Safe and effective method of treating il23 with Anti-psoriatic specific antibodies

Abstract

To provide a pharmaceutical composition for use in a method of treating psoriatic arthritis.SOLUTION: A pharmaceutical composition for use in a method for treating psoriatic arthritis in a patient, the pharmaceutical composition comprising an antibody to IL-23, the method comprising administering to the patient an antibody to IL-23 in a clinically proven safe and clinically proven effective amount, wherein the patient has been shown to have an inadequate response to, or intolerance to, standard non-biologic therapy for psoriatic arthritis, wherein said patient is a responder to said treatment with said antibody.SELECTED DRAWING: None

Description

[Technical Field]

[0001] 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 an anti-IL-23 specific antibody and a method for treating psoriatic arthritis. Certain pharmaceutical compositions of antibodies (e.g., glycerol) that are safe and effective for patients with the disease. This relates to methods of administering cumab.

[0002] (Sequence Listing) This application has been filed electronically in ASCII format and is incorporated by reference in its entirety. Including the Sequence Listing incorporated herein. An ASCII copy of this is available at http: / / www.ncbi.nlm.nih.gov / pubmed / 118881. It was created on the 5th of the month and the file name is JBI5144WOPCT11SEQLIST.txt and its size is 79,736 bytes. [Background technology]

[0003] Interleukin (IL)-12 has two disulfides The bound glycosylated protein subunits (p35 and p36) were identified due to their approximate molecular weight. It is a secreted heterodimeric cytokine composed of two proteins (denoted p40 and p40). IL-12 is produced primarily by antigen-presenting cells and is expressed by T cells or natural killer (nat It binds to a two-chain receptor complex expressed on the surface of NK cells. It promotes cell-mediated immunity by activating the IL-12 receptor β-1 (IL-12Rβ1) chain. binds to the p40 subunit of IL-12 and mediates the primary interaction between IL-12 and its receptor. However, intracellular signaling (e.g., STAT4 phosphorylation) and the second receptor chain, IL-12Rβ2, confers activation of receptor-bearing cells. IL-12 signaling in parallel with antigen presentation is Towards a T helper 1 (Th1) phenotype characterized by interferon gamma (IFNγ) production γTh1 cells are thought to be able to differentiate into T cells against some intracellular pathogens. These findings may promote immune responses to tumors, generate complementary antibody isotypes, and contribute to tumor immunosurveillance. This suggests that IL-12 is an important component of the host defense immune system. can be done.

[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 (e.g., STAT3 phosphorylation) and subsequent IL-17 production by T cells. The second component of the IL-23 receptor complex, IL-23R, is the IL-23p19 ligase. Recent studies have shown that the biological functions of IL-23 and IL-12 are different. , showed that despite the structural similarities between these two cytokines, they are distinct.

[0005] Neutralization of IL-12 by antibodies has been shown to improve the efficacy of psoriasis and multiple sclerosis. osis (MS), rheumatoid arthritis, inflammatory bowel disease, insulin-dependent (type 1) diabetes mellitus IL-12 and Th1 are effective in treating animal models of uveitis and uveitis. Abnormal regulation of cell populations has been linked to many immune-mediated diseases. These studies targeted the shared p40 subunit and therefore the role of IL-12 and IL-23. Both were neutralized in vivo. Therefore, it is possible that IL-12 or IL-23 mediates the disease. whether this was mediated by the cytokines, or whether both cytokines could be inhibited to achieve disease suppression. It is unclear whether IL-23 blockade is necessary. Studies have shown that IL-23 blockade is as effective as anti-IL-12p40 strategies. and the like. This study confirmed the specific role of IL-23 in immune-mediated diseases. There is increasing evidence that neutralizing IL-23 without inhibiting the IL-12 pathway provides effective therapy for immune-mediated diseases that have limited impact on important host defense immune mechanisms. This would represent a significant improvement over current treatment options.

[0006] Psoriasis is a common condition that can affect people with psoriatic arthritis (PsA), depression, and other conditions. Significant comorbidities such as diabetes, cardiovascular disease, hypertension, obesity, diabetes, metabolic syndrome, and Crohn's disease Psoriasis is a common chronic immune-mediated skin disease associated with psoriasis vulgaris, the most common form of the disease. The lesions are erythematous, sharply demarcated, and covered with silvery white scales. It is painful, often disfiguring and disabling, and a significant proportion of psoriasis patients develop hand / nail damage. Psoriasis can affect the health-related quality of life (HR). It adversely affects quality of life (QoL) to a significant extent and interferes with daily activities beyond the physical skin symptoms. For example, psoriasis can impose physical and psychosocial burdens on families, spouses, It has a negative impact on social and work relationships and is associated with higher rates of depression and increased suicidal tendencies. It is being used.

[0007] Psoriatic arthritis (PsA) can present with a variety of symptoms, including 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 The increased use of biologics (e.g., tumor necrosis factor [TNF]) has a significant economic burden. -necrosis-factor][TNF]α inhibitors, ustekinumab, secukinumab Despite the use of other drugs (e.g., apremilast), heterogeneous disease components Novel PsA therapies that can provide high levels of efficacy and safety in treating PsA There is a significant unmet need for

[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. Although the epidemiology of psoriasis is not well defined, genetic and protein analyses have demonstrated that IL-1 IL-12, IL-23, and their downstream molecules are overexpressed in psoriatic lesions, and some Several therapies used to treat psoriasis have been shown to be associated with the severity of the disease. They regulate the levels of IL-12 and IL-23, which are suspected to contribute to their efficacy. Th1 and Th17 cells are involved in the production of vasodilators, chemoattractants, and adhesion to endothelial cells. They may produce effector cytokines that induce the expression of molecules, which in turn induce the expression of monocytes. and neutrophil recruitment, T cell infiltration, angiogenesis, and keratinocyte activation and hyperplasia. Activated keratinocytes promote neutrophil, monocyte, T cell, and dendritic cell trafficking. They are able to produce chemoattractant factors that inhibit inflammation and keratinocyte hyperproliferation. A reproductive cycle 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) inhibits the p19 IL-2 binds to the subunit and is required for terminal differentiation of T helper (Th) 17 cells A fully human IgG1 lambda monoclonal antibody that inhibits intracellular and downstream signaling of 3 IL-12 / 23 or downstream IL-17 or IL-17R (e.g., Targeted biologics (e.g., quinumab, secukinumab, ixekizumab, and brodalumab) are It has consistently demonstrated robust efficacy in Phase 2 / 3 psoriasis / PsA trials. Summary of the Invention [Means for solving the problem]

[0010] In a first aspect, the present invention provides an anti-IL-23 specific antibody (also referred to as an IL-23p19 antibody). a method for treating psoriatic arthritis in a patient, the method comprising administering guselkumab subcutaneously to the patient, Regarding the treatment method, the anti-IL-23 specific antibody is administered at the first dose, 4 weeks thereafter, and 8 weeks thereafter. The doses are administered at intervals of 0, 4, 8, 16, 24, 32, 40, and It is administered at 48 weeks.

[0011] In another embodiment, the compositions used in the methods of the present invention comprise a concentration of from about 1.0 μg / mL to about 1000 PHARMACEUTICAL COMPOSITIONS COMPRISING AN ANTI-IL-23 SPECIFIC ANTI-IL-23 ANTIBODY IN AN AMOUNT OF 50 mg / mL, PARTICULARLY 50 mg OR 100 mg In a preferred embodiment, the anti-IL-23 specific antibody is present in an amount of 100 ml of the pharmaceutical composition. g / mL guselkumab, 7.9% (w / v) sucrose, 4.0 mM histidine , 6.9 mM L-histidine monohydrochloride monohydrate, and 0.053% (w / v) Polysol The diluent is water at standard conditions.

[0012] In one embodiment of the methods of the invention, PsA patients are at least 18 years of age and have a mean age of 18 years or older, and at least 18 years of age. Significant improvement in ACR20 response to guselkumab (58% vs. 18.4%) achieved consistently higher ACR50 and ACR10 responses over time through 24 weeks. Achieved 70 responses.

[0013] In another aspect of the invention, the pharmaceutical composition comprises: (i) a compound selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 20, and SEQ ID NO: (ii) the heavy chain CDR amino acid sequence of SEQ ID NO:50, SEQ ID NO:56, and SEQ ID NO: and the light chain CDR amino acid sequence of No. 73. The pharmaceutical composition contained 100 mg / mL of an anti-IL23 specific antibody and 7.9% (w / v) of sucrose. cellulose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, It contains 0.053% (w / v) polysorbate 80, and the diluent is water at normal conditions.

[0014] Another aspect of the method of the present invention includes administering a pharmaceutical composition, the pharmaceutical composition comprising SEQ ID NO: The guselkumab heavy chain variable region amino acid sequence of SEQ ID NO: 106 and the guselkumab light chain variable region amino acid sequence of SEQ ID NO: 116 and a 100 mg / mL concentration of an isolated pharmaceutical composition having an antibody having a chain variable region amino acid sequence. IL-23 specific antibody, 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate and 0.053% (w / v) polysorbate The diluent is water at normal conditions. [Brief explanation of the drawings]

[0015] [Figure 1] A schematic overview of the trial study is shown. Note that one patient who completed 44 weeks of treatment with study drug was lost to follow-up and did not attend the 56-week follow-up visit. [Figure 2A] Proportions of patients achieving ACR20 (2A), ACR50 (2B), ACR70 (2C), and Minimal Disease Activity (MDA) (2D) responses over time are shown in the modified intention-to-treat (mITT / FAS) population using NRI for treatment failure, early withdrawal, and missing data. P values ​​are from the CMH study. P values ​​for ACR50 (except week 24), ACR70, and MDA at week 16 were calculated post hoc. ACR20 / 50 / 70 - American College of Rheumatology 20 / 50 / 70% improvement = proportion of patients with at least 20%, 50%, and 70% improvement in signs or symptoms of psoriatic arthritis according to ACR criteria, CMH - Cochran-Mantel-Haenszel, MDA - minimal disease activity, FAS - full analyses set, mITT - modified intention to treat. [Figure 2B]Proportions of patients achieving ACR20 (2A), ACR50 (2B), ACR70 (2C), and Minimal Disease Activity (MDA) (2D) responses over time are shown in the modified intention-to-treat (mITT / FAS) population using NRI for treatment failure, early withdrawal, and missing data. P values ​​are from the CMH study. P values ​​for ACR50 (except week 24), ACR70, and MDA at week 16 were calculated post hoc. ACR20 / 50 / 70 - American College of Rheumatology 20 / 50 / 70% improvement = proportion of patients with at least 20%, 50%, and 70% improvement in signs or symptoms of psoriatic arthritis according to ACR criteria, CMH - Cochran-Mantel-Haenszel, MDA - minimal disease activity, FAS - full analyses set, mITT - modified intention to treat. [Figure 2C] Proportions of patients achieving ACR20 (2A), ACR50 (2B), ACR70 (2C), and Minimal Disease Activity (MDA) (2D) responses over time are shown in the modified intention-to-treat (mITT / FAS) population using NRI for treatment failure, early withdrawal, and missing data. P values ​​are from the CMH study. P values ​​for ACR50 (except week 24), ACR70, and MDA at week 16 were calculated post hoc. ACR20 / 50 / 70 - American College of Rheumatology 20 / 50 / 70% improvement = proportion of patients with at least 20%, 50%, and 70% improvement in signs or symptoms of psoriatic arthritis according to ACR criteria, CMH - Cochran-Mantel-Haenszel, MDA - minimal disease activity, FAS - full analyses set, mITT - modified intention to treat. [Figure 2D]Proportions of patients achieving ACR20 (2A), ACR50 (2B), ACR70 (2C), and Minimal Disease Activity (MDA) (2D) responses over time are shown in the modified intention-to-treat (mITT / FAS) population using NRI for treatment failure, early withdrawal, and missing data. P values ​​are from the CMH study. P values ​​for ACR50 (except week 24), ACR70, and MDA at week 16 were calculated post hoc. ACR20 / 50 / 70 - American College of Rheumatology 20 / 50 / 70% improvement = proportion of patients with at least 20%, 50%, and 70% improvement in signs or symptoms of psoriatic arthritis according to ACR criteria, CMH - Cochran-Mantel-Haenszel, MDA - minimal disease activity, FAS - full analyses set, mITT - modified intention to treat. [Figure 3A]The proportions of patients achieving MDA (3A) and VLDA (3B) at weeks 16 and 24 (full analysis set; NRI) and the proportion of patients achieving active disease status, as well as the mean changes from baseline at weeks 16 and 24 for the PsA-specific composite endpoints of PASDAS (3C, 3D), GRACE (3E, 3F), mCPDAI (3G, 3H), and DAPSA (3I, 3J) (full analysis set; missing data carried forward). DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAppa) Composite score, mCPDAI = modified Composite Psoriatic Disease Activity Index, MDA = minimal disease activity, NRI = nonresponder imputation, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 3B]The proportions of patients achieving MDA (3A) and VLDA (3B) at weeks 16 and 24 (full analysis set; NRI) and the proportion of patients achieving active disease status, as well as the mean changes from baseline at weeks 16 and 24 for the PsA-specific composite endpoints of PASDAS (3C, 3D), GRACE (3E, 3F), mCPDAI (3G, 3H), and DAPSA (3I, 3J) (full analysis set; missing data carried forward). DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAppa) Composite score, mCPDAI = modified Composite Psoriatic Disease Activity Index, MDA = minimal disease activity, NRI = nonresponder imputation, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 3C]The proportions of patients achieving MDA (3A) and VLDA (3B) at weeks 16 and 24 (full analysis set; NRI) and the proportion of patients achieving active disease status, as well as the mean changes from baseline at weeks 16 and 24 for the PsA-specific composite endpoints of PASDAS (3C, 3D), GRACE (3E, 3F), mCPDAI (3G, 3H), and DAPSA (3I, 3J) (full analysis set; missing data carried forward). DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAppa) Composite score, mCPDAI = modified Composite Psoriatic Disease Activity Index, MDA = minimal disease activity, NRI = nonresponder imputation, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 3D]The proportions of patients achieving MDA (3A) and VLDA (3B) at weeks 16 and 24 (full analysis set; NRI) and the proportion of patients achieving active disease status, as well as the mean changes from baseline at weeks 16 and 24 for the PsA-specific composite endpoints of PASDAS (3C, 3D), GRACE (3E, 3F), mCPDAI (3G, 3H), and DAPSA (3I, 3J) (full analysis set; missing data carried forward). DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAppa) Composite score, mCPDAI = modified Composite Psoriatic Disease Activity Index, MDA = minimal disease activity, NRI = nonresponder imputation, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 3E]The proportions of patients achieving MDA (3A) and VLDA (3B) at weeks 16 and 24 (full analysis set; NRI) and the proportion of patients achieving active disease status, as well as the mean changes from baseline at weeks 16 and 24 for the PsA-specific composite endpoints of PASDAS (3C, 3D), GRACE (3E, 3F), mCPDAI (3G, 3H), and DAPSA (3I, 3J) (full analysis set; missing data carried forward). DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAppa) Composite score, mCPDAI = modified Composite Psoriatic Disease Activity Index, MDA = minimal disease activity, NRI = nonresponder imputation, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 3F]The proportions of patients achieving MDA (3A) and VLDA (3B) at weeks 16 and 24 (full analysis set; NRI) and the proportion of patients achieving active disease status, as well as the mean changes from baseline at weeks 16 and 24 for the PsA-specific composite endpoints of PASDAS (3C, 3D), GRACE (3E, 3F), mCPDAI (3G, 3H), and DAPSA (3I, 3J) (full analysis set; missing data carried forward). DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAppa) Composite score, mCPDAI = modified Composite Psoriatic Disease Activity Index, MDA = minimal disease activity, NRI = nonresponder imputation, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 3G]The proportions of patients achieving MDA (3A) and VLDA (3B) at weeks 16 and 24 (full analysis set; NRI) and the proportion of patients achieving active disease status, as well as the mean changes from baseline at weeks 16 and 24 for the PsA-specific composite endpoints of PASDAS (3C, 3D), GRACE (3E, 3F), mCPDAI (3G, 3H), and DAPSA (3I, 3J) (full analysis set; missing data carried forward). DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAppa) Composite score, mCPDAI = modified Composite Psoriatic Disease Activity Index, MDA = minimal disease activity, NRI = nonresponder imputation, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 3H]The proportions of patients achieving MDA (3A) and VLDA (3B) at weeks 16 and 24 (full analysis set; NRI) and the proportion of patients achieving active disease status, as well as the mean changes from baseline at weeks 16 and 24 for the PsA-specific composite endpoints of PASDAS (3C, 3D), GRACE (3E, 3F), mCPDAI (3G, 3H), and DAPSA (3I, 3J) (full analysis set; missing data carried forward). DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAppa) Composite score, mCPDAI = modified Composite Psoriatic Disease Activity Index, MDA = minimal disease activity, NRI = nonresponder imputation, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 3I]The proportions of patients achieving MDA (3A) and VLDA (3B) at weeks 16 and 24 (full analysis set; NRI) and the proportion of patients achieving active disease status, as well as the mean changes from baseline at weeks 16 and 24 for the PsA-specific composite endpoints of PASDAS (3C, 3D), GRACE (3E, 3F), mCPDAI (3G, 3H), and DAPSA (3I, 3J) (full analysis set; missing data carried forward). DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAppa) Composite score, mCPDAI = modified Composite Psoriatic Disease Activity Index, MDA = minimal disease activity, NRI = nonresponder imputation, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 3J]The proportions of patients achieving MDA (3A) and VLDA (3B) at weeks 16 and 24 (full analysis set; NRI) and the proportion of patients achieving active disease status, as well as the mean changes from baseline at weeks 16 and 24 for the PsA-specific composite endpoints of PASDAS (3C, 3D), GRACE (3E, 3F), mCPDAI (3G, 3H), and DAPSA (3I, 3J) (full analysis set; missing data carried forward). DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAppa) Composite score, mCPDAI = modified Composite Psoriatic Disease Activity Index, MDA = minimal disease activity, NRI = nonresponder imputation, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 4A]Mean changes from baseline at week 24 in SF-36 PCS scores by disease activity according to the PsA-specific composite endpoints of PASDAS (4A), GRACE (4B), mCPDAI (4C), and DAPSA (4D) (guselkumab-treated patients in the full analysis set; missing data were last observed and carried forward) are shown. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, PASDAS = Psoriatic Arthritis Disease Activity Score, PCS = physical component summary, PsA = psoriatic arthritis, SF-36 = 36-item Short Form Health Survey. [Figure 4B] Mean changes from baseline at week 24 in SF-36 PCS scores by disease activity according to the PsA-specific composite endpoints of PASDAS (4A), GRACE (4B), mCPDAI (4C), and DAPSA (4D) (guselkumab-treated patients in the full analysis set; missing data were last observed and carried forward) are shown. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, PASDAS = Psoriatic Arthritis Disease Activity Score, PCS = physical component summary, PsA = psoriatic arthritis, SF-36 = 36-item Short Form Health Survey. [Figure 4C]Mean changes from baseline at week 24 in SF-36 PCS scores by disease activity according to the PsA-specific composite endpoints of PASDAS (4A), GRACE (4B), mCPDAI (4C), and DAPSA (4D) (guselkumab-treated patients in the full analysis set; missing data were last observed and carried forward) are shown. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, PASDAS = Psoriatic Arthritis Disease Activity Score, PCS = physical component summary, PsA = psoriatic arthritis, SF-36 = 36-item Short Form Health Survey. [Figure 4D] Mean changes from baseline at week 24 in SF-36 PCS scores by disease activity according to the PsA-specific composite endpoints of PASDAS (4A), GRACE (4B), mCPDAI (4C), and DAPSA (4D) (guselkumab-treated patients in the full analysis set; missing data were last observed and carried forward) are shown. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, PASDAS = Psoriatic Arthritis Disease Activity Score, PCS = physical component summary, PsA = psoriatic arthritis, SF-36 = 36-item Short Form Health Survey. [Figure 5A]The proportion of patients achieving MDA (5A) and VLDA (5B), and the proportion of patients achieving disease activity, as well as the mean change from baseline after 24 weeks for the PsA-specific composite endpoints of PASDAS (5C, 5D), GRACE (5E, 5F), mCPDAI (5G, 5H), and DAPSA (5I, 5J) (efficacy analysis population after 24 weeks; measured data). Measurement data from the same population at 24 weeks are included as a reference. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, MDA = minimal disease activity, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 5B] The proportion of patients achieving MDA (5A) and VLDA (5B), and the proportion of patients achieving disease activity, as well as the mean change from baseline after 24 weeks for the PsA-specific composite endpoints of PASDAS (5C, 5D), GRACE (5E, 5F), mCPDAI (5G, 5H), and DAPSA (5I, 5J) (efficacy analysis population after 24 weeks; measured data). Measurement data from the same population at 24 weeks are included as a reference. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, MDA = minimal disease activity, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 5C]The proportion of patients achieving MDA (5A) and VLDA (5B), and the proportion of patients achieving disease activity, as well as the mean change from baseline after 24 weeks for the PsA-specific composite endpoints of PASDAS (5C, 5D), GRACE (5E, 5F), mCPDAI (5G, 5H), and DAPSA (5I, 5J) (efficacy analysis population after 24 weeks; measured data). Measurement data from the same population at 24 weeks are included as a reference. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, MDA = minimal disease activity, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 5D] The proportion of patients achieving MDA (5A) and VLDA (5B), and the proportion of patients achieving disease activity, as well as the mean change from baseline after 24 weeks for the PsA-specific composite endpoints of PASDAS (5C, 5D), GRACE (5E, 5F), mCPDAI (5G, 5H), and DAPSA (5I, 5J) (efficacy analysis population after 24 weeks; measured data). Measurement data from the same population at 24 weeks are included as a reference. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, MDA = minimal disease activity, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 5E]The proportion of patients achieving MDA (5A) and VLDA (5B), and the proportion of patients achieving disease activity, as well as the mean change from baseline after 24 weeks for the PsA-specific composite endpoints of PASDAS (5C, 5D), GRACE (5E, 5F), mCPDAI (5G, 5H), and DAPSA (5I, 5J) (efficacy analysis population after 24 weeks; measured data). Measurement data from the same population at 24 weeks are included as a reference. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, MDA = minimal disease activity, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 5F] The proportion of patients achieving MDA (5A) and VLDA (5B), and the proportion of patients achieving disease activity, as well as the mean change from baseline after 24 weeks for the PsA-specific composite endpoints of PASDAS (5C, 5D), GRACE (5E, 5F), mCPDAI (5G, 5H), and DAPSA (5I, 5J) (efficacy analysis population after 24 weeks; measured data). Measurement data from the same population at 24 weeks are included as a reference. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, MDA = minimal disease activity, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 5G]The proportion of patients achieving MDA (5A) and VLDA (5B), and the proportion of patients achieving disease activity, as well as the mean change from baseline after 24 weeks for the PsA-specific composite endpoints of PASDAS (5C, 5D), GRACE (5E, 5F), mCPDAI (5G, 5H), and DAPSA (5I, 5J) (efficacy analysis population after 24 weeks; measured data). Measurement data from the same population at 24 weeks are included as a reference. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, MDA = minimal disease activity, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 5H] The proportion of patients achieving MDA (5A) and VLDA (5B), and the proportion of patients achieving disease activity, as well as the mean change from baseline after 24 weeks for the PsA-specific composite endpoints of PASDAS (5C, 5D), GRACE (5E, 5F), mCPDAI (5G, 5H), and DAPSA (5I, 5J) (efficacy analysis population after 24 weeks; measured data). Measurement data from the same population at 24 weeks are included as a reference. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, MDA = minimal disease activity, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 5I]The proportion of patients achieving MDA (5A) and VLDA (5B), and the proportion of patients achieving disease activity, as well as the mean change from baseline after 24 weeks for the PsA-specific composite endpoints of PASDAS (5C, 5D), GRACE (5E, 5F), mCPDAI (5G, 5H), and DAPSA (5I, 5J) (efficacy analysis population after 24 weeks; measured data). Measurement data from the same population at 24 weeks are included as a reference. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, MDA = minimal disease activity, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 5J] The proportion of patients achieving MDA (5A) and VLDA (5B), and the proportion of patients achieving disease activity, as well as the mean change from baseline after 24 weeks for the PsA-specific composite endpoints of PASDAS (5C, 5D), GRACE (5E, 5F), mCPDAI (5G, 5H), and DAPSA (5I, 5J) (efficacy analysis population after 24 weeks; measured data). Measurement data from the same population at 24 weeks are included as a reference. DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, MDA = minimal disease activity, PASDAS-Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis, VLDA = very low disease activity. [Figure 6A]Comparative statistics assessing guselkumab treatment effect detected at week 24 by the PsA-specific composite endpoints of PASDAS, GRACE, mCPDAI, and DAPSA: standardized mean difference (6A), effect size (6B), and standardized response mean (6C) (full analysis set; last observation carried forward for missing data) are shown. CI = confidence interval, DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, PASDAS = Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis. [Figure 6B] Comparative statistics assessing guselkumab treatment effect detected at week 24 by the PsA-specific composite endpoints of PASDAS, GRACE, mCPDAI, and DAPSA: standardized mean difference (6A), effect size (6B), and standardized response mean (6C) (full analysis set; last observation carried forward for missing data) are shown. CI = confidence interval, DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, PASDAS = Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis. [Figure 6C] Comparative statistics assessing guselkumab treatment effect detected at week 24 by the PsA-specific composite endpoints of PASDAS, GRACE, mCPDAI, and DAPSA: standardized mean difference (6A), effect size (6B), and standardized response mean (6C) (full analysis set; last observation carried forward for missing data) are shown. CI = confidence interval, DAPSA = Disease Activity Index for Psoriatic Arthritis, GRACE = Group for Research and Evaluation of Psoriasis and Psoriatic Arthritis (GRAppa) composite score, mCPDAI = modified composite Psoriasis Disease Activity Index, PASDAS = Psoriatic Arthritis Disease Activity Score, PsA = psoriatic arthritis. [Figure 7A]The percentage of patients whose dactylitis resolved over time is shown. [Figure 7B] The percentage of patients whose dactylitis resolved over time is shown. DETAILED DESCRIPTION OF THE INVENTION

[0016] As used herein, methods of treating psoriasis include the use of isolated, recombinant, and / or synthetic anti-psoriasis antibodies. L-23-specific human antibodies and diagnostic and therapeutic compositions, methods, and devices for administration .

