CN117337302A - Methods of treating psoriatic arthritis patients with inadequate response to TNF therapy with anti-IL 23 specific antibodies - Google Patents

Abstract

A method of treating psoriatic arthritis in a patient exhibiting an inadequate response to treatment with anti-TNF therapy by administering an IL-23 specific antibody, e.g., gu Saiku mab, in a clinically proven safe and clinically proven effective amount, and which patient achieves significant ACR20/50/70, IGA, HAQ-DI, CRP, SF-36PCS/MCS, MDA, VLDA, tendinitis, dactylitis and LEI/dactylitis improvement as measured at 16, 24 and 48 weeks after initial treatment.

Description

Methods of treating psoriatic arthritis patients with inadequate response to TNF therapy with anti-IL 23 specific antibodies

Electronically submitted reference sequence listing

The present application contains a sequence listing submitted electronically via EFS-Web as an ASCII formatted sequence listing, with a file name of "JBIT 6473 WOCCT 1SEQLIST. Txt", a creation date of 2022, 3, 4 and a size of 9KB. This sequence listing submitted via EFS-Web is part of this specification and is incorporated by reference herein in its entirety.

Technical Field

The present invention relates to methods of treating psoriatic arthritis using antibodies that bind to human IL-23 protein. In particular, the invention relates to methods of administering an anti-IL-23 specific antibody (e.g., antilincomab) that is safe and effective for patients with psoriatic arthritis.

Background

Interleukin (IL) -12 is a secreted heterodimeric cytokine consisting of 2 disulfide-linked glycosylated protein subunits, designated p35 and p40 according to their approximate molecular weights. IL-12 is produced primarily by antigen presenting cells and drives cell-mediated immunity by binding to double-stranded receptor complexes expressed on the surface of T cells or Natural Killer (NK) cells. The IL-12 receptor beta-1 (IL-12Rbeta 1) chain binds to the p40 subunit of IL-12, thereby providing the primary interaction between IL-12 and its receptor. However, it is the IL-12p35 linkage of the second receptor chain IL-12Rβ2 that confers intracellular signaling (e.g., STAT4 phosphorylation) and activation of receptor-bearing cells. IL-12 signaling concurrent with antigen presentation is thought to cause T-cell differentiation to the T helper 1 (Th 1) phenotype, characterized by the production of interferon gamma (IFNγ). Th1 cells are believed to promote immunity to some intracellular pathogens, produce complement fixing antibody isoforms, and aid in tumor immune monitoring. Thus, IL-12 is considered an important component of host defensive immune mechanisms.

It was found that the p40 protein subunit of IL-12 can also be associated with a separate protein subunit designated p19 to form the novel cytokine IL-23.IL-23 also signals through double-stranded receptor complexes. Since the p40 subunit is shared between IL-12 and IL-23, the IL-12Rβ1 chain is also shared between IL-12 and IL-23. However, IL-23p19 ligation of IL-23R, the second component of the IL-23 receptor complex, confers IL-23-specific intracellular signaling (e.g., STAT3 phosphorylation) and subsequent IL-17 production by T cells. Recent studies have demonstrated that the biological function of IL-23 differs from that of IL-12, despite the structural similarity between these two cytokines.

Dysregulation of IL-12 and Th1 cell populations has been associated with many immune-mediated diseases, because neutralization of IL-12 with antibodies is effective in treating animal models of psoriasis, multiple Sclerosis (MS), rheumatoid arthritis, inflammatory bowel disease, insulin-dependent (type 1) diabetes, and uveitis. However, since these studies target the common p40 subunit, both IL-12 and IL-23 are neutralized in vivo. Thus, it is not clear whether IL-12 or IL-23 mediates disease, or whether inhibition of both cytokines is required to achieve disease suppression. Studies have confirmed that IL-23 inhibition may provide an equivalent benefit to the anti-IL-12 p40 strategy by neutralization of specific antibodies to IL-23p19 deficient mice or IL-23. Thus, there is increasing evidence that IL-23 has a specific role in immune-mediated diseases. Thus, neutralizing IL-23 without inhibiting the IL-12 pathway may provide an effective therapy for immune-mediated diseases with limited impact on important host defense immune mechanisms. This would represent a significant improvement over current treatment options.

Psoriasis is a common chronic immune-mediated skin disease with significant complications such as psoriatic arthritis (PsA), depression, cardiovascular disease, hypertension, obesity, diabetes, metabolic syndrome and Crohn's disease. Plaque psoriasis is the most common form of the disease and appears as a well-defined erythema lesion with white silver scale on top. Plaque is itchy, painful, often devastating and disabling to the patient, and a substantial proportion of psoriatic patients have plaque on the hands, nails, face, feet, and genitals. Thus, psoriasis has significant negative effects on health-related quality of life (HRQoL), including imposing physical and psychological burden beyond the symptoms of physical skin and interfering with daily activities. For example, psoriasis has a negative impact on family, spouse, social and work relationships and is associated with a higher incidence of depression and an increased propensity for suicide.

Psoriatic arthritis (PsA) is a multi-system disease characterized by joint inflammation and psoriasis, with a variety of clinical and radiological manifestations including dactylitis, tendinitis, sacroiliac arthritis, and/or joint deformity. The functional impairment, reduced quality of life and increased utilization of healthcare resources associated with poorly controlled PSAs present a significant economic burden. Despite the availability of biological agents (e.g., tumor necrosis factor [ TNF ] alpha inhibitors, you-tec-mab, secukinumab) and other agents (e.g., apremilast), there is a significant unmet need for new PsA therapies that can provide high levels of efficacy and safety in the treatment of heterogeneous disease components.

Histological characterization of psoriasis lesions showed thickened epidermis resulting from abnormal keratinocyte proliferation and differentiation, dermal infiltration and co-localization of cd3+ T lymphocytes and dendritic cells. Although the etiology of psoriasis is not well defined, genetic and protein analysis has shown that IL-12, IL-23 and downstream molecules thereof are overexpressed in psoriasis lesions, and some may be associated with the severity of psoriasis disease. Some therapies for the treatment of psoriasis regulate the levels of IL-12 and IL-23, which presumably contribute to their efficacy. Th1 and Th17 cells can produce effector cytokines that induce the production of vasodilators, chemoattractants, and expression of adhesion molecules on endothelial cells, which in turn promote monocyte and neutrophil recruitment, T cell infiltration, neovascularization, and keratinocyte activation and proliferation. Activated keratinocytes can produce chemoattractant factors that promote neutrophil, monocyte, T cell and dendritic cell trafficking, thereby establishing a cycle of inflammation and keratinocyte hyperproliferation.

Elucidation of the pathogenesis of psoriasis has led to effective biotherapeutics targeting tumor necrosis factor-alpha (TNF-alpha), interleukin (IL) -12 and IL-23, and recently, individually targeting IL-17 as well as IL-23 (including archaebankizumab). Gusaikumab (also known as CNTO 1959, in order toSold) is a fully human IgG1 lambda monoclonal antibody that binds to the p19 subunit of IL-23 and inhibits intracellular and downstream signaling of IL-23, which is required for terminal differentiation of T helper cells (Th 17). The current use of gulcomab is approved in the united states, the european union, and other countries of the world for the treatment of moderate to severe plaque psoriasis and active psoriatic arthritis. In addition, the gulku mab is being evaluated for several other immune-mediated disorders, including generalized pustular psoriasis, erythrodermic psoriasis, palmoplantar pustulosis, hidradenitis suppurativa, crohn's disease, and ulcerative colitis.

Disclosure of Invention

The present invention relates to the treatment of psoriatic arthritis (PsA). In particular, the invention relates to a clinically proven safe and effective method of treating PsA by administering an anti-IL-23 specific antibody to a subject.

In one general aspect, the invention relates to a method of treating psoriatic arthritis (PsA) in a subject in need thereof who is non-responder, hyporesponsive (refractory) and/or intolerant to anti-tnfα therapy, such as an anti-tnfα antibody, comprising subcutaneously administering to the subject an effective amount of an anti-IL-23 antibody (also referred to as an IL-23p19 antibody), such as Gu Saiku mab, wherein the anti-IL-23 antibody is administered once every 4 weeks (q 4 w). Preferably, the subject achieves at least a 20% improvement in the american college of rheumatology core set disease index (ACR 20) after treatment without clinically significant adverse events.

In embodiments, the anti-tnfα therapy is selected from the group consisting of etanercept, adalimumab, golimumab or cetuximab therapy, infliximab, or biological analogs of these molecules.

In certain embodiments, an anti-IL-23 antibody comprises a heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH 1) amino acid sequence of SEQ ID NO. 1, CDRH2 of SEQ ID NO. 2, and CDRH3 of SEQ ID NO. 3; and the light chain variable region comprises the complementarity determining region light chain 1 (CDRL 1) amino acid sequence of SEQ ID NO. 4, CDRL2 of SEQ ID NO. 5 and CDRL3 of SEQ ID NO. 6.

In certain embodiments, an anti-IL-23 antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO. 7 and a light chain variable region of the amino acid sequence of SEQ ID NO. 8.

In certain embodiments, an anti-IL-23 antibody comprises the heavy chain amino acid sequence of SEQ ID NO. 9 and the light chain amino acid sequence of SEQ ID NO. 10.

In certain embodiments, the anti-IL-23 antibody is administered at a total dose of 25mg to 200mg, preferably about 50mg to about 150mg, more preferably about 100mg per administration.

In certain embodiments, the subject is a responder to treatment with an anti-IL-23 antibody and is identified as having a statistically significant improvement in disease activity, wherein disease activity is determined by one or more criteria selected from the group consisting of: 20% improvement in the american college core set disease index (ACR 20), 50% improvement in the american college core set disease index (ACR 50), 70% improvement in the american college core set disease index (ACR 70), health assessment questionnaire disability index (HAQ-DI), overall assessment by researchers (IGA), disease activity score 28 (DAS 28) C-reactive protein (CRP), resolution of tendinitis, resolution of dactylitis, litz tendinitis index (LEI), dactylitis assessment score, brief health investigation of psychological and physiological component summary (MCS and PCS) (SF-36), realization of Minimum Disease Activity (MDA), and realization of Very Low Disease Activity (VLDA).

In another general aspect, the invention relates to a method of treating psoriatic arthritis in a subject in need thereof, the method comprising subcutaneously administering an anti-IL-23 antibody to the subject, wherein the anti-IL-23 antibody is administered at an initial dose, a dose 4 weeks later, and a dosing interval once every 8 weeks later (q 8 w), and wherein the subject has at least one psoriatic plaque having a diameter of ≡2cm or a recorded history of nail changes or plaque psoriasis consistent with psoriasis. Preferably, the subject achieves at least a 20% improvement in the american college of rheumatology core set disease index (ACR 20) after treatment without clinically significant adverse events.

In certain embodiments, the subject has an inadequate response to standard therapy for PsA. Optionally, during treatment according to embodiments of the invention, standard therapy is also administered to the subject.

The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages will be apparent from the following detailed description and the appended claims.

Drawings

The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. It should be understood that the invention is not limited to the precise embodiments shown in the drawings.

Fig. 1A-1D show key secondary results of COSMOS by week 48. Primary analysis by week 24 and post hoc NRI analysis of HAQ-DI scores at week 48 (fig. 1A), ACR50 response (fig. 1B), SF-36PCS scores (fig. 1C), and PASI100 response (fig. 1D). After 24 weeks, analysis was performed using NRI, including the inclusion of EE patients into non-responders (see patient and method). Results for placebo → the antiku mab group at week 48 were reported for patients that did not enter EE and crossed Gu Saiku mab at week 24. ACR50, improvement of greater than or equal to 50% of American society of rheumatology response criteria; CI, confidence interval; GUS, gusaiku monoclonal antibody; HAQ-DI, health assessment questionnaire-disability index; LS, least squares; PASI100, 100% improvement in psoriasis area and severity index; PBO, placebo; Q8W, once every 8 weeks; SF-36PCS, physiological components of 36 concise health surveys are summarized.

Detailed Description

As used herein, methods of treating psoriatic arthritis include administering isolated, recombinant and/or synthetic anti-IL-23 specific human antibodies as well as diagnostic and therapeutic compositions, methods and devices.

As used herein, "anti-IL-23 specific antibody," "anti-IL-23 antibody," "antibody portion," or "antibody fragment" and/or "antibody variant" and the like include any protein or peptide comprising: the molecule comprises at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one Complementarity Determining Region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy or light chain variable region, a heavy or light chain constant region, a framework region, or any portion thereof, or at least a portion of an IL-23 receptor or binding protein that may be incorporated into an antibody of the invention. Such antibodies optionally further affect specific ligands, such as, but not limited to, such antibodies modulate, decrease, increase, antagonize, agonize, alleviate, mitigate, block, inhibit, eliminate, and/or interfere with at least one IL-23 activity or binding, or IL-23 receptor activity or binding, in vitro, in situ, and/or in vivo. As one non-limiting example, a suitable anti-IL-23 antibody, designated portion or variant of the invention may bind to at least one IL-23 molecule, or designated portion, variant or domain thereof. Suitable anti-IL-23 antibodies, designated portions or variants may also optionally affect at least one of IL-23 activity or function, such as, but not limited to, RNA, DNA or protein synthesis, IL-23 release, IL-23 receptor signaling, membrane IL-23 cleavage, IL-23 activity, IL-23 production and/or synthesis.

The term "antibody" is also intended to encompass antibodies, digested fragments, specific portions and variants thereof, including antibody mimics or antibody portions comprising the structure and/or function of a mimetic antibody or specific fragment or portion thereof, including single chain antibodies and fragments thereof. Functional fragments include antigen-binding fragments that bind to mammalian IL-23. For example, the invention encompasses antibody fragments capable of binding to IL-23 or a portion thereof, including but not limited to Fab fragments (e.g., obtained by papain digestion), fab 'fragments (e.g., obtained by pepsin digestion and partial reduction), and F (ab') ₂ Fragments (e.g., obtained by pepsin digestion), facb fragments (e.g., obtained by plasmin digestion), pFc fragments (e.g., obtained by pepsin or plasmin digestion), fd fragments (e.g., obtained by pepsin digestion, partial reduction, and reaggregation), fv, or scFv fragments (e.g., obtained by molecular biology techniques) (see, e.g., colligan, immunology, supra).

Such fragments may be produced by enzymatic cleavage, synthetic or recombinant techniques, as known in the art and/or as 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, the code F (ab') ₂ The combinatorial genes of the heavy chain portion are designed to include a C encoding a heavy chain _H 1 domain and/or hinge region. The individual portions of the antibodies may be chemically linked together by conventional techniques, or may be prepared as a continuous protein using genetic engineering techniques.

As used herein, the term "human antibody" refers to an antibody that: wherein substantially each part of the protein (e.g. CDR, framework, C _L 、C _H Domain (e.g. C _H 1、C _H 2、C _H 3) Hinge (V) _L 、V _H ) Is substantially non-immunogenic in humans, with only small sequence changes or alterations. A "human antibody" may also be an antibody derived from or closely matching human germline immunoglobulin sequences. Human antibodies may include amino acid residues not encoded by germline immunoglobulin sequences (e.g., mutations introduced in vitro by random mutagenesis or site-specific mutagenesis, or mutations introduced in vivo by somatic mutation). Typically, this means that human antibodies are substantially non-immune in humans. Human antibodies have been classified into groups based on their amino acid sequence similarity. Thus, using a sequence similarity search, antibodies with similar linear sequences can be selected as templates to produce human antibodies. Similarly, antibodies designating genus primate (monkey, baboon, chimpanzee, etc.), rodent (mouse, rat, rabbit, guinea pig, hamster, etc.), and other mammals represent specific antibodies of these species, subgenera, genus, subfamily, family. Furthermore, chimeric antibodies may include any combination of the above antibodies. Such changes or alterations optionally and preferably maintain or reduce immunogenicity in humans or other species relative to unmodified antibodies. Thus, human antibodies are different from chimeric or humanized antibodies.

It should be noted that human antibodies may 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 may comprise a linking peptide that is not present in the native human antibody. For example, fv may comprise a connecting peptide, such as two to about eight glycine or other amino acid residues, connecting the heavy and light chain variable regions. Such connecting peptides are considered to be of human origin.

Bispecific antibodies, xenogenous specific antibodies, xenogenous conjugated antibodies or similar antibodies, which are monoclonal antibodies, preferably human antibodies or humanized antibodies, having binding specificities for at least two different antigens, may also be used. In this case, one of the binding specificities is for at least one IL-23 protein and the other is for any other antigen. Methods for preparing bispecific antibodies are known in the art. Typically, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, nature 305:537 (1983)). Due to the random distribution of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a mixture of potentially 10 different antibody molecules, only one of which has the correct bispecific structure. Purification of the correct molecule (usually by affinity chromatography steps) is quite cumbersome and the yield of the product is low. Similar procedures are disclosed in, for example, the following documents: WO 93/08829, U.S. Pat. Nos. 6210668, 6193967, 6132992, 6106833, 6060285, 6037453, 6010902, 5989530, 5959084, 5959083, 5932448, 5833985, 5821333, 5807706, 5643759, 5601819, 5582996, 5496549, 4676980, WO 91/00360, WO 92/00373, EP 03089, traunecker et al, EMBO J.10:3655 (1991), suresh et al, methods in Enzymology121:210 (1986), each of which is incorporated herein by reference in its entirety.

anti-IL-23 specific antibodies (also referred to as IL-23 specific antibodies) (or anti-IL-23 antibodies) useful in the methods and compositions of the invention may optionally have the following characteristics: binds with high affinity to IL-23 and optionally and preferably has low toxicity. In particular, antibodies, specific fragments or variants of the invention (wherein the individual components, such as the variable, constant and framework regions, are individually and/or collectively optionally and preferably have low immunogenicity) may be used in the invention. Antibodies useful in the present invention are optionally characterized in that they can be used for long periods of time in the treatment of patients, measurably alleviating symptoms and have low and/or acceptable toxicity. Low or acceptable immunogenicity and/or high affinity, as well as other suitable properties, may help achieve therapeutic results. "Low immunogenicity" is defined herein as eliciting a significant HAHA, HACA or HAMA response in less than about 75%, or preferably less than about 50% of the treated patients, and/or eliciting a low titer (less than about 300, preferably less than about 100, as measured by a double antigen enzyme immunoassay) in the treated patients (Elliott et al, lancet 344:1125-1127 (1994), which is incorporated herein by reference in its entirety). "hypoimmunogenicity" may also be defined as the occurrence of titratable levels of antibody against IL-23 in patients treated with anti-IL-23 antibody during the treatment period occurring in less than 25% of patients treated with recommended doses of the recommended course of therapy, preferably in less than 10% of patients treated with recommended doses of the recommended course of therapy.

As used herein, the terms "clinically proven effective" and "clinically proven effective" in the context of a dose, dose regimen, treatment or method refer to the clinically proven effectiveness of a particular dose, dose or treatment regimen. Efficacy may be measured based on changes in the course of the disease in response to agents of the invention based on clinical trials performed (e.g., phase 3 clinical trials and earlier clinical trials). For example, an anti-IL-23 antibody of the invention (e.g., anti-IL-23 antibody, antilinku mab) is administered to a patient in an amount and for a time sufficient to induce an improvement, preferably a sustained improvement, in at least one indicator reflecting the severity of the disease being treated. Various indicators reflecting the degree of disease, disorder or condition in a subject can be evaluated to determine whether the amount and time of treatment is sufficient. Such indicators include, for example, clinically recognized indicators of disease severity, symptoms, or manifestations of the condition under consideration. The extent of improvement is typically determined by a physician, who can make this determination based on the sign, symptom, biopsy, or other test result, and can also make this determination using a questionnaire administered to the subject, such as a quality of life questionnaire developed for a given disease. For example, the anti-IL-23 antibodies of the invention may be administered to effect an improvement in a psoriatic arthritis-related condition in a patient. Improvement may be indicated by an improvement in the disease activity index, by an improvement in clinical symptoms, or by any other measure of disease activity.

In one embodiment, preliminary criteria for rheumatoid arthritis improvement of the American College of Rheumatology (ACR) may be used to determine the efficacy of psoriatic arthritis treatment in a subject. ACR criteria measures improvement in tenderness or swollen joint counts and improvement in three of the following five parameters: acute phase reactants (such as settling velocity); patient assessment; a physician evaluates; pain scale; disability/function questionnaires. ACR criteria are expressed as ACR 20 (20% improvement in tended or swollen joint count and 20% improvement in three of the other five criteria), ACR 50 (50% improvement in tended or swollen joint count and 50% improvement in three of the other five criteria), and ACR 70 (70% improvement in tended or swollen joint count and 70% improvement in three of the other five criteria) (see Felson D T et al, archritis Rheum 1995; 38:727-35).

In another embodiment, the efficacy of treatment of psoriatic arthritis in a subject is determined by a Psoriasis Area and Severity Index (PASI), which is a disease index used to assess the severity/extent of skin disease, e.g., pasi75=75% improvement, pasi90=90% improvement and pasi100=substantially clear plaque. Metrics of efficacy may also include one or more of health assessment questionnaire disability index (HAQ-DI), tendinitis/dactylitis improvement in patients with baseline tendinitis/dactylitis, changes in SF-36 psychological and physiological component summary (MCS and PCS) scores, and achievement of Minimum Disease Activity (MDA) standard scores.

The term "clinically proven safe" when it relates to a dose, dosage regimen, treatment, or method of treatment with an anti-IL-23 antibody of the invention (e.g., anti-IL-23 antibody antique-ku-mab) refers to a relatively low or reduced frequency, and/or low or reduced severity, of adverse events (known as AE or TEAE) occurring during treatment from a clinical trial performed (e.g., phase 2 clinical trial and earlier clinical trial) as compared to a standard of care or another comparator. An adverse event is an adverse medical event that occurs in a patient administered a drug. In particular, when referring to a dose, dosage regimen or treatment with an anti-IL-23 antibody of the invention, "clinically proven safe" refers to a relatively low or reduced frequency, and/or a low or reduced severity of adverse events associated with administration of the anti-IL-23 antibody if considered to be due, likely or very likely to be due to use of the antibody.

As used herein, unless otherwise indicated, the term "clinically validated" (used alone or in modifying the terms "safe" and/or "effective") may mean that a clinical trial has proven to be effective, wherein the clinical trial has met approval standards of the united states food and drug administration, EMEA, or corresponding national regulatory authorities. For example, a clinical study may be a full sample size, randomized, double blind study for clinically confirming the efficacy of a drug.

Practicality of use

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

Such methods may include administering to a cell, tissue, organ, animal or patient in need of such modulation, treatment, alleviation, 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. The effective amount may comprise an amount of about 0.001mg/kg to 500mg/kg per single administration (e.g., bolus), multiple administrations, or continuous administration, or achieve a serum concentration of 0.01 μg/ml to 5000 μg/ml per single administration, multiple administrations, or continuous administration, or any effective range or value thereof, using known methods as described herein or known in the relevant art.

Citation(s)

All publications or patents cited herein, whether or not specifically indicated, are incorporated herein by reference in their entirety as they show the state of the art upon which this invention pertains and/or provide a description and practice of the invention. Publication refers to any scientific publication or patent publication, or any other information that may be obtained in any media format, including all record formats, electronic formats, or print formats. The following references are incorporated by reference herein in their entirety: ausubel et al, editions, "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, "anti-bodies, a Laboratory Manual", cold Spring Harbor, NY (1989); colligan et al, "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).

Antibody-production and production useful in the present invention

The at least one anti-IL-23 antibody used in the methods of the invention may optionally be prepared by a cell line, a mixed cell line, immortalized cells, or clonal populations of immortalized cells, as is well known in the art. See, e.g., ausubel et al, editions, "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, "anti-bodies, a Laboratory Manual", cold Spring Harbor, NY (1989); colligan et al, "Current Protocols in Immunology", john Wiley & Sons, inc., NY (1994-2001); colligan et al, "Current Protocols in Protein Science", john Wiley & Sons, NY, NY (1997-2001), each of which is incorporated herein by reference in its entirety.

Human antibodies specific for human IL-23 protein or fragments thereof, such as isolated IL-23 protein and/or portions thereof (including synthetic molecules such as synthetic peptides), may be produced against suitable immunogenic antigens. Other specific or generic mammalian antibodies can be similarly produced. The preparation of the immunogenic antigen and the generation of monoclonal antibodies may be performed using any suitable technique.

In one mode, the hybridoma is produced by fusing a suitable immortal cell line (e.g., a myeloma cell line such as, but not limited to, 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 A, etc., or heteromyeloma, fusion products thereof, or any cell or fusion cell derived therefrom, or any other suitable cell line known in the art) (see, e.g., www.atcc.org, www.lifetech.com., etc.), such as, but not limited to, isolated or cloned spleen, peripheral blood, lymph, tonsil or other cells containing immune or B cells, or any other cell expressing a heavy or light chain constant or variable or framework or CDR sequence, as an endogenous or heterologous nucleic acid, such as recombinant or endogenous, viral, bacterial, algal, prokaryotic, amphibian, insect, reptile, fish, mammal, rodent, horse, sheep, goat, sheep, primate, eukaryotic, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single-stranded, double-stranded or triple-stranded, hybrid, or the like, or any combination thereof. See, e.g., ausubel, supra, and Colligan, immunology, supra, chapter 2, incorporated by reference in its entirety.

Antibody-producing cells may also be obtained from peripheral blood, or preferably spleen or lymph nodes, of a human or other suitable animal that has been immunized with the antigen of interest. Any other suitable host cell may also be used to express a heterologous or endogenous nucleic acid encoding an antibody, specific fragment or variant thereof of the invention. The 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 of the desired specificity may be selected by a suitable assay (e.g., ELISA).

Other suitable methods of producing or isolating antibodies with the requisite specificity may be used, including, but not limited to, methods of selecting recombinant antibodies from peptide or protein libraries (e.g., without limitation, phage, ribosomes, oligonucleotides, RNA, cDNA, etc. display libraries; for example, available from Cambridge antibody Technologies, cambridge shire, UK; morphoSys, martinsreid/Planegg, DE; biovation, aberdeen, scotland, UK, bioInvent, lund, sweden, dyax, enzon, affymax/Biosite, xoma, berkeley, CA, ixsys. See, e.g., EP368,684, PCT/GB91/01134, PCT/GB92/01755, PCT/GB92/002240, PCT/GB92/00883, PCT/GB93/00605, U.S. 08/350260 (5/12/94), PCT/GB94/01422, PCT/GB94/02662, PCT/GB97/01835, (CAT/MRC), WO90/14443, WO90/14424, WO90/14430, PCT/US94/1234, WO92/18619, WO96/07754, (Scrilpps), WO96/13583, WO97/08320 (MohoSys), WO95/16027 (Invent), WO 88/0690/WO 90/069, PCT/GB94/01422, PCT/GB94/02662, PCT/GB97/01835, (PCT/MRC), WO90/14424, WO90/14430, WO 94/1234, WO92/18619 (WO 92/MV32), WO 92/7492/3803, WO 92/FIG. 9 (WO 92/FIG. 9, WO 92/FIG. F.F.F, WO 92/F, WO 92/F.F.F, WO 92/F.F, WO 92/F.F.K.K.K.K, WO 92/F.K, WO 92/K, WO 97/XK 3, WO 35 (F, WO 3, WO 35, each incorporated herein by reference in its entirety)) or dependent on immunization of transgenic animals (e.g., SCID mice, nguyen et al, microbiol. Immunol.41:901-907 (1997); sandhu et al, crit.Rev.Biotechnol.16:95-118 (1996); eren et al, immunol.93:154-161 (1998), each of which is incorporated herein by reference in its entirety and related patents and applications), are capable of producing a complete set of human antibodies, as known in the art and/or as described herein. Such techniques include, but are not limited to, ribosome display (Hanes et al, proc. Natl. Acad. Sci. USA,94:4937-4942 (month 5 1997); hanes et al, proc. Natl. Acad. Sci. USA,95:14130-14135 (month 11 1998)); single Cell antibody production techniques (e.g., selected lymphocyte antibody methods ("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 droplets and flow cytometry (Powell et al, biotechnol.8:333-337 (1990), one Cell Systems, cambridge, MA; gray et al, J.Imm. Meth.182:155-163 (1995)), kenny et al, bio/Technol.13:787-790 (1995)), B Cell selection (Steenbaks et al, molecular biol. Reports 19:125-134 (1994)), progress et al, biotech, vol 5, "Borrek 35, amerson, 1988).

