Safe and effective method for treating psoriatic arthritis with Anti-il23 specific antibody

Abstract

To provide a pharmaceutical composition for use in a method for treating psoriatic arthritis.SOLUTION: Disclosed is a pharmaceutical composition comprising an anti-IL-23 antibody for use in a method for treating psoriatic arthritis, where the method comprises subcutaneously administering to a subject about 50 mg to about 150 mg of the anti-IL-23 antibody, the antibody comprises a heavy chain variable region and a light chain variable region, where the heavy chain variable region comprises a complementarity determining region heavy chain 1 (CDRH1) of specific amino acid sequence, a CDRH2 of specific amino acid sequence and a CDRH3 of specific amino acid sequence, and the light chain variable region comprises a complementarity determining region light chain 1 (CDRL1) of specific amino acid sequence, CDRL2 of specific amino acid sequence and CDRL3 of specific amino acid sequence, where the subject achieves at least 20% improvement according to the American College of Rheumatology core data set criteria (ACR20).SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Sequence Listing) This application has been filed electronically in ASCII format and is incorporated by reference in its entirety. Contains a Sequence Listing incorporated herein. An ASCII copy of this is available on May 27, 2020. It was created on the date and is named JBI6102WOPCT1SEQLIST.txt. The size is 12,288 bytes.

[0002] FIELD OF THE INVENTION The present invention provides a method for treating psoriatic arthritis with an antibody that binds to human IL-23 protein. Specifically, the present invention relates to a method for treating psoriatic arthritis. and a method for administering an anti-IL-23 specific antibody, e.g., guselkumab, which is effective in treating IL-23-associated leukemia. . [Background technology]

[0003] Interleukin (IL)-12 is a glycosaminoglycan consisting of two disulfide-linked glycosaminoglycans. The purified protein subunits (denoted p35 and p40 because of their approximate molecular weight) IL-12 is a secreted heterodimeric cytokine composed of the IL-12 receptor and IL-13 receptors. It is mainly produced by antigen-presenting cells and stimulates T cells or natural killer (N) K) Stimulates cell-mediated immunity by binding to a two-chain receptor complex expressed on the surface of cells. The IL-12 receptor beta-1 (IL-12Rβ1) chain binds to the p40 subunit of IL-12. It binds to the mitochondrial membrane, resulting in the primary interaction between IL-12 and its receptor. These proteins mediate intracellular signaling (e.g., STAT4 phosphorylation) and activation of receptor-bearing cells. It confers IL-12p35 ligation of the second receptor chain, IL-12Rβ2. IL-12 signaling, which parallels antigen presentation, promotes the production of interferon-γ (IFNγ It is thought to induce T cell differentiation toward the T helper 1 (Th1) phenotype, characterized by the production of Th1 cells promote immunity against some intracellular pathogens and complement antibody responses. This suggests that IL-12 may contribute to tumor immune surveillance by generating IL-12-dependent IL-12 receptors. It is thought to be an important component of the host defense immune system.

[0004] The p40 protein subunit of IL-12 also binds to a separate protein designated p19. It has been discovered that IL-23 can associate with a protein subunit to form a novel cytokine, IL-23. IL-23 also signals through a two-chain receptor complex. The p40 subunit IL-12Rβ1 chain is shared between IL-12 and IL-23. However, IL-23-specific intracellular signaling is also shared between the two. signaling (e.g., STAT3 phosphorylation) and subsequent IL-17 production by T cells. It is the second component of the IL-23 receptor complex, IL-23R, that confers IL-23p1 9 ligation. Recent studies have demonstrated that the biological functions of IL-23 and IL-12 Despite the structural similarities between these two cytokines, their biological functions are distinct. showed.

[0005] Neutralization of IL-12 by antibodies has been shown to be effective in treating psoriasis, multiple sclerosis (MS), Rheumatoid arthritis, inflammatory bowel disease, insulin-dependent (type 1) diabetes mellitus, and uveitis Abnormal regulation of IL-12 and Th1 cell populations for efficacy in treating animal models has been associated with many immune-mediated diseases. However, these studies share By targeting the 40 subunit, both IL-12 and IL-23 were neutralized in vivo. Therefore, it is unclear whether IL-12 or IL-23 mediated the disease or It is unclear whether both cytokines need to be inhibited to achieve disease control. Studies have shown that IL-23 inhibition may offer benefits comparable to anti-IL-12p40 strategies. This was confirmed by IL-23p19-deficient mice or by neutralizing IL-23 with a specific antibody. There is growing evidence for a specific role of IL-23 in immune-mediated diseases. Neutralizing IL-23 without inhibiting the IL-12 pathway is an important host defense immune mechanism. This can provide an effective treatment for immune-mediated diseases with limited impact on the immune system. would represent a significant improvement over current treatment options.

[0006] Psoriasis is associated with psoriatic arthritis (PsA), depression, cardiovascular disease, and hypertension. Common chronic conditions with significant comorbidities such as hypertension, obesity, diabetes, metabolic syndrome, and Crohn's disease It is an immune-mediated skin disease. Plaque psoriasis is the most common form of the disease. The lesions are erythematous, sharply demarcated, and covered with silvery white scales. The patches are pruritic and painful. It is often disfiguring and disabling, and a significant proportion of people with psoriasis develop psoriasis on the hands / nails, face, and feet. Therefore, psoriasis affects health-related quality of life (HRQoL). These adverse effects go beyond physical skin symptoms to include: These include physical and psychosocial burdens that interfere with daily activities. For example, psoriasis can negatively affect family, spouse, social, and work relationships. It has been linked to higher rates of depression and increased suicidal tendencies.

[0007] Psoriatic arthritis (PsA) includes dactylitis, enthesitis, sacroiliitis, and / or joint deformities It is a multisystem disease characterized by arthritis and psoriasis with various clinical and radiological manifestations. Functional impairment, reduced quality of life, and health care resources associated with poorly controlled PsA Increased utilization of biologics (e.g., tumor necrosis factor [TNF]) has a significant economic burden. osis-factor, TNF]α inhibitors, ustekinumab, secukinumab), and other drugs (e.g. Despite the use of steroids (e.g., apremilast), high levels of steroids are not tolerated when treating heterogeneous disease components. The key issues that remain to be addressed are new PsA treatments that can provide effective and safe There is a huge need.

[0008] Histological characterization of psoriatic lesions reveals lesions due to abnormal keratinocyte proliferation and differentiation. Skin thickening and cutaneous infiltration and colocalization of CD3+ T lymphocytes and dendritic cells were evident. The etiology of psoriasis has not been fully elucidated, but genetic and protein analysis have been reported. Analysis revealed that IL-12, IL-23, and their downstream molecules are overexpressed in psoriatic lesions. It has been shown that some of these compounds may correlate with the severity of psoriasis disease. Some treatments have been shown to contain IL-12 and IL-2, which are thought to contribute to their efficacy. Th1 and Th17 cells regulate the levels of vasodilators, chemoattractants, and Produces effector cytokines that induce the production of substances and the expression of adhesion molecules on endothelial cells These, in turn, include monocyte and neutrophil recruitment, T cell infiltration, angiogenesis, and Activated keratinocytes promote the activation and hyperplasia of keratinocytes. They are capable of producing chemoattractant factors that promote leukocyte, T cell, and dendritic cell trafficking. Thus, a cycle of inflammation and keratinocyte hyperproliferation is established.

[0009] The pathogenesis of psoriasis is being elucidated through the involvement of tumor necrosis factor-α (TNF-α), interleukin (IL-1), targeting both IL-12 and IL-23, and more recently IL-17 and IL-23 alone , which has resulted in effective biological treatment (Phase 1 and 2 clinical trials using guselkumab Guselkumab (also known as CNTO1959, TREMFYA ) binds to the p19 subunit of IL-23 and induces T helper (Th) 17 cell proliferation. Completely inhibits the intracellular and downstream signaling of IL-23, which is required for terminal differentiation of cells. Guselkumab is a human IgG1 lambda monoclonal antibody. It is used to treat moderate to severe bronchitis. It is currently approved in the United States, the European Union, and other countries for the treatment of plaque psoriasis. Guselkumab is effective in the treatment of generalized pustular psoriasis, erythrodermic psoriasis, palmoplantar pustulosis, hidradenitis suppurativa, and psoriatic arthritis. in several other immune-mediated diseases, including psoriasis (PsA), and Crohn's disease It is highly rated. Summary of the Invention [Means for solving the problem]

[0010] The present invention relates to the treatment of psoriatic arthritis (PsA). Specifically, the present invention provides a method for treating psoriatic arthritis in a subject. Clinically proven safety of administering IL-23-specific antibodies to treat PsA and relates to an effective method.

[0011] In one general aspect, the present invention provides a method for treating psoriatic arthritis (PSA) in a subject in need of treatment. sA), comprising administering an anti-IL-23 antibody (IL-23p1), such as guselkumab, 9 antibody) to a subject, Preferably, the subject is a patient with clinically significant The American College of Rheumatology Core Set Disease Index (ACR2) was significantly improved after treatment without any significant adverse events. Achieve at least a 20% improvement in

[0012] In certain embodiments, the anti-IL-23 antibody comprises a heavy chain variable region and a light chain variable region, The chain variable region is the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, SEQ ID NO: a CDRH2 amino acid sequence of SEQ ID NO:2 and a CDRH3 amino acid sequence of SEQ ID NO:3; The variable region is the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, SEQ ID NO: The CDRL2 amino acid sequence is SEQ ID NO:5, and the CDRL3 amino acid sequence is SEQ ID NO:6.

[0013] In certain embodiments, the 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.

[0014] In certain embodiments, the anti-IL-23 antibody has a heavy chain amino acid sequence of SEQ ID NO: 9 and a heavy chain amino acid sequence of SEQ ID NO: and the light chain amino acid sequence of No. 10.

[0015] In certain embodiments, the anti-IL-23 antibody is administered at a dose of 25 mg to 200 mg, preferably The total dose is preferably about 50 mg to about 150 mg, more preferably about 100 mg.

[0016] In certain embodiments, the subject is a responder to treatment with an anti-IL-23 antibody and has a disease Patients were identified as having a statistically significant improvement in disease activity, which was measured by the following groups: The disease is determined by one or more criteria selected from the American College of Rheumatology Core Set Diseases. 20% improvement in the American College of Rheumatology Core Set Disease Index (ACR20), 50% improvement in the American College of Rheumatology Core Set Disease Index improvement (ACR50), 70% improvement in the American College of Rheumatology Core Set Disease Index (ACR70 ), Health Assessment Questionnaire Disability Index (HAQ-DI), Investigator's Global Assessment (IG) A), Disease Activity Score 28 (DAS28), C-reactive protein (CRP), enthesitis Resolution of dactylitis, resolution of dactylitis, Leeds Enthesitis Index (LEI), dactylitis rating score, mental and physical Short-Form Health Survey (MCS and PCS) in Physical Component Summaries SF-36), achievement of minimal disease activity (MDDA), and based on total modified VDH-S score LS mean change from line and achievement of very low disease activity (VLDA).

[0017] In certain embodiments, subjects achieve an ACR with guselkumab versus placebo by week 24 of treatment. Achieving a significant improvement in 20 responses (62.9% vs. 32.9%).

[0018] In another general aspect, the present invention provides a method for treating psoriatic arthritis in a subject in need thereof. The method comprises subcutaneously administering an anti-IL-23 antibody to a subject, is administered at an initial dose, a dose 4 weeks later, and then once every 8 weeks (q8w) thereafter. Subjects must have at least one psoriatic plaque ≥ 2 cm in diameter or a history of psoriasis prior to treatment. and / or a documented history of plaque psoriasis or corresponding nail changes. or subjects met the American College of Rheumatology (ACR) standard of care (ACR) standard of care (ACR) for 24 hours after treatment without any clinically significant adverse events. Achieve at least a 20% improvement in Core Set Disease Index (ACR20).

[0019] In certain embodiments, the anti-IL-23 antibody comprises a heavy chain variable region and a light chain variable region, The chain variable region is the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, SEQ ID NO: a CDRH2 amino acid sequence of SEQ ID NO:2 and a CDRH3 amino acid sequence of SEQ ID NO:3; The variable region is the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, SEQ ID NO: The CDRL2 amino acid sequence is SEQ ID NO:5, and the CDRL3 amino acid sequence is SEQ ID NO:6.

[0020] In certain embodiments, the 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, or the anti-IL-23 antibody comprises a light chain variable region of the sequence It comprises a heavy chain amino acid sequence of SEQ ID NO:9 and a light chain amino acid sequence of SEQ ID NO:10.

[0021] In certain embodiments, the anti-IL-23 antibody is administered at a dose of 25 mg to 200 mg, preferably The total dose is preferably about 50 mg to about 150 mg, more preferably about 100 mg.

[0022] In certain embodiments, the subject has had an inadequate response to standard treatment for PsA. Optionally, the subject also receives standard of care during treatment according to embodiments of the present invention.

[0023] The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages These points will become apparent from the following detailed description, drawings, and appended claims. [Brief explanation of the drawings]

[0024] [Figure 1] 1 shows an outline of a clinical trial according to an embodiment of the present application. [Figure 2] Median serum guselkumab concentrations (μg / mL) and IQ ranges through week 24 in study CNTO1959PSA3002 are shown. [Figure 3] Median serum guselkumab concentrations (μg / mL) and IQ ranges through week 24 in study CNTO1959PSA3002 are shown. [Figure 4] 1 shows a line graph of the number of subjects achieving an ACR20 response by visit through week 24 based on a composite estimate for study CNTO1959PSA3002. [Figure 5] 1 shows a line graph of the number of subjects achieving an ACR50 response by visit through week 24 based on a composite estimate for study CNTO1959PSA3002. [Figure 6] 1 shows a line graph of the number of subjects achieving an ACR70 response by visit through week 24 based on a composite estimate for study CNTO1959PSA3002. [Figure 7] Figure 1 shows the proportion of subjects achieving an ACR 20 response (composite estimate) at week 24 by trough serum guselkumab (composite) concentration (quartiles) at week 20 in study CNTO1959PSA3002. [Figure 8] Figure 1 shows the proportion of subjects achieving an ACR 50 response (composite estimate) at week 24 by trough serum guselkumab (composite) concentration (quartiles) at week 20 in study CNTO1959PSA3002. [Figure 9] Proportion of subjects achieving IGA response (composite estimate) at Week 24 by trough serum guselkumab (composite) concentration (quartiles) at Week 20; PK analysis was performed on subjects with psoriatic lesions ≥ 3% of body surface area (BSA) and an IGA score ≥ 2 (mild) at baseline (Study CNTO1959PSA3002). [Figure 10] 1 shows a schematic of another clinical trial according to an embodiment of the present invention. [Figure 11] Median serum guselkumab concentrations (μg / mL) and IQ ranges through week 24 in study CNTO1959PSA3001 are shown. [Figure 12] Median serum guselkumab concentrations (μg / mL) and IQ ranges through week 24 in study CNTO1959PSA3001 are shown. [Figure 13] 1 shows a line graph of the number of subjects achieving an ACR20 response by visit through week 24 based on a composite estimate for study CNTO1959PSA3001. [Figure 14] 1 shows a line graph of the number of subjects achieving an ACR50 response by visit through week 24 based on a composite estimate for study CNTO1959PSA3001. [Figure 15] 1 shows a line graph of the number of subjects achieving an ACR70 response by visit through week 24 based on a composite estimate for study CNTO1959PSA3001. [Figure 16] Figure 1 shows the proportion of subjects achieving an ACR 20 response (composite estimate) at week 24 by trough serum guselkumab (composite) concentration (quartiles) at week 20 in study CNTO1959PSA3001. [Figure 17] Figure 1 shows the proportion of subjects achieving an ACR 50 response (composite estimate) at week 24 by trough serum guselkumab (composite) concentration (quartiles) at week 20 in study CNTO1959PSA3001. [Figure 18] Proportion of subjects achieving IGA response (composite estimate) at week 24 by trough serum guselkumab (composite) concentration (quartiles) at week 20; PK analysis was performed on subjects with psoriatic lesions ≥ 3% of body surface area (BSA) and an IGA score of ≥ 2 (mild) at baseline (Study CNTO1959PSA3001). [Figure 19] Mean PROMIS-29 T-scores at baseline (dashed line) and week 24 (solid line) are shown. [Figure 20]Clinically meaningful improvement (≥ 5 points) in PROMIS-29 T-score at 24 weeks. [Figure 21A] Figure 1 shows the change from baseline to week 24 in FACIT-Fatigue in patients with psoriatic arthritis in the Discover 1 (A) and Discover 2 (B) studies. [Figure 21B] Figure 1 shows the change from baseline to week 24 in FACIT-Fatigue in patients with psoriatic arthritis in the Discover 1 (A) and Discover 2 (B) studies. [Figure 22A] Shown are (A) NRI and (B) observed ACR20 responses through week 52. Patients randomized to PBO crossed over to GUSq4w at week 25. [Figure 22B] Shown are (A) NRI and (B) observed ACR20 responses through week 52. Patients randomized to PBO crossed over to GUSq4w at week 25. [Figure 23A] Shown are (A) NRI and (B) observed ACR50 responses through week 52. Patients randomized to PBO crossed over to GUSq4w at week 25. [Figure 23B] Shown are (A) NRI and (B) observed ACR50 responses through week 52. Patients randomized to PBO crossed over to GUSq4w at week 25. [Figure 24A] Shown are (A) NRI and (B) observed ACR70 responses through week 52. Patients randomized to PBO crossed over to GUSq4w at week 25. [Figure 24B] Shown are (A) NRI and (B) observed ACR70 responses through week 52. Patients randomized to PBO crossed over to GUSq4w at week 25. [Figure 25A] Observed ACR20 response rates from weeks 24 to 52 are shown for (A) prior TNFi use and (B) TNFi-naive patients. [Figure 25B] Observed ACR20 response rates from weeks 24 to 52 are shown for (A) prior TNFi use and (B) TNFi-naive patients. [Figure 26A]Observed ACR50 response rates from weeks 24 to 52 are shown for (A) prior TNFi use and (B) TNFi-naive patients. [Figure 26B] Observed ACR50 response rates from weeks 24 to 52 are shown for (A) prior TNFi use and (B) TNFi-naive patients. [Figure 27A] Observed ACR70 response rates from weeks 24 to 52 are shown for (A) prior TNFi use and (B) TNFi-naive patients. [Figure 27B] Observed ACR70 response rates from weeks 24 to 52 are shown for (A) prior TNFi use and (B) TNFi-naive patients. [Figure 28] Based on observed data, the number of subjects who achieved an Investigator Global Assessment (IGA) response from visits 24 through 52 weeks is shown. [Figure 29] Based on observed data, the number of subjects who achieved a PASI90 response by visits from week 24 to week 52 is shown. [Figure 30] Based on observed data, a summary of the change from baseline in HAQ-DI scores by visit from week 24 to week 52 is shown. [Figure 31] Based on observed data, the number of subjects who achieved resolution of dactylitis by visits from week 24 to week 52 is shown. [Figure 32] Based on observed data, the number of subjects who achieved enthesitis resolution by visits from week 24 to week 52 is shown. [Figure 33] Based on observed data, a summary of the change from baseline in SF-36 PCS scores by visit from week 24 to week 52 is shown. [Figure 34] Based on observed data, a summary of the change from baseline in SF-36 MCS scores by visit from week 24 to week 52 is shown. DETAILED DESCRIPTION OF THE INVENTION

[0025] As used herein, the method of treating psoriatic arthritis includes using isolated, recombinant and / or Synthetic anti-IL-23 specific human antibodies and diagnostic and therapeutic compositions and methods of administration , and the device.

[0026] As used herein, "anti-IL-23 specific antibody," "anti-IL-23 antibody," "anti "Antibody portion", "antibody fragment" and / or "antibody variant", etc., may be incorporated into the antibody of the present invention. At least one complementarity determining region (CDR) or a CDR of the heavy or light chain that can be embedded in the or a ligand-binding portion thereof, a heavy or light chain variable region, a heavy or light chain constant region, framework regions, or any portion thereof, or the IL-23 receptor or binding protein a small portion of an immunoglobulin molecule, such as, but not limited to, at least a portion of a protein Such antibodies include any protein or peptide-containing molecule that contains at least a portion of the antibody. Optionally, further specific ligands may be affected, including but not limited to: Such antibodies may be used in vitro, in situ, and / or in vivo to inhibit at least one IL-1. modulate, reduce, or enhance IL-23 activity or binding, or IL-23 receptor activity or binding , antagonize, promote, reduce, mitigate, block, inhibit, neutralize and / or interfere. Therefore, preferred anti-IL-23 antibodies, specified portions or variants of the present invention comprise at least one capable of binding to the IL-23 molecule or a specified portion, variant, or domain thereof Suitable anti-IL-23 antibodies, specified portions, or variants may also optionally contain at least one It can affect at least one IL-23 activity or function, but not all such activities. The properties or functions include synthesis of RNA, DNA, or protein, release of IL-23, IL-23 receptor signaling, cleavage of membrane IL-23, activity of IL-23, IL-2 These include, but are not limited to, the production and / or synthesis of 3.

[0027] The term "antibody" includes antibody mimetics or antibodies such as single chain antibodies and fragments thereof. a portion of an antibody that mimics the structure and / or function of, or a specified fragment or portion thereof It is further intended to encompass antibodies, digest fragments, specified portions, and variants thereof, including Functional fragments include antigen-binding fragments that bind to mammalian IL-23. , Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial by reduction), and F(ab')2 (e.g., by pepsin digestion), facb (e.g., , by plasmin digestion), pFc' (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction, and reassembly), Fv, or scFv (e.g., IL-23 fragments, including but not limited to those fragments obtained by molecular biology techniques. or antibody fragments capable of binding to portions thereof are encompassed by the present invention (see, e.g., Collier, supra). gan, Immunology).

[0028] Such fragments may be any fragment known in the art and / or described herein. Antibodies can be produced by enzymatic cleavage, synthetically, or recombinantly. Using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site, various Various truncated forms can also be produced. For example, the gene encoding the F(ab')2 heavy chain portion can be The combination of the heavy chain C H DNA sequence encoding one domain and / or hinge region The various portions of the antibody can be chemically coupled by conventional techniques. or can be prepared as a contiguous protein using genetic engineering techniques. do.

[0029] As used herein, the term "human antibody" refers to an antibody in which substantially all portions of the protein (e.g., For example, 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-specific in humans with only minor sequence changes or mutations. "Human antibody" also refers to an antibody that is immunogenic. Human antibodies can be antibodies derived from or closely matched to a human antibody sequence. Amino acid residues not encoded by germline immunoglobulin sequences (e.g., in vitro by the introduction of random or site-specific mutations in vivo or by the In many cases, this is because human antibodies are Human antibodies are essentially non-immunogenic in humans. They are classified into groups based on sequence similarity. Therefore, sequence similarity searches can be used to An antibody with a similar linear sequence is then selected as a template for generating a human antibody. Similarly, names can be selected from primates (monkeys, baboons, chimpanzees, etc.), rodents, etc. (mouse, rat, rabbit, guinea pig, hamster, etc.) and other mammalian antibodies. Such species, subgenus, genus, subfamily, and family specific antibodies are designated. Furthermore, chimeric antibodies are also referred to as chimeric antibodies. Such changes or mutations may optionally include any combination of: or retain immunogenicity in humans or other species compared to the unmodified antibody. Thus, a human antibody is distinct from a chimeric antibody or a humanized antibody.

[0030] Human antibodies are functionally rearranged human immunoglobulins (e.g., heavy and / or light chains). ) produced by non-human animals, or prokaryotic or eukaryotic cells, capable of expressing the gene Furthermore, when the human antibody is a single-chain antibody, it is possible to generate a natural human antibody. For example, an Fv may contain a linker peptide not found in a heavy chain variable region and a light chain variable region. A linker peptide of 2 to about 8 glycine or other amino acid residues that connects the variable region Such linker peptides are considered to be of human origin.

[0031] Also, preferred monoclonal antibodies have binding specificities for at least two different antigens. Bispecific antibodies, heterospecific antibodies, heterologous antibodies, preferably human antibodies or humanized antibodies Alternatively, antibodies or similar antibodies may be used, in which case one of the binding specificities is at least one against the IL-23 protein and the other against any other antigen Methods for producing bispecific antibodies are known in the art. The recombinant production of target antibodies is based on the co-expression of two immunoglobulin heavy-light chain pairs, The two heavy chains have different specificities (Milstein and Cuello, Na ture, 305:537 (1983). Random combination of immunoglobulin heavy and light chains. To combine these hybridomas (quadromas), ten different antibody molecules are produced. This produces a mixture of possible nucleotides, only one of which has the correct bispecific structure. Purification of such molecules (usually done by affinity chromatography steps) is quite tedious. and the yield of the product is low. A similar procedure is described, for example, in WO 93 / 08829. , U.S. Patent Nos. 6,210,668, 6,193,967, and 6,132,99 No. 2, No. 6,106,833, No. 6,060,285, No. 6,037,453 No. 6,010,902, No. 5,989,530, No. 5,959,084 , No. 5,959,083, No. 5,932,448, No. 5,833,985, Same No. 5,821,333, Same No. 5,807,706, Same No. 5,643,759, Same No. No. 5,601,819, No. 5,582,996, No. 5,496,549, No. No. 4,676,980, International Publication No. 91 / 00360, International Publication No. 92 / 00373 , European Patent No. 03089, Traunecker et al., EMBO J.10 :3655(1991), Suresh et al., Methods in Enz and Physiology 121:210 (1986), each of which is incorporated by reference. and is incorporated herein in its entirety by reference thereto.

[0032] Anti-IL-23 specific antibodies (IL-23 specific) useful in the methods and compositions of the invention Antibodies against IL-23 (also called specific antibodies) have high affinity binding to IL-23. and optionally and preferably, having low toxicity. Specifically, individual components such as variable regions, constant regions, and frameworks are individually The present invention provides a method for the preparation of a medicament for the treatment ... Antibodies, specified fragments, or variants thereof are useful in the present invention. Antibodies capable of administering the therapeutic agent of the present invention have measurable alleviation of symptoms and low and / or acceptable toxicity. Additionally, it may be optionally characterized by its ability to treat patients for long periods of time. Acceptable immunogenicity and / or high affinity, as well as other favorable properties, contribute to the therapeutic results obtained. "Low immunogenicity" as used herein refers to approximately 75% of patients treated. % or preferably less than about 50% significantly HAHA, HACA or HAMA Increased response and / or lower titers (double antigen enzyme immunoassay) in treated patients defined as an increase in β-glucan (β-glucan) of less than about 300, preferably less than about 100, as measured by β-glucan (Elliott et al., Lancet 344:1125-1127) 1994), which is incorporated herein by reference in its entirety. During the recommended course of treatment, fewer than 25% of patients treated at the recommended dose, preferably Anti-IL-23 antibody therapy in patients treated with anti-IL-23 antibodies occurs in less than 10% of patients. It can also be defined as the incidence of titratable levels of antibodies to -23 antibody.

[0033] The terms "clinically proven effective" and "clinically proven effective" refer to the dosage, administration, As used herein in the context of a dosage regimen, treatment, or method, a specific dose, administration, or the clinically proven effectiveness of a treatment regimen. Based on clinical trials, e.g., Phase 3 and earlier, the disease responds to the agents of the invention. For example, the anti-IL-23 antibody of the present invention (e.g., The anti-IL-23 antibody guselkumab) is used to evaluate the efficacy of at least one IL-23 inhibitor, which reflects the severity of the disorder being treated. and administering the drug to the patient in an amount and for a time sufficient to cause improvement, preferably sustained improvement, in the indicators of To determine whether the amount and duration of treatment is adequate, Various indicators that reflect the extent of a subject's disease, disorder, or condition can be assessed. For example, clinical perception of disease severity, symptoms, or manifestations of the disorder of interest. Improvement is determined entirely by the physician, who will then may be based on signs, symptoms, biopsy, or other test results and may be administered to a subject Employing questionnaires, such as quality of life questionnaires developed for a given disease, For example, the anti-IL-23 antibodies of the present invention may be used to treat a patient condition associated with psoriatic arthritis. This improvement can be achieved by improving disease activity indices, reducing clinical symptoms, This can be demonstrated by remission, or any other measure of disease activity.

[0034] In one embodiment, the effectiveness of treating psoriatic arthritis in a subject is correlated with improvement in rheumatoid arthritis. The American College of Rheumatology (ACR) preliminary criteria can be used to determine AC The R criteria consisted of an improvement in the number of tender or swollen joints and an improvement in three of the following five parameters: Measure: acute phase reactants (e.g., sedimentation rate); patient assessment; physician assessment; pain scale; and Disability / Function Questionnaire. ACR criteria are ACR 20 (20 tender or swollen joint counts). 10 percent improvement in 3 of the other 5 criteria), ACR 50 (50 percent improvement in tender or swollen joint count and three of the other five criteria) 50 percent improvement), and ACR 70 (70 percent improvement in tender or swollen joint counts) (Fel) son DT,et al.Arthritis Rheum 1995;38:72 See 7-35).

[0035] In another embodiment, the effectiveness of treating psoriatic arthritis in a subject is measured by measuring the severity / progression of skin disease. The Psoriasis Area and Severity Index (PASI), an index of disease used to assess the extent of ) for example, PASI75 = 75% improvement, PASI90 = 90% improvement. PASI 100 = plaque substantially removed. The HAQ-DI questionnaire was used to measure the enthesitis / dactylitis score in patients with baseline enthesitis / dactylitis. Improvement of the fire, SF-36 mental and physical component summaries (MCS and PCS) may also include one or more of a change in score and achievement of a minimal disease activity (MDA) criteria score. .

[0036] In another embodiment, the efficacy of treating psoriatic arthritis in a subject is assessed by a vdH-S score. It is decided that.

[0037] The term "clinically proven safety" refers to the safety of the anti-IL-23 antibodies of the present invention (e.g., anti-IL-2 3) When the dose, administration regimen, treatment or method using guselkumab is a clinical trial, e.g., a Phase 2 clinical trial, conducted in comparison with a therapeutic agent or another comparator. and treatment-emergent adverse events (AEs or TEAEs) from previous clinical trials. a relatively low or reduced frequency and / or a low or reduced severity of An adverse event is an untoward medical occurrence in a patient receiving a drug. In particular, when it comes to dosages, administration regimens or treatments with the anti-IL-23 antibodies of the present invention: Clinically proven safety may be due to the use of anti-IL-23 antibodies, with a high probability Comparison of adverse events associated with antibody administration if considered likely or very likely refers to a relatively low or reduced frequency and / or a relatively low or reduced severity.

[0038] As used herein, unless otherwise specified, the term "clinically proven" (independently or used to modify the terms "safety" and / or "effectiveness") Clinical trials that meet the approval standards of the US Food and Drug Administration, EMEA, or corresponding national regulatory agencies For example, clinical trials are used to verify the efficacy of a drug. A randomized, double-blind trial of adequate size used to clinically prove efficacy. It is also possible.

[0039] usefulness The isolated nucleic acids of the present invention encode at least one anti-IL-23 antibody or a specified variant thereof. The compounds can be used to produce mutants, which can be used to diagnose, monitor, regulate, treat, or alleviate the symptoms of psoriasis. the production of cells, tissues, organs or animals (mammals and The invention can be used to measure or act on animals (including humans and animals).

[0040] Such methods include those for such regulation, treatment, alleviation, prevention, or reduction of symptoms, or for the treatment or prevention of symptoms. administering at least one anti-IL-1 receptor to a cell, tissue, organ, animal, or patient in need thereof The effective amount may include administering an effective amount of a composition or pharmaceutical composition comprising the antibody. These may be performed and determined using known methods, as described herein or as known in the relevant art. When administered, the dose is about 0.001 to 5 per single (e.g., bolus), multiple, or continuous administration. 00 mg / kg or 0.01 to 5000 μg per single, multiple, or continuous dose An amount that achieves a serum concentration of 100 mg / mL or any range or value therein. good.

[0041] References All publications or patents cited herein, whether specifically designated or not, are hereby incorporated by reference. which are incorporated herein in their entirety by reference to represent prior art at the time of the present invention; and / or A publication is a document recorded in electronic or printed form that describes and enables the invention. Any scientific publication or patent available in any media format, including any The following documents are incorporated herein by reference in their entirety: :Ausubel,et al.,ed.,Current Protocols i n Molecular Biology,John Wiley&Sons,Inc. ,NY,NY(1987-2001),Sambrook,et al.,Molecu lar Cloning:A Laboratory Manual,2nd Edit ion, Cold Spring Harbor, NY (1989), Harlow a nd Lane,antibodies,a Laboratory Manual,C old Spring Harbor, NY (1989), Colligan, et a l.,eds.,Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994-2001), Colli gan et al.,Current Protocols in Protein Science,John Wiley&Sons,NY,NY,(1997-2001 ).

