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

Abstract

A method of treating mild to moderate psoriasis in a patient comprises administering an antibody specific for IL-23, e.g., guselkumab, in an initial subcutaneous administration and subsequent administrations such that the patient responds to the antibody and meets one or more clinical endpoints.

Description

[Technical field]

[0001] (Reference to electronically submitted sequence listing) The sequence listing of the present application has been submitted electronically through the Patent Center at the U.S. Patent and Trademark Center as an XML format sequence listing with the filename "JBI6708WOPCT1SEQLIST.xml", created on March 23, 2023, and 11 kilobytes (KB) in size. This submitted sequence listing is a part of the present specification and is incorporated by reference in its entirety herein.

[0002] FIELD OF THEINVENTION The present invention is directed to methods for treating mild to moderate psoriasis with antibodies that bind to human IL23. In particular, the present invention relates to doses and dosing regimens and uses and methods for administering anti-IL23 specific antibodies and certain pharmaceutical compositions of the antibodies. [Background technology]

[0003] Guselkumab (Tremfya® from Janssen Biotech, Inc.) is a fully human immunoglobulin G1 lambda (IgG1 lambda) monoclonal antibody (mAb) that binds to the p19 subunit of human interleukin (IL)-23 with high specificity and affinity. Guselkumab's binding to the p19 subunit of IL-23 blocks the binding of cell surface IL-23 receptors to extracellular IL-23, resulting in inhibition of IL-23-specific intracellular signaling and downstream activation and cytokine production. Guselkumab is currently approved for the treatment of adults with moderate to severe plaque psoriasis or moderate to severe psoriatic arthritis (PsA) in the United States, European Union, Canada, several Latin American countries, and the Asia-Pacific region. Guselkumab is also approved in Japan for the treatment of generalized pustular psoriasis, erythrodermic psoriasis, and palmoplantar pustulosis. In addition, guselkumab is being evaluated worldwide in both ulcerative colitis and Crohn's disease, as well as in several other immune-mediated dermatological and rheumatic diseases.

[0004] Plaque psoriasis is a chronic immune-mediated disorder characterized by raised, sharply demarcated, red patches with silvery scales that affects 2-3% of the population. Psoriasis is associated with multiple comorbidities, including autoimmune disease, neuropathies, cardiometabolic disease, and inflammatory bowel disease. Approximately 80% of the psoriasis population has mild to moderate disease.

[0005] Traditionally, severity has been classified into three categories: mild, moderate, and severe, based on body surface area (BSA) and the Psoriasis Area and Severity Index (PASI). Patients with "mild" disease have traditionally been treated with topical therapies, while those with "moderate-to-severe" disease have been candidates for systemic therapy. Severity eligibility criteria for newer randomized controlled trials of psoriasis treatments for moderate-to-severe psoriasis are generally set at 10% or greater BSA involvement. The American and International Dermatological Societies have assessed that treatment decisions using these artificially designed cutoffs based on quantitative measures such as BSA exclude a large proportion of patients, who are significantly affected by undertreated disease. It is widely recognized that patients with localized subtypes, such as those with facial, genital, palmoplantar, scalp, and nail involvement, may suffer greatly from their localized psoriasis, but in many cases do not meet the traditional definition of severe disease unless the skin involvement is at least 10% BSA. Both the International Psoriasis Council (IPC) and the American Academy of Dermatology (AAD)-National Psoriasis Foundation (NPF) have recently publicly announced their rejection of the mild, moderate, and severe categories, accepting a binary definition of candidates for topical therapy or systemic therapy, including biologics.

[0006] The IPC suggests that candidates for systemic therapy include patients with (1) BSA ≥ 10%, or (2) disease involving special areas (hands / feet, nails, face, scalp, and genitals), or (3) failure of topical therapy. Similarly, the AAD-NPF guidelines acknowledge that psoriasis can be severe regardless of BSA if it has severe emotional consequences, occurs in selected sites such as, but not limited to, the hands, feet, scalp, face, or genital areas, or causes intractable pruritus.

[0007] Consistent with the gaps identified above, the 2003-2011 NPF survey revealed 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 undertreated. Another study examining the correlation of the Dermatology Life Quality Index (DLQI) with BSA and PASI highlighted concerns that treatment decisions based on threshold assessments of disease measures alone (BSA or PASI) may result in undertreatment of some patients who experience a high burden of disease, finding that the patient population surveyed in this study would be classified as having mild to moderate disease if assessed by objective severity measures alone, yet their DLQI indicated high impact or severe disease.

[0008] It is becoming accepted by the dermatology community and psoriasis patients that highly effective systemic therapy with biologic agents should be considered even in situations where traditional scoring systems indicate mild to moderate disease severity. To address this unmet need, numerous sponsors and academic investigators have conducted clinical studies to evaluate the efficacy and safety of advanced systemic therapies in patients with lower BSA-involved psoriasis.

[0009] As a result, patients with mild to moderate psoriasis represent an undertreated population. There remains a 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 [Means for solving the problem]

[0010] In a first aspect, the present invention relates to a method of treating a subject (patient) suffering from mild to moderate psoriasis, comprising administering to the patient an initial dose of an antibody specific for anti-IL23 (also called IL23p19 or IL23p19 subunit antibody), e.g., guselkumab, at the initiation of treatment, and at certain intervals thereafter, preferably a booster dose about 4 weeks after the initial dose, then about every 8 weeks after the booster dose, e.g., at weeks 0, 4, 12, 20, 28, 36, 44, and / or 52. Moreover, in another embodiment, the treatment continues for 100 weeks or more after initiation of treatment.

[0011] In one embodiment, a subject is administered an anti-IL23 specific antibody subcutaneously in a dose of 100 mg at the initial dose, at a boost dose 4 weeks after the initial dose, and every 8 weeks after the boost dose.

[0012] In another embodiment, the composition used in the methods of the invention comprises a pharmaceutical composition comprising an antibody specific for anti-IL23.

[0013] In one embodiment, patients with mild to moderate psoriasis achieve significant improvement in a clinical and / or exploratory endpoint selected from the group consisting of: (i) Achievement of a clear (0) or minimal (1) IGA score with at least ≥ 2 grade improvement from baseline at Week 16; (ii) achievement of BSA ≤ 1% at week 16; (iii) achievement of an IGA score of clear (0) at week 16; (iv) achievement of a PASI 90 response at week 16; (v) achievement of a PASI 100 response at week 16; (vi) achieving a Scalp-Specific Investigator's Global Assessment (ss-IGA) score of no disease (0) or very mild disease, and having at least a 2-grade improvement from baseline at week 16 and a baseline ss-IGA score of ≥ 2; (vii) achieving a ≥ 4 point reduction (improvement) from baseline in the Patient Outcomes for Psoriasis Symptoms and Signs (PSSD) Itch score at week 16 in participants with a PSSD Itch score ≥ 4 at baseline; (viii) achievement of BSA ≤ 1% at week 16; (ix) achievement of an IGA score of clear (0) at week 16, (x) achievement of PASI 90 response at week 16; (xi) achievement of PASI 100 response at week 16; (xii) In randomized participants with scalp psoriasis and an ss-IGA score of ≥ 2 at baseline, achievement of an ss-IGA score of no disease (0) or very mild disease at week 16 and having at least a 2-grade improvement from baseline; (xiii) achievement of a PSSD symptom score of 0 at week 24 for apremilast in randomized participants with a baseline PSSD symptom score ≥ 1; (xiv) achieving a ≥ 4 point reduction (improvement) from baseline in PSSD itch score at week 16 in participants with a PSSD itch score ≥ 4 at baseline; and (xv) Percent improvement from baseline in the Nail Psoriasis Severity Index (NAPSI) at week 16 in randomized participants with nail psoriasis at baseline.

[0014] In preferred embodiments, the endpoint may be measured about 16, 24, 48 weeks or more after initial treatment.

[0015] In another aspect of the 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 with 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, and 0.053% (w / v) polysorbate 80 of the pharmaceutical composition, wherein the diluent is standard water.

[0016] Another aspect of the method of the present invention comprises administering a pharmaceutical composition comprising an isolated anti-IL23 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 of 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, and 0.053% (w / v) polysorbate 80 of the pharmaceutical composition, where the diluent is standard water for use in treating patients with mild to moderate psoriasis according to the doses and dosing regimens described herein.

[0017] A further aspect of the method of the invention comprises administering a pharmaceutical composition comprising an isolated anti-IL23 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 of 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, and 0.053% (w / v) polysorbate 80 of the pharmaceutical composition, where the diluent is standard water.

[0018] In yet a further embodiment, the method of the invention comprises administering a pharmaceutical composition comprising the antibody guselkumab (Tremfya® from Janssen Biotech, Inc.), optionally in a composition with 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, and 0.053% (w / v) polysorbate 80 of the pharmaceutical composition, where the diluent is standard water.

[0019] The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages will become apparent from the following detailed description, the drawings, and the appended claims. [Brief description of the drawings]

[0020] [Figure 1] A schematic diagram of the trial design is shown below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] As used herein, methods of treating subjects suffering from mild to moderate psoriasis include administering isolated, recombinant, and / or synthetic anti-IL-23 specific human antibodies and diagnostic and therapeutic compositions, methods, and devices.

[0022] 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 molecule comprising at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one complementarity determining region (CDR) or ligand binding portion thereof of a heavy or light chain, 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 be incorporated into an antibody of the invention. Such antibodies optionally further affect a specific ligand, for example, but not limited to, such antibodies modulate, reduce, enhance, antagonize, stimulate, reduce, ameliorate, block, inhibit, abrogate, and / or prevent at least one IL-23 activity or binding, or IL-23 receptor activity or binding, in vitro, in situ, and / or in vivo. As non-limiting examples, suitable anti-IL-23 antibodies, specified portions, or variants of the invention can bind to at least one IL-23 molecule or a specified portion, variant, or domain thereof. Suitable anti-IL-23 antibodies, specified portions, or variants can also, optionally, affect at least one IL-23 activity or function, including, 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.

[0023] The term "antibody" is further intended to encompass antibodies, digested fragments thereof, specific portions, and variants thereof, including antibody mimetics or portions of antibodies that mimic the structure and / or function of antibodies, such as single chain antibodies and fragments thereof, or specific fragments or portions thereof. Functional fragments include antigen-binding fragments that bind to mammalian IL-23. For example, antibody fragments capable of binding to IL-23 or portions thereof, including but not limited to Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab')2 (e.g., by pepsin digestion), facb (e.g., by plasmin digestion), pFc' (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction, and reassembly), Fv, or scFv (e.g., by molecular biology techniques) fragments are encompassed by the present invention (see, e.g., Colligan, Immunology, supra).

[0024] Such fragments can be produced by enzymatic cleavage, synthetic, or recombinant techniques known in the art and / or described herein. Antibodies can also be produced in a variety of 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 of genes encoding a F(ab')2 heavy chain portion can be used to encode the C(ab')2 heavy chain portion. H The antibody can be designed to contain DNA sequences encoding the antibody domain and / or hinge region. The various portions of the antibody can be joined chemically by conventional techniques, or can be prepared as a contiguous protein using genetic engineering techniques.

[0025] As used herein, the term "human antibody" refers to an antibody that is human and contains substantially all parts of the protein (e.g., CDRs, frameworks, C L , C H Domain (e.g., C H 1. C H 2. C H 3), Hinge (V L , V H)) that are substantially non-immunogenic in humans with only minor sequence changes or mutations. A "human antibody" may be an antibody derived from or closely corresponding to a human germline immunoglobulin sequence. A human antibody may contain amino acid residues not encoded by a germline immunoglobulin sequence (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). In many cases, this means that the human antibody is substantially non-immunogenic in humans. Human antibodies have been classified into groups based on the similarity of their amino acid sequences. Thus, using sequence similarity searches, antibodies with similar linear sequences can be selected as templates for creating human antibodies. Similarly, antibodies with names including primates (monkeys, baboons, chimpanzees, etc.), rodents (mouse, rats, rabbits, guinea pigs, hamsters, etc.), and other mammals designate antibodies specific for such species, subgenus, genus, subfamily, and family. Furthermore, chimeric antibodies can include any combination of the above. Such changes or mutations optionally and preferably retain or reduce immunogenicity in humans or other species compared to the unmodified antibody. Thus, a human antibody is distinct from a chimeric antibody or a humanized antibody.

[0026] It is noted that human antibodies can be produced by non-human animals or prokaryotic or eukaryotic cells capable of expressing functionally rearranged human immunoglobulin (e.g., heavy and / or light chain) genes. Furthermore, when the human antibody is a single-chain antibody, it can contain a linker peptide not found in naturally occurring human antibodies. For example, an Fv can contain a linker peptide, such as 2 to about 8 glycine or other amino acid residues, connecting the variable region of the heavy chain and the variable region of the light chain. Such a linker peptide is considered to be of human origin.

[0027] Bispecific, heterospecific, heterobinding or similar antibodies may also be used, which are monoclonal, preferably human or humanized, antibodies with binding specificities for at least two different antigens, one of which is for at least one IL-23 protein and the other for any other antigen. Methods for producing bispecific antibodies are known in the art. Traditionally, recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-light chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature 305:537 (1983)). Due to the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a possible mixture of 10 different antibody molecules, of which only one has the correct bispecific structure. Purification of the correct molecule (usually done by affinity chromatography steps) is quite laborious and the product yield is low. Similar procedures are described, for example, in 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, 5,989,530, 5,959,084, 5,959,083, 5,989,530, 5,959,084, 5,959,085, 5,989,530 ...89,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,5 Nos. 32448, 5833985, 5821333, 5807706, 5643759, 5601819, 5582996, 5496549, 4676980, WO 91 / 00360, WO 92 / 00373, EP 03089, Traunecker et al., EMBO J. 10:3655 (1991), and Suresh et al., Methods in Enzymology 121:210 (1986), each of which is incorporated herein by reference in its entirety.

[0028] Anti-IL-23 specific antibodies (also referred to as IL-23 specific antibodies) (or antibodies against IL-23) useful in the methods and compositions of the invention can be characterized by optionally having high affinity binding to IL-23, and optionally and preferably low toxicity. In particular, the antibodies of the invention, specific fragments or variants thereof, in which the individual components such as the variable region, constant region and framework, individually and / or collectively, optionally and preferably have low immunogenicity, are useful in the invention. Antibodies that can be used in the present invention are optionally characterized by the ability to treat patients for extended periods of time with measurable alleviation of symptoms and low and / or acceptable toxicity. Low or acceptable immunogenicity and / or high affinity, as well as other favorable properties, can contribute to the therapeutic results obtained. "Low immunogenicity" is defined herein as raising a significant HAHA, HACA, or HAMA response in less than about 75%, or preferably less than about 50%, of treated patients, and / or raising low titers (less than about 300, preferably less than about 100, as measured by double antigen enzyme immunoassay) in treated patients (Elliott et al., Lancet 344:1125-1127 (1994), incorporated herein by reference in its entirety). "Low immunogenicity" can also be defined as the incidence of titrable levels of antibodies to an anti-IL-23 antibody in patients treated with an anti-IL-23 antibody when occurring in less than 25% of treated patients, preferably less than 10% of treated patients, at the recommended dose over the recommended course of treatment during the treatment period.