[0017] 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. at least one IL-23 activity or binding, or IL-23 receptor activity or binding , modulate, reduce, increase, antagonize, promote, mitigate, alleviate, block, inhibit, neutralize and / or interfere By way of non-limiting example, suitable anti-IL-23 antibodies, specified portions or variants of the present invention include: , at least one IL-23 molecule or a specified portion, variant, or domain thereof. Suitable anti-IL-23 antibodies, specific portions, or variants may also be any Selectively, RNA, DNA, or protein synthesis, IL-23 release, IL-23 receptor stimulatory activity, signaling, membrane IL-23 cleavage, IL-23 activity, IL-23 production and / or synthesis, etc. and also affect at least one IL-23 activity or function, including, but not limited to, It can be used.

[0018] The term "antibody" is further intended to encompass antibodies, fragments, specified portions, and variants thereof. This includes antibody mimetics, or compounds that mimic the structure and / or function of antibodies. It includes a portion of an antibody or a specific fragment or part thereof, and includes single chain antibodies and fragments thereof. The functional fragments include antigen-binding fragments that bind to mammalian IL-23. For example, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial by chemical reduction), and F(ab')2 (e.g., by pepsin digestion), facb (e.g., pFc' (e.g., by pepsin or plasmin digestion) , Fd (e.g., by pepsin digestion, partial reduction, and reassembly), Fv or scFv ( For example, fragments thereof (obtained by molecular biology techniques) include, but are not limited to, IL-2 Antibody fragments capable of binding to 3 or portions thereof are encompassed by the present invention (see, e.g., Collins et al., supra). (See igan, Immunology).

[0019] Such fragments may be any fragment known in the art and / or as described herein. Antibodies can also be produced by enzymatic cleavage, synthetic or recombinant techniques, such as those described above. Using an antibody gene in which a stop codon of the formula (I) has been introduced upstream of the natural stop site, various truncations were For example, the combination of genes encoding the F(ab')2 heavy chain moiety can be , C for heavy chain H Designed to contain DNA sequences encoding the 1 domain and / or hinge region The various portions of the antibody can be conjugated chemically or genetically by conventional techniques. Engineered as a contiguous protein can.

[0020] 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-human in nature with only minor sequence changes or mutations. A "human antibody" also refers to an antibody that is derived from human germline immunoglobulin sequences. Human antibodies may be derived from or closely matched to germline immunoglobulins. Amino acid residues not encoded in the gene sequence (e.g., in vitro random or by site-directed mutagenesis or by somatic mutation in vivo In many cases, this is because a human antibody may contain mutations that are similar to those found in humans. Human antibodies are antibodies that are substantially non-immunogenic due to the similarity of their amino acid sequences. Therefore, sequence similarity searches can be used to identify similar An antibody having the linear sequence of can be selected as a template for generating a human antibody. Similarly, primates (monkeys, baboons, chimpanzees, etc.), rodents (mice, rats, rabbits, Antibodies directed against mammals (guinea pigs, hamsters, etc.) and other mammals are not intended to be used for purposes of identifying such species, subgenus, genus, Subfamily and family specific antibodies are also shown. Additionally, chimeric antibodies include any combination of the above. Such changes or mutations are optionally, and preferably, alterations or mutations that are more specific than the unmodified antibody. , retaining or reducing immunogenicity in humans or other species. are distinct from chimeric or humanized antibodies.

[0021] Human antibodies are functionally rearranged human immunoglobulins (e.g., heavy and / or light chains). ) produced by a non-human animal or prokaryotic or eukaryotic cell capable of expressing the gene Furthermore, when a human antibody is a single-chain antibody, it is possible to obtain a fragment that is not found in natural human antibodies. For example, an Fv may comprise a heavy chain variable region and a light chain variable region. A linker peptide, such as 2 to about 8 glycine or other amino acid residues, that connects the domains Such linker peptides are considered to be of human origin.

[0022] Also, monoclonal antibodies having binding specificities for at least two different antigens are preferred. or human or humanized antibodies, bispecific, heterospecific, heterobinding, or similar antibodies. In this case, one of the binding specificities is a specific antibody to at least one IL-23 tag. One is directed against a protein and the other against any other antigen. Methods for producing bispecific antibodies are known in the art. The synthesis is based on the co-expression of two immunoglobulin heavy-light chain pairs, where the two heavy chains are different. (Milstein and Cuello, Nature, 305: 537 (1983)). Due to the random assortment of immunoglobulin heavy and light chains, These hybridomas (quadromas) produce a possible mixture of 10 different antibody molecules. Only one of these has the correct bispecific structure. Purification of the correct molecule (usually The affinity chromatography step is quite laborious and the yield of the product is low. Similar procedures are described, for example, in WO 93 / 08829, U.S. Pat. No. 10,668, No. 6,193,967, No. 6,132,992, No. 6,10 No. 6,833, No. 6,060,285, No. 6,037,453, No. 6,010 , No. 902, No. 5,989,530, No. 5,959,084, No. 5,959, No. 083, No. 5,932,448, No. 5,833,985, No. 5,821,3 No. 33, No. 5,807,706, No. 5,643,759, No. 5,601,81 No. 9, No. 5,582,996, No. 5,496,549, No. 4,676,980 No. 91 / 00360, WO 92 / 00373, European Patent No. 030 No. 89, Traunecker et al., EMBO J.10:3655(199 1), Suresh et al.,Methods in Enzymology 1 21:210 (1986), each of which is incorporated herein by reference in its entirety. be incorporated into the book.

[0023] 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 and / or collectively, the antibodies of the present invention, optionally and preferably having low immunogenicity. , and specified fragments or variants thereof are useful in the present invention. The antibody can optionally provide measurable relief of symptoms and low and / or tolerable Characterized by the ability to treat patients for long periods with low or well-tolerated toxicity. The immunogenicity and / or high affinity of the compound, 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 entire recommended course of therapy, 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 titer levels of antibodies to -23 antibodies.

[0024] 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 2 clinical trials, and previous clinical trials, For example, the anti-IL-23 antibody of the present invention (e.g., For example, the anti-IL-23 antibody guselkumab) is a marker for at least one marker that reflects the severity of the disorder being treated. Amount and duration sufficient to cause improvement, preferably sustained improvement, in at least one indicator The amount and duration of the treatment is determined to be sufficient. To assess the severity of a disease, disorder, or condition, various indicators can be evaluated. Suitable indicators include, for example, clinically relevant information about disease severity, symptoms, or manifestations of the disorder of interest. The degree of improvement is assessed overall by the physician, who then The determination of the presence or absence of a disease can be based on signs, symptoms, biopsy, or other test results, and can be made based on the subject's questionnaires administered to patients, such as quality of life questionnaires developed for a given disease. For example, the anti-IL-23 antibody of the present invention can be used to treat psoriatic arthritis. The therapeutic agent may be administered to achieve an improvement in the patient's condition, which improvement may be measured by a disease activity index. This can be demonstrated by improvement in symptoms, remission of clinical symptoms, or any other measure of disease activity. One indicator of such disease is the ACR 20% response criterion (ACR20). Psoriasis Area and Severity Index The Patients with Skin Illness Index (PASI) is a disease assessment tool used to assess the severity / extent of skin disease. For example, PASI75 = 75% improvement, PASI90 = 90% improvement, and and PASI 100 = lesions virtually eliminated. Efficacy measures were also included: HAQ-DI, Improvement of enthesitis / dactylitis in patients with baseline enthesitis / dactylitis, SF-36 mental component summary Changes in (MCS) and physical component summary (PCS) scores, and minimal disease It may also include achieving a medical activity (MDA) criteria score.

[0025] 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 it comes to the dose, administration regimen, treatment or method using guselkumab, or compared to another comparator, e.g., a clinical trial being conducted, e.g., a phase 2 clinical trial; and treatment-emergent adverse events from previous clinical trials. (AE) or treatment-emergent adverse events ( Relatively low or reduced frequency and / or low or low incidence of TEAEs (also referred to as TEAEs) An adverse event is an untoward medical event in a patient receiving a drug. In particular, the dose, administration regimen, or treatment with the anti-IL-23 antibodies of the present invention is a therapeutic event. When related to therapies, clinically proven safety means that the cause is due to the use of anti-IL-23 antibodies. Possible, likely, or very likely adverse events associated with antibody administration Lower or reduced frequency and / or lower or reduced severity of adverse events Refers to the degree.

[0026] As used herein, unless otherwise specified, the term "clinically proven" (independently or to modify the terms "safe" and / or "effective") are used in clinical trials. Clinical trials are approved by the US Food and Drug Administration, EMEA, or corresponding national authorities. It means that the drug meets the regulatory approval criteria. In an adequately sized randomized double-blind study used to clinically prove the effectiveness of the agent It's okay to have it.

[0027] usefulness The isolated nucleic acids of the present invention comprise at least one anti-IL-23 antibody or specific variant thereof. can be used to diagnose, monitor, regulate, treat, alleviate, or improve the symptoms of psoriasis. To help prevent or reduce the incidence of such diseases, cells, tissues, organs or animals (mammals and The present invention can be used to measure or act on organisms, including animals and humans.

[0028] Such methods include those for modulating, treating, alleviating, preventing, or reducing symptoms, effects, or mechanisms. The present invention relates to a method for treating a cell, tissue, organ, animal, or patient in need thereof, comprising administering at least one anti-IL-23 antibody to the cell, tissue, organ, animal, or patient in need thereof. The effective amount may include administering an effective amount of a composition or pharmaceutical composition containing the compound. When performed and determined using known methods, as described in the literature or as known in the relevant art. , about 0.001 to 500 ml per single (e.g., bolus), multiple, or continuous administration g / kg or serum concentrations of 0.01 to 500 g / kg per single, multiple, or continuous administration 0 μg / mL, or any effective range or value therein. good.

[0029] References All publications or patents cited herein, whether specifically named or not, are incorporated by reference in their entirety. , which is incorporated herein by reference in its entirety and represents the state of the art at the time of the present invention; and The publication may be any scientific publication or patent application, or may be a publication that provides a description and / or enables the use of the invention. Available in any media format, including patent publications, or any recorded electronic or printed form The following documents are incorporated herein by reference in their entirety: :Ausubel,et al.,ed.,Current Protocols in Molecular Biology,John Wiley&Sons,Inc., NY, NY (1987-2001), Sambrook, et al., Molecule ar Cloning:A Laboratory Manual,2nd Editi on, Cold Spring Harbor, NY (1989), Harlow an d Lane,antibodies,a Laboratory Manual,Co ld Spring Harbor, NY (1989), Colligan, et al. .,eds.,Current Protocols in Immunology,J ohn Wiley&Sons, Inc., NY (1994-2001), Collig an et al.,Current Protocols in Protein S science,John Wiley&Sons,NY,NY,(1997-2001) .

[0030] Antibodies of the invention - production and manufacture 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.

[0031] A preferred anti-IL-23 antibody has the heavy chain variable region amino acid sequence of SEQ ID NO: 106 and the heavy chain variable region amino acid sequence of SEQ ID NO: and a light chain variable region amino acid sequence of SEQ ID NO: 5, SEQ ID NO: 20, and SEQ ID NO: 116. The heavy chain CDR amino acid sequence of SEQ ID NO: 44 and SEQ ID NO: 50, SEQ ID NO: 56, and SEQ ID NO: 7 Guselkumab (also referred to as CNTO1959) having the light chain CDR amino acid sequence of Other anti-IL-23 antibodies have the sequences listed herein, the entire contents of which are incorporated by reference. No. 7,935,344, which is incorporated herein by reference.

[0032] 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 may be carried out using any suitable technique. It is possible.

[0033] 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, MLA144, ACT IV, MOLT4, DA-1, JURKAT, WE HI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA144, N Myeloma cell lines such as AMALWA and NEURO 2A, or heteromyelomas, or fusions thereof the product, or any cell or fusion cell derived therefrom, or any other cell or fusion cell known in the art. any other suitable cell line of the Atcc Group (see, for example, www.atcc.org, www.lifet ech.com), including, but not limited to, isolated or cloned antibody-producing tissues such as the spleen, peripheral blood, lymph, tonsils, or other immune or B-cell-containing cells Viable cells, or endogenous or heterologous nucleic acids, recombinant or endogenous, viral, bacterial, Algae, prokaryotes, amphibians, insects, reptiles, fish, mammals, rodents, horses, sheep, goats, and hoofs Azalea, primates, eukaryotes, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single, Either as duplex or triplex, hybridized, etc., or any combination thereof. Either the heavy or light chain constant or variable, or framework or CDR sequences are generated. Hybridomas are produced by fusing the cells with any other cells that express the same. See Ausubel and Colligan, Immunology chapter 2 No. 6,239,999, filed on Oct. 1, 2003, which is incorporated herein by reference in its entirety.

[0034] Antibody-producing cells can also be isolated from the peripheral blood of humans or other suitable animals immunized with an antigen of interest, or The cells may also be obtained preferably from the spleen or lymph nodes. Cells may also be used to express heterologous or endogenous antibodies encoding the antibodies, specified fragments, or variants thereof of the present invention. Hybridomas or recombinant cells can be used to express nucleic acids of isolated using selective culture conditions or other suitable known methods, and isolated by limiting dilution or cell culture. Antibodies with the desired specificity can be cloned by cell sorting or other known methods. The cells that give rise to the lysosome can be selected by a suitable assay (e.g., ELISA). do.

[0035] Selecting recombinant antibodies from a peptide or protein library (for example, but not limited to, Dissolving bacteriophages, ribosomes, oligonucleotides, RNA, cDNA, etc. Play libraries, e.g., Cambridge Antibody Technology gies (Cambridgeshire, UK), MorphoSys (Martin sreid / Planegg,DE), Biovation(Aberdeen,Sco tland, UK), BioInvent (Lund, Sweden), Dyax Co. rp., Enzon, Affymax / Biosite, Xoma(Berkeley, CA), available from Ixsys, e.g., European Patent No. 368,684, International Patent No. Application No. PCT / GB91 / 01134, International Application No. PCT / GB92 / 01755, International Application No. PCT / GB92 / 002240, International Application No. PCT / GB92 / 00883, International Application No. PCT / GB93 / 00605, U.S. Patent Application No. 08 / 350260 (5 / 12 / 94), International Application No. PCT / GB94 / 01422, International Application No. PCT / GB94 / 02 662, International Application No. PCT / GB97 / 01835, (CAT / MRC), International Publication No. 90 / 14443;WO 90 / 14424;WO 90 / 14430; International Application No. PCT / US94 / 1234, International Publication No. 92 / 18619, International Publication No. 6 / 07754, (Scripps), WO 96 / 13583, WO 9 7 / 08320 (MorphoSys), WO 95 / 16027 (BioIn vent), WO 88 / 06630, WO 90 / 3809 (Dyax) , U.S. Patent No. 4,704,692 (Enzon), International Application PCT / US91 / 029 No. 89 (Affymax), International Publication No. 89 / 06283, European Patent No. 371998 , European Patent No. 550400, (Xoma), European Patent No. 229046, International Application PC T / US91 / 07149 (Ixsys), or stochastically generated peptides or Proteins - U.S. Patent Nos. 5,723,323, 5,763,192, and 581,447 No. 6, No. 5817483, No. 5824514, No. 5976862, International Publication 86 / 05803, European Patent No. 590689 (Ixsys, Applied Mo The predecessors of the American Neurological Evolution (AME), each of which is incorporated herein by reference in its entirety. incorporated herein) or known in the art and / or described herein. Transgenic animals capable of producing a repertoire of human antibodies are described. Dependent on immunization (e.g., SCID mice, Nguyen et al., Micro biol.Immunol.41:901-907(1997), Sandhu et al. al., Crit. Rev. Biotechnol. 16:95-118 (1996), Eren et al., Immunol. 93:154-161 (1998) (each , which are incorporated by reference in their entireties, and related patents and applications, including, but not limited to, methods Using any other suitable method to generate or isolate antibodies of the required specificity, including but not limited to: Such techniques include ribosome display (Hanes et al., Pr oc.Natl.Acad.Sci.USA,94:4937-4942(May 19 97);Hanes et al.,Proc.Natl.Acad.Sci.USA, 95:14130-14135 (Nov. 1998)), single-cell antibody generation technology (e.g. , Selected Lymphocyte Antibody Method ("SLAM") (U.S. Patent No. 5,627,052, Wen et al.,J.Immunol.17:887-892(1987);Babcoo k et al.,Proc.Natl.Acad.Sci.USA 93:7843- 7848 (1996)), gel microdroplets et), and flow cytometry (Powell et al., Biotechno l.8:333-337(1990);One Cell Systems(Cambr idge,MA);Gray et al.,J.Imm.Meth.182:155- 163(1995);Kenny et al.,Bio / Technol.13:78 7-790(1995)), B cell selectors (Steenbakkers et al., Molec.Biol.Reports 19:125-134(1994);Jona k et al.,Progress Biotech,Vol.5,In Vitro Immunization in Hybridoma Technology,Bo rrebaeck, ed., Elsevier Science Publishers BV, Amsterdam, Netherlands (1988) However, the present invention is not limited to these.

[0036] Methods for engineering or humanizing non-human or human antibodies can also be used, and Generally, humanized or engineered antibodies are antibodies that are derived from non-human, For example, but not limited to, mice, rats, rabbits, non-human primates, or other mammals. These non-human amino acid residues are often These residues are called "import" residues and are typically "import" variable, constant residues of known human sequences. , or replaced by residues taken from other domains.

[0037] Known human Ig sequences are disclosed, for example, at www.ncbi.nlm.nih.gov / Ig / . gov / entrez / query.fcgi, www.ncbi.nih.gov / i gblast, www.atcc.org / phage / hdb.html, www.m rc-cpe.cam.ac.uk / ALIGNMENTS.php、www.kaba tdatabase.com / top.html、ftp.ncbi.nih.gov / repository / kabat、www.sciquest.com / 、www.a bcam.com / 、www.antibodyresource.com / onlin ecomp.html、www.public.iastate.edu / ~pedro / research_tools.html、www.whfreeman.com / i mmunology / CH05 / kuby05.htm、www.hhmi.org / g rants / lectures / 1996 / vlab / 、www.path.cam.a c.uk / ~mrc7 / mikeimages.html、mcb.harvard.e du / BioLinks / Immunology.html、www.immunolo gylink.com、pathbox.wustl.edu / ~hcenter / in dex.html、www.appliedbiosystems.com、www.n al.usda.gov / awic / pubs / antibody、www.m.ehi me-u.ac.jp / ~yasuhito / Elisa.html、www.biod esign.com、www.cancerresearchuk.org、www.b iotech.ufl.edu、www.isac-net.org、baserv.u ci.kun.nl / ~jraats / links1.html、www.recab. uni-hd.de / immuno.bme.nwu.edu、www.mrc-cpe .cam.ac.uk、www.ibt.unam.mx / vir / V_mice.ht ml, http: / / www.bioinf.org.uk / abs, antibod y.bath.ac.uk, www.unizh.ch, www.cryst.bbk. ac.uk / ~ubcg07s, www.nimr.mrc.ac.uk / CC / cca ewg / ccaewg.html, www.path.cam.ac.uk / ~mrc7 / humanisation / TAHHP.html, www.ibt.unam.mx / vir / structure / stat_aim.html, www.biosci. missouri.edu / smithgp / index.html, www.jeri ni.de, Kabat et al., Sequences of Proteins of Immunological Interest,USDept.Heal th (1983), each of which is incorporated herein by reference in its entirety.

[0038] Such imported sequences may be used to reduce immunogenicity or to improve the performance of the present invention. As known in the art, binding, affinity, on-rate, off-rate, avidity, specificity, affinity, etc. can be used to reduce, enhance or modify the shelf life or any other suitable property. In general, the CDR residues are directly and most substantially involved in influencing antigen binding. Therefore, the non-human sequences in the variable and constant regions are replaced with human or other amino acids. The CDR sequences may be altered while retaining some or all of the non-human or human CDR sequences.

[0039] Antibodies are optionally humanized or human antibodies, which have high affinity for antigens and To this end, they can be engineered while retaining their biological and other beneficial properties. , optionally humanized (or human) antibodies using three-dimensional models of the parental and humanized sequences. These can be prepared by a process of analysis of the parental sequences and various conceptual humanized products. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Illustrate the likely three-dimensional conformations of selected candidate immunoglobulin sequences. Computer programs are available to display and interpret these displays. and analysis of the likely role of residues in the function of candidate immunoglobulin sequences. , i.e., analysis of residues that affect the ability of a candidate immunoglobulin to bind to its antigen. In this way, desired antibody properties, such as increased affinity for the target antigen(s), can be achieved. From the consensus and import sequences, framework (FR) sequences are generated so that the desired characteristics are achieved. ) residues can be selected and combined.

[0040] 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 this embodiment, the light chain human germline frameworks are V1-11, V1-13, V1-16, V1-17, V1-18, V1-19, V1-20, V1-21, V1-22, V1-23, V1-24, V1-25, V1-26, V1-27, V1-28, V1-29, V1-30, V1-31, V1-32, 1-17, V1-18, V1-19, V1-2, V1-20, V1-22, V1-3, V 1-4, V1-5, V1-7, V1-9, V2-1, V2-11, V2-13, V2-1 4, 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, Selected from V5-2, V5-4, and V5-6.

[0041] 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.

[0042] 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., two or three regions such as FR2 and FR3) In certain embodiments, at least FRL1, FRL2, FRL3 In other embodiments, at least FRH1, FRH2, or FRL4 are fully human. In some embodiments, at least FRL, FRH3, or FRH4 is fully human. FRL1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., human germline). or a human consensus sequence for a particular framework (as described above for known human Ig In another embodiment, the sequence comprises at least FRH1. , FRH2, FRH3, or FRH4 is a germline sequence (e.g., human germline). or a human consensus sequence for a particular framework. In the present invention, the framework regions are fully human framework regions.

[0043] 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 No. 90 / 14443, International Publication No. 90 / 14424, International Publication No. 90 / 14430 , European Patent No. 229246 (each of which is incorporated by reference in its entirety and the references therein). any known method, including but not limited to those described in the literature (including the literature used in This can be done using the method of

[0044] In certain embodiments, the antibody comprises an altered (eg, mutated) Fc region. For example, in some embodiments, the Fc region reduces or inhibits the effector functions of the antibody. In some embodiments, the Fc region is modified to enhance IgM, IgM The isotype is selected from IgA, IgG, IgE, or other isotypes. Alternatively or additionally, amino acid modifications and C1q binding and / or C1q cleavage in the Fc region of the IL-23 binding molecule may be used. or in combination with one or more additional amino acid modifications that alter complement-dependent cytotoxicity function. It may be useful to use a starting polypeptide of particular interest that binds to C1q. and exhibits complement-dependent cytotoxicity (CDC). A polypeptide that has the ability to mediate CDC further comprises one or more of these activities. It may be modified to enhance both C1q and / or its complement dependence. Amino acid modifications that modify the cytotoxicity function are described, for example, in WO 0042072. and incorporated by reference.

[0045] 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 ( antibody-dependent cell-mediated cytotox Altered effector function by altering ADCC activity The Fc region of the human IL-23-specific antibody of the present invention can be designed to have the following structure: An "effector function" refers to a function that activates or reduces a biological activity (e.g., in a subject). Examples of effector functions include, but are not limited to, C1q binding. , CDC, Fc receptor binding, ADCC, phagocytosis, cell surface receptors (e.g., B cell receptor These effector functions include downregulation of the BCR (BCR). When the Fc region is required to bind to a binding domain (e.g., an antibody variable domain), There are many different test methods (e.g., Fc binding assay, ADCC assay, CDC assay) that can be used. This can be assessed using various assays.

