Methods of treating mild to moderate psoriasis with IL-23 specific antibodies

Abstract

A method of treating mild to moderate psoriasis in a patient by administering an IL-23-specific antibody, e.g., a paleobukumab, in an initial dose and a subsequent dose in order to respond the patient to the antibody and satisfy one or more of the clinical endpoints.

Description

[0001] Reference sequence listing submitted electronically

[0002] The sequence listing of the present application is submitted electronically as an XML formatted sequence listing via the United States Patent and Trademark Center Patent Center, with a file name of "JBI6708WOPCT1SEQLIST.xml", a creation date of March 23, 2023, and a size of 11 kilobytes (KB). The submitted sequence listing is part of the present specification and is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention relates to methods for treating mild to moderate psoriasis with antibodies that bind to human IL23. In particular, the present invention relates to dosages and dosing regimens, uses and methods for administering anti-IL23 specific antibodies and specific pharmaceutical compositions of the antibodies. Background Art

[0004] Guselkumab (Janssen Biotech, Inc. ) is a fully human immunoglobulin G1λ (IgG1λ) monoclonal antibody (mAb) that binds to the p19 subunit of human interleukin (IL)-23 with high specificity and affinity. Binding of guselkumab to the IL-23p19 subunit blocks the binding of extracellular IL-23 to the cell surface IL-23 receptor, thereby inhibiting IL-23-specific intracellular signaling and downstream activation and cytokine production. Guselkumab is currently approved in the United States, the European Union, Canada, several countries in Latin America, and the Asia-Pacific region for the treatment of adults with moderate to severe plaque psoriasis or moderate to severe psoriatic arthritis (PsA). In Japan, guselkumab is also approved for the treatment of generalized pustular psoriasis, erythrodermic psoriasis, and palmoplantar pustulosis. In addition to this, guselkumab is being evaluated globally in ulcerative colitis and Crohn's disease, as well as several other immune-mediated dermatological and rheumatic diseases.

[0005] Plaque psoriasis is a chronic, immune-mediated disorder characterized by raised, well-demarcated, erythematous plaques with silvery scaling that affects 2%-3% of the population. Psoriasis is associated with multiple comorbidities, including autoimmune diseases, neurological disorders, cardiometabolic diseases, and inflammatory bowel disease. Approximately 80% of people with psoriasis have mild to moderate disease.

[0006] Typically, severity is classified into 3 categories based on body surface area (BSA) and Psoriasis Area and Severity Index (PASI): mild, moderate and severe. Patients with "mild" disease are usually already treated with topical therapy, while patients with "moderate to severe" disease are already candidates for systemic therapy. The severity eligibility criteria for randomized controlled trials of new psoriasis therapies for moderate to severe psoriasis are usually set at 10% or more BSA involvement. The American and International Dermatology Associations have evaluated that treatment decisions using these artificially designed cutoffs based on quantitative measurements (such as BSA) exclude most patients who are significantly affected by undertreated diseases. For example, it has been well established that patients with local subtypes (such as involvement of the face, genitals, palms and soles, scalp and nails) may have severe localized psoriasis, but if the skin involvement is not at least 10% BSA, they usually cannot meet the traditional definition of severe disease. Both the International Psoriasis Council (IPC) and the American Academy of Dermatology (AAD)-National Psoriasis Foundation (NPF) have recently published publications rejecting the mild, moderate, and severe categories in favor of a dichotomous definition: candidates for topical therapy or candidates for systemic therapy including biologics.

[0007] The IPC proposes that candidates for systemic therapy include those with (1) BSA ≥ 10%, or (2) disease involving specific areas (hands / feet, nails, face, scalp, and genitals), or (3) who have failed topical therapy. The AAD-NPF guidelines similarly acknowledge that psoriasis may be severe regardless of BSA when it has severe emotional consequences, when it occurs in selected locations (including but not limited to the hands, feet, scalp, face, or genital areas), or when it causes persistent pruritus.

[0008] Consistent with the above disparity, a 2003-2011 NPF survey showed that 30% of patients with moderate psoriasis (defined as 3%-10% BSA) were treated with topical medications alone, and 24%-36% of these patients felt they were undertreated. Another study on the correlation of the Dermatology Life Quality Index (DLQI) with BSA and PASI highlighted the concern that treatment decisions based solely on threshold assessments of disease measures (BSA or PASI) may result in undertreatment of a subset of patients experiencing a high burden of disease; the study found that if the group of patients examined in the study had been assessed only by objective severity measures, they would have been classified as having mild to moderate disease, but their DLQI indicated high-impact or severe disease.

[0009] The dermatologic medical community and patients with psoriasis are accepting that systemic therapy with highly potent biologic agents should be considered even in cases where traditional scoring systems indicate mild to moderate disease severity. To address this unmet need, a number of sponsors and academic researchers have conducted clinical studies to evaluate the efficacy and safety of advanced systemic therapies in patients with psoriasis at lower BSA involvement.

[0010] Therefore, patients with mild to moderate psoriasis represent an underserved population. There remains an unmet medical need for an effective, convenient and safe treatment for mild to moderate psoriasis that is well tolerated compared to currently available treatment options. Summary of the invention

[0011] In a first aspect, the present invention relates to a method for treating a subject (patient) with mild to moderate psoriasis, the method comprising administering to the patient an anti-IL23 specific antibody (also referred to as IL23p19 or IL23p19 subunit antibody), such as guselkumab, at an initial dose at the start of treatment and at a time interval thereafter, preferably at an additional dose 4 weeks after the initial dose, and then at a dose about every 8 weeks after the additional dose, for example at 0 weeks, 4 weeks, 12 weeks, 20 weeks, 28 weeks, 36 weeks, 44 weeks and / or 52 weeks. In addition, in another embodiment, treatment is continued up to 100 weeks or more after the start of treatment.

[0012] In one embodiment, the subject receives an anti-IL23-specific antibody subcutaneously at an initial dose of 100 mg, with additional doses of the antibody 4 weeks after the initial dose and every 8 weeks after the additional doses.

[0013] In another aspect, the composition for use in the method of the present invention includes a pharmaceutical composition comprising: an anti-IL23 specific antibody.

[0014] In one embodiment, the mild to moderate psoriasis patient achieves significant improvement in a clinical endpoint and / or an exploratory endpoint selected from the group consisting of:

[0015] (i) achieve an IGA score of clear (0) or minimal (1) and at least ≥2 grade improvement from baseline at Week 16;

[0016] (ii) achieve BSA ≤ 1% at week 16;

[0017] (iii) achieved an IGA score of clear (0) at week 16;

[0018] (iv) achieving PASI 90 response at week 16;

[0019] (v) achieve PASI 100 response at week 16;

[0020] (vi) achieve a scalp-specific investigator global assessment (ss-IGA) score of no disease (0) or minimal disease at Week 16 with at least a 2-grade improvement from baseline and an ss-IGA score of ≥2 at baseline;

[0021] (vii) among participants with a Psoriasis Symptoms and Signs Diary (PSSD) pruritus score ≥4 at baseline, achieve a reduction (improvement) in PSSD pruritus score of ≥4 points from baseline at Week 16;

[0022] (viii) achieve BSA ≤ 1% at week 16;

[0023] (ix) achieve an IGA score of clear (0) at week 16;

[0024] (x) achieve PASI 90 response at week 16;

[0025] (xi) achieve PASI 100 response at week 16;

[0026] (xii) among randomized participants with scalp psoriasis and an ss-IGA score ≥2 at baseline, achieve an ss-IGA score of no disease (0) or minimal disease at Week 16 with at least a 2-grade improvement from baseline;

[0027] (xiii) among randomized participants with a baseline PSSD symptom score ≥1, achieving a PSSD symptom score of 0 at week 24 relative to apremilast;

[0028] (xiv) achieve a ≥4-point reduction (improvement) in PSSD pruritus scores from baseline at Week 16 among participants with a PSSD pruritus score ≥4 at baseline; and

[0029] (xv) Percent improvement from baseline in the Nail Psoriasis Severity Index (NAPSI) at Week 16 among randomized participants with nail psoriasis at baseline.

[0030] In preferred embodiments, endpoints can be measured at about 16 weeks, 24 weeks, 48 ​​weeks, or more after initial treatment.

[0031] In another aspect of the present invention, a pharmaceutical composition comprises an isolated anti-IL23 specific antibody having CDR sequences comprising: (i) heavy chain CDR amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3; and (ii) light chain CDR amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, optionally in a composition comprising: 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water under standard conditions.

[0032] Another aspect of the method of the present invention comprises administering a pharmaceutical composition comprising an isolated anti-IL-23-specific antibody having a heavy chain variable region amino acid sequence of SEQ ID NO: 7 and a light chain variable region amino acid sequence of SEQ ID NO: 8, optionally in a composition comprising: 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water under standard conditions, for treating patients with mild to moderate psoriasis according to the doses and dosing regimens described herein.

[0033] Another aspect of the method of the present invention comprises administering a pharmaceutical composition comprising an isolated anti-IL-23-specific antibody having a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10, optionally in a composition comprising: 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water under standard conditions.

[0034] In yet another embodiment, the methods of the invention comprise administering a pharmaceutical composition comprising the antibody guselkumab (available as a The antibody guselkumab is optionally in a composition comprising: 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water under standard conditions.

[0035] The 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, the accompanying drawings, and the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] In the attached picture:

[0037] Figure 1 A schematic diagram showing the clinical trial design described below is shown.

[0038] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] As used herein, methods of treating a subject with mild to moderate psoriasis comprise administering isolated, recombinant and / or synthetic anti-IL-23 specific human antibodies as well as diagnostic and therapeutic compositions, methods and devices.

[0040] As used herein, "anti-IL-23 specific antibodies", "anti-IL-23 antibodies", "antibody portions" or "antibody fragments" and / or "antibody variants" and the like include any protein or peptide containing the following molecules: the molecule comprises at least a portion of an immunoglobulin molecule, such as but not limited to, at least one complementary determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy or light chain variable region, a heavy or light chain constant region, a framework region or any portion thereof, or at least a portion of an IL-23 receptor or binding protein that can bind to a portion of the antibody of the present invention. Such antibodies optionally further affect specific ligands, such as but not limited to, such antibodies modulate, reduce, increase, antagonize, agonize, moderate, mitigate, block, inhibit, eliminate and / or interfere with 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, specified portions or variants of the present invention can bind to at least one IL-23 molecule, or specified portions, variants or domains thereof. Suitable anti-IL-23 antibodies, specified portions or variants may also optionally affect at least one of IL-23 activities or functions, such as, but not limited to, RNA, DNA or protein synthesis, IL-23 release, IL-23 receptor signaling, membrane IL-23 cleavage, IL-23 activity, IL-23 production and / or synthesis.

[0041] The term "antibody" is also intended to encompass antibodies, digested fragments, specified portions and variants thereof, including antibody mimetics or antibody portions comprising structures and / or functions that mimic antibodies or specified fragments or portions thereof, including single-chain antibodies and fragments thereof. Functional fragments include antigen-binding fragments that bind to mammalian IL-23. For example, the present invention encompasses antibody fragments that can bind to IL-23 or portions thereof, including but not limited to Fab fragments (e.g., obtained by papain digestion), Fab' fragments (e.g., obtained by pepsin digestion and partial reduction) and F(ab')2 fragments (e.g., obtained by pepsin digestion), facb fragments (e.g., obtained by plasmin digestion), pFc' fragments (e.g., obtained by pepsin or plasmin digestion), Fd fragments (e.g., obtained by pepsin digestion, partial reduction and reaggregation), Fv or scFv fragments (e.g., obtained by molecular biology techniques) (see, e.g., Colligan, Immunology, supra).

[0042] Such fragments can be produced by enzymatic cleavage, synthesis or recombinant techniques, as known in the art and / or as 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 stop site. For example, a combination gene encoding a F(ab')2 heavy chain portion can be designed to include a C sequence encoding a heavy chain. H 1 domain and / or hinge region DNA sequence. The various parts of the antibody can be chemically linked together using conventional techniques, or can be prepared as a contiguous protein using genetic engineering techniques.

[0043] As used herein, the term "human antibody" refers to antibodies in which substantially every portion of the protein (e.g., CDR, framework, C L , C H Domains (e.g. C H 1. C H 2. C H 3) Hinge (V L 、V H)) is substantially non-immunogenic in humans, with only small sequence changes or alterations. "Human antibodies" can also be antibodies derived from human germline immunoglobulin sequences or closely matched thereto. Human antibodies can include amino acid residues that are not encoded by germline immunoglobulin sequences (e.g., mutations introduced by random mutagenesis or site-specific mutagenesis in vitro, or mutations introduced by somatic mutations in vivo). Generally, this means that human antibodies are substantially non-immunogenic in humans. Human antibodies have been classified into groups based on their amino acid sequence similarity. Therefore, using sequence similarity searches, antibodies with similar linear sequences can be selected as templates to produce human antibodies. Similarly, antibodies belonging to primates (monkeys, baboons, chimpanzees, etc.), rodents (mice, rats, rabbits, guinea pigs, hamsters, etc.) and other mammals represent specific antibodies of these species, subgenus, genus, subfamily, and family. In addition, chimeric antibodies can include any combination of the above antibodies. Such changes or alterations can optionally and preferably maintain or reduce immunogenicity in humans or other species relative to unmodified antibodies. Thus, human antibodies are distinguished from chimeric or humanized antibodies.

[0044] It should be noted that human antibodies can be produced by non-human animals or prokaryotic or eukaryotic cells that can express functionally rearranged human immunoglobulin (e.g., heavy chain and / or light chain) genes. In addition, when the human antibody is a single-chain antibody, it may include a connecting peptide that is not present in natural human antibodies. For example, Fv may include a connecting peptide that connects the heavy chain variable region and the light chain variable region, such as two to about eight glycine or other amino acid residues. Such connecting peptides are considered to be human.

[0045] Bispecific antibodies, heterospecific antibodies, heterogeneous conjugated antibodies or similar antibodies can also be used, which are monoclonal antibodies with binding specificity for at least two different antigens, preferably human antibodies or humanized antibodies. 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 preparing bispecific antibodies are known in the art. Generally, the recombinant production of bispecific antibodies is based on the coexpression of two immunoglobulin heavy chain-light chain pairs, wherein the two heavy chains have different specificities (Milstein and Cuello, Nature 305:537 (1983)). Due to the random distribution of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a mixture of possible 10 different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule (usually performed by affinity chromatography steps) is quite cumbersome, and the product yield is low. Similar procedures are disclosed in, for example, WO 93 / 08829, U.S. Pat. Nos. 6,210,668, 6,193,967, 6,132,992, 6,106,833, 6,060,285, 6,037,453, 6,010,902, 5,989,530, 5,959,084, 5,959,083, 5,932,448, 5,833,985, 5,821,333, 5,807,706, 5,643,759, 5,601,819, 5,582,996, 5,496,549, 4,676,980, 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 incorporated herein by reference in its entirety.

[0046] Anti-IL-23 specific antibodies (also referred to as IL-23 specific antibodies) (or anti-IL-23 antibodies) that can be used in the methods and compositions of the present invention may optionally have the following characteristics: bind to IL-23 with high affinity, and optionally and preferably have low toxicity. Specifically, the antibodies, specific fragments or variants of the present invention (in which the individual components, such as variable regions, constant regions and framework regions, individually and / or collectively, optionally and preferably have low immunogenicity) can be used in the present invention. The antibodies that can be used in the present invention are optionally characterized in that they can be used to treat patients for a long time, can measurably reduce symptoms and have low toxicity and / or acceptable toxicity. Low or acceptable immunogenicity and / or high affinity, as well as other suitable characteristics, can help achieve therapeutic results. "Low immunogenicity" is defined herein as eliciting a significant HAHA, HACA or HAMA response in less than about 75%, or preferably less than about 50% of treated patients, and / or eliciting a low titer in treated patients (less than about 300, preferably less than about 100 as measured by a dual antigen enzyme immunoassay) (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 titratable levels of antibodies to anti-IL-23 antibodies in patients treated with anti-IL-23 antibodies during the treatment period occurring in less than 25% of patients treated with the recommended dose for the recommended course of therapy, preferably occurring in less than 10% of patients treated with the recommended dose for the recommended course of therapy.

