A safe and effective method for treating lupus with anti-IL12 / IL23 antibodies

Abstract

A method of treating active systemic lupus erythematosus (SLE) in a patient by administering a clinically proven, safe, and clinically proven, effective amount of an anti-IL-12 / IL-23p40 antibody or an anti-IL-23 antibody, such as the anti-IL-12 / IL-23p40 antibody ustekinumab, wherein the patient achieves a significant improvement in disease activity.

Description

Technical Field

[0001] (Sequence Listing) This application has been electronically filed in ASCII format and includes a sequence listing that is hereby incorporated by reference in its entirety. A copy of the ASCII was created on September 6, 2018, has the name JBI5139WOPCTSEQLIST.txt, and is 13 / 382 bytes in size.

[0002] (Field of the Invention) The present invention relates to a method for treating lupus with an antibody that binds to human IL-12 and / or human IL-23 protein. Specifically, the present invention relates to a method for treating active systemic lupus erythematosus (SLE) in a patient by administering a clinically proven safe and clinically proven effective amount of an anti-IL-12 / IL-23p40 antibody or an anti-IL-23 antibody, such as ustekinumab, an anti-IL-12 / IL-23p40 antibody, and a specific pharmaceutical composition of the antibody.

Background Art

[0003] Interleukin (IL)-12 is a secreted heterodimeric cytokine composed of two disulfide-bonded glycosylated protein subunits (designated p35 and p40 for their approximate molecular weights). IL-12 is produced mainly by antigen-presenting cells and promotes cellular immunity by binding to a two-chain receptor complex expressed on the surface of T cells or natural killer (NK) cells. The IL-12 receptor β-1 (IL-12Rβ1) chain binds to the p40 subunit of IL-12, providing the primary interaction between IL-12 and its receptor. However, it is the ligation of the second receptor chain, IL-12Rβ2, to IL-12p35 that confers intracellular signaling (e.g., STAT4 phosphorylation) and activation of receptor-bearing cells (Presky et al, 1996). IL-12 signaling in parallel with antigen presentation is thought to cause T cell differentiation toward a T helper 1 (Th1) phenotype characterized by interferon γ (IFNγ) production (Trinchieri, 2003). Th1 cells are thought to promote immunity against several intracellular pathogens, generate complement-fixing antibody isotypes, and contribute to tumor immune surveillance. Thus, IL-12 is considered an important component of the host defense immune mechanism.

[0004] The p40 protein subunit of IL-12 has also been found to be able to associate with a distinct protein subunit designated p19 to form a new cytokine, IL-23 (Oppman et al, 2000). IL-23 also signals through a two-chain receptor complex. Since the p40 subunit is shared between IL-12 and IL-23, the IL-12Rβ1 chain is also shared between IL-12 and IL-23. However, it is the ligation of the second component of the IL-23 receptor complex, IL-23p19, that confers IL-23-specific intracellular signaling (e.g., STAT3 phosphorylation) and subsequent IL-17 production by T cells (Parham et al (2002), Aggarwal et al (2003)). Recent studies have shown that the biological functions of IL-23 and IL-12 are different, despite the structural similarities between these two cytokines (Langrish et al, 2005).

[0005] Neutralization of IL-12 by antibodies is effective in the treatment of animal models of psoriasis, multiple sclerosis (MS), rheumatoid arthritis, inflammatory bowel disease, insulin-dependent (type 1) diabetes mellitus, and uveitis, and thus abnormal regulation of IL-12 and the Th1 cell population has been associated with many immune-mediated diseases (Leonard et al (1995), Hong et al (1999), Malfait et al (1998), Davidson et al (1998)). IL-12 has also been shown to play an important role in the etiology of SLE in two independent mouse models of systemic lupus erythematosus (Kikawada et al. 2003; Dai et al. 2007).

[0006] Systemic lupus erythematosus (SLE) is a complex, chronic, heterogeneous autoimmune disease of unknown etiology that can affect almost all organ systems and follows a relapsing and remitting disease course. Systemic lupus erythematosus occurs far more frequently in women than in men, with some studies reporting a nine-fold or greater frequency, and often presents in the childbearing years of 15 to 45 years of age. This disease is more commonly seen in African-Caribbean, Asian, and Hispanic populations. In SLE, the immune system attacks the body's cells and tissues, resulting in inflammation and tissue damage that can harm the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous system. Approximately half of the subjects diagnosed with SLE who have a disease threatening the organs may take several years to diagnose subjects without organ involvement. Some of the main symptoms in newly diagnosed lupus patients are arrhythmia (62%) and skin symptoms (new photosensitivity; 20%), persistent fever and malaise. 39 The estimated annual incidence of lupus varies from 1.8 to 7.6 cases per 100,000 people, and the prevalence worldwide ranges from 14 to 172 cases per 100,000 people. 39Patients with mild disease mostly have skin rashes and joint pain and require more aggressive treatment; regimens include non-steroidal anti-inflammatory drugs (NSAIDs), anti-malarial drugs (e.g., hydroxychloroquine, chloroquine, or quinacrine), and / or low-dose corticosteroids. Patients with more severe disease can experience various serious conditions depending on the organ systems involved, including potential renal failure, endocarditis or myocarditis, pneumonia, pregnancy complications, stroke, neurological complications, vasculitis, and cytopenia associated with risks of bleeding or infection. Common treatments for more severe disease include methotrexate (MTX), azathioprine, cyclophosphamide, cyclosporine, high-dose corticosteroids, biological B-cell cytotoxic agents, or B-cell regulatory factors, and other immunomodulatory agents. Patients with severe SLE have a shortened lifespan of 10 - 30 years, mainly due to the disease, standard care therapies, and / or complications of accelerated atherosclerotic disease. In addition, SLE substantially affects quality of life, work productivity, and medical costs. Existing therapies for SLE are generally either cytotoxic agents or immunomodulatory agents and can have significant safety risks. Newer treatments for SLE provide only slightly more benefit than standard care therapies.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0007] Accordingly, there is a great unmet need for new alternative treatments that can provide significant benefits in this disease without incurring high safety risks.

MEANS FOR SOLVING THE PROBLEMS

[0008] For simplicity, general and preferred embodiments are defined respectively by the independent and dependent claims appended hereto, which are incorporated herein by reference. Other preferred embodiments, features, and advantages will become apparent from the following detailed description of the invention in conjunction with the accompanying drawings.

[0009] In certain embodiments, the present invention provides a clinically proven safe and clinically proven effective method for treating lupus in a patient, comprising administering to the patient an anti-IL-12 and / or anti-IL-23 antibody intravenously (IV) and / or subcutaneously (SC).

[0010] In certain embodiments, the present invention provides a clinically proven safe and clinically proven effective method for treating lupus in a patient, comprising administering to the patient an anti-IL-12 and / or anti-IL-23 antibody intravenously (IV) and / or subcutaneously (SC), wherein the anti-IL-12 and / or anti-IL-23 antibody is an anti-IL-12 / 23p40 antibody.

[0011] In certain embodiments, the present invention provides a clinically proven safe and clinically proven effective method for treating lupus in a patient, comprising administering to the patient an anti-IL-12 and / or anti-IL-23 antibody intravenously (IV) and / or subcutaneously (SC), wherein the anti-IL-12 and / or anti-IL-23 antibody is anti-IL-12 / 23p40.

[0012] In certain embodiments, the present invention provides a clinically proven safe and clinically proven effective method for treating lupus in a patient, comprising administering to the patient an anti-IL-12 and / or anti-IL-23 antibody intravenously (IV) and / or subcutaneously (SC), wherein the anti-IL-12 and / or anti-IL-23 antibody is an anti-IL-12 / 23p40 antibody (corresponding to ustekinumab (Stelara® of Janssen Biotech, Inc.)) comprising (i) the heavy chain CDR amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, and (ii) the light chain CDR amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6.

[0013] In certain embodiments, the invention provides a clinically proven safe and clinically proven effective method for treating lupus in a patient, comprising administering to the patient an anti-IL-12 and / or anti-IL-23 antibody intravenously (IV) and / or subcutaneously (SC), wherein the anti-IL-12 and / or anti-IL-23 antibody is an anti-IL-12 / 23p40 antibody (corresponding to ustekinumab (Stelara® of Janssen Biotech, Inc.)) comprising (i) the heavy chain variable domain amino acid sequence of SEQ ID NO: 7 and (ii) the light chain variable domain amino acid sequence of SEQ ID NO: 8.

[0014] In certain embodiments, the invention provides a clinically proven safe and clinically proven effective method for treating lupus in a patient, comprising administering to the patient an anti-IL-12 and / or anti-IL-23 antibody intravenously (IV) and / or subcutaneously (SC), wherein the anti-IL-12 and / or anti-IL-23 antibody is an anti-IL-12 / 23p40 antibody ustekinumab (Stelara®) (corresponding to ustekinumab (Stelara® of Janssen Biotech, Inc.)) comprising (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain variable domain amino acid sequence of SEQ ID NO: 11.

[0015] In certain embodiments, the invention provides a composition comprising an anti-IL-12 and / or anti-IL-23 antibody for use in a clinically proven safe and clinically proven effective method for treating lupus in a patient, comprising administering to the patient a pharmaceutical composition comprising the anti-IL-12 and / or anti-IL-23 antibody intravenously (IV) and / or subcutaneously (SC).

[0016] In certain embodiments, the invention provides a composition comprising an anti-IL-12 and / or anti-IL-23 antibody for use in a clinically proven safe and clinically proven effective method of treating lupus in a patient, the method comprising intravenous (IV) and / or subcutaneous (SC) administration of a pharmaceutical composition comprising the anti-IL-12 and / or anti-IL-23 antibody, wherein the anti-IL-12 and / or anti-IL-23 antibody is an anti-IL-12 / 23p40 antibody.

[0017] In certain embodiments, the invention provides a composition comprising an anti-IL-12 and / or anti-IL-23 antibody for use in a clinically proven safe and clinically proven effective method of treating lupus in a patient, the method comprising intravenous (IV) and / or subcutaneous (SC) administration of a pharmaceutical composition comprising the anti-IL-12 and / or anti-IL-23 antibody, wherein the anti-IL-12 and / or anti-IL-23 antibody is an anti-IL-12 / 23p40 antibody.

[0018] In certain embodiments, the invention provides a composition comprising an anti-IL-12 and / or anti-IL-23 antibody for use in a clinically proven safe and clinically proven effective method of treating lupus in a patient, the method comprising intravenous (IV) and / or subcutaneous (SC) administration of a pharmaceutical composition comprising the anti-IL-12 and / or anti-IL-23 antibody, wherein the anti-IL-12 and / or anti-IL-23 antibody is an anti-IL-12 / 23p40 antibody comprising (i) the heavy chain CDR amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, and (ii) the light chain CDR amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6.

[0019] In certain embodiments, the present invention provides a composition comprising an anti-IL-12 and / or anti-IL-23 antibody for use in a clinically proven safe and clinically proven effective method of treating lupus in a patient, the method comprising administering to the patient an anti-IL-12 and / or anti-IL-23 antibody-containing pharmaceutical composition intravenously (IV) and / or subcutaneously (SC), wherein the anti-IL-12 and / or anti-IL-23 antibody is an anti-IL-12 / 23p40 antibody comprising (i) the heavy chain variable domain amino acid sequence of SEQ ID NO: 7 and (ii) the light chain variable domain amino acid sequence of SEQ ID NO: 8.

[0020] In certain embodiments, the present invention provides a composition comprising an anti-IL-12 and / or anti-IL-23 antibody for use in a clinically proven safe and clinically proven effective method of treating lupus in a patient, the method comprising administering to the patient an anti-IL-12 and / or anti-IL-23 antibody-containing pharmaceutical composition intravenously (IV) and / or subcutaneously (SC), wherein the anti-IL-12 and / or anti-IL-23 antibody is ustekinumab (Stelara®), an anti-IL-12 / 23p40 antibody comprising (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain amino acid sequence of SEQ ID NO: 11.

[0021] In certain embodiments, the present invention provides a pharmaceutical composition for intravenous (IV) administration comprising an anti-IL-12 / 23p40 antibody comprising (i) the heavy chain CDR amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and (ii) the light chain CDR amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 in a solution comprising 10 mM L-histidine, 8.5% (w / v) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL disodium EDTA dehydrate at pH 6.0.

[0022] In certain embodiments, the present invention provides a pharmaceutical composition for subcutaneous (SC) administration comprising an anti-IL-12 / 23p40 antibody comprising (i) the heavy chain CDR amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, and (ii) the light chain CDR amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, in a solution comprising 6.7 mM L-histidine, 7.6% (w / v) sucrose, 0.004% (w / v) polysorbate 80, at pH 6.0.

[0023] In certain embodiments, the present invention provides a pharmaceutical composition for intravenous (IV) administration comprising an anti-IL-12 / 23p40 antibody comprising (i) the heavy chain variable domain amino acid sequence of SEQ ID NO: 7, and (ii) the light chain variable domain amino acid sequence of SEQ ID NO: 8, in a solution comprising 10 mM L-histidine, 8.5% (w / v) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL disodium EDTA dehydrate, at pH 6.0.

[0024] In certain embodiments, the present invention provides a pharmaceutical composition for subcutaneous (SC) administration comprising an anti-IL-12 / 23p40 antibody comprising (i) the heavy chain variable domain amino acid sequence of SEQ ID NO: 7, and (ii) the light chain variable domain amino acid sequence of SEQ ID NO: 8, in a solution comprising 6.7 mM L-histidine, 7.6% (w / v) sucrose, 0.004% (w / v) polysorbate 80, at pH 6.0.

[0025] In certain embodiments, the present invention provides a pharmaceutical composition for intravenous (IV) administration comprising ustekinumab (Stelara®), an anti-IL-12 / 23p40 antibody, comprising (i) the heavy chain amino acid sequence of SEQ ID NO: 10, and (ii) the light chain amino acid sequence of SEQ ID NO: 11, in a solution comprising 10 mM L-histidine, 8.5% (w / v) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL disodium EDTA dehydrate, at pH 6.0.

[0026] In certain embodiments, the present invention provides a pharmaceutical composition for subcutaneous (SC) administration comprising ustekinumab (Stelara®), an anti-IL-12 / 23p40 antibody, which comprises (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain amino acid sequence of SEQ ID NO: 11, in a solution comprising 6.7 mM L-histidine, 7.6% (w / v) sucrose, 0.004% (w / v) polysorbate 80 at pH 6.0.

[0027] In certain embodiments, the present invention provides a method for treating lupus in a patient comprising subcutaneous administration of an anti-IL-23 specific antibody (also referred to as an IL-23p19 antibody), such as guselkumab, risankizumab (BI-655066), and tildrakizumab (MK-322).