[0046] For example, having improved C1q binding and improved FcγRIII binding (e.g., Human IL-23 (also known as IL-23) with both improved ADCC and improved CDC activity Alternatively, we can generate mutant Fc regions of anti-IL-23 antibodies. If it is desired to reduce or eliminate target function, the mutated Fc region may have reduced CDC activity. The gene can be engineered with reduced activity and / or reduced ADCC activity. In the present invention, only one of these activities may be increased, optionally simultaneously with the other activities. may be reduced (e.g., have improved ADCC activity and reduced CDC activity) (To generate Fc region variants, and vice versa).

[0047] Fc mutations alter interactions with neonatal 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).

[0048] 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 refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation can also be achieved using 5-hydroxyproline or 5-hydroxylysine. Although it may be possible to use hydroxyamino acids, sugars attached to hydroxyamino acids, most commonly serine or threonine, , N-acetylgalactosamine, galactose, or xylose. The recognition sequence for enzymatic attachment of the carbohydrate moiety to the asparagine side chain peptide sequence is Asparagine-X-serine and Asparagine-X-threonine, where X is other than proline Therefore, any of these peptide sequences in a polypeptide The presence of provides a potential glycosylation site.

[0049] 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 glycosylation sites that are not present in the polypeptide The Fc region of a human IL-23-specific antibody can be modified by adding cosyl groups. The addition of glycosylation sites to the amino acid sequence can be modified to include one or more of the above tripeptide sequences. This is successfully achieved by modifying 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. The modification may be the addition of one or more serine or threonine residues to the sequence of the native polypeptide; or by substitution (for O-linked glycosylation sites). Changing 297 to Ala can eliminate one of the glycosylation sites.

[0050] 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 9954342 ... Publication No. 03011878, Patent Publication No. 20030003097A1, and Umana e t al.,Nature Biotechnology,17:176-180,Fe b. 1999, all of which are specifically incorporated herein by reference in their entireties. are incorporated into the system.

[0051] 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.

[0052] Transgenic mice capable of generating a repertoire of human antibodies that bind to human antigens The cloning agent can be produced 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. 0463 151(B1) to Kucherlapate et al. European Patent No. 0710 719(A1) to Apate et al., U.S. Patent No. 5 to Surani et al. ,545,807, Bruggemann et al., International Publication No. 90 / 04036, Bru European Patent No. 0438 474(B1) to Ggemann et al., European Patent No. Lonberg et al. No. 0814 259(A2), Lonberg et al., UK Patent No. 2 272 44 No. 0(A), Lonberg et al. Nature 368:856-859(1 994), Taylor et al., Int. Immunol. 6(4)579-5 91(1994), Green et al, Nature Genetics 7:1 3-21 (1994), Mendez et al., Nature Genetics 15:146-156 (1997), Taylor et al., Nucleic Acids Research 20(23):6287-6295(1992), Tu aillon et al., Proc Natl Acad Sci USA 90( 8) 3720-3724 (1993), Lonberg et al., Int Rev. Immunol 13(1):65-93(1995), and Fishwald et al. al., Nat Biotechnol 14(7):845-851(1996), (Each of which is incorporated herein by reference in its entirety.) Generally, these mouse The sequence comprises at least one functionally rearranged or functionally rearrangeable gene. at least one transgene comprising DNA from a human immunoglobulin locus The endogenous immunoglobulin loci of such mice can be disrupted or deleted to produce endogenous genes. The ability of the animal to produce the antibody encoded by the offspring can be eliminated.

[0053] 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 components with novel functions or structures Antibody screening of peptide display libraries is well known in the art. The length of the displayed peptide sequence is 3 to 5,000 or more. Amino acids, frequently 5-100 amino acids long, mostly about 8-25 amino acids long In addition to direct chemical synthesis methods for generating peptide libraries, several synthetic methods are available. Recombinant DNA methods have also been described. One type involves the use of bacteriophages or cells, Each bacteriophage or cell is involved in the display of peptide sequences on its surface. , which contain the nucleotide sequence encoding the particular displayed peptide sequence. Such methods are described in WO 91 / 17271, WO 91 / 18980, WO 91 / 19981, WO 91 / 19982, WO 91 / 19983, WO 91 / 19984, WO 91 / 19985, WO 91 / 19986, WO 91 / 19987, WO 91 / 19989, WO / 19818 and 93 / 08278.

[0054] Other systems for generating libraries of peptides include in vitro chemical synthesis and The present invention relates to both recombinant DNA and recombinant methods. See U.S. Patent Nos. 43 and 96 / 19256. Also, U.S. Patent Nos. 5,658,777, ... See also U.S. Pat. Nos. 5,643,768 and 5,643,768. Peptide Display Libraries , vectors, and screening kits were purchased from Invitrogen (Carlsbad, CA) and Cambridge Antibody Technologies (Cam These are commercially available from sources such as Enzo U.S. Patent Nos. 4,704,692, 4,939,666, and 494,677, assigned to No. 8, No. 5260203, No. 5455030, No. 5518889, No. 55 No. 34621, No. 5656730, No. 5763733, No. 5767260, No. 5856456, No. 5223409 and No. 540348 assigned to Dyax No. 4, No. 5571698, No. 5837500, and No. 5837500 assigned to Affymax. No. 5427908, No. 5580717, Cambridge antibody T No. 5885793, assigned to Genentech, No. 5750373 assigned to Xoma, No. 5618920 assigned to Xoma, No. 559 No. 5898, No. 5576195, No. 5698435, No. 5693493, No. No. 5698417, Colligan (supra), Ausubel (supra), or S (supra). See Ambrook, each of the above patents and publications is incorporated herein by reference in its entirety. be incorporated into the book.

[0055] 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. It can also be prepared using at least one anti-IL-23 antibody encoding the antibody. The animal can be provided using known methods, including but not limited to: However, U.S. Patent Nos. 5,827,690, 5,849,992, and 4,873,3 No. 16, No. 5,849,992, No. 5,994,616, No. 5,565,36 See US Pat. Nos. 5,304,489, et al., each of which is incorporated by reference in its entirety. is incorporated herein).

[0056] 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) and further preparing a method for the treatment of IL-23-positive ... 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. a commercially available protein with biological activity equivalent to that of a protein synthesized or purified from a natural source It has been used to express mammalian proteins at production levels. For example, Hood et al. t al.,Adv.Exp.Med.Biol.464:127-147(1999) and the references cited therein. Antibodies have also been used to identify tobacco seeds and potato tubers. Large amounts of antibodies can also be obtained from transgenic plant seeds containing antibody fragments such as single-chain antibodies (scFv). For example, Conrad et al., Plant Mol. Bi ol.38:101-109 (1998) and the references cited therein. Thus, the antibodies of the present invention can also be produced using transgenic plants according to known methods. For example, Fischer et al., Biotechn ol.Appl.Biochem.30:99-108(Oct.,1999),Ma et al.,Trends Biotechnol.13:522-7(1995), Ma et al., Plant Physiol. 109:341-6 (1995), Whitelam et al.,Biochem.Soc.Trans.22:940 See also, U.S. Pat. No. 6,944,1994, and the references cited therein. , which is incorporated herein by reference in its entirety.

[0057] 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 1 0 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 Or Any range or value of K, including but not limited to D can be combined with can.

[0058] 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 literature.) The measured affinity of a particular antibody-antigen interaction is , may differ when measured under different conditions (e.g., salt concentration, pH). Affinity and other antigen binding parameters (e.g., K D , K. a , K. d ) is preferably measured by , standardized solutions of antibody and antigen, and standardized buffers such as those described herein. This is done using

[0059] 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 concepts The present invention relates to a method for the production of a nucleic acid molecule comprising the nucleic acid sequence of the present invention, or a deposited vector containing at least one of these sequences. The present invention provides a method for producing a human IL-23 antibody comprising the steps of: The nucleic acid molecules can be synthesized using methods described herein or known in the art. can be obtained.

[0060] 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, or single-stranded, or any combination thereof. Any portion of at least one strand of DNA or RNA may be: It may be the coding strand, also known as the sense strand, or may be called the antisense strand. It may also be a non-coding strand.

[0061] The isolated nucleic acid molecule used in the methods of the present invention optionally contains one or more introns. An open reading frame (O RF), for example, but not limited to, at least one heavy or light chain CDR1, CDR2, At least one identified CDR, such as CDR2, and / or CDR3. nucleic acid molecules comprising a portion thereof, an anti-IL-23 antibody or a nucleic acid molecule comprising a coding sequence of a variable region thereof, and and nucleic acid molecules substantially different from those described above, but due to the degeneracy of the genetic code, and / or at least one anti-IL-23 antibody known in the art. It is understood that the term "genetic code" may also include nucleic acid molecules containing nucleotide sequences encoding the same. Such codes are well known in the art. Therefore, those skilled in the art will be able to easily identify the codes that can be used in the methods of the present invention. To generate such modified nucleic acid variants encoding specific anti-IL-23 antibodies for use in See, for example, Ausubel et al., supra, where such Nucleic acid variants are encompassed by the present invention. Non-limiting examples of isolated nucleic acid molecules include: HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR 2, and nucleic acids encoding LC CDR3.

[0062] a nucleic acid molecule comprising a nucleic acid encoding an anti-IL-23 antibody as described herein; Examples include those that themselves encode the amino acid sequence of an antibody fragment, whole antibodies or parts thereof, The coding sequence for the portion, the coding sequence for the antibody, fragment or portion, and additional sequences, e.g. non-coding sequences, with or without the additional coding sequences mentioned above, such as at least one intron and 5' and 3' sequences, such as splicing and polyadenylation signals (e.g., Plays a role in transcription, mRNA processing, including ribosome binding and stability of mRNA together with additional non-coding sequences, including but not limited to transcribed, non-translated sequences that serve as , at least one signal leader or fusion peptide coding sequence, additional amino acids Additional coding sequences encoding amino acids, e.g., amino acids that provide additional functionality, are also included. Thus, the antibody encoding sequence can be, but is not limited to, an antibody a sequence encoding a peptide that facilitates purification of the fused antibody, including a fragment or portion thereof; It can be fused to a marker sequence.

[0063] 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 and / or to identify, isolate, or generate partial or full-length clones in a compiled library using the In some embodiments, the polynucleotide can be isolated and amplified. or otherwise complementary to cDNA from a human or mammalian nucleic acid library. , a genomic sequence or a cDNA sequence.

[0064] 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. cDNA libraries may be normalized to increase the representation of rare sequences. Stringency is used with sequences that have reduced sequence identity to a target sequence. Low or moderate hybridization conditions are typical, but not exclusive. The medium and high integrity conditions are optionally used for sequences with higher identity. Low stringency conditions are used for clones with approximately 70% sequence identity. Allows selective hybridization of sequences and allows for the identification of orthologous or paralogous sequences. can be used to determine

[0065] Optionally, the polynucleotide encodes at least a portion of an antibody. The nucleotides are capable of selectively hybridizing to polynucleotides encoding the antibodies of the present invention. For example, Ausubel, supra, See Colligan, supra, each of which is incorporated herein by reference in its entirety. can be.

[0066] 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, (b) purification techniques, and / or combinations thereof. do.

[0067] The nucleic acid may comprise 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 nucleic acid. It can also be used to insert translatable sequences, which can aid in the isolation of polynucleotides. and can be used to aid in the isolation of translated polynucleotides of the present invention. The hexahistidine 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 referred to as polynucleotides of the invention. The present invention relates to a vector, adapter, or linker for the cloning and / or expression of a gene.

[0068] Additional sequences may be added to such cloning and / or expression sequences to facilitate cloning and / or expression. or their function in expression can be optimized to aid 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. )

[0069] 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 invention can be subjected to stringent conditions. The oligonucleotide probes selectively hybridize to cDNA or genomic DNA. A library is used to identify desired sequences. RNA isolation and cDNA library The construction of NA and genomic libraries is well known to those skilled in the art (see, for example, Ausu, supra). bel, or see Sambrook above.)

[0070] 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 isolate homologous genes in the same or different organisms. , can hybridize to genomic DNA or cDNA sequences. Various degrees of hybridization stringency can be used in the assay. It is clear that either the hybridization or the washing medium may be harsh. As the hybridization conditions become more stringent, duplex formation occurs. For this to occur, the degree of complementarity between the probe and the target must be high. The degree of denaturation varies with temperature, ionic strength, pH, and the use of partially denaturing solvents such as formamide. The presence of a specific molecule can be controlled by one or more of the following: The stringency of the reaction can be determined by, for example, manipulating the formamide concentration within 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) required can be determined by 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 variations within the primers may result in streaks in the hybridization and / or wash media. It should be understood that this can be compensated for by reducing efficiency.

[0071] 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.

[0072] Known methods for amplifying DNA or RNA include the polymerase chain reaction (PCR). PCR) and related amplification processes (e.g. and Mullis et al., U.S. Patent Nos. 4,683,195, 4,683,202, and 4,683,202. Nos. 4,800,159, 4,965,188, and Tabor et al., No. 4,795,6 Nos. 99 and 4,921,794, Innis's No. 5,142,033, Wil Son et al., U.S. Pat. No. 5,122,464; Innis, U.S. Pat. No. 5,091,310; Gyl Lensten et al., US Pat. No. 5,066,584; Gelfand et al., US Pat. No. 4,889,888; No. 18, Silver et al., No. 4,994,370, Biswas, No. 4,766, 067; see Ringold, 4,656,134), and double-stranded D Using antisense RNA against a target sequence as a template for RNA synthesis NA-mediated amplification (U.S. Patent No. 5,130,238 to Malek et al., under the trade name NASBA) These include, but are not limited to, the following documents (the entire contents of which are incorporated herein by reference): (See, e.g., Ausubel, supra, or Sambrook, supra.) See .)

[0073] 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, e.g., For example, cloning a nucleic acid sequence encoding a protein to be expressed, To detect the presence of desired mRNA, for nucleic acid sequencing, or for other purposes These may be useful for generating nucleic acids for use as probes for in vitro amplification. Examples of techniques sufficient to guide one skilled in the art through the breadth method are found in Berger, supra; Sam, supra Brook and Ausubel, supra, and Mullis et al., U.S. Pat. No. 4,683,200. No. 2 (1987), and Innis, et al., PCR Protocols A Guide to Methods and Applications,Eds.,A Academic Press Inc, San Diego, CA (1990) Commercially available kits for genomic PCR amplification are known in the art. See vantage-GC Genomic PCR Kit (Clontech). In addition, for example, the T4 gene 32 protein (Boehringer Mann heim) can be used to improve the yield of long PCR products.

[0074] 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 single-stranded 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 sequence of the base may be limited, longer sequences can be obtained by ligation of shorter sequences. You will realize that you can.

[0075] 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 identify at least one A recombinant expression cassette can be constructed that can be introduced into a desired host cell. The expression cassette typically directs transcription of the polynucleotide in the intended host cell. It includes a polynucleotide that is operably linked to a transcription initiation regulatory sequence that directs the transcription of the target gene. Both heterologous (i.e., endogenous) promoters can be utilized to direct expression of the nucleic acid. do.

[0076] In some embodiments, isolated elements that function as promoters, enhancers, or other elements The nucleic acid thus obtained can be used in combination with a polynucleotide of the invention to up- or down-regulate expression of the polynucleotide. The non-heterologous form of the nucleotide can be introduced into the appropriate location (upstream, downstream, or within an intron). For example, mutations, deletions and / or substitutions can be made in vivo or in vitro. By transfection, the endogenous promoter can be altered.

[0077] 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.

[0078] The polynucleotide may optionally be a vector containing a selectable marker for propagation in a host. Generally, plasmid vectors are 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 so, package it in vitro using an appropriate packaging cell line. The vector can then be transduced into a host cell.

[0079] 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.

[0080] The expression vector preferably contains at least one selectable marker, although this is optional. Such markers include, for example, methotrexate for eukaryotic cell culture. rexate)(MTX), dihydrofolate reductase (dihydrofolate reductase) (DHFR, U.S. Patent Nos. 4,399,216, 4,634, No. 665, No. 4,656,134, No. 4,956,288, No. 5,149,6 No. 36, No. 5,179,017, ampicillin, neomycin (G418), mycobacterium Phenolic acid or glutamine synthetase ) (GS, U.S. Patent Nos. 5,122,464, 5,770,359, 5,82 No. 7,739) resistance genes and methods for culturing in E. coli and other bacteria or prokaryotes These include, but are not limited to, tetracycline or ampicillin resistance genes for (The above patents are incorporated herein by reference in their entirety.) Suitable for the above host cells Suitable culture media and conditions are known in the art. Introduction of the vector construct into the host cell will be readily apparent to those skilled in the art. Acid calcium transfection, DEAE-dextran mediated transfection , cationic lipid-mediated transfection, electroporation, transduction, infection or by other known methods, such as those described in Sambro, supra. ok, chapters 1-4 and 16-18, Ausubel above, chapters 1, 9, 13, 15, Chapter 16 and the like.

[0081] 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.

[0082] Those skilled in the art will appreciate that various methods are available for expressing nucleic acids encoding proteins for use in the methods of the present invention. Alternatively, the nucleic acid may be expressed in a manner similar to that described above, e.g., by a nucleic acid encoding an antibody. By switching it on (by manipulation) in a host cell containing the gene encoding the Such methods can be expressed in cells. Nos. 5,641,670, 5,733,746, and 5,733,761 and are well known in the art, as described in incorporated herein.

[0083] An example of a cell culture useful for the production of antibodies, specified portions or variants thereof is mammalian Mammalian cell lines are often in the form of a monolayer of cells, but suspensions of mammalian cells can also be used. Alternatively, a bioreactor can be used. Several suitable host cell lines have been developed in the art, including COS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-165 1), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., A ATCC CRL1610) and BSC-1 (e.g., ATCC CRL-26) cell lines, os-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2 / 0 Examples of such cells include A. coli, Ag14, 293 cells, and HeLa cells. a Type Culture Collection,Manassas,Va(w Preferred host cells include myeloma and lymphoma cells. Particularly preferred host cells include cells of lymphoid origin, such as lymphoma cells. Ag8.653 cells (ATCC accession number CRL-1580) and SP2 / 0-Ag14 cells In a particularly preferred embodiment, the recombinant cell The cells were P3X63Ab8.653 or SP2 / 0-Ag14 cells.

[0084] 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. 5,3 No. 85,839), HSV tk promoter, pgk (phosphoglycerate kinase) promoter, EF-1α promoter (U.S. Patent No. 5,266,491), at least another human immunoglobulin promoter, enhancer, and / or ribosome binding site RNA splice sites, polyadenylation sites (e.g., SV40 large T Ag polyadenylation sites), addition sites), and processing information sites such as transcription termination sequences, but are not limited to these. The expression control sequences may include one or more of the expression control sequences not included in the expression control sequences described in, for example, Ausubel et al., supra. See Sambrook et al., supra. Useful for producing the nucleic acids or proteins of the invention Other such cells are known and / or may be used, for example, in the American Type The Culture Collection's catalog of cell lines and hybridomas (www .atcc.org) or other known or commercial sources.

[0085] 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.

[0086] 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 ("HPLC") can also be used for purification. Colligan, Current Protocols in Immunolo gy or Current Protocols in Protein Science ,John Wiley & Sons,NY,NY (1997-2001), e.g. See Chapters 1, 4, 6, 8, 9, and 10, each of which is incorporated herein by reference in its entirety. will be incorporated into

[0087] Antibodies for use in the methods of the present invention include naturally purified products, products of chemical synthetic procedures, and the like. and recombinant techniques from eukaryotic hosts, including, for example, yeast, higher plants, insects, and mammalian cells. Depending on the host utilized in a recombinant production procedure, antibodies may be produced by It may be glycosylated or non-glycosylated, but is preferably glycosylated. Such methods are described in Sambrook, supra, Sections 17.37-17.42, supra. Ausubel, Chapters 10, 12, 13, 16, 18, and 20, Colliga supra. Many standard laboratory manuals, such as Protein Science, Chapters 12-14, manual, all of which are incorporated herein by reference in their entireties.

[0088] Anti-IL-23 antibody The anti-IL-23 antibodies of the present invention can be incorporated into immunoglobulin molecules, at least a portion of, for example, but not limited to, at least one ligand binding moiety (li LBP, including but not limited to heavy metal binding portion The complementarity determining regions (CDRs) of the heavy or light chain or the ligand-binding portions thereof, Variable regions, framework regions (e.g., FR1, FR2, FR3, FR4, or their fragments, and optionally containing at least one substitution, insertion, or deletion), heavy or light chains Chain constant region (e.g., at least one C H 1, Hinge 1, Hinge 2, Hinge 3, Hinge 4 , C H 2 or C H 3, or a fragment thereof, and optionally at least one any protein or peptide containing a mutation, substitution, insertion, or deletion, or any part thereof The antibody may be human, mouse, rabbit, rat, rodent, primate, or Any mammal, including but not limited to, any combination thereof. , or may be derived therefrom.

[0089] 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, such as IgG1, IgG2, IgG3, or IgG4 (e.g., γ1, γ2, γ3, γ4). Antibodies of this type are referred to herein as At least one human light chain (e.g., Transgenic mice or other transgenic mice containing transgenes for IgG, IgA, and IgM. It can be prepared by utilizing a transgenic non-human mammal. In embodiments, the anti-IL-23 human antibody comprises an IgG1 heavy chain and an IgG1 light chain.

[0090] 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 It is composed of at least one extracellular, soluble, hydrophilic, external, or cytoplasmic portion.

[0091] 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. The sequence may be derived from a non-human CD40 gene or may correspond exactly to the germline sequence. CDRs from a synthetic library derived from R can be used. These CDRs It may be formed by the incorporation of conservative substitutions from the original non-human sequence. In the antibody or antigen-binding portion or variant, the corresponding CDR1, 2 and / or 3 amino acids at least one light chain CDR (i.e., CDR1, CDR2, and / or can have an antigen-binding region comprising at least a portion of the CDR3).

[0092] Such antibodies can be prepared using conventional techniques of 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 conventional techniques, various portions of the antibody (e.g., CDRs, frames) can be isolated. They can be prepared by chemically bonding together polymers (polymers).

[0093] Anti-IL-23 specific antibodies have heavy or light chain variable regions with defined amino acid sequences. For example, in a preferred embodiment, the antibody may include at least one of anti-IL-2 3. The antibody optionally comprises at least one heavy chain polypeptide having the amino acid sequence of SEQ ID NO: 106. variable region, and / or optionally at least one having the amino acid sequence of SEQ ID NO: 116 The antibody binds to human IL-23 and contains at least one of the light chain variable regions of the antibody. Antibodies comprising a chain or light chain variable region may be prepared using any of the methods known in the art and / or described herein. Phage display (Katsube, Y., et al., Int J Mol. Me d,1(5):863-868(1998)) or those who adopt transgenic animals. For example, functionally rearranged human IgG can be prepared using any suitable method, including the use of a recombinant human IgG. a human immunoglobulin heavy chain transgene capable of undergoing functional rearrangement; a transgene comprising DNA from the purine light chain locus; and a transgenic mouse comprising the can be immunized with human IL-23 or a fragment thereof to induce the production of antibodies. If so, antibody-producing cells can be isolated and cultured as described herein and / or As is known in the art, hybridomas or other immortalized antibody producing Alternatively, the antibody, specified portion or variant can be cultured in a suitable host cell. Within the host cell, the encoding nucleic acid or a portion thereof can be used for expression.

[0094] The present invention also provides amino acids within sequences that are substantially the same as the amino acid sequences described herein. The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs comprising the amino acid. Such antibodies or antigen-binding fragments and antibodies comprising such chains or CDRs have high affinity (e.g. For example, K D is about 10 -9 M or less) and can bind to human IL-23. Amino acid sequences that are substantially the same as the sequences set forth in Conservative amino acid substitutions include sequences containing amino acid deletions and / or insertions. have chemical and / or physical properties (e.g., charge, structure, polarity, It refers to the substitution of a first amino acid with a second amino acid that has hydrophobic / hydrophilic properties. Substitutions include, but are not limited to, replacing one amino acid with another amino acid within the following group: Contains: lysine (K), arginine (R), and histidine (H); aspartic acid salt (D) and glutamate (E); asparagine (N), glutamine (Q), serine ( S), threonine (T), tyrosine (Y), K, R, H, D, and E; alanine (A), Valine (V), Leucine (L), Isoleucine (I), Proline (P), Phenylanine threonine (F), tryptophan (W), methionine (M), cysteine ​​(C), and glycine (G); F, W, and Y; C, S, and T.

