Methods for evaluating and treating psoriatic arthritis using anti-IL23 antibodies

Abstract

A method for treating psoriatic arthritis in a subject by measuring the Psoriasis Index DAPSA low disease activity (LDA) and the Investigator's Global Assessment (IGA), and adjusting or maintaining the dosage and dosing interval when administering an IL23 antibody, such as guselkumab, to evaluate the treatment of the subject with the IL23 antibody.

Description

Technical Field

[0001] (Reference to Electronically Submitted Sequence Listing) This application includes a sequence listing in XML format that has the file name "JBI6721WOPCT1 Sequence Listing.xml", a creation date of May 11, 2023, and a size of 11 Kb, and was electronically submitted via the Patent Center of the United States Patent and Trademark Office. The sequence listing submitted via the Patent Center is part of this specification and is hereby incorporated by reference in its entirety.

[0002] (Field of the Invention) The present invention relates to a method for evaluating treatment and treating psoriatic arthritis using an antibody that binds to human IL23 protein. In particular, this relates to a method for evaluating treatment with an IL23 antibody using a composite index and treating based on the evaluation with an IL23 antibody, such as guselkumab.

[0003] (Background of the Invention) Psoriatic arthritis is a chronic inflammatory arthritis of the peripheral and axial joints that affects approximately 0.02% - 0.25% of the general population. In patients with psoriasis, the prevalence of PsA ranges from 6% - 48%. However, arthritis does not correlate with the extent of the psoriatic skin disease. Psoriatic arthritis is a multifaceted disease that affects joints, soft tissues, and skin, all of which can impact quality of life. The disease burden can be severe, and some patients develop erosive arthritis leading to bone erosion and loss of joint structure. Some patients even require surgical intervention to relieve pain and restore function of severely damaged joints. Psoriatic arthritis is not only associated with functional impairment and reduced quality of life but also with early death due to an increased prevalence of cardiovascular and respiratory diseases compared to the general population.

[0004] Current treatment options for PsA include nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroid injections, low-dose systemic steroids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs, such as methotrexate [MTX], sulfasalazine [SSZ], and leflunomide [LEF]), and immunosuppressive drugs (such as cyclosporine A, tacrolimus). The addition of biologic therapies for PsA, including TNFα inhibitors (etanercept, infliximab, adalimumab, golimumab, certolizumab), ustekinumab (an IL-12 / IL-23 inhibitor), guselkumab (an IL-23 inhibitor), and secukinumab (an IL-17 inhibitor), either alone or in addition to conventional DMARDs, has significantly improved skin and joint responses in patients. Guselkumab (also known as CNTO1959 and sold as Tremfaya®) is a fully human IgG1 lambda monoclonal antibody that binds to the p19 subunit of IL-23 and inhibits the intracellular and downstream signaling of IL-23 required for the terminal differentiation of T helper (Th) 17 cells. Guselkumab is currently approved in the United States, the European Union, and other countries for the treatment of moderate to severe plaque psoriasis and active psoriatic arthritis. In addition, guselkumab is being evaluated in several other immune-mediated disorders, including but not limited to Crohn's disease and ulcerative colitis.

[0005] Composite indices are valuable tools for assessing the multidimensional nature of PsA and evaluating treatment. The Psoriatic Arthritis Disease Activity Score (PASDAS) provides a robust assessment of both the joint and skin domains but is cumbersome to use in clinical practice. The Disease Activity Index for Psoriatic Arthritis (DAPSA) is relatively easy to use but does not assess skin disease.

[0006] There is a need to evaluate the treatment of PsA using improved composite indices to aid in treatment decisions.

[0007] (Summary of the Invention) The present invention relates to the treatment of psoriastic arthritis (PsA). In particular, the present invention relates to evaluating a subject being treated for PsA with an IL23 antibody (or anti-IL23 antibody) and treating the subject based on the evaluation. In one aspect, this relates to evaluating treatment using a composite index and maintaining or adjusting treatment based on the evaluation using the composite index.

[0008] In a preferred embodiment, the present invention uses the Psoriasis Index DAPSA low disease activity (LDA) and the Investigator Global Assessment (IGA) by the treating physician to evaluate a subject being treated for PsA with an IL23 antibody, and when DASPA LDA (score ≤ 14) and IGA ≤ 1 are achieved, it predicts that the subject will achieve minimal disease activity (MDA) or the American College of Rheumatology 50 response criteria (ACR50) response, and relates to a method of adjusting or maintaining treatment and treating the subject based on the evaluation.

[0009] In additional embodiments, the evaluation results in an adjustment of the treatment with an IL23 antibody selected from the group consisting of adjusting the dosing interval to every 4 weeks or every 8 weeks and adjusting the dose to 50 mg, 100 mg, and / or 200 mg. If DASPA LDA (score ≤ 14) and IGA ≤ 1 are not achieved, one aspect of the invention is to increase the dose of the IL23 antibody administered, for example, increasing the dose from 50 mg to 100 mg or 200 mg, and / or decreasing the dosing interval, for example, from every 8 weeks to every 4 weeks.

[0010] In certain embodiments, the IL23 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the amino acid sequence of complementarity determining region heavy chain 1 (CDRH1) of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, and CDRH3 of SEQ ID NO: 3, and the light chain variable region comprising the amino acid sequence of complementarity determining region light chain 1 (CDRL1) of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0011] In certain embodiments, the IL23 antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8.

[0012] In certain embodiments, the IL23 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10.

[0013] In certain embodiments, the IL23 antibody is administered at a total dose of 25 mg to 200 mg per administration, preferably about 50 mg to about 150 mg, more preferably about 100 mg.

[0014] In certain embodiments, the subject is a responder to treatment with an IL-23 antibody and is identified as having a statistically significant improvement in disease activity, where disease activity is determined by one or more criteria selected from the group consisting of a 20% improvement in the American College of Rheumatology core set disease index (ACR20), a 50% improvement in the American College of Rheumatology core set disease index (ACR50), a 70% improvement in the American College of Rheumatology core set disease index (ACR70), the Health Assessment Questionnaire Disability Index (HAQ-DI), the Investigator's Global Assessment (IGA), the Disease Activity Score 28 (DAS28), C-reactive protein (CRP), resolution of enthesitis, resolution of dactylitis, the Leeds enthesitis index (LEI), the dactylitis assessment score, the Short Form Health survey (SF-36) in the mental and physical component summary (MCS and PCS), achievement of minimal disease activity (MDA), and achievement of very low disease activity (VLDA).

[0015] In certain embodiments, the subject achieves a significant improvement in the ACR20 response for guselkumab compared to placebo by week 24 of treatment.

[0016] In another general aspect, the invention relates to a method of treating psoriatic arthritis in a subject in need thereof, comprising administering an IL23 antibody subcutaneously to the subject, wherein the IL23 antibody is administered at an initial dose, a dose 4 weeks after the initial dose, and then at an administration interval of once every 4 weeks (q4w) or once every 8 weeks (q8w).

[0017] In certain embodiments, the IL23 antibody is administered at a total dose of from 25 mg to 200 mg per administration, preferably from about 50 mg to about 150 mg, more preferably about 100 mg per administration.

[0018] In certain embodiments, the subject has had an inadequate response to standard treatments for PsA. Optionally, the subject is also receiving standard treatment during treatment according to embodiments of the invention.

[0019] In specific embodiments of the invention, the IL23 can be tildrakizumab, mirikizumab, or risankizumab.

[0020] Details of one or more embodiments of the invention are set forth in the description below. Other features and advantages will be apparent from the following detailed description, drawings, and appended claims.

Brief Description of the Drawings

[0021] The above summary, and the following detailed description of the preferred embodiments of the present application, will be better understood when read in conjunction with the accompanying drawings. However, it should be understood that the present application is not limited to the embodiments shown in the drawings themselves.

Figure 1

[0022] (Detailed Description of the Invention) As used herein, methods of treating psoriatic arthritis include administering an isolated, recombinant, and / or synthetic anti-IL-23 specific human antibody, diagnostic and therapeutic compositions, methods, and devices.

[0023] As used herein, "IL23 antibody", "anti-IL-23 specific antibody", "anti-IL-23 antibody", "antibody portion", or "antibody fragment", and / or "antibody variant", etc. include at least one complementarity determining region (CDR) of the heavy or light chain or its ligand-binding portion, the heavy or light chain variable region, the heavy or light chain constant region, the framework region, or any part thereof, or at least a part of the IL-23 receptor or binding protein, etc., which can be incorporated into the antibodies of the present invention, but are not limited thereto, and include any protein or peptide-containing molecule containing at least a part of an immunoglobulin molecule. Such antibodies can optionally further affect and limit more specific ligands. For example, such antibodies can regulate, reduce, increase, antagonize, stimulate, alleviate, relieve, block, inhibit, suppress, and / or prevent at least one IL-23 activity or binding, or IL-23 receptor activity or binding in vitro, in situ, and / or in vivo. As a non-limiting example, suitable anti-IL-23 antibodies, specific portions, or variants of the present invention can bind to at least one IL-23 molecule, or a specific portion, variant, or domain thereof. Suitable anti-IL-23 antibodies, specific portions, or variants can also optionally affect at least one IL-23 activity or function, and such activities or functions include, but are not limited to, RNA, DNA, or protein synthesis, release of IL-23, signal transduction of the IL-23 receptor, cleavage of membrane IL-23, IL-23 activity, production and / or synthesis of IL-23, etc.

[0024] The term "antibody" is further intended to encompass antibodies, their digestive fragments, specific portions, and variants, including antibody mimetics, or including single-chain antibodies and their fragments, or portions of antibodies that mimic the structure and / or function of an antibody or a specific fragment or portion 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 partial reduction), and F(ab')2 (e.g., by pepsin digestion), facb (e.g., by plasmin digestion), pFc' (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction, and reassembly), Fv or scFv (e.g., by molecular biological techniques) fragments, among others, antibody fragments that can bind to IL-23 or a portion thereof are encompassed by the present invention (see, e.g., Colligan, Immunology supra).

[0025] Such fragments are known in the art and / or can be generated by enzymatic cleavage, synthesis, or recombinant techniques described herein. Antibodies can also be produced in various truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural termination site. For example, combinations of genes encoding the F(ab')2 heavy chain portion can be designed to include DNA sequences encoding the C H 1 domain and / or the hinge region. Various portions of an antibody can be chemically conjugated by conventional techniques or prepared as contiguous proteins using genetic engineering techniques.

[0026] As used herein, the term "human antibody" refers to substantially all portions of a protein (e.g., CDRs, frameworks, C L 、C H domains (e.g., C H 1, C H 2, C H 3), hinge (V L 、V Hrefers to an antibody that has only minor sequence changes or mutations and is substantially non-immunogenic in humans. A "human antibody" may be an antibody derived from or strictly corresponding to a human germline immunoglobulin sequence. A human antibody may contain amino acid residues not encoded by the germline immunoglobulin sequence (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). Often, this means that the human antibody is substantially non-immunogenic in humans. Human antibodies are classified into groups based on the similarity of their amino acid sequences. Thus, sequence similarity searches can be used to select antibodies with similar linear sequences as templates for generating human antibodies. Similarly, antibodies named including primates (such as monkeys, apes, chimpanzees, etc.), rodents (such as mice, rats, rabbits, guinea pigs, hamsters, etc.), and other mammals specify antibodies specific to such species, subgenera, genera, subfamilies, and families. Furthermore, chimeric antibodies can include any combination of the above. Such changes or mutations can optionally and preferably retain or reduce immunogenicity in humans or other species compared to the unmodified antibody. Thus, human antibodies are different from chimeric or humanized antibodies.

[0027] It is pointed out that human antibodies can be produced by non-human animals or prokaryotic or eukaryotic cells capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and / or light chain) genes. Furthermore, when a human antibody is a single-chain antibody, it can contain a linker peptide not found in native human antibodies. For example, Fv can contain a linker peptide such as 2 to about 8 glycine or other amino acid residues that connect the variable region of the heavy chain and the variable region of the light chain. Such a linker peptide is regarded as being of human origin.

[0028] Also, bispecific antibodies, heterospecific antibodies, heteroconjugate antibodies, or similar antibodies that are monoclonal, preferably human antibodies or humanized antibodies, having binding specificity for at least two different antigens can be used. In this case, one of the binding specificities is for at least one IL-23 protein and the other is for any other antigen. Methods for producing bispecific antibodies are known in the art. Conventionally, the recombinant production of bispecific antibodies has been based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature 305:537 (1983)). Due to the random combination of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a possible mixture of 10 different antibody molecules, only one of which has the correct bispecific structure. The purification of the correct molecule (usually performed by affinity chromatography steps) is quite cumbersome and the yield of the product is low. Similar procedures are disclosed in, for example, WO 93 / 08829, US Pat. Nos. 6210668, 6193967, 6132992, 6106833, 6060285, 6037453, 6010902, 5989530, 5959084, 5959083, 5932448, 5833985, 5821333, 5807706, 5643759, 5601819, 5582996, 5496549, 4676980, WO 91 / 00360, WO 92 / 00373, EP 03089, Traunecker et al., EMBO J. 10:3655 (1991), Suresh et al., Methods in Enzymology 121:210 (1986), each of which is hereby incorporated by reference in its entirety.

[0029] Antibodies specific for anti-IL-23 (also referred to as antibodies specific for IL-23) (or antibodies against IL-23), which are useful in the methods and compositions of the present invention, can be characterized, optionally, by high-affinity binding to IL-23 and, optionally and preferably, having low toxicity. Specifically, individual components such as variable regions, constant regions, and frameworks, individually and / or collectively, optionally and preferably, the antibodies of the present invention, specific fragments thereof, or variants having low immunogenicity are useful in the present invention. Antibodies that can be used in the present invention are optionally characterized by the ability to treat patients over a long period of time with a measurable alleviation of symptoms and low and / or acceptable toxicity. Low or acceptable immunogenicity, and / or high affinity, and other suitable properties can contribute to the treatment results obtained. "Low immunogenicity" as used herein refers to raising a significant HAHA, HACA, or HAMA response in less than about 75%, or preferably less than about 50%, of the patients being treated and / or raising a low titer (less than about 300, preferably less than about 100, as measured by a double antigen enzyme immunoassay) in the patients being treated (Elliott et al., Lancet 344:1125-1127 (1994), which is incorporated herein by reference in its entirety). "Low immunogenicity" can also be defined as the incidence of an incremental level of antibodies against the anti-IL-23 antibody in patients treated with the anti-IL-23 antibody when it occurs in less than 25%, preferably less than 10%, of the patients treated at the recommended dose over the recommended treatment course during the treatment period.

