. The polypeptide sequence is identical, i.e., 100% identical, to the reference sequence of the SEQ ID NO. Alternatively, a specific sequence may be identified in comparison to the reference sequence so that the percent identity is less than 100%. It may contain up to an integer number of amino acid modifications. Such modifications include at least one amino acid a deletion, substitution (including conservative and non-conservative substitution), or insertion of The modification may occur at the amino or carboxy terminal positions of the reference polypeptide sequence, or at either It may occur anywhere between the terminal positions, individually between amino acids of the reference sequence, or within the reference sequence. They may be dispersed among either one or more adjacent groups. The number of amino acid changes is calculated by multiplying the total number of amino acids in the above SEQ ID NO by the respective percent identity. multiplied by the numerical percentage (divided by 100) of the amino acid in the above sequence number, By subtraction from the total, or by n.sub.a.ltorsim.x.sub.a-(x.sub.ay) It is decided, where n.sub.a is the number of amino acid changes and x.sub.a is the amino acid sequence of the above SEQ ID NO: is the total number of amino acids in the is 0.80, 0.85 for 85%, etc., and x.sub.a and y are not integers. Any product that is smaller than x.sub.a is truncated to the nearest integer before being subtracted from x.sub.a.

[0110] Exemplary heavy and light chain variable region sequences, and portions thereof, are set forth in the SEQ ID NOs. The antibodies of the present invention, or specific variants thereof, may comprise any number of adjacent amino acids derived from the antibodies of the present invention. The number of amino acid residues can be 10 to 10 times the number of adjacent residues in the anti-IL-23 antibody. 100%. Optionally, this subsequence of contiguous amino acids is selected from the group of integers consisting of: , at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 11 0, 120, 130, 140, 150, 160, 170, 180, 190, 200, 21 0, 220, 230, 240, 250 or more amino acids in length, or any of the amino acids therein Further, the number of such subsequences is at least 2, 3, 4, or It can be any integer selected from the group consisting of 1 to 20, such as 5.

[0111] As one of skill in the art will recognize, the present invention provides a method for the preparation of at least one biologically active antibody of the present invention. Biologically active antibodies include natural (non-synthetic), endogenous, or related and known antibodies. At least 20%, 30%, or 40%, preferably at least 50%, 60% %, or 70%, and most preferably at least 80%, 90%, or 95% to 100% or more (including but not limited to, up to 10 times the specific activity) Methods for assaying and quantitatively measuring enzyme activity and substrate specificity are well known to those skilled in the art. .

[0112] In another aspect, the present invention provides a method for preparing a compound according to any one of the methods described herein that is modified by the covalent attachment of an organic moiety. Such modifications may result in improved pharmacokinetic properties (e.g., It is possible to produce antibodies or antigen-binding fragments with increased serum half-life in vivo. The organic moiety may be a linear or branched hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. In certain embodiments, the hydrophilic polymeric group can have a molecular weight of from about 800 to about 120,000 daltons, polyalkane glycol (e.g., polyethylene glycol) polyethylene glycol (PEG), polypropylene glycol (polypropylene glycol) lycol, PPG), carbohydrate polymers, amino acid polymers or polyvinylpyrrolidone The fatty acid group or fatty acid ester group may contain from about 8 to about 40 carbon atoms. do.

[0113] The modified antibodies and antigen-binding fragments may be prepared by direct or indirect covalent attachment to the antibody. or more than one organic moiety may be attached to the antibody or antigen-binding fragment of the invention. Each organic moiety was independently a hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. As used herein, the term "fatty acid" refers to monocarboxylic and dicarboxylic acids. As used herein, the term "hydrophilic polymeric group" includes octanoic acid. It refers to an organic polymer that is more soluble in water than in ethanol. For example, polylysine is an organic polymer that is more soluble in water than ethanol. It has a higher solubility in water than methacrylate. Antibodies are encompassed by the present invention. Suitable hydrophilic polymers for modifying the antibodies of the present invention include They can be linear or branched, for example, polyalkane glycols (e.g., PEG, Monomethoxy-polyethylene glycol (mPEG) ), PPG, etc.), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides, etc. ), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, polyasparagine), acid, etc.), polyalkane oxides (e.g., polyethylene oxide, polypropylene oxide, etc.), Preferably, the antibody of the present invention is modified with The hydrophilic polymer has a molecular weight of about 800 to about 150,000 daltons as an individual molecular entity. For example, PEG 5000 and PEG 20,000 You can use the subscript The letters are the average molecular weight (Daltons) of the polymer. The hydrophilic polymer groups are 1 to about 6. The fatty acid or fatty acid ester group may be substituted with an alkyl group, a fatty acid group, or a fatty acid ester group. The hydrophilic polymers substituted with acid ester groups can be prepared by utilizing a suitable method. For example, a polymer containing an amine group can be bonded to a fatty acid or fatty acid ester. Activated carboxylates on fatty acids or fatty acid esters that can be linked to carboxylates (e.g., activated with N,N-carbonyldiimidazole) onto the hydride on the polymer. It can be linked to a hydroxyl group.

[0114] Fatty acids and fatty acid esters suitable for modifying antibodies of the invention can be saturated. Suitable for modifying antibodies of the invention. Suitable fatty acids include, for example, n-dodecanoate (C 12 , laurate), n-tetradecane Citrate (C 14 , myristate), n-octadecanoate (C 18 , stearates ), n-eicosanoic acid salt (C 20 , arachidate), n-docosanoate (C 22 , Behe phosphate), n-triacontanoate (C 30 ), n-tetracontanoate (C 40 ), System -Δ9-octadecanoate (C 18 , oleate), all cis-Δ5,8,11,1 4-Eicosatetraenoic acid salt (C 20, arachidonate), octanedioic acid, tetradecane Suitable fatty acid esters include octadecanedioic acid, docosanedioic acid, and the like. The monoesters of dicarboxylic acids include monoesters of dicarboxylic acids containing a single or branched chain lower alkyl group. The alkyl group can contain 1 to about 12, preferably 1 to about 6, carbon atoms.

[0115] The modified human antibodies and antigen-binding fragments can be modified, for example, by reacting them with one or more modifying agents. As used herein, "modified" refers to a compound that is a hydroxyl group of a hydroxy group. The term "agent" refers to any suitable organic group (e.g., hydrophilic polymers, fatty acids, lipids) that contains an activating group. An "activating group" means a group that, under appropriate conditions, reacts with a second chemical group to form a a chemical moiety or a compound capable of forming a covalent bond between the modifying agent and a second chemical group For example, amine-reactive activating groups include tosylate, mesylate, halo(chloride), and Electrophilic groups such as hydroxyl, bromo, fluoro, and iodo, N-hydroxysuccinimidyl esters, esters (N-hydroxysuccinimidyl esters, NHS), etc. Can react with thiols Suitable activating groups include, for example, maleimide, iodoacetyl, acrylolyl, and pyridyl. disulfide, 5-thiol-2-nitrobenzoic acid thiol (TNB-thiol), etc. The aldehyde functional group can be linked to an amine- or hydrazide-containing molecule. The azide group reacts with a trivalent phosphorus group to form a phosphoramidate or phosphorimide bond. Suitable methods for introducing activating groups into molecules are well known in the art. (e.g., Hermanson, GT, Bioconjugate Techniques,Academic Press:San Diego,CA(1 996). The activating group is an organic group (e.g., hydrophilic polymer, fatty acid, fatty acid ester). directly to the linker moiety, e.g., a divalent C1-C 12 group (wherein one or Two or more carbon atoms may be replaced by heteroatoms such as oxygen, nitrogen, or sulfur. Suitable linker moieties include, for example, tetraethylene glycol, -(CH2)3-, -NH-(CH2)6-NH-, -(CH2)2-NH-, and -C H2-O-CH2-CH2-O-CH2-CH2-O-CH-NH-. A modifying agent containing a carbon moiety is, for example, 1-ethyl-3-(3-dimethylaminopropyl)carbonyl. In the presence of benzodiimide (EDC), mono-Boc-alkyldiamines (e.g., mono- Boc-ethylenediamine, mono-Boc-diaminohexane) is reacted with a fatty acid, Produced by forming an amide bond between a free amine and a fatty acid carboxylate The Boc protecting group can be removed by trifluoroacetic acid (TFA). A primary carboxylate which can be removed from the product by treatment and linked to another carboxylate as described. The amine can be exposed or reacted with maleic anhydride to form the resulting The resulting product can be cyclized to produce an activated maleimide derivative of a fatty acid (e.g., See, for example, WO 92 / 16221 (Thompson et al.), which is incorporated herein by reference. (The disclosure of which is incorporated herein by reference).

[0116] The modified antibodies are produced by reacting a human antibody or antigen-binding fragment with a modifying agent. For example, the organic moiety can be an amine-reactive modifying agent, such as NHS of PEG. Esters can be used to couple to antibodies in a non-site specific manner. reducing disulfide bonds (e.g., intrachain disulfide bonds) of the antibody or antigen-binding fragment In this case, a modified human antibody or antigen-binding fragment can also be prepared. The reduced antibody or antigen-binding fragment is reacted with a thiol-reactive modifying agent to form the modified antibody or antigen-binding fragment of the present invention. The organic moiety that is bound to a specific site on the antibody of the present invention can be used to produce an antibody that is specifically designed for this purpose. Modified human antibodies and antigen-binding fragments containing the nucleotides 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, Conjugate Chem., 3:147-153 (1992), Werlen et al. Bioconjugate Chem.,5:411~417(1994), Kumar an et al., Protein Sci. 6(10):2233-2241 (1997), It oh et al., Bioorg. Chem., 24(1):59-68(1996), Cape llas et al.,Biotechnol.Bioeng.,56(4):456~463(1 997), and Hermanson, GT, Bioconjugate Tech niques, Academic Press: San Diego, CA (1996) The compounds can be prepared using any suitable method, such as those described in

[0117] The methods of the present invention also include the use of compounds of the present invention that are provided in non-naturally occurring compositions, mixtures, or forms. At least one of the methods described herein and / or known in the art at least two, at least three, at least four, at least five, at least six, or The composition further comprises an anti-IL-23 antibody. The product may be 70-100% of the contiguous amino acids of the above SEQ ID NOs, or a specific fragment, domain, or fragment thereof. or a variant thereof, Also, one or two full-length, C- and / or N-terminal deletion variants, domains, fragments, or specific Preferred anti-IL-23 antibody compositions include non-naturally occurring compositions containing certain variants. , an anti-IL-23 antibody sequence described herein, for example, 70 to 100% of the above SEQ ID NOs. or at least one CDR or LBP of a particular fragment, domain, or variant thereof Containing at least one or two full-length, fragment, domain, or variant portions More preferred compositions include, for example, 70 to 100% of the above SEQ ID NOs., or specific examples thereof. The composition contains 40 to 99% of at least one of the fragments, domains, or variants. The percentages of the ingredients may be as known in the art or as described herein. , weight, volume, concentration, molarity, or liquid or dry solution, mixture by molar concentration as a solid, suspension, emulsion, particle, powder, or colloid. do.

[0118] Antibody compositions containing additional therapeutically active ingredients The antibody compositions used in the methods of the present invention may optionally further comprise an anti-infective agent, a cardiovascular agent, or iovascular (CV) drugs, central nervous system (CNS) drugs, autonomic Autonomic nervous system (ANS) medications, respiratory medications, gastrointestinal medications, GI tract acting agents, hormonal agents, fluid or electrolyte balancing agents, hemodynamic agents, antitumor agents, immunomodulatory agents Selected from at least one of the following: medicines, eye, ear or nose medicines, topical medicines, nutritional medicines, etc. Such a drug may comprise an effective amount of at least one compound or protein. The art has extensive knowledge of the various formulations, indications, dosages, and administration of each of the compounds described herein. are well known (see, for example, Nursing 2001 Handbook of Drugs, 21 st edition,Spri nghouse Corp., Springhouse, PA, 2001, Health Professional's Drug Guide 2001,ed.,Shan non,Wilson,Stang,Prentice-Hall,Inc,Upper Saddle River, NJ, Pharmacotherapy Handbook ,Wells et al.,Appleton & Lange,Stamford, (See CT).

[0119] Examples of drugs that can be combined with the antibodies of the present methods include anti-infective drugs, ampicillin-resistant Staphylococcus aureus (MSA), and methicillin-resistant Staphylococcus aureus (MSA). antiprotozoal, anthelmintic, antifungal, antimalarial, antituberculous or At least one antimycobacterial drug, aminoglycoside, penicillin, cephalosporin, tetracycline Lacycline, sulfonamides, fluoroquinolones, antivirals, macrolide anti-infectives The drug may be at least one selected from the group consisting of hormonal drugs, anti-infective drugs, and various anti-infective drugs. is a corticosteroid, an androgen, or at least one anabolic steroid , estrogen, or at least one progestin, gonadotropin, antidiabetic agent, or at least one glucagon, thyroid hormone, thyroid hormone antagonist, pituitary hormone At least one ceftriaxone may be selected from the group consisting of cephalosporins, cephalosporins, and parathyroid mimetics. Alosporins include cefaclor, cefadroxil, cefazolin sodium, and cefdinir. Cefepime hydrochloride, cefixime, cefmetazole sodium, cefonicid sodium cefoperazone sodium, cefotaxime sodium, cefotetan disodium , cefoxitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime ceftibuten, ceftizoxime sodium, ceftriaxone sodium, cefroxone Cefuroxime sodium, cephalexin hydrochloride, cephalexin monohydrate The compound may be at least one selected from the group consisting of cefradine, cephradine, and loracarbef.

[0120] At least one corticosteroid is betamethasone, betamethasone acetate, Betamethasone or betamethasone sodium phosphate, betamethasone sodium phosphate, cholesteryl acetate Tisone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, acetate Fludrocortisone, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, Tilprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate Prednisolone, Prednisolone acetate, Prednisolone sodium phosphate, Tebut Prednisolone, prednisone, triamcinolone, triamcinolone acetonide, and and triamcinolone diacetate. Another type of androgenic or anabolic steroid is danazol, fluoxymethane, Nandrolone, Methyltestosterone, Nandrolone Decanoate, Nandrolone Phenpropionate , Testosterone, Testosterone Cypionate, Testosterone Enanthate, Propionate At least one selected from testosterone acid and transdermal testosterone can be done.

[0121] At least one immunosuppressant is azathioprine, basiliximab, cyclosporine, Daclizumab, lymphocyte immunoglobulin, muromonab-CD3, mycophenolate mofetil mycophenolate mofetil, mycophenolate mofetil hydrochloride, sirolimus, and tacrolimus. There may be at least one.