Methods for engineering or humanizing non-human or human antibodies may also be used, and are well known in the art. Generally, humanized or engineered antibodies have one or more amino acid residues from a non-human source such as, but not limited to, mice, rats, rabbits, non-human primates, or other mammals. They are typically taken from the "input" variable, constant, or other domains of a known human sequence. These non-human amino acid residues are substituted with residues commonly referred to as "import" residues, which are typically taken from "import" varying, constant or other domains of known human sequences.

Known human Ig sequences are disclosed, for example www.ncbi.nlm.nih.gov/entrez/query. Fcgi; www.ncbi.nih.gov/igblast; www.atcc.org/phase/hdb. www.mrc-cpe.cam.ac.uk/ALIGNMENTS.php; www.kabatdatabase.com/top. ftp.ncbi.nih.gov/repositisource/kabat; www.sciquest.com; www.abcam.com; www.antibodyresource.com/onlinecomp. www.public.iastate.edu/-pedro/research tools. www.whfreeman.com/immunology/CH05/kuby05. Htm; www.hhmi.org/grads/options/1996/vlab; www.path.cam.ac.uk/-mrc/mikeimages.html; mcb.harvard.edu/BioLink/immunology.html; www.immunologylink.com; pathbox.wust.edu/-hcenter/index.html; www.appliedbiosystems.com; www.nal.usda.gov/awic/pubs/anti; www.m.ehime-u.ac.jp/-yasuhito/elisa.html; www.biodesign.com; www.cancerresearchuk.org; www.biotech.ufl.edu; www.isac-net. Org; baserv.uci.kun.nl/-jraats/links 1. Html; www.recab.uni-hd.de/imuno.bme.nwu.edu; www.mrc-cpe.cam.ac.uk; www.ibt.unam.mx/vir/V_micro.html; http:// www.bioinf.org.uk/abs; anti. www.unizh.ch; www.cryst.bbk.ac.uk/-ubcg 07s; www.nimr.mrc.ac.uk/CC/ccaawg/ccaawg.html; www.path.cam.ac.uk/-mrc/humation/TAHHP.html; www.ibt.unam.mx/vir/structure/stat_aid. www.biosci.missouri.edu/smithgp/index. Html; www.jerini.de; kabat et al, "Sequences of Proteins of Immunological Interest", U.S. Dept. Health (1983), each of which is incorporated herein by reference in its entirety.

Such input sequences may be used to reduce immunogenicity or to reduce, enhance or modify binding, affinity, binding rate, dissociation rate, avidity, specificity, half-life, or any other suitable feature, as known in the art. Generally, CDR residues are directly and substantially mostly involved in influencing antigen binding. Thus, non-human CDR sequences or portions or all of human CDR sequences are retained, while non-human sequences of the variable and constant regions may be replaced with human amino acids or other amino acids.

Antibodies may also optionally be humanized or human antibodies designed to retain high affinity for antigen and other advantageous biological properties. To achieve this goal, humanized (or human) antibodies can also optionally be prepared by analysis of the parent sequence and various conceptual humanized products using three-dimensional models of the parent and humanized sequences. Three-dimensional immunoglobulin models are generally available and familiar to those skilled in the art. Computer programs are available that illustrate and display the possible three-dimensional conformational structures of selected candidate immunoglobulin sequences. These displayed assays allow for analysis of the likely role of the residues in the functional functioning of the candidate immunoglobulin sequence, i.e., analysis of residues that affect the ability of the candidate immunoglobulin to bind to its antigen. In this way, framework (FR) residues can be selected and combined from consensus and input sequences to enable desired antibody characteristics, such as increased affinity for the target antigen.

In addition, the human IL-23 specific antibodies used in the methods of the invention may include a human germline light chain framework. In particular embodiments, the sequence of the light chain germline sequence is selected from the group consisting of human VK including, but not limited to, A1, a10, a11, a14, a17, a18, a19, A2, a20, a23, a26, a27, A3, a30, A5, A7, B2, B3, L1, L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23, L24, L25, L4/18a, L5, L6, L8, L9, O1, O11, O12, O14, O18, O2, O4, and O8. In certain embodiments, the light chain human germline framework is selected from the group consisting of: 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.

In other embodiments, the human IL-23 specific antibodies used in the methods of the invention may include a human germline heavy chain framework. In particular 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.

In particular 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 2 or 3 sub-regions, such as FR2 and FR 3). 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 a human consensus sequence comprising a particular framework (readily available at the source of the known human Ig sequences described above). In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., human germline) or a human consensus sequence comprising a particular framework. In a preferred embodiment, the framework region is a fully human framework region.

Humanization or engineering of the antibodies of the invention may be performed using any known method, such as, but not limited to, those described below, winter (Jones et al, nature 321:522 (1986); riechmann et al, nature 332:323 (1988); verhoeyen et al, science 239:1534 (1988)); sims et al, J.Immunol.151:2296 (1993); chothia and Lesk, J.mol.biol.196:901 (1987); carter et al, proc.Natl.Acad.Sci.U.S. A.89:4285 (1992); presta et al, J.Immunol.151:2623 (1993); U.S. patent: 5723323, 5976862, 5824514, 5817483, 5814476, 5763192, 5723323, 5,766886, 5714352, 6204023, 6180370, 5693762, 5530101, 5585089, 5225539, 4815567; PCT/: US98/16280, US96/18978, US91/09630, US91/05939, US94/01234, GB89/01334, GB91/01134, GB92/01755; WO90/14443, WO90/14424, WO90/14430, EP229246 are each incorporated herein by reference in its entirety, including the references cited therein.

In certain embodiments, the antibody comprises an altered (e.g., mutated) Fc region. For example, in some embodiments, the Fc region has been altered to reduce or enhance the effector function of the antibody. In some embodiments, the Fc region is of a isotype selected from IgM, igA, igG, igE or other isotype. Alternatively or in addition, it may be useful to combine amino acid modifications with one or more other amino acid modifications that alter C1q binding and/or complement-dependent cytotoxicity functions of the Fc region of the IL-23 binding molecule. The specific starting polypeptide of interest may be a polypeptide that binds to C1q and exhibits Complement Dependent Cytotoxicity (CDC). Polypeptides having pre-existing C1q binding activity, optionally also having the ability to mediate CDC, may be modified such that one or both of these activities are enhanced. Amino acid modifications that alter C1q and/or modify its complement dependent cytotoxic function are described, for example, in WO0042072, hereby incorporated by reference.

As disclosed above, one can design the Fc region of the human IL-23 specific antibodies of the invention with altered effector function, e.g., by modifying C1q binding and/or fcγr binding, thereby altering Complement Dependent Cytotoxicity (CDC) activity and/or antibody dependent cell mediated cytotoxicity (ADCC) activity. The "effector function" is responsible for activating or reducing biological activity (e.g., in a subject). Examples of effector functions include, but are not limited to: c1q binding; CDC; fc receptor binding; ADCC; phagocytosis; down-regulation of cell surface receptors (e.g., B cell receptors; BCR), and the like. Such effector function may require the Fc region to be combined with a binding domain (e.g., an antibody variable domain), and may be assessed using a variety of assays (e.g., fc binding assays, ADCC assays, CDC assays, etc.).

For example, one can generate a variant Fc region of a human IL-23 (or anti-IL-23) antibody having improved C1q binding and improved fcyriii binding (e.g., having both improved ADCC activity and improved CDC activity). Alternatively, variant Fc regions with reduced CDC activity and/or reduced ADCC activity may be designed if reduced or eliminated effector function is desired. In other embodiments, only one of these activities may be increased, and optionally, other activities may also be decreased (e.g., to produce an Fc region variant with improved ADCC activity but reduced CDC activity (or vice versa)).

Fc mutations can also be introduced in the design to alter their interactions with neonatal Fc receptors (FcRn) and improve their pharmacokinetic properties. Collections of human Fc variants with improved binding to FcRn have been described (Shields et al, (2001), high resolution mapping of the binding site on human IgG for FcGamma RI, fcGamma RII, fcGamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R, J.biol. Chem. 276:6591-6604).

Another type of amino acid substitution is used to alter the glycosylation pattern of the Fc region of a human IL-23 specific antibody. Glycosylation of the Fc region is typically N-linked or O-linked. N-linked refers to the attachment of the 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 hydroxy amino acid, most commonly serine or threonine, but 5-hydroxyproline or 5-hydroxylysine may also be used. Recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain peptide sequence are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid other than proline. Thus, the presence of any of these peptide sequences in the polypeptide creates a potential glycosylation site.

Glycosylation patterns can be altered, for example, by deleting one or more glycosylation sites found in the polypeptide, and/or adding one or more glycosylation sites not present in the polypeptide. The addition of glycosylation sites to the Fc region of a human IL-23-specific antibody can conveniently be accomplished by altering the amino acid sequence to contain one or more of the tripeptide sequences described above (for N-linked glycosylation sites). An exemplary glycosylation variant has an amino acid substitution of heavy chain residue Asn 297. Alterations (for O-linked glycosylation sites) may also be made by adding or substituting one or more serine or threonine residues to the sequence of the original polypeptide. In addition, one glycosylation site can be removed to change Asn297 to Ala.

In certain embodiments, the human IL-23 specific antibodies of the invention are expressed in cells that express β (1, 4) -N-acetylglucosamine transferase III (GnT III), such that GnT III adds GlcNAc to the human IL-23 antibody. Methods of producing antibodies in this manner are provided in WO/9954342, WO/03011878, patent publication 20030003097A1 and Umana et al, nature Biotechnology,17:176-180, 1999, month 2; all of these documents are specifically incorporated by reference herein in their entirety.

anti-IL-23 antibodies can also optionally be produced by immunization of transgenic animals (e.g., mice, rats, hamsters, non-human primates, etc.) capable of producing a complete set of human antibodies, as described herein and/or as known in the art. Cells that produce human anti-IL-23 antibodies can be isolated and immortalized from such animals using suitable methods, such as those described herein.

A whole set of human antibodies that can be produced in conjunction with human antigen can be produced by known methods (e.g., 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; jakobovits et al, WO 98/50433; jakobovits et al, WO 98/24893; lonberg et al, WO 98/24884; lonberg et al, WO 97/13852; lonberg et al, WO 94/25585; kucherlinate et al, WO 96/34096; kucherlinate et al, EP 0463 151B1;Kucherlapate et al, EP 0710 719A1;Surani et al, and patents 5,545,807, bruggen et al, WO 90/04036; brugge 0438 474B1;Lonberg et al, EP 0814 259A2;Lonberg et al, GB 2A, lonberg et al, WO 98/249; lonberg et al, 1994; men et al, 1994-7, 1997-1997) and (1997-25, 1997-35; men's, 1997-25, 1996; men's, 1997-25, 1995-7) and (1997-7) by means of the methods of, such as described in U.S. Pat. No. 6, WO 97-25, 1995, WO 96/34096, WO 94, 1996, and 1996, and F.7, 1997, respectively. Generally, these mice comprise at least one transgene comprising DNA from at least one human immunoglobulin locus that has undergone a functional rearrangement or that may undergo a functional rearrangement. Endogenous immunoglobulin loci in such mice can be disrupted or deleted to eliminate the ability of the animal to produce antibodies encoded by the endogenous genes.

Screening for antibodies that specifically bind to similar proteins or fragments can be conveniently accomplished using peptide display libraries. This method involves screening a large collection of peptides for individual members having a desired function or structure. Antibody screening of peptide display libraries is well known in the art. The peptide sequences displayed may be 3 to 5000 or more amino acids in length, often 5 to 100 amino acids in length, and typically about 8 to 25 amino acids in length. In addition to the direct chemical synthesis methods used to generate peptide libraries, several recombinant DNA methods have been described. One type involves displaying peptide sequences on the surface of phage or cells. Each phage or cell contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in PCT patent publications 91/17271, 91/18980, 91/19818 and 93/08278.

Other systems for generating peptide libraries have aspects of both in vitro chemical synthesis methods and recombinant methods. See PCT patent publications 92/05258, 92/14843 and 96/19256. See also U.S. 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, calif.) and Cambridge antibody Technologies (Cambridge shire, UK). See, for example, U.S. patent nos. 4704692, 4939666, 4946778, 5260203, 5455030, 5518889, 5534621, 5656730, 5763733, 5767260, 5856456, assigned to Enzon;5223409, 5403484, 5571698, 5837500, assigned to Dyax,5427908, 5580717, assigned to Affymax;5885793, assigned to Cambridge antibody Technologies;5750373, assigned to Genentech,5618920, 5595898, 5576195, 5698435, 5693493, 5698417, assigned to Xoma, colligan, supra; ausubel, supra; or Sambrook, supra, each of the above patents and publications are incorporated by reference herein in their entirety.

The use of at least one anti-IL 23 antibody encoding nucleic acid to provide transgenic animals or mammals, such as goats, cows, horses, sheep, rabbits, etc., may also produce antibodies for use in the methods of the invention, which transgenic animals or mammals are capable of producing such antibodies in their milk. Such animals may be provided using known methods. See, for example, but not limited to, U.S. patent 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 by reference herein in its entirety.

Antibodies useful in the methods of the invention may also be prepared using at least one anti-IL 23 antibody encoding nucleic acid to provide transgenic plants and cultured plant cells (such as, but not limited to, tobacco and maize) that produce such antibodies, specific parts or variants thereof in plant parts thereof or cells cultured from plant parts. As a non-limiting example, transgenic tobacco leaves expressing recombinant proteins have been successfully used to provide large amounts of recombinant proteins, for example using inducible promoters. See, e.g., cramer et al, curr. Top. Microbol. Immunol.240:95-118 (1999), and references cited therein. Likewise, transgenic maize has also been used to express mammalian proteins on a commercial production scale, with biological activities equivalent to those produced in other recombinant systems or purified from natural sources. See, for example, hood et al, adv. Exp. Med. Biol.464:127-147 (1999), and references cited therein. Antibodies, including antibody fragments, such as single chain antibodies (scFv), can also be produced in large quantities from transgenic plant seeds, including tobacco seeds and potato tubers. See, for example, conrad et al Plant mol. Biol.38:101-109 (1998), and references cited therein. Thus, the antibodies of the invention can also be produced using transgenic plants according to known methods. See, for example, fischer et al, biotechnol. Appl. Biochem.30:99-108 (Oct., 1999); ma et al, trends Biotechnol.13:522-7 (1995); ma et al Plant Physiol.109:341-6 (1995); whitelam et al, biochem. Soc. Trans.22:940-944 (1994); and references cited therein. Each of the above references is incorporated by reference herein in its entirety.

Antibodies used in the methods of the invention can have a wide range of affinities (K _D ) Binds human IL-23. In a preferred embodiment, the human mAb optionally binds human IL-23 with high affinity. For example, the human mAb can be equal to or less than about 10 ^{- 7} M, such as but not limited to 0.1-9.9 (or any range or value therein) ×10 ^-7 、10 ^-8 、10 ^-9 、10 ^-10 、10 ^-11 、10 ^-12 、10 ^-13 Or K of any range or value therein _D Binds human IL-23.

The affinity or avidity of an antibody for an antigen can be determined experimentally using any suitable method. (see, e.g., berzofsky et al, "anti-body-Antigen Interactions", in Fundamental Immunology, paul, W.E. editions, raven Press: new York, N.Y. (1984); kuby, janis Immunology, W.H. Freeman and Company: new York, N.Y. (1992); and methods described herein). If measured under different conditions (e.g., salt concentration, pH), the affinity of the particular antibody-antigen interaction measured will be different. Thus, affinity and other antigen binding parameters (e.g., K _D 、K _a 、K _d ) Preferably with standard solutions of antibodies and antigens and standard buffers (e.g., buffers as described herein).

Nucleic acid molecules

Using the information provided herein, e.g., nucleotide sequences encoding at least 70% to 100% of the contiguous amino acids of at least one of the light or heavy chain variable or CDR regions described herein, as well as other sequences disclosed herein, designated fragments, variants, or consensus sequences thereof, or preservation vectors comprising at least one of these sequences, nucleic acid molecules of the invention encoding at least one anti-IL-23 antibody can be obtained using methods described herein or as known in the art.

The nucleic acid molecules of the 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 produced by cloning or synthesis, or any combination thereof. The DNA may be triplex, double stranded or single stranded or any combination thereof. Any portion of at least one strand of DNA or RNA may be the coding strand, also referred to as the sense strand, or it may be the non-coding strand, also referred to as the antisense strand.

The isolated nucleic acid molecules used in the methods of the invention may include the following: a nucleic acid molecule comprising an Open Reading Frame (ORF) optionally having one or more introns, for example, but not limited to, at least one designated portion of at least one CDR, such as CDR1, CDR2, and/or CDR3 of at least one heavy or light chain; nucleic acid molecules comprising a variable region for use in an anti-IL-23 antibody; and nucleic acid molecules comprising nucleotide sequences that are significantly different from those described above, but which, due to the degeneracy of the genetic code, still encode at least one anti-IL-23 antibody as described herein and/or as known in the art. Of course, the genetic code is well known in the art. Thus, it should be routinely possible for one of skill in the art to produce such degenerate nucleic acid variants that encode specific anti-IL-23 antibodies for use in the methods of the present invention. See, e.g., ausubel et al, supra, and such nucleic acid variants are included in the 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.

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

Polynucleotides that selectively hybridize to polynucleotides as described herein

The methods of the invention use isolated nucleic acids that hybridize under selective hybridization conditions to the polynucleotides disclosed herein. Thus, the polynucleotides of the present embodiments can be used to isolate, detect, and/or quantify nucleic acids comprising such polynucleotides. For example, polynucleotides of the invention may be used to identify, isolate or amplify partial or full length clones in a registered library. In some embodiments, the polynucleotide is an isolated genomic sequence or a cDNA sequence, or is complementary to a cDNA from a human or mammalian nucleic acid library.

Preferably, the cDNA library comprises at least 80% of the full length sequence, preferably at least 85% or 90% of the full length sequence, and more preferably at least 95% of the full length sequence. cDNA libraries can be normalized to increase the expression of rare sequences. Low or medium stringency hybridization conditions are generally, but not exclusively, used for sequences having reduced sequence identity relative to the complementary sequence. Medium and high stringency conditions can optionally be used for sequences of greater identity. Low stringency conditions allow for selective hybridization of sequences having about 70% sequence identity, and can be used to identify orthologous or paralogous sequences.

Optionally, the polynucleotide will encode at least a portion of an antibody. The polynucleotides comprise nucleic acid sequences that can be used for selective hybridization with polynucleotides encoding antibodies of the invention. See, for example, ausubel (supra); colligan (supra), each incorporated by reference herein in its entirety.

Construction of nucleic acids

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

The nucleic acid may conveniently comprise a sequence other than a polynucleotide of the invention. For example, multiple cloning sites comprising one or more endonuclease restriction sites may be inserted into the nucleic acid to aid in the isolation of the polynucleotide. In addition, translatable sequences may be inserted to aid in the isolation of translated polynucleotides of the invention. For example, the hexahistidine tag sequences provide a convenient means for purifying the proteins of the present invention. The nucleic acids of the invention (except for the coding sequences) are optionally vectors, adaptors or linkers for cloning and/or expressing the polynucleotides of the invention.

Additional sequences may be added to such cloning and/or expression sequences to optimize their function in cloning and/or expression to aid in isolation of the polynucleotide or to improve its introduction into a cell. The use of cloning vectors, expression vectors, adaptors and linkers is well known in the art. (see, e.g., ausubel, supra; or Sambrook, supra).

Recombinant methods for constructing nucleic acids

The isolated nucleic acid composition (such as RNA, cDNA, genomic DNA, or any combination thereof) can be obtained from a biological source using a variety of cloning methods known to those of skill in the art. In some embodiments, oligonucleotide probes that selectively hybridize under stringent conditions to polynucleotides of the invention are used to identify a desired sequence in a cDNA or genomic DNA library. Isolation of RNA, and construction of cDNA and genomic libraries are well known to those of ordinary skill in the art. (see, e.g., ausubel, supra; or Sambrook, supra).

Nucleic acid screening and separation methods

cDNA or genomic libraries can be screened using probes based on the sequences of polynucleotides used in the methods of the invention, such as those disclosed herein. Probes can be used to hybridize to genomic DNA or cDNA sequences to isolate homologous genes in the same or different organisms. Those skilled in the art will appreciate that hybridization of various degrees of stringency can be employed in the assay; and the hybridization or washing medium may be stringent. As the conditions for hybridization become more stringent, a higher degree of complementarity must exist between the probe and target to allow duplex formation to occur. The degree of stringency can be controlled by one or more of temperature, ionic strength, pH, and the presence of partially denaturing solvents (such as formamide). For example, the polarity of the reactant solution is varied by manipulating the concentration of formamide, for example, in the range of 0% to 50%, to thereby conveniently vary the stringency of hybridization. The degree of complementarity (sequence identity) required for detectable binding will vary depending upon the stringency of the hybridization medium and/or the wash medium. The degree of complementarity will optimally be 100% or 70% to 100% or any range or value therein. It will be appreciated, however, that minor sequence variations in the probes and primers can be compensated for by reducing the stringency of the hybridization and/or wash medium.

Methods of amplifying RNA or DNA are well known in the art and can be used according to the present invention without undue experimentation based on the teachings and guidance presented herein.

Known DNA or RNA amplification methods include, but are not limited to, polymerase Chain Reaction (PCR) and related amplification methods (see, e.g., U.S. Pat. nos. 4,683,195, 4,683,202, 4,800,159, 4,965,188 to Mullis et al, 4,795,699 and 4,921,794 to Tabor et al, 5,142,033 to inis, 5,122,464 to Wilson et al, 5,091,310 to inis, 5,066,584 to gillenten et al, 4,889,818 to gelfan et al, 4,994,370 to Silver et al, 4,766,067 to biswans, 4,656,134 to Ringold) and RNA-mediated amplification using antisense RNA of a target sequence as a template for double stranded DNA synthesis (U.S. Pat. No. 5,130,238 to Malek et al, trade name NASBA), the entire contents of which are incorporated herein by reference. ( See, e.g., ausubel, supra; or Sambrook, supra. )

For example, the sequences of polynucleotides and related genes used in the methods of the invention can be amplified directly from genomic DNA or cDNA libraries using Polymerase Chain Reaction (PCR) techniques. For example, PCR and other in vitro amplification methods can also be used to clone nucleic acid sequences encoding the proteins to be expressed, prepare nucleic acids for use as probes to detect the presence of a desired mRNA in a sample, for nucleic acid sequencing, or for other purposes. Examples of techniques sufficient to guide the skilled artisan throughout the in vitro amplification method can be found in Berger (supra), sambrook (supra), and Ausubel (supra), and us patent 4,683,202 (1987) to Mullis et al; and Innis et al PCR Protocols A Guide to Methods and Applications, eds., academic Press Inc., san Diego, calif. (1990). Commercially available kits for genomic PCR amplification are known in the art. See, e.g., advantage-GC Genomic PCR Kit (Clontech). In addition, for example, the T4 gene 32 protein (Boehringer Mannheim) can be used to increase the yield of long PCR products.

Synthetic methods for constructing nucleic acids

The isolated nucleic acids used in the methods of the invention may also be prepared by direct chemical synthesis by known methods (see, e.g., ausubel et al, supra). Chemical synthesis typically results in single stranded oligonucleotides that can be converted into double stranded DNA by hybridization to complementary sequences, or by polymerization with a DNA polymerase using the single strand as a template. Those skilled in the art will recognize that while chemical synthesis of DNA may be limited to sequences of about 100 bases or more, longer sequences may be obtained by ligating shorter sequences.

Recombinant expression cassette

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

In some embodiments, an isolated nucleic acid that is a promoter, enhancer, or other element may be introduced at a suitable location (upstream, downstream, or within an intron) of a polynucleotide of the invention in a non-heterologous form so as to up-regulate 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.

Vectors and host cells

The invention also relates to vectors comprising the isolated nucleic acid molecules, host cells genetically 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, for example, sambrook et al (supra); ausubel et al (supra), each incorporated by reference in its entirety.

The polynucleotide may optionally be linked to a vector comprising a selectable marker for propagation in a host. Generally, plasmid vectors are introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it may be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.

The DNA insert should be operably linked to an appropriate promoter. The expression construct will also contain a transcription start site, a termination site and a ribosome binding site for translation in the transcribed region. The coding portion of the mature transcript expressed by the construct will preferably include a translation initiation at the beginning of the mRNA to be translated and a stop codon (e.g., UAA, UGA or UAG) at the appropriate position at the end of the mRNA, with UAA and UAG being preferred for mammalian or eukaryotic cell expression.

The expression vector will preferably, but optionally, include at least one selectable marker. Such markers include, for example, but are not limited to: suitable culture media and conditions for the above-described host cells are known in the art, and suitable vectors will be apparent to the skilled artisan, the vector constructs being introduced into the host cells by calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transfection or the like, and the methods described in chapters 1-16, 16-16 and 16. The like are accomplished by the methods of calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transfection or the like, and the methods described in chapters 1-16, 16-16 and 16-16, such as chapter 1-16, and the like, for eukaryotic cell cultures, methotrexate (MTX), dihydrofolate reductase (DHFR), U.S. Pat. No. 4,399,216;4,634,665;4,656,134;4,956,288;5,149,636, 5,179, and 7, as well as for E.coli (E.coli) and other bacteria or prokaryotes.

At least one antibody used in the methods of the invention may be expressed in a modified form (such as a fusion protein) and may include not only secretion signals, but also additional heterologous functional regions. For example, regions of additional amino acids (particularly charged amino acids) may be added to the N-terminus of the antibody to improve stability and persistence in the host cell during purification or during subsequent handling and storage. Likewise, peptide moieties may be added to the antibodies of the invention to aid in purification. Such regions may be removed prior to final preparation of the antibody or at least one fragment thereof. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, chapters 17.29-17.42 and chapters 18.1-18.74; ausubel, supra, chapters 16, 17 and 18.

Those skilled in the art will recognize that many expression systems may be used to express nucleic acids encoding proteins for use in the methods of the invention. Alternatively, the nucleic acid may be expressed in a host cell by opening (by manipulation) in a host cell containing endogenous DNA encoding the antibody. Such methods are well known in the art, for example, as described in U.S. Pat. nos. 5,580,734, 5,641,670, 5,733,746, and 5,733,761, which are incorporated herein by reference in their entirety.