[0030] The terms "clinically proven efficacy" and "clinically proven to be effective" as used herein in the context of a dosage, dosing regimen, treatment or method mean the clinically proven efficacy of a particular dosage, administration, or treatment regimen. Efficacy can be measured based on changes during the course of a disease in response to the agent of the invention, based on clinical trials conducted, e.g., phase 3 and earlier clinical trials. For example, an anti-IL-23 antibody of the invention (e.g., the anti-IL-23 antibody guselkumab) is administered to a subject in an amount and for a time sufficient to cause improvement, preferably sustained improvement, in at least one measure that reflects the severity of the disorder being treated. To determine whether the amount and time of such treatment is sufficient, various measures can be evaluated that reflect the degree of the subject's disease, disorder, or condition. Such measures include, for example, clinically recognized measures of disease severity, symptoms, or manifestations of the disorder in question. The degree of improvement is generally determined by a physician, who can make this determination based on signs, symptoms, biopsies, or other test results, and can also employ questionnaires administered to the subject, e.g., questionnaires regarding quality of life developed for a given disease. For example, an anti-IL-23 antibody of the invention can be administered to achieve improvement in the condition of a patient associated with psoriatic arthritis. This improvement can be demonstrated by improvement in a disease activity index, remission of clinical symptoms, or any other measure of disease activity.

[0031] In one embodiment, the effectiveness of the treatment of psoriatic arthritis in a subject can be determined using the preliminary criteria of the American College of Rheumatology (ACR) for improvement in rheumatoid arthritis. The ACR criteria measure improvement in the number of tender or swollen joints, and improvement in three of the following five parameters: acute phase reactants (such as erythrocyte sedimentation rate); patient assessment; physician assessment; pain scale; and disability / function questionnaire. The ACR criteria are shown as ACR20 (20% improvement in the number of tender or swollen joints, and 20% improvement in three of the other five criteria), ACR50 (50% improvement in the number of tender or swollen joints, and 50% improvement in three of the other five criteria), and ACR70 (70% improvement in the number of tender or swollen joints, and 70% improvement in three of the other five criteria) (see Felson D T, et al. Arthritis Rheum 1995;38:727-35).

[0032] In another embodiment, the effectiveness of the treatment of psoriatic arthritis in a subject is determined by the Psoriasis Area and Severity Index (PASI), which is a disease index used to assess the severity / extent of the skin disease. For example, PASI75 = 75% improvement, PASI90 = 90% improvement, PASI100 = plaques substantially removed. Measures of effectiveness can also include one or more of the Health Assessment Questionnaire Disability Index (HAQ-DI), improvement in enthesitis / dactylitis in patients with baseline enthesitis / dactylitis, changes in the mental and physical component summary (MCS and PCS) scores of the SF-36, and achievement of the Minimal Disease Activity (MDA) criteria score.

[0033] The term "clinically proven safety", when referring to the dosage, administration regimen, treatment or method with an anti-IL-23 antibody of the present invention (e.g., the anti-IL-23 antibody guselkumab), refers to a relatively low or reduced frequency and / or low or reduced severity of adverse events (referred to as AE or TEAE) occurring during treatment, as compared to standard treatment or another comparator, for example, from clinical trials being conducted, for example, phase 2 clinical trials, and previous clinical trials. An adverse event is an undesirable medical occurrence in a patient administered a pharmaceutical product. In particular, when related to the dosage, administration regimen or treatment with an anti-IL-23 antibody of the present invention, clinically proven safety refers to a relatively low or reduced frequency and / or low or reduced severity of adverse events related to the administration of the antibody when the cause is likely, highly likely, or very highly likely to be due to the use of the anti-IL-23 antibody.

[0034] As used herein, unless otherwise noted, the term "clinically proven" (used alone or to modify the terms "safety" and / or "efficacy") shall mean proven by clinical trials that meet the approval criteria of the US Food and Drug Administration, EMEA, or corresponding national regulatory agencies. For example, the clinical trial may be a randomized double-blind trial of appropriate size used to clinically prove the effect of the drug.

[0035] Usefulness The isolated nucleic acid of the present invention can be used for the production of at least one anti-IL-23 antibody or a specific variant thereof, and the antibody or variant can be used to diagnose, observe, regulate, treat, alleviate the symptoms of psoriasis, assist in preventing its occurrence, or reduce its symptoms, for measuring or acting on cells, tissues, organs, or animals (including mammals and humans).

[0036] Such a method can comprise administering to a cell, tissue, organ, animal, or patient in need of modulating, treating, alleviating, preventing, or reducing a symptom, effect, or mechanism, an effective amount of a composition or pharmaceutical composition comprising at least one anti-IL-23 antibody. The effective amount can be an amount of from about 0.001 to 500 mg / kg per single (e.g., bolus), multiple, or continuous administration, or an amount that achieves a serum concentration of from 0.01 to 5000 μg / mL per single, multiple, or continuous administration, or any effective range or value therein, as determined and effected using known methods described herein or known in the relevant art.

[0037] Cited References All publications or patents cited herein, whether or not specifically designated, are hereby incorporated by reference in their entirety, to show the state of the art at the time of the invention and / or to provide support for the description and enablement of the invention. Publications refer to any scientific publication or patent gazette or any other information available in any media format, including any that are recorded in electronic or print format. The following references are hereby incorporated 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., Molecular Cloning: A Laboratory Manual, 2 ndEdition, Cold Spring Harbor, NY (1989), Harlow and Lane, antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989), Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994 - 2001), Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997 - 2001).

[0038] Antibody - production and generation useful for the present invention At least one anti - IL - 23 used in the method of the present invention can optionally be produced by a cell line, mixed cell line, immortalized cell, or clonal population of immortalized cells well - known in the art. For example, Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987 - 2001), Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2, each of which is hereby incorporated by reference in its entirety. nd See Edition, Cold Spring Harbor, NY (1989), Harlow and Lane, antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989), Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994 - 2001), Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997 - 2001).

[0039] Human antibodies specific for the human IL-23 protein or fragments thereof can be raised against suitable immunogenic antigens such as isolated IL-23 protein and / or a portion thereof (including synthetic molecules such as synthetic peptides). Other specific or general mammalian antibodies can be produced similarly. Preparation of the immunogenic antigen and production of monoclonal antibodies can be carried out using any suitable technique.

[0040] In one approach, a suitable immortal cell line (e.g., but not limited to, myeloma cell lines such as Sp2 / 0, Sp2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, L243, P3X63Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5, U937, MLA 144, ACT IV, MOLT4, DA-1, JURKAT, WEHI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA 144, NAMALWA, NEURO 2A, or heteromyelomas, their fusion products, or any cell or fusion cell derived therefrom, or any other suitable cell line well known in the art) (see, e.g., www.atcc.org, www.lifetech.com., etc.) is fused with an antibody-producing cell such as, but not limited to, an isolated or cloned spleen, peripheral blood, lymph, tonsil, or other immune or B cell-containing cell, or any other cell expressing a constant or variable, or framework or CDR sequence of a heavy or light chain, as either a recombinant or endogenous, virus, bacterium, alga, prokaryote, amphibian, insect, reptile, fish, mammal, rodent, horse, sheep, goat, primate, eukaryote, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single, double or triple stranded, hybridized, etc., or any combination thereof, to produce a hybridoma. See, e.g., Ausubel, supra, and Chapter 2 of Colligan, Immunology, supra, which are hereby incorporated by reference in their entirety.

[0041] Antibody-producing cells can also be obtained from the peripheral blood of humans or other suitable animals immunized with the antigen of interest, or preferably from the spleen or lymph nodes. Heterologous or endogenous nucleic acids encoding the antibodies, specific fragments or variants of the invention can also be expressed using any other suitable host cells. Fusion cells (hybridomas) or recombinant cells can be isolated using selective culture conditions or other suitable known methods and cloned by limiting dilution or cell sorting or other known methods. Cells producing antibodies with the desired specificity can be selected by suitable assays (e.g., ELISA).

[0042] Methods for selecting recombinant antibodies from peptide or protein libraries, but not limited to these, can be used to produce or isolate antibodies with the required specificity, and other suitable methods can be used (for example, display libraries such as bacteriophage, ribosome, oligonucleotide, RNA, cDNA, etc., but not limited to these, for example, available from Cambridge antibody Technologies, Cambridgeshire, UK, MorphoSys, Martinsreid / Planegg, DE, Biovation, Aberdeen, Scotland, UK, BioInvent, Lund, Sweden, Dyax Corp., Enzon, Affymax / Biosite, Xoma, Berkeley, CA, Ixsys.).For example, European Patent No. 368,684, International Application PCT / GB91 / 01134, International Application No. GB92 / 01755, International Application No. GB92 / 002240, International Application No. GB92 / 00883, International Application No. GB93 / 00605, US Patent Application No. 08 / 350260 (5 / 12 / 94), International Application No. GB94 / 01422, International Application No. GB94 / 02662, International Application No. GB97 / 01835, (CAT / MRC), International Publication No. 90 / 14443, International Publication No. 90 / 14424, International Publication No. 90 / 14430, International Application No. US94 / 1234, International Publication No. 92 / 18619, International Publication No. 96 / 07754, (Scripps), International Publication No. 96 / 13583, International Publication No. 97 / 08320 (MorphoSys), International Publication No. 95 / 16027 (BioInvent), International Publication No. 88 / 06630, International Publication No. 90 / 3809 (Dyax), US Patent 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 (Ixsys), or a probabilistically generated peptide or protein - US Patent Nos. 5723323, 5763192, 5814476, 5817483, 5824514, 5976862, International Publication No. 86 / 05803, European Patent No. 590689 (Ixsys, the predecessor of Applied Molecular Evolution (AME), each incorporated herein by reference in its entirety), or depending on immunization of transgenic animals capable of producing a repertoire of human antibodies known in the art and / or described herein (e.g., SCID mice, each incorporated herein by reference in its entirety, Nguyen et 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, but are not limited to, ribosome display (Hanes et al., Proc. Natl. Acad. Sci. USA, 94:4937-4942 (May 1997), Hanes et al., Proc. Natl. Acad. Sci. USA, 95:14130-14135 (Nov. 1998)), single cell antibody production techniques (e.g., selected lymphocyte antibody method, "SLAM") (U.S. Patent No. 5,627,052, Wen et al., J. Immunol. 17:887-892 (1987); Babcock et al., Proc. Natl. Acad. Sci. USA 93:7843-7848 (1996)), gel microdroplets and flow cytometry (Powell et al., Biotechnol. 8:333-337 (1990), One Cell Systems, Cambridge, MA, Gray et al., J. Imm. Meth. 182:155-163 (1995), Kenny et al., Bio / Technol. 13:787-790 (1995)), B cell selections (Steenbakkers et al., Molec. Biol. Reports 19:125-134 (1994), Jonak et al., Progress Biotech, Vol. 5, In Vitro Immunization in Hybridoma Technology, Borrebaeck, ed., Elsevier Science Publishers B.V., Amsterdam, Netherlands (1988)).

[0043] Methods for engineering or humanizing non-human or human antibodies can also be used and are known in the art. Generally, humanized or engineered antibodies have one or more amino acid residues from non-human sources, such as, but not limited to, mouse, rat, rabbit, non-human primate, or other mammalian sources. These non-human amino acid residues are often replaced by residues often referred to as "import" residues, which are typically obtained from the "import" variable domains, constant domains, or other domains of known human sequences.

[0044] Known human Ig sequences are, for example, available at: :www.ncbi.nlm.nih.gov / entrez / query.fcgi, www.ncbi.nih.gov / igblast, www.atcc.org / phage / hdb.html, www.mrc-cpe.cam.ac.uk / ALIGNMENTS.php, www.kabatdatabase.com / top.html, ftp.ncbi.nih.gov / repository / kabat, www.sciquest.com, www.abcam.com, www.antibodyresource.com / onlinecomp.html, www.public.iastate.edu / ~pedro / research_tools.html, www.whfreeman.com / immunology / CH05 / kuby05.htm, www.hhmi.org / grants / lectures / 1996 / vlab, www.path.cam.ac.uk / ~mrc7 / mikeimages.html, mcb.harvard.edu / BioLinks / Immunology.html, www.immunologylink.com, pathbox.wustl.edu / ~hcenter / index.html, www.appliedbiosystems.com, www.nal.usda.gov / awic / pubs / antibody, www.m.ehime-u.ac.jp / ~yasuhito / Elisa.html, www.biodesign.com, www.cancerresearchuk.org, www.biotech.ufl.edu, www.isac-net.org, baserv.uci.kun.nl / ~jraats / links1.html, www.recab.uni-hd.de / immuno.bme.nwu.edu, www.mrc-cpe.cam.ac.uk, 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 / ~ubcg07s, www.nimr.mrc.ac.uk / CC / ccaewg / ccaewg.It is disclosed in html, www.path.cam.ac.uk / ~mrc7 / humanisation / TAHHP.html, www.ibt.unam.mx / vir / structure / stat_aim.html, www.biosci.missouri.edu / smithgp / index.html, www.jerini.de, Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Dept. Health (1983).

[0045] Using such imported sequences, immunogenicity can be reduced or, as known in the art, binding, affinity, association rate constant, dissociation rate constant, binding activity, specificity, half-life, or any other suitable property can be reduced, enhanced, or modified. Generally, CDR residues directly and substantially affect antigen binding. Thus, non-human CDR sequences or part or all of human CDR sequences can be maintained while replacing non-human sequences of the variable and constant regions with human amino acids or other amino acids.

[0046] The antibody can optionally be a humanized or human antibody engineered while retaining high affinity for the antigen and other advantageous biological properties. To achieve this objective, humanized (or human) antibodies can be prepared, optionally, by a process of analyzing the parental and various theoretical humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are generally available and well known to those skilled in the art. Computer programs are available that illustrate and display a likely three-dimensional conformation for selected immunoglobulin sequence candidates. By examining these displays, it is possible to analyze the likely role that residues play in the function of the immunoglobulin sequence candidate, i.e., to analyze the residues that affect the antigen-binding ability of the immunoglobulin candidate. In this way, framework (FR) residues can be selected and combined from the consensus and import sequences so as to achieve desired antibody properties such as enhanced affinity for the target antigen.