[0122] At least one topical anti-infective agent is acyclovir, amphotericin B, azelaic acid cyclovir, or Ream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole le, econazole nitrate, erythromycin, gentamicin sulfate, ketoconazole, acetic acid Mafenide, metronidazole (topical), miconazole nitrate, mupirocin, naftifuric acid hydrochloride acetaminophen, neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, tetrahydrochloride Rubinafine, terconazole, tetracycline hydrochloride, tioconazole, and tolnaf At least one scabicide or The pediculicide is selected from crotamiton, lindane, permethrin, and pyrethrins. The at least one topical corticosteroid may be at least one selected from the group consisting of dihydrotestosterone, hydroxybenzoates, benzodiazepines ... Betamethasone propionate, betamethasone valerate, clobetasol propionate, desonil Dexamethasone, dexamethasone sodium phosphate, diacetate Florazone, fluocinolone acetonide, fluocinonide, flurandrenolide, propionate Fluticasone nitrate, halcionide, hydrocortisone, hydrocortisone acetate hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, and trimethoprim-3 amcinolone acetonide. Nursing 2001 Drug Handbook, pages 1098-1136 Please refer to.)

[0123] The anti-IL-23 antibody composition may be administered to cells, tissues, organs, or tissues in need of such modulation, treatment, or therapy. At least one anti-IL-23 antibody is contacted with or administered to a patient, animal, or subject. and optionally further comprising at least one TNF antagonist (e.g., but not limited to, TN Fc. F chemical or protein antagonists, TNF monoclonal or polyclonal antibodies or or fragments thereof, soluble TNF receptors (e.g., p55, p70, or p85) or fragments thereof, a synthetic polypeptide, or a small molecule TNF antagonist, such as TNF binding protein I or I I (TBP-1 or TBP-II), nerelimonmab, infliximab etanercept, CDP-571, CDP-870, afelimomab, Lenercept, etc.), antirheumatic drugs (e.g., methotrexate, auranofin, Thioglucose, azathioprine, etanercept, sodium gold thiomalate, hydrochloride roxychloroquine sulfate, leflunomide, sulfasalazine), immunizing agents, immunoglobulins immunosuppressants (e.g., azathioprine, basiliximab, cyclosporine, dacrylamide, at least one selected from the group consisting of fluticasone, fluoxetine, fluoxetine-1, fluoxetine-2, fluoxetine-3, fluoxetine-4, fluoxetine-5, fluoxetine-6, fluoxetine-7, fluoxetine-8, fluoxetine-9, fluoxetine-10, fluoxetine-11, fluoxetine-12, fluoxetine-1 Further comprising at least one of any suitable and effective amount of the composition or pharmaceutical composition. Non-limiting examples of such cytokines include IL-1 to IL-40 (e.g., For example, IL-1, IL-2, etc.), but are not limited to these. Suitable dosages are well known in the art. See, for example, Wells et al. al., eds., Pharmacotherapy Handbook, 2 nd E dition,Appleton and Lange,Stamford,CT(20 00), PDR Pharmacopoeia, Tarascon Pocket Ph armacopoeia 2000,Deluxe Edition,Tarascon Publishing, Loma Linda, CA (2000). Each of these documents is incorporated herein by reference in its entirety.

[0124] The anti-IL-23 antibody compounds, compositions, or mixtures used in the methods of the present invention may further comprise dilutions. agents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc. The composition may contain at least one of any suitable auxiliary agent, including but not limited to, pharmaceutically acceptable salts, Non-limiting examples of methods for preparing such sterile solutions are described in the art. and is well known in, for example, Gennaro, Ed., Remington's Ph.D. Armaceutical Sciences, 18 th Edition, Mack Publishing Co. (Easton, PA) 1990, among others. Non-limiting examples include anti-IL-1 antibodies known in the art or described herein. -23 A pharmaceutical composition suitable for the administration mode, solubility, and / or stability of the antibody, fragment, or variant composition A pharmaceutically acceptable carrier can be routinely selected.

[0125] Pharmaceutical excipients and additives useful in the present compositions include, but are not limited to: , proteins, peptides, amino acids, lipids and carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, Sugars including tetrasaccharides and oligosaccharides, alditols, aldonic acids, esterified sugars, and other derivatives sugars, and polysaccharides or sugar polymers), which may be present alone or in combination. They may be contained alone or in combination in an amount of 1 to 99.99% by weight or volume. Protein excipients include human serum albumin (HSA). Serum albumin, recombinant human albumin (rHA), Examples of amino acids / antibodies that can also function in buffering capacity include lactic acid bacteria and casein. Body components include alanine, glycine, arginine, betaine, histidine, and glutamate. amino acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, metha Examples include onine, phenylalanine, and aspartame. is glycine.

[0126] Suitable carbohydrate excipients for use in the present invention include, for example, fructose, maltose, Monosaccharides such as lactose, galactose, glucose, D-mannose, and sorbose, Disaccharides such as sucrose, trehalose, and cellobiose, raffinose, melezitol, Polysaccharides such as maltodextrin, dextran, and starches, mannitol, xylitol, Lactitol, maltitol, lactitol, xylitol, sorbitol (glucitol), Preferred carbohydrates for use in the present invention include alditols such as myo-inositol. The compound additives are mannitol, trehalose, and raffinose.

[0127] The anti-IL-23 antibody composition may also include a buffering agent or pH adjusting agent, typically Buffers are salts prepared from organic acids or bases. Representative buffers include citric acid, Acids, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid salts The composition may be prepared using any of the following buffers: organic acid salts, tris, tromethamine hydrochloride, or phosphate buffers. Preferred buffers for use in are organic acid salts such as citric acid.

[0128] Furthermore, the anti-IL-23 antibody composition may contain polyvinylpyrrolidone, ficoll (a polymeric sugar), , dextrates (e.g., cyclodextrin, such as 2-hydroxypropyl-β-cyclodextrin) Chlorodextrin), polyethylene glycol, flavoring agent, antibacterial agent, sweetener, antioxidant, Antistatic agents, surfactants (e.g., polyisoprene such as "TWEEN 20" and "TWEEN 80") sorbates), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol The composition may include polymeric excipients / additives such as cellulose acetate (C10), cellulose acetate (C12), and chelating agents (e.g., EDTA).

[0129] These and other compounds suitable for use in anti-IL-23 antibody, portion or variant compositions according to the invention are and additional known pharmaceutical excipients and / or additives are known in the art, e.g. ``Remington: The Science & Practice of P. harmacy,” 19 th ed., Williams & Williams, (1 995), and "Physician's Desk Reference," 52 nd ed., Medical Economics, Montvale, NJ (1998) and JP 2004-102663, the disclosures of which are incorporated herein by reference in their entireties. Alternatively, additive materials may include carbohydrates (e.g., monosaccharides and alditols) and buffers (e.g., citric acid) or polymeric agents. Exemplary carrier molecules are mucopolysaccharides, hyaluronic acid, These may be useful for intra-articular delivery.

[0130] formulation As mentioned above, the present invention preferably uses a phosphate buffer solution containing saline or a selected salt. Stable formulations that are buffers, as well as stock solutions and formulations containing preservatives, and pharmaceutically acceptable and for pharmaceutical or veterinary use comprising at least one anti-IL-23 antibody in a formulation acceptable for administration. A suitable multi-use preserved formulation is provided. The preserved formulation comprises at least one phenanthrene in an aqueous diluent. cresol, m-cresol, p-cresol, o-cresol, chlorocresol, benzene alcohol, phenylmercuric nitrate, phenoxyethanol, formaldehyde, chlorobenzene Alcohol, magnesium chloride (e.g., hexahydrate), alkylparaben (methyl, ethyl , propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, dehydroacetic acid sodium, and thimerosal, or a mixture thereof. As known in the art, the present invention includes at least one known preservative. 0.001 to 5%, or any range or value therein, e.g., 0.001, 0.003 ,0.005,0.009,0.01,0.02,0.03,0.05,0.09,0. 1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1. 1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2. 1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3. 1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4. 3, 4.5, 4.6, 4.7, 4.8, 4.9, etc., or any range or value therein Any suitable concentration or mixture of may be used. Non-limiting examples include preservatives No additives, 0.1-2% m-cresol (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (e.g., 0.5, 0.9, 1 0.1, 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%), 0.0005~1.0% Alky Paraben (e.g., 0.00075, 0.0009, 0.001, 0.002, 0.0 05, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.0 9, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%) .

[0131] As mentioned above, the method of the present invention involves the use of packaging materials and, optionally, buffers formulated in an aqueous diluent. a solution of at least one anti-IL-23 specific antibody together with an agent and / or preservative; Also, one vial and a product containing this packaging material are used, and this solution is 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66 The present invention includes a label stating that the packaging can be preserved for 72 hours or more. a first vial containing a lyophilized anti-IL-23 specific antibody; and a formulated buffer. and a second vial containing an aqueous diluent of the buffer or preservative. The dressing contains anti-IL-23 specific antibodies reconstituted in an aqueous diluent, which are retained for more than 24 hours. The label includes a label instructing the patient to form a solution that can be administered intravenously.

[0132] The anti-IL-23 specific antibodies used in accordance with the present invention may be any of those described herein or of the Produced from mammalian cells or transgenic preparations known in the art It may be produced by recombinant means, including by recombinant DNA technology, or purified from other biological sources.

[0133] The range of anti-IL-23 specific antibodies is approximately 1.0 μg / mL for wet / dry systems upon reconstitution. It is included in an amount that will give a concentration of about 1000 mg / ml, but lower and higher concentrations are also available. The temperature can be varied and depends on the intended delivery vehicle; for example, in a solution formulation, the transdermal This is distinct from pulmonary, transmucosal, or osmotic or micropump methods.

[0134] Preferably, the aqueous diluent optionally further comprises a pharmaceutically acceptable preservative. New preservatives include phenol, m-cresol, p-cresol, o-cresol, and chloroform. Benzyl alcohol, alkylparaben (methyl, ethyl, propyl, butylparaben) Benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and and thimerosal, or a mixture thereof. The concentration of preservative used in the composition is sufficient to produce an antimicrobial effect. will vary depending on the preservative selected and is readily determined by one of skill in the art.

[0135] Other excipients, such as isotonicity agents, buffers, antioxidants, and preservative enhancers, are optional. An isotonic agent such as glycerin may be added to the diluent at a known concentration. Preferably, a physiologically tolerable buffer is added to improve pH. The formulation provides pH control from about pH 4 to about pH 10, and preferably from 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 6.8 to about 7.8. Suitable buffers include phosphate buffers, most preferably sodium phosphate, especially sodium phosphate buffers. Contains phosphate buffered saline (PBS).

[0136] Other additives, such as Tween 20 (polyoxyethylene (20) sorbitan mononitrate) laurate), Tween 40 (Polyoxyethylene (20) Sorbitan Monopalmitate Tween 80 (Polyoxyethylene (20) Sorbitan Monooleate), Pl Uronic F68 (Polyoxyethylene Polyoxypropylene Block Copolymer) and PEG (polyethylene glycol), or a pharmaceutically acceptable solubilizer. Resorbate 20 or 80 or Poloxamer 184 or 188, Pluroni Nonionic surfactants such as Polyl (registered trademark), other block copolymers Polymers and chelating agents such as EDTA and EGTA are optionally added to the formulation or composition. These additives can be added to reduce aggregation. This is particularly useful when a plastic or other container is used. The presence of the anti-inflammatory agent reduces the tendency of the protein to aggregate.

[0137] The formulation contains at least one anti-IL-23 antibody and phenol, m-cresol, p-cresol, Resole, o-cresol, chlorocresol, benzyl alcohol, alkylparaben (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride thimerosal, sodium dehydroacetate, and thimerosal, or a mixture thereof. and a preservative selected from the group consisting of: The mixture of at least one anti-IL-23 specific antibody and a preservative in an aqueous diluent can be This is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, e.g. A quantity of at least one anti-IL-23 specific antibody in a buffer solution is added to a desired concentration of the antibody. and a desired preservative in a sufficient amount of buffer solution to provide the protein and preservative. Variations on this process will be recognized by those skilled in the art, for example, the order of addition of components, The use of additional excipients, the temperature and pH during preparation of the formulation, all affect the dosage concentration and dose used. It is a factor that can be optimized for the given means.

[0138] The formulation may be prepared as a clear solution or in 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. A combination comprising a vial of lyophilized anti-IL-23 specific antibody, reconstituted in a vial of It can be provided to patients as a single solution vial or as a dual vial. Any dual vial requiring configuration can be reused multiple times and can be used in single or multiple This allows for a larger number of patient treatment cycles to be met, thus providing a more convenient treatment option than is currently available. A therapeutic regimen can be provided.

[0139] The product is useful for administration over a period ranging from immediate to 24 hours or more. The products claimed by this invention offer significant benefits to patients. Optionally, safe storage at temperatures between about 2°C and about 40°C may be performed to maintain the biological activity of the protein over time. The packaging label indicates the solution can be stored for 6, 12, 18, 24, or 36 hours. It may be noted that the composition may be retained and / or used for 48, 72, or 96 hours or more. If a stored diluent is used, such label shall be valid for a maximum of 1 to 12 months, 6 months, This may include up to one and a half and / or two years of use.

[0140] Solutions of anti-IL-23 specific antibodies are prepared by mixing at least one antibody in an aqueous diluent. The mixture can be prepared by a process comprising: To prepare a suitable diluent, for example, a small amount of water or buffer may be added. At least one antibody is provided in a solution containing the desired concentration of protein, and optionally a preservative or buffer. Variations on this process will be recognized by those skilled in the art. For example, the order of addition of the components, whether additional excipients are used, the temperature and p H are all factors that can be optimized with respect to the dosage concentration and means of administration used.

[0141] The claimed product is available as a clear solution or in a second vial containing an aqueous diluent. at least one lyophilized vial of anti-IL-23 specific antibody, which is reconstituted in a It can be provided to patients as a single solution vial or as a combination vial containing Each required dual vial can be reused multiple times and can be used for single or multiple patients. treatment cycles and therefore more convenient treatment regimes than are currently available. Provides a

[0142] The claimed product is a clear solution or a second vial containing an aqueous diluent. a combination comprising a vial of at least one lyophilized anti-IL-23 specific antibody, By providing vials to pharmacies, clinics, or other such institutions and facilities; It can be given indirectly to the patient, in which case the clear solution can be given in a volume of up to 1 liter or more. The container may contain a larger volume, and from this larger container, a smaller volume of at least one anti- The solution is withdrawn one or more times and transferred to a smaller vial and distributed by the pharmacy or clinic. can be provided to customers and / or patients.