[0047] The term "safety" as it relates to a dose, dose regimen, treatment or method performed with an anti-IL-23 antibody of the 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 AEs or TEAEs) occurring during treatment from a clinical trial conducted (e.g., a Phase 2 clinical trial and earlier clinical trials) compared to the standard of care or another comparator. An adverse event is an undesirable medical occurrence in a patient administered a drug. Specifically, when it relates to a dose, dose regimen or treatment performed with an anti-IL-23 antibody of the invention, "safety" means a relatively low or reduced frequency and / or low or reduced severity of adverse events associated with the administration of the antibody if the attribution is considered likely, likely or very likely to be due to the use of the anti-IL-23 antibody.

[0048] Utilities

[0049] The isolated nucleic acids of the present invention can be used to produce at least one anti-IL-23 antibody or a specified variant thereof, which can be used to measure or affect cells, tissues, organs or animals (including mammals and humans) to diagnose, monitor, regulate, treat, alleviate, help prevent the occurrence of mild to moderate psoriasis or alleviate the symptoms of mild to moderate psoriasis.

[0050] Such methods may include administering an effective amount of a composition or pharmaceutical composition containing at least one anti-IL-23 antibody to a cell, tissue, organ, animal or patient in need of such modulation, treatment, alleviation, prevention or reduction of a symptom, effect or mechanism. The effective amount may include an amount of about 0.001 mg / kg to 500 mg / kg per single administration (e.g., bolus), multiple administrations or continuous administration, or to achieve a serum concentration of 0.01 μg / ml to 5000 μg / ml per single administration, multiple administrations or continuous administration, or any effective range or value therein, the effective amount being administered and determined using known methods as described herein or known in the relevant art.

[0051] Citation

[0052] All publications or patents cited herein, whether explicitly stated or not, are incorporated herein by reference in their entirety as they demonstrate the state of the art at the time of the present invention and / or provide a description and enablement of the present invention. A publication is any scientific publication or patent publication, or any other information available in any media format, including all recorded, electronic or printed formats. The following references are incorporated herein by reference in their entirety: Ausubel et al., eds., "Current Protocols in Molecular Biology", John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook et al., "Molecular Cloning: A Laboratory Manual", 2nd ed., 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).

[0053] Antibodies of the invention—production and generation

[0054] As is well known in the art, at least one anti-IL-23 antibody used in the methods of the invention may optionally be produced by a cell line, a mixed cell line, an immortalized cell, or a clonal population of immortalized cells. See, e.g., Ausubel et al., eds., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook et al., "Molecular Cloning: A Laboratory Manual", 2nd ed., 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), each of which is incorporated herein by reference in its entirety.

[0055] A preferred anti-IL-23 antibody is guselkumab (also known as CNTO1959), which has a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10; a heavy chain variable region amino acid sequence of SEQ ID NO: 7 and a light chain variable region amino acid sequence of SEQ ID NO: 8; and a heavy chain CDR amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3; and a light chain CDR amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. Other anti-IL-23 antibodies have the sequences listed herein and are described in U.S. Pat. No. 7,935,344, the entire contents of which are incorporated herein by reference.

[0056] Human antibodies specific for human IL-23 protein or fragments thereof, such as isolated IL-23 protein and / or portions thereof (including synthetic molecules, such as synthetic peptides), can be generated against appropriate immunogenic antigens. Other specific or general mammalian antibodies can be similarly generated. Preparation of immunogenic antigens and generation of monoclonal antibodies can be performed using any suitable technique.

[0057] In one approach, hybridomas are generated by fusion with a suitable immortalized cell line (e.g., a myeloma cell line such as, but not limited to, Sp2 / 0, Sp2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, L243, P3X63Ag8.653, Sp2 SA3, Sp2MAI, 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, etc., or heteromyeloma, its fusion product, or any cell or fusion cell derived therefrom, or any other suitable cell line known in the art) (see, for example, www.atcc.org, www.lifetech.com., etc.) and antibody-producing cells, such as but not limited to isolated or cloned spleen, peripheral blood, lymph, tonsil or other immune or B cell-containing cells, or any other cell expressing heavy or light chain constant or variable or framework or CDR sequences, as endogenous or heterologous nucleic acid, such as recombinant or endogenous, viral, bacterial, algae, prokaryotic, amphibian, insect, reptile, fish, mammal, rodent, horse, sheep, goat, sheep, primate, eukaryotic, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single-stranded, double-stranded or triple-stranded, hybrid, etc. or any combination thereof. See, e.g., Ausubel, supra, and Colligan, Immunology, supra, Chapter 2, which are incorporated herein by reference in their entireties.

[0058] 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 spleen or lymph nodes. Any other suitable host cell can also be used to express heterologous or endogenous nucleic acids encoding antibodies of the present invention, their specific fragments or variants. Fusion cells (hybridomas) or recombinant cells can be separated using selective culture conditions or other suitable known methods, and can be cloned by limiting dilution or cell sorting or other known methods. Cells producing antibodies with desired specificity can be selected by suitable assays (e.g., ELISA).

[0059] Other suitable methods for producing or isolating antibodies with the requisite specificity may be used, including, but not limited to, methods for selecting recombinant antibodies from peptide or protein libraries (e.g., but not limited to, phage, ribosome, oligonucleotide, RNA, cDNA, etc. display libraries; e.g., available from Cambridge Antibody Technologies, Cambridgeshire, UK; MorphoSys, Martinsreid / Planegg, DE; Biovation, Aberdeen, Scotland, UK; BioInvent, Lund, Sweden; Dyax, Enzon, Affymax / Biosite; Xoma, Berkeley, CA; Ixsys).See, for example, EP 368,684, PCT / GB91 / 01134; PCT / GB92 / 01755; PCT / GB92 / 002240; PCT / GB92 / 00883; PCT / GB93 / 00605; US 08 / 350260(5 / 12 / 94); PCT / GB94 / 01422; PCT / GB94 / 02662; PCT / GB97 / 01835; (CAT / MRC); WO90 / 14443; WO90 / 14424; WO90 / 14430; PCT / US94 / 12 US 4,704,692 (Enzon); PCT / US91 / 02989 (Affymax); WO89 / 06283; EP 371 998; EP 550 400 (Xoma); EP 229 046; PCT / US91 / 07149 (Ixsys); or randomly generated peptides or proteins - US 5723323, 5763192, 5814476, 5817483, 5824514, 5976862, WO 86 / 05803, EP 590689 (Ixsys, predecessor of Applied Molecular Biology Evolution (AME), each of which is incorporated herein by reference in its entirety)) or relying on immunization of transgenic animals (e.g., SCID mice, 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), each of which is incorporated herein by reference in its entirety and related patents and applications) to produce a full repertoire of human antibodies, as known in the art and / or as described herein.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 (November 1998)); single cell antibody generation techniques (e.g., selected lymphocyte antibody method ("SLAM") (U.S. Pat. No. 5,627,052, Wen et al., J. Immunol. 17:887-892 (1987); Babcook et al., Proc. Natl. Acad. Sci. USA 93:7843-7848 (1996)); gel droplet 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 selection (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 BV, Amsterdam, Netherlands (1988)).

[0060] Also can be used for non-human or human antibody is carried out engineering or humanization method, these methods are well known in the art.Generally speaking, humanization or engineered antibody has one or more amino acid residues from non-human source, and this non-human source is for example but not limited to mouse, rat, rabbit, non-human primate or other mammal.They are generally taken from the "input" variable domain, constant domain or other domain of known human sequence.These non-human amino acid residues are replaced by the residue commonly referred to as "input" residue, and the residue is usually taken from the "input" variation, constant or other domain of known human sequence.

[0061] Such imported sequences can be used to reduce immunogenicity or reduce, enhance or modify binding, affinity, binding rate, dissociation rate, avidity, specificity, half-life or any other suitable characteristic, as known in the art. Typically, the CDR residues are directly and substantially mostly involved in influencing antigen binding. Thus, a portion or all of the non-human CDR sequence or the human CDR sequence is retained, while the non-human sequences of the variable and constant regions can be replaced with human amino acids or other amino acids.

[0062] Antibodies can also be optionally humanized or human antibodies that are designed to retain high affinity for antigens and other favorable biological properties. In order to achieve this goal, humanized (or human) antibodies can also be optionally prepared using the three-dimensional model of the parent and humanized sequences through the analytical process of the parental sequence and various conceptual humanized products. The three-dimensional immunoglobulin model is usually available and is familiar to those skilled in the art. The computer program that illustrates and displays the possible three-dimensional conformational structure of the selected candidate immunoglobulin sequence is available. The detection of these displays enables the possible role of the residue in the functioning of the candidate immunoglobulin sequence to be analyzed, i.e., the residues that affect the ability of the candidate immunoglobulin to bind to its antigen. In this way, framework (FR) residues can be selected and combined from the common and input sequences, so that the desired antibody characteristics can be achieved, such as the increased affinity to the target antigen.

[0063] In addition, the human IL-23-specific antibodies used in the methods of the present invention may include human germline light chain frameworks. In a specific embodiment, the light chain germline sequences are selected from the sequence of human VK 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.

[0064] In other embodiments, the human IL-23-specific antibodies used in the methods of the present invention may include a human germline heavy chain framework. In specific 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, VH3-31, VH3-32, VH3-33, VH3-34, VH3-35, VH3-36, VH3-37, VH3-38, VH3-39, VH3-40, VH3-41, VH3-42, VH3-43, VH3-44, VH3-45, VH3-46, VH3-47, VH3-48, VH3-49, VH3-50, VH3-51, VH3-52, VH3-53, VH3-54, VH3-55, VH3-56, VH3-57, VH3-58, VH3-59, VH3-60, VH3-61, VH3-62, VH3-63, VH3-64, VH3-65 -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.

[0065] In specific embodiments, the light chain variable region and / or the heavy chain variable region include a framework region or at least a portion of a framework region (e.g., comprising 2 or 3 subregions, such as FR2 and FR3). In certain embodiments, at least FRL1, FRL2, FRL3, or FRL4 is completely human. In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is completely human. In some embodiments, at least FRL1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., human germline) or a human consensus sequence comprising a specific framework (easily available at the source of the known human Ig sequences described above). In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., human germline) or a human consensus sequence comprising a specific framework. In preferred embodiments, the framework region is a complete human framework region.

[0066] Humanization or engineering of the antibodies of the invention can be performed using any known method, such as, but not limited to, 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. USA, 89:4285 (1992); Presta et al., J. Immunol. 151:2623 (1993); U.S. Patents 5723323, 5976862, 5824514, 5817483, 5814476, 576 90 / 14443, WO 90 / 14424, WO 90 / 14430, EP 229246, each of which is incorporated herein by reference in its entirety (including the references cited therein).

[0067] In certain embodiments, the antibody comprises an altered (e.g., mutated) Fc region. For example, in some embodiments, the Fc region has been altered to reduce or enhance the effector function of the antibody. In some embodiments, the Fc region is an isotype selected from IgM, IgA, IgG, IgE or other isotypes. Alternatively or in addition, it may be useful to combine the amino acid modification with one or more additional amino acid modifications, which change the C1q binding and / or complement dependent cytotoxicity function of the Fc region of the IL-23 binding molecule. The specific purpose starting polypeptide can be a polypeptide that binds to C1q and displays complement dependent cytotoxicity (CDC). A polypeptide having a pre-existing C1q binding activity, optionally also having the ability to mediate CDC, can be modified so that one or both of these activities are enhanced. Amino acid modifications that change C1q and / or modify its complement dependent cytotoxicity function are described in, for example, WO0042072, which is hereby incorporated by reference.

[0068] As disclosed above, one can design the Fc region of the human IL-23-specific antibodies of the invention with altered effector functions, for example by modifying C1q binding and / or FcγR binding, thereby altering complement dependent cytotoxicity (CDC) activity and / or antibody dependent cell-mediated cytotoxicity (ADCC) activity. "Effector functions" are responsible for activating or reducing biological activity (e.g., in a subject). Examples of effector functions include, but are not limited to: C1q binding; CDC; Fc receptor binding; ADCC; phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor; BCR), etc. Such effector functions may require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and may be assessed using various assays (e.g., Fc binding assays, ADCC assays, CDC assays, etc.).

[0069] For example, one can generate 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). Alternatively, if it is desired to reduce or eliminate effector function, a variant Fc region with reduced CDC activity and / or reduced ADCC activity can be designed. In other embodiments, only one of these activities can be increased, and optionally, the other activity can also be reduced (e.g., to generate an Fc region variant with improved ADCC activity but reduced CDC activity (or vice versa)).

[0070] Fc mutations can also be introduced in the design to change 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).

[0071] Another type of amino acid substitution is used to alter the glycosylation pattern of the Fc region of the human IL-23-specific antibody. 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, but 5-hydroxyproline or 5-hydroxylysine may also be used. The recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain peptide sequence are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline. Thus, the presence of any of these peptide sequences in a polypeptide creates a potential glycosylation site.

[0072] The glycosylation pattern can be altered, 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 glycosylation sites to the Fc region of a human IL-23 specific antibody can be conveniently accomplished by altering the amino acid sequence so that it contains one or more of the above tripeptide sequences (for N-linked glycosylation sites). An exemplary glycosylation variant has an amino acid substitution of heavy chain residue Asn 297. The alteration can also be made by adding or substituting one or more serine residues or threonine residues to the sequence of the original polypeptide (for O-linked glycosylation sites). In addition, a glycosylation site can be removed and Asn 297 can be changed to Ala.

[0073] In certain embodiments, the human IL-23-specific antibodies of the invention are expressed in cells expressing β(1,4)-N-acetylglucosamine transferase III (GnT III), such that GnT III adds GlcNAc to the human IL-23 antibody. Methods for producing antibodies in this manner are provided in WO / 9954342, WO / 03011878, Patent Publication 20030003097A1, and Umana et al., Nature Biotechnology, 17:176-180, February 1999; all of which are specifically incorporated herein by reference in their entirety.

[0074] As described herein and / or as known in the art, anti-IL-23 antibodies may also be optionally produced by immunizing transgenic animals capable of producing a full repertoire of human antibodies (e.g., mice, rats, hamsters, non-human primates, etc.) Human anti-IL-23 antibody-producing cells may be isolated from such animals and immortalized using appropriate methods, such as those described herein.

[0075] Transgenic mice that can produce a full repertoire of human antibodies that bind to human antigens can be generated by known methods (e.g., but not limited to, U.S. Patents: 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.; Jakobovits et al., WO 98 / 50433; Jakobovits et al., WO 98 / 24893; Lonberg et al., WO 98 / 24884; Lonberg et al., WO 97 / 13852; Lonberg et al., WO 94 / 25585; Kucherlapate et al., WO 96 / 34096; Kucherlapate et al., EP 0 463 151 B1; Kucherlapate et al., EP 0 710 719A1; Surani et al., U.S. Patent 5,545,807; Bruggemann et al., WO90 / 04036; Bruggemann et al., EP 0438474B1; Lonberg et al., EP 0814 259A2; Lonberg et al., GB2 272 440 A; 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 from at least one human immunoglobulin locus that has undergone or is capable of undergoing functional rearrangement. The endogenous immunoglobulin loci in such mice can be disrupted or deleted to eliminate the ability of the animal to produce antibodies encoded by the endogenous genes.