[0042] Antibodies Useful in the Invention - Production and Generation The at least one anti-IL-23 used in the methods of the invention optionally comprises a IL-23 antibody that is ... Any cell line, mixed cell line, immortalized cell, or clonal population of immortalized cells known in the art may be used. For example, Ausubel, et al., ed., Curr. rent Protocols in Molecular Biology,John Wiley & Sons, Inc., NY, NY (1987-2001), Sambro ok,et al.,Molecular Cloning:A Laboratory Manual,2nd Edition,Cold Spring Harbor,N Y (1989), Harlow and Lane, antibodies, a Lab. oratory Manual,Cold Spring Harbor,NY(198 9), Colligan,et al.,eds.,Current Protocol s in Immunology,John Wiley&Sons,Inc.,NY( 1994-2001), Colligan et al.,Current Proto cols in Protein Science,John Wiley&Sons, See NY, NY, (1997-2001), each of which is incorporated herein by reference in its entirety. be incorporated into the book.

[0043] Human antibodies specific for human IL-23 protein or fragments thereof include isolated IL-23 Suitable molecules such as proteins and / or parts thereof (including synthetic molecules such as synthetic peptides) Other specific or general mammalian antibodies may be raised against the immunogenic antigen. Preparation of immunogenic antigens and generation of monoclonal antibodies can be carried out using any suitable technique. It can be done using.

[0044] In one approach, a suitable immortal cell line (e.g., but not limited to, Sp2 / 0, S p2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, L243, P3X6 3Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5 , U937, MLA 144, ACT IV, MOLT4, DA-1, JURKAT, W EHI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA 144 Myeloma cell lines such as NAMALWA, NEURO 2A, or heteromyelomas, The fusion product, or any cell or fusion cell derived therefrom, or any cell or fusion cell derived therefrom, or any cell or fusion product ... Any other suitable cell line known in the art) (see, for example, www.atcc.org, www.lif etech.com), including, but not limited to, isolated or cloned Antibody cells such as spleen, peripheral blood, lymph, tonsils, or other immune or B cell-containing cells recombinant or endogenous, viral, cellular, or endogenous nucleic acid, either in somatic cells or as endogenous or heterologous nucleic acid. Fungi, algae, prokaryotes, amphibians, insects, reptiles, fish, mammals, rodents, horses, sheep, goats , sheep, primates, eukaryotes, genomic DNA, cDNA, rDNA, mitochondrial DNA A or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, simple as single-, double- or triple-stranded, hybridized, etc., or any combination thereof Either the heavy or light chain constant or variable, or framework or CDR sequences Hybridomas are produced by fusing the cells with any other cells that express the above gene. See Ausubel, supra, and Colligan, Immunology, chapter 2, supra. and JP 2004-1026634, both of which are incorporated herein by reference in their entireties.

[0045] Antibody-producing cells can also be isolated from the peripheral blood of humans or other suitable animals immunized with an antigen of interest, or Preferably, the host cells may be obtained from the spleen or lymph nodes. can be used to produce heterologous nucleic acids encoding antibodies, specified fragments or variants thereof of the invention Endogenous nucleic acids may also be expressed. Hybridomas or recombinant cells may be selected. The cells are isolated using selective culture conditions or other suitable known methods, such as limiting dilution or cell sorting. Antibodies with the desired specificity can be cloned by other known methods. Producing cells can be selected by a suitable assay (eg, ELISA).

[0046] Examples include methods for selecting recombinant antibodies from peptide or protein libraries. Any suitable method for producing or isolating antibodies with the required specificity, including but not limited to: Other methods can be used (e.g., bacteriophage, ribosome, oligonucleotide Display libraries including, but not limited to, nucleotides, RNA, and cDNA For example, Cambridge Antibody Technologies, mbridgeshire, UK, MorphoSys, Martinsreid / Pl anegg, DE, Biovation, Aberdeen, Scotland, UK, BioInvent, Lund, Sweden, Dyax Corp., Enzon, A ffymax / Biosite, Xoma, Berkeley, CA, from Ixsys. (See, for example, European Patent No. 368,684, International Application No. PCT / GB91 / 01134, International Application No. PCT / GB92 / 01755, International Application No. PCT / GB92 / No. 002240, International Application No. PCT / GB92 / 00883, International Application No. PCT / GB93 / 00605, U.S. Patent Application No. 08 / 350260 (5 / 12 / 94), International Application P CT / GB94 / 01422, International Application PCT / GB94 / 02662, International Application P CT / GB97 / 01835, (CAT / MRC), International Publication No. 90 / 14443, International Publication No. 90 / 14424, International Publication No. 90 / 14430, International Application No. PCT / US 94 / 1234, WO 92 / 18619, WO 96 / 07754 (Sc ripps), WO 96 / 13583, WO 97 / 08320 (Mor phoSys), WO 95 / 16027 (BioInvent), WO 8 8 / 06630 WO 90 / 3809 (Dyax), U.S. Pat. No. 92 (Enzon), International Application No. PCT / US91 / 02989 (Affymax), International Publication No. 89 / 06283, European Patent No. 371998, European Patent No. 550400 , (Xoma), European Patent No. 229046, International Application No. PCT / US91 / 07149 (Ixsys), or stochastically generated peptides or proteins - U.S. Pat. No. 723323, No. 5763192, No. 5814476, No. 5817483 , Patent Nos. 5824514, 5976862, International Publication No. 86 / 05803, European Patent No. Patent No. 590689 (Ixsys, Applied Molecular Evolution) ion) (AME) predecessor, each of which is incorporated herein by reference in its entirety) or Repertoires of human antibodies known in the art and / or described herein It relies on immunization of transgenic animals capable of producing LEs (e.g., SC ID mouse, Nguyen et al.,Microbiol.Immunol.41 :901-907(1997), Sandhu et al., Crit.Rev.Bi otechnol.16:95-118(1996), Eren et al., Imm. 93:154-161 (1998) (each of which is incorporated by reference in its entirety) ) Such techniques include ribosome display (Hanes et al., Proc. Natl.Acad.Sci.USA,94:4937-4942(May 1997) , Hanes et al., Proc. Natl. Acad. Sci. USA, 95: 14130-14135 (Nov. 1998)), single-cell antibody production technology (e.g., selection Lymphocyte Antibody Method ("SLAM") (U.S. Patent No. 5,627,052, Wen et al. al., J. Immunol. 17:887-892 (1987), Babcook e t al.,Proc.Natl.Acad.Sci.USA 93:7843-784 8 (1996)), gel microdroplets and flow cytometry (Powel l 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 (Stee nbakkers et al.,Molec.Biol.Reports 19:12 5-134 (1994), Jonak et al., Progress Biotec h,Vol.5,In Vitro Immunization in Hybrido ma Technology,Borrebaeck,ed.,Elsevier Sc. ience Publishers BV,Amsterdam,Netherla nds (1988)), but are not limited to these.

[0047] Methods for engineering or humanizing non-human or human antibodies can be used as well, Generally, humanized or modified antibodies are antibodies that are derived from non-human, e.g. , including but not limited to, mice, rats, rabbits, non-human primates, or other mammalian subjects. These non-human amino acid residues are often These residues are often replaced by residues called "import" residues. The bases are typically "import" variable domains, constant domains, or other fragments of known human sequences. is obtained from the domain of

[0048] Such imported sequences may be used to reduce immunogenicity or to enhance the ability of the polypeptides to bind to polypeptides that are known in the art. As known in the art, binding, affinity, association rate constant, dissociation rate constant, avidity, specificity The compounds may be used to reduce, enhance or modify the half-life, or any other suitable property. In general, the CDR residues directly and most substantially influence antigen binding. Thus, it is possible to modify the variable regions while maintaining some or all of the non-human or human CDR sequences. Replacing non-human sequences in the ribosomal and constant regions with human amino acids or other amino acids. It is also possible.

[0049] Antibodies may optionally be humanized, or human antibodies may have high affinity for antigens. To this end, they can be modified while retaining their sex and other advantageous biological properties. Optionally, a three-dimensional model of the parental and humanized sequences is used to identify the parental and various humanized sequences. Humanized (or human) antibodies can be prepared by a process of analyzing theoretical humanized products. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. The likely three-dimensional conformations of selected immunoglobulin sequence candidates are analyzed. Computer programs are available for illustrating and displaying these displays. This allows for the analysis of the likely role of residues in the function of the candidate immunoglobulin sequence. In other words, it becomes possible to analyze residues that affect the antigen-binding ability of immunoglobulin candidates. This allows for desirable antibody properties, such as enhanced affinity for the target antigen(s), to be achieved. Framework (FR) residues were selected from the consensus and import sequences so that You can choose and combine.

[0050] In addition, the human IL-23 specific antibodies used in the methods of the present invention contain human germline light chain fragments. In certain embodiments, the light chain germline sequence may comprise the sequences A1, A10, A 11, A14, A17, A18, A19, A2, A20, A23, A26, A27, A3 , A30, A5, A7, B2, B3, L1, L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23, L24, L25, L4 / 18 a, L5, L6, L8, L9, O1, O11, O12, O14, O18, O2, O4, and The VK sequences are selected from human VK sequences, including, but not limited to, O8 and O9. In terms of structure, the light chain human germline frameworks are 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.

[0051] In another embodiment, the human IL-23 specific antibody used in the methods of the invention is human genital IL-23 specific. In certain embodiments, the heavy chain may comprise a human germline heavy chain framework. Frameworks: 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, VH 3-38, 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.

[0052] In certain embodiments, the light chain variable region and / or the heavy chain variable region comprises framework regions: or at least a portion of a framework region (e.g., 2 or 3, such as FR2 and FR3) In certain embodiments, the FRL1 gene comprises at least one subregion (FRL1, FRL2, and FRL3). In another embodiment, at least FRL1, FRL2, FRL3, or FRL4 is fully human. FRH2, FRH3, or FRH4 is fully human. At least FRL1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., a sequence of a human the human consensus sequence for a particular framework (see above). In other embodiments, the antibody comprises at least Each of FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., a human germline sequence). sequence) or contains a human consensus sequence for a particular framework. In a preferred embodiment, the framework regions are completely human framework regions.

[0053] The humanization or engineering of the antibodies of the present invention can be carried out according to the methods described in Winter (Jones et al., Nature 321:522(1986), Riechmann et al.,Na ture 332:323 (1988), Verhoeyen et al. nce 239:1534(1988)), Sims et al., J. Immuno l.151:2296(1993), Chothia and Lesk, J. Mol. Biol.196:901(1987), Carter et al., Proc.Na tl.Acad.SCi.USA89:4285(1992), Presta e t al., J. Immunol. 151:2623 (1993), U.S. Patent No. 5723 No. 323, No. 5976862, No. 5824514, No. 5817483, No. No. 5814476, No. 5763192, No. 5723323, No. 5,76688 No. 6, No. 5714352, No. 6204023, No. 6180370, No. 56 No. 93762, No. 5530101, No. 5585089, No. 5225539, No. 4816567, International Application PCT / :US98 / 16280, US96 / 189 No. 78, US91 / 09630, US91 / 05939, US94 / 01234, GB89 / 01334, GB91 / 01134, GB92 / 01755, International Publication European Patent Nos. 90 / 14443, 90 / 14424, 90 / 14430, No. 229246 (each of which is incorporated by reference in its entirety and the references cited therein). using any known method, such as, but not limited to, those described in This can be done as follows.

[0054] In certain embodiments, the antibody comprises an altered (e.g., mutated) Fc region. For example, in some embodiments, the Fc region may be used to reduce the effector functions of an antibody. In some embodiments, the Fc region is modified to reduce or enhance Ig is an isotype selected from M, IgA, IgG, IgE, or other isotypes Alternatively or additionally, amino acid modifications and C1q binding of the Fc region of the IL-23 binding molecule may be used. and / or one or more additional amino acid modifications that alter complement-dependent cytotoxicity function. Starting polypeptides of particular interest are those that bind to C1q. It may be a compound that exhibits complement-dependent cytotoxicity (CDC). Polypeptides having the ability to mediate CDC and optionally further having the ability to mediate CDC are The antibody may be modified to enhance one or both of its activities. Amino acid modifications that modify the complement-dependent cytotoxicity function of the polypeptides described in, for example, WO 02 / 064444 are also described. No. 042072, which is incorporated herein by reference.

[0055] As disclosed above, for example, C1q binding and / or FcγR binding may be modified, By this, complement-dependent cytotoxicity (CDC) activity and / or antibody-dependent cell-mediated cytotoxicity ( By altering antibody-dependent cell-mediated cytotoxicity (ADCC) activity, Thus, the Fc region of the human IL-23 specific antibody of the present invention having altered effector functions An "effector function" is a function that induces a biological activity (e.g., in a subject). Examples of effector functions include but are not limited to: Although not specific to the immune system, C1q binding, CDC, Fc receptor binding, ADCC, phagocytosis, and cell surface downregulation of receptors (e.g., B cell receptors, BCR). Such effector functions are achieved by the Fc region being linked to a binding domain (e.g., an antibody variable domain). A variety of test methods (e.g., Fc binding assays, A DCC assay, CDC assay, etc.) can be used to evaluate the activity of the antibody.

[0056] For example, having improved C1q binding and improved FcγRIII binding (e.g., Human IL-23 (also known as IL-23) with both improved ADCC activity and improved CDC activity Alternatively, the effector If it is desired to reduce or eliminate function, the variant Fc region may have reduced CDC activity. The antibody can be modified to increase its activity and / or to reduce its ADCC activity. In the present invention, only one of these activities may be enhanced, optionally with the other activity being enhanced at the same time. may be reduced (e.g., have improved ADCC activity and reduced CDC activity) (To generate Fc region variants, and vice versa).

[0057] Fc mutations alter interactions with fetal Fc receptors (FcRn) and their pharmacokinetics Genes can also be engineered and introduced to improve properties. A collection of improved human Fc variants has been described (Shields et al., 2002). 001).High resolution mapping of the bind ing site on human IgG1 for FcγRI,FcγRII, FcγRIII,and FcRn and design of IgG1 vari ants with improved binding to the FcγR,J .Biol.Chem.276:6591-6604).

[0058] Another type of amino acid substitution is the glycosylation paclitaxel of the Fc region of a human IL-23-specific antibody. Glycosylation of the Fc region is typically N-linked or O-linked. N-linked is the attachment of the carbohydrate moiety to the side chain of an asparagine residue O-linked glycosylation also refers to 5-hydroxyproline or 5-hydroxylysine. May be used, but hydroxyamino acids, most commonly serine or threonine one of the sugars N-acetylgalactosamine, galactose, or xylose Refers to attachment. Recognition for enzymatic addition of carbohydrate moieties to asparagine side chain peptide sequences. The sequences are asparagine-X-serine and asparagine-X-threonine, where X is a promoter. Any amino acid other than ribonucleotides. Therefore, any of these amino acids can be present in a polypeptide. The presence of the peptide sequence provides a potential glycosylation site.

[0059] A glycosylation pattern can refer to, for example, one or more glycosylations found on a polypeptide. Deleting a site(s) and / or one or more groups that are not present in the polypeptide The Fc of human IL-23-specific antibodies can be modified by adding glycosylation sites. The addition of glycosylation sites to the region can be accomplished by modifying the region to include one or more of the above tripeptide sequences. This is successfully achieved by altering the amino acid sequence (in the case of N-linked glycosylation sites). An exemplary glycosylation variant has an amino acid substitution at residue Asn297 of the heavy chain. This alteration may be achieved by the addition of one or more serine or threonine residues to the original polypeptide sequence, or by substitution with these (in the case of O-linked glycosylation sites). Additionally, changing Asn 297 to Ala removes one of the glycosylation sites. can.

[0060] In certain embodiments, the human IL-23-specific antibodies of the invention inhibit the GnT III G A beta(1,4)-N-acetylglucosamine derivative was synthesized to add 1cNAc to the human IL-23 antibody. Expressed in cells expressing glucosaminyltransferase III (GnT III) Methods for producing antibodies in such a manner are described in WO 9954342, WO 9954343, WO 9954344, WO 9954345, WO 9954346, WO 9954347, WO 9954348, WO 9954349 ... 03011878, Patent Publication No. 20030003097(A1), and Umana et al.,Nature Biotechnology,17:176-180,F eb.1999, all of which are incorporated herein by reference in their entireties. be physically incorporated.

[0061] The anti-IL-23 antibody also optionally comprises any of the antibodies described herein and / or in the art. As is known in the art, transgenic mice capable of producing a repertoire of human antibodies have been developed. produced by immunization of a matched animal (e.g., mouse, rat, hamster, non-human primate, etc.) Cells that produce human anti-IL-23 antibodies may be produced by the methods described herein. They may be isolated from such animals and immortalized using any suitable method.

[0062] Transgenic mice capable of producing a repertoire of human antibodies that bind to human antigens The mice can be made by known methods, including but not limited to: However, U.S. Patent Nos. 5,770,428 and 5,569, issued to Lonberg et al. No. 825, No. 5,545,806, No. 5,625,126, No. 5,625,8 Nos. 25, 5,633,425, 5,661,016, and 5,789, No. 650, Jakobovits et al., International Publication No. 98 / 50433, Jakobovi WO 98 / 24893 to ts et al., WO 98 / 2488 to Lonberg et al. No. 4, International Publication No. 97 / 13852, Lonberg et al. No. 94 / 25585, Kucherlapate et al., International Publication No. 96 / 34096, European Patent No. 0463151(B1) to Kucherlapate et al. European Patent No. 0710719(A1) to Pate et al., U.S. Patent No. 5,555 to Surani et al. 45,807, Bruggemann et al., International Publication No. 90 / 04036, Brugg European Patent No. 0438474(B1) to Emann et al., European Patent No. 0438474(B1) to Lonberg et al. 814259(A2), Lonberg et al., UK Patent No. 2272440(A), Lonberg et al. Nature 368:856-859 (1994), T aylor et al., Int. Immunol. 6(4)579-591 (19 94), Green et al., Nature Genetics 7:13-21( 1994), Mendez et al., Nature Genetics 15:1 46-156(1997), Taylor et al., Nucleic Acids Research 20(23):6287-6295(1992), Tuaillo n et al., Proc Natl Acad Sci USA 90(8)372 0-3724(1993), Lonberg et al., Int Rev Immu nol 13(1):65-93(1995), and Fishwald et al., Nat Biotechnol 14(7):845-851(1996), these are (Each is incorporated herein by reference in its entirety.) Generally, these mice are functionally reproducible. At least one human immunoglobulin capable of undergoing constructed or functional rearrangement The mouse contains at least one transgene containing DNA from the phospho-phosphoryl locus. The endogenous immunoglobulin loci of the mouse are disrupted or deleted to allow the endogenous genes of the mouse to be expressed. The ability to produce antibodies encoded by the vector can be eliminated.

[0063] Screening of antibodies for specific binding to similar proteins or fragments can be performed using peptide This can be successfully achieved using a hand-display library. Screening large collections of peptides for individual members with novel functions or structures Antibody screening of peptide display libraries involves The length of the displayed peptide sequence is generally between 3 and 5,000. More than 100 amino acids in length, often 5 to 100 amino acids in length, and most often about 8 to 25 In addition to direct chemical synthesis methods for creating peptide libraries, Several recombinant DNA methods have also been described. One type involves the use of bacteriophages or Each bacteriophage or cell contains the nucleotide sequence that encodes the particular displayed peptide sequence. Such methods are described in WO 91 / 17271, WO 91 / 18980, WO 91 / 1 9818 and 93 / 08278.

[0064] Other systems for generating peptide libraries include in vitro chemical synthesis and Both aspects of the recombinant method are included. See U.S. Pat. Nos. 5,658,754 and 96 / 19256. See also U.S. Pat. Nos. 5,643,768 and 5,643,768. Peptide display libraries, vectors, and the like. The vector and screening kit were purchased from Invitrogen (Carlsbad, CA). ) and Cambridge antibody Technologies (Cambr It is commercially available from sources such as Enzon (Hillsbridge, UK). Assigned U.S. Patent Nos. 4,704,692, 4,939,666, and 4,946,778 , No. 5260203, No. 5455030, No. 5518889, No. 5534 No. 621, No. 5656730, No. 5763733, No. 5767260, No. 5767260, No. 5763733, No. 5767260, No. No. 5,856,456, U.S. Patent Nos. 5,223,409 and 5,4034 assigned to Dyax No. 84, No. 5571698, No. 5837500, assigned to Affymax National Patent No. 5427908, No. 5580717, Cambridge Antibo U.S. Patent No. 5,885,793, assigned to Genen Technologies, U.S. Patent No. 5,750,373 assigned to tech, U.S. Patent No. 5,750,373 assigned to Xoma No. 618920, No. 5595898, No. 5576195, No. 5698435 , No. 5693493, No. 5698417, Colligan supra, Au supra See, e.g., EP 1 166 563, or Sambrook, supra. Each is incorporated herein by reference in its entirety.

[0065] The antibodies used in the methods of the present invention may also be derived from goats, cows, horses, and other animals that produce such antibodies in their milk. The nucleic acid can be used to provide a transgenic animal or mammal, such as a mouse, sheep, rabbit, or the like. The antibody may also be prepared using at least one anti-IL-23 antibody encoding such an antibody. Animals can be prepared using known methods, including but not limited to: , U.S. Patent Nos. 5,827,690, 5,849,992, and 4,873,31 No. 6, No. 5,849,992, No. 5,994,616, No. 5,565,362 Nos. 5,304,489, et al., each of which is incorporated by reference in its entirety. (incorporated herein).

[0066] The antibodies used in the methods of the present invention may be used in plant parts or cells cultured therefrom. Transgenic plants and cultured cells that produce such antibodies, specified portions, or variants. providing plant cells (e.g., but not limited to, tobacco and corn) The nucleic acid encoding at least one anti-IL-23 antibody is further prepared to As a non-limiting example, for example, an inducible promoter can be used to express a recombinant protein. Transgenic tobacco leaves expressing the protein have been successfully used to produce large amounts of recombinant protein. For example, Cramer et al., Curr. Top. Micro bol. Immunol. 240:95-118 (1999) and the texts cited therein Transgenic maize has also been shown to be viable in other recombinant systems. have biological activity equivalent to that of proteins synthesized or purified from natural sources. It has been used to express mammalian proteins at commercial production levels. ood et al.,Adv.Exp.Med.Biol.464:127-147( 1999) and the references cited therein. The antibody may be a single chain antibody (scFv). Transgenic plants, such as tobacco seeds and potato tubers, containing antibody fragments such as It has also been produced in large quantities from the seeds of plants such as Conrad, Plant Mol. B Iol. 38:101-109 (1998) and the references cited therein. Therefore, the antibodies of the present invention can also be produced using transgenic plants according to known methods. For example, Fischer et al., Biotech nol.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.22:94 See also, pp. 0-944 (1994), and the references cited therein. Each is incorporated herein by reference in its entirety.

[0067] The antibodies used in the methods of the present invention have a wide range of affinities (K D ) to human IL-23 In a preferred embodiment, the human mAb is optionally capable of binding with high affinity. For example, a human mAb can bind to human IL-23. about 10 -7 M or less, for example, 0.1 to 9.9 (or any range or value therein) x 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 or Any range or value in the range, including but not limited to: D can be combined with Cut.

[0068] The affinity or avidity of an antibody for an antigen can be determined experimentally using any suitable method. (See, for example, Berzofsky, et al., "Antibody- Antigen Interactions,” In Fundamental Imm. unology, Paul, WE, Ed., Raven Press: New Yo rk, NY (1984), Kuby, Janis Immunology, WHFr eeman and Company: New York, NY (1992), and Honmei (See methods described in the supplement.) Compatibility may differ when measured under different conditions (e.g., salt concentration, pH). Therefore, affinity and other antigen binding parameters (e.g., K D、 K a , K. d ) measurement is preferred or standard solutions of antibodies and antigens, and standard buffers, such as those described herein. This is done using

[0069] nucleic acid molecule For example, the light chain or At least 70 to 10 contiguous amino acids of at least one of the heavy chain variable or CDR regions Nucleotide sequences encoding 0%, specified fragments, variants or their concomitants The present invention also relates to the use of the sas sequences, or a deposited vector containing at least one of these sequences. 100226634. The information provided in the above is used to construct a nucleic acid encoding at least one anti-IL-23 antibody of the present invention. The nucleic acid molecules can be obtained using methods described herein or known in the art. It is possible.

[0070] The nucleic acid molecules of the present invention may be in the form of mRNA, hnRNA, tRNA or any other form. in the form of RNA, or cDNA obtained by cloning or produced synthetically and genomic DNA, or any of these forms of DNA. The DNA may be triple-stranded, double-stranded, single-stranded, or a combination of these. Any combination of any portion of at least one strand of DNA or RNA The DNA may be the coding strand, also known as the sense strand, or may be called the antisense strand. It may also be the non-coding strand.

[0071] The isolated nucleic acid molecule used in the methods of the present invention optionally contains one or more introns. An open reading frame (ORF) having, for example, the following: at least one heavy or light chain CDR1, CDR2, and / or CDR3 of the A nucleic acid molecule comprising at least one specified portion of at least one CDR, such as R3. , a nucleic acid molecule comprising a coding sequence of an anti-IL-23 antibody or a variable region thereof, and a nucleic acid molecule comprising the above-mentioned nucleic acid molecule. Although substantially different, due to the degeneracy of the genetic code, the sequences described herein and / or in the art may be used interchangeably. Nucleotides encoding at least one anti-IL-23 antibody known in the art are also provided. It will be appreciated that the genetic code may include nucleic acid molecules containing the sequence of the gene. Therefore, those skilled in the art will be able to easily identify specific anti-I antibodies for use in the methods of the present invention. It is routine to generate such modified nucleic acid variants encoding the L-23 antibody. See, e.g., Ausubel et al., supra, and such nucleic acid variants are within the scope of the present invention. Non-limiting examples of isolated nucleic acid molecules include HC CDR1, HC CDR2, HC CDR3, HC CDR4, HC CDR5, HC CDR6, HC CDR7, HC CDR8, HC CDR9, HC CDR10, HC CDR11, HC CDR12, HC CDR13, HC CDR14, HC CDR15, HC CDR16, HC CDR17, HC CDR18 HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR Nucleic acids encoding 3 are also included.

[0072] As described herein, nucleic acid molecules comprising nucleic acids encoding anti-IL-23 antibodies include The antibody fragment itself may encode the amino acid sequence of a full-length antibody or a fragment of a full-length antibody. The coding sequence for a portion of the antibody, fragment or portion thereof, as well as additional sequences, e.g. with or without additional coding sequences as described above, e.g., at least one intron. , non-coding 5' and 3' sequences, such as splicing and polyadenylation signals (e.g. In transcription, mRNA processing, including, for example, ribosome binding and stability of mRNA Additional non-coding sequences, including but not limited to transcribed and untranslated sequences, play a role in a coding sequence for at least one signal leader or fusion peptide, and additional coding sequences encoding additional amino acids, e.g., amino acids that provide additional functions. Therefore, the sequence encoding the antibody can be any of the following: For example, the marker sequence can be fused to an antibody to which it is fused. A sequence encoding a peptide that facilitates the purification of the antibody, including fragments or portions thereof.

[0073] Polynucleotides that selectively hybridize to the polynucleotides described herein The method of the present invention provides a method for selectively hybridizing to the polynucleotides disclosed herein. The present invention uses isolated nucleic acids that hybridize under hybridization conditions. Polynucleotides of the embodiments are useful for isolating, detecting, and analyzing nucleic acids comprising such polynucleotides. For example, the polynucleotides of the present invention can be used to quantify to identify, isolate, or amplify partial or full-length clones in the deposited library. In some embodiments, the polynucleotide can be isolated, or otherwise complementary to the cDNA of a human or mammalian nucleic acid library. It is a genome sequence or a cDNA sequence.

[0074] Preferably, the cDNA library contains at least 80% of the full-length sequences, preferably the full-length It contains at least 85% or 90% of the sequence, more preferably at least 95% of the full-length sequence. This cDNA library can be normalized to increase the representation of rare sequences. Low or medium stringency, using sequences with low sequence identity to the complementary sequence The hybridization conditions are typical, but not limited to, the following. For higher sequences, medium and high stringency conditions may optionally be used. Low stringency conditions allow selective hybridization of sequences with approximately 70% sequence identity. This allows for the identification of orthologous or paralogous sequences. Cut.

[0075] Optionally, the polynucleotide encodes at least a portion of an antibody. The nucleic acid fragments are capable of selectively hybridizing to a polynucleotide encoding an antibody of the present invention. For example, Ausubel, supra, See Colligan, supra, each of which is incorporated herein by reference in its entirety. can be.

[0076] Nucleic acid construction Isolated nucleic acids can be prepared by (a) recombinant methods; (b) synthetic methods, as are well known in the art; (c) synthesis techniques, (d) purification techniques, and / or (e) combinations thereof. can be done.

[0077] The nucleic acids can conveniently include sequences in addition to the polynucleotides of the present invention. For example, a multiple cloning site containing one or more endonuclease restriction sites may be inserted into the nucleobase. The translatable sequence can be inserted into a nucleic acid to aid in the isolation of the polynucleotide. can be inserted to aid in the isolation of the translated polynucleotide of the present invention. For example, a hexa-histidine marker sequence provides a convenient means for purifying the proteins of the present invention. The nucleic acids of the invention (excluding coding sequences) are optionally prepared as polynucleotides of the invention. vectors, adapters, or linkers for cloning and / or expression of peptides .

[0078] Additional sequences may be added to such cloning and / or expression sequences to facilitate cloning and expression. and / or optimizing their function in expression, aiding in the isolation of polynucleotides. This can improve the transfer of polynucleotides into cells. The use of vectors, expression vectors, adapters, and linkers is well known in the art. (See, e.g., Ausubel, supra, or Sambrook, supra. )

[0079] Recombinant methods for constructing nucleic acids Isolated nuclei, such as RNA, cDNA, genomic DNA, or any combination thereof Acid compositions can be obtained from biological sources using any number of cloning methods known to those of skill in the art. In some embodiments, the polynucleotides of the present invention can be subjected to stringent PCR. Oligonucleotide probes that selectively hybridize under optimal conditions are prepared from cDNA or is used to identify desired sequences in genomic DNA libraries; RNA isolation; and Construction of cDNA and genomic libraries is well known to those skilled in the art (see, e.g., Au, supra). See subel, or Sambrook, supra.)

[0080] Nucleic Acid Screening and Isolation Methods Polynucleotide sequences for use in the methods of the invention, such as those disclosed herein, Screening a cDNA or genomic library using sequence-based probes Probes can be used to hybridize to genomic DNA or cDNA sequences. By combining these sequences, it is possible to isolate homologous genes from the same or different organisms. Various degrees of hybridization stringency can be used in Either the hybridization or the washing medium can be made stringent. It will be clear that the more stringent the hybridization conditions, the greater the likelihood of duplex formation. The degree of complementarity between the probe and target should be high when formation occurs. The degree of sensitivity is affected by variables such as temperature, ionic strength, pH, and formamide. The hybridization rate can be controlled by one or more of the following: The stringency of the reaction can be determined by, for example, operating the formamide concentration in the range of 0% to 50%. This can be successfully altered by changing the polarity of the reaction solution. The degree of complementarity (sequence identity) achieved may vary depending on the hybridization medium and / or the wash medium. The degree of complementarity varies depending on the stringency of the target nucleic acid. Optimally, the degree of complementarity is 100% or 70%. ~100%, or any range or value therein. However, Minor sequence differences in primers may result in changes in the hybridization and / or wash media. It should be understood that this can be compensated for by reducing the intransitivity.

[0081] Methods for amplifying RNA or DNA are well known in the art and are described herein. Based on the teachings and guidance provided, one can make use of the present invention without undue experimentation.

[0082] Known methods for DNA or RNA amplification include polymerase chain reaction (PCR) and related related amplification processes (e.g., Mullis et al., U.S. Pat. No. 4,683,195; ...). No. 4,683,202, No. 4,800,159, No. 4,965,188, Tab U.S. Patent Nos. 4,795,699 and 4,921,794 to Orr et al.; U.S. Patent No. 5,142,033, Wilson et al., U.S. Patent No. 5,122,464, U.S. Patent No. 5,091,310 to Innis and U.S. Patent No. 5,091,310 to Gyllensten et al. ,066,584, Gelfand et al., U.S. Pat. No. 4,889,818, Silve U.S. Patent No. 4,994,370 to R. et al., U.S. Patent No. 4,766,067 to Biswas See, e.g., 4,656,134 to Ringold), and double-stranded DNA synthesis. RNA mediators that use antisense RNA to a target sequence as a template for synthesis and NASBA (U.S. Patent No. 5,130,238 to Malek et al.). and the like, including, but not limited to, the entire contents of which are incorporated herein by reference. (See, e.g., Ausubel, supra, or Sambrook, supra.) stomach.)

[0083] For example, using polymerase chain reaction (PCR) techniques, genomic DNA or cDNA Polynucleotides and related genes used in the methods of the present invention can be isolated directly from the library. PCR and other in vitro amplification methods can also be used to amplify sequences, e.g., expression cloning a nucleic acid sequence encoding a protein of interest; Probes for detecting the presence of RNA, for nucleic acid sequencing, or for other purposes It may be useful for generating nucleic acids for use as a nucleic acid sequence by in vitro amplification methods. Examples of techniques sufficient to guide one skilled in the art are found in Berger, supra; Sambrook, supra; and and Ausubel, supra, as well as U.S. Pat. No. 4,683,202 to Mullis et al. 987), and Innis, et al., PCR Protocols A Guide e to Methods and Applications,Eds.,Acade MIC Press Inc, San Diego, CA (1990). Commercially available kits for PCR amplification are known in the art. See age-GC Genomic PCR Kit (Clontech). In addition, for example, T4 gene 32 protein (Boehringer Mannheim ) can be used to improve the yield of long PCR products.