[0143] Approved devices that include single-vial systems include pens for delivering solutions. syringe devices, e.g., BD Pens, BD Autojector®, Humaject®, NovoPen®, B-DPen® ), AutoPen®, and OptiPen®, Genotrop inPen(R), Genotronorm Pen(R), Humatr o Pen(R), Reco-Pen(R), Roferon Pen(R) (registered trademark), Biojector (registered trademark), Iject (registered trademark), J-tip N needle-Free Injector (registered trademark), Intraject (registered trademark) ), Medi-Ject (registered trademark), Smartject (registered trademark), etc. (Bect on Dickensen (Franklin Lakes, NJ, www.becto ndickenson.com), Disetronic (Burgdorf, Swit) zerland, www.disetronic.com), Bioject(Port land,Oregon(www.bioject.com), National Me dical Products,Weston Medical(Peterboro gh, UK, www.weston-medical.com), Medi-Ject Corp (Minneapolis, MN, www.mediject.com) (manufactured or developed by the company) and similar suitable devices. Recognized devices, including IV systems, include cryopreservation devices for delivering reconstituted solutions. Pen-type syringe systems for reconstituting syrup-dried drugs in cartridges, e.g., Hum Other suitable devices include the atroPen® and the like. These include pre-filled syringes, auto-injectors, needleless syringes, and needleless IV infusion sets. can be.

[0144] The product may contain packaging, which may contain information required by regulatory authorities as well as The packaging material of the present invention, when applicable, provides the conditions under which the product can be used. At least one anti-IL-23 antibody is reconstituted with an aqueous diluent to form a solution, and the solution is incubated for 2 to 24 hours. Over the above period, this solution will be used for two vial products, wet and dry. Provide instructions to patients. Single vial solution product, prefilled syringe, or self-administered In the case of syringes, the label should state that such solutions should be used for a period of not less than 2 to 24 hours. This product is useful for human pharmaceutical product applications.

[0145] The formulations used in the methods of the present invention comprise an anti-IL-23 antibody and a selected buffer, preferably a process comprising mixing saline or a phosphate buffer containing a selected salt. The anti-IL-23 antibody and the buffer may be mixed in an aqueous diluent by Conventional dissolution and mixing procedures are used to prepare suitable formulations, e.g. A quantity of at least one antibody in water or buffer is added to the desired concentration of protein and buffer. and the desired buffer in a quantity of water sufficient to provide. A variation of this process is For example, the order of addition of the components, whether or not additional additives are used, etc. The temperature and pH of the formulation are all optimized for the dosage concentration and means of administration used. This is a factor that can be used.

[0146] The methods of the present invention involve administering various useful and acceptable The present invention provides a pharmaceutical composition comprising the formulation. Such pharmaceutical compositions may contain "standard" of water and routine methods well known to those skilled in the art. A buffering component such as histidine monohydrochloride hydrate is provided first, followed by an appropriate non-final volume of "Standard" amounts of water diluent, sucrose, and polysorbate 80 may be added. Finally, the isolated antibody can be added using water as a diluent. The volume of the pharmaceutical composition is adjusted to the desired final volume under "quasi-state" conditions. Several other methods suitable for preparing pharmaceutical compositions are recognized.

[0147] The pharmaceutical compositions contain the indicated mass of each component per volume unit of water or are "standardized" in the As used herein, the term "aqueous solution" refers to an aqueous solution or suspension having a pH indicated by the "state." In this context, the term "standard conditions" means a temperature of 25°C ± 2°C and a pressure of 1 atmosphere. The term "substate" is used in the art to refer to a single art-recognized temperature or is used to refer to a set of pressures, rather than to refer to "standard state" conditions Specify the temperature and pressure used to describe a solution or suspension containing a particular composition This is the reference condition because the volume of a solution is in part a function of temperature and pressure. Those skilled in the art will appreciate that equivalent pharmaceutical compositions to those disclosed herein can be produced at other temperatures and pressures. It is recognized that such pharmaceutical compositions can be produced in the same manner as disclosed herein. The above-defined "standard state" conditions (e.g., 25°C ± 2°C and 1 atmosphere) pressure) should be determined.

[0148] Importantly, such pharmaceutical compositions contain "about" a certain amount of hydroxybenzoate per unit volume of the pharmaceutical composition. (e.g., "about 0.53 mg of L-histidine"), or The pH value of the pharmaceutical composition may be about a certain value. The isolated antibody may be administered while in a pharmaceutical composition or after the isolated antibody has been in a pharmaceutical composition. After removal from the pharmaceutical composition (e.g., by dilution), the isolated antibody present in the pharmaceutical composition The number given is "about" the number of times that the component can be bound to a peptide chain. The mass value or pH value of the isolated antibody after it is incorporated into a pharmaceutical composition. A given value is "about" if the binding activity of the antibody is maintained and detectable.

[0149] Competitive binding assays were performed to determine whether IL-23-specific mAbs bind to similar or different epitopes. Determine whether Abs bind and / or compete with each other. Competing mAb is added, followed by biotinylated hrIL-23. For positive controls, the same mAb was used as a competitor mAb ("self-competition") for coating. IL-23 binding may be detected using streptavidin. The results will determine whether the mAbs recognize similar or partially overlapping epitopes on IL-23. Indicates whether

[0150] In one embodiment of the pharmaceutical composition, the isolated antibody concentration is about 7 mL per mL of pharmaceutical composition. In another embodiment of the pharmaceutical composition, the pH is about 5.5 to about 6.5. be.

[0151] Stable or preserved formulations may be prepared as clear solutions or in aqueous diluents without preservatives or buffers. and a second vial containing at least one lyophilized anti-I antibody. It can be provided to the patient as a dual vial containing a vial of the L-23 antibody. Either single solution vials or dual vials requiring reconstitution are reused multiple times. can satisfy single or multiple patient treatment cycles and therefore are This provides a more convenient treatment regimen than is currently available.

[0152] Another formulation or method for stabilizing an anti-IL-23 antibody is to form a clear solution of a lyophilized powder containing the antibody. Non-transparent solutions include formulations containing microparticle suspensions, Such microparticles may be microspheres, microparticles, nanoparticles, nanospheres, or liposomes. and compositions containing anti-IL-23 antibodies in structures of various sizes known variously as Such relatively homogeneous, essentially spherical microparticle formulations containing an active agent are disclosed in U.S. Pat. As taught in US Pat. No. 5,589,330, an aqueous phase containing an active agent and a polymer and a non-aqueous phase and then evaporating the non-aqueous phase to cause coalescence of the particles from the aqueous phase. Porous microparticles can be formed as taught in U.S. Pat. No. 4,818,542. As described above, a first phase containing an active agent and a polymer dispersed in a continuous solvent is used, Prepared by removing this solvent from the suspension by freeze-drying or dilution-extraction-precipitation. Preferred polymers for such preparations are gelatin, agar, starch, arabinogalactose, Cutaneous, Albumin, Collagen, Polyglycolic Acid, Polylactic Acid, Glycolide-L(-) Lactide Poly(epsilon-caprolactone), Poly(epsilon-caprolactone-CO -lactic acid), poly(epsilon-caprolactone-co-glycolic acid), poly(β-hydroxybenzoate) Poly(alkyl-2-cyanoacrylate), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate), acrylate), poly(hydroxyethyl methacrylate), polyamide, poly(amino acid) , poly(2-hydroxyethyl DL-aspartamide), poly(ester urea), poly (L-phenylalanine / ethylene glycol / 1,6-diisocyanatohexane) and natural or synthetic copolymers selected from the group consisting of poly(methyl methacrylate) or is a polymer. Particularly preferred polymers are polyglycolic acid, polylactic acid, glycolide -L(-) lactide poly(epsilon-caprolactone), poly(epsilon-caprolactone) Poly(epsilon-co-lactic acid), and poly(epsilon-caprolactone-co-glycolic acid) It is a polyester that is useful as a solvent to dissolve the polymer and / or the active substance. For example, water, hexafluoroisopropanol, methylene chloride, tetrahydrofuran, hexafluoroisopropanol, Active ingredient: acetone, benzene, or hexafluoroacetone sesquihydrate. The process of dispersing a first phase into a second phase is accomplished by forcing the first phase through an orifice in a nozzle with pressure. The method can include influencing droplet formation through

[0153] Dry powder formulations can be prepared, for example, by spray drying or solvent extraction by evaporation or by aqueous or or precipitation of the crystalline composition followed by one or more steps to remove the non-aqueous solvent. It may also be obtained as a result of processes other than freeze-drying, such as solvent extraction by spray-drying. The preparation of antibody-based formulations is taught in U.S. Patent No. 6,019,968. The powder composition provides a solution or slurry of the antibody and, optionally, a respirable dry powder. The excipients may be produced by spray drying the excipients in a solvent under conditions for Examples include polar compounds such as water and ethanol, which can be easily dried. The stability of the compound can be improved by carrying out the spray drying procedure in the absence of oxygen, e.g., under a nitrogen blanket. This can be enhanced by using nitrogen as a drying gas or another relatively dry The formulations are typically hydrofluoroalkanes such as those taught in WO 9916419. A dispersion of a plurality of porous microstructures dispersed in a suspension medium containing a can propellant. The resulting dispersion can be administered to the patient's lungs using a metered dose inhaler. Equipment useful in industrial manufacturing is manufactured by Buchi Ltd. or Niro Corp. It is constructed.

[0154] anti-IL-23 antibodies in either a stable or preserved formulation or in solution as described herein The present invention can be administered by SC or IM injection, transdermal, pulmonary, mucosal, implanted, or other suitable route, as is well known in the art. pump, osmotic pump, cartridge, micropump, or other pump as would be understood by one of ordinary skill in the art. Administration to a patient in accordance with the present invention can be via a variety of delivery methods, including by means of a

[0155] Therapeutic applications The present invention also provides a method for producing a compound comprising the steps of: The IL-23 antibodies of the present invention can be used to, for example, in a cell, tissue, organ, animal, or patient. A therapeutically effective amount of an IL-23 specific antibody is administered or contacted to a cell, tissue, organ, animal, or provides a method for modulating or treating Crohn's disease in a patient.

[0156] Any of the methods of the present invention may be used to treat cells, tissues, or tissues in need of such modulation, treatment, or therapy. administering to the organism, animal, or patient an effective amount of a composition or pharmaceutical composition comprising an anti-IL-23 antibody. Such methods may optionally include a concurrent use of a therapeutic agent for the treatment of such a disease or disorder. The administration or combination therapy may further comprise administering the at least one anti-IL-23 antibody. Administering the body, specific parts thereof, or variants thereof may include administering at least one TNF antagonist (e.g., For example, but not limited to, chemical or protein TNF antagonists, TNF monoclonal antibodies, monoclonal or polyclonal antibodies or fragments, soluble TNF receptors (e.g., p55 , p70, or p85) or fragments, fusion polypeptides thereof, or small molecule TNF antagonists , e.g., TNF-binding protein I or II (TBP-1 or TBP-II), Nerelimo infliximab, etanercept (Enbrel™), Adalimumab (Humira™), CDP-571, CDP-870, Afelim Mab, Lenercept, etc.), antirheumatic drugs (e.g., methotrexate, auranofin , aurothioglucose, azathioprine, sodium gold thiomalate, hydroxysulfate chloroquine, leflunomide, sulfasalazine), muscle relaxants, narcotics, nonsteroidal anti-inflammatory drugs Anti-inflammatory drugs (non-steroid anti-inflammatory drugs, NSAIDs), analgesics, anesthetics, sedatives, Local anesthetics, neuromuscular blockers, antibacterials (e.g., aminoglycosides, antifungals, antiparasitics) , antivirals, carbapenams, cephalosporins, fluoroquinolones, macrolides, Penicillins, sulfonamides, tetracyclines, and other antibacterial agents, psoriasis medications, corticosteroids Corticosteroids, anabolic steroids, diabetes-related drugs, minerals, nutritional drugs, thyroid medications, Vitamins, calcium-related hormones, antidiarrheals, antitussives, antiemetics, antineoplastics, laxatives, anticoagulants 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, antimetabolites, mitotic inhibitors, radiopharmaceuticals, antidepressants, Antimanic drugs, antipsychotic drugs, antianxiety drugs, sleeping pills, sympathomimetics, stimulants, donepezil, tacrine antiasthma medications, beta-agonists, inhaled steroids, leukotriene inhibitors, methylquinone Santin, cromolyn, epinephrine or analogues, dornase alfa (Pulmozyme ), a cytokine or a cytokine antagonist, Suitable dosages may be determined by methods known in the art. See, for example, Wells et al., eds., Pharmacothe rapy Handbook, 2 nd Edition, Appleton and L ange, Stamford, CT (2000), PDR Pharmacopoeia ,Tarascon Pocket Pharmacopoeia 2000,Delu xe Edition, Tarascon Publishing, Loma Lind a, CA (2000), Nursing 2001 Handbook of Drugs. s,21 st edition,Springhouse Corp.,Springh ouse, PA, 2001, Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Pren. See Tice-Hall, Inc., Upper Saddle River, NJ Each of these references is incorporated herein by reference in its entirety.

[0157] Treatment Typically, treatment of Crohn's disease involves administering an effective amount or dosage of an anti-IL-23 antibody composition. This is affected by the specific activity of the active agent contained in the composition. , in total, on average, at least about 0.01 to 5 per kilogram of patient per administration. 000 milligrams of anti-IL-23 antibody, preferably in the range of 000 milligrams per single or multiple dose. That is, at least about 0.1 to 100 milligrams of antibody per kilogram of patient. Alternatively, the effective serum concentration is 0.1 to 5000 μg / mL of serum per single or multiple dose. Suitable dosages will be known to medical practitioners and will, of course, depend on the particular The therapeutic effect of the compound will depend on the underlying disease state, the specific activity of the composition being administered, and the particular patient undergoing treatment. In some cases, repeated administration, i.e., specific monitoring, may be required to achieve the desired therapeutic dose. It may be necessary to provide repeated individual doses of monitored or metered doses. In this case, the individual administrations are repeated until the desired daily dose or effect is achieved.

[0158] Preferred dosages are optionally 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 4 0, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 , 54, 55, 56, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 8 1, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 , 95, 96, 97, 98, 99, and / or 100-500 mg / kg / dose, or may include any range, value, or percentage thereof, or may be administered in single or multiple doses. 0.1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9, 2.0, 2. 5, 2.9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5. 9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9. 0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 20, 1 2.5, 12.9, 13.0, 13.5, 13.9, 14.0, 14.5, 4.9, 5. 0, 5.5, 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8 .5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 12, 12.5, 12.9, 13.0, 13.5, 13.9, 14, 14.5 , 15, 15.5, 15.9, 16, 16.5, 16.9, 17, 17.5, 17.9, 18, 18.5, 18.9, 19, 19.5, 19.9, 20, 20.5, 20.9, 2 1, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50 , 55, 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2 500, 3000, 3500, 4000, 4500, and / or 5000 μg / mL The serum concentration of the present invention may be included to achieve a serum concentration of, or any range, value, or percentage thereof. .