Exemplary cell cultures useful for producing antibodies, specific portions or variants thereof are mammalian cells. The mammalian cell system will typically be in the form of a monolayer of cells, but mammalian cell suspensions or bioreactors may also be used. Many suitable host cell lines capable of expressing intact glycosylated proteins have been developed in the art, including COS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-1651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., ATCC CRL 1610) and BSC-1 (e.g., ATCC CRL-26) cell lines, cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2/0-Ag14, 293 cells, heLa cells, etc., which are readily available from, for example, the American type culture Collection (Manassas, va (www.atcc.org)). Preferred host cells include cells of lymphoid origin, such as myeloma cells and lymphoma cells. Particularly preferred host cells are P3X63Ag8.653 cells (ATCC accession number CRL-1580) and SP2/0-Ag14 cells (ATCC accession number CRL-1851). In a particularly preferred embodiment, the recombinant cell is a P3X63Ab8.653 or SP2/0-Ag14 cell.

Expression vectors for these cells may include one or more of the following expression control sequences, such as but not limited to: an origin of replication; promoters (e.g., late or early SV40 promoter, CMV promoter (U.S. Pat. No. 5,168,062; U.S. Pat. No. 5,385,839), HSV tk promoter, pgk (phosphoglycerate kinase) promoter, EF-1. Alpha. Promoter (U.S. Pat. No. 5,266,491), at least one human immunoglobulin promoter, enhancers and/or processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites (e.g., SV40 large-T Ag poly A addition sites), and transcription terminator sequences see, e.g., ausubel et al (supra); sambrook et al (supra); other cells useful in producing nucleic acids or proteins of the invention are also known and/or may be obtained, e.g., from the American type culture Collection cell line and hybridoma catalog (www.atcc.org), or other known sources or commercial sources.

When eukaryotic host cells are used, polyadenylation or transcription termination sequences are typically incorporated into the vector. An example of a termination sequence is a polyadenylation sequence from the bovine growth hormone gene. Sequences for accurate splicing of transcripts may also be included. An example of a splicing sequence is the VP1 intron from SV40 (Sprague et al, J. Virol.45:773-781 (1983)). In addition, the gene sequences that control replication in the host cell may be incorporated into vectors, as known in the art.

Purification of antibodies

anti-IL-23 antibodies can be recovered and purified from recombinant cell cultures by well known methods including, but not limited to, protein a purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxyapatite chromatography, and lectin chromatography. High performance liquid chromatography ("HPLC") may also be used for purification. See, e.g., colligan, current Protocols in Immunology or Current Protocols in Protein Science, john Wiley & Sons, NY, (1997-2001), e.g., chapters 1, 4, 6, 8, 9, 10, each of which is incorporated by reference herein in its entirety.

Antibodies useful in the methods of the invention include naturally purified products, products of chemical synthetic procedures, and products produced by recombinant techniques from eukaryotic hosts including, for example, yeast, higher plant, insect, and mammalian cells. Depending on the host employed in the recombinant production method, the antibody may be glycosylated or may be non-glycosylated, with glycosylated being preferred. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, sections 17.37-17.42; ausubel, supra, chapter 10, chapter 12, chapter 13, chapter 16, chapter 18 and chapter 20; colligan, protein Science, supra, chapters 12-14, all of which are incorporated herein by reference in their entirety.

anti-IL-23 antibodies

anti-IL-23 antibodies (also referred to herein as "anti-IL-23 specific antibodies") useful in methods according to embodiments of the invention include any protein or peptide comprising: the part is divided intoThe sub-comprises at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one Ligand Binding Portion (LBP), such as, but not limited to, a Complementarity Determining Region (CDR) of a heavy or light chain 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 also at least one substitution, insertion or deletion), a heavy or light chain constant region (e.g., comprising at least one C _H 1. Hinge 1, hinge 2, hinge 3, hinge 4, C _H 2 or C _H 3 or fragments thereof, optionally further comprising at least one substitution, insertion or deletion), or they may be incorporated into any portion of the antibody. Antibodies may include or be derived from any mammal, such as, but not limited to, human, mouse, rabbit, rat, rodent, primate, or any combination thereof, and the like.

The isolated antibodies used in the methods of the invention comprise the antibody amino acid sequences disclosed herein encoded by any suitable polynucleotide, or any isolated or prepared antibody. Preferably, the human antibody or antigen-binding fragment binds human IL-23, thereby partially or substantially neutralizing at least one biological activity of the protein. Antibodies, or designated portions or variants thereof, that partially or preferably substantially neutralize at least one biological activity of at least one IL-23 protein or fragment may bind to the protein or fragment, thereby inhibiting activity mediated through binding of IL-23 to 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% to 120%, preferably at least about 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% or more, depending on the assay. The ability of 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 as described herein and/or as known in the art. The human antibody may be of any type (IgG, igA, igM, igE, igD, etc.) or isotype and may comprise a K or lambda light chain. In one embodiment, the human antibody comprises an IgG heavy chain or a defined fragment, e.g., at least one of isotypes IgG1, igG2, igG3, or IgG4 (e.g., γ1, γ2, γ3, γ4). Antibodies of this type may be prepared as described herein and/or as known in the art by using transgenic mice or other transgenic non-human mammals that contain at least one human light chain (e.g., igG, igA, and IgM) transgene. In another embodiment, the anti-IL-23 human antibody comprises an IgG1 heavy chain and an IgG1 light chain.

The antibodies bind to at least one designated epitope that is specific for at least one IL-23 protein, subunit, fragment, portion, or any combination thereof. The at least one epitope may comprise at least one antibody binding region comprising at least a portion of a protein, the epitope preferably being constituted by at least one extracellular, soluble, hydrophilic, external or cytoplasmic portion of the protein.

Generally, a human antibody or antigen binding fragment will comprise an antigen binding region comprising at least one human complementarity determining region (CDR 1, CDR2, and CDR 3) or a variant of at least one heavy chain variable region and at least one human complementarity determining region (CDR 1, CDR2, and CDR 3) or a variant of at least one light chain variable region. CDR sequences may be derived from human germline sequences or closely match these germline sequences. For example, CDRs from a synthetic library of original non-human CDRs may be used. These CDRs can be formed by incorporating conservative substitutions from the original non-human sequence. In another specific embodiment, an antibody or antigen binding portion or variant may have an antigen binding region comprising at least a portion of at least one light chain CDR (i.e., CDR1, CDR2, and/or CDR 3) having the amino acid sequence of the corresponding CDR1, CDR2, and/or CDR 3.

Such antibodies can be prepared by the following method: the various portions (e.g., CDRs, frameworks) of the antibody are chemically linked together using conventional techniques, using conventional techniques of recombinant DNA technology, or by using any other suitable method to prepare and express the nucleic acid molecule(s) encoding the antibody.

In one embodiment, an anti-IL-23 antibody useful in the invention comprises a heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH 1) amino acid sequence of SEQ ID NO. 1, CDRH2 of SEQ ID NO. 2, and CDRH3 of SEQ ID NO. 3; and the light chain variable region comprises the complementarity determining region light chain 1 (CDRL 1) amino acid sequence of SEQ ID NO. 4, CDRL2 of SEQ ID NO. 5 and CDRL3 of SEQ ID NO. 6.

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

A more preferred anti-IL-23 useful in the present invention is Costuzumab (also known as CNTO1959, toSales).

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

Antibody compositions comprising additional therapeutically active ingredients

The composition used in the method of the invention may optionally further comprise an effective amount of at least one compound or protein selected from at least one of the following: anti-infective agents, cardiovascular (CV) system agents, central Nervous System (CNS) agents, autonomic Nervous System (ANS) agents, respiratory tract agents, gastrointestinal (GI) tract agents, hormonal agents, agents for humoral or electrolyte balance, hematologic agents, antineoplastic agents, immunomodulating agents, ophthalmic, otic or nasal agents, topical agents, nutritional agents, statin agents, and the like. Such drugs are well known in the art and include the formulation, indication, administration and administration of each of the drugs given herein (see, e.g., "numbing 2001 Handbook of Drugs", 21 st edition, springrouse corp., springrouse, PA,2001; "Health Professional's Drug Guide 2001", ed., shannon, wilson, stang, pre-Hall, inc, upper Saddle River, NJ; "Pharmcotherapy Handbook", wells et al, editions, appleton & Lange, stamford, CT, each of which is incorporated herein by reference in its entirety).

As an example of a drug that can be combined with an antibody for use in the method of the present invention, the anti-infective drug may be at least one selected from the group consisting of: antimalarial or antiprotozoal agents, antihelminthic agents, antifungal agents, antimalarial agents, antitubercular agents or at least one antimalarial, aminoglycoside, penicillin, cephalosporin, tetracyclines, sulfonamide agents, fluoroquinolones, antivirals, macrolide antiinfectives and other antiinfectives. The hormonal agent may be at least one selected from the group consisting of: corticosteroids, androgens or at least one anabolic steroid, estrogen or at least one progesterone, gonadotrophin, antidiabetic agent or at least one glucagon, thyroid hormone antagonist, pituitary hormone and parathyroid hormone-like agent. The at least one cephalosporin may be at least one selected from the group consisting of: cefaclor, cefadroxil, cefazolin sodium, cefdinir, cefepime hydrochloride, cefixime, cefmetazole sodium, cefnesium sodium, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime sodium, ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cefprozil hydrochloride, cefalexin, cefprozil monohydrate, and chlorocarbon.

The at least one corticosteroid may be at least one selected from the group consisting of: betamethasone acetate or betamethasone sodium phosphate, betamethasone sodium phosphate cortisone acetate, dexamethasone acetate dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone acetate, hydrocortisone cyclopentanepropionate, hydrocortisone sodium phosphate hydrocortisone sodium succinate, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone acetate, prednisolone sodium phosphate, prednisolone tert-butyl ethyl ester, prednisone, triamcinolone acetonide and triamcinolone diacetate. The at least one androgen or anabolic steroid may be at least one selected from the group consisting of: danazol, fluoxytestosterone, methyltestosterone, nandrolone decanoate, nandrolone phenylpropionate, testosterone cyclopentanepropionate, testosterone heptanoate, testosterone propionate, and testosterone transdermal systems.

The at least one immunosuppressant may be at least one selected from the group consisting of: azathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immunoglobulins, moruzumab-CD 3, mycophenolate mofetil hydrochloride, sirolimus and tacrolimus.

The at least one topical anti-infective agent may be at least one selected from the group consisting of: acyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole, econazole nitrate, erythromycin, gentamicin sulfate, ketoconazole, sulfamilone 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 may be at least one selected from the group consisting of: crotamiton, lindane, plodin and pyrethrin. The at least one topical corticosteroid may be at least one selected from the group consisting of: betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desonide, desoxymethasone, dexamethasone sodium phosphate, diflorasone acetate, fluocinolone acetonide, fludrolide, fluticasone propionate, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate and triamcinolone acetonide. (see, e.g., nursing 2001 Drug Handbook, pages 1098-1136.)

The anti-IL-23 antibody composition may further comprise any suitable and effective amount of at least one of a composition or pharmaceutical composition comprising at least one anti-IL-23 antibody in contact with or administered to a cell, tissue, organ, animal or patient in need of modulation, treatment or therapy of such, the composition or pharmaceutical composition optionally further comprising at least one agent selected from the group consisting of: at least one TNF antagonist (such as, but not limited to, TNF chemical or protein antagonists, TNF monoclonal or polyclonal antibodies or fragments, soluble TNF receptors (such as p55, p70 or p 85) or fragments thereof, fusion polypeptides, or small molecule TNF antagonists (such as TNF binding protein I or II (TBP-1 or TBP-II)), nereimomab (nereimomab), infliximab, etanercept (etanercept), CDP-571, CDP-870, alfimomab (afelimab), lennaproxipp (lenercept), etc.), antirheumatic agents (such as methotrexate, auranofin, thioglucogold, azathioprine, etanercept), sodium thiomalate, hydroxychloroquine sulfate, leflunomide (leflunomide), sulfasalazine), immunoinhibitors, immunoglobulins (such as basiliximab, cyclosporin, daclizumab), cytokine antagonists or cytokine antagonists. Non-limiting examples of such cytokines include, but are not limited to, any of IL-1 through IL-23, and the like. (e.g., IL-1, IL-2, etc.). Suitable dosages are well known in the art. See, e.g., wells et al, edit, "Pharmacotherapy Handbook", 2 nd edition, appleton and Lange, stamford, CT (2000); "PDR Pharmacopoeia, tarascon Pocket Pharmacopoeia 2000", deluxe, eds., tarascon Publishing, loma Linda, calif. (2000), each of these references is incorporated herein by reference in its entirety.

The anti-IL-23 antibody compounds, compositions, or combinations used in the methods of the invention may further comprise at least one of any suitable adjuvants, such as, but not limited to, diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, and the like. Pharmaceutically acceptable adjuvants are preferred. Non-limiting examples and methods of preparing such sterile solutions are well known in the art, such as, but not limited to, gennaro editions, remington's Pharmaceutical Sciences, 18 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 can be selected in a conventional manner, as is well known in the art or as described herein.

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

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

The anti-IL-23 antibody composition may further comprise a buffer or pH adjuster; typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; tris (hydroxymethyl) aminomethane hydrochloride or phosphate buffers. Preferred buffers for use in the compositions of the present invention are organic acid salts, such as citrate.

In addition, the anti-IL-23 antibody composition may include polymeric excipients/additives such as polyvinylpyrrolidone, polysucrose (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 chelators (e.g., EDTA).

These and additional known pharmaceutical excipients and/or additives suitable for use in the anti-IL-23 antibodies, portions or variant compositions according to the invention are known in the art, for example, as listed in the following documents: "Remington: the Science & Practice of Pharmacy", 19 th edition, williams & Williams, (1995), and "Physician's Desk Reference", 52 th edition, medical Economics, montvale, NJ (1998), the disclosures of which are incorporated herein by Reference in their entirety. Preferred carrier or excipient materials are carbohydrates (e.g., sugar and alditols) and buffers (e.g., citrate) or polymeric reagents. An exemplary carrier molecule is mucopolysaccharide hyaluronic acid, which may be used for intra-articular delivery.

Formulations

As indicated above, the present invention provides stable formulations suitable for pharmaceutical or veterinary use, preferably comprising phosphate buffer with saline or selected salts, as well as preservative solutions and formulations comprising preservatives, and multi-purpose preservative formulations comprising at least one anti-IL-23 antibody in a pharmaceutically acceptable formulation. The preservative formulation comprises at least one known preservative or is optionally selected from the group consisting of: at least one of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl benzoates (methyl, ethyl, propyl, butyl, and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof, dissolved in an aqueous diluent. Any suitable concentration or mixture as known in the art may be used, for example 0.001% to 5% or any range or value therein, such as but not limited to: 0.001, 0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9 or any range or value therein. Non-limiting examples include: preservative-free, 0.1% to 2% m-cresol (e.g., 0.2%, 0.3%, 0.4%, 0.5%, 0.9%, 1.0%), 0.1% to 3% benzyl alcohol (e.g., 0.5%, 0.9%, 1.1%, 1.5%, 1.9%, 2.0%, 2.5%), 0.001% to 0.5% merthiolate (e.g., 0.005%, 0.01%), 0.001% to 2.0% phenol (e.g., 0.05%, 0.25%, 0.28%, 0.5%, 0.9%, 1.0%), 0.0005% to 1.0% alkyl p-hydroxybenzoate (e.g., 0.00075%, 0.0009%, 0.001%, 0.002%, 0.005%, 0.0075%, 0.009%, 0.01%, 0.02%, 0.05%, 0.075%, 0.09%, 0.1%, 0.2%, 0.3%, 0.5%, 0.75%, 0.9%, 1%, and the like.

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

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

The range of anti-IL-23 specific antibodies includes the amount produced upon reconstitution, if in a wet/dry system, from about 1.0 μg/ml to about 1000mg/ml, although lower and higher concentrations are also possible and depending on the intended delivery vehicle, for example, the solution formulation will be different from transdermal patches, pulmonary, transmucosal, or osmotic or micropump methods.

Preferably, the aqueous diluent further optionally comprises a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of: phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl p-hydroxybenzoates (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal or mixtures thereof. The concentration of preservative used in the formulation is that which is sufficient to produce an antimicrobial effect. This concentration depends on the preservative selected and is readily determined by the skilled artisan.

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

Other additives such as pharmaceutically acceptable solubilizers, such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate), tween 40 (polyoxyethylene (20) sorbitan monopalmitate), tween 80 (polyoxyethylene (20) sorbitan monooleate), pluronic F68 (polyoxyethylene polyoxypropylene block copolymer) and PEG (polyethylene glycol) or nonionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188,Polyols, other block copolymers, and chelates such as EDTA and EGTA may optionally be added to the formulation or composition to reduce aggregation. These additives are particularly useful if pumps or plastic containers are used to apply the formulation. The presence of a pharmaceutically acceptable surfactant reduces the tendency of the protein to aggregate.

The formulation may be prepared by a method comprising mixing at least one anti-IL-23 specific antibody and a preservative in an aqueous diluent, the preservative selected from the group consisting of: phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl p-hydroxybenzoates (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal or mixtures thereof. The at least one anti-IL-23 specific antibody and preservative are mixed in an aqueous diluent using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a measured amount of at least one anti-IL-23 specific antibody in a buffer is combined with a desired preservative in the buffer in an amount sufficient to provide the desired concentration of protein and preservative. Variations of this method will be recognized by those of ordinary skill in the art. For example, the order of addition of the ingredients, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that can be optimized for the concentration and mode of administration used.

These formulations may be provided to the patient as clear solutions or as dual vials comprising a vial of lyophilized anti-IL-23 specific antibody reconstituted with a second vial containing water, preservative and/or excipient, preferably phosphate buffer and/or saline and selected salts in an aqueous diluent. A single solution vial or dual vials requiring reconstitution may be reused multiple times and may meet a single or multiple cycles of patient treatment and thus may provide a more convenient treatment regimen than currently available.

The articles of the present invention may be used for applications ranging from immediate to twenty-four hours or more. Thus, the claimed article of the invention provides significant advantages to the patient. The formulations of the present invention may optionally be safely stored at a temperature of about 2 ℃ to about 40 ℃ and retain the biological activity of the protein for a long period of time, allowing the packaging label indicator solution to be maintained and/or used for a period of 6, 12, 18, 24, 36, 48, 72 or 96 hours or more. Such labels may include use periods of up to 1-12 months, half a year, and/or two years if a preservative diluent is used.

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

The claimed product may be provided to a patient as a clear solution or as dual vials comprising a vial of lyophilized at least one anti-IL-23 specific antibody reconstituted with a second vial containing an aqueous diluent. A single solution vial or dual vials requiring reconstitution may be reused multiple times and may meet a single or multiple cycles of patient treatment and thus provide a more convenient treatment regimen than currently available.

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

Recognized devices including single vial systems include pen injector devices for delivering solutions, such as BD Pens, BD And Genotronorm/>Humatro /> Roferon/> J-tip Needle-Free /> for example, devices including a dual vial system as recognized by Becton Dickensen (Franklin Lakes, N.J., www.bectondickenson.com), disetronic (Burgdorf, switzerland, www.disetronic.com; bioject, portland, oregon (www.bioject.com)), national Medical Products, weston Medical (Peterborough, UK, www.weston-medium.com), medi-select Corp (Minneapolis, MN, www.mediject.com), and the like include pen-type injector systems for reconstitution of lyophilized drug in a cartridge for delivery of the reconstituted solution, such as >Examples of other suitable devices include prefilled syringes, auto-syringes, needleless syringes, and needleless IV infusers.

These products may include packaging materials. The packaging material provides conditions under which the product may be used, in addition to information required by regulatory authorities. For a dual vial, wet/dry product, the packaging material of the present invention provides instructions to the patient: where applicable, at least one anti-IL-23 antibody is reconstituted in an aqueous diluent to form a solution, and the solution is used for a period of 2 hours to 24 hours or more. For single vials, solution products, pre-filled syringes or auto-syringes, the label indicates that such solutions can be used for 2 hours to 24 hours or more. The product can be used for human medicine products.

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

The methods of the present invention provide pharmaceutical compositions comprising various formulations useful and acceptable for administration to a human or animal patient. Such pharmaceutical compositions are prepared using "standard state" water as a diluent and conventional methods well known to those of ordinary skill in the art. For example, the buffer components (such as histidine and histidine monohydrochloride hydrate) may be provided first, followed by the addition of appropriate non-final volumes of water diluent, sucrose, and polysorbate 80 in the "standard state". The isolated antibody may then be added. Finally, the volume of the pharmaceutical composition is adjusted to the desired final volume under "standard state" conditions using water as diluent. Those skilled in the art will recognize many other methods suitable for preparing pharmaceutical compositions.

These pharmaceutical compositions may be aqueous solutions or suspensions, which in the "standard state" contain each component of a specified mass per unit volume of water or have a specified pH. As used herein, the term "standard state" refers to a temperature of 25 ℃ +/-2 ℃ and a pressure of 1 atmosphere. The term "standard state" is not used in the art to refer to a single art-recognized temperature or pressure, but rather is a reference state that is designated to describe a temperature and pressure of a solution or suspension having a particular composition under the reference "standard state" conditions. This is because the volume of the solution is partially a function of temperature and pressure. Those skilled in the art will recognize that pharmaceutical compositions comparable to those disclosed herein may be produced at other temperatures and pressures. It should be determined whether such pharmaceutical compositions are identical to those disclosed herein under the above-identified "standard state" conditions (e.g., 25 c +/-2 c and 1 atmosphere pressure).

Importantly, such pharmaceutical compositions can contain a component mass of "about" a certain value (e.g., "about 0.53mg L-histidine") or a pH value of about a certain value per unit volume of the pharmaceutical composition. An isolated antibody present in a pharmaceutical composition is "about" a given value if it is capable of binding a peptide chain at the same time as the isolated antibody is present in the pharmaceutical composition or after the isolated antibody is removed from the pharmaceutical composition (e.g., by dilution). In other words, when the binding activity of an isolated antibody is maintained and detectable after the isolated antibody is placed in a pharmaceutical composition, a value such as a component mass value or pH value is "about" the given value.

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

One aspect of the methods of the invention is to administer to a patient a pharmaceutical composition comprising:

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

The stable or preserved formulation may be provided to the patient in the form of a clear solution or in dual vials comprising a vial of lyophilized at least one anti-IL-23 antibody reconstituted with a second vial containing a preservative or buffer and excipients in an aqueous diluent. A single solution vial or dual vials requiring reconstitution may be reused multiple times and may meet a single or multiple cycles of patient treatment and thus provide a more convenient treatment regimen than currently available.

Other formulations or methods of stabilizing an anti-IL-23 antibody may produce solutions other than a clear solution of a lyophilized powder comprising the antibody. Formulations comprising suspensions of particles, which are anti-IL-23 antibody-containing compositions having variable size structures and each referred to as microspheres, microparticles, nanoparticles, nanospheres or liposomes, are included in non-clear solutions. Such relatively uniform, substantially spherical particulate formulations containing the active agent may be formed by contacting an aqueous phase containing the active agent and polymer with a non-aqueous phase and then evaporating the non-aqueous phase to cause the particles to coalesce from the aqueous phase, as taught in U.S. patent 4,589,330. Porous microparticles may be prepared using a first phase comprising the active agent and polymer dispersed in a continuous solvent and removing the solvent from suspension by freeze drying or dilution-extraction-precipitation, as taught in us patent 4,818,542. Preferred polymers for such preparation are natural or synthetic copolymers or polymers selected from the group consisting of: gelatin agar, starch, arabinogalactan, albumin, collagen, polyglycolic acid, polylactic acid, glycolide-L (-) lactide, poly (epsilon-caprolactone), poly (epsilon-caprolactone-CO-lactic acid), poly (epsilon-caprolactone-CO-glycolic acid), poly (beta-hydroxybutyric acid), polyethylene oxide, polyethylene, poly (alkyl 2-cyanoacrylate), poly (hydroxyethyl methacrylate), polyamides, poly (amino acids), poly (2-hydroxyethyl DL-asparagine), poly (ester urea), poly (L-phenylalanine/ethylene glycol/1, 6-diisocyanatohexane) and poly (methyl methacrylate). Particularly preferred polymers are polyesters such as polyglycolic acid, polylactic acid, glycolide-L (-) lactide, poly (epsilon-caprolactone), poly (epsilon-caprolactone-CO-lactic acid) and poly (epsilon-caprolactone-CO-glycolic acid). Solvents that may be used to dissolve the polymer and/or active include: water, hexafluoroisopropanol, dichloromethane, tetrahydrofuran, hexane, benzene or hexafluoroacetone sesquihydrate. The method of dispersing the active-containing phase with the second phase may include applying pressure to force the first phase through an orifice in the nozzle to effect droplet formation.

Dry powder formulations may be produced by methods other than lyophilization, such as solvent extraction by spray drying or by evaporation, or by precipitation of a crystalline composition, followed by one or more steps to remove aqueous or non-aqueous solvents. The preparation of spray-dried antibody preparations is taught in us patent 6,019,968. The antibody-based dry powder composition may be prepared by spray drying a solution or slurry of the antibody and optional excipients in a solvent under conditions that provide an inhalable dry powder. The solvent may include polar compounds such as water and ethanol, which may be easily dried. The stability of the antibody may be enhanced by performing the spray drying procedure in the absence of oxygen, such as under a nitrogen blanket or by using nitrogen as a drying gas. Another relatively dry formulation is a dispersion of a plurality of perforated microstructures dispersed in a suspending medium that typically contains a hydrofluoroalkane propellant, as taught in WO 9916419. The stabilized dispersion may be administered to the patient's lungs using a metered dose inhaler. The equipment that can be used in the commercial preparation of spray-dried medicaments is manufactured by Buchi ltd.

anti-IL-23 antibodies in a stable or preserved formulation or solution described herein may be administered to a patient according to the invention via a variety of delivery methods, including SC or IM injections; transdermal, pulmonary, transmucosal, implant, osmotic pump, cartridge, micropump, or other means known to those skilled in the art.

Therapeutic application

In one general aspect, the present application provides methods for modulating or treating psoriatic arthritis in a cell, tissue, organ, animal or patient as known in the art or as described herein using at least one IL-23 antibody of the invention, e.g., administering a therapeutically effective amount of an IL-23 specific antibody to the cell, tissue, organ, animal or patient, or contacting the cell, tissue, organ, animal or patient with the therapeutically effective amount of an IL-23 specific antibody.

Any of the methods of the invention can comprise administering an effective amount of a composition or pharmaceutical composition comprising an anti-IL-23 antibody to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy. Such methods may optionally further comprise co-administration or combination therapy for treating such diseases or disorders, wherein administering the at least one anti-IL-23 antibody, designated portion or variant thereof further comprises administering before, concurrently with, and/or after at least one agent selected from the group consisting of: at least one TNF antagonist (such as but not limited to a TNF chemical antagonist or protein antagonist, a TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (such as p55, p70 or p 85) or fragment thereof, a fusion polypeptide, or a small molecule TNF antagonist such as TNF binding protein I or II (TBP-1 or TBP-II), nemumomab, infliximab, etanercept (Enbrel) ^TM ) Adalimumab (Humira) ^TM ) CDP-571, CDP-870, african monoclonal antibody, lenacil, etc.), antirheumatic drugs (e.g., methotrexate, auranofin, thioglucogold, azathioprine, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxants, anesthetics (narcotic), non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, anesthetics (anestic), sedatives, local anesthetics, neuromuscular blocking agents, antimicrobial agents (e.g., aminoglycosides, antifungals, antiparasitics, antiviral, carbapenems, cephalosporins, fluoroquinolones, macrolides, penicillins, sulfanilotics, tetracyclines, other antimicrobial agents), antipsoriatic agents, corticosteroids, anabolic steroids, diabetes-related agents, minerals, nutraceuticals, thyroid agents, vitamins, calcium-related hormones, antidiarrheals, anti-diarrhea agents, antiulcer agents, light-weight agents, anticoagulants, erythropoietics (e.g., erythropoiesis), erythropoiesis (e.g., leujin-CSF), leujogin, fog-sand, g., G-sandImmune inoculants, immunoglobulins, immunosuppressants (e.g., basiliximab, cyclosporine, daclizumab), growth hormone, hormone replacement drugs, estrogen receptor modulators, mydriatic agents, ciliary muscle paralysis agents, alkylating agents, antimetabolites, mitotic inhibitors, radiopharmaceuticals, antidepressants, antimanic agents, antipsychotics, anxiolytics, hypnotics, sympathomimetics, stimulants, donepezil, tacrine, asthma drugs, beta agonists, inhaled steroids, leukotriene inhibitors, methylxanthines, cromolyn, epinephrine or the like, alfa-enzymes (Pulmozyme), cytokines or cytokine antagonists. Suitable dosages are well known in the art. See, e.g., wells et al, edit, "Pharmacotherapy Handbook", 2 nd edition, appleton and Lange, stamford, CT (2000); "PDR Pharmacopoeia, tarascon Pocket Pharmacopoeia 2000", luxury version, tarascon Publishing, loma Linda, CA (2000); "Nursing 2001Handbook of Drugs, 21 st edition", springrouse corp., springrouse, PA,2001; "Health Professional's Drug Guide 2001", shannon, wilson, stang et al, prentice-Hall, inc, upper Saddle River, NJ, each of which is incorporated herein by reference in its entirety.