[0076] Peptide display libraries can be used to conveniently realize the screening of antibodies that specifically bind to similar proteins or fragments. This method involves screening individual members with desired functions or structures from a large number of peptides. Antibody screening of peptide display libraries is well known in the art. The length of the displayed peptide sequence can be 3 to 5000 or more amino acids, often 5 to 100 amino acids, and generally about 8 to 25 amino acids. In addition to direct chemical synthesis methods for producing peptide libraries, several recombinant DNA methods have also been described. One type involves displaying peptide sequences on phage or cell surfaces. Each phage or cell contains a nucleotide sequence encoding the specifically displayed peptide sequence. This type of method is described in PCT patent publications 91 / 17271, 91 / 18980, 91 / 19818 and 93 / 08278.

[0077] Other systems for generating peptide libraries have aspects of both in vitro chemical synthesis methods and recombinant methods. See PCT Patent Publications 92 / 05258, 92 / 14843, and 96 / 19256. See also U.S. Patents 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). See, e.g., U.S. Patents 4704692, 4939666, 4946778, 5260203, 5455030, 5518889, 5534621, 5656730, 5763733, 5767260, 5856456, assigned to Enzon; ​​5223409, 5403484, 5571698, 5837500, assigned to Dyax, 5427908, 5580717, assigned to Affymax; 5885793, assigned to Cambridge antibody Technologies; 5750373, assigned to Genentech, 5618920, 5595898, 5576195, 5698435, 5693493, 5698417, assigned to Xoma, Colligan, supra; Ausubel, supra; or Sambrook, supra, each of which is incorporated herein by reference in its entirety.

[0078] The antibodies used in the methods of the present invention can also be prepared using at least one anti-IL23 antibody encoding nucleic acid to provide transgenic animals or mammals, such as goats, cows, horses, sheep, rabbits, etc., which are capable of producing such antibodies in their milk. Such animals can be provided using known methods. See, for example, but not limited to, U.S. Patents 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.

[0079] The antibodies used in the methods of the present invention can have a wide range of affinities (K D ) binds to human IL-23. In a preferred embodiment, the human mAb can optionally bind to human IL-23 with high affinity. For example, the human mAb can be equal to or less than about 10 - 7 M, such as but not limited to 0.1-9.9 (or any range or value thereof)×10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 or any range or value thereof D Binds human IL-23.

[0080] The affinity or avidity of an antibody for an antigen can be determined experimentally using any suitable method. (See, e.g., Berzofsky et al., "Antibody-Antigen Interactions", In Fundamental Immunology, Paul, WE, ed., Raven Press: New York, NY (1984); Kuby, Janis Immunology, WH Freeman and Company: New York, NY (1992); and methods described herein). If measured under different conditions (e.g., salt concentration, pH), the affinity of a particular antibody-antigen interaction measured will be different. Therefore, affinity and other antigen binding parameters (e.g., K D , K a , K d ) is preferably measured using standard solutions of antibody and antigen and a standard buffer (eg, the buffer described herein).

[0081] Nucleic acid molecules

[0082] Using the information provided herein, for example, a nucleotide sequence encoding at least 70% to 100% of the contiguous amino acids of at least one of the light chain or heavy chain variable region or CDR region described herein, as well as other sequences disclosed herein, specific fragments, variants or consensus sequences thereof, or a deposited vector comprising at least one of these sequences, a nucleic acid molecule of the present invention encoding at least one anti-IL-23 antibody can be obtained using methods described herein or as known in the art.

[0083] Nucleic acid molecules of the present invention can be the form of RNA, such as mRNA, hnRNA, tRNA or any other form, or the form of DNA, including but not limited to, cDNA and genomic DNA produced by cloning or synthesis, or any combination thereof. DNA can be triple-stranded, double-stranded or single-stranded or any combination thereof. Any part of at least one chain of DNA or RNA can be a coding strand, also referred to as a sense strand, or it can be a non-coding strand, also referred to as an antisense strand.

[0084] The isolated nucleic acid molecules used in the methods of the present invention may include the following nucleic acid molecules: nucleic acid molecules comprising an open reading frame (ORF), the ORF optionally having one or more introns, for example but not limited to at least one specific portion of at least one CDR, such as CDR1, CDR2 and / or CDR3 of at least one heavy or light chain; nucleic acid molecules comprising coding sequences for anti-IL-23 antibodies or variable regions; and nucleic acid molecules comprising nucleotide sequences that differ significantly from those described above, but due to the degeneracy of the genetic code, still encode at least one anti-IL-23 antibody as described herein and / or as known in the art. Of course, the genetic code is well known in the art. Therefore, it should be possible for those skilled in the art to routinely generate such degenerate nucleic acid variants encoding the specific anti-IL-23 antibodies used in the methods of the present invention. See, for example, Ausubel et al., supra, and 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.

[0085] As indicated herein, nucleic acid molecules comprising nucleic acids encoding anti-IL-23 antibodies may include, but are not limited to, those nucleic acids encoding amino acid sequences of antibody fragments alone; coding sequences for the entire antibody or a portion thereof; coding sequences for antibodies, fragments or portions thereof, and additional sequences, such as coding sequences for at least one signal leader peptide or fusion peptide with or without the aforementioned additional coding sequences, such as at least one intron, together with additional non-coding sequences, including but not limited to non-coding 5' and 3' sequences, such as transcribed non-translated sequences that play a role in transcription, mRNA processing, including splicing and polyadenylation signals (e.g., ribosome binding and stabilization of mRNA); additional coding sequences encoding additional amino acids, such as those that provide additional functions. Thus, the sequence encoding the antibody may be fused to a marker sequence, such as a sequence encoding a peptide that can facilitate purification of the fusion antibody comprising an antibody fragment or portion.

[0086] Polynucleotides that selectively hybridize to a polynucleotide as described herein

[0087] The method of the present invention uses isolated nucleic acids that hybridize to the polynucleotides disclosed herein under selective hybridization conditions. Therefore, the polynucleotides of the present embodiment can be used to separate, detect and / or quantitatively contain nucleic acids of such polynucleotides. For example, the polynucleotides of the present invention can be used to identify, separate or amplify partial or full-length clones in a deposited library. In some embodiments, the polynucleotides are isolated genomic sequences or cDNA sequences, or are complementary to cDNAs from human or mammalian nucleic acid libraries.

[0088] Optionally, the polynucleotide will encode at least a portion of an antibody. The polynucleotide comprises a nucleic acid sequence that can be used to selectively hybridize with a polynucleotide encoding an antibody of the invention. See, e.g., Ausubel (supra); Colligan (supra), each of which is incorporated herein by reference in its entirety.

[0089] Construction of nucleic acids

[0090] The isolated nucleic acid can be prepared using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, and / or (d) combinations thereof, as is well known in the art.

[0091] The nucleic acid can conveniently comprise sequences other than the polynucleotide of the present invention. For example, a multiple cloning site comprising one or more endonuclease restriction sites can be inserted into the nucleic acid to help the separation of the polynucleotide. In addition, a translatable sequence can be inserted to help separate the polynucleotide of the present invention translated. For example, a six-histidine tag sequence provides a convenient means for purifying the protein of the present invention. The nucleic acid of the present invention (excluding the coding sequence) is optionally a vector, adapter or joint for cloning and / or expressing the polynucleotide of the present invention.

[0092] Additional sequences can be added to such cloning and / or expression sequences to optimize their function in cloning and / or expression, to aid in the isolation of the polynucleotide, or to improve the introduction of the polynucleotide into a cell. The use of cloning vectors, expression vectors, adapters and linkers is well known in the art. (See, e.g., Ausubel, supra; or Sambrook, supra).

[0093] Recombinant methods for constructing nucleic acids

[0094] The isolated nucleic acid composition (such as RNA, cDNA, genomic DNA or any combination thereof) can be obtained from biological sources using a variety of cloning methods known to those skilled in the art. In some embodiments, oligonucleotide probes selectively hybridized with polynucleotides of the present invention under stringent conditions are used to identify the desired sequence in a cDNA or genomic DNA library. The separation of RNA, and the construction of cDNA and genomic libraries are well known to those of ordinary skill in the art. (See, for example, Ausubel, supra; or Sambrook, supra).

[0095] Recombinant expression cassette

[0096] The present invention uses a recombinant expression cassette comprising a nucleic acid. Nucleic acid sequences, such as cDNA or genomic sequences encoding the antibodies used in the methods of the present invention, can be used to construct a recombinant expression cassette that can be introduced into at least one desired host cell. The recombinant expression cassette will typically contain a polynucleotide operably linked to a transcription initiation regulatory sequence that directs transcription of the polynucleotide in a predetermined host cell. Both heterologous and non-heterologous (i.e., endogenous) promoters can be used to direct expression of nucleic acids.

[0097] In some embodiments, an isolated nucleic acid as a promoter, enhancer or other element can be introduced at an appropriate position (upstream, downstream or in an intron) of a non-heterologous form of a polynucleotide of the present invention to up-regulate or down-regulate the expression of the polynucleotide. For example, an endogenous promoter can be altered in vivo or in vitro by mutation, deletion and / or substitution.

[0098] Vectors and host cells

[0099] The present invention also relates to vectors comprising isolated nucleic acid molecules, host cells genetically engineered with recombinant vectors, and preparation of at least one anti-IL-23 antibody by recombinant techniques well known in the art. See, e.g., Sambrook et al. (supra); Ausubel et al. (supra), each of which is incorporated herein by reference in its entirety.

[0100] Antibody purification

[0101] 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, hydroxyapatite chromatography, and lectin chromatography. High performance liquid chromatography ("HPLC") can also be used for purification. See, e.g., Colligan, Current Protocols in Immunology or Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2001), e.g., Chapters 1, 4, 6, 8, 9, 10, each of which is incorporated herein by reference in its entirety.

[0102] The antibodies used in the methods of the present invention include naturally purified products, products of chemical synthesis operations, and products produced by recombinant technology from eukaryotic hosts, including, for example, yeast, higher plants, insects, and mammalian cells. Depending on the host used in the recombinant production method, the antibody may be glycosylated or non-glycosylated, with glycosylated being preferred. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Sections 17.37-17.42; Ausubel, supra, Chapters 10, 12, 13, 16, 18, and 20; Colligan, Protein Science, supra, Chapters 12-14, all of which are incorporated herein by reference in their entirety.

[0103] Anti-IL-23 antibodies

[0104] The anti-IL-23 antibodies according to the present invention include any protein or peptide containing the following molecules: the molecule comprises at least a portion of an immunoglobulin molecule, such as but not limited to at least one ligand binding portion (LBP) (such as but not limited to the complementarity determining region (CDR) of a heavy chain or light chain or its ligand binding portion), a heavy chain or light chain variable region, a framework region (e.g., FR1, FR2, FR3, FR4 or fragments thereof, optionally comprising at least one substitution, insertion or deletion), a heavy chain or light chain constant region (e.g., comprising at least one CDR ... H 1. Hinge 1, Hinge 2, Hinge 3, Hinge 4, C H 2 or C H 3 or their fragments, optionally comprising at least one substitution, insertion or deletion), or any part thereof that can be incorporated into an antibody. The antibody may include or be derived from any mammal, such as but not limited to humans, mice, rabbits, rats, rodents, primates, or any combination thereof.

[0105] The isolated antibodies used in the methods of the present invention comprise an antibody amino acid sequence encoded by any suitable polynucleotide disclosed herein, 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. Antibodies or specific portions or variants thereof that partially or preferably substantially neutralize at least one biological activity of at least one IL-23 protein or fragment may bind to the protein or fragment, thereby inhibiting the activity mediated by binding of IL-23 to the IL-23 receptor or by 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% to 120%, preferably at least about 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% or more, depending on the assay. The ability of the anti-IL-23 antibody to inhibit IL-23-dependent activity is preferably assessed by at least one suitable IL-23 protein or receptor assay as described herein and / or as known in the art. The human antibody can be of any type (IgG, IgA, IgM, IgE, IgD, etc.) or isotype, and can contain kappa or lambda light chains. In one embodiment, the human antibody comprises an IgG heavy chain or a defined fragment, e.g., at least one of the isotypes IgG1, IgG2, IgG3, or IgG4 (e.g., γ1, γ2, γ3, γ4). Antibodies of this type can be prepared as described herein and / or as known in the art by using transgenic mice or other transgenic non-human mammals that comprise at least one human light chain (e.g., IgG, IgA, and IgM) transgene. In another embodiment, the anti-IL-23 human antibody comprises an IgG1 heavy chain and an IgG1 light chain.

[0106] 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 may comprise at least one antibody binding region that comprises at least a portion of a protein, the epitope preferably consisting of at least one extracellular, soluble, hydrophilic, external, or cytoplasmic portion of a protein.

[0107] Generally speaking, human antibodies or antigen-binding fragments will include such an antigen-binding region, which includes at least one human complementary determining region (CDR1, CDR2 and CDR3) or a variant of at least one heavy chain variable region and at least one human complementary determining region (CDR1, CDR2 and CDR3) or a variant of at least one light chain variable region. The CDR sequence can be derived from human germline sequences or closely matched to these germline sequences. For example, CDRs derived from a synthetic library of original non-human CDRs can be used. These CDRs can be formed by incorporating conservative substitutions from original non-human sequences. In another specific embodiment, an antibody or antigen-binding portion or variant can have an antigen-binding region, which includes at least a portion of at least one light chain CDR (i.e., CDR1, CDR2 and / or CDR3) having an amino acid sequence with corresponding CDR1, CDR2 and / or CDR3.

[0108] Such antibodies can be prepared by chemically joining together the various portions of the antibody (e.g., CDRs, frameworks) using conventional techniques, by preparing and expressing nucleic acid molecules (i.e., one or more) encoding the antibody using conventional techniques of recombinant DNA technology, or by using any other suitable method.

[0109] The anti-IL-23 specific antibody may comprise at least one of a heavy chain variable region or a light chain variable region having a defined amino acid sequence. For example, in a preferred embodiment, the anti-IL-23 antibody comprises at least one heavy chain variable region and / or at least one light chain variable region, the at least one heavy chain variable region optionally having an amino acid sequence of SEQ ID NO: 7, and the at least one light chain variable region optionally having an amino acid sequence of SEQ ID NO: 8. For example, in another preferred embodiment, the anti-IL-23 antibody comprises at least one heavy chain and / or at least one light chain, the at least one heavy chain optionally having an amino acid sequence of SEQ ID NO: 9, and the at least one light chain optionally having an amino acid sequence of SEQ ID NO: 10. Antibodies that bind to human IL-23 and comprise a defined heavy chain or light chain variable region can be prepared as known in the art and / or as described herein using suitable methods such as phage display (Katsube, Y. et al., Int J Mol. Med, 1(5): 863-868 (1998)) or methods using transgenic animals. For example, human IL-23 or its fragment can be used to immunize transgenic mice containing a functionally rearranged human immunoglobulin heavy chain transgene and a transgenic DNA from a human immunoglobulin light chain locus that may undergo functional rearrangement to induce the production of antibodies. If necessary, cells producing antibodies can be separated, and hybridomas or other immortalized antibody-producing cells can be prepared as described herein and / or as known in the art. Alternatively, encoding nucleic acids or portions thereof can be used to express antibodies, specific parts or variants in suitable host cells.