[0029] The term "safety", when referring to an administration, dosing regimen, treatment or method with an anti-IL-23 antibody of the present invention (e.g., the anti-IL-23 antibody guselkumab), refers to a relatively low or reduced frequency and / or a low or reduced severity of treatment-emergent adverse events (also referred to as AEs or TEAEs), e.g., from an conducted clinical trial, e.g., a Phase 2 clinical trial, and earlier clinical trials, compared to a standard of care or another comparison standard. An adverse event is an untoward medical occurrence in a patient administered a medicinal product. In particular, when referring to an administration, dosing regimen or treatment with an anti-IL-23 antibody of the present invention, clinically proven safety refers to a relatively low or reduced frequency and / or a low or reduced severity of adverse events associated with administration of the antibody, when the cause is considered possible, probable, or highly likely to be due to the use of the anti-IL-23 antibody.

[0030] usefulness The isolated nucleic acids of the present invention can be used to produce at least one anti-IL-23 antibody or specific variants 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 onset of, or reduce the symptoms of mild to moderate psoriasis.

[0031] Such methods may include administering to a cell, tissue, organ, animal, or patient in need of such modulation, treatment, amelioration, prevention, or reduction of a symptom, effect, or mechanism an effective amount of a composition or pharmaceutical composition comprising at least one anti-IL-23 antibody. An effective amount may include an amount of about 0.001-500 mg / kg per single (e.g., bolus), multiple, or continuous administration, or an amount that achieves a serum concentration of 0.01-5000 μg / mL per single, multiple, or continuous administration, or any effective range or value therein, performed and determined using known methods described herein or known in the relevant art.

[0032] References All publications or patents cited herein, whether specifically stated or not, are incorporated herein by reference in their entirety, indicating the prior art at the time of the invention and / or providing a description and enabling of the invention. A publication refers to any scientific publication or patent publication or any other information available in any media format, including all recorded in electronic or printed form. The following documents are incorporated herein by reference in their entirety: Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2 nd Edition, Cold Spring Harbor, NY (1989), Harlow and Lane, antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989), Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994-2001), Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2001).

[0033] Antibodies of the Invention - Production and Purification At least one anti-IL-23 used in the methods of the invention can optionally be produced by a cell line, mixed cell line, immortalized cell, or clonal population of immortalized cells, as known in the art, see, for example, Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2002; and, 2003, Immunotherapy and Immunotherapy, 1999, 144:1311-1320, each of which is incorporated herein by reference in its entirety. nd Edition, Cold Spring Harbor, NY(1989), Harlow and Lane, antibodies, a Laboratory Manual, Cold Spring Harbor, NY(1989), Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY(1994-2001), Colligan et al., Current Protocols in Protein Science, John Wiley & See Sons, NY, NY, (1997-2001).

[0034] A preferred anti-IL-23 antibody is guselkumab (also called 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 heavy chain CDR amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 and light chain CDR amino acid sequences 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. Patent No. 7,935,344, the entire contents of which are incorporated herein by reference.

[0035] Human antibodies specific for human IL-23 protein or fragments thereof can be raised against suitable immunogenic antigens, such as isolated IL-23 protein and / or portions thereof (including synthetic molecules such as synthetic peptides). Other specific or general mammalian antibodies can be similarly produced. Preparation of immunogenic antigens and production of monoclonal antibodies can be carried out using any suitable technique.

[0036] In one approach, a suitable immortal cell line (e.g., but not limited to, Sp2 / 0, Sp2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, L243, P3X63Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5, U937, MLA 144, ACT IV, MOLT4, DA-1, JURKAT, WEHI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA 144, NAMALWA, NEURO Myeloma cell lines such as 2A, or heteromyelomas, fusion products thereof, or any cells or fusion cells derived therefrom, or any other suitable cell line known in the art) (see, for example, www.atcc.org, www.lifetech.com, etc.), antibody producing cells such as isolated or cloned spleen, peripheral blood, lymph, tonsil, or other immune or B cell containing cells, or recombinant or endogenous, viral, bacterial, or other nucleic acids, either as endogenous or heterologous. With any other cell expressing the heavy or light chain constant or variable, or framework or CDR sequences, either as algae, prokaryote, amphibian, insect, reptile, fish, mammal, rodent, horse, ovine, caprine, ovine, primate, eukaryote, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single, double or triple stranded, hybridized, etc., or as any combination thereof, to produce a hybridoma. See, e.g., Ausubel, supra, and Colligan, Immunology, supra, Chapter 2, both of which are incorporated herein by reference in their entireties.

[0037] Antibody producing cells can also be obtained from the peripheral blood, or preferably the spleen or lymph nodes, of humans or other suitable animals immunized with the antigen of interest. Any other suitable host cells can also be used to express heterologous or endogenous nucleic acid encoding the antibody of the invention, specific fragments or variants thereof. Fused cells (hybridomas) or recombinant cells can be isolated using selective culture conditions or other suitable known methods and cloned by limiting dilution or cell sorting or other known methods. Cells producing antibodies with the desired specificity can be selected by a suitable assay (e.g., ELISA).

[0038] Other methods suitable for producing or isolating antibodies with the required specificity can be used, including, but not limited to, recombinant antibody selection from peptide or protein libraries (e.g., display libraries such as, but not limited to, bacteriophage, ribosomal, oligonucleotide, RNA, cDNA, etc., available from, e.g., Cambridge Antibody Technologies, Cambridgeshire, UK; MorphoSys, Martinsreid / Planegg, DE; Biovation, Aberdeen, Scotland, UK; BioInvent, Lund, Sweden; Dyax Corp., Enzon, Affymax / Biosite, Xoma, Berkeley, CA, Ixsys.(Available from, e.g., European Patent No. 368,684, International Application No. PCT / GB91 / 01134, International Application No. PCT / GB92 / 01755, International Application No. PCT / GB92 / 002240, International Application No. PCT / GB92 / 00883, International Application No. PCT / GB93 / 00605, U.S. Patent Application No. 08 / 350260 (5 / 12 / 94), International Application No. PCT / GB94 / 01422, International Application No. PCT / GB94 / 02662, International Application PCT / GB97 / 01835, (CAT / MRC), International Publication No. WO 90 / 14443, International Publication No. WO 90 / 14424, International Publication No. WO 90 / 14430, International Application No. US94 / 1234, International Publication No. WO 92 / 18619, International Publication No. WO 96 / 07754, (Scripps), International Publication No. WO 96 / 13583, International Publication No. WO 97 / 08320 (Mo rphoSys), WO 95 / 16027 (BioInvent), WO 88 / 06630, WO 90 / 3809 (Dyax), U.S. Patent No. 4,704,692 (Enzon), International Application No. US91 / 02989 (Affymax), WO 89 / 06283, EP 371998, EP 550400, (Xoma), EP 229 046, International Application No. US91 / 07149 (Ixsys), or stochastically generated peptides or proteins - U.S. Pat. Nos. 5,723,323, 5,763,192, 5,814,476, 5,817,483, 5,824,514, 5,976,862, WO 86 / 05803, EP 590689 (Ixsys), Applied Molecular Evolution (Applied Antibody production can be achieved by either immunization with transgenic animals capable of producing a repertoire of human antibodies, such as mice (predecessors of the American College of Molecular Evolution (AME)), each of which is incorporated herein by reference in its entirety), or by immunization of transgenic animals capable of producing a repertoire of human antibodies, as known in the art and / or described herein (e.g., SCID mice, each of which is incorporated herein by reference in its entirety; Nguyen et al., Microbiol. Immunol. 41:901-907 (1997); Sandhu et al., Crit. Rev. Biotechnol. 16:95-118 (1996); Eren et al., Immunol.93:154-161 (1998), and related patents and applications. Such techniques include ribosome display (Hanes et al., Proc. Natl. Acad. Sci. USA, 94:4937-4942 (May 1997); Hanes et al., Proc. Natl. Acad. Sci. USA, 95:14130-14135 (Nov. 1998)), single cell antibody production techniques (e.g., the 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 microdroplets and flow cytometry (Powell et al., J. Immunol. 1999, 11:111-111 (1998)). 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 selectors (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)).

[0039] Methods for engineering or humanizing non-human or human antibodies can also be used and are known in the art. Generally, a humanized or modified antibody has one or more amino acid residues derived from a non-human source, such as, but not limited to, mouse, rat, rabbit, non-human primate, or other mammalian source. These non-human amino acid residues are replaced by residues often referred to as "import" residues, which are typically taken from an "import" variable, constant, or other domain of a known human sequence.

[0040] Such imported sequences can be used to reduce immunogenicity, or to reduce, enhance, or modify binding, affinity, binding rate constant, dissociation rate constant, avidity, specificity, half-life, or any other suitable property, as known in the art. Generally, CDR residues directly and most substantially affect antigen binding. Thus, non-human sequences in variable and constant regions can be replaced with human or other amino acids, while maintaining some or all of the non-human or human CDR sequences.

[0041] Antibodies may optionally be humanized, or human antibodies may be modified while retaining high affinity for the antigen and other favorable biological properties. To this end, humanized (or human) antibodies may optionally be prepared by a process of analysis of the parental sequences and various theoretical humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformations of selected candidate immunoglobulin sequences. Inspection of these displays allows analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., analysis of residues that influence the antigen-binding ability of the candidate immunoglobulin. In this way, framework (FR) residues can be selected and combined from the consensus and import sequences so that desired antibody properties, such as enhanced affinity for the target antigen, are achieved.

[0042] In addition, antibodies specific for human IL-23 used in the methods of the invention may comprise a human germline light chain framework. In certain embodiments, the light chain germline sequence is selected from a human VK sequence, 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.

[0043] In other embodiments, the antibodies specific for human IL-23 used in the methods of the invention may comprise a human germline heavy chain framework. In certain embodiments, the heavy chain human germline framework is selected from the group consisting of VH1-18, VH1-2, VH1-24, VH1-3, VH1-45, VH1-46, VH1-58, VH1-69, VH1-8, VH2-26, VH2-5, VH2-70, VH3-11, VH3-13, VH3-15, VH3-16, VH3-20, VH3-21, VH3-23, VH3-30, VH3- 33, VH3-35, VH3-38, VH3-43, VH3-48, VH3-49, VH3-53, VH3-64, VH3-66, VH3-7, VH3-72, VH3-73, VH3-74, VH3-9, VH4-28, VH4-31, VH4-34, VH4-39, VH4-4, VH4-59, VH4-61, VH5-51, VH6-1, and VH7-81.

[0044] In certain embodiments, the light chain variable region and / or the heavy chain variable region comprises a framework region, or at least a portion of a framework region (e.g., comprising two or three subregions, such as FR2 and FR3). In certain embodiments, at least FRL1, FRL2, FRL3, or FRL4 is fully human. In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is fully human. In some embodiments, at least FRL1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., human germline) or comprises a human consensus sequence for a particular framework (which are readily available at the sources of known human Ig sequences mentioned above). In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., human germline) or comprises a human consensus sequence for a particular framework. In preferred embodiments, the framework regions are fully human framework regions.

[0045] Humanization or engineering of the antibodies of the present invention may be carried out in accordance with the methods described by 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. al., J.Immunol.151:2623 (1993), U.S. Patent No. 5723323, U.S. Patent No. 5976862, U.S. Patent No. 5824514, U.S. Patent No. 5817483, U.S. Patent No. 5814476, U.S. Patent No. 5763192, U.S. Patent No. 5723323, U.S. Patent No. 5,76 6886, 5714352, 6204023, 6180370, 5693762, 5530101, 5585089, 5225539, 4816567, International Application No. US98 / 16280, US9 This can be done using any known method, such as, but not limited to, those described in US91 / 09630, US91 / 05939, US94 / 01234, International Application Nos. GB89 / 01334, GB91 / 01134, GB92 / 01755, International Publication Nos. WO 90 / 14443, WO 90 / 14424, WO 90 / 14430, and European Patent No. 229246 (each of which is incorporated by reference in its entirety, including the references cited therein).

[0046] In certain embodiments, the antibody comprises an altered (e.g., mutated) Fc region. For example, in some embodiments, the Fc region is 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 further amino acid modifications that alter the C1q binding and / or complement dependent cytotoxicity function of the Fc region of the IL-23 binding molecule. Starting polypeptides of particular interest may be those that bind C1q and exhibit complement dependent cytotoxicity (CDC). Polypeptides with existing C1q binding activity, and optionally further with the ability to mediate CDC, may be modified to enhance one or both of these activities. Amino acid modifications that alter C1q and / or modify its complement dependent cytotoxicity function are described, for example, in WO 0042072, which is incorporated herein by reference.

[0047] As disclosed above, the Fc region of the antibody specific for human IL-23 of the present invention can be engineered 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. An "effector function" serves to activate or reduce a 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), and the like. Such effector functions may require the Fc region to bind to a binding domain (e.g., an antibody variable domain) and can be assessed using a variety of test methods (e.g., Fc binding assays, ADCC assays, CDC assays, and the like).

[0048] For example, variant Fc regions of human IL-23 (or anti-IL-23) antibodies can be generated that have improved C1q binding and improved FcγRIII binding (e.g., that have both improved ADCC activity and improved CDC activity). Alternatively, where it is desired to reduce or eliminate effector function, variant Fc regions can be modified to have reduced CDC activity and / or reduced ADCC activity. In other embodiments, only one of these activities may be enhanced, optionally with the other activity reduced at the same time (e.g., to generate Fc region variants with improved ADCC activity and reduced CDC activity, and vice versa).

[0049] Fc mutations can also be engineered and introduced to alter interactions 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).

[0050] Another type of amino acid substitution serves to modify the glycosylation pattern of the Fc region of an antibody specific for human IL-23. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars, N-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. The recognition sequences for enzymatic attachment of a 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 provides a potential glycosylation site.