[0084] Synthetic methods for constructing nucleic acids The isolated nucleic acids used in the methods of the present invention can also be prepared by direct chemical synthesis using known methods. They can also be prepared by chemical synthesis (see, for example, Ausubel et al., supra). , generally by hybridization with a complementary sequence or by separating a single strand from a template single strand that can be converted into double stranded DNA by polymerization with DNA polymerase used as Those skilled in the art will appreciate that chemical synthesis of DNA involves over 100 different methods. Although the base sequence may be limited, longer sequences can be obtained by ligation of shorter sequences. You will realize that you can get more out of it.

[0085] Recombinant Expression Cassette The present invention uses recombinant expression cassettes containing nucleic acids. The cDNA or genomic sequence encoding the antibody to be used is used to generate at least one desired A recombinant expression cassette can be constructed that can be introduced into a host cell. An expression cassette typically directs transcription of a polynucleotide in an intended host cell. It includes polynucleotides that are operably linked to transcription initiation regulatory sequences, rather than to a heterologous or non-heterologous sequence. Both species (i.e., endogenous) promoters can be used to direct expression of the nucleic acid. .

[0086] In some embodiments, it functions as a promoter, enhancer, or other element. The isolated nucleic acid can be used in a polypeptide of the invention to up- or down-regulate expression of the polynucleotide. by introducing a non-heterologous form of a nucleotide into the appropriate position (upstream, downstream, or within an intron). For example, by mutation, deletion and / or substitution in vivo or in vitro. , the endogenous promoter can be altered.

[0087] Vectors and host cells The present invention provides vectors containing isolated nucleic acid molecules, recombinant vectors, and methods for producing recombinant nucleic acid molecules. and the expression of at least one antibody by recombinant techniques well known in the art. The production of IL-23 antibodies is also contemplated. See, e.g., Sambrook et al., supra; Ausu et al., supra. See bel et al., each of which is incorporated herein by reference in its entirety.

[0088] The polynucleotide may optionally be a vector containing a selectable marker for propagation in a host. Generally, the plasmid vector is prepared by calcium phosphate precipitation. The vector is introduced into a precipitate such as a globulin or in a complex with a charged lipid. If the virus is to be transfected, it is packaged in vitro using an appropriate packaging cell line and then transfected into the host cells. Can be transduced.

[0089] The DNA insert should be operably linked to an appropriate promoter. The tract contains the transcription start site, transcription termination site, and, within the transcribed region, the ribosomal region for translation. The coding portion of the mature transcript expressed by the construct preferably further comprises a nucleotide sequence binding site. or a start and stop codon (e.g., U) appropriately positioned at the end of the mRNA to be translated. AA, UGA, or UAG), and for mammalian or eukaryotic cell expression, AA and UAG are preferred.

[0090] The expression vector preferably includes at least one selectable marker, although this is optional. Such markers include, for example, methotrexate for eukaryotic cell culture. rexate, MTX), dihydrofolate reductase (DHFR, U.S. Patent Nos. 4,399,216, 4,634,665, and 4,656,13 No. 4, No. 4,956,288, No. 5,149,636, No. 5,179,017 No., ampicillin, neomycin (G418), mycophenolic acid or glutamine Setase (GS, U.S. Patent Nos. 5,122,464, 5,770,359, No. 5,827,739) resistance genes and in E. coli and other bacteria or prokaryotes including, but not limited to, tetracycline or ampicillin resistance genes for culture. (The above patents are incorporated herein by reference in their entirety.) Suitable culture media and conditions for such vectors are known in the art. It will be readily apparent to those skilled in the art. The transfection was carried out by calcium phosphate transfection, DEAE-dextran mediated transfection, and transfection, cationic lipid-mediated transfection, electroporation This can be achieved by injection, transduction, infection or other known methods. See Sambrook, supra, chapters 1-4 and 16-18; Ausubel, supra, Chapters 1, 9, 13, 15, 16, etc. are described in the art.

[0091] At least one antibody used in the methods of the present invention may be a modified antibody, such as a fusion protein. The vector may be expressed in a form that includes not only a secretion signal but also additional heterologous functional regions. For example, A region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the antibody to enhance its activity during purification or subsequent processing. This can improve stability and persistence in host cells during processing and storage. Peptide moieties can also be added to the antibodies of the invention to facilitate purification. Such regions can be removed prior to final preparation of another fragment. Sambrook, supra, Chapters 17.29-17.42 and 18.1-18.74; Many standard laboratory manuals, such as Ausubel, supra, Chapters 16, 17, and 18 is described in.

[0092] Those skilled in the art will appreciate that various methods are available for expressing nucleic acids encoding proteins used in the methods of the present invention. Numerous expression systems are available that are well known. Alternatively, the nucleic acid may be expressed as an endogenous antibody encoding nucleic acid. By switching it on (by manipulation) in the host cell containing the DNA Such methods are described in U.S. Patent Nos. 5,580,734, 5, 641,670, 5,733,746, and 5,733,761. These methods are well known in the art, as described in the literature, and are incorporated herein by reference in their entirety. will be incorporated into

[0093] An example of a cell culture useful for producing antibodies, specified portions or variants thereof is mammalian cell culture. Mammalian cell lines often take the form of a monolayer of cells, but mammalian cells Suspension or bioreactor systems can also be used. Intact glycosylated proteins can be expressed. Several suitable host cell lines capable of producing microbial cells have been developed in the art, including CO S-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL- 1651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., ATCC CRL1610) and BSC-1 (e.g., ATCC CRL-26) cells strain, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP 2 / 0-Ag14, 293 cells, HeLa cells, etc., which are rican Type Culture Collection,Manassas,V The preferred host cells are bone marrow cells and are readily available from the National Atomic Energy Agency (NAEA) at www.atcc.org. Particularly preferred host cells include cells derived from the lymphatic system, such as myeloma and lymphoma cells. The cells were P3X63Ag8.653 cells (ATCC accession number CRL-1580) and SP2 1 / 0-Ag14 cells (ATCC Accession No. CRL-1851). In one embodiment, the recombinant cells are P3X63Ab8.653 or SP2 / 0-Ag14 cells. .

[0094] Expression vectors for these cells include an origin of replication, a promoter (e.g., late or early SV40 gene), and 40 promoter, CMV promoter (U.S. Patent No. 5,168,062, U.S. Patent No. 5, No. 385,839), HSV tk promoter, pgk (phosphoglycerate kinase ) promoter, EF-1α promoter (U.S. Patent No. 5,266,491), a human immunoglobulin promoter, enhancer, and / or ribosome binding site; sites, RNA splice sites, polyadenylation sites (e.g., SV40 large T Ag polynucleotides), These include, but are not limited to, transcription termination sequences, transcriptional termination sequences, and other processing information sites. The vector may contain one or more expression control sequences, including, but not limited to, those described in, for example, Ausubel et al., supra. See Sambrook et al., supra. Other useful cells are known and / or may be used, for example, in the American Type Culture Collection. Culture Collection cell line and hybridoma catalog (www www.atcc.org) or other known or commercial sources.

[0095] When eukaryotic host cells are used, polyadenylation or transcription termination sites are typically included in the vector. An example of a termination sequence is the polyadenylation sequence from the bovine growth hormone gene. Sequences for accurate splicing of the transcript may also be included. An example of a splicing sequence is the VP1 intron from SV40 (Sprague , et al., J. Virol. 45:773-781(1983)). As is known in the art, genetic sequences for controlling replication within a host cell are used to It can be incorporated into the controller.

[0096] Antibody purification Anti-IL-23 antibodies were purified using protein A, ammonium sulfate or ethanol precipitation, and acid extraction. extraction, anion or cation exchange chromatography, phosphocellulose chromatography -, hydrophobic interaction chromatography, affinity chromatography, hydroxy Examples include lurepatite chromatography and lectin chromatography. The protein can be recovered and purified from recombinant cell culture by well-known methods, including but not limited to, High performance liquid chromatography (HPL) C") can also be used for purification. For example, Colligan, Current P rotocols in Immunology or Current Protocol s in Protein Science,John Wiley & Sons,N See, for example, chapters 1, 4, 6, 8, 9, and 10 of Y, NY (1997-2001). and each is incorporated herein by reference in its entirety.

[0097] The antibodies used in the method of the present invention include naturally purified products, products produced by chemical synthesis techniques, and the like. and recombinantly produced from eukaryotic hosts, including, for example, yeast, higher plants, insects, and mammalian cells. Depending on the host utilized in the recombinant production procedure, The body may be glycosylated or non-glycosylated, but glycosylated Such a method is described in Sambrook, supra, Sections 17.37-17.42. , Ausubel, supra, Chapters 10, 12, 13, 16, 18, and 20, Col, supra Many standard procedures, such as Ligan, Protein Science, Chapters 12-14, Laboratory manuals, all of which are incorporated herein by reference in their entirety.

[0098] Anti-IL-23 antibody Also referred to herein as "anti-IL-23 specific antibodies" useful in methods according to embodiments of the present invention The anti-IL-23 antibody is a small molecule of immunoglobulin that can be incorporated into the antibody. and a moiety, such as, but not limited to, at least one ligand binding moiety. complementarity determining portion (LBP), for example, but not limited to, the complementarity determining region of a heavy or light chain (CDRs) or their ligand-binding portions, heavy or light chain variable regions, framework regions (e.g. For example, FR1, FR2, FR3, FR4, or fragments thereof, and optionally at least a heavy or light chain constant region (e.g., containing at least one substitution, insertion, or deletion); 1C H 1, Hinge 1, Hinge 2, Hinge 3, Hinge 4, C H 2 or C H 3, or fragments thereof, and optionally containing at least one substitution, insertion, or deletion. ), or any portion thereof. The body may be a human, mouse, rabbit, rat, rodent, primate, or any combination thereof. may include or be derived from any mammal, including but not limited to mammals such as mammals. .

[0099] The isolated antibodies used in the methods of the present invention may be synthesized by any suitable polynucleotide. The encoded amino acid sequence of the antibody disclosed herein, or any isolated or prepared Preferably, the human antibody or antigen-binding fragment binds to human IL-23 and This partially or substantially neutralizes at least one biological activity of the protein. At least one biological activity of at least one IL-23 protein or fragment is retained. Antibodies, or specified portions or variants thereof, that are partially or preferably substantially neutralizing IL-23 receptor. inhibiting activities mediated by IL-23 or through other IL-23-dependent or -mediated mechanisms As used herein, the term "neutralizing antibody" refers to a neutralizing antibody that can be used to detect a specific antibody, depending on the assay. and 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, 9 Refers to antibodies that can inhibit IL-23-dependent activity by 7, 98, 99, 100% or more. The ability of an anti-IL-23 antibody to inhibit IL-23-dependent activity is preferably determined by the methods described herein. At least one suitable IL-23 as described and / or known in the art Human antibodies can be evaluated by protein or receptor assays. IgA, IgM, IgE, IgD, etc.) or isotype, In one embodiment, the human antibody may comprise an IgG heavy chain or a defined fragment. fragments, e.g., IgG1, IgG2, IgG3, or IgG4 (e.g., γ1, γ2, γ3 , γ4). Antibodies of this type are referred to herein as and / or known in the art, Transgenic mice or other mice containing transgenes (IgG, IgA, and IgM) It can be prepared by utilizing transgenic non-human mammals. In another embodiment, the anti-IL-23 human antibody comprises an IgG1 heavy chain and an IgG1 light chain. nothing.

[0100] The antibody is an antibody that binds to at least one IL-23 protein, subunit, fragment, portion, or It binds to at least one specified epitope specific for any combination of these. The at least one epitope comprises at least one protein comprising at least a portion of the protein. The epitope may comprise one antibody binding region, and the epitope preferably is one of the from at least one extracellular portion, soluble portion, hydrophilic portion, outer portion, or cytoplasmic portion It is composed of:

[0101] Generally, a human antibody or antigen-binding fragment contains at least one human complementarity-determining region (CDR variants of at least one heavy chain variable region, and at least Each of the complementarity determining regions (CDR1, CDR2, and CDR3) is human, or at least one The CDR sequences are derived from human germline variants of the antigen-binding region of the light chain variable region. It may be derived from a germline sequence or may be an exact match to a germline sequence. Alternatively, CDRs from a synthetic library derived from the original non-human CDRs can be used. These CDRs are formed by the incorporation of conservative substitutions from the original non-human sequence. In another particular embodiment, the antibody or antigen-binding portion or variant may comprise a corresponding CDR. at least one light chain CDR (i.e., C and an antigen-binding region comprising at least a portion of CDR1, CDR2, and / or CDR3. It is possible.

[0102] Such antibodies can be prepared using conventional techniques involving recombinant DNA technology to encode the antibodies (i.e., by preparing and expressing one or more) nucleic acid molecules, or by any other suitable method. By using the method, various portions of the antibody (e.g., CDRs, They can be prepared by chemically bonding together the polymers (framework).

[0103] In one embodiment, an anti-IL-23 antibody useful in the present invention comprises a heavy chain variable region and a light chain variable region. the heavy chain variable region comprises the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1; the light chain variable region comprises a CDRH2 of sequence SEQ ID NO: 1, a CDRH3 of sequence SEQ ID NO: 2, and a CDRH4 of sequence SEQ ID NO: 3; Complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5 and CDRL3 of SEQ ID NO:6.

[0104] A preferred anti-IL-23 antibody useful in the present invention has a heavy chain 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.

[0105] A more preferred anti-IL-23 antibody useful in the present invention is guselkumab (CNTO1959). (also called and sold as TREMFYA).

[0106] Other anti-IL-23 antibodies useful in the present invention include those described in U.S. Pat. No. 7,935,344. These include, but are not limited to, those having sequences described in the above, the entire contents of which are incorporated herein by reference. is incorporated herein by reference.

[0107] Antibody compositions containing additional therapeutically active ingredients The antibody compositions used in the methods of the present invention may optionally further comprise an anti-infective agent, a cardiovascular (ca Cardiovascular (CV) drugs, central nervous system (CNS) drugs, Autonomic nervous system (ANS) drugs, respiratory drugs, gastrointestinal drugs , GI tract acting drugs, hormonal drugs, fluid or electrolyte balancing drugs, hemodynamic drugs, antitumor drugs, immunomodulatory drugs Select at least one of the following: antihistamines, eye, ear or nose medications, topical medications, nutritional medications, etc. Such a drug may comprise an effective amount of at least one compound or protein that: The respective formulations, indications, dosages, and administrations set forth herein are well known in the art. is well known (e.g., Nursing 2001 Handbook of Drug s,21 st edition,Springhouse Corp.,Springh ouse, PA, 2001, Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Pren. tice-Hall, Inc., Upper Saddle River, NJ, Phar mcotherapy Handbook,Wells et al.,Appleto See, Nelson & Lange, Stamford, CT, each of which is incorporated herein by reference. (Incorporated into

[0108] Examples of drugs that can be combined with the antibodies of the present methods include anti-infective drugs, ampicillin-resistant antiprotozoal, anthelmintic, antifungal, antimalarial, antituberculous or At least one antimycobacterial drug, aminoglycoside, penicillin, cephalosporin, tetracycline Lacycline, sulfonamides, fluoroquinolones, antivirals, macrolide anti-infectives The hormonal drug may be at least one selected from the group consisting of steroids, anti-inflammatory drugs, and various anti-infective drugs. steroids, androgens, or at least one anabolic steroid, estrogens a steroid, or at least one progestin, a gonadotropin, an antidiabetic agent, or at least one A type of glucagon, thyroid hormone, thyroid hormone antagonist, pituitary hormone, and At least one cephalosporin may be selected from the group consisting of parathyroid mimetics. Phosphorus is cefaclor, cefadroxil, cefazolin sodium, cefdinir, hydrochloride Cefepime, cefixime, cefmetazole sodium, cefonicid sodium, cef Operazone sodium, cefotaxime sodium, cefotetan disodium, cefo Cefoxitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime, cef Thibuten, ceftizoxime sodium, ceftriaxone sodium, cefuroxime axone Cetyl, cefuroxime sodium, cephalexin hydrochloride, cephalexin monohydrate, cef The active ingredient may be at least one selected from the group consisting of benzodiazepine, benzocaine, and loracarbef.

[0109] At least one corticosteroid is betamethasone, betamethasone acetate, Betamethasone or betamethasone sodium phosphate, betamethasone sodium phosphate, cholesteryl acetate Tisone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, acetate Fludrocortisone, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, Tilprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate Prednisolone, Prednisolone acetate, Prednisolone sodium phosphate, Tebut Prednisolone, prednisone, triamcinolone, triamcinolone acetonide, and and triamcinolone diacetate. Androgenic or anabolic steroids include danazol, fluoxymesterone, Chilled testosterone, nandrolone decanoate, nandrolone phenpropionate, test Testosterone, Testosterone Cypionate, Testosterone Enanthate, Test Propionate The active ingredient may be at least one selected from the group consisting of steroids, and testosterone transdermal systems.

[0110] At least one immunosuppressant is selected from the group consisting of azathioprine, basiliximab, cyclosporine, Daclizumab, lymphocyte immunoglobulin, muromonab-CD3, mycophenolate mofetil mycophenolate mofetil, mycophenolate hydrochloride, sirolimus, and tacrolimus. There can be at least one type.

[0111] At least one topical anti-infective agent is selected from the group consisting of acyclovir, amphotericin B, azelaic acid cyclosporin, and cyclosporin B. Ream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole le, econazole nitrate, erythromycin, gentamicin sulfate, ketoconazole, acetic acid Mafenide, metronidazole (topical), miconazole nitrate, mupirocin, naftifuric acid hydrochloride acetaminophen, neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, tetrahydrochloride Rubinafine, terconazole, tetracycline hydrochloride, tioconazole, and tolnaf At least one scabicide or The pediculicide is selected from crotamiton, lindane, permethrin, and pyrethrins. The at least one topical corticosteroid may be dipropionate. Betamethasone valerate, betamethasone valerate, clobetasol propionate, desonide, desodorant Ximethasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate , fluocinolone acetonide, fluocinonide, flurandrenolide, flupropionate Ticazone, halcionide, hydrocortisone, hydrocortisone acetate, butyrate Hydrocortisone valerate, hydrocortisone valerate, mometasone furoate, and triamcinolone The compound may be at least one selected from the group consisting of acetonides (e.g., Nursing 2 See pages 1098-1136 of the 001 Drug Handbook.)

[0112] The anti-IL-23 antibody composition can be administered to cells, tissues, organs, or tissues in need of such modulation, treatment, or therapy. At least one anti-IL-23 antibody is contacted with or administered to a physician, animal, or patient. and optionally further comprising at least one TNF antagonist (e.g., but not limited to, TNF NF chemical or protein antagonists, TNF monoclonal or polyclonal antibodies or fragments thereof, soluble TNF receptors (e.g., p55, p70, or p85) or fragments thereof fusion polypeptides, or small molecule TNF antagonists, such as TNF binding protein I or II (TBP-1 or TBP-II), nerelimonmab, infliximab Mab, etanercept, CDP-571, CDP-870, afelimoma antirheumatic drugs (e.g., methotrexate, auranofin, Aurothioglucose, azathioprine, etanercept, sodium gold thiomalate, Hydroxychloroquine sulfate, leflunomide, sulfasalazine), immunization agents, immunoglobulins robrin, immunosuppressants (e.g., basiliximab, cyclosporine, daclizumab), any suitable compound containing at least one selected from the group consisting of cytokines and cytokine antagonists; The composition may further comprise an effective amount of at least one of a composition or a pharmaceutical composition. Non-limiting examples of cytokines include IL-1 to IL-23 (e.g., IL-1 The appropriate dosage is determined by the method described above. It is well known in the art. See, for example, Wells et al., eds., Pha Ramacotherapy Handbook, 2 nd Edition, Applet on and Lange, Stamford, CT (2000), PDR Pharm. acopoeia, Tarascon Pocket Pharmacopoeia 2 000,Deluxe Edition,Tarascon Publishing,L See Oma Linda, CA (2000), each of which is incorporated by reference in its entirety. The body is incorporated herein.

[0113] The anti-IL-23 antibody compounds, compositions, or mixtures used in the methods of the present invention may further comprise dilutions. agents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc. The composition may contain at least one of any suitable auxiliary agent, including but not limited to, pharmaceutically acceptable salts, Non-limiting examples of and methods for preparing such sterile solutions are known in the art. These methods are well known in the art and are described, for example, in Gennaro, Ed., Remington's Pharmaceutical Sciences, 18 th Edition,Ma ck Publishing Co. (Easton, PA), 1990, etc. This invention is not limited to the above. the mode of administration, solubility, and / or stability of the anti-IL-23 antibody, fragment, or variant composition. Suitable pharmaceutically acceptable carriers for the preparation of the pharmaceutical composition can be routinely selected.

[0114] Pharmaceutical excipients and additives useful in the present compositions include, but are not limited to, proteins Proteins, peptides, amino acids, lipids and carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and sugars including oligosaccharides, alditols, aldonic acids, esterified sugars, and other derivative sugars; and polysaccharides or sugar polymers), which may be present alone or in combination. , alone or in combination, in an amount of 1 to 99.99% by weight or volume. The excipients include serum albumin, such as human serum albumin (HSA). Recombinant human albumin (rHA), gelatin, Representative amino acids / antibody components that can also function in buffering capacity include Contains alanine, glycine, arginine, betaine, histidine, glutamic acid, asparagus Glucosamine, cysteine, lysine, leucine, isoleucine, valine, methionine, phenyl Alanine, aspartame, etc. One of the preferred amino acids is glycine. .

[0115] Suitable carbohydrate excipients for use in the present invention include, for example, fructose, maltose, Monosaccharides such as lactose, galactose, glucose, D-mannose, and sorbose, Disaccharides such as sucrose, trehalose, and cellobiose, raffinose, melezitol, Polysaccharides such as maltodextrin, dextran, and starches, mannitol, xylitol, Lactitol, maltitol, lactitol, xylitol, sorbitol (glucitol), Preferred carbohydrates for use in the present invention include alditols such as myo-inositol. The compound additives are mannitol, trehalose, and raffinose.

[0116] The anti-IL-23 antibody composition may also include a buffering agent or pH adjusting agent, typically Buffers are salts prepared from organic acids or bases. Representative buffers include citric acid, Acids, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid salts The composition may be prepared using any of the following buffers: organic acid salts, tris, tromethamine hydrochloride, or phosphate buffers. Preferred buffers for use in are organic acid salts such as citric acid.

[0117] Furthermore, the anti-IL-23 antibody composition may contain polyvinylpyrrolidone, ficoll (a polymeric sugar), , dextrates (e.g., 2-hydroxypropyl-β-cyclodextrin, etc.) Cyclodextrin), polyethylene glycol, flavoring agent, antibacterial agent, sweetener, antioxidant, Antistatic agents, surfactants (e.g., polyisoprene such as "TWEEN 20" and "TWEEN 80") resorbates), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol may contain polymeric excipients / additives such as chelating agents (e.g., EDTA) .

[0118] These and other compounds suitable for use in anti-IL-23 antibody, portion or variant compositions according to the invention and additional known pharmaceutical excipients and / or additives are known in the art, e.g. For example, "Remington: The Science & Practice of Ph armacy,” 19 thed., Williams & Williams, (1995 ), and "Physician's Desk Reference," 52 nd ed ,Medical Economics,Montvale, NJ (1998) and US Pat. No. 6,269,099, the disclosures of which are incorporated herein by reference in their entireties. The body or additive materials include carbohydrates (e.g., monosaccharides and alditols) and buffers (e.g., chloramphenicol). An exemplary carrier molecule is the mucopolysaccharide, hyaluronic acid, which These may be useful for intra-articular delivery.

[0119] formulation As mentioned above, the present invention preferably uses a phosphate buffer solution containing saline or a selected salt. Stable formulations that are buffers, as well as stock solutions and formulations containing preservatives, and pharmaceutically acceptable Suitable for pharmaceutical or veterinary use comprising at least one anti-IL23 antibody in a formulation suitable for administration. The present invention provides a versatile, multi-use preservative formulation comprising at least one known i.e., at least one of phenol, m-cresol, p-cresol, o-cresol chlorcresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol , formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), aldehyde Parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, chloride Benzethonium, sodium dehydroacetate, and thimerosal, or mixtures thereof and optionally containing a preservative selected from the group consisting of: For example, 0.001 to 5%, or 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, Such as, but not limited to, 4.8, 4.9, or any range or value therein. Any suitable concentration or mixture of any range or value therein may be used. Typical examples include no preservatives, 0.1-2% m-cresol (e.g., 0.2, 0. 3. 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (e.g. , 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001~0.5 % thimerosal (e.g., 0.005, 0.01), 0.001-2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.000 5-1.0% alkylparaben(s) (e.g., 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02 ,0.05,0.075,0.09,0.1,0.2,0.3,0.5,0.75,0. 9, 1.0%).

[0120] As mentioned above, the method of the present invention involves the use of packaging materials and, optionally, buffers formulated in an aqueous diluent. a solution of at least one anti-IL-23 specific antibody together with an agent and / or preservative; Also, one vial and a product containing this packaging material are used, and this solution is 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66 The present invention includes a label stating that the packaging can be stored for 72 hours or more. a first vial containing a lyophilized anti-IL-23 specific antibody; and a formulated buffer. and a second vial containing an aqueous diluent of the buffer or preservative. The dressing contains anti-IL-23 specific antibodies reconstituted in an aqueous diluent, which are retained for more than 24 hours. The label includes a label instructing the patient to form a solution that can be administered intravenously.

[0121] The anti-IL-23 specific antibodies used in accordance with the present invention may be any of those described herein or of the It can be produced from mammalian cells or transgenic preparations known in the art. It may be produced by recombinant means, including recombinant human leukocytes, or purified from other biological sources.

[0122] The range of anti-IL-23 specific antibodies is approximately 1.0 μg / mL for wet / dry systems upon reconstitution. It is contained in an amount that gives a concentration of about 1000 mg / mL to about 1000 mg / mL, but lower and higher concentrations are also available. The temperature can be varied and depends on the intended delivery vehicle; for example, in a solution formulation, the transdermal This is distinct from pulmonary, transmucosal, or osmotic or micropump methods.

[0123] Preferably, the aqueous diluent optionally further comprises a pharmaceutically acceptable preservative. New preservatives include phenol, m-cresol, p-cresol, o-cresol, and chloroform. Benzyl alcohol, alkylparaben (methyl, ethyl, propyl, butyl Benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and Thimerosal or mixtures thereof. The concentration of preservative used is sufficient to produce an antimicrobial effect. The amount of preservative used will vary and can be easily determined by one skilled in the art.

[0124] Other excipients, such as isotonicity agents, buffers, antioxidants, and preservative enhancers, are optional. Optionally and preferably, an isotonic agent such as glycerin may be added to the diluent. Preferably, a physiologically tolerable buffer is added to improve the stability. The formulation provides excellent pH control, ranging from about pH 4 to about pH 10, and preferably from about pH 5 to about pH 6. A wide pH range is preferred, including the range of about 6.0 to about 8.0. Preferably, the formulation of the present invention has a pH of about 6.8 to about 7.8. Suitable buffers include phosphate buffers, most preferably sodium phosphate, especially phosphate. Contains phosphate buffered saline (PBS).

[0125] Other additives, such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate) rate), Tween 40 (Polyoxyethylene (20) sorbitan monopalmitate) , Tween 80 (Polyoxyethylene (20) sorbitan monooleate), Plur onic F68 (polyoxyethylene polyoxypropylene block copolymer), and and PEG (polyethylene glycol), or a pharmaceutically acceptable solubilizer. Poloxamer 20 or 80 or Poloxamer 184 or 188, Pluronic Nonionic surfactants such as Polyls®, other block copolymers, and Optionally adding chelating agents such as EDTA and EGTA to the formulation or composition These additives can be used in pumps or other devices to administer the formulation. This is particularly useful when plastic containers are used. Its presence reduces the tendency of the protein to aggregate.

[0126] The formulation comprises at least one anti-IL-23 specific antibody and phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylpa Laven (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzyl chloride from the group consisting of thimerosal, sodium dehydroacetate, and thimerosal or mixtures thereof and a preservative selected from the group consisting of: The present invention provides a method for the preparation of a pharmaceutical composition comprising administering to a patient an anti-IL-23 specific antibody in an aqueous diluent containing at least one anti-IL-23 specific antibody and a preservative. Blending is carried out using conventional dissolution and blending procedures. To prepare a suitable formulation: For example, a quantity of at least one anti-IL-23 specific antibody in a buffer solution is added to a desired concentration and a desired preservative in a sufficient amount of buffer solution to provide the protein and preservative. Variations on this process will be recognized by those skilled in the art. For example, The order of addition of ingredients, whether additional excipients are used, and the temperature and pH at which the formulation is prepared can all be adjusted depending on the formulation used. These are factors that can be optimized with respect to the dosage concentration and route of administration.

[0127] The formulation may be prepared as a clear solution or in a mixture of water, preservatives and / or excipients, preferably phosphate. salt buffer and / or saline, and a second solution containing the selected salt in an aqueous diluent. A combination comprising a vial of lyophilized anti-IL-23 specific antibody, reconstituted in a vial of It can be provided to patients as a single solution vial or as a dual vial. Any dual vial requiring configuration can be reused multiple times and can be used in single or multiple This allows for a larger number of patient treatment cycles to be met, thus providing a more convenient treatment option than is currently available. A therapeutic regimen can be provided.

[0128] The product is useful for administration over a period ranging from immediate to 24 hours or more. The products claimed by this invention offer significant benefits to patients. Optional safe storage at temperatures between about 2°C and about 40°C ensures long-term biological activity of the protein. The packaging label therefore indicates that the solution is available in 6, 12, 18, 24, 36, Demonstrate that it can be retained and / or used for periods of 48, 72, or 96 hours or more. If a stored diluent is used, the label shall state a maximum of 1 to 1 This may include use for up to 2 months, 6 months, 18 months, and / or 2 years.

[0129] Solutions of anti-IL-23 specific antibodies are prepared by mixing at least one antibody in an aqueous diluent. The mixture can be prepared by a process comprising: To prepare a suitable diluent, for example, a small amount of water or buffer may be added. At least one antibody, a desired concentration of protein, and optionally a preservative or buffer. Variations on this process will be recognized by those skilled in the art. For example, the order of addition of the components, whether additional excipients are used, and the time and place of preparation of the formulation. The temperature and pH of the solution can all be optimized for the dosage concentration and administration means used. It is a factor.

[0130] The claimed product is available as a clear solution or in a second vial containing an aqueous diluent. at least one lyophilized vial of anti-IL-23 specific antibody, which is reconstituted in a It can be provided to patients as a single solution vial or as a combination vial containing Each required dual vial can be reused multiple times and can be used for single or multiple patients. treatment cycles and therefore more convenient treatment regimes than are currently available. Provides a

[0131] The claimed product is a clear solution or a second vial containing an aqueous diluent. a combination comprising a vial of at least one lyophilized anti-IL-23 specific antibody, By providing vials to pharmacies, clinics, or other such institutions and facilities; It can be given indirectly to the patient, in which case the clear solution can be given in a volume of up to 1 liter or more. The container may contain a larger volume, and from this larger container, a smaller volume of at least one anti- The solution is withdrawn one or more times and transferred to a smaller vial and distributed by the pharmacy or clinic. can be provided to customers and / or patients.

[0132] Approved devices that contain single-vial systems include BD Pens, BD Autoj ector(registered trademark), Humaject(registered trademark), NovoPen(registered trademark) , BD® Pen, AutoPen®, and OptiPen® Registered trademark), GenotropinPen (registered trademark), Genotronorm Pen n(registered trademark), Humatro Pen(registered trademark), Reco-Pen(registered trademark) , Roferon Pen (registered trademark), Biojector (registered trademark), Iject (registered trademark), J-tip Needle-Free Injector (registered trademark), Intraject (registered trademark), Medi-Ject (registered trademark), Smartjec Pen-type injector devices for solution delivery, such as the Becton ® Dickensen (Franklin Lakes, NJ, www.bectond ickenson.com), Disetronic (Burgdorf, Switze) rland, www.disetronic.com), Bioject, Portla nd, Oregon (www.bioject.com), National Medi. cal Products,Weston Medical(Peterborough ,UK,www.weston-medical.com), Medi-Ject Co. Manufactured by rp (Minneapolis, MN, www.mediject.com) Dual vial systems include: Approved devices that contain Pen for reconstituting lyophilized medication in a cartridge for delivery of a lyophilized solution Other suitable devices include pre-filled injector systems. These include syringes, auto-injectors, needleless syringes, and needleless IV infusion sets.