[0159] Alternatively, the dose administered may be determined based on the pharmacodynamic characteristics of the particular drug and its method and route of administration. , the recipient's age, health status and weight, the nature and severity of symptoms, the type of concurrent treatment, the frequency of treatment, The dosage of the active ingredient may vary depending on known factors such as the amount of the active ingredient administered and the desired effect. It can be about 0.1 to 100 milligrams per kilogram of weight. Usually, it is 0.1 to 50, preferably Preferably, 0.1 to 10 milligrams / kilogram / dose, or sustained release form, is used to achieve the desired results. It is effective to obtain

[0160] By way of non-limiting example, treatment of humans or animals may be achieved using a single dose, intravenous administration, or multiple doses. Use 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 2 9th, 30th, 31st, 32nd, 33rd, 34th, 35th, 36th, 37th, 38th, 39th or 40th day On at least one of the following days, or in addition, 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 3 6, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 1, or in at least one of weeks 50, 51, or 52, or in addition, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, At least one of the 18th, 19th, or 20th years, or any combination thereof 0.1 to 100 mg / kg per day, e.g., 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90, or 100 mg / kg of the compound of the present invention It may be provided as a single or periodic dose of at least one antibody.

[0161] Dosage forms (compositions) suitable for internal administration generally contain about 0.001 ml of the active ingredient per unit or container. These pharmaceutical compositions contain 100 mg to about 500 mg of the active ingredient. The component is typically present in an amount of about 0.5 to 99.999% by weight, based on the total weight of the composition. .

[0162] For parenteral administration, the antibody may be administered in combination with or separately from a pharmaceutically acceptable parenteral vehicle. Individually provided as a solution, suspension, emulsion, particles, powder, or lyophilized powder. Examples of such vehicles include water, saline, Ringer's solution, dextrose, and the like. The non-volatile oils and liposomes are used as the bases for the formulation. An aqueous vehicle can also be used. The vehicle or lyophilized powder must be isotonic and chemically stable. Additives to maintain consistency (e.g., sodium chloride, mannitol, and For stability, buffers and preservatives may be included. The formulation may be prepared using any known or suitable method. sterilized by appropriate techniques.

[0163] Suitable pharmaceutical carriers are described in Remington's Pharmaceuticals, a standard reference text in this field. This is described in the latest edition of A. Osol's Journal of Medical Sciences.

[0164] Alternative administration In order to administer a pharmaceutically effective amount of an anti-IL-23 antibody, many known and well-known methods can be used in accordance with the present invention. The method developed can be used. In the following description, pulmonary administration is used, Other modes of administration may be used in accordance with the present invention with suitable results. The specific antibody may be present in the carrier as a solution, emulsion, colloid or suspension, or dried. As a dry powder, by inhalation, or as described herein or in the art. using any of a variety of devices and methods suitable for administration by other methods known in the art; can be delivered.

[0165] Parenteral Formulation and Administration Parenteral formulations are typically made with 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 according to known methods using suitable emulsifying agents or wetting agents and Injectable solutions can be prepared by using, for example, aqueous solutions, sterile solutions, and suspensions. It can be a non-toxic parenterally administrable diluent such as an injection solution or a suspension in a solvent. Usable vehicles or solvents include water, Ringer's solution, isotonic saline, etc. As a usual solvent or suspending medium, sterile fixed oils can be used. For the purposes of this application, natural, synthetic or semi-synthetic fatty oils or fatty acids, natural, synthetic or semi-synthetic Any kind of undesirable substance, including synthetic monoglycerides, diglycerides or triglycerides Volatile oils and fatty acids can be used. Parenteral administration is well known in the art. The conventional injection means is a gas-pressurized needleless injection device as described in U.S. Pat. No. 5,851,198. and the laser drilling device described in U.S. Pat. No. 5,839,446. These include, but are not limited to, those incorporated herein by reference in their entireties. can be.

[0166] alternative delivery The present invention further provides parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraabdominal, intracapsular, soft tissue, Intraosseous, intrasinus, intracavity, intracerebellum, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intrabone, Intrapelvic, pericardial, abdominal, pleural, prostatic, pulmonary, rectal, renal, retinal, spinal cord, and rectal cavity Intravesical, intrathoracic, intrauterine, intravesical, intralesional, bolus, intravaginal, rectal, oral, sublingual, nasal The present invention relates to the administration of anti-IL-23 antibodies by intravenous or transdermal means. in the form of a liquid solution or suspension, parenterally (subcutaneously, intramuscularly, or intravenously) or any other In particular, but not limited to, creams and suppositories for use in administering For use in vaginal or rectal administration, not in semi-solid form, tablets or capsules For oral or sublingual administration, or as a powder, in forms such as, but not limited to, nasal sprays or aerosols, or certain medications, but are not limited to In the form of intranasal or transdermal patches, Chemical enhancers such as dimethyl sulfoxide are used to either induce Junginger, et al., "Dru g Permeation Enhancement;” Hsieh, DS, Eds. .,pp.59-90(Marcel Dekker,Inc.New York 19 94), or the application of preparations containing proteins and peptides to the skin (WO 98 / No. 53847), or for creating a transient delivery pathway, such as electroporation, or application of an electric field to increase the mobility of charged drugs through the skin, such as ontophoresis; or the application of ultrasound, such as sonophoresis (U.S. Pat. Nos. 4,309,989 and 4,766,769). 7,402) and the like. It can be formulated for transdermal use, such as in a lotion, suspension, or patch delivery system. (The above publications and patents are incorporated herein by reference in their entireties.)

[0167] 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 disclosure of which is expressly incorporated herein by reference.

[0168] Embodiment The present invention provides the following non-limiting embodiments. 1. A method of treating Crohn's disease in a patient, comprising administering to a subject an antibody specific for IL23. An initial subcutaneous administration of 0 mg, followed by a subcutaneous administration of 400 mg approximately 4 weeks after the initial administration, and administering to the patient a subcutaneous dose of 400 mg about 8 weeks after the first dose. 2. 100 mg or 200 mg of antibody administered at about 8 weeks, followed by administration at about every 4 weeks or about every 8 weeks 2. The method of embodiment 1, further comprising administering 3. Further comprising administering 200 mg of the antibody about every 4 weeks after the administration at about 8 weeks. 3. The method of embodiment 2. 4. Further comprising administering 100 mg of the antibody about every 8 weeks after the administration at about 8 weeks. 3. The method of embodiment 2. 5. The patient is a responder to the antibody and achieves clinical endpoint approximately 12 weeks after the first dose. The clinical endpoint was identified as meeting the criteria for a CDAI of 150 points. Clinical remission at 12 weeks, defined as less than (<) 1 point, or Crohn's disease abruption endoscopy Measured by at least a 50% improvement from baseline in score (SES-CD). 2. The method of embodiment 1, wherein the endoscopic response is determined as endoscopic response. 6. The patient is identified as meeting the clinical endpoint and Patients were randomly assigned to receive the steroids if (i) their CDAI measured approximately 24 weeks after the first dose was less than 150 points (< (ii) clinical remission defined as a mean daily stool frequency (SF) ≤ 3 and a mean daily abdominal Pain (AP) score ≤ 1, and from baseline measured approximately 12 weeks after the first dose Patient-reported outcome (PRO)-2 remission, defined as no worsening of AP or SF and (iii) the CDAI score measured approximately 12 weeks after the first administration. Consists of a clinical response defined as a ≥100-point reduction from baseline 2. The method of embodiment 1, selected from the group: 7. The antibody comprises a light chain variable region and a heavy chain variable region, and the light chain variable region is the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4; the CDRL2 amino acid sequence of SEQ ID NO: 5, and comprising the CDRL3 amino acid sequence of SEQ ID NO:6, the heavy chain variable region is 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 antibody comprises the CDRH3 amino acid sequence of SEQ ID NO: 3, and the patient is a responder to the antibody. 2. The method of embodiment 1, wherein the method is considered to be 8. The patient is a responder to the antibody and meets one of the following clinical endpoints: (i) change from baseline in Crohn's Disease Activity Index (CDAI) score; (ii) clinical remission, defined as a CDAI of less than (<) 150 points; (iii) A decrease of 100 points or more from baseline in the CDAI score clinical response defined as or CDAI score <150; (iv) defined based on the mean daily stool frequency (SF) and mean daily abdominal pain (AP) scores; Patient-reported outcome (PRO)-2 remission; (v) Clinical response based on CDAI score and C-reactive protein (CRP) or fecal color Clinical biomarkers, defined using a decrease from baseline in leprotectin Carr's success; (vi) Endoscopic success, as measured by the Simplified Endoscopic Score for Crohn's Disease (SES-CD) Gong; (vii) Endoscopy, as measured by the Simplified Endoscopy Score for Crohn's Disease (SES-CD) Targeted remission; (viii) CDAI < 15 for the majority of all visits between Weeks 12 and 48 sustained clinical remission at week 48, defined as 0; (ix) CDAI score <150 at Week 48 and COLLECT at Week 48 Corticosteroid-naïve patients at week 48 were defined as those not receiving corticosteroids. Id-free clinical remission; (x) fatigue response based on the Patient-Reported Outcomes Measurement Information System (PROMIS); and (xi) Endoscopic success, as measured by the Simplified Endoscopic Score for Crohn's Disease (SES-CD) Success 8. The method of embodiment 7, wherein the method is identified as satisfying 9. The clinical endpoint is at 4, 8, 12, 16, 20, 28, 32, or 48 days after initial treatment. 9. The method of embodiment 8, wherein the measurement is after 36, 40, 44, and / or 48 weeks. 10. The antibody is a pharmaceutical composition containing 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) poly sorbate 80, and the diluent is water at normal conditions. How to post. 11. Patient is receiving one or more additional medications used to treat Crohn's disease. 2. The method of embodiment 1, further comprising: 12. The additional drug is an immunosuppressant, a non-steroidal anti-inflammatory drug, or -inflammatory drugs, NSAIDs), methotrexate (MTX), B cell surface marker antibody, anti-CD20 antibody, rituximab, TNF inhibitor, corticosteroid 12. The method of embodiment 11, wherein the agonist is selected from the group consisting of an agonist, an antagonist, an antagonistic agent ... 13. The antibody comprises a light chain variable region amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region amino acid sequence of SEQ ID NO: 7. 2. The method of embodiment 1, comprising a region amino acid sequence. 14. The antibody has a light chain amino acid sequence of SEQ ID NO: 10 and a heavy chain amino acid sequence of SEQ ID NO: 9. 2. The method of claim 1, comprising a column. 15. The patient has not responded to or is intolerant to biologic therapy for Crohn's disease (Bio-nonresponse). 2. The method of embodiment 1, wherein the method is considered to be 16. The patient is considered to be unresponsive or intolerant to conventional therapy for Crohn's disease (Con non-response). 2. The method of embodiment 1, wherein 17. The method of embodiment 1, wherein the Crohn's disease is moderately to severely active Crohn's disease. How to post. 18. The patient has endoscopic evidence of active Crohn's disease prior to administration of the first dose. 18. The method of embodiment 17. 19. The patient has had moderate to severe activity for at least 3 months prior to the administration of the first dose. 18. The method of embodiment 17, wherein the patient has Crohn's disease. 20. A method for treating moderately to severely active Crohn's disease in a patient, comprising administering to the patient: ) An initial subcutaneous administration of 400 mg of an antibody specific for IL23, followed by 4 weeks after the initial administration. Patients were administered a subcutaneous dose of 400 mg, followed by a subcutaneous dose of 400 mg approximately 8 weeks after the initial dose. (ii) administering a 200 mg dose of antibody at about 8 weeks and thereafter about every 4 weeks thereafter; and administering a 100 mg dose of the antibody at about 8 weeks thereafter about every 8 weeks thereafter. and the antibody has a light chain variable region amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region amino acid sequence of SEQ ID NO: 7. The patient achieves a clinical endpoint approximately 12 weeks after the first administration. By being identified as meeting the criteria, the patient is deemed to be a responder to the antibody and has met the criteria for the clinical endpoint. Endpoint at week 12, defined as a CDAI < 150 points Clinical remission or Simplified Endoscopic Score for Crohn's Disease (SES-CD) from baseline wherein the endoscopic response is measured by at least a 50% improvement in [Example]

[0169] Example 1 Preclinical evidence implicating IL-23 as a target in Crohn's disease Genetic and animal model studies implicate IL-1 in driving the pathophysiology of Crohn's disease The contribution of IL-2 and IL-23 to inflammatory bowel disease (IBD) was investigated. Emerging evidence suggests that blocking IL-23 alone can reduce IL-1 expression. These results suggest that blocking both IL-12 and IL-23 may be a more effective strategy than blocking both IL-12 and IL-23. do.

[0170] Early observations from genetic and animal model data suggest that Crohn's disease may potentially be due to IL-1 IL-1 and IL-23 induce Th1 and Th17 pathways, respectively. These results suggest that the effect is mediated by IL-2 and / or IL-23. Increasing evidence suggests that IL-23 plays a key role in cancer. A gene-wide association study identified a polymorphism in the IL-23R gene associated with Crohn's disease. The role of IL-23 in driving intestinal inflammation has been demonstrated in several mouse models. Mice treated with IL-23 antibody showed attenuated inflammation and increased expression of the p19 subunit of IL-23. Mice with a genetic deletion of β-lactamase are protected in several models of intestinal inflammation.

[0171] Clinical experience with IL-12 / 23-targeted therapy (ustekinumab) in Crohn's disease The Phase 3 program for ustekinumab in Crohn's disease includes intravenous ustekinumab Two 8-week studies evaluating the efficacy and safety of intravenous (IV) delivery; and Subcutaneous (SC) maintenance administration of ustekinumab over a total treatment period of 52 weeks The study included one maintenance trial evaluating efficacy and safety. Ustekinumab is effective in treating Crohn's disease. Biologically eligible patients, i.e., patients who have failed conventional therapy and those who are currently receiving biologic therapy, The full range of patients who did not respond was evaluated. At week 0, ustekinumab was administered at approximately 6 mg / kg. After a single IV induction dose of Approximately 21% and 40% (compared to approximately 7% and 20%, respectively, of placebo-treated participants) Clinical remission was achieved at week 1 (assessed by Crohn's Disease Activity Index [CDAI]). Patients were successfully IV-initiated and re-randomized to receive 90 mg every 8 weeks (q8w) or 90 mg every 12 weeks (q8w). Among participants who received weekly (q12w) ustekinumab SC maintenance therapy, Approximately 53% and 49% of participants receiving placebo maintenance achieved 52 weeks of treatment compared with 36% of participants receiving placebo maintenance. The patient was in clinical remission.