[0095] Amino acid code The amino acids constituting the anti-IL-23 antibodies of the present invention are often abbreviated. The nucleotide sequence can be expressed as its one-letter code, its three-letter code, its name, or the codon of three nucleotides (compound This can be expressed by representing the amino acid by a number (or a number), and is well known in the art. It is well understood (Alberts, B., et al., Molecular Biol ogy of The Cell,Third Ed.,Garland Publis (See Hing, Inc., New York, 1994).

[0096] [Table 1]

[0097] The anti-IL-23 antibodies used in the methods of the present invention are naturally occurring IL-23 antibodies, as specified herein. Substitution, deletion, or addition of one or more amino acids, either by natural mutation or human manipulation It may include addition.

[0098] The number of amino acid substitutions a skilled artisan would make depends on many factors, including those described above. Specifically, the amino acid substitutions, insertions, or deletions of a given anti-IL-23 antibody, fragment, or variant The numbers are as specified herein: 40, 30, 20, 19, 18, 17, 16, 15 , 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, e.g., 1~ Not exceeding 30 or any range or value therein.

[0099] Functionally essential amino acids within the anti-IL-23 specific antibody were identified by site-directed mutagenesis. or by methods known in the art, such as alanine scanning mutagenesis. can be identified (e.g., Ausubel, supra, Chapters 8, 15; Cunningham and Wells,Science 244:1081-10 85 (1989)). The latter procedure introduces one alanine substitution mutation at each residue in the molecule. The resulting substitution mutant molecules are then subjected to, for example, but not limited to, The antibodies are tested for at least one biological activity, such as IL-23 neutralizing activity. The sites that are crucial for this purpose are also identified by structural analysis such as crystallization, nuclear magnetic resonance, or photoaffinity labeling. (Smith, et al., J. Mol. Biol. 2002, 2003). 24:899-904 (1992) and de Vos, et al., Science 255:306-312(1992)).

[0100] The anti-IL-23 antibody may be selected from the group consisting of at least one of SEQ ID NOs: 5, 20, 44, 50, 56, and 73. At least one portion, sequence, selected from five to all of one adjacent amino acid. These may include, but are not limited to, a sequence, a column ...

[0101] The IL-23 antibody or specific portion or variant thereof includes at least 3 of the above SEQ ID NOs. 5 to 17 adjacent amino acids of the above SEQ ID NO: 5 to 17 adjacent amino acids of the above SEQ ID NO: 10 adjacent amino acids, 5 to 11 adjacent amino acids of the above SEQ ID NO: 7 adjacent amino acids, at least 5 to 9 adjacent amino acids selected from the above SEQ ID NO: It may include, but is not limited to, one moiety, sequence, or combination.

[0102] The anti-IL-23 antibody further optionally comprises any of the above SEQ ID NOS: 5, 17, 10, 11, 7, 9 At least one polypeptide of 70-100% of the 1, 119, or 108 contiguous amino acids In one embodiment, the immunoglobulin chain, or a portion thereof (e.g., The amino acid sequence of the variable region (CDR) corresponds to at least one of the above SEQ ID NOs. The amino acid sequence of the nucleotide ... 4, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87 , 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 For example, the light chain variable region has the amino acid sequence can be compared with the above SEQ ID NOs, or the amino acid sequence of the heavy chain CDR3 can be compared with the above SEQ ID NOs. Preferably, the amino acid sequence is 70 to 100% identical (i.e., 9 0, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or any of these The range or value of the desired value can be calculated using a suitable computer, as is known in the art. It is determined using an algorithm.

[0103] As known in the art, "identity" is determined by comparing sequences. a relationship between two or more polypeptide sequences or two or more polynucleotide sequences, In the art, "identity" is also determined by the match between strings of such sequences. "sequence relatedness" refers to the degree of sequence relatedness between polypeptide or polynucleotide sequences, as defined by the "Identity" and "similarity" are defined in the Computational Molecular Biology,Lesk,AM,ed.,Oxford University Press, New York, 1988, Biocomputing:Informa tics and Genome Projects, Smith, DW, ed. Academic Press, New York, 1993, Computer An alysis of Sequence Data,Part I,Griffin,A .M.,and Griffin,HG,eds.,Humana Press,N. ew Jersey,1994, Sequence Analysis in Mole cular Biology,von Heinje,G.,Academic Pre ss, 1987, and Sequence Analysis Primer, Gribs kov, M. and Devereux, J., eds., M Stockton Pr. ess, New York, 1991, and Carillo, H., and Lipm an,D.,Siam J.Applied Math.,48:1073(1988) These can be easily prepared by known methods, including but not limited to those described in In addition, the percent identity value can be calculated using Vector NTI It is a component of Suite 8.0 (Informax, Frederick, MD). The amino acid and nucleotide sequences are generated using the default AlignX settings. This can be obtained from a sequence alignment.

[0104] Preferred methods to determine identity are to find the largest match between the sequences tested. Methods to determine identity and similarity are publicly available computer-aided methods. To determine identity and similarity between two sequences, A preferred computer program method is that of the GCG program package (Devere ux, J., et al., Nucleic Acids Research 12(1 ):387(1984)), BLASTP, BLASTN, and FASTA (Atsch ul,SFet al.,J.Molec.Biol.215:403-410(1 990). The BLAST X program is available from NCBI and and other sources (BLAST Manual, Altschul, S., et al., N CBINLM NIH Bethesda,Md.20894:Altschul,S. , et al., J. Mol. Biol. 215:403-410 (1990) The well-known Smith Waterman algorithm is also available to determine identity. It can be used to

[0105] Preferred parameters for polypeptide sequence comparison include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Bi ol.48:443-453(1970)Comparison matrix:BLOSSUM62 fr om Hentikoff and Hentikoff,Proc.Natl.Aca d.Sci,USA.89:10915-10919(1992), Gap penalty: 12 Gap length penalty: 4 A useful program for these parameters is Genetics Computer G Publicly available as the "Gap" program from the Madison, Wis. group. The above parameters are the default parameters for peptide sequence comparison (terminal (Just as there is no penalty for caps.)

[0106] Preferred parameters for polynucleotide comparison include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Bi ol.48:443-453(1970) Comparison matrix: match = +10, mismatch = 0 Gap penalty: 50 Gap length penalty: 3 " from Genetics Computer Group, Madison Wis. These are available as programs with default parameters for nucleic acid sequence comparison. is.

[0107] By way of example, a polynucleotide sequence can be identical to another sequence, i.e., 100% identical. may contain one or up to a certain integer number of nucleotide changes compared to the reference sequence Such alterations include deletions, substitutions (including transitions and transversions) of at least one nucleotide, or an insertion, wherein the alteration is at the 5' or 3' end of the reference nucleotide sequence. may occur at the end positions or anywhere between these end positions and may be between nucleotides of the reference sequence Nucleotides may be present individually or interspersed in one or more adjacent groups within the reference sequence. The number of nucleotide changes corresponds to the total number of nucleotides in the sequence and the corresponding percent identity number. Multiply by the percentage (divided by 100) and subtract that product from the total number of nucleotides in the sequence. Pulling, or by n.sub.n.ltorsim.x.sub.n-(x.sub.ny) It is decided, where n.sub.n is the number of nucleotide changes and x.sub.n is the number of nucleotides in the sequence. The total number of leucocytes, y is, for example, 0.70 for 70% and 0 for 80%. .80, 0.85 for 85%, 0.90 for 90%, and 0 for 95%. 95, and any non-integer product of x.sub.n and y is Round down to the nearest integer before subtracting.

[0108] Alterations to the polynucleotide sequence encoding the above SEQ ID NOs may be made by adding a number to the coding sequence. Create sense, missense, or frameshift mutations, thereby modifying The polypeptide encoded by the polynucleotide can then be altered. In addition, the polypeptide sequence may be 100% identical to the reference sequence of the above SEQ ID NO. A specific sequence is compared to the reference sequence so that it is identical or has an identity of less than 100%. The amino acid sequence may include up to an integer number of amino acid changes. Such changes include deletion of at least one amino acid, substitutions (including conservative and non-conservative substitutions), or insertions, and the alterations are selected from the group consisting of: at the amino or carboxy terminal positions of the reference polypeptide sequence, or between these terminal positions The amino acid sequence may occur anywhere between the amino acids of the reference sequence, either individually or adjacent to one or more amino acids in the reference sequence. The number of amino acid changes for a given % identity is , the total number of amino acids in the above SEQ ID NO: The corresponding numerical percent identity (1 00) and subtract the product from the total number of amino acids in the sequence , or by n.sub.a.ltorsim.x.sub.a-(x.sub.ay) It is decided, where n.sub.a is the number of amino acid changes and x.sub.a is the number of amino acid changes in the above SEQ ID NO. is the total number of amino acids, and y is, for example, 0.70 for 70% and 0 for 80%. .80 for 85%, 0.85 for 85%, etc., for any integers x.sub.a and y. Any missing product is truncated to the nearest integer before being subtracted from x.sub.a.

[0109] Exemplary heavy and light chain variable region sequences, and portions thereof, are set forth in the SEQ ID NOs. The antibodies of the invention or specified variants thereof may be any number of adjacent amino acids from an antibody of the invention. The number of adjacent residues may be 10 to 100% of the number of adjacent residues in the anti-IL-23 antibody. Optionally, this subsequence of contiguous amino acids is selected from the group of integers consisting of at least Also about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 , 130, 140, 150, 160, 170, 180, 190, 200, 210, 220 , 230, 240, 250, or more amino acids in length, or any range therein Furthermore, the number of such subsequences is at least 1 to 2, such as 2, 3, 4, or 5. It may be any integer selected from the group consisting of 0.

[0110] As will be apparent to one skilled in the art, the present invention includes a method for producing a human ovarian tumor comprising administering to a subject a subject a biologically active antibody of the present invention. Biologically active antibodies include natural (non-synthetic), endogenous, or related and known antibodies. At least 20%, 30%, or 40%, and preferably at least 50% of that of the antibody %, 60%, or 70%, and most preferably at least 80%, 90%, or 95% Having a specific activity of 100% or more (including but not limited to up to 10 times the specific activity). Methods for assaying and quantitatively determining activity and substrate specificity are well known to those skilled in the art.

[0111] In another aspect, the present invention provides a method for preparing a compound according to any one of the methods described herein that is modified by the covalent attachment of an organic moiety. Such modifications may result in improved pharmacokinetic properties (e.g., and generating antibodies or antigen-binding fragments with increased serum half-life in vivo. The organic moiety can be a linear or branched hydrophilic polymeric group, a fatty acid group, or a fatty acid ester. In certain embodiments, the hydrophilic polymeric group can be a ester group. 00 to about 120,000 daltons, and polyalkane glycols (e.g., polyethylene glycols). Polyethylene glycol (PEG), polypropylene glycol (PPG), carbohydrate polymers , an amino acid polymer or polyvinylpyrrolidone, and a fatty acid group or a fatty acid ester. The terephthalate group can contain from about 8 to about 40 carbon atoms.

[0112] The modified antibodies and antigen-binding fragments may be covalently attached to an antibody, either directly or indirectly. Each organic moiety attached to an antibody or antigen-binding fragment of the invention may comprise: It can independently be a hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. As used, the term "fatty acid" includes monocarboxylic and dicarboxylic acids. As used herein, the term "hydrophilic polymeric group" refers to a polymer that is more soluble in water than in octane. For example, polylysine has a higher affinity for water than octane. Therefore, antibodies modified by covalent bonding of polylysine are included in the present invention. Suitable hydrophilic polymers for modifying the antibodies of the invention can be linear or branched, for example. For example, polyalkane glycols (e.g., PEG, monomethoxy-polyethylene glycol) (mPEG, PPG, etc.), carbohydrates (e.g., dextran, cellulose, oligo sugars, polysaccharides, etc.), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, poly Aspartic acid, etc.), polyalkane oxides (e.g., polyethylene oxide, poly propylene oxide, etc.), and polyvinylpyrrolidone. The hydrophilic polymers that modify the body are composed of individual molecules of about 800 to about 150,000 daltons. For example, PEG 5000 and PEG 20,000 Use where the subscript is the average molecular weight of the polymer in Daltons. The hydrophilic polymer group is The fatty acid may be substituted with 1 to about 6 alkyl groups, fatty acid groups, or fatty acid ester groups. Hydrophilic polymers substituted with fatty acid or fatty acid ester groups can be prepared using suitable methods. For example, a polymer containing amine groups can be prepared by reacting a fatty acid or The activated fatty acid or fatty acid ester can be linked to the carboxylic acid salt of the ester. Carboxylate salts (e.g., activated with N,N-carbonyldiimidazole) are added to poly( The linker can be linked to a hydroxyl group on a mer.

[0113] Fatty acids and fatty acid esters suitable for modifying antibodies of the invention may be saturated. Suitable lipids for modifying the antibodies of the invention may contain one or more unsaturated units. Examples of fatty acids include n-dodecanoic acid salts (C 12 , laurate), n-tetradecane Acid acid (C 14 , myristate), n-octadecanoate (C 18 , stearates), n-Eicosanoic acid salt (C 20 , arachidate), n-docosanoate (C 22 , behenic acid ), n-triacontanoate (C 30 ), n-tetracontanoate (C 40 ), cis-Δ 9-octadecanoate (C 18 , oleate), all cis-Δ5,8,11,14- Eicosatetraenoate (C 20 , arachidonate), octanedioic acid, tetradecane Suitable fatty acid esters include octadecanedionic acid, octadecanedionic acid, docosanedioic acid, and the like. Esters include monoesters of dicarboxylic acids containing straight or branched chain lower alkyl groups. The lower alkyl group may contain 1 to about 12, preferably 1 to about 6, carbon atoms.

[0114] The modified human antibodies and antigen-binding fragments can be subjected to a suitable treatment, such as by reacting them with one or more modifying agents. As used herein, the term "modifying agent" refers to a compound that can be prepared using a method such as Suitable organic groups containing activating groups (e.g., hydrophilic polymers, fatty acids, fatty acid esters) are intended. An "activating group" is a group that, under appropriate conditions, reacts with a second chemical group, thereby forming a modifier. A chemical moiety or functional group that can form a covalent bond with a second chemical group. For example, amine-reactive activating groups include tosylate, mesylate, halo (chloro, bromo, fluoro). Electrophilic groups such as fluorine, iodo, and N-hydroxysuccinimidyl ester (NHS) Examples of activating groups that can react with thiols include maleimide, iodine, and the like. acetyl, acrylolyl, pyridyl disulfide, 5-thiol-2-nitrobenzoic acid The aldehyde functional group can be an amine or The azide group can be reacted with a trivalent phosphorus group to form a hydrazide-containing molecule. A phosphoramidate or phosphorimide bond can be formed. Suitable methods for introducing .alpha.-hydroxybenzoates are known in the art (e.g., Herma nson,GT,Bioconjugate Techniques,Academ (See, e.g., Electron Microscopy Press: San Diego, CA (1996)). is bonded directly to an organic group (e.g., a hydrophilic polymer, a fatty acid, a fatty acid ester) or to a phosphorus Car moiety, e.g., divalent C1-C 12 A group (wherein one or more carbon atoms are oxygen, nitrogen, or may be substituted with a heteroatom such as sulfur. The car portion may be, for example, tetraethylene glycol, -(CH2)3-, -NH-(CH2 )6-NH-, -(CH2)2-NH- and -CH2-O-CH2-CH2-O-CH2 -CH2-O-CH-NH-. Modifiers containing a linker moiety include, for example, 1-ethyl- In the presence of 3-(3-dimethylaminopropyl)carbodiimide (EDC), mono-Bo c-Alkyldiamines (e.g., mono-Boc-ethylenediamine, mono-Boc-diamin By reacting methylaminohexane with fatty acids, free amines and fatty acid carboxylates are obtained. The Boc protecting group can be converted to a trifluoromethyl group by forming an amide bond between the The product was removed by treatment with trifluoroacetic acid (TFA) and another carboxylic acid was obtained as described. This can expose a primary amine that can be coupled to a salt or can be reacted with maleic anhydride and cyclizing the resulting product to form an activated maleimide derivative of the fatty acid. (See, e.g., Thompsons, 1999, the entire teachings of which are incorporated herein by reference. See WO 92 / 16221 to N. et al.).

[0115] The modified antibodies are produced by reacting a human antibody or antigen-binding fragment with a modifying agent. For example, the organic moiety can be an amine-reactive modifying agent, such as NHS of PEG. By employing esters, binding to antibodies can be achieved in a non-site-specific manner. Reducing disulfide bonds (e.g., intrachain disulfide bonds) of an antibody or antigen-binding fragment In this case, a modified human antibody or antigen-binding fragment can also be prepared by: The reduced antibody or antigen-binding fragment is reacted with a thiol-reactive modifying agent to form the modified antibody or antigen-binding fragment of the invention. It is possible to produce antibodies with specific structures. Modified human antibodies and antigen-binding fragments containing the nucleotides ##STR00001## can be synthesized by reverse proteolysis (Fisch et al. al.,Bioconjugate Chem.,3:147-153(1992),W Erlen et al.,Bioconjugate Chem.,5:411-41 7(1994), Kumaran et al., Protein Sci.6(10) :2233-2241(1997), Itoh et al.,Bioorg.Chem .,24(1):59-68(1996),Capellas et al.,Biot echnol.Bioeng.,56(4):456-463(1997)) and Her manson,GT,Bioconjugate Techniques,Acad , a method described in Electron Microwave Imaging, Inc., San Diego, CA (1996), It can be prepared using any suitable method.

[0116] The methods of the present invention also include those described herein and / or known in the art. At least one of the non-naturally occurring compositions, mixtures, or forms is provided, such as Two, at least three, at least four, at least five, at least six or more anti-IL-1 antibodies The present invention also provides an anti-IL23 antibody composition comprising an IL23 antibody. Such a composition comprises a IL23 antibody having a sequence adjacent to the above sequence. From 70-100% of the adjacent amino acids, or a specified fragment, domain, or variant thereof At least one or two complete amino acid sequences of an anti-IL-23 antibody selected from the group consisting of including full-length, C- and / or N-terminal deletion variants, domains, fragments, or specified variants. Preferred anti-IL23 antibody compositions include non-naturally occurring compositions containing, for example, the 70-100% of the anti-IL23 antibody sequence described herein, or a specified fragment thereof At least one CDR or LBP-containing portion of the polypeptide, domain, or variant thereof may comprise at least one of the CDRs or LBP-containing portions. More preferred compositions include at least one or two full-length, fragment, domain, or variant. The substance may be, for example, 70 to 100% of the above-mentioned sequence numbers, or a specified fragment or domain thereof. or at least one of the variants thereof. The percentage of such a composition is , by weight, volume, as known in the art or as described herein. Amount, concentration, molarity, or the amount of a liquid or dry solution, mixture, suspension, emulsion, by molality as a powder, particle, powder, or colloid.

[0117] 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 (c Cardiovascular (CV)-acting drugs, central nervous system (CNS)-acting drugs CNS drugs, autonomic nervous system us system (ANS) medications, respiratory tract medications, gastrointestinal ) (GI) tract acting agents, hormonal agents, fluid or electrolyte balancing agents, hemodynamic agents, antitumor agents, immunological agents At least one of the following drugs is selected: modulators, eye, ear or nose drugs, topical drugs, nutritional drugs, etc. The agent may comprise an effective amount of at least one compound or protein that is capable of acting as a therapeutic agent. , including the respective formulations, indications, dosages, and administrations set forth herein, (e.g., Nursing 2001 Handbook of Dr. gs,21 st edition,Springhouse Corp.,Spring house, PA, 2001, Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Pre. ntice-Hall, Inc., Upper Saddle River, NJ, Pha rmcotherapy Handbook,Wells et al.,Applet See Matthews & Lange, Stamford, CT, each of which is incorporated herein by reference. (Incorporated into the specification).

[0118] 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.

[0119] 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, Methyltestosterone, Nandrolone Decanoate, Nandrolone Phenpropionate, Test Testosterone, Testosterone Cypionate, Testosterone Enanthate, Testosterone Propionate The testosterone may be at least one selected from the group consisting of testosterone and transdermal testosterone.

[0120] At least one immunosuppressant is selected from the group consisting of azathioprine, basiliximab, cyclosporine, Daclizumab, lymphocyte immunoglobulin, muromonab-CD3, mycophenolate mofetil mycophenolate mofetil, mycophenolate mofetil hydrochloride, sirolimus, and tacrolimus. There can be at least one type.

[0121] 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.)

[0122] 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, etanercept, CDP-571, CDP -870, afelimomab, lenercepit, etc.), antirheumatic drugs (e.g., methotrexate auranofin, aurothioglucose, azathioprine, etanercept, gold Sodium olamiate, hydroxychloroquine sulfate, leflunomide, sulfasalazine ), immunosuppressants, immunoglobulins, immunosuppressants (e.g., basiliximab, cyclosporin, at least one selected from the group consisting of benzodiazepine, daclizumab, cytokines, and cytokine antagonists and further comprising at least one of any suitable and effective amount of a composition or pharmaceutical composition comprising a species. Non-limiting examples of such cytokines include IL-1 to IL-23. (e.g., IL-1, IL-2, etc.), but are not limited to these. Appropriate dosages are well known in the art. See, for example, Wells et al. l.,eds.,Pharmacotherapy Handbook,2 nd Edi tion, Appleton and Lange, Stamford, CT (2000 ), PDR Pharmacopoeia, Tarascon Pocket Phar macopoeia 2000, Deluxe Edition, Tarascon P Publishing, Loma Linda, CA (2000). each of which is incorporated herein by reference in its entirety.

[0123] 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 administration method, 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.

[0124] 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; Included alone or in combination are 1 to 99.99% by weight or volume. Exemplary Proteins Excipients include serum albumins such as human serum albumin (HSA), recombinant human albumin (HRA), and Examples of buffering agents that can also function include rHA, gelatin, and casein. Typical amino acids / antibody building blocks include alanine, glycine, arginine, betaine, and histidine. gin, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, Examples of preferred amino acids include valine, methionine, phenylalanine, and aspartame. One of the amino acids is glycine.

[0125] Carbohydrate excipients suitable for use in the present invention include, for example, fructose, maltose, Monosaccharides such as sucrose, galactose, glucose, D-mannose, and sorbose, lactose, sugars, disaccharides such as trehalose and cellobiose, raffinose, melezitose, maltodextrin, Polysaccharides such as xylitol, dextran, and starches, mannitol, xylitol, Lucititol, lactitol, xylitol, sorbitol (glucitol), myoinositol Preferred carbohydrate excipients for use in the present invention include alditols such as sorbitol, ... , mannitol, trehalose, and raffinose.

[0126] 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. Suitable buffers for use in are organic acid salts such as citric acid.

[0127] In addition, 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) .

[0128] 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 th ed., 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 carrier or excipient materials may include carbohydrates (e.g., monosaccharides and alditols) and buffers (e.g., Exemplary carrier molecules are mucopolysaccharides, hyaluronic acid, which may be useful for intra-articular delivery.

[0129] formulation As mentioned above, the present invention preferably uses saline or a phosphate salt containing selected salts. Buffered, stable formulations, and preservative-containing storage solutions and formulations, and pharmaceutical Preferred for pharmaceutical or veterinary use are those comprising at least one anti-IL23 antibody in an acceptable formulation. The present invention provides a suitable multi-use preserved formulation. The preserved formulation comprises at least one known , i.e., at least one of phenol, m-cresol, p-cresol, o-cresol , chlorocresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol, Formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl Paraben (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzyl chloride thimerosal, sodium dehydroacetate, and thimerosal, or a mixture thereof. As is known in the art, the present invention also includes a preservative selected from the group consisting of: 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, 4.8, 4.9, or any range or value therein, Any suitable concentration or mixture of any range or value of may be used. As for preservative-free, 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 to 0.5% Rosal (e.g., 0.005, 0.01), 0.001 to 2.0% phenol (e.g., For example, 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005 to 1. 0% alkylparaben(s) (e.g., 0.00075, 0.0009, 0.00 1, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.0 5, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1. 0%), etc.

[0130] As mentioned above, the method of the present invention involves the use of packaging and, optionally, a buffer formulated in an aqueous diluent. A small amount of a solution containing at least one anti-IL-23 specific antibody with a buffer and / or preservative. and a product containing at least one vial of such solution, and the packaging material is , 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 6 6. The label includes a description that the product can be stored for 72 hours or more. packaging material, a first vial containing a lyophilized anti-IL-23 specific antibody, and a formulated and a second vial containing an aqueous diluent of the buffer or preservative, The packaging material is designed to preserve the anti-IL-23 specific antibody reconstituted in an aqueous diluent for at least 24 hours. The composition includes a label instructing the patient to form a solution that can be easily administered.

[0131] 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.

[0132] The range of anti-IL-23 specific antibodies is approximately 1.0 μg / mL for wet / dry systems upon reconstitution. It is included in an amount that will give a concentration of 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.

[0133] 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, butylparaben) Benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and Thimerosal or mixtures thereof. The concentration of preservative used is sufficient to produce an antimicrobial effect. This will vary depending on the preservative selected and is readily determined by one of skill in the art.