[0133] The product may include packaging that, in addition to information required by regulatory authorities, The packaging material of the present invention, if applicable, provides the conditions under which the product can be used. Each anti-IL-23 antibody is reconstituted with an aqueous diluent to form a solution, and the solution is incubated for 2 to 24 hours or more. The instructions stated that this solution should be used for two vials of wet / dry product over a period of time. Provide to patient. In the case of single vial solution products, pre-filled syringes, or auto-injectors, In such cases, the label shall indicate that such solution can be used for a period of 2 to 24 hours or more. The product is useful for human pharmaceutical product applications.

[0134] The formulations used in the methods of the present invention comprise an anti-IL-23 antibody and a selected buffer, preferably The process involves mixing saline or a phosphate buffer containing a selected salt. The anti-IL-23 antibody and the buffer are mixed in an aqueous diluent, and the resulting mixture is then mixed with the buffer. Conventional dissolution and mixing procedures are used to prepare suitable formulations, for example: A quantity of at least one antibody in water or buffer is added to the desired concentration of protein and buffer. and a desired buffer in a sufficient amount of water to provide a For example, the order of addition of the components, the amount of additional additives, etc., will be recognized by those skilled in the art. Whether or not it is used, the temperature and pH during preparation of the formulation, and the dosage concentration and administration method used It is a factor that can be optimized.

[0135] The methods of the present invention include a variety of formulations that are useful and acceptable for administration to a human or animal patient. The pharmaceutical composition includes water at "normal" conditions as a diluent, and It is prepared using routine methods well known to those skilled in the art. For example, histidine and histidine-1 The buffer components, such as hydrochloride hydrate, are provided first, followed by the appropriate non-final volume of “standard” A water diluent, sucrose, and polysorbate 80 may then be added. Finally, "standard conditions" using water as the diluent can be used. The volume of the pharmaceutical composition is adjusted to the desired final volume under the above conditions. We recognize several other methods that may be suitable.

[0136] The pharmaceutical compositions contain the indicated mass of each component per volume unit of water or are "standardized" in the As used herein, the term "aqueous solution" refers to an aqueous solution or suspension having a pH indicated by the "state." In this context, the term "standard conditions" means a temperature of 25°C ± 2°C and a pressure of 1 atmosphere. The term "quasi-state" is used in the art to refer to a single temperature or pressure It is not used to refer to a set of forces, but instead refers to a particular composition under "standard state" conditions A reference condition that specifies the temperature and pressure used to describe a solution or suspension containing This is because the volume of the solution is in part a function of temperature and pressure. It is recognized that pharmaceutical compositions equivalent to those disclosed herein may be prepared at other temperatures and pressures. Such pharmaceutical compositions may be considered equivalent to those disclosed herein as defined above. It should be determined under defined "standard state" conditions (e.g., 25°C ± 2°C and 1 atmosphere pressure). It is.

[0137] Importantly, such pharmaceutical compositions contain "approximately" 100 mg of 10 ... containing a specific value of component mass (e.g., "approximately 0.53 mg of L-histidine") The mass or pH value of the components present in the pharmaceutical composition may be about a specified value. The isolated antibody may be present in a pharmaceutical composition or may be removed from a pharmaceutical composition. After removal (e.g., by dilution), the isolated antibody present in the pharmaceutical composition is The mass of the component is "approximately" the given number if it can be attached to the chain. The values, such as the pH value or the like, of the isolated antibody after the isolated antibody is incorporated into a pharmaceutical composition. A given value is "about" when binding activity is maintained and detectable.

[0138] Competitive binding assays were performed to determine whether IL-23-specific mAbs bind to similar or different epitopes. Determine whether Abs bind and / or compete with each other. Competing mAb is added, followed by biotinylated hrIL-23. For positive controls, the same mAb was used as a competitor mAb ("self-competition") for coating. IL-23 binding may be detected using streptavidin. The results will determine whether the mAbs recognize similar or partially overlapping epitopes on IL-23. Indicates whether

[0139] One aspect of the methods of the present invention involves administering a pharmaceutical composition to a patient.

[0140] In one embodiment of the pharmaceutical composition, the isolated antibody concentration is about 7 mL per mL of pharmaceutical composition. In another embodiment of the pharmaceutical composition, the pH is about 5.5 to about 6.5. be.

[0141] Stable or preserved formulations may be prepared as clear solutions or in aqueous diluents without preservatives or buffers and at least one lyophilized anti-I antibody, which is reconstituted in a second vial containing an excipient; It can be provided to the patient as a dual vial containing a vial of the L-23 antibody. Either single solution vials or dual vials requiring reconstitution are reused multiple times. can satisfy single or multiple patient treatment cycles and therefore are This provides a more convenient treatment regimen than is currently available.

[0142] Other formulations or methods for stabilizing anti-IL-23 antibodies include permeation of lyophilized powders containing the antibodies. The solution may be other than a clear solution. Non-clear solutions include formulations containing particulate suspensions, Such particles may be microspheres, microparticles, nanoparticles, nanospheres, or liposomes. Compositions containing anti-IL-23 antibodies within structures of various sizes known variously as globulins. Such relatively homogeneous, essentially spherical microparticle formulations containing an active agent are disclosed in U.S. Pat. As taught in US Pat. No. 4,589,330, an aqueous phase containing an active agent and a polymer and a non-aqueous phase and then evaporating the non-aqueous phase to cause coalescence of the particles from the aqueous phase. Porous microparticles can be formed as taught in U.S. Pat. No. 4,818,542. As shown, a first phase containing an active agent and a polymer dispersed in a continuous solvent is used, and a frozen It can be prepared by removing this solvent from the suspension by drying or dilution-extraction-precipitation. Preferred polymers for such preparations are gelatin, agar, starch, arabinogalactose, Protein, albumin, collagen, polyglycolic acid, polylactic acid, glycolide-L(-) lactate Poly(epsilon-caprolactone), Poly(epsilon-caprolactone-co-lactate) Acid), Poly(epsilon-caprolactone-co-glycolic acid), Poly(β-hydroxy Poly(alkyl-2-cyanoacrylate), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate) acrylate), poly(hydroxyethyl methacrylate), polyamide, poly(amino acid), poly Poly(2-hydroxyethyl DL-aspartamide), poly(ester urea), poly(L -phenylalanine / ethylene glycol / 1,6-diisocyanatohexane) and poly (methyl methacrylate), natural or synthetic copolymers or polymers selected from the group consisting of Particularly preferred polymers are polyglycolic acid, polylactic acid, glycolide-L (-) Lactide Poly(epsilon-caprolactone), Poly(epsilon-caprolactone) poly(epsilon-co-lactic acid), and poly(epsilon-caprolactone-co-glycolic acid), etc. It is a polyester of the formula: are water, hexafluoroisopropanol, methylene chloride, tetrahydrofuran, hexa Examples of the active substance-containing phase include benzene, hexafluoroacetone sesquihydrate, and the like. The process of dispersing the first phase into the second phase is performed by forcing the first phase through an orifice in a nozzle. This can include influencing droplet formation through

[0143] Dry powder formulations can be prepared, for example, by spray drying or solvent extraction by evaporation or by aqueous or or dissolution by precipitation of the crystalline composition followed by one or more steps to remove the non-aqueous solvent. Spray-dried antibody formulations may also be obtained as a result of processes other than freeze-drying, such as solvent extraction. The preparation is taught in U.S. Patent No. 6,019,968. Antibody-Based Dry Powder Compositions The article comprises a solution or slurry of the antibody and, optionally, a respirable dry powder. The excipients can be produced by spray drying in a solvent under conditions such as: Easily dryable polar compounds such as water and ethanol are included. The properties can be improved by carrying out the spray drying procedure in the absence of oxygen, e.g., under a nitrogen blanket, or This can be enhanced by using nitrogen as the drying gas. The formulations are typically hydrofluoric acid, as taught in WO 9916419. A dispersion of a plurality of porous microstructures dispersed in a suspension medium containing an oroalkane propellant. The stabilized dispersion can be administered to a patient's lungs using a metered dose inhaler. Equipment useful in the commercial manufacture of It is manufactured more.

[0144] The anti-IL-23 antibodies in any of the stable or preserved formulations or solutions described herein may , SC or IM injection, transdermal, transpulmonary, transmucosal, implanted, as is well known in the art. a pump, an osmotic pump, a cartridge, a micropump or any other pump known in the art. There are various delivery methods covered by the present invention, including other means that will be appreciated by those skilled in the art. can be administered to

[0145] therapeutic application In one general aspect, the present application also provides a method for producing a compound according to any of the preceding claims, including, but not limited to, any compound known in the art or described herein. Thus, at least one IL-23 antibody of the present invention can be used to treat, for example, cells, tissues, organs, A therapeutically effective amount of an IL-23 specific antibody is administered to or contacted with an animal or patient to produce cells, tissues, or tissues. Also provided are methods for modulating or treating psoriatic arthritis in a tissue, organ, animal, or patient. do.

[0146] Any of the methods of the present invention may be used to treat cells, tissues, or tissues in need of such modulation, treatment, or therapy. administering to an organ, animal, or patient an effective amount of a composition or pharmaceutical composition comprising an anti-IL-23 antibody; Such methods may optionally include administering a compound to treat such a disease or disorder. The co-administration or combination therapy may further comprise administering to a subject the at least one anti-IL-2 3. Administering the antibody, specified portion, or variant thereof, may be effective in inhibiting the production of at least one TNF antagonist. Anti-TNF drugs (e.g., but not limited to, chemical or protein-based TNF antagonists, TNF Monoclonal or polyclonal antibodies or fragments, soluble TNF receptors (e.g. , p55, p70, or p85) or fragments thereof, fusion polypeptides thereof, or small molecule TN F antagonists, e.g., TNF-binding protein I or II (TBP-1 or TBP-II), Nelerimumab, infliximab, etanercept (Enbrel (trademark) adalimumab (Humira™), CDP-571, CDP-870, antirheumatic drugs (e.g., methotrexate, orazone, etc.), phenofin, aurothioglucose, azathioprine, sodium gold thiomalate, hirsutite sulfate hydroxychloroquine, leflunomide, sulfasalazine), muscle relaxants, narcotics, nonsteroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, anesthetics, Sedatives, local anesthetics, neuromuscular blocking agents, antibacterial agents (e.g., aminoglycosides, antifungals, antimycotics) Parasitic drugs, antivirals, carbapenems, cephalosporins, fluoroquinolones, macrophages antibacterial drugs), antipsoriasis drugs , corticosteroids, anabolic steroids, diabetes-related drugs, minerals, nutritional drugs, Glandular agents, vitamins, calcium-related hormones, antidiarrheals, antitussives, antiemetics, antineoplastic agents, laxatives anticoagulants, erythropoietin (e.g., epoetin alfa), filgrastim ( For example, G-CSF, Neupogen), sargramostim (GM-CSF, Leuk ine), immunizing agents, immunoglobulins, immunosuppressants (e.g., basiliximab, cyclosporine), sporin, daclizumab), growth hormone, hormone replacement drugs, estrogen receptor modulators , mydriatics, cycloplegics, alkylating agents, antimetabolites, mitotic inhibitors, radiopharmaceuticals, anti-inflammatory drugs Depressants, antimanics, antipsychotics, antianxiety drugs, hypnotics, sympathomimetics, stimulants, donepezil , tacrine, asthma medications, beta-agonists, inhaled steroids, leukotriene inhibitors, Methylxanthines, cromolyn, epinephrine or analogues, dornase alfa (P ulmozyme), cytokines or cytokine antagonists It further includes administering one or more of the following before, simultaneously with, and / or after the other. It is well known in the art. See, for example, Wells et al., eds., Pha Ramacotherapy Handbook, 2 nd Edition, Applet on and Lange, Stamford, CT (2000), PDR Pharm. acopoeia, Tarascon Pocket Pharmacopoeia 2 000,Deluxe Edition,Tarascon Publishing,L oma Linda, CA (2000), Nursing 2001 Handbook of Drugs, 21 st edition, Springhouse Corp. ,Springhouse,PA,2001,Health Professional 's Drug Guide 2001, ed., Shannon, Wilson, St. ang,Prentice-Hall,Inc,Upper Saddle River , NJ, each of which references is incorporated herein by reference in its entirety. It can be enjoyed.

[0147] Treatment Typically, treatment of psoriatic arthritis ranges from moderate to severe depending on the specific activity of the active agent contained in the composition. In total, at least about 0.01 to 500 mg / kg of patient body weight per dose Anti-IL-23 antibodies in the milligram range, preferably in a single or multiple doses, are administered to the patient's body. Anti-IL-23 antibodies in the range of at least about 0.1 to 100 milligrams of antibody per kilogram of body weight. This is achieved by administering an effective amount or dose of the composition. The dosage may include a serum concentration of 0.1 to 5000 μg / mL per single or multiple dose. Suitable dosages are known to medical practitioners and will, of course, vary depending on the particular disease state, administration, It will depend on the specific activity of the composition being treated and the particular patient being treated. Repeated administration, i.e., specific monitored or metered doses, may be required to obtain the desired therapeutic dose. It may be necessary to provide separate doses, in which case the separate doses should be administered on the desired day. Repeated until dose or effect is achieved.

[0148] Preferred doses are optionally 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 1 3, 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, 5 3, 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, 9 4, 95, 96, 97, 98, 99 and / or 100-500 μg / kg / dose, or includes any range, value, or fraction thereof, or 0 per single or multiple dose. .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 0.5, 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, 1 8.5, 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 in serum The concentration may be included to obtain a concentration, or any range, value, or fraction thereof.

[0149] Alternatively, the dose administered may be determined based on the pharmacodynamic characteristics of the particular drug and its method and route of administration. , the recipient's age, health condition and weight, the nature and severity of symptoms, the type of concurrent treatment, treatment The dosage of the active ingredient may vary depending on known factors such as frequency, and the desired effect. , about 0.1 to 100 milligrams per kilogram of body weight. Usually, it is 0.1 to 50 , preferably 0.1 to 10 milligrams / kilogram / dose, or in sustained release form. It is effective in obtaining results.

[0150] As a non-limiting example, human or animal treatment may be performed using single, infusion, or multiple doses. , 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, At least one of the following days: 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 At least once a day, or in addition, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 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, 5 In at least one of weeks 1 or 52, or in addition, 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or in at least one of the 20 years, or any combination thereof, 0.1 to 100 mg / kg per dose, for example, 0.5, 0.9, 1.0, 1.1, 1.5, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 1 8, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40 , 45, 50, 60, 70, 80, 90, or 100 mg / kg of the composition of the present invention It may be provided as a single or periodic dose of one antibody.

[0151] Dosage forms (compositions) suitable for internal administration generally contain about 0.001 ml of the active ingredient per unit or container. These pharmaceutical compositions contain 100 mg to about 500 mg of the active ingredient. The component is typically present in an amount of about 0.5 to 99.999% by weight, based on the total weight of the composition. .

[0152] For parenteral administration, the antibody may be administered either in combination with a pharmaceutically acceptable parenteral vehicle or separately. provided as a solution, suspension, emulsion, particles, powder, or lyophilized powder, Examples of such vehicles include water, saline, Ringer's solution, dextrose, etc. solutions, and 1-10% human serum albumin. Non-aqueous solutions such as liposomes and fixed oils. A vehicle or lyophilized powder may also be used. The vehicle or lyophilized powder must be isotonic and chemically stable. Additives to maintain stability (e.g., sodium chloride for isotonicity, mannitol; chemical stabilizers) The formulation may contain any known or suitable additives (e.g., buffers and preservatives). Sterilized by technology.

[0153] Suitable pharmaceutical carriers are described in Remington's, a standard reference text in this field. Published in the latest edition of Pharmaceutical Sciences, A. Osol It has been done.

[0154] Alternative administration In order to administer a pharmaceutically effective amount of an anti-IL-23 antibody, many known and well-known methods can be used in accordance with the present invention. In the following description, pulmonary administration is used, but However, other modes of administration may be used in accordance with the present invention with suitable results. The trispecific antibody may be present in a carrier as a solution, emulsion, colloid or suspension, or As a dry powder, by inhalation, or by other methods described herein or in the art. using any of a variety of devices and methods suitable for administration by other methods known in the art. , can be delivered.

[0155] Parenteral Formulation and Administration Parenteral formulations are typically made with sterile water or saline, polyethylene glycol, Even if it contains polyalkylene glycols such as ethanol, vegetable oils, hydrogenated naphthalene, etc. Aqueous or oily suspensions for injection may be prepared according to known methods using suitable emulsifying agents or wetting agents and Injectable preparations can be prepared by using, for example, aqueous solutions, sterile injectable solutions, and suspensions. It may also be a non-toxic parenterally administrable diluent such as a suspension in a solvent. The vehicle or solvent may be water, Ringer's solution, isotonic saline, or the like. As a solvent or suspending medium, sterile, fixed oils can be used. , natural or synthetic or semi-synthetic, fatty oils or fatty acids, natural or synthetic or semi-synthetic, Any type of fixed oil, including monoglycerides, diglycerides, or triglycerides Parenteral administration is known in the art and is commonly used in the art. Conventional injection means, gas-pressurized needleless injections such as those described in U.S. Pat. No. 5,851,198 injection devices and laser perforation devices such as those described in U.S. Pat. No. 5,839,446. These include, but are not limited to, drilling devices, which are incorporated herein by reference in their entirety. be incorporated into the book.

[0156] alternative delivery The present invention further provides parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraperitoneal, intracapsular, intrachondral, Intracavitary, intracavity, intracerebellum, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic , in the pericardium, in the abdominal cavity, in the pleura, in the prostate, in the lungs, in the rectum, in the kidneys, in the retina, in the spinal cord, in the synovial bursa Intrathoracic, intrauterine, intravesical, intralesional, bolus, intravaginal, rectal, oral, sublingual, intranasal, The anti-IL-23 antibody composition is administered parenterally or transdermally. Oral (subcutaneous, intramuscular or intravenous) or any other administration, especially liquid solutions or suspensions In particular, semi-prepared formulations for use in various forms, such as, but not limited to, creams and suppositories. In solid form, such as tablets or capsules, for use in vaginal or rectal administration. For oral or sublingual administration, or in the form of powder, nasal spray, etc. or in the form of, but not limited to, aerosols, or certain medications, intracavity, or by modifying the skin structure or increasing the drug concentration in transdermal patches. For either, chemical promoters such as dimethyl sulfoxide (Junging er et al., In “Drug Permeation Enhancement”; h,DS,Eds.,pp.59-90(Marcel Dekker,Inc.N New York 1994, incorporated herein by reference in its entirety), or protein application of a formulation containing proteins and peptides to the skin (WO 98 / 53847); or For creating transient transport pathways, such as electroporation, or iontophoresis, application of an electric field to increase the mobility of a charged drug through the skin, such as thoracotomy, or ultrasound Ultrasound applications such as wave introduction (U.S. Pat. Nos. 4,309,989 and 4,767,400) 2) using an oxidizing agent that enables gel, ointment, lotion, suspension or patch delivery The drug may be prepared in a form such as, but not limited to, a transdermal delivery system (see above). The above publications and patents are incorporated herein by reference in their entireties.

[0157] Having generally described the present invention, the same is provided by way of illustration and not limitation. This will be more readily understood by reference to the following examples, which are not intended to be exhaustive. Further details of the present invention are illustrated by the following non-limiting examples. The disclosures of all citations are expressly incorporated herein by reference.

[0158] Embodiment Embodiment 1 is a method for treating psoriatic arthritis (PsA) in a subject in need thereof. The method comprises administering to a subject a safe and effective amount of an anti-IL-23 antibody and a pharmaceutically acceptable carrier. The method comprises subcutaneously administering a pharmaceutical composition comprising the compound, wherein the pharmaceutical composition is administered once every four weeks (4w). It is a method that is given.

[0159] Embodiment 1a is the method of embodiment 1, wherein the anti-IL-23 antibody comprises a heavy chain variable region and a light chain variable region. The heavy chain variable region comprises a complementarity determining region heavy chain 1 (CDRH1) of SEQ ID NO: 1. the amino acid sequence of CDRH2 of SEQ ID NO:2, and the CDRH3 amino acid sequence of SEQ ID NO:3 The light chain variable region comprises the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4. the amino acid sequence of SEQ ID NO:5, the CDRL2 amino acid sequence of SEQ ID NO:6, and the CDRL3 amino acid sequence of SEQ ID NO:7. Contains the acid sequence.

[0160] Embodiment 1b is the method of embodiment 1, wherein the antibody has 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.

[0161] Embodiment 1c is the method of embodiment 1, wherein the antibody has the amino acid sequence of SEQ ID NO:9 and a light chain having the amino acid sequence of SEQ ID NO: 10.

[0162] Embodiment 1d is the method of embodiment 1, wherein the antibody is administered every 4 weeks (4w). It is administered once.

[0163] Embodiment 2 is the method of any one of embodiments 1 to 1b, wherein the antibody is administered 25mg to 200mg per dose, e.g., 25mg, 50mg, 75mg, 100mg, 12 Total doses of 5 mg, 150 mg, 175 mg, and 200 mg, or any dose in between It is administered in doses.

[0164] Embodiment 2a is the method of embodiment 2, wherein the total dose is about 50 to about 100 mg / dose. It is 150mg.

[0165] Embodiment 2b is the method of embodiment 2, wherein the total dose is about 100 ml per dose. g.

[0166] Embodiment 3 is the method of any one of embodiments 1-2b, wherein the subject has PsA. have an inadequate response to standard treatment.

[0167] Embodiment 3a is the method of embodiment 3, wherein the standard of care is a non-biologic disease-modifying Antirheumatic drugs (DMARDs), oral corticosteroids, apremilast, nonsteroidal and at least one selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs).

[0168] Embodiment 3b is the method of embodiment 3, wherein the standard of care is to administer to the subject ≦25 mg / mL methotrexate (MTX) administered weekly, sulfasalazine administered at ≤3 g / day to subjects hydroxychloroquine (HCQ) administered to subjects at ≤400 mg / day ), or leflunomide (LEF) administered to the subject at a dose of ≦20 mg / day It is a commonly used DMARD.

[0169] Embodiment 3c is the method of embodiment 3, wherein the standard of care is ≦10 mg / day of prothrombin. It is an oral corticosteroid administered to subjects in amounts equivalent to rednisone.

[0170] Embodiment 3d is the method of embodiment 3, wherein the standard of care is approved by a regulatory agency. An NSAID or other analgesic administered to a subject at its approved marketed dose.

[0171] Embodiment 3e is the method of embodiment 3, wherein the standard of care is approved by a regulatory agency. Apremilast administered to subjects at its approved marketed dose.

[0172] Embodiment 3f is the method of any one of embodiments 3-3e, wherein the subject is a biological They are naive to conventional treatment.

[0173] Embodiment 3g is the method of any one of embodiments 3-3e, wherein the subject is Ps have previously received at least one biologic treatment for A.

[0174] Embodiment 3h is the method of embodiment 3g, wherein the subject has at least one biological have an inadequate response to conventional treatment.

[0175] Embodiment 3i is the method of embodiment 3g or 3h, wherein the biologic therapy is Cumab, ustekinumab, secukinumab (AIN457), anti-tumor necrosis factor alpha (TNFα ) agents (e.g., adalimumab, etanercept, infliximab. Golimumab subcutaneous [S C] or intravenous [IV], certolizumab pegol, or their respective biosimilars ), tildrakizumab (MK3222), ixekizumab (LY2439821), Lodalumab (AMG827), risankizumab (BI-655066), or PsA or Other investigational biologic treatments for psoriasis include:

[0176] Embodiment 3j is the method of embodiment 3i, wherein the subject is a patient receiving anti-tumor necrosis factor alpha (TN Fα) Non-responder to treatment.

[0177] Embodiment 3k is the method of any one of embodiments 1-3j, wherein the subject is Previous plaque psoriasis of at least 3% body surface area (BSA).

[0178] Embodiment 3l is the method of any one of embodiments 1 to 3j, wherein the subject is Prior to this, at least one psoriatic plaque ≥ 2 cm in diameter or nail changes consistent with psoriasis, or have a documented history of psoriasis.

[0179] Embodiment 3m is the method of any one of embodiments 1 to 3l, optionally comprising: The method further comprises administering to the subject a standard of care treatment for PsA.

[0180] Embodiment 3n is the method of any one of embodiments 1-3l, optionally comprising: The method further comprises administering to the subject a biological therapy for PsA.

[0181] Embodiment 4 is the method of any one of embodiments 1 to 3n, wherein the subject is an antibody. and are identified as responders to treatment with EGFR and as having a statistically significant improvement in disease activity; Disease activity was measured as a 20% improvement in the American College of Rheumatology Core Set Disease Index (ACR20), 50% improvement in the American College of Rheumatology Core Set Disease Index (ACR50), American College of Rheumatology Core Set 70% improvement in the Acute Criteria for Disease Index (ACR70), Health Assessment Questionnaire Disability Index (HAQ-DI), Investigator Global Assessment (IGA), Disease Activity Score 28 (DAS28) C response Reactive protein (CRP), enthesitis resolution, dactylitis resolution, Leeds enthesitis index (L EI), Dactylitis Assessment Score, Mental and Physical Component Summary (MCS and PCS) ) Short Form Health Survey (SF-36), Achieving Minimal Disease Activity (MDA) LS mean change from baseline in modified vdH-S total score, and very low disease activity The method is determined by one or more criteria selected from the group consisting of: achievement of high dynamic range (VLDA);

[0182] Embodiment 4a is the method of embodiment 4, wherein the improvement is within 16, 20, 24 hours of initial treatment. Measured after 4 or 28 weeks.

[0183] Embodiment 4b is the method of any one of embodiments 4-4a, wherein the improvement is The measurements are taken 16 weeks after treatment.

[0184] Embodiment 4c is the method of any one of embodiments 4-4a, wherein the improvement is The measurements are taken 24 weeks after treatment.

[0185] Embodiment 5 is the method of any one of embodiments 4 to 4c, wherein the subject is Responders to antibody therapy and meet the American College of Rheumatology criteria by week 24 of antibody treatment Statistical improvement in disease activity as determined by a 20% improvement in the Asset Disease Index (ACR20) are identified as having significant improvement in

[0186] Embodiment 5a is the method of any one of embodiments 4 to 4c, wherein the subject is an antibody. Responders to treatment with the antibody, as determined by the American College of Rheumatology (ACR) by week 16 of treatment with the antibody. Disease activity statistics as determined by a 20% improvement in the Core Set Disease Index (ACR20) are identified as having a significant improvement in clinical outcomes.

[0187] Embodiment 5b is the method of any one of embodiments 4 to 4c, wherein the subject is an antibody. Responders to treatment with antibody and meet the American College of Rheumatology criteria by week 24 of antibody treatment Statistical improvement in disease activity as determined by a 50% improvement in the Asset Disease Index (ACR50) are identified as having significant improvement in

[0188] Embodiment 5c is the method of any one of embodiments 4-4c, wherein the subject is an antibody. Responders to treatment with antibody and meet the American College of Rheumatology criteria by week 16 of antibody treatment Statistical improvement of disease activity as determined by a 50% improvement in the Acetopathic Criteria for Disease (ACR50) score identified as having significant improvement.

[0189] Embodiment 5d is the method of any one of embodiments 4-4c, wherein the subject is an antibody. Responders to treatment with antibody and meet the American College of Rheumatology criteria by week 24 of antibody treatment Statistical improvement in disease activity as determined by a 70% improvement in the Asset Disease Index (ACR70) are identified as having significant improvement in

[0190] Embodiment 5e is the method of any one of embodiments 4-4c, wherein the subject is an antibody. Responders to treatment with antibody and have a Health Assessment Questionnaire impairment score by week 24 of treatment with antibody. Statistically significant improvement in disease activity as determined by the Harm Index (HAQ-DI) be identified.

[0191] Embodiment 5f is the method of any one of embodiments 4-4c, wherein the subject is an antibody. Responders to treatment with the antibody and have a disease activity score of 0.01 or higher by week 24 of treatment with the antibody. Statistics of disease activity determined by C-reactive protein (CRP) 28 (DAS28) are identified as having a significant improvement in clinical outcomes.

[0192] Embodiment 5g is the method of any one of embodiments 4-4c, wherein the subject is an antibody Responders to treatment with the antibody, as determined by the investigator, by week 24 of treatment with the antibody. Global Assessment (IGA) of 0 (clear) or 1 (minimum) and / or the basis of the IGA Subjects were identified as having achieved a ≥2 grade reduction from baseline in BSA have ≥3% psoriatic lesions and an IGA score of ≥2.

[0193] Embodiment 5h is the method of any one of embodiments 4-4c, wherein the subject is an antibody Responders to treatment with the antibody, with resolution of arthritis by 24 weeks of treatment with the antibody Patients are identified as having a statistically significant improvement in disease activity as determined by the NIH standard of care.

[0194] Embodiment 5i is the method of any one of embodiments 4-4c, wherein the subject is an antibody Responders to treatment with antibody, as determined by resolution of dactylitis by week 24 of antibody treatment. Patients are identified as having a statistically significant improvement in disease activity as determined.

[0195] Embodiment 5j is the method of any one of embodiments 4-4c, wherein the subject is an antibody Responders to treatment with antibody and have had enthesitis of the digitorum enthesitis by week 24 of antibody treatment Patients were identified as having a statistically significant improvement in disease activity as determined by the LEI. Be separated.

[0196] Embodiment 5k is the method of any one of embodiments 4-4c, wherein the subject is an antibody Responders to treatment with antibody, with a score of 0-3 (0 = none) by week 24 of antibody treatment. and disease activity as determined by a dactylitis assessment score (1 = mild, 2 = moderate, 3 = severe). are identified as having a statistically significant improvement in

[0197] Embodiment 51 is the method of any one of embodiments 4 to 4c, wherein the subject is an antibody. Responders to treatment with short-form antibody by week 24 of treatment with the antibody Statistically significant improvement in disease activity as determined by the SF-36 Health Survey It is identified as

[0198] Embodiment 5m is the method of any one of embodiments 4 to 4c, wherein the subject is an antibody Responders to treatment with antibody, with mental and physical improvements by week 24 of antibody treatment Summary of disease activity as determined by component summary (MCS and PCS) scores are identified as having a statistically significant improvement.

[0199] Embodiment 5n is the method of any one of embodiments 4 to 4c, wherein the subject is an antibody. Responders to treatment with antibody and minimal disease activity (MdA) by week 24 of antibody-based treatment Patients are identified as having a statistically significant improvement in disease activity as determined by the DA criteria.

[0200] Embodiment 5o is the method of any one of embodiments 4-4c, wherein the subject is an antibody. Responders to treatment with rituximab, determined by the achievement of very low disease activity (VLDA) Patients are identified as having a statistically significant improvement in disease activity as determined by the FDA.

[0201] Embodiment 5p is the method of any one of embodiments 4-4c, wherein the subject is an antibody. Responders to treatment with IVF and a reduction in the total modified vdH-S score from baseline Patients are identified as having a statistically significant improvement in disease activity as determined by S-mean change.

[0202] Embodiment 6 is the method of any one of embodiments 4 to 5o, wherein the improvement is at least 12, 24, 36, 48, 60, 72, or 84 weeks , or any time therebetween.

[0203] Embodiment 7 is the method according to any one of embodiments 1 to 6, wherein the anti-IL-23 antibody is guselkumab.

[0204] Embodiment 8 is the method of any one of embodiments 1 to 7, wherein the subject has psoriatic joint disease. The method further includes administering one or more additional drugs used in the treatment of inflammation.

[0205] Embodiment 8a is the method of embodiment 8, wherein the additional agent is an immunosuppressant, a nonsteroidal anti-inflammatory drug, or a combination thereof. Nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface markers -antibodies, anti-CD20 antibodies, rituximab, TNF-inhibitors, corticosteroids, and co- The compound is selected from the group consisting of irritation modifiers.

[0206] Embodiment 9 is a method of treating psoriatic arthritis (PsA) in a subject, comprising administering to a subject a therapeutically effective amount of psoriatic arthritis (PsA) that is safe and effective. A pharmaceutical composition comprising an effective amount of an anti-IL-23 antibody and a pharmaceutically acceptable carrier is administered subcutaneously to a subject. The pharmaceutical composition comprises administering an initial dose, a dose four weeks later, and every eight weeks thereafter. The treatment is administered once every 8 weeks. Subjects must have at least one lesion ≥ 2 cm in diameter before treatment. psoriatic plaques, or nail changes consistent with psoriasis, or a documented history of plaque psoriasis It has.

[0207] Embodiment 9a is the method of embodiment 9, wherein the anti-IL-23 antibody comprises the heavy chain variable region and a light chain variable region, and the heavy chain variable region comprises the complementarity determining regions heavy chain 1 (CDRs) of SEQ ID NO: 1. H1) amino acid sequence, CDRH2 of SEQ ID NO: 2, and CDRH3 of SEQ ID NO: 3, The chain variable region is the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, SEQ ID NO: The CDRL comprises CDRL2 of SEQ ID NO:5, and CDRL3 of SEQ ID NO:6.

[0208] Embodiment 9b is the method of embodiment 9, wherein the antibody has 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.

[0209] Embodiment 9c is the method of embodiment 9, wherein the anti-IL-23 antibody is selected from the group consisting of SEQ ID NO: 9 It comprises a heavy chain amino acid sequence of SEQ ID NO:10 and a light chain amino acid sequence of SEQ ID NO:10.