[0110] The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs comprising amino acid sequences substantially identical to those described herein. Preferably, such antibodies or antigen-binding fragments and antibodies comprising such chains or CDRs can bind with high affinity (e.g., less than or equal to about 10 -9 M of K D) binds to human IL-23. Amino acid sequences substantially identical to the sequences described herein include sequences with conservative amino acid substitutions and amino acid deletions and / or insertions. Conservative amino acid substitutions refer to the replacement of a first amino acid with a second amino acid having chemical and / or physical properties (e.g., charge, structure, polarity, hydrophobicity / hydrophilicity) similar to the first amino acid. Conservative substitutions include, but are not limited to, replacing one amino acid with another in the following groups: lysine (K), arginine (R), and histidine (H); aspartic acid (D) and glutamic acid (E); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D, and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine ​​(C), and glycine (G); F, W, and Y; C, S, and T.

[0111] Amino acid code

[0112] The amino acids constituting the anti-IL-23 antibodies of the present invention are generally abbreviated. Amino acids may be represented by their single letter codes, three letter codes, names, or trinucleotide codons, thereby indicating the amino acid names, as is well known in the art (see Alberts, B. et al., "Molecular Biology of The Cell", 3rd edition, Garland Publishing, Inc., New York, 1994):

[0113] Single letter code Three letter code name trinucleotide codon A Ala Alanine GCA,GCC,GCG,GCU C Cys Cysteine UGC,UGU D Asp Aspartic acid GAC,GAU E Glu Glutamate GAA,GAG F Phe Phenylalanine UUC,UUU G Gly Glycine GGA,GGC,GGG,GGU H His Histidine CAC,CAU I Ile Isoleucine AUA, AUC, AUU K Lys Lysine AAA,AAG L Leu Leucine UUA,UUG,CUA,CUC,CUG,CUU M Met Methionine AUG N Asn Asparagine AAC,AAU P Pro Proline CCA, CCC, CCG, CCU Q Gln Glutamine CAA, CAG R Arg Arginine AGA, AGG, CGA, CGC, CGG, CGU S Ser Serine AGC,AGU,UCA,UCC,UCG,UCU T Thr Threonine ACA,ACC,ACG,ACU V Val Valine GUA,GUC,GUG,GUU W Trp Tryptophan UGG yes Tyr Tyrosine UAC,UAU

[0114] As described herein, the anti-IL-23 antibodies used in the methods of the invention may include one or more amino acid substitutions, deletions or additions resulting from natural mutations or from human manipulation.

[0115] The anti-IL-23 antibody may include, but is not limited to, at least a portion, sequence, or combination of 5 to all contiguous amino acids selected from at least one of SEQ ID NOs: 1, 2, 3, 4, 5, and 6.

[0116] The IL-23 antibody or specified portion or variant may include, but is not limited to, at least one portion, sequence or combination selected from: at least 3 to 5 contiguous amino acids of the above-mentioned SEQ ID NO; 5 to 17 contiguous amino acids of the above-mentioned SEQ ID NO, 5 to 10 contiguous amino acids of the above-mentioned SEQ ID NO, 5 to 11 contiguous amino acids of the above-mentioned SEQ ID NO, 5 to 7 contiguous amino acids of the above-mentioned SEQ ID NO; 5 to 9 contiguous amino acids of the above-mentioned SEQ ID NO.

[0117] The anti-IL-23 antibody may also optionally comprise a polypeptide of at least one of 70%-100% of the above SEQ ID NOs. In one embodiment, the amino acid sequence of an immunoglobulin chain or portion thereof (e.g., variable region, CDR) has about 70%-100% identity (e.g., 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any range or value therein) with the amino acid sequence of the corresponding chain of at least one of the above SEQ ID NOs. For example, the amino acid sequence of the light chain variable region can be compared with the sequence of the above SEQ ID NOs, or the amino acid sequence of the heavy chain CDR3 can be compared with the above SEQ ID NOs. Preferably, 70% to 100% amino acid identity (i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any range or value therein) is determined using a suitable computer algorithm as known in the art.

[0118] As known in the art, "identity" is a relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by comparing the sequences. In the art, "identity" also means the degree of sequence relatedness between polypeptide or polynucleotide sequences, as determined by the match between strings of such sequences. "Identity" and "similarity" can be readily calculated by known methods, including but not limited to "Computational Molecular Biology, Lesk", edited by AM, Oxford University Press, New York, 1988; "Biocomputing: Informatics and Genome Projects", edited by Smith, DW, Academic Press, New York, 1993; "Computer Analysis of Sequence Data", Part I, edited by Griffin, AM and Griffin, HG, Humana Press, New Jersey, 1994; "Sequence Analysis in Molecular Biology", von Heinje, G., Academic Press, 1987; and "Sequence Analysis Primer", edited by Gribskov, M. and Devereux, J., M Stockton Press, New York, 1991; and those described in Carillo, H. and Lipman, D., Siam J. Applied Math., 48:1073 (1988). In addition, percent identity values ​​can be obtained from amino acid and nucleotide sequence alignments generated using the AlignX component of Vector NTI Suite 8.0 (Informax, Frederick, MD) using default settings.

[0119] Preferred methods for determining identity are designed to give the largest match between test sequences. Methods for determining identity and similarity are codified in publicly available computer programs. Preferred computer program methods for determining similarity between two sequences include, but are not limited to, the GCG program package (Devereux, J. et al., Nucleic Acids Research 12(1):387(1984)), BLASTP, BLASTN and FASTA (Atschul, SF et al., J. Molec. Biol., 215:403-410(1990)). The BLAST X program is available from NCBI and other sources (BLAST Manual, Altschul, S. et al., NCBINLMNIH Bethesda, Md. 20894: Altschul, S. et al., J. Mol. Biol., 215:403-410(1990)). The well-known Smith Waterman algorithm can also be used to determine identity.

[0120] Preferred parameters for polypeptide sequence comparisons include the following:

[0121] (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443-453 (1970) Comparison matrix: BLOSSUM62, from Hentikoff and Hentikoff, Proc. Natl. Acad. Sci, USA. 89:10915-10919 (1992)

[0122] Open Shot Penalty: 12

[0123] Gap length penalty: 4

[0124] A program that can be used with these parameters is publicly available as the "gap" program from Genetics Computer Group, Madison Wis. The foregoing parameters are the default parameters for peptide sequence comparisons (along with no terminal gap penalty).

[0125] Preferred parameters for polynucleotide comparisons include the following:

[0126] (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48: 443-453 (1970)

[0127] Comparison matrix: match = +10, mismatch = 0

[0128] Open field penalty: 50

[0129] Gap length penalty: 3

[0130] Available as the "gap" program from Genetics Computer Group, Madison Wis. These parameters are the default parameters for nucleic acid sequence comparisons.

[0131] By way of example, a polynucleotide sequence may be identical to another sequence, i.e., 100% identical, or it may include up to a certain integer number of nucleotide changes compared to a reference sequence. Such changes are selected from the group consisting of at least one nucleotide deletion, substitution (including conversion and transversion) or insertion, and wherein the changes may occur at the 5' or 3' terminal position of the reference nucleotide sequence or at any position between these terminal positions, individually interspersed in the nucleotides of the reference sequence, or interspersed in one or more adjacent groups within the reference sequence. The number of nucleotide changes is determined by multiplying the total number of nucleotides in the sequence by the numerical percentage of the corresponding percentage identity (divided by 100) and subtracting the product from the total number of nucleotides in the sequence, or:

[0132] n.sub.n.ltorsim.x.sub.n-(x.sub.ny), where n.sub.n is the number of nucleotide changes, x.sub.n is the total number of nucleotides in the sequence, and y is, for example, 0.70 (for 70%), 0.80 (for 80%), 0.85 (for 85%), 0.90 (for 90%), 0.95 (for 95%), etc., and where any non-integer product of x.sub.n and y is rounded to the nearest integer before being subtracted from x.sub.n.

[0133] Alterations in the polynucleotide sequence encoding the above SEQ ID NO may produce nonsense mutations, missense mutations or frameshift mutations in the coding sequence, thereby altering the polypeptide encoded by the polynucleotide following such alterations. Similarly, the polypeptide sequence may be identical to the reference sequence of the above SEQ ID NO, i.e., 100% identical, or the polypeptide sequence may include up to a certain integer number of amino acid changes compared to the reference sequence, such that the percentage identity is less than 100%. Such alterations are selected from the group consisting of at least one amino acid deletion, substitution (including conservative substitutions and non-conservative substitutions) or insertion, and wherein the alterations may occur at the amino terminal position or carboxyl terminal position of the reference polypeptide sequence or at any position between these terminal positions, interspersed individually in the amino acids of the reference sequence or interspersed in one or more contiguous groups within the reference sequence. For a given % identity, the number of amino acid changes is determined by multiplying the total number of amino acids in the above SEQ ID NO by the numerical percentage of the corresponding percentage identity (divided by 100), and then subtracting the product from the total number of amino acids in the above SEQ ID NO, or:

[0134] n.sub.a.ltorsim.x.sub.a-(x.sub.ay), wherein n.sub.a is the number of amino acid changes, x.sub.a is the total number of amino acids in the above SEQ ID NO, and y is, for example, 0.70 (corresponding to 70%), 0.80 (corresponding to 80%), 0.85 (corresponding to 85%), etc., and wherein any non-integer product of x.sub.a and y is rounded to the nearest integer before being subtracted from x.sub.a.

[0135] Exemplary heavy and light chain variable region sequences and portions thereof are provided in the above SEQ ID NOs.Antibodies of the invention, or specific variants thereof, may comprise any number of contiguous amino acid residues from an antibody of the invention, wherein the number is selected from an integer between 10% and 100% of the number of contiguous residues in an anti-IL-23 antibody.

[0136] The methods of the present invention also use anti-IL-23 antibody compositions comprising at least one, at least two, at least three, at least four, at least five, at least six or more of the anti-IL-23 antibodies thereof, which are provided in a non-naturally occurring composition, mixture or form as described herein and / or as known in the art. Such compositions include non-naturally occurring compositions comprising at least one or two full-length sequences, C-terminal and / or N-terminal deleted variants, domains, fragments or specific variants of an anti-IL-23 antibody amino acid sequence selected from the group consisting of 70% to 100% of the contiguous amino acids of the above SEQ ID NO or a specific fragment, domain or variant thereof. Preferred anti-IL-23 antibody compositions comprise at least one or two full-length, fragments, domains or variants as at least one CDR or LBP containing a portion of an anti-IL-23 antibody sequence described herein, for example, 70% to 100% of the above SEQ ID NO or a specific fragment, domain or variant thereof. More preferred compositions comprise, for example, 70% to 100% of the above SEQ ID NOs or 40% to 99% of at least one of their specified fragments, domains or variants. Such composition percentages are calculated by weight, volume, concentration, molarity or weight-molality of a liquid or anhydrous solution, mixture, suspension, emulsion, granule, powder or colloid, as known in the art or as described herein.

[0137] Antibody compositions comprising additional therapeutically active ingredients

[0138] The composition used in the method of the present invention may also optionally contain an effective amount of at least one compound or protein selected from at least one of the following: anti-infective drugs, cardiovascular (CV) system drugs, central nervous system (CNS) drugs, autonomic nervous system (ANS) drugs, respiratory tract drugs, gastrointestinal (GI) tract drugs, hormonal drugs, drugs for fluid or electrolyte balance, hematological drugs, anti-tumor drugs, immunomodulatory drugs, ophthalmic drugs, ear drugs or nasal drugs, topical drugs, nutritional drugs, statins, etc. Such drugs are well known in the art, including the formulation, indications, dosing, and administration of each drug given herein (see, e.g., "Nursing 2001 Handbook of Drugs," 21st ed., Springhouse Corp., Springhouse, PA, 2001; "Health Professional's Drug Guide 2001," Shannon, Wilson, Stang, eds., Prentice-Hall, Inc, Upper Saddle River, NJ; "Pharmcotherapy Handbook," Wells et al., eds., Appleton & Lange, Stamford, CT, each of which is incorporated herein by reference in its entirety).

[0139] As an example of drugs that can be combined with the antibodies used in the methods of the present invention, the anti-infective drug can be at least one selected from the following: anti-amoebic drugs or antiprotozoal drugs, anti-helminthic drugs, anti-fungal drugs, anti-malarial drugs, anti-tuberculosis drugs or at least one anti-leprosy drug, aminoglycosides, penicillins, cephalosporins, tetracyclines, sulfonamide drugs, fluoroquinols, antivirals, macrolide anti-infective drugs and other anti-infective drugs. Hormone drugs can be at least one selected from the following: corticosteroids, androgens or at least one anabolic steroid, estrogens or at least one progesterone, gonadotropins, anti-diabetic drugs or at least one glucagon, thyroid hormones, thyroid hormone antagonists, pituitary hormones and parathyroid hormone-like drugs. The at least one cephalosporin can be at least one selected from the following: cefaclor, cefdroxil, cefazolin sodium, cefdinir, cefepime hydrochloride, cefixime, cefmetazole sodium, cefonicid sodium, cefoperazone sodium, ceftriaxone sodium, cefotetan disodium, cefxitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime, ceftibuten, cefuroxime sodium, ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cefalexin hydrochloride, cefalexin monohydrate, cephradine and loracarb.

[0140] The at least one corticosteroid can be at least one selected from the group consisting of betamethasone, betamethasone acetate or betamethasone sodium phosphate, betamethasone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tert-butyl ethyl ester, prednisone, triamcinolone, triamcinolone acetonide and triamcinolone diacetate. The at least one androgen or anabolic steroid may be at least one selected from the group consisting of danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate, nandrolone phenylpropionate, testosterone, testosterone cypionate, testosterone enanthate, testosterone propionate, and a testosterone transdermal system.

[0141] The at least one immunosuppressant may be at least one selected from the group consisting of azathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immunoglobulin, muromonab-CD3, mycophenolate mofetil, mycophenolate mofetil hydrochloride, sirolimus, and tacrolimus.

[0142] The at least one topical anti-infective agent may be at least one selected from the group consisting of 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, nitrofuracil, nystatin, silver sulfadiazine, terbinafine hydrochloride, terconazole, tetracycline hydrochloride, tioconazole and tolnaftate. The at least one scabicide or pediculicide may be at least one selected from the group consisting of crotamiton, lindane, permethrin and pyrethrin. The at least one topical corticosteroid may be at least one selected from the group consisting of betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desoneconate, desoximetasone, dexamethasone, dexamethasone sodium phosphate, diflorasone acetate, fluocinolone acetonide, fluocinolone acetonide, flurandrenolide, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, and triamcinolone acetonide. (See, e.g., pages 1098-1136 of Nursing 2001 Drug Handbook.)

[0143] The anti-IL-23 antibody composition may also comprise any suitable and effective amount of at least one of a composition or pharmaceutical composition comprising at least one anti-IL-23 antibody contacted or administered to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy, and optionally further comprising at least one agent selected from the group consisting of at least one TNF antagonist (e.g., but not limited to, a chemical antagonist or protein antagonist of TNF, a monoclonal or polyclonal antibody or fragment of TNF, a soluble TNF receptor (e.g., p55, p70 or p85) or a fragment thereof, a fusion polypeptide, or a small molecule TNF F antagonists, such as TNF binding protein I or II (TBP-1 or TBP-II), nerelimonmab, infliximab, etanercept, CDP-571, CDP-870, afelimomab, lenafcept, etc.), anti-rheumatic drugs (such as methotrexate, auranofin, gold thioglucose, azathioprine, etanercept, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), immunity, immunoglobulin, immunosuppressant (such as basiliximab, cyclosporine, daclizumab), cytokine or cytokine antagonist. Non-limiting examples of such cytokines include, but are not limited to, any one of IL-1 to IL-40, etc. (such as IL-1, IL-2, etc.). Suitable dosages are well known in the art. See, e.g., Wells et al., eds., "Pharmacotherapy Handbook", 2nd edition, Appleton and Lange, Stamford, CT (2000); "PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000", Deluxe edition, Tarascon Publishing, LomaLinda, CA (2000), each of which is incorporated herein by reference in its entirety.