[0028] In certain embodiments, the composition used in the method of the present invention comprises a pharmaceutical composition comprising an anti-IL-23 specific antibody in an amount of about 1.0 μg / ml to about 1000 mg / ml, specifically in an amount of 50 mg or 100 mg. In a preferred embodiment, the anti-IL-23 specific antibody is guselkumab at 100 mg / mL of the pharmaceutical composition, and comprises 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, and 0.053% (w / v) polysorbate 80, and the diluent is water at standard conditions.

[0029] In certain embodiments, the composition used in the method of the present invention comprises an isolated anti-IL23 specific antibody, such as guselkumab at 100 mg / mL of the pharmaceutical composition, 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, and 0.053% (w / v) polysorbate 80, and the diluent is water at standard conditions.

[0030] In certain embodiments, the method of the invention comprises administering a pharmaceutical composition comprising an isolated anti-IL-23 specific antibody, such as guselkumab, at 100 mg / mL. The pharmaceutical composition contains 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, and 0.053% (w / v) polysorbate 80, and the diluent is water at standard conditions.

[0031] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, and the light chain variable region comprising the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6.

[0032] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, and the light chain variable region comprising the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w).

[0033] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, the light chain variable region comprises the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6, and the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or the antibody is administered as an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and the initial IV dose is 6.0 mg / kg ± 1.5 mg / kg.

[0034] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, the light chain variable region comprises the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6, and the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or the antibody is administered as an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and the initial IV dose is 260 mg for patients with a body weight of ≧ 35 kg to ≦ 55 kg, 390 mg for patients with a body weight of > 55 kg to ≦ 85 kg, and 520 mg for patients with a body weight of > 85 kg.

[0035] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, the light chain variable region comprises the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6, the antibody is administered at an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or the antibody is administered at an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and the SC dose is 90 mg.

[0036] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, the light chain variable region comprising the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6, the antibody being administered at an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or the antibody being administered at an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), the patient being a responder to treatment with the antibody, and having a statistically significant improvement in disease activity as determined by an improvement in the systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) score of ≧4 (SRI-4 response) with an improvement starting at week 12 of treatment and a response lasting up to 48 weeks by week 24 of treatment with the antibody.

[0037] In certain embodiments, the invention provides a method of treating a patient's active systemic lupus erythematosus (SLE) comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, the light chain variable region comprising the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6, the antibody being administered at an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or the antibody being administered at an initial subcutaneous (SC) dose, followed by SC doses every 8 weeks (q8w), the patient being a responder to treatment with the antibody, having an improvement starting at week 12 of treatment, and having a statistically significant reduction as defined by a new British Isles Lupus Assessment Group (BILAG) flare risk of ≧1 new BILAG A domain score, or ≧2 new BILAG B domain scores, by week 24 of treatment with the antibody.

[0038] In certain embodiments, the invention provides a method of treating a patient's active systemic lupus erythematosus (SLE) comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, the light chain variable region comprising the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6, the antibody being administered at an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or the antibody being administered at an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), the patient being a responder to treatment with the antibody, having improvement starting at week 12 after the start of treatment, and there being a statistically significant increase in the proportion of patients having a 50% improvement from baseline in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score for patients treated with the antibody compared to patients treated with placebo.

[0039] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, the light chain variable region comprising the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6, the antibody being administered at an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or the antibody being administered at an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and the patient being identified as a responder to treatment with the antibody and having a statistically significant improvement in disease activity as determined by a 50% improvement from baseline joint disease activity starting at week 12 of treatment and by week 24 of treatment with the antibody.

[0040] In certain embodiments, the invention provides a method of treating a patient's active systemic lupus erythematosus (SLE) comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, the antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, the light chain variable region comprising the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6, the antibody being administered at an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or the antibody being administered at an initial subcutaneous (SC) dose, followed by SC doses every 8 weeks (q8w), the patient being identified as a responder to treatment with the antibody and having a statistically significant improvement in disease activity by week 24 of treatment that is sustained through 1 year of treatment, the disease activity being determined by one or more criteria selected from the group consisting of a decrease from baseline in the systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) score of ≧4 (SRI-4 response), the proportion of patients having a 50% improvement from baseline in the cutaneous lupus erythematosus disease area and severity index (CLASI) score, and a 50% improvement from baseline in joint disease activity.

[0041] In certain embodiments, the invention provides a method of treating a patient's active systemic lupus erythematosus (SLE) comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, the antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, a CDRH2 amino acid sequence of SEQ ID NO: 2, and a CDRH3 amino acid sequence of SEQ ID NO: 3, the light chain variable region comprising a complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, a CDRL2 amino acid sequence of SEQ ID NO: 5, and a CDRL3 amino acid sequence of SEQ ID NO: 6, the antibody being administered at an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or the antibody being administered at an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), the antibody for use in IV administration being in a pharmaceutical composition comprising a solution containing 10 mM L-histidine, 8.5% (w / v) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL disodium EDTA dehydrate, at pH 6.0.

[0042] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, the light chain variable region comprises the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6, the antibody is administered at an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or the antibody is administered at an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and the antibody for use in SC administration is in a pharmaceutical composition comprising a solution containing 6.7 mM L-histidine, 7.6% (w / v) sucrose, 0.004% (w / v) polysorbate 80 at pH 6.0.

[0043] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, the light chain variable region comprises the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6, and the method further comprises administering to the patient one or more additional agents used to treat lupus.

[0044] In certain embodiments, the present invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3, the light chain variable region comprises the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO: 6, and the method further comprises administering to the patient one or more additional agents used to treat lupus, the additional agent being selected from the group consisting of immunosuppressants, non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface marker antibodies, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, anti-malarial drugs, mycophenolate mofetil, mycophenolic acid, azathioprine, 6-mercaptopurine, belimumab, anti-CD20 antibodies, rituximab, corticosteroids, and costimulatory modulators.

[0045] In certain embodiments, the present invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8.

[0046] In certain embodiments, the present invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w).

[0047] In certain embodiments, the present invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and wherein the initial IV dose is 6.0 mg / kg ± 1.5 mg / kg.

[0048] In certain embodiments, the present invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and wherein the initial IV dose is 260 mg for patients with a body weight of ≥ 35 kg to ≤ 55 kg, 390 mg for patients with a body weight of > 55 kg to ≤ 85 kg, and 520 mg for patients with a body weight of > 85 kg.

[0049] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by SC doses every 8 weeks (q8w), and wherein the initial SC dose is 90 mg.

[0050] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by SC doses every 8 weeks (q8w), and wherein the patient is a responder to treatment with the antibody and has a statistically significant improvement in disease activity determined by an improvement starting at week 12 of treatment and a decrease from baseline in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥ 4 by week 24 of treatment with the antibody (SRI-4 response).

[0051] In certain embodiments, the invention provides a method of treating a patient's active systemic lupus erythematosus (SLE) comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and wherein the patient is a responder to treatment with the antibody and has improvement starting at week 12 of treatment and has a statistically significant reduction in the risk of a new British Isles Lupus Assessment Group (BILAG) flare defined as a new BILAG A domain score of ≧1 or a new BILAG B domain score of ≧2 by week 24 of treatment with the antibody.

[0052] In certain embodiments, the invention provides a method of treating a patient's active systemic lupus erythematosus (SLE) comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and wherein the patient is a responder to treatment with the antibody and has improvement starting at week 12 of treatment and has a statistically significant increase in the proportion of patients having a 50% improvement from baseline in the cutaneous lupus erythematosus disease area and severity index (CLASI) score for patients treated with the antibody compared to patients treated with placebo.

[0053] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and wherein the patient is a responder to treatment with the antibody, and is characterized as having improvement starting at week 12 of treatment and a statistically significant improvement in disease activity determined by a 50% improvement from baseline joint disease activity by week 24 of treatment with the antibody.

[0054] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and wherein the patient is a responder to treatment with the antibody, and is characterized as having a statistically significant improvement in disease activity by week 24 of treatment, which is sustained throughout 1 year of treatment, and wherein disease activity is determined by one or more criteria selected from the group consisting of a decrease from baseline in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≧4 (SRI-4 response), the proportion of patients having a 50% improvement from baseline in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score, and a 50% improvement from baseline joint disease activity.

[0055] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and wherein the antibody for use in IV administration is in a pharmaceutical composition comprising a solution containing 10 mM L-histidine, 8.5% (w / v) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL disodium EDTA dehydrate, at pH 6.0.

[0056] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and wherein the antibody for use in SC administration is in a pharmaceutical composition comprising a solution containing 6.7 mM L-histidine, 7.6% (w / v) sucrose, 0.004% (w / v) polysorbate 80, at pH 6.0.

[0057] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, and the method further comprises administering to the patient one or more additional agents used to treat lupus.

[0058] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, and the method further comprises administering to the patient one or more additional agents used to treat lupus, wherein the additional agents are selected from the group consisting of immunosuppressive agents, non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface marker antibodies, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, anti-malarial drugs, mycophenolate mofetil, mycophenolic acid, azathioprine, 6-mercaptopurine, belimumab, anti-CD20 antibodies, rituximab, corticosteroids, and costimulatory modulators.

[0059] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises (i) a heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) a light chain amino acid sequence of SEQ ID NO: 11, and comprises the anti-IL-12 / 23p40 antibody ustekinumab (Stelara®).

[0060] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain amino acid sequence of SEQ ID NO: 11, and wherein the antibody is ustekinumab (Stelara®), an anti-IL-12 / 23p40 antibody, and wherein the antibody is administered by an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered by an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w).

[0061] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain amino acid sequence of SEQ ID NO: 11, and wherein the antibody is ustekinumab (Stelara®), an anti-IL-12 / 23p40 antibody, and wherein the antibody is administered by an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered by an initial subcutaneous (SC) dose, followed by subcutaneous (SC) doses every 8 weeks (q8w), and wherein the initial IV dose is 6.0 mg / kg ± 1.5 mg / kg.

[0062] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain amino acid sequence of SEQ ID NO: 11, the anti-IL-12 / 23p40 antibody ustekinumab (Stelara®), wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by SC doses every 8 weeks (q8w), and wherein the initial IV dose is 260 mg for patients weighing ≧35 kg to ≦55 kg, 390 mg for patients weighing >55 kg to ≦85 kg, and 520 mg for patients weighing >85 kg.

[0063] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain amino acid sequence of SEQ ID NO: 11, the anti-IL-12 / 23p40 antibody ustekinumab (Stelara®), wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by SC doses every 8 weeks (q8w), and wherein the SC dose is 90 mg.

[0064] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain amino acid sequence of SEQ ID NO: 11, the anti-IL-12 / 23p40 antibody ustekinumab (Stelara®), wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by SC doses every 8 weeks (q8w), and the patient is a responder to treatment with the antibody and has a statistically significant improvement in disease activity as determined by a decrease from baseline in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥4 by week 24 of treatment with the antibody (SRI-4 response).

[0065] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain amino acid sequence of SEQ ID NO: 11, the anti-IL-12 / 23p40 antibody ustekinumab (Stelara®), wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by SC doses every 8 weeks (q8w), and the patient is a responder to treatment with the antibody and has a statistically significant reduction as defined by ≥1 new British Isles Lupus Assessment Group (BILAG) A domain score, or ≥2 new BILAG B domain scores, in the risk of a new BILAG flare by week 24 of treatment with the antibody.

[0066] In certain embodiments, the invention provides a method of treating a patient's active systemic lupus erythematosus (SLE) comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises anti-IL-12 / 23p40 antibody ustekinumab (Stelara®) comprising (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain amino acid sequence of SEQ ID NO: 11, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0 followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose followed by SC doses every 8 weeks (q8w), and there is a statistically significant increase in the proportion of patients having a 50% improvement from baseline in the cutaneous lupus erythematosus disease area and severity index (CLASI) score for patients treated with the antibody compared to patients treated with placebo.

[0067] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises an anti-IL-12 / 23p40 antibody ustekinumab (Stelara®) comprising (i) a heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) a light chain amino acid sequence of SEQ ID NO: 11, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by SC doses every 8 weeks (q8w), and wherein the patient is identified as a responder to treatment with the antibody and has a statistically significant improvement in disease activity by week 24 of treatment, which is sustained through 1 year of treatment, and wherein disease activity is determined by one or more criteria selected from the group consisting of a decrease from baseline in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≧4 (SRI-4 response), the proportion of patients having a 50% improvement from baseline in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score, and a 50% improvement from baseline in joint disease activity.

[0068] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises an anti-IL-12 / 3p40 antibody ustekinumab (Stelara®) comprising (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain amino acid sequence of SEQ ID NO: 11, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by SC doses every 8 weeks (q8w), and wherein the antibody for use in IV administration is in a pharmaceutical composition comprising a solution containing 10 mM L-histidine, 8.5% (w / v) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL disodium EDTA dehydrate, at pH 6.0.

[0069] In certain embodiments, the invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises an anti-IL-12 / 23p40 antibody ustekinumab (Stelara®) comprising (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain amino acid sequence of SEQ ID NO: 11, and wherein the antibody is administered as an initial intravenous (IV) dose at week 0, followed by subcutaneous (SC) doses every 8 weeks (q8w), or wherein the antibody is administered as an initial subcutaneous (SC) dose, followed by SC doses every 8 weeks (q8w), and wherein the antibody for use in SC administration is in a pharmaceutical composition comprising a solution containing 6.7 mM L-histidine, 7.6% (w / v) sucrose, 0.004% (w / v) polysorbate 80, at pH 6.0.

[0070] In certain embodiments, the present invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain amino acid sequence of SEQ ID NO: 11, and wherein the anti-IL-12 / 23p40 antibody is ustekinumab (Stelara®), and wherein the method further comprises administering to the patient one or more additional agents used to treat lupus.

[0071] In certain embodiments, the present invention provides a method of treating active systemic lupus erythematosus (SLE) in a patient, comprising administering to the patient an anti-IL-12 / IL-23p40 antibody in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises (i) the heavy chain amino acid sequence of SEQ ID NO: 10 and (ii) the light chain amino acid sequence of SEQ ID NO: 11, and wherein the anti-IL-12 / IL-23p40 antibody is ustekinumab (Stelara®), and wherein the method further comprises administering to the patient one or more additional agents used to treat lupus, and wherein the additional agents are selected from the group consisting of immunosuppressive agents, non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface marker antibodies, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, anti-malarial drugs, mycophenolate mofetil, mycophenolic acid, azathioprine, 6-mercaptopurine, belimumab, anti-CD20 antibodies, rituximab, corticosteroids, and costimulatory modulators. BRIEF DESCRIPTION OF THE DRAWINGS

[0072]

Figure 1

Figure 2

Figure 3

Mode for Carrying Out the Invention

[0073] As used herein, a method of treating lupus includes administering isolated, recombinant and / or synthetic anti-IL-12, IL-23, and IL12 / 23p40 human antibodies, as well as diagnostic and therapeutic compositions, methods, and devices.