[0051] The glycosylation pattern can be modified, for example, by deleting one or more glycosylation sites found in the polypeptide and / or adding one or more glycosylation sites not present in the polypeptide. Addition of glycosylation sites to the Fc region of an antibody specific for human IL-23 is conveniently achieved by modifying the amino acid sequence to include one or more of the above tripeptide sequences (for N-linked glycosylation sites). A representative glycosylation variant has an amino acid substitution of residue Asn297 of the heavy chain. This modification may also be performed by the addition of, or substitution by, one or more serine or threonine residues to the original polypeptide sequence (for O-linked glycosylation sites). In addition, changing Asn 297 to Ala can remove one of the glycosylation sites.

[0052] In certain embodiments, the antibodies specific for human IL-23 of the invention are expressed in cells expressing beta(1,4)-N-acetylglucosaminyltransferase III (GnT III), such that GnT III adds GlcNAc to the human IL-23 antibody. Methods for producing antibodies in such a manner are provided in WO 9954342, WO 03011878, JP 20030003097(A1), and Umana et al., Nature Biotechnology, 17:176-180, Feb. 1999, all of which are expressly incorporated herein by reference in their entirety.

[0053] Anti-IL-23 antibodies may also optionally be generated by immunization of transgenic animals (e.g., mice, rats, hamsters, non-human primates, etc.) capable of producing a repertoire of human antibodies, as described herein and / or known in the art. Cells producing human anti-IL-23 antibodies may be isolated and immortalized from such animals using suitable methods, such as those described herein.

[0054] Transgenic mice capable of producing a repertoire of human antibodies that bind to human antigens can be produced using known methods (such as, but not limited to, U.S. Pat. Nos. 5,770,428, 5,569,825, 5,545,806, 5,625,126, 5,625,825, 5,633,425, 5,661,016, and 5,789,650 issued to Lonberg et al., WO 98 / 50433 to Jakobovits et al., WO 98 / 24893 to Jakobovits et al., WO 98 / 2491 to Lonberg et al., each of which is incorporated herein by reference in its entirety). No. 884 to Lonberg et al., International Publication No. WO 97 / 13852 to Lonberg et al., International Publication No. WO 94 / 25585 to Lonberg et al., International Publication No. WO 96 / 34096 to Kucherlapate et al., European Patent No. 0463151(B1) to Kucherlapate et al., European Patent No. 0710719(A1) to Kucherlapate et al., U.S. Pat. No. 5,545,807 to Surani et al., International Publication No. WO 90 / 04036 to Bruggemann et al., European Patent No. 0438474(B1) to Bruggemann et al., European Patent No. 0814259(A2) to Lonberg et al., UK Patent No. 2272440(A) to Lonberg et al., 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. 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)).Generally, these mice contain at least one transgene that comprises DNA derived from at least one human immunoglobulin locus that has been functionally rearranged, or is capable of undergoing functional rearrangement. The endogenous immunoglobulin loci of such mice can be disrupted or deleted to eliminate the ability of the mice to produce antibodies encoded by endogenous genes.

[0055] Screening of antibodies for specific binding to similar proteins or fragments can be successfully accomplished using peptide display libraries. The method involves screening a large collection of peptides for individual members with the desired function or structure. Antibody screening of peptide display libraries is well known in the art. The displayed peptide sequences can be 3-5000 or more amino acids long, frequently 5-100 amino acids long, and often about 8-25 amino acids long. In addition to direct chemical synthesis methods for creating peptide libraries, several recombinant DNA methods have also been described. One type involves the display of peptide sequences on the surface of bacteriophages or cells. Each bacteriophage or cell contains a nucleotide sequence that codes for a particular displayed peptide sequence. Such methods are described in WO 91 / 17271, WO 91 / 18980, WO 91 / 19818, and WO 93 / 08278.

[0056] Other systems for generating peptide libraries include aspects of both in vitro chemical synthesis and recombinant methods. See WO 92 / 05258, WO 92 / 14843, and WO 96 / 19256. See also U.S. Patent Nos. 5,658,754 and 5,643,768. Peptide display libraries, vectors, and screening kits are commercially available from suppliers such as Invitrogen (Carlsbad, CA) and Cambridge antibody Technologies (Cambridgeshire, UK). See, e.g., U.S. Patent Nos. 4,704,692, 4,939,666, 4,946,778, 5,260,203, 5,455,030, 5,518,889, 5,534,621, 5,656,730, 5,763,733, 5,767,260, and 5,856,456 all assigned to Enzon; ​​U.S. Patent Nos. 5,223,409, 5,403,484, 5,571,698, and 5,837,500 all assigned to Dyax; U.S. Patent Nos. 5,427,908 and 5,580,717 all assigned to Affymax; Cambridge antibody See U.S. Patent No. 5,885,793 assigned to Eppendorf Technologies, U.S. Patent No. 5,750,373 assigned to Genentech, U.S. Patent Nos. 5,618,920, 5,595,898, 5,576,195, 5,698,435, 5,693,493, 5,698,417 assigned to Xoma, Colligan, supra, Ausubel, supra, or Sambrook, supra. Each of the above patents and publications is incorporated herein by reference in its entirety.

[0057] The antibodies used in the methods of the invention can also be prepared using nucleic acids encoding at least one anti-IL23 antibody to provide transgenic animals or mammals, such as goats, cows, horses, sheep, rabbits, etc., that produce such antibodies in their milk. Such animals can be provided using known methods. See, for example, but not limited to, U.S. Patent Nos. 5,827,690, 5,849,992, 4,873,316, 5,849,992, 5,994,616, 5,565,362, 5,304,489, etc., each of which is incorporated herein by reference in its entirety.

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

[0059] The affinity or avidity of an antibody for an antigen can be determined experimentally using any suitable method. (See, e.g., Berzofsky, et al., "Antibody-Antigen Interactions," 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 therein.) The affinity measured for a particular antibody-antigen interaction can be different when measured under different conditions (e.g., salt concentration, pH). Thus, affinity and other antigen binding parameters (e.g., K D , K a , K d Measurements of ) are preferably performed using standardized solutions of antibody and antigen, and standardized buffers, such as those described herein.

[0060] nucleic acid molecule Using the information provided herein, such as, for example, a nucleotide sequence encoding at least 70-100% of the contiguous amino acids of at least one of the light or heavy chain variable or CDR regions described herein, a particular fragment, variant, or consensus sequence thereof, or a deposited vector containing at least one of these sequences, among other sequences disclosed herein, a nucleic acid molecule of the invention encoding at least one anti-IL-23 antibody can be obtained using methods described herein or known in the art.

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

[0062] The isolated nucleic acid molecules used in the methods of the present invention may include nucleic acid molecules that include an open reading frame (ORF) with at least one particular portion of at least one CDR, such as, but not limited to, at least one heavy or light chain CDR1, CDR2, and / or CDR3, optionally including one or more introns, nucleic acid molecules that include coding sequences for anti-IL-23 antibodies or variable regions, and nucleic acid molecules that include substantially different nucleotide sequences than those described above, but still encode at least one anti-IL-23 antibody described herein and / or known in the art due to the degeneracy of the genetic code. Of course, the genetic code is well known in the art. Thus, it would be a routine task for the skilled artisan to generate such degenerate nucleic acid variants that encode the specific anti-IL-23 antibodies used in the methods of the present invention. See, for example, Ausubel et al., supra. Such nucleic acid variants are encompassed by 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.

[0063] As described herein, nucleic acid molecules comprising nucleic acids encoding anti-IL-23 antibodies can include those that themselves encode the amino acid sequence of an antibody fragment, sequences encoding the full length of an antibody or a portion of an antibody, coding sequences for an antibody, fragment or portion, and additional sequences, such as at least one intron, with or without the aforementioned additional coding sequences, including, but not limited to, non-coding 5' and 3' sequences, e.g., transcribed non-translated sequences that play a role in transcription, mRNA processing, including splicing and polyadenylation signals (e.g., ribosome binding and stability of mRNA), as well as additional non-coding sequences, but not limited to, coding sequences for at least one signal leader or fusion peptide, additional coding sequences encoding additional amino acids, e.g., amino acids that provide additional functions. Thus, the antibody coding sequence can be fused to a marker sequence, e.g., a marker sequence is a sequence that encodes a peptide that facilitates purification of an antibody comprising the antibody fragment or portion to which it is fused.

[0064] Polynucleotides that selectively hybridize to the polynucleotides described herein The method of the present invention uses isolated nucleic acids that hybridize under selective hybridization conditions to the polynucleotides disclosed herein. Thus, the polynucleotides of the present embodiment can be used to isolate, detect, and / or quantify nucleic acids that contain such polynucleotides. For example, the polynucleotides of the present invention can be used to identify, isolate, or amplify partial or full-length clones in a deposited library. In some embodiments, the polynucleotides are genomic or cDNA sequences that are isolated or otherwise complementary to cDNAs in a human or mammalian nucleic acid library.

[0065] Optionally, the polynucleotide encodes at least a portion of an antibody. The polynucleotide comprises a nucleic acid sequence that can be used for selective hybridization to a polynucleotide encoding an antibody of the present invention. See, e.g., Ausubel, supra; Colligan, supra, each of which is incorporated herein by reference in its entirety.

[0066] Nucleic acid construction An isolated nucleic acid can be produced using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, and / or (d) combinations thereof, as are well known in the art.

[0067] The nucleic acid may conveniently contain sequences in addition to the polynucleotide of the invention. For example, a multiple cloning site containing one or more endonuclease restriction sites may be inserted into the nucleic acid to aid in the isolation of the polynucleotide. Also, a translatable sequence may be inserted to aid in the isolation of the translated polynucleotide of the invention. For example, a hexahistidine marker sequence provides a convenient means for purifying the protein of the invention. The nucleic acid of the invention (excluding the coding sequence) is optionally a vector, adapter, or linker for cloning and / or expression of the polynucleotide of the invention.

[0068] 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 polynucleotides, or to improve the introduction of polynucleotides into cells. The use of cloning vectors, expression vectors, adapters, and linkers is well known in the art. (See, e.g., Ausubel, supra, or Sambrook, supra.)

[0069] Recombinant methods for constructing nucleic acids Isolated nucleic acid compositions, such as RNA, cDNA, genomic DNA, or any combination thereof, can be obtained from biological sources using any number of cloning methods known to those of skill in the art. In some embodiments, oligonucleotide probes that selectively hybridize under stringent conditions to the polynucleotides of the present invention are used to identify desired sequences in cDNA or genomic DNA libraries. Isolation of RNA and construction of cDNA and genomic libraries are well known to those of skill in the art. (See, e.g., Ausubel, supra, or Sambrook, supra).

[0070] Recombinant Expression Cassettes The present invention employs recombinant expression cassettes comprising nucleic acids. Nucleic acid sequences, such as cDNA or genomic sequences encoding an antibody used in the methods of the present invention, can be used to construct recombinant expression cassettes that can be introduced into at least one desired host cell. Recombinant expression cassettes typically comprise a polynucleotide that is operably linked to a transcription initiation regulatory sequence that directs transcription of the polynucleotide in the intended host cell. Both heterologous and non-heterologous (i.e., endogenous) promoters can be utilized to direct expression of the nucleic acid.

[0071] In some embodiments, isolated nucleic acids that function as promoters, enhancers, or other elements can be introduced into a suitable location (upstream, downstream, or within an intron) of a non-heterologous form of a polynucleotide of the invention to up- or down-regulate expression of the polynucleotide. For example, endogenous promoters can be altered in vivo or in vitro by mutation, deletion, and / or substitution.

[0072] Vectors and host cells The present invention also relates to vectors comprising the isolated nucleic acid molecules, host cells engineered with the recombinant vectors, and the production 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).

[0073] Antibody purification Anti-IL-23 antibodies can be recovered and purified from recombinant cell cultures by well-known methods, including, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, and lectin chromatography. High performance liquid chromatography ("HPLC") can also be used for purification. See, 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.

[0074] Antibodies for use in the methods of the invention include naturally purified products, products of chemical synthetic processes, and products produced by recombinant techniques from eukaryotic hosts, including, for example, yeast, higher plants, insect, and mammalian cells. Depending on the host utilized in a recombinant production process, the antibody may be glycosylated or non-glycosylated, but is preferably glycosylated. 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.

[0075] Anti-IL-23 antibody. The anti-IL-23 antibodies of the present invention comprise 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, a heavy or light chain complementarity determining region (CDR) or a ligand binding portion thereof, a heavy or light chain variable region, a framework region (e.g., FR1, FR2, FR3, FR4, or a fragment thereof, and optionally, including at least one substitution, insertion, or deletion), a heavy or light chain constant region (e.g., at least one CDR, FR5, FR6, FR7, FR8, FR9, FR10, FR11, FR12, FR13, FR14, FR15, FR16, FR17, FR18, FR19, FR19, FR119, FR120, FR130, FR140, FR151, FR161, FR172, FR183, FR194, FR195, FR196, FR197, FR198, FR19 ... H 1, Hinge 1, Hinge 2, Hinge 3, Hinge 4, C H 2 or C H 3, or a fragment thereof, and optionally further comprising at least one substitution, insertion, or deletion), or any portion thereof. The antibody can include or be derived from any mammal, such as, but not limited to, human, mouse, rabbit, rat, rodent, primate, or any combination thereof.

[0076] The isolated antibodies used in the methods of the invention include the amino acid sequences of the antibodies disclosed herein encoded by any suitable polynucleotide, or any isolated or prepared antibody. Preferably, the human antibodies or antigen-binding fragments bind to human IL-23, thereby partially or substantially neutralizing at least one biological activity of the protein. Antibodies, or specified portions or variants thereof, that partially or preferably substantially neutralize at least one biological activity of at least one IL-23 protein or fragment, can bind to the protein or fragment, thereby inhibiting an activity mediated through binding of IL-23 to the IL-23 receptor, or through other IL-23-dependent or mediated mechanisms. As used herein, the term "neutralizing antibody" refers to an antibody that can inhibit IL-23-dependent activity by about 20-120%, preferably at least about 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% or more, depending on the assay. The ability of an anti-IL-23 antibody to inhibit IL-23-dependent activity is preferably assessed by at least one suitable IL-23 protein or receptor assay described herein and / or known in the art. Human antibodies may be of any class (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and may include a kappa or lambda light chain. In one embodiment, the human antibody comprises an IgG heavy chain or defined fragment, e.g., at least one of the following isotypes: IgG1, IgG2, IgG3, or IgG4 (e.g., γ1, γ2, γ3, γ4). Antibodies of this type can be prepared by utilizing transgenic mice or other non-human transgenic mammals that contain at least one human light chain (e.g., IgG, IgA, and IgM) transgene as described herein and / or known in the art. In another embodiment, the anti-IL-23 human antibody comprises an IgG1 heavy chain and an IgG1 light chain.