[0144] The anti-IL-23 antibody compounds, compositions or combinations used in the methods of the present invention may further comprise at least one of any suitable adjuvants, such as but not limited to diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, and the like. Pharmaceutically acceptable adjuvants are preferred. Non-limiting examples and methods for preparing such sterile solutions are well known in the art, such as but not limited to Gennaro, ed., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co. (Easton, PA) 1990. A pharmaceutically acceptable carrier suitable for the mode of administration, solubility and / or stability of the anti-IL-23 antibody, fragment or variant composition may be selected in a conventional manner, as is well known in the art or as described herein.

[0145] Pharmaceutical excipients and additives for the compositions of the present invention include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides; derivatized sugars, such as sugar alcohols, aldonic acids, esterified sugars, and the like; and polysaccharides or sugar polymers), which may be present alone or in combination, and which may have 1-99.99% by weight or volume alone or in combination. Exemplary protein excipients include serum albumin, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid / antibody components that may also function in terms of buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. A preferred amino acid is glycine.

[0146] Carbohydrate excipients suitable for use in the present invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, etc.; disaccharides such as lactose, sucrose, trehalose, cellobiose, etc.; polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starch, etc.; and sugar alcohols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), inositol, etc. Preferred carbohydrate excipients for use in the present invention are mannitol, trehalose, and raffinose.

[0147] The anti-IL-23 antibody composition may also include a buffer or pH adjuster; typically, the buffer is a salt prepared from an organic acid or 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 or phosphate buffers. Preferred buffers for the compositions of the present invention are organic acid salts such as citrate.

[0148] In addition, the anti-IL-23 antibody composition may include polymer excipients / additives such as polyvinyl pyrrolidone, polysucrose (polymeric sugar), dextrose binders (e.g., cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin), polyethylene glycol, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN 20" and "TWEEN 80"), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA).

[0149] These and additional known pharmaceutical excipients and / or additives suitable for use with the anti-IL-23 antibody, portion or variant compositions according to the invention are known in the art, for example, as listed in: "Remington: The Science & Practice of Pharmacy", 19th edition, Williams & Williams, (1995), and "Physician's Desk Reference", 52nd edition, Medical Economics, Montvale, NJ (1998), the disclosures of which are incorporated herein by reference in their entirety. Preferred carrier or excipient materials are carbohydrates (e.g., sugars and alditols) and buffers (e.g., citrate) or polymeric agents. An exemplary carrier molecule is the mucopolysaccharide hyaluronic acid, which can be used for intra-articular delivery.

[0150] preparation

[0151] As indicated above, the present invention provides stable formulations suitable for pharmaceutical or veterinary use, preferably comprising a phosphate buffer with saline or a selected salt, and preservative solutions and formulations containing preservatives, as well as multi-purpose preservative formulations, which contain at least one anti-IL-23 antibody in a pharmaceutically acceptable formulation. The preservative formulation includes at least one known preservative or is optionally selected from the group consisting of at least one phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl benzoates (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof, dissolved in an aqueous diluent. Any suitable concentration or mixture as known in the art may be used, for example 0.001% to 5% or any range or value therein, such as but not limited to: 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, 2.10, 2.20, 2.30, 2.40, 2.50, 2.60, 2.70, 2.80, 2.90, 3.11 4.5, 4.6, 4.7, 4.8, 4.9, or any range or value therein. Non-limiting examples include: no preservatives, 0.1% to 2% meta-cresol (e.g., 0.2%, 0.3%, 0.4%, 0.5%, 0.9%, 1.0%), 0.1% to 3% benzyl alcohol (e.g., 0.5%, 0.9%, 1.1%, 1.5%, 1.9%, 2.0%, 2.5%), 0.001% to 0.5% thimerosal (e.g., 0.005%, 0.01%), 0.001% to 2.0% phenol (e.g., 0.05%, 0.25%, 0.05%). .28%, 0.5%, 0.9%, 1.0%), 0.0005% to 1.0% alkyl paraben (e.g., 0.00075%, 0.0009%, 0.001%, 0.002%, 0.005%, 0.0075%, 0.009%, 0.01%, 0.02%, 0.05%, 0.075%, 0.09%, 0.1%, 0.2%, 0.3%, 0.5%, 0.75%, 0.9%, 1.0%), and the like.

[0152] As noted above, the methods of the present invention use an article of manufacture comprising packaging material and at least one vial containing a solution of at least one anti-IL-23-specific antibody and a specified buffer and / or preservative (optionally dissolved in an aqueous diluent), wherein the packaging material comprises a label indicating that such solution can be stored for a period of 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 18 hours, 20 hours, 24 hours, 30 hours, 36 hours, 40 hours, 48 ​​hours, 54 hours, 60 hours, 66 hours, 72 hours or longer. The present invention also uses an article of manufacture comprising packaging material, a first vial and a second vial, wherein the first vial contains a lyophilized anti-IL-23-specific antibody and the second vial contains an aqueous diluent with a specified buffer or preservative, wherein the packaging material comprises a label instructing the patient to reconstitute the anti-IL-23-specific antibody in the aqueous diluent to form a solution that can be stored for a period of 24 hours or longer.

[0153] The anti-IL-23 specific antibodies used according to the invention may be prepared by recombinant means, including preparation from mammalian cells or transgenic preparations, or may be purified from other biological sources, as described herein or as known in the art.

[0154] Ranges for anti-IL-23 specific antibodies include the amount produced upon reconstitution, if in a wet / dry system, at concentrations of about 1.0 μg / ml to about 1000 mg / ml, although lower and higher concentrations are possible and depend on the intended delivery vehicle, e.g., solution formulations will vary from transdermal patches, pulmonary, transmucosal, or osmotic or micropump approaches.

[0155] Preferably, the aqueous diluent also optionally comprises a pharmaceutically acceptable preservative. Preferred preservatives include those preservatives selected from the group consisting of the following items: phenol, meta-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (methyl ester, ethyl ester, propyl ester, butyl ester etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal or their mixture. The concentration of the preservative used in the preparation is a concentration that is enough to produce an antimicrobial effect. This concentration depends on selected preservative and is easily determined by the technician.

[0156] Other excipients such as isotonic agents, buffers, antioxidants and preservative enhancers can be optionally and preferably added to the diluent. Isotonic agents such as glycerol are often used in known concentrations. Preferably, a physiologically tolerated buffer is added to provide improved pH control. The formulation can cover a wide pH range, such as about pH 4 to about pH 10, with a preferred range of about pH 5 to about pH 9, and a most preferred range of about 6.0 to about 8.0. Preferably, the formulation of the present invention has a pH between about 6.8 and about 7.8. Preferred buffers include phosphate buffers, most preferably sodium phosphate, particularly phosphate buffered saline (PBS).

[0157] Other additives, such as pharmaceutically acceptable solubilizers, 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) or nonionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, Polyols, other block copolymers, and chelates such as EDTA and EGTA can optionally be added to the formulation or composition to reduce aggregation. These additives are particularly useful if 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.

[0158] The formulation can be prepared by a method comprising mixing at least one anti-IL-23 specific antibody and a preservative in an aqueous diluent, the preservative being 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 a mixture thereof. The at least one anti-IL-23 specific antibody and the preservative are mixed in an aqueous diluent using conventional dissolution and mixing procedures. In order to prepare a suitable formulation, for example, a measured amount of at least one anti-IL-23 specific antibody in a buffer is combined with the desired preservative in a buffer in an amount sufficient to provide the desired concentration of protein and preservative. Variations of this method will be recognized by those of ordinary skill in the art. For example, the order in which the ingredients are added, whether additional additives are used, the temperature and pH during formulation preparation are all factors that can be optimized for the concentration and mode of administration used.

[0159] These formulations can be provided to patients as clear solutions or as dual vials, comprising a vial of lyophilized anti-IL-23 specific antibody reconstituted with a second vial containing water, preservatives and / or excipients in an aqueous diluent, preferably phosphate buffer and / or saline and selected salts. Either a single solution vial or a dual vial requiring reconstitution can be reused multiple times and can satisfy single or multiple cycles of patient treatment, and thus can provide a more convenient treatment regimen than currently available treatment regimens.

[0160] The articles of manufacture of the invention can be used for administration from immediately to twenty-four hours or longer. Thus, the articles of manufacture of the invention as claimed provide significant advantages for patients. The formulations of the invention can optionally be safely stored at temperatures of about 2°C to about 40°C and retain the biological activity of the protein for a long period of time, thereby allowing the package label to indicate that the solution can be kept and / or used for a period of 6, 12, 18, 24, 36, 48, 72 or 96 hours or longer. If a preservative diluent is used, such labeling may include a shelf life of up to 1-12 months, half a year, one and a half years, and / or two years.

[0161] The solution of anti-IL-23 specific antibody can be prepared by a method including mixing at least one antibody in an aqueous diluent. Mixing is performed using conventional dissolution and mixing procedures. In order to prepare a suitable diluent, for example, at least one antibody measured in water or a buffer is combined in an amount sufficient to provide the protein and an optional preservative or buffer to the desired concentration. Variations of this method will be recognized by those of ordinary skill in the art. For example, the order in which the ingredients are added, whether additional additives are used, the temperature and pH during preparation of the formulation are all factors that can be optimized for the concentration and mode of administration used.

[0162] The claimed product can be provided to the patient as a clear solution or as a dual vial comprising a vial of lyophilized at least one anti-IL-23 specific antibody reconstituted with a second vial of an aqueous diluent. Either the single solution vial or the dual vial requiring reconstitution can be reused multiple times and can satisfy single or multiple cycles of patient treatment and thus provide a more convenient treatment regimen than currently available treatment regimens.

[0163] The claimed product can be provided to patients indirectly by providing a pharmacy, clinic or other such institution or unit with a clear solution or dual vials comprising a vial of lyophilized at least one anti-IL-23 specific antibody reconstituted with a second vial containing an aqueous diluent. In this case, the volume size of the clear solution can be up to one liter or even larger, thereby providing a large reservoir from which smaller portions of the at least one antibody solution can be withdrawn one or more times for transfer to smaller vials and provided to their customers and / or patients by the pharmacy or clinic.

[0164] Recognized devices that include a single vial system include pen-type injector devices for delivering solutions, such as the BD Pen, BD and J-tip Needle-Free Medi- 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 dual vial systems include those pen-type injector systems for reconstituting a lyophilized drug in a cartridge that delivers the reconstituted solution, such as Examples of other suitable devices include pre-filled syringes, autoinjectors, needle-free syringes, and needle-free IV infusion sets.

[0165] These products may include packaging materials. In addition to providing information required by regulatory agencies, the packaging materials also provide conditions under which the product can be used. For dual vial, wet / dry products, the packaging materials of the present invention provide instructions to patients: when applicable, reconstitute at least one anti-IL-23 antibody in an aqueous diluent to form a solution and use the solution within a period of 2 hours to 24 hours or longer. For single vial, solution products, prefilled syringes or automatic injectors, the label indicates that this solution can be used within 2 hours to 24 hours or longer. The product can be used for human drug product purposes.

[0166] The formulation used in the method of the present invention can be prepared by the following method: the method comprises mixing the anti-IL-23 antibody and a selected buffer, the selected buffer preferably being a phosphate buffer containing saline or a selected salt. The anti-IL-23 antibody and the buffer are mixed in an aqueous diluent using conventional dissolution and mixing procedures. For example, to prepare a suitable formulation, a measured amount of at least one antibody in water or a buffer is mixed with the desired buffer in an amount of water sufficient to provide the desired concentration of protein and buffer. Variations of this method will be recognized by those of ordinary skill in the art. For example, the order in which the ingredients are added, whether additional additives are used, the temperature and pH during formulation preparation are all factors that can be optimized for the concentration and mode of administration used.

[0167] The method of the present invention provides pharmaceutical compositions, which include various preparations useful and acceptable for use to human or animal patients. Such pharmaceutical compositions are prepared using the water of "standard state" as a diluent and conventional methods well known to those of ordinary skill in the art. For example, a buffer component (such as histidine and histidine monohydrochloride hydrate) can be provided first, followed by adding a suitable non-final volume of water diluent, sucrose and polysorbate 80 under "standard state". The separated antibody can then be added. Finally, water is used as a diluent, and the volume of the pharmaceutical composition is adjusted to the required final volume under "standard state" conditions. Those skilled in the art will recognize that many other methods are suitable for preparing pharmaceutical compositions.

[0168] These pharmaceutical compositions can be aqueous solutions or suspensions, which contain each component of a specified mass per unit volume of water or have a specified pH under "standard conditions". As used herein, the term "standard conditions" refers to a temperature of 25°C + / - 2°C and a pressure of 1 atmosphere. The term "standard conditions" is not used in the art to represent a single art-recognized temperature or pressure, but rather a reference state, which is specified to describe the temperature and pressure of a solution or suspension having a specific composition under reference to the "standard state" conditions. This is because the volume fraction of the solution is a function of temperature and pressure. Those skilled in the art will recognize that pharmaceutical compositions comparable to those disclosed herein can be produced at other temperatures and pressures. Such pharmaceutical compositions should be determined under the above-described "standard state" conditions (e.g., 25°C + / - 2°C and a pressure of 1 atmosphere) to determine whether they are the same as those disclosed herein.

[0169] Importantly, such pharmaceutical compositions may contain a component mass of "about" a certain value (e.g., "about 0.53 mg L-histidine") per unit volume of the pharmaceutical composition or have a pH value of about a certain value. If the separated antibody present in the pharmaceutical composition is able to bind to the peptide chain while the separated antibody is present in the pharmaceutical composition or after the separated antibody is removed from the pharmaceutical composition (e.g., by dilution), the component mass or pH value present in the pharmaceutical composition is "about" a given value. In other words, a value such as a component mass value or pH value is "about" a given value when the binding activity of the separated antibody is maintained and detectable after the separated antibody is placed in the pharmaceutical composition.

[0170] Competitive binding assays were performed to determine whether IL-23 specific mAbs bind to similar or different epitopes and / or compete with each other. Abs were coated individually on ELISA plates. Competing mAbs were added, followed by biotinylated hrIL-23. For positive controls, the same mAb can be used to coat as a competitive mAb ("self-competition"). IL-23 binding was detected using streptavidin. These results demonstrate whether mAbs recognize similar or partially overlapping epitopes on IL-23.

[0171] In one aspect of the method of the present invention, a pharmaceutical composition is administered to a patient, the pharmaceutical composition comprising:

[0172] In one embodiment of the pharmaceutical composition, the isolated antibody concentration is from about 77 mg to about 104 mg per ml of the pharmaceutical composition. In another embodiment of the pharmaceutical composition, the pH is from about 5.5 to about 6.5.

[0173] The stable or preserved formulation can be provided to the patient in the form of a clear solution or a dual vial comprising a vial of lyophilized at least one anti-IL-23 antibody reconstituted with a second vial containing a preservative or buffer and excipients in 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 cycles of patient treatment, and thus provide a more convenient treatment regimen than currently available treatment regimens.