[0074] As used herein, "anti-IL-12 antibody", "anti-IL-23 antibody", "anti-IL-12 / 23p40 antibody", "IL-12 / 23p40 antibody", "antibody portion", or "antibody fragment", and / or "antibody variant", etc. include any protein or peptide-containing molecule that includes at least a part of an immunoglobulin molecule, such as at least one complementarity determining region (CDR) of a heavy or light chain or its ligand-binding portion, a heavy or light chain variable region, a heavy or light chain constant region, a framework region, or any part thereof, or at least a part of an IL-12 and / or IL-23 receptor or binding protein, etc., but are not limited thereto. Such antibodies further affect a specific ligand, and, without limitation, such antibodies optionally regulate, decrease, increase, antagonize, activate, alleviate, mitigate, block, inhibit, suppress, and / or interfere with at least one IL-12 / 23 activity or binding, or IL-12 / 23 receptor activity or binding in vitro, in situ, and / or in vivo. As a non-limiting example, a preferred anti-IL-12 / 23p40 antibody, identified portion, or variant of the present invention can bind to at least one IL-12 / 23 molecule, or an identified portion, variant, or domain thereof. A preferred anti-IL-12 / 23p40 antibody, identified portion, or variant can also optionally affect at least one of IL-12 / 23 activities or functions, such as, but not limited to, RNA, DNA, or protein synthesis, IL-12 / 23 release, IL-12 / 23 receptor signaling, membrane IL-12 / 23 cleavage, IL-12 / 23 activity, IL-12 / 23 production, and / or synthesis.

[0075] The term "antibody" is further intended to encompass antibodies, their digestion fragments, specific portions, and variants, including antibody mimetics, or portions of antibodies that mimic the structure and / or function of an antibody, or specific fragments or parts thereof, including single-chain antibodies and fragments thereof. Functional fragments include antigen-binding fragments that bind to mammalian IL-12 / 23. For example, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab')2 (e.g., by pepsin digestion), facb (e.g., by plasmin digestion), pFc' (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction, and reassembly), Fv or scFv (e.g., by molecular biological techniques) fragments, among others, and antibody fragments capable of binding to IL-12 / 23 or a portion thereof are encompassed by the present invention (see, e.g., Colligan, Immunology supra).

[0076] Such fragments can be generated by enzymatic cleavage, synthesis, or recombinant techniques as known in the art and / or as described herein. Antibodies can also be generated in various truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural termination site. For example, combinations of genes encoding the F(ab')2 heavy chain portion can be designed to include DNA sequences encoding the C H 1 domain and / or the hinge region of the heavy chain. Various portions of the antibody can be chemically conjugated by conventional techniques or prepared as contiguous proteins using genetic engineering techniques.

[0077] As used herein, the term "human antibody" refers to antibodies in which substantially all portions of the protein (e.g., CDRs, frameworks, C L 、C H domains (e.g., C H 1, C H 2, C H 3), hinge (V L 、V H)) refers to an antibody that is substantially non-immunogenic in humans with only minor sequence changes or mutations. A "human antibody" may also be an antibody derived from or strictly identical to a human germline immunoglobulin sequence. A human antibody may contain amino acid residues not encoded by the germline immunoglobulin sequence (e.g., mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutations in vivo). In many cases, this means that the human antibody is substantially non-immunogenic in humans. Human antibodies are classified into groups based on the similarity of their amino acid sequences. Thus, sequence similarity searches can be used to select antibodies with similar linear sequences as templates for generating human antibodies. Similarly, antibodies designated from primates (such as monkeys, baboons, chimpanzees, etc.), rodents (such as mice, rats, rabbits, guinea pigs, hamsters, etc.) and other mammals represent antibodies specific to such species, subgenera, genera, subfamilies, and families. Furthermore, chimeric antibodies can include any combination of the above. Such changes or mutations optionally and preferably retain or reduce immunogenicity in humans or other species compared to the non-modified antibody. Thus, human antibodies are different from chimeric or humanized antibodies.

[0078] It is pointed out that human antibodies can be produced by non-human animals, or prokaryotic or eukaryotic cells, that are capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and / or light chain) genes. Moreover, when a human antibody is a single-chain antibody, it may contain a linker peptide not found in natural human antibodies. For example, Fv may contain a linker peptide such as 2 to about 8 glycine or other amino acid residues that connect the variable region of the heavy chain and the variable region of the light chain. Such linker peptides are considered to be of human origin.

[0079] Anti-IL-12 / 23p40 antibodies (also referred to as IL-12 / 23p40 antibodies) (or antibodies against IL-23) that are useful in the methods and compositions of the present invention may optionally be characterized by high affinity binding to IL-12 / 23p40 (or IL-23), and optionally and preferably low toxicity. Specifically, individual components such as variable regions, constant regions, and frameworks, individually and / or collectively, optionally and preferably have low immunogenicity, and antibodies of the present invention, their identified fragments, or variants are useful in the present invention. Antibodies that can be used in the present invention are optionally characterized by the ability to treat patients over a long period of time with a measurable alleviation of symptoms and low and / or acceptable toxicity. Low or acceptable immunogenicity, and / or high affinity, and other suitable properties can contribute to the therapeutic results obtained. "Low immunogenicity" as used herein means that in less than about 75%, or preferably less than about 50%, of the patients being treated, there is a significant increase in HAHA, HACA or HAMA responses, and / or there is an increase in low titers (less than about 300, preferably less than about 100 as measured by a double antigen enzyme immunoassay) in the patients being treated (Elliott et al., Lancet 344:1125-1127 (1994), which is hereby incorporated by reference in its entirety). "Low immunogenicity" can also be defined as the incidence of antibodies at titration levels against anti-IL-12 antibodies in patients treated with anti-IL-12 antibodies when it occurs in less than 25%, preferably less than 10%, of the patients being treated during the course of the recommended therapy at the recommended dose during the treatment period.

[0080] The terms "clinically proven effectiveness" and "clinically proven effective" as used herein in the context of a dosage, dosing regimen, treatment or method mean the effectiveness of a particular dosage, administration, treatment regimen. The effectiveness can be measured based on changes during the course of a disease in response to the agent of the invention. For example, an anti-IL12 / 23p40 or anti-IL23 antibody of the invention (e.g., the anti-IL12 / 23p40 antibody ustekinumab) is administered to a subject in an amount and for a time sufficient to cause improvement, preferably sustained improvement, in at least one indicator reflecting the severity of the disorder being treated. To determine whether the amount and time of such treatment is sufficient, various indicators reflecting the degree of the subject's illness, disease or condition can be evaluated. Such indicators include, for example, clinically recognized indicators of disease severity, symptoms, or manifestations of the disorder in question. The degree of improvement is generally determined by a physician, who can make this determination based on signs, symptoms, biopsies, or other test results, and can also employ questionnaires administered to the subject, such as questionnaires regarding quality of life developed for a given disease. For example, an anti-IL12 / 23p40 or anti-IL23 antibody of the invention can be administered to achieve improvement in the condition of a patient associated with systemic lupus erythematosus (SLE). This improvement can be demonstrated by improvement in disease activity indices, remission of clinical symptoms, or any other measurement of disease activity. One such disease indicator is the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score. The SLEDAI-2K is an established and effective disease activity index for systemic lupus erythematosus (SLE) based on the presence of 24 features in 9 organ systems and measures disease activity in SLE patients over the past 30 days. Features are scored when more severe features with higher scores within the past 30 days are present, and these scores are added to determine a total SLEDAI-2K score in the range of 0-105. Other disease activity indices for the evaluation of systemic lupus erythematosus (SLE) disease activity include, for example, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), and the British Isles Lupus Assessment Group (BILAG) index.The CLASI index consists of two scores. The first score summarizes the disease activity, and the second score is a measure of the damage done by the disease. The scores are calculated by simple addition based on the degree of symptoms. Higher activity and damage scores indicate worsened disease activity. The BILAG index is a measure of disease activity consisting of 97 questions in 9 organ systems, each of which is placed into one of 5 categories (A, B, C, D, E) depending on the presence of the item. Higher scores indicate more disease involvement.

[0081] The term "clinically demonstrated safety", when referring to the dosage, administration regimen, treatment or method with an anti-IL12 / 23p40 or anti-IL23 antibody of the present invention (e.g., the anti-IL12 / 23p40 antibody ustekinumab), refers to the favorable risk:benefit ratio by the acceptable frequency and / or acceptable severity of treatment-emergent adverse events (referred to as AE or TEAE) under the administration of the test drug compared to standard care or another comparator drug. An adverse event is an unfavorable medical occurrence in a patient administered a pharmaceutical product. In particular, the safety associated with the dosage, administration regimen or treatment with an anti-IL12 / 23p40 or anti-IL23 specific antibody of the present invention refers to the acceptable frequency and / or acceptable severity of adverse events associated with the administration of the antibody when the adverse event is considered to be possible, likely or very likely due to the use of the anti-IL12 / 23p40 or anti-IL23 specific antibody.

[0082] As used herein, unless otherwise specified, the term "clinically demonstrated" (used alone or used to modify the terms "safety" and / or "effective") shall mean proven by a clinical trial that meets the approval criteria of the US Food and Drug Administration, the EMEA, or the corresponding national regulatory agency. For example, the clinical trial may be a randomized double-blind trial of appropriate size used to clinically demonstrate the effect of the drug.

[0083] Usefulness The isolated nucleic acid of the present invention can be measured or act in a cell, tissue, organ, or animal (including mammals and humans) to diagnose, monitor, regulate, treat, alleviate, help prevent the development of, or reduce the symptoms of at least one IL-12 / 23 state selected from, but not limited to, at least one of an immune disorder or disease, a cardiovascular disorder or disease, an infectious, malignant and / or neurological disorder or disease, or other known or specific IL-12 / 23-related conditions, and can be used to produce at least one anti-IL-12 / 23p40 (or anti-IL-23) antibody or a specified variant thereof.

[0084] Such methods can include administering to a cell, tissue, organ, animal, or patient in need of such regulation, treatment, alleviation, prevention, or reduction of symptoms, effects, or mechanisms, an effective amount of a composition or pharmaceutical composition comprising at least one anti-IL-12 / 23p40 (or anti-IL-23) antibody. The effective amount, when determined using known methods as described herein or as known in the relevant art, can be an amount of about 0.001 to 500 mg / kg per single (e.g., bolus), multiple, or continuous administration, or an amount that achieves a serum concentration of 0.01 to 5000 μg / mL per single, multiple, or continuous administration, or can include any effective range or value therein.

[0085] Cited References All publications or patents cited in this specification, whether specifically designated or not, are hereby incorporated by reference in their entirety into this specification, showing the state of the art at the time of the present invention and / or providing an explanation and usability of the present invention. Publications refer to any scientific publication or patent gazette, or any other information available in any media format, including any recorded electronic or printed format. The following documents are hereby incorporated by reference in their entirety into this specification: Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987 - 2001), Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor, NY (1989), Harlow and Lane, antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989), Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994 - 2001), Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997 - 2001).

[0086] Antibody production and preparation of the present invention At least one anti-IL-12 / 23p40 (or anti-IL-23) used in the method of the present invention can optionally be produced by a cell line, mixed cell line, immortalized cell, or clonal population of immortalized cells well known in the art. For example, see Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2001), Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor, NY (1989), Harlow and Lane, antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989), Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994-2001), Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2001), each of which is hereby incorporated by reference in its entirety.

[0087] A preferred anti-IL-12 / 23p40 antibody has the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8, and the heavy chain CDR amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, and the light chain CDR amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, and is ustekinumab (Stelara®). A preferred anti-IL-23 antibody is guselkumab (also known as CNTO1959). Other anti-IL-23 antibodies have the sequences listed herein, the entire contents of which are incorporated herein by reference in U.S. Patent No. 7,935,344.

[0088] Human antibodies specific for human IL-12 / 23p40 or IL-23 protein or fragments thereof can be raised against suitable immunogenic antigens such as isolated IL-12 / 23p40 protein, IL-23 protein, and / or portions thereof (including synthetic molecules such as synthetic peptides). Other specific or general mammalian antibodies can likewise be raised. Preparation of the immunogenic antigen and generation of monoclonal antibodies can be carried out using any suitable technique.

[0089] In one approach, a suitable immortal cell line (e.g., but not limited to, myeloma cell lines such as Sp2 / 0, Sp2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, L243, P3X63Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5, U937, MLA144, ACT IV, MOLT4, DA-1, JURKAT, WEHI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA144, NAMALWA, NEURO 2A, or heteromyelomas, their fusion products, or any cell or fusion cell derived therefrom, or any other suitable cell line known in the art) (see, e.g., www.atcc.org, www.lifetech.com, etc.) is fused with an antibody-producing cell such as, but not limited to, an isolated or cloned spleen, peripheral blood, lymph, tonsil, or other immune or B cell-containing cell, or any other cell expressing a constant or variable, or framework or CDR sequence of a heavy or light chain, as either a recombinant or endogenous, viral, bacterial, algal, prokaryotic, amphibian, insect, reptilian, fish, mammalian, rodent, equine, ovine, caprine, bovine, primate, eukaryotic, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single, double or triple stranded, hybridizable, etc., or any combination thereof, to produce a hybridoma. See, e.g., Ausubel and Colligan, Immunology chapter 2, which is incorporated herein by reference in its entirety.

[0090] Antibody-producing cells can also be obtained from the peripheral blood of humans or other suitable animals immunized with the antigen of interest, or preferably from the spleen or lymph nodes. Any other suitable host cells can also be used to express a heterologous or endogenous nucleic acid encoding the antibody, specified fragment or variant thereof of the present invention. Fusion cells (hybridomas) or recombinant cells are isolated using selective culture conditions or other suitable known methods and can be cloned by limiting dilution or cell sorting or other known methods. Cells producing antibodies with the desired specificity can be selected by a suitable assay (e.g., ELISA).