[0210] Embodiment 10 is the method of any one of embodiments 9 to 9c, wherein the antibody is administered A total dose of 25 mg to 200 mg per dose, e.g., 25 mg, 50 mg, 75 mg per dose mg, 100mg, 125mg, 150mg, 175mg, and 200mg, or any combination in between The drug is administered at any dose.

[0211] Embodiment 10a is the method of embodiment 10, wherein the total dose is about 50 to about 100 mg / dose. It is 150mg.

[0212] Embodiment 10b is the method of embodiment 10, wherein the total dose is about 100 mg / dose. mg.

[0213] Embodiment 11 is the method of any one of embodiments 9 to 10b, wherein the subject is P have an inadequate response to standard treatment for sA.

[0214] Embodiment 11a is the method of embodiment 11, wherein the standard of care is a non-biologic disease. Modified antirheumatic drugs (DMARDs), oral corticosteroids, apremilast, nonsteroidal anti-inflammatory drugs and nonsteroidal anti-inflammatory drugs (NSAIDs).

[0215] Embodiment 11b is the method of embodiment 11, wherein the standard of care is to provide the subject with a ≤25 min methotrexate (MTX) administered at ≤3 g / week, sulfonamide administered at ≤3 g / day salazine (SSZ), hydroxychloroquine (H) administered to subjects at ≤400 mg / day CQ), or leflunomide (LEF) administered to the subject at ≤20 mg / day It is the DMARD of choice.

[0216] Embodiment 11c is the method of embodiment 11, wherein the standard of care is ≦10 mg / day is an oral corticosteroid administered to a subject in an amount equivalent to 100 mg of prednisone.

[0217] Embodiment 11d is the method of embodiment 11, wherein the standard of care is The term "analgesic" refers to an NSAID or other analgesic administered to a subject at its approved marketed dose.

[0218] Embodiment 11e is the method of embodiment 11, wherein the standard of care is The compound is apremilast administered to subjects at its approved marketed dose.

[0219] Embodiment 11f is the method of any one of embodiments 11 to 11e, wherein the subject Naive to biological treatment.

[0220] Embodiment 11g is the method of any one of embodiments 11 to 11e, wherein the subject , and have received at least one prior biologic treatment for PsA.

[0221] Embodiment 11h is the method of embodiment 11g, wherein the subject has at least one living have an inadequate response to chemotherapy.

[0222] Embodiment 11i is the method of embodiment 11g or 11h, wherein the biological therapy is Guselkumab, ustekinumab, secukinumab (AIN457), anti-tumor necrosis factor alpha (T NFα) agents (e.g., adalimumab, etanercept, infliximab, golimumab subcutaneous [SC] or intravenous [IV], certolizumab pegol, or their respective biologics Similar), tildrakizumab (MK3222), ixekizumab (LY2439821 ), brodalumab (AMG827), risankizumab (BI-655066), or Ps A or other investigational biologic treatments for psoriasis.

[0223] Embodiment 11j is the method of embodiment 11i, wherein the subject is administered anti-tumor necrosis factor alpha ( non-responders to TNFα treatment.

[0224] Embodiment 11k is the method of any one of embodiments 9 to 11j, wherein the subject is Have plaque psoriasis of at least 3% of body surface area (BSA) before treatment.

[0225] Embodiment 11l is the method of any one of embodiments 9 to 11j, wherein the subject is Prior to treatment, patients had at least one psoriatic plaque ≥ 2 cm in diameter or nail changes consistent with psoriasis. have a documented history of psoriasis, psoriasis, or plaque psoriasis.

[0226] Embodiment 11m is the method of any one of embodiments 9 to 11l, optionally comprising: Preferably, the method further comprises administering to the subject a standard of care treatment for PsA.

[0227] Embodiment 11n is the method of any one of embodiments 9 to 11l, optionally comprising: Preferably, the method further comprises administering to the subject a biologic therapy for PsA.

[0228] Embodiment 12 is the method of any one of embodiments 9 to 11n, wherein the subject is an anti- Responders to treatment with the drug and have a statistically significant improvement in disease activity. Disease activity was assessed by a 20% improvement in the American College of Rheumatology Core Set Disease Index (ACR2). 0), 50% improvement in the American College of Rheumatology Core Set Disease Index (ACR50), American College of Rheumatology 70% improvement in Core Set Disease Index (ACR70), Health Assessment Questionnaire Disability Index (HAQ-D) I), Investigator Global Assessment (IGA), Disease Activity Score 28 (DAS28 ) C-reactive protein (CRP), resolution of enthesitis, resolution of dactylitis, Leeds enthesitis dactylitis Number of patients (LEI), Dactylitis Assessment Score, Mental and Physical Component Summary (MCS and Short Form Health Survey (SF-36) in PCS, Achieving Minimal Disease Activity (M and achieving very low disease activity (VLDA). It is determined by the above criteria.

[0229] Embodiment 12a is the method of embodiment 12, wherein the improvement is within 16, 20 days of initial treatment. , measured after 24 or 28 weeks.

[0230] Embodiment 12b is the method of any one of embodiments 12-12a, wherein the improvement is Measured 16 weeks after initial treatment.

[0231] Embodiment 12c is the method of any one of embodiments 12 and 12a, wherein the improvement is Measured 24 weeks after initial treatment.

[0232] Embodiment 13 is the method of any one of embodiments 12 to 12c, wherein the subject is Responders to antibody therapy and by week 24 of antibody therapy, the American College of Rheumatology Disease activity as determined by a 20% improvement in the American College of Cardiology Core Set Disease Index (ACR20) are identified as having a statistically significant improvement in

[0233] Embodiment 13a is the method of any one of embodiments 12 to 12c, wherein the subject , responders to antibody treatment, and by week 16 of antibody treatment, Disease activity as determined by a 20% improvement in the Association for Clinical Research Core Set Disease Index (ACR20) are identified as having a statistically significant improvement in sexual function.

[0234] Embodiment 13b is the method of any one of embodiments 12 to 12c, wherein the subject , responders to antibody treatment, and by week 24 of antibody treatment, the American College of Rheumatology Statistically significant improvement in disease activity as determined by the American College of Cardiology 130% improvement criteria (ACR130) are identified as having significant improvements.

[0235] Embodiment 13c is the method of any one of embodiments 12-12c, wherein the subject , responders to antibody treatment, and by week 16 of antibody treatment, the American College of Rheumatology Statistically significant improvement in disease activity as determined by the American College of Cardiology 130% improvement criteria (ACR130) are identified as having significant improvements.

[0236] Embodiment 13d is the method of any one of embodiments 12-12c, wherein the subject , responders to antibody treatment, and by week 24 of antibody treatment, the American College of Rheumatology Disease activity as determined by a 70% improvement in the American College of Cardiology Core Set Disease Index (ACR70) identified as having a statistically significant improvement.

[0237] Embodiment 13e is the method of any one of embodiments 12-12c, wherein the subject , responders to antibody-based treatment, and health assessment by week 24 of antibody-based treatment Statistically significant improvement in disease activity as determined by the Hazard Assessment Questionnaire-Disability Index (HAQ-DI) It is identified as having

[0238] Embodiment 13f is the method of any one of embodiments 12-12c, wherein the subject , responders to antibody treatment, with no significant improvement in disease activity by week 24 of antibody treatment. Disease activity determined by C-reactive protein (CRP) score 28 (DAS28) are identified as having a statistically significant improvement in

[0239] Embodiment 13g is the method of any one of embodiments 12-12c, wherein the subject , responders to antibody treatment, and by week 24 of antibody treatment, the investigator Global Assessment (IGA) of 0 (clear) or 1 (minimum) and / or Subjects were identified as having achieved a ≥2-grade reduction from baseline and Have psoriatic lesions of ≥3% of the BSA and an IGA score of ≥2.

[0240] Embodiment 13h is the method of any one of embodiments 12-12c, wherein the subject , responders to antibody treatment, with resolution of periostitis by week 24 of antibody treatment are identified as having a statistically significant improvement in disease activity as determined by

[0241] Embodiment 13i is the method of any one of embodiments 12-12c, wherein the subject , responders to antibody treatment, and dactylitis by week 24 of antibody treatment. Patients are identified as having a statistically significant improvement in disease activity as determined by resolution of ≥100% of the ≥100% disease severity.

[0242] Embodiment 13j is the method of any one of embodiments 12 to 12c, wherein the subject , responders to antibody treatment, and by week 24 of antibody treatment, the Leeds tendon attachment Those with a statistically significant improvement in disease activity as determined by the Leukemia Index (LEI) and identified.

[0243] Embodiment 13k is the method of any one of embodiments 12-12c, wherein the subject , responders to antibody treatment, with a 0-3(( Disease as determined by a dactylitis rating score (0 = none, 1 = mild, 2 = moderate, 3 = severe) Patients are identified as having a statistically significant improvement in activity.

[0244] Embodiment 13l is the method of any one of embodiments 12-12c, wherein the subject , responders to antibody-based treatment, and short-term survival by week 24 of antibody-based treatment Statistically significant improvement in disease activity as determined by the SF-36 Health Survey Identified as possessing goodness.

[0245] Embodiment 13m is the method of any one of embodiments 12 to 12c, wherein the subject , responders to antibody treatment, and by week 24 of antibody treatment, mental and Disease activity determined by physical component summary (MCS and PCS) scores are identified as having a statistically significant improvement in sexual function.

[0246] Embodiment 13n is the method of any one of embodiments 12-12c, wherein the subject Responders to antibody treatment with minimal disease activity by week 24 of antibody treatment Patients identified as having a statistically significant improvement in disease activity as determined by the Multidisciplinary Approach to Disease Activity (MDA) criteria can be.

[0247] Embodiment 13o is the method of any one of embodiments 12-12c, wherein the subject , responders to antibody-based treatment and by achieving very low disease activity (VLDA) Patients are identified as having a statistically significant improvement in disease activity as determined by the NIH standard of care.

[0248] Embodiment 14 is the method of any one of embodiments 12-13o, wherein the improvement comprises: At least 12, 24, 36, 48, 60, 72, or 8 weeks Maintained for 4 weeks, or any time thereafter.

[0249] Embodiment 15 is the method according to any one of embodiments 9 to 14, wherein the method comprises administering an anti-IL-23 The antibody is guselkumab.

[0250] Embodiment 16 is the method of any one of embodiments 9 to 15, wherein the method is for treating psoriatic arthritis. The method further comprises administering to the subject one or more additional agents used in the treatment of

[0251] Embodiment 16a is the method of embodiment 16, wherein the additional agent is an immunosuppressant, a non- Steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface markers antibody, anti-CD20 antibody, rituximab, TNF-inhibitor, corticosteroid, and and costimulatory modifiers.

[0252] Embodiment 17 is for the treatment of psoriatic arthritis (PsA) in a subject in need thereof. 2. Use of an anti-IL-23 antibody in the manufacture of a medicament for the treatment of IL-23, wherein the antibody is administered in a safe and effective amount of an anti-IL-23 antibody. A pharmaceutical composition comprising the L-23 antibody and a pharmaceutically acceptable carrier is administered subcutaneously to the subject.

[0253] Embodiment 17a is the use of embodiment 17, wherein the anti-IL-23 antibody has a heavy chain variable The heavy chain variable region comprises a complementarity determining region heavy chain 1 (C ) of SEQ ID NO: 1 and a light chain variable region. CDRH1) amino acid sequence of SEQ ID NO:2, CDRH2 of SEQ ID NO:3, and CDRH3 of SEQ ID NO:4 The light chain variable region has the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4. It contains CDRL2 of sequence number 5 and CDRL3 of sequence number 6.

[0254] Embodiment 17b is the use of embodiment 17, wherein the antibody comprises 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.

[0255] Embodiment 17c is the use of embodiment 17, wherein the antibody comprises the amino acid sequence of SEQ ID NO: 9. and a light chain of the amino acid sequence of SEQ ID NO: 10.

[0256] Embodiment 17d is the use of embodiment 1, wherein the antibody is administered every 4 weeks (4w). It is administered once.

[0257] Embodiment 18 is the use of any one of embodiments 17 to 17d, wherein the antibody is A total dose of 25 mg to 200 mg per dose, e.g., 25 mg, 50 mg, Total doses of 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, and 200 mg or any dosage therebetween.

[0258] Embodiment 18a is the use of embodiment 18, wherein the total dose is about 50-60 mg / dose. It is about 150 mg.

[0259] Embodiment 18b is the use of embodiment 18, wherein the total dose is about 100 mg / dose. mg.

[0260] Embodiment 19 is the use of any one of embodiments 17 to 18b, wherein the subject is have an inadequate response to standard treatment for PsA.

[0261] Embodiment 19a is the use of embodiment 19, wherein the standard of care is a non-biologic disease. Modified antirheumatic drugs (DMARDs), oral corticosteroids, apremilast, nonsteroidal anti-inflammatory drugs and nonsteroidal anti-inflammatory drugs (NSAIDs).

[0262] Embodiment 19b is the use of embodiment 19, wherein the standard of care is for the subject to receive ≤25 minutes of treatment. methotrexate (MTX) administered at ≤3 g / week, sulfonamide administered at ≤3 g / day salazine (SSZ), hydroxychloroquine (H) administered to subjects at ≤400 mg / day CQ), or leflunomide (LEF) administered to the subject at ≤20 mg / day It is the DMARD of choice.

[0263] Embodiment 19c is the use of embodiment 19, wherein the standard of care is ≦10 mg / day is an oral corticosteroid administered to a subject in an amount equivalent to 100 mg of prednisone.

[0264] Embodiment 19d is the use of embodiment 19, wherein the standard of care is The term "analgesic" refers to an NSAID or other analgesic administered to a subject at its approved marketed dose.

[0265] Embodiment 19e is the use of embodiment 19, wherein the standard of care is The compound is apremilast administered to subjects at its approved marketed dose.

[0266] Embodiment 19f is the use of any one of embodiments 19 to 19e, wherein the subject is Naive to biological treatment.

[0267] Embodiment 19g is the use of any one of embodiments 19 to 19e, wherein the subject is , and have received at least one prior biologic treatment for PsA.

[0268] Embodiment 19h is the use of embodiment 19g, wherein the subject has at least one genetic disorder. have an inadequate response to chemotherapy.

[0269] Embodiment 19i is the use of embodiment 19g or 19h, wherein the biological therapy is Guselkumab, ustekinumab, secukinumab (AIN457), anti-tumor necrosis factor alpha (T NFα) agents (e.g., adalimumab, etanercept, infliximab, golimumab subcutaneous [SC] or intravenous [IV], certolizumab pegol, or their respective biologics Similar), tildrakizumab (MK3222), ixekizumab (LY2439821 ), brodalumab (AMG827), risankizumab (BI-655066), or Ps A or other investigational biologic treatments for psoriasis.

[0270] Embodiment 19j is the use of embodiment 19i, wherein the subject is administered anti-tumor necrosis factor alpha ( are non-responders to TNFα treatment.

[0271] Embodiment 19k is the use of any one of embodiments 17 to 19j, wherein the subject is , have plaque psoriasis of at least 3% of body surface area (BSA) before treatment.

[0272] Embodiment 19l is the use of any one of embodiments 17 to 19j, wherein the subject is Prior to treatment, at least one psoriatic plaque ≥ 2 cm in diameter or nail lesions consistent with psoriasis Have a documented history of change or plaque psoriasis.

[0273] Embodiment 19m is the use of any one of embodiments 17 to 19l, wherein the subject is , and optionally receive standard treatment for PsA.

[0274] Embodiment 19n is the use of any one of embodiments 17 to 19l, wherein the subject is , and is optionally administered a biological treatment for PsA.

[0275] Embodiment 20 is the method of any one of embodiments 17 to 19n, wherein the subject is Identified as responders to antibody treatment and having a statistically significant improvement in disease activity Disease activity was measured as a 20% improvement in the American College of Rheumatology Core Set Disease Index (ACR20). , 50% improvement in the American College of Rheumatology Core Set Disease Index (ACR50), American College of Rheumatology 70% improvement in Core Set Disease Index (ACR70), Health Assessment Questionnaire Disability Index (HAQ-D) I), Investigator Global Assessment (IGA), Disease Activity Score 28 (DAS28 ) C-reactive protein (CRP), resolution of enthesitis, resolution of dactylitis, Leeds enthesitis dactylitis Number of patients (LEI), Dactylitis Assessment Score, Mental and Physical Component Summary (MCS and Short Form Health Survey (SF-36) in PCS, Achieving Minimal Disease Activity (M DA), LS mean change from baseline in total modified vdH-S score, and very low achieved disease activity (VLDA) can be.

[0276] Embodiment 20a is the use of embodiment 20, wherein the improvement is at least one of the following: Measured after 24 or 28 weeks.

[0277] Embodiment 20b is the use of any one of embodiments 20 to 20a, wherein the improvement is Measured 16 weeks after initial treatment.

[0278] Embodiment 20c is the use of any one of embodiments 20 to 20a, wherein the improvement is Measured 24 weeks after initial treatment.

[0279] Embodiment 21 is the use of any one of embodiments 20 to 20c, wherein the subject is Responders to antibody treatment who were rated by the American College of Rheumatology by week 24 of antibody treatment Disease activity as determined by a 20% improvement in the Association for Clinical Core Set Disease Index (ACR20) identified as having a statistically significant improvement.

[0280] Embodiment 21a is the use according to any one of embodiments 20 to 20c, wherein the subject is , responders to antibody-based treatment, and by week 16 of antibody-based treatment, Disease activity as determined by a 20% improvement in the ACR20 score are identified as having a statistically significant improvement in

[0281] Embodiment 21b is the use of any one of embodiments 20 to 20c, wherein the subject is Responders to antibody therapy who meet the criteria for the American College of Rheumatology (ACR) criteria by week 24 of antibody therapy The statistical significance of disease activity as determined by a 50% improvement in the Association of Clinical Core Set Disease Index (ACR50) was confirmed. are identified as having a statistically significant improvement.

[0282] Embodiment 21c is the use of any one of embodiments 20 to 20c, wherein the subject is , responders to antibody treatment, and by week 16 of antibody treatment, the American College of Rheumatology Disease activity as determined by a 50% improvement in the Association for Clinical Research and Clinical Practice (ACR50) score identified as having a statistically significant improvement.

[0283] Embodiment 21d is the use of any one of embodiments 20 to 20c, wherein the subject is , responders to antibody treatment, and by week 24 of antibody treatment, the American College of Rheumatology Disease activity as determined by a 70% improvement in the American College of Cardiology Core Set Disease Index (ACR70) identified as having a statistically significant improvement.

[0284] Embodiment 21e is the use of any one of embodiments 20 to 20c, wherein the subject is , responders to antibody treatment and complete a health assessment questionnaire by week 24 of antibody treatment. Statistically significant improvement in disease activity as determined by the Haemophilia Questionnaire Disability Index (HAQ-DI) It is identified as

[0285] Embodiment 21f is the use of any one of embodiments 20 to 20c, wherein the subject is , responders to antibody treatment, with no significant improvement in disease activity by week 24 of antibody treatment. Disease activity determined by C-reactive protein (CRP) score 28 (DAS28) are identified as having a statistically significant improvement in

[0286] Embodiment 21g is the use of any one of embodiments 20 to 20c, wherein the subject is , responders to antibody treatment, and by week 24 of antibody treatment, the investigator Global Assessment Index (IGA) of 0 (clear) or 1 (minimum) and / or IG Subjects were identified as having achieved a ≥2 grade reduction from baseline in A and were Patients with psoriatic lesions of ≥3% of BSA and an IGA score of ≥2 were included.

[0287] Embodiment 21h is the use of any one of embodiments 20 to 20c, wherein the subject is , responders to antibody treatment, and by week 24 of antibody treatment, enthesitis Patients are identified as having a statistically significant improvement in disease activity as determined by resolution of ≥100% of the ≥100% disease severity.

[0288] Embodiment 21i is the use of any one of embodiments 20 to 20c, wherein the subject is , responders to antibody treatment, with resolution of dactylitis by 24 weeks of antibody treatment. Patients are identified as having a statistically significant improvement in disease activity as determined by the method.

[0289] Embodiment 21j is the use of any one of embodiments 20 to 20c, wherein the subject is Responders to antibody treatment, with Leeds tendon attachment by week 24 of antibody treatment identified as having a statistically significant improvement in disease activity as determined by the Leukemia Index (LEI) will be done.

[0290] Embodiment 21k is the use of any one of embodiments 20 to 20c, wherein the subject is , responders to antibody treatment, with a 0-3(( Disease as determined by a dactylitis rating score (0 = none, 1 = mild, 2 = moderate, 3 = severe) Patients are identified as having a statistically significant improvement in activity.

[0291] Embodiment 21l is the use of any one of embodiments 20 to 20c, wherein the subject is , responders to antibody treatment, and short-form by week 24 of antibody treatment Statistically significant improvement in disease activity as determined by the SF-36 Health Survey It is identified as having

[0292] Embodiment 21m is the use according to any one of embodiments 20 to 20c, wherein the subject is Responders to antibody treatment who have a mental sequence number of 1 or more by week 24 of antibody treatment Disease as determined by the Physical Component Summary (MCS) score Patients are identified as having a statistically significant improvement in disease activity.

[0293] Embodiment 21n is the use according to any one of embodiments 20 to 20c, wherein the subject is Responders to antibody treatment with minimal disease activity by week 24 of antibody treatment Patients were identified as having a statistically significant improvement in disease activity as determined by the Multidisciplinary Approach to Disease (MDA) criteria. do.

[0294] Embodiment 21o is the use of any one of embodiments 20 to 20c, wherein the subject is Responders to antibody-based treatment and by achieving very low disease activity (VLDA) Patients are identified as having a statistically significant improvement in disease activity as determined by the NIH standard of care.

[0295] Embodiment 21p is the use according to any one of embodiments 20 to 20c, wherein the subject is Responders to antibody treatment who have a reduction in total modified vdH-S score from baseline Identified as having a statistically significant improvement in disease activity as determined by LS mean change .

[0296] Embodiment 22 is the use of any one of embodiments 20 to 21o, wherein the improvement is At least 12, 24, 36, 48, 60, 72, or 8 weeks Maintained for 4 weeks, or any time thereafter.

[0297] Embodiment 23 is the use according to any one of embodiments 17 to 22, wherein the anti-IL-2 3The antibody is guselkumab.

[0298] Embodiment 24 is the use of any one of embodiments 17 to 23, wherein the subject is a dry eye. The patient will receive one or more additional medications used to treat idiopathic arthritis.

[0299] Embodiment 24a is the use of embodiment 24, wherein the additional agent is an immunosuppressant, a non- Steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface markers antibody, anti-CD20 antibody, rituximab, TNF-inhibitor, corticosteroid, and and costimulatory modifiers.

[0300] Embodiment 25 relates to the manufacture of a medicament for treating psoriatic arthritis (PsA) in a subject. The present invention relates to the use of an anti-IL-23 antibody in a patient receiving a treatment for IL-23 ... and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is administered subcutaneously after a first administration, The treatment was repeated 4 weeks later, followed by once every 8 weeks (q8w). at least one previous psoriatic plaque ≥ 2 cm in diameter or nail changes consistent with psoriasis, or has a documented history of plaque psoriasis.

[0301] Embodiment 25a is the use of embodiment 25, wherein the anti-IL-23 antibody has a heavy chain variable The heavy chain variable region comprises a complementarity determining region heavy chain 1 (C ) of SEQ ID NO: 1 and a light chain variable region. CDRH1) amino acid sequence of SEQ ID NO:2, CDRH2 of SEQ ID NO:3, and CDRH3 of SEQ ID NO:4 The light chain variable region has the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4. It contains CDRL2 of sequence number 5 and CDRL3 of sequence number 6.

[0302] Embodiment 25b is the use of embodiment 25, wherein the antibody comprises 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.

[0303] Embodiment 25c is the use of embodiment 25, wherein the anti-IL-23 antibody is selected from the group consisting of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO:10.

[0304] Embodiment 26 is the use of any one of embodiments 25 to 25c, wherein the antibody is A total dose of 25 mg to 200 mg per dose, e.g., 25 mg, 50 mg, Total doses of 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, and 200 mg or any dosage therebetween.

[0305] Embodiment 26a is the use of embodiment 26, wherein the total dose is about 50-60 mg / dose. It is about 150 mg.

[0306] Embodiment 26b is the use of embodiment 26, wherein the total dose is about 100 mg / dose. mg.

[0307] Embodiment 27 is the use of any one of embodiments 25 to 26b, wherein the subject is have an inadequate response to standard treatment for PsA.

[0308] Embodiment 27a is the use of embodiment 27, wherein the standard of care is a non-biologic disease. Modified antirheumatic drugs (DMARDs), oral corticosteroids, apremilast, nonsteroidal anti-inflammatory drugs and nonsteroidal anti-inflammatory drugs (NSAIDs).

[0309] Embodiment 27b is the use of embodiment 27, wherein the standard of care is for the subject to receive ≤25 minutes of treatment. methotrexate (MTX) administered at ≤3 g / week, sulfonamide administered at ≤3 g / day salazine (SSZ), hydroxychloroquine (H) administered to subjects at ≤400 mg / day CQ), or leflunomide (LEF) administered to the subject at ≤20 mg / day It is the DMARD of choice.

[0310] Embodiment 27c is the use of embodiment 27, wherein the standard of care is ≦10 mg / day is an oral corticosteroid administered to a subject in an amount equivalent to 100 mg of prednisone.

[0311] Embodiment 27d is the use of embodiment 27, wherein the standard of care is The term "analgesic" refers to an NSAID or other analgesic administered to a subject at its approved marketed dose.

[0312] Embodiment 27e is the use of embodiment 27, wherein the standard of care is The compound is apremilast administered to subjects at its approved marketed dose.

[0313] Embodiment 27f is the use of any one of embodiments 27 to 27e, wherein the subject are biological treatment naive.

[0314] Embodiment 27g is the use of any one of embodiments 27 to 27e, wherein the subject have received at least one prior biologic treatment for PsA.

[0315] Embodiment 27h is the use of embodiment 27g, wherein the subject has at least one live have an inadequate response to chemotherapy.

[0316] Embodiment 27i is the use of embodiment 27g or 27h, wherein the biological therapy is Guselkumab, ustekinumab, secukinumab (AIN457), anti-tumor necrosis factor alpha (T NFα) agents (e.g., adalimumab, etanercept, infliximab, golimumab subcutaneous [SC] or intravenous [IV], certolizumab pegol, or their respective biologics Similar), tildrakizumab (MK3222), ixekizumab (LY2439821 ), brodalumab (AMG827), risankizumab (BI-655066), or Ps A or other investigational biologic treatments for psoriasis.

[0317] Embodiment 27j is the use of embodiment 27i, wherein the subject is administered anti-tumor necrosis factor alpha ( are non-responders to TNFα treatment.

[0318] Embodiment 27k is the use of any one of embodiments 25 to 27j, wherein the subject is , have plaque psoriasis of at least 3% of body surface area (BSA) before treatment.

[0319] Embodiment 27l is the use of any one of embodiments 25 to 27j, wherein the subject is Prior to treatment, at least one psoriatic plaque ≥ 2 cm in diameter or nail lesions consistent with psoriasis Have a documented history of change or plaque psoriasis.

[0320] Embodiment 27m is the use of any one of embodiments 25 to 27l, wherein the subject is , and optionally receive standard treatment for PsA.

[0321] Embodiment 27n is the use of any one of embodiments 25 to 27l, wherein the subject , and is optionally administered a biological treatment for PsA.

[0322] Embodiment 28 is the use of any one of embodiments 25 to 27n, wherein the subject is Responders to antibody treatment, those with a statistically significant improvement in disease activity Disease activity was defined as a 20% improvement in the American College of Rheumatology Core Set Disease Index (ACR 20), 50% improvement in the American College of Rheumatology Core Set Disease Index (ACR50), American College of Rheumatology 70% improvement in the Association of Clinical Core Set Disease Index (ACR70), Health Assessment Questionnaire Disability Index (HAQ- DI), Investigator Global Assessment (IGA), Disease Activity Score 28 (DAS2 8) C-reactive protein (CRP), resolution of enthesitis, resolution of dactylitis, enthesitis of Leeds Index (LEI), Dactylitis Assessment Score, Mental and Physical Component Summary (MCS and Short Form Health Survey (SF-36) (MCS and PCS), Consists of achieving Minimal Disease Activity (MDA) and Very Low Disease Activity (VLDA) The determination is made by one or more criteria selected from the group.

[0323] Embodiment 28a is the use of embodiment 28, wherein the improvement is 16, 20, or 30 days after initial treatment. Measured after 24 or 28 weeks.

[0324] Embodiment 28b is the use of any one of embodiments 28 to 28a, wherein the improvement is Measured 16 weeks after initial treatment.

[0325] Embodiment 28c is the use of any one of embodiments 28 to 28a, wherein the improvement is Measured 24 weeks after initial treatment.

[0326] Embodiment 29 is the use of any one of embodiments 28 to 28c, wherein the subject is Responders to antibody therapy and by week 24 of antibody therapy, the American College of Rheumatology Disease activity as determined by a 20% improvement in the American College of Cardiology Core Set Disease Index (ACR20) are identified as having a statistically significant improvement in

[0327] Embodiment 29a is the use of any one of embodiments 28 to 28c, wherein the subject is , responders to antibody treatment, and by week 16 of antibody treatment, the American College of Rheumatology Disease activity as determined by a 20% improvement in the Association for Clinical Core Set Disease Index (ACR20) identified as having a statistically significant improvement.

[0328] Embodiment 29b is the use of any one of embodiments 28 to 28c, wherein the subject is , responders to antibody treatment, and by week 24 of antibody treatment, Statistically significant improvement in disease activity as determined by the Association of Community Response Criteria for 130% Improvement (ACR130) are identified as having significant improvements.

[0329] Embodiment 29c is the use of any one of embodiments 28 to 28c, wherein the subject is , responders to antibody treatment, and by week 16 of antibody treatment, the American College of Rheumatology Statistically significant improvement in disease activity as determined by the American College of Cardiology 130% improvement criteria (ACR130) are identified as having significant improvements.

[0330] Embodiment 29d is the use of any one of embodiments 28 to 28c, wherein the subject is , responders to antibody treatment, and by week 24 of antibody treatment, the American College of Rheumatology Disease activity as determined by a 70% improvement in the American College of Cardiology Core Set Disease Index (ACR70) are identified as having a statistically significant improvement in

[0331] Embodiment 29e is the use of any one of embodiments 28 to 28c, wherein the subject is , responders to antibody treatment, and by week 24 of antibody treatment, health assessment Statistically significant improvement in disease activity as determined by the Hazard Assessment Questionnaire-Disability Index (HAQ-DI) It is identified as having

[0332] Embodiment 29f is the use of any one of embodiments 28 to 28c, wherein the subject is , responders to antibody treatment, with no significant improvement in disease activity by week 24 of antibody treatment. Disease activity determined by C-reactive protein (CRP) score 28 (DAS28) are identified as having a statistically significant improvement in

[0333] Embodiment 29g is the use of any one of embodiments 28 to 28c, wherein the subject is , responders to antibody treatment, and by week 24 of antibody treatment, the investigator Global Assessment (IGA) of 0 (clear) or 1 (minimum) sequence number / or baseline Subjects were identified as having achieved a ≥2 grade reduction in BSA from baseline. Have ≥3% psoriatic lesions and an IGA score of ≥2.

[0334] Embodiment 29h is the use of any one of embodiments 28 to 28c, wherein the subject is , responders to antibody treatment, with enthesitis by week 24 of antibody treatment Patients are identified as having a statistically significant improvement in disease activity as determined by resolution.

[0335] Embodiment 29i is the use of any one of embodiments 28 to 28c, wherein the subject is , responders to antibody treatment, with resolution of dactylitis by 24 weeks of antibody treatment are identified as having a statistically significant improvement in disease activity as determined by

[0336] Embodiment 29j is the use of any one of embodiments 28 to 28c, wherein the subject is , responders to antibody treatment, and by week 24 of antibody treatment, It was found to have a statistically significant improvement in disease activity as determined by the Lesion Inflammation Index (LEI). Be separated.

[0337] Embodiment 29k is the use of any one of embodiments 28 to 28c, wherein the subject is , responders to antibody treatment, with a 0-3(( Disease severity was determined by a dactylitis rating score (0 = none, 1 = mild, 2 = moderate, 3 = severe). Patients are identified as having a statistically significant improvement in disease activity.

[0338] Embodiment 291 is the use of any one of embodiments 28 to 28c, wherein the subject is , responders to antibody treatment, and short-form by week 24 of antibody treatment Statistically significant improvement in disease activity as determined by the SF-36 Health Survey It is identified as having

[0339] Embodiment 29m is the use of any one of embodiments 28 to 28c, wherein the subject is , responders to antibody treatment, and by week 24 of antibody treatment, mental and Disease activity determined by physical component summary (MCS and PCS) scores are identified as having a statistically significant improvement in sexual function.

[0340] Embodiment 29n is the use of any one of embodiments 28 to 28c, wherein the subject is Responders to antibody treatment with minimal disease activity by week 24 of antibody treatment Patients identified as having a statistically significant improvement in disease activity as determined by the MDA criteria do.