[0174] Other formulations or methods for stabilizing anti-IL-23 antibodies can produce solutions other than clear solutions containing a lyophilized powder of the antibody. Among the non-clear solutions are formulations containing suspensions of particles, which are compositions containing anti-IL-23 antibodies, which compositions have structures of variable size and are each referred to as microspheres, microparticles, nanoparticles, nanospheres or liposomes. Such relatively uniform, substantially spherical particle formulations containing active agents can be formed by contacting an aqueous phase containing an active agent and a polymer with a non-aqueous phase, and then evaporating the non-aqueous phase to agglomerate the particles from the aqueous phase, as taught in U.S. Pat. No. 4,589,330. Porous microparticles can be prepared using a first phase containing an active agent and a polymer dispersed in a continuous solvent, and removing the solvent from the suspension by freeze drying or dilution-extraction-precipitation, as taught in U.S. Pat. No. 4,818,542. Preferred polymers 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(ε-caprolactone), poly(ε-caprolactone-CO-lactic acid), poly(ε-caprolactone-CO-glycolic acid), poly(β-hydroxybutyric acid), polyethylene oxide, polyethylene, poly(2-alkyl cyanoacrylate), poly(hydroxyethyl methacrylate), polyamide, poly(amino acid), poly(2-hydroxyethyl DL-asparagine), 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(ε-caprolactone), poly(ε-caprolactone-co-lactic acid) and poly(ε-caprolactone-co-glycolic acid). Solvents that can be used to dissolve the polymer and / or the active include: water, hexafluoroisopropanol, dichloromethane, tetrahydrofuran, hexane, benzene or hexafluoroacetone sesquihydrate. The method of dispersing the phase containing the active substance with the second phase can include applying pressure to force the first phase through an orifice in a nozzle to achieve droplet formation.

[0175] Dry powder formulations can be produced by methods other than freeze drying, such as by spray drying or solvent extraction by evaporation, or by precipitation of crystalline compositions, followed by one or more steps to remove aqueous or non-aqueous solvents. The preparation of spray-dried antibody products is taught in U.S. Patent No. 6,019,968. Antibody-based dry powder compositions can be prepared by spray drying a solution or slurry of an antibody and an optional excipient in a solvent under conditions that provide a respirable dry powder. The solvent can include polar compounds that can be easily dried, such as water and ethanol. The stability of the antibody can be enhanced by performing a spray drying procedure in the absence of oxygen, such as under a nitrogen blanket or by using nitrogen as a drying gas for a spray drying procedure. Another relatively dry preparation is a dispersion of multiple perforated microstructures dispersed in a suspension medium, the suspension medium typically comprising a hydrofluorocarbon propellant, as taught in WO 9916419. Stabilized dispersions can be administered to the patient's lungs using a metered dose inhaler. Equipment that can be used in the commercial preparation of spray-dried drugs is manufactured by Buchi Ltd. or Niro Corp.

[0176] The anti-IL-23 antibodies in the stable or preserved formulations or solutions described herein can be administered to patients according to the present invention via a variety of delivery methods, including SC or IM injection; transdermal, pulmonary, transmucosal, implants, osmotic pumps, cartridges, minipumps or other means known to the skilled artisan, as are well known in the art.

[0177] Therapeutic applications

[0178] The present invention also provides methods of using at least one IL-23 antibody of the present invention to modulate or treat mild to moderate psoriasis in a cell, tissue, organ, animal or patient as known in the art or as described herein, e.g., administering a therapeutically effective amount of an IL-23-specific antibody to the cell, tissue, organ, animal or patient, or contacting the cell, tissue, organ, animal or patient with the therapeutically effective amount of the IL-23-specific antibody.

[0179] Any of the methods of the present invention may comprise administering an effective amount of a composition or pharmaceutical composition comprising an anti-IL-23 antibody to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy. Such methods may optionally further comprise co-administration or combination therapy for treating such diseases or disorders, wherein administration of the at least one anti-IL-23 antibody, specified portion or variant thereof further comprises prior to, concurrently with and / or after administration of at least one agent selected from the group consisting of: at least one TNF antagonist (e.g., but not limited to, a chemical antagonist or protein antagonist of TNF, a monoclonal or polyclonal antibody or fragment of TNF, a soluble TNF receptor (e.g., p55, p70 or p85) or a fragment thereof, a fusion polypeptide, or a small molecule TNF antagonist such as TNF binding protein I or II (TBP-1 or TBP-II), nerimumab, infliximab, etanercept (Enbrel TM ), adalimumab (Humira TM), CDP-571, CDP-870, afelimomab, lenafemab, etc.), antirheumatic drugs (e.g., methotrexate, auranofin, gold thioglucosinolate, azathioprine, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxants, narcotics, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blockers, antimicrobial agents (e.g., aminoglycosides, antifungals, antiparasitics, antivirals, carbapenems, cephalosporins, fluoroquinolones, macrolides, penicillins, sulfonamides, tetracyclines, other antimicrobial agents), antipsoriatic agents, corticosteroids, anabolic steroids, diabetes-related agents, minerals, nutrients, thyroid agents, vitamins, calcium-related hormones, antidiarrheals, antitussives, antiemetics The present invention relates to an agent, an anti-ulcer agent, a laxative, an anticoagulant, an erythropoietin (e.g., erythropoietin α), a filgrastim (e.g., G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), an immunizing agent, an immunoglobulin, an immunosuppressant (e.g., basiliximab, cyclosporine, daclizumab), a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic agent, a ciliary muscle paralytic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, an antimanic agent, an antipsychotic, an antianxiety drug, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma drug, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromoglycine, an epinephrine or an analog, alpha dornase (Pulmozyme), a cytokine or a cytokine antagonist. Suitable dosages are well known in the art. See, e.g., Wells et al., eds., "Pharmacotherapy Handbook," 2nd ed., 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, 21st ed.," Springhouse Corp., Springhouse, PA, 2001; "Health Professional's Drug Guide 2001," Shannon, Wilson, Stang, eds., Prentice-Hall, Inc, Upper Saddle River, NJ, each of which is incorporated herein by reference in its entirety.

[0180] Medical treatment

[0181] Typically, treatment of mild to moderate psoriasis is achieved by administering an effective amount or dose of an anti-IL-23 antibody composition, which, depending on the specific activity of the active agent contained in the composition, amounts to a range of at least about 0.01 mg to 500 mg of anti-IL-23 antibody per kg of patient per dose, and preferably at least about 0.1 mg to 100 mg of antibody per kg of patient per single or multiple administrations. Alternatively, effective serum concentrations may include 0.1 g / ml-5000 μg / ml serum concentrations per single or multiple administrations. Suitable doses are known to medical practitioners and will, of course, depend on the specific disease state, the specific activity of the composition to be administered, and the specific patient undergoing treatment. In some cases, in order to achieve the desired therapeutic amount, it may be necessary to provide repeated administrations, i.e., repeated single administrations of a specific monitored dose or metered dose, wherein the single administrations may be repeated until the desired daily dose or effect is achieved.

[0182] 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, , 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 to 500 mg / kg / administration, or any range, value or fraction thereof, or for achieving a serum concentration of 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, 1 500, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 and / or 5000 μg / ml serum concentration / single or multiple administrations, or any range, value or fraction thereof.

[0183] Alternatively, the dosage administered may vary according to known factors, such as the pharmacodynamic properties of a particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of symptoms, the type of concurrent treatment, the frequency of treatment, and the desired effect. Typically, the dosage of the active ingredient may be about 0.1 to 100 mg / kg body weight. Typically, 0.1 mg / kg to 50 mg / kg, preferably 0.1 mg / kg to 10 mg / kg, per administration or in a sustained release form, is effective in obtaining the desired result.

[0184] As a non-limiting example, the treatment of a human or animal may be on at least one of days 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, or alternatively or in addition thereto, in sections 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 weeks, or alternatively or in addition, in at least one of years 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, using a single dose, an infusion dose or repeated doses at 0.1 mg / kg to 100 mg / kg (such as 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / kg) of at least one antibody of the invention.

[0185] Dosage forms (compositions) suitable for internal administration usually contain about 0.001 mg to about 500 mg of active ingredient per unit or container. In these pharmaceutical compositions, the active ingredient is generally present in an amount of about 0.5% to 99.999% by weight based on the total weight of the composition.

[0186] For parenteral administration, the antibody can be formulated as a solution, suspension, emulsion, granule, powder or lyophilized powder, which is provided in combination or separately with a pharmaceutically acceptable parenteral medium. Examples of such media are water, saline, Ringer's solution, dextrose solution and 1% to 10% human serum albumin. Liposomes and non-aqueous media, such as fixed oils, can also be used. The medium or lyophilized powder may contain additives to maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives). The formulation can be sterilized by known or suitable techniques.

[0187] Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in the field.

[0188] Alternative administration

[0189] Many known and developed modes can be used to administer a pharmaceutically effective amount of an anti-IL-23 antibody according to the present invention. Although pulmonary administration is used in the description below, other modes of administration can also be used according to the present invention with suitable results. The IL-23-specific antibodies of the present invention can be delivered as a solution, emulsion, colloid or suspension in a carrier or as a dry powder using any of a variety of devices and methods suitable for administration by inhalation or other means described herein or known in the art.

[0190] Parenteral preparations and administration

[0191] Preparations for parenteral administration may contain sterile water or saline as common excipients, polyalkylene glycols such as polyethylene glycol, oils of plant origin, hydrogenated naphthalene, etc. Aqueous or oily suspensions for injection can be prepared according to known methods using appropriate emulsifiers or wetting agents and suspending agents. Injectable medicaments can be non-toxic, non-orally administered diluents, such as aqueous solutions, sterile injections, or suspensions in solvents. As available media or solvents, water, Ringer's solution, isotonic saline, etc. are allowed to be used; as common solvents or suspending solvents, sterile fixed oils can be used. For these purposes, any type of fixed oil and fatty acid can be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids; natural or synthetic or semi-synthetic glycerol monoesters or diglycerides or triglycerides. Parenteral administration is known in the art and includes, but is not limited to, conventional forms of injection, pneumatic needle-free injection devices as described in US Pat. No. 5,851,198, and laser perforator devices as described in US Pat. No. 5,839,446, which are incorporated herein by reference in their entirety.

[0192] Alternative delivery

[0193] The present invention also contemplates administration of an anti-IL-23 antibody by parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraperitoneal, intracapsular, intracartilaginous, intracavitary, intracerebellar, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, vaginal, rectal, oral, sublingual, intranasal, or transdermal routes. Anti-IL-23 antibody compositions can be prepared for parenteral (subcutaneous, intramuscular or intravenous) or any other administration, particularly in the form of liquid solutions or suspensions; for vaginal or rectal administration, particularly in semisolid form, such as, but not limited to, creams and suppositories; for oral or sublingual administration, such as, but not limited to, tablet or capsule form; or intranasal, such as, but not limited to, powders, nasal drops or aerosols or certain medicament forms; or transdermal, such as, but not limited to, gels, ointments, emulsions, suspensions or patch delivery systems containing chemical enhancers such as dimethyl sulfoxide to change the skin structure or increase the drug concentration in the transdermal patch (Junginger et al., "Drug Permeation Enhancement", Hsieh, DS, ed., pp. 59-90, (Marcel Dekker, Inc. New York 1994, incorporated herein by reference in its entirety), or containing oxidizing agents that enable the application of formulations containing proteins and peptides to the skin (WO 98 / 53847), or applying an electric field to produce a transient transport pathway, such as electroporation, or increasing the mobility of charged drugs through the skin, such as iontophoresis, or applying ultrasound, such as transdermal absorption of ultrasound (U.S. Pat. Nos. 4,309,989 and 4,767,402) (the above publications and patents are incorporated herein by reference in their entirety).

[0194] Having generally described the present invention, it will be more readily understood by reference to the following examples, which are given by way of example only and are not intended to be limiting. Further details of the present invention are described by the following non-limiting examples. The disclosures of all citations in the specification are expressly incorporated herein by reference.

[0195] Example 1 - Treatment of Mild to Moderate Psoriasis with IL23 Antibodies

[0196] A study evaluating the safety of guselkumab compared with placebo and apremilast in the treatment of mild to moderate psoriasis A Phase 3, multicenter, randomized, double-blind, placebo- and active comparator-controlled study of efficacy and safety (SPECTREM)

[0197] The primary objective of this study is to evaluate the efficacy of guselkumab compared with placebo and apremilast in participants with mild to moderate psoriasis. Other secondary objectives of this study are safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity.

[0198] The study will directly investigate the safety and efficacy of guselkumab 100 mg subcutaneous (SC) injection given at Weeks 0, 4, and then every 8 weeks (q8w) compared with placebo and apremilast 30 mg twice daily (BID) after standard up-titration in the treatment of participants with mild to moderate plaque psoriasis.

[0199] The primary endpoint will be the proportion of participants with an Investigator Global Assessment (IGA) score of 0 (clear) or 1 (minimal) at Week 16, a reduction of at least 2 points from baseline, compared to placebo. The first important secondary endpoint will be IGA 0 / 1 at Week 16, compared to the active comparator (apremilast). Additional controlled secondary endpoints and other endpoints are outlined in the Endpoints section below.

[0200] Approximately 450 eligible participants will be randomized 1:1:1 to receive guselkumab 100 mg SC at weeks 0 and 4, followed by standard up-titration with apremilast q8w followed by 30 mg twice daily (BID), or placebo. Randomization will be stratified by baseline IGA score (mild [2] or moderate [3]) and study center to ensure balance between treatment groups with respect to baseline severity of psoriasis. Approximately 30% of randomized participants will have a baseline IGA score of mild (2), and approximately 70% will have a baseline IGA score of moderate (3).

[0201] There will be 2 database locks (DBLs) in this study, at Week 24 and Week 56. The Week 24 DBL will be conducted after all participants complete the Week 24 visit (or discontinue the study), and unblinded data will be provided only to selected Sponsor and Contract Research Organization (CRO) team members involved in analyzing the data and preparing the Week 24 DBL analysis. All other Sponsor, Site, and CRO personnel directly involved in the conduct of the study will remain blinded to treatment assignment until the Week 56 DBL and related analyses have been completed.

[0202] The study design and treatment assignments are described below and Figure 1 Further described in .

[0203] Study population

[0204] The target population was adult men or women with a diagnosis of mild to moderate plaque psoriasis, with or without PsA, for at least 6 months. Participants with non-plaque forms of psoriasis (e.g., erythrodermic, guttate, or pustular) or with drug-induced psoriasis (e.g., new onset or exacerbation of psoriasis due to beta-blockers, calcium channel blockers, or lithium) were excluded.

[0205] Participants must have mild to moderate psoriasis, defined as BSA 2%-15%, IGA 2 or 3, and PASI 2-15. Participants must be candidates for systemic therapy or phototherapy for psoriasis and must have had an inadequate response or intolerance to at least 1 prior topical therapy. Participants must not have received advanced therapy including apremilast, guselkumab, and other oral immunomodulatory therapies or biologic therapies (ie, no prior exposure to treatment for psoriasis, psoriatic arthritis, or any other indication that could impact the assessment of psoriasis).

[0206] Inclusion criteria - participant population

[0207] 1. Participant gender (biologically): male and female

[0208] 2. Age of participants:

[0209] 3Minimum age: 18 (or the legal age of consent in the jurisdiction where the research is conducted)

[0210] 4 Plaque psoriasis (with or without PsA) diagnosed at least 6 months before first dose of study drug

[0211] 5. Candidates for phototherapy or systemic treatment of psoriasis

[0212] 6BSA 2%-15% at screening and associated at baseline

[0213] 7 with IGA 2 or 3 at screening and at baseline

[0214] 8 with PASI 2-15 at screening and at baseline

[0215] 9 Participants must have had inadequate control or intolerance to at least one topical therapy for the treatment of psoriasis (including topical corticosteroids, topical retinoids or vitamin D analogs, calcipotriene and betamethasone dipropionate ointment or foam, tacrolimus, pimecrolimus, or anthralin / anthraquinone) at screening and at baseline.