[0091] Selecting recombinant antibodies from peptide or protein libraries (e.g., display libraries such as, but not limited to, bacteriophage, ribosome, oligonucleotide, RNA, cDNA, etc., e.g., Cambridge antibody Technologies, Cambridgehire, UK, MorphoSys, Martinsreid / Planegg, DE, Biovation, Aberdeen, Scotland, UK, BioInvent, Lund, Sweden, Dyax Corp., Enzon, Affymax / Biosite, Xoma, Berkeley, CA, Ixsys. For example, European Patent No. 368,684, International Application PCT / GB91 / 01134, International Application PCT / GB92 / 01755, International Application PCT / GB92 / 002240, International Application PCT / GB92 / 00883, International Application PCT / GB93 / 00605, U.S. Patent Application No. 08 / 350260 (5 / 12 / 94), International Application PCT / GB94 / 01422, International Application PCT / GB94 / 02662, International Application PCT / GB97 / 01835, (CAT / MRC), International Publication No. 90 / 14443, International Publication No. 90 / 14424, International Publication No. 90 / 14430, International Application PCT / US94 / 1234, International Publication No. 92 / 18619, International Publication No. 96 / 07754, (Scripps), International Publication No. 96 / 13583, International Publication No. 97 / 08320 (MorphoSys), International Publication No. 95 / 16027 (BioInvent), International Publication No. 88 / 06630, International Publication No. 90 / 3809 (Dyax), U.S. Patent No. 4,704,692 (Enzon), International Application PCT / US91 / 02989 (Affymax), International Publication No. 89 / 06283, European Patent No. 371998, European Patent No. 550400, (Xoma), European Patent No. 229046, International Application PCT / US91 / 07149 (Ixsys), or probabilistically generated peptides or proteins - U.S. Patent Nos. 5723323, 5763192, 5814476, 5817483, 5824514, 5976862, International Publication No. 86 / 05803, European Patent No. 590689 (Ixsys, the predecessor of Applied Molecular Evolution (AME), each of which is incorporated herein by reference in its entirety), or depends on immunization of transgenic animals capable of producing a repertoire of human antibodies known in the art and / or described herein (e.g., SCID mice, Nguyen et al., Microbiol. Immunol. 41:901-907 (1997), Sandhu et al., Crit. Rev. Biotechnol. 16:95-118 (1996), Eren et al., Immunol. 93: 154-161 (1998) (each is incorporated by reference in its entirety), as well as related patents and applications), other suitable methods for generating or isolating antibodies of the required specificity can be used, including but not limited to these. Such techniques include ribosome display (Hanes et al., Proc. Natl. Acad. Sci. USA, 94: 4937-4942 (May 1997), Hanes et al., Proc. Natl. Acad. Sci. USA, 95: 14130-14135 (Nov. 1998)), single-cell antibody generation techniques (e.g., selected lymphocyte antibody method ("SLAM") (U.S. Patent No. 5,627,052, Wen et al., J. Immunol. 17: 887-892 (1987); Babcock et al., Proc. Natl. Acad. Sci. USA 93: 7843-7848 (1996)), gel microdroplet, and flow cytometry (Powell et al., Biotechnol. 8: 333-337 (1990), One Cell Systems, Cambridge, MA, Gray et al., J. Imm. Meth. 182: 155-163 (1995); Kenny et al., Bio / Technol. 13: 787-790 (1995)), B cell selections (Steenbakkers et al., Molec. Biol. Reports 19: 125-134 (1994), Jonak et al., Progress Biotech, Vol. 5, In Vitro Immunization in Hybridoma Technology, Borrebaeck, ed., Elsevier Science Publishers B.V., Amsterdam, Netherlands (1988)), but are not limited to these.

[0092] Methods for engineering or humanizing non-human or human antibodies can similarly be used and are well known in the art. Generally, humanized or engineered antibodies have one or more amino acid residues from a non-human source, such as, but not limited to, mouse, rat, rabbit, non-human primate, or other mammalian sources. These non-human amino acid residues are often referred to as "import" residues and are typically replaced with residues taken from the "import" variable, constant, or other domains of known human sequences.

[0093] Known human Ig sequences are disclosed, for example, www.ncbi.nlm.nih.gov / entrez / query.fcgi; www.ncbi.nih.gov / igblast; www.atcc.org / phage / hdb.html; www.mrc-cpe.cam.ac.uk / ALIGNMENTS.php; www.kabatdatabase.com / top.html;ftp.ncbi.nih.gov / repository / kabat; www.sciquest.com; www.abcam.com; www.antibodyresource.com / onlinecomp.html; www.public.iastate.edu / ~pedro / research_tools.html; www.whfreeman.com / immunology / CH05 / kuby05.html; www.hhmi.org / grants / lectures / 1996 / vlab; www.path.cam.ac.uk / ~mrc7 / mikeimages.html; www.mcb.harvard.edu / BioLinks / Immunology.html; www.immunologylink.com;pathbox.wustl.edu / ~hcenter / index.html; www.appliedbiosystems.com; www.nal.usda.gov / awic / pubs / antibody; www.m.ehime-u.ac.jp / ~yasuhito / Elisa.html; www.biodesign.com; www.cancerresearchuk.org; www.biotech.ufl.edu; www.isac-net.org;baserv.uci.kun.nl / ~jraats / links1.html; www.recab.uni-hd.de / immuno.bme.nwu.edu; www.mrc-cpe.cam.ac.uk; www.ibt.unam.mx / vir / V_mice.html; www.bioinf.org.uk / abs;antibody.bath.ac.uk; www.unizh.ch; www.cryst.bbk.ac.uk / ~ubcg07s; www.nimr.mrc.ac.uk / CC / ccaewg / 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.jerini.de; Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Dept. Health (1983), and Each of the above is hereby incorporated by reference in its entirety.

[0094] Such imported sequences can be used to reduce immunogenicity or to reduce, enhance or modify binding, affinity, on-rate, off-rate, binding activity, specificity, half-life, or any other appropriate property, as known in the art. Generally, CDR residues are most directly and substantially involved in their effect on antigen binding. Thus, while non-human sequences of the variable and constant regions can be replaced with human or other amino acids, some or all of the non-human or human CDR sequences are maintained.

[0095] Antibodies can optionally be humanized or human antibodies can be engineered while retaining high affinity for the antigen and other favorable biological properties. To achieve this, optionally, humanized (or human) antibodies can be prepared by an analytical process of the parental and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are generally available and well known to those skilled in the art. Computer programs are available that illustrate and display the likely three-dimensional conformation of selected candidate immunoglobulin sequences. By examining these displays, it is possible to analyze the likely role of residues in the function of the candidate immunoglobulin sequence, i.e., the residues that affect the ability of the candidate immunoglobulin to bind its antigen. In this way, framework (FR) residues can be selected and combined from consensus and imported sequences so as to achieve desired antibody properties such as an increase in affinity for the target antigen(s).

[0096] In addition, the human anti-IL-12 / 23p40 (or anti-IL-23) specific antibody used in the method of the present invention may include a human germline light chain framework. In certain embodiments, the light chain germline sequence is selected from human VK sequences including, but not limited to, A1, A10, A11, A14, A17, A18, A19, A2, A20, A23, A26, A27, A3, A30, A5, A7, B2, B3, L1, L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23, L24, L25, L4 / 18a, L5, L6, L8, L9, O1, O11, O12, O14, O18, O2, O4, and O8. In certain embodiments, the light chain human germline framework is selected from V1-11, V1-13, V1-16, V1-17, V1-18, V1-19, V1-2, V1-20, V1-22, V1-3, V1-4, V1-5, V1-7, V1-9, V2-1, V2-11, V2-13, V2-14, V2-15, V2-17, V2-19, V2-6, V2-7, V2-8, V3-2, V3-3, V3-4, V4-1, V4-2, V4-3, V4-4, V4-6, V5-1, V5-2, V5-4, and V5-6.

[0097] In other embodiments, the human anti-IL-12 / 23p40 (or anti-IL-23) specific antibody used in the method of the present invention may include a human germline heavy chain framework. In certain embodiments, this heavy chain human germline framework is selected from VH1-18, VH1-2, VH1-24, VH1-3, VH1-45, VH1-46, VH1-58, VH1-69, VH1-8, VH2-26, VH2-5, VH2-70, VH3-11, VH3-13, VH3-15, VH3-16, VH3-20, VH3-21, VH3-23, VH3-30, VH3-33, VH3-35, VH3-38, VH3-43, VH3-48, VH3-49, VH3-53, VH3-64, VH3-66, VH3-7, VH3-72, VH3-73, VH3-74, VH3-9, VH4-28, VH4-31, VH4-34, VH4-39, VH4-4, VH4-59, VH4-61, VH5-51, VH6-1, and VH7-81.

[0098] In certain embodiments, the light chain variable region and / or the heavy chain variable region comprise a framework region, or at least a portion of a framework region (e.g., two or three sub-regions such as FR2 and FR3). In certain embodiments, at least FRL1, FRL2, FRL3, or FRL4 is fully human. In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is fully human. In some embodiments, at least FRL1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., human germline), or comprises a human consensus sequence for a particular framework (readily available from known sources of human Ig sequences as described above). In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., human germline), or comprises a human consensus sequence for a particular framework. In preferred embodiments, the framework region is a fully human framework region.

[0099] Humanization or engineering of the antibodies of the present invention can be performed using any known method such as those described in Winter (Jones et al., Nature 321:522 (1986), Riechmann et al., Nature 332:323 (1988), Verhoeyen et al., Science 239:1534 (1988)), Sims et al., J. Immunol. 151:2296 (1993), Chothia and Lesk, J. Mol. Biol. 196:901 (1987), Carter et al., Proc. Natl. Acad. Sci. U.S.A. 89:4285 (1992); Presta et al., J. Immunol. 151-2623 (1993), U.S. Patent Nos. 5,723,323, 5,976,862, 5,824,514, 5,817,483, 5,814,476, 5,763,192, 5,723,323, 5,766,886, 5,714,352, 6,204,023, 6,180,370, 5,693,762, 5,530,101, 5,585,089, 5,225,539, 4,816,567, International Application PCT / :US98 / 16280, US96 / 18978, US91 / 09630, US91 / 05939, US94 / 01234, GB89 / 01334, GB91 / 01134, GB92 / 01755, International Publication Nos. 90 / 14443, 90 / 14424, 90 / 14430, European Patent No. 229,246 (each incorporated by reference in its entirety into the specification, including the documents cited therein), etc., but not limited thereto.

[0100] In certain embodiments, the antibody comprises a modified (e.g., mutated) Fc region. For example, in some embodiments, the Fc region is modified to reduce or enhance the effector function of the antibody. In some embodiments, the Fc region is an isotype selected from IgM, IgA, IgG, IgE, or other isotypes. Alternatively, or additionally, it may be useful to combine amino acid modifications with one or more further amino acid modifications that alter the C1q binding and / or complement-dependent cytotoxicity function of the Fc region of the IL-23 binding molecule. The starting polypeptide for a particular purpose may be one that binds to C1q and exhibits complement-dependent cytotoxicity (CDC). A polypeptide having existing C1q binding activity and optionally further the ability to mediate CDC may be modified such that one or both of these activities are enhanced. Amino acid modifications that modify C1q and / or its complement-dependent cytotoxic function are described, for example, in WO 00 / 42072 and incorporated by reference.

[0101] As disclosed above, for example, by modifying C1q binding and / or FcγR binding, thereby altering the complement-dependent cytotoxicity (CDC) activity and / or antibody-dependent cell-mediated cytotoxicity (ADCC) activity, the Fc region of the human anti-IL-12 / 23p40 (or anti-IL-23) specific antibody of the present invention having an altered effector function can be designed. "Effector function" plays a role in activating or reducing biological activity (e.g., in a subject). Examples of effector functions include, but are not limited to, C1q binding, CDC, Fc receptor binding, ADCC, phagocytosis, downregulation of cell surface receptors (e.g., B cell receptor, BCR), etc. Such effector functions may require the Fc region to bind to a binding domain (e.g., the antibody variable domain) and can be evaluated using a variety of test methods (e.g., Fc binding assay, ADCC assay, CDC assay, etc.).

[0102] For example, a variant Fc region of a human anti-IL-12 / 23p40 (or anti-IL-23) antibody having improved C1q binding and improved FcγRIII binding (e.g., having both improved ADCC activity and improved CDC activity) can be generated. Alternatively, if it is desired to reduce or eliminate effector function, the variant Fc region can be engineered with reduced CDC activity and / or reduced ADCC activity. In other embodiments, only one of these activities may be increased, and optionally, the other activity may be reduced simultaneously (e.g., to generate an Fc region variant having improved ADCC activity and reduced CDC activity, and the reverse Fc region variant).

[0103] Fc mutations can also be engineered and introduced to modify their interaction with the neonatal Fc receptor (FcRn) and improve their pharmacokinetic properties. The collection of human Fc mutants with improved binding to FcRn has been described (Shields et al., (2001). High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FCγR, J. Biol. Chem. 276:6591-6604).

[0104] Another type of amino acid substitution serves to alter the glycosylation pattern of the Fc region of a human anti-IL-12 / 23p40 (or anti-IL-23) specific antibody. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars, N-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. The recognition sequences for the enzymatic attachment of carbohydrate moieties to asparagine side chain peptide sequences are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid other than proline. Thus, the presence of any of these peptide sequences in a polypeptide results in potential glycosylation sites.

[0105] The glycosylation pattern can be altered, for example, by deleting one or more glycosylation site(s) found in the polypeptide and / or adding one or more glycosylation site(s) not present in the polypeptide. Addition of a glycosylation site to the Fc region of a human IL-23 specific antibody is successfully achieved by modifying the amino acid sequence to include one or more of the above tripeptide sequences (in the case of an N-linked glycosylation site). An exemplary glycosylation variant has an amino acid substitution at residue Asn297 of the heavy chain. This modification may be done by the addition or substitution of one or more serine or threonine residues to the sequence of the original polypeptide (in the case of an O-linked glycosylation site). In addition, changing Asn 297 to Ala can remove one of the glycosylation sites.

[0106] In certain embodiments, the human anti-IL-12 / 23p40 (or anti-IL-23) specific antibody of the invention is expressed in cells that express beta (1,4)-N-acetylglucosaminyltransferase III (GnT III) such that GnT III adds GlcNAc to the human anti-IL-12 / 23p40 (or anti-IL-23) antibody. Methods for producing antibodies in such a manner are provided in WO 99 / 54342, WO 03 / 011878, JP 20030003097A1, and Umana et al., Nature Biotechnology, 17:176-180, Feb. 1999, all of which are specifically incorporated herein by reference in their entirety.

[0107] The human anti-IL-12 / 23p40 (or anti-IL-23) antibody can also optionally be generated by immunization of transgenic animals (e.g., mice, rats, hamsters, non-human primates, etc.) that are capable of producing a repertoire of human antibodies as described herein and / or known in the art. Cells producing the human anti-IL-12 / 23p40 (or anti-IL-23) antibody can be isolated from such animals and immortalized using suitable methods such as those described herein.