[0341] Embodiment 29o is the use of any one of embodiments 28 to 28c, wherein the subject is Responders to antibody-based treatment and by achieving very low disease activity (VLDA) Patients are identified as having a statistically significant improvement in disease activity as determined by the NIH standard of care.

[0342] Embodiment 30 is the use of any one of embodiments 28 to 29o, wherein the improvement is At least 12, 24, 36, 48, 60, 72, or 8 weeks Maintained for 4 weeks, or any time thereafter.

[0343] Embodiment 31 is the use according to any one of embodiments 25 to 30, wherein the anti-IL-2 3The antibody is guselkumab.

[0344] Embodiment 32 is the use of any one of embodiments 25 to 31, wherein the subject is a dry eye. The patient will receive one or more additional medications used to treat idiopathic arthritis.

[0345] Embodiment 32a is the use of embodiment 32, wherein the additional agent is an immunosuppressant, a non- Steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface markers Marker antibodies, anti-CD20 antibodies, rituximab, TNF-inhibitors, corticosteroids, co-administration The compound is selected from the group consisting of irritation modifiers. [Example]

[0346] Abbreviations and Acronyms ACR American College of Rheumatology AMDF Arithmetic mean of desirability functions AE Adverse Event ALT alanine aminotransferase ANOVA analysis of variance ARC Predicted Events Review Committee AST aspartate aminotransferase BASDAI Bass Ankylosing Spondylitis Disease Activity Index BCG Bacillus Calmette-Guerin Below the lowest quantifiable analyte concentration of the BQL assay BSA body surface area CASPAR Classification Criteria for Psoriatic Arthritis CRF Case Report Form (paper or electronic format as appropriate for this study) CRP C-reactive protein DAS28 Disease Activity Score 28 DBL Database Lock DLQI Skin Life Quality Index DMARDs Disease-modifying antirheumatic drugs DMC Data Monitoring Committee DNA deoxyribonucleic acid ECG electrocardiogram eC-SSRS Electronic Columbia-Suicide Severity Rating Scale eDC Electronic Data Capture EDTA Ethylenediaminetetraacetic acid EQ-5D EuroQol 5-dimensional questionnaire FACIT Functional Assessment of Chronic Illness Therapy FAS Complete Analysis Set FSH follicle-stimulating hormone GCP Good Clinical Practice GRACE GRAPPA composite score GRAppa Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis HAQ Health Assessment Questionnaire HAQ-DI Health Assessment Questionnaire Disability Index HBV Hepatitis B virus HCP Health Care Professional HCQ Hydroxychloroquine HCV Hepatitis C virus HIV human immunodeficiency virus ICF Informed Consent Form ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IEC Independent Ethics Committee IGA Global Investigator Assessment IJA Independent Joint Assessor IL Interleukin IRB Institutional Review Board IV (intravenous) IWRS Interactive Web Response System JAK Janus kinase JSN Joint space narrowing LEF Leflunomide LEI Leeds Enthesitis Index mAb Monoclonal antibody MCP metacarpophalangeal joint mCPDAI Modified Composite Psoriasis Disease Activity Index MCS Mental Component Summary MDA minimal disease activity MI multiple imputation method MRI Magnetic Resonance Imaging MTX methotrexate NAb neutralizing antibody NSAIDs (nonsteroidal anti-inflammatory drugs) PASDAS Psoriatic Arthritis Disease Activity Score PASI Psoriasis Area and Severity Index PCS Physical Component Summary PD Pharmacodynamics PFS Prefilled Syringe PFS-U UltraSafe PLUSTM Passive Needle Guard Prefilled Syringes Globally Rated by PGA Physicians PIP Proximal Interphalangeal Joint PK Pharmacokinetics PQC Product Quality Complaint PRO Patient-reported outcomes (paper or electronic format as appropriate for this study) PROMIS-29 Patient-Reported Outcomes Measurement Information System-29 PsA (psoriatic arthritis) PsARC Psoriatic Arthritis Response Criteria q4w every 4 weeks q8w every 8 weeks RA Rheumatoid Arthritis RNA ribonucleic acid SAE Severe Adverse Event SAP Statistical Analysis Planning SC subcutaneous SD standard deviation SDC Minimal Detectable Change SF-36 36-item Short Form Health Survey SSZ sulfasalazine SUSAR Suspected Unexpected Severe Adverse Reaction TB Tuberculosis Th17 T helper 17 TNFα tumor necrosis factor α UV ultraviolet light VAS visual analog scale vdH-S van der Heide-Schaap (score) WPAI Work Productivity and Activity Impairment Questionnaire

[0347] Example 1: Efficacy of Subcutaneously Administered Guselkumab in Subjects with Active Psoriatic Arthritis A phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate efficacy and safety (CNTO 1959PSA3002) (CNTO1959PSA3002) is biologically naive and does not respond to standard treatments (e.g. have had an inadequate response to non-biologic DMARDs, apremilast, and NSAIDs A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Guselkumab in Patients with Active PsA This is a three-arm study. The study will have a screening period of up to 6 weeks, and a follow-up period from week 0 to week 24. The study period lasted approximately 2 years (i.e., 12 months) including a placebo-controlled period and an active treatment period from week 24 to week 100. From the blinded treatment period (100 weeks) and the safety follow-up period of 12 weeks after the last dose of study drug Approximately 684 subjects were enrolled in this study. loids, and selected non-biologic DMARDs (MTX, SSZ, hydroxychloroquine) Concomitant use of stable doses of HCl (HCQ, limited to LEF) was permitted but not required.

[0348] The objective of this Phase 3 trial is to evaluate the efficacy of steroids in reducing symptoms, improving physical function, and slowing the progression of structural damage. To identify the clinical efficacy of guselkumab in the treatment of PsA and The objective of this study was to evaluate the safety profile.

[0349] method Test Plan A diagrammatic representation of the study design is shown in Figure 1. At week 0, all inclusion and exclusion criteria were met. Approximately 684 subjects were randomly assigned to the study and were asked about their baseline non-biologic DMARD use (yes, no). ) and the most recent available CRP value before randomization (<2.0 mg / dL vs. ≥2.0 mg / The following three treatments were randomized in a 1:1:1 ratio using a permuted block randomization method stratified by dL: were randomly assigned to one of the treatment groups. Group I (n=228): Guselkubab 100mg SC every 4 weeks (q4w), Administered from week 0 to week 100. Group II (n=228): Guselkumab 100mg SC at weeks 0 and 4 After that, q8w (12 weeks, 20 weeks, 28 weeks, 36 weeks, 44 weeks, 52 weeks, 60 weeks) Weeks 68, 76, 84, 92, and 100) and at other visits ( Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, Week 56, Week 64, Week 7 Placebo injections were administered at weeks 2, 80, 88, and 96 to maintain blinding. Group III (n=228): Placebo SC q4w from week 0 to week 20 , crossover at week 24, and guselkumab 100mg S from week 24 to week 100 Administer C q4w.

[0350] The group that showed a <5% improvement from baseline in tender and swollen joint counts at week 16 All subjects in I, II, and III were considered to meet the early withdrawal (EE) criteria. These subjects continued on the dosing regimen randomized at Week 0, but were excluded from the study if tolerated. Titration of one dose of the concomitant medication to a stable dose of the medication completed by the 24-week visit The dose was initiated or increased by 20 mg / kg / day up to the maximum tolerated dose as specified in the protocol.

[0351] Efficacy assessments included joint assessment (swollen and tender joint counts), patient pain assessment, and patient-reported illness. Global Assessment of Disease Activity (arthritis and psoriasis), Patient Global Assessment of Disease Activity ( arthritis), physician global assessment of disease activity, and Health Assessment Questionnaire Disability Index (HAQ). DI), CRP, patient's assessment of skin disease activity, body surface area (BSA) of psoriasis, psoriasis surface area Psoriasis Area and Severity Index (PASI), Investigator Global Assessment (IGA), Skin Skin Life Quality Index (DLPI), Enthesitis Assessment, Ankylosing Spondylitis Disease Activity The BASDAI index (BASDAI) was used in subjects with the major PsA subtype of spondylitis with peripheral arthritis. were evaluated by imaging assessment (Van der Heijde-Sharpe [VDH-S] score), the American College of Rheumatology ( ACR) response, minimal disease activity (MDA) and very low disease activity (VLDA), psoriatic joints Psoriasis Disease Activity Score (PASDAS), Group Test and Assessment of Psoriasis and Psoriatic Arthritis ( GRAPPA) composite score (GRACE) index, Disease Activity Index score 28 (DAS28 ) CRP, modified Composite Psoriasis Disease Activity Index (mCPDAI), psoriatic arthritis disease activity index Psoriatic Arthritis Responder Criteria (DAPSA), Modified Psoriatic Arthritis Responder Criteria (PsARC), 36-item short form The questionnaire used was the SF-36 (FaceTime Health Survey) and the EuroQol 5-dimensional questionnaire (EQ 5D questionnaire). , and the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue.

[0352] Study population The target population is those with active PsA who are biologically naive and have inadequate resistance to standard treatments. had a satisfactory response (e.g., non-biologic DMARDs, apremilast, and / or NSAs) ID) consisted of adult males or females. Furthermore, to enrich the population for radiographic progression, To increase the power to detect the effect of treatment on radiographic endpoints, CRP ≥ 0.6 mg / dL was A biologically naive population with

[0353] Inclusion criteria To be eligible for this study, subjects must be 18 years of age or older at the time of informed consent. Patients were diagnosed with PsA at least 6 months before the first dose of study drug and had PsA at screening. Patients were required to meet the ClA classification criteria for psoriatic arthritis (CASPAR)48. ≥ 5 tenderness and ≥ 5 swelling at both screening and baseline Active PsA as defined by joint involvement and CRP ≥ 0.6 mg / kg at screening Subjects were required to have a history of non-biologic DMARDs (≥3 months), Apremira, or ≥ 4 months, and / or NSAIDs (≥ 4 weeks) Patients had to have documented evidence of an inadequate response or intolerance to the drug.

[0354] Subjects were required to have at least one of the following PsA subsets: distant DIP joint involvement, polyarticular arthritis without rheumatoid nodules, destructive arthritis, non- Symmetric peripheral arthritis, spondylitis with peripheral arthritis. Additionally, subjects must have at least one diameter ≥ 2 cm psoriatic plaques, or nail changes consistent with psoriasis, or documented plaque psoriasis Patients had to have a history of active plaque psoriasis.

[0355] Subjects were required to be on a stable dose of a non-biologic DMARD (MTX [≤25 mg / week], SSZ [≦3g / day], HCQ [≦400mg / day], or LEF [≦20mg / day] limited), low-dose oral corticosteroids (≤10 mg prednisone or or equivalent), or NSAIDs and other analgesic treatments. If not using these medications at baseline, ≥ 4 weeks ( MTX, SSZ, HCQ), ≥ 12 weeks (LEF), or ≥ 2 weeks (NSA If you have any questions about the drug, please contact your doctor or pharmacist. In addition, subjects were screened for laboratory test results and TB history and test results. meet the criteria for birth control, agree to use appropriate birth control methods, and avoid prolonged sun exposure. It was necessary to avoid dew and to avoid the use of tanning booths or other sources of ultraviolet light during the test.

[0356] Dosage and Administration All study medications (guselkumab and placebo) were administered by SC injection. Clinical efficacy, safety, and PK data of guselkumab in subjects with rheumatoid arthritis and a phase 2 study (C Based on the exposure-response model analysis using data from NTO1959PSA2001, Two dose regimens were selected for evaluation in the Phase 3 PsA program for cumab, and eligible Subjects were randomly assigned to receive one of three treatments at week 0: Guselkumab 100mg q4w: guselkumab 100mg from week 0 to week 100 SCq4w. Guselkumab 100 mg at weeks 0 and 4, followed by q8w (hereafter referred to as guselkumab 100 mg) 00mg q8w group): guselkumab 100mg SC (weeks 0 and 4) ), followed by q8w(12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 9 Week 2 and 100), and other visits (8, 16, 24, 32, 40, 48, 56, 6 Blinding was maintained by placebo injections at weeks 4, 72, 80, 88, and 96. Placebo: Placebo SC q4w from weeks 0 to 20, with crossover at week 24 Then, guselkumab 100mg SC q4w from weeks 24 to 100.

[0357] Rationale for a dosing regimen of guselkumab 100 mg at weeks 0 and 4, then every 8 weeks This dosing regimen was used in a Phase 2 trial of PsA (CNTO1959PSA2001) and It was evaluated in three global Phase 3 trials for psoriasis: CNTO1959, PSA2001. The study showed that in patients with active PsA and psoriasis covering ≥ 3% of their body surface area, All important aspects of PsA, including signs and symptoms, physical function, psoriasis, enthesitis, dactylitis, and quality of life Robust efficacy and clinically meaningful improvements were observed with this dosing regimen in key areas Additionally, a Phase 3 psoriasis trial demonstrated efficacy in treating plaque psoriasis in patients with moderate to severe psoriasis. A significant benefit was also observed with this dose regimen. An additional dose was included at week 4 to ensure steady-state levels of trafuguselkumab were achieved. The booster dose at week 4 ensured that the serotonin levels did not decrease more than those measured in the first 12 weeks. Cmax and Ctrough were approximately 21% and 18%, respectively, lower than the steady-state values. The dose is slightly higher than that of the control group, which may result in a more rapid onset of response. This dosing regimen is q8w during maintenance, i.e., q8w from week 24 onwards. results in substantially higher levels of efficacy at 24 weeks than achieved by is not expected. The safety of this dosing regimen has been established in a large-scale psoriasis development program. The safety profile in a Phase 2 study in patients with psoriasis, PsA, and RA This matches what is seen in the program.

[0358] Rationale for the guselkumab 100 mg every 4 weeks dosing regimen More frequent dosing, including a 100 mg q4w dose regimen, may be effective in preventing structural damage. We aimed to determine whether greater efficacy could be achieved in PsA, including adverse events. Model analysis based on data from CNTO 1959 PSA 2001 shows higher or Suggests that more frequent dosing regimens may achieve better efficacy in PsA is doing. Treatment with the 100mg q4w dosing regimen was associated with increased risk of psoriasis in the Phase 3 psoriasis program. Based on safety analysis, it was predicted to provide acceptable safety. Guselkumab was studied in a Phase 2 rheumatoid arthritis trial (200 mg q8w) has an acceptable safety profile in multiple patient populations, including higher dose regimens It has been shown that

[0359] Overall, the guselkumab (100 mg q4w and 100 The two-dose regimen of guselkumab (mg q8w) provides the optimal benefit / risk profile for guselkumab in PsA. It was expected that this would provide an adequate assessment of the profile.

[0360] Study medication will be administered at the facility by a Health Care Professional (HCP) at weeks 0 and 4. Beginning at week 8, at the discretion of the investigator and subject, and as appropriate and documented, After training, subjects will be given the option to self-administer study medication at the investigational site under the supervision of an HCP. The patient received either a steroid or continued study medication injections administered by the HCP.

[0361] The administration of the study drug at the facility at week 24 will be performed ±4 days from the scheduled administration date of the study drug. Study drug administration was to be separated by at least 14 days.

[0362] Efficacy assessment Primary endpoint The primary endpoint is the proportion of subjects achieving an ACR 20 response at 24 weeks.

[0363] Key secondary endpoints 1. Change from baseline in HAQ-DI score at week 24. 2. Proportion of subjects achieving an ACR 50 response at 24 weeks. 3. Psoriatic lesions of ≥ 3% of BSA and an IGA score of ≥ 2 (mild) at baseline Among subjects with IGA (i.e., 0 [clear] or 1 [clear] from baseline) at Week 24, Percentage of subjects with a psoriasis response (minimal and ≧2 grade reduction). 4. Proportion of subjects achieving an ACR 20 response at Week 16. 5. Change from baseline in modified vdH-S score at week 24. 6. Among subjects with enthesitis at baseline, the improvement of enthesitis at week 24 Percentage of subjects with resolution. 7. Among subjects with enthesitis at baseline, those who achieve resolution of dactylitis at Week 24 Percentage of subjects who have 8. Enthesitis at Week 24 in subjects with enthesitis at baseline Change from baseline in score (based on LEI). 9. In subjects with dactylitis at baseline, baseline dactylitis score at Week 24 A change from Sline. 10. Change from baseline in SF-36 PCS at Week 24. 11. Change from baseline in DAS28 MCS at Week 24. 12. Change from baseline in SF-36 MCS at Week 24. 13. Proportion of patients achieving an ACR 50 response at week 16. 14. Proportion of patients achieving an ACR 70 response at 24 weeks.

[0364] Other secondary endpoints Endpoints related to reduction of signs and symptoms and physical function 1. ACR 20, ACR 50, and ACR at sequential visits up to 24 weeks Percentage of subjects achieving 70 responses. 2. From baseline through week 24 during the ACR component with longitudinal visits Percentage change from . 3. Changes in HAQ-DI scores from baseline to week 24 at longitudinal visits change. 4. Among subjects with a baseline HAQ-DI score of ≥ 0.35, the subjects who have Clinically meaningful improvement in HAQ-DI score (from baseline to baseline) over time Percentage of subjects achieving a ≥ 0.35 improvement. 5. Subjects who achieved DAS28(CRP) response by sequential visits up to week 24 ratio. 6. Subjects who have achieved DAS28(CRP) remission by sequential visits up to week 24 ratio. 7. Changes in DAS28(CRP) from baseline at sequential visits up to week 24 change. 8. Achieved response based on modified PsARC with sequential visits through week 24 Percentage of subjects. 9. Among subjects with enthesitis at baseline, the number of enthesitis cases by visit up to week 24 Percentage of subjects with resolution of enthesitis. 10. Subjects with dactylitis at baseline and at subsequent visits up to week 24 , Percentage of subjects with resolution of dactylitis. 11. Subjects with enthesitis at baseline at longitudinal visits up to week 24 Change from baseline in enthesitis score (based on LEI) at each question. 12. In subjects with dactylitis at baseline, longitudinal visits up to week 24 Change from baseline in dactylitis score. 13. Change from baseline in PASDAS by longitudinal visits through week 24. 14. Change from baseline in GRACE index by longitudinal visits up to week 24 . 15. Change from baseline in WPAI scores over time through week 24 . 16. Changes in mCPDAI scores from baseline to week 24 at longitudinal visits change. 17. Changes from baseline in DAPSA scores at sequential visits up to week 24 ification. 18. Percentage of subjects achieving MDA by time-course visit through week 24. 19. Among subjects with spondylitis and peripheral joint involvement as the primary arthritic manifestation of PsA BASDAI score ≥ 20 from baseline at sequential visits through week 24 %, ≥ 50%, ≥ 70%, and ≥ 90% improvement.

[0365] Skin disease-related endpoints 1. Psoriatic lesions of ≥ 3% of the BSA and an IGA score of ≥ 2 (mild) at baseline Among subjects with PASI score, the PASI score at the time point up to 24 weeks is Percentage of subjects achieving ≥ 75%, ≥ 90%, and 100% improvement. 2. Psoriatic lesions of ≥ 3% of the BSA and an IGA score of ≥ 2 (mild) at baseline Among subjects with an IGA score of 0 (clear) at time-course visits up to week 24 The percentage of subjects who 3. Psoriatic lesions of ≥ 3% of BSA and an IGA score of ≥ 2 (mild) at baseline PASI scores from baseline to 24 weeks of follow-up visits in subjects with Changes in et al. 4. Have a baseline DLQI score of >1 at baseline and dry skin of ≥3% of BSA Among subjects with ecchymoses and an IGA score of ≥2 (mild), follow-up visits up to week 24 Percentage of subjects achieving a DLQI score of 0 or 1 by question. 5. Have a baseline DLQI score of ≥ 5 at baseline and a dryness of ≥ 3% of BSA Among subjects with ecchymoses and an IGA score of ≥2 (mild), follow-up visits up to week 24 Percentage of subjects achieving a ≥ 5-point improvement in DLQI score by questionnaire. 6. Psoriatic lesions of ≥ 3% of BSA and an IGA score of ≥ 2 (mild) at baseline DLQI scores from baseline to 24 weeks of follow-up visits in subjects with Changes in et al. 7. Psoriatic lesions of ≥ 3% of BSA and an IGA score of ≥ 2 (mild) at baseline Among subjects with PASI 75 response and ACR at time-course visits up to week 24 Percentage of subjects achieving both 20 responses. 8. Psoriatic lesions of ≥ 3% of BSA and an IGA score of ≥ 2 (mild) at baseline Among subjects with PASI 75 response and PsAR at time-course visits up to week 24 C Percentage of subjects achieving both responses.

[0366] Endpoints related to joint structure damage 1. Change from baseline in modified vdH-S score at week 24. 2. Change from baseline in modified vdH-S erosion score at week 24. 3. Change from baseline in modified vdH-S JSN score at week 24. 4. Area and lesions at week 24 (i.e., hand erosion, hand JSN, foot erosion, foot JSN) Change from baseline in modified vdH-S score by type of N subscore. 5. Subjects with a change from baseline in modified vdH-S score of ≤0 at Week 24 and the proportion of subjects with a change from baseline of ≦0.5. 6. A change from baseline in modified vdH-S erosion score of ≤0 at week 24 and the proportion of subjects with a change from baseline of ≤0.5. 7. Achieve a change of ≤0 from baseline in modified vdH-S JSN score at week 24 and the proportion of subjects with a change from baseline of ≦0.5. 8. Subjects with radiographic progression from baseline (based on SDC) at Week 24 ratio. 9. Progression of radiographic joint erosion from baseline at Week 24 (based on SDC) ) the proportion of subjects with 10. Radiographic progression of JSN erosions from baseline at Week 24 (based on SDC) The proportion of subjects with a disability (based on 11. Pencil-in-cup deformity or total osteolytic deformity at 24 weeks Percentage of subjects with

[0367] Health-related quality of life related endpoints 1. SF-36 PCS scores from baseline through 24 week visits Changes in. 2. SF-36 MCS scores from baseline through 24 week visits Changes in. 3. SF-36 domain scores from baseline to 24 weeks Changes in et al. 4. SF-36 MCS score at baseline and subsequent visits up to week 24 Percentage of subjects achieving ≥ 5-point improvement from baseline. 5. SF-36 PCS scores at baseline and subsequent visits up to week 24 Percentage of subjects achieving ≥ 5-point improvement from baseline. 6. Change from baseline in FACIT fatigue by longitudinal visits through week 24. 7. The baseline FACIT fatigue score improvement over time visits up to 24 weeks Percentage of subjects achieving ≥ 4-point improvement from baseline. 8. EQ-5D VAS and EQ-5D index scores at time-course visits up to week 24 Change from baseline in a.

[0368] Baseline disease characteristics of PsA against the ACR core set of measures Baseline clinical characteristics of PsA from the ACR Core Set of Outcome Measures were moderate to severe. Subjects with severe active PsA were comparable across treatment groups However, median CRP was significantly higher in the guselkumab 100 mg q8w group (1. 310 mg / dL), the guselkumab 100 mg q4w group (1.160 mg / dL) and the placebo group (1.155 mg / dL; Table 1). Ta;).

[0369] [Table 1-1]

[0370] [Table 1-2]

[0371] result Pharmacokinetic, immunogenic, pharmacodynamic, and pharmacological outcomes Patients who received at least one dose of guselkumab and had at least one sample taken after guselkumab administration A total of 492 subjects with at least one valid sample were included in the PK evaluation. Subjects who received steroids were excluded from PK evaluation.

[0372] Figure 2 shows the trough serum guselkumab levels by guselkumab treatment group and visits up to week 24. Median cumab concentrations and range of IQ scores are shown in the graph. SC administration of guselkumab After administration, trough serum guselkumab concentrations were 20% higher in the guselkumab 100 mg q8w group. By week 12, the guselkumab 100 mg q4w group had achieved a generally stable state. In the guselkumab 100 mg q8w group, steady-state response was achieved at week 20 (Figure 2). The median trough serum guselkumab concentration was 1.05 μg / mL. In the 00mg q4w group, steady-state trough serum guselkumab levels at week 12 were The median rucumab concentration was 3.35 μg / mL and was maintained through week 24 (3.98 μg / mL). Steady-state trough serum guselkumab in the guselkumab 100 mg q4w group Mab concentrations were approximately 3-4 times higher than those in the guselkumab 100 mg q8w group (Fig. 2).

[0373] In the guselkumab 100 mg q8w group, subjects who met the EE criteria and those who did not were randomly assigned to receive the The median steady-state trafuguselkumaab concentrations at week 20 in subjects who received trafuguselkuma were 0.58 and 0.62, respectively. In the guselkumab 100 mg q4w group, the EE group Steady-state trafuguselkumaab concentrations at week 12 in subjects who met and did not meet the criteria The median values ​​were 2.86 and 3.43 μg / mL, respectively. Median fugselkumab concentrations appeared to be lower in subjects who met EE criteria However, the number of subjects who met the EE criteria was small in each treatment group (n ≤ 13). Please note that:

[0374] Incidence of antibodies to guselkumab Antibody evaluation for guselkumab requires patients who have received at least one dose of guselkumab. 490 subjects with adequate specimens for detection of antibodies to guselkumab were included .

[0375] The overall incidence of antibodies to guselkumab by week 24 was low in patients with PsA The incidence of rheumatoid arthritis was 2.0%, 10 / 490 (Table 2). Guselkumab 100 mg q8w group The incidence of antibodies to guselkumab by week 24 was 2.0% (5 / 247). In the guselkumab 100 mg q4w group, there was no significant difference in response to guselkumab up to 24 weeks. The incidence of antibodies was 2.1% (5 / 243). The highest titer of antibodies to guselkumab observed in the group was 1:640.

[0376] Efficacy of guselkumab with and without MTX at baseline The incidence of antibodies was 1.4% (4 / 284 cases) and 2.9% (6 / 206 cases), respectively. The effect of guselkumab on patients with and without DMARD use at baseline was The incidence of antibodies was 1.8% (6 / 337) and 2.6% (4 / 153), respectively. Overall, subjects taking MTX or DMARDs concomitantly The incidence of antibodies to guselkumab was lower by week 24 compared with non-treated controls. However, the number of subjects who tested positive for antibodies to guselkumab was small, and MT The incidence of antibodies to guselkumab was low, regardless of concomitant use of X or DMARDs. Please note:

[0377] [Table 2]

[0378] Antibodies and pharmacokinetics of guselkumab Serum guselkumab concentrations up to week 24 in subjects treated with guselkumab were compared across treatment groups. The serum guselkumab levels were summarized by antibody status to guselkumab and guselkumab up to week 24. The median antibody concentration and IQ range were assessed by guselkumab antibody status up to week 24. This is shown graphically in Figure 3. Subjects who tested positive for antibodies to guselkumab up to week 24 Individual serum guselkumab concentrations were also listed.

[0379] Median serum guselkumab concentrations were Subjects who were antibody-positive to guselkumab were compared with subjects who were antibody-negative to guselkumab. However, the incidence of HIV-positive patients with anti-guselkumab antibodies was significantly lower than that of patients with anti-guselkumab antibodies (Figure 3). The number of subjects was very small (n=10), and the impact of immunogenicity on the PK of guselkumab cannot be determined. It should be noted that there are limitations to any definitive conclusions.

[0380] Efficacy Results Primary Efficacy Endpoint ACR 20 response at 24 weeks Global (non-US) and US-specific multiplicity testing procedures (global and US-specific adjustments) The proportion of subjects achieving an ACR 20 response at week 24 was 1.2% based on both groups (both groups, p<0.001). In this case, both guselkumab 100 mg q4w and guselkumab 100 mg q8w groups in the steroid group (63.7% and 64.1%, respectively) compared with the placebo group (32.9%). The results were significantly higher (Table 3).

[0381] [Table 3]

[0382] Primary secondary endpoint analysis Change from baseline in HAQ-DI score through week 24. At week 24, the reduction from baseline in HAQ-DI scores was 9.2% based on the composite estimate. in both the guselkumab 100 mg q4w and guselkumab 100 mg q8w groups , was significantly greater than the placebo group (global and US-specific both adjusted p<0.001; Table 4).

[0383] [Table 4]

[0384] Psoriasis IGA response at week 24 543 subjects (73.5%) with psoriatic lesions of ≥3% of the BSA and an IGA score of ≥2 %) of patients receiving both guselkumab 100 mg q4w and guselkumab 100 mg q8w In the group, based on composite estimates, there was a significant difference in psoriasis IG at week 24 compared with the placebo group A score of 0 (clear) or 1 (minimal) and a decrease of 2 or more grades from baseline The proportion of subjects with HIV / AIDS who received HIV / AIDS was significantly higher (both global and US-specific adjusted p<0.001). ;Table 5)).

[0385] [Table 5]

[0386] Change from baseline in modified vdH-S score at week 24 At week 24, based on treatment-directed estimates, guselkumab significantly increased the risk of death compared with placebo. In both the 100 mg q4w group and the guselkumab 100 mg q8w group, However, the change from baseline in the modified vdH-S score was numerically small (less progression). ) was confirmed (Table 6).

[0387] [Table 6]

[0388] Change from baseline in SF-36 PCS at week 24 At week 24, improvement from baseline in SF-36 PCS scores was significantly greater than the composite estimate. Based on this, both guselkumab 100 mg q4w and guselkumab 100 mg q8w groups The results showed that the serotonin-releasing hormone (SHR) levels in the serotonin-releasing hormone group were numerically greater than those in the placebo group (Table 7).

[0389] [Table 7]

[0390] Change from baseline in SF-36 MCS at week 24 At week 24, improvement from baseline in SF-36 MCS score was significantly greater than the composite estimate. Based on this, both guselkumab 100 mg q4w and guselkumab 100 mg q8w groups The results showed that the serotonin-releasing hormone (SHR) levels in the serotonin-releasing hormone group were numerically greater than those in the placebo group (Table 8).

[0391] [Table 8]

[0392] Resolution of enthesitis at week 24 Of the 506 patients (68.5%) who had enthesitis at baseline, The proportion of subjects whose ulcerative colitis resolved was significantly higher than in the placebo group (30.3%, respectively, nominal p = 0.01). 017, p<0.001, Table 9). The incidence was higher in both groups (43.5% and 53.8%, respectively) receiving Mab 100 mg q8w. Based on the CNTO1959PSA3001 data alone, the baseline is based on the LEI. Of the 222 patients (58.3%) who developed enthesitis due to the steroid, the enthesitis resolved at 24 weeks. The proportion of subjects who achieved the steroid effect was significantly higher than in the placebo group (27.3%, nominal p=0.013 and p=0.0 94, Table 9), compared with the guselkumab 100 mg q4w group (47.9%) and The incidence was numerically higher in the selkuma 100 mg q8w group (40.3%). The treatment effect was numerically greater in the guselkumab group than in the placebo group, and A pooled analysis of endpoints was possible at both doses.

[0393] [Table 9]

[0394] Resolution of dactylitis at 24 weeks Based solely on the data from CNTO1959PSA3002, patients with dactylitis at baseline Of the 331 subjects (44.8%) who underwent treatment, the proportion of subjects whose dactylitis resolved at 24 weeks was 44.8%. The placebo group (38.4%, nominal p<0.001 and p=0.007, Table 10 and Table 11, respectively) 11) compared with the guselkumab 100 mg q4w group and guselkumab 100 mg The incidence rates were higher in the q8w group (63.6% and 56.8%, respectively). Based on PSA3001 data alone, 142 patients ( The percentage of subjects whose dactylitis resolved at 24 weeks was significantly higher than that of the placebo group (49.3%). 0.1%, nominal p=0.212 and p=0.088, Tables 10 and 11, respectively). Selkumab 100 mg q4w group (63.2%) and guselkumab 100 mg q The treatment effect was numerically higher in the 8-week group (65.3%). The outcome was numerically greater in the guselkumab group than in the placebo group, and for this endpoint A pooled analysis could be performed at both doses.

[0395] [Table 10]

[0396] [Table 11]

[0397] The key secondary endpoints were multiplicity controlled in the global (non-US) trial procedures. , conditionally controlled in US-specific testing procedures Change from baseline in DAS28(CRP) at 24 weeks The reduction from baseline in DAS28(CRP) score at 24 weeks was based on a composite estimate. Based on this, both guselkumab 100 mg q4w and guselkumab 100 mg q8w groups The results showed that the effect of acetaminophen on the serotonin receptor agonist (SAR) was significantly greater than that of the placebo group (both globally). p<0.001 after adjustment (Table 12).

[0398] [Table 12-1]

[0399] [Table 12-2]

[0400] ACR 20 response at 16 weeks The proportion of subjects achieving an ACR 20 response at week 16 was based on a composite estimate and was significantly higher than placebo Compared with the guselkumab 100 mg q4w and guselkumab 100 mg q8 was numerically higher in both groups of w (Table 13).

[0401] [Table 13]

[0402] ACR 50 response at 24 weeks The proportion of subjects achieving an ACR 50 response at week 24 was based on a composite estimate and was significantly higher than placebo Compared with the guselkumab 100 mg q4w and guselkumab 100 mg q8 was numerically higher in both groups of w (Table 14).