Medical treatment

Typically, the treatment of psoriatic arthritis is accomplished by administering an effective amount or dose of an anti-IL-23 antibody composition, which, depending on the specific activity of the active agent contained in the composition, amounts to a range of at least about 0.01 mg to 500mg of anti-IL-23 antibody per kilogram of patient on average per dose, preferably at least about 0.1 mg to 100 mg of antibody per kilogram of patient per single or multiple administrations. Alternatively, the effective serum concentration may comprise a serum concentration of 0.1 to 5000 μg/ml per single or multiple administrations. Suitable dosages are known to the medical practitioner and will of course depend on the particular disease state, the specific activity of the composition to be administered, and the particular patient undergoing treatment. In some cases, in order to achieve a desired therapeutic amount, it may be necessary to provide repeated administrations, i.e., repeated individual administrations of a particular monitored or metered dose, wherein individual administrations may be repeated until a desired daily dose or effect is achieved.

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

Alternatively, the dosage administered may vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; age, health, and weight of the recipient; the nature and extent of the symptoms, the nature of the concurrent treatment, the frequency of treatment, and the desired effect. Typically the dosage of the active ingredient may be about 0.1 to 100mg/kg body weight. Typically, each administration or administration in a slow release form of from 0.1mg/kg to 50 mg/kg, preferably from 0.1mg/kg to 10 mg/kg, is effective to achieve the desired result.

As one non-limiting example, the treatment of the human or animal may be on at least one of days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or alternatively or in addition, on at least one of weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52, or alternatively or in addition, at least one of years 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or any combination thereof, is provided as one or regular administration of at least one antibody of the invention of 0.1mg/kg to 100mg/kg, such as 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90, or 100mg/kg, using a single, infusion, or repeated administration.

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

For parenteral administration, the antibodies may be formulated as solutions, suspensions, emulsions, granules, powders or lyophilized powders, which are provided in association with or separately from a pharmaceutically acceptable parenteral medium. Examples of such media are water, saline, ringer's solution, dextrose solution, and 1% to 10% human serum albumin. Liposomes and non-aqueous media such as fixed oils can also be used. The medium or lyophilized powder may contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives). The formulation may be sterilized by known or suitable techniques.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, a.osol's latest version (standard reference text in this field).

Alternative application

Many modes of known and developed are useful for administering pharmaceutically effective amounts of anti-IL-23 antibodies according to the present invention. Although pulmonary administration is used in the following description, other modes of administration may be used in accordance with the present invention with appropriate results. The IL-23 specific antibodies of the 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 other means described herein or known in the art.

Parenteral formulations and administration

Formulations for parenteral administration may contain sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like as conventional excipients. Aqueous or oily suspensions for injection may be prepared according to known methods by using suitable emulsifying or wetting agents and suspending agents. The injectable medicament may be a nontoxic, non-orally administrable diluent such as an aqueous solution in a solvent, a sterile injectable solution or a suspension. As a usable medium or solvent, water, ringer's solution, isotonic saline, or the like is allowed to be used; as the common solvent or suspension solvent, sterile fixed oils may be employed. For these purposes, any type of non-volatile oils and fatty acids may be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids; natural or synthetic or semisynthetic mono-or diglycerides or triglycerides. Parenteral administration is known in the art and includes, but is not limited to, injection in conventional form, pneumatic needle-free injection devices as described in U.S. patent 5,851,198, and laser perforator devices as described in U.S. patent 5,839,446, which are incorporated herein by reference in their entirety.

Alternative delivery

The invention also relates to the administration of an anti-IL-23 antibody by: parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intrabronchial, intra-abdominal, intracapsular, intracartilaginous, intracavity, cerebellar, intracerebroventricular, intracolonic, endocervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intracardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus injection, vaginal, rectal, buccal, sublingual, intranasal, or transdermal modes. anti-IL-23 antibody compositions may be prepared for parenteral (subcutaneous, intramuscular or intravenous) or any other administration, particularly in the form of liquid solutions or suspensions; for vaginal or rectal administration, particularly semi-solid forms such as, but not limited to, creams and suppositories; for oral or sublingual administration, such as but not limited to tablet or capsule form; or intranasally, such as but not limited to in the form of a powder, nasal drops or aerosol or some pharmaceutical agent; or transdermal, such as but not limited to, gels, ointments, emulsions, suspensions, or patch delivery systems containing chemical enhancers such as dimethyl sulfoxide to alter the skin structure or increase the drug concentration in transdermal patches (Junginger et al, "Drug Permeation Enhancement", hsieh, d.s. editors, pages 59-90, (Marcel Dekker, inc. New York 1994, incorporated herein by reference in its entirety), or oxidizing agents that enable the application of protein and peptide-containing formulations to the skin (WO 98/53847), or the application of electric fields to create transient transport pathways such as electroporation, or to increase the mobility of charged drugs through the skin such as iontophoresis, or the application of ultrasound such as transdermally absorbed ultrasound (us patents 4,309,989 and 4,767,402) (the publications and patents described above are incorporated herein by reference in their entirety).

Having generally described the invention, the same will be more readily understood by reference to the following examples, which are given by way of illustration only and are not intended to be limiting. Further details of the invention are illustrated by the following non-limiting examples. The disclosures of all references in the specification are expressly incorporated herein by reference.

Description of the embodiments

Embodiment 1 is a method of treating psoriatic arthritis (PsA) in a subject in need thereof, wherein the subject exhibits inadequate therapeutic response to treatment with an anti-TNF therapy, such as an anti-tnfα antibody, or other therapy, the method comprising subcutaneously administering to the subject a pharmaceutical composition comprising a safe and effective amount of an anti-IL-23 antibody and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is administered once every 4 four weeks (4 w).

Embodiment 1a is the method of embodiment 1, wherein the anti-IL-23 antibody comprises a heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH 1) amino acid sequence of SEQ ID No. 1, CDRH2 of SEQ ID No. 2, and CDRH3 of SEQ ID No. 3; and the light chain variable region comprises the complementarity determining region light chain 1 (CDRL 1) amino acid sequence of SEQ ID NO. 4, CDRL2 of SEQ ID NO. 5 and CDRL3 of SEQ ID NO. 6.

Embodiment 1b is the method according to embodiment 1, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO. 7 and a light chain variable region of the amino acid sequence of SEQ ID NO. 8.

Embodiment 2 is the method of any one of embodiments 1 to 1c, wherein the antibody is administered at a total dose of 25mg to 200mg per administration, such as 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, and 200mg per administration, or any dose therebetween.

Embodiment 2a is the method of embodiment 2, wherein the total dose is about 50mg to about 150mg per administration.

Embodiment 2b is the method of embodiment 2, wherein the total dose is about 100mg per administration.

Embodiment 3 is the method according to any one of embodiments 1 to 2b, wherein the subject has an inadequate response to standard therapy for PsA.

Embodiment 3a is the method of embodiment 3, wherein the standard therapy is at least one selected from the group consisting of: abiotic disease modifying antirheumatic drugs (DMARDs), oral corticosteroids, apremilast, non-steroidal anti-inflammatory drugs (NSAIDs).

Embodiment 3b is the method according to embodiment 3, wherein the standard therapy is a DMARD selected from the group consisting of: methotrexate (MTX) at 25 mg/week or less, sulfasalazine (SSZ) at 3 g/day or less, hydroxychloroquine (HCQ) at 400 mg/day or Leflunomide (LEF) at 20 mg/day or less is administered to the subject.

Embodiment 3c is the method according to embodiment 3, wherein the standard therapy is an oral corticosteroid administered to the subject in an amount equivalent to ∈10 mg/day prednisone.

Embodiment 3d is the method according to embodiment 3, wherein the standard therapy is an NSAID or other analgesic administered to the subject in a commercial dose approved by a regulatory agency.

Embodiment 3e is the method according to embodiment 3, wherein the standard therapy is apremilast administered to the subject at a commercially available dose approved by a regulatory agency.

Embodiment 3f is the method according to any one of embodiments 3 to 3e, wherein the subject is untreated with a biologic.

Embodiment 3g is the method of any one of embodiments 3 to 3e, wherein the subject has previously received at least one biological treatment for PsA.

Embodiment 3h is the method of embodiment 3g, wherein the subject has an inadequate response to the at least one biological treatment.

Embodiment 3i is the method of embodiment 3g or 3h, wherein the biologic therapy is selected from the group consisting of: the therapeutic agents may be selected from the group consisting of coumarone, you-tec-mab, secukinumab (AIN 457), anti-tumor necrosis factor alpha (tnfa) agents such as adalimumab, etanercept, infliximab, subcutaneous [ SC ] or intravenous [ IV ] golimumab, cetuzumab or their respective biological analogs, tiramer-mab (MK 3222), iszumumab (LY 2439821), budaruzumab (AMG 827), risperiduzumab (BI-655066), or other research biotherapy for PsA or psoriasis.

Embodiment 3j is the method according to embodiment 3i, wherein the subject is a non-responder to anti-tumor necrosis factor alpha (tnfa) treatment.

Embodiment 3k is the method according to any one of embodiments 1 to 3j, wherein the subject has plaque psoriasis of at least 3% Body Surface Area (BSA) prior to the treatment.

Embodiment 3l is the method according to any one of embodiments 1 to 3j, wherein the subject has at least one psoriatic plaque ≡2cm in diameter or a nail change conforming to psoriasis or a medical history of plaque psoriasis records prior to the treatment.

Embodiment 3m is the method according to any one of embodiments 1 to 3l, optionally further comprising administering to the subject a standard therapy for PsA.

Embodiment 3n is the method according to any one of embodiments 1 to 3l, optionally further comprising administering to the subject a biologic therapy for PsA.

Embodiment 4 is the method according to any one of embodiments 1 to 3n, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, wherein disease activity is determined by one or more criteria selected from the group consisting of: 20% improvement in the american college core set disease index (ACR 20), 50% improvement in the american college core set disease index (ACR 50), 70% improvement in the american college core set disease index (ACR 70), health assessment questionnaire disability index (HAQ-DI), overall assessment by researchers (IGA), disease activity score 28 (DAS 28) C-reactive protein (CRP), resolution of tendinitis, resolution of dactylitis, litz tendinitis index (LEI), dactylitis assessment score, brief health investigation of psychological and physiological component summary (MCS and PCS) (SF-36), realization of Minimum Disease Activity (MDA), and realization of Very Low Disease Activity (VLDA).

Embodiment 4a is the method of embodiment 4, wherein the improvement is measured 16, 20, 24, 28, or 48 weeks after the initial treatment.

Embodiment 4b is the method of any one of embodiments 4 to 4a, wherein the improvement is measured 16 weeks after initial treatment.

Embodiment 4c is the method of any one of embodiments 4 to 4a, wherein the improvement is measured 24 weeks or 48 weeks after initial treatment.

Embodiment 5 is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by a 20% improvement in the american college of rheumatology core set disease index (ACR 20) at week 24 or week 48 of treatment with the antibody.

Embodiment 5a is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by a 20% improvement in the american college of rheumatology core set disease index (ACR 20) at week 16 of treatment with the antibody.

Embodiment 5b is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by a 50% improvement in the american college of rheumatology core set disease index (ACR 50) at week 24 or week 48 of treatment with the antibody.

Embodiment 5c is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by a 50% improvement in the american college of rheumatology core set disease index (ACR 50) at week 16 of treatment with the antibody.

Embodiment 5d is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by a 70% improvement in the american college of rheumatology core set disease index (ACR 70) at week 24 or week 48 of treatment with the antibody.

Embodiment 5e is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by health assessment of questionnaire disability index (HAQ-DI) at week 24 or week 48 of treatment with the antibody.

Embodiment 5f is the method according to any one of embodiments 4 to 4C, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by disease activity score 28 (DAS 28) C-reactive protein (CRP) at week 24 or week 48 of treatment with the antibody.

Embodiment 5g is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as achieving an overall assessment (IGA) reduction of 0 (clearance) or 1 (min) and/or ≡2 IGA from baseline by the researcher at week 24 of treatment with the antibody, wherein the subject has a BSA score of > = 3% psoriasis involvement and > = 2 at baseline.

Embodiment 5h is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by regression of Shi Jijian end-inflammatory at week 24 or week 48 of treatment with the antibody.

Embodiment 5i is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by resolution of dactylitis at week 24 or week 48 of treatment with the antibody.

Embodiment 5j is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by the tendinitis index (LEI) at week 24 or week 48 of treatment with the antibody Shi Lici.

Embodiment 5k is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by an dactylitis assessment score of 0-3 (0 = absent, 1 = mild, 2 = moderate, 3 = severe) at week 24 or week 48 of treatment with the antibody.

Embodiment 5l is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by a Shi Jianming (SF-36) health survey at week 24 or week 48 of treatment with the antibody.

Embodiment 5m is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by the mental and physiological component summary (MCS and PCS) scores at week 24 or week 48 of treatment with the antibody.

Embodiment 5n is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by Minimum Disease Activity (MDA) criteria at week 24 or week 48 of treatment with the antibody.

Embodiment 5o is the method according to any one of embodiments 4 to 4c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by the realization of Very Low Disease Activity (VLDA).

Embodiment 6 is the method of any one of embodiments 4 to 5o, wherein the improvement is maintained for at least 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, 72 weeks, or 84 weeks, or any time therebetween.

Embodiment 7 is the method of any one of embodiments 1 to 6, wherein the anti-IL-23 antibody is archaebankab.

Embodiment 8 is the method of any one of embodiments 1 to 7, further comprising administering to the subject one or more additional drugs for treating psoriatic arthritis.

Embodiment 8a is the method of embodiment 8, wherein the additional drug is selected from the group consisting of: immunosuppressants, non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface marker antibodies, anti-CD 20 antibodies, rituximab, TNF inhibitors, corticosteroids, and co-stimulatory modulators.

Embodiment 9 is a method of treating psoriatic arthritis (PsA) in a subject, the method comprising subcutaneously administering to the subject a pharmaceutical composition comprising a safe and effective amount of an anti-IL-23 antibody and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is administered at an initial dose, a dose 4 weeks later, and a dosing interval once every 8 weeks later (q 8 w), and wherein the subject has at least one psoriatic plaque of diameter ≡2cm or a recorded history of nail changes or plaque psoriasis consistent with psoriasis prior to the treatment.

Embodiment 9a is the method of embodiment 9, wherein the anti-IL-23 antibody comprises a heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH 1) amino acid sequence of SEQ ID No. 1, CDRH2 of SEQ ID No. 2, and CDRH3 of SEQ ID No. 3; and the light chain variable region comprises the complementarity determining region light chain 1 (CDRL 1) amino acid sequence of SEQ ID NO. 4, CDRL2 of SEQ ID NO. 5 and CDRL3 of SEQ ID NO. 6.

Embodiment 9b is the method of embodiment 9, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO. 7 and a light chain variable region of the amino acid sequence of SEQ ID NO. 8.

Embodiment 9c is the method of embodiment 9, wherein the anti-IL-23 antibody comprises the heavy chain amino acid sequence of SEQ ID NO. 9 and the light chain amino acid sequence of SEQ ID NO. 10.

Embodiment 10 is the method of any one of embodiments 9 to 9c, wherein the antibody is administered at a total dose of 25mg to 200mg per administration, such as 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, and 200mg per administration, or any dose therebetween.

Embodiment 10a is the method of embodiment 10, wherein the total dose is about 50mg to about 150mg per administration.

Embodiment 10b is the method of embodiment 10, wherein the total dose is about 100mg per administration.

Embodiment 11 is the method according to any one of embodiments 9 to 10b, wherein the subject has an inadequate response to standard therapy for PsA.

Embodiment 11a is the method of embodiment 11, wherein the standard therapy is at least one selected from the group consisting of: abiotic disease modifying antirheumatic drugs (DMARDs), oral corticosteroids, apremilast, non-steroidal anti-inflammatory drugs (NSAIDs).

Embodiment 11b is the method of embodiment 11, wherein the standard therapy is a DMARD selected from the group consisting of: methotrexate (MTX) at 25 mg/week or less, sulfasalazine (SSZ) at 3 g/day or less, hydroxychloroquine (HCQ) at 400 mg/day or Leflunomide (LEF) at 20 mg/day or less is administered to the subject.

Embodiment 11c is the method of embodiment 11, wherein the standard therapy is an oral corticosteroid administered to the subject in an amount equivalent to ∈10 mg/day prednisone.

Embodiment 11d is the method of embodiment 11, wherein the standard therapy is an NSAID or other analgesic administered to the subject in a commercially available dose approved by a regulatory agency.

Embodiment 11e is the method of embodiment 11, wherein the standard therapy is apremilast administered to the subject at a commercially available dose approved by a regulatory agency.

Embodiment 11f is the method according to any one of embodiments 11 to 11e, wherein the subject is untreated with a biologic.

Embodiment 11g is the method of any one of embodiments 11 to 11e, wherein the subject has previously received at least one biological treatment for PsA.

Embodiment 11h is the method of embodiment 11g, wherein the subject has an inadequate response to the at least one biological treatment.

Embodiment 11i is the method of embodiment 11g or 11h, wherein the biologic therapy is selected from the group consisting of: the therapeutic agents may be selected from the group consisting of coumarone, you-tec-mab, secukinumab (AIN 457), anti-tumor necrosis factor alpha (tnfa) agents such as adalimumab, etanercept, infliximab, subcutaneous [ SC ] or intravenous [ IV ] golimumab, cetuzumab or their respective biological analogs, tiramer-mab (MK 3222), iszumumab (LY 2439821), budaruzumab (AMG 827), risperiduzumab (BI-655066), or other research biotherapy for PsA or psoriasis.

Embodiment 11j is the method according to embodiment 11i, wherein the subject is a non-responder to anti-tumor necrosis factor alpha (tnfa) treatment.

Embodiment 11k is the method according to any one of embodiments 9 to 11j, wherein the subject has plaque psoriasis of at least 3% Body Surface Area (BSA) prior to the treatment.

Embodiment 11l is the method according to any one of embodiments 9 to 11j, wherein the subject has at least one psoriatic plaque ≡2cm in diameter or a nail change conforming to psoriasis or a medical history of plaque psoriasis records prior to the treatment.

Embodiment 11m is the method according to any one of embodiments 9 to 11l, optionally further comprising administering to the subject a standard therapy for PsA.

Embodiment 11n is the method according to any one of embodiments 9 to 11l, optionally further comprising administering to the subject a biologic therapy for PsA.

Embodiment 12 is the method according to any one of embodiments 9 to 11n, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, wherein disease activity is determined by one or more criteria selected from the group consisting of: 20% improvement in the american college core set disease index (ACR 20), 50% improvement in the american college core set disease index (ACR 50), 70% improvement in the american college core set disease index (ACR 70), health assessment questionnaire disability index (HAQ-DI), overall assessment by researchers (IGA), disease activity score 28 (DAS 28) C-reactive protein (CRP), resolution of tendinitis, resolution of dactylitis, litz tendinitis index (LEI), dactylitis assessment score, brief health investigation of psychological and physiological component summary (MCS and PCS) (SF-36), realization of Minimum Disease Activity (MDA), and realization of Very Low Disease Activity (VLDA).

Embodiment 12a is the method of embodiment 12, wherein the improvement is measured 16, 20, 24, or 28 weeks after the initial treatment.

Embodiment 12b is the method of any one of embodiments 12 to 12a, wherein the improvement is measured 16 weeks after initial treatment.

Embodiment 12c is the method of any one of embodiments 12 to 12a, wherein the improvement is measured 24 weeks after initial treatment.

Embodiment 13 is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by a 20% improvement in the american college of rheumatology core set disease index (ACR 20) at week 24 or week 48 of treatment with the antibody.

Embodiment 13a is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by a 20% improvement in the american college of rheumatology core set disease index (ACR 20) at week 16 of treatment with the antibody.

Embodiment 13b is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by american college of rheumatology 130% improvement criteria (ACR 130) at week 24 or week 48 of treatment with the antibody.

Embodiment 13c is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by the american college of rheumatology 130% improvement standard (ACR 130) at week 16 of treatment with the antibody.

Embodiment 13d is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by a 70% improvement in the american college of rheumatology core set disease index (ACR 70) at week 24 or week 48 of treatment with the antibody.

Embodiment 13e is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by health assessment of questionnaire disability index (HAQ-DI) at week 24 or week 48 of treatment with the antibody.

Embodiment 13f is the method according to any one of embodiments 12 to 12C, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by disease activity score 28 (DAS 28) C-reactive protein (CRP) at week 24 or week 48 of treatment with the antibody.

Embodiment 13g is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as achieving a 0 (clearance) or 1 (minimal) and/or ≡2 reduction in overall assessment (IGA) of the researcher relative to baseline at week 24 of treatment with the antibody, wherein the subject has a BSA score of > = 3% psoriasis involvement and > = 2 at baseline.

Embodiment 13h is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by regression of Shi Jijian end-inflammatory at week 24 or week 48 of treatment with the antibody.

Embodiment 13i is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by resolution of dactylitis at week 24 or week 48 of treatment with the antibody.

Embodiment 13j is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by the tendinitis index (LEI) at week 24 or week 48 Shi Lici of treatment with the antibody.

Embodiment 13k is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity as determined by an dactylitis assessment score of 0-3 (0 = absent, 1 = mild, 2 = moderate, 3 = severe) at week 24 of treatment with the antibody.

Embodiment 13l is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by a Shi Jianming (SF-36) health survey at week 24 or week 48 of treatment with the antibody.

Embodiment 13m is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by the mental and physiological component summary (MCS and PCS) scores at week 24 or week 48 of treatment with the antibody.

Embodiment 13n is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by Minimum Disease Activity (MDA) criteria at week 24 or week 48 of treatment with the antibody.

Embodiment 13o is the method according to any one of embodiments 12 to 12c, wherein the subject is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity, as determined by the realization of Very Low Disease Activity (VLDA).

Embodiment 14 is the method of any one of embodiments 12 to 13o, wherein the improvement is maintained for at least 12 weeks, 24 weeks, 36 weeks, 48 weeks, 60 weeks, 72 weeks, or 84 weeks, or any time therebetween.

Embodiment 15 is the method of any one of embodiments 9 to 14, wherein the anti-IL-23 antibody is archaebankab.

Embodiment 16 is the method of any one of embodiments 9 to 15, further comprising administering to the subject one or more additional drugs for treating psoriatic arthritis.

Embodiment 16a is the method of embodiment 16, wherein the additional drug is selected from the group consisting of: immunosuppressants, non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface marker antibodies, anti-CD 20 antibodies, rituximab, TNF inhibitors, corticosteroids, and co-stimulatory modulators.

Examples

List of terms abbreviations and definitions

ACR American college of rheumatology

AE adverse events

ALT alanine aminotransferase

AST aspartate aminotransferase

BSA body surface area

BMI body mass index

Classification criterion for CASPAR psoriatic arthritis

CMH Cochran-Mantel-Haenszel

CRF case report forms

CRP C reactive protein

CSR clinical study report

Disease activity of DAPSA psoriatic arthritis

DAS28 CRP disease Activity score 28-Joint count with C-reactive protein

Quality of life index for DLQI skin disease

Antirheumatic drugs for DMARDs to ameliorate disease

DRC data review Committee

eC-SSRS electronic Columbia suicide severity rating scale

eDC electronic data capture

Functional assessment of FACIT chronic therapies

Good clinical practice of GCP

HAQ-DI health assessment questionnaire disability index

HCQ hydroxychloroquine

HIV human immunodeficiency virus

ICF informed consent

IEC independent ethics committee

Overall evaluation of IGA researchers

IL-23 interleukin 23

IV intravenous (intravenous ground)

IWRS interactive network response system

JAK Janus kinase

LEF leflunomide

Lei litz tendinitis index

LS least squares (average)

MCS psychological component summary

MDA minimal disease activity

Meddra supervision active medical dictionary

MI multiple interpolation

MMRM repeated measurement hybrid model

MTX methotrexate

NSAID nonsteroidal anti-inflammatory drug

PsARC psoriasis arthritis response criteria

PASDAS psoriatic arthritis disease activity score

PASI psoriasis area and severity index

PCS physiological component summary

PFS-U with UltraSafe PLUS ^TM Prefilled syringe with passive needle protection sleeve

PRO patient reported results

PsA psoriatic arthritis

q8w every 8 weeks

SAE serious adverse events

SC subcutaneous (subcutaneous ground)

SF-36 concise health survey

SPARCC Canadian spinal arthritis research Association

SSZ sulfasalazine

Tuberculosis of TB

Adverse events triggered by TEAE treatment

Failure of TF treatment

TNF alpha tumor necrosis factor alpha

VAS vision analog scale

Very low disease activity of VLDA

WBC white blood cells

Example 1: evaluation of involvement in the treatment of active psoriatic arthritis and inadequate response to anti-tumor necrosis factor Efficacy and safety of subcutaneously administered coumarone in patients phase 3b, multicenter, randomized, double-blind, placebo-controlled study (COSMOS)

Target object：

The main objective of this study was to evaluate the efficacy of Gu Saiku mab relative to placebo in participants with active PsA and inadequate response to anti-tnfα therapy by assessing the reduction of signs and symptoms of joint disease. The primary endpoint was the proportion of participants who achieved the American College of Rheumatology (ACR) 20 response at week 24.

A secondary objective was to evaluate the efficacy of the archaebankab relative to placebo in improving body function, improving general and disease-specific health-related quality of life and patient reported health outcomes, and improving psoriasis skin lesions. The safety and tolerability of the archaebankab among the participants who received at least one dose of intervention was also a key secondary objective of the study.

Method：

This was a phase 3 randomized, double-blind, placebo-controlled, multicenter, 2-arm study to evaluate Gu Saiku mab in participants with insufficient or intolerant response to 1 or 2 anti-tnfa treatments with active PsA. The study included a placebo-controlled period from week 0 to week 24, a positive treatment period from week 24 to week 48 (the last study intervention at week 44), and a 12-week safety follow-up period from week 44 to week 56. At the time of the report, the study is ongoing; however, the placebo-controlled period from week 0 to week 24 has been completed and reported.