[0108] Transgenic mice capable of generating a repertoire of human antibodies that bind to human antigens can be generated by known methods (e.g., but not limited to, U.S. Patent Nos. 5,770,428, 5,569,825, 5,545,806, 5,625,126, 5,625,825, 5,633,425, 5,661,016, and 5,789,650 issued to Lonberg et al., International Publication Nos. 98 / 50433, 98 / 24893, 98 / 24884, 97 / 13852, 94 / 25585, 96 / 34096 issued to Kucherlapate et al., European Patent Nos. 0463 151 (B1), 0710 719 (A1) issued to Kucherlapate et al., U.S. Patent No. 5,545,807 issued to Surani et al., International Publication No. 90 / 04036, European Patent No. 0438 474 (B1) issued to Bruggemann et al., European Patent No. 0814 259 (A2) issued to Lonberg et al., British Patent No. 2 272 440 (A) issued to Lonberg et al., Lonberg et al., Nature 368:856 - 859 (1994), Taylor et al., Int. Immunol. 6(4) 579 - 591 (1994), Green et al., Nature Genetics 7:13 - 21 (1994), Mendez et al., Nature Genetics 15:146 - 156 (1997), Taylor et al., Nucleic Acids Research 20(23):6287 - 6295 (1992), Tuaillon et al., Proc Natl Acad Sci USA 90(8) 3720 - 3724 (1993), Lonberg et al., Int Rev Immunol 13(1):65 - 93 (1995), and Fishwald et al., Nat Biotechnol 14(7):845 - 851 (1996), each of which is hereby incorporated by reference in its entirety).Generally, these mice contain at least one transgene comprising DNA from at least one human immunoglobulin locus that has been functionally rearranged or is capable of undergoing functional rearrangement. The endogenous immunoglobulin loci of such mice can be disrupted or deleted to ablate the animal's ability to produce antibodies encoded by the endogenous genes.

[0109] Screening of antibodies for specific binding to a similar protein or fragment can be successfully accomplished using a peptide display library. This method involves screening a large collection of peptides for individual components with desired functions or structures. Antibody screening of peptide display libraries is well known in the art. The length of the displayed peptide sequences can be from 3 to 5000 or more amino acids, frequently from 5 to 100 amino acids in length, and often about 8 to 25 amino acids in length. In addition to direct chemical synthesis methods for creating peptide libraries, several recombinant DNA methods have also been described. One type involves the display of peptide sequences on the surface of bacteriophage or cells. Each bacteriophage or cell contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in International Publication Nos. 91 / 17271, 91 / 18980, 91 / 19818, and 93 / 08278.

[0110] Other systems for creating libraries of peptides have aspects of both in vitro chemical synthesis and recombinant methods. See International Publications Nos. WO 92 / 05258, WO 92 / 14843, and WO 96 / 19256. See also U.S. Pat. Nos. 5,658,754 and 5,643,768. Peptide display libraries, vectors, and screening kits are commercially available from suppliers such as Invitrogen (Carlsbad, CA) and Cambridge Antibody Technologies (Cambridgeshire, UK). For example, U.S. Pat. Nos. 4,704,692, 4,939,666, 4,946,778, 5,260,203, 5,455,030, 5,518,889, 5,534,621, 5,656,730, 5,763,733, 5,767,260, 5,856,456, assigned to Enzon; 5,223,409, 5,403,484, 5,571,698, 5,837,500, assigned to Dyax; 5,427,908, 5,580,717, assigned to Affymax; 5,885,793, assigned to Cambridge Antibody Technologies; 5,750,373, assigned to Genentech; 5,618,920, 5,595,898, 5,576,195, 5,698,435, 5,693,493, 5,698,417, assigned to Xoma; Colligan (supra), Ausubel (supra), or Sambrook (supra). Each of the above patents and publications is hereby incorporated by reference in its entirety.

[0111] The antibodies used in the method of the present invention can also be prepared using at least one anti-IL-12 / 23p40 (or anti-IL-23) antibody encoding a nucleic acid to provide transgenic animals or mammals such as goats, cows, horses, sheep, rabbits, etc. that produce such antibodies in milk. Such animals can be provided using known methods. For example, but not limited to, see U.S. Patent Nos. 5,827,690; 5,849,992; 4,873,316; 5,849,992; 5,994,616; 5,565,362; 5,304,489, etc. (each of which is hereby incorporated by reference in its entirety).

[0112] The antibodies used in the method of the present invention can be further prepared using at least one anti-IL-12 / 23p40 (or anti-IL-23) antibody-encoding nucleic acid to provide such antibodies, specified portions, or variants in plant parts or cells cultured therefrom, transgenic plants, and cultured plant cells (such as, but not limited to, tobacco and maize). As non-limiting examples, for instance, inducible promoters have been successfully used to provide large amounts of recombinant proteins using transgenic tobacco leaves that express the recombinant proteins. See, for example, Cramer et al., Curr. Top. Microbol. Immunol. 240:95-118 (1999) and the references cited therein. Also, transgenic maize has been used to express mammalian proteins at commercial production levels that have biological activities equivalent to proteins produced in other recombinant systems or purified from natural sources. See, for example, Hood et al., Adv. Exp. Med. Biol. 464:127-147 (1999) and the references cited therein. Antibodies have also been produced in large quantities from transgenic plant seeds containing antibody fragments such as single-chain antibodies (scFv), including tobacco seeds and potato tubers. See, for example, Conrad et al., Plant Mol. Biol. 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. See, for example, Fischer et al., Biotechnol. Appl. Biochem. 30:99-108 (Oct., 1999), Ma et al., Trends Biotechnol. 13:522-7 (1995), Ma et al., Plant Physiol. 109:341-6 (1995); Whitelam et al., Biochem. Soc. Trans. 22:940-944 (1994); and the references cited therein. Each of the above references is hereby incorporated by reference in its entirety into this specification.

[0113] The antibodies used in the method of the present invention are capable of binding to human IL-12 / 23p40 or IL-23 with a wide range of affinities (K D ). In a preferred embodiment, the human mAb is optionally capable of binding to human IL-12 / 23p40 or IL-23 with high affinity. For example, the human mAb binds human IL-12 / 23p40 or IL-23 at about 10 -7 M or less, for example, but not limited to, 0.1 to 9.9 (or any range or value therein) X10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 , or any range or value therein, such as K D .

[0114] The affinity or binding activity 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 Immunology, Paul, W.E., Ed., Raven Press: New York, NY (1984), Kuby, Janis Immunology, W.H. Freeman and Company: New York, NY (1992), and the methods described herein.) The measured affinity of a particular antibody-antigen interaction can vary when measured under different conditions (e.g., salt concentration, pH). Thus, the measurement of affinity and other antigen-binding parameters (e.g., K D , K a , K d ) is preferably performed using a standardized solution of the antibody and antigen, and a standardized buffer such as the buffers described herein.

[0115] Nucleic acid molecule Among other sequences disclosed herein, for example, using the information provided herein such as a nucleotide sequence encoding at least 70-100% of at least one adjacent amino acid of a light or heavy chain variable or CDR region described herein, a specified fragment, variant or consensus sequence thereof, or a deposited vector containing at least one of these sequences, the nucleic acid molecule of the invention encoding at least one IL-12 / IL-23p40 or IL-23 antibody can be obtained as described herein or using methods known in the art.

[0116] The nucleic acid molecule of the invention may be in the form of RNA such as mRNA, hnRNA, tRNA or any other form, or in the form of DNA including but not limited to cDNA and genomic DNA obtained by cloning or synthetically produced, or any combination thereof. The DNA may be triple-stranded, double-stranded or single-stranded, or any combination thereof. Any part of at least one strand of the DNA or RNA may be a coding strand, also known as a sense strand, or a non-coding strand, also called an antisense strand.

[0117] The isolated nucleic acid molecules used in the method of the present invention can include an open reading frame (ORF) optionally having one or more introns, for example, but not limited to, at least one specific portion of at least one CDR, such as CDR1, CDR2, and / or CDR3 of at least one heavy or light chain, a nucleic acid molecule containing a coding sequence of an anti-IL-12 / IL-23p40 or IL-23 antibody or variable region, and a nucleic acid molecule that is substantially different from the above-described nucleic acid molecules but, due to the degeneracy of the genetic code, still encodes at least one anti-IL-12 / IL-23p40 or IL-23 antibody described herein and / or known in the art. Of course, the genetic code is well known in the art. Thus, it would be routine for those skilled in the art to generate such degenerate nucleic acid variants that encode the specific anti-IL-12 / IL-23p40 or IL-23 antibodies used in the method of the present invention. See, for example, Ausubel et al. above, such nucleic acid variants are included in the present invention. Non-limiting examples of isolated nucleic acid molecules include nucleic acids encoding HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, respectively.

[0118] As described herein, nucleic acid molecules comprising a nucleic acid encoding an anti-IL-12 / IL-23p40 or IL-23 antibody include those that by themselves encode the amino acid sequence of an antibody fragment, the coding sequence of a whole antibody or a part thereof, the coding sequence of an antibody, fragment or portion, and additional sequences, such as at least one intron, etc., with or without the aforementioned additional coding sequences, non-coding 5' and 3' sequences, such as transcribed untranslated sequences involved in transcription, mRNA processing, including splicing and polyadenylation signals (e.g., ribosome binding and stability of mRNA), and additional non-coding sequences, including but not limited to, the coding sequence of at least one signal leader or fusion peptide, additional coding sequences encoding additional amino acids, such as amino acids providing additional functionality, etc., but not limited thereto. Thus, the sequence encoding the antibody can be fused to a marker sequence, such as a sequence encoding a peptide that facilitates the purification of a fused antibody containing an antibody fragment or portion.

[0119] A polynucleotide that selectively hybridizes to the polynucleotide described herein The methods of the present invention use isolated nucleic acids that hybridize under selective hybridization conditions to the polynucleotides disclosed herein. Thus, the polynucleotides of this embodiment can be used to isolate, detect, and / or quantify nucleic acids containing such polynucleotides. For example, the polynucleotides of the present invention can be used to identify, isolate, or amplify partial or full-length clones in an accumulated library. In some embodiments, the polynucleotide is an isolated or otherwise genomic or cDNA sequence complementary to cDNA from a human or mammalian nucleic acid library.

[0120] Preferably, the cDNA library comprises at least 80% of the full-length sequence, preferably at least 85% or 90% of the full-length sequence, more preferably at least 95% of the full-length sequence. The cDNA library may be normalized to increase the expression level of rare sequences. Low or moderate stringency hybridization conditions are typical, but not exclusive, for use with sequences having reduced sequence identity to the complementary sequence. Medium and high stringency conditions can optionally be used for sequences having higher identity. Low stringency conditions allow selective hybridization of sequences having about 70% sequence identity and can be utilized to identify orthologous or paralogous sequences.

[0121] Optionally, the polynucleotide encodes at least a portion of an antibody. The polynucleotide includes nucleic acid sequences that can be utilized for selective hybridization to a polynucleotide encoding an antibody of the invention. See, for example, Ausubel, supra, and Colligan, supra, each of which is incorporated herein by reference in its entirety.

[0122] Construction of Nucleic Acids Isolated nucleic acids can be made using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, and / or combinations thereof, as is well known in the art.

[0123] In addition to the polynucleotides of the invention, the nucleic acids can include a well-defined sequence. For example, a multiple cloning site containing one or more endonuclease restriction sites can be inserted into the nucleic acid to facilitate isolation of the polynucleotide. Also, a translatable sequence can be inserted to facilitate isolation of the translated polynucleotide of the invention. For example, a hexahistidine marker sequence provides a convenient means for purifying the protein of the invention. The nucleic acids of the invention (excluding the coding sequence) are optionally vectors, adapters, or linkers for cloning and / or expression of the polynucleotides of the invention.

[0124] Additional arrays can be added to such cloning and / or expression arrays to optimize their functions in cloning and / or expression and can be used to aid in the isolation of polynucleotides or to improve the introduction of polynucleotides into cells. The use of cloning vectors, expression vectors, adapters, and linkers is well known in the art. (See, for example, Ausubel supra or Sambrook supra.)

[0125] Recombinant methods for constructing nucleic acids Isolated nucleic acid compositions such as RNA, cDNA, genomic DNA, or any combination thereof can be obtained from biological sources using any number of cloning methods known to those of skill in the art. In some embodiments, oligonucleotide probes that selectively hybridize to the polynucleotides of the invention under stringent conditions are used to identify the desired sequences within a cDNA or genomic DNA library. The isolation of RNA and the construction of cDNA and genomic libraries are well known to those of skill in the art. (See, for example, Ausubel supra or Sambrook supra.)

[0126] Methods for screening and isolating nucleic acids Using a probe based on the sequence of a polynucleotide used in the method of the present invention, such as those disclosed herein, a cDNA or genomic library can be screened. The probe can be hybridized to genomic DNA or cDNA sequences to isolate homologous genes in the same or different organisms. One of ordinary skill in the art can use various degrees of hybridization stringency in the assay, and it will be apparent that either the hybridization or wash medium can be stringent. As the conditions for hybridization become more stringent, the degree of complementarity between the probe and the target should increase for duplex formation to occur. The degree of stringency can be controlled by one or more of temperature, ionic strength, pH, and the presence of a partially denaturing solvent such as formamide. For example, the stringency of hybridization can be readily altered by changing the polarity of the reaction solution by manipulating the formamide concentration in the range of, for example, 0% to 50%. The degree of complementarity (sequence identity) required for detectable binding varies according to the stringency of the hybridization medium and / or wash medium. The degree of complementarity is optimally 100%, or 70 to 100%, or any range or value therein. However, it should be understood that minor sequence variations within the probe and primer can be compensated for by decreasing the stringency of the hybridization and / or wash medium.

[0127] Methods for amplifying RNA or DNA are well known in the art and can be used in accordance with the present invention without undue experimentation based on the teachings and guidance presented herein.

[0128] Known methods of DNA or RNA amplification include polymerase chain reaction (PCR) and related amplification processes (see, e.g., U.S. Pat. Nos. 4,683,195, 4,683,202, 4,800,159, 4,965,188 to Mullis et al., 4,795,699 and 4,921,794 to Tabor et al., 5,142,033 to Innis, 5,122,464 to Wilson et al., 5,091,310 to Innis, 5,066,584 to Gyllensten et al., 4,889,818 to Gelfand et al., 4,994,370 to Silver et al., 4,766,067 to Biswas, 4,656,134 to Ringold), and RNA-mediated amplification using antisense RNA as a template for double-stranded DNA synthesis (U.S. Pat. No. 5,130,238 to Malek et al., having the trade name NASBA), but are not limited thereto (the entire contents of these documents are incorporated herein by reference). (See, e.g., Ausubel supra, or Sambrook supra.)

[0129] For example, using polymerase chain reaction (PCR) technology, the sequences of the polynucleotides and related genes used in the method of the present invention can be amplified directly from genomic DNA or cDNA libraries. PCR and other in vitro amplification methods are also useful, for example, for cloning nucleic acid sequences encoding proteins to be expressed, for detecting the presence of desired mRNA in a sample, for nucleic acid sequencing, or for generating nucleic acids for use as probes for other purposes. Examples of techniques sufficient to guide those skilled in the art in in vitro amplification methods can be found in Berger, Sambrook, and Ausubel supra, as well as Mullis et al. U.S. Patent No. 4,683,202 (1987), and Innis, et al., PCR Protocols A Guide to Methods and Applications, Eds., Academic Press Inc, San Diego, CA (1990). Commercially available kits for genomic PCR amplification are known in the art. See, for example, Advantage-GC Genomic PCR Kit (Clontech). In addition, for example, the yield of long PCR products can be improved using T4 gene 32 protein (Boehringer Mannheim).