[0172] Clinical experience with IL-23-targeted therapy in Crohn's disease First, IL-12 / 23p40 antagonists (briakinumab and ustekinumab) Clinical trials have established the potential therapeutic role of IL-23 in Crohn's disease. Sutekinumab (STELARA®) has recently been shown to treat moderately to severely active clonal These programs target IL-12 and IL-23. Both blockades have been shown to be effective in treating Crohn's disease, but they operate at two sites The relative contribution of Cain could not be determined.

[0173] Two anti-IL-23 antagonists, risankizumab (formerly BI-655066) and Recent studies of brazikumab (formerly MEDI2070, AMG 139) and brazikumab showed moderate to severe cerebrospinal fluid smears. Efficacy, clinical signs, and efficacy of IL-23 blockade in participants with moderate to severe active Crohn's disease Improvement of signs and symptoms, reduction of inflammatory biomarkers, and primarily in biologically resistant Crohn's disease Phase 2 results reported demonstrating efficacy in improving endoscopic findings in participants with The magnitude of efficacy observed in each of these trials was greater with ustekinumab (anti-IL- 12 / 23), and showed the potential for improved efficacy compared with crossover comparisons and relatively small The limitations of small Phase 2 IL-23 trials are recognized.

[0174] A crossover comparison of clinical remission rates with IL-23 blockade compared with ustekinumab showed improved These results suggest the possibility of improved efficacy. In both studies, The induction dose used was the approved ustekinumab dose (approximately 6 mg / kg IV at week 0). It is noteworthy that the number of cross-sectional meta-analyses was significantly higher than that of the Lisanki study. This suggests that administering izumab may result in a higher endpoint of the dose-response curve.

[0175] Furthermore, a phase 2 study with risankizumab also showed that response rates were maximal after 6 months of treatment. The study suggested that the dose may not be reached. With a dose of 0 mg IV, a clinical remission rate of approximately 50% was observed in all treated patients. and other studies containing ustekinumab in similar study populations at similar follow-up times. This was significantly higher than previously reported remission rates for the drug. Of participants who continued maintenance treatment (180 mg SC q8w), approximately 70% achieved remission within one year. did.

[0176] Currently, the GALAXI clinical program is investigating the efficacy and safety of GALAXI compared to previous conventional or biologic therapies. Participants with moderately to severely active Crohn's disease who demonstrated an adequate response or poor tolerance In this study, we evaluated an intravenous (IV) induction dose of guselkumab followed by a subcutaneous (SC) maintenance dose. There are three separate trials under the GALAXI protocol (Phase 2 G GALAXI 1 and Phase 3 trials GALAXI 2 and GALAXI 3. Results from Study 1 show that IV guselkumab induction demonstrated major clinical efficacy at 12 weeks showed greater improvements compared with placebo across sexual and endoscopic outcome measures. Indicates that.

[0177] Comprehensive Rationale for Guselkumab in Crohn's Disease In summary, genetic and preclinical evidence are combined to explore the underlying pathophysiology of IBD. This suggests a significant role for selective targeting of IL-23 in the node. Available clinical experience with two IL-23 antagonists and approved IL-12 / 23 antagonists (U) Established evidence from sutekinumab and IL-2 in the treatment of Crohn's disease, respectively This study demonstrates proof of mechanism and proof of concept for targeting 3. Available evidence provides support for investigating guselkumab in the treatment of Crohn's disease. Provide.

[0178] In the current trial, the sponsor's interest is in the use of guselk for the induction phase of Crohn's disease treatment. The objective of this study was to evaluate SC administration of mabs. Subcutaneous delivery of biological agents is expected to be an important advance across many disease areas. SC and IV routes of administration have become valuable alternatives to IV administration. Although the cokinetic and PK profiles differ, SC administration is effective, safe, and well tolerated. It has been proven to be well tolerated and is administered to patients in a favorable environment for the patient or their caregiver. It allows for greater flexibility in administration and is easier for the patient or their caregiver to administer. SC administration is generally preferred by patients and healthcare providers due to its ease of administration. In summary, SC administration is more invasive and , making it an attractive alternative to time-consuming IV infusions.

[0179] The results of GALAXI 1 and the potential benefits of SC-guided administration to patients and healthcare systems Considering this, the aim of this study was to evaluate the efficacy and safety of steroids in participants with moderate to severe active Crohn's disease. Efficacy, safety, and PK / pharmacodynamics of guselkumab SC induction compared to placebo The aim is to evaluate the PD (physical dynamics) profile.

[0180] Clinical Protocol Protocol Title-GRAVII Efficacy of subcutaneous guselkumab induction therapy in participants with moderately to severely active Crohn's disease A randomized, double-blind, placebo-controlled, parallel-group, multicenter trial to evaluate efficacy and safety Experience

[0181] Synopsis Short Title: Subcutaneous guselkumab induction in participants with moderately to severely active Crohn's disease Phase 3 trials to evaluate the efficacy and safety of the therapy

[0182] Throughout the protocol, the term "study intervention" refers to the study medication.

[0183] Objectives and Endpoints The objective of this study is to evaluate the efficacy of guselkumab SC in moderately to severely active Crohn's disease. The endpoint at week 12 was the combined guselkumab induction group. (guselkumab 400 mg SC at weeks 0, 4, and 8) compared with placebo The 24-week endpoint was based on the data from each guselkumab group (weeks 0, 4, and 8). guselkumab 400 mg SC in one arm, followed by guselkumab 200 mg SC in the other arm in the other group, 100 mg SC every 4 weeks [q4w] and 100 mg SC every 8 weeks [q8w]) versus placebo. The tertiary endpoints are based on a comparison with the control group. Analyses will be performed at applicable time points up to 24 weeks. do.

[0184] [Table 2]

[0185] hypothesis The co-primary hypothesis of this study was that among participants with moderate to severe active Crohn's disease: Guselkumab was superior to placebo in inducing clinical remission at week 12, Cumab was superior to placebo in inducing endoscopic response at 12 weeks. be.

[0186] Overall Plan This is a randomized controlled trial to evaluate the efficacy and safety of subcutaneous (SC) induction administration of guselkumab. This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study. The target population is radiographic, histological, and Colitis, ileitis, or ileitis previously confirmed by histology and / or endoscopy Adults with moderate to severely active Crohn's disease (lasting at least 3 months) with ileocolitis To be eligible for the study, participants must have endoscopic evidence of active Crohn's disease. There must also be evidence of previous conventional therapy (oral corticosteroids or immunomodulatory agents). Zathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [ MTX]; CON non-response) or biologic therapy (infliximab, adalimumab, certobacter Lizumab pegol, vedolizumab, or approved biosimilars of these agents; B Inadequate response or poor tolerance to IO (non-response) must be demonstrated.

[0187] Two groups based on prior treatment involving the target population are briefly described below.

[0188] Non-response or intolerance to conventional therapy (CON non-response) Participants were receiving the following conventional Crohn's disease therapy: oral corticosteroids (prednisone, desonide, and beclomethasone dipropionate) or the immunomodulator azathioprine (AZA), 6-mercaptopurine (6-MP), or methotrexate (MTX) had an inadequate response to or was poorly tolerated by at least one of these It is necessary to do so.

[0189] Corticosteroid dependence (i.e., successful treatment without recurrence of Crohn's disease symptoms) Participants who demonstrated an inability to taper corticosteroids (as indicated by a variance in the ... corticosteroid tapering pathway) were also eligible.

[0190] Participants were randomly assigned to receive biologic therapy (i.e., infliximab, adalimumab, certolizumab, bupegol, vedolizumab, or approved biosimilars of these agents may have never had a history of steroid therapy, or may have been exposed to biologic therapy with an inadequate response or intolerance is not required.

[0191] Non-response or intolerance to biologic therapy (BIO non-response) Participants were required to receive at least one or more biologic therapies (i.e., infliximab , adalimumab, certolizumab pegol, vedolizumab, or any of the approved biosimilars) approved locally for the treatment of Crohn's disease. The patient must have had an inadequate response or been poorly tolerated with the treatment. Inadequate response was defined as primary nonresponse (i.e., no initial response) or secondary nonresponse (i.e., (i.e., initial response followed by loss of response).

[0192] Participants with previous exposure to IL-12 / 23 or IL-23 agents were ineligible for this study. do.

[0193] Overall, the trials included 12 weeks of induction therapy and at least 12 weeks of maintenance therapy. At week 24, all participants entered the extension phase. The study will continue until the last participant completes the 48-week assessment. The study was unblinded after database lock (DBL) was completed at week 48. Placebo participants who were not rescued with guselkumab during the open-label portion of the study The study intervention was discontinued and final efficacy and safety (FES) was assessed. All other participants will continue guselkumab treatment through week 96. do.

[0194] The total study duration will be up to 109 weeks. The study will include the following phases: 1. Screening phase: up to 5 weeks 2. Main treatment phase: 24 weeks 3. Extension treatment phase: 72 weeks 4. Post-treatment phase (FES follow-up visit): Approximately 12 weeks after the last administration of study intervention Until later

[0195] Generally, oral 5-aminosalicylates were used for the treatment of Crohn's disease at baseline. compounds, oral corticosteroids, conventional immunomodulators (AZA, 6-MP, or MTX), Participants receiving antibiotics and / or enteral nutrition were excluded from the study, with the exception of oral cosmic steroids. Stable dosing should be maintained for the specified period prior to baseline and through Week 48. All participants who received corticosteroids at week 0 were discontinued at week 12. Patients should begin tapering their steroid dose. This tapering should be done only if medically feasible. Participants who discontinue the study intervention early will be asked to withdraw from the study intervention. All randomized participants should return for a SID (Surgical Indication Discontinuation) visit. Participants will complete a FES follow-up visit approximately 12 weeks after the last dose of study intervention. should be.

[0196] Efficacy, safety, pharmacokinetics (PK), immunogenicity, and biomarkers are assessed according to the activity schedule. The study will be evaluated according to the Schedule of Activities (SoA). Blood samples for this purpose will only be collected from participants who consent to this component of the protocol. (where permitted by local regulations).

[0197] Database locks will occur at weeks 24, 48, and the last participant as shown in the SoA. Planned upon completion of last scheduled assessment. Add additional DBLs as needed. It is possible.

[0198] Number of participants The target sample size is 318 participants. Inadequate response to biologic therapy or poor tolerance comprise approximately 35% to 65% of the population.

[0199] Intervention group and duration The total study duration will be up to 109 weeks. The study will include the following phases: 1. Screening phase: up to 5 weeks 2. Main treatment phase: 24 weeks 3. Extension treatment phase: 72 weeks 4. Post-treatment phase (FES follow-up visit): Approximately 12 weeks after the last administration of study intervention Until later

[0200] At week 0, eligible participants were randomized in a 1:1:1 ratio to one of the following SC treatments: Attach. 106 participants received guselkumab 400 mg SC at weeks 0, 4, and 8. followed by guselkumab 200 mg SC every 4 weeks (q4w) until week 24 106 participants received guselkumab 400 mg SC at weeks 0, 4, and 8, followed by Guselkumab 100mg SC every 8 weeks (q8w) until week 24 106 participants were randomly assigned to placebo SC q4w from week 0 to week 24.

[0201] Table 2 describes the study interventions.

[0202] [Table 3]

[0203] Randomization was based on baseline Crohn's Disease Activity Index (CDAI) score (≤300 or >3 00), baseline Simplified Endoscopy Score for Crohn's Disease (SES-CD) score (≤12 or >12), and baseline (week 0) BIO non-response status (yes or no) It is stratified by

[0204] During the extension phase, all participants continue to receive the same treatment regimen they were receiving at week 24.

[0205] No guselkumab rescue was performed during the open-label portion of the study after DBL at week 48 Placebo participants will discontinue the study intervention and attend the FES follow-up visit. All other participants Patients will continue guselkumab treatment through 96 weeks.

[0206] Those in the placebo group who met at least one of the rescue criteria at weeks 12 and 16 All participants received rescue treatment, i.e., habituation at weeks 16, 20, and 24. Rucumab 400 mg SC followed by guselkumab 100 mg SC every 8 weeks (q8w) To maintain the blind, groups meeting at least one of the rescue criteria were Participants randomized to selcumab continued their assigned treatment regimen and received placebo Receive a blinded sham rescue matched by SC injection.

[0207] Ustekinumab in the Phase 3 Crohn's Disease Program (IM-UNITI) Maintenance Study The sponsor is investigating the efficacy and safety of ustekinumab (IL-12 / 23) in participants with Crohn's disease. The effect of single-dose adjustment of steroids (antagonists) was evaluated. Participants were randomized to receive placebo, Ustekinumab 90 mg q12w or ustekinumab 90 mg q8w (approved) In the ustekinumab 90 mg q8w group, 28 participants were They met specified loss of response criteria and underwent sham dose adjustment. After 16 weeks, 32.1% had clinical These results suggest that clinical response was achieved in 46.4% of patients after 16 weeks. Some underserved / lost participants may benefit from continuing the same dosing regimen over time. Therefore, the guselkumab group in this study Instead of receiving conditioning, they receive a blinded sham rescue.

[0208] Phase 2 dose-ranging study of IV guselkumab in Crohn's disease (GALAXI 1) Based on data from the study, a single SC induction guselkumab dosing regimen (0 400 mg SC at weeks 1, 4, and 8 of GALAXI 1. The eye analysis showed that 1200 mg was administered IV at weeks 0, 4, and 8, respectively. Similar efficacy was demonstrated with 600 mg and 200 mg guselkumab induction doses. There was no clear dose / exposure response within the range of guselkumab IV induction doses administered. , for confirmatory evaluation in the Phase 3 guselkumab trials (GALAXI 2 and 3), 20 An IV induction dosing regimen of 0 mg was selected.

[0209] Guselkumab SC (TREMFYA® SmPC 2021; TREMFYA (R) USPI 2020)) has an estimated bioavailability of approximately 50%. When administered intravenously, 400 mg SC guselkumab provides comparable overall guselkumab efficacy to 200 mg IV guselkumab. Population PK modeling and simulation are expected to result in selkumab exposure (AUC). With this regimen, peak concentrations were higher than with the 200 mg IV induction regimen, but Trough concentrations following a 0 mg SC induction dosing regimen compared with an IV induction dosing regimen Non-inferiority demonstrated. Biologics approved for both IV and SC administration Experience from the study demonstrated non-inferior trough concentrations with similar overall exposure (mean steady-state serum study intervention concentration [ Cavg,ss]) results in equivalent efficacy for both routes of administration. In addition, the serum peak concentration during the induction phase is This may not be the primary driver of efficacy at week 0, week 4, and A single guselkumab induction regimen of 400 mg SC at week 1 and week 8 was administered to patients with moderate to severe rheumatoid arthritis. To be evaluated in participants with active Crohn's disease.