[0077] The antibody binds to at least one particular epitope specific for at least one IL-23 protein, subunit, fragment, portion, or any combination thereof, which may comprise at least one antibody binding region that comprises at least a portion of the protein, preferably comprising at least one extracellular, soluble, hydrophilic, exoportion, or cytoplasmic portion of the protein.

[0078] Generally, a human antibody or antigen-binding fragment comprises an antigen-binding region that comprises at least one human complementarity determining region (CDR1, CDR2, and CDR3) or variant of at least one heavy chain variable region, and at least one human complementarity determining region (CDR1, CDR2, and CDR3) or variant of at least one light chain variable region. The CDR sequences can be derived from human germline sequences or can match exactly to germline sequences. For example, CDRs from a synthetic library derived from the original non-human CDRs can be used. These CDRs can be formed by incorporation of conservative substitutions from the original non-human sequence. In another specific embodiment, the antibody or antigen-binding portion or variant can have an antigen-binding region that comprises at least a portion of at least one light chain CDR (i.e., CDR1, CDR2, and / or CDR3) with the corresponding CDR1, 2, and / or 3 amino acid sequence.

[0079] Such antibodies can be prepared by preparing and expressing a nucleic acid molecule encoding the antibody (i.e., one or more) using conventional techniques involving recombinant DNA technology, or by chemically linking together the various portions of the antibody (e.g., CDRs, framework) using conventional techniques, or by using any other suitable method.

[0080] Antibodies specific for anti-IL-23 can comprise at least one of a heavy or light chain variable region having a defined amino acid sequence. For example, in a preferred embodiment, an anti-IL-23 antibody comprises at least one of a heavy chain variable region, optionally having the amino acid sequence of SEQ ID NO: 7, and / or at least one of a light chain variable region, optionally having the amino acid sequence of SEQ ID NO: 8. For example, in a preferred embodiment, an anti-IL-23 antibody comprises at least one of a heavy chain variable region, optionally having the amino acid sequence of SEQ ID NO: 9, and / or at least one of a light chain variable region, optionally having the amino acid sequence of SEQ ID NO: 10. Antibodies that bind to human IL-23 and comprise a defined heavy or light chain variable region can be prepared using suitable methods, such as those employing phage display (Katsube, Y., et al., Int J Mol. Med, 1(5):863-868 (1998)) or transgenic animals, as known in the art and / or described herein. For example, a transgenic mouse containing a functionally rearranged human immunoglobulin heavy chain transgene and a transgene containing DNA from a human immunoglobulin light chain locus capable of undergoing functional rearrangement can be immunized with human IL-23 or a fragment thereof to induce the production of antibodies. If desired, antibody-producing cells can be isolated and hybridomas or other immortalized antibody-producing cells can be prepared as described herein and / or known in the art. Alternatively, antibodies, particular portions or variants can be expressed using the encoding nucleic acid or a portion thereof in a suitable host cell.

[0081] The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs that contain amino acids in sequences that are substantially the same as the amino acid sequences described herein. Preferably, such antibodies or antigen-binding fragments and antibodies that contain such chains or CDRs have high affinity (e.g., about 10 -9 K below M D) can bind to human IL-23. Amino acid sequences that are substantially the same as the sequences described herein include sequences containing conservative amino acid substitutions as well as amino acid deletions and / or insertions. A conservative amino acid substitution refers to the replacement of a first amino acid with a second amino acid that has chemical and / or physical properties (e.g., charge, structure, polarity, hydrophobicity / hydrophilicity) similar to those of the first amino acid. Conservative substitutions include, but are not limited to, replacing one amino acid with another within the following groups: lysine (K), arginine (R), and histidine (H); aspartate (D) and glutamate (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.

[0082] Amino acid code The amino acids constituting the anti-IL-23 antibodies of the present invention are often abbreviated. Amino acid abbreviations can be provided by representing the amino acid by its one-letter code, its three-letter code, name, or three nucleotide codons, as is well understood in the art (see Alberts, B. et al., Molecular Biology of The Cell, 3rd ed., Garland Publishing, Inc., New York (1994)).

[0083] [Table 1]

[0084] The anti-IL-23 antibodies used in the methods of the invention may contain one or more amino acid substitutions, deletions, or additions, either by natural mutation or by human manipulation, as specified herein.

[0085] An anti-IL-23 antibody can include, but is not limited to, at least one portion, sequence, or combination selected from all five of at least one of the contiguous amino acids of SEQ ID NOs: 1, 2, 3, 4, 5, and 6.

[0086] The IL-23 antibody or specific 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 SEQ ID NO:, 5 to 17 contiguous amino acids of the above SEQ ID NO:, 5 to 10 contiguous amino acids of the above SEQ ID NO:, 5 to 11 contiguous amino acids of the above SEQ ID NO:, 5 to 7 contiguous amino acids of the above SEQ ID NO:, or 5 to 9 contiguous amino acids of the above SEQ ID NO:.

[0087] The anti-IL-23 antibody can optionally further comprise at least one polypeptide that is 70-100% identical to 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) to 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 to the sequence of the above SEQ ID NOs, or the amino acid sequence of the heavy chain CDR3 can be compared to the above SEQ ID NOs. Preferably, 70-100% 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 known in the art.

[0088] "Identity," as known in the art, 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, those described in Computational Molecular Biology, Lesk, AM, ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, DW, ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, AM, and Griffin, HG, eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; and Carillo, H., and Lipman, D., Siam J. Applied Math., 48:1073 (1988). Additionally, percent identity values ​​can be obtained from amino acid and nucleotide sequence alignments generated using default settings in AlignX, a component of Vector NTI Suite 8.0 (Informax, Frederick, MD).

[0089] Preferred methods for determining identity are designed to obtain the highest degree of correspondence between the sequences tested. Methods for determining identity and similarity are codified in publicly available computer programs. Preferred computer program methods for determining identity and 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)). BLAST X programs are publicly available from NCBI and other sources (BLAST Manual, Altschul, S., et al., NCBINLM NIH Bethesda, Md. 20894: Altschul, S., et al., J. Mol. Biol. 215:403-410 (1990). The well-known Smith Waterman algorithm may also be used to determine identity.

[0090] Preferred parameters for polypeptide sequence comparisons include the following: (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), Gap penalty: 12 Gap length penalty: 4 A program useful with these parameters is publicly available as the "Gap" program from the Genetics Computer Group, Madison Wis. The aforementioned parameters are the default parameters for peptide sequence comparisons (as well as no penalty for end gaps).

[0091] Preferred parameters for polynucleotide comparisons include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443-453 (1970) Comparison matrix: match = +10, mismatch = 0 Gap penalty: 50 Gap length penalty: 3 Available as the "Gap" program from the Genetics Computer Group, Madison Wis. These are the default parameters for nucleic acid sequence comparisons.

[0092] By way of example, a polynucleotide sequence may be identical to another sequence, i.e., 100% identical, or may contain up to a certain integer number of nucleotide alterations compared to a reference sequence. Such alterations may be selected from the group consisting of deletion, substitution (including transitions and transversions), or insertion of at least one nucleotide, which may occur at the 5' or 3' terminal position of the reference nucleotide sequence, or anywhere between these terminal positions, and may be distributed either individually among the nucleotides of the reference sequence, or in one or more adjacent groups within the reference sequence. The number of nucleotide alterations may be determined by multiplying the total number of nucleotides in the sequence by the numerical percentage of the corresponding percent identity (divided by 100) and subtracting the product from the total number of nucleotides in the sequence, or is determined by n.sub.n.ltorsim.x.sub.n-(x.sub.ny), where n.sub.n is the number of nucleotide alterations, 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 any non-integer product of x.sub.n and y is rounded down to the nearest integer before subtraction from x.sub.n.

[0093] Modification of a polynucleotide sequence encoding the above SEQ ID NO may create nonsense, missense, or frameshift mutations in the coding sequence, thereby modifying the polypeptide encoded by the polynucleotide after such modification. Similarly, a polypeptide sequence may be identical to the reference sequence of the above SEQ ID NO, i.e., 100% identical, or may contain up to a certain integer number of amino acid modifications compared to the reference sequence such that the percent identity is less than 100%. Such modifications are selected from the group consisting of deletion, substitution (including conservative and non-conservative substitution), or insertion of at least one amino acid, which may occur at the amino or carboxy terminal position of the reference polypeptide sequence or anywhere between these terminal positions, and may be distributed either individually between the amino acids of the reference sequence, or in one or more adjacent groups within the reference sequence. The number of amino acid changes for a given percent identity may be calculated by multiplying the total number of amino acids in the above SEQ ID NO by the numerical percent of the respective percent identity (divided by 100) and subtracting the product from the total number of amino acids in the above SEQ ID NO, or is determined by n.sub.a.ltorsim.x.sub.a-(x.sub.ay), where n.sub.a is the number of amino acid changes, x.sub.a is the total number of amino acids in the sequence ID, and y is, for example, 0.70 for 70%, 0.80 for 80%, 0.85 for 85%, etc., and any non-integer product of x.sub.a and y is rounded down to the nearest integer before subtraction from x.sub.a.

[0094] Representative heavy and light chain variable region sequences, and portions thereof, are set forth in the SEQ ID NOs: 1 and 2 above. An antibody of the invention, or a specified variant thereof, can comprise any number of contiguous amino acid residues from an antibody of the invention, the number being selected from the group of integers consisting of 10-100% of the number of contiguous residues in an anti-IL-23 antibody.

[0095] The methods of the invention also employ 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 said anti-IL-23 antibodies provided in a non-naturally occurring composition, mixture, or form as described herein and / or known in the art. Such compositions include non-naturally occurring compositions comprising at least one or two full-length, C- and / or N-terminal deletion mutants, domains, fragments, or specific variants of an anti-IL-23 antibody amino acid sequence selected from the group consisting of 70-100% of the contiguous amino acids of the SEQ ID NOs. above, or specific fragments, domains, or variants thereof. A preferred anti-IL-23 antibody composition comprises at least one or two full-length, fragments, domains, or variants as at least one CDR- or LBP-containing portion of an anti-IL-23 antibody sequence described herein, e.g., 70-100% of the SEQ ID NOs. above, or specific fragments, domains, or variants thereof. More preferred compositions comprise, for example, 70-100% of at least one of the above SEQ ID NOs, or specific fragments, domains, or variants thereof, 40-99%. Such composition percentages may be by weight, volume, concentration, molarity, or molar concentration as a liquid or dry solution, mixture, suspension, emulsion, particle, powder, or colloid, as known in the art or as described herein.

[0096] Antibody compositions containing further therapeutically active ingredients The antibody compositions used in the methods of the invention can optionally further comprise an effective amount of at least one compound or protein selected from at least one of anti-infective agents, cardiovascular (CV) system acting agents, central nervous system (CNS) agents, autonomic nervous system (ANS) agents, respiratory agents, gastrointestinal (GI) tract acting agents, hormonal agents, fluid or electrolyte balancing agents, hemodynamic agents, anti-neoplastic agents, immunomodulatory agents, ophthalmic, otic or nasal agents, topical agents, nutritional agents, etc. Such drugs are well known in the art, including the formulations, indications, dosages, and administration of each as set forth herein (see, e.g., Nursing 2001 Handbook of Drugs, 21st Edition, each of which is incorporated herein by reference in its entirety). st edition, Springhouse Corp., Springhouse, PA, 2001; Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc., Upper Saddle River, NJ; Pharmacotherapy Handbook, Wells et al., Appleton & Lange, Stamford, CT).

[0097] As examples of drugs that can be combined with the antibodies of the method of the present invention, the anti-infective drug can be at least one selected from amebicide or at least one antiprotozoal drug, anthelmintic drug, antifungal drug, antimalarial drug, antituberculous drug or at least one antilepromycotic drug, aminoglycoside, penicillin, cephalosporin, tetracycline, sulfonamide, fluoroquinolone, antiviral drug, macrolide anti-infective drug, and miscellaneous anti-infective drugs. The hormonal drug can be at least one selected from corticosteroid, androgen, or at least one anabolic steroid, estrogen, or at least one progestin, gonadotropin, antidiabetic drug, or at least one glucagon, thyroid hormone, thyroid hormone antagonist, pituitary hormone, and parathyroid mimetic drug. The at least one cephalosporin can be at least one selected from cefaclor, cefadroxil, cefazolin sodium, cefdinir, cefepime hydrochloride, cefixime, cefmetazole sodium, cefonicid sodium, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime sodium, ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cephalexin hydrochloride, cephalexin monohydrate, cephradine, and loracarbef.

[0098] The at least one corticosteroid can be at least one selected from 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 tebutate, prednisone, triamcinolone, triamcinolone acetonide, and triamcinolone diacetate. The at least one androgenic or anabolic steroid can be at least one selected from danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate, nandrolone phenpropionate, testosterone, testosterone cypionate, testosterone enanthate, testosterone propionate, and a testosterone transdermal system.

[0099] The at least one immunosuppressant can be at least one selected from azathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immunoglobulin, muromonab-CD3, mycophenolate mofetil, mycophenolate mofetil hydrochloride, sirolimus, and tacrolimus.

[0100] The at least one topical anti-infective can be at least one selected from acyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole, econazole nitrate, erythromycin, gentamicin sulfate, ketoconazole, mafenide acetate, metronidazole (topical), miconazole nitrate, mupirocin, naftifine hydrochloride, neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, terbinafine hydrochloride, terconazole, tetracycline hydrochloride, tioconazole, and tolnaftate. The at least one scabicide or pediculicide can be at least one selected from crotamiton, lindane, permethrin, and pyrethrins. The at least one topical corticosteroid can be at least one selected from betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate, fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasone propionate, halcionide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, and triamcinolone acetonide. (See, e.g., pages 1098-1136 of Nursing 2001 Drug Handbook.)

[0101] Anti-IL-23 antibody compositions comprise at least one anti-IL-12 / 23p40 or IL-23 antibody that is contacted with or administered to a cell, tissue, organ, animal, or subject in need of such modulation, treatment, or therapy, and optionally at least one TNF antagonist (such as, but not limited to, a TNF chemical or protein antagonist, a TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70, or p85) or fragment, a fusion polypeptide thereof, or a small molecule TNF antagonist, such as TNF binding protein I or II (TBP-1 or TBP-II), nerelimonmab, infliximab, or ribozyme inhibitors (e.g., ribozyme inhibitors), ... The composition or pharmaceutical composition may further include at least one of any suitable and effective amount of compositions or pharmaceutical compositions further including at least one selected from the group consisting of antirheumatic drugs (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), immunizing agents, immunoglobulins, immunosuppressants (e.g., azathioprine, basiliximab, cyclosporine, daclizumab), cytokines, or cytokine antagonists. Non-limiting examples of such cytokines include, but are not limited to, any of IL-1 to IL-40, etc. (e.g., IL-1, IL-2, etc.). Suitable dosages are well known in the art. For example, Wells et al., eds., Pharmacotherapy Handbook, 2 nd Edition, Appleton and Lange, Stamford, CT (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), each of which is incorporated herein by reference in its entirety.