Number of participants (planning and analysis)：

The planned total sample amount to achieve 90% of the ability to detect statistically significant treatment differences at the primary endpoint was about 245 participants (163 in the archaebankab group, 82 in the placebo group). At week 0, a total of 285 participants received study intervention at random; 96 subjects received placebo at random, and 189 subjects received Gu Saiku mab at a ratio of 2:1, randomized with the displacement block, which was stratified at the study level with baseline non-biological DMARD usage (yes/no) and prior exposure to 1 or 2 anti-tnfα drugs.

Group I: gu Saiku mab SC 100mg was administered at weeks 0 and 4 followed by placebo SC every 8 weeks (weeks 12, 20, 28, 36) to 44 and placebo SC at 24 to maintain blindness.

Group II: placebo SC were administered at weeks 0, 4, 12 and 20, crossing 100mg of Gu Saiku mab SC administered at weeks 24, 28, 36 and 44.

The duration of treatment planned in the study was 44 weeks, the double blind treatment period was 24 weeks, and the active treatment period was 20 weeks.

Diagnostic and primary inclusion criteria：

Qualified participants must have ≡3 tender joints and ≡3 swollen joints and have an inadequate or intolerance to anti-tnfα therapy, defined as the presence of active PsA (as assessed by the investigator) despite prior treatment with 1 or 2 anti-tnfα agents. Stable doses of selected non-biological DMARDs (MTX, SSZ, HCQ, LEF), oral corticosteroids (up to 10mg/d prednisone or equivalent) and NSAIDs/analgesics are allowed but not required.

Test product, dose and mode of administration：

All study interventions (archaebankizumab and placebo) were administered by SC injection. Participants in the placebo group received placebo at weeks 0 and 4, then every 8 weeks to 20, and 100mg of SC antikumamab at week 24, week 28, then every 8 weeks to 44. Participants in the group of coumarone received 100mg coumarone regimen at weeks 0 and 4 and then every 8 weeks.

Early disengagement：

At week 16, participants with <5% improvement over baseline in both tenderness and swollen joint numbers were eligible for early decubitus (EE). At any time after early disengagement, the participant may begin or increase the dose of one of the concomitant medications allowed up to the maximum allowable dose as specified in the regimen. Participants in the group of coumarone who met early disqualification received placebo at week 16 and Gu Saiku mab at week 20, followed by Gu Saiku mab every 8 weeks, with no change in the number and frequency of planned coumarone doses. Participants in the placebo group eligible for early disqualification will receive Gu Saiku mab at weeks 16 and 20 and then Gu Saiku mab every 8 weeks.

Duration of treatment：

The duration of treatment planned in the study was 44 weeks, the double blind treatment period was 24 weeks, and the active treatment period was 20 weeks. The study will remain blind to the initial treatment assignment until the final database is locked. Efficacy and safety of the coumarone mab up to week 24 is described in detail in this clinical study report.

Evaluation criterion：

The assessment of arthritis includes joint assessment (swelling and tendering joint counts), pain assessment of participants, overall assessment of disease activity (arthritis) by the patient, and overall assessment of disease activity by the physician on the Visual Analog Scale (VAS). Toe and tendinosis were also evaluated. Key efficacy measures for PsA response at week 24 included ACR response and HAQ-DI scores.

Given the diversity and highly individual nature of the domains involved in PsA (e.g., skin/nail disease, peripheral arthritis, dactylitis/tendinitis, axitic disease), a comprehensive index has been developed to more comprehensively assess disease activity and potentially identify agents with robust efficacy in all manifestations. The activity index includes a psoriatic arthritis disease activity score (PASDAS), a grepa composite score (GRACE), a Complex Psoriatic Disease Activity Index (CPDAI), a psoriatic arthritis response criterion (PsARC), and a psoriatic arthritis disease activity index (DAPSA). Disease states may be used to describe overall disease states such as DAPSA remission, minimal Disease Activity (MDA), or Very Low Disease Activity (VLDA).

Psoriasis response was assessed based on the overall assessment of psoriasis by the Investigator (IGA), the quality of life index of the skin Disease (DLQI), and the area and severity index of Psoriasis (PASI). The results reported by other patients were the SF-36 questionnaire and functional assessment of chronic disease therapy (facility) -fatigue, as well as the overall assessment of joint, skin and pain burden by the participants.

Safety assessments include Adverse Events (AE), serious Adverse Events (SAE), injection sites and allergic reactions, clinical laboratory parameters (hematology and chemistry; urine pregnancy test), electronic Columbia suicide severity rating scale (eC-SSRS), physical examination, vital signs, electrocardiogram (ECG; week 0 only), and early detection of Tuberculosis (TB).

Inclusion criteria

Participants must meet the following key inclusion criteria to be recruited into the study:

men or women at least 18 years old (or legal age in the jurisdiction in which the study is conducted).

PsA was diagnosed for at least 6 months prior to the first administration of study intervention and met the classification criteria for psoriatic arthritis (casar) at screening.

Have active PsA, defined by ≡3 tumescent joints and ≡3 tender joints at screening and baseline.

At least 1 PsA subgroup: distal interphalangeal joint involvement, polyarthritis without rheumatoid nodules, destructive arthritis, asymmetric peripheral arthritis or spondylitis with peripheral arthritis.

Has active plaque psoriasis, has at least one psoriasis plaque with a diameter of ≡2cm or a recorded history of nail changes or plaque psoriasis consistent with psoriasis.

Insufficient response to anti-tnfα therapy, defined as the presence of active PsA despite previous treatment with 1 or 2 anti-tnfα agents and any of the following:

lack of benefit of anti-tnfα therapy after at least 12 weeks of etanercept, adalimumab, golimumab or cetuximab therapy (or biosimilar) and/or at least 14 weeks of dose regimen of infliximab (or biosimilar).

Etanercept, adalimumab, golimumab, cetuximab, or infliximab (or biological analog) intolerance to anti-tnfα therapy.

If currently non-biological DMARDs (limited to MTX, SSZ, HCQ or LEFs) are used, the participants should receive treatment at least 3 months prior to the first administration of the study intervention; the dose must be stable for at least 4 weeks prior to the first administration study intervention and the abiotic DMARD should not produce serious toxic side effects. If MTX, SSZ or HCQ is not currently used, it is not acceptable for at least 4 weeks prior to the first administration study intervention. If no LEF is currently used, it is not accepted at least 12 weeks prior to the first administration of study intervention.

If MTX is used, the route of administration and the dose must be stable and the dose must be 25 mg/week or less; if SSZ is accepted, the dosage must be 3 g/day or less; if HCQ is accepted, the dosage must be less than or equal to 400 mg/day; if LEF is received, the dose must be 20 mg/day or less.

If the PsA is currently treated with NSAIDs or other analgesics, the participants must continue a steady dose for at least 2 weeks prior to the first administration of the study intervention. If no NSAID or other analgesic is currently used to treat PsA, then NSAID or other analgesic treatment cannot be received within 2 weeks prior to the first administration study intervention.

If the PsA is currently treated with an oral corticosteroid, the participants must last a steady dose equivalent of +.10 mg/day of prednisone at least 2 weeks before the first administration of the study intervention. If no oral corticosteroid is currently used, the participants must not receive an oral corticosteroid for at least 2 weeks prior to the first administration of the study intervention.

Exclusion criteria

Participants meeting any of the following key exclusion criteria were excluded from participation in the study:

other inflammatory diseases with which the evaluation of the efficacy of the archaebacteria therapy may be confounded, including but not limited to RA, axial spinal arthritis (which does not include primary diagnosis of PsA with spondylitis), systemic lupus erythematosus or lyme disease.

More than 2 different anti-tnfa agents have been accepted.

Receive an anti-tnfa agent in the following time frame prior to the first study intervention administration:

infliximab (or biological analogue), golimumab IV-within 8 weeks

Golimumab SC, adalimumab (or biosimilar), cetuximab-within 6 weeks

Etanercept (or biosimilar) -within 4 weeks

Previously treated with antikumab.

Any biological treatment (except for anti-tnfa agents) has previously been received.

Tofacitinib, barytinib, regoratinib, pefacitinib (ASP 015K), dectinib (VX-509), or any other JAK inhibitor has previously been accepted.

Any systemic immunosuppressant was previously received within 4 weeks of the first study intervention.

Receive abiotic DMARDs (except MTX, SSZ, HCQ, LEF) within 4 weeks prior to the first administration of study intervention.

Accept 2 or more (designated) abiotic DMARDs at baseline.

Apremilast was received 4 weeks prior to the first study intervention.

Phototherapy or any systemic drug/treatment that may affect psoriasis assessment was received within 4 weeks after the first study administration.

Topical drugs/treatments that may affect psoriasis assessment have been used within 2 weeks after the first administration of study dry matter.

Epidural, intra-articular, intramuscular or IV corticosteroids were received 4 weeks prior to the first administration study intervention.

Lithium was accepted within 4 weeks of the first administration of any study intervention.

Experimental antibodies or biological therapies (in addition to the anti-tnfa agents described in the inclusion criteria) or any other experimental therapies were received 90 days or 5 half-lives (whichever was longer) before the first administration of study intervention, or were currently recruited to another study using study agents or protocols.

Have a history or current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurological, hematologic, rheumatic (other than PsA), psychotic, genitourinary or metabolic disorders.

Have unstable suicidal thoughts or suicidal behavior during the last 6 months and are confirmed by researchers to be at risk based on evaluation by mental health professionals.

Research intervention information

In the assembly with UltraSafe PLUS ^TM In a disposable prefilled syringe with passive needle protection sleeve (PFS-U), the archakuzumab was supplied for this study as a sterile liquid for SC injection; the product contains no preservative. Each disposable PFS-U contained 100mg of Gusaiku mab in 1mL of solution. In PFS-U, placebo is supplied as sterile liquid for SC injection. Each disposable PFS-U contains 1mL of solution. The sources of the archaebankab and placebo are stored under refrigerated conditions of 2 ℃ to 8 ℃ and protected from exposure to light.

Randomization and blind method

Randomization of

Center randomization was performed in this study. On week 0, based on a computer-generated randomization protocol, participants were randomized at a 2:1 ratio to receive both the coumarone and placebo, respectively. Randomization was balanced based on a displacement block randomization method and stratified by baseline abiotic DMARD use (yes or no) and by prior exposure to anti-tnfa agents (yes or no). An interactive network response system (IWRS) assigns a unique intervention code that specifies an intervention assignment and matching research intervention for that participant.

Blind

The participants were assigned a random number at baseline visit, which was used to instruct the venue to assign a pharmaceutical kit to each participant. The randomized code is maintained within an interactive network response system (IWRS). No randomization code was provided to the investigator. To maintain the study blind, study intervention containers have multipart labels that contain the appropriate regulatory requirements of the clinical supply, while not identifying the study intervention contained therein.

Blindness of treatment distribution can only be broken when a particular urgent treatment is affected by the participant's knowledge of treatment distribution.

Sponsor personnel blinded patient level data for data analysis and clinical study reporting at week 24 database lock were recorded prior to the database lock. All venue personnel and participants remain blind to the treatment distribution until the final database is locked.

Dosage and administration

All study interventions (archaebankizumab and placebo) were administered by Subcutaneous (SC) injection. Based on the evaluation of this dosing regimen in the phase 2 study of PsA (CNTO 1959PsA 2001) and the phase 3 study of psoriasis, a 100mg dose regimen of vasokumab at weeks 0 and 4 and then every 8 weeks (q 8 w) was selected for this study.

In the study of CNTO1959PSA2001, robust efficacy and clinically significant improvements were observed using this dosing regimen in all important areas of PsA, including joint signs and symptoms, body function, psoriasis, tendinitis, dactylitis and quality of life for psoriatic patients with active PsA and > 3% BSA. In addition, in phase 3 psoriasis studies, significant benefits of this dose regimen were also observed for plaque psoriasis in moderate to severe psoriasis patients. In the phase 3 PsA study, an additional dosing regimen (every 4 weeks; q4 w) was included. However, this dosage regimen is not expected to result in significantly higher levels of efficacy than achieved by q8w administration during maintenance.

The safety of this q8w dose regimen has been established in the large psoriasis development program. Furthermore, the safety profile in phase 2 studies in patients with PsA and RA was consistent with that observed in psoriasis procedures. The results of the PsA phase 3 procedure were not available when designing the current study.

Participants in the placebo group received placebo at weeks 0 and 4, then every 8 weeks to 20, and 100mg of SC antikumamab at week 24, week 28, then every 8 weeks to 44. At weeks 0 and 4, study interventions were administered by a Health Care Professional (HCP) at the study site. Beginning at week 12, at the discretion of the investigator and the participants, and after appropriate and recorded training, the participants have the option of self-administering the study agent at the study site under the supervision of the HCP or continuing study agent injection by the HCP. To limit the impact of the covd-19 pandemic, the protocol was modified to allow self-administration of subcutaneous injections of study interventions outside the study site after week 24, in cases where site visits were not possible in view of national, regional or local restrictions. Since this is relevant only after week 24, this cannot affect the results reported in this document. All visits up to the 24-week time point were conducted within the appropriate time frame as originally planned for the study (with exception reporting as major protocol bias).

The following key efficacy evaluations were performed to assess signs and symptoms of PsA associated with the primary and secondary endpoints of the study.

Joint evaluation: tenderness of each of the 68 joints was assessed by a designated independent joint evaluator (IJA) and swelling of each of the 66 joints (hip was excluded because of inability to assess swelling of the hip) which was not involved in any other study except joint assessment and tendinitis and dactylitis assessment. If it is physically impossible to evaluate a joint, the joint is designated as "non-evaluable" only by IJA.

Pain assessment of patient: participants were asked to evaluate their average pain on a 100mm Visual Analog Scale (VAS), with the left end indicating "no pain" and the right end indicating "worst possible pain".

Overall assessment of disease activity (arthritis and psoriasis) by patients: participants were asked to evaluate how they had felt their psoriasis and arthritis during the past week on a 100mm VAS, with the left end indicating "excellent" and the right end indicating "bad".

Overall evaluation of disease activity (arthritis) by patient: participants were asked to evaluate how they had felt their arthritis during the past week on a 100mmVAS, with the left end indicating "excellent" and the right end indicating "bad".

Physician overall assessment of disease activity: the physician is required to evaluate the patient for arthritis on a 100mm VAS, with the left end indicating "no arthritis activity" and the right end indicating "hyperactive arthritis".

American society of rheumatology (ACR) response: ACR 20 is defined as an ≡20% improvement over baseline in both the swollen joint count (66 joints) and the tender joint count (68 joints), and the ≡20% improvement over baseline in 3 of the following 5 assessments (pain assessment of patient on VAS, overall assessment of disease activity (arthritis, patient and physician VAS), overall assessment of disease activity by physician (VAS), HAQ-DI and CRP). ACR 50 and ACR 70 are similarly defined, except that the improvement threshold relative to baseline is 50% and 70%, respectively.

Health assessment questionnaire disability index (HAQ-DI): tools for 20 questions assess the difficulty of a person to complete a task in 8 functional areas (dressing, getting up, eating, walking, hygiene, stretching hands, grasping and activities of daily living). The response in each functional domain starts from 0, indicating no difficulty, to 3, indicating that no task can be performed in that domain (i.e., a lower score indicates better function). In PsA, a score decrease of 0.35 has been determined to be indicative of clinically significant improvement.

C-reactive protein (CRP): the serum concentration of CRP, a biomarker of total inflammatory burden, was measured by a high sensitivity method in a central laboratory.

Evaluation of skin disease activity by patient: participants were asked to evaluate how they had felt their psoriasis during the past week on a 100mm VAS, with the left end indicating "excellent" and the right end indicating "bad".

Body surface area of psoriasis (BSA): psoriasis BSA was measured using the palm method at week 0. The size of the body surface area with psoriasis lesions was estimated based on the number of palms of the participants, with each palm (from the root of the wrist to the proximal interphalangeal joint including the thumb) being equivalent to 1% BSA.

Overall evaluation of researchers (IGA): IGA records the assessment of participants for psoriasis at a given time point. The induration, erythema and scaling of the overall lesions were graded using 0 (no evidence), 1 (minimum), 2 (mild), 3 (moderate) and 4 (severe) scales. The IGA scores for psoriasis are based on the average of the induration, erythema and scale scores. Patients were assessed for psoriasis as clear (0), minimal (1), mild (2), moderate (3) or severe (4).

Psoriasis area and severity index or (PASI): a system for evaluating and grading the severity of psoriasis lesions and their response to therapy. In a PASI system, the body is divided into 4 regions: head, torso, upper limbs, and lower limbs. Each of these areas was evaluated for the percentage of the area involved, which translates into a numerical score ranging from 0 (no indication was involved) to 6 (90% to 100% involvement), and erythema, induration, and scaling, each rated on a scale of 0 to 4. PASI produces a numerical score that can range from 0 (no psoriasis) to 72. The PASI 50 response is defined as ≡50% improvement in PASI score over baseline; PASI 75, PASI 90, and PASI 100 are similarly defined.

Toe inflammation assessment: for each finger, the presence and severity of toe inflammation was assessed in both the hand and foot using a scoring system of 0 to 3 (0-no toe, 1-mild toe, 2-moderate toe, 3-severe toe). The results are summed to produce a final score ranging from 0 to 60.

Tendinosis evaluation: tendinitis is assessed using the litz tendinitis index (LEI) and the canadian institute of Spondyloarthritis (SPARCC) tendinitis index.

-LEI, tools specific for PsA patient verification, count the number of painful tendon ends in: left and right lateral humeral epicondyles, left and right medial femoral condyles, and left and right Achilles tendons. The LEI index ranges from 0 to 6.

The SPARCC tendinotefuran index was developed from the general population of spinal arthritis (i.e., not limited to PsA or AS), and the number of painful tendinoteurs in: left and right supraspinatus insertion, left and right medial humeral epicondylitis, left and right lateral humeral epicondylitis, left and right greater trochanter, left and right quadriceps to patella, left and right patella to tibia, left and right Achilles tendon insertion, and left and right plantar fascia. The SPARCC tendinitis index ranges from 0 to 16.

Minimal disease activity: the PsA MDA standard is a combination of 7 outcome measures used in PsA. If the participant satisfies 5 of the 7 outcome measures, it is classified as implementing MDA: the joint pressure pain count is less than or equal to 1; the count of swollen joints is less than or equal to 1; psoriasis activity and severity index is less than or equal to 1; the pain VAS score of the participants is less than or equal to 15; the overall disease activity VAS (arthritis and psoriasis) score of the participants is less than or equal to 20; HAQ-DI score was 0.5 or less; the endpoint of the tenderness tendon is less than or equal to 1.

Psoriasis arthritis disease activity score: the PASDAS (range 0-10) was calculated using the following variables: participant total VAS (arthritis and psoriasis, reaching 0-100), physician total VAS (range 0-100), swollen joint count (0-66), tenderness joint count (0-68), CRP level (mg/L), tendinitis (measured by LEI), dactylitis count (2 different counts are used: [1] score each finger from 0-3 and recode to 0-1, with any score >0 equal to 1, and [2] score each finger of tenderness 0-1), and finally, PCS scale of SF 36 health survey.

Group of studies and evaluations of psoriasis and psoriatic arthritis composite scores: grace is the composite score of the study and evaluation group of psoriasis and psoriatic arthritis (GRAPPA) derived as GRACE index= (1-amdF). Times.10, where amdF is the arithmetic mean of the desired function. AMDF is calculated by transforming the following variables using a predefined algorithm and expressing the total score as an average with a score range of 0-1, where 1 indicates a better state than 0: tended joint count (0-68), swollen joint count (0-66), HAQ-DI score (0-3), overall assessment of disease activity by participants (arthritis and psoriasis, 0 100 VAS), assessment of skin disease activity by participants (0-100 VAS), overall assessment of disease activity by participants (arthritis, 0-100 VAS), PASI score (0-72), and psoriatic arthritis quality of life index (PsAQOL) score.

Disease activity index score 28: DAS28 CRP is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP, and overall assessment of disease activity (GH) by participants. The set of 28 joint counts is based on an assessment of shoulder, elbow, wrist, metacarpophalangeal joint (MCP) 1, MCP2, MCP3, MCP4, MCP5, proximal interphalangeal (PIP 1), PIP2, PIP3, PIP4, PIP5 joints and knee joints of both right and left lower limbs.

Disease activity index of psoriatic arthritis: the DAPSA score is calculated as the sum of the following components: tenderness joint count (0-68), tumescent joint count (0-66), CRP levels (mg/dL), pain assessment of participants (0-10 VAS), and overall assessment of disease activity by participants (arthritis, 0-10 VAS).

Modified psoriatic arthritis response criteria: a participant is considered a responder if it has an improvement in at least 2 of the following criteria (including at least 1 of the joint criteria), but no deterioration in the other criteria: the count of swollen joints (66 joints) is not less than 30 percent reduced; the joint count of tenderness (68 joints) is not less than 30 percent; an ≡20% improvement in overall assessment of disease (arthritis) by participants on VAS; and > 20% improvement in the overall assessment of disease by physicians on VAS.

Improved complex psoriasis disease activity index: the mCPDAI evaluates 4 domains (joint, skin, tendinous and digital inflammation). The mCPDAI score was calculated using the following evaluation: joints (66 swollen joint counts and 68 tender joint counts), HAQ-DI, PASI, dactylitis, and tendinitis. Within each domain, scores are assigned according to predefined cut-off values (ranges 0-3). The scores for each domain were then added together to give a final score range of 0 (none) to 12 (severe).

Papanic ankylosing spondylitis disease activity index: a participant self-evaluation questionnaire originally developed for ankylosing spondylitis consisted of 6 questions related to 5 major symptoms of the disease. Only the participants with spondylitis of peripheral arthritis (primary arthritic manifestations as their PsA (as assessed by the investigator)) had completed BASDAI, using 6 10-unit VAS measures to indicate the extent of their symptoms in the past week, based on the following criteria: fatigue, spinal pain, joint pain, tendinitis, qualitative morning stiffness, quantitative morning stiffness. A higher score indicates greater disease severity and a 50% or 2 score reduction is considered clinically significant.

36-concise health survey (SF-36): health status and quality of life were assessed using a multi-domain instrument with 36 items administered by study participants themselves. It includes 8 component tables covering the functional range: physical function, physical role function, physical pain, general mental well-being (psychological distress and happiness), emotional role function, social function, vitality (energy and fatigue), and general health perception. The scoring produces Physiological Component Summary (PCS), psychological component summary (MCS), and component table scores. A higher score represents better results, an increase of 5 points is considered clinically significant.

Functional assessment of chronic disease therapy (FACIT) -fatigue: the facility-fatigue questionnaire consisted of 13 questions that evaluate the participants' fatigue and tiredness levels over the past 7 days. Each question was rated in 5 minutes (0=no; 1=few; 2=slight; 3=quite many; 4=very many). Scores ranged from 0 to 52, with lower scores reflecting more severe fatigue. In rheumatology, a 4 point change is considered significant and has been used in the PsA population.

Biomarkers and methods for their use

Serum and stool samples were collected from all subjects for analysis of pharmacodynamic biomarkers. The samples will be used to better understand the biology of PsA, provide a biological assessment of patient response to treatment with coumarone, analyze differences between responders and non-responders, and determine whether markers can be used to classify patients as potential responders prior to treatment.

In addition, the samples will be used to analyze proteins associated with inflammation and spondyloarthropathies. Markers associated with PsA biology will be measured, including but not limited to Th17, IL-17A, IL-17F, IL-21, IL-22 and IL-23, metabolomics and bone homeostasis pathways. Ribonucleic acids from whole blood samples will be used in gene expression analysis to determine the molecular profile of PsA and to assess changes in gene expression following treatment with the archaebacterium.

Summary of demographics at baseline

A summary of demographic characteristics at baseline is given in table 1. The proportion of male participants in the placebo group (54.2%, n=52) was high in the Yu Gusai pool mab group (45.5%, n=86). Placebo group (91.7 kg [22.58 kg)]) The average (SD) body weight in the middle participants was also higher than that of the Gu Saiku mab group (83.6 kg [17.40 kg)]) This is consistent with a higher proportion of men in the group. Baseline characteristics of placebo and archaebankizumab groups were measured at age (mean SD]Respectively=49.1 [12.14 ]]Annual sum 49.1[12.31 ]]Years) and BMI (average [ SD ]]Respectively = 30.7[7.12 ]]kg/m ² And 29.0[5.86 ]]kg/m ² ) Balanced in aspect. The archaebankab group had a higher proportion of elderly participants (age ≡65 years) (10.6%, n=20 and 7.3%, n=7) than the placebo group. The participants in both study groups were most frequently obese, with BMI at baseline of > 30kg/m for placebo and archaebankin groups ² The participant ratio of (a) was 45.3% (n=43) and 39.2% (n=74), respectively.

Keyword: iq=quartile range

Summary of psoriatic arthritis characteristics at baseline

The occurrence of different subtypes of psoriatic arthritis is balanced between the two groups. Polyarthritis without rheumatoid nodules (41.7%, [ n=40 ] and 39.4%, [ n=74 ]) and asymmetric peripheral arthritis (37.5% [ n=36 ] and 35.1% [ n=66 ]) were the most frequently reported subtypes in placebo and archaebankab groups, respectively. At baseline, participants in the placebo and the archaebankizumab groups were diagnosed with PsA for 8.7 (7.20) and 8.3 (7.77) years on average (SD), respectively. Except for 1 participant in the archaebankab group, all participants randomized in the study did not receive the combination procedure.

The PsA disease characteristics of the ACR component at baseline are summarized in table 2. The average (SD) numbers of swollen and tender joints (10.2 [6.75] and 21.0[13.21], respectively) were higher in the archaebacterium group than in the placebo group (9.0 [5.69] and 18.2[10.68], respectively). Within a scale of 0 to 10, the average (SD) VAS scores for pain assessments for patients in placebo and in the archaebankizumab group were 6.03 (1.813) and 6.46 (1.873), respectively. For disease activity rated on a scale of 1 to 10, the mean (SD) VAS scores for the overall assessment of the physician were 6.42 (1.743) and 6.87 (1.511) in the placebo and the archaebankab groups, respectively. The mean (SD) VAS scores for the overall evaluation of patients were 6.22 (1.739) and 6.52 (1.749) in the placebo and the archaebankizumab groups, respectively. The average (SD) HAQ-DI scores for the placebo and the archaebankizumab groups were 1.2227 (0.59747) and 1.3305 (0.60157), respectively.

The average (SD) CRP levels for the placebo and the archaebankizumab groups were 1.154mg/dL (2.5358 mg/dL) and 1.225mg/dL (1.9583 mg/dL), respectively.

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Keyword: acr=iq=quartile range, iq=quartile range

A summary of PsA disease characteristics at baseline for signs and symptoms other than ACR components is presented in table 3. Average (SD) DAS28 CRP levels observed in placebo and archaebankizumab groups were 4.57 (0.770) and 4.90 (1.002), respectively. The average (SD) numbers of swollen and tender joints (5.9 [4.05] and 10.6[6.46], respectively) were higher in the archaebacterium group than in the placebo group (4.7 [3.16] and 8.6[5.34], respectively) using 28 instead of 66/68 joint counts. Based on LEI, 66.7% (n=64) of the participants in the placebo group and 67.4% (n=126) of the participants in the archaebanking mab group had tendinitis, with average (SD) scores of 2.7 (1.45) and 2.9 (1.53) on the LEI tendinitis scale (ranging from 1 to 6), respectively. Based on the SPARCC tendinitis index, 76.0% (n=73) of the participants in the placebo group and 70.6% (n=132) of the participants in the archaebacterium group had tendinitis, and the average (SD) was scored as 5.1 (3.31) and 5.5 (3.80) on the SPARCC tendinitis index (ranging from 1 to 16), respectively. In the placebo and the archaebankizumab groups, dactylitis was reported by 37.5% (n=36) and 35.8% (n=67) participants, respectively. Within a scale of 1 to 60, the mean Scores (SD) for the participants of the placebo and the archaebankab groups were 7.4 (8.31) and 6.7 (6.47), respectively.