[0210] Two guselkumab maintenance dosing regimens (200 mg SC q4w and 100 mg SC C q8w) will be evaluated in this study. These are being evaluated in the ongoing Phase 3 GALAXI trial. By choosing the same maintenance dosing regimen, SC induction followed by SC maintenance regimen (this study) versus IV induction followed by SC maintenance regimen This will allow for a crossover comparison of the two Guselkumab trials. Maintenance dosing regimen (i.e., 200 mg SC q4w and 100 mg SC q8w) w) provides approximately a four-fold dose range of exposure, which is comparable to maintenance in the treatment of Crohn's disease. Supports dose / exposure response assessment of therapy.

[0211] Randomization minimizes bias in the allocation of participants to each intervention group and ensures that known and unknown participants are included. Attributes (e.g., demographic and baseline characteristics) are evenly balanced between intervention groups It is used to increase the likelihood and validity of statistical comparisons between intervention groups. To minimize imbalances between groups, randomization was performed based on factors that influence prognosis or treatment response. stratified by baseline CDAI score, SES-CD score, and (Stratified by core and BIO non-response status).

[0212] Screening of eligible participants will be conducted within 5 weeks prior to administration of the study intervention. The inclusion and exclusion criteria for enrolling participants are described below.

[0213] Inclusion criteria Each potential participant must meet all of the following criteria to be enrolled in the study: 1. Be 18 years of age or older (or the legal age of consent in the jurisdiction where the study is being conducted) Male or female (according to the reproductive organs and functions assigned by the chromosome pairs). 2. Confirmed by radiography, histology, and / or endoscopy at any time in the past , colitis, ileitis, or ileocolitis, of at least 3 months duration (minimum 12 weeks have Crohn's disease or fistulizing Crohn's disease (defined as 3. Clinically unaffected, defined as a baseline CDAI score ≥ 220 and ≤ 450 Have active Crohn's disease: a. Based on the unweighted CDAI component of the number of liquid or very loose stools , whether the average number of SFs per day is ≥ 4 or b. Average daily AP score based on unweighted CDAI components of AP ≧2 4. Based on the presence of ulceration in at least one of the five ileocolonic segments: Screening SES-CD score ≥ 6 (or for participants with isolated ileal disease) by the facility endoscopy reading at screening endoscopy defined as ≥4 Patients with endoscopic evidence of active ileocolonic Crohn's disease when evaluated by the A defined ulceration component score is obtained: a. Minimum score of 1 for the component "ulcer size" and b. Minimum score of 1 for the "ulcerated surface" component 5. Extensive colitis for more than 8 years or limited to the colon for more than 10 years Participants who had a medical condition a. Complete colonoscopy to assess for the presence of dysplasia within 1 year prior to the first administration of study intervention Have you ever had a speculum examination? or b. Biopsy surveillance for dysplasia as a baseline endoscopy during the screening period The results from these surveillance biopsies will be used to guide the study intervention. Before the first dose of dysplasia (low-grade, high-grade, or indeterminate dysplasia in reactive atypia), The test must be negative for HIV-1 (anti-HIV formation).

[0214] Concomitant or previous medications administered 6. Previous or current medications for Crohn's disease include at least one of the following: You need to: a. Oral corticosteroids (including budesonide and beclomethasone dipropionate) ) and / or current treatment with immunomodulatory agents (AZA, 6-MP, MTX) or b. The following therapy: oral corticosteroids (budesonide and beclomethasone dipropionate) at least one of the following: antihistamines (including rifabutin) or immunomodulators (AZA, 6-MP, MTX) History of non-response or poor tolerance to or c. Corticosteroid dependence (i.e., without recurrence of Crohn's disease symptoms) History of inability to successfully taper corticosteroids or d. At least one of the administrations is approved topically for the treatment of Crohn's disease The above biologic agents (i.e., infliximab, adalimumab, certolizumab pegol, dolizumab, or approved biosimilars for these agents) had previously demonstrated a lack of response (i.e., primary non-responders) or had an initial response but continued treatment The method resulted in loss of response (i.e., secondary non-responders) or intolerance Note: Participants meeting criteria 6a-c were not receiving biologic therapy (i.e., infliximab, Adalimumab, certolizumab pegol, vedolizumab, or any other approved The patient may not have received or been exposed to these biologic therapies (or biosimilars). Patients may have had previous treatment with no poor response or intolerance. 7. Comply with all of the following requirements for concomitant medications to treat Crohn's disease: The following medications are stable in dosages that meet the requirements listed below or are not listed below: is acceptable, provided that it is discontinued before baseline within the time frame specified: a. At least 2 weeks of stable oral 5-ASA compound administration; or if recently discontinued In this case, the outage must have lasted at least two weeks. b. Oral corticosteroids at a prednisone equivalent dose of 40 mg / day or less, or 9 mg / day g / day budesonide or 5 mg / day beclomethasone dipropionate, and at least Two weeks of stable administration; or if recently discontinued, at least two weeks after discontinuation It is necessary. c. At least 12 weeks of conventional immunomodulatory agents (i.e., AZA, 6-MP, or M TX) and had been on stable therapy for at least 4 weeks; or if recently discontinued, at least Both were suspended for four weeks. d. If antibiotics are given as first-line treatment for Crohn's disease, they should be administered without cessation for at least 3 weeks. or if recently discontinued, must have been discontinued for at least 3 weeks There is a need. e. If enteral nutrition is used as the primary treatment for Crohn's disease, it must be taken for at least two weeks. or if recently discontinued, for at least two weeks It is necessary to say.

[0215] Laboratory Test Screening 8. Have laboratory screening test results within the following parameter ranges and meet the laboratory parameters: If one or more of the parameters are out of range, the laboratory will One retest of the values ​​is allowed: Hemoglobin ≥ 8.0 g / dL b. White blood cells (WBC) ≧3.0×103 / μL c. Neutrophils ≧1.5×103 / μL d. Platelets ≧100×103 / μL e. Serum creatinine ≤ 1.5 mg / dL f. Alanine transaminase (ALT) (or asparagus) Aspartate transaminase (AST) ≤ 2 × upper limit of normal (upper r limit of normal (ULN) Total bilirubin (TBilirubin) ≤ 1.5 x ULN (known diuretic) An isolated total bilirubin >1.5 × ULN is acceptable in participants with Behr's syndrome Gilbert syndrome is suggested by a direct bilirubin <30%.

[0216] tuberculosis Potential participants are eligible if they meet all of the following TB screening criteria: is considered to be: Note: Interferon gamma release assay (IGRA) testing is available from QuantiFER Contains either ON-TB® or T-SPOT® TB. a. No history of active TB or no history or physical examination at the time of screening On examination, the patient exhibits signs or symptoms suggestive of active TB. b. No history of latent TB before screening. Exceptions are made for participants who meet one of the following criteria: 1. Are you currently receiving treatment for latent TB? or 2. Initiate treatment for latent TB before the first dose of study intervention Note: For participants with a history of treated latent TB, prior to the first dose of study intervention Prior TB treatment should be validated and adequate documentation should be provided. It is the investigator's responsibility to provide the information. or IGRA in screening for participants currently undergoing treatment for latent TB. No exam is required. c. You have not had recent close contact with someone with active TB. If you have had contact, Such participants will be referred to a physician specializing in TB to determine whether treatment is warranted. This assessment should be properly documented and, if treatment is recommended, participants should be Appropriate treatment must be received before the first dose of the intervention. d. Have a negative IGRA test result within 2 months prior to the first dose of the study intervention, or 1. Have a history of adequately treated latent TB as described above. 2. Active TB has been eliminated and appropriate treatment for latent TB has been initiated before the first dose of the study intervention The patient had a newly identified positive IGRA test result. 3. Have a false-positive IGRA test as determined by: Initial IGRA tests suspected to be false positives should be repeated. to determine whether the initial test can be considered a false positive if the initial test is not positive. Participants should be referred to a physician specializing in TB. This evaluation is conducted at the beginning of the study intervention. However, if a repeat test is positive, It is considered a true positive and participants are eligible if they have eliminated active TB and Only if appropriate treatment for latent TB has been initiated as described above. Note: Indeterminate / borderline results should be addressed. e. No abnormalities suggestive of active or inactive TB in the 3 months prior to the first dose of study intervention Chest radiograph (both postero-anterior and lateral views) within 1 month of the date of the procedure, or as required by local / national regulations, if applicable. or chest computed tomography (CT).

[0217] contraception 9. Female fertility requires a negative serum pregnancy test result at screening. There is a need. 10. Prior to randomization, women must: a. Inability to give birth or b. Reproductive capacity, and If heterosexually active, a highly effective method of contraception (used consistently and correctly) If the failure rate is <1% per year, the study intervention is administered while the patient is receiving it and at the last dose. agree to maintain highly effective methods for 12 weeks after the initial dose (end of relevant systemic exposure). Note: The method selected must comply with local / regional regulations / guidelines for highly effective contraception. The requirements must be met. Note: If a participant's fertility changes after the start of the study (e.g., if a premenarchal woman reaches menarche), experienced) or pregnancy risk changes (e.g., a woman who is not heterosexually active becomes sexually active). women should start using highly effective contraceptive methods. 11. Women are required to use oocytes (eggs) for assisted reproduction purposes during the study and for 12 weeks after the last dose of study intervention. You must agree not to donate any eggs or oocytes. 12. During the study and for at least 12 weeks after the last dose of study intervention, male participants a. Persons who are sexually active with women of childbearing potential should use barrier contraception (i.e., spermicide). Condoms or spermicide foam with spermicide foam / gel / film / cream / suppository Female condom with suppository / occlusion cap [separator or must agree to the use of a cervical / vault cap b. Anyone who is sexually active with a pregnant woman should use a condom. 13. Participants must agree not to donate sperm for reproductive purposes. I understand the purpose of the study and the procedures involved, and I am willing to participate in the study. You will need to sign an informed consent form (ICF) be. Note: In jurisdictions where the legal age of consent is greater than 18, participants and their legally acceptable representatives Informed consent must be obtained and signed by both the patient and the researcher. 14. If you agree to provide a voluntary DNA sample for research: A separate ICF must be signed (if local regulations permit). Refusal to consent to a sample will not exclude a participant from participation in the study. . Note: In jurisdictions where the legal age of consent is greater than 18, participants and their legally acceptable representatives Informed consent must be obtained and signed by both the patient and the researcher. 15. Completes assessments, adheres to visit schedules, and adheres to lifestyle restrictions. You are willing and able to comply with all specified requirements, including but not limited to: Cut.

[0218] Exclusion criteria Potential participants who meet any of the following criteria will be excluded from participating in the study: 1. Symptomatic stenosis or stricture, short bowel syndrome, or other conditions that may be expected to require surgery If you have complications of Crohn's disease, such as other symptoms, assess your response to therapy. otherwise, guselkumab may be used. This confounds the ability to assess the effectiveness of treatment with 2. Current or suspected abscess. Recent skin and anal abscesses are not recommended for further treatment. At least 3 weeks prior to baseline, or unless a need for surgery is anticipated For intra-abdominal abscesses, if drained and adequately treated 8 weeks prior to baseline Participants with active fistulas will be excluded if surgery is not anticipated. and no currently identified abscesses may be included. 3. Any type of bowel resection within 24 weeks or any other resection within 12 weeks prior to the first dose of study intervention. Have undergone any other major abdominal or other surgery. 4. If you have a draining (i.e., functioning) stoma or ostomy. 5. At screening endoscopy if not removed prior to study entry Presence of adenomatous colon polyps or history of unremoved adenomatous colon polyps. 6. Clostridioides difficile (C) within 4 months prior to the first dose of study intervention Clostridium difficile, formerly Clostridium difficile ( Positive stool culture or other test for enteropathogens, including Clostridium dificile toxin unless repeat tests are negative and there are no signs of ongoing infection with the pathogen. Ku. Note: Treatment and repeat testing can occur during the current screening period.

[0219] Concomitant or previous medications administered 7. If you have taken any of the following prescription medications or therapies within the specified period: a.Received IV corticosteroids within 3 weeks of baseline b. Within 8 weeks of baseline, cyclosporine, tacrolimus, sirolimus, or received mycophenolate mofetil c. Received 6-thioguanine within 4 weeks of baseline d. Biological agents: 1. Within 8 weeks of baseline, anti-TNFα therapy (e.g., infliximab, etanercept, certolizumab pegol, adalimumab, golimumab) 2.Received vedolizumab within 12 weeks from baseline 3. Within 12 weeks of baseline or within 5 half-lives of baseline, whichever is longer patients who received other immunomodulatory biological agents, including approved and investigational biological agents e. Within 4 weeks of baseline or within 5 half-lives of baseline, whichever is longer , received any study intervention. f. Non-autologous stem cell therapy (e.g., Prochyma) within 12 months of baseline l), natalizumab, efalizumab, or biologic agents that deplete B or T cells ( For example, rituximab, alemtuzumab, or visilizumab). g. Within 3 weeks of baseline, Crohn's disease was diagnosed by apheresis (e.g., Adac Patients were treated with total parenteral nutrition (TPN) or total parenteral nutrition (TAN). 8. Ustekinumab, briakinumab, brazikumab, guselkumab, mirikizumab, and risankizumab, Previous exposure to targeted biological agents.