[0134] 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 from about pH 4 to about pH 10, and preferably from about pH 5 to about A wide pH range, such as a pH range of 9, and most preferably a range of about 6.0 to about 8.0 Preferably, the formulations of the present invention have a pH of about 6.8 to about 7.8. Suitable buffers include phosphate buffers, most preferably sodium phosphate, In particular, phosphate buffered saline (PBS).

[0135] 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 and chelating agents such as EDTA and EGTA may optionally be added to the formulation or composition to These additives can reduce aggregation. This is particularly useful when a plastic container is used. The presence reduces the tendency of the protein to aggregate.

[0136] 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.

[0137] 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 dual vial. Any single or combination vial requiring reconstitution can be reused multiple times. can satisfy multiple patient treatment cycles and is therefore more convenient than currently available It is possible to provide a suitable treatment regimen.

[0138] 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, such label should contain a maximum of 1-1 This may include use for up to 2 months, 6 months, 18 months, and / or 2 years.

[0139] 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.

[0140] 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 All required combination vials are multi-use and can be used for single or multiple patient treatments. cycles, thus providing a more convenient treatment regimen than is currently available. provide.

[0141] 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 larger container may contain a larger volume of at least one antibody. The solution is withdrawn one or more times and transferred to a smaller vial and dispensed by the pharmacy or clinic. It can be provided to customers and / or patients.

[0142] Approved devices that contain single-vial systems include BD Pens, BD Autoj ector(R), Humaject(R), NovoPen(R) , BD® Pen, AutoPen®, and OptiPen® trademark), GenotropinPen (registered trademark), Genotronorm Pen ( Registered trademark), Humatro Pen (registered trademark), Reco-Pen (registered trademark), R oferon Pen (registered trademark), Biojector (registered trademark), Iject (registered trademark) (Registered Trademark), J-tip Needle-Free Injector (Registered Trademark), In traject (registered trademark), Medi-Ject (registered trademark), Smartject ( Pen-type injector devices for solution delivery, such as Becton D ickensen(Franklin Lakes, NJ, www.bectondic kenson.com), Disetronic (Burgdorf, Switzerl) and, www.disetronic.com), Bioject, Portland ,Oregon(www.bioject.com),National Medica l Products,Weston Medical(Peterborough,U K, www.weston-medical.com), Medi-Ject Corp. Manufactured by (Minneapolis, MN, www.mediject.com) (These devices have been developed) and similar suitable devices. Approved devices include those that deliver reconstituted solutions, such as HumatroPen®. A pen-type injector system for reconstituting a drug that has been lyophilized in a cartridge for delivery. Examples of other suitable devices include pre-filled syringes, autoinjectors, and These include needleless injectors, needleless syringes, and needleless IV infusion sets.

[0143] The product may include packaging that, in addition to information required by regulatory authorities, The packaging material of the present invention, if applicable, provides conditions under which the product can be used. The anti-IL-23 antibody is reconstituted with an aqueous diluent to form a solution and incubated for a period of 2 to 24 hours or more. and provide instructions to patients that this solution should be used for the wet / dry two-vial product. For single-vial solution products, pre-filled syringes, or auto-injectors, label indicates that such a solution can be used for a period of 2 to 24 hours or more. It is useful for pharmaceutical product applications.

[0144] The formulations used in the methods of the present invention comprise an anti-IL-23 antibody and a selected buffer, preferably a process comprising mixing saline or a phosphate buffer containing a selected salt. The anti-IL-23 antibody and the buffer can be mixed in an aqueous diluent. This is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, e.g. , a quantity of at least one antibody in water or buffer is added to a desired concentration of protein and buffer. and a desired buffer in a sufficient amount of water to provide the agent. The various modes of addition will be recognized by those skilled in the art. For example, the order of addition of the components, the presence of additional additives, etc. The use of acetaldehyde, the temperature and pH during preparation of the formulation, and the dosage concentration and administration method used are all important. It is a factor that can be optimized.

[0145] 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 can be 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, the antibody can be added under "standard" conditions using water as the diluent. The volume of the pharmaceutical composition is then adjusted to the desired final volume. Recognize some other ways.

[0146] The pharmaceutical compositions contain the indicated mass of each component per volume unit of water or are "standardized" in the The aqueous solution may be an aqueous solution or suspension having a pH indicated in the "state" of the invention. Here, the term "standard conditions" means a temperature of 25°C + / - 2°C and a pressure of 1 atmosphere. The term "standard conditions" is used in the art to refer to a single art-recognized set of temperatures or It is not used to refer to pressure, but instead refers to a particular composition under "standard state" conditions. The temperature and pressure are reference conditions used to describe solutions or suspensions containing volatile organic compounds. 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 may be prepared at other temperatures and pressures. The equivalence of such pharmaceutical compositions to those disclosed herein is determined by the above-defined "standard" method. should be determined under "quasi-state" conditions (e.g., 25°C + / - 2°C and 1 atmosphere pressure). .

[0147] Importantly, such pharmaceutical compositions contain "about" a certain amount of hydroxybenzoate per unit volume of the pharmaceutical composition. (e.g., "about 0.53 mg L-histidine") or about The pH value of the pharmaceutical composition may be a specific value. The isolated antibody may be present in a pharmaceutical composition or may be removed from a pharmaceutical composition. After being added (e.g., by dilution), the isolated antibody present in the pharmaceutical composition may be depolymerized to form a peptide chain. When a compound can be combined with a given value, it is "about" the mass value of the component or The pH and other values ​​are determined based on the binding of the isolated antibody after placing the isolated antibody in a pharmaceutical composition. "About" a given value when activity is maintained and detectable.

[0148] 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

[0149] One aspect of the methods of the present invention involves administering a pharmaceutical composition to a patient.

[0150] 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.

[0151] Stable or preserved formulations may be prepared as clear solutions or in aqueous diluents without preservatives or buffers. and a second vial containing at least one lyophilized anti-inflammatory drug. It can be provided to the patient as a combination vial containing a vial of the L-23 antibody. Any solution vials or combination vials requiring reconstitution may be reused multiple times. can satisfy single or multiple patient treatment cycles and therefore are currently available This provides a more convenient treatment regimen.

[0152] 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 active agents are disclosed in U.S. Pat. As taught in US Pat. No. 4,589,330, the aqueous phase containing the active agent and polymer is by contacting the non-aqueous phase with an aqueous phase and then evaporating the non-aqueous phase to cause coalescence of the particles from the aqueous phase. Porous microparticles can be formed by the method 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. It can be prepared by removing this solvent from the suspension by freeze-drying or dilution-extraction-precipitation. Preferred polymers for such preparations are gelatin, agar, starch, arabinoga Lactan, albumin, collagen, polyglycolic acid, polylactic acid, glycolide-L(- ) lactide poly(epsilon-caprolactone, poly(epsilon-caprolactone-C O-lactic acid), poly(epsilon-caprolactone-co-glycolic acid), poly(β-hydroxybenzoate) Hydroxybutyric acid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoa) acrylate), poly(hydroxyethyl methacrylate), polyamide, poly(amino acid ), poly(2-hydroxyethyl DL-aspartamide), poly(ester urea), poly (L-phenylalanine / ethylene glycol / 1,6-diisocyanatohexane) and poly(methyl methacrylate), a natural or synthetic copolymer selected from the group consisting of Particularly preferred polymers are polyglycolic acid, polylactic acid, glycolic acid, Do-L(-)lactide Poly(epsilon-caprolactone), Poly(epsilon-caprolactone) lactone-co-lactic acid), and poly(epsilon-caprolactone-co-glycolic acid) ) and other polyesters. Solvents useful for dissolving the polymer and / or active agent. Examples include water, hexafluoroisopropanol, methylene chloride, tetrahydrofuran, The active ingredient is hexane, benzene, or hexafluoroacetone sesquihydrate. The process of dispersing the first phase into the second phase involves forcing this first phase through an orifice in a nozzle. The step of passing the liquid forcefully through the nozzle to affect droplet formation can be included.

[0153] Dry powder formulations can be prepared, for example, by spray drying, or solvent extraction by evaporation, or by aqueous or Solvent extraction by precipitation of the crystalline composition followed by one or more steps to remove the non-aqueous solvent. The antibody formulation may also be obtained as a result of processes other than lyophilization, such as spray-drying. Antibody-based dry powder compositions are taught in U.S. Patent No. 6,019,968. under conditions to provide a solution or slurry of the body, and optionally, a respirable dry powder. The excipients in the solvent can be produced by spray drying. The stability of antibodies is affected by oxygen-inhibiting agents, such as polar compounds like water and ethanol. The spray drying procedure may be carried out under, for example, a nitrogen blanket, or in the presence of a drying gas. This can be enhanced by using nitrogen as a saturant. Another relatively dry formulation is Typically hydrofluoroalkanes such as those taught in WO 9916419. It is a dispersion of a plurality of porous microstructures dispersed in a suspension medium containing a propellant. The resulting dispersion can be administered to the patient's lungs using a metered dose inhaler. Equipment useful in the manufacture of these devices is manufactured by Buchi Ltd. or Niro Corp. It is being done.

[0154] 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. The present invention can be used in conjunction with various delivery methods, including other means that will be understood by those skilled in the art. It can be administered to a patient.

[0155] therapeutic application The present invention also provides a method for producing a compound comprising the steps of: The IL-23 antibodies of the present invention can be used to, for example, in a cell, tissue, organ, animal, or patient. A therapeutically effective amount of an IL-23 specific antibody is administered or contacted to a cell, tissue, organ, animal, or The present invention also provides a method for controlling or treating psoriasis in a patient.

[0156] 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 the organism, 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 in combination with at least one TNF antagonist ( For example, but not limited to, chemical or protein TNF antagonists, TNF monoclonal antibodies, monoclonal or polyclonal antibodies or fragments, soluble TNF receptors (e.g., p5 5, p70, or p85) or fragments thereof, fusion polypeptides thereof, or small molecule TNF antagonists Drugs such as TNF-binding protein I or II (TBP-1 or TBP-II), Nereli Monmab, infliximab, etanercept (Enbrel™), adalimumab (adalilumab) (Humira(TM)), CDP-571, CDP-870 , afelimomab, lenercepit, etc.), antirheumatic drugs (e.g., methotrexate, -Lanofin, aurothioglucose, azathioprine, sodium gold thiomalate, sulfur Hydroxychloroquine, leflunomide, sulfasalazine), muscle relaxants, narcotics, nonsteroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs rug) (NSAIDs), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blockers, antibiotics (e.g., aminoglycosides, antifungals, antiparasitics, antivirals, carbapenems, Phalosporins, fluoroquinolones, macrolides, penicillins, sulfonamides, tetracyclines Lacycline, other antibiotics), psoriasis medications, corticosteroids, anabolic steroids Ids, diabetes-related drugs, minerals, nutritional drugs, thyroid medications, vitamins, calcium-related hormones , antidiarrheals, antitussives, antiemetics, antineoplastics, laxatives, anticoagulants, erythropoietin (e.g., epoetin alfa), filgrastim (e.g., G-CSF, Neupogen), Sargramostim (GM-CSF, Leukine), immunomodulator, immunoglobulin, immunoglobulin immunosuppressants (e.g., basiliximab, cyclosporine, daclizumab), growth hormone, Hormone replacement drugs, estrogen receptor modulators, mydriatics, cycloplegics, alkylating agents, Antimetabolites, antimitotics, radiopharmaceuticals, antidepressants, antimanics, antipsychotics, anxiolytics, sleep aids Sleeping pills, sympathomimetics, stimulants, donepezil, tacrine, asthma medications, beta-agonists , inhaled steroids, leukotriene inhibitors, methylxanthines, cromolyn, epinephrine or analogs, dornase alfa (Pulmozyme), cytokines or At least one cytokine antagonist is administered before, simultaneously with, and / or after the administration of the compound. Suitable dosages are well known in the art. ells et al., eds., Pharmacotherapy Handboo k,2 nd Edition,Appleton and Lange,Stamfor d, CT(2000), PDR Pharmacopoeia, Tarascon Po cket Pharmacopoeia 2000,Deluxe Edition,T arascon Publishing, Loma Linda, CA (2000), N ursing 2001 Handbook of Drugs,21 st editi on,Springhouse Corp.,Springhouse,PA,2001 , Health Professional's Drug Guide 2001,e d.,Shannon,Wilson,Stang,Prentice-Hall,In c, Upper Saddle River, NJ, and see these references. each of which is incorporated herein by reference in its entirety.

[0157] Treatment Typically, treatment of psoriatic arthritis ranges from 0.1 to 1.5 times, 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 milligram range of anti-IL-23 antibody, and preferably in single or multiple doses per patient of an anti-IL-2 antibody in the range of at least about 0.1 to 100 milligrams per kilogram of body weight. 3. The effect is achieved by administering an effective amount or dose of the antibody composition. Serum concentrations may include serum concentrations of 0.1 to 5000 μg / ml per single or multiple dose. Appropriate dosages are known to medical practitioners and will, of course, vary depending on the particular disease state. The specific activity of the composition being administered and the specific patient undergoing treatment will depend on the individual. This means that repeated administration, i.e., specific monitored or metered doses, may be required to achieve the desired therapeutic dose. It may be necessary to provide repeated individual doses, in which case the individual doses may be Repeat until daily dose or effect is achieved.

[0158] 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 mg / 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, 18.5, 18.9, 19, 19.5, 19.9, 20, 20.5, 20.9, 21, 2 2, 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 of serum The concentration may be included to obtain a concentration, or any range, value, or fraction thereof.

[0159] Alternatively, the dose administered may be determined based on the pharmacokinetic characteristics of the particular drug and its method and route of administration. , the recipient's age, health and weight, the nature and severity of symptoms, the type of concurrent treatment, and the frequency of treatment. The dosage of the active ingredient may vary depending on known factors such as the dosage, the amount of the active ingredient, and the desired effect. It can be about 0.1 to 100 milligrams per kilogram of weight. Usually, it is 0.1 to 50, preferably Preferably, 0.1 to 10 milligrams / kilogram / dose, or a sustained release form, is used to achieve desirable results. It is effective to obtain

[0160] 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.

[0161] Dosage forms (compositions) suitable for internal administration generally contain about 0.001 milligrams per unit or container. These pharmaceutical compositions contain from about 1000 mg to about 500 mg of the active ingredient. is typically present in an amount of about 0.5 to 99.999% by weight, based on the total weight of the composition.

[0162] 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. The solution contains 1-10% human serum albumin. Non-aqueous vehicles such as liposomes and fixed oils A vehicle or lyophilized powder may be used that maintains isotonicity and chemical stability. additives (e.g., sodium chloride for isotonicity, mannitol; The formulation may contain various additives (e.g., buffering agents and preservatives). Thus, it is sterilized.

[0163] 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.

[0164] Alternative administration In order to administer a pharmaceutically effective amount of an anti-IL-23 antibody, in accordance with the present invention, many known methods can be used. In the following description, pulmonary administration is used. However, other modes of administration may be used in accordance with the present invention with suitable results. The IL-23 specific antibody may be present in a carrier as a solution, emulsion, colloid, or suspension. or as a dry powder, by inhalation or by administration of any of the methods described herein or in the art. Any of a variety of devices and methods suitable for administration by other methods known in the art. can be used to deliver.

[0165] Parenteral Formulation and Administration Parenteral formulations contain sterile water or saline, polyethylene glycol, and PEG as common excipients. It may contain 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 suspensions. Injectable preparations can be prepared, for example, in aqueous solutions, sterile injectable solutions or The vehicle may be a non-toxic, parenterally administrable diluent such as a suspension in a solvent. The solvent or solvent may be water, Ringer's solution, isotonic saline, etc. For these purposes, sterile, fixed oils can be used as a suspending solvent. Natural, synthetic or semi-synthetic fatty oils or fatty acids, natural, synthetic or semi-synthetic mono- Any type of fixed oil, including glycerides, diglycerides, or triglycerides, and Fatty acids can be used. Parenteral administration is known in the art and is conventional. Injection means, a gas-pressurized needleless injector such as that described in U.S. Pat. No. 5,851,198 Devices and laser drilling machines such as those described in U.S. Pat. No. 5,839,446 devices, which are incorporated herein by reference in their entirety. To be incorporated.

[0166] 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; "Hsieh, DS, Eds., pp.59-90 (Marcel Dekker, Inc. New York 1994, which is incorporated herein by reference in its entirety), or The application of protein and peptide-containing preparations to the skin (WO 98 / 53847 No. 10 / 2009, or to create transient transport pathways, such as by electroporation, or Application of an electric field to increase the mobility of charged drugs through the skin, such as in iontophoresis or the application of ultrasound, such as sonophoresis (U.S. Pat. Nos. 4,309,989 and 4,777,626). 67,402) with an oxidizing agent that enables the preparation of gels, ointments, lotions, suspensions or The compositions may be prepared transdermally, in forms such as, but not limited to, patch delivery systems. (The above publications and patents are incorporated herein by reference in their entirety.)

[0167] Having generally described the invention, the same are offered by way of illustration and not limitation. This will be more readily understood by reference to the following non-exhaustive examples. Further details of the present invention are illustrated by the following non-limiting examples. The teachings are expressly incorporated herein by reference. [Example]

[0168] Materials and Methods patient Patients enrolled in the study were aged 18 years or older, had PsA for 6 months or more, and met the classification criteria for psoriatic arthritis. Classification Criteria for Psoriatic Arthritis)(CASPAR);(Taylor W.et al.Arthr Rheum 2006,54:2665-73), and three or more Tender joints and swollen joints in three or more places, C-reactive protein protein][CRP]≧0.3mg / dL, body surface area of ​​plaque psoriasis (body s surface area (BSA) ≥ 3% and standard treatment (non-biologic treatment for ≥ 3 months) Disease-modifying anti-rheumatic drugs atic drugs [DMARDs], oral corticosteroids or nonsteroidal anti-inflammatory drugs for 4 weeks or more nonsteroidal anti-inflammatory drugs inadequate response to antihistamines [NSAIDs] or intolerance to such therapy Patients who had received a previous anti-TNFα agent were allowed, but had not received the previous anti-TNFα agent for 8 to 12 weeks. After a washout period, the incidence was limited to 20% of participants. Patients had severe, progressive, or Have a history of or current symptoms of an uncontrolled medical condition or have had non-melanoma within the past 5 years Patients were ineligible if they had a current or history of malignant disease, except for NMSC. Patients with a history or symptoms of active tuberculosis (TB) were excluded. If you have received adalimumab or other anti-TNF-α therapy within 3 months, Received other treatments targeting IL-12 / 23, IL-17, or IL-23 within 6 months or any systemic immunosuppressant (e.g., methotrexate) within 4 weeks or received phototherapy, they were ineligible to participate.

[0169] Experimental design The experiment was conducted in seven countries (Canada, Germany) from March 27, 2015 to January 17, 2017. rmany, Poland, Romania, Russia, Spain, United The study was a double-blind, placebo-controlled trial conducted at 34 sites in the United States. Patients were randomized 2:1 (stratified by prior anti-TNFα use) at weeks 0, 4, and Patients received either guselkumab 100 mg or placebo subcutaneously every 8 weeks (q8w). The dosing regimen was selected based on the dose-response in psoriasis, with higher doses (200 mg q12w) did not provide incremental benefit.

[0170] At week 16, all patients with <5% improvement in swollen and tender joint counts were randomized to receive open-label Uscos Early withdrawal from tekinumab (placebo → ustekinumab, guselkumab → ustekinumab) Patients continuing on placebo were eligible to be transferred to the final follow-up at week 56. guselkumab 100 mg at weeks 24, 28, and q8w through week 44 with rivaroxaban. (placebo → guselkumab). MTX (≦25 mg / week), oral corticosteroids Steroids (≤10 mg / day prednisone / equivalent) and NSAIDs were discontinued until week 24. Although stable doses were tolerated, they were not required. Nomid (≤20 mg / day) was tolerated after week 24. Other DMARDs and biologics was banned until the 56th week.

[0171] This study (NCT02319759) was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice Guidelines. The study was conducted in accordance with the guidelines of the National Institutes of Health (NEJM). The study was approved by the ethics committee, and patients provided written informed consent. Janssen Research & Development, LLC is a research and development company. Funding for the analysis of data (BD / YW / YZ / WB / XLX). All authors acknowledge Jan Supported by a SSEN-funded medical writer, who interpreted the data and prepared the manuscript All authors submitted the manuscript for publication and contributed data to the protocol. The decision was made to certify the accuracy / completeness of the data and the test fidelity.

[0172] The Institutional Review Board or Ethics Committee must approve the protocol and Before the start of the study, patients provided written informed consent.

[0173] evaluation Independent assessors assessed joints for tenderness (N=68) and swelling (N=66, excluding hips). Patients were asked to rate their pain (0-100 mm visual analog scale). visual analog scale (VAS)), global disease activity (0-100 mm VAS), and physical function (Health Assessment Questionnaire Disability Index [Health Assessment Questionnaire]) uestionnaire Disability Index][HAQ-DI]) Investigators completed a global assessment of disease activity (VAS scale 0-100 mm) and serum C The RP was measured. The joint assessor also performed the Leeds Enthesitis Index (LEES). The total score of 0 to 60 using the Lesitis Index (LEI) and the enthesitis score were Each finger / toe was scored on a scale of 0 (no dactylitis) to 3 (severe dactylitis) depending on whether it was present or absent. The severity of dactylitis was assessed by the stenosis-related marker.

[0174] The Psoriasis Area and Severity Index (PASI) assessed the severity / extent of skin disease. 36 The Short Form (SF-36) Health Survey measures mental and physical health and quality of life. The primary endpoint was ACR 20% response at 24 weeks (ACR The secondary endpoint was the proportion of patients who achieved ACR2 at 16 weeks. 0, and PASI75 / 90 / 100, ACR50 / 70, and HAQ-D up to 56 weeks I, improvement of enthesitis / dactylitis in patients with baseline enthesitis / dactylitis, SF- Changes in 36 mental and physical component summaries (MCS and PCS) scores, and This included achieving minimal disease activity (MDA) criteria. Adverse events (AEs) were monitored.

[0175] Statistical analysis: Efficacy analyses up to week 24 were performed in the modified intention-to-treat (mITT) population (full analysis set; The comparison of treatment groups was performed using the randomized and treated patients. A Cochran-Mantel-Haenszel study stratified by prior TNFα inhibitor use and mixed models for repeated measures, analysis of variance, or will for continuous endpoints. The Coxon rank sum test was used. To control for type I error of multiplicity, Two secondary analyses (PASI75, HAQ-DI change) were conducted to confirm the success of the primary analysis / prior hypothesis. (α = 0.05; two-sided) were used as a condition for the sequential analysis. Further analysis details are available online. Served at the Inn.

[0176] Data processing rules were applied to all efficacy analyses up to week 24. Treatment failure criteria were met. Patients who failed treatment, withdrew early, or had missing data were randomly assigned to a 2-week follow-up period after treatment failure / withdrawal. By week 4, patients were considered non-responders with split ACR / MDA responses. 24 For continuous endpoints up to week 1, patients with missing baseline data were excluded. Last observation carried forward was used to impute missing data after baseline or data after early withdrawal. ACR / MDA response by week 56 was also assessed for treatment failure, early withdrawal, or missing data. Post hoc analyses were performed in the mITT population using non-responder imputation (NRI) .

[0177] result patient Of the 251 patients screened, 149 received placebo (N=49) or Seventeen (34.7%) placebo-treated patients were randomized to guselkumab (N=100). 10 (10.0%) guselkumab-treated patients switched to ustekinumab at week 16. Three patients (6.1%) who received placebo were eligible for early withdrawal. One patient (3.4%) in the guselkumab group and six patients (6.0%) in the guselkumab group remained on study treatment through week 44. The medication was discontinued (Figure 1).

[0178] Baseline characteristics were generally similar between groups, with moderate to severe arthritis. The mean BSA / PASI scores appeared to be somewhat higher with guselkumab compared with placebo, More patients in the guselkumab group had baseline dactylitis / enthesis inflammation compared with the placebo group However, the difference was not statistically significant. Most patients (87.9%) had a Previously administered DMARDs. 44.3% were receiving MTX at baseline. 8.7% had previously received anti-TNFα agents (Table 1).

[0179] Efficacy during the placebo-controlled period (weeks 0-24) The primary endpoint was met during the placebo-controlled period (weeks 0–24). 58 0% vs. 18.4% of guselkumab-treated vs. placebo-treated patients (P<0.001). ACR20 response was achieved at week 24. Sensitivity analyses were performed (Table S1), and the results were consistent with those of the control group with MTX. The efficacy and safety of guselkumab versus placebo for ACR20 response was consistent regardless of the use of guselkumab (Table 2). Significant improvement was observed by week 4 (21.0% vs. 0, p<0.001) and by week 16 The ACR50 and CR6 were maximal at 60.0% vs. 16.3%, P<0.001, Fig. 2A. ACR70 (Figure 2B, Figure 2C) responses were significantly higher than placebo-treated patients over time through week 24. , was consistently higher among guselkumab-treated patients (ACR50: 34.0% vs. 10.2%) , P=0.002, ACR70: 14.0% vs. 2.0%, P=0.023 [calculated post hoc] ) (Table 2). Significant improvements were observed in all ACR components at 24 weeks ( P<0.001) (Table S2). Physical function assessed by the HAQ-DI was significantly higher at 24 weeks. Guselkumab significantly improved HAQ from baseline compared with placebo -LSMean difference in DI change [95% CI]: -0.31 [-0.47, -0. 15], P<0.001) (Table 2).