[0130] Synthetic methods for constructing nucleic acids The isolated nucleic acids used in the method of the present invention can also be prepared by direct chemical synthesis by known methods (see, for example, Ausubel et al. supra). Chemical synthesis generally generates single-stranded oligonucleotides that can be converted to double-stranded DNA by hybridization with complementary sequences or by polymerization with DNA polymerase using the single strand as a template. Those skilled in the art will recognize that while chemical synthesis of DNA may be limited to sequences of about 100 bases or more, longer sequences can be obtained by ligation reactions of shorter sequences.

[0131] Recombinant expression cassette The present invention uses a recombinant expression cassette containing a nucleic acid. A recombinant expression cassette can be constructed using a nucleic acid sequence, such as a cDNA or genomic sequence encoding an antibody used in the methods of the present invention, which can be introduced into at least one desired host cell. A recombinant expression cassette typically contains a polynucleotide operably linked to a transcriptional initiation regulatory sequence that directs transcription of the polynucleotide in the intended host cell. Both heterologous and non-heterologous (i.e., endogenous) promoters can be utilized to direct the expression of the nucleic acid.

[0132] In some embodiments, an isolated nucleic acid that functions as a promoter, enhancer, or other element can be introduced at an appropriate position (upstream, downstream, or within an intron) of a non-heterologous form of the polynucleotide of the present invention to upregulate or downregulate the expression of the polynucleotide. For example, the endogenous promoter can be altered by mutation, deletion, and / or substitution, either in vivo or in vitro.

[0133] Vectors and Host Cells The present invention also relates to vectors containing isolated nucleic acid molecules, host cells genetically engineered with recombinant vectors, and the production of at least one anti-IL-23 antibody by recombinant techniques well known in the art. See, for example, Sambrook et al. and Ausubel et al. supra, each of which is incorporated herein by reference in its entirety.

[0134] The polynucleotide can optionally be ligated into a vector containing a selectable marker for growth of the host. Generally, plasmid vectors are introduced into a precipitate such as a calcium phosphate precipitate or into a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into the host cell.

[0135] The DNA insert should be operably linked to an appropriate promoter. The expression construct further includes a transcription start site, a transcription termination site, and a ribosome binding site for translation within the transcribed region. The coding portion of the mature transcript expressed by the construct preferably includes a translation starting with appropriate start and stop codons (e.g., UAA, UGA, or UAG) appropriately positioned at the end of the mRNA to be translated, with UAA and UAG being preferred for expression in mammalian or eukaryotic cells.

[0136] The expression vector preferably includes at least one selectable marker, but this is optional. Such markers include, for example, methotrexate (MTX) for eukaryotic cell culture, dihydrofolate reductase (DHFR, U.S. Patent Nos. 4,399,216; 4,634,665; 4,656,134; 4,956,288; 5,149,636; 5,179,017), ampicillin, neomycin (G418), mycophenolic acid, or glutamine synthetase (GS, U.S. Patent Nos. 5,122,464; 5,770,359; 5,827,739) resistance genes, and tetracycline or ampicillin resistance genes for culture in E. coli and other bacteria or prokaryotes, but are not limited thereto (the above patents are hereby incorporated by reference in their entirety). Appropriate culture media and conditions for the above host cells are known in the art. Appropriate vectors will be readily apparent to the person skilled in the art. Introduction of the vector construct into the host cell can be affected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid mediated transfection, electroporation, transduction, infection, or other known methods. Such methods are described in the art, such as the above Sambrook, Chapters 1-4 and 16-18, the above Ausubel, Chapters 1, 9, 13, 15, 16, etc.

[0137] At least one antibody used in the method of the present invention can be expressed in a modified form such as a fusion protein, and can include not only a secretion signal but also additional heterologous functional regions. For example, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of the antibody to improve stability and persistence in host cells during purification or subsequent processing and storage. Also, a peptide moiety can be added to the antibody of the present invention to facilitate purification. Such regions can be removed prior to the final preparation of the antibody or at least one fragment thereof. Such methods are described in many standard laboratory manuals such as Sambrook, supra, Chapters 17.29-17.42 and 18.1-18.74, and Ausubel, supra, Chapters 16, 17 and 18.

[0138] One skilled in the art is familiar with numerous expression systems available for the expression of nucleic acids encoding the proteins used in the method of the present invention. Alternatively, the nucleic acid can be expressed in a host cell containing endogenous DNA encoding the antibody by (operatively) switching it on. Such methods are well known in the art as described in U.S. Pat. Nos. 5,580,734, 5,641,670, 5,733,746, and 5,733,761, which are hereby incorporated by reference in their entirety.

[0139] An example of cell culture useful for the production of an antibody, a specifically identified portion thereof, or a variant is mammalian cells. Mammalian cell lines often take the form of a monolayer of cells, but suspensions of mammalian cells or bioreactors can also be used. Many suitable host cell lines capable of expressing intact glycosylated proteins have been developed in the art, including COS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-1651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., ATCC CRL1610), and BSC-1 (e.g., ATCC CRL-26) cell lines, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2 / 0-Ag14, 293 cells, HeLa cells, etc., which are readily available, for example, from the American Type Culture Collection, Manassas, Va (www.atcc.org). Preferred host cells include cells of lymphoid origin such as myeloma and lymphoma cells. Particularly preferred host cells are P3X63Ag8.653 cells (ATCC accession number CRL-1580) and SP2 / 0-Ag14 cells (ATCC accession number CRL-1851). In a particularly preferred embodiment, the recombinant cells are P3X63Ab8.653 or SP2 / 0-Ag14 cells.

[0140] The expression vectors of these cells can include one or more of the expression control sequences such as, but not limited to, an origin of replication, a promoter (e.g., late or early SV40 promoter, CMV promoter (U.S. Patent Nos. 5,168,062; 5,385,839), HSV tk promoter, pgk (phosphoglycerate kinase) promoter, EF-1α promoter (U.S. Patent No. 5,266,491), at least one human immunoglobulin promoter, an enhancer, and / or a ribosome binding site, an RNA splice site, a polyadenylation site (e.g., SV40 large T Ag polyadenylation site), and a processing information site such as a transcription termination sequence. See, for example, Ausubel et al. and Sambrook et al. supra. Other cells useful for the production of the nucleic acids or proteins of the present invention are known and / or available, for example, from the American Type Culture Collection Catalogue of Cell Lines and Hybridomas (www.atcc.org) or other known or commercial sources.

[0141] When eukaryotic host cells are utilized, typically a polyadenylation or transcription termination sequence is incorporated into the vector. An example of a termination sequence is the polyadenylation sequence from the bovine growth hormone gene. Sequences for accurate splicing of transcription can likewise be included. An example of a splicing sequence is the VP1 intron from SV40 (Sprague, et al., J. Virol. 45:773-781 (1983)). In addition, as is known in the art, gene sequences for controlling replication within the host cell can be incorporated into the vector.

[0142] Purification of Antibodies Anti-IL-12 / IL-23p40 or IL-23 antibodies can be recovered and purified from recombinant cell cultures by well-known methods including, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, and lectin chromatography. High performance liquid chromatography ("HPLC") can also be used for purification. For example, reference is made to, for example, Chapters 1, 4, 6, 8, 9, 10 of Colligan, Current Protocols in Immunology or Current Protocols in Protein Science, John Wiley & Sons, NY, NY (1997-2001), each of which is incorporated herein by reference in its entirety.

[0143] Antibodies used in the methods of the invention include naturally purified products, products of chemical synthetic procedures, and products produced recombinantly from eukaryotic hosts including, for example, yeast, higher plants, insects, and mammalian cells. Depending on the host used in the recombinant production procedure, the antibody may or may not be glycosylated, but is preferably glycosylated. Such methods are described in many standard laboratory manuals such as the above Sambrook, Sections 17.37-17.42, the above Ausubel, Chapters 10, 12, 13, 16, 18, and 20, the above Colligan, Protein Science, Chapters 12-14, all of which are incorporated herein by reference in their entirety.

[0144] Anti-IL-12 / IL-23p40 or IL-23 antibody The anti-IL-12 / 23p40 or IL-23 antibody according to the present invention comprises at least a part of an immunoglobulin molecule that can be incorporated into an antibody, for example, but not limited to, at least one ligand binding portion (LBP), for example, but not limited to, a complementarity determining region (CDR) of a heavy chain or a light chain or a ligand binding portion thereof, a variable region of a heavy chain or a light chain, a framework region (e.g., FR1, FR2, FR3, FR4, or fragments thereof, further optionally including at least one substitution, insertion, or deletion), a constant region of a heavy chain or a light chain (e.g., at least one C H 1, hinge 1, hinge 2, hinge 3, hinge 4, C H 2, or C H 3, or fragments thereof, further optionally including at least one substitution, insertion, or deletion), or any protein or peptide-containing molecule comprising any portion thereof. The antibody can include or be derived from any mammal, such as, but not limited to, human, mouse, rabbit, rat, rodent, primate, or any combination thereof.

[0145] The isolated antibodies used in the method of the present invention include the amino acid sequences of the antibodies disclosed herein encoded by any suitable polynucleotide, or any isolated or prepared antibody. Preferably, a human antibody or antigen-binding fragment binds to human IL-12 / IL-23p40 or IL-23, thereby partially or substantially neutralizing at least one biological activity of the protein. An antibody or a specified portion or variant thereof that partially or preferably substantially neutralizes at least one biological activity of at least one IL-12 / IL-23p40 or IL-23 protein or fragment binds to the protein or fragment, thereby inhibiting the activity of IL-12 / IL-23p40 or IL-23 mediated through binding to the IL-12 and / or IL-23 receptor or through other IL-12 / IL-23p40 or IL-23-dependent or mediated mechanisms. As used herein, the term "neutralizing antibody" refers to an antibody that can inhibit IL-12 / IL-23p40 or IL-23-dependent activity by about 20-120% depending on the assay, preferably at least about 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% or more. The ability of an anti-IL-12 / 23p40 or IL-23 antibody to inhibit IL-12 / IL-23p40 or IL-23-dependent activity is preferably evaluated by at least one suitable IL-12 / IL-23p40 or IL-23 protein or receptor assay described herein and / or known in the art. Human antibodies can be of any class (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and can include kappa or lambda light chains. In one embodiment, the human antibody includes at least one isotype of an IgG heavy chain or defined fragment, such as IgG1, IgG2, IgG3, or IgG4 (e.g., γ1, γ2, γ3, γ4). Antibodies of this type can be prepared by utilizing transgenic mice or other transgenic non-human mammals that include at least one human light chain (e.g., IgG, IgA, and IgM) transgene described herein and / or known in the art.In another embodiment, the anti-IL-23 human antibody comprises an IgG1 heavy chain and an IgG1 light chain.

[0146] The antibody binds to at least one identified epitope specific for at least one IL-12 / IL-23p40 or IL-23 protein, subunit, fragment, moiety, or any combination thereof. This at least one epitope can comprise at least one antibody-binding region that comprises at least a portion of the protein, and this epitope preferably consists of at least one extracellular, soluble, hydrophilic, external, or cytoplasmic portion of the protein.

[0147] Generally, a human antibody or antigen-binding fragment comprises an antigen-binding region that comprises at least one human complementarity-determining region (CDR1, CDR2, and CDR3) or variant of at least one heavy-chain variable region, and at least one human complementarity-determining region (CDR1, CDR2, and CDR3) or variant of at least one light-chain variable region. The CDR sequences may be derived from human germline sequences or may be strictly identical to germline sequences. For example, CDRs from synthetic libraries derived from the original non-human CDRs can be used. These CDRs can be formed by incorporation of conservative substitutions from the original non-human sequences. In another particular embodiment, the antibody or antigen-binding portion or variant can have an antigen-binding region that comprises at least a portion of at least one light-chain CDR (i.e., CDR1, CDR2, and / or CDR3) having the amino acid sequence of the corresponding CDR1, 2, and / or 3.

[0148] Such antibodies can be prepared by using conventional techniques of recombinant DNA technology to prepare and express nucleic acid molecules that encode the antibody (i.e., one or more), or by chemically conjugating various portions of the antibody (e.g., CDRs, frameworks) together using any other suitable method, using conventional techniques.

[0149] Anti-IL-12 / IL-23p40 or IL-23 specific antibodies can comprise at least one of a heavy or light chain variable region having a defined amino acid sequence. For example, in a preferred embodiment, the anti-IL-12 / IL-23p40 or IL-23 antibody comprises an anti-IL-12 / IL-23p40 antibody having a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. Anti-IL-12 / IL-23p40 or IL-23 specific antibodies can comprise at least one of a heavy or light chain having a defined amino acid sequence. In another preferred embodiment, the anti-IL-12 / IL-23p40 or IL-23 antibody comprises an anti-IL-12 / IL-23p40 antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO: 11. Antibodies that bind to human IL-12, IL-23p40 or IL-23 and comprise a defined heavy or light chain variable region can be prepared using suitable methods known in the art and / or described herein, such as methods employing phage display (Katsube, Y., et al., Int J Mol. Med, 1(5):863-868 (1998)) or transgenic animals. For example, a transgenic mouse comprising a functionally rearranged human immunoglobulin heavy chain transgene and a transgene comprising DNA from a human immunoglobulin light chain locus capable of undergoing functional rearrangement can be immunized with human IL-12 / IL-23p40 or IL-23 or a fragment thereof to induce antibody production. If desired, antibody-producing cells can be isolated and hybridomas or other immortalized antibody-producing cells can be prepared as described herein and / or as known in the art. Alternatively, an antibody, identified portion or variant can be expressed in a suitable host cell using the encoding nucleic acid or a portion thereof.

[0150] The invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs that contain amino acids within a sequence that is substantially the same as the amino acid sequences described herein. Preferably, such antibodies or antigen-binding fragments and antibodies containing such chains or CDRs have a high affinity (e.g., K D is about 10 -9 M or less) and can bind to human IL-12 / IL-23p40 or IL-23. Amino acid sequences that are substantially the same as the sequences described herein include sequences containing conservative amino acid substitutions, as well as amino acid deletions and / or insertions. Conservative amino acid substitutions refer to replacing a first amino acid with a second amino acid that has similar chemical and / or physical properties (e.g., charge, structure, polarity, hydrophobicity / hydrophilicity) to that of the first amino acid. Conservative substitutions include, but are not limited to, replacing one amino acid with another within the following groups: lysine (K), arginine (R), and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D, and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine (C), and glycine (G); F, W, and Y; C, S, and T.

[0151] Amino acid code The anti-IL-12 / IL-23p40 or IL-23 antibodies of the invention are often abbreviated. Amino acid notations can be indicated by their one-letter code, their three-letter code, name, or the codon(s) of three nucleotides that encode the amino acid, which are well understood in the art (see Alberts, B., et al., Molecular Biology of The Cell, Third Ed., Garland Publishing, Inc., New York, 1994).