[0220] Infections or predisposing factors: 9. History of latent or acute granulomatous infection prior to screening, including: Histoplasmosis or coctidioidomycosis. Participants with radiographic evidence of possible coccidioidomycosis will be excluded. 10. Respiratory tract infections, bronchiectasis, recurrent kidney / urinary tract infections (e.g., pyelonephritis, bladder skin wounds, including but not limited to open, draining, or infected skin wounds or ulcers History of or ongoing chronic or recurrent infections. 11. A chest radiograph must be obtained within 12 weeks prior to the first dose of study intervention. Tumors, previously unrecognized lung pathologies, as well as TB, histoplasmosis, or coccidiosis Undiagnosed pulmonary infections, including but not limited to active or latent infections from geoidomycosis Results showing abnormalities suggestive of pathology will be excluded. A chest CT scan is also acceptable. Information on the eligibility of a history of latent TB is available. For details, please see the inclusion criteria9. 12. History of human immunodeficiency virus (HIV) antibody positivity or HI at screening V test positive. 13. Hepatitis C virus (HCV) infection, unless one of the following conditions is met: rus, HCV): a. HCV RNA negative at least 12 weeks after completing antiviral treatment have a history of successful treatment, defined as a negative HCV RNA test result at screening Will it have any effect? or b. HCV seropositive but negative at least 12 weeks prior to screening have an RNA test result and have a negative HCV RNA test result at screening. 14. Test positive for hepatitis B virus (HBV) infection (Appendix 4 [Section 10.4]). Note: Participants who are ineligible for this study due to HIV, HCV, or HBV test results Consultation with a physician with expertise in treating these infections is recommended. 15. Bacillus Calmette-Guerin (BCG) vaccination within 12 months or screening Any other live bacterial or live viral vaccination within 4 weeks prior to vaccination or during the study I plan to receive such a vaccine. 16. Nontuberculous mycobacterial infection or clinically significant opportunistic infection (e.g., cytomegalovirus, viral colitis, pneumocystis, invasive aspergillosis) or If you have had one. 17. Clinically significant infection (i.e., hepatitis, sepsis, pneumonia, or pyelonephritis) have had a history of breast cancer, been hospitalized for an infection, or been in the 8 weeks prior to the first dose of the study intervention had been treated with parenteral antibiotics for an infection within the previous year. Treated and resolved infections that are not considered clinically significant do not need to be excluded ( i.e., acute upper respiratory tract infection, uncomplicated urinary tract infection). 18. Currently have signs or symptoms of clinically significant infection. At the investigator's discretion Ongoing infections that are not considered clinically significant do not need to be excluded (i.e., acute upper respiratory tract infection, uncomplicated urinary tract infection). 19. Have evidence of herpes zoster infection within 8 weeks prior to the first dose of study intervention. 20. During the 6 weeks prior to baseline, (a) confirmed severe acute respiratory syndrome coronavirus SARS-CoV-2 (coronavirus disease 2019 [COVID-19]) infected (test positive), or (b) suspected SARS-CoV-2 infection (documented test (c) known SARS-CoV-2 infection or (d) clinical features without outcome had either close contact with a person with suspected COVID-19 infection or had been in close contact with a person with suspected COVID-19 infection. Exception: Have a documented negative result from a validated SARS-CoV-2 test Cases may be included. a. Obtained at least two weeks after the above conditions (a), (b), and (c) (present) (If present, time was measured from the resolution of important clinical features, e.g., fever, cough, and dyspnea) and b. During the period between the negative test result and the baseline examination visit, any of the above conditions (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k ... b) and (c) do not exist Note about COVID-19 related exclusions: COVID-19 related tests (presence of SARS-CoV-2 virus and its effects) The field of immunology (including immunotherapy) is rapidly evolving. Additional testing may be required by the investigator. If deemed necessary, as part of screening and / or during testing, may be performed in accordance with regulations / guidance / standards of care. Caution: For individuals who may be at higher risk for severe COVID-19 disease Therefore, when comparing the potential benefits and risks of enrolling in a trial and when considering the cost of participating in a trial, During this time, we will follow guidance from local health authorities.

[0221] Malignant tumor or high probability of malignant tumor: 21.Currently have a malignant tumor or have a history of a malignant tumor within 5 years prior to screening (Appropriately treated and at least 3 months [minimum 12 weeks] prior to first administration of study intervention) Non-melanoma skin cancer with no evidence of recurrence in the past [defined as a 'cancerous' condition] or that has been treated and is at the first sign of a study intervention (excluding cervical intraepithelial neoplasia with no evidence of recurrence for at least 3 months prior to the first dose). 22. Known history of lymphoproliferative disorders, including lymphoma, monoclonal gamma globulin of undetermined significance history of erythrocyte sedimentation; or possible lymphoproliferative disorders such as lymphadenopathy or splenomegaly There are suggestive signs and symptoms.

[0222] Coexisting medical conditions or past medical history 23. Severe, progressive, or uncontrolled renal, genitourinary, hematological, endocrine, cardiac, History of vascular, pulmonary, rheumatic, neurological, psychiatric, or metabolic disorders, or signs and symptoms thereof It has. 24. If you have had a transplanted organ (corneal transplant >12 weeks prior to screening) (Excluding). 25. Inadequate tolerance of venipuncture or blood samples required during the study Lack of adequate venous access for collection. 26. Diagnostic and Statistical Drug or History of alcohol abuse. 27. Suicidal thoughts with the intention to carry them out (ideation level 4) and specific plans in the past 6 months and suicidal ideation with intent (ideation level 5), or suicidal behavior (actual suicide attempt, suspected suicide attempt). At the time of screening for suicide attempts (suicide attempts aborted, failed suicide attempts, or preparatory behaviors for a suicide attempt) The Columbia-Suicide Severity Rating Scale (C-SS) have disturbing suicidal thoughts or behaviors, which can be defined as a 'RS' rating, and are not receiving treatment from a mental health professional Patients are deemed at risk by the investigator based on their assessment. ("Ideation Level 1"), nonspecific active suicidal thoughts ("Ideation Level 2"), and actions Active suicidal ideation (no plan) by any means with no intention to commit suicide ("Ideation Level 3"), or The C-SSRS scores for non-suicidal self-injury behaviors determined by the investigator to be at risk were used. Participants may not be randomly assigned. 28. Known allergy, hypersensitivity, or intolerance to guselkumab or its excipients. do. 29. Became pregnant during enrollment in this study or within 12 weeks after the last dose of study intervention. are pregnant or breastfeeding or planning to become pregnant. 30. Child has a history of breast cancer during enrollment in this study or within 12 weeks after the last dose of study intervention. He is a man who plans to become a father.

[0223] General 31. Currently participating in any other study using an investigational drug or procedure during the conduct of this study. or intends to participate. 32. In the opinion of the investigator, participation is not in the participant's best interest (e.g., impair health) or prevent, limit, or disrupt the evaluations prescribed in the protocol Any condition that may cause 33. An employee of the investigator or trial site who works under the direction of the investigator or trial site. Similarly, if a person is directly involved in the presentation or other examinations under the If you are a family member of the investigator.

[0224] Efficacy and safety of guselkumab for SC induction and subsequent SC maintenance in Crohn's disease A 24-week study period is considered sufficient to evaluate the efficacy of this study. The subsequent guselkumab dosing regimen is being evaluated in the ongoing guselkumab Phase 3 Crohn's disease trial (GA). Same as in LAXI 2 and 3). After 24 weeks, 400 mg SC induction Between the (this study) dosing regimen and the 200 mg IV induction (GALAXI) dosing regimen As a result, no differences in guselkumab concentrations or exposure are expected. The trial will be 24 weeks long with an extension period between the two trials. The extension period will be determined by the investigator as a benefit from the study intervention. Participants who are deemed to be successful will be given access to treatment for approximately two years. The hop phase (approximately 12 weeks after the last dose of study intervention) is the final efficacy and safety data In addition to assessing PK and antibodies to guselkumab, is designed to collect

[0225] Biomarkers and DNA collection To evaluate the cellular and molecular mechanisms of action of guselkumab or to evaluate its role in clinical outcomes population subgroups that may help explain inter-individual variability or differ in their response to an intervention Biomarker samples (if permitted by local regulations) may be collected to help identify PD mutations associated with the IL-23 pathway and response to guselkumab will be collected. Serum biomarkers will be collected from whole blood of all participants to assess risk. To assess the effect of the study intervention on nucleic acid (RNA) expression profiles, all participants Whole blood samples will be collected from participants to assess cellular and molecular changes within the intestinal mucosal tissue. Ileocolonic biopsies will also be obtained from all participants. The goal of biomarker analysis is to identify the specific risk factors for Crohn's disease. To further define the mechanism of action of selective blockade of IL-23 by guselkumab in patients with IL-23-positive leukemia and to evaluate the interventional-clinical outcomes. The purpose is to help evaluate the relationship between the two.

[0226] An optional pharmacogenomics substudy is planned. Genetic variations may influence intervention distribution and response. may be an important influencing factor for inter-individual differences in disease susceptibility and prognosis. The goal of the pharmacogenomics component is to: DNA will be collected to assess whether it may affect the PK, PD, efficacy, safety, or tolerability of guselkumab. This will allow the identification of genetic factors that may contribute to Crohn's disease or response to guselkumab treatment. The focus of this analysis is to identify genetic factors associated with Crohn's disease and Gusel's disease. Evaluation of genetic single nucleotide polymorphisms associated with response to mab treatment.

[0227] Biomarkers and DNA samples can be used to help address emerging problems. This could allow for the development of safer, more effective, and ultimately more personalized therapies. can.

[0228] Patient-reported outcomes of health-related quality of life Patient-reported outcome measures (i.e., IBDQ, PROMIS-29) were used to assess disease progression. Patient-specific and overall health-related quality of life (HRQO) The benefit of guselkumab treatment on patients with rheumatoid arthritis (HLA) was assessed. Patient-reported outcomes were assessed using a Collected only in countries where translations are available.

[0229] Tapering oral corticosteroids Participants on corticosteroids were more likely to achieve corticosteroid-free clinical remission than those on other therapies. Considering that this is an important goal, From the second week onwards, the dose is forced to be tapered.

[0230] Intervention description Guselkumab is provided in two dosage strengths: via the YpsoMate autoinjector (PFS Guselkumab 200 mg / 2 mL in a single-dose prefilled syringe with UltraSafe Plus(TM) Passive Needle Guard(P 100 mg / 1 mL in a single-dose prefilled syringe with FS-U. Placebo was administered as a single dose of 2 mL in PFS-Y and as a single dose of 1 mL in PFS-U. Provided.

[0231] Efficacy evaluation Efficacy assessment includes: CDAI PRO-2 (unweighted total number of liquid or very loose stools and abdominal pain [AP] score) CDAI component) Endoscopic evaluation of the intestinal mucosa based on the presence or absence of mucosal ulcers and SES-CD Histological evaluation Inflammatory pharmacodynamics (P) including C-reactive protein (CRP) and fecal calprotectin D) marker, Fistula evaluation Inflammatory Bowel Disease Questionnaire (IBDQ) and Patient-Reported Outcomes Measurement Information System (PRO) PRO scales for assessing health-related quality of life outcomes, including the MIS-29; Includes the Bristol Stool Form Scale (BSFS) and AP-Numerical Rating Scale (NRS) Patient-reported symptom scale

[0232] Pharmacokinetic evaluation Serum samples were analyzed to identify specific or potential markers that have been validated by or under the supervision of the sponsor. The concentration of guselkumab will be determined using a highly sensitive immunoassay method.

[0233] Pharmacogenomic (DNA) evaluation Pharmacogenomic blood samples, if required (if permitted by local regulations) To allow for pharmacogenomics research, participants must consent separately to this component of the study. Participation in pharmacogenomics research is voluntary. Deoxyribonucleic acid ( DNA samples are analyzed to identify genetic factors that may be associated with clinical response.

[0234] Pharmacodynamic and biomarker evaluation Inflammatory PD markers (CRP and fecal calprotectin) were measured in blood and fecal samples. Biomarker assessment will be performed to examine biological response to treatment and provide a baseline. To identify biomarkers associated with selkumab treatment and / or Crohn's disease. Where permitted by local regulations, relevant biopsy samples in serum, whole blood, and ileal colon biopsy samples This includes evaluation of biomarkers.

[0235] Immunogenicity assessment Serum samples were screened for antibodies that bind to guselkumab, and confirmed positives were Other analyses will be performed to assess the stability of antibodies to guselkumab. The immunogenicity of guselkumab can be validated and / or further characterized.

[0236] Safety evaluation Safety assessments included adverse events (AEs), clinical tests, vital signs and physical examinations, screening, and Monitoring electrocardiograms, suicidality assessments, concomitant medication reviews, injection site reactions, and hypersensitivity reactions This includes screening, tuberculosis evaluation, and other infection evaluation.

[0237] statistical methods Sample size determination Using a two-sided chi-square test at the 0.05 significance level, the difference between the combined guselkumab group and the placebo group was Clinical remission at week 12 and endoscopic response at week 12 (co-primary endpoints) were achieved between The sample size was determined by the power to detect a significant difference in the 50% vs. 15% for resolution (guselkumab vs. placebo) and 30% for endoscopic response The study demonstrated that guselkumab therapy significantly improved the co-primary endpoint compared with placebo. The sample size is also sized to achieve >90% power for the , providing >90% power for all secondary endpoints.

[0238] Efficacy analysis Descriptive statistics (e.g., mean, median, standard deviation [SD], interquartile range, minimum, and maximum) ) are used to summarize continuous variables. Categorical variables are summarized using counts and percentages. Use graphical data displays (e.g., line plots) to summarize data It is also possible.

[0239] Analyses appropriate for categorical data (e.g., chi-squared test or Cochran-Mantel-Hall, as appropriate) Cochran-Mantel-Haenszel (CMH) chi-square test or logistic regression The proportion of participants achieving a selected endpoint (e.g., clinical response) is calculated using Rarely, Fisher's exact test is used for treatment comparisons. Parameters are based on analysis of variance (ANOVA) or Comparisons were made using analysis of covariance (ANCOVA). When assumptions are in question, van der Waerden canonical scores are used. Use ANOVA or ANCOVA for A.

[0240] The co-primary endpoints (clinical remission at 12 weeks and endoscopic response at 12 weeks) were Treatment group, population, variables, Intercurrent Event (ICE) strategies, and population-level summary based on estimates After considering the ICE strategy, the results for the co-primary endpoints are analyzed. Participants with missing responder status were considered non-responders for that co-primary endpoint. It is considered to be.

[0241] Statistical tests are performed at a significance level of 0.05 (two-sided). Type I error is The co-primary endpoint is controlled for the endpoint and the secondary endpoint. The study will first examine clinical remission at 12 weeks, followed by endoscopic response at 12 weeks. The three secondary analyses listed below are both contingent on the success of the primary endpoint analysis. It is carried out sequentially. Clinical remission at 24 weeks (CDAI score <150) PRO-2 remission at 12 weeks (AP daily average score ≤1 and stool frequency (SF)) Daily average score ≤ 3, i.e., AP ≤ 1 and SF ≤ 3, and A (defined as no worsening of P or SF) Clinical response (reduction from baseline in CDAI ≥ 100 points) at week 12 or clinical remission) For endpoints where multiplicity was not controlled, apparent p-values ​​are presented.

[0242] Safety analysis AEs, serious adverse events (SAEs), infections, infection site reactions, (haematological and chemical) tests These include, but are not limited to, changes in lab parameters, and suicidal thoughts and behaviors. Safety data are summarized. All reported treatment-emergent AEs were included in the analysis. It can be enjoyed.