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Keyword: psA = psoriatic arthritis, IQ = quartile range, LEI = litz tendinitis index, DAS28 = disease activity index score 28 using CRP, CRP = C-reactive protein, SPARCC = canadian institute of spondyloarthritis, pasda = psoriatic arthritis disease a

Summary of psoriasis characteristics at baseline

A summary of the psoriatic disease characteristics at baseline is given in table 4. A total of 61 (63.5%) participants in the placebo group and 120 (63.4%) participants in the archaebankab group reported psoriasis skin disease at baseline. Among these participants, scalp psoriasis (78.7% [ n=48 ] and 82.5% [ n=99 ] in placebo and archaebacterium groups, respectively) and nail psoriasis (78.7% [ n=48 ] and 79.2% [ n=95 ] in placebo and archaebacterium groups, respectively) were the most commonly reported types of psoriasis at baseline. In the placebo and the archaebankizumab groups, hand and/or foot involvement was reported by 21.3% (n=13) and 23.3% (n=28) participants, respectively. At baseline, the extent of psoriasis (in terms of BSA) was most frequently <3% (34.4%, n=33) and > 3% and <10% (27.1%, n=26) in the placebo group, and > 20% (31.7%, n=60) and > 3% and <10% (29.1%, n=55) in the archaebankab group. PASI scores were most frequently <12 in placebo group (67.7%, n=65) and in the archaebankab group (63.3%, n=119); the average (SD) PASI score was 9.2 (9.41) in the placebo group and 11.7 (11.87) in the archaebankab group. The proportion of participants with IGA score > 2 was 69.8% (n=67) and 78.8% (n=149) in the placebo and the guluroumab groups, respectively. The overall patient assessment of arthritis and psoriasis based on the average (SD) VAS score was 6.4 (1.75) and 6.8 (1.80) in the placebo and the archaebankab groups, respectively. The average (SD) VAS scores from patient assessment of dermatological activity were 5.6 (2.40) and 6.3 (2.35) in the placebo and the archaebankab groups, respectively. Average (SD) baseline DLQI scores were 12.4 (7.34) and 13.5 (6.80) in placebo and archaebankizumab groups, respectively, and very large and extremely large effects of psoriasis on quality of life were reported in both groups of participants (58.3% [ n=56 ] and 63.6% [ n=119 ], respectively).

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Keyword: iq=quartile range, dlqi=dermatological quality of life index, pasi=psoriasis area and severity index, vas=visual analog scale

Previous and concomitant medication/therapy

A summary of the previous medications received by the participants (recorded at baseline) is presented in table 5. The types of previous therapies and medications (recorded at baseline) received by the participants in both study groups were similar. Adalimumab (33.3% [ n=32 ] and 30.2% [ n=57 ]) and diclofenac (29.2% [ n=28 ] and 22.2% [ n=42 ]) are the most frequently used PsA-related drugs in the placebo and the guluroumab groups, respectively. Folic acid is the most frequently accepted prior drug (41.7% [ n=40 ] and 32.3% [ n=61 ] in placebo and archaebankizumab groups, respectively) that is not associated with PsA or psoriasis.

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Keyword: psA = psoriatic arthritis

A summary of previous abiotic, DMARD, immunosuppressant, steroid, NSAID, or apremilast treatments received by the participants at baseline is presented in table 6.

Most of the participants in the placebo and the archaebankizumab groups had previously received abiotic DMARDs, immunosuppressives, or apremilast (94.8% [ n=91 ] and 93.7% [ n=177 ], respectively). All participants in both groups also reported the use of previous anti-tnfα drugs, most of which received 1 previous anti-TNF drug (88.5% [ n=85 ] and 88.4[ n=167 ] in the placebo and the coumarone groups, respectively). Methotrexate is the most frequently accepted DMARD, accepted by 91.7% (n=88) and 90.5% (n=171) participants in the placebo and the coumarone groups, respectively. Only a small fraction of the participants (< 6%) in both groups reported previous immunosuppressant or apremilast therapies.

Keyword: DMARD = disease modifying antirheumatic drug, NSAID = nonsteroidal anti-inflammatory drug, psA = psoriatic arthritis, TNF = tumor necrosis factor

A summary of concomitant medications after baseline frequently accepted by participants up to week 24 is presented in table 7. Up to week 24 of the study, concomitant drug use was balanced in the placebo group (77.1% [ n=74 ]) and the archaebankab group (70.4% [ n=133 ]). Participants in both groups received immunosuppressants such as methotrexate most frequently (53.1% [ n=51 ] and 55.6% [ n=105 ] in placebo and archaebankizumab groups, respectively). Concomitant use of acetaminophen (3.1% [ n=3 ] and 5.8% [ n=11 ]) and glucocorticoids (4.2% [ n=4 ] and 5.3% [ n=10 ]) was limited, but constituted the other most commonly accepted concomitant drugs in the placebo and the coumarone groups, respectively (table 7).

All participants randomized in the study had previously been treated with MTX, with > 3 years of exposure reported most frequently (51.1% [ n=45 ] in the placebo group and 45.0% [ n=77 ] in the archaebankab group). The maximum dose of MTX received over the last 3 months was similar for the participants in both groups (average [ SD ] in placebo and archaebankizumab groups = 10.7[8.12] and 10.5[8.09 ]). More than half of the participants in the two groups chose to continue with MTX during the study (58.0% [ n=51 ] and 61.4% [ n=105 ] in the placebo and the gulcomab groups, respectively).

Up to week 24, the combination protocol of 2 (2.1%) participants in the placebo group and 1 (0.5%) participant in the archaebankab group was reported. One (1.0%) of the participants in the placebo group and 4 (2.1%) of the participants in the archaebankab group received a combination injection until week 24 of the study.

A summary of the protocol bias up to week 24 is presented in table 8. Major regimen bias up to week 24 of the study was reported for 34 (35.4%) participants in the placebo group and 45 (23.8%) participants in the archaebankab group. The main cause of the deviation of the regimen is "receiving the wrong treatment or incorrect dose" (16.7% [ n=16 ] and 11.1% [ n=21 ] in placebo and archaebankizumab groups, respectively); however, most of these are related to study interventions administered outside the access window. A total of 8 (8.3%) participants in the placebo group and 12 (6.3%) participants in the gulf-mab group were incorrectly led to early break-away, although the early break-away criteria were not met. The "other" causes of the primary regimen bias were recorded for 14 (14.6%) and 27 (14.3%) participants in the placebo and the archaebankizumab groups, respectively.

The treatment compliance was high for both study groups until week 24, with an average (SD) rate of 99.8% (2.04%) in the placebo group and 99.6% (4.06%) in the archaebankizumab group. In the placebo group, the average (SD) compliance rate of placebo injection was 99.7% (3.40%). A total of 45 participants in the placebo group were assigned early break-away and received Gu Saiku mab injections prior to week 24. Among these participants, the compliance rate of the injection of the coumarone was 100.0%. In the group of the coumarone antibodies, the average (SD) compliance rate of the coumarone antibody injection was 99.6% (4.06%). A total of 39 participants in the archaebankab group were assigned early weaning and received placebo injections at week 16 with 100.0% compliance.

A summary of the participants meeting the criteria for treatment failure up to week 24 is presented in table 9. At week 24, 54.2% (n=52) and 27.0% (n=51) of the participants in the placebo and the archaebankizumab groups, respectively, met 1 or more treatment failure criteria. The largest proportion of the participants in the two study groups were classified as treatment failure due to early withdrawal at week 16 (46.9% [ n=45 ] and 20.6% [ n=39 ] in placebo and archaebankin groups, respectively). This also included 20 participants (8 and 12 in placebo and archaebankizumab groups, respectively) who were incorrectly guided to early break-off at week 16, but did not meet the early break-off criteria.

Keyword: DMARD = antirheumatic drug to ameliorate disease

A summary of the treatment exposures before week 24 is presented in table 10. Most (> 92%) of the participants in both groups had received ≡4 study interventions prior to week 24 visit. Of these 84 participants met early break-away criteria at week 16; early weaning participants (45 out of 96 participants) in the placebo group received Gu Saiku mab doses at weeks 16 and 20, while early weaning participants (39 out of 189 participants) in the archaebankab group received placebo at week 16. Participants in the placebo (early break away) and the coumarone mab groups received Gu Saiku mab up to week 24 received average (SD) 2.0 (0.15) and 3.9 (0.44) SC doses of coumarone mab, respectively. The total average (SD) dose of the coumarone mab was 197.8mg (14.91 mg) in the placebo early release group and 389.4mg (43.69 mg) in the coumarone mab group. The average (SD) duration of the follow-up for both groups was similar (23.8 weeks [2.14 weeks ] and 23.9 weeks [1.50 weeks ] for placebo and archaebankab groups, respectively).

Keyword: iq=quartile range

^a Duration of study visit (week) =date of last visit or last contact or last evaluation (based on last time) until 24 th week visit-reference date +1)/7.

Statistical method：

Curative effect：

The primary analysis of efficacy included all randomized participants who received at least 1 dose (full or partial) of study agent. In efficacy analysis, participants were analyzed in their assigned randomized treatment groups, regardless of the treatment they received. For the binary response efficacy endpoint, a therapeutic comparison was made using the Cochran-Mantel-Haenszel (CMH) test, which was stratified by baseline use of the non-biological DMARD (yes, no) and prior exposure to 1 or 2 anti-tnfα. The magnitude of the treatment difference was estimated by the difference in response rate between the group of coumarone antibodies and the placebo group with 95% Confidence Interval (CI) and p-value calculated based on Wald statistics.

For continuous endpoints, treatment comparisons were made using a mixed effect model repeat measurement (MMRM) model. The model included all available data from 2 treatment groups to week 24. The difference in treatment between the archaebankab group and the placebo group was estimated by the difference in LSmeans. The 95% CI of the difference between the LSmeans and p values was calculated.

All treatment group comparisons will be performed at a bilateral alpha level of 0.05 unless otherwise indicated.

To control overall type 1 error rate, the primary endpoint and the secondary endpoint were tested in a fixed order. The first secondary endpoint (change in HAQ-DI score from baseline at week 24) was tested only if the primary endpoint (the proportion of participants who achieved ACR 20 response at week 24) was positive (p < 0.05). Similarly, the second secondary endpoint (the proportion of participants who achieved ACR 50 response at week 24), the third secondary endpoint (the change in SF-36PCS score from baseline at week 24) and the fourth secondary endpoint (the proportion of participants who achieved PASI 100 response at week 24) were tested only if the previous secondary endpoint was positive (p < 0.05). In the event that one of the primary or secondary endpoints is tested negatively and the formal test is stopped, then a 95% confidence interval and a nominal, unadjusted p-value are sequentially generated for the remaining endpoints.

Nominal p-values for exploratory analysis are reported.

Most efficacy analyses are based on comprehensive measures that evaluate treatment effects based on variable measures and concurrent events defined in terms of Treatment Failure (TF) criteria. The participant was considered TF from the earliest date he/she met any of the following TF criteria until week 24:

discontinuing study drug injection for any reason.

Termination of study participation for any reason.

Doses of either the non-biological DMARD (MTX, SSZ, HCQ, LEF) or oral corticosteroid were initiated or increased for PsA over baseline.

Disable drug/therapy for PsA onset regimen.

Meets early disengagement criteria.

This estimate acknowledges that meeting the TF criteria is a detrimental result. Thus, TF means no response for the responder type of endpoint, and no change from baseline for the continuous endpoint.

Safety of：

The safety analysis group included all participants who received at least 1 (full or partial) study dose. In safety analysis, participants were analyzed for treatment they received, regardless of which treatment group they were randomized to. Adverse events, laboratory analyte values and vital sign measurements triggered by treatment during the study are summarized. Adverse events caused by treatment were coded according to the regulatory active medical dictionary (MedDRA) version 23.0.

Results：

Study population：

Of the 285 participants randomized at week 0 (96 in placebo, 189 in the archaebankab group), 5 participants (2 [2.1% ], 3 [1.6% ] in the placebo group) discontinued the study by week 24. In the placebo group, 1 participant withdrawn consent, and 1 participant discontinued for "other" reasons. In the archaebankab group, 2 participants withdrawn consent, 1 loss of visit.

Demographic characteristics of participants in placebo and archaebankizumab groups were determined at age (mean SD]Respectively=49.1 [12.14 ]]Annual sum 49.1[12.31 ]]Years) and BMI (average [ SD ]]Respectively = 30.7[7.12 ]]kg/m2 and 29.0[5.86 ]]kg/m ² ) Balanced in aspect. Participants in both study groups were most frequently obese and had BMI > 30kg/m at baseline ² (45.3% [ n=43 in placebo and archaebankizumab groups, respectively]And 39.2% [ n=74 ]]). The archaebankab group had a higher proportion of elderly participants (age ≡65 years) (10.6%, n=20 and 7.3%, n=7) than the placebo group. The proportion of male participants in the placebo group (54.2%, n=52) was high in the Yu Gusai pool mab group (45.5%, n=86).

PsA characteristics at baseline：

Polyarthritis without rheumatoid nodules (41.7%, [ n=40 ] and 39.4%, [ n=74 ]) and asymmetric peripheral arthritis (37.5% [ n=36 ] and 35.1% [ n=66 ]) were the most frequently reported subtypes in placebo and archaebankab groups, respectively. For the ACR component, the average (SD) numbers of swollen and tender joints were 9.0 (5.69) and 18.2 (10.68), respectively, in the placebo group and 10.2 (6.75) and 21.0 (13.21), respectively, in the archaebankab group. The average (SD) HAQ-DI scores for the placebo and the archaebankizumab groups were 1.2227 (0.59747) and 1.3305 (0.60157), respectively. Similar average (SD) CRP levels (1.154 [2.5358] and 1.225[1.9583 ]) were observed in the placebo and the archaebankab groups.

Based on LEI, 66.7% (n=64) of the participants in the placebo group and 67.4% (n=126) of the participants in the archaebankab group had tendinitis. In the placebo and the archaebankizumab groups, dactylitis was reported by 37.5% (n=36) and 35.8% (n=67) participants, respectively.

Psoriasis characteristics at baseline：

A total of 61 (63.5%) participants in the placebo group and 120 (63.4%) participants in the archaebankab group reported psoriasis skin disease at baseline. In the case of BSA, the extent of psoriasis is most frequently <3% (34.4%, n=33) and > 3% and <10% (27.1%, n=26) in the placebo group, and > 20% (31.7%, n=60) and > 3% and <10% (29.1%, n=55) in the archaebankab group. Average (SD) PASI scores were 9.2 (9.41) and 11.7 (11.87) in placebo and archaebankizumab groups, respectively. The proportion of participants with IGA score > 2 was 69.8% and 78.8% in placebo and archaebankizumab groups, respectively. Scalp psoriasis (78.7% [ n=48 ] and 82.5% [ n=99 ] in placebo and archaebacterium groups, respectively) and nail psoriasis (78.7% [ n=48 ] and 79.2% [ n=95 ] in placebo and archaebacterium groups, respectively) are the most commonly reported types of psoriasis at baseline. In the placebo and the archaebankizumab groups, hand and/or foot involvement was reported by 21.3% (n=13) and 23.3% (n=28) participants, respectively. Baseline DLQI scores indicated a very large and extremely large impact of psoriasis on quality of life in both groups of participants (58.3% [ n=56 ] and 63.6% [ n=119 ] in placebo and archaebankizumab groups, respectively).

Treatment failure：

At week 24, 54.2% (n=52) and 27.0% (n=51) of the participants in the placebo and the archaebankizumab groups, respectively, met 1 or more treatment failure criteria. The largest proportion of the participants in the two study groups were classified as treatment failure due to early withdrawal at week 16 (46.9% [ n=45 ] and 20.6% [ n=39 ] in placebo and archaebankin groups, respectively). This also included 20 participants (8 and 12 in placebo and archaebankizumab groups, respectively) who were incorrectly guided to early break-off at week 16, but did not meet the early break-off criteria. Thus, the proportion of participants correctly guided EE was 38.5% (n=37) and 14.3% (n=27) for the placebo and the archaebankab groups, respectively.

Exposure degree：

Most (> 92%) of the participants in both groups had received ≡4 study interventions prior to week 24 visit. Participants in the placebo group (early break-off) and the group receiving SC and up to week 24 received average (SD) 2.0 (0.15) and 3.9 (0.44) doses of the archaeolizumab, respectively. This translates to a total average (SD) dose of 197.8mg (14.91 mg) of 2 times of the injection of the coumarone in the placebo (early break away) group and 389.4mg (43.69 mg) of the 4 times of the injection of the coumarone in the coumarone group.

Efficacy results：

The primary analysis of efficacy was performed using comprehensive measures in the total analysis set.

The main analysis is as follows: ACR20 response at week 24：

ACR20 response is defined as ≡20% improvement over baseline in both the tender joint count (68 joints) and the swollen joint count (66 joints), and ≡20% improvement over baseline in at least 3 of the 5 additional ACR-specified assessments. On week 24, based on the integrated measures, a significantly higher proportion of the participants in the archaebankizumab group achieved ACR20 responses (44.4% [ n=84 ] and 19.8% [ n=19 ]) than the placebo group; the percentage difference between the groups favoring the coumarone mab (95% CI) was 24.6 (14.1, 35.2; p < 0.001). See tables 11 and 12 below.

Keyword: acr=american college of rheumatology, ci=confidence interval, cmh=cochran-Mantel-Haenszel, crp=c-reactive protein, dmard=antirheumatic drug to ameliorate disease, HAQ-di=health assessment questionnaire disability index, tnf=tumor necrosis factor

^a The participants have an observed ACR20 response status or meet TF criteria.

^b Defined as observations that did not meet any TF criteria prior to this visitAnd (5) an arriving responder.

^c Participants with data loss are assumed to be non-responders.

^d The confidence interval is based on Wald statistics.

^e The p-value was based on the CMH test, stratified by baseline using abiotic DMARDs (yes, no) and prior exposure to anti-tnfa agents (1 or 2).

^h ACR 20 response is defined as an ≡20% improvement over baseline in both the tender joint count (68 joints) and the swollen joint count (66 joints), and the ≡20% improvement over baseline is in at least 3 of the following 5 assessments: pain assessment of the patient, overall assessment of disease activity by the physician, HAQ-DI and CRP.

Note that: under comprehensive strategies, treatment effects are evaluated not only based on variable measurements, but also based on concurrency events defined in TF standards. A participant is considered to be a non-responder if the participant meets any TF criteria.

Secondary analysis：

Changes in HAQ-DI from baseline to week 24：

HAQ-DI measures the functional status of participants, scoring on a scale of 0 to 3, with lower scores indicating higher function. At week 24, a significantly greater average decrease (LS mean (95% CI) =0.178 [ -0.269, -0.086] and-0.009 [ -0.120, -0.102 ]) was observed in the archaebacterium group compared to the placebo group. The average difference between the groups favoring the coumarone mab (95% CI) was-0.169 (-0.279, -0.059, p=0.003). See tables 13 and 14.

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Keyword: HAQ-di=health assessment questionnaire-disability index, ci=confidence interval, iq=quartile range, mmrm=mixed model of repeated measurements

^a Defined as the change from baseline using observed data or 0 (no improvement) if participants met TF criteria before week 24.

^b Participants observed a change from baseline at this visit or met TF criteria prior to this visit.

^c LSmeans and p values are based on a mixed model of duplicate measurements (MMRM) under random deletion (MAR) assumption of missing data

^d The HAQ score is the average of the calculated class scores (dressing, getting up, eating, walking, hygiene, grasping, and daily life). Lower scores indicate better functionality.

Note that: under comprehensive strategies, treatment effects are evaluated not only based on variable measurements, but also based on concurrency events defined in TF standards. If the participant meets any TF criteria, the participant is assigned a score that the continuous variable does not improve.

ACR50 response at week 24：

ACR50 response is defined as ≡50% improvement over baseline in ACR response criteria. At week 24, a significantly greater proportion of the participants in the archaebankizumab group (19.6%, n=37) achieved ACR50 response than the placebo group (5.2%, n=5). The percentage difference between the groups favoring the coumarone mab (95% CI) was 14.3 (7.2, 21.4; p=0.001). See tables 15 and 16.

Keyword: acr=american college of rheumatology, ci=confidence interval, cmh=cochran-Mantel-Haenszel, crp=c-reactive protein, dmard=antirheumatic drug to ameliorate disease, HAQ-di=health assessment questionnaire disability index, tnf=tumor necrosis factor

^a The participants have an observed ACR 50 response status or meet TF criteria.

^b Defined as the observed responders that did not meet any TF criteria prior to this visit.

^c Participants with data loss are assumed to be non-responders.

^d The confidence interval is based on Wald statistics.

^e The p-value was based on the CMH test, stratified by baseline using abiotic DMARDs (yes, no) and prior exposure to anti-tnfa agents (1 or 2).

^h ACR 50 response is defined as an ≡50% improvement over baseline in both the tender joint count (68 joints) and the swollen joint count (66 joints), and an ≡50% improvement over baseline in at least 3 of the 5 assessments (pain assessment of patient, overall assessment of disease activity by physician, HAQ-DI and CRP).

Note that: under comprehensive strategies, treatment effects are evaluated not only based on variable measurements, but also based on concurrency events defined in TF standards. A participant is considered to be a non-responder if the participant meets any TF criteria.

SF-36PCS change from baseline to week 24：

At week 24, a significantly greater improvement in SF-36PCS score over baseline was observed in the archaebankab group compared to placebo group (LS mean [95% CI ] respectively = 3.514[2.314,4.715] and-0.387 [ -1.841,1.067 ]). The difference in LS mean between the groups favoring the coumarone mab was 3.901 (95% ci=2.457, 5.346; p < 0.001). See tables 17 and 18.

PASI 100 response at week 24 among participants with BSA > 3% and IGA score > 2 at baseline：

At week 24, the proportion of those participants who achieved PASI 100 response in the Gu Saiku mab group was significantly higher than in the placebo group (30.8% [ n=41 ] and 3.8% [ n=2 ], respectively). The percentage difference between the groups favoring the coumarone mab (95% CI) was 27.4 (17.9, 36.8; p < 0.001). See tables 19 and 20.

Exploratory analysis

The change in the 24-week SF-36MCS score from baseline was calculated based on an 8-scale SF-36 instrument, with higher scores indicating better health. At week 24, the LS mean (95% CI) change in SF-36 scores was numerically higher in the Gusaikomab group (2.095 [0.540,3.650 ]) than in the placebo group (0.364 [ -1.525,2.252 ]). The average difference between the groups (95% CI) was 1.731 (-0.144,3.606). Although similar results were obtained from the analysis using all observed 24-week data, whether or not TF criteria were met, the average difference between groups (95% ci) (0.909 [ -1.222,3.040 ]) was lower than the results from the main analysis. For analysis to correct EE errors by ignoring the EE TF standard, the average difference (95% CI) (2.075 [0.178,3.972 ]) between groups favoring the archaemagglutinin is greater than that obtained in the main analysis.

At baseline, a total of 64 (66.7%) participants in the placebo group and 126 (67.4%) participants in the archaebankab group had tendinitis, LEI score >0. Changes in tendinitis from baseline were measured at week 24 with LEI. LEI was calculated based on 6 tendinitis sites, negative changes from baseline indicating improvement. At week 24, a greater improvement of tendinitis over baseline was observed in the archaebankizumab group compared to the placebo group (LS mean [95% CI ] respectively = -1.377[ -1.738, -1.015] and-0.680 [ -1.125, -0.235 ]). The average difference between the groups favoring the archaebankizumab (95% CI) was-0.697 (-1.145, -0.248). Similar results were obtained for analysis using all observed 24-week data, whether or not TF criteria were met (supplemental analysis 1); however, the average difference between groups (95% CI) (-0.269 [ -0.728,0.189 ]) was lower than the results of the primary analysis.

Changes from baseline in tendinitis at week 24 were measured in participants with a SPARCC score of >0 at baseline. The SPARCC measurement of tendinitis is based on applying pressure to the 16 tendinitis ends of interest and evaluating pain at that site, and a negative score indicates improvement. At week 24, a greater improvement of tendinitis relative to baseline was observed in the archaebankizumab group compared to the placebo group (LS mean [95% CI ] respectively = -2.049[ -2.719, -1.380] and-1.150 [ -1.978, -0.322 ]). An average difference of-0.899 (-1.735, -0.063) (95% CI) was observed between the groups favoring the archaebankizumab. Similar results were obtained for analysis using all observed 24-week data, whether or not TF criteria were met; however, the average difference between groups (95% CI) (-0.496 [ -1.403,0.412 ]) was lower than the primary analysis.

A total of 36 (37.5%) participants in the placebo group and 67 (35.8%) participants in the archaebankab group had dactylitis at baseline. Changes from baseline in dactylitis were measured in participants with dactylitis at baseline. The digital inflammation was scored on a scale of 0 to 60, with a maximum score of 3 for each finger, and a negative change from the baseline score indicating improvement. At week 24, participants in the archaebankizumab group recorded a greater average decrease in numerical value relative to baseline in the dactylitis score compared to the placebo group (LS mean [95% CI ] respectively = -2.488[ -3.704, -1.273] and-1.282 [ -2.695,0.131 ]). An average difference of-1.206 (-2.621,0.208) was observed between the groups (95% CI). Regardless of whether TF criteria were met, a comparison was observed in the analysis using all observed 24-week data, with the mean improvement in dactylitis in the archaebacterium group (95% CI) (0.323 [ -1.087,1.733 ]) being lower than in the placebo group.

The change from baseline in FACIT-F scores at week 24 was measured. The FACIT-F score is in the range of 0-52, with higher scores indicating less fatigue. At week 24, a greater average increase in FACIT-F score was observed in the Costuzumab group (4.607 [3.102,6.113 ]) compared to the placebo group (1.050 [ -0.780,2.881 ]). The average difference between the groups favoring the archaebankizumab (95% CI) was 3.557 (1.741,5.373). The analysis using all observed 24-week data was similar to the primary analysis, regardless of whether TF criteria were met. However, the average difference (95% CI) between the groups favoring the archaebankab (2.979 [0.859,5.098 ]) was less than the average difference of the primary analysis.

Changes from baseline in swelling and tenderness joint counts caused by visit up to week 24 were measured. Tenderness and swelling joints were counted from a total of 68 and 66 rated joints, respectively. The change at each time point was measured from baseline 0 (no improvement), with positive values indicating an increase in the swollen or tender joint and negative values indicating a decrease in the swollen or tender joint. Improvement of the tended and swollen joints after treatment with the coumarone mab was evident from week 8, where average (95% CI) differences between groups of-3.308 (-5.487, -1.129) and-1.847 (-3.074, -0.620), respectively, were observed, favoring coumarone mab. The divergence between interventions at week 8 increased over time, and average differences (95% CI) in the nociception and swelling joint counts at week 24 were observed for-3.965 (-6.046, -1.884) and-2.433 (-3.638, -1.228) favoring the coumarone, respectively.