[0403] [Table 14]

[0404] ACR 50 response at 16 weeks The proportion of subjects achieving an ACR 50 response at week 16 was based on a composite estimate and was significantly higher than placebo Compared with the guselkumab 100 mg q4w and guselkumab 100 mg q8 was numerically higher in both groups of w (Table 15).

[0405] [Table 15]

[0406] ACR 70 response at 24 weeks The proportion of subjects achieving an ACR 70 response at Week 24 was 100% higher than placebo based on a composite estimate. Compared with the guselkumab 100 mg q4w and guselkumab 100 mg q was numerically higher in both 8w groups (Table 16).

[0407] [Table 16]

[0408] Key secondary endpoints are conditionally controlled only in US-specific trial procedures. Change from baseline in enthesitis score at 24 weeks. Based on CNTO1959PSA3002 data alone, 506 Of 506 (68.5%) subjects at baseline, 506 (68.5%) subjects received placebo. Compared with the guselkumab 100 mg q4w and guselkumab 100 mg In both q8w groups, the LEI scores at Week 24 were significantly higher than those at baseline. A numerically greater reduction was observed in the sham group (nominal P=0.002 and p<0.001). Table 17). Based on the CNTO1959PSA3001 data alone, Of the 222 (58.3%) subjects with ≥18% CI at baseline, , compared with the placebo group, guselkumab 100 mg q4w and guselkumab 10 Baseline LEI scores at Week 24 in both the 0mg q8w group A significant decrease in the values ​​from the line was observed (nominal P=0.004 and p=0.185 ) Table 17). In both studies, the treatment effect was significantly greater in the galactomab group compared with the placebo group. There were significant differences in both groups for both doses for this endpoint. We were able to perform a rule analysis.

[0409] [Table 17-1]

[0410] [Table 17-2]

[0411] Change from baseline in dactylitis score at week 24 Based solely on the data from CNTO1959PSA3002, patients with dactylitis at baseline Of the 331 subjects (44.8%) who underwent treatment, the reduction in dactylitis score from baseline at 24 weeks was The guselkumab 100 mg q4w group and the guselkumab 100 mg q8w group In both groups, the results were numerically greater than those in the placebo group (both nominal). p = 0.002, Table 18). Based on the CNTO1959PSA3001 data only, Among 142 patients (37.3%) who had dactylitis at baseline, 142 patients (37.3%) had dactylitis at 24 weeks. The reduction from baseline in scores was greater in the guselkumab 100 mg group than in the placebo group. The results were greater in both the q4w and guselkumab 100 mg q8w groups. (nominal p = 0.225 and p = 0.121, respectively, Table 18). The therapeutic effect was numerically greater in the guselkumab group compared with the placebo group, and this endpoint A pooled analysis could be performed for pts at both doses.

[0412] [Table 18-1]

[0413] [Table 18-2]

[0414] Other efficacy endpoints related to reduction of joint signs and symptoms ACR20, ACR50, and ACR70 responses by week 24 At week 24, proportion of subjects with ACR 20, ACR 50, and ACR 70 responses was numerically increased in both guselkumab-treated groups compared with the placebo group ( All nominal p<0.001) (Figures 4, 5, and 6).

[0415] ACR component measurements up to 24 weeks The seven components of the ACR response were swollen and tender joint counts, patient pain assessment ( VAS), patient and physician global assessment of disease activity (VAS), HAQ DI, and All items of the ACR except for swollen joint count were significantly higher than those in the placebo group. Significant numerical improvements were seen in both guselkumab groups as early as week 4 and at week 8 Significant numerical improvements were observed in both guselkumab groups compared with the placebo group. Improvement in each CR parameter was greater at 24 weeks in both guselkumab groups compared with the placebo group. The increase continued until

[0416] At week 24, guselkumab 100 mg q4w group compared with placebo group Baseline ACR components for the guselkumab 100mg q8w and guselkumab 100mg q8w groups The median percent changes from baseline were: Swollen joint count: -65.5%, compared with -81.5% and -85.7%, respectively Tender joint count: -66.7% and -60.0% compared to -33.3%, respectively Patient-rated pain: -38.45% compared to -11.59% and -3. 7.21% Patient Global Assessment of Disease Activity: -13.33%, respectively, compared with -37.09% and -34.04% Physician Global Assessment of Disease Activity: -34.57%, compared with -10.57%, respectively. -63.86% and -62.87% HAQ-DI: -33.3333% compared to -8.3333%, respectively 27.2727% CRP: -17.494%, compared to -48.218% and -53.1%, respectively 75%

[0417] PASI 50, PASI 75, PASI 90, and PASI by 24 weeks 100 Responses At week 24, guselkumab 100 mg q4w and guselkumab 100 mg q8w Loop through responses of PASI 50, PASI 75, PASI 90, PASI 100 The proportion of subjects with steroid use who had steroid use compared with the placebo group was as follows (all nominal): p<0.001): PASI 50: 90.2% and 92.6%, respectively, compared with 37.7%. PASI 75: 78.3% and 79.0% compared to 23.0%, respectively PASI 90: 60.9% and 68.8%, respectively, compared to 9.8%. PASI 100: 44.6% and 45.5%, compared to 2.7%, respectively

[0418] PASI 75 and ACR 20 response by 24 weeks 5. Patients with psoriatic skin lesions of ≥3% of BSA and an IGA score of ≥2 at baseline Of these, 43 patients (73.5%) achieved both a PASI 75 response and an ACR 20 response. The proportion of subjects in the guselkumab group was significantly higher at weeks 16 and 24 compared with the placebo group. Both PASI responses and Consistent with ACR response over time, both PASI 75 and ACR 20 improved from week 16 to week 2. The treatment was escalated to week 4, with the guselkumab 100 mg q4w group and the guselkumab 100 mg The results were generally similar between the q8w group.

[0419] At week 24, PASI 75 and ACR 20 responses were achieved based on composite estimates The proportion of subjects was numerically higher in both guselkumab groups compared with the placebo group. (all nominal p<0.001).

[0420] [Table 19]

[0421] PASI 75 and modified PsARC response by week 24 Subjects with psoriatic skin lesions of ≥ 3% of BSA and an IGA score of ≥ 2 at baseline 543 patients (73.5%) achieved both a PASI 75 response and a modified PsARC response. The proportion of subjects achieving placebo was comparable in both guselkumab treatment groups at weeks 16 and 24. The results were numerically greater than those in the Sebo group (nominal p<0.001 for both groups). The incidence of steroid use increased from week 16 to week 24 in the guselkumab 100 mg q4w group. and guselkumab 100 mg q8w groups were generally similar.

[0422] At week 24, the proportion of subjects achieving PASI 75 and modified PsARC response was 60 in the cumab 100 mg q4w and guselkumab 100 mg q8w groups, respectively. 9% and 65.3% in the placebo group, compared with 15.3% in the placebo group (both (also nominal p<0.001).

[0423] Psoriasis IGA response by week 24 Subjects with psoriatic skin lesions of ≥ 3% of BSA and an IGA score of ≥ 2 at baseline Among 543 patients (73.5%), at weeks 16 and 24, the guselkumab group compared with the placebo group, the IGA response for psoriasis was 0 (clear) or 1 (minimal). and the proportion of subjects with a grade ≥2 reduction from baseline increased.

[0424] At week 16, the guselkumab 100 mg q4w group and the guselkumab 100 mg q8 A numerically high proportion of subjects in both w groups (65.8% and 62.5%, respectively) achieved a psoriasis IGA response compared with the placebo group (15.3%; both nominal p<0.05). 001). The rate increased from weeks 16 to 24, and the rate of patients receiving guselkumab 100 mg q4w The results were generally similar between the guselkumab 100 mg q8w group and the guselkumab 100 mg q8w group.

[0425] Psoriasis IGA score 0 (clear) by week 24 Subjects with psoriatic skin lesions of ≥ 3% of BSA and an IGA score of ≥ 2 at baseline Of 543 patients (73.5%), a numerically greater proportion of patients in the placebo group Elephants achieved an IGA score of 0 (clear) in both guselkumab groups at weeks 16 and 24. The rate increased from week 16 to week 24 and was achieved with guselkumab 100 mg q4 w group and the guselkumab 100 mg q8w group were similar.

[0426] At week 24, the proportion of subjects achieving an IGA score of 0 (clear) was significantly higher than in the placebo group. 7.7% in the guselkumab 100 mg q4w group and guselkumab 100 mg q4w group compared with 7.7% in the mg q8w group and 50.5% and 50.0%, respectively (both nominal p<0.05). .001).

[0427] [Table 20]

[0428] Other efficacy endpoints related to enthesitis Resolution of enthesitis over time by 24 weeks At week 16, subjects who achieved enthesitis resolution based on the composite estimate were randomly assigned to placebo. 40.6% in the guselkumab 100 mg q4w group compared with 30.9% in the loop group; and 47.5% in the guselkumab 100 mg q8w group (nominal p = 0.070, p=0.002). Response rates increased between weeks 16 and 24 in both groups. Response rates were significantly higher in the guselkumab 100 mg q8w group from weeks 8 to 24. This was numerically higher than in the guselkumab 100 mg q4w group.

[0429] At week 16, baseline data was obtained based solely on the CNTO1959PSA3001 data. Of the 222 subjects (58.3%) who had enthesitis, the enthesitis resolved. The proportion of subjects was numerically smaller in the guselkumab q8w group compared with the placebo group Therefore, pooling the 16-week data from these studies is However, both studies showed a significant therapeutic effect. was numerically greater in the guselkumab 100 mg q4w group compared with the placebo group; This endpoint was analyzed in a pooled analysis of the guselkumab 100 mg q4w group. It was possible to do so.

[0430] Pooled data of CNTO1959PSA3001 and CNTO1959PSA3002 Among 728 subjects (65.0%) who had enthesitis at baseline based on the Based on the estimated values, the proportion of subjects with enthesitis resolution at 16 weeks was 10.5% compared to the placebo group. In comparison, the guselkumab 100 mg q4w group had a higher incidence of 42.0%.

[0431] Use all observational data collected for the endpoint and apply treatment failure rules The analysis based on treatment plan estimates at week 16 based on pooled data that did not include the primary analysis This confirmed the results.

[0432] Change from baseline in enthesitis score over time Consistent with data on the proportion of subjects achieving enthesitis resolution over time, CNTO Based on data from 1959PSA3002 alone, enthesitis was assessed up to 24 weeks. At each visit, the mean LEI score was significantly higher in both guselkumab groups compared with the placebo group. A significant numerical drop from baseline was observed.

[0433] At week 16, the reduction from baseline in LEI scores was significantly greater than that of the placebo group, based on the composite estimate. The LEI score was numerically greater in both guselkumab groups compared to the placebo group. The reduction in serotonin levels continued to increase from week 16 to week 24 in both guselkumab groups. The results showed that the guselkumab 100 mg q4w group was significantly more effective than the guselkumab 100 mg q8w group. were generally larger than the group.

[0434] Based on data from CNTO1959PSA3001 alone at week 16, baseline In 222 (58.3%) subjects with enthesitis, the baseline LEI score was The reduction in change from baseline was greater in the Gucelc group compared with the placebo group, based on the composite estimate. In both trials, the treatment effect was numerically greater than that of the placebo group. The results for this endpoint were numerically greater in both guselkumab groups compared with A pooled analysis could be performed at both doses.

[0435] Pooled data of CNTO1959PSA3001 and CNTO1959PSA3002 In 728 subjects (65.0%) with enthesitis at baseline, 16 The reduction from baseline in LEI scores at week 1 was significantly greater in the placebo group (-0.93; guselkumab 100 mg q4 compared with guselkumab 100 mg q4 (nominal p<0.001 and p=0.038, respectively) w group (-1.42) and guselkumab 100 mg q8w group (-1.23). Both were observed to be numerically large based on the composite estimates.

[0436] Other efficacy endpoints related to dactylitis Resolution of dactylitis over time by 24 weeks Based on CNTO1959PSA3002 data only, had dactylitis at baseline Of the 331 subjects (44.8%), the number of subjects who achieved resolution of dactylitis was 24 weeks. At each week visit, there were numerically greater increases in both guselkumab groups compared with the placebo group. Ta.

[0437] At week 16, subjects who achieved resolution of dactylitis based on the composite estimate were significantly more likely to be in the placebo group than in the placebo group. 36.4% in the guselkumab 100 mg q4w group, compared with 52.1% in the guselkumab 100 mg q4w group and 36.4% in the guselkumab 100 mg q4w group. and 45.0% in the cumab 100 mg q8w group (nominal p=0.0 24, p=0.192). Response rates increased between weeks 16 and 24 in both groups. The response rate was significantly higher in the guselkumab 100 mg q4w group than in the guselkumab 100 mg q4w group from weeks 4 to 24. This was numerically higher than in the cumab 100 mg q8w group.

[0438] At week 16, based on CNTO1959PSA3001 data alone, Of the 142 (37.3%) subjects with dactylitis in the line, 43. 6%) compared with guselkumab 100 mg q4w and guselkumab 100 mg q8w In both groups (57.9% and 59.2%, respectively), the mean age at 16 weeks was 16.2 years based on the composite estimate. The proportion of subjects with dactylitis resolution was numerically higher in the 12-week group (nominal p = 0.169 and p =0.124). In both studies, the treatment effect was greater for both guselkumab than for the placebo group. The loop is numerically larger, and a pooled analysis of both doses will be performed for this endpoint. I was able to do it.

[0439] Pooled data of CNTO1959PSA3001 and CNTO1959PSA3002 Among 473 subjects (42.2%) who had dactylitis at baseline, placebo compared with the group (39.0%; nominal p = 0.008 and p = 0.053, respectively). Guselkumab 100 mg q4w group and guselkumab 100 mg q8w group ( Both groups had dactylitis at week 16 based on a combined estimate (53.5% and 49.4%, respectively). The percentage of subjects who resolved the issue was high.

[0440] Change from baseline in dactylitis score to week 24 Consistent with data on the proportion of subjects achieving resolution of dactylitis over time, CNTO195 9Based on data from PSA3002 alone, dactylitis was assessed from week 2 to week 24. Baseline dactylitis scores were significantly lower in both guselkumab groups compared with the placebo group at visit 1. Significant numerical reductions from baseline were observed. The effect was observed at 16 and 24 weeks. The difference was greater in the guselkumab 100 mg q4 wk group compared with the guselkumab 100 mg q8 wk group. It was.

[0441] Other efficacy endpoints associated with BASDAI Only subjects with spondylitis and peripheral arthritis as the primary joint manifestation of PsA were included in the BASDAI. Completed. Subjects with spondylitis and peripheral arthritis at baseline received guselkumab 100mg g q4w, guselkumab 100 mg q8w, and placebo in 86, 73, and 100 mg, respectively. 99 patients were included. They had spondylitis and peripheral arthritis at baseline and a baseline BASD score. For subjects with an AI score >0, guselkumab 100 mg q4w, guselkumab 100 mg The numbers were 83, 67, and 92 in the q8w and placebo groups, respectively.

[0442] Of the 258 subjects (34.9%) who had spondylitis and peripheral arthritis at baseline, At each visit where BASDAI was assessed from Week 8 to Week 24, baseline BASDAI scores were The reduction from baseline was numerically greater in both guselkumab groups compared with the placebo group The reduction in BASDAI score was significantly greater in the guselkumab-treated group than in the control group (Table 21). The results were generally similar between the two groups.

[0443] At week 24, based on the composite estimate, the decline from baseline in BASDAI was consistent with Both the lucumab 100 mg q4w group and the guselkumab 100 mg q8w group were confirmed to be numerically greater than those in the placebo group (nominal p<0.05). .001).

[0444] [Table 21-1]

[0445] [Table 21-2]

[0446] Achieve a 5-point improvement from baseline in SF 36 MCS score by week 24 Target A clinically meaningful improvement of ≥ 5 points from baseline in the SF-36 MCS score The proportion of subjects achieving the 24-week target was significantly higher in both guselkumab groups compared with the placebo group from weeks 8 to 24. This rate was numerically greater in the guselkumab 100 mg q4w group. In the 24-week group, the increase in ≥ 5 points from baseline The proportion of subjects who achieved improvement was 42.3% in the guselkumab 100 mg q8w group. The response rate was highest at week 16 for the guselkumab 100 mg q8w group. In the 8-24 week period, numerically significant differences were observed between the guselkumab 100 mg q4w group and the guselkumab 100 mg q4w group. was expensive.

[0447] At week 24, subjects will have an improvement of ≥ 5 points from baseline in the SF-36 MCS score. The proportions of patients receiving guselkumab 100 mg q4w and guselkumab 100 mg q4w were based on a composite estimate. The rates were 34.3% and 37.5% in the 1 mg q8w group, respectively, compared with 10.2% in the placebo group. and 30.9% for loop (nominal p=0.424 and p=0.124, respectively).

[0448] For each SF-36 scale assessed, a numerical change from baseline in the normative score Large increases were observed in both guselkumab groups compared with placebo from weeks 8 to 24. The increase from baseline in normative scores was observed in the guselkumab 1 group. In the guselkumab 100 mg q8w group, And generally, they were expensive.

[0449] At week 24, guselkumab 100 mg q4w and 100 mg q8w Group vs. placebo group: baseline scores on normative SF-36 subscales The estimated LS means of these changes were: Physical function: 6.624 and 6.703 compared to 3.254, respectively Physical roles: 6.241 and 6.549 compared to 3.365, respectively · Bodily pain: 7.739 and 7.811 compared to 3.482, respectively General health: 5.269 and 5.794 compared to 2.290, respectively Vitality: 7.009 and 7.373 compared to 3.835, respectively Social functioning: 5.922 and 5.806 compared to 2.978, respectively Emotional role: 4.255 and 4.382 compared to 1.813, respectively Mental health: 4.767 and 4.490 compared to 2.335, respectively

[0450] FACIT-Fatigue score Change from baseline in FACIT-Fatigue score through week 24 A numerically greater increase (improvement) from baseline in the FACIT-Fatigue score At each visit where FACIT fatigue was assessed, both guselkumab groups were significantly lower than placebo groups. was observed in the sham group (weeks 8, 16, and 24; all nominal p<0.001). (Table 22). Scores continued to increase over time in the guselkumab group through week 24, with At the visit, the guselkumab 100 mg q8w group received guselkumab 100 mg q The numbers were higher than those in the 4w group.

[0451] [Table 22-1]

[0452] [Table 22-2]

[0453] EQ-5D-5L Questionnaire At week 24, the placebo group (LS mean: 0.053, nominal p<0.00) 1) compared with the guselkumab 100 mg q4w group (LS mean: 0.116) and EQ in both selcumab 100 mg q8w groups (LS mean: 0.115) Numerically significant increases from baseline in -5D index scores were observed.

[0454] At week 24, the placebo group (LS mean: 6.796, nominal p<0.00) 1) compared with the guselkumab 100 mg q4w group (LS mean: 18.089) and guselkumab 100 mg q8w group (LS mean: 18.371). Numerically significant increases from baseline in EQ-5D health status VAS scores were observed. Ta.

[0455] Change from baseline in PASDAS to week 24 A numerically significant decrease (improvement) in the PASDAS score from baseline is S was assessed at each visit (weeks 8, 16, and 24; all nominal p<0.001; ) was observed in both guselkumab groups compared with the placebo group.

[0456] At week 24, a numerically significant reduction from baseline in PASDAS scores was observed in patients with placebo. compared with the Sebo group (LS mean: -1.336; nominal p<0.001 for both). Selkumab 100 mg q4w group (LS mean: -2.399) and guselkumab 10 Based on the composite estimate, both the 0 mg q8w group (LS mean: -2.403) and It was noticed.

[0457] Change from baseline in GRACE index through week 24. The GRACE index was assessed at each visit (weeks 16 and 24; all nominal p<0.00). 1) The GRACE index was significantly higher in both guselkumab groups compared with the placebo group. A significant numerical decline (improvement) from the baseline was observed. The decline in the GRACE index was due to was similar between guselkumab at each visit.

[0458] At week 24, a numerically greater reduction from baseline in the GRACE index was observed compared with placebo. group (LS mean: -1.197; both nominal p<0.001). Kumab 100 mg q4w group (LS mean: -2.589) and guselkumab 100 mg g The observed difference based on the composite estimates was 0.01 for both the q8w group (LS mean: -2.592). It was.

[0459] Change from baseline in mCPDAI to week 24 At each visit where the mCPDAI score was assessed (weeks 16 and 24, nominal p<0.01). .001) in both guselkumab groups compared with the placebo group. A numerically significant decrease (improvement) from baseline was observed. Below, the guselkumab 100mg q8w group compared with the guselkumab 100mg q8w group at both visits. It was slightly higher in the cumab 100 mg q4w group.

[0460] At week 24, a numerically significant reduction from baseline in mCPDAI scores was observed in patients with placebo. Compared with the Sebo group (LS mean: -1.30; both nominal p<0.001), Rucumab 100 mg q4w group (LS mean: -3.09) and guselkumab 100 mg g q8w group (LS mean: -2.94) and both groups (LS mean: -2.94) observed based on the composite estimates. Ta.

[0461] Low disease activity based on mCPDAI by week 24 At baseline, the proportion of subjects with low disease activity based on the mCPDAI index was Guselkumab 100 mg q4w group, guselkumab 100 mg q8w group, placebo The rates were 1.6%, 6.5%, and 1.6% in the groups, respectively.

[0462] Consistent with the change from baseline in mCPDAI scores over time, The proportion of subjects achieving low disease activity based on the serotonin-dependent agonist was significantly higher than the placebo group at week 16. Compared with the guselkumab 100 mg q4w group and the guselkumab 100 mg q8w group, The group had higher rates (34.4% and 34.7%, respectively) (12.6%; nominal p<0.05 for both). 001). The rate increased in the guselkumab group from weeks 16 to 24, and The values ​​were higher in the guselkumab 100 mg q8w group compared with the 100 mg q4 group. It was.

[0463] At week 24, the proportion of subjects achieving low disease activity based on the mCPDAI score was Based on pooled estimates, 14.2% of patients in the guselkumab 100 mg group experienced a morbidity and mortality increase compared with 14.2% in the placebo group. 41.2% in the q4w group and 46.4% in the guselkumab 100 mg q8w group (all nominal p<0.001).

[0464] MDA criteria up to 24 weeks At baseline, one patient in the guselkumab 100 mg q4w group (0. 4%) of subjects met MDA criteria (Table 23).

[0465] The proportion of subjects who met MDA criteria at weeks 16 and 24 was 0.01% compared with the placebo group (all was numerically greater in both guselkumab groups compared with refractory cerebrospinal fluid (nominal p<0.001). The proportion of patients who met MDA criteria was 100 mg / day at both visits. Numerically, the guselkumab 100 mg q8w group had a significantly higher mean mean mean of 4 weeks compared with the 4w group. It was expensive.

[0466] [Table 23]

[0467] VLDA criteria up to 24 weeks At baseline, subjects in the guselkumab or placebo groups were The proportion of subjects who met the VLDA criteria at 16 and 24 weeks was low. was numerically greater in both guselkumab groups compared with the placebo group. At both visits, the guselkumab group had a significantly higher mean ... The rate was slightly higher in the 100 mg q4w group.

[0468] At week 24, the proportion of subjects who met the VLDA criteria based on the composite score was 4 in the 100 mg q4w group and the guselkumab 100 mg q8w group, respectively. 9% and 4.4% in the placebo group, compared with 1.2% in the placebo group (n = 1). p=0.018 and p=0.032, respectively).

[0469] Efficacy and Pharmacokinetics The relationship between selected efficacy endpoints and trough serum guselkumab concentrations was assessed by PK analysis. The following analyses were based on the clinical efficacy data set without imputation of missing data. The combined estimate and respective trough serum guselkumab concentrations were used: - ACR 20 or ≥ 12 weeks based on steady-state trough serum guselkumab concentrations at week 12 or ACR 50 response or change from baseline in DAS28(CRP). Serum guselkumab steady-state trough serum guselkumab concentrations at week 20 ACR 20 or ACR 50 response at week 1 or 24, or DAS28 (CRP ) change from baseline. Week 24 IGA response (beta) according to steady-state trough serum guselkumab concentrations at week 20 (Subjects with psoriatic lesions ≥ 3% of BSA and an IGA score ≥ 2 at baseline).

[0470] ACR 20 and ACR 50 responses and trough serum guselkumab concentrations ACR20 and ACR5 outcomes at week 12 by quartiles of torafugu-selkumaab concentration at week 12 No clear exposure-response relationship was observed for the zero response rate.

[0471] ACR 2 at Week 20 or Week 24 by quartile of torafuguselkumab concentration at Week 20 No consistent exposure-response relationship was observed for response rates (Figure 7). ACR50 response rates at 20 and 24 weeks by lafuxelkuma concentration quartiles appeared to have a weak exposure-response relationship (Figure 8).

[0472] Change from baseline in DAS28 (CRP) by trough serum guselkumab concentration DAS28(CRP) at week 12 by quartiles of selcumab concentration at week 12 No clear exposure-response relationship was observed for mean changes from baseline (20 DAS28(CR) at 20 or 24 weeks by quartile of torafuguselkumab concentration at week 20 No clear exposure-response relationship was observed for the mean change from baseline in P.

[0473] IGA response and trough serum guselkumab concentrations In subjects with psoriatic lesions ≥ 3% of BSA and an IGA score ≥ 2 at baseline There was a clear correlation between IGA response at week 24 by quartiles of trafuguselkumaab concentration at week 20. No clear exposure-response relationship was observed (Figure 9).

[0474] Summary of effectiveness Primary endpoint The proportion of subjects achieving an ACR 20 response at week 24 was significantly higher in patients receiving guselkumab 100 mg q4 The rates were 63.7% and 64.1% in the guselkumab 100 mg q8w and guselkumab 100 mg q8w groups, respectively. This was significantly higher than the 32.9% in the placebo group (both adjusted p<0.01). 001).

[0475] Key secondary endpoints Key secondary multiplicity controlled in both global (non-US) and US-specific testing procedures endpoint HAQ-DI scores at week 24 were significantly higher in the guselkumab 100 mg q4w group (L S mean: -0.4004) and guselkumab 100 mg q8w group (LS mean: -0 0.3672) were significantly higher than the placebo group (LS mean: -0.1300, global and A significant reduction from baseline was observed compared with the US and US (adjusted p<0.001). It was. 54 patients with psoriatic lesions of ≥3% of the BSA and an IGA score of ≥2 at baseline Of the subjects in the placebo group (19.1%), 3 (73.5%) received steroids. Both the coumab 100 mg q4w and guselkumab 100 mg q8w groups (6 8.5% and 70.5% had a psoriasis IGA score of 0 (clear) or 1 (minimal) at 24 weeks. ) and a ≥2-grade reduction from baseline (global and US-specific adjusted p <0.001). Change from baseline in modified vdH-S score at week 24 was significantly greater than that in the placebo group. (LS mean: 0.95) compared with the guselkumab 100 mg q4w group (LS mean : 0.29) and both the guselkumab 100 mg q8w group (LS mean: 0.52). Numerically smaller (less progression) rates were observed in global (outside the US) and US Based on the inherent multiplicity testing procedure, the LS mean difference was 0.05% for the GSS group compared with the placebo group. The difference was statistically significant in the cumab 100 mg q4w group (adjusted global p = 0.006, adjusted US-specific p=0.011, respectively), guselkumab 100mg q was not significant in the 8w group (adjusted global p = 0.068 and adjusted p = 0.068, respectively). (US-specific p=0.072 after treatment). Change from baseline in modified vdH-S score at 24 weeks The reduction in CI was not significant in this group, and the remaining key secondary endpoints were , in the global (outside the US) specific trial procedures for the guselkumab 100mg q8w group, Statistical significance was not formally tested (adjusted p=0.068). At 24 weeks, the SF-36 PCS score was significantly higher than in the placebo group (LS mean: 3.42 ) compared with the guselkumab 100 mg q4w group (LS mean: 7.04) and guselkumab In both groups, baseline was 1.08 mg q8w (LS mean: 7.39). Numerical improvements were seen from the global (non-US) specific multiplicity testing procedure. Based on the mean mean mean ≥100 mg q4w in the guselkumab 100 mg q4w group compared with the placebo group, The change in CI was statistically significant (adjusted p=0.006) with guselkumab 100 mg q8 The w group was not formally tested. Based on US-specific testing procedures, Compared with the guselkumab 100 mg q4w group and the guselkumab 100 mg In both q8w groups, the mean changes were statistically significant (all adjusted p = 0.011). At week 24, the SF-36 MCS score was significantly higher than in the placebo group (LS mean: 2.14 ), compared with the guselkumab 100 mg q4w group (LS mean: 4.22) and In both the selkuma 100 mg q8w group (LS mean: 4.17), There was a significant numerical improvement from the baseline. Based on the study procedures, the guselkumab 100 mg q4w group showed a significant improvement compared with the placebo group. The mean change was statistically significant (adjusted p=0.006) for guselkumab 100 mg / kg. The mg q8w group was not formally tested. Compared with the placebo group, the guselkumab 100 mg q4w group or the guselkumab In the cumab 100 mg q8w group, the mean change was not statistically significant (either (Adjusted p=0.072). Pool design of CNTO1959PSA3001 and CNTO1959PSA3002 Of the 728 subjects (65.0%) who had enthesitis at baseline based on the data, The proportion of subjects whose enthesitis resolved at 24 weeks was 29.4% compared with the placebo group. The guselkumab 100 mg q4w group and the guselkumab 100 mg q8w group were The figures were higher in the global (non-US) market (44.9% and 49.6%, respectively). Based on the multiplicity testing procedure, guselkumab 100 mg was associated with a significant improvement in efficacy compared with placebo. The proportion of subjects whose enthesitis resolved was significantly higher in the q4w group (adjusted p = 0.0 06), no formal testing was performed in the guselkumab 100 mg q8w group. Based on the multiplicity study procedure, guselkumab 100 mg was associated with a significant improvement in efficacy compared with placebo. Tendon attachment was observed in both the q4w and guselkumab 100 mg q8w groups. The proportion of subjects whose ulcerative colitis resolved was significantly higher (both adjusted p = 0.030). Pool design of CNTO1959PSA3001 and CNTO1959PSA3002 Among 473 patients (42.2%) who had dactylitis at baseline based on the data, The percentage of subjects whose dactylitis resolved after 24 h was significantly higher in the Guserk group than in the placebo group (42.2%). Both guselkumab 100 mg q4w and guselkumab 100 mg q8w groups (6 3.5% and 59.4%, respectively. Based on the protocol, the percentage of subjects whose dactylitis resolved was significantly higher in the guselkumab 100 mg q4w group than in the control group. was significantly higher in the guselkumab 10 group compared with the placebo group (adjusted p=0.006). The 0 mg q8w group was not formally tested. The proportion of subjects with resolution of dactylitis was significantly higher in the guselkumab 100mg group compared to the placebo group. g q4w group and guselkumab 100 mg q8w group (adjusted p=0.011 and p=0.030, respectively). Controlled for multiplicity in global (non-US) testing procedures and US-specific testing Key secondary endpoints conditionally controlled in the procedure The following key secondary endpoints were evaluated in a global (outside the US) study protocol: Furthermore, these endpoints correlated with the primary endpoint. and ACR 20 response at 24 weeks was significantly higher in the Gcel group compared with the placebo group. Both the kumab 100 mg q4w group and the guselkumab 100 mg q8w group Based on US-specific trial procedures, both guselkumab and rheumatoid arthritis were randomly assigned to the rheumatoid arthritis subtype. Dose was also tested (all nominal p<0.001). The reduction from baseline in DAS28 (CRP) scores at 24 weeks was significantly greater than that of placebo. compared with the group (LS mean: -0.97, both globally adjusted p<0.001). Selkumab 100 mg q4w group (LS mean: -1.62) and guselkumab 100 mg q8w group (LS mean: -1.59). The following key secondary endpoints were evaluated using global (non-US) multiplicity study procedures: Based on the order of progression, the guselkumab 100 mg q4w group had a significantly higher mean mean mean compared with the placebo group. Statistical significance was achieved (adjusted p=0.006. Guselkumab 100mg q8w group The endpoint for this study was change from baseline in modified vdH-S score at week 24. The guselkumab 100 mg q8w group had a significantly lower risk of death compared with the placebo group because the The statistical significance of loop w could not be assessed. The proportion of subjects with an ACR 20 response at week 16 was 33.7% compared with the placebo group. %) compared with guselkumab 100 mg q4w and guselkumab 100 mg q8w was numerically higher in both groups (55.9% and 55.2%, respectively; nominal p<0.001 ). The proportion of subjects with an ACR 50 response at week 24 was significantly higher than in the placebo group (14.2 %; nominal p<0.001) compared with guselkumab 100 mg q4w and guselkumab The incidence was numerically higher in the 100 mg q8w group (33.1% and 31.5%, respectively). Ta. The proportion of subjects with an ACR 50 response at week 16 was significantly higher than in the placebo group (9.3%). ; nominal p<0.001) compared with guselkumab 100 mg q4w and guselkumab 1 00 mg q8w group (20.8% and 28.6%, respectively). The proportion of subjects with an ACR 70 response at week 24 was significantly higher than in the placebo group (4.1%). (nominal p<0.001) compared with guselkumab 100 mg q4w and guselkumab 10 were numerically higher in the 0 mg q8w group (13.1% and 18.5%, respectively). Key secondary endpoints conditionally controlled only by US-specific trial procedures Both guselkumab 100 mg q4w and guselkumab 100 mg q8w groups In the study, the incidence of enthesitis at 24 weeks and dactylitis at 24 weeks was significantly lower than in the placebo group. As the resolution achieved statistical significance, CNTO1959PSA3001 and CN Based on pooled data from TO1959PSA3002, both doses of guselkumab , change from baseline in enthesitis score at 24 weeks and baseline in dactylitis score at 24 weeks Variation from baseline was formally assayed using US-specific testing procedures. Pool design of CNTO1959PSA3001 and CNTO1959PSA3002 Of the 728 subjects (65.0%) who had enthesitis at baseline based on the data, The reduction from baseline in LEI scores at week 24 was significantly greater than in the placebo group (LS mean: -1.02, both nominal p<0.001) compared with guselkumab 100 mg q4w group (LS mean: -1.59) and guselkumab 100 mg q8w group (LS mean Both the mean and mean values ​​(average: -1.52) were observed to be numerically significant. Pool design of CNTO1959PSA3001 and CNTO1959PSA3002 In 473 patients (42.2%) who had dactylitis at baseline based on the data, Kumab 100 mg q4w group (LS mean: -5.97) and guselkumab 100 mg There was no significant difference in the placebo group (L S mean: -4.21, nominal p=0.002 and p<0.001, respectively) compared with 24 A numerically greater reduction from baseline in dactylitis scores at week 1 was observed. Other secondary efficacy analyses Other efficacy endpoints related to reduction of joint signs and symptoms - For each ACR component from Week 2 to Week 24, except for the number of swollen joints at Week 2 Both guselkumab groups showed a median improvement from baseline compared with the placebo group. The percentage of good results was numerically large. At week 24, the proportion of subjects achieving a modified PsARC response was guselkumab 100 mg q4w and guselkumab 100 mg q8w groups were 68.6% and 72.6%, respectively. % in the placebo group, compared with 44.7% in the placebo group (both nominal p<0. 001). Proportion of subjects achieving low disease activity or remission based on the DAPSA index at week 24 was 18.3% in the placebo group compared with 18.3% in the guselkumab 100 mg q4w and guselkumab groups. The rates were 35.5% and 38.7% in the cumab 100 mg q8w group, respectively (both (also nominal p<0.001).