[0216] 10. Not received advanced therapy including apremilast, guselkumab, and other oral immunomodulatory therapies or biologic therapies (i.e., no prior exposure to treatment for psoriasis, psoriatic arthritis, or any other indication that could impact the assessment of psoriasis)

[0217] 11 In the opinion of the researchers, according to the Product labeling, considering appropriate candidates for apremilast therapy

[0218] 12 Prior to the first dose of study drug, women must:

[0219] a. Not of childbearing potential: premenopausal; postmenopausal (>45 years with at least 12 months of amenorrhea, or any age with at least 6 months of amenorrhea and serum follicle-stimulating hormone level >40 IU / L); permanent infertility (e.g., tubal occlusion / ligation, hysterectomy, bilateral salpingectomy); or otherwise unable to conceive

[0220] b. Be of childbearing potential and practice a highly effective method of birth control consistent with local regulations regarding the use of contraceptive methods for participants in clinical research: for example, confirmed use of oral, injectable, or implantable hormonal contraceptive methods; insertion of an intrauterine contraceptive device (IUD) or intrauterine system (IUS); barrier method: condom or occlusive cap (diaphragm or cervical / vault cap) plus spermicidal foam / gel / film / cream / suppository; sterilization of the male partner (the vasectomized partner should be the participant's only partner); complete abstinence (when this is consistent with the participant's preferred and usual lifestyle)

[0221] NOTE: If a female participant's reproductive potential changes after the start of the study (e.g., an inactive female becomes heterosexually active, a premenstrual female experiences menarche), she must begin practicing a highly effective method of contraception, as described previously.

[0222] 13 Females of childbearing potential must have a negative urine pregnancy test at screening week 0 and consent to a urine pregnancy test prior to receiving the injection

[0223] 14 Women must agree not to donate eggs (ovum, oocytes) for assisted reproduction purposes during the study and for at least 12 weeks after the last guselkumab administration

[0224] 15 Men who are sexually active with women of reproductive potential and who have not undergone a vasectomy must agree to use a barrier method of contraception (e.g., condoms [with spermicidal foam / gel / film / cream / suppository], or partner uses an occlusive cap [diaphragm or cervical / vault cap] plus spermicidal foam / gel / film / cream / suppository) during the study and for at least 12 weeks after receiving the last guselkumab administration. All men must also agree not to donate sperm during the study and for at least 12 weeks after receiving the last guselkumab administration.

[0225] Related infectious diseases

[0226] 16 Agree not to receive live viral or live bacterial vaccinations during the study or within 12 weeks after the last administration of the study intervention.

[0227] 17 agreed not to receive Bacillus Calmette-Guérin (BCG) vaccination during the study and within 12 weeks after the last administration of the study intervention.

[0228] 18. Advise patients to be up to date on age-appropriate vaccinations prior to screening in accordance with local routine medical guidelines. For study patients who have recently received a locally approved (and including emergency use authorized) COVID-19 vaccine prior to study entry, follow applicable local vaccine labels, guidelines, and standards of care for patients receiving immune-targeted therapies when determining the appropriate interval between vaccination and study enrollment.

[0229] 19 Screen the laboratory test results within the following parameters. If one or

[0230] If more than one is outside the range, a single retest of the laboratory value is allowed:

[0231] a. Hemoglobin ≥10 g / dL (SI: ≥100 g / L)

[0232] b. White blood cell ≥3.5×103 / μL (SI: ≥3.5GI / L)

[0233] c. Neutrophil count ≥1.5×103 / μL (SI: ≥1.5GI / L)

[0234] d. Platelet count ≥100×103 / μL (SI: ≥100GI / L)

[0235] e. Serum creatinine ≤1.5 mg / dL (SI: ≤137 μmol / L)

[0236] f. Aspartate aminotransferase ≤ 2 × upper limit of normal (ULN)

[0237] g. Alanine aminotransferase ≤ 2×ULN

[0238] NOTE: During the 6-week screening period, 1 repeat screening laboratory test is allowed (a-

[0239] e) The investigator may consider a participant eligible if the previous abnormal laboratory test results are within the acceptable range for repeat testing at the central laboratory.

[0240] other

[0241] 20 Agree to avoid prolonged sun exposure and avoid using tanning booths or other ultraviolet light sources during the study.

[0242] 21 is willing and able to abide by the prohibitions and restrictions set forth in this Agreement.

[0243] 22 must sign [(or his or her legal representative must sign)] an Informed Consent Form (ICF) indicating that he or she understands the purpose and required procedures of the study and is willing to participate in this study.

[0244] Exclusion criteria - Psoriasis

[0245] 1. Have a non-plaque form of psoriasis (e.g., erythrodermic, guttate, or pustular).

[0246] 2. Currently suffering from drug-induced psoriasis (e.g., new onset of psoriasis or exacerbation of psoriasis caused by beta blockers, calcium channel blockers, or lithium).

[0247] 3 Psoriasis flare / rebound (defined as a sudden worsening of psoriasis requiring use of prohibited medications) within 4 weeks of signing the ICF or between the screening and baseline visits.

[0248] 4. Prior treatment with any biologics for the treatment of psoriasis, psoriatic psoriasis, or any other indication that may affect the evaluation of psoriasis, including but not limited to TNF inhibitors (e.g., adalimumab, etanercept, infliximab, or certolizumab), IL-17 inhibitors (secukinumab, ixekizumab), IL-12 / 23 inhibitors (ustekinumab), IL-23 inhibitors (e.g., guselkumab, risankizumab, or tildrakizumab, etc.).

[0249] 5 had previously received apremilast.

[0250] 6 received phototherapy within 4 weeks of the first administration of study intervention.

[0251] 7. Receipt of any systemic immunosuppressant (e.g., methotrexate [MTX], azathioprine, cyclosporine, 6-thioguanine, mercaptopurine, mycophenolate mofetil, tacrolimus, acitretin) or anakinra within 4 weeks of the first administration of study drug.

[0252] 8. Any systemic medication that may affect psoriasis or IGA evaluation has been received within 4 weeks of the first administration of study drug, including but not limited to oral or injectable corticosteroids, retinoids, 1,25-dihydroxyvitamin D3 and analogs, psoralen, sulfasalazine, hydroxyurea, and fumaric acid derivatives.

[0253] 9. Use of topical medications that may affect psoriasis or IGA assessments within 2 weeks of the first administration of study medication (including but not limited to topical corticosteroids, topical retinoids or vitamin D analogs, calcipotriene and betamethasone dipropionate ointment or foam, tacrolimus, pimecrolimus or anthralin / anthraquinone, experimental topical medications such as taparinof or roflumilast, coal tar derivatives).

[0254] 10. Patients received herbal treatments, Korean medicines, or Chinese medicines that may affect psoriasis or IGA evaluation within 4 weeks of the first administration of study medication.

[0255] 11. Have received biologic therapy or experimental antibodies or within the prior 12 weeks or 5 half-lives (whichever is longer) of any study drug administration or are currently participating in another study using an investigational agent or procedure.

[0256] 12 Currently receiving lithium, antimalarials, or intramuscular (IM) gold, or have received lithium, antimalarials, or IM gold within 4 weeks of the first administration of study drug.

[0257] Coexisting medical conditions or past medical history

[0258] 13. History or current signs or symptoms of severe, progressive or uncontrolled renal, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurological, hematological, rheumatological, psychiatric or metabolic disorders.

[0259] 14 Unstable cardiovascular disease within the last 3 months, defined as recent clinical deterioration (e.g., unstable angina, rapid atrial fibrillation) or hospitalization for cardiac disease within the last 3 months.

[0260] 15. Currently have a known malignancy or have a history of malignancy within 5 years prior to screening (exceptions are non-melanoma skin cancer that has been adequately treated with no evidence of recurrence at least 3 months before the first dose of study drug, or cervical carcinoma in situ that has been treated with no evidence of recurrence at least 3 months before the first dose of study drug).

[0261] 16. History of lymphoproliferative disorder, including lymphoma; history of monoclonal gammopathy of undetermined significance; or signs and symptoms suggestive of a possible lymphoproliferative disorder (such as lymphadenopathy or splenomegaly).

[0262] 17. Patients who had received an organ transplant (>3 months before the first administration of study drug, excluding corneal transplant).

[0263] 18 Known intolerance or hypersensitivity to any biological drug, or known hypersensitivity or clinically significant reaction to murine, chimeric or human proteins, mAbs or antibody fragments.

[0264] 19 Before signing the informed consent and randomization, participants had a history of suicide attempts at any time in their lifetime or had a serious mental illness requiring hospitalization in the past 3 years before signing the informed consent.

[0265] 20 Unstable suicidal ideation or behavior in the past 6 months, defined as the following electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) scores at screening: suicidal ideation with intent to act (“4”), suicidal ideation with specific plan and intent (“5”), or suicide attempt (interrupted suicide attempt, abandoned suicide attempt, or preparatory behavior toward suicide attempt) and investigator confirmation of risk based on evaluation by a mental health professional. The final decision to exclude a participant will be made at the discretion of a trained mental health professional.

[0266] 21 A history of an infected joint prosthesis or previous antibiotic treatment for an infection in a joint prosthesis if the prosthesis was not removed or replaced.

[0267] 22 Known allergy or hypersensitivity to any component of Apremilast.

[0268] 23 Known allergy, hypersensitivity or intolerance to guselkumab or its excipients (refer to the Investigator's Manual).

[0269] 24 Pregnant, breastfeeding, or planning to become pregnant (both males and females) at the time of enrollment in this study and within 12 weeks after the last dose of study drug.

[0270] 25 Had major surgery (e.g., requiring general anesthesia and hospitalization) within 8 weeks prior to screening, will not fully recover from such surgery, or have such surgery planned during the participant's expected study participation period (56 weeks).

[0271] NOTE: Participants scheduled for surgical procedures under local anesthesia may participate.

[0272] 26 Known to have had substance abuse (drug or alcohol) problems in the past 12 months.

[0273] 27 There is evidence that skin conditions can interfere with the clinical assessment of psoriasis

[0274] Infection or susceptibility to infection

[0275] 28 History of chronic or recurrent infectious disease, including but not limited to chronic kidney infection, chronic chest infection (e.g., bronchiectasis), recurrent urinary tract infection (recurrent pyelonephritis or chronic non-remitting cystitis), fungal infection (mucocutaneous candidiasis), or skin wounds or ulcers that are open, oozing, or infected.

[0276] 29 Have or have had a serious infection (e.g., sepsis, pneumonia, or pyelonephritis) during the 2 months prior to screening, or have been hospitalized or received intravenous antibiotics for a clinically relevant infection.

[0277] 30 Have or have had herpes zoster within 2 months before screening.

[0278] 31 Received or expected to receive any live viral or bacterial vaccination within 3 months before the first dose of study drug, planned to receive such vaccine during the study or within 4 weeks after the last dose of study intervention. For BCG vaccine, see exclusion criteria 32.

[0279] 32 had received BCG vaccine within 12 months after screening.

[0280] 33 Chest X-ray performed within 3 months before the first dose of study drug showing abnormalities suggestive of malignancy or current active infection, including TB.

[0281] 34Meet any of the following tuberculosis (TB) screening criteria:

[0282] a. Have a history of active TB or show signs or symptoms suggestive of active TB during history and / or physical examination at screening.

[0283] b. History of untreated latent TB prior to screening. Participants who are currently receiving treatment or will start treatment for latent TB prior to the first administration of the study intervention are excluded.

[0284] NOTE: For participants with a history of treated latent TB, documentation of adequate treatment prior to the first administration of study intervention is required. The investigator is responsible for verifying the adequacy of prior TB treatment and providing appropriate documentation. Participants with a history of treated latent TB or ongoing latent TB treatment do not require QuantiFERON- (QFT) test.

[0285] c. Recent close contact with an individual with active TB. An exception may be made if such participants are referred to a physician specializing in TB to determine if treatment is necessary. This evaluation must be adequately documented, and if treatment is recommended, the participant must receive appropriate treatment prior to the first administration of the study intervention.

[0286] d. Positive QFT test result within 2 months prior to the first administration of study intervention. Exceptions are the following participants:

[0287] - History of adequately treated latent TB as described above.

[0288] - Have a newly identified positive QFT test result in which active TB has been excluded and appropriate treatment for latent TB has been initiated prior to the first administration of study intervention.

[0289] - Have a false-positive QFT test determined by:

[0290] o Suspected false positive initial QFT test must be repeated. If the repeat test is not positive, the participant must be referred to a physician specializing in TB to determine whether the initial test can be considered a false positive. This evaluation must be adequately documented prior to the first administration of the study intervention. However, if the repeat test is positive, it is considered a true positive and the participant is eligible only if active TB has been excluded as described above and appropriate treatment for latent TB has been initiated.

[0291] NOTE: Indeterminate / borderline results should be handled as outlined in protocol section 8.2.7.

[0292] e. Abnormalities suggestive of active or inactive TB on chest X-ray or chest computed tomography within 3 months prior to the first administration of study intervention.

[0293] 35 Hepatitis B virus (HBV) infection test was positive (Protocol Annex 5).

[0294] 36 Seropositive for antibodies to hepatitis C virus (HCV) unless the participant meets one of the following criteria:

[0295] a. Have a successful treatment history (defined as HCV RNA negativity for at least 12 weeks after completing antiviral therapy) and have a negative HCV RNA test result at screening, or

[0296] b. Although seropositive, had a negative HCV RNA test result at least 12 weeks prior to Screening and had a negative HCV RNA test result at Screening.

[0297] 37 History of active granulomatous infection including histoplasmosis or coccidioidomycosis prior to screening. See exclusion criterion 34 for information on eligibility with a history of latent TB.

[0298] 38 Patients with nontuberculous mycobacterial infection or opportunistic infection (e.g., cytomegalovirus, pneumocystis carinii, aspergillosis).

[0299] 39 were infected with human immunodeficiency virus (HIV, HIV antibody serology was positive).

[0300] 40 Any of the following during the 6 weeks prior to baseline:

[0301] a) confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) / COVID 19 infection (positive test), or

[0302] b) suspected SARS-CoV-2 infection (clinical features without documented test results), or

[0303] c) Close contact with persons known or suspected to be infected with SARS-Cov-2.

[0304] Exceptions to this criterion may be granted if the participant has a documented negative result for a validated SARS-CoV-2 test:

[0305] Obtained at least 2 weeks after conditions (a), (b), (c) above (timed from resolution of key clinical features (if present, e.g., fever, cough, dyspnea))

[0306] as well as

[0307] All of the above conditions (a), (b), (c) were absent during the period between the negative test result and the baseline study visit.

[0308] Notes on COVID-related exclusions:

[0309] The field of COVID-related testing (testing for the presence of and immunity to the SARS-CoV-2 virus) is rapidly evolving. Additional testing may be performed as part of screening and / or during the study if deemed necessary by the investigator and in accordance with current regulations / guidance from regulatory agencies / standards of care.

[0310] For those who may be at higher risk for severe COVID-19 illness, follow guidance from local health authorities when weighing the potential benefits and risks of study inclusion and during study participation.

[0311] General

[0312] 41 Unable or unwilling to undergo multiple venipunctures due to poor tolerance or difficulty accessing the vein.

[0313] 42Reside in an institution ordered by a court or authority.

[0314] 43 Any condition that the investigator determines is not in the best interest of the participant (e.g., impairs health) or that may prevent, limit, or confound protocol-specified assessments.

[0315] 44 are employees of the investigator or research center who are directly involved in the proposed study or other research under the guidance of the investigator or research center, and family members of the employees or investigators.

[0316] Lifestyle considerations

[0317] Prohibited and restricted treatments during the study period:

[0318] -Corticosteroids (topical, intralesional, shampoo, oral)

[0319] - Coal tar, lotion carbide (LCD), and any other topical medications that may be used to treat psoriasis (calcipotriol, tacrolimus, etc.)

[0320] Participants were required to avoid prolonged sun exposure and to refrain from using tanning booths or other sources of UV light during the study.

[0321] Permitted concomitant medications: Topical emollients, e.g. wait.