[0180] PASI 75 / 90 response was observed by week 4 (data not shown) and placebo by week 24. The PASI75 score was significantly higher for guselkumab than for bolus (78.6% vs. 12.5%). %, and PASI90: 66.3% vs. 6.3%, P<0.001, Table 2). Zero responses were significantly higher at 24 weeks (39.8% vs. 6.3%, P<0.001).

[0181] Among patients with baseline enthesitis, 56.6% vs. 29.0% of patients had guselkumab Treated vs. placebo-treated patients had improved enthesitis at 24 weeks (P = 0.012 Similar findings were observed for dactylitis resolution at 24 weeks (55.2% vs. 17. 4%, P = 0.001) (Table 2). Cumulab resulted in significantly greater improvements in LEI / dactylitis scores than placebo (Both had a median percent improvement from baseline of 100.0% vs. 33.3%) A significantly higher proportion of guselkumab-treated patients than placebo-treated patients Patients achieved an MDA response at week 24 (23.0% vs. 2.0%, P = 0.001, Table 2) Guselkumab significantly improved SF-36 PCS (baseline score) scores by week 24 compared with placebo. mean change from baseline: 6.59 vs. 0.46, P<0.001) and MCS (baseline The mean change from baseline was 4.95 vs. 0.42, P = 0.002, and the scores were significantly improved. (Table 2).

[0182] Efficacy after 24 weeks Consistent with the 24-week results, efficacy outcomes were significantly higher than placebo vs. Guselk at 24 weeks. Among patients who improved rapidly after switching to guselkumab and continued on guselkumab, On-treatment efficacy assessment) and maintained until week 56 (final follow-up visit). ACR / MDA responses up to week 56 were measured using NRI (Figures 2A-2D). , or indicated based on measurement data (Table S3).

[0183] safety Guselkumab was generally well tolerated. Through 24 weeks, guselkumab-treated patients 36.0% of patients and 32.7% of placebo-treated patients reported ≥1 AE. Week 0 → Guselkumab-treated patients through week 56, including 46% of patients receiving guselkumab at week 44 39.5% of patients reported ≥1 AE. The incidence of AEs was similar regardless of concomitant MTX use. and longer guselkumab exposure did not show a disproportionate increase (Table 3).

[0184] No deaths, anaphylactic / serum sickness-like reactions, or suicidal ideation were reported through week 56. Serious AEs occurred in 1 placebo (2.0%, joint injury) patient and 1 placebo (2.0%, joint injury) patient through week 24. One guselkumab (1.0%, myocardial infarction) patient and five patients through week 56 Further guselkumab-treated patients (osteoarthritis, pneumonia, pupillary anomaly, radial fracture, ulcerated cornea) All serious AEs were not related to the study drug by the investigators. The patient with myocardial infarction had multiple risk factors (male, over 45 years old, hypertension, hypertension, hyperlipidemia, family history of early coronary artery disease [under 55 years old], obesity, history of tobacco use) , had atherosclerosis at baseline and had previously undergone carotid endarterectomy Two (1.6%) guselkumab-treated patients were discharged at week 44 (last study) due to AEs. The patient was treated with guselkumab and discontinued treatment until the end of the drug administration period (Table 3). With the exception of one case of basal cell carcinoma (frequently outdoors), no other malignancies have occurred. No injection site reactions were reported among 750 guselkumab doses.

[0185] Infections identified by the researchers occurred in both guselkumab-treated and placebo-treated patients through week 24. 16.0% and 24.0% of patients treated with morphine, respectively, and by week 56, all patients Severe infections occurred in 20.9% of rucumab-treated patients. Severe infections included two bouts of acute pneumonia (17 9 / 209) and subsequently discontinued treatment with guselkumab in 1 patient (0.8%). A 78-year-old woman was treated. No candidiasis, active tuberculosis, or opportunistic infections were reported. There wasn't.

[0186] Five (3.9%) guselkumab-treated patients experienced the AE of neutropenia / decreased neutrophil count. Four of them also reported leukopenia / WBC. Until now, National Cancer Institute (NCI) - Adverse Events Common Terminology Criteria (CTCAE, Common Terminology Criteria for or AEs) Grade 2 (1000-1500 cells / mm 3 ) or Grade 3 ( 500~1000 cells / mm 3 ) neutropenia in 3 patients (3.0%) and 2 patients (MT) This occurred in 1 (1.0%, without MTX) and 1 (1.0%, without MTX) guselkumab-treated patient. Patients with grade 3 neutropenia discontinued treatment and subsequently recovered spontaneously. The decrease in neutrophil counts was observed at only one visit among each of the three patients and did not change over consecutive visits. In these four patients, the disease resolved spontaneously with guselkumab until final follow-up. No infections were reported. NCI-CTCAE grade 1 (1.0-3.0x upper limit of normal). [upper limit of normal][ULN] or higher Alanine aminotransferase (ALT) or aspartate aminotransferase The proportion of patients with elevated AST (aspartate aminotransferase) was significantly higher at week 24 between placebo and guselkumab. By week 56, 4 (3.1%) guselkumab-treated patients (3 5 (3.9%) (those with chronic liver disease at baseline) showed elevated ALT. Four patients, including one with glaucoma, used MTX. The NCI-CTCAE grade 2 (3.0- AST elevations meeting 5.0xULN were observed in guselkumab-treated patients through week 56. Grade 3 (5.0–20.0 x ULN) or higher ALT / AST elevation occurred in one (2.0%) placebo-treated patient.

[0187] By week 56, 4.7% of guselkumab-treated patients had non-neutralizing antibodies to guselkumab. Unexpected safety findings in patients who discontinued ustekinumab early The outcome was not observed until week 56 (Table 3).

[0188] Consideration Recently approved in the United States for treating moderate to severe psoriasis Human monoclonal anti-IL-23p19 antibody (Janssen Biotech, Invitrogen) c, TREMFYA (registered trademark) https: / / www.tremfyahcp.co guselkumab, a first-in-class treatment for PsA, is being evaluated for efficacy in PsA. This POC study evaluated guselkumab 100mg at weeks 0, 4, and q8w. g significantly reduces joint and skin disorders, enthesitis / dactylitis, and improves physical function / quality of life The study met its primary and all secondary endpoints. At the post-baseline evaluation, significant improvements in joint and skin conditions were observed, and all ACR components were components, as well as demographic / disease characteristics (data not shown), and prior / concomitant medications. Improvements were consistently observed in the subgroup of patients for whom the treatment was defined (Table 2). The efficacy of guselkumab was well maintained over a period of ~1 year. IL-2 in PsA pathogenesis, consistent with findings from previous PsA ustekinumab trials Both guselkumab and ustekinumab were effective in treating moderate to severe rheumatoid arthritis. showed a very high clinical response rate in clinical trials for psoriasis (Leonardi CL et al.Lancet 2008,371:1665-74, Papp KA et al,Lancet 2008,371:1675-84,Blauvelt Ae. t al,2017,76:405-417, Reich K et al, J Am Acad Dermatol 2017,76:418-31 also found that psoriasis and PsA Both highlight the central role of IL-23.

[0189] Genetic polymorphisms in the IL-23 / IL-23R gene are associated with psoriasis, PsA, and IBD. (Bowes J et al, Ann Rheum Dis 20 11,70:1641-44, Duerr RH et al.Science 200 6,314:1461-3, Liu Y et al.PLoS Genet 2008 ,4(3):e1000041, Nair RP et al.Nat Genet 2 009,41:199-204. Patients with PsA have an increased risk of IBD (Orcha rd TR et al,Gut 1998,42:387-91, and in many cases, I show a gut bacterial profile similar to that of BD patients (Scher JU et al, Art HR 2015,67:128-39. Therefore, in PsA The common immune-mediated inflammatory pathway of the “skin-joint-gut axis” is microbiome-induced / mediated. Ustekinumab may be a treatment for Crohn's disease. (CD) effectively (Feagan BG et al, N Engl JM ed 2016,375:1946-60, and two drugs targeting IL-23p19 The agent (risankizumab / MEDI2070) has shown promising results in an upcoming Phase 2 CD study. Sands BE et al, J.gastro.2017,S0016-5 085(17)35401-X, Feagan BG et al, Lancet 20 17,389:1699-709. Conversely, two anti-IL-17 agents (secukinumab / broda) lumab) did not improve or worsen CD in a phase 2 trial (Targan SR et al,Am J Gastroenterol 2016,111:1599-6 07, Hueber W et al.Gut 2012,61:1693-700, New-onset / worsening IBD was reported in phase 3 secukinumab and ixekizumab studies. (Baeten D et al.N Engl J Med 2015,373: 2534-48, Gordon KB et al, N Engl J Med 201 6,375:345-56. Herein, none of the patients had baseline IBD, No IBD AEs were reported. The efficacy of guselkumab in IBD will be evaluated in future clinical trials. Requires evaluation in testing.

[0190] In our PsA population, guselkumab safety up to week 56 was comparable to that observed in psoriasis. This is generally consistent with what was predicted (Blauvelt A. et al., 2017, 76 :405-417, Reich K et al, J Am Acad Dermato. l 2017,76:418-31), the frequency of AEs, including infections, was significantly higher than that of placebo up to 24 weeks. The incidence of NCI-CTCAE grade 2 / 3 neutropenia was 4 patients (4.0%). % of guselkumab-treated patients experienced ≥ 56 weeks of treatment and were not related to MTX use. Neutrophil homeostasis / tissue trafficking is mediated by IL-17 / granulocyte colony-stimulating factor-cytokinin. It is regulated by an immunoregulatory loop (Krstic A et al., Immunol Re s 2012;52:34-41, IL-17 plays an important role in granulopoiesis. (Rahman P et al,Arthritis Rheum 2008;58 :1020-5, Langley RG et al, N Engl J Med 20 14;371:326-38, Novartis Pharmaceuticals C orporation.COSENTYX(R), https: / / www.ph arma.us.novartis.com / sites / www.pharma.us .novartis.com / files / cosentyx.pdf). Next anti-IL- 17In large-scale Phase 3 trials of antibodies, increased incidence of grade 1 / 2 / 3 neutropenia Additional reports include secukinumab (Langley RG et al, N Engl J Med 2014;371:326-38, Novartis Pharmaceut icals Corporation.COSENTYX(R), https: / / www.pharma.us.novartis.com / sites / www.ph arma.us.novartis.com / files / cosentyx.pdf) , ixekizumab (Eli Lilly and Company, http: / / pi .lilly.com / us / taltz-uspi.pdf), and brodalumab (L ebwohl et al,N Engl J Med 2015;373:1318- 28) However, in a combined analysis of two large phase 3 guselkumab psoriasis trials, (Blauvelt A. et al, 2017, 76: 405-417, Reich K et al,J Am Acad Dermatol 2017,76:418- 31), no cases of grade 3 or grade 4 neutropenia were observed, and no cases of grade 2 neutropenia were observed. The incidence of hypovolemia was 0.7% in the placebo (3 / 416) and placebo-controlled 16-week periods. The efficacy was comparable to guselkumab 100 mg (6 / 821, 0.7%) treatment up to 48 weeks. Grade 4 neutropenia was not observed until the end of the study, and grade 3 neutropenia occurred in 1 / 13 of the patients. 63 (0.1%) guselkumab-treated patients and 2 / 576 (0.3%) adalimumab-treated patients The frequency of grade 2 neutropenia was significantly higher in guselkumab-treated patients ( between patients treated with adalimumab (22 / 1363, 1.6%) and those treated with adalimumab (16 / 576, 2.8%). Guselkumab did not significantly affect liver transaminases, glucose, or lipids. There was no significant effect on other laboratory parameters, such as neutrophil counts, liver enzymes, and blood glucose levels in PsA patients. The effects of guselkumab on cerebrospinal fluid and other laboratory parameters will be further investigated in a larger Phase 3 study. will be evaluated.

[0191] Study limitations include small sample size, relatively short duration, and dose-response assessment. The lack of an active control also limits comparison with other PsA therapies. ACR20 response was assessed as an appropriate outcome measure for this phase 2 POC study with limited sample size. ACR50, which may have more clinical significance, was selected as the primary endpoint. Both were evaluated as endpoints, and both showed significant improvement with guselkumab treatment. Participants had psoriasis BSA ≥ 3% and therefore no psoriasis or limited psoriasis P The efficacy and safety of guselkumab in patients with sA require further evaluation. Too few patients were exposed to NFα inhibitors to reliably estimate clinical response in this population. The clinical significance of the PsA subtype cannot be determined and is unclear for patients with specific PsA subsets (e.g., psoriatic spondylitis). The numbers were also similar. The small imbalance in efficacy findings was due to the small number of placebo patients. It is not expected to affect interpretation.

[0192] Therefore, among patients with active PsA and psoriasis with BSA ≥ 3%, guselkumab has a favorable safety profile that is probably different from that of IL-17 inhibitors, and Significant improvements in physical function, psoriasis, enthesitis, dactylitis, and quality of life were observed. To identify the key roles of 23 and validate them as therapeutic targets in PsA.

[0193] Additional clinical indicators Routine Assessment of Patient Index Data f Patient Index Data)(RAPID3) The Routine Assessment of Patient Index Data 3 (RAPID3) also demonstrated a significant association between psoriatic arthritis (P sA) was used to evaluate the effect of guselkumab (GUS) on patients. RAPID 3 (0-30) for pain and general health, Multidimensional Health Assessment Questionnaire (Multi- Dimensional Health Assessment Questionna The MDHAQ (Medical Health Assessment Questionnaire) is derived from a numerical rating scale (0-10). A change of 5.1 in PsA was considered a minimally important difference (MID) in PsA. nt difference (MID) and RAPID3 ≤ 3.0 PsA remission was defined as follows.

[0194] Phase 2 trials have shown that patients with rheumatoid arthritis are at increased risk of developing rheumatoid arthritis, regardless of current or prior treatment with standard of care regimens, including anti-TNFα agents. Patients with active PsA and plaque psoriasis ≥ 3% body surface area were randomized 2:1 to receive psoriasis treatment regardless of the severity of the condition. GUS10 was administered at weeks 0, 4, and every 8 weeks (q8w) thereafter until week 44. 0 mg (n=100) or placebo (PBO, n=49) was administered subcutaneously. Week 16 and a <5% improvement from baseline in both swollen and tender joint counts. Patients from either group were eligible for early withdrawal to open-label ustekinumab. Week 24 All remaining PBO patients were converted to receive GUS 100 mg, followed by G US was administered at week 28 and q8w thereafter until week 44. Changes in RAPID3 The proportion of patients achieving MID and PsA disease activity scores (PAs) were compared between treatments. SDAS), GRACE index, Disease Activity in Psoriatic Arthritis (DAPSA) and Modified The correlation between the composite psoriasis disease activity index (mCPDAI) and the RAPID3 score was evaluated using the Spear Evaluation was performed using man correlation.

[0195] The mean RAPID3 score (SD) at baseline was 16.9 (5.19). At 24 weeks, patients in the GUS group had a significantly higher mortality rate than those in the PBO group (0.57 ± 0.51, p < 0.00). A statistically significant and larger improvement was achieved with RAPID3 than with 01 (5.81+ / -6.0), and 50% of patients in the GUS group experienced MI compared with 20.4% in the PBO group. The remission rate was higher in the GUS group than in the PBO group (14.0%). At week 44, patients who continued guselkumab had a significantly higher EGFR response rate (2.4% vs. 2.4%, p=0.022). The mean (SD) improvement in patients further increased from week 24 onwards (6.36 [6.205] to 7. 48[6.310]). Among patients who switched from PBO to GUS at 24 weeks, RA The mean (SD) improvement on PID3 was 2.28 (5.06) compared with 2.28 (5.06) at week 24 on placebo. 0.244) to 7.60 (6.588) at 44 weeks after switching to GUS. The RAPID3 score was significantly higher than the PASDAS score (r=0.84, p<0.00) at 16 weeks. 1), GRACE index (r=0.89, p<0.001), DAPSA (r=0.77, p<0.001) and mCPDAI (r=0.65, p<0.001). .

[0196] Lead Enthesitis Index (LEI) Enthesitis was assessed using the Leeds Enthesitis Index (LEI). Enthesitis during 24 weeks of double-blind treatment, with LOCF imputation for early withdrawal The scores were analyzed. Enthesitis after 24 weeks was analyzed using the measurement data.

[0197] Of the 149 total patients with active PsA, 107 (72%) had baseline (PBO N=31, mean [SD] LEI=2.6 [1.48], median [range]=2. 0[1,6];GUS N=76, mean (SD) LEI=2.7[1.54], median [ 85 patients presented with enthesitis at 24 weeks (PBO → GUS) GUS → GUS N=18; GUS → GUS N=67). With the exception of CRP and IL-1, baseline characteristics of the enthesitis subset were similar to those of the overall population Guselkumab significantly improved mean (SD) change from baseline by week 8, PBO:- 0.4 [1.59], GUS: -1.2 [1.65], p = 0.037), and at 24 weeks (mean [SD] change from baseline, PBO: -0.7 [1.53], GUS: After 24 weeks, the LEI was significantly reduced (-1.5 [1.81], p=0.045). The O→GUS group was significantly lower than the GUS→GUS group (week 56: mean [SD] change from BL = -1.9 [1.59], 70.8% of recovered patients achieved rapid and sustained recovery ( Week 56: Mean [SD] change from BL = −2.1 [1.65], 62 for recovered patients. 5%). Guselkumab also significantly increased the percentage of patients whose enthesitis resolved. Improvement in enthesitis was observed at each enthesitis site evaluated. In patients, improvement was greater in ACR20 responders than in non-responders. Improvement in joint inflammation was associated with an increase in the number of tender joints (R = 0.37, p = 0.001) and swollen joints (R = 0.27 , p=0.020), physician's global assessment of disease activity (R=0.47, p<0.0001) and and reduction in patients' global assessment of disease activity (R=0.32, p=0.005), SF36 PC The changes in S (R = 0.27, p = 0.02) and MCS (R = 0.35, p = 0.002) It correlated with

[0198] Guselkumab treatment correlates with improvement in joint symptoms and patient-reported outcomes in active PsA It results in rapid and sustained improvement of enthesitis in patients with

[0199] dactylitis index Each finger was scored from 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe). Dactylitis was assessed using a total score of 0 to 60. A sensitivity analysis of change up to week 24 (total score 20) was performed. (EE) used LOCF imputation to measure dactylitis scores during 24 weeks of double-blind treatment. The dactylitis after 24 weeks was evaluated using the measurement data.

[0200] Of the 149 patients, 81 had a baseline PBO (PBO N=23, mean [SD]=3 .9 [3.01]; GUS N = 58, mean [SD] = 6.5 [6.15]) and presented with dactylitis. However, 66 patients remained in the active treatment period (PBO → GUS N = 16; GU S→GUS N=50). The dactylitis subset was assessed by the number of swollen joints, the number of tender joints, and CRP. Baseline characteristics were similar to the overall population, except for a higher median value for 16. At weeks 1 and 24, the GUS group showed a significant and greater reduction in dactylitis scores (24 Mean [SD] change from baseline at week 1, PBO: -0.4 [6.06]; GUS: -3.8 [4.93], p=0.006), and the number of patients who recovered from dactylitis was 100% compared with the PBO group. The percentage of dactylitis was higher (Figures 7A and 7B). The mean [SD] change from baseline at week 24, PBO: -0.2 [3.0 4]; GUS: -2.1 [2.21], p=0.003). Improvement of dactylitis observed at 24 weeks Improvement was maintained in the GUS→GUS group (week 56: mean [SD] change from BL = -5.5 [4.84], 75% of recovered patients, PBO → GUS group (56th week: from BL Mean [SD] change = -4.4 [3.50], 93.7% of recovered patients were GUS → G The improvement of dactylitis was significantly greater in GUS-treated patients than in non-responders. and ACR20 / ACR50 responders (Table S5), and TJC (R = 0.38 , p=0.004), SJC (R=0.50, p<0.0001), and HAQ-DI score It correlated significantly with improvement in CORE (R = 0.33, p = 0.013).

[0201] GUS is effective in relieving symptoms of dactylitis in patients with active PsA. The effect on joint function correlates with improvement in joint symptoms and physical function.

[0202] Composite endpoints PASDAS, GRACE, mCPDAI, and DAPSA Psoriatic Arthritis Disease Activity Score (PASDAS), GRAppa Composite Score (GRAC E) Indicators, modified Composite Psoriasis Disease Activity Index (mCPDAI), and disease activity index for psoriatic arthritis The Disease Activity Index (DAPSA) assesses disease activity in psoriatic arthritis (PsA) This composite index was recently developed to address the diverse and highly individual differences in psoriatic arthritis (PsA). Considering the different clinical and radiological manifestations, the composite index is more effective than the traditional scoring system. Compared with MRI, it is more useful in assessing disease activity and defining clinically meaningful therapeutic targets. In recent years, several PsA composite indices have been proposed, but currently, there are no composite disease activity measures. There is no consensus within the rheumatology community regarding the choice of PsA-specific complex Performance data for these indications are lacking. The efficacy of acetaminophen was evaluated in a phase 2 study in patients with active PsA. Performance was assessed using standardized mean differences, effect sizes, and standardized response means.

[0203] Materials and Methods ethics This study (NCT02319759) complies with the Declaration of Helsinki and the Good Clinical Practice Guidelines. The study was conducted in accordance with the guidelines of the ethics committee of each institution. The patient provided written informed consent.

[0204] Experimental design As reported (Deodhar 2018), this double-blind, placebo-controlled, parallel, two-group study Patients enrolled in this multicenter study were centrally randomized (2:1) to receive Guselkumab. Patients were given subcutaneously either the steroid or placebo. The study drugs were provided in identical pre-filled syringes. All patients received the same number of injections at the same time points.

[0205] Patients randomized to guselkumab were randomized to receive 100 mg / kg bw at 0, 4, 12, 20, 28, 36, and 44 weeks. Patients received 100 mg of guselkumab in each eye, and a placebo at week 24. Patients randomized to placebo at weeks 0, 4, 12, and 20, and Patients received 100 mg of guselkumab at weeks 1, 36, and 44.

[0206] Patients with <5% improvement in swollen and tender joint counts (TJC and SJC) at 16 weeks were considered non- Blinded ustekinumab (Janssen Biotech, Inc., Horsham, PA, USA), i.e., according to the approved country-specific prescribing information. and early withdrawal from placebo to ustekinumab or guselkumab to ustekinumab at week 44. The final follow-up visit was at 56 weeks.

[0207] patient Eligible patients had PsA for ≥6 months and met the classification criteria for psoriatic arthritis (CASP). AR) (Taylor 2006), three or more tender joints and three or more tender joints Swollen joints, C-reactive protein (CRP) ≥ 0.3 mg / dL, psoriasis vulgaris BSA ≥ 3% and inadequate response to standard therapy (Deodhar 2018) Adults were included. Patients who had received one prior anti-tumor necrosis factor-α agent were tolerated, but 8 After a 12-week washout, this was limited to 20% of participants. (MTX; ≤25 mg / week), oral corticosteroids (≤10 mg / day prednisone / equivalent), and nonsteroidal anti-inflammatory drugs were permitted but not required for up to 24 weeks. Rufasalazine (≤3 g / day) and leflunomide (≤20 mg / day) were discontinued after 24 weeks. Other disease-modifying antirheumatic drugs (DMARDs) and biologics were prohibited.

[0208] procedure Independent assessors assessed joint tenderness (N=68) and swelling (N=66, excluding buttocks) Patients were assessed for pain (0-100 mm visual analog scale [VAS]), overall disease activity, and mobility (VAS 0–100 mm for arthritis, psoriasis, and both), and physical function ( The researchers reported the Global Assessment of Disease Activity (VAS, 0-100 mm). The assessor also completed a questionnaire and measured serum CRP for each finger and toe (total score 0-10). 60) were assessed for dactylitis (0 - none to 3 - severe) and enthesitis was assessed using the LEI. The PASI assessed the severity and extent of skin disease. The SF-36 assessed physical and mental health. Global HRQoL was assessed. Key efficacy assessments were at screening, baseline, and 4 weeks. The study was conducted every 36, 44, and 56 weeks.