Changes from baseline in DAS28 CRP at week 24 were measured. DAS28 combines the total assessment of tenderness joint count (28 joints), tumescent joint count (28 joints), CRP, and patient activity with higher scores indicating greater PsA severity. At week 4, a greater decrease in average DAS28 score was observed in the group of palace mab compared to the placebo group of palace mab. The average difference between the groups favoring the archaebankizumab (95% CI) was-0.272 (-0.449, -0.095). The differences between groups were maintained over time, increasing from week 4 to week 24; at week 24, the average difference (95% CI) between the groups favoring the archaebankab was-0.655 (-0.898, -0.412). Similar results were obtained for analysis using all observed 24-week data, whether or not TF criteria were met; at week 4, the average difference between groups (95% CI) was-0.259 (-0.439, -0.079). The difference between the subsequent time point groups increased, and the average difference between the 24 th week group (95% CI) was-0.474 (-0.728, -0.221).

The change in DAPSA score from baseline was measured. The DAPSA score is a combination of the tenderness and swollen joint count, CRP, pain assessment of the patient, and overall assessment of the patient's activity on the arthritic disease, and a higher DAPSA score indicates greater disease severity. At week 24, a greater average (95% CI) decrease in DAPSA score relative to baseline was observed in the Costuzumab group (-14.541 [ -17.639, -11.443 ]) compared to the placebo group (-5.754 [ -9.517, -1.991 ]). The average difference between the groups favoring the archaebankizumab (95% CI) was-8.787 (-12.538, -5.036). The observed 24-week data analysis results were consistent with the results of the primary analysis, however the difference between the groups (95% CI) (-5.764 [ -9.595, -1.933 ]) was of lower magnitude.

The proportion of participants who achieved an improvement in BASDAI score of ≡20%,. Gtoreq.50%,. Gtoreq.70% and ≡90% over baseline by visit up to week 24 was measured. BASDAI is based on 6 problems associated with 5 major symptoms of ankylosing spondylitis by self-assessment of patients. A higher score indicates greater disease severity and a 50% or 2 score reduction is considered clinically significant. Of the placebo group (26 [27.1% ]) and the archaebankizumab group (47 [25.0% ]), of the subgroups of participants with spondylitis and peripheral joint involvement (as their primary arthritic manifestations), a similar proportion of participants in the placebo group and the archaebankizumab group achieved. Score improvement of > 70% and > 90% (2.8% [ n=6 ] and 2.1% [ n=1 ], respectively) was observed only in the archaebankizumab group.

Changes from baseline through visit up to week 24 were measured. The mCPDAI score was calculated from a combination of tenderness and swollen joint counts, HAQ-DI, PASI, DLQI, digital inflammation and tendinitis. The final score ranged from 0 to 12, with higher scores indicating more severe disease. At weeks 16 and 24, a greater average (95% CI) decrease in the mCPDAI score relative to baseline was observed in the group of Costuzumab (1.913 [ -2.334, -1.493] and-1.853 [ -2.318, -1.388], respectively) compared to the placebo group (-0.560 [ -1.061, -0.058] and-0.426 [ -0.981, -0.130], respectively). The average differences (95% CI) between the groups favoring the archaebankab at weeks 16 and 24 were-1.354 (-1.850, -0.858) and-1.428 (-1.974, -0.881), respectively. Similar results were obtained from analysis using all observed 24-week data, regardless of whether TF criteria were met, however, at week 24 (-0.864 [ -1.389, -0.339 ]), the magnitude of the difference between the groups of antikumab (95% CI) was lower compared to the primary analysis.

The measurement is based on a comprehensive measure of change in the Grace score at week 24 from baseline. The GRACE index score is calculated from the arithmetic mean of the expectation function (AMDF). AMDF is a function of the tenderness and swelling joint count, HAQ-D score, overall patient assessment of disease activity (arthritis and psoriasis), patient assessment of skin disease activity, overall patient assessment of disease activity (arthritis), PASI score, and quality of life index score for psoriatic arthritis. A higher GRACE score indicates greater disease severity. At weeks 16 and 24, a larger average decrease in GRACE score (95% CI) relative to baseline was observed in the group of Costuzumab (-1.451, -1.749, -1.153, and-1.538, -1.850), respectively, compared to the placebo group (-0.363, -0.720, -0.005, and-0.287, -0.663,0.088, respectively). This indicated a decrease in disease activity from baseline to week 24 in the Gu Saiku mab group. The average differences (95% CI) between the groups favoring the archaebankab at weeks 16 and 24 were-1.089 (-1.446, -0.731) and-1.251 (-1.626, -0.876), respectively. Similar results were obtained from analysis using all observed 24-week data, regardless of whether TF criteria were met, however, the size of the difference (95% CI) (-0.815 [ -1.181, -0.450 ]) between the groups favoring the coumarone at week 24 was lower compared to the main analysis.

Results were measured for participants who achieved low disease activity (.ltoreq.2.3) based on GRACE up to week 24. At weeks 16 and 24, lower disease activity was observed in a greater proportion of the participants in the group of coumarone antibodies (15.3% [ n=29 ] and 17.5% [ n=33 ]) than in the placebo group (5.2% [ n=5 ] and 3.1% [ n=3 ], respectively). The percentage difference (95% CI) between the 16 th and 24 th week groups favoring the archaebankab was 10.1 (3.4, 16.8) and 14.3 (7.9, 20.6), respectively. At baseline, a total of 64 (66.7%) participants in the placebo group and 126 (67.4%) participants in the archaebankab group had tendinitis, LEI score >0.

At week 24, tendinitis regression was defined as the absence of tendinitis in participants with at least 1 (6 total) tendinitis sites at baseline. At week 24, a higher proportion of the participants in the archaebankizumab group (39.7% [ n=50 ]) reported resolution of tendinitis than the placebo group (18.8% [ n=12 ]). At week 24, the percentage difference (95% CI) between the groups favoring the coumarone mab was 21.6 (8.8, 34.4). Similar results were obtained from analysis using all observed 24-week data, whether or not TF criteria were met; however, the percentage difference (95% CI) (11.0 [ -3.7, 25.7 ]) between the groups favoring the archaebankab was lower than the percentage difference obtained from the primary analysis.

The proportion of participants who had tendinitis (LEI) resolved by visit up to week 24 based on a comprehensive measure and analysis using all observed data at week 24, whether or not TF standard analysis 1 was met, among those who had tendinitis (LEI) at baseline, was presented in accessory TEFENL05 and accessory TEFENL06, respectively.

A total of 36 (37.5%) participants in the placebo group and 67 (35.8%) participants in the archaebankab group had dactylitis at baseline. The proportion of participants who achieved resolution of the digital inflammation at week 24 was measured. The digital inflammation was scored on a scale of 0 to 60 with a maximum score of 3 for each finger (hand and foot). Resolution of dactylitis is defined as the 0 score of participants scoring above zero at baseline. At week 24, a greater proportion of the participants in the archaebankizumab group (44.8%, n=30) achieved resolution of dactylitis than the placebo group (25.0%, n=9). A percentage difference of 19.9 (2.7, 37.1) (95% CI) was observed between the groups favoring the archaebankab. Analysis results using all observed 24-week data, whether or not TF criteria were met, were compared to the primary analysis; a numerically greater proportion of the participants in the placebo group (63.9%, n=23) achieved resolution of the dactylitis than the archaebacterium group (59.7%, n=40). The percent difference between the groups (95% CI) was-3.0 (-21.8, 15.8).

The proportion of participants who achieved MDA and VLDA at week 24 was measured. Minimum Disease Activity (MDA) is defined as achieving 5 of the following 7 criteria: the pain joint count is less than or equal to 1, the swelling joint count is less than or equal to 1, the psoriasis activity and severity index is less than or equal to 1, the pain assessment of a patient is less than or equal to 15, the overall assessment of the disease activity of the patient is less than or equal to 20, the HAQ-DI score is less than or equal to 0.5, and the endpoint of the pain tendon is less than or equal to 1. Very Low Disease Activity (VLDA) is obtained if all 7 criteria below are met. At week 24, a greater proportion of the participants in the archaebankizumab group (14.8%, n=28) achieved MDA responses than the placebo group (3.1%, n=3). The percentage difference (95% CI) between the groups favoring the archaebankab was 11.7 (5.6, 17.7). The results of the analysis using all observed 24 th week data were consistent with the primary analysis, whether or not TF criteria were met; the percentage difference between the groups favoring the archaebankizumab (95% CI) was 11.6 (4.7, 18.5). At week 24, 7 (3.7%) participants in the Gu Saiku mab group achieved VLDA response, while none of the participants in the placebo group achieved VLDA response. Regardless of whether TF criteria are met, the results obtained from the analysis using all observed 24-week data are consistent with the primary analysis.

At weeks 16 and 24, a greater proportion of the participants in the archaebankab group (10.6% [ n=20 ] and 14.8% [ n=28 ], respectively) achieved MDA responses than the placebo group (3.1%, n=3 at both time points). The percentage difference (95% CI) between the groups favoring the coumarone mab at week 16 and week 24 was 7.5 (1.9, 13.0) and 11.7 (5.6, 17.7), respectively. The results of the analysis using all observed 24 th week data were consistent with the primary analysis, whether or not TF criteria were met; the percentage difference (95% ci) between the groups favoring the coumarone mab at week 16 and week 24 was 7.5 (1.5, 13.5) and 11.6 (4.7, 18.5), respectively. At week 16, 3 (1.6%) and 1 (1.0%) participants in the Gu Saiku mab group had achieved VLDA responses. By week 24, 7 (3.7%) participants in the Gu Saiku mab group achieved VLDA responses; by week 24, no participants in the placebo group achieved VLDA responses.

Security results:

the data set for safety analysis up to week 24 was：

Take placebo: this included 96 participants randomly assigned to the placebo group at week 0. Of these, 51 participants received placebo only at week 24 and 45 received placebo until conversion to coumarone at week 16. For this group, only the safety when placebo is taken is described.

Conversion from placebo to archaebankizumab before week 24: this included 45 participants, who were randomly assigned to the placebo group, but who met early break-away criteria and converted to coumarone at week 16. For this group, only the safety events when the coumarone mab was taken are described.

Random distribution to the archaebankizumab: this included 189 participants, who were randomly assigned to the group of coumarone antibodies at week 0 and received only coumarone antibodies until week 24. Participants in the group who were assigned early on week 16 who left the placebo injection to maintain blindness were also considered part of the group.

Combined antique-saikomab: this included 234 participants that received at least 1 dose of the archaebankzumab up to week 24, and included those that received Gu Saiku mab at week 0 Zhou Suiji (189 participants), plus those from the placebo group that converted to archaebankzumab prior to week 24 after early break-off (45 participants).

Summary of AEs up to week 24：

Up to week 24, 86 (36.8%) participants in the 46 (47.9%) participants and the combined group of coumarone administration of placebo reported at least one TEAE, of which 3 (3.1%) and 8 (3.4%) reported at least one Serious Adverse Event (SAE), respectively, and 2 (2.1%) and 5 (2.1%) discontinued study intervention due to AE, respectively. Of the participants who converted to coumarone after early break-off, 6 (13.3%) reported at least one TEAE,1 (2.2%) reported at least one SAE, and no one discontinued the study intervention due to AE. The vast majority (> 95%) of the participants in each group reported only mild or moderate intensity AEs. Death was not reported until week 24.

Related TEAE up to week 24：

In the placebo group, infection and infestation (n= 8,8.3%) were the most frequently reported treatment-induced AEs considered to be relevant to study intervention. In the combination group of the coumarone antibodies, TEAE considered reasonably relevant to the study intervention was reported by 27 (11.5%) participants, 2 of which had been converted to the coumarone antibody after early detachment. The most frequently reported TEAEs with reasonable causal relationship to the archaebankizumab are infection and infestation (n= 10,4.3%), general disorder and administration site status (n= 6,2.6%) and abnormalities in laboratory studies (n= 6,2.6%).

Serious adverse events up to week 24：

Up to week 24, 3 (3.1%) placebo-administered participants and 8 (3.4%) participants in the combined group of coumarone experienced at least one SAE, of which 1 had been converted to coumarone after early break-off.

Other significant adverse events：

Up to week 24, 2 (2.1%) participants taking placebo and 5 (2.1%) participants in the combined group of coumarone discontinued study intervention after one or more TEAEs.

Conclusion at week 24：

In this study, 100mg of coumarone was treated at weeks 0 and 4 and then every 8 weeks, indicating superiority of coumarone over placebo for the primary endpoint of ACR 20 response at week 24. Based on a predefined grading test protocol, the superiority of the archaebankab over placebo was determined at week 24 relative to all 4 key secondary endpoints: HAQ-DI, ACR 50 response, SF-36PCS, and PASI 100.

In general, the archaebankenomab exhibits strong efficacy against signs and symptoms of joint and skin psoriasis, improves physical function, and improves physiological components of health-related quality of life.

In this study, the archaebankab dosing regimen was safe and well tolerated up to week 24. The safety profile of Gu Saiku mab in psoriatic arthritis patients of this population refractory to anti-TNF therapy is generally consistent with that demonstrated in psoriatic or untreated psoriatic arthritis indications.

Week 48 efficacy results

Before week 48, 11.6% and 13.5% of subjects in the GUS and PBO groups, respectively, discontinued study medication. The most common causes of discontinuation of study agents were adverse events (31.8% and 23.1, respectively), lack/loss of efficacy (22.7% and 23.1, respectively), and subject withdrawal (22.7% and 23.1, respectively). Of the subjects continuing to study the agent after week 24 (174 and 87, respectively, included in FAS 2) in the GUS and PBO groups, 4.0% and 4.6% of the subjects discontinued study the agent after week 24 and before week 48, respectively. Before week 48, 45.0% and 45.8% of subjects with one or more major regimen deviations were reported in the GUS and PBO groups, respectively, of which 24.7% and 20.5% were attributed to covd-19, respectively. Based on the medical examination of the data, a total of 11 subjects were excluded from each regimen analysis at week 56, as the primary regimen deviation affected the 48 week efficacy analysis.

ACR response

The proportion of subjects who achieved ACR20/50/70 response over the period of weeks 4 to 48 is summarized below. As shown in tables 21 and 22 below, the overall observed proportion of subjects who achieved ACR20 responses in GUS randomized subjects was 54.9% at week 24, and further up to 72.3% at week 48. Of the subjects directed to week 16 EE, 36.8% achieved ACR20 response at week 24, and 58.3% achieved ACR20 response at week 48. Among those subjects without week 16 EE, 59.6% observed ACR20 response at week 24, and 76.2% observed ACR20 response at week 48. ACR20 was achieved at week 24 and study continued until week 48 of GUS randomized subjects 91.2% maintained ACR20 at week 48, regardless of EE route.

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Keyword: acr=american college of rheumatology, crp=c reactive protein, dmard=antirheumatic drug to ameliorate disease,

HAQ-DI = health assessment questionnaire disability index, TNF = tumor necrosis factor

^a ACR20 response is defined as an improvement of ≡20% over baseline in both the tender joint count (68 joints) and the swollen joint count (66 joints), and an improvement of ≡20% over baseline in 5 assessments (pain assessment of patient, patient versus disease Overall assessment of activity, overall assessment of disease activity by a physician, HAQ-DI and CRP).

Keyword: acr=american college of rheumatology, crp=c-reactive protein, dmard=antirheumatic drug to ameliorate disease, HAQ-di=health assessment questionnaire disability index, tnf=tumor necrosis factor

^a ACR 20 response is defined as an ≡20% improvement over baseline in both the tender joint count (68 joints) and the swollen joint count (66 joints), and an ≡20% improvement over baseline in at least 3 of the 5 assessments (pain assessment of patient, overall assessment of disease activity by physician, HAQ-DI and CRP).

Full analysis set 2 included all randomized subjects still on study treatment at week 24.

As shown in tables 23 and 24 below, 13.2% and 26.7% ACR50 responses were observed at week 24 for subjects who were guided to week 16 EE and subjects who were not guided to week 16 EE, respectively, in GUS randomized subjects. At week 48, this increased to 41.7% and 50.4%, respectively. Overall, 48.5% achieved ACR50 response at week 48. ACR50 was achieved at week 24 and the study continued until week 48 of GUS randomized subjects, 94.6% maintained ACR50 at week 48, regardless of EE route.

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Keyword: acr=american college of rheumatology, crp=c-reactive protein, dmard=antirheumatic drug to ameliorate disease, HAQ-di=health assessment questionnaire disability index, tnf=tumor necrosis factor

^a ACR 50 response is defined as an ≡50% improvement over baseline in both the tender joint count (68 joints) and the swollen joint count (66 joints), and an ≡50% improvement over baseline in at least 3 of the 5 assessments (pain assessment of patient, overall assessment of disease activity by physician, HAQ-DI and CRP).

Keyword: acr=american college of rheumatology, crp=c-reactive protein, dmard=antirheumatic drug to ameliorate disease, HAQ-di=health assessment questionnaire disability index, tnf=tumor necrosis factor

^a ACR 50 response is defined as an ≡50% improvement over baseline in both the tender joint count (68 joints) and the swollen joint count (66 joints), and an ≡50% improvement over baseline in at least 3 of the 5 assessments (pain assessment of patient, overall assessment of disease activity by physician, HAQ-DI and CRP).

Full analysis set 2 included all randomized subjects still on study treatment at week 24.

As shown in tables 25 and 26 below, 2.6% and 10.3% ACR70 responses were observed at week 24, respectively, in GUS randomized subjects, for subjects who were lead to week 16 EE and those who were free of EE. At week 48, ACR70 response rates increased to 22.2% and 30.1%, respectively. Overall, 28.4% achieved ACR70 response at week 48. ACR70 was achieved at week 24 and study continued until week 48 of GUS randomized subjects 81.3% achieved ACR70 at week 48.

Keyword: acr=american college of rheumatology, crp=c reactive protein, dmard=antirheumatic drug to ameliorate disease,

HAQ-DI = health assessment questionnaire disability index, TNF = tumor necrosis factor

^a ACR70 response is defined as an improvement of > 70% over baseline in both the tender joint count (68 joints) and the swollen joint count (66 joints), and an improvement of > 70% over baseline in at least 3 of the 5 assessments (pain assessment of patient, overall assessment of disease activity by physician, HAQ-DI and CRP).

Keyword: acr=american college of rheumatology, crp=c-reactive protein, dmard=antirheumatic drug to ameliorate disease, HAQ-di=health assessment questionnaire disability index, tnf=tumor necrosis factor

^a ACR 70 response is defined as an improvement of > 70% over baseline in both the tender joint count (68 joints) and the swollen joint count (66 joints), and an improvement of > 70% over baseline in at least 3 of the 5 assessments (pain assessment of patient, overall assessment of disease activity by physician, HAQ-DI and CRP).

Full analysis set 2 included all randomized subjects still on study treatment at week 24.

HAQ-DI

As shown in Table 27 below, GUS randomized subjects improved on average by 0.29 score at week 24 and 0.47 score at week 48 starting with an average HAQ-DI of 1.33 at baseline. Subjects who were led to week 16 EE had a slightly higher baseline than 1.31 compared to those without EE: 1.42. although the improvement was smaller in GUS randomized subjects who were guided to EE at week 24 compared to GUS subjects without EE, which was-0.18 compared to-0.32, the improvement between these groups was similar at week 48, respectively: compared to-0.48, is-0.43.

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Keyword: HAQ-DI = health assessment questionnaire disability index, IQ = quartile range.

^a The HAQ score is the average of the calculated class scores (dressing, getting up, eating, walking, hygiene, grasping, and daily life). Lower scores indicate better functionality.

SF36-PCS

As shown in Table 28 below, GUS randomization was initiated with an average SF36-PCS score of 33.0 from baseline

Subjects were on average improved by 5.83 points at week 24 and 8.44 points at week 48. Compared to those without EE, subjects directed to EE had a slightly lower baseline than 33.3: 31.8. average improvements were 5.11 and 6.02 at week 24 and 7.83 and 8.60 at week 48, respectively.

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Keyword: iq=quartile range, pcs=physiological component summary, SF-36=conciseness-36 (term).

^a PCS was calculated based on 8 scales of SF-36 health related quality of life instruments with 36 questions. The higher the score, the better the health condition.

PASI response

PASI100, PASI90, and PASI75 responses were evaluated in subjects with an overall evaluation (IGA) score of ≡3% Body Surface Area (BSA) psoriasis involvement and ≡2 (mild) at baseline (recruitment) (55% and 70% of the overall PBO and GUS population, respectively).

As shown in table 29 below, the overall observed proportion of subjects who achieved PASI100 response in GUS randomized subjects was 41.1% at week 24 and increased to 66.1% at week 48. In GUS subjects who had been led to week 16 EE, 53.6% achieved a PASI100 response at week 48, while in those without EE, 69.9% achieved a PASI100 response at week 48. The overall response at week 48 was 84.3% for PASI90 and 93.4% for PASI 75.

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Keyword: bsa=body surface area, crp=c-reactive protein, iga=overall assessment by the investigator, dmard=anti-rheumatic drug to improve disease, pasi=psoriasis area and severity index, tnf=tumor necrosis factor ^a PASI scores are a combination of areas of involvement of erythema, induration, and scaling states on the body. PASI scores in the range of 0 to 72, with higher scores indicating more severe disease. PASI 100 response is defined as 100% improvement in PASI score over baseline.

Joint tenderness count

As shown in table 30 below, for GUS randomized subjects, the average number of tender joints at baseline was 21.0, the average improvement was-10.1 at week 24 and-12.9 at week 48. Subjects who were led to week 16 EE had on average more joints with tenderness at baseline than those without EE than those with 20.5: 22.9. for patients with or without EE, the average improvement was-6.3 and-11.1 at week 24 and-12.0 and-13.2 at week 48, respectively.

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Keyword: iq=quartile range.

^a The tenderness joint count is the total number of tenderness joints in 68 joints evaluated for tenderness.

Swollen joint count

As shown in table 31 below, for GUS randomized subjects, the average number of swollen joints at baseline was 10.2, the average improvement was-6.7 at week 24 and-8.5 at week 48. Subjects who were led to week 16 EE had on average more swollen joints at baseline than those without EE than 9.7: 12.4. average improvements were-6.0 and-6.9 at week 24 and-9.8 and-8.2 at week 48, respectively.

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Keyword: iq=quartile range.

^a The swollen joint count is the total number of swollen joints in the 66 joints evaluated for swelling.

MDA state

As shown in table 32 below, the overall observed proportion of subjects who achieved MDA in GUS randomized subjects was 17.4% at week 24 and 32.5% at week 48. In subjects who were led to EE at week 16, 5.3% achieved MDA at week 24 and 22.2% achieved MDA at week 48, and in those without EE, this was 20.5% at week 24 and 35.3% at week 48.

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Keyword: crp=c-reactive protein, dmard=antirheumatic drug to ameliorate disease, mda=minimal disease activity, tnf=tumor necrosis factor

^a If 5 of the following 7 criteria are met (tender joint count. Ltoreq.1, swollen joint count. Ltoreq.1, psoriasis activity and severity index. Ltoreq.1, pain assessment of the patient. Ltoreq.15, overall assessment of patient to disease activity. Ltoreq.20, HAQ-DI score)

MDA is realized when the end point of the tenderness tendon is less than or equal to 0.5 and less than or equal to 1).

Resolution of tendinitis

Resolution of tendinitis was assessed in 67% of subjects with tendinitis in baseline (LEI > 0), GUS and PBO populations. As shown in table 33 below, the overall observed proportion of subjects achieving resolution of tendinitis in GUS randomized subjects was 52.0% at week 24 and 67.50% at week 48. In subjects who led to EE at week 16, 61.5% achieved resolution of tendinitis at week 48, and in those without EE, this was 69.3%.

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Keyword: crp=c reactive protein, dmard=antirheumatic drug to ameliorate disease, lei=litz tendinitis index, tnf=tumor necrosis factor

^a Tendinitis score is a total score of 6 evaluation sites (left and right: lateral humeral epicondylitis, medial femoral condyle, achilles tendon insertion), ranging from 0 to 6. Negative changes from baseline indicate improvement. When the subject having at least one tenderness tendinous at baseline had no tenderness tendinous in the 6 sites included in LEI, tendinous inflammation was determined to resolve.

FACIT-fatigue improvement

As shown in Table 34, the total observed proportion of subjects with an improvement of ≡4 over baseline in the FACIT-fatigue score was 58.5% at week 24 and 69.0% at week 48 in GUS randomized subjects. Of GUS subjects directed to week 16 EE, 60.0% achieved a.gtoreq.4 score improvement in FACIT-fatigue at week 48, as compared to 71.3% in EE-free subjects.

Keyword: crp=c-reactive protein, dmard=antirheumatic drug to improve disease, ffacit=functional assessment of chronic disease therapy, tnf=tumor necrosis factor

^a The FACIT-fatigue score was calculated based on a FACIT-fatigue questionnaire that included 13 questions, each of which was ranked on a 5-score scale (0-4). The FACIT-fatigue score may be in the range of 0 to 52, with a higher score indicating less fatigue.

Safety up to week 56：

Week 56 safety was assessed in all randomized and treated participants receiving at least 1 dose of archakurimab (partial or complete) based on actual treatment received during the study, irrespective of the randomized allocated treatment. This is also referred to as a security analysis set. The key security events are summarized in table 35 below.

Up to week 56, a total of 49.8% of the subjects reported at least one adverse event. For patients crossing GUS at week 16 or week 24, this was 46.7% and 44.4%, respectively. For patients randomly assigned to GUS, there were more patients reporting adverse events during the first 24 weeks (42.3%) than patients reporting adverse events during the follow-up period after week 24 (30.5%). In GUS randomized subjects, 3.7% had Severe Adverse Events (SAE) up to week 24 and 2.9% had SAE during the follow-up period after week 24. SAE were reported at 4.4% in PBO randomized patients crossing GUS at week 16 and those who hybridized at week 24. Overall, 2.5% of subjects reported adverse events leading to discontinuation of the administration of the coumarone, mainly 24 weeks (2.1% versus 1.7%) prior to the study.

Up to week 56, 21.9% of GUS treated subjects had at least one infection identified by the investigator. For GUS randomized subjects, infection was reported more frequently during the first 24 weeks (21.2%) than during the follow-up period (9.2%) after weeks 24 to 56. Of the subjects randomly assigned to PBO, 15.6% reported infection after the 16 th week crossover and 13.3% reported infection after the 24 th week crossover. Two subjects (0.7%) reported one or more severe infections, one GUS randomized subject and one PBO randomized subject reported pneumonia.

Up to week 56, overall, 1.8% (n=5) GUS treated subjects had at least one injection site response.

Malignancy was reported in 1 (0.5%) subjects up to week 56. This malignancy reported in the GUS group at study week 19 was prostate cancer. Considering the subject's history of chronic prostatitis, and the relatively short interval between study treatment initiation and cancer diagnosis, causal relationships were assessed as independent of study treatment.

Death, opportunistic infections, tuberculosis, suicidal ideation or behavior, and allergic or serological reactions were not reported until week 56.

By week 56, the most common treatment-induced adverse event System Organ Categories (SOCs) observed were infection and infestation (20.8%), with the most common AEs reported being nasopharyngitis (5.7%) and upper ventilator infection (3.6%).

By week 56, an increase in alanine Aminotransferase (ALT) serum levels was reported as AE in 11 subjects (3.9%), one of which reached SAE designation. Elevated aspartate Aminotransferase (AST) serum levels were reported as AE in 6 subjects (2.2%). For one subject (0.4%), elevated liver enzymes were reported as SAE. Further details of these SAEs will be provided in CSR.

By week 56, a decrease in neutrophil and white blood cell counts (reported as adverse events) of 1.1% and 1.1%, respectively, was observed. None of these events reached the SAE threshold.