[0323] Sequence and duration of study phases / periods

[0324] 1. Screening period - up to about 6 weeks

[0325] 2. Blinded treatment period - Week 0 - Week 24

[0326] - At week 0, participants will be randomized in a 1:1:1 ratio within each stratum to guselkumab (100 mg SC at weeks 0 and 4, then q8w), apremilast, or placebo for the first 16 weeks

[0327] - Primary endpoint of IGA 0 / 1 evaluating guselkumab versus placebo at Week 16

[0328] - The first major secondary endpoint of IGA 0 / 1 evaluating guselkumab versus apremilast at Week 16

[0329] - At week 16, participants receiving placebo will switch to guselkumab in a blinded fashion (weeks 0 and 4, then q8w); at week 24, participants receiving apremilast will switch to guselkumab in a blinded fashion (weeks 0 and 4, then q8w)

[0330] - All treatment groups will receive study treatment until Week 44 (last treatment dose)

[0331] 3. Efficacy and safety follow-up phase - Week 44 to Week 56

[0332] - Final efficacy visit will be performed at week 48

[0333] - Final safety follow-up will be conducted at Week 56

[0334] Choice of placebo control and active comparator

[0335] Placebo

[0336] A placebo-controlled design was selected to provide a robust assessment of the efficacy of guselkumab 100 mg SC at Week 0, Week 4, and q8w in mild to moderate psoriasis. The placebo-controlled design was designed to minimize participant and investigator bias in evaluating the efficacy and safety of guselkumab in the selected patient population (U.S. Food and Drug Administration [FDA] Guidance for Industry E10).

[0337] Otezla (Apremilast)

[0338] Apremilast, a specific phosphodiesterase type 4 (PDE4) inhibitor, was approved in 2014 for moderate to severe plaque psoriasis and active PsA. In December 2021, it became the first advanced oral medicine approved for the treatment of mild to moderate plaque psoriasis, demonstrating statistically significant and clinically meaningful improvements across multiple efficacy measures. Apremilast was selected as the active comparator because as an advanced oral therapy it is safer than conventional systemic therapies such as methotrexate or cyclosporine while achieving meaningful levels of efficacy in mild to moderate psoriasis, providing a valuable and relevant benchmark for comparison with guselkumab. Participants randomized to Apremilast will be dosed according to the labeled dosing regimen for plaque psoriasis.

[0339] hypothesis

[0340] The hypothesis is that (i) guselkumab is superior to placebo and (ii) guselkumab is superior to apremilast in the treatment of mild to moderate psoriasis defined by BSA 2%-15%, IGA 2 or 3, and PASI 2-15. The study is designed to show the difference between guselkumab and placebo at Week 16 and between guselkumab and apremilast at Weeks 16 and 24.

[0341] Table 1 - Objectives and endpoints

[0342]

[0343]

[0344]

[0345]

[0346] Table 2 - Study interventions

[0347]

[0348]

[0349] Statistical considerations

[0350] Sample size: Assuming a two-sided alpha level of 0.05 or 0.001, a sample size of approximately 450 participants (150 participants in each treatment group) would allow at least 90% power to detect a 45% difference in treatment effect between guselkumab (60%) and placebo (15%) for the primary endpoint and a 30% difference in treatment effect between guselkumab (60%) and apremilast (30%) for the first important secondary endpoint.

[0351] Table 3 shows the power calculations for detecting a treatment difference under some assumptions about the primary endpoint and the first important secondary endpoint. For the other multiple controlled important secondary endpoints, a sample size of 150 per group would allow at least 90% power, assuming a treatment effect difference of approximately 35% to 70%, based on available data from the studies cited below (Table 4).

[0352] Table 3: Efficacy calculations for the primary endpoint and the first important secondary endpoint

[0353]

[0354] Table 4: Reference studies for primary endpoints and selected important secondary endpoints

[0355]

[0356]

[0357] Statistical methods :

[0358] Descriptive statistics (e.g., mean, median, standard deviation [SD], interquartile range [IQ] range, minimum, and maximum) will be used to summarize continuous variables. Counts and percentages will be used to summarize categorical variables. Graphical data displays (e.g., line graphs) can also be used to summarize data.

[0359] The Cochran-Mantel-Haenszel (CMH) chi-square statistical test will be used for the primary endpoint. In the primary efficacy analysis, data from all randomized participants will be analyzed according to their assigned group. Participants who start prohibited medications or therapies that may improve psoriasis before Week 16 due to lack of efficacy or discontinue the study intervention due to an AE of worsening psoriasis will be considered non-responders to the primary endpoint at Week 16.

[0360] Analysis applicable to categorical data (e.g., chi-square test, CMH chi-square test, or logistic regression, as appropriate) will be used to compare the proportion of participants achieving the selected endpoint (e.g., clinical response). In the case of rare events, Fisher's exact test will be used for treatment comparison. Unless otherwise specified, continuous response parameters will be compared using analysis of variance (ANOVA) or analysis of covariance (ANCOVA). If the normality assumption is considered, ANOVA or ANCOVA on van der Waerden normality scores will be used.

[0361] The overall type I error rate will be controlled at a significance level of 0.05 (two-sided).

[0362] The present invention can be described in conjunction with the following numbered embodiments: :

[0363] 1. Use of an antibody specific for IL23 for treating mild to moderate psoriasis in a patient, wherein the antibody comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region comprises:

[0364] the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:4;

[0365] The CDRL2 amino acid sequence of SEQ ID NO:5; and

[0366] The CDRL3 amino acid sequence of SEQ ID NO:6,

[0367] The heavy chain variable region comprises:

[0368] the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1;

[0369] The CDRH2 amino acid sequence of SEQ ID NO:2; and

[0370] The CDRH3 amino acid sequence of SEQ ID NO: 3, and the use enables the patient to produce a clinical response.

[0371] 2. The use according to embodiment 1, wherein the antibody is administered at an initial dose, a dose about 4 weeks after the initial dose, and a dose about 12 weeks after the initial dose.

[0372] 3. The use according to embodiment 2, wherein the antibody is administered subcutaneously.

[0373] 4. The use according to embodiment 1, wherein the initial dose and the dose about 4 weeks after the initial dose and the dose about 12 weeks after the initial dose are 100 mg of the antibody.

[0374] 5. The use according to embodiment 1, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint and / or an exploratory endpoint, wherein the clinical endpoint

[0375] Points come from the group consisting of:

[0376] (i) achieve an IGA score of clear (0) or minimal (1) and at least ≥2 grade improvement from baseline;

[0377] (ii) achieve BSA ≤ 1%;

[0378] (iii) achieve an IGA score of clear (0);

[0379] (iv) achieving a PASI 90 response;

[0380] (v) achieve PASI 100 response;

[0381] (vi) achieve a scalp-specific investigator global assessment (ss-IGA) score of no disease (0) or minimal disease with at least a 2-grade improvement from baseline and an ss-IGA score of ≥2 at baseline;

[0382] (vii) among participants with a Psoriasis Symptoms and Signs Diary (PSSD) pruritus score ≥4 at baseline, achieve a reduction (improvement) in PSSD pruritus score of ≥4 points from baseline;

[0383] (viii) achieve a PSSD symptom score of 0 among randomized participants with a baseline PSSD symptom score ≥1; and

[0384] (ix) Percent improvement from baseline in the Nail Psoriasis Severity Index (NAPSI) among randomized participants with nail psoriasis at baseline.

[0385] 6. The use according to embodiment 5, wherein the clinical endpoint is measured at about 16 weeks, 24 weeks, 48 ​​weeks and / or 96 weeks after the initial treatment.

[0386] 7. The use according to embodiment 6, wherein the clinical endpoint is measured about 16 weeks after the initial treatment.

[0387] 8. The use according to any one of embodiments 5 to 7, wherein the clinical endpoint is compared with the clinical endpoint of patients treated with Apremilast.

[0388] 9. The use according to embodiment 1, wherein the antibody comprises a light chain variable region amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region amino acid sequence of SEQ ID NO: 7.

[0389] 10. The use according to embodiment 1, wherein the antibody comprises a light chain amino acid sequence of SEQ ID NO: 10 and a heavy chain amino acid sequence of SEQ ID NO: 9.

[0390] 11. The use according to embodiment 9 or 10, wherein the antibody is in a composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water under standard conditions.

[0391] 12. The use according to embodiment 1, further comprising the use of one or more additional drugs for treating mild to moderate psoriasis.

[0392] 13. The use according to embodiment 12, wherein the additional drug is selected from the group consisting of: immunosuppressants, non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface marker antibodies, anti-CD20 antibodies, rituximab, TNF inhibitors, corticosteroids and co-stimulatory modulators.

[0393] 14. Use of an antibody specific for IL23 for treating mild to moderate psoriasis in a patient, (i) an initial subcutaneous dose of 100 mg of the antibody, (ii) a subcutaneous dose of 100 mg of the antibody approximately 4 weeks after the initial dose, and (iii) a subcutaneous dose of 100 mg of the antibody approximately every 8 weeks after the dose approximately 4 weeks after the initial dose, wherein the antibody comprises a light chain variable region amino acid sequence of SEQ ID NO:8 and a heavy chain variable region amino acid sequence of SEQ ID NO:7, and the patient becomes a responder to the antibody by being identified as meeting a clinical endpoint approximately 16 weeks after the initial dose, wherein the clinical endpoint is selected from the group consisting of: (i) achieving an IGA score of clear (0) or minimal (1) with at least ≥2 grade improvement from baseline; (ii) achieving BSA ≤1%; (iii) achieving an IGA score of clear (0); (iv) achieving a PASI 90 response and (v) achieving a PASI 100 response.

[0394] Sequence Listing

[0395] <210> 1

[0396] <211> 5

[0397] <212> PRT

[0398] <213> Homo sapiens

[0399] <400>1

[0400] Asn Tyr Trp Ile Gly 1 5

[0402] <210>2

[0403] <211>17

[0404] <212>PRT

[0405] <213>Homo sapiens

[0406] <400>2

[0407] Ile Ile Asp Pro Ser Asn Ser Tyr Thr Arg Tyr Ser Pro Ser Phe Gln 1 5 10 15

[0409] Gly

[0410] <210>3

[0411] <211>8

[0412] <212>PRT

[0413] <213>Homo sapiens

[0414] <400>3

[0415] Trp Tyr Tyr Lys Pro Phe Asp Val 1 5

[0417] <210>4

[0418] <211>14

[0419] <212>PRT

[0420] <213>Homo sapiens

[0421] <400>4

[0422] Thr Gly Ser Ser Ser Asn Ile Gly Ser Gly Tyr Asp Val His 1 5 10

[0424] <210>5

[0425] <211>7

[0426] <212>PRT

[0427] <213> Homo sapiens

[0428] <400> 5

[0429] Gly Asn Ser Lys Arg Pro Ser 1 5

[0431] <210> 6

[0432] <211> 11

[0433] <212> PRT

[0434] <213> Homo sapiens

[0435] <400> 6

[0436] Ala Ser Trp Thr Asp Gly Leu Ser Leu Val Val 1 5 10

[0438] <210> 7

[0439] <211> 117

[0440] <212> PRT

[0441] <213> Homo sapiens

[0442] <400> 7

[0443]

[0444] <210> 8

[0445] <211> 111

[0446] <212> PRT

[0447] <213> Homo sapiens

[0448] <400> 8

[0449]

[0450] The heavy and light chain amino acids sequenced for guselkumab are shown below (complementarity determining regions are shown in bold and variable regions are underlined):

[0451] Heavy chain (SEQ ID NO:9)

[0452] <210> 9

[0453] <211> 447

[0454] <212> PRT

[0455] <213> Homo sapiens

[0456] <400> 9

[0457]

[0458]

[0459] Light chain (SEQ ID NO: 10)

[0460] <210> 10

[0461] <211> 217

[0462] <212> PRT

[0463] <213> Homo sapiens

[0464] <400> 10

[0465]

Claims

1. A method of treating mild to moderate psoriasis in a patient, the method comprising administering to the patient an antibody specific for IL23, wherein the antibody comprises a light chain variable region and a heavy chain variable region, the light chain variable region comprising: the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:4; The CDRL2 amino acid sequence of SEQ ID NO:5; and The CDRL3 amino acid sequence of SEQ ID NO:6, 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, wherein the patient is a responder to the antibody.

2. The method of claim 1, wherein the antibody is administered at an initial dose, a dose about 4 weeks after the initial dose, and a dose about 12 weeks after the initial dose.

3. The method of claim 2, wherein the initial dose and the dose about 4 weeks after the initial dose and the dose about 12 weeks after the initial dose are about 100 mg of the antibody.

4. The method of claim 3, wherein the antibody is administered subcutaneously.

5. The method of claim 4, further comprising administering a maintenance dose of the antibody about every 8 weeks after administering the dose about 12 weeks after the initial dose.

6. The method of claim 1, wherein the patient becomes a responder to the antibody by being identified as meeting a clinical endpoint.

7. The method of claim 6, wherein the clinical endpoint is selected from the group consisting of: (i) achieve an IGA score of clear (0) or minimal (1) and at least ≥2 grade improvement from baseline; (ii) achieve BSA ≤ 1%; (iii) achieve an IGA score of clear (0); (iv) achieving a PASI 90 response; (v) achieve PASI 100 response; (vi) achieve a scalp-specific investigator global assessment (ss-IGA) score of no disease (0) or minimal disease with at least a 2-grade improvement from baseline and an ss-IGA score of ≥2 at baseline; (vii) among participants with a Psoriasis Symptoms and Signs Diary (PSSD) pruritus score ≥4 at baseline, achieve a reduction (improvement) in PSSD pruritus score of ≥4 points from baseline; (viii) achieve a PSSD symptom score of 0 among randomized participants with a baseline PSSD symptom score ≥1; and (ix) Percent improvement from baseline in the Nail Psoriasis Severity Index (NAPSI) among randomized participants with nail psoriasis at baseline.

8. The method of claim 7, wherein the clinical endpoint is measured about 16 weeks after the initial dose.

9. The method of claim 7, wherein the clinical endpoint is measured at about 24 weeks, 52 weeks, and / or 104 weeks after initial treatment.

10. The method of claim 9, wherein the clinical endpoint is measured about 24 weeks after initial treatment.

11. The method according to any one of claims 7 to 10, wherein the clinical endpoint is compared with the clinical endpoint of patients treated with Apremilast.

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

7.

13. The method of claim 1, wherein the antibody comprises a light chain amino acid sequence of SEQ ID NO: 10 and a heavy chain amino acid sequence of SEQ ID NO:

9.

14. The method of claim 12 or 13, wherein the antibody is in a composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) polysorbate 80 of the pharmaceutical composition; and wherein the diluent is water under standard conditions.

15. The method of claim 1, further comprising administering to the patient one or more additional medications for the treatment of mild to moderate psoriasis.

16. The method of claim 15, wherein the additional drug is selected from the group consisting of: immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface marker antibodies, anti-CD20 antibodies, rituximab, TNF inhibitors, corticosteroids, and co-stimulatory modulators.

17. A method of treating mild to moderate psoriasis in a patient, the method comprising administering to the patient (i) an initial subcutaneous dose of 100 mg of an antibody specific for IL23, (ii) a subcutaneous dose of 100 mg of the antibody approximately 4 weeks after the initial dose, (iii) a subcutaneous dose of 100 mg of the antibody approximately 12 weeks after the initial dose, and (iv) a subcutaneous dose of 100 mg of the antibody approximately every 8 weeks after the dose approximately 12 weeks after the initial dose, wherein the antibody comprises a light chain variable region amino acid sequence of SEQ ID NO:8 and a heavy chain variable region amino acid sequence of SEQ ID NO:7, and the patient becomes a responder to the antibody by being identified as meeting a clinical endpoint approximately 24 weeks after the initial dose, wherein the clinical endpoint is a change from baseline in modified Rodman Skin Score (mRSS).

Images