[0047] In addition, the antibody specific for human IL-23 used in the methods of the invention can include a human germline light chain framework. In certain embodiments, the light chain germline sequence is selected from human VK sequences including, but not limited to, A1, A10, A11, 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 / 18a, L5, L6, L8, L9, O1, O11, O12, O14, O18, O2, O4, and O8. In certain embodiments, the light chain human germline framework is selected from 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.

[0048] In other embodiments, the antibody specific for human IL-23 used in the methods of the invention may comprise a human germline heavy chain framework. In certain embodiments, the heavy chain human germline framework is selected from 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, VH3-20, VH3-21, VH3-23, VH3-30, VH3-33, VH3-35, VH3-38, VH3-43, VH3-48, VH3-49, VH3-53, VH3-64, VH3-66, VH3-7, VH3-72, VH3-73, VH3-74, VH3-9, VH4-28, VH4-31, VH4-34, VH4-39, VH4-4, VH4-59, VH4-61, VH5-51, VH6-1, and VH7-81.

[0049] In certain embodiments, the light chain variable region and / or the heavy chain variable region comprise a framework region, or at least a portion of a framework region (e.g., comprising two or three sub-regions such as FR2 and FR3). In certain embodiments, at least FRL1, FRL2, FRL3, or FRL4 is fully human. In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is fully human. In some embodiments, at least FRL1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., human germline), or comprises a human consensus sequence for a particular framework (readily available from sources of known human Ig sequences as described above). In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., human germline), or comprises a human consensus sequence for a particular framework. In preferred embodiments, the framework region is a complete human framework region.

[0050] Humanization or engineering of the antibodies of the present invention can be performed using any known method, such as those described in Winter (Jones et al., Nature 321:522 (1986), Riechmann et al., Nature 332:323 (1988), Verhoeyen et al., Science 239:1534 (1988)), Sims et al., J. Immunol. 151:2296 (1993), Chothia and Lesk, J. Mol. Biol. 196:901 (1987), Carter et al., Proc. Natl. Acad. Sci. U.S.A. 89:4285 (1992), Presta et al., J. Immunol. 151:2623 (1993), U.S. Patent Nos. 5,723,323, 5,976,862, 5,824,514, 5,817,483, 5,814,476, 5,763,192, 5,723,323, 5,766,886, 5,714,352, 6,204,023, 6,180,370, 5,693,762, 5,530,101, 5,585,089, 5,225,539, 4,816,567, International Application Nos. US98 / 16280, US96 / 18978, US91 / 09630, US91 / 05939, US94 / 01234, International Application Nos. GB89 / 01334, GB91 / 01134, GB92 / 01755, International Publication Nos. 90 / 14443, 90 / 14424, 90 / 14430, European Patent No. 229246 (each incorporated by reference in its entirety and including the documents cited therein), but not limited thereto.

[0051] In certain embodiments, the antibody comprises a modified (e.g., mutated) Fc region. For example, in some embodiments, the Fc region is modified to reduce or enhance the effector function of the antibody. In some embodiments, the Fc region is an isotype selected from IgM, IgA, IgG, IgE, or other isotypes. Alternatively, or additionally, it may be useful to combine amino acid modifications with one or more further amino acid modifications that modify the C1q binding and / or complement-dependent cytotoxicity function of the Fc region of the IL-23 binding molecule. Particular polypeptides of interest may bind to C1q and exhibit complement dependent cytotoxicity (CDC). Polypeptides having existing C1q binding activity and optionally further having the ability to mediate CDC may be modified such that one or both of these activities are enhanced. Amino acid modifications that modify C1q and / or its complement-dependent cytotoxic function are described, for example, in WO 0042072, which is incorporated herein by reference.

[0052] As disclosed above, for example, by modifying C1q binding and / or FcγR binding, thereby changing the complement-dependent cytotoxicity (CDC) activity and / or the antibody-dependent cell-mediated cytotoxicity (ADCC) activity, the Fc region of the human IL-23 specific antibody of the present invention having an altered effector function can be designed. "Effector function" serves to activate or reduce biological activity (e.g., in a subject). Examples of effector functions include, but are not limited to, C1q binding, CDC, Fc receptor binding, ADCC, phagocytosis, downregulation of cell surface receptors (e.g., B cell receptor, BCR). Such effector functions may require the Fc region to bind to a binding domain (e.g., the antibody variable domain) and can be evaluated using a variety of test methods (e.g., Fc binding assay, ADCC assay, CDC assay, etc.).

[0053] For example, a variant Fc region of a human IL-23 (or anti-IL-23) antibody having improved C1q binding and improved FcγRIII binding (e.g., having both improved ADCC activity and improved CDC activity) can be generated. Alternatively, if it is desired to reduce or eliminate the effector function, the variant Fc region can be engineered to have reduced CDC activity and / or reduced ADCC activity. In other embodiments, only one of these activities may be enhanced, and optionally, the other activity may be reduced simultaneously (e.g., to generate an Fc region variant having improved ADCC activity but reduced CDC activity, and the reverse Fc region variant).

[0054] Fc variants can also be engineered and introduced to modify their interaction with the neonatal Fc receptor (FcRn) and improve their pharmacokinetic properties. A collection of human Fc variants with improved binding to FcRn has been described (Shields et al., (2001). High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FCγR, J. Biol. Chem. 276:6591-6604).

[0055] Another type of amino acid substitution acts to modify the glycosylation pattern of the Fc region of an antibody specific for human IL-23. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars, N-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. The recognition sequences for the 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. Thus, the presence of any of these peptide sequences in a polypeptide results in a potential glycosylation site.

[0056] The glycosylation pattern can be modified, for example, by deleting one or more glycosylation sites found in the polypeptide and / or adding one or more glycosylation sites not present in the polypeptide. Addition of a glycosylation site to the Fc region of an antibody specific for human IL-23 is successfully achieved by modifying the amino acid sequence to include one or more of the above tripeptide sequences (in the case of an N-linked glycosylation site). Representative glycosylation variants have an amino acid substitution at residue Asn297 of the heavy chain. This modification may be done by addition or substitution of one or more serine or threonine residues to the original polypeptide sequence (in the case of an O-linked glycosylation site). Additionally, changing Asn 297 to Ala can remove one of the glycosylation sites.

[0057] In certain embodiments, the antibody specific for human IL-23 of the invention is expressed in cells that express beta(1,4)-N-acetylglucosaminyltransferase III (GnT III) such that GnT III adds GlcNAc to the human IL-23 antibody. Methods for producing antibodies in such a manner are provided in International Publication Nos. WO 99 / 54342, WO 03 / 011878, JP 2003-0003097 (A1), and Umana et al., Nature Biotechnology, 17:176-180, Feb. 1999, all of which are hereby expressly incorporated by reference in their entirety.

[0058] The anti-IL-23 antibody may also optionally be generated by immunization of transgenic animals (e.g., mice, rats, hamsters, non-human primates, etc.) that can generate a repertoire of human antibodies as described herein and / or known in the art. Cells producing the human anti-IL-23 antibody can be isolated and immortalized from such animals using suitable methods such as those described herein.

[0059] Transgenic mice capable of generating a repertoire of human antibodies that bind to human antigens can be generated by known methods (e.g., U.S. Patent Nos. 5,770,428, 5,569,825, 5,545,806, 5,625,126, 5,625,825, 5,633,425, 5,661,016, and 5,789,650 issued to Lonberg et al., International Publication Nos. 98 / 50433 and 98 / 24893 issued to Jakobovits et al., International Publication Nos. 98 / 24884, 97 / 13852, and 94 / 25585 issued to Lonberg et al., International Publication No. 96 / 34096 issued to Kucherlapate et al., European Patent Nos. 0463151 (B1) and 0710719 (A1) issued to Kucherlapate et al., U.S. Patent No. 5,545,807 issued to Surani et al., International Publication No. 90 / 04036 issued to Bruggemann et al., European Patent No. 0438474 (B1) issued to Bruggemann et al., European Patent No. 0814259 (A2) issued to Lonberg et al., British Patent No. 2272440 (A) issued to Lonberg et al., Lonberg et al., Nature 368:856 - 859 (1994), Taylor et al., Int. Immunol. 6(4) 579 - 591 (1994), Green et al., Nature Genetics 7:13 - 21 (1994), Mendez et al., Nature Genetics 15:146 - 156 (1997), Taylor et al., Nucleic Acids Research 20(23):6287 - 6295 (1992), Tuaillon 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., Nat Biotechnol 14(7):845 - 851 (1996), each of which is incorporated herein by reference in its entirety).Generally, these mice contain at least one transgene comprising DNA derived from at least one human immunoglobulin locus that has been functionally rearranged or is capable of undergoing functional rearrangement. The endogenous immunoglobulin locus of such mice can be disrupted or deleted to eliminate the mouse's ability to produce antibodies encoded by the endogenous genes.

[0060] Screening of antibodies for specific binding to similar proteins or fragments can be successfully achieved using peptide display libraries. The method involves screening a large collection of peptides for individual members having a desired function or structure. Antibody screening of peptide display libraries is well known in the art. The displayed peptide sequences can be from 3 to 5000 or more amino acids in length, frequently 5 to 100 amino acids in length, and often about 8 to 25 amino acids in length. In addition to direct chemical synthesis methods for creating peptide libraries, several recombinant DNA methods have also been described. One type involves the display of peptide sequences on the surface of bacteriophage or cells. Each bacteriophage or cell contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. WO 91 / 17271, WO 91 / 18980, WO 91 / 19818, and WO 93 / 08278.

[0061] Other systems for creating peptide libraries have aspects of both in vitro chemical synthesis and recombinant methods. See International Publications Nos. WO 92 / 05258, WO 92 / 14843, and WO 96 / 19256. See also U.S. Pat. Nos. 5,658,754 and 5,643,768. Peptide display libraries, vectors, and screening kits are commercially available from suppliers such as Invitrogen (Carlsbad, CA) and Cambridge Antibody Technologies (Cambridgeshire, UK). For example, see U.S. Pat. Nos. 4,704,692, 4,939,666, 4,946,778, 5,260,203, 5,455,030, 5,518,889, 5,534,621, 5,656,730, 5,763,733, 5,767,260, 5,856,456, assigned to Enzon; U.S. Pat. Nos. 5,223,409, 5,403,484, 5,571,698, 5,837,500, assigned to Dyax; U.S. Pat. Nos. 5,427,908, 5,580,717, assigned to Affymax; U.S. Pat. No. 5,885,793, assigned to Cambridge Antibody Technologies; U.S. Pat. No. 5,750,373, assigned to Genentech; U.S. Pat. Nos. 5,618,920, 5,595,898, 5,576,195, 5,698,435, 5,693,493, 5,698,417, assigned to Xoma; see also Colligan, Ausubel, or Sambrook, supra. Each of the above patents and publications is hereby incorporated by reference in its entirety.

[0062] The antibodies used in the method of the present invention can also be prepared using at least one anti-IL23 antibody encoding a nucleic acid in order to provide transgenic animals or mammals such as goats, cows, horses, sheep, rabbits, etc. that produce such antibodies in milk. Such animals can be provided using known methods. For example, but not limited to, see U.S. Patent Nos. 5,827,690, 5,849,992, 4,873,316, 5,849,992, 5,994,616, 5,565,362, 5,304,489, etc., each of which is incorporated herein by reference in its entirety.

[0063] The antibodies used in the method of the present invention can additionally be prepared using at least one anti-IL23 antibody encoding a nucleic acid in order to provide transgenic plants and cultured plant cells (such as, but not limited to, tobacco and corn) that produce such antibodies, specific moieties, or variants in plant parts or cells cultured therefrom. As a non-limiting example, for instance, transgenic tobacco leaves expressing recombinant proteins have been successfully used, using an inducible promoter, to provide large amounts of recombinant proteins. See, for example, Cramer et al., Curr. Top. Microbol. Immunol. 240:95-118 (1999) and the references cited therein. Also, transgenic corn has been used to express mammalian proteins having biological activity equivalent to proteins produced in other recombinant systems or purified from natural sources at commercial production levels. See, for example, Hood et al., Adv. Exp. Med. Biol. 464:127-147 (1999) and the references cited therein. Antibodies have also been produced in large quantities from seeds of transgenic plants containing antibody fragments such as single chain antibodies (scFv) including tobacco seeds and potato tubers. See, for example, Conrad et al., Plant Mol. Biol. 38:101-109 (1998) and the references cited therein. Thus, the antibodies of the present invention can also be produced using transgenic plants according to known methods. See, for example, Fischer et al., Biotechnol. Appl. Biochem. 30:99-108 (Oct., 1999), Ma et al., Trends Biotechnol. 13:522-7 (1995), Ma et al., Plant Physiol. 109:341-6 (1995), Whitelam et al., Biochem. Soc. Trans. 22:940-944 (1994), and the references cited therein. Each of the above references is hereby incorporated by reference in its entirety into this specification.

[0064] The antibodies used in the method of the present invention can bind to human IL-23 with a wide range of affinities (K D ). In a preferred embodiment, the human mAb can optionally bind to human IL-23 with high affinity. For example, the human mAb can bind human IL-23 at about 10 -7 M or less, for example, but not limited to, 0.1 - 9.9 (or any range or value therein) × 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 , or any range or value therein, such as K D .

[0065] The affinity or binding activity of an antibody for an antigen can be determined experimentally using any suitable method. (See, for example, Berzofsky, et al., “Antibody - Antigen Interactions,” Fundamental Immunology, Paul, W.E., Ed., Raven Press: New York, NY (1984), Kuby, Janis Immunology, W.H. Freeman and Company: New York, NY (1992), and the methods described herein). The affinity measured for a particular antibody - antigen interaction can vary when measured under different conditions (e.g., salt concentration, pH). Thus, the measurement of affinity and other antigen - binding parameters (e.g., K D , K a , K d ) is preferably performed using a standardized solution of the antibody and antigen and a standardized buffer such as the buffers described herein.

[0066] Nucleic acid molecule Among other sequences disclosed herein, for example, using the information provided herein such as nucleotide sequences encoding at least 70-100% of at least one adjacent amino acid of a light or heavy chain variable or CDR region described herein, specific fragments, variants, or consensus sequences thereof, or a deposited vector containing at least one of these sequences, the nucleic acid molecule of the present invention encoding at least one anti-IL-23 antibody can be obtained using methods described herein or known in the art.

[0067] The nucleic acid molecule of the present invention can be in the form of RNA such as mRNA, hnRNA, tRNA, or any other form, or in the form of DNA including, but not limited to, cDNA and genomic DNA obtained by cloning or produced synthetically, or any combination thereof. The DNA can be triple-stranded, double-stranded or single-stranded, or any combination thereof. Any portion of at least one strand of the DNA or RNA can be the coding strand, also known as the sense strand, or the non-coding strand, also called the antisense strand.