[0152]

Table 1

[0153] Array Exemplary anti-IL-12 / IL-23p40 antibody sequence - STELARA® (ustekinumab) Amino acid sequence of the anti-IL-12 / IL-23p40 antibody complementarity determining region heavy chain 1 (CDRH1): (SEQ ID NO: 1) TYWLG

[0154] Amino acid sequence of the anti-IL-12 / IL-23p40 antibody complementarity determining region heavy chain 2 (CDRH2): (SEQ ID NO: 2) IMSPVDSDIRYSPSFQG

[0155] Amino acid sequence of the anti-IL-12 / IL-23p40 antibody complementarity determining region heavy chain 3 (CDRH3): (SEQ ID NO: 3) RRPGQGYFDF

[0156] Amino acid sequence of the anti-IL-12 / IL-23p40 antibody complementarity determining region light chain 1 (CDRL1): (SEQ ID NO: 4) RASQGISSWLA

[0157] Amino acid sequence of the anti-IL-12 / IL-23p40 antibody complementarity determining region light chain 2 (CDRL2): (SEQ ID NO: 5) AASSLQS

[0158] Amino acid sequence of the anti-IL-12 / IL-23p40 antibody complementarity determining region light chain 3 (CDRL3): (SEQ ID NO: 6) QQYNIYPYT

[0159] Amino acid sequence of the anti-IL-12 / IL-23p40 antibody variable heavy chain region (CDR underlined): (SEQ ID NO: 7)

[0160]

Chemical Structure

[0161] Amino acid sequence of the anti-IL-12 / IL-23p40 antibody variable light chain region (CDR underlined): (SEQ ID NO: 8)

[0162]

Chemical Structure

[0163] Amino acid sequence of the anti-IL-12 / IL-23p40 antibody heavy chain (CDR underlined): (SEQ ID NO: 10)

[0164]

Chemical Structure

[0165] Amino acid sequence of the anti-IL-12 / IL-23p40 antibody light chain (CDR underlined): (SEQ ID NO: 11)

[0166]

Chemical Structure

[0167] Amino acid sequence of IL-12 Amino acid sequence of human interleukin (IL)-12 having α and β subunits: (SEQ ID NO: 9)

[0168]

Chemical Structure

[0169] The anti-IL-12 / IL-23p40 or IL-23 antibodies used in the methods of the present invention may contain one or more amino acid substitutions, deletions, or additions, either by natural mutation or human manipulation, as specified herein.

[0170] The number of amino acid substitutions that a person skilled in the art can make is based on a number of factors including those described above. Generally speaking, the number of amino acid substitutions, insertions or deletions in a given anti-IL-12 / IL-23p40 or IL-23 antibody, fragment or variant is 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, for example, 1 to 30 or any range or value therein that does not exceed this, as specified herein.

[0171] Amino acids in an anti-IL-12 / IL-23p40 or IL-23-specific antibody that are functionally essential can be identified by methods known in the art such as site-directed mutagenesis or alanine scanning mutagenesis (for example, Ausubel, supra, Chapters 8, 15; Cunningham and Wells, Science 244:1081-1085 (1989)). In the latter procedure, one alanine substitution mutation is introduced for each residue within the molecule. The resulting mutant molecules are then tested for biological activity such as, but not limited to, at least one IL-12 / IL-23p40 or IL-23 neutralizing activity. Sites that are extremely important for antibody binding can also be identified by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith, et al., J. Mol. Biol. 224:899-904 (1992) and de Vos, et al., Science 255:306-312 (1992)).

[0172] An anti-IL-12 / IL-23p40 or IL-23 antibody can comprise, but is not limited to, at least one portion, sequence, or combination selected from 5 to all of at least one of the adjacent amino acids of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 10, or 11.

[0173] IL-12 / IL-23p40, or an IL-23 antibody, or a specific portion or variant, can include, but is not limited to, at least one portion, sequence, or combination selected from at least 3 to 5 contiguous amino acids of the above sequence numbers, 5 to 17 contiguous amino acids of the above sequence numbers, 5 to 10 contiguous amino acids of the above sequence numbers, 5 to 11 contiguous amino acids of the above sequence numbers, 5 to 7 contiguous amino acids of the above sequence numbers, and 5 to 9 contiguous amino acids of the above sequence numbers.

[0174] The anti-IL-12 / IL-23p40 or IL-23 antibody can further optionally include at least one polypeptide that is 70 to 100% of 5, 17, 10, 11, 7, 9, 119, 108, 449, or 214 contiguous amino acids of the above sequence numbers. In one embodiment, the amino acid sequence of an immunoglobulin chain, or a portion thereof (e.g., variable region, CDR), has about 70 to 100% identity (e.g., 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or any range or value therein) with the amino acid sequence of at least one corresponding chain of the above sequence numbers. For example, the amino acid sequence of the light chain variable region can be compared with the above sequence numbers, or the amino acid sequence of the heavy chain CDR3 can be compared with the above sequence numbers. Preferably, 70 to 100% amino acid identity (i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or any range or value therein) is determined using appropriate computer algorithms as known in the art.

[0175] As is known in the art, "identity" is a relationship between two or more polypeptide sequences or two or more polynucleotide sequences, which is determined by comparing the sequences. In the art, "identity" also means the degree of sequence relatedness between polypeptide or polynucleotide sequences, such that it is determined by the match between the threads of such sequences. "Identity" and "similarity" can be readily calculated by known methods, including but not limited to those described in Computational Molecular Biology, Lesk, A.M., ed., Oxford University Press, New York, 1988, Biocomputing: Informatics and Genome Projects, Smith, D.W., ed., Academic Press, New York, 1993, Computer Analysis of Sequence Data, Part I, Griffin, A.M., and Griffin, H.G., eds., Humana Press, New Jersey, 1994, Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987, and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991, and Carillo, H., and Lipman, D., Siam J. Applied Math., 48:1073 (1988). In addition, values for the percentage of identity can be obtained from amino acid and nucleotide sequence alignments created using the default settings of AlignX, a component of Vector NTI Suite 8.0 (Informax, Frederick, MD).

[0176] Preferred methods for determining identity are designed to obtain a maximum match between the sequences being tested. Methods for determining identity and similarity are embodied in publicly available computer programs. Preferred computer program methods for determining identity and similarity between two sequences include, but are not limited to, the GCG program package (Devereux, J., et al., Nucleic Acids Research 12(1):387(1984)), BLASTP, BLASTN, and FASTA (Atschul, S.F. et al., J. Molec. Biol. 215:403-410(1990)). The BLAST X program is publicly available from NCBI and other sources (BLAST Manual, Altschul, S., et al., NCBINLM NIH Bethesda, Md. 20894: Altschul, S., et al., J. Mol. Biol. 215:403-410(1990)). The well-known Smith Waterman algorithm can also be used to determine identity.

[0177] Preferred parameters for polypeptide sequence comparison include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443-453(1970) Comparison matrix: BLOSSUM62 from Hentikoff and Hentikoff, Proc. Natl. Acad. Sci, USA. 89:10915-10919(1992), Gap penalty: 12 Gap length penalty: 4 A program useful with these parameters is publicly available as the "Gap" program from Genetics Computer Group, Madison Wis. The foregoing parameters are the default parameters for peptide sequence comparison (similar to no penalty for terminal gaps).

[0178] Preferred parameters for polynucleotide comparison include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443-453 (1970) Comparison matrix: match = +10, mismatch = 0 Gap penalty: 50 Gap length penalty: 3 Available as the "Gap" program from Genetics Computer Group, Madison Wis. These are the default parameters for nucleic acid sequence comparison.

[0179] As an example, a polynucleotide sequence can be identical to another sequence, i.e., 100% identical, or can include nucleotide changes up to a certain integer compared to a reference sequence. Such changes are selected from the group consisting of at least one nucleotide deletion, substitution (including transversions and transitions), or insertion, and the changes can occur at the 5' or 3' end positions of the reference nucleotide sequence, or anywhere between these end positions, either individually between the nucleotides of the reference sequence or interspersed among any of one or more adjacent groups of nucleotides within the reference sequence. The number of nucleotide changes is obtained by multiplying the total number of nucleotides in the sequence by the numerical percentage of the corresponding percent identity (divided by 100), and subtracting that product from the total number of nucleotides in the sequence, or, n.sub.n.ltorsim.x.sub.n-(x.sub.n.y), where n.sub.n is the number of nucleotide changes, x.sub.n is the total number of nucleotides in the sequence, y is, for example, 0.70 for 70%, 0.80 for 80%, 0.85 for 85%, 0.90 for 90%, 0.95 for 95%, etc., and the product of x.sub.n and y that is not an integer is rounded down to the nearest integer before subtracting from x.sub.n.

[0180] Changes to the polynucleotide sequence encoding the above sequence number can create nonsense, missense, or frameshift mutations in this coding sequence, thereby allowing the polypeptide encoded by the polynucleotide to be altered after such changes. Similarly, the polypeptide sequence can be identical to the reference sequence of the above sequence number, i.e., 100% identical or contain amino acid changes up to a certain integer compared to the reference sequence such that the identity rate is less than 100%. Such changes are selected from the group consisting of at least one amino acid deletion, substitution (including conservative and non-conservative substitutions), or insertion, and the changes can occur at the amino or carboxy terminal positions of the reference polypeptide sequence or anywhere between these terminal positions, and can be scattered individually between the amino acids of the reference sequence or in any of one or more adjacent groups within the reference sequence. The number of amino acid changes for a given percent identity is determined by multiplying the total number of amino acids of the above sequence number by the numerical percentage (divided by 100) of each percent identity, and then subtracting that product from the total number of amino acids of the above sequence number, or by n.sub.a.ltorsim.x.sub.a-(x.sub.a.y) (where n.sub.a is the number of amino acid changes, x.sub.a is the total number of amino acids of the above sequence number, y is, for example, 70% is 0.70, 80% is 0.80, 85% is 0.85, etc., and any non-integer product of x.sub.a and y is rounded to the nearest integer unit before subtracting it from x.sub.a).

[0181] The sequences of exemplary heavy and light chain variable regions, and portions thereof, are shown by the above sequence numbers. The antibodies of the present invention, or identified variants thereof, can include any number of adjacent amino acid residues from the antibodies of the present invention, the number being selected from the group of integers consisting of 10 to 100% of the number of adjacent residues in the anti-IL-12 / IL-23p40 or IL-23 antibody. Optionally, this subsequence of adjacent amino acids is at least 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 or value therein. Further, the number of such subsequences can be any integer selected from the group consisting of 1 to 20, such as at least 2, 3, 4, or 5.

[0182] As will be apparent to those skilled in the art, the present invention includes at least one bioactive antibody of the present invention. A bioactive antibody has at least 20%, 30%, or 40%, and preferably at least 50%, 60%, or 70%, and most preferably at least 80%, 90%, or 95% to 100% or more (including up to 10-fold the maximum specific activity, although not limited thereto) of the specific activity of natural (non-synthetic), endogenous, or related, and known antibodies. Methods for the assay and quantitative measurement of enzyme activity and substrate specificity are well known to those skilled in the art.

[0183] In another aspect, the invention relates to human antibodies and antigen-binding fragments described herein that are modified by covalent attachment of an organic moiety. Such modifications can generate antibodies or antigen-binding fragments with improved pharmacokinetic properties (e.g., increased in vivo serum half-life). The organic moiety can be a linear or branched hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. In certain embodiments, the hydrophilic polymer group has a molecular weight of about 800 to about 120,000 daltons and can be a polyalkane glycol (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)), a carbohydrate polymer, an amino acid polymer, or polyvinyl pyrrolidone, and the fatty acid group or fatty acid ester group can contain about 8 to about 40 carbon atoms.

[0184] The modified antibodies and antigen-binding fragments can include one or more organic moieties that are covalently attached to the antibody either directly or indirectly. Each organic moiety attached to the antibody or antigen-binding fragment of the invention can independently be a hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. As used herein, the term "fatty acid" includes monocarboxylic acids and dicarboxylic acids. As used herein, the term "hydrophilic polymer group" means an organic polymer that is more soluble in water than octane. For example, polylysine is more soluble in water than octane. Thus, an antibody modified by covalent attachment of polylysine is encompassed by the invention. Suitable hydrophilic polymers for modifying the antibodies of the invention can be linear or branched and include, for example, polyalkane glycols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG, etc.), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides, etc.), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, polyaspartic acid, etc.), polyalkane oxides (e.g., polyethylene oxide, polypropylene oxide, etc.), and polyvinyl pyrrolidone. Preferably, the hydrophilic polymer for modifying the antibodies of the invention has a molecular weight of about 800 to about 150,000 daltons as an individual entity. For example, PEG 5000 and PEG 20,000It can be used, and the subscript is the average molecular weight (Dalton) of the polymer. The hydrophilic polymer group can 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 by utilizing appropriate methods. For example, a polymer containing an amine group can be linked to the carboxylate of a fatty acid or fatty acid ester, and an activated carboxylate on the fatty acid or fatty acid ester (for example, activated with N,N-carbonyldiimidazole) can be linked to the hydroxyl group on the polymer.

[0185] Fatty acids and fatty acid esters suitable for modifying the antibodies of the present invention may be saturated or may contain one or more unsaturated units. Examples of fatty acids suitable for modifying the antibodies of the present invention include, for example, n-dodecanoate (C 12 , laurate), n-tetradecanoate (C 14 , myristate), n-octadecanoate (C 18 , stearate), n-eicosanoate (C 20 , arachidate), n-docosanoate (C 22 , behenate), n-triacontanoate (C 30 ), n-tetracosanoate (C 40 ), cis-Δ9-octadecenoate (C 18 , oleate), all cis-Δ5,8,11,14-eicosatetraenoate (C 20 , arachidonate), octanedioic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, and the like. Suitable fatty acid esters include mono-esters of dicarboxylic acids containing a straight-chain or branched-chain lower alkyl group. The lower alkyl group may contain 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms.