[0102] The anti-IL-23 antibody compound, composition, or mixture used in the method of the present invention may further comprise at least one of any suitable auxiliary agent, such as, but not limited to, a diluent, a binder, a stabilizer, a buffer, a salt, a lipophilic solvent, a preservative, an adjuvant, etc. Pharmaceutically acceptable auxiliary agents are preferred. Methods for preparing such sterile solutions and non-limiting examples thereof are well known in the art and are described, for example, in Gennaro, Ed., Remington's Pharmaceutical Sciences, 1896, 1999, 1998, 19 ... th Edition, Mack Publishing Co. (Easton, PA) 1990. Pharmaceutically acceptable carriers suitable for the mode of administration, solubility, and / or stability of the anti-IL-23 antibody, fragment, or variant compositions well known in the art or described herein can be routinely selected.

[0103] Pharmaceutical excipients and additives useful in the present compositions include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., saccharides including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides, derivatized sugars such as alditols, aldonic acids, esterified sugars, and polysaccharides or sugar polymers), which may be present alone or in combination and comprise 1-99.99% by weight or volume, alone or in combination. Representative protein excipients include serum albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acids / antibody components that may also function in a buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. One preferred amino acid is glycine.

[0104] 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, starches, etc., alditols such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), myo-inositol, etc. Preferred carbohydrate additives for use in the present invention are mannitol, trehalose, and raffinose.

[0105] The anti-IL-23 antibody composition may also include a buffer or pH adjusting agent, typically 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, tromethamine hydrochloride, or phosphate buffers. A preferred buffer for use in the composition is an organic acid salt such as citric acid.

[0106] Additionally, anti-IL-23 antibody compositions may include polymeric excipients / additives such as polyvinylpyrrolidone, Ficoll (a polymeric sugar), dextrates (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).

[0107] These and additional known pharmaceutical additives and / or excipients suitable for use in the anti-IL-23 antibody, portion or variant compositions according to the invention are known in the art and are described, for example, in "Remington: The Science & Practice of Pharmacy," 1999. thed., Williams & Williams, (1995) and "Physician's Desk Reference", 52 nd ed., Medical Economics, Montvale, NJ (1998), the disclosures of which are incorporated herein by reference in their entireties. Preferred carrier or excipient materials are carbohydrates (e.g., monosaccharides and alditols) and buffers (e.g., citric acid) or polymeric agents. Exemplary carrier molecules are mucopolysaccharides, hyaluronic acid, which may be useful for intra-articular delivery.

[0108] formulation As mentioned above, the present invention provides stable formulations, preferably saline or phosphate buffer with selected salts, as well as preservative-containing preservative solutions and formulations, and versatile preservative formulations suitable for pharmaceutical or veterinary use, comprising at least one anti-IL-23 antibody in a pharma- ceutically acceptable formulation. The preservative formulations include at least one known preservative, optionally selected from the group consisting of at least one phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof, in an aqueous diluent. As known in the art, the range may be from 0.001 to 5%, or any range or value therein, for example, 0.001, 0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.7, 3.8, 3.9, 3.1, 3.2 ...3, 3.4, 3.5, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, Any suitable concentration or mixture may be used, such as 0.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, etc., or any range or value therein.Non-limiting examples include no preservatives, 0.1-2% m-cresol (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (e.g., 0.005, 0.01), 0.001-2.0% phenol (e.g., Examples of suitable alkylparabens include 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005 to 1.0% alkylparaben (for example, 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%), and the like.

[0109] As discussed above, the methods of the invention employ an article of manufacture comprising a packaging material and at least one vial containing a solution of at least one anti-IL-23 specific antibody, optionally with a buffer and / or preservative formulated in an aqueous diluent, the packaging material including a label indicating that such solution can be maintained for 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72 hours or more. The invention further employs an article of manufacture comprising a packaging material and a first vial containing a lyophilized anti-IL-23 specific antibody and a second vial containing an aqueous diluent of the formulated buffer or preservative, the packaging material including a label instructing a patient to reconstitute the anti-IL-23 specific antibody with the aqueous diluent to form a solution that can be maintained for 24 hours or more.

[0110] Antibodies specific for anti-IL-23 used in accordance with the present invention may be produced by recombinant means, including production from mammalian cells or transgenic preparations, or may be purified from other biological sources, as described herein or known in the art.

[0111] Antibody specific for IL-23 ranges include those amounts that yield a concentration of about 1.0 μg / mL to about 1000 mg / mL upon reconstitution for wet / dry systems, although lower and higher concentrations are workable and depend on the intended delivery vehicle, e.g., for solution formulations, as opposed to transdermal patch, pulmonary, transmucosal, or osmotic or micropump methods.

[0112] Preferably, the aqueous diluent further comprises a pharma- ceutically acceptable preservative, optionally. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof. The concentration of the preservative used in the formulation is sufficient to produce an antimicrobial effect. Such concentration will vary depending on the preservative selected, and can be easily determined by those skilled in the art.

[0113] Other excipients, such as isotonicity agents, buffers, antioxidants, and preservative enhancers, can be optionally and preferably added to the diluent. An isotonicity agent, such as glycerin, is generally used at a known concentration. A physiologically tolerable buffer is preferably added to provide improved pH control. The formulations can cover a wide range of pH, such as from about pH 4 to about pH 10, and preferably from about pH 5 to about pH 9, and most preferably from about 6.0 to about 8.0. Preferably, the formulations of the present invention have a pH of about 6.8 to about 7.8. Suitable buffers include phosphate buffers, most preferably sodium phosphate, especially phosphate buffered saline (PBS).

[0114] Other additives, such as pharma- ceutically 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 non-ionic surfactants, such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polyl, other block copolymers, and chelating agents, such as EDTA and EGTA, can be optionally added to the formulation or composition to reduce aggregation. These additives are particularly useful when pumps or plastic containers are used to administer the formulation. The presence of pharma-ceutically acceptable surfactants reduces the tendency of proteins to aggregate.

[0115] The formulations can be prepared by a process that includes mixing at least one anti-IL-23 antibody with a preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof, in an aqueous diluent. Mixing at least one anti-IL-23 specific antibody with a preservative in an aqueous diluent is performed using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a quantity of at least one anti-IL-23 specific antibody in a buffer solution is combined with a desired preservative in a sufficient amount of buffer solution to provide the desired concentration of protein and preservative. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, the use or non-use of additional additives, the temperature and pH during preparation of the formulation are all factors that can be optimized for the administration concentration and administration means used.

[0116] The formulation can be provided to the patient as a clear solution or as a dual vial containing a vial of lyophilized anti-IL-23 specific antibody reconstituted with a second vial containing water, preservatives and / or excipients, preferably phosphate buffer and / or saline, and the selected salt in an aqueous diluent. Either the single solution vial or the dual vial requiring reconstitution can be reused multiple times to satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0117] The product is useful for administration over a period ranging from immediate to 24 hours or more. Thus, the products claimed by the present invention provide significant benefits to patients. The formulations of the present invention can optionally be safely stored at temperatures between about 2° C. and about 40° C. and retain the biological activity of the protein for extended periods of time, and thus the packaging label can state that the solution can be stored and / or used for 6, 12, 18, 24, 36, 48, 72, or 96 hours or more. When using a preserved diluent, such label can include use up to 1-12 months, half a year, one and a half years, and / or up to two years.

[0118] A solution of an antibody specific for anti-IL-23 can be prepared by a process that includes mixing at least one antibody in an aqueous diluent. The mixing is carried out using conventional dissolving and mixing procedures. To prepare a suitable diluent, for example, a certain amount of at least one antibody in water or a buffer is combined in an amount sufficient to provide a desired concentration of protein, and optionally a preservative or buffer. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, whether or not additional additives are used, the temperature and pH at which the formulation is prepared are all factors that can be optimized for the administration concentration and administration means used.

[0119] The claimed products can be provided to patients as clear solutions or as dual vials containing a vial of at least one lyophilized anti-IL-23 specific antibody that is reconstituted with a second vial containing an aqueous diluent. Either the single solution vial or the dual vial requiring reconstitution can be reused multiple times to satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0120] The claimed products can be provided indirectly to patients by providing a pharmacy, clinic, or other such institution or facility with a dual vial containing a clear solution or a vial of at least one lyophilized antibody specific to anti-IL-23 reconstituted in a second vial containing an aqueous diluent, where the clear solution can be up to a liter or even more in volume, from which smaller amounts of the at least one antibody solution can be removed one or more times from the larger container and transferred to smaller vials and provided to customers and / or patients by the pharmacy or clinic.

[0121] Approved devices that include single vial systems include pen-type injection devices for delivering solutions, such as BD Pens, BD Autojector®, Humaject®, NovoPen®, B-DPen®, AutoPen®, and OptiPen®, GenotropinPen®, Genotronorm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®, Iject®, J-tip Needle-Free Injector®, Intraject®, Medi-Ject®, Smartject®, and the like (Becton Dickensen (Franklin Suitable devices include those manufactured or developed by 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 pen-type syringe systems, such as HumatroPen®, for reconstituting lyophilized medication in a cartridge to deliver the reconstituted solution. Examples of suitable other devices include pre-filled syringes, auto-injectors, needleless syringes, and needleless IV infusion sets.

[0122] The product may include packaging. The packaging provides the conditions under which the product may be used, as well as any information required by regulatory agencies. The packaging of the present invention, when applicable, provides instructions to the patient to reconstitute at least one anti-IL-23 antibody with an aqueous diluent to form a solution and use the solution for a period of 2-24 hours or more in a wet / dry two vial product. In the case of a single vial solution product, pre-filled syringe, or autoinjector, the label indicates that such solution may be used for a period of 2-24 hours or more. The product is useful for human pharmaceutical product applications.

[0123] The formulations used in the methods of the present invention can be prepared by a process that includes mixing an anti-IL-23 antibody and a selected buffer, preferably saline or a phosphate buffer containing a selected salt. Mixing the anti-IL-23 antibody and the buffer in an aqueous diluent is performed using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a quantity of at least one antibody in water or buffer is combined with a desired buffer in a sufficient amount of water to provide the desired concentration of protein and buffer. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, whether or not additional additives are used, the temperature and pH at which the formulation is prepared are all factors that can be optimized for the administration concentration and administration means used.

[0124] The method of the present invention provides pharmaceutical compositions including various formulations that are useful and acceptable for administration to human or animal patients. Such pharmaceutical compositions are prepared using "standard" water as a diluent and routine methods well known to those skilled in the art. For example, buffer components such as histidine and histidine monohydrochloride hydrate may be provided first, followed by the addition of an appropriate non-final volume of "standard" water diluent, sucrose, and polysorbate 80. The isolated antibody may then be added. Finally, the volume of the pharmaceutical composition is adjusted to the desired final volume under "standard" conditions using water as a diluent. Those skilled in the art will recognize several other methods suitable for the preparation of pharmaceutical compositions.

[0125] A pharmaceutical composition may be an aqueous solution or suspension containing the indicated mass of each component per volume unit of water or having the indicated pH at "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 refer to a single set of art-recognized temperatures or pressures, but is instead a reference condition that specifies the temperature and pressure used to describe a solution or suspension containing a particular composition under reference "standard conditions" conditions. This is because the volume of a solution is, in part, a function of temperature and pressure. Those skilled in the art will recognize that pharmaceutical compositions equivalent to those disclosed herein can be produced at other temperatures and pressures. The equivalence of such pharmaceutical compositions to those disclosed herein should be determined under "standard conditions" conditions defined above (e.g., 25°C ± 2°C and a pressure of 1 atmosphere).

[0126] Importantly, such a pharmaceutical composition may contain "about" a certain value of the mass of a component (e.g., "about 0.53 mg of L-histidine") or have a certain value of the pH value per unit volume of the pharmaceutical composition. The mass or pH value of a component present in the pharmaceutical composition is "about" a given numerical value when the isolated antibody is present in the pharmaceutical composition or when the isolated antibody is present in the pharmaceutical composition after it is removed from the pharmaceutical composition (e.g., by dilution) and can bind to a peptide chain. That is, the mass value or pH value or other value of a component is "about" a given numerical value when the binding activity of the isolated antibody is maintained and detectable after the isolated antibody is placed in the pharmaceutical composition.

[0127] Competitive binding analysis is performed to determine whether IL-23 specific mAbs bind similar or different epitopes and / or compete with each other. Abs are individually coated onto ELISA plates. Competing mAbs are added, followed by biotinylated hrIL-23. For a positive control, the same mAb for coating can be used as a competing mAb ("self-competition"). IL-23 binding is detected using streptavidin. These results indicate whether the mAbs recognize similar or partially overlapping epitopes on IL-23.

[0128] One aspect of the methods of the invention involves administering a pharmaceutical composition to a patient.

[0129] In one embodiment of the pharmaceutical composition, the isolated antibody concentration is about 77 to about 104 mg per mL of pharmaceutical composition. In another embodiment of the pharmaceutical composition, the pH is about 5.5 to about 6.5.

[0130] The stable or preserved formulations can be provided to patients as clear solutions or as dual vials containing a vial of at least one lyophilized anti-IL-23 antibody that is reconstituted with a second vial containing a preservative or buffer and additives in an aqueous diluent. Either the single solution vial or the dual vial requiring reconstitution can be reused multiple times to satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0131] Other formulations or methods of stabilizing anti-IL-23 antibodies may be other than clear solutions of lyophilized powders containing the antibodies. Non-clear solutions include formulations containing particulate suspensions, which are compositions containing anti-IL-23 antibodies in structures of various sizes known variously as microspheres, microparticles, nanoparticles, nanospheres, or liposomes. Such relatively homogeneous essentially spherical particulate formulations containing active agents can be formed by contacting an aqueous phase containing active agents and polymers with a non-aqueous phase, as taught in U.S. Pat. No. 4,589,330, and then evaporating the non-aqueous phase to cause coalescence of particles from the aqueous phase. Porous microparticles can be prepared by using a first phase containing active agents and polymers dispersed in a continuous solvent, and removing the solvent from the suspension by lyophilization or dilution-extraction-precipitation, as taught in U.S. Pat. No. 4,818,542. Preferred polymers for such preparations are gelatin agar, starch, arabinogalactan, albumin, collagen, polyglycolic acid, polylactic acid, glycolide-L(-)lactide, poly(epsilon-caprolactone, poly(epsilon-caprolactone-co-lactic acid), poly(epsilon-caprolactone-co-glycolic acid), poly(β-hydroxybutyric acid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate), poly(hydroxyethyl methacrylate), polyamide, poly(amino acids), poly(2-hydroxyethyl DL-aspartamide), poly(ester urea), poly(L-phenylalanine / ethylene glycol), poly( ... The preferred polymers are natural or synthetic copolymers or polymers selected from the group consisting of poly(methyl methacrylate), poly(glycol / 1,6-diisocyanatohexane), and poly(methyl methacrylate). Particularly preferred polymers are polyesters such as polyglycolic acid, polylactic acid, glycolide-L(-)lactide poly(epsilon-caprolactone, poly(epsilon-caprolactone-co-lactic acid), and poly(epsilon-caprolactone-co-glycolic acid). Solvents useful for dissolving the polymer and / or active agent include water, hexafluoroisopropanol, methylene chloride, tetrahydrofuran, hexane, benzene, or hexafluoroacetone sesquihydrate.The process of dispersing the active-containing phase into the second phase can include forcing the first phase through orifices in a nozzle under pressure to affect droplet formation.