[0068] Isolated nucleic acid molecules used in the method of the present invention may optionally include one or more introns, for example, but not limited to, at least one specific portion of at least one CDR, such as at least one of CDR1, CDR2, and / or CDR3 of at least one heavy or light chain, a nucleic acid molecule comprising an open reading frame (ORF), a nucleic acid molecule comprising a coding sequence of an anti-IL-23 antibody or a variable region, and a nucleic acid molecule comprising a nucleotide sequence substantially different from the foregoing, but still encoding at least one anti-IL-23 antibody described herein and / or known in the art due to the degeneracy of the genetic code. Of course, the genetic code is well known in the art. Thus, it would be routine for one of ordinary skill in the art to create such degenerate nucleic acid variants encoding specific anti-IL-23 antibodies used in the methods of the present invention. See, for example, Ausubel et al. supra. Such nucleic acid variants are included in the present invention. Non-limiting examples of isolated nucleic acid molecules include nucleic acids encoding HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, respectively.

[0069] As described herein, nucleic acid molecules comprising a nucleic acid encoding an anti-IL-23 antibody include those that encode the amino acid sequence of an antibody fragment by itself, sequences encoding an entire antibody or a portion thereof, coding sequences of an antibody, fragment or portion, and additional sequences, such as at least one intron, etc., with or without the aforementioned additional coding sequences, non-coding 5' and 3' sequences, such as transcribed untranslated sequences involved in transcription, mRNA processing, including splicing and polyadenylation signals (e.g., ribosome binding and stability of mRNA), and can include, but are not limited to, additional non-coding sequences, together with at least one signal leader or coding sequence of a fusion peptide, additional coding sequences encoding additional amino acids, such as amino acids providing additional functions, etc., but are not limited thereto. Thus, the sequence encoding the antibody can be fused to a marker sequence, for example, the marker sequence is a sequence encoding a peptide that facilitates the purification of an antibody containing the antibody fragment or portion to which it is fused.

[0070] A polynucleotide that selectively hybridizes to the polynucleotide described herein The methods of the invention use isolated nucleic acids that hybridize under selective hybridization conditions to the polynucleotides disclosed herein. Thus, the polynucleotides of this embodiment can be used to isolate, detect, and / or quantify nucleic acids containing such polynucleotides. For example, the polynucleotides of the invention can be used to identify, isolate, or amplify partial-length or full-length clones in a deposited library. In some embodiments, the polynucleotide is an isolated or otherwise genomic or cDNA sequence that is complementary to cDNA of a human or mammalian nucleic acid library.

[0071] Preferably, the cDNA library contains at least 80% of the full-length sequence, preferably at least 85% or 90% of the full-length sequence, more preferably at least 95% of the full-length sequence. This cDNA library can be normalized to increase the expression level of rare sequences. Low or medium stringency hybridization conditions, which typically use sequences with low sequence identity to the complementary sequence, are typical but not limited to this. For sequences with higher identity, medium and high stringency conditions can optionally be used. Low stringency conditions allow for the selective hybridization of sequences with about 70% sequence identity and can be used to specifically identify orthologous or paralogous sequences.

[0072] Optionally, the polynucleotide encodes at least a portion of an antibody. The polynucleotide includes nucleic acid sequences that can be used for selective hybridization to the polynucleotide encoding the antibody of the present invention. For example, see Ausubel and Colligan above, each of which is hereby incorporated by reference in its entirety.

[0073] Construction of Nucleic Acids Isolated nucleic acids can be made using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, and / or (d) combinations thereof, as is well known in the art.

[0074] In addition to the polynucleotides of the present invention, convenient sequences can be included in the nucleic acids. For example, a multiple cloning site containing one or more endonuclease restriction sites can be inserted into the nucleic acid to facilitate the isolation of the polynucleotide. Also, a translatable sequence can be inserted to facilitate the isolation of the translated polynucleotide of the present invention. For example, a hexahistidine marker sequence provides a convenient means for purifying the protein of the present invention. The nucleic acids of the present invention (excluding the coding sequence) are optionally vectors, adapters, or linkers for the cloning and / or expression of the polynucleotides of the present invention.

[0075] Additional sequences can be added to such cloning and / or expression sequences to optimize their functions in cloning and / or expression, to aid in the isolation of polynucleotides, or to improve the introduction of polynucleotides into cells. The use of cloning vectors, expression vectors, adapters, and linkers is well known in the art. (See, for example, Ausubel supra, or Sambrook supra).

[0076] Recombinant methods for constructing nucleic acids Isolated nucleic acid compositions such as RNA, cDNA, genomic DNA, or any combination thereof can be obtained from biological sources using any number of cloning methods known to those of skill in the art. In some embodiments, oligonucleotide probes that selectively hybridize to the polynucleotides of the invention under stringent conditions are used to identify the desired sequences within cDNA or genomic DNA libraries. The isolation of RNA, as well as the construction of cDNA and genomic libraries, are well known to those of skill in the art. (See, for example, Ausubel supra, or Sambrook supra)

[0077] Methods for screening and isolating nucleic acids Using a probe based on the sequence of a polynucleotide used in the method of the present invention, such as those disclosed herein, cDNA or genomic libraries can be screened. The probe can be used to hybridize to genomic DNA or cDNA sequences to isolate homologous genes from the same or different organisms. One skilled in the art can use various degrees of hybridization stringency in the assay and understand that either the hybridization or washing medium can be made stringent. The more stringent the hybridization conditions, the greater the degree of complementarity between the probe and the target when double-stranded formation occurs. The degree of stringency can be controlled by one or more of temperature, ionic strength, pH, and the presence of a partially denaturing solvent such as formamide. For example, the stringency of hybridization can be successfully altered by changing the polarity of the reaction solution by manipulating the formamide concentration within a range of, for example, 0% to 50%. The degree of complementarity (sequence identity) required for detectable binding varies depending on the stringency of the hybridization medium and / or washing medium. The degree of complementarity is optimally 100%, or 70 to 100%, or any range or value therein. However, it should be understood that minor differences in the sequences in the probe and primer can be compensated for by reducing the stringency of the hybridization and / or washing medium.

[0078] Methods for amplifying RNA or DNA are well known in the art and can be used in accordance with the present invention based on the teachings and guidance presented herein without undue experimentation.

[0079] Known methods of DNA or RNA amplification include polymerase chain reaction (PCR) and related amplification processes (see, for example, U.S. Pat. Nos. 4,683,195, 4,683,202, 4,800,159, 4,965,188 to Mullis et al., U.S. Pat. Nos. 4,795,699 and 4,921,794 to Tabor et al., U.S. Pat. No. 5,142,033 to Innis, U.S. Pat. No. 5,122,464 to Wilson et al., U.S. Pat. No. 5,091,310 to Innis, U.S. Pat. No. 5,066,584 to Gyllensten et al., U.S. Pat. No. 4,889,818 to Gelfand et al., U.S. Pat. No. 4,994,370 to Silver et al., U.S. Pat. No. 4,766,067 to Biswas, U.S. Pat. No. 4,656,134 to Ringold), and RNA-mediated amplification using antisense RNA as a template for double-stranded DNA synthesis (U.S. Pat. No. 5,130,238 to Malek et al., trade name NASBA), but are not limited thereto, and the entire contents of these documents are incorporated herein by reference. (See, for example, Ausubel, supra, or Sambrook, supra.)

[0080] For example, using polymerase chain reaction (PCR) technology, the polynucleotides and related gene sequences used in the method of the present invention can be amplified directly from genomic DNA or cDNA libraries. PCR and other in vitro amplification methods can also be useful, for example, for cloning nucleic acid sequences encoding a protein to be expressed, for detecting the presence of a desired mRNA in a sample, for nucleic acid sequencing, or for generating nucleic acids to be used as probes for other purposes. Examples of techniques sufficient to guide one of ordinary skill in the art in in vitro amplification methods can be found in Berger, Sambrook, and Ausubel, supra, as well as U.S. Patent No. 4,683,202 to Mullis et al. (1987), and Innis, et al., PCR Protocols A Guide to Methods and Applications, Eds., Academic Press Inc., San Diego, CA (1990). Commercially available kits for genomic PCR amplification are known in the art. See, for example, Advantage-GC Genomic PCR Kit (Clontech). Additionally, for example, the yield of long PCR products can be improved using T4 gene 32 protein (Boehringer Mannheim).

[0081] Synthetic methods for constructing nucleic acids The isolated nucleic acids used in the method of the present invention can also be prepared by direct chemical synthesis by known methods (see, for example, Ausubel et al., supra). Chemical synthesis generally produces single-stranded oligonucleotides that can be converted to double-stranded DNA by hybridization with a complementary sequence or by polymerization with a DNA polymerase using the single strand as a template. One of ordinary skill in the art will recognize that chemical synthesis of DNA can be limited to sequences of about 100 or more bases, but longer sequences can be obtained by ligation of shorter sequences.

[0082] Recombinant expression cassette The present invention uses a recombinant expression cassette containing a nucleic acid. A recombinant expression cassette can be constructed using a nucleic acid sequence, such as a cDNA or genomic sequence encoding an antibody used in the methods of the present invention, which can be introduced into at least one desired host cell. A recombinant expression cassette typically contains a polynucleotide operably linked to a transcriptional initiation regulatory sequence that directs transcription of the polynucleotide in the intended host cell. Both heterologous and non-heterologous (i.e., endogenous) promoters can be utilized to direct the expression of the nucleic acid.

[0083] In some embodiments, an isolated nucleic acid that functions as a promoter, enhancer, or other element can be introduced at an appropriate position (upstream, downstream, or within an intron) of a non-heterologous form of the polynucleotide of the present invention to upregulate or downregulate the expression of the polynucleotide. For example, the endogenous promoter can be altered in vivo or in vitro by mutation, deletion, and / or substitution.

[0084] Vectors and Host Cells The present invention also relates to vectors containing isolated nucleic acid molecules, host cells genetically engineered using recombinant vectors, and the production of at least one anti-IL-23 antibody by recombinant techniques well known in the art. See, for example, Sambrook et al. and Ausubel et al., supra, each of which is incorporated herein by reference in its entirety.

[0085] The polynucleotide can optionally be ligated into a vector containing a selectable marker for growth of the host. Generally, plasmid vectors are introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into the host cell.

[0086] The DNA insert should be operably linked to an appropriate promoter. The expression construct further includes a transcription start site, a transcription termination site, and a ribosome binding site for translation within the transcribed region. The coding portion of the mature transcript expressed by the construct preferably includes translation starting with appropriate start and stop codons (e.g., UAA, UGA, or UAG) appropriately positioned at the end of the mRNA to be translated, with UAA and UAG being preferred for mammalian or eukaryotic cell expression.

[0087] It is preferred but optional that the expression vector contains at least one selectable marker. Such markers include, for example, methotrexate (MTX) for eukaryotic cell culture, dihydrofolate reductase (DHFR, U.S. Pat. Nos. 4,399,216, 4,634,665, 4,656,134, 4,956,288, 5,149,636, 5,179,017), ampicillin, neomycin (G418), mycophenolic acid, or glutamine synthetase (GS, U.S. Pat. Nos. 5,122,464, 5,770,359, 5,827,739) resistance genes, and tetracycline or ampicillin resistance genes for culture in E. coli and other bacteria or prokaryotes, but are not limited thereto (the above patents are hereby incorporated by reference in their entirety). Suitable culture media and conditions for the above host cells are known in the art. Suitable vectors will be readily apparent to those skilled in the art. Introduction of the vector construct into the host cell can be achieved by calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other known methods. Such methods are described in the art, such as in Sambrook, supra, Chapters 1-4 and 16-18, Ausubel, supra, Chapters 1, 9, 13, 15, 16, etc.

[0088] At least one antibody used in the method of the present invention can be expressed in a modified form such as a fusion protein and can include 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 improve stability and persistence in host cells during purification or subsequent processing and storage. Also, a peptide moiety can be added to the antibody of the present invention to facilitate purification. Such regions can be removed prior to the final preparation of the antibody or at least one fragment thereof. Such methods are described in many standard laboratory manuals such as the above-mentioned Sambrook, Chapters 17.29 - 17.42 and 18.1 - 18.74, and the above-mentioned Ausubel, Chapters 16, 17, and 18.

[0089] One skilled in the art is familiar with numerous expression systems available for the expression of nucleic acids encoding the proteins used in the method of the present invention. Alternatively, the nucleic acid can be expressed in a host cell containing endogenous DNA encoding the antibody by (operatively) switching it on. Such methods are well known in the art as described in U.S. Patent Nos. 5,580,734, 5,641,670, 5,733,746, and 5,733,761, which are hereby incorporated by reference in their entirety.

[0090] One example of a cell culture useful for the production of an antibody, a specific portion or variant thereof, is mammalian cells. Mammalian cell lines often take the form of a monolayer of cells, although suspensions of mammalian cells or bioreactors can also be used. Several suitable host cell lines capable of expressing intact glycosylated proteins have been developed in the art, including COS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-1651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., ATCC CRL1610) and BSC-1 (e.g., ATCC CRL-26) cell lines, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2 / 0-Ag14, 293 cells, HeLa cells, etc., which are readily available, for example, from the American Type Culture Collection (Manassas, Va) (www.atcc.org). Preferred host cells include cells derived from lymphoid systems such as myeloma and lymphoma cells. Particularly preferred host cells are P3X63Ag8.653 cells (ATCC deposit number CRL-1580) and SP2 / 0-Ag14 cells (ATCC deposit number CRL-1851). In a particularly preferred embodiment, the recombinant cells are P3X63Ab8.653 or SP2 / 0-Ag14 cells.

[0091] The expression vectors of these cells can contain one or more of the expression control sequences, such as, but not limited to, an origin of replication, a promoter (e.g., a late or early SV40 promoter, CMV promoter (U.S. Patent Nos. 5,168,062 and 5,385,839), HSV tk promoter, pgk (phosphoglycerate kinase) promoter, EF-1 alpha promoter (U.S. Patent No. 5,266,491), at least one human immunoglobulin promoter, an enhancer, and / or a ribosome binding site, an RNA splice site, a polyadenylation site (e.g., the SV40 large T Ag polyadenylation site), and processing information sites such as a transcription termination sequence. See, for example, Ausubel et al. and Sambrook et al. supra. Other cells useful for the production of the nucleic acids or proteins of the present invention are well known and / or are available, for example, from the American Type Culture Collection Catalogue of Cell Lines and Hybridomas (www.atcc.org) or other well-known or commercial sources.