[0209] Outcome As reported (Deodhar A et al. Lancet, 2018, 39 1:2213-24), patients were classified as follows: TJC ≤ 1 / 68, SJC ≤ 1 / 6 6, PASI≦1, patient pain VAS≦15, patient global disease activity VAS (arthritis and psoriasis) ≤20, HAQ-DI ≤0.5, and tenderness at the insertion point score ≤1 (Coates 2010). Patients who met all seven criteria achieved MDA ( Coates LC et al,AnnRheum Dis 2010;69:48- 53).

[0210] PASDAS (Helliwell 2013, Helliwell 2014b) is a the patient's overall VAS (arthritis and psoriasis, 0-100 mm), the physician's overall VAS (0-10 0mm), TJC, SJC, CRP (rescaled to mg / L), enthesitis ( LEI), dactylitis (scores of 0–3 were recoded to 0–1, and any score greater than 0 was recoded to 0–1). The disease activity was calculated using the SF-36 PCS score (which was equivalent to 1). The cutoff was very low (≦1.9), low (>1.9 to ≦3.2), moderate (>3.2 ~<5.4), high (≥5.4) (Helliwell PS et al, Ann R Heum Dis 2010,69:48-53).

[0211] GRACE uses a predefined algorithm to transform the following variables and calculate the total score in the range The arithmetic mean of the desirability function calculated by expressing it as an average between 0 and 1 tic Mean of the Desirability Function)(A MDF), where 1 indicates better than 0: TJC, SJC, HAQ -DI, patient's overall VAS (arthritis and psoriasis, 0-100mm), patient's skin disease activity Assessment VAS (0-100mm), patient's global assessment VAS (arthritis, 0-100mm), PASI, derived PsAQoL index (PsAQoL = 25.355 + [2.367 × HAQ-DI]-[0.234×SF-36 PCS score]-[0.244×SF-3 6 mental component summary score). GRACE then evaluates the following disease activity: Calculated as (1-AMDF) x 10 using the following cutoffs: low (≤2.3), medium (≤2.3), moderate (>2.3 to <4.7), high (≥4.7) (Helliwell PS et al. l,Ann Rheum Dis 2010,69:48-53,Helliwell PS et al, Arthritis Care Res 2014b;66:749 -56).

[0212] The PsA (mCPDA) was used to assess four domains (articular, skin, enthesitis, and dactylitis). The modified CPDAI (Mumtaz2011) for I) is based on TJC, SJC, and HAQ- Calculations were based on DI, PASI, and dactylitis / enthesis scores. Within each domain, 0 Scores of 10 to 3 were assigned according to predefined cutoffs and summed to obtain a total score of 0 to 12. The adjusted disease activity cutoff ([CPDAI / 15]x12) was defined as low (≤3. 2), moderate (>3.2 to <6.4), and high (≥6.4) (Helliwell PS et al, Arthritis Care Res 2014b;66:74 9-56).

[0213] DAPSA was used to measure TJC, SJC, CRP (mg / dL), and pain VAS (0-10) scores. The score was calculated as the sum of the patient's assessment and the patient global assessment VAS (arthritis, 0-10) (Hell iwell2014b). Disease activity cutoffs were remission (≤4), low (>4 to ≤14) ), moderate (>14 to ≦28), and high (>28) (Schoels MM et al, Ann Rheum Dis 2016;75:811-8).

[0214] statistical analysis All efficacy analyses up to week 24 were performed using randomized data handling rules. Patients who received at least one dose of study drug were included (full analysis set). Patients who met the failure criteria (i.e., discontinued study drug due to lack of efficacy / worsening PsA) Initiation or increase of MTX or oral corticosteroids for PsA or initiated a drug and / or therapy prohibited by the protocol) The patient was considered a non-responder to MDA / VLDA up to 24 weeks after treatment failure. This was also the case for patients with missing data or who withdrew early at week 16. For continuous endpoints derived from continuous variables up to the end of the study, and response endpoints, Patients with missing baseline data were excluded. Missing data after enrollment or early withdrawal were imputed. After 24 weeks, all patients The patients were given the ultimate treatment and no statistical comparisons were planned. Therefore, the measurement data were used to 29 patients who switched from placebo to guselkumab early and 24 patients who did not switch at week 16 At week 24 among 86 guselkumab-randomized patients who did not discontinue study drug before week 1 The subsequent data were summarized and the 24-week data of these patients were included as a reference. John 9.2 (SAS Institute, Inc. (Cary, NC, USA)) Statistical analysis was performed using.

[0215] We investigated the correlation between improvements in disease activity detected by each PsA composite index and improvements in HRQoL. To assess the SF-36 PCS score by disease activity status among guselkumab-treated patients, The mean improvements from baseline to week 24 in Changes in composite index scores at weeks 1 and 24 were summarized using descriptive statistics and analyzed by analysis of variance (ANOVA). Between-treatment ratios of change in composite indices were calculated using an analysis of variance (ANOVA). Comparisons between treatments were performed to determine the proportion of patients achieving very low disease activity or remission. Post hoc tests were performed using the Shir exact test.

[0216] The relative performance of each index was evaluated using the treatment group effect size (ES); The absolute mean difference between baseline and week 24 values ​​was calculated based on the standard deviation [SD] at baseline. The ES value was used to evaluate the small ( <0.20), small (≥0.20 to <0.50), medium (≥50 to <0.80), or large (≥0.80) to classify the treatment effect (Altman 1991). Additional comparison statistics is the standardized mean difference es) (SMD); absolute mean difference from baseline [guselkumab-placebo (Primary score [SD] divided by pooled SD of change from baseline at week 24) and and treatment group standardized response means ) (SRM); absolute mean change from baseline to baseline at week 24 Residual disease activity criteria (CRP ≤ upper limit of normal [0 .287mg / dL], dactylitis score=0, enthesitis LEI score=0, PASI≦1, T The proportion of patients who met the criteria (defined as JC ≤ 1 / 68, SJC ≤ 1 / 66) at 24 weeks and PsA-specific composite endpoints of low disease activity / remission, MDA, or VLDA. Achievement was assessed among patients.

[0217] result Breakdown and baseline characteristics This phase 2 trial was conducted in 34 locations (Canada, Germany, Poland, Rome) The study was conducted in the following countries: Italy, Italy, Spain, the United States, and the Netherlands. Screening began on March 27, 2015, and the last patient visit was January 1, 2017. The case was completed on the 17th of the month. The patient breakdown has been reported (Deodhar 2018). Specifically, 149 patients were randomly assigned to receive either placebo (N=49) or guselkumab 100 mg (N= 17 (34.7%) of 49 placebo-treated patients and 100 (34.7%) of 49 placebo-treated patients were randomized to placebo-treated patients. 10 / 100 (10.0%) selkuma-treated patients switched early to ustekinumab at week 16. In the placebo group, 29 of 49 (59.2%) patients were eligible for withdrawal. 28 placebo-to-guselkumab patients were switched to guselkumab at week 24. Patients completed the study through week 44. 86 of 100 patients in the guselkumab group (8 6.0%) patients completed week 24 and continued guselkumab treatment, and 84 patients completed week 4 The study was completed by the fourth week.

[0218] Baseline characteristics were generally similar between randomized groups, with moderate to severe disability and substantial disability. At the beginning of the study, 71.8% of patients showed severe arthritis (mean HAQ-DI: 1.39). % and 54.4% presented with enthesitis and dactylitis, respectively (Deodhar 2018) Baseline mean PASDAS (6.5), GRACE (6.1), and mCPDAI (7 .5), and DAPSA (46.7) scores also showed moderate to severe changes across treatment groups. Furthermore, patients with moderate to severe disease activity at baseline The percentage of patents is PASDAS (both 100%), GRACE (both 100%), mCPDAI (both ~96%), and DAPSA (100% and 99% ) The composite index was comparable between the treatment groups (Figures 3C-3J).

[0219] Validation of a PsA-specific composite index using the SF-36 PCS as an anchor The change from baseline to week 24 in SF-36 PCS scores was The disease activity status defined by each PsA composite index in patients treated with umab was consistent. Specifically, the greatest improvement in SF-36 PCS was remitted / very low / low observed at 24 weeks in patients with active disease (9.5-12.9 across all indices); This improvement was moderate (4.1-6.4, p<0.05) or high (0.6 significantly higher than that observed in patients with disease activity of 0.05% (0.05% ~2.7, p<0.001). (Fig. 4A to Fig. 4D).

[0220] Effect of guselkumab on PsA-specific composite endpoints Placebo-controlled period: Guselkumab compared to placebo significantly improved PASDAS (mean change: -2.5 vs. -0.5, respectively), GRACE (-2.7 vs. -0.4), mCPDAI (- The composite index was evaluated using the PD-L1 / PD-L2 ratio (-3.9 vs. -0.8) and the DAPSA (-23.1 vs. -5.0) When evaluated (all p<0.001; Figures 3D, 3F, 3H, and 3J), the difference from baseline Disease activity was significantly improved from 0 to 24 weeks. PASDAS (35.0% vs. 4.1%, p<0.001), GRACE (29.6% vs. 2.1%, p<0.001), mCPDA I (51.0% vs. 16.7%, p<0.001), and DAPSA (40.0% vs. 12. placebo-treated patients consistently showed a significant improvement in schizophrenia as assessed by a composite index of 2% (p<0.01). A significantly higher proportion of guselkumab-treated patients achieved low disease activity than those without.

[0221] Furthermore, more patients had a ≥18% risk of developing autism based on the PASDAS (8.0% vs. 0, p=0.053). Significantly more patients achieved very low disease activity and achieved DAPSA remission (12.0%). p<0.01) (Figures 3C, 3E, 3G, and 3I). As previously reported (Deodhar 2018), 2.0% of placebo-treated patients As a result, 23% of guselkumab-treated patients achieved MDA (p=0.001) (Figure 3A). A similar response pattern was observed for VLDA (i.e., no placebo-treated patients). vs. 6% of guselkumab-treated patients (p=0.076)) (Figure 3B).

[0222] Active treatment period: In the efficacy analysis population after 24 weeks, PsA complications at 44 weeks The observed mean changes in the combined Disease Activity Index score are shown in Figures 5D, 5F, 5H, and 5J. Data from the same cohort at 24 weeks are included for reference. The improvement achieved with selkuma was sustained through week 44 in patients randomized to guselkumab. In placebo-randomized patients who received guselkumab from weeks 24 to 44, Similar improvements were achieved with placebo-to-guselkumab at week 24. Among these, the proportion of patients with low disease activity was 24 weeks before guselkumab administration. Higher at week 44 than at week 44 (i.e., PASDAS very low + low: 39.3 at week 44) % vs. 7.1% at 24 weeks, GRACE: 39.3% vs. 7.1%, respectively, mCPDAI : 75.0% vs. 25.0%, respectively, and DAPSA remission+low: 50.0% vs. 20.7%), observed at week 44 among patients receiving guselkumab after week 0 The results were generally consistent with those reported in the PASDAS (i.e., 28.6% and 30.1%, respectively). %, GRACE: 39.3% and 42.2%, respectively, mCPDAI: 75.0% % and 63.9%, and DAPSA: 35.7% and 32.1%, respectively.,Fig. 5C,Fig. 5E, 5G, and 5I). In patients randomized to guselkumab, PASDAS and DAPSA The response rate of low disease activity was maintained from week 24 to week 44 (last on trial). Treatment effectiveness assessment, i.e., PASDAS 29.1% → 30.1% and DAPS A: 31.4% → 32.1%, PASDAS: very low disease activity (9.3% → 15 .7%), DAPSA remission (12.8% → 19.0%) (Figure 5C, Figure 5I), MDA (2 The response of IL-16 (6.7% → 34.5%) and VLDA (7.0% → 13.1%) (Figures 5A and 5B) All response speeds increased from week 24 to week 44.

[0223] Performance of PsA-specific composite endpoints in detecting treatment effect at 24 weeks SMD (5.16–8.13), ES (1.12–2.29), and SRM (1.14 The ~1.58) statistic demonstrated that guselkumab significantly improved the efficacy of various PsA endpoints, regardless of the composite endpoint used. showed that it elicited significant efficacy compared to placebo in treating various symptoms (Figure 6 Based on SMD, PASDAS (8.14) and GRACE (8.84) ) index was significantly superior to the mCPDAI (7. 21) and DAPSA (5.16) appeared to be more sensitive (Figure 6A). The SRM statistic also significantly improved the PASDAS (2. 29 and 1.58) and GRACE index (2.18 and 1.55, respectively) AI (1.72 and 1.40, respectively) and DAPSA (1.12 and 1.14, respectively) ) showed higher sensitivity than the conventional method (Figure 6B, Figure 6C).

[0224] Low / very low disease activity, remission, and MD at 24 weeks based on PsA composite index Assessment of residual disease activity among guselkumab-treated patients who achieved A or VLDA PASDAS / GRACE / mCPDAI low or very low disease activity and / or or in ≥ 80% of patients achieving MDA / VLDA, residual skin disease criteria (PASI ≤1) were met, and 75.0% of patients achieved DAPSA remission, and 75.0% of patients achieved DAPSA low 70.4% of patients achieving low disease activity also demonstrated PASI ≤ 1. 100% of patients achieve very low disease activity, DAPSA remission, and / or VLDA In the study, 87.5% of patients achieved MDA, as well as PASDAS and GRAC. 74.1 of patients achieving low disease activity based on E, mCPDAI, and DAPSA ~79.3% of patients met the residual TJC criteria (≤1). showed that 100% of patients achieving VLDA had very low disease activity on the PASDAS scale. , DAPSA remission, and / or MDA in only ~60% of patients, and P Achieved low disease activity based on ASDAS, GRACE, mCPDAI, and DAPSA PsA-specific indicators or MDA / V were met in only 30-40% of patients. The majority of patients who achieve low or very low disease activity or remission with LDA have enthesitis None had dactylitis or dactylitis, but >50% had high CRP (>0.287 mg / dL) All patients who achieved very low disease activity on the PASDAS and all patients who achieved DAPSA remission ~91% of patients who completed the study also met MDA criteria, whereas <40% also met VLDA criteria. fulfilled (Table S4).

[0225] Consideration Guselkumab is indicated for patients with active PsA affected by psoriasis and ≥3% BSA. demonstrated efficacy in a phase 2 trial in patients (Deodhar A et al, Lanc et.2018,391:2213-24). This report from the same study used a composite index. The efficacy of guselkumab was evaluated using the PASDAS / GRACE / mCPDAI / DAPSA scores significantly decreased compared with placebo-treated patients Significantly more guselkumab-treated patients achieved MDA and low disease activity compared with placebo-treated patients Overall, PASDAS / GRACE demonstrated a significant advantage over mCPDAI / D in detecting treatment effects. It was more sensitive than APSA.

[0226] The MDA and VLDA assess joint, skin, and enthesitis disease along with physical function, and both Both are used as response criteria (defining low and very low disease activity, respectively). PASDAS and GRACE are large international cohorts of PsA patients. It was developed using longitudinal observational data from a study (Helliwell 2013). The PASDAS includes the joint, skin, dactylitis, enthesitis, acute phase response, and HRQoL domains. Compared to GRACE, it weights patient and physician global assessments more heavily, while GRACE weights its Equal emphasis is placed on each of the main dimensions (joints, skin, function, QoL, global assessment). Domain-based mCPDAI assessing directional and peripheral joints, skin, enthesitis, and dactylitis used a method to classify disease severity derived from published literature and expert consensus. Although a predetermined cutoff is used, the DAPSA was developed from a clinical cohort of PsA patients. The subjects were assessed for joint disease, acute phase response, and patient assessment of pain and overall disease activity. In this study, the above PsA-specific indices were anchored by the SF-36 PCS score. If this is a component of PASDAS, it will be verified using The results are as follows: remission / very low / low disease according to each index at 24 weeks. The greatest improvements in SF-36 PCS scores occurred in patients with active disease, and these improvements The benefit was observed in patients with moderate or high disease activity at 24 weeks It is noteworthy that the PASDAS, GRACE, and The combined measurement of DAPSA and radiological findings from the golimumab GO-REVEAL PsA trial was also included. The indices were externally validated in PsA using imaging data. It was possible to differentiate the progression of structural damage in peripheral joints with respect to disease outcome (Hell iwell PS et al,Arthritis Care Res 2018,7 0:797-800).

[0227] As reported herein, further efficacy evaluation of guselkumab in Phase 2 PsA trials is ongoing. The values ​​were compared for MDA, VLDA, PASDAS, GRACE, mCPDAI, and DAPSA. Based on the data, guselkumab significantly reduced disease activity from week 0 to week 24 compared with placebo. In addition, patients with cerebrospinal fluid (CSF) showed significantly greater reductions in cerebrospinal fluid (CSF) than placebo-treated patients. Coumab-treated patients demonstrated low disease activity according to each of the PsA-specific composite measures. Improvements in disease activity were maintained through week 44 in patients randomized to guselkumab. The results were observed at 24 weeks and 44 weeks in placebo vs. guselkumab patients. met the primary efficacy endpoint of the trial (i.e., ACR20 response at 24 weeks: 58% vs. 18%, p<0.0001) (Deodhar 2018), as well as the There was also agreement on a common composite measure of disease activity (MDA / VLDA) assessed by the criteria. For example, VLDA, PASDAS, very low disease activity on the more severe side, and DA Response rates based on PSA response were 0.01 at week 24 in patients who continued to receive guselkumab. It is important to note that the results were further improved beyond those reported in Table 5 (Figure 5A-5J).

[0228] Based on SMD, ES, and SRM, PASDAS and AMDF-based GRACE The index will detect changes in disease activity conferred by guselkumab treatment and assess these effects. more sensitive than the mCPDAI and DAPSA indices in distinguishing between placebo and Consistently, data from the golimumab GO-REVEAL trial in PsA Previous analyses using data showed that PASDAS and AMDF were significantly superior to mCPDAI and DAPSA. (Helliwell 2014). SDAS encompasses a broader spectrum of disease symptoms than, for example, DAPSA in most joints. weighted criteria that can take into account the larger effect size. PASDAS was also derived from real patient data using regression analysis. Such methods give more emphasis (weight) to domains that show the greatest change. Both GRACE and CPDAI are modular measurements. Although they cover many important domains, their modular structure Most patients in this study had polyarticular disease and high levels of It must also be remembered that patients have been treated with drugs that have shown clinical efficacy in other situations. , the relative performance of these composite indices may vary.

[0229] Regarding residual disease activity, after guselkumab treatment, PASDAS, GRACE, and mCP were assessed. Based on DAI, DAPSA, and MDA / VLDA indices, low, very low, or tolerant >70% of patients who achieved satisfactory disease activity had mostly residual skin disease, enthesitis, and dactylitis. or no tender joints. Previous assessment based on the golimumab GO-REVEAL trial Consistent results were obtained in (Helliwell 2014). However, P Tertile of patients achieving ASDAS very low disease activity, DAPSA remission, or MDA >1 of the 2016 data, and low disease activity in PASDAS, GRACE, mCPDAI, and DAPSA. In the majority of patients achieving remission / low Despite achieving an active disease state, the majority of these patients have incomplete chronic inflammation. The patients still had elevated CRP levels, indicating a complete recovery. None of the small targets represent a total resolution of disease activity.

[0230] Of all the composite indices evaluated, VLDA appears to represent the most rigorous (achieved by only 13.1% of guselkumab-treated patients at week 44). However, achievement of VLDA was minimal across all aspects of disease assessed except for CRP. The small number of patients achieving VLDA in this study should be documented. However, Tight Control of PsA (TICO) Patients receiving standard or biologic DMARDs in either the PA) trial or observational cohort study Consistent results were recently reported based on a retrospective analysis of 347 patients who received the drug (Co ates LC et al,Arthritis Rheumatol 2018,7 0:345-355). In this paper, we consider the PASDAS to be a comprehensive approach to achieving very low disease activity. All patients and 20 / 22 (90.9%) who achieved DAPSA remission also achieved MDA. However, 15 / 23 (65.2%) patients who met the MDA criteria had a very high PASDAS score. 13 / 23 (56.5%) patients did not achieve low disease activity and met DAPSA remission criteria. This is because the PASDAS very low disease activity and DAPSA remission criteria are more This suggests that it is more stringent and more difficult to achieve than the MDA.

[0231] The future challenge for composite measurement is to strike the right balance between comprehensiveness and feasibility, especially in clinics. Composite indices such as PASDAS and GRACE are Although complex and time-consuming to perform completely, it is a complete evaluation of any patient with PsA. It can be argued that the evaluation of all clinical domains is necessary for the evaluation of these composite indices. If it is worth collecting additional data on some of the In clinics, simply collecting the data required for DAPSA is incomplete. New composite indices may encourage incomplete assessment and give a false impression of overall disease activity. Should it only be used in clinical trials? Currently, the answer is yes (Coate s 2018a), but with further use and evolution, an "abbreviated" version is available for clinical use. Outside of dedicated centers, the use of composite measures may be more complex and clinically relevant. While this may be limited to patients with clinical symptoms, patients with "minimal" symptoms may be able to receive traditional therapy. This can be easily managed using the

[0232] Regarding limitations, the current analysis is limited by the small size of the phase 2 trial from which the data were derived. Furthermore, the SF-36 PCS score is a component of the PASDAS. , and therefore was not an independent criterion in the PASDAS validation. It is also limited by the small number of patients who achieve low / very low / remission disease activity. .

[0233] In conclusion, regardless of the PsA-specific composite endpoint used, guselkumab The efficacy of EGFR-1000 was significantly improved by week 44, and was maintained at week 44. In agreement with the results reported in Deodhar A et al., Lancet. 2018, 3 91:2213-24), these findings suggest that guselkumab may be effective in treating a variety of clinical symptoms of PsA. Effectively treat the condition and achieve clinically meaningful treatment targets such as low / minimal disease activity or remission. The composite score assessed is based on the response or disease involved. There is no uniformity in any of the domains, and the selection of composite scores in clinical trials and clinics This indicates that the choice must be carefully considered to optimize feasibility and performance. .

[0234] Abbreviations and Acronyms AE Adverse Event BCC basal cell carcinoma BMI Body Mass Index BSA body surface area DLQI Skin Condition Questionnaire f-PGA Doctor's Global Assessment of Fingernails hf-PGA General Physician Assessment of the Hand and / or Foot HRQoL Health-related quality of life IGA Investigator's Global Assessment IL Interleukin NAPSI Nail Psoriasis Area and Severity Index NMSC non-melanoma skin cancer PASI Psoriasis Area and Severity Index PRO Patient-reported outcomes PSSD Psoriasis Symptom and Sign Diary SAE serious adverse event ss-IGA scalp-specific investigator's global assessment TNFα inhibitors Tumor necrosis factor-α inhibitors

[0235] table

[0236] [Table 2]

[0237] [Table 3-1]

[0238] [Table 3-2]

[0239] [Table 4-1]

[0240] [Table 4-2]

[0241] [Table 4-3]

[0242] [Table 5]

[0243] [Table 6]

[0244] [Table 7-1]

[0245] [Table 7-2]

[0246] [Table 8]

[0247] [Table 9]

[0248] Further embodiments of the present invention Certain further embodiments of the present invention, in accordance with the disclosure elsewhere herein, are described below. The features of the embodiments of the invention described above as relating to the invention disclosed herein are , also relates to each and every one of these numbered further embodiments. 1. Administered subcutaneously (SC) at a clinically proven safe and clinically proven effective dose an antibody against IL-23 for use in treating a subject or patient with psoriatic arthritis body.

[0249] 2. Have psoriatic arthritis at a clinically proven safe and clinically proven effective dose 1. An antibody against IL-23 for use in treating a subject or patient, the antibody comprising a light chain a light chain variable region and a heavy chain variable region, wherein the light chain variable region is a light chain complementarity determining region 1 (CDRL1) amino acid sequence of SEQ ID NO: 50; the CDRL2 amino acid sequence of SEQ ID NO: 56; a CDRL3 amino acid sequence of SEQ ID NO: 73; the heavy chain variable region a heavy chain complementarity determining region 1 (CDRH1) amino acid sequence of SEQ ID NO: 5; the CDRH2 amino acid sequence of SEQ ID NO: 20; and a CDRH3 amino acid sequence of SEQ ID NO: 44.

[0250] 3. Have psoriatic arthritis at a clinically proven safe and clinically proven effective dose 1. An antibody against IL-23 for use in treating a subject or patient, the antibody having the sequence A light chain variable region of the amino acid sequence of SEQ ID NO: 116 and a heavy chain variable region of the amino acid sequence of SEQ ID NO: 106 and a region.

[0251] 4. The first dose is administered at week 0, followed by administration at week 4 and every 8 weeks thereafter (q8 The use of embodiment 2 or 3, followed by administration of

[0252] 5. The use according to embodiment 4, wherein the dose is between 25 mg and 200 mg.

[0253] 6. The use according to embodiment 5, wherein the dose is 50 mg or 100 mg.

[0254] 7. The use according to embodiment 6, wherein the dose is 100 mg.