[0132] Dry powder formulations may also result from processes other than freeze-drying, such as, for example, spray drying, or solvent extraction by evaporation, or by precipitation of a crystalline composition followed by one or more steps to remove the aqueous or non-aqueous solvent. The preparation of spray-dried antibody formulations is taught in U.S. Pat. No. 6,019,968. Antibody-based dry powder compositions can be produced by spray drying a solution or slurry of antibody and, optionally, excipients in a solvent under conditions to provide a respirable dry powder. Solvents include polar compounds, such as water and ethanol, that are easily dried. Antibody stability can be enhanced by performing the spray-drying procedure in the absence of oxygen, for example under a nitrogen blanket, or by using nitrogen as the drying gas. Another relatively dry formulation is a dispersion of multiple porous microstructures dispersed in a suspension medium that typically includes a hydrofluoroalkane propellant, as taught in WO 9916419. The stabilized dispersion can be administered to the lungs of a patient using a metered dose inhaler. Equipment useful in the commercial production of spray dried drugs is manufactured by Buchi Ltd. or Niro Corp.

[0133] Anti-IL-23 antibodies, either in the stable or preserved formulations or in solution described herein, can be administered to a patient in accordance with the present invention via a variety of delivery methods well known in the art, such as SC or IM injection, transdermal, transpulmonary, transmucosal, implants, osmotic pumps, cartridges, micropumps, or other means understood by those of skill in the art.

[0134] Therapeutic Applications The present invention also provides methods for modulating or treating mild to moderate psoriasis in a cell, tissue, organ, animal, or patient using at least one IL-23 antibody of the present invention, e.g., by administering to or contacting the cell, tissue, organ, animal, or patient with a therapeutically effective amount of an antibody specific for IL-23, as known in the art or described herein.

[0135] Any of the methods of the invention may comprise administering to a cell, tissue, organ, animal, or patient in need of such modulation, treatment, or therapy an effective amount of a composition or pharmaceutical composition comprising an anti-IL-23 antibody. Such methods may optionally further comprise co-administration or combination therapy for the treatment of such a disease or disorder, wherein administering the at least one anti-IL-23 antibody, specified portion, or variant thereof, is in combination with at least one TNF antagonist (such as, but not limited to, a chemical or proteinaceous TNF antagonist, a TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70, or p85) or fragment, a fusion polypeptide thereof, or a small molecule TNF antagonist, such as a TNF binding protein. TBP-1 or TBP-II, nerelimonumab, infliximab, etanercept (Enbrel™), adalimumab (Humira™), CDP-571, CDP-870, afelimomab, lenercept, etc.), antirheumatic drugs (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, sodium aurothiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxants, narcotics, non-steroidal anti-inflammatory drugsdrugs, NSAIDs), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blockers, antibacterials (e.g., aminoglycosides, antifungals, antiparasitics, antivirals, carbapenams, cephalosporins, fluoroquinolones, macrolides, penicillins, sulfonamides, tetracyclines, other antibacterials), psoriasis medications, corticosteroids, anabolic steroids, diabetes medications, minerals, nutritional drugs, thyroid medications, vitamins, calcium-related hormones, antidiarrheals, antitussives, antiemetics, antineoplastics, laxatives, anticoagulants, erythropoietin (e.g., epoetin alfa), filgrastim (e.g., G-CSF, Neupogen), sargramostim (GM-CSF, Leukine), The method further comprises administering, before, simultaneously, and / or after at least one selected from an immunological agent, an immunoglobulin, an immunosuppressant (e.g., basiliximab, cyclosporine, daclizumab), a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, an antimanic drug, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma drug, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or an analogue, dornase alfa (Pulmozyme), a cytokine, or a cytokine antagonist. Suitable dosages are well known in the art. See, for example, Wells et al., eds., Pharmacotherapy Handbook, 2 nd Edition, Appleton and Lange, Stamford, CT (2000), PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), Nursing 2001 Handbook of Drugs, 21 stedition, Springhouse Corp., Springhouse, PA, 2001; Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc., Upper Saddle River, NJ, each of which is incorporated herein by reference in its entirety.

[0136] Treatment Typically, treatment of mild to moderate psoriasis is effected by administering an effective amount or dosage of an anti-IL-23 antibody composition, which, depending on the specific activity of the active agent contained in the composition, ranges from at least about 0.01 to 500 milligrams of anti-IL-23 antibody per kilogram of patient per administration, on average, in total, and preferably at least about 0.1 to 100 milligrams of antibody per kilogram of patient per single or multiple administrations. Alternatively, an effective serum concentration may include a serum concentration of 0.1 to 5000 μg / mL per single or multiple administrations. Suitable dosages are known to medical practitioners and will, of course, depend on the specific disease state, the specific activity of the composition administered, and the specific patient undergoing treatment. In some cases, it may be necessary to provide repeated administrations, i.e., repeated individual administrations of a particular monitored or metered administration, to achieve the desired therapeutic dose, where the individual administrations are repeated until the desired daily dose or effect is obtained.

[0137] Preferred doses are optionally 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70 , 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and / or 100-500 mg / kg / dose, or any range, value, or fraction thereof, or 0.1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9, 2.0, 2.5, 2.9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5, 6.9, 7.0, 7.0, 7.5 ... .5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 20, 12.5, 12.9, 13.0, 13.5, 13.9, 14.0, 14.5, 4.9, 5.0, 5.5., 5.9, 6.0, 6.5, 6.9 , 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 12, 12.5, 12.9, 13.0, 13.5, 13.9, 14, 14.5, 15, 15.5, 15.9, 16, 16.5, 16.9 , 17, 17.5, 17.9, 18, 18.5, 18.9, 19, 19.5, 19.9, 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, and / or 5000 μg / mL, or any range, value or fraction thereof.

[0138] Alternatively, the dose administered may vary depending on known factors such as the pharmacodynamic characteristics of the particular agent and its method and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, type of concurrent treatment, frequency of treatment, and the desired effect. The dose of active ingredient may typically be about 0.1 to 100 milligrams per kilogram of body weight. Typically, 0.1 to 50, preferably 0.1 to 10 milligrams per kilogram per dose, or in sustained release form, is effective to obtain the desired results.

[0139] As non-limiting examples, treatment of humans or animals may be performed using a single dose, intravenous administration, or multiple doses over 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 days. or additionally, on at least one day of eyes 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, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 11 0.1 to 100 mg / kg per day, for example, 0.5, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 1.9, 1.10, 1.20, 1.40, 1.65, 1.80, 1.95, 1.99, 1.99, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 14, 15, 16, 17, 18, 19, or 20 years, or any combination thereof. The antibody may be provided as a single or periodic dose of 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.

[0140] Dosage forms (compositions) suitable for internal administration generally contain about 0.001 milligrams to about 500 milligrams of active ingredient per unit or container. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.5 to 99.999% by weight based on the total weight of the composition.

[0141] For parenteral administration, the antibody may be formulated as a solution, suspension, emulsion, particle, powder, or lyophilized powder, provided together with or separately from a pharma- ceutical acceptable parenteral vehicle. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and 1-10% human serum albumin. Non-aqueous vehicles such as liposomes and fixed oils can also be used. The vehicle or lyophilized powder may contain additives that maintain isotonicity and chemical stability (e.g., sodium chloride for isotonicity, mannitol, buffers and preservatives for chemical stability). The formulation is sterilized by known or suitable techniques.

[0142] Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

[0143] Alternative Administration Many known and developed modes can be used in accordance with the present invention to administer a pharma- ceutical effective amount of an anti-IL-23 antibody. Although pulmonary administration is used in the following description, other modes of administration may be used in accordance with the present invention to obtain suitable results. The IL-23-specific antibodies of the present invention can be delivered in a carrier, as a solution, emulsion, colloid or suspension, or as a dry powder, using any of a variety of devices and methods suitable for administration by inhalation or by other methods described herein or known in the art.

[0144] Parenteral Formulation and Administration Preparations for parenteral administration may contain sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydrogenated naphthalenes, etc. as common excipients. Aqueous or oily suspensions for injection can be prepared by using appropriate emulsifiers or wetting agents and suspending agents according to known methods. Injections can be non-toxic parenterally administrable diluents such as aqueous solutions, sterile injections, or suspensions in solvents. Usable vehicles or solvents include water, Ringer's solution, isotonic saline, etc., and sterile fixed oils can be used as normal solvents or suspension solvents. For these purposes, any kind of fixed oils and fatty acids, including natural, synthetic, or semi-synthetic fatty oils or fatty acids, natural, synthetic, or semi-synthetic monoglycerides, diglycerides, or triglycerides, can be used. Parenteral administration is known in the art and includes, but is not limited to, conventional injection means, the gas pressurized needleless injection device described in U.S. Pat. No. 5,851,198, and the laser perforator device described in U.S. Pat. No. 5,839,446, which are incorporated herein by reference in their entireties.

[0145] alternative delivery The invention further relates to administration of anti-IL-23 antibodies by parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intrabronchial, intraabdominal, intracapsular, intrachondral, intrasinus, intracavity, intracerebellar, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, intravaginal, rectal, buccal, sublingual, intranasal or transdermal means. The anti-IL-23 antibody compositions can be administered parenterally (subcutaneously, intramuscularly, or intravenously), particularly in the form of liquid solutions or suspensions, for use in vaginal or rectal administration, particularly in semi-solid forms such as, but not limited to, creams and suppositories, for oral or sublingual administration, such as, but not limited to, tablets or capsules, or intranasally, such as, but not limited to, powders, nasal drops or aerosols, or certain agents, or with chemical enhancers such as dimethylsulfoxide to either modify the skin structure or increase the drug concentration in transdermal patches (Junginger, et al. In "Drug Permeation Enhancement;" Hsieh, DS, Eds., pp. 59-90 (Marcel Dekker, Inc. New York, 1999), which are incorporated herein by reference in their entirety). 1994), or application of protein and peptide containing formulations to the skin (WO 98 / 53847), or application of an electric field to create a transient transport pathway, such as electroporation, or to increase the mobility of a charged drug through the skin, such as iontophoresis, or application of ultrasound, such as sonophoresis (U.S. Pat. Nos. 4,309,989 and 4,767,402), for transdermal use, such as, but not limited to, gels, ointments, lotions, suspensions, or patch delivery systems (the above publications and patents are incorporated herein by reference in their entireties).

[0146] Having generally described the present invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting. Further details of the present invention are illustrated by the following non-limiting examples. The disclosures of all citations herein are expressly incorporated herein by reference.

[0147] Example 1 - Treating mild to moderate psoriasis with IL23 antibodies A Phase 3, Multicenter, Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Study to Evaluate the Safety and Efficacy of Guselkumab Versus Placebo and Apremilast for the Treatment of Mild-to-Moderate Psoriasis (SPECTREM) The primary objective of this study is to evaluate the efficacy of guselkumab versus placebo and apremilast in participants with mild to moderate psoriasis. Other secondary objectives of the study are safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity.

[0148] This study will directly investigate the safety and efficacy of subcutaneous (SC) injections of 100 mg guselkumab given at weeks 0, 4, and every 8 weeks (q8w) thereafter compared with placebo and apremilast, both 30 mg twice daily (BID) after standard ascending titration, in treating participants with mild-to-moderate plaque psoriasis.

[0149] The primary endpoint is the proportion of participants with an Investigator Global Assessment (IGA) score of 0 (clear) or 1 (minimal) in participants with at least a 2-point reduction from baseline at Week 16 compared to placebo. The first key secondary endpoint is an IGA of 0 / 1 at Week 16 compared to the active comparator (apremilast). Additional control secondary endpoints and other endpoints are outlined in the Endpoints section below.

[0150] Approximately 450 eligible participants will be randomized 1:1:1 to receive either guselkumab 100 mg SC at weeks 0 and 4 and then q8w, apremilast 30 mg twice daily (BID) followed by standard titration, or placebo. Randomization will be stratified by baseline IGA score (mild [2] or moderate [3]) and study site to ensure balance between treatment arms for baseline severity of psoriasis. Approximately 30% of randomized participants will have a baseline IGA score of mild (2) and approximately 70% of participants will have a baseline IGA score of moderate (3).

[0151] There are two database locks (DBLs) in this study, at weeks 24 and 56. The week 24 DBL will be performed after all participants have completed the week 24 visit (or discontinued the study) and unblinded data will be available only to select sponsor and Contract Research Organization (CRO) team members involved in analyzing and preparing the data for the week 24 DBL. All other sponsor, site, and CRO investigators directly involved in the conduct of the study will remain blinded to treatment assignment until the week 56 DBL and associated analyses are completed.

[0152] The study design and treatment assignments are further described below and in FIG.

[0153] Study population The target population is adult men or women with a diagnosis of mild to moderate plaque type psoriasis with or without PsA for at least 6 months. Participants with non-plaque forms of psoriasis (e.g., erythrodermic psoriasis, guttate psoriasis, or pustular psoriasis) or drug-induced psoriasis (e.g., new onset or exacerbation of psoriasis from beta-blockers, calcium channel blockers, or lithium) are excluded.

[0154] Participants must have mild to moderate psoriasis, defined as a BSA of 2-15%, an IGA of 2 or 3, and a PASI of 2-15. Participants must be candidates for either systemic or phototherapy for psoriasis and must have had an inadequate response or intolerance to at least one prior topical therapy. Participants must be naïve (i.e., not previously treated for psoriasis, psoriatic arthritis, or any other indication that may affect the assessment of psoriasis) to advanced therapy, including apremilast, guselkumab, and other oral immunomodulatory or biologic therapies.