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

[0093] Purification of Antibodies Anti-IL-23 antibodies can be recovered and purified from recombinant cell cultures by well-known methods including, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, and lectin chromatography. High performance liquid chromatography (HPLC) can also be used for purification. See, for example, Colligan, Current Protocols in Immunology or Current Protocols in Protein Science, John Wiley & Sons, NY, NY (1997-2001), Chapters 1, 4, 6, 8, 9, 10, which are hereby incorporated by reference in their entirety.

[0094] Antibodies used in the methods of the invention include naturally purified products, products of chemical synthetic procedures, and products produced recombinantly from eukaryotic hosts including, for example, yeast, higher plants, insects, and mammalian cells. Depending on the host used in the recombinant production process, the antibodies can be glycosylated or non-glycosylated, with glycosylation being preferred. Such methods are described in many standard laboratory manuals including, but not limited to, Sambrook, Sections 17.37-17.42, Ausubel, Chapters 10, 12, 13, 16, 18, and 20, and Colligan, Protein Science, Chapters 12-14, all of which are hereby incorporated by reference in their entirety.

[0095] Anti-IL-23 antibody. An anti-IL-23 antibody, which is useful in the method according to an embodiment of the present invention and is also referred to herein as an "anti-IL-23 specific antibody", can be incorporated into an antibody and includes at least a part of an immunoglobulin molecule, for example, but not limited to, at least one ligand binding portion (LBP), for example, but not limited to, a complementarity determining region (CDR) of a heavy chain or a light chain or a ligand binding portion thereof, a variable region of a heavy chain or a light chain, a framework region (for example, FR1, FR2, FR3, FR4, or a fragment thereof, and further optionally including at least one substitution, insertion, or deletion), a constant region of a heavy chain or a light chain (for example, at least one C H 1, hinge 1, hinge 2, hinge 3, hinge 4, C H 2, or C H 3, or a fragment thereof, and further optionally including at least one substitution, insertion, or deletion), or any protein or peptide-containing molecule including any part thereof. The antibody can include or be derived from any mammal, such as, but not limited to, human, mouse, rabbit, rat, rodent, primate, or any combination thereof.

[0096] The isolated antibodies used in the method of the present invention include the amino acid sequences of the antibodies disclosed herein encoded by any suitable polynucleotide, or any isolated or prepared antibody. Preferably, the human antibody or antigen-binding fragment binds to human IL-23, thereby partially or substantially neutralizing at least one biological activity of the protein. An antibody, or a specific portion or variant thereof, that partially or preferably substantially neutralizes at least one biological activity of at least one IL-23 protein or fragment binds to the protein or fragment, thereby inhibiting the activity mediated through the binding of IL-23 to the IL-23 receptor, or through other IL-23-dependent or mediated mechanisms. As used herein, the term "neutralizing antibody" refers to an antibody that can inhibit IL-23-dependent activity by about 20-120%, preferably at least about 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% or more, depending on the assay. The ability of an anti-IL-23 antibody to inhibit IL-23-dependent activity is preferably evaluated by at least one suitable IL-23 protein or receptor assay described herein and / or known in the art. Human antibodies can be of any class (such as IgG, IgA, IgM, IgE, IgD, etc.) or isotype and can include kappa or lambda light chains. In one embodiment, the human antibody includes at least one isotype of an IgG heavy chain or defined fragment, such as IgG1, IgG2, IgG3, or IgG4 (e.g., γ1, γ2, γ3, γ4). Antibodies of this type can be prepared by utilizing transgenic mice or other non-human transgenic mammals that contain at least one human light chain (e.g., IgG, IgA, and IgM) transgene described herein and / or known in the art. In another embodiment, the anti-IL-23 human antibody includes an IgG1 heavy chain and an IgG1 light chain.

[0097] The antibody binds to at least one specific epitope that is specific for at least one IL-23 protein, subunit, fragment, portion, or any combination thereof. The at least one epitope can include at least one antibody-binding region that includes at least a portion of the protein, and this epitope preferably consists of at least one extracellular portion, soluble portion, hydrophilic portion, outer portion, or cytoplasmic portion of the protein.

[0098] Generally, a human antibody or antigen-binding fragment includes an antigen-binding region that includes at least one human complementarity-determining region (CDR1, CDR2, and CDR3) or a variant of at least one heavy-chain variable region, and at least one human complementarity-determining region (CDR1, CDR2, and CDR3) or a variant of at least one light-chain variable region. The CDR sequences can be derived from human germline-type sequences or can be strictly identical to germline-type sequences. For example, CDRs from synthetic libraries derived from original non-human CDRs can be used. These CDRs can be formed by incorporation of conservative substitutions derived from the original non-human sequences. In another specific embodiment, the antibody or antigen-binding portion or variant can have an antigen-binding region that includes at least a portion of at least one light-chain CDR (i.e., CDR1, CDR2, and / or CDR3) having the amino acid sequence of the corresponding CDR1, 2, and / or 3.

[0099] Such antibodies can be prepared by using conventional techniques related to recombinant DNA technology to prepare and express nucleic acid molecules (i.e., one or more) encoding the antibody, or by chemically bonding together various portions of the antibody (e.g., CDRs, frameworks) using any other suitable method using conventional techniques.

[0100] In one embodiment, the anti-IL-23 antibody useful in the present invention includes a heavy chain variable region and a light chain variable region. The heavy chain variable region includes the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, and CDRH3 of SEQ ID NO: 3. The light chain variable region includes the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0101] A preferred anti-IL-23 antibody useful in the present invention includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8.

[0102] A more preferred anti-IL-23 antibody useful in the present invention is guselkumab (also called CNTO1959 and sold as Tremfaya®).

[0103] Other anti-IL-23 antibodies useful in the present invention include, but are not limited to, those having the sequences described in U.S. Patent No. 7,935,344, the entire content of which is incorporated herein by reference).

[0104] Antibody composition containing additional therapeutic active ingredients The antibody composition used in the method of the present invention may optionally further include an effective amount of at least one compound or protein selected from at least one of anti-infective drugs, cardiovascular (CV) system acting drugs, central nervous system (CNS) drugs, autonomic nervous system (ANS) drugs, respiratory drugs, gastrointestinal (GI) tract acting drugs, hormonal drugs, body fluid or electrolyte balance drugs, blood acting drugs, anti-tumor drugs, immunomodulatory drugs, drugs for eyes, ears or nose, topical acting drugs, nutritional drugs, etc. Such drugs are well known in the art including each of the formulations, indications, dosages, and administrations shown herein (e.g., Nursing 2001 Handbook of Drugs, 21, each of which is incorporated herein by reference in its entirety). stFor reference, see the 2001 edition, Springhouse Corp., Springhouse, PA; the 2001 Health Professional’s Drug Guide, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, Upper Saddle River, NJ; and the Pharmcotherapy Handbook, Wells et al., Appleton & Lange, Stamford, CT).

[0105] Examples of drugs that can be combined with the antibodies of the method of the present invention include anti-infective drugs, which can be amoebicides or at least one antiprotozoal drug, anthelmintics, antifungal drugs, antimalarial drugs, antituberculosis drugs or at least one antibacterial drug, aminoglycosides, penicillins, cephalosporins, tetracyclines, sulfonamides, fluoroquinolones, antiviral drugs, macrolide anti-infective drugs, and at least one selected from various anti-infective drugs. Hormonal drugs can be corticosteroids, androgens, or at least one anabolic steroid, estrogens, or at least one progestin, gonadotropins, antidiabetic drugs, or at least one glucagon, thyroid hormones, thyroid hormone antagonists, pituitary hormones, and parathyroid-like drugs. At least one cephalosporin can be at least one selected from cefaclor, cephradroxil, cefazolin sodium, cefdinir, cefepime hydrochloride, cefixime, cefmetazole sodium, cefonicid sodium, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime, cefibutene, ceftezoxime sodium, ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cephalexin hydrochloride, cephalexin monohydrate, cefradine, and loracarbef.

[0106] At least one corticosteroid can be at least one selected from betamethasone, betamethasone acetate or sodium betamethasone phosphate, sodium betamethasone phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, sodium hydrocortisone phosphate, sodium succinate hydrocortisone, methylprednisolone, methylprednisolone acetate, sodium succinate methylprednisolone, prednisolone, prednisolone acetate, prednisolone phosphate sodium, prednisolone tebutate, prednisone, triamcinolone, triamcinolone acetonide, and triamcinolone diacetate. At least one androgen or anabolic steroid can be at least one selected from danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate, nandrolone phenylpropionate, testosterone, testosterone cypionate, testosterone enanthate, testosterone propionate, and transdermal testosterone.

[0107] At least one immunosuppressant can be at least one selected from azathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immunoglobulin, muromonab - CD3, mycophenolate mofetil, mycophenolate mofetil hydrochloride, sirolimus, and tacrolimus.

[0108] At least one topical anti-infective agent can be at least one selected from acyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole, econazole nitrate, erythromycin, gentamicin sulfate, ketoconazole, mafenide acetate, metronidazole (topical), miconazole nitrate, mupirocin, naftifine hydrochloride, neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, terbinafine hydrochloride, terconazole, tetracycline hydrochloride, tioconazole, and tolnaftate. At least one scabicide or pediculicide can be at least one selected from crothiamide, lindane, permethrin, and pyrethrin. At least one topical corticosteroid can be at least one selected from betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desonide, desoxymethasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate, fluocinonide acetonide, fluocinonide, flurandrenolide, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, and triamcinolone acetonide. (See, for example, pages 1098-1136 of Nursing 2001 Drug Handbook.)

[0109] The anti-IL-23 antibody composition comprises at least one anti-IL-23 antibody that is contacted with or administered to cells, tissues, organs, animals, or patients in need of such regulation, treatment, or therapy, and optionally further comprises at least one TNF antagonist (for example, but not limited to, TNF chemical or protein antagonists, TNF monoclonal or polyclonal antibodies or fragments, soluble TNF receptors (for example, p55, p70, or p85) or fragments, their fusion polypeptides, or small molecule TNF antagonists, such as TNF binding protein I or II (TBP-1 or TBP-II), nerelimonmab, infliximab, etanercept, CDP-571, CDP-870, afelimomab, renercept, etc.), anti-rheumatic drugs (for example, methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, sodium aurothiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), immunizing substances, immunoglobulins, immunosuppressive drugs (for example, azathioprine, basiliximab, cyclosporine, daclizumab), cytokines or cytokine antagonists, and can further comprise at least one of any suitable and effective amount of a composition or a pharmaceutical composition. Non-limiting examples of such cytokines include any of IL-1 to IL-23, etc. (for example, IL-1, IL-2, etc.), but are not limited thereto. Suitable dosages are well known in the art. For example, see Wells et al., eds., Pharmacotherapy Handbook, 2 nd nd Edition, Appleton and Lange, Stamford, CT (2000), PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), each of which is hereby incorporated by reference in its entirety.

[0110] The anti-IL-23 antibody compounds, compositions, or mixtures used in the method of the present invention may further contain at least one of any suitable adjuvants, such as, but not limited to, diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc. Pharmaceutically acceptable adjuvants are preferred. Methods for preparing such sterile solutions and non-limiting examples thereof are well known in the art, for example, Gennaro, Ed., Remington’s Pharmaceutical Sciences, 18 th Edition, Mack Publishing Co. (Easton, PA) 1990, but not limited thereto. Pharmaceutically acceptable carriers that are well known in the art or suitable for the mode of administration, solubility, and / or stability of the anti-IL-23 antibody, fragment, or variant composition described herein can be routinely selected.

[0111] Pharmaceutical excipients and additives useful in the present composition include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., saccharides including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides, alditols, aldonic acids, derivatized sugars such as esterified sugars, and polysaccharides or sugar polymers), which may be present alone or in combination and are included in an amount of 1 to 99.99% by weight or volume, alone or in combination. Representative protein excipients include serum albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, etc. Representative amino acid / antibody components that can also function in buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, etc. One of the preferred amino acids is glycine.

[0112] Examples of carbohydrate excipients suitable for use in the present invention include monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, etc., disaccharides such as lactose, sucrose, trehalose, cellobiose, etc., polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starches, etc., and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), myo-inositol, etc. Preferred carbohydrate additives for use in the present invention are mannitol, trehalose, and raffinose.

[0113] The anti-IL-23 antibody composition can also contain a buffer or a pH adjuster. Typically, the buffer is a salt prepared from an organic acid or a base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, tris, tromethamine hydrochloride, or phosphate buffers. Preferred buffers for use in the present composition are organic acid salts such as citric acid.

[0114] Additionally, the anti-IL-23 antibody composition can contain polymer excipients / additives such as polyvinylpyrrolidone, ficoll (polymer sugar), dextrates (such as cyclodextrins like 2-hydroxypropyl-β-cyclodextrin), polyethylene glycol, flavoring agents, antibacterial agents, sweeteners, antioxidants, antistatic agents, surfactants (such as polysorbates like "TWEEN20" and "TWEEN80"), lipids (such as phospholipids, fatty acids), steroids (such as cholesterol), and chelating agents (such as EDTA).

[0115] These and additional known pharmaceutical excipients and / or additives suitable for use in the anti-IL-23 antibody, fragment or variant compositions according to the present invention are known in the art and are described, for example, in "Remington: The Science & Practice of Pharmacy," 19 thed., Williams & Williams, (1995), and "Physician’s Desk Reference," 52 nd ed., Medical Economics, Montvale, NJ (1998), and these disclosures are hereby incorporated by reference in their entirety. Preferred carrier or additive materials are carbohydrates (e.g., monosaccharides and alditols) and buffering agents (e.g., citric acid) or polymeric agents. Exemplary carrier molecules are mucopolysaccharides, hyaluronic acid, which may be useful for intra-articular delivery.

[0116] Formulation As described above, the present invention preferably provides a stable formulation which is a phosphate buffer containing physiological saline or a selected salt, a storage solution and a formulation containing a preservative, and a multi-purpose storage formulation suitable for pharmaceutical or veterinary use containing at least one anti-IL-23 antibody in a pharmaceutically acceptable formulation. The storage formulation contains at least one known preservative optionally selected from the group consisting of at least one of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof, in an aqueous diluent. As is known in the art, any suitable concentration or mixture of 0.001 to 5%, or any range or value therein, for example, 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 can be used.As non-limiting examples, there may be mentioned those without preservatives added, 0.1 to 2% of m-cresol (for example, 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1 to 3% of benzyl alcohol (for example, 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001 to 0.5% of thimerosal (for example, 0.005, 0.01), 0.001 to 2.0% of phenol (for example, 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005 to 1.0% of alkyl paraben (for example, 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%) and the like.