[0476] Other efficacy endpoints related to physical function HAQ-DI response rate at 24 weeks (HAQ-DI score ≥ 0.3 at baseline) 5 (defined as an improvement of ≥ 0.35 from baseline) were compared with placebo 56.1% in the guselkumab 100 mg q4w group compared with 31.4% in the q4w group; The rate was 50.0% in the guselkumab 100 mg q8w group (all nominal p<0.0). 001). Other efficacy endpoints related to skin disease Patients with psoriatic lesions of ≥ 3% of the BSA and an IGA score of ≥ 2 (mild) at baseline Of the 543 (73.5%) subjects: Both guselkumab groups achieved PASI 50 and PAS scores at weeks 16 and 24. The proportion of subjects with PASI 75, PASI 90, and PASI 100 responses was significantly higher than placebo. The results were numerically higher compared to the Bo group (all nominal p<0.001). At week 24, the proportion of subjects who had both a PASI 75 and ACR 20 response was , guselkumab 100 mg q4w and guselkumab 100 mg q8w groups, respectively. The incidence rates were 57.1% and 56.8% in the placebo group, compared with 11.5% in the placebo group. (all nominal p<0.001). Proportion of subjects achieving both PASI 75 and modified PsARC responses at week 24 The guselkumab 100 mg q4w and guselkumab 100 mg q8w groups The mortality rates were 60.9% and 65.3%, respectively, compared with 15.3% in the placebo group. (all nominal p<0.001). The proportion of subjects achieving an I, GA score of 0 (clear) at week 24 was 1.5% with guselkumab 1. 50 in the guselkumab 100 mg q4w group and the guselkumab 100 mg q8w group, respectively. 5% and 50.0% in the placebo group, compared with 7.7% in the placebo group (both nominal p<0.001). At 24 weeks, DLQI scores were significantly higher in the placebo group (37.8%) than in the placebo group (37.8%). Rucumab 100 mg q4w group (86.8%) vs. guselkumab 100 mg q8w Clinically meaningful improvement from baseline of ≥ 5 points in the group (83.3%) The proportion of subjects achieving this was numerically higher (all nominal p<0.001). Other efficacy endpoints related to enthesitis and dactylitis Enthesitis at baseline based solely on CNTO1959PSA3002 data Of the 506 patients (68.5%) who had tendon attachment, The number of subjects with resolution of inflammation was significantly higher in both guselkumab groups compared with the placebo group. The number was higher in the group. - Patients with dactylitis at baseline based solely on data from CNTO1959PSA3002 Of the 331 patients (44.8%) who were receiving placebo at each visit from week 2 to week 24, Numerically more subjects achieved resolution of dactylitis in both guselkumab groups compared with the control group. It was. Other efficacy endpoints related to BASDAI Among 258 subjects (34.9%) who had spondylitis and peripheral arthritis at baseline, BASDAI was compared with the placebo group at each visit evaluated from Weeks 8 to 24. Numerically significant reductions from baseline were observed in both guselkumab groups. The proportion of subjects who achieved an improvement of ≥20%, ≥50%, and ≥70% was ≥100% at weeks 8 to 24. were numerically greater in both guselkumab groups compared with the placebo group.

[0477] Other efficacy endpoints related to structural joint damage The proportion of subjects with a change from baseline in modified vdH-S score ≤ 0 was 67.7% in the guselkumab 100 mg q4w group compared with 64.7% in the placebo group 0.3% in the guselkumab 100 mg q8w group and 63.4% in the guselkumab 100 mg q8w group (nominal p=0.555 and p=0.751). The proportion of subjects with a change from baseline in modified vdH-S erosion score ≤0 was 71.4% in the guselkumab 100 mg q4w group compared with 66.8% in the sebo group %, and 66.3% in the guselkumab 100 mg q8w group (nominal p = 0.268 and p=0.867). - Subjects whose modified vdH-S JSN score changed from baseline to ≤0 at week 24 The rate of ≥100% in the guselkumab 100 mg q4w group was 78.6% compared with 78.6% in the placebo group. The rates were 80.2% in the guselkumab group and 78.8% in the guselkumab 100 mg q8w group ( nominal p = 0.669 and p = 0.903, respectively).

[0478] Other efficacy endpoints related to health-related quality of life and other patient-reported outcomes At week 24, a clinically meaningful improvement from baseline in the SF-36 PCS score ≥ The percentage of subjects achieving a 5-point improvement was 40.2% in the placebo group compared with 10.2% in the 55 in the lucumab 100 mg 4w and guselkumab 100 mg q8w groups, respectively. 9% and 60.1% (both nominal p<0.001). At week 24, the SF-36 MCS score must be improved from baseline by a clinically meaningful amount or more. The proportion of subjects achieving a 5-point or greater improvement was 30.9% in the placebo group. , guselkumab 100 mg q4w and guselkumab 100 mg q8w groups. The rates were 34.3% and 37.5%, respectively (nominal p=0.424 and p=0.124). . At week 24, the FACIT-Fatigue score improved by ≥ 4 points from baseline The proportion of subjects receiving guselkumab 100 mg q4w was 45.5% compared with 45.5% in the placebo group. The rates were 59.6% in the guselkumab 100 mg q8w group and 60.5% in the guselkumab 100 mg q8w group. (nominal p=0.002 and p<0.001, respectively). At week 24, guselkumab 100 mg q4w group (LS mean: 0.116) and guselkumab 100 mg q8w group (LS mean: 0.115). compared with the placebo group (LS mean: 0.053, nominal p<0.001 for both). Numerically significant increases from baseline in EQ-5D index scores were observed. At week 24, the placebo group (LS mean: 6.796, nominal p<0.05) 001), compared with the guselkumab 100 mg q4w group (LS mean: 18.08 9) and guselkumab 100 mg q8w group (LS mean: 18.371) Numerically significant increases from baseline in EQ-5D health status VAS scores were observed. Ta.

[0479] Improvement in composite disease activity score The proportion of subjects who met MDA criteria at 24 weeks was 6.1% in the placebo group. In the guselkumab 100 mg q4w group, 18.8% The rate was 25.0% in the q8w group (both nominal p<0.001). Other PsA composite disease activity scores, including the S, GRACE index, and mCPDAI score, However, at 24 weeks, greater improvements were observed in both groups compared with the placebo group ( All nominal p<0.001).

[0480] Efficacy and Pharmacokinetics ACR50 at Week 24 by quartiles of steady-state trafuguselkumaab concentrations at Week 20 Although the exposure-response relationship for response rates appeared weak, there was a consistent increase in ACR20 response rates at 24 weeks. No dew-response relationship was observed. Week 20 or Week 24 by steady-state trafuguselkumaab concentration quartiles at Week 20 There was a clear exposure-response relationship for the mean change from baseline in DAS28(CRP) There was none. Patients with psoriatic lesions of ≥ 3% of the BSA and an IGA score of ≥ 2 (mild) at baseline Week 24 IGA by quartiles of steady-state selcumab concentrations at week 20 in subjects There was no clear exposure-response relationship for response.

[0481] Efficacy and antibodies to guselkumab In subjects who tested positive for antibodies to guselkumab by week 24, The presence of antibodies against guselkumab did not preclude ACR responses. The number of subjects who were positive for guselkumab was small (n=10), and antibodies to guselkumab were not clinically effective. There are limitations to making clear conclusions about the impact on

[0482] Safety Results Adverse events An overall summary of AEs reported through Week 24 is provided in Table 24. Mean number of study drug doses was consistent across treatment groups.

[0483] [Table 24]

[0484] The proportion of subjects experiencing one or more AEs at week 24 was significantly higher in the group compared with the placebo group. Slightly higher in the selkuma-treated group: guselkumab 100 mg q4w guselkumab 46.1% in the group, 46.0% in the guselkumab 100 mg q8w group, and 40.7% in the placebo group.

[0485] The most frequently reported SOC for AEs was infections and infestations, with 43% of events in this SOC The overall frequency was similar between treatment groups (guselkumab 100 mg q4w group 17.6% of the group, 15.7% of the guselkumab 100 mg q8w group, and 17.6% of the placebo group The second most common SOC was clinical trials, of which 17.1% were in the Botox group. The incidence of AEs was higher in the guselkumab treatment group than in the placebo group (guselkumab 1 14.3% in the guselkumab 100 mg q4w group and 14.3% in the guselkumab 100 mg q8w group 14.5% of the group and 7.7% of the placebo group.

[0486] Most severe AEs with a frequency ≥ 5% in any treatment group by Week 24 Common PTs are listed in Table 25. The most commonly reported PT was increased ALT (guselkumab 10.2% in the 100 mg q4w group and 10.2% in the guselkumab 100 mg q8w group 6.0% in the placebo group and 4.5% in the placebo group, followed by AST increase (guselkumab 4.5% in the 100 mg q4w group and 5% in the guselkumab 100 mg q8w group The ALT AES was 0.6% in the placebo group and 2.4% in the placebo group. were reported more frequently in the guselkumab-treated group compared with the guselkumab group. guselkumab 100 mg q4w group compared with guselkumab 100 mg q8w group It was higher.

[0487] [Table 25]

[0488] Adverse events up to week 24 by baseline age group Age was divided into the following groups: <45 years (n = 340), ≥45 years to <65 years (n = 366), ≥ 65 years (n = 33), and ≥ 75 years (n = 1). Guselkumab treatment group The proportion of subjects reporting AEs was higher in the <45 year age group compared to the placebo group The incidence rates were similar in the ≥45 to <65 year age group. AEs were reported in the ≥65 year age group. The proportion of subjects who received guselkumab 100 mg q4w was 100 mg was higher than in the q8w and placebo groups; however, the number of subjects in this age group was There were few: <45 years (n=340): guselkumab 100mg q4w, guselkumab 100 The rates were 47.2%, 47.7%, and 33.7% in the 1 mg q8w and placebo groups, respectively. %. ≥45 to <65 years (n=366): Guselkumab 100mg q4w, Guselkumab The rates were 44.4%, 45.9%, and 49.9% in the mab 100 mg q8w and placebo groups, respectively. and 46.6%. ≥ 65 years (n=33): guselkumab 100mg q4w, guselkumab 100m g q8w and placebo groups: 54.5%, 27.3%, and 36.4%, respectively .

[0489] Adverse events from baseline use of non-biologic DMARDs up to week 24 Subjects were divided into the following groups: none (n=227), MTX (n=443), any Non-MTX DMARDs (n=69), SSZ (n=31), HCQ (n=3), LEF (n=35), and any DMARD (n=512).

[0490] The proportion of subjects with AEs reported by week 24 was 0.01 vs. 0.01 in each subgroup. The incidence of rheumatoid arthritis was slightly higher in the guselkumab-treated group compared with the baseline. Compared with the subgroup with no MTX or any DMARDs The proportion of subjects reporting AEs was generally higher in the groups: None (n=227): Guselkumab 100 mg q4w, guselkumab 100 mg 46.7%, 34.6%, and 29.7% in the q8w and placebo groups, respectively. Methotrexate (n=443): Guselkumab 100mg q4w, guselkumab The mortality rates were 46.6%, 52.5%, and 45% in the 100 mg q8w and placebo groups, respectively. .5%. Any DMARD (n=512): guselkumab 100mg q4w, guselkumab The mortality rates were 45.9%, 51.2%, and 45.9% in the 100 mg q8w and placebo groups, respectively. .3%.

[0491] The number of subjects in the remaining subgroups was very small. The files are generally consistent with the overall population, and specific patterns are identified in these subjects. There wasn't.

[0492] Consistent with the overall population, the most common SOC for reported AEs was the most common in clinical trials. All subgroups showed no benefit except for the non-biologic DMARD subgroup. The most common infectious and parasitic diseases were:

[0493] Severe adverse events The proportion of subjects reporting one or more AEs of severe intensity was low, with guselkumab 100 mg 0.8% in the q4w group, 0.4% in the guselkumab 100 mg q8w group, and The rate was 0.8% in the placebo group. All events were isolated.

[0494] immune-related adverse events By week 24, the proportion of subjects experiencing at least one reasonably related AE was significantly higher than that of the treatment group. were similar across groups (16.3 in the guselkumab 100 mg q4w group). %, 16.9% in the guselkumab 100 mg q8w group, and 1% in the placebo group 4.2%).

[0495] death No deaths were reported in this study through 24 weeks.

[0496] Severe adverse events The proportion of subjects experiencing one or more SAEs at week 24 was 1.0% with guselkumab 100 mg q4 3.3% in the guselkumab 100 mg q8w group, 1.2% in the guselkumab 100 mg q8w group, and The incidence rate was 2.8% in the Sebo group (Table 26). All events were isolated and unspecified. No SAEs of this pattern were identified.

[0497] [Table 26-1]

[0498] [Table 26-2]

[0499] Serious adverse events up to week 24 by baseline age group There was no specific pattern of association between SAEs at baseline and age. <45 years (n=340): guselkumab 100mg q4w, guselkumab 100 mg q8w, and 4.6%, 0%, and 1.0% in the placebo group, respectively. ≥45 to <65 years (n=366): Guselkumab 100mg q4w, guselkumab The incidence rates were 2.4%, 2.8%, and 4.0% in the 100 mg q8w and placebo groups, respectively. 6%. ≥ 65 years (n=33): No events were reported.

[0500] Serious adverse events through week 24 due to baseline use of non-biologic DMARDs The proportion of subjects with an SAE was significantly higher across treatment groups in each subgroup in which an SAE was reported. The results were roughly the same. None (n=227): Guselkumab 100 mg q4w, guselkumab 100 mg q8, and 4.0%, 0, and 2.7% in the placebo group, respectively. Methotrexate (n=443): Guselkumab 100mg q4w, guselkumab The incidence rates were 3.4% and 2.1% in the 100 mg q8 and placebo groups, respectively. , and 3.2%. Any DMARD (n=512): guselkumab 100mg q4w, guselkumab The incidence rates were 2.9%, 1.8%, and 3.0% in the fluoxetine 100 mg q8 and placebo groups, respectively. and 2.9%.

[0501] No SAEs were reported in the remaining subgroups.

[0502] Reasonably related serious adverse events By week 24, the proportion of subjects experiencing at least one reasonably relevant SAE was low (0.4% in the guselkumab 100 mg q4w group, 0.4% in the q8w group and 1.2% in the placebo group.

[0503] Example 2: Active psoriatic arthritis, including subjects previously treated with a biologic anti-TNFα agent A Phase 3 multicenter randomized controlled trial evaluating the efficacy and safety of subcutaneous administration of guselkumab in subjects with Randomized, double-blind, placebo-controlled study (CNTO1959PSA3001) The trial (CNTO1959PSA3001) was conducted in patients receiving standard of care (e.g., non-biologic DMARDs). In subjects with active PsA who have an inadequate response to anticoagulants (e.g., apremilast, NSAIDs), This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, three-arm study of selkuma. Subjects (approximately 30%) may have been previously treated with up to two anti-TNFα agents. The study consisted of a screening period of up to 6 weeks and a blinded treatment period of approximately 1 year (i.e., 52 weeks). A placebo-controlled period from Week 0 to Week 24 and an experimental period from Week 24 to Week 52 were conducted. The study will involve approximately 360 participants, including a 52-week treatment period and an 8-week safety follow-up period. The study was designed to enroll subjects with active psoriatic arthritis (PsA). This study was conducted to evaluate the clinical efficacy, safety, and pharmacokinetics (PK) of selkumaab. Secondary objectives were to evaluate guselkumab treatment with: Effective in improving psoriasis skin lesions Improved physical function

[0504] method Test Plan Overview Figure 10 shows a diagram of the test design.

[0505] At week 0, approximately 360 subjects who met all inclusion and exclusion criteria were enrolled at baseline Non-biologic DMARD use (yes, no) and previous exposure to anti-TNFα agents (yes, no) Using permuted block randomization stratified by (none) in a 1:1:1 ratio, They were randomly assigned to one of three treatment groups: Group I (n=120): Guselkumab SC 100mg every 4 weeks (q4w) , administered from week 0 to week 48. Group II (n=120): Guselkumab SC 100mg at weeks 0 and 4 Administered q8w (weeks 12, 20, 28, 36, and 44), and other Placebo injections at visits (weeks 8, 16, 24, 32, 40, and 48) was performed to maintain blinding. Group III (n=120): Placebo SC q4w from week 0 to week 20 Patients were then crossed over at week 24 to receive guselkumab 100 mg q4w until week 48. did.

[0506] At week 16, patients had a <5% improvement from baseline in both swollen and tender joint counts. All subjects in groups I, II, and III achieved early escape (EE) ) criteria were considered met. These subjects remained on the dose regimen and were considered to have met the The dose of one of the permitted concurrent medications was determined according to the protocol. Patients were allowed to start or increase their dose up to the maximum tolerated dose as determined and completed by the 24-week visit. The dose was gradually increased until a stable dose was reached.

[0507] Efficacy assessments included joint assessment (swollen joint count and tender joint count), patient pain assessment, and patient Global assessment of disease activity by the patient (arthritis and psoriasis), BALB assessment (arthritis), Physician Global Assessment of Disease Activity, Health Assessment Questionnaire-Disability Index CRP), patient assessment of skin disease activity, body surface area (BSA) of psoriasis, area of ​​psoriasis and Severity Index (PASI), Investigator's Global Assessment of Infection (IGA), Dactylitis Assessment, Enthesitis Assessment Based on the Leeds Enthesitis Index, and the Canadian Spondyloarthritis Research Consortium SPARCC criteria, Bass Ankylosing Spondylitis Disease Activity Index (BASDAI; peripheral For subjects with the major PsA subtype of spondylitis with arthritis, minimal disease activity (MDA) and very low disease activity (VLDA), disease activity score for psoriatic arthritis ( PASDAS), psoriasis and psoriatic arthritis (GRAPPA) composite score (GRACE) index Group study and evaluation of the Disease Activity Score 28 (DAS28) using CRP, psoriasis Disease Activity Index for Psoriatic Arthritis (DAPSA), and Psoriatic Arthritis Response Criteria (PsARC), 36-item Short Form Health Survey (SF-36), Functional Assessment of Chronic Illness (FACI) T)-Fatigue, Patient-Reported Outcomes Measurement Information System (PROMIS)-29.

[0508] Safety evaluation included adverse events (AEs), serious adverse events (SAEs), injection site reactions and allergic reactions. Allergic reactions, laboratory tests (blood, chemistry, urine pregnancy test), electronic Columbia suicide severity assessment Rating scale (eC-SSRS), physical examination, vital signs, electrocardiogram (ECG, week 0 only) ), and early detection of tuberculosis (TB).

[0509] Specimens for analysis of pharmacodynamic biomarkers were collected from all subjects.

[0510] Study population The target population is those not receiving standard treatment (non-biologic DMARDs, apremilast, NSAIDs, etc.). The participants consisted of adult men or women with active PsA who had an inadequate response to other treatments (e.g., steroids, anticoagulants, etc.). Approximately 30% of the study population may have received up to two previous anti-TNFα agents.

[0511] To be eligible for this study, subjects must be 18 years of age or older at the time of informed consent. Patients with PsA who have been diagnosed with PsA at least 6 months prior to the first dose of the study drug and who have not undergone screening Patients were required to meet the Classification Criteria for Psoriatic Arthritis (CASPAR) 42. ≥3 tenderness and ≥3 distension at both screening and baseline Active PsA as defined by section and CRP ≥ 0.3 mg / kg at screening Subjects were required to have a history of non-biologic DMARDs (≥3 months), apremias, or for standard PsA treatments including steroids (≥ 4 months), and / or NSAIDs (≥ 4 weeks). Patients were required to have documented evidence of inadequate response or intolerance. Subjects with prior exposure to Fα agents were allowed but were limited to approximately 30% of the study population .

[0512] Subjects were required to have at least one of the following PsA subsets: distant DIP joint involvement, polyarticular arthritis without rheumatoid nodules, destructive arthritis, non- Symmetric peripheral arthritis, spondylitis with peripheral arthritis. Additionally, subjects must have at least one diameter ≥ 2 cm psoriatic plaques, or nail changes consistent with psoriasis, or documented plaque psoriasis Patients had to have a history of active plaque psoriasis.

[0513] Subjects were required to be on a stable dose of a non-biologic DMARD (MTX [≤25 mg / week], SSZ [≦3g / day], HCQ [≦400mg / day], or LEF [≦20mg / day] limited), low-dose oral corticosteroids (≤10 mg prednisone or or equivalent), or NSAID and other analgesic treatment could be continued. Subjects who were not using these medications at baseline were excluded from the study drug intake for ≥ 4 weeks (M TX, SSZ, HCQ), ≥ 12 weeks (LEF), or ≥ 2 weeks (NSAI (In the case of oral corticosteroids, oral steroids, and other analgesics, these drugs must be discontinued before In addition, subjects were screened for laboratory test results and TB history and test results. meet the criteria for birth control, agree to use appropriate birth control methods, and avoid prolonged sun exposure. It was necessary to avoid dew and to avoid the use of tanning booths or other sources of ultraviolet light during the test.

[0514] Dosage and Administration All study medications (guselkumab and placebo) were administered by SC injection. Clinical efficacy, safety, and PK data of guselkumab in subjects with rheumatoid arthritis and a phase 2 study (C Based on the exposure-response model analysis using data from NTO1959PSA2001, Two dose regimens were selected for evaluation in the Phase 3 PsA program for cumab, and eligible Subjects were randomly assigned to receive one of three treatments at week 0: Guselkumab 100mg q4w: SC guselkumab 100mg from week 0 to week 48 I received g q4w. Guselkumab 100 mg at weeks 0 and 4, followed by q8w (hereafter referred to as guselkumab 100 mg q8w group): Subjects received SC guselkumab 100 mg q8w at weeks 0 and 4. 00 mg q8w (weeks 12, 20, 28, 36, and 44), and at other visits (8, Patients received placebo injections at weeks 16, 24, 32, 40, and 48 to maintain blinding. Placebo: SC placebo q4w from weeks 0 to 20, with crossover at week 24 They then received SC guselkumab 100mg q4w from weeks 24 to 48.

[0515] Rationale for a dosing regimen of guselkumab 100 mg at weeks 0 and 4, then every 8 weeks This dosing regimen was used in a Phase 2 study of PsA (CNTO1959PSA2001) and It was evaluated in three global Phase 3 trials for psoriasis and steroids: CNTO1959, PSA200 In one study, joint signs and symptoms, physical function, psoriasis, enthesitis, dactylitis, and active P All important domains of PsA, including quality of life, in patients with psoriasis with ≥ 3% of sA and BSA This dosing regimen resulted in robust efficacy and clinically meaningful improvements in Additionally, a Phase 3 psoriasis trial demonstrated efficacy in treating plaque psoriasis in patients with moderate to severe psoriasis. A significant benefit was also observed with this dose regimen. An additional dose was included at week 4 to ensure that trafuguselkumab levels were achieved at steady-state levels. The booster dose at week 4 ensured that the serotonin levels did not decrease more than those measured in the first 12 weeks. Cmax and Ctrough were approximately 21% and 18%, respectively, lower than the steady-state values. The dose is slightly higher than that of the control group, which may result in a more rapid onset of response. This dosing regimen is q8w during maintenance, i.e., q8w from week 24 onwards. results in substantially higher levels of efficacy at 24 weeks than achieved by is not expected. The safety of this dosing regimen has been established in a large psoriasis development program. Additionally...

Claims

1. 1. A method of treating psoriatic arthritis in a subject in need thereof, comprising administering to said subject about 5 The method comprises subcutaneously administering 0 mg to about 150 mg of an anti-IL-23 antibody, wherein the antibody is a heavy chain-compatible antibody. a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region is a complementarity determining region of SEQ ID NO: 1 1 (CDRH1), SEQ ID NO:2 (CDRH2), and SEQ ID NO:3 (CDRH3). wherein the light chain variable region comprises the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:

4. a CDRL2 of SEQ ID NO:5, and a CDRL3 of SEQ ID NO:6, At least a 20% improvement in the American College of Rheumatology Core Set Disease Index (ACR20) after treatment A method for achieving this.

2. The antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a heavy chain variable region of the amino acid sequence of SEQ ID NO: 8 and a light chain variable region of claim 1.

3. the antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 9, a light chain amino acid sequence of SEQ ID NO: 10, The method of claim 1 , comprising:

4. 10. The method of claim 1, wherein the antibody is administered at a dose of about 100 mg per administration.

5. 5. The method of claim 4, wherein the antibody is administered once every four weeks (q4w).

6. 10. The method of claim 1, wherein ACR20 is achieved after about a 24-week treatment period.

7. 10. The method of claim 1, wherein ACR20 is achieved after about a 52-week treatment period.

8. After the treatment, the subject has a 50% improvement in the American College of Rheumatology Core Set Disease Index (ACRI). R50), 70% improvement in the American College of Rheumatology Core Set Disease Index (ACR70), health rating Hazard Assessment Questionnaire Disability Index (HAQ-DI), Investigator's Global Assessment (IGA), Disease DAS28 activity score, C-reactive protein (CRP), enthesitis resolution, finger Resolution of inflammation, Leeds Enthesitis Index (LEI), Thyroiditis Assessment Score, mental and physical comp Short Form Health Survey (SF-) in Component Summary (MCS and PCS) 36), achievement of minimal disease activity (MDA), very low disease activity (VLDA), and Spondylitis Orthostatus Activity Index (BASDAI), GRappa Composite Score (GRACE), Psoriasis Psoriasis Disease Activity Score (PASDAS), modified Composite Psoriasis Disease Activity Index (mCPDA) Psoriasis Area and Severity Index (PASI), Skin Life Quality Index (DLQI) ), Functional Assessment of Chronic Illness Therapy (FACIT), Patient-Reported Outcomes Measurement Information System-2 9 (PROMIS-29), and vdH-S score 10. The method of claim 1, further achieving an improvement in disease activity as determined by one criterion. 。

9. the subject has an American College of Rheumatology Core Set Disease Index score of at least 50% after the treatment 9. The method of claim 8, further achieving an improvement in ACR50.

10. The subject has a Health Assessment Questionnaire Disability Index (HA) score of 1 or more after a treatment period of at least about 24 weeks.

9. The method of claim 8, further achieving an improvement in Q-DI.

11. The subject has a Disease Activity Score of 28 (DAS2) or higher after a treatment period of at least about 24 weeks. 8) The method according to claim 8, further achieving an improvement in C-reactive protein (CRP).

12. The subject is evaluated by a global investigator assessment after a treatment period of at least about 24 weeks. (IGA) of 0 (clear) or 1 (minimal), or a decrease of 2 or more grades The present invention further achieves the above object, wherein the subject has psoriatic lesions of 3% or more of the body surface area (BSA).

9. The method of claim 8, wherein the patient exhibits an IGA score of 2 or greater at baseline before the treatment.

13. The subject has had an inadequate response to standard treatment for the PsA, and optionally, 10. The method of claim 1, wherein the subject also receives the standard of care during the treatment.

14. 1. A method of treating psoriatic arthritis in a subject in need thereof, comprising administering once at week 0: Once every 4 weeks and once every 8 weeks (q8w) thereafter, the subject receives approximately 50 mg to 150 mg and subcutaneously administering an anti-IL-23 antibody of the formula (I) to the subject, wherein the antibody comprises a heavy chain variable region and a light chain variable region. the heavy chain variable region comprises a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1; the light chain variable region comprises the amino acid sequence of SEQ ID NO: 1, a CDRH2 of SEQ ID NO: 2, and a CDRH3 of SEQ ID NO: 3; The region is a complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, a complementarity determining region light chain 2 (CDRL3) amino acid sequence of SEQ ID NO: 5, and a CDRL2 of SEQ ID NO: 6, and a CDRL3 of SEQ ID NO: 6, wherein said subject has a diameter of ≥ 2 mm prior to said treatment. cm of at least one psoriatic plaque, or nail changes consistent with psoriasis, or plaque dryness and the subject has a documented history of sclerosis, and the subject has a low or no score on the American College of Rheumatology Core Set Disease Index. A method that achieves at least a 20% improvement (ACR20).

15. The antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a heavy chain variable region of the amino acid sequence of SEQ ID NO: 8 and a light chain variable region of claim 14.

16. the antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 9, a light chain amino acid sequence of SEQ ID NO: 10, 16. The method of claim 15, comprising:

17. 15. The method of claim 14, wherein the antibody is administered at a dose of about 100 mg per administration.

18. 18. The method of claim 17, wherein an ACR20 is achieved after about a 24-week treatment period.

19. 20. The method of claim 18, wherein ACR20 is achieved after about a 52-week treatment period.

20. After the treatment, the subject has a 50% improvement in the American College of Rheumatology Core Set Disease Index (ACRI). R50), 70% improvement in the American College of Rheumatology Core Set Disease Index (ACR70), health rating Hazard Assessment Questionnaire Disability Index (HAQ-DI), Investigator's Global Assessment (IGA), Disease DAS28 activity score, C-reactive protein (CRP), enthesitis resolution, finger Resolution of inflammation, Leeds Enthesitis Index (LEI), Dactylitis Assessment Score, Mental and Physical Components Short Form Health Survey (SF-36) in Component Summary (MCS and PCS) ), Achievement of Minimal Disease Activity (MDA), Very Low Disease Activity (VLDA), Basaltosis Spondylitis Activity Index (BASDAI), GRAppa Composite Score (GRACE), Psoriasis-related Arthritis Disease Activity Score (PASDAS), modified Composite Psoriasis Disease Activity Index (mCPDAI) , Psoriasis Area and Severity Index (PASI), Skin Life Quality Index (DLQI), Functional Assessment of Chronic Illness Therapy (FACIT), Patient-Reported Outcomes Measurement Information System-29 ( PROMIS-29), and vdH-S score 20. The method of claim 19, further achieving an improvement in disease activity as determined by the following criteria:

21. the subject has an American College of Rheumatology Core Set Disease Index score of at least 50% after the treatment 21. The method of claim 20, further achieving an improvement in ACR50.

22. The subject has a Health Assessment Questionnaire Disability Index (HA) score of 1 or more after a treatment period of at least about 24 weeks.

21. The method of claim 20, further achieving an improvement in Q-DI.

23. The subject has a Disease Activity Score of 28 (DAS2) or higher after a treatment period of at least about 24 weeks. 8) The method according to claim 20, further achieving an improvement in C-reactive protein (CRP).

24. The subject is evaluated by a global investigator assessment after a treatment period of at least about 24 weeks. (IGA) of 0 (clear) or 1 (minimal), or a decrease of 2 or more grades The present invention further achieves the above object, wherein the subject has psoriatic lesions of 3% or more of their body surface area (BSA), 21. The method of claim 20, wherein the patient exhibits an IGA score of 2 or greater at baseline before treatment.

25. 10. The method of claim 1, wherein the subject has had an inadequate response to standard treatment for PsA. How to do it.

26. 26. The method of claim 25, wherein the subject also receives the standard of care during the treatment.

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