[0255] 8. The patient is a responder to antibody therapy and has achieved 24 weeks of antibody therapy. By the time of the American College of Rheumatology Those with a statistically significant improvement in disease activity as determined by the ACR20 standard 8. The use according to any one of embodiments 1 to 7, characterized in that

[0256] 9. The patient is a responder to antibody therapy and has achieved 16 weeks of antibody therapy. By the time of the American College of Rheumatology Those with a statistically significant improvement in disease activity as determined by the ACR20 standard 8. The use according to any one of embodiments 1 to 7, characterized in that

[0257] 10. The patient is a responder to antibody therapy and has completed 24 weeks of antibody therapy. Psoriasis Area and Severity Index 75, 90, and 100 (PASI 75 / 90 / 10) scores were obtained by the eye. 0) are identified as having a statistically significant improvement in disease activity , The use according to any one of embodiments 1 to 7.

[0258] 11. The patient is a responder to antibody therapy and has completed 24 weeks of antibody therapy. American College of Rheumatology 50% and statistically significant improvement in disease activity as determined by the 70% improvement criteria (ACR50 / 70). The use according to any one of embodiments 1 to 7, characterized as having a significant improvement.

[0259] 12. The patient is a responder to antibody therapy and has completed 24 weeks of antibody therapy. Disease activity as determined by the Health Assessment Questionnaire-Disability Index (HAQ-DI) 8. The method of any one of embodiments 1 to 7, wherein the method is identified as having a statistically significant improvement. Use of the above.

[0260] 13. The patient is a responder to antibody therapy and has completed 24 weeks of antibody therapy. Statistical significance of disease activity as determined by the Leeds Enthesitis Index (LEI) Use according to any one of embodiments 1 to 7, which is identified as having a significant improvement .

[0261] 14. The patient is a responder to antibody therapy and has completed 24 weeks of antibody therapy. The dactylitis was assessed by a dactylitis rating scale of 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe). and the embodiments identified as having a statistically significant improvement in disease activity as determined by The use according to any one of aspects 1 to 7.

[0262] 15. The patient is a responder to antibody therapy and has completed 24 weeks of antibody therapy. Disease activity as determined by the Short Form-36 (SF-36) health survey by the end of the study period 8. The method of any one of embodiments 1 to 7, wherein the method is identified as having a statistically significant improvement. Use of the above.

[0263] 16. The patient is a responder to antibody therapy and has completed 24 weeks of antibody therapy. By the time of the eye, the mental and physical component summary (MCS and PCS) scores 1, wherein the patient is identified as having a statistically significant improvement in disease activity as determined by The use according to any one of claims 1 to 7.

[0264] 17. The patient is a responder to antibody therapy and has completed 24 weeks of antibody therapy. Statistically significant disease activity as determined by minimal disease activity (MDA) criteria by the end of the study period The use according to any one of embodiments 1 to 7, which is identified as having an improvement.

[0265] 18. The patient is a responder to antibody therapy and has completed 24 weeks of antibody therapy. Disease activity as determined by the Psoriatic Arthritis Disease Activity Score (PASDAS) Any one of embodiments 1 to 7, wherein the Use as described.

[0266] 19. The patient is a responder to antibody therapy and has completed 24 weeks of antibody therapy. Summary of disease activity as determined by the GRAppa Composite Score (GRACE) index 8. The method of claim 1, wherein the method is characterized as having a statistically significant improvement. Use of.

[0267] 20. The patient is a responder to antibody therapy and has completed 24 weeks of antibody therapy. Disease activity as determined by the modified Composite Psoriasis Disease Activity Index (mCPDAI) 8. The method of any one of embodiments 1 to 7, wherein the method is identified as having a statistically significant improvement. Use of the above.

[0268] 21. The patient is a responder to antibody therapy and has completed 24 weeks of antibody therapy. Disease activity as determined by the Disease Activity Index for Psoriatic Arthritis (DAPSA) Any one of embodiments 1 to 7, wherein the patient is identified as having a statistically significant improvement in motility. The use described in one.

[0269] 22. The patient is a responder to antibody therapy and has completed 24 weeks of antibody therapy. Determined by Routine Assessment of Patient Index Data 3 (RAPID3) Any of embodiments 1 to 7, identified as having a statistically significant improvement in disease activity. Use as described in any one of the following:

[0270] 23. The patient is a responder to antibody treatment and has demonstrated disease progression by week 24 of treatment. Patients were identified as having a statistically significant improvement in disease activity, and disease activity was assessed by the American and the College of Rheumatology 20% Improvement Criteria (ACR20 ), American College of Rheumatology 50% improvement criteria (ACR50), Psoriasis Area and Severity Index 75, 90, and 100 (PASI75 / 90 / 100), American College of Rheumatology y 50% and 70% improvement criteria (ACR50 / 70), Health Assessment Questionnaire Disability Index (H AQ-DI), Leeds Enthesitis Index (LEI), Dactylitis Assessment Score (0 = absent, 1 = 1 = mild, 2 = moderate, 3 = severe), changes in the Short Form Health Survey (SF-36), mental Changes in the Physical and Physical Component Summaries (MCS and PCS), Minimal Disease Activity (M Achievement of psoriatic arthritis disease activity score (PASDAS), GRAppa composite score The GRACE index, the modified Composite Psoriasis Disease Activity Index (mCPDAI), and the psoriatic arthritis index Routine assessment of Disease Activity Scores for Patients with HIV / AIDS (DAPSA) and patient index data3 (RAPID3) The use according to any one of aspects 1 to 7.

[0271] 24.ACR20, ACR50, ACR70, PASI70, PASI90, PSAI 100, MDA, HAQ-DI, LEI / Dactylitis, SF-36 PCS, PASDAS, G RACE, mCPDAI, DAPSA, RAPID3 or MCS score is 1 in 10 patients with initial treatment The use of embodiment 23, measured after 6, 20, 24, or 28 weeks.

[0272] 25. The antibody is in a composition, the composition comprising 100 mg / mL of the antibody in a pharmaceutical composition; 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine and 0.053% (w / v) polysorbate 80, The use according to any one of embodiments 1 to 7, wherein is water at standard conditions.

[0273] 26. The composition further comprises one or more additional agents used to treat psoriatic arthritis. 8. The use according to any one of embodiments 1 to 7, comprising

[0274] 27. Additional medications include immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate, or MTX, anti-B cell surface marker antibody, anti-CD20 antibody, rituximab, TN F inhibitors, corticosteroids, and costimulatory modulators. 26. Use according to claim 26.

[0275] 28. The antibody reduces symptoms or induces a clinical response in patients with psoriatic arthritis. or induce or maintain clinical remission, inhibit disease progression, or have a therapeutic effect in patients The use according to any one of embodiments 1 to 7, which is effective in inhibiting complications of a disease .

Claims

1. A method of treating psoriatic arthritis in a patient, comprising administering a clinically proven antibody to IL-23. administering to said patient a safe and clinically proven effective amount of said antibody, comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region is a light chain complementarity determining region 1 (CDRL1) amino acid sequence of SEQ ID NO: 50; a CDRL2 amino acid sequence of SEQ ID NO: 56; a CDRL3 amino acid sequence of SEQ ID NO: 73; the heavy chain variable region a heavy chain complementarity determining region 1 (CDRH1) amino acid sequence of SEQ ID NO: 5; a CDRH2 amino acid sequence of SEQ ID NO: 20; and a CDRH3 amino acid sequence of SEQ ID NO:

44.

2. The antibody is administered subcutaneously at week 0, subcutaneously at week 4, and every 8 weeks thereafter (q8 10. The method of claim 1, wherein the compound is administered by subcutaneous administration of acetaminophen (w).

3. The method of claim 2, wherein the antibody is administered at a dose of 25 mg to 200 mg.

4. 3. The method of claim 2, wherein the antibody is administered in a dose of 50 mg or 100 mg.

5. 3. The method of claim 2, wherein the antibody is administered at a dose of 100 mg.

6. the patient is a responder to the treatment with the antibody, and By the 24th week of treatment, y Statistically significant improvement in disease activity as determined by the 20% improvement criteria (ACR20) The method of claim 5 , wherein the method is identified as having

7. the patient is a responder to the treatment with the antibody, and By the 16th week of treatment, the American College of Rheumatol Statistically significant improvement in disease activity as determined by the Acute Criteria for 20% Improvement (ACR20) The method of claim 5 identified as having an improvement.

8. the patient is a responder to the treatment with the antibody, and Psoriasis Area and Severity Index (Psoriasis Area and Severity Index) was assessed by 24 weeks of treatment. Severity Index) 75, 90, and 100 (PASI 75 / 90 / 10) 0) are identified as having a statistically significant improvement in disease activity The method according to claim 5 .

9. the patient is a responder to the treatment with the antibody, and By the 24th week of treatment, y Disease activity as determined by 50% and 70% improvement criteria (ACR50 / 70) The method of claim 5, wherein the method is identified as having a statistically significant improvement.

10. the patient is a responder to the treatment with the antibody, and The number of patients with dementia as determined by the Health Assessment Questionnaire Disability Index (HAQ-DI) by 24 weeks of treatment 6. The method of claim 5, wherein the patient is identified as having a statistically significant improvement in disease activity.

11. the patient is a responder to the treatment with the antibody, and By the 24th week of treatment, the Leeds enthesitis index (LEE) was Those with a statistically significant improvement in disease activity as determined by the LEI (Likely a randomized controlled trial). The method of claim 5, wherein the method is identified as:

12. the patient is a responder to the treatment with the antibody, and By the 24th week of treatment, dactylitis was assessed on a scale of 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe). identified as having a statistically significant improvement in disease activity as determined by the score The method of claim 5 .

13. the patient is a responder to the treatment with the antibody, and Disease as determined by the Short Form 36 (SF-36) Health Survey by week 24 of treatment 6. The method of claim 5, wherein the patient is identified as having a statistically significant improvement in disease activity.

14. the patient is a responder to the treatment with the antibody, and Mental and Physical Component Summary (MCS and PCS) scores by 24 weeks of treatment identified as having a statistically significant improvement in disease activity as determined by The method of claim 5.

15. the patient is a responder to the treatment with the antibody, and Statistics of disease activity as determined by minimal disease activity (MDA) criteria by week 24 of treatment.

6. The method of claim 5, wherein the method is identified as having a statistically significant improvement.

16. the patient is a responder to the treatment with the antibody, and By week 24 of treatment, as determined by the Psoriatic Arthritis Disease Activity Score (PASDAS).

6. The method of claim 5, wherein the patient is identified as having a statistically significant improvement in disease activity. 。

17. the patient is a responder to the treatment with the antibody, and GRAAppa Composite Score (GRAAppa Composite score) by 24 weeks of treatment orE) (GRACE) index.

6. The method of claim 5, wherein the method is characterized as

18. the patient is a responder to the treatment with the antibody, and Modified Composite Psoriasis Disease Activity Index (MCA) was assessed by 24 weeks of treatment. e Psoriatic Disease Activity Index) (mCPD and identified as having a statistically significant improvement in disease activity as determined by AI. The method of claim 5 .

19. the patient is a responder to the treatment with the antibody, and By week 24 of treatment, the disease activity score was as determined by the Disease Activity Index for Psoriatic Arthritis (DAPSA).

6. The method of claim 5, wherein the patient is identified as having a statistically significant improvement in disease activity measured by method.

20. the patient is a responder to the treatment with the antibody, and Routine Assessment of Patient Index Data 3 by Week 24 of Treatment essence of Patient Index Data 3) (RAPID3) and (iii) a patient is identified as having a statistically significant improvement in disease activity as determined by The method according to claim 5.

21. The patient is a responder to the treatment with the antibody and has been treated for up to 24 weeks of treatment have already been identified as having a statistically significant improvement in disease activity, and disease activity is American College of Rheumatology 20% improvement criteria (A CR20), American College of Rheumatology 5 0% improvement criteria (ACR50), Psoriasis Area and Severity Index 75, 90, and 100 (PA SI75 / 90 / 100), American College of Rheumatology 50% and 70% Improvement Criteria (ACR50 / 70), Health Assessment Questionnaire Functional Impairment The HAQ-DI, Leeds Enthesitis Index (LEI), and Dactylitis Assessment Score (0 = none) were used. 1 = mild, 2 = moderate, 3 = severe), and changes in the Short-Form Health Survey (SF-36) Changes in mental and physical component summaries (MCS and PCS), minimal disease activity Achievement of mobility (MDA), Psoriatic Arthritis Disease Activity Score (PASDAS), GRAAppa composite score (GRACE) index, modified composite psoriasis disease activity index (mCPDAI), psoriatic Disease Activity Index for Arthritis (DAPSA) and Patient Index Data 3 (RAPID3) The method according to claim 5 .

22. ACR20, ACR50, ACR70, PASI70, PASI90, PSAI100 , MDA, HAQ-DI, LEI / Dactylitis, SF-36 PCS, PASDAS, GRAC E. mCPDAI, DAPSA, RAPID3 or MCS score is 16, 2 or higher in the initial treatment.

6. The method of claim 5, wherein the measurement is made after 0, 24, or 28 weeks.

23. 6. The method of claim 5, wherein the antibody is guselkumab administered subcutaneously.

24. The antibody is in a composition, and the composition comprises 100 mg / mL of antibody in a pharmaceutical composition. , 7.9% (w / v) sucrose, 4.0 mM histidine, and 6.9 mM L-histidine. stidine monohydrochloride monohydrate and 0.053% (w / v) polysorbate 80.

24. The method of claim 23, wherein the diluent is water at normal conditions.

25. administering to said patient one or more additional medications used to treat psoriatic arthritis. The method of claim 1 further comprising:

26. The additional drug may be an immunosuppressant, a nonsteroidal anti-inflammatory drug (NSAID), methotrexate, or Cert (MTX), anti-B cell surface marker antibody, anti-CD20 antibody, rituximab, TNF 26. The compound of claim 25, wherein the compound is selected from the group consisting of a steroid inhibitor, a corticosteroid, and a costimulatory modulator. The method described below.

27. The antibody reduces symptoms of psoriatic arthritis or induces a clinical response in the patient. or induce or maintain clinical remission, inhibit progression of the disease, or 10. The method of claim 1, wherein the method is effective in inhibiting disease complications in a mammal.

28. A method of treating psoriatic arthritis in a patient, comprising administering to said patient an antibody against IL-23. and administering to a subject a complete and effective amount of the antibody having the amino acid sequence of SEQ ID NO:

116. and a heavy chain variable region of the amino acid sequence of SEQ ID NO:

106.

29. The antibody is administered subcutaneously at week 0, subcutaneously at week 4, and every 8 weeks thereafter (q8 29. The method of claim 28, wherein the compound is administered by subcutaneous administration of HCl.w).

30. 29. The method of claim 28, wherein the antibody is administered at a dose of 25 mg to 200 mg.

31. 29. The method of claim 28, wherein the antibody is administered at a dose of 50 mg or 100 mg.

32. 29. The method of claim 28, wherein the antibody is administered at a dose of 100 mg.

33. the patient is a responder to the treatment with the antibody, and By the 24th week of treatment, y Statistically significant improvement in disease activity as determined by the 20% improvement criteria (ACR20) 33. The method of claim 32, wherein the marker is identified as having:

34. the patient is a responder to the treatment with the antibody, and By the 16th week of treatment, y Statistically significant improvement in disease activity as determined by the 20% improvement criteria (ACR20) 33. The method of claim 32, wherein the marker is identified as having:

35. the patient is a responder to the treatment with the antibody, and The Psoriasis Area and Severity Index 75, 90, and 100 (PASI 75 / 100) scores were assessed by the 24th week of treatment. as having a statistically significant improvement in disease activity as determined by a 90 / 100 scale The method of claim 32, wherein the

36. the patient is a responder to the treatment with the antibody, and By the 24th week of treatment, Disease activity as determined by 50% and 70% improvement criteria (ACR50 / 70) 33. The method of claim 32, wherein the patient is identified as having a statistically significant improvement in

37. the patient is a responder to the treatment with the antibody, and The number of patients with dementia as determined by the Health Assessment Questionnaire Disability Index (HAQ-DI) by 24 weeks of treatment 33. The method of claim 32, wherein the patient is identified as having a statistically significant improvement in disease activity. 。

38. the patient is a responder to the treatment with the antibody, and Disease activity as determined by the Leeds Enthesitis Index (LEI) by 24 weeks of treatment 33. The method of claim 32, wherein the patient is identified as having a statistically significant improvement in

39. the patient is a responder to the treatment with the antibody, and By the 24th week of treatment, dactylitis was assessed on a scale of 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe). identified as having a statistically significant improvement in disease activity as determined by the score 33. The method of claim 32.

40. the patient is a responder to the treatment with the antibody, and Disease as determined by the Short Form 36 (SF-36) Health Survey by week 24 of treatment 33. The method of claim 32, wherein the patient is identified as having a statistically significant improvement in disease activity. 。

41. the patient is a responder to the treatment with the antibody, and Mental and Physical Component Summary (MCS and PCS) scores by 24 weeks of treatment identified as having a statistically significant improvement in disease activity as determined by 33. The method of claim 32.

42. the patient is a responder to the treatment with the antibody, and Statistics of disease activity as determined by minimal disease activity (MDA) criteria by week 24 of treatment.

33. The method of claim 32, wherein the patient is identified as having a statistically significant improvement.

43. the patient is a responder to the treatment with the antibody, and By week 24 of treatment, as determined by the Psoriatic Arthritis Disease Activity Score (PASDAS).

33. The method of claim 32, which is identified as having a statistically significant improvement in disease activity. Law.

44. the patient is a responder to the treatment with the antibody, and Disease as determined by the GRAAppa Composite Score (GRACE) index by 24 weeks of treatment 33. The method of claim 32, wherein the patient is identified as having a statistically significant improvement in activity.

45. the patient is a responder to the treatment with the antibody, and The disease progression as determined by the modified Composite Psoriasis Disease Activity Index (mCPDAI) by week 24 of treatment was assessed.

33. The method of claim 32, wherein the patient is identified as having a statistically significant improvement in disease activity. 。

46. the patient is a responder to the treatment with the antibody, and By week 24 of treatment, the disease activity score was as determined by the Disease Activity Index for Psoriatic Arthritis (DAPSA).

33. The method of claim 32, wherein the patient is identified as having a statistically significant improvement in disease activity measured by How to do it.

47. the patient is a responder to the treatment with the antibody, and By week 24 of treatment, by routine assessment of patient index data 3 (RAPID3) 33. The patient is identified as having a statistically significant improvement in disease activity as determined by the method of claim 32. The method described below.

48. The patient is a responder to the treatment with the antibody and has been treated for up to 24 weeks of treatment have already been identified as having a statistically significant improvement in disease activity, and disease activity is American College of Rheumatology 20% improvement criteria (A CR20), American College of Rheumatology 5 0% improvement criteria (ACR50), Psoriasis Area and Severity Index 75, 90, and 100 (PA SI75 / 90 / 100), American College of Rheumatology 50% and 70% Improvement Criteria (ACR50 / 70), Health Assessment Questionnaire Functional Impairment The HAQ-DI, Leeds Enthesitis Index (LEI), and Dactylitis Assessment Score (0 = none) were used. 1 = mild, 2 = moderate, 3 = severe), and changes in the Short-Form Health Survey (SF-36) Changes in mental and physical component summaries (MCS and PCS), minimal disease activity Achievement of mobility (MDA), Psoriatic Arthritis Disease Activity Score (PASDAS), GRAAppa composite score (GRACE) index, modified composite psoriasis disease activity index (mCPDAI), psoriatic Disease Activity Index for Arthritis (DAPSA) and Patient Index Data 3 (RAPID3) 33. The method of claim 32.

49. ACR20, ACR50, ACR70, PASI70, PASI90, PSAI100 , MDA, HAQ-DI, LEI / Dactylitis, SF-36 PCS, PASDAS, GRAC E. mCPDAI, DAPSA, RAPID3 or MCS score is 16, 2 or higher in the initial treatment.

33. The method of claim 32, wherein the measurement is made after 0, 24, or 28 weeks.

50. 33. The method of claim 32, wherein the antibody is guselkumab administered subcutaneously.

51. The antibody is in a composition, and the composition comprises 100 mg / mL of antibody in a pharmaceutical composition. , 7.9% (w / v) sucrose, 4.0 mM histidine, and 6.9 mM L-histidine. stidine monohydrochloride monohydrate and 0.053% (w / v) polysorbate 80.

51. The method of claim 50, wherein the diluent is water at normal conditions.

52. administering to said patient one or more additional medications used to treat psoriatic arthritis.

30. The method of claim 28, further comprising:

53. The additional drug may be an immunosuppressant, a nonsteroidal anti-inflammatory drug (NSAID), methotrexate, or Cert (MTX), anti-B cell surface marker antibody, anti-CD20 antibody, rituximab, TNF 52. The compound of claim 52, wherein the compound is selected from the group consisting of a steroid inhibitor, a corticosteroid, and a costimulatory modulator. The method described below.

54. The antibody reduces symptoms of psoriatic arthritis or induces a clinical response in the patient. or induce or maintain clinical remission, inhibit progression of the disease, or 29. The method of claim 28, wherein the method is effective in inhibiting disease complications in the rat.

55. A method for treating psoriatic arthritis in patients who are non-responders to TNF inhibitors. Therefore, antibodies against IL-23 are administered to said patients in a clinically proven, safe and clinically proven manner. and administering to the subject an effective amount of the antibody, wherein the antibody comprises a light chain variable region and a heavy chain variable region. and wherein the light chain variable region comprises the light chain complementarity determining region 1 (CDRL1) amino acid sequence of SEQ ID NO:

50. the CDRL2 amino acid sequence of SEQ ID NO:56 and the CDRL3 amino acid sequence of SEQ ID NO:73 and the heavy chain variable region comprises a heavy chain complementarity determining region 1 (CDRH1) of SEQ ID NO:

5. ) amino acid sequence of SEQ ID NO: 20, and CDRH2 amino acid sequence of SEQ ID NO: 44 and a three amino acid sequence.

56. The TNF inhibitor is adalimumab or etanercept 56. The method of claim 55, wherein the agonist is ernacept.

57. The patient has a PASI 70 / 90 / 100 and / or ACR 20 / 50 / 70 score By measuring, non-responders to TNF inhibitors are determined.

57. The method of claim 56.

58. A method for treating psoriatic arthritis in patients who are non-responders to TNF inhibitors. Therefore, antibodies against IL-23 are administered to said patients in a clinically proven, safe and clinically proven manner. and administering to a subject an effective amount of the antibody having a light chain of the amino acid sequence of SEQ ID NO:

116. and a heavy chain variable region of the amino acid sequence of SEQ ID NO:

106.

59. 59. The method of claim 58, wherein the TNF inhibitor is adalimumab or etanercept. 。

60. The patient has a PASI 70 / 90 / 100 and / or ACR 20 / 50 / 70 score By measuring, non-responders to TNF inhibitors are determined.

60. The method of claim 59.

61. For the treatment of moderate to severe psoriatic arthritis in adult patients who are candidates for systemic treatment or phototherapy. a method of treating a patient with an antibody against IL-23, the method comprising administering to said patient an antibody against IL-23 in a clinically proven, safe and effective manner; and administering to a subject a clinically proven effective amount of the antibody, wherein the antibody has a light chain of SEQ ID NO:

50. Complementarity determining region 1 (CDRL1) amino acid sequence and CDRL2 amino acid sequence of SEQ ID NO:56 and the CDRL3 amino acid sequence of SEQ ID NO: 73 and the heavy chain complementarity determining region 1 ( CDRH1) amino acid sequence of SEQ ID NO:20 and CDRH2 amino acid sequence of SEQ ID NO:44 and a CDRH3 amino acid sequence of The antibody was administered by subcutaneous injection at a concentration of 100 mg per day, and the antibody was diluted to 7.9% (w / v). cellulose, 4.0 mM histidine, and 6.9 mM L-histidine monohydrochloride monohydrate and 0.053% (w / v) polysorbate 80. The method is as follows: the concentration is 100 mg / mL in a medium, and the diluent is water at standard conditions.

62. For the treatment of moderate to severe psoriatic arthritis in adult patients who are candidates for systemic treatment or phototherapy. a method of treating a patient with an antibody against IL-23, the method comprising administering to said patient an antibody against IL-23 in a clinically proven, safe and effective manner; and administering to a subject a clinically proven effective amount of the antibody of SEQ ID NO:

116. a light chain variable region of the amino acid sequence of SEQ ID NO: 106; and a heavy chain variable region of the amino acid sequence of SEQ ID NO: 107; Doses consist of 100 ml administered by subcutaneous injection at weeks 0, 4, and every 8 weeks thereafter. g, and the antibody was dissolved in 7.9% (w / v) sucrose, 4.0 mM histidine, and , 6.9 mM L-histidine monohydrochloride monohydrate, and 0.053% (w / v) Polysol and bate 80 at a concentration of 100 mg / mL in a single-dose pre-filled syringe containing The diluent is water at standard conditions.

Images