[0117] As described above, the method of the present invention uses a product comprising a packaging material and at least one vial containing a solution of at least one antibody specific for anti-IL-23, optionally with a buffer and / or a preservative formulated in an aqueous diluent, the packaging material comprising a label stating that it can hold such a solution for 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72 hours or more. The present invention further uses a product comprising a packaging material, a first vial containing a lyophilized antibody specific for anti-IL-23, and a second vial containing an aqueous diluent of a formulated buffer or preservative, the packaging material comprising a label instructing the patient to reconstitute the antibody specific for anti-IL-23 with the aqueous diluent to form a solution that can be held for 24 hours or more.

[0118] The antibody specific for anti-IL-23 used according to the present invention can be produced by recombinant means including production from mammalian cells or transgenic preparations, as described herein or known in the art, or can be purified from other biological sources.

[0119] The range of anti-IL-23 specific antibodies is included in an amount that, in the case of wet / dry systems, provides a concentration of from about 1.0 μg / mL to about 1000 mg / mL upon reconstitution, although lower and higher concentrations are also workable and depend on the intended delivery vehicle. For example, in solution formulations, it is different from transdermal patches, the lung, transmucosal, or osmotic or micropump methods.

[0120] Preferably, the aqueous diluent optionally further comprises a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof. The concentration of the preservative used in the formulation is a concentration sufficient to produce an antibacterial effect. Such concentration varies depending on the preservative selected and can be readily determined by one of ordinary skill in the art.

[0121] Other excipients, such as tonicity agents, buffers, antioxidants, and preservative enhancers, can be added optionally and preferably to the diluent. Tonicity agents such as glycerin are generally used at known concentrations. Preferably, a physiologically tolerated buffer is added to provide improved pH control. The formulation can cover a wide range of pH ranges, such as from about pH 4 to about pH 10, and preferably from about pH 5 to about pH 9, and most preferably from about 6.0 to about 8.0. Preferably, the formulation of the present invention has a pH of from about 6.8 to about 7.8. Suitable buffers include phosphate buffers, most preferably sodium phosphate, particularly phosphate buffered saline (PBS).

[0122] Other additives, such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymer), and PEG (polyethylene glycol), etc., pharmaceutically acceptable solubilizers, or nonionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polyl, other block copolymers, and chelating agents such as EDTA and EGTA can be optionally added to the formulation or composition to reduce aggregation. These additives are particularly useful when a pump or plastic container is used to administer the formulation. The presence of a pharmaceutically acceptable surfactant reduces the tendency of the protein to aggregate.

[0123] The formulation can be prepared by a process comprising mixing at least one anti-IL-23 antibody with a preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (such as methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or a mixture thereof in an aqueous diluent. The mixing of at least one antibody specific for anti-IL-23 with the preservative in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a certain amount of at least one antibody specific for anti-IL-23 in a buffer solution is combined with the desired preservative in a sufficient amount of buffer solution to provide the desired concentrations of the protein and the preservative. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, the presence or absence of additional additives, the temperature and pH during formulation preparation are all factors that can be optimized with respect to the administration concentration and means of administration used.

[0124] The formulation can be provided to patients as a dual vial containing a vial of lyophilized anti-IL-23 specific antibody, which is reconstituted as a clear solution or in a second vial containing water, preservative and / or excipient, preferably a phosphate buffer and / or saline, and a selected salt in an aqueous diluent. Either a single solution vial or a dual vial requiring reconstitution can be reused multiple times and can fulfill single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than currently available.

[0125] The product is useful for administration over a period ranging from immediately up to 24 hours or more. Thus, the product claimed by the present invention provides a great benefit to patients. The formulation of the present invention can optionally be safely stored at a temperature of about 2°C to about 40°C and can retain the biological activity of the protein for a long period of time, and thus, can indicate by the packaging label that the solution can be held and / or used over 6, 12, 18, 24, 36, 48, 72, or 96 hours or more. When using the stored diluent, such label can include use up to 1 to 12 months, six months, one and a half years, and / or two years.

[0126] A solution of an anti-IL-23 specific antibody can be prepared by a process comprising mixing at least one antibody in an aqueous diluent. Mixing is carried out using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, a quantity of at least one antibody in water or buffer is combined in an amount sufficient to provide the desired concentration of protein and optionally a preservative or buffer. Variations of this process are recognized by those skilled in the art. For example, the order of addition of components, the presence or absence of additional additives, the temperature and pH during formulation preparation are all factors that can be optimized with respect to the administration concentration and means of administration used.

[0127] The claimed product can be provided to a patient as a dual vial containing a vial of at least one anti-IL-23 specific antibody that is lyophilized and returned as a transparent solution or in a second vial containing an aqueous diluent. Either a single solution vial or a dual vial requiring reconstitution can be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0128] The claimed product can be indirectly provided to a patient by providing a dual vial containing a vial of at least one anti-IL-23 specific antibody that is lyophilized and returned as a transparent solution or in a second vial containing an aqueous diluent to a pharmacy, clinic, or other such institutions and facilities. The transparent solution in this case may have a volume of up to 1 liter or even more, and smaller amounts of at least one antibody solution can be removed one or more times from this large container and transferred to smaller vials and provided to customers and / or patients by a pharmacy or clinic.

[0129] Recognized devices that include a single vial system include pen-type syringe devices for the delivery of solutions, such as the BD Pen, BD Autojector®, Humaject®, NovoPen®, B-D® Pen, AutoPen®, and OptiPen®, GenotropinPen®, Genotronorm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®, Iject®, J-tip Needle-Free Injector®, Intraject®, Medi-Ject®, Smartject®, for example, those manufactured or developed by Becton Dickensen (Franklin Lakes, NJ, www.bectondickenson.com), Disetronic (Burgdorf, Switzerland, www.disetronic.com), Bioject (Portland, Oregon (www.bioject.com), National Medical Products, Weston Medical (Peterborough, UK, www.weston-medical.com), Medi-Ject Corp (Minneapolis, MN, www.mediject.com)), and similar suitable devices. Recognized devices that include a dual vial system include pen-type syringe systems for reconstituting freeze-dried drugs in a cartridge for delivery of the reconstituted solution, such as the HumatroPen®, etc. Examples of other suitable devices include pre-filled syringes, auto-injectors, needle-free syringes, and needle-free IV infusion sets.

[0130] The product may include a packaging material. The packaging material provides the conditions under which the product can be used, in addition to the information required by the regulatory authorities. The packaging material of the present invention, where applicable, provides the patient with instructions to reconstitute at least one anti-IL-23 antibody with an aqueous diluent to form a solution and use this solution in two vial products, wet / dry, over a period of 2 to 24 hours or more. In the case of a single vial solution product, prefilled syringe, or autoinjector, the label indicates that such a solution can be used over a period of 2 to 24 hours or more. The product is useful for human pharmaceutical product applications.

[0131] The formulation used in the method of the present invention can be prepared by a process that includes mixing an anti-IL-23 antibody and a selected buffer, preferably phosphate buffer containing physiological saline or a selected salt. The mixing of the anti-IL-23 antibody and the buffer in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a certain amount of at least one antibody in water or buffer is combined with the desired buffer in an amount of water sufficient to provide the desired concentration of protein and buffer. Variations of this process are recognized by those skilled in the art. For example, the order of addition of the components, the use or non-use of additional additives, the temperature and pH during formulation preparation are all factors that can be optimized with respect to the dosage concentration and means of administration used.

[0132] The method of the present invention is useful for administration to human or animal patients and provides a pharmaceutical composition comprising various acceptable formulations. Such pharmaceutical compositions are prepared using "standard state" water as a diluent and conventional methods well known to those skilled in the art. For example, buffer components such as histidine and histidine monohydrochloride monohydrate can be provided first, followed by the addition of an appropriate non-final volume of "standard state" water diluent, sucrose, and polysorbate 80. The isolated antibody can then be added. Finally, water is used as a diluent to adjust the volume of the pharmaceutical composition to the desired final volume under "standard state" conditions. Those skilled in the art will recognize several other methods suitable for the preparation of pharmaceutical compositions.

[0133] The pharmaceutical composition may contain each component of the indicated mass per unit volume of water, or may be an aqueous solution or suspension having a pH of the indicated "standard state". As used herein, the term "standard state" means a temperature of 25°C ± 2°C and a pressure of 1 atmosphere. The term "standard state" is not used in the art to refer to a single set of temperature or pressure recognized by the art, but instead is a reference state that specifies the temperature and pressure used to describe a solution or suspension containing a particular composition under the reference "standard state" conditions. This is because the volume of the solution is a function of temperature and pressure. One of ordinary skill in the art will recognize that pharmaceutical compositions equivalent to those disclosed herein can be produced at other temperatures and pressures. Whether such a pharmaceutical composition is equivalent to that disclosed herein should be determined under the "standard state" conditions defined above (e.g., 25°C ± 2°C and a pressure of 1 atmosphere).

[0134] Importantly, such a pharmaceutical composition may contain a mass of a component of "about" a particular value per unit volume of the pharmaceutical composition (e.g., "about 0.53 mg of L-histidine"), or may have a pH value of about a particular value. The mass or pH value of the component present in the pharmaceutical composition is "about" a given numerical value when the isolated antibody can bind to the peptide chain, either when the isolated antibody is present in the pharmaceutical composition or after the isolated antibody has been removed from the pharmaceutical composition (e.g., by dilution). That is, a value such as the mass value or pH value of the component is "about" a given numerical value when the binding activity of the isolated antibody is maintained and detectable after the isolated antibody is placed in the pharmaceutical composition.

[0135] Perform competitive binding analysis to determine whether the IL-23 specific mAbs bind to similar or different epitopes and / or compete with each other. Individually coat the Abs on ELISA plates. Add competing mAbs, followed by biotinylated hrIL-23. For the positive control, the same mAb used for coating may be used as the competing mAb (“self-competition”). IL-23 binding is detected using streptavidin. These results indicate whether the mAbs recognize similar or partially overlapping epitopes on IL-23.

[0136] In one embodiment of the pharmaceutical composition, the concentration of the isolated antibody is about 77 to about 104 mg per mL of the pharmaceutical composition. In another embodiment of the pharmaceutical composition, the pH is about 5.5 to about 6.5.

[0137] The stable or preservative formulation can be provided to the patient as a dual vial containing a vial of at least one anti-IL-23 antibody that is lyophilized and reconstituted either as a clear solution or in a second vial containing a preservative or buffer and additives in an aqueous diluent. Either the single solution vial or the dual vial that requires reconstitution can be reused multiple times and can fulfill single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0138] Other formulations or methods for stabilizing an anti-IL-23 antibody may be other than a clear solution of a lyophilized powder containing the antibody. Examples of non-clear solutions include formulations containing a microparticle suspension, where the microparticles are a composition containing the anti-IL-23 antibody within structures of various sizes, known variously as microspheres, microparticles, nanoparticles, nanospheres, or liposomes. Such relatively homogeneous, essentially spherical microparticle formulations containing an active agent can be formed, as taught in U.S. Patent No. 4,589,330, by contacting an aqueous phase and a non-aqueous phase containing the active agent and a polymer, and then evaporating the non-aqueous phase to cause aggregation of the particles from the aqueous phase. Porous microparticles can be prepared, as taught in U.S. Patent No. 4,818,542, using a first phase containing an active agent and a polymer dispersed in a continuous solvent, and removing this solvent from the suspension by lyophilization or dilution-extraction-precipitation. Polymers preferred for such preparations are natural or synthetic copolymers or polymers selected from the group consisting of gelatin agar, starch, arabinogalactan, 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(beta-hydroxybutyric acid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate), poly(hydroxyethyl methacrylate), polyamide, poly(amino acid), poly(2-hydroxyethyl DL-aspartoamide), poly(ester urea), poly(L-phenylalanine / ethylene glycol / 1,6-diisocyanatohexane), and poly(methyl methacrylate). Particularly preferred polymers are polyesters such as polyglycolic acid, polylactic acid, glycolide-L(-)lactide poly(epsilon-caprolactone), poly(epsilon-caprolactone-CO-lactic acid), and poly(epsilon-caprolactone-CO-glycolic acid). Solvents useful for dissolving the polymer and / or the active substance include water, hexafluoroisopropanol, methylene chloride, tetrahydrofuran, hexane, benzene, or hexafluoroacetone sesquihydrate.The process of dispersing the active substance-containing phase into the second phase can include forcing the first phase through an orifice in a nozzle under pressure to act on droplet formation.

[0139] Dry powder formulations may be obtained as a result of processes other than lyophilization, such as, for example, spray drying, or solvent extraction by evaporation, or solvent extraction by precipitation of a crystalline composition followed by one or more steps to remove aqueous or non-aqueous solvents. The preparation of spray-dried antibody formulations is taught in U.S. Patent No. 6,019,968. Antibody-based dry powder compositions can be produced by spray drying a solution or slurry of the antibody and, optionally, an excipient in a solvent under conditions that provide a respirable dry powder. Suitable solvents include polar compounds that can be readily dried, such as water and ethanol. The stability of the antibody can be enhanced by performing the spray drying procedure in the absence of oxygen, such as under a nitrogen blanket, or by using nitrogen as the drying gas. Another relatively dry formulation is a dispersion of a plurality of porous microstructures typically containing a hydrofluoroalkane propellant, as taught in International Publication No. 9916419. The stabilized dispersion can be administered to a patient's lungs using a metered dose inhaler. Equipment useful in the commercial manufacture of spray-dried drugs is manufactured by Buchi Ltd. or Niro Corp.

[0140] The anti-IL-23 antibody, either in a stable or preservative formulation or solution described herein, can be administered to a patient according to the present invention via various delivery methods such as SC or IM injection, transdermal, transpulmonary, transmucosal, implantation, osmotic pump, cartridge, micropump, or other means understood by those skilled in the art.

[0141] Therapeutic Applications In one general aspect, the present invention provides a method for modulating or treating psoriasis in a cell, tissue, organ, animal, or patient by administering or contacting a therapeutically effective amount of an IL-23 specific antibody to the cell, tissue, organ, animal, or patient using at least one IL-23 antibody of the present invention, which is known in the art or as described herein.