[0186] Modified human antibodies and antigen-binding fragments can be prepared using suitable methods, such as reacting with one or more modifying agents. As used herein, the term "modifying agent" means a suitable organic group containing an activating group (e.g., a hydrophilic polymer, a fatty acid, a fatty acid ester). An "activating group" is a chemical moiety or functional group that can react with a second chemical group under suitable conditions to form a covalent bond between the modifying agent and the second chemical group. For example, amine-reactive activating groups include electrophilic groups such as tosylate, mesylate, halo (chloro, bromo, fluoro, iodo), and N-hydroxysuccinimidyl esters (NHS). Activating groups capable of reacting with thiols include, for example, maleimide, iodoacetyl, acryloyl, pyridyldisulfide, 5-thiol-2-nitrobenzoic acid thiol (TNB-thiol), and the like. Aldehyde functional groups can be linked to amine- or hydrazide-containing molecules, and azide groups can react with trivalent phosphorus groups to form phosphoramidate or phosphorimide bonds. Suitable methods for introducing activating groups into molecules are known in the art (see, for example, Hermanson, G.T., Bioconjugate Techniques, Academic Press: San Diego, CA (1996)). The activating group can be directly attached to an organic group (e.g., a hydrophilic polymer, a fatty acid, a fatty acid ester), or through a linker moiety, such as a divalent C1-C 12It can be bonded via a group (where one or more carbon atoms may be substituted with a heteroatom such as oxygen, nitrogen, or sulfur). Suitable linker moieties include, for example, tetraethylene glycol, -(CH2)3-, -NH-(CH2)6-NH-, -(CH2)2-NH- and -CH2-O-CH2-CH2-O-CH2-CH2-O-CH-NH-. The modifier containing the linker moiety can be produced, for example, by reacting a mono-Boc-alkyl diamine (e.g., mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to form an amide bond between the free amine and the fatty acid carboxylate. The Boc protecting group can be removed from the product by treatment with trifluoroacetic acid (TFA) to expose a primary amine that can be coupled to another carboxylate as described, or it can be reacted with maleic anhydride and the resulting product cyclized to produce an activated maleimide derivative of the fatty acid (see, for example, International Publication No. 92 / 16221 of Thompson et al., the entire disclosure of which is incorporated herein by reference).

[0187] Modified antibodies can be produced by reacting a human antibody or antigen-binding fragment with a modifying agent. For example, an organic moiety can be attached to an antibody in a non-site-specific manner by employing an amine-reactive modifying agent, such as an NHS ester of PEG. Modified human antibodies or antigen-binding fragments can also be prepared by reducing the disulfide bonds (e.g., intra-chain disulfide bonds) of the antibody or antigen-binding fragment. At this time, it is possible to produce the modified antibody of the present invention by reacting the reduced antibody or antigen-binding fragment with a thiol-reactive modifying agent. Modified human antibodies and antigen-binding fragments containing an organic moiety bound to a specific site of the antibody of the present invention can be prepared using suitable methods such as those described in retroproteolysis (Fisch et al., Bioconjugate Chem., 3:147-153 (1992), Werlen et al., Bioconjugate Chem., 5:411-417 (1994), Kumaran et al., Protein Sci. 6(10):2233-2241 (1997); Itoh et al., Bioorg.Chem., 24(1):59-68 (1996), Capellas et al., Biotechnol.Bioeng., 56(4):456-463 (1997)) and Hermanson, G.T., Bioconjugate Techniques, Academic Press: San Diego, CA (1996).

[0188] The method of the present invention also uses an anti-IL-12 / IL-23p40 or IL-23 antibody composition comprising at least one, at least two, at least three, at least four, at least five, at least six or more of its anti-IL-12 / IL-23p40 or IL-23 antibodies provided in a non-naturally occurring composition, mixture, or form, as described herein and / or known in the art. Such a composition comprises a non-naturally occurring composition comprising at least one or two full-length, C- and / or N-terminal deletion mutants, domains, fragments, or specified mutants of the amino acid sequence of an anti-IL-12 / IL-23p40 or IL-23 antibody selected from the group consisting of 70-100% of the adjacent amino acids of the above sequence, or a specified fragment, domain, or variant thereof. Preferred anti-IL-12 / IL-23p40 or IL-23 antibody compositions comprise, for example, at least one or two full-lengths, fragments, domains, or variants as at least one CDR or LBP-containing portion of the anti-IL-12 / IL-23p40 or IL-23 antibody sequence described herein, which is 70-100% of the above sequence number, or a specified fragment, domain, or variant thereof. Even more preferred compositions comprise, for example, 40-99% of at least one of the above sequence numbers, such as 70-100%, or a specified fragment, domain, or variant thereof. The percentages of such compositions are by weight, volume, concentration, molarity, or molarity as a liquid or dry solution, mixture, suspension, emulsion, particle, powder, or colloid, as known in the art or as described herein.

[0189] Antibody composition comprising further therapeutic active ingredients The antibody composition used in the method of the present invention can optionally further contain an effective amount of at least one compound or protein selected from at least one of anti-infective agents, cardiovascular (CV) system acting agents, central nervous system (CNS) agents, autonomic nervous system (ANS) agents, respiratory agents, gastrointestinal (GI) tract acting agents, hormonal agents, body fluid or electrolyte balance agents, blood acting agents, anti-tumor agents, immunomodulating agents, eye, ear or nose agents, topical acting agents, nutritional agents, etc. Such drugs are well known in the art, including the respective formulations, indications, dosages, and administrations shown herein (for example, Nursing 2001 Handbook of Drugs, 21 st edition, Springhouse Corp., Springhouse, PA, 2001, Health Professional’s Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, Upper Saddle River, NJ, Pharmcotherapy Handbook, Wells et al., Appleton&Lange, Stamford, CT are referred to, each of which is incorporated herein by reference).

[0190] Examples of drugs that can be combined with the antibodies of the method of the present invention include, as anti-infective drugs, amoebicides or at least one antiprotozoal drug, anthelmintics, antifungal drugs, antimalarial drugs, antituberculosis drugs or at least one antibacterial drug, aminoglycosides, penicillins, cephalosporins, tetracyclines, sulfonamides, fluoroquinolones, antiviral drugs, macrolide anti-infective drugs, and at least one selected from various anti-infective drugs. Hormonal drugs can be at least one selected from corticosteroids, androgens, or at least one anabolic steroid, estrogens, or at least one progestin, gonadotropins, antidiabetic drugs, or at least one glucagon, thyroid hormones, thyroid hormone antagonists, pituitary hormones, and parathyroid-like drugs. At least one cephalosporin can be at least one selected from cefaclor, cefadroxil, cefazolin sodium, cefdinir, cefepime hydrochloride, cefixime, cefmetazole sodium, cefonicid sodium, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime, cefibutene, cefizoxime sodium, ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cephalexin hydrochloride, cephalexin monohydrate, cefradine, and loracarbef.

[0191] At least one corticosteroid can be at least one selected from betamethasone, betamethasone acetate or sodium betamethasone phosphate, sodium betamethasone phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, sodium dexamethasone phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, sodium hydrocortisone phosphate, sodium succinate hydrocortisone, methylprednisolone, methylprednisolone acetate, sodium succinate methylprednisolone, prednisolone, prednisolone acetate, sodium prednisolone phosphate, prednisolone tebutate, prednisone, triamcinolone, triamcinolone acetonide, and triamcinolone diacetate. At least one androgen or anabolic steroid drug can be at least one selected from danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate, nandrolone phenylpropionate, testosterone, testosterone cypionate, testosterone enanthate, testosterone propionate, and testosterone transdermal preparation.

[0192] At least one immunosuppressant can be at least one selected from azathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immunoglobulin, muromonab-CD3, mycophenolate mofetil, mycophenolate mofetil hydrochloride, sirolimus, 6-mercaptopurine, methotrexate, mizoribine, and tacrolimus.

[0193] At least one topical anti-infective agent can be at least one selected from acyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole, econazole nitrate, erythromycin, gentamicin sulfate, ketoconazole, mafenide acetate, metronidazole (topical), miconazole nitrate, mupirocin, naftifine hydrochloride, neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, terbinafine hydrochloride, terconazole, tetracycline hydrochloride, tioconazole, and tolnaftate. At least one scabicide or pediculicide can be at least one selected from crothiamide, lindane, permethrin, and pyrethrin. At least one topical corticosteroid can be at least one selected from betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desonide, desoxymethasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate, fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, and triamcinolone acetonide. (See, for example, pages 1098-1136 of Nursing 2001 Drug Handbook.)

[0194] An anti-IL-12 / IL-23p40 or IL-23 antibody composition comprises at least one anti-IL-12 / 23p40 or IL-23 antibody that is contacted with or administered to cells, tissues, organs, animals, or patients in need of such regulation, treatment, or therapy, and optionally further comprises at least one agent selected from TNF antagonists (e.g., but not limited to, TNF chemical or protein antagonists, TNF monoclonal or polyclonal antibodies or fragments, soluble TNF receptors (e.g., p55, p70, or p85) or fragments, fusion polypeptides thereof, 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, renercept, etc.), antirheumatic drugs (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, sodium aurothiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), immunizations, immunoglobulins, immunosuppressive agents (e.g., basiliximab, cyclosporine, daclizumab), cytokines or cytokine antagonists, and can further comprise at least one of any suitable and effective amount of a composition or pharmaceutical composition. Non-limiting examples of such cytokines include, but are not limited to, any of IL-1 to IL-23, etc. (e.g., IL-1, IL-2, etc.). Appropriate dosages are well known in the art. For example, see Wells et al., eds., Pharmacotherapy Handbook, 2 nd nd Edition, Appleton and Lange, Stamford, CT (2000), PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), each of which is hereby incorporated by reference in its entirety.

[0195] The anti-IL-12 / IL-23p40 or IL-23 antibody compounds, compositions, or mixtures used in the method of the present invention may further include at least one of any suitable adjuvants such as, but not limited to, diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc. Pharmaceutically acceptable adjuvants are preferred. Non-limiting examples and methods for preparing such sterile solutions are well known in the art, for example, Gennaro, Ed., Remington’s Pharmaceutical Sciences, 18 th Edition, Mack Publishing Co. (Easton, PA), 1990, etc., but not limited thereto. Pharmaceutically acceptable carriers suitable for the administration method, solubility, and / or stability of anti-IL-23 antibody, fragment, or variant compositions, which are well known in the art or as described herein, can be routinely selected.

[0196] Pharmaceutical excipients and additives useful in the present composition include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., saccharides including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides, alditols, aldonic acids, derivatized sugars such as esterified sugars, and polysaccharides or sugar polymers), which may be present alone or in combination and are included in an amount of 1 to 99.99% by weight or volume alone or in combination. Exemplary protein excipients include serum albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, etc. Representative amino acid / antibody components that can also function in buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, etc. One of the preferred amino acids is glycine.

[0197] Examples of carbohydrate excipients suitable for use in the present invention include monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, etc., disaccharides such as lactose, sucrose, trehalose, cellobiose, etc., polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starches, etc., and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), myo-inositol, etc. Preferred carbohydrate excipients for use in the present invention are mannitol, trehalose, and raffinose.

[0198] The anti-IL-12 / IL-23p40 or IL-23 antibody composition may also contain a buffer or a pH adjuster. Typically, the buffer is a salt prepared from an organic acid or a base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, tris, tromethamine hydrochloride, or phosphate buffers. A buffer suitable for use in the present composition is an organic acid salt such as citric acid.

[0199] In addition, the anti-IL-12 / IL-23p40 or IL-23 antibody composition may contain polymer excipients / additives such as polyvinylpyrrolidone, ficoll (polymer sugar), dextrates (such as cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin), polyethylene glycol, flavoring agents, antibacterial agents, sweeteners, antioxidants, antistatic agents, surfactants (such as polysorbates such as "TWEEN20" and "TWEEN80"), lipids (such as phospholipids, fatty acids), steroids (such as cholesterol), and chelating agents (such as EDTA).

[0200] These and additional known pharmaceutical excipients and / or additives suitable for use in the anti-IL-12 / IL-23p40 or IL-23 antibody, fragment or variant compositions according to the invention are known in the art and are described, for example, in "Remington: The Science & Practice of Pharmacy", 19th ed., Williams & Williams, (1995), and "Physician’s Desk Reference", 52 nd ed, Medical Economics, Montvale, NJ (1998), the disclosures of which are hereby incorporated by reference in their entirety. Preferred carrier or excipient materials are carbohydrates (e.g., monosaccharides and alditols) and buffers (e.g., citrate) or polymeric reagents. Exemplary carrier molecules are mucopolysaccharides, hyaluronic acid, which may be useful for intra-articular delivery.

[0201] Formulations As described above, the present invention preferably provides a stable formulation containing a phosphate buffer containing physiological saline or a selected salt, a storage solution and a formulation containing a preservative, and a multi-purpose storage formulation suitable for pharmaceutical or veterinary use containing at least one anti-IL-12 / IL-23p40 or IL-23 antibody. The storage formulation contains, in an aqueous diluent, a preservative optionally selected from the group consisting of 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 parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or a mixture thereof. As is known in the art, any suitable concentration or mixture of any of the ranges or values therein, such as 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, can be used.As non-limiting examples, there may be mentioned preservative-free, 0.1 to 2% m-cresol (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1 to 3% benzyl alcohol (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001 to 0.5% thimerosal (e.g., 0.005, 0.01), 0.001 to 2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005 to 1.0% alkyl parabens (e.g., 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%) and the like.

[0202] As described above, the method of the present invention uses a product comprising a packaging material and at least one vial containing a solution of at least one anti-IL-12 / IL-23p40 or IL-23 antibody, optionally with a buffer and / or a preservative formulated in an aqueous diluent, and the packaging material comprises a label stating that it can hold such a solution for 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72 hours or more. The present invention further uses a product comprising a packaging material, a first vial containing a lyophilized anti-IL-12 / IL-23p40 or IL-23 antibody, and a second vial containing an aqueous diluent of a formulated buffer or preservative, and the packaging material comprises a label instructing the patient to reconstitute the anti-IL-12 / IL-23p40 or IL-23 antibody with the aqueous diluent to form a solution that can be held for 24 hours or more.

[0203] The anti-IL-12 / IL-23p40 or IL-23 antibody used according to the present invention can be produced by recombinant means including production from mammalian cells or transgenic formulations as described herein or known in the art, or can be purified from other biological sources.

[0204] The range of the anti-IL-12 / IL-23p40 or IL-23 antibody is included in an amount that can obtain a concentration of about 1.0 μg / ml to about 1000 mg / ml when rediluting in the case of wet / dry systems, but lower and higher concentrations are also workable and depend on the intended delivery vehicle. For example, in solution formulations, it is different from transdermal patches, lungs, transmucosal, or osmotic or micropump methods.

[0205] Preferably, the aqueous diluent optionally further contains a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal or mixtures thereof. The concentration of the preservative used in the formulation is a concentration sufficient to produce an antibacterial effect. Such a concentration varies depending on the selected preservative and can be easily determined by those skilled in the art.

[0206] Other excipients, such as isotonic agents, buffers, antioxidants, and preservative enhancers, can be added optionally and preferably to the diluent. Isotonic agents such as glycerin are commonly used at known concentrations. Preferably, a physiologically tolerable buffer is added to provide improved pH control. The formulation can be targeted to a wide range of pH ranges, such as from about pH 4 to about pH 10, and preferably from about pH 5 to about pH 9, and most preferably from about 6.0 to about 8.0. Preferably, the formulation of the present invention has a pH of about 6.8 to about 7.8. Suitable buffers include phosphate buffers, and most preferably, sodium phosphate, especially phosphate buffered saline (PBS).

[0207] Other additives, such as solubilizing agents pharmaceutically acceptable, such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymer), and PEG (polyethylene glycol), or nonionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polyls, other block copolymers, and chelating agents such