As shown in table 36 below, the results of the additional secondary endpoints evaluated at week 24 also show the numerical benefits of the coumarone relative to placebo for achieving ACR70, MDA and VLDA and for achieving PASI75 and PASI90 in patients with psoriasis ≡3% BSA and IGA ≡2 at baseline. These analyses were performed using non-responder interpolation. Of the participants with tendinitis or dactylitis at baseline, a numerically higher proportion of the archaebankrimab had tendinitis or dactylitis resolved at week 24, respectively, than placebo patients. The proportion of patients achieving a score of > 4 improvement (reflecting clinically significant improvement) in FACIT-F was higher in the archaebankizumab group than in the placebo group. In the archaebankab group, the mean variation of LS from baseline in SF-36MCS score was also numerically greater.

After 24 weeks, responses and mean improvement of secondary endpoints in patients randomly assigned to the archaebacterium at baseline continued or improved numerically until week 48. In patients crossing from placebo to coumarone at week 24, the response rate and mean change of the secondary endpoint increased at week 48.

Evaluation Gu Saiku mab randomization patients achieved maintenance of response of ACR20, ACR50, or ACR70 response at week 24; in these patients, responses were maintained at week 48 at 83.3% (70/84), 81.1% (30/37) and 86.7% (13/15), respectively.

Unless otherwise indicated, the data shown are N (%) or N/N (%)

^a Up to week 24, patients interrupting study agent/study participation, starting or increasing the allowable csDMARD/oral corticosteroid dose beyond the baseline of PsA, starting regimen-prohibited PsA drugs/therapies, or meeting EE criteria (including those incorrectly assigned to EE) were considered non-responders or did not improve over baseline at a later time point for any reason. After week 24, patients who met the EE criteria (excluding those that were incorrectly assigned to EE) and who discontinued study medication/study participation for any reason were considered non-responders or did not improve over baseline at a later time point; missing data is estimated as unresponsive or multiple interpolations (assuming random missing).

^b CI based on Wald statistics ^c Based on the unadjusted (nominal) p-value of the Cochran-Mantel-Haenszel test, layering by baseline use (Yes/No) of csDMARD and previous exposure to TNFi (1/2)

^d In patients with LEI score of 1 or more at baseline

^e In patients with DSS scores of > 1 at baseline

^f In patients with > 3% BSA psoriasis involvement and IGA > 2 at baseline

^g LSmeans and unadjusted (nominal) p values of the hybrid model based on repeated measurements under the random missing assumption of missing data. LS averages were determined only up to week 24.

^h After week 24, multiple interpolations of the 0 change and missing data (assuming random missing) were used to determine the average change from baseline for patients who discontinued or met the EE criteria prior to week 24 (excluding patients who were incorrectly assigned to EE).

ACR, american college of rheumatology; BSA, body surface area; CI, confidence interval; csDMARD, a conventionally synthesized antirheumatic drug for improving diseases; DSS, digital inflammatory severity score; EE, early detachment; FACIT-F, functional assessment of chronic disease therapy-fatigue; IGA, overall assessment of psoriasis by researchers; LEI, litz tendinitis index; MDA, minimal disease activity; PASI, psoriasis area and severity index;

PsA, psoriatic arthritis; Q8W, once every 8 weeks; SF-36MCS, summary of psychological components of 36 brief health survey profiles; SD: standard deviation; TNFi, tumor necrosis factor-inhibitor; VLDA, very low disease activity

Discussion and week 48/56 conclusions

Overall, COSMOS test evaluates efficacy and safety of Gu Saiku mab (GUS) 100mg at weeks 0, 4 and then q8w up to week 44, and demonstrates in efficacy: (i) Superiority of GUS relative to PBO for its primary endpoint of ACR20 response at week 24, (ii) superiority of GUS relative to PBO for all 4 key secondary endpoints at week 24 (based on predefined grading test protocol): HAQ-DI, ACR50 responses, SF36-PCS and PASI100, (iii) benefits of GUS relative to PBO on exploratory endpoints such as resolution of tendinitis and dactylitis, SF-36, facility-fatigue, etc., (iv) high maintenance of response in combined results (ACR 20:91.2%; ACR50:94.6%; ACR70: 81.3%) up to week 48 of GUS treatment, and (v) high patient retention observed in study (up to week 48 above 85%).

In general, up to 48 weeks of therapy, GUS showed strong efficacy against signs and symptoms of joint and skin psoriasis, improving physical functions and physiological components of health-related quality of life. In this study, GUS dosing regimen was safe and well tolerated up to week 56. The safety profile of the poorest mab up to 56 Zhou Gusai in psoriatic arthritis patients of this population refractory to anti-TNF therapy is generally consistent with that demonstrated in psoriatic or psoriatic arthritis indications that have not received biological treatment. For all results evaluated after week 24, a trend was observed to increase the benefit over time. Considering that these trends are based on "observed" data, appropriate non-respondents and multiple interpolation techniques will be applied to these observations to confirm the findings. These and other exploratory analyses will be reported in clinical study reports, including the effect of converting PBO patients to GUS.

Overall theoretical basis of research

The study of the archaebankizumab in this phase 3b PsA clinical study was supported by: robust efficacy results and favorable safety profiles for phase 3 studies in psoriasis (including subgroups of patients with PsA) and for phase 2a studies and two phase 3 studies using archaebacterium in PsA.

Phase 3 studies of archakuzumab in psoriasis included 2 larger placebo and activity comparator control studies (CNTO 1959PSO3001[ VOYAGE-1] and CNTO1959PSO3002[ VOYAGE-2 ]), including participants with active PsA at baseline (18.6% and 18.0%, respectively). These studies consistently demonstrate that the archaebankab is highly effective and that the treatment results in rapid, substantial and clinically significant improvement of psoriasis in this population. The archatock mab is equally effective in all sub-populations compared to the overall population, as defined by gender, baseline age, baseline body weight, race, geographic region, presence or absence of PsA at baseline, and history of psoriasis treatment. In both studies, the gulcomab was statistically superior to placebo or adalimumab (p < 0.001) for the common primary and all primary secondary endpoints.

Phase 2a studies of archaebankab in PsA, CNTO1959, 2001 demonstrated significant improvement of symptoms, including joint symptoms, body function, psoriasis, tendinitis, dactylitis, and quality of life of participants with active PsA and > 3% of psoriatic Body Surface Area (BSA). Primary and all secondary endpoints were met in this study, with efficacy maintained during about 1 year of exposure in the participants of the archaebankab group. These data were confirmed in 2 registered phase 3 studies (CNTO 1959PSA3001[ DISCOVER-1] and CNTO1959PSA3002[ DISCOVER-2 ]), validating Gu Saiku mab as a potent therapeutic intervention in PsA.

Phase 3 studies (DISCOVER program) included primarily patients who did not receive biological therapy. The purpose of this study (CNTO 1959PSA3003[ COSMOS ") was to further define clinical efficacy (signs and reduction of symptoms of joint and psoriasis skin diseases) and to evaluate the safety of Gu Saiku mab in treating patients with active PSA who had previously failed (i.e., refractory) or intolerant anti-tnfα therapy.

The invention also includes pharmaceutical compositions and packages of anti-IL-23 antibodies for treating psoriatic arthritis in a subject having inadequate response to anti-TNF therapy, wherein the antibodies comprise: (i) A heavy chain variable region and a light chain variable region, the heavy chain variable region comprising: the complementarity determining region heavy chain 1 (CDRH 1) amino acid sequence of SEQ ID NO. 1, the CDRH2 amino acid sequence of SEQ ID NO. 2, and the CDRH3 amino acid sequence of SEQ ID NO. 3; and the light chain variable region comprises: the complementarity determining region light chain 1 (CDRL 1) amino acid sequence of SEQ ID NO. 4, the CDRL2 amino acid sequence of SEQ ID NO. 5, and the CDRL3 amino acid sequence of SEQ ID NO. 6; (ii) A heavy chain variable region of the amino acid sequence of SEQ ID NO. 7 and a light chain variable region of the amino acid sequence of SEQ ID NO. 8; or (iii) the heavy chain of the amino acid sequence of SEQ ID NO. 9 and the light chain of the amino acid sequence of SEQ ID NO. 10.

The invention may be described in connection with the following numbered embodiments:

1. use of an anti-IL-23 antibody for treating psoriatic arthritis in a subject in need thereof, wherein the subject exhibits an insufficient response to treatment with anti-TNF therapy, wherein about 50mg to about 150mg of the antibody is administered subcutaneously to the subject once every 4 weeks (q 4 w), and wherein the antibody comprises a heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH 1) amino acid sequence of SEQ ID NO:1, CDRH2 of SEQ ID NO:2, and CDRH3 of SEQ ID NO:3, and a light chain variable region comprising the complementarity determining region light chain 1 (CDRL 1) amino acid sequence of SEQ ID NO:4, CDRL2 of SEQ ID NO:5, and CDRL3 of SEQ ID NO:6, and wherein the subject achieves at least a 20% improvement in the american college of rheumatology core set disease index (ACR 20) after the treatment.

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

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

4. The use according to embodiment 1, wherein the antibody is administered at a dose of about 100mg per administration.

5. The use according to embodiment 1, wherein the ACR20 is effected after a treatment period of about 24 weeks.

6. The use according to embodiment 5, wherein the ACR20 is achieved or maintained after a treatment period of about 48 weeks.

7. The use according to embodiment 1, wherein the anti-TNF therapy is an anti-tnfα antibody or a tnfα non-antibody antagonist.

8. The use according to embodiment 7, wherein the anti-tnfα is adalimumab, golimumab, cetuximab therapy, infliximab and/or a biological analogue thereof, and the tnfα non-antibody antagonist is etanercept and/or a biological analogue thereof.

9. The use according to embodiment 1, wherein after the treatment the subject further achieves an improvement in disease activity determined by at least one criterion selected from the group consisting of: the U.S. rheumatology society core set disease index 50% improvement (ACR 50), the U.S. rheumatology society core set disease index 70% improvement (ACR 70), the health assessment questionnaire disability index (HAQ-DI), the overall assessment of researchers (IGA), the disease activity score 28 (DAS 28) C-reactive protein (CRP), resolution of tendinitis, resolution of dactylosin, litz tendinitis index (LEI), dactylitis assessment score, conciseness health investigation (SF-36) of psychological and physiological component summary (MCS and PCS), realization of Minimum Disease Activity (MDA), very Low Disease Activity (VLDA), ankylosing spondylitis disease activity index (BASDAI), graace comprehensive score (GRACE), psoriatic arthritis disease activity score (pasda), modified complex psoriatic disease activity index (cpmdai), psoriasis Area and Severity Index (PASI), dermatological quality of life index (DLQI), functional assessment of chronic therapy (FACIT) and patient reported outcome measurement information system-29 (proc-29).

10. The use according to embodiment 1, wherein the subject further achieves at least a 50% improvement in the american college of rheumatology core set disease index (ACR 50) after the treatment.

11. The use according to embodiment 1, wherein the subject further achieves an improvement in health assessment questionnaire disability index (HAQ-DI) after a treatment period of at least about 24 weeks or about 48 weeks.

12. The use according to embodiment 1, wherein the subject further achieves an improvement in disease activity score 28 (DAS 28) C-reactive protein (CRP) after a treatment period of at least about 24 weeks or about 48 weeks.

13. The use according to embodiment 1, wherein the subject further achieves a 0 (clearance) or 1 (minimum) or 2 or higher IGA reduction in the overall assessment (IGA) of the researcher after a treatment period of at least about 24 weeks or at least about 48 weeks, wherein the subject has a Body Surface Area (BSA) psoriasis involvement of 3% or greater and an IGA score of 2 or greater at baseline prior to treatment.

14. The use according to embodiment 1, wherein the subject is not responsive to standard therapy for PsA, optionally the standard therapy is also administered to the subject during treatment.

15. Use of an anti-IL-23 antibody in a subject in need thereof, wherein the subject shows an insufficient response to treatment with an anti-TNF therapy, wherein about 50mg to about 150mg of the anti-IL-23 antibody is administered subcutaneously to the subject at 0 Zhou Yici, once every 4 weeks and once every 8 weeks thereafter (q 8 w), wherein the antibody comprises a heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH 1) amino acid sequence of SEQ ID NO:1, the CDRH2 of SEQ ID NO:2 and the CDRH3 of SEQ ID NO:3, and a light chain variable region comprising the complementarity determining region light chain 1 (CDRL 1) amino acid sequence of SEQ ID NO:4, the CDRL2 of SEQ ID NO:5 and the CDRL3 of SEQ ID NO:6, and wherein the subject has at least one psoriasis plaque or nail change consistent with psoriasis or a sign of psoriasis prior to the treatment, and the subject achieves an improvement in the index of at least 20% of the heart rate of the disease.

16. The use according to embodiment 15, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO. 7 and a light chain variable region of the amino acid sequence of SEQ ID NO. 8.

17. The use according to embodiment 16, wherein the antibody comprises the heavy chain amino acid sequence of SEQ ID NO. 9 and the light chain amino acid sequence of SEQ ID NO. 10.

18. The use according to embodiment 15, wherein the antibody is administered at a dose of about 100mg per administration.

19. The use according to embodiment 1 or 15, wherein the ACR20 is effected after a treatment period of about 24 weeks or about 48 weeks.

20. The use according to embodiment 15, wherein the anti-TNF therapy is an anti-tnfα antibody or a tnfα non-antibody antagonist.

21. The use according to embodiment 20, wherein the anti-tnfα is adalimumab, golimumab, cetuximab therapy, infliximab and/or a biological analogue thereof, and the tnfα non-antibody antagonist is etanercept and/or a biological analogue thereof.

22. The use according to embodiment 15, wherein after the treatment the subject further achieves an improvement in disease activity determined by at least one criterion selected from the group consisting of: the U.S. rheumatology society core set disease index 50% improvement (ACR 50), the U.S. rheumatology society core set disease index 70% improvement (ACR 70), the health assessment questionnaire disability index (HAQ-DI), the overall assessment of researchers (IGA), the disease activity score 28 (DAS 28) C-reactive protein (CRP), resolution of tendinitis, resolution of dactylosin, litz tendinitis index (LEI), dactylitis assessment score, conciseness health investigation (SF-36) of psychological and physiological component summary (MCS and PCS), realization of Minimum Disease Activity (MDA), very Low Disease Activity (VLDA), ankylosing spondylitis disease activity index (BASDAI), graace comprehensive score (GRACE), psoriatic arthritis disease activity score (pasda), modified complex psoriatic disease activity index (cpmdai), psoriasis Area and Severity Index (PASI), dermatological quality of life index (DLQI), functional assessment of chronic therapy (FACIT) and patient reported outcome measurement information system-29 (proc-29).

23. The use according to embodiment 15, wherein the subject further achieves at least a 50% improvement in the american college of rheumatology core set disease index (ACR 50) after the treatment.

24. The use according to embodiment 15, wherein the subject further achieves an improvement in health assessment questionnaire disability index (HAQ-DI) after a treatment period of at least about 24 weeks or about 48 weeks.

25. The use according to embodiment 15, wherein the subject further achieves improvement in disease activity score 28 (DAS 28) C-reactive protein (CRP) after a treatment period of at least about 24 weeks or at least about 48 weeks.

26. The use according to embodiment 15, wherein the subject further achieves a 0 (clearance) or 1 (minimum) or 2 or higher IGA reduction in the overall assessment (IGA) of the researcher after a treatment period of at least about 24 weeks, wherein the subject has a Body Surface Area (BSA) psoriasis involvement of 3% or greater and an IGA score of 2 or greater at baseline prior to treatment.

27. The use according to embodiment 1, wherein the subject has an inadequate response to standard therapy for PsA.

28. The use according to embodiment 27, wherein the subject is also administered the standard therapy during the treatment.

29. A pharmaceutical composition of anti-IL-23 antibodies for use in treating psoriatic arthritis in a subject in need of treatment with anti-TNF therapy, the pharmaceutical composition comprising

The composition comprises:

a. an antibody comprising: (i) A heavy chain variable region and a light chain variable region, the heavy chain variable region comprising: the complementarity determining region heavy chain 1 (CDRH 1) amino acid sequence of SEQ ID NO. 1, the CDRH2 amino acid sequence of SEQ ID NO. 2, and the CDRH3 amino acid sequence of SEQ ID NO. 3; and the light chain variable region comprises: the complementarity determining region light chain 1 (CDRL 1) amino acid sequence of SEQ ID NO. 4, the CDRL2 amino acid sequence of SEQ ID NO. 5, and the CDRL3 amino acid sequence of SEQ ID NO. 6; (ii) A heavy chain variable region of the amino acid sequence of SEQ ID NO. 7 and a light chain variable region of the amino acid sequence of SEQ ID NO. 8; or (iii) a heavy chain of the amino acid sequence of SEQ ID NO. 9 and a light chain of the amino acid sequence of SEQ ID NO. 10; and

b. a package comprising one or more pharmaceutical product tag elements comprising data from a randomized, double-blind, placebo-controlled clinical study of adult males and females with moderate to severe active psoriatic arthritis who have an inadequate response to anti-TNF therapy.

30. A method of marketing a pharmaceutical product comprising a archakurimab, the method comprising: manufacturing the archaebanking monoclonal antibody; promoting that the therapy comprising the archaebankab is safe and effective for treating a subject suffering from active psoriatic arthritis who exhibits an insufficient response to treatment with an anti-TNF therapy, wherein performing the steps a) and b) results in the purchase of the pharmaceutical product by a healthcare professional (HCP); thereby selling the pharmaceutical product.

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<110> Janssen Biotech, Inc.

Hsia, Elizabeth

Karyekar, Chetan

Kollmeier, Alexa

Noel, Wim

Vigueras, Jaime Oliver

Schubert-Wlodarczyk, Agata

Shawi, May

Taliadouros, Virginia

Theander, Elke

Xu, Xie

<120> treatment of inadequate response to TNF therapy with anti-IL 23 specific antibodies

Is a method for treating psoriatic arthritis patients

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<141> 2022-03-09

<150> 63/160078

<151> 2021-03-12

<151> 63/188707

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Claims (30)

1. A method of treating psoriatic arthritis in a subject in need thereof, wherein the subject exhibits an insufficient response to treatment with anti-TNF therapy, the method comprising subcutaneously administering to the subject about 50mg to about 150mg of an anti-IL-23 antibody once every 4 weeks (q 4 w), wherein the antibody comprises a heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH 1) amino acid sequence of SEQ ID NO:1, CDRH2 of SEQ ID NO:2, and CDRH3 of SEQ ID NO:3, and a light chain variable region comprising the complementarity determining region light chain 1 (CDRL 1) amino acid sequence of SEQ ID NO:4, CDRL2 of SEQ ID NO:5, and CDRL3 of SEQ ID NO:6, and wherein the subject achieves at least a 20% improvement in the american collectile disease index (ACR 20) after the treatment.

2. The method of claim 1, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID No. 7 and a light chain variable region of the amino acid sequence of SEQ ID No. 8.

3. The method of claim 1, wherein the antibody comprises the heavy chain amino acid sequence of SEQ ID No. 9 and the light chain amino acid sequence of SEQ ID No. 10.

4. The method of any one of claims 1 to 3, wherein the antibody is administered at a dose of about 100mg per administration.

5. The method of any one of claims 1-4, wherein the ACR20 is achieved after a treatment period of about 24 weeks.

6. The method of claim 5, wherein the ACR20 is achieved or maintained after a treatment period of about 48 weeks.

7. The method of any one of claims 1-6, wherein the anti-TNF therapy is an anti-tnfa antibody or tnfa non-antibody antagonist.

8. The method of claim 7, wherein the anti-tnfa is adalimumab, golimumab, cetuximab therapy, infliximab and/or a biological analog thereof, and the tnfa non-antibody antagonist is etanercept and/or a biological analog thereof.

9. The method of any one of claims 1 to 8, wherein following the treatment, the subject further achieves an improvement in disease activity determined by at least one criterion selected from the group consisting of: the U.S. rheumatology society core set disease index 50% improvement (ACR 50), the U.S. rheumatology society core set disease index 70% improvement (ACR 70), the health assessment questionnaire disability index (HAQ-DI), the overall assessment of researchers (IGA), the disease activity score 28 (DAS 28) C-reactive protein (CRP), resolution of tendinitis, resolution of dactylosin, litz tendinitis index (LEI), dactylitis assessment score, conciseness health investigation (SF-36) of psychological and physiological component summary (MCS and PCS), realization of Minimum Disease Activity (MDA), very Low Disease Activity (VLDA), ankylosing spondylitis disease activity index (BASDAI), graace comprehensive score (GRACE), psoriatic arthritis disease activity score (pasda), modified complex psoriatic disease activity index (cpmdai), psoriasis Area and Severity Index (PASI), dermatological quality of life index (DLQI), functional assessment of chronic therapy (FACIT) and patient reported outcome measurement information system-29 (proc-29).

10. The method of any one of claims 1-9, wherein the subject further achieves at least a 50% improvement in american college of rheumatology core set disease index (ACR 50) following the treatment.

11. The method of any one of claims 1-10, wherein the subject further achieves an improvement in health assessment questionnaire disability index (HAQ-DI) after a treatment period of at least about 24 weeks or about 48 weeks.

12. The method of any one of claims 1-11, wherein the subject further achieves improvement in disease activity score 28 (DAS 28) C-reactive protein (CRP) after a treatment period of at least about 24 weeks or about 48 weeks.

13. The method of any one of claims 1 to 12, wherein the subject further achieves a reduction in overall assessment (IGA) of a researcher of 0 (clearance) or 1 (minimum) or 2 or higher IGA after a treatment period of at least about 24 weeks or at least about 48 weeks, wherein the subject has a Body Surface Area (BSA) psoriasis involvement of 3% or greater and an IGA score of 2 or higher at baseline prior to the treatment.

14. The method of any one of claims 1 to 13, wherein the subject is not responsive to standard therapy for PsA, optionally the standard therapy is also administered to the subject during the treatment.

15. A method for treating psoriatic arthritis in a subject in need of treatment exhibiting inadequate response to anti-TNF therapy, the method comprising subcutaneously administering to the subject about 50mg to about 150mg of an anti-IL-23 antibody at Zhou Yici, once every 4 weeks and once every 8 weeks thereafter (q 8 w), wherein the antibody comprises a heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH 1) amino acid sequence of SEQ ID NO:1, the CDRH2 of SEQ ID NO:2 and the CDRH3 of SEQ ID NO:3, and a light chain variable region comprising the complementarity determining region light chain 1 (CDRL 1) amino acid sequence of SEQ ID NO:4, the l2 of SEQ ID NO:5 and the CDRL3 of SEQ ID NO:6, and wherein the subject has at least one psoriasis of diameter ≡2cm or nail change or type consistent with psoriasis prior to the treatment, and the subject has an index of improvement in the history of rheumatism of at least 20% of the heart disease (ACR is achieved).

16. The method of claim 15, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID No. 7 and a light chain variable region of the amino acid sequence of SEQ ID No. 8.

17. The method of claim 16, wherein the antibody comprises the heavy chain amino acid sequence of SEQ ID No. 9 and the light chain amino acid sequence of SEQ ID No. 10.

18. The method of any one of claims 15 to 17, wherein the antibody is administered at a dose of about 100mg per administration.

19. The method of any one of claims 1-18, wherein the ACR20 is achieved after a treatment period of about 24 weeks or about 48 weeks.

20. The method of any one of claims 15-19, wherein the anti-TNF therapy is an anti-tnfa antibody or tnfa non-antibody antagonist.

21. The method of claim 20, wherein the anti-tnfa is adalimumab, golimumab, cetuximab therapy, infliximab and/or a biological analog thereof, and the tnfa non-antibody antagonist is etanercept and/or a biological analog thereof.

22. The method of any one of claims 15 to 21, wherein following the treatment, the subject further achieves an improvement in disease activity determined by at least one criterion selected from the group consisting of: the U.S. rheumatology society core set disease index 50% improvement (ACR 50), the U.S. rheumatology society core set disease index 70% improvement (ACR 70), the health assessment questionnaire disability index (HAQ-DI), the overall assessment of researchers (IGA), the disease activity score 28 (DAS 28) C-reactive protein (CRP), resolution of tendinitis, resolution of dactylosin, litz tendinitis index (LEI), dactylitis assessment score, conciseness health investigation (SF-36) of psychological and physiological component summary (MCS and PCS), realization of Minimum Disease Activity (MDA), very Low Disease Activity (VLDA), ankylosing spondylitis disease activity index (BASDAI), graace comprehensive score (GRACE), psoriatic arthritis disease activity score (pasda), modified complex psoriatic disease activity index (cpmdai), psoriasis Area and Severity Index (PASI), dermatological quality of life index (DLQI), functional assessment of chronic therapy (FACIT) and patient reported outcome measurement information system-29 (proc-29).

23. The method of any one of claims 15-22, wherein the subject further achieves at least a 50% improvement in american college of rheumatology core set disease index (ACR 50) following the treatment.

24. The method of any one of claims 15-23, wherein the subject further achieves an improvement in health assessment questionnaire disability index (HAQ-DI) after a treatment period of at least about 24 weeks or about 48 weeks.

25. The method of any one of claims 15-24, wherein the subject further achieves improvement in disease activity score 28 (DAS 28) C-reactive protein (CRP) after a treatment period of at least about 24 weeks or at least about 48 weeks.

26. The method of any one of claims 15 to 25, wherein the subject further achieves a reduction in overall assessment (IGA) of a researcher of 0 (clearance) or 1 (minimum) or 2 or higher IGA after a treatment period of at least about 24 weeks, wherein the subject has a Body Surface Area (BSA) psoriasis involvement of 3% or greater and an IGA score of 2 or higher at baseline prior to the treatment.

27. The method of any one of claims 1 to 26, wherein the subject has an inadequate response to standard therapy for PsA.

28. The method of claim 27, wherein the subject is also administered the standard therapy during the treatment.

29. A pharmaceutical composition of an anti-IL-23 antibody for treating psoriatic arthritis in a subject in need of treatment with anti-TNF therapy that exhibits inadequate response, the pharmaceutical composition comprising:

a. an antibody comprising: (i) A heavy chain variable region and a light chain variable region, the heavy chain variable region comprising: the complementarity determining region heavy chain 1 (CDRH 1) amino acid sequence of SEQ ID NO. 1, the CDRH2 amino acid sequence of SEQ ID NO. 2, and the CDRH3 amino acid sequence of SEQ ID NO. 3; and the light chain variable region comprises: the complementarity determining region light chain 1 (CDRL 1) amino acid sequence of SEQ ID NO. 4, the CDRL2 amino acid sequence of SEQ ID NO. 5, and the CDRL3 amino acid sequence of SEQ ID NO. 6; (ii) A heavy chain variable region of the amino acid sequence of SEQ ID NO. 7 and a light chain variable region of the amino acid sequence of SEQ ID NO. 8; or (iii) a heavy chain of the amino acid sequence of SEQ ID NO. 9 and a light chain of the amino acid sequence of SEQ ID NO. 10; and

b. a package comprising one or more pharmaceutical product tag elements comprising data from a randomized, double-blind, placebo-controlled clinical study of adult males and females with moderate to severe active psoriatic arthritis who have an inadequate response to anti-TNF therapy.

30. A method of selling a pharmaceutical product comprising a archaebankizumab, the method comprising: manufacturing the archaebanking monoclonal antibody; promoting that a therapy comprising archaebankizumab is safe and effective for treating a subject suffering from active psoriatic arthritis who exhibits an insufficient response to treatment with anti-TNF therapy, wherein performing said steps a) and b) results in the purchase of said pharmaceutical product by a Health Care Professional (HCP); thereby selling the pharmaceutical product.