[0142] Any method of the present invention may include administering to a cell, tissue, organ, animal, or patient in need of such regulation, treatment, or therapy an effective amount of a composition or pharmaceutical composition comprising an anti-IL-23 antibody. Such methods can optionally further include co-administration or combination therapy for treating such a disease or disorder, wherein administering the at least one anti-IL-23 antibody, a particular portion thereof, or variant is with at least one TNF antagonist (e.g., but not limited to, a chemical or proteinaceous TNF antagonist, a TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70, or p85) or fragment, a fusion polypeptide thereof, or a small molecule TNF antagonist, e.g., TNF binding protein I or II (TBP-1 or TBP-II), neralimomab, infliximab, etanercept (Enbrel™), adalimumab (Humira™), CDP-571, CDP-870, afelimomab, renercept, etc.), an anti-rheumatic drug (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, sodium aurothiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), a muscle relaxant, an anesthetic, a non-steroidal anti-inflammatory drug (NSAID), an analgesic, a narcotic, a sedative, a local anesthetic, a neuromuscular blocking agent, an antibacterial agent (e.g., an aminoglycoside, an antifungal, an antiparasitic, an antiviral, a carbapenem, a cephalosporin, a fluoroquinolone, a macrolide, a penicillin, a sulfonamide, a tetracycline, and other antibacterial agents), a psoriasis therapeutic agent, a corticosteroid, an anabolic steroid, a diabetes-related drug, a mineral, a nutritional agent, a thyroid agent, a vitamin, a calcium-related hormone, an antidiarrheal agent, an antitussive agent, an antiemetic agent, an antitumor agent, a laxative, an anticoagulant, erythropoietin (e.g., epoetin alpha), filgrastim (e.g., G-CSF, Neupogen), sargramostim (GM-CSF, Leukine), an immunopotentiator, an immunoglobulin, an immunosuppressant (e.g., basiliximab, cyclosporine, daclizumab), a growth hormone, a hormone replacement agent, an estrogen receptor modulator, a mydriatic agent, a cycloplegic agent, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, an antimanic agent, an antipsychotic agent,Further comprising administering at least one selected from the group consisting of anxiolytics, hypnotics, sympathomimetics, stimulants, donepezil, tacrolimus, asthma therapeutics, beta-agonists, inhaled steroids, leukotriene inhibitors, methylxanthines, cromolyn, epinephrine or analogs, dornase alfa (Pulmozyme), cytokines or cytokine antagonists, either before, simultaneously, and / or after. Suitable dosages are well known in the art. For example, Wells et al., eds., Pharmacotherapy Handbook, 2, nd Edition, Appleton and Lange, Stamford, CT (2000), PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), Nursing 2001 Handbook of Drugs, 21 st edition, Springhouse Corp., Springhouse, PA, 2001, Health Professional’s Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, Upper Saddle River, NJ. Each of these references is hereby incorporated by reference in its entirety.

[0143] Therapeutic treatment Typically, the treatment of psoriasis is affected by administering an effective amount or dosage of an anti-IL-23 antibody composition, which, depending on the specific activity of the active agent contained in the composition, is in total, on average, per dose, at least about 0.01 to 500 milligrams of anti-IL-23 antibody per kilogram of patient, preferably at least about 0.1 to 100 milligrams of antibody per kilogram of patient per dose for single or multiple administrations. Alternatively, an effective serum concentration can include a serum concentration of 0.1 to 5000 μg / ml per single or multiple administrations. Suitable dosages are known to medical practitioners and will of course depend on the specific disease state, the specific activity of the composition being administered, and the specific patient being treated. In some cases, it may be necessary to provide repeated administrations, i.e., repeated individual administrations of specific monitored or metered administrations, to achieve the desired therapeutic amount, in which case the individual administrations are repeated until the desired daily dose or effect is obtained.

[0144] Preferred dosages may optionally include 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 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, 40, 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, 81, 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 any range, value or fraction thereof, or 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, 12.5, 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, 21, 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, 2500, 3000, 3500, 4000, 4500, and / or 5000 μg / ml, or any range, value or fraction thereof, which achieve a serum concentration may be included.

[0145] Alternatively, the administered dosage can vary depending on known factors such as the pharmacodynamic characteristics of a particular agent and its method and route of administration, the age, health status and weight of the recipient, the nature and degree of the symptoms, the type of co-therapy, the treatment frequency, and the desired effect. The dosage of the active ingredient can usually be about 0.1 to 100 milligrams per kilogram of body weight. Usually, 0.1 to 50, preferably 0.1 to 10 milligrams / kg / dose, or a sustained release form, is effective to obtain the desired result.

[0146] By way of non-limiting example, treatment of a human or animal can be by single, infusion or repeated dosing, on at least one day of, alternatively or additionally, day 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 or 40; alternatively or additionally, week 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, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52; alternatively or additionally, year 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; or any combination thereof, at a dosage of 0.1 to 100 mg / kg per day, for example, 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, as a single or periodic dosage of at least one antibody of the present invention.

[0147] Dosage forms (compositions) suitable for in vivo administration generally contain from about 0.001 milligram to about 500 milligrams of the active ingredient per unit or container. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.5 to 99.999% by weight, based on the total weight of the composition.

[0148] For parenteral administration, the antibody can be formulated as a solution, suspension, emulsion, particle, powder, or lyophilized powder, either combined with a pharmaceutically acceptable parenteral vehicle or provided separately. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and 1 to 10% human serum albumin. Non-aqueous vehicles such as liposomes and fixed oils can also be used. The vehicle or lyophilized powder can contain additives to maintain isotonicity and chemical stability (e.g., sodium chloride, mannitol for isotonicity, buffers and preservatives for chemical stability). The formulation is sterilized by known or suitable techniques.

[0149] Suitable pharmaceutical carriers are described in the latest edition of Remington’s Pharmaceutical Sciences, A. Osol, a standard reference text in the field.

[0150] Alternative Administration To administer a pharmaceutically effective amount of the anti-IL-23 antibody, many known and developed modes can be used according to the present invention. Although pulmonary administration is used in the following description, other modes of administration can be used according to the present invention to obtain suitable results. The IL-23 specific antibody of the present invention can be delivered in a carrier, as a solution, emulsion, colloid or suspension, or as a dry powder, by inhalation or using any of a variety of devices and methods suitable for administration by other methods described herein or known in the art.

[0151] Parenteral Formulations and Administration Formulations for parenteral administration may contain, as common excipients, sterile water or physiological saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydrogenated naphthalene, etc. Aqueous or oily suspensions for injection can be prepared by using appropriate emulsifying or wetting agents and suspending agents according to known methods. Injectables can be non-toxic parenterally administrable diluents such as, for example, aqueous solutions, sterile injectable solutions or suspensions in solvents. Acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic physiological saline, etc., and for normal solvents or suspending solvents, sterile non-volatile oils can be used. For these purposes, all kinds of non-volatile oils and fatty acids can be used, including natural or synthetic or semi-synthetic, fatty oils or fatty acids, natural or synthetic or semi-synthetic, monoglycerides or diglycerides or triglycerides. Parenteral administration is known in the art and includes, but is not limited to, conventional injection means, the gas pressurized needleless injection device described in U.S. Patent No. 5,851,198, and the laser perforator device described in U.S. Patent No. 5,839,446, which are hereby incorporated by reference in their entirety.

[0152] Alternative Delivery The present invention further relates to the administration of an anti-IL-23 antibody by parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intra-bronchial, intra-abdominal, intra-capsular, intra-cartilaginous, intra-cavity, intra-cerebellar, intra-ventricular, intra-colonic, intra-cervical, intra-gastric, intra-hepatic, intra-myocardial, intra-osseous, intra-pelvic, intra-pericardial, intra-peritoneal, intra-pleural, intra-prostatic, intra-pulmonary, intra-rectal, intra-renal, intra-retinal, intra-spinal, intra-synovial, intra-thoracic, intra-uterine, intra-vesical, intra-lesional, bolus, intravaginal, rectal, intra-oral, sublingual, intra-nasal, or transdermal means. The IL-23 antibody composition is in particular in the form of a liquid solution or suspension, for parenteral (subcutaneous, intramuscular, or intravenous) or any other administration, in particular in a semi-solid form such as creams and suppositories, but not limited thereto, for use in vaginal or rectal administration, in a form such as tablets or capsules, but not limited thereto, for oral or sublingual administration, or in a form such as powders, nasal sprays or aerosols, or certain specific agents, but not limited thereto, for intra-nasal use, or for either modifying the skin structure or increasing the drug concentration in a transdermal patch, using a chemical enhancer such as dimethyl sulfoxide (Junginger, et al. In "Drug Permeation Enhancement;" Hsieh, D.S., Eds., pp. 59-90 (Marcel Dekker, Inc. New York 1994), which is hereby incorporated by reference in its entirety, or the application of a formulation containing proteins and peptides to the skin (International Publication No. WO 98 / 53847), or the application of an electric field to create a transient transport pathway such as electroporation or to increase the mobility of a charged drug through the skin such as iontophoresis, or the application of ultrasound such as sonophoresis (U.S. Patent Nos. 4,309,989 and 4,767,402), using an oxidizing agent, which is not limited, but can be prepared for transdermal use in, for example, gels, ointments, lotions, suspensions or patch delivery system. (The above publications and patents are hereby incorporated by reference in their entirety).

[0153] Although the present invention has been generally described above, the same will be more readily understood by reference to the following examples, which are provided as examples but not intended to be limiting. Further, the details of the present invention are illustrated by the following non-limiting examples. All cited disclosures of this specification are expressly incorporated herein by reference.

Example

[0154] Example 1: Evaluation and treatment using a composite index Analyses were performed using pooled data from the Phase 3 DISCOVER-1 and DISCOVER-2 studies of guselkumab (GUS) for the treatment of active PsA to (1) describe the rate of achievement of a new composite endpoint that combines low disease activity (LDA) (score ≤ 14, including remission) of the Psoriatic Arthritis Disease Activity Index (DAPSA) and a Physician's Global Assessment (IGA) of the psoriasis score ≤ 1 (range = 0 [clear] to 4 [severe]), (2) determine whether early (week 16) DAPSA LDA + IGA ≤ 1 predicts future achievement of minimal disease activity (MDA) or American College of Rheumatology (ACR) 50 response criteria, and (3) compare the performance of DAPSA LDA + IGA ≤ 1 with that of low disease activity (LDA) of the Psoriatic Arthritis Disease Activity Score (PASDAS) (score ≤ 3.2).

[0155] Methods: Patients (pts) with active PsA despite standard therapy (DISCOVER-1: ≥ 3 swollen + ≥ 3 tender joints, CRP ≥ 0.3 mg / dL, approximately 30% had previously used up to 2 TNF inhibitors; DISCOVER-2: ≥ 5 swollen + ≥ 5 tender joints, CRP ≥ 0.6 mg / dL, all pts were biologic-naïve) were randomized 1:1:1 to GUS 100 mg at Weeks 0, 4, then every 4 weeks (Q4W) or every 8 weeks (Q8W), or placebo (PBO) that crossed over to GUS Q4W at Week 24. In both studies, GUS vs PBO efficacy was compared at Week 24 (primary endpoint). The number (%) of patients with DAPSA LDA + IGA ≤ 1 was determined at Week 24 for patients randomized to GUS or PBO. For all GUS-randomized patients, baseline variables related to DAPSA LDA + IGA ≤ 1 and PASDAS LDA at Week 16, and predictors of DAPSA LDA + IGA ≤ 1 or PASDAS LDA at Week 16 to achieve ACR50, MDA, and DAPSA LDA at Week 52 were evaluated using logistic regression models.

[0156] DAPSA score = tender joint count (TJC) + swollen joint count (SJC) + patient pain assessment + patient global assessment of joint activity + C-reactive protein (CRP). LDA = score ≤ 14, high disease activity = score > 28. IGA measures psoriasis severity from 0 (clear) to 4 (severe).

[0157] Results: At week 24, DAPSA LDA + IGA ≤ 1 was met by 37% (277 / 748) of GUS-treated patients versus 13% (48 / 372) of the PBO group. At week 16, 27% (203 / 748) of GUS-randomized patients had DAPSA LDA + IGA ≤ 1 and 22% (164 / 748) had PASDAS LDA. Of the 73% (545 / 748) of patients who did not have DAPSA LDA + IGA ≤ 1 at week 16, the majority (77% [418 / 545]) had IGA ≤ 1 but did not have DAPSA LDA. 4% (23 / 545) had DAPSA LDA but did not have IGA ≤ 1 and 19% (104 / 545) had neither component. Baseline predictors of DAPSA LDA + IGA ≤ 1 at week 16 were male sex, lower dactylitis score, lower Health Assessment Questionnaire Disability Index (HAQ-DI) score, lower tender joint count (TJC), and higher Psoriasis Area and Severity Index (PASI) score. Baseline predictors of PASDAS LDA at week 16 were younger age, lower dactylitis score, lower HAQ-DI score, lower TJC, and higher PASI score. As shown (Figure 1), patients who had DAPSA LDA + IGA ≤ 1 and PASDAS LDA at week 16 were significantly more likely to achieve ACR50, MDA, and DAPSA LDA at week 52 than patients who did not respond at week 16. Odds ratios (OR) for achievement of ACR50, MDA, and DAPSA LDA responses at week 52 were similar for patients who had DAPSA LDA + IGA ≤ 1 and for patients who had PASDAS LDA at week 16. OR for achievement of ACR50 and MDA at week 52 were higher for patients who had both DAPSA LDA and IGA ≤ 1 at week 16 (9.5 and 10.7) compared to patients who had DAPSA LDA but did not have IGA ≤ 1 (6.5 and 3.5) or patients who had IGA ≤ 1 but did not have DAPSA LDA (1.6 and 1.5).

[0158] Conclusion: DAPSA LDA at week 16 predicted achievement of the stringent treatment targets of ACR50 and MDA at week 52 (future). The association with week 52 response was greater when adding IGA ≤ 1 at week 16 to DAPSA LDA. DAPSA LDA + IGA ≤ 1 at week 16 as a predictor of ACR50 and MDA responses at week 52 functioned similarly to PASDAS LDA. The new composite of DAPSA LDA + IGA ≤ 1 could be a reliable predictor of long-term PsA skin and joint responses, which is more practical to implement than PASDAS.