[0155] Study Inclusion Criteria - Participant Population 1. Participant gender (biological): both male and female 2Age of participants: 3 Minimum Age: 18 years of age (or the legal age recognized in the jurisdiction in which the test is being conducted) 4. Have a diagnosis of psoriasis vulgaris (with or without PsA) for at least 6 months prior to the first dose of study drug 5. Candidates for phototherapy or systemic treatment of psoriasis 6. Have 2%-15% involved BSA at screening and baseline 7. Have an IGA of 2 or 3 at screening and baseline 8. PASI 2-15 at screening and baseline 9 Participants must have had inadequate control with or intolerance to at least one topical therapy for the treatment of psoriasis (e.g., topical corticosteroids, topical retinoid or vitamin D analog preparations, calcipotriol-betamethasone dipropionate ointment or foam, tacrolimus, pimecrolimus, or anthralin / dithranol) both at screening and baseline. 10. Naïve to advanced therapy (i.e., not previously treated for psoriasis, psoriatic arthritis, or any other indication that may affect the evaluation of psoriasis), including apremilast, guselkumab, and other oral immunomodulatory or biologic therapies. 11 Patients who, in the opinion of the investigator, are considered suitable candidates for apremilast therapy according to the Otezla® product labeling approved in their country 12Prior to the first dose of study drug, women must meet one of the following criteria: a. Not of childbearing potential: Premenarche; Postmenopausal (age >45 years with at least 12 months of amenorrhea or any age with at least 6 months of amenorrhea and follicle-stimulating hormone levels >40 IU / L); Post permanent sterilization (e.g., tubal occlusion / ligation, hysterectomy, bilateral salpingectomy); or unable to conceive for another reason. b. Practice highly effective contraception consistent with local regulations regarding the use of contraception for participants of childbearing potential and participating in clinical trials: e.g., established use of hormonal methods of contraception by oral, injection, or implant; placement of an intrauterine device or system; barrier methods: condoms or occlusive caps (diaphragms or cervical / vaginal vault caps) + spermicidal foam / gel / film / cream / suppositories; sterilization of male partner (a vasectomized partner must be the participant's only partner); true abstinence (if this is consistent with the participant's preferred usual lifestyle) NOTE: If a female participant's fertility changes after study initiation (e.g., a sexually inactive woman becomes sexually active or a premenarchal woman experiences menarche), she must begin using a highly effective method of contraception as described above. 13Women of childbearing potential must have a negative urine pregnancy test at screening week 0 and agree to a urine pregnancy test before receiving an infusion. 14Women must agree not to donate eggs (eggs, oocytes) for assisted reproductive purposes during the study and for at least 12 weeks after receiving their last dose of guselkumab. 15Men who are sexually active with women of childbearing potential and who do not have a vasectomy must agree to use a barrier method of contraception (e.g., either condoms [with spermicidal foam / gel / film / cream / suppository] or occlusive caps [diaphragm or cervical / vaginal vault caps] + spermicidal foam / gel / film / cream / suppository) during the study and for at least 12 weeks after receiving their last dose of guselkumab. All men must agree not to donate semen during the study and for at least 12 weeks after receiving their last dose of guselkumab.

[0156] Infectious disease related 16. Agree not to receive live viral or live bacterial vaccinations during the study or within approximately 12 weeks after the last dose of study intervention. 17 Agree not to receive Bacille Calmette-Guerin (BCG) vaccination during the study and for approximately 12 weeks after the last dose of study intervention. 18 Patients are encouraged to receive scheduled age-appropriate vaccinations prior to screening per local treatment guidelines for routine practice. For study patients who received a local regulatory authority approved (and / or emergency use authorization) COVID-19 vaccine immediately prior to study enrollment, follow applicable local regulatory authority vaccine labeling, guidelines, and standards of care for patients receiving immune-targeted therapies when determining the appropriate interval between vaccination and study enrollment. 19. If a patient has laboratory screening test results within the following parameter ranges and one or more of the test values ​​are out of range, one retest of the test values ​​is permitted: Hemoglobin ≥ 10g / dL (SI: ≥ 100g / L) b.White blood cells ≧3.5×103 / μL (SI:≧3.5GI / L) c. Neutrophils ≧1.5×103 / μL (SI:≧1.5GI / L) d. Platelets ≧100×103 / μL (SI:≧100GI / L) e. Serum creatinine ≦1.5mg / dL (SI: ≦137μmol / L) f. Aspartate aminotransferase ≦2× upper limit of normal (ULN) g. Alanine aminotransferase ≤ 2 x ULN NOTE: One repeat of the screening laboratory tests (a-e) is permitted during the 6-week screening phase, and the investigator may consider a participant eligible if previous abnormal laboratory test results are within acceptable ranges on repeat testing at the central laboratory.

[0157] others 20Agree to avoid prolonged sun exposure and the use of tanning chambers or other sources of ultraviolet light during the study. 21 Willing and able to abide by the prohibitions and restrictions specified in this Protocol. 22 Each person must sign (or their legally acceptable representative must sign) an informed consent form (ICF) indicating that they understand the purpose of the study and the procedures it will entail, and are willing to take part in the study.

[0158] Exclusion Criteria – Psoriasis 1. Have a non-vulgar form of psoriasis (eg, erythrodermic psoriasis, guttate psoriasis, or pustular psoriasis). 2. Have current drug-induced psoriasis (e.g., new onset or exacerbation of psoriasis from beta-blockers, calcium channel blockers, or lithium). 3. Having psoriasis flare / rebound (defined as a sudden worsening of psoriasis requiring administration of prohibited medication) within 4 weeks of signing the ICF or between the screening and baseline visits. 4. Has previously received any biologic used to treat psoriasis, psoriatic arthritis, 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.). 5. Have previously received apremilast. 6. Have received phototherapy within 4 weeks of the first dose of study intervention. 7. Have received any systemic immunosuppressant (e.g., methotrexate [MTX], azathioprine, cyclosporine, 6-thioguanine, mercaptopurine, mycophenolate mofetil, tacrolimus, acitretin) or anakinra within 4 weeks of the first dose of study drug. 8. Within 4 weeks of the first dose of study drug, patients had received any systemic medication that may affect psoriasis or IGA assessment, including but not limited to oral or injectable corticosteroids, retinoids, 1,25 dihydroxyvitamin D3 and analogs, psoralens, sulfatalazine, hydroxyurea, fumaric acid derivatives, etc. 9. Have used topical medications within 2 weeks of the first dose of study drug that may affect psoriasis or the IGA assessment (e.g., but not limited to, topical corticosteroids, topical retinoids, or vitamin D analog preparations, calcipotriene and betamethasone dipropionate ointment or foam, tacrolimus, pimecrolimus, or experimental topical agents such as anthralin / dithranol, tapinarof or roflumilast, coal tar derivatives, etc.). 10. Within 4 weeks of the first dose of study drug, you have received herbal treatments or traditional Taiwanese, Korean, or Chinese medicines that may affect your psoriasis or IGA assessment. 11Has received biologic therapy or an experimental antibody within the past 12 weeks or within 5 half-lives of any study drug administration (whichever is longer), or is enrolled in another study using the investigational drug or procedure. 12Currently receiving lithium, antimalarials, or intramuscular (IM) gold, or have received lithium, antimalarials, or IM gold within 4 weeks of the first dose of study drug.

[0159] Coexisting medical conditions or history 13. Have a history of or current signs of serious, advanced, or uncontrolled renal, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurological, hematological, rheumatic, psychiatric, or metabolic disorders. 14. Have unstable cardiovascular disease defined as a recent clinical exacerbation (e.g., unstable angina, tachycardial atrial fibrillation) in the last 3 months or cardiac hospitalization within the last 3 months. 15Current malignancy or history of malignancy within 5 years prior to screening (excluding non-melanoma skin cancer that has been adequately treated and has had no evidence of recurrence for at least 3 months prior to first study drug administration, or cervical intraepithelial neoplasia that has been treated and has had no evidence of recurrence for at least 3 months prior to first study drug administration). 16 History of lymphoproliferative disorders such as lymphoma, history of monoclonal gammopathy of undetermined significance, or signs and symptoms suggestive of a possible lymphoproliferative disorder such as lymphadenopathy or splenomegaly. 17. Having a transplanted organ (excluding corneal transplantation more than 3 months prior to first administration of study drug). 18 Known intolerance or hypersensitivity to any biological drug challenge, or known allergic or clinically significant reaction to murine, chimeric, or human proteins, mAbs, or antibody fragments. 19. The participant had a history of suicide attempt at any time in the participant's life prior to signing informed consent and randomization, or a major psychiatric illness requiring hospitalization within the past 3 years prior to signing informed consent. 20 Unstable suicidal thoughts or behaviors, which can be defined as an electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) rating of suicidal ideation with intent to act (4), suicidal ideation with specific plans and intentions (5), or suicide planning in the past 6 months (interrupted suicide attempt, aborted suicide attempt, or preparatory behavior to make a suicide attempt) at screening and identified by the investigator as at risk based on evaluation by a mental health professional. The final decision to exclude participants is made at the discretion of a trained mental health professional. 21 had a history of an infected joint prosthesis or had received antibiotics for a suspected infection of a joint prosthesis if the prosthesis had not been removed or replaced. 22 Known allergy or hypersensitivity to any component of apremilast. 23 Known allergy, hypersensitivity, or intolerance to guselkumab or any of its excipients (see Investigator Brochure). 24. Pregnant, breastfeeding, or planning pregnancy while enrolled in this study and within 12 weeks after the last dose of study drug (both men and women). 25 Has had major surgery (e.g., requiring general anesthesia and hospitalization) within 8 weeks prior to screening, or has not fully recovered from such surgery, or has such surgery planned during the period in which the participant is expected to participate in the study (56 weeks). Note: Participants who are scheduled for surgical treatment performed under local anesthesia are eligible to participate. 26 past 12 Known to have had a substance abuse problem (drugs or alcohol) within the past month. 27 There is evidence that skin conditions may interfere with the clinical evaluation of psoriasis.

[0160] Infection or predisposition to infection 28 Have a history of chronic or recurrent infections, including but not limited to chronic kidney infections, chronic chest infections (e.g., bronchiectasis), recurrent urinary tract infections (recurrent pyelonephritis or chronic persistent cystitis), fungal infections (e.g., mucocutaneous candidiasis), or open, draining, or infected skin wounds or ulcers. 29 Have or have had a serious infection (e.g., sepsis, pneumonia, or pyelonephritis) or have been hospitalized or received intravenous antibiotics for a clinically relevant infection in the 2 months prior to screening. 30 Have had shingles or have had it within 2 months prior to screening. 31 Received or anticipated to receive any live viral or bacterial vaccination within 3 months prior to the first dose of study drug, and plan to receive such a vaccination during the investigational product or within 4 months after the last dose of study intervention. For BCG vaccination, see exclusion criteria 32. 32 had received BCG vaccination within 12 months of screening. 33 Have a chest x-ray taken within 3 months prior to the first dose of study drug that shows abnormalities suggestive of malignancy or current active infection, including TB. Meet any of the following 34 tuberculosis (TB) screening criteria: Have a history of active TB or exhibit signs or symptoms suggestive of active TB on screening history and / or physical examination. b. Have a history of untreated latent TB prior to screening. Exceptions will be made for participants who are currently receiving treatment or who will begin treatment for latent TB prior to the first dose of study intervention. NOTE: For participants with a history of treated latent TB, adequate documentation of treatment must occur prior to the first dose of study intervention. It is the investigator's responsibility to verify the adequacy of prior TB treatment and provide appropriate documentation. QuantiFERON-TB® (QFT) testing is not required for screening participants with a history of treated latent TB or currently being treated for latent TB. c. Recent close contact with someone with active TB. Exceptions will be made if such participants are referred to a physician with TB expertise to determine whether treatment is warranted. This evaluation must be appropriately documented, and if treatment is recommended, participants must receive appropriate treatment prior to the first dose of study intervention. d. Have a positive QFT test result within 2 months prior to first dose of study intervention. Exceptions will be made for the following participants: - Have a history of adequately treated latent TB as described above. - Have a newly confirmed positive QFT test result indicating that active TB has been cleared and appropriate treatment for latent TB has been initiated prior to the first dose of study intervention. - Has a false positive QFT test as determined by: ○ An initial QFT test suspected to be false positive should be repeated. If the repeat test is not positive, the participant should be referred to a physician with TB expertise to determine whether the initial test can be considered a false positive. This assessment should be appropriately documented before the first administration of the study intervention. However, if the repeat test is positive, it will be considered a true positive and the participant will be eligible only if active TB has been eliminated and appropriate treatment for latent TB has been initiated as described above. Note: Equivocal / Borderline results should be handled according to the instructions outlined in Section 8.2.7. e. Have a chest x-ray or chest computed tomography within 3 months prior to the first dose of study intervention that shows abnormalities suggestive of active or inactive TB. 35 Test positive for hepatitis B virus (HBV) infection (Protocol Appendix 5). 36 You are seropositive for antibodies to hepatitis C virus (HCV) unless you meet one of the following conditions: a. Have a history of successful treatment (defined as being negative for HCV RNA at least 12 weeks after completing antiviral treatment) and have a negative HCV RNA test result at screening, or b. Being seropositive and having a negative HCV RNA test result for at least 12 weeks prior to screening and having a negative HCV RNA test result at the time of screening. 37 History of active granulomatous infection (e.g., histoplasmosis or coctidioidomycosis) prior to screening. See exclusion criteria 34 for information on eligibility of history of latent TB. 38 History of nontuberculous mycobacterial or opportunistic infections (e.g., cytomegalovirus, pneumocystis, aspergillosis). 39. Being infected with the human immunodeficiency virus (HIV, serologically positive for HIV antibodies). 40 During the 6 weeks prior to baseline, had any of the following: a) Confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) / COVID 19 infection (positive test), or b) SARS-CoV-2 infection is suspected (clinical features without documented test results), or c) Close contact with a person with known or suspected SARS-Cov-2 infection. Participants have a documented negative result to a validated SARS-CoV-2 test: At least 2 weeks after the onset of conditions (a), (b), or (c) above (measured from the resolution of significant clinical features, if present, e.g., fever, cough, and dyspnea), AND, during the period between the negative test result and the baseline visit, all of the above conditions (a), (b), and (c) are not present. Exceptions to this rule may be granted in certain cases. Notes on COVID-related exclusions: The field of COVID-related testing (for the presence of and immunity to the SARS-CoV2 virus) is rapidly evolving. Additional testing, if deemed necessary by the Investigator, may be performed as part of screening and / or during the study, in accordance with current regulations / guidance / standard of care from authorities. For individuals who may be at higher risk for severe COVID-19 illness, we will follow guidance from local health authorities when weighing the potential benefits and risks of enrolling in and participating in the study.