[0243] Other analyses Pharmacokinetic analysis Serum guselkumab concentrations over time will be summarized for each treatment group using descriptive statistics. Population PK modeling may be performed when appropriate. PK analysis of these populations If performed, the results of these analyses will be presented in a separate report.

[0244] Pharmacokinetic / pharmacodynamic analysis The relationship between serum guselkumab concentrations and efficacy measures is analyzed graphically. Where possible, suitable exposure-response models should be developed to characterize the relationship between serum guselkumab exposure and efficacy. The results of population PK / PD analysis can be analyzed using separate techniques. Present in the report.

[0245] Pharmacogenomics analysis Genetic (DNA) analysis requires signed consent to participate in a pharmacogenomics substudy. These analyses are considered exploratory and will be published in separate technical reports. It can be stopped.

[0246] Biomarker analysis If permitted by local regulations, serially obtained serum protein samples and whole blood samples Changes in nucleic acid (RNA) levels will be summarized by intervention group. The relationship between line levels and changes from baseline and response to treatment RNA analysis will be summarized in a separate technical report.

[0247] Immunogenicity analysis The incidence and titers of antibodies to guselkumab will be summarized for all participants who received guselkumab and had an adequate sample to detect antibodies to guselkumab (i.e., participants with at least one sample obtained after the first dose of guselkumab). The incidence of neutralizing antibodies to guselkumab will be summarized for participants who tested positive for antibodies to guselkumab and had a sample evaluable for neutralizing antibodies to guselkumab. The following aspects may be included. [1] A method of treating Crohn's disease in a patient, comprising administering to the patient an initial subcutaneous dose of 400 mg of an antibody specific for IL23, followed by a subcutaneous dose of 400 mg about 4 weeks after the initial dose, and a subcutaneous dose of 400 mg about 8 weeks after the initial dose. [2] The method according to [1] above, further comprising administering 100 mg or 200 mg of the antibody approximately every 4 weeks or approximately every 8 weeks after the administration approximately 8 weeks after the initial administration. [3] The method according to [2] above, further comprising administering 200 mg of the antibody approximately every four weeks after the administration approximately eight weeks after the initial administration. [4] The method according to [2] above, further comprising administering 100 mg of the antibody approximately every 8 weeks after the administration approximately 8 weeks after the initial administration. [5] The method of [1] above, wherein the patient is identified as a responder to the antibody and meets a clinical endpoint approximately 12 weeks after the first administration, wherein the clinical endpoint is clinical remission at week 12, defined as a CDAI of less than (<) 150 points, or endoscopic response as measured by at least a 50% improvement from baseline in the Simplified Endoscopy Score for Crohn's Disease (SES-CD). [6] The method of [1] above, wherein the patient is identified as meeting a clinical endpoint, the clinical endpoint being selected from the group consisting of: (i) clinical remission, defined as a CDAI score of less than (<) 150 points measured about 24 weeks after the first administration; (ii) patient-reported outcome (PRO)-2 remission, defined as an average daily stool frequency (SF) of ≦3 and an average daily abdominal pain (AP) score of ≦1, and no worsening of AP or SF from baseline measured about 12 weeks after the first administration; and (iii) clinical response, defined as a reduction of ≧100 points from baseline in the CDAI score measured about 12 weeks after the first administration. [7] The antibody comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region is the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4; the CDRL2 amino acid sequence of SEQ ID NO: 5, and comprising the CDRL3 amino acid sequence of SEQ ID NO:6, the heavy chain variable region 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 method according to [1] above, wherein the antibody comprises the CDRH3 amino acid sequence of SEQ ID NO: 3, and the patient is considered to be a responder to the antibody. [8] The patient is a responder to the antibody and has one of the following clinical endpoints: (xii) change from baseline in Crohn's Disease Activity Index (CDAI) score; (xiii) clinical remission, defined as a CDAI of less than (<) 150 points; (xiv) clinical response, defined as a decrease from baseline in the CDAI score of 100 points or more (≥) or a CDAI score of <150; (xv) Patient-Reported Outcome (PRO)-2 remission, defined based on mean daily stool frequency (SF) and mean daily abdominal pain (AP) scores; (xvi) clinical biomarker response, defined using clinical response based on CDAI score and reduction from baseline in C-reactive protein (CRP) or fecal calprotectin; (xvii) endoscopic response, as measured by the Simple Endoscopic Score for Crohn's Disease (SES-CD); (xviii) endoscopic remission, as measured by the Simplified Endoscopic Score for Crohn's Disease (SES-CD); (xiv) sustained clinical remission at week 48, defined as a CDAI <150 for the majority of all visits between weeks 12 and 48; (xx) Corticosteroid-free clinical remission at Week 48, defined as a CDAI score of <150 at Week 48 and no corticosteroids at Week 48; (xxi) fatigue response based on the Patient-Reported Outcomes Measurement Information System (PROMIS); and (xxii) Endoscopic response, as measured by the Simplified Endoscopic Score for Crohn's Disease (SES-CD) The method according to [7] above, which is identified as satisfying the following. [9] The method according to [8] above, wherein the clinical endpoint is measured 4, 8, 12, 16, 20, 28, 32, 36, 40, 44, and / or 48 weeks after initial treatment.

[10] The method of [7] above, wherein the antibody is present in a pharmaceutical composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; and 0.053% (w / v) polysorbate 80, and the diluent is water at standard conditions.

[11] The method according to [1] above, further comprising administering to the patient one or more additional drugs used to treat Crohn's disease.

[12] The method according to

[11] above, wherein the additional drug is selected from the group consisting of immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface marker antibodies, anti-CD20 antibodies, rituximab, TNF inhibitors, corticosteroids, and costimulatory modulators.

[13] The method described in [1] above, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO: 8 and the heavy chain variable region amino acid sequence of SEQ ID NO: 7.

[14] The method described in [1] above, wherein the antibody comprises the light chain amino acid sequence of SEQ ID NO: 10 and the heavy chain amino acid sequence of SEQ ID NO: 9.

[15] The method according to [1] above, wherein the patient is considered to be biotherapy non-responsive or intolerant (Bio-non-responsive) for Crohn's disease.

[16] The method according to [1] above, wherein the patient is considered to be non-responsive or intolerant to conventional therapy (Con non-responsive) for Crohn's disease.

[17] The method according to [1] above, wherein the Crohn's disease is moderate to severe active Crohn's disease.

[18] The method of

[17] above, wherein the patient has endoscopic evidence of active Crohn's disease prior to administration of the first dose.

[19] The method according to

[17] above, wherein the patient has had moderate to severe active Crohn's disease for at least 3 months prior to administration of the first dose.

[20] A method of treating moderately to severely active Crohn's disease in a patient, comprising: (i) administering to the patient an initial subcutaneous dose of 400 mg of an antibody specific for IL23, followed by a subcutaneous dose of 400 mg about 4 weeks after said initial dose, and a subcutaneous dose of 400 mg about 8 weeks after said initial dose; and (ii) administering further doses of 200 mg of the antibody about 8 weeks after said initial dose and thereafter about every 4 weeks thereafter, or 100 mg of the antibody about 8 weeks after said initial dose and thereafter about every 8 weeks thereafter, wherein the antibody is selected from the group consisting of SEQ ID NO: and a light chain variable region amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region amino acid sequence of SEQ ID NO: 7, wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint approximately 12 weeks after the first administration, the clinical endpoint being clinical remission at week 12 defined as a CDAI of less than (<) 150 points or endoscopic response as measured by at least a 50% improvement from baseline in the Simplified Endoscopy Score for Crohn's Disease (SES-CD).

[0248] Sequence Listing [Table 4-1]

[0249] [Table 4-2]

[0250] [Table 4-3]

[0251] The amino acid sequences of the heavy and light chains of guselkumab are shown below (complementarity determining regions are shown in bold and variable regions are underlined): Heavy chain (SEQ ID NO: 9) [Table 4-4]

[0252] [Table 4-5]

[0253] Light chain (SEQ ID NO: 10) [Table 4-6]

[0254] [Table 4-7]

Claims

1. 1. A pharmaceutical composition for use in a method of treating Crohn's disease in a patient, the pharmaceutical composition comprising an antibody specific for IL23, the method comprising administering to the patient an initial subcutaneous dose of 400 mg of the antibody specific for IL23, a subcutaneous dose of 400 mg about 4 weeks after the initial dose, and a subcutaneous dose of 400 mg about 8 weeks after the initial dose.

2. The pharmaceutical composition of claim 1, wherein the method further comprises administering 100 mg or 200 mg of the antibody about every 4 weeks or about every 8 weeks after administration about 8 weeks after the initial administration.

3. The pharmaceutical composition of claim 2, wherein the method further comprises administering 200 mg of the antibody approximately every four weeks after administration approximately eight weeks after the initial administration.

4. The pharmaceutical composition of claim 2, wherein the method further comprises administering 100 mg of the antibody approximately every 8 weeks after the administration approximately 8 weeks after the initial administration.

5. 2. The pharmaceutical composition of claim 1, wherein the patient is identified as a responder to the antibody and meets a clinical endpoint about 12 weeks after the first administration, wherein the clinical endpoint is clinical remission at week 12 defined as a CDAI of less than (<) 150 points or endoscopic response as measured by at least a 50% improvement from baseline in the Simplified Endoscopy Score for Crohn's Disease (SES-CD).

6. 2. The pharmaceutical composition of claim 1, wherein the patient is identified as meeting a clinical endpoint selected from the group consisting of: (i) clinical remission, defined as a CDAI score of less than (<) 150 points measured about 24 weeks after the first administration; (ii) Patient-Reported Outcome (PRO)-2 remission, defined based on an average daily stool frequency (SF) of ≦3 and an average daily abdominal pain (AP) score of ≦1, and no worsening of AP or SF from baseline measured about 12 weeks after the first administration; and (iii) clinical response, defined as a reduction of ≧100 points from baseline in CDAI score measured about 12 weeks after the first administration.

7. The antibody comprises a light chain variable region and a heavy chain variable region, and the light chain variable region comprises: the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4; the CDRL2 amino acid sequence of SEQ ID NO:5, and comprising the CDRL3 amino acid sequence of SEQ ID NO:6, the heavy chain variable region 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 2. The pharmaceutical composition of claim 1, comprising the CDRH3 amino acid sequence of SEQ ID NO: 3, wherein the patient is considered a responder to the antibody.

8. The patient is a responder to the antibody and meets the following clinical endpoints: (i) change from baseline in Crohn's Disease Activity Index (CDAI) score; (ii) clinical remission, defined as a CDAI of less than (<) 150 points; (iii) clinical response, defined as a 100-point or greater (≥) reduction from baseline in CDAI score or a CDAI score <150; (iv) Patient-Reported Outcome (PRO)-2 remission, defined based on mean daily stool frequency (SF) and mean daily abdominal pain (AP) scores; (v) clinical biomarker response, defined using clinical response based on CDAI score and reduction from baseline in C-reactive protein (CRP) or fecal calprotectin; (vi) endoscopic response as measured by the Simple Endoscopic Score for Crohn's Disease (SES-CD); (vii) endoscopic remission as measured by the Simplified Endoscopic Score for Crohn's Disease (SES-CD); (viii) sustained clinical remission at Week 48, defined as a CDAI <150 for the majority of all visits between Weeks 12 and 48; (ix) Corticosteroid-free clinical remission at Week 48, defined as a CDAI score of <150 at Week 48 and no corticosteroids at Week 48; (x) fatigue response based on the Patient-Reported Outcomes Measurement Information System (PROMIS); and (xi) Endoscopic response, as measured by the Simplified Endoscopic Score for Crohn's Disease (SES-CD). The pharmaceutical composition of claim 7, characterized as satisfying the following:

9. 9. The pharmaceutical composition of claim 8, wherein the clinical endpoint is measured 4, 8, 12, 16, 20, 28, 32, 36, 40, 44, and / or 48 weeks after initial treatment.

10. 8. The pharmaceutical composition of claim 7, wherein the antibody is present in a composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) polysorbate 80, and the diluent is water at standard conditions.

11. The pharmaceutical composition of claim 1, wherein the method further comprises administering to the patient one or more additional drugs used to treat Crohn's disease.

12. 12. The pharmaceutical composition of claim 11, wherein the additional drug is selected from the group consisting of an immunosuppressant, a nonsteroidal anti-inflammatory drug (NSAID), methotrexate (MTX), an anti-B cell surface marker antibody, an anti-CD20 antibody, rituximab, a TNF inhibitor, a corticosteroid, and a costimulatory modulator.

13. The pharmaceutical composition of claim 1 , wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO: 8 and the heavy chain variable region amino acid sequence of SEQ ID NO:

7.

14. 2. The pharmaceutical composition of claim 1, wherein the antibody comprises a light chain amino acid sequence of SEQ ID NO: 10 and a heavy chain amino acid sequence of SEQ ID NO:

9.

15. 10. The pharmaceutical composition of claim 1, wherein the patient is considered a biotherapy non-responder or intolerant (Bio-non-responder) for Crohn's disease.

16. 2. The pharmaceutical composition of claim 1, wherein the patient is considered conventional therapy non-responsive or intolerant (Con non-responsive) for Crohn's disease.

17. 2. The pharmaceutical composition according to claim 1, wherein the Crohn's disease is moderate to severe active Crohn's disease.

18. 18. The pharmaceutical composition of claim 17, wherein the patient has endoscopic evidence of active Crohn's disease prior to administration of the first dose.

19. 18. The pharmaceutical composition of claim 17, wherein the patient has moderate to severe active Crohn's disease for at least three months prior to administration of the first dose.

20. 1. A pharmaceutical composition for use in a method for treating moderately to severely active Crohn's disease in a patient, the pharmaceutical composition comprising an antibody specific for IL23, the method comprising: (i) administering to the patient an initial subcutaneous dose of 400 mg of the antibody specific for IL23, a subcutaneous dose of 400 mg about 4 weeks after the initial dose, and a subcutaneous dose of 400 mg about 8 weeks after the initial dose; and (ii) administering further doses of 200 mg of the antibody about 8 weeks after the initial dose and thereafter about every 4 weeks thereafter, or a subcutaneous dose of 100 mg of the antibody about 8 weeks after the initial dose and thereafter about every 8 weeks thereafter. and administering to the patient a therapeutically effective amount of the antibody, wherein the antibody comprises a light chain variable region amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region amino acid sequence of SEQ ID NO: 7, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint approximately 12 weeks after the first administration, the clinical endpoint being clinical remission at week 12 defined as a CDAI of less than (<) 150 points or an endoscopic response measured by at least a 50% improvement from baseline in the Simplified Endoscopy Score for Crohn's Disease (SES-CD).

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