[0159] Composite index values for patients can be used to maintain or adjust treatment with an IL23 antibody (e.g., guselkumab antibody) based on whether the patient is predicted to have LDA and / or be a responder at a later time point (e.g., 52 weeks after the start of treatment). For example, if a patient achieves DASPA LDA + IGA ≤ 1 at week 16 or week 24 (or a time point after the index is measured), the dose and / or dosing interval can be maintained, or the dose can be decreased (from 200 mg to 100 mg, or from 100 mg to 50 mg), and / or the dosing interval can be increased (from every 4 weeks to every 8 weeks). In contrast, if a patient does not achieve DASPA LDA + IGA ≤ 1 at week 16 or week 24 (or a time point after the index is measured), or has DASPA HDA at week 16 or week 24 (or a time point after the index is measured), the dose can be increased (from 100 mg to 200 mg, or from 50 mg to 100 mg), and / or the dosing interval can be decreased (from every 8 weeks to every 4 weeks).

[0160] The following table presents data supporting this analysis.

[0161]

Table 1

[0162]

Table 2

[0163] Those skilled in the art will understand that modifications can be made to the embodiments described above without departing from the broad inventive concept. Accordingly, the present invention is not limited to the specific embodiments disclosed, but is intended to cover modifications within the spirit and scope of the present application as defined by this description.

[0164] The present invention can be described with reference to the following numbered embodiments. 1. A method of evaluating treatment in a subject in need thereof and using IL23 to treat psoriatic arthritis, comprising: measuring DAPSA low disease activity (LDA) and IGA≦1 in a subject treated for psoriatic arthritis with an IL23 antibody; determining whether the subject has achieved DAPSA low disease activity (LDA) and / or IGA≦1; maintaining or adjusting treatment parameters selected from the dosing interval and dose of the IL23 antibody based on the evaluation; administering the IL23 antibody to the subject at a dosing interval and dose based on the adjusted or maintained treatment parameters, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, and the light chain variable region comprises the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6. A method comprising the above. 2. The use according to embodiment 1, wherein the measuring is about 16 or 24 weeks after the first administration of the IL23 antibody. 3. The use according to embodiment 2, wherein the subject achieves DAPSA LDA and IGA≦1. 4. The use according to embodiment 3, wherein the dosing interval for treatment is adjusted from every 4 weeks to every 8 weeks. 5. The use according to embodiment 3, wherein the dose is adjusted from 100 mg to 50 mg. 6. The use according to embodiment 2, wherein the subject fails to achieve DAPSA LDA and IGA ≤ 1 and / or the subject has high DAPSA disease activity with a score > 28. 7. The use according to embodiment 6, wherein the dosing interval for treatment is adjusted from every 8 weeks to every 4 weeks. 8. The use according to embodiment 6, wherein the dose is adjusted from 100 mg to 200 mg or from 50 mg to 100 mg. 9. The use according to embodiment 1, wherein the antibody comprises the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8. 10. The use according to embodiment 1, wherein the antibody comprises the heavy chain amino acid sequence of SEQ ID NO: 10 and the light chain amino acid sequence of SEQ ID NO: 11. 11. The use according to embodiment 1, wherein the pharmaceutical composition for intravenous administration further comprises a solution containing 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, and 0.053% (w / v) polysorbate 80 of the pharmaceutical composition, and the diluent is water under standard conditions. 12. The use according to any one of embodiments 1 to 11, wherein the subject achieves at least a 20% improvement (ACR20) in the American College of Rheumatology Core Set disease index after treatment and / or the treatment inhibits or reduces the progression on the X-ray image of psoriatic arthritis, which is maintained for at least about 100 weeks of the treatment period. 13. The use according to embodiment 12, wherein ACR20 is achieved and maintained after about 100 weeks of the treatment period. 14. After treatment, the subject achieves an improvement in disease activity determined by at least one criterion selected from the group consisting of 50% improvement in the American College of Rheumatology Core Set disease index (ACR50), 70% improvement in the American College of Rheumatology Core Set disease index (ACR70), Health Assessment Questionnaire Disability Index (HAQ-DI), global assessment by the treating investigator (IGA), Disease Activity Score 28 (DAS28) C-reactive protein (CRP), resolution of enthesitis, resolution of dactylitis, Leeds Enthesitis Index (LEI), dactylitis assessment score, summary of mental and physical component summaries (MCS and PCS) of the Short Form Health Survey (SF-36), achievement of minimal disease activity (MDA), very low disease activity (VLDA), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), GRAppa Composite Score (GRACE), Psoriatic Arthritis Disease Activity Score (PASDAS), modified composite psoriasis disease activity index (mCPDAI), Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), Functional Assessment of Chronic Illness Therapy (FACIT), and Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29), and maintains it after a treatment period of about 100 weeks, the use according to any one of Embodiments 1 to 11. 15. The subject achieves at least 50% improvement in the American College of Rheumatology Core Set disease index (ACR50) after treatment and maintains it after a treatment period of about 100 weeks, the use according to any one of Embodiments 1 to 11. 16. The subject achieves an improvement in the Health Assessment Questionnaire Disability Index (HAQ-DI) after at least about 100 weeks of treatment and maintains it after a treatment period of about 100 weeks, the use according to any one of Embodiments 1 to 11. 17. The subject achieves an improvement in the Disease Activity Score 28 (DAS28) C-reactive protein (CRP) after at least about 100 weeks of treatment and maintains it after a treatment period of about 100 weeks, the use according to any one of Embodiments 1 to 11. 18. The use according to any one of embodiments 1 to 11, wherein the subject achieves and maintains an overall assessment (IGA) of 0 (clear) or 1 (minimal) by the treating investigator, or a reduction of 2 grades or more in IGA, after a treatment period of at least about 100 weeks, and the subject has psoriatic lesions on at least 3% of the body surface area (BSA) and an IGA score of 2 or more at the pre-treatment baseline. 19. A method for evaluating treatment in a subject in need thereof and treating psoriatic arthritis, comprising: administering to the subject an antibody comprising the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8; measuring DAPSA low disease activity (LDA) and IGA ≤ 1 in a subject treated for psoriatic arthritis with an IL23 antibody about 16 or 24 weeks after the first administration of the IL23 antibody; determining whether the subject has achieved DAPSA low disease activity (LDA) and / or IGA ≤ 1; adjusting treatment parameters selected from the administration interval and dose of the IL23 antibody based on the assessment of subjects who achieve DAPSA LDA and IGA ≤ 1; administering the IL23 antibody to the subject at an administration interval and dose based on the adjusted treatment parameters, wherein the administration interval is adjusted from every 4 weeks to every 8 weeks and the dose is adjusted from 100 mg to 50 mg. 20. A method for evaluating treatment in a subject in need thereof and treating psoriatic arthritis, comprising: administering to the subject an antibody comprising the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8; measuring DAPSA low disease activity (LDA) and IGA ≤ 1 in a subject treated for psoriatic arthritis with an IL23 antibody about 16 or 24 weeks after the first administration of the IL23 antibody; determining whether the subject has achieved DAPSA low disease activity (LDA) and / or IGA ≤ 1 and / or DAPSA high disease activity with a score > 28; Based on the evaluation of subjects who do not achieve DAPSA LDA and / or IGA≤1 and / or subjects with high DAPSA disease activity with a score>28, adjusting the treatment parameters selected from the administration interval and dose of the IL23 antibody, administering the IL23 antibody to the subject at the administration interval and dose based on the adjusted treatment parameters, wherein the administration interval is adjusted from every 8 weeks to every 4 weeks, and the dose is adjusted from 50 mg to 100 mg or from 100 mg to 200 mg, a method comprising.

[0165]

Table 3

Claims

1. A pharmaceutical composition for use in a method of treating psoriatic arthritis by administering an IL23 antibody, which evaluates the treatment in a subject that requires it, The pharmaceutical composition comprises an IL23 antibody, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the complementary determination region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, and the light chain variable region comprising the complementarity determination region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO:

6. The aforementioned method, To measure DAPSA low disease activity (LDA) and IGA ≤ 1 in subjects treated for psoriatic arthritis with IL23 antibody, The purpose is to determine whether the subject has achieved DAPSA low disease activity (LDA) and / or IGA ≤ 1, Based on the evaluation, maintain or adjust the therapeutic parameters selected from the administration interval and dose of the IL23 antibody, Administering IL23 antibodies to the subject at dosage intervals and doses based on adjusted or maintained therapeutic parameters, A pharmaceutical composition containing the following:

2. The pharmaceutical composition according to claim 1, wherein the measurement is performed about 16 or 24 weeks after the first administration of the IL23 antibody.

3. The pharmaceutical composition according to claim 2, wherein the subject achieves DAPSA LDA and IGA ≤ 1.

4. The pharmaceutical composition according to claim 3, wherein the administration interval for treatment is adjusted to every four weeks to every eight weeks.

5. The pharmaceutical composition according to claim 3, wherein the dose is adjusted from 100 mg to 50 mg.

6. The pharmaceutical composition according to claim 2, wherein the subject does not achieve DAPSA LDA and IGA ≤ 1, and / or the subject has high DAPSA disease activity with a score > 28.

7. The pharmaceutical composition according to claim 6, wherein the administration interval for treatment is adjusted from every 8 weeks to every 4 weeks.

8. The pharmaceutical composition according to claim 6, wherein the dose is adjusted from 100 mg to 200 mg or from 50 mg to 100 mg.

9. The pharmaceutical composition according to claim 1, wherein the antibody comprises the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO:

8.

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

11.

11. The pharmaceutical composition for intravenous administration further comprises a solution containing 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, and 0.053% (w / v) polysorbate 80 of the pharmaceutical composition, wherein the diluent is water at standard conditions, as described in claim 1.

12. The pharmaceutical composition according to claim 1, wherein the subject achieves at least a 20% improvement (ACR20) in the American College of Rheumatology Core Set Disease Index after the treatment, and / or the treatment inhibits or reduces the radiographic progression of psoriatic arthritis, and this is maintained for at least about 100 weeks of treatment.

13. The pharmaceutical composition according to claim 12, wherein the ACR20 is achieved or maintained after a treatment period of approximately 100 weeks.

14. Following the aforementioned treatment, the subjects achieved a 50% improvement in the American College of Rheumatology Core Set Disease Index (ACR50), a 70% improvement in the American College of Rheumatology Core Set Disease Index (ACR70), the Health Assessment Questionnaire Disability Index (HAQ-DI), Investigator's Overall Assessment (IGA), Disease Activity Score 28 (DAS28), C-reactive protein (CRP), resolution of enthesitis, resolution of dactylitis, Leeds Enthesitis Index (LEI), Dactylitis Assessment Score, Short Health Survey (SF-36) in the Mental and Physical Component Summary (MCS and PCS), achievement of minimal disease activity (MDA), and very low disease activity. The pharmaceutical composition according to claim 1, which achieves and maintains improvement in disease activity after a treatment period of about 100 weeks, as determined by at least one criterion selected from the group consisting of (VLDA), Barth's Ankylosing Spondylitis Activity Index (BASDAI), GRAPPA Composite Score (GRACE), Psoriatic Arthritis Disease Activity Score (PASDAS), Modified Composite Psoriasis Disease Activity Index (mCPDAI), Psoriasis Area and Severity Index (PASI), Dermatological Quality of Life Index (DLQI), Functional Assessment of Treatment for Chronic Diseases (FACIT), and Patient Reported Outcome Measurement Information System-29 (PROMIS-29).

15. The pharmaceutical composition according to claim 1, wherein the subject achieves at least a 50% improvement in the American College of Rheumatology Core Set Disease Index (ACR50) after the treatment and maintains this improvement after a treatment period of approximately 100 weeks.

16. The pharmaceutical composition according to claim 1, wherein the subject achieves and maintains an improvement in the Health Assessment Questionnaire Disability Index (HAQ-DI) after a treatment period of at least approximately 100 weeks.

17. The pharmaceutical composition according to claim 1, wherein the subject achieves and maintains an improvement in disease activity score 28 (DAS28) C-reactive protein (CRP) after a treatment period of at least approximately 100 weeks.

18. The pharmaceutical composition according to claim 1, wherein the subject achieves and maintains an Investigator's Overall Assessment (IGA) of 0 (clear) or 1 (minimum) or a reduction of 2 or more grades in the IGA after a treatment period of at least approximately 100 weeks, and the subject has 3% or more body surface area (BSA) psoriatic lesions and an IGA score of 2 or more at baseline before the treatment.

19. A pharmaceutical composition for use in a method of treating psoriatic arthritis by administering an IL23 antibody, which evaluates the treatment in a subject that requires it, The pharmaceutical composition comprises an IL23 antibody containing the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO:

8. The aforementioned method, Administering the aforementioned IL23 antibody to the subject, Approximately 16 or 24 weeks after the initial administration of the IL23 antibody, DAPSA low disease activity (LDA) and IGA ≤ 1 are measured in subjects treated for psoriatic arthritis with the IL23 antibody, The purpose is to determine whether the subject has achieved DAPSA low disease activity (LDA) and / or IGA ≤ 1, Based on the evaluation of the subject to achieve DAPSA LDA and IGA ≤ 1, the therapeutic parameters selected from the administration interval and dose of the IL23 antibody are adjusted. The IL23 antibody is administered to the subject at intervals and doses based on adjusted therapeutic parameters, wherein the interval is adjusted from every 4 weeks to every 8 weeks, and the dose is adjusted from 100 mg to 50 mg. A pharmaceutical composition containing the following:

20. A pharmaceutical composition for use in a method of treating psoriatic arthritis by administering an IL23 antibody, which evaluates the treatment in a subject that requires it, The pharmaceutical composition comprises an IL23 antibody containing the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO:

8. The aforementioned method, Administering the aforementioned IL23 antibody to the subject, Approximately 16 or 24 weeks after the initial administration of the IL23 antibody, DAPSA low disease activity (LDA) and IGA ≤ 1 are measured in subjects treated for psoriatic arthritis with the IL23 antibody, To determine whether the subject has achieved DAPSA low disease activity (LDA) and / or IGA ≤ 1 and / or DAPSA high disease activity with a score > 28, Based on the assessment of subjects who do not achieve DAPSA LDA and IGA ≤ 1 and / or subjects who have DAPSA high disease activity with a score > 28, the therapeutic parameters selected from the administration interval and dose of IL23 antibody are adjusted. Administering IL23 antibody to the subject at dosing intervals and doses based on adjusted therapeutic parameters, wherein the dosing interval is adjusted from every 8 weeks to every 4 weeks, and the dose is adjusted from 50 mg to 100 mg or from 100 mg to 200 mg. A pharmaceutical composition containing the following:

Images