[0161] general 41 Unable or unwilling to undergo multiple venipunctures due to poor tolerance or difficult venous access. 42 Subjects are living in an institution by order of a court or other authority. 43 Any circumstances such that, in the opinion of the investigator, participation would not be in the subject's best interests (e.g., compromises welfare) or which might prevent, limit, or confound protocol-specific evaluations. 44 An employee of the investigator or trial site who is directly involved in the proposed study or other studies under the direction of the investigator or trial site, or a family member of such an employee or investigator.

[0162] Lifestyle Considerations Prohibited and restricted therapies under investigation: -Corticosteroids (topical, intralesional, shampoo, oral) - Coal tar, liquid carbonis detergent (LCD), and any other topical medications that can be used to treat psoriasis (calcipotriene, tacrolimus, etc.)

[0163] Participants must avoid prolonged sun exposure during the study and must not use tanning chambers or other sources of ultraviolet light.

[0164] Permitted Concomitant Medications: Topical emollients, e.g., Eucerin®, Vaseline®, Lubriderm®, etc.

[0165] Sequence and duration of study phases / periods 1. Screening phase: up to 6 weeks 2. Blinded treatment period - Weeks 0 to 24 At week 0, participants will be randomized in a 1:1:1 ratio per stratum to guselkumab (100 mg subcutaneously at weeks 0 and 4, then q8w), apremilast, or placebo for the first 16 weeks. - The primary endpoint of IGA 0 / 1 for guselkumab vs. placebo will be assessed at Week 16. - The first major secondary endpoint of IGA 0 / 1 for guselkumab vs. apremilast will be assessed at Week 16. At week -16, participants receiving placebo will be switched to guselkumab (weeks 0 and 4, then q8w) in a blinded fashion, and at week 24, participants receiving apremilast will be switched to guselkumab (weeks 0 and 4, then q8w) in a blinded fashion. - All treatment arms will receive study treatment through Week 44 (last treatment dose).

[0166] 3. Efficacy and safety follow-up phase - Weeks 44 to 56 - Final efficacy visit will be performed at Week 48 -Final safety follow-up visit will be at Week 56

[0167] Selection of placebo and active comparators placebo A placebo-controlled design was chosen to provide a robust evaluation of the efficacy of guselkumab 100 mg subcutaneously at weeks 0, 4, and q8w in mild-to-moderate psoriasis. The placebo-controlled design is intended to minimize participant and investigator bias in evaluating the efficacy and safety of guselkumab in selected patient populations (Food and Drug Administration [FDA] Guidance for Industry E10).

[0168] Otezla (apremilast) 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 approved modern oral medication for the treatment of mild to moderate plaque psoriasis, given its demonstration of statistically significant and clinically meaningful improvements in multiple efficacy measures. Apremilast was selected as the active comparator because, as a modern oral therapy, it is safer than traditional systemic therapies such as methotrexate or cyclosporine while simultaneously achieving a significant level of efficacy in mild to moderate psoriasis, thus providing a valuable and relevant benchmark for comparison with guselkumab. Participants randomized to apremilast will receive doses according to the labeled dosing regimen for plaque psoriasis.

[0169] hypothesis We hypothesize that (i) guselkumab is superior to placebo and (ii) guselkumab is superior to apremilast in treating mild-to-moderate psoriasis as defined by a BSA of 2 to 15%, an IGA of 2 or 3, and a PASI of 2 to 15. The study is designed to show the difference between guselkumab and placebo at week 16 and between guselkumab and apremilast at both weeks 16 and 24.

[0170] [Table 2-1]

[0171] [Table 2-2]

[0172] [Table 2-3]

[0173] [Table 3]

[0174] Statistical considerations: Sample Size: A sample size of approximately 450 participants (150 participants per treatment group) will allow at least 90% power to detect a 45% treatment effect difference between guselkumab (60%) and placebo (15%) for the primary endpoint, and a 30% treatment effect difference between guselkumab (60%) and apremilast (30%) for the first major secondary endpoint, assuming a two-sided alpha level of 0.05 or 0.001.

[0175] Table 3 shows power calculations to detect a treatment difference using several assumptions for the primary endpoint and the first major secondary endpoint. For the other multiplicity controlled major secondary endpoints, if we assume a treatment effect difference of approximately 35% to 70%, based on available data from the trials referenced below (Table 4), a sample size of 150 per group would allow for a power of at least 90%.

[0176] [Table 4]

[0177] [Table 5]

[0178] statistical methods Continuous variables are summarized using descriptive statistics (e.g., mean, median, standard deviation [SD], interquartile range [IQ], minimum, and maximum). Categorical variables are summarized using counts and percentages. Graphical data displays (e.g., line plots) can also be used to summarize the data.

[0179] The Cochran-Mantel-Haenszel (CMH) chi-square statistical test is used for the primary endpoint. In the primary efficacy analysis, data from all randomized participants are analyzed according to their assigned group. Participants who discontinue the study intervention due to lack of efficacy or due to AEs of worsening psoriasis and start prohibited medications or treatments that may improve psoriasis before week 16 are considered non-responders to the primary endpoint at week 16.

[0180] Analyses appropriate for categorical data (e.g., chi-square test, or CMH chi-square test, or logistic regression, if appropriate) are used to compare the proportion of participants achieving the selected endpoint (e.g., clinical response). Rarely, Fisher's exact test is used for treatment comparisons. Continuous response parameters are compared using analysis of variance (ANOVA) or analysis of covariance (ANCOVA) unless otherwise stated. When the assumption of normality is in question, ANOVA or ANCOVA on van der Waerden normal scores is used.

[0181] The overall type I error rate is controlled at a significance level of 0.05 (2-tailed).

[0182] The present invention can be described with reference to the following numbered embodiments. Embodiment 1. Use of an antibody specific for IL23 for the treatment of mild to moderate psoriasis in a patient, the antibody comprising 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 comprising the CDRL3 amino acid sequence of SEQ ID NO:6, The heavy chain variable region The complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO:1; the CDRH2 amino acid sequence of SEQ ID NO:2, and 3, and wherein the use results in a clinical response in a patient. Embodiment 2. The use of embodiment 1, wherein the antibody is administered at a first dose, at a dose about 4 weeks after the first dose, and at a dose about 12 weeks after the first dose. Embodiment 3. The use of embodiment 2, wherein the antibody is administered subcutaneously. Embodiment 4. The use of embodiment 1, wherein the first dose and the dose about 4 weeks after the first dose and the dose about 12 weeks after the first dose are 100 mg of antibody.

[0041] Embodiment 5. The patient is confirmed as a responder to the antibody and meets clinical and / or exploratory endpoints, wherein the clinical endpoint is: (i) achievement of a clear (0) or minimal (1) IGA score with at least ≥ 2 grade improvement from baseline; (ii) achieving BSA ≤ 1%; (iii) achieving an IGA score of clear (0); (iv) achievement of a PASI 90 response; (v) achieving a PASI 100 response; (vi) achieving a Scalp-Specific Investigator's Global Assessment (ss-IGA) score of absence (0) or very mild disease, and having at least a 2-grade improvement from baseline and an ss-IGA score of ≥ 2 at baseline; (vii) achieving a ≥ 4 point reduction (improvement) from baseline in the Psoriasis Symptom and Sign Diary (PSSD) itch score in participants with a PSSD ≥ 4 at baseline; (viii) achievement of a PSSD symptom score of 0 in randomized participants with a baseline PSSD symptom score ≥ 1; and (ix) Percentage of improvement from baseline in Nail Psoriasis Severity Index (NAPSI) in randomized participants with nail psoriasis at baseline The use according to embodiment 1, wherein the compound is selected from the group consisting of: Embodiment 6. The use of embodiment 5, wherein the clinical endpoint is measured at about 16, 24, 48, and / or 96 weeks after initial treatment. Embodiment 7. The use of embodiment 6, wherein the clinical endpoint is measured about 16 weeks after the initial treatment. Embodiment 8. The use according to any one of embodiments 5 to 7, wherein the clinical endpoints are compared with clinical endpoints of patients being treated with apremilast. Embodiment 9. The use according to embodiment 1, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO:8 and the heavy chain variable region amino acid sequence of SEQ ID NO:7. Embodiment 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. Embodiment 11. The use according to embodiment 9 or 10, wherein the antibody is present in a pharmaceutical composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, and 0.053% (w / v) polysorbate 80, and the diluent is water at standard conditions. Embodiment 12. The use of embodiment 1, further comprising the use of one or more additional drugs used to treat mild to moderate psoriasis. Embodiment 13. The use of embodiment 12, wherein the additional drug is selected from the group consisting of immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface marker antibodies, anti-CD20 antibodies, rituximab, TNF inhibitors, corticosteroids, and costimulatory regulators. Embodiment 14. Use of an antibody specific for IL23 for the treatment of mild to moderate psoriasis in a patient, comprising: (i) an initial 100 mg subcutaneous administration of the antibody, (ii) a subcutaneous administration of 100 mg of the antibody about 4 weeks after the initial administration, and (iii) a subcutaneous administration of 100 mg of the antibody about every 8 weeks after the administration about 4 weeks after the initial administration, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO:8 and the heavy chain variable region amino acid sequence of SEQ ID NO:7, and the patient is a responder to the antibody by being confirmed to meet a clinical endpoint about 16 weeks after the initial administration, the clinical endpoint being selected from the group consisting of: (i) achievement of a clear (0) or minimal (1) IGA score with at least a ≧2 grade improvement from baseline, (ii) achievement of a BSA≦1%, (iii) achievement of a clear (0) IGA score, (iv) achievement of a PASI 90 response, and (v) achievement of a PASI 100 response. JPEG2025512860000009.jpg222151JPEG2025512860000010.jpg218140JPEG2025512860000011.jpg211162 JPEG2025512860000012.jpg227137JPEG2025512860000013.jpg224138JPEG2025512860000014.jpg167137

Claims

1. A pharmaceutical composition for use in a method of treating mild to moderate psoriasis in patients, The aforementioned pharmaceutical composition contains an antibody specific to IL23, The method includes administering an antibody specific to IL23 to the patient. The antibody comprises a light chain variable region and a heavy chain variable region, and the light chain variable region is The amino acid sequence of the complementarity-determining region light chain 1 (CDRL1) of sequence number 4, The CDRL2 amino acid sequence of Sequence ID No. 5, and The CDRL3 amino acid sequence of SEQ ID NO: 6 is included, The aforementioned heavy chain variable region is The amino acid sequence of the complementarity-determining region heavy chain 1 (CDRH1) of SEQ ID NO: 1, The CDRH2 amino acid sequence of Sequence ID No. 2, and Containing the CDRH3 amino acid sequence of Sequence ID No. 3, A pharmaceutical composition in which the patient is a responder to the antibody.

2. The pharmaceutical composition according to claim 1, wherein the antibody is administered in the first dose, in a dose approximately four weeks after the first dose, and in a dose approximately twelve weeks after the first dose.

3. The pharmaceutical composition according to claim 2, wherein the initial dose, the dose administered approximately 4 weeks after the initial dose, and the dose administered approximately 12 weeks after the initial dose are approximately 100 mg of the antibody.

4. The pharmaceutical composition according to claim 3, wherein the antibody is administered subcutaneously.

5. The pharmaceutical composition according to claim 4, further comprising the method of administering the antibody at maintenance doses approximately every 8 weeks after the administration approximately 12 weeks after the initial administration.

6. The pharmaceutical composition according to claim 1, wherein the patient is confirmed to be a responder to the antibody by meeting the clinical endpoint.

7. The aforementioned clinical endpoint is (i) Achieving a clear (0) or minimum (1) IGA score with an improvement of at least ≥2 grades from baseline. (ii) Achievement of BSA ≤ 1%, (iii) Clear (0) IGA score achieved, (iv) Achievement of PASI 90 response, (v) Achievement of PASI 100 responses, (vi) Achievement of a Scalp-Specific Investigator's Global Assessment (ss-IGA) score of disease absence (0) or very mild disease, and improvement of at least two grades from baseline and a baseline ss-IGA score of ≥2. (vii) Achievement of a reduction (improvement) of ≥4 points from baseline in the Psoriasis Symptom and Sign Diary (PSSD) itch score in participants with a PSSD itch score ≥4 at baseline. (viiii) Achievement of a PSSD symptom score of 0 in randomized participants with a baseline PSSD symptom score ≥ 1, and (ix) Rate of improvement from baseline in the Nail Psoriasis Severity Index (NAPSI) in randomized participants who had nail psoriasis at baseline. A pharmaceutical composition according to claim 6, selected from the group consisting of the following.

8. The pharmaceutical composition according to claim 7, wherein the clinical endpoint is measured approximately 16 weeks after the first dose.

9. The pharmaceutical composition according to claim 7, wherein the clinical endpoint is measured approximately 24 weeks, 52 weeks, and / or 104 weeks after initial treatment.

10. The pharmaceutical composition according to claim 9, wherein the clinical endpoint is measured approximately 24 weeks after initial treatment.

11. The pharmaceutical composition according to any one of claims 7 to 10, wherein the clinical endpoint is compared with the clinical endpoint of a patient being treated with apremilast.

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

7.

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

9.

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

15. The pharmaceutical composition according to claim 1, further comprising administering to the patient one or more additional agents used to treat mild to moderate psoriasis.

16. The pharmaceutical composition according to claim 15, wherein the additional agent is selected from the group consisting of immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface marker antibodies, anti-CD20 antibodies, rituximab, TNF inhibitors, corticosteroids, and costimulatory moduli.

17. A pharmaceutical composition for use in a method of treating mild to moderate psoriasis in patients, The aforementioned pharmaceutical composition contains an antibody specific to IL23, The method includes (i) administering 100 mg of the IL23-specific antibody as an initial subcutaneous dose to the patient, (ii) administering 100 mg of the antibody as a subcutaneous dose approximately 4 weeks after the initial dose, (iii) administering 100 mg of the antibody as a subcutaneous dose approximately 12 weeks after the initial dose, and (iv) administering 100 mg of the antibody as a subcutaneous dose approximately every 8 weeks thereafter, approximately 12 weeks after the initial dose. The antibody comprises the light chain variable region amino acid sequence of SEQ ID NO: 8 and the heavy chain variable region amino acid sequence of SEQ ID NO:

7. A pharmaceutical composition in which the patient is confirmed to be a responder to the antibody by meeting the clinical endpoint approximately 24 weeks after the initial dose, wherein the clinical endpoint is a change from baseline in the Modified Rodnan Skin Score (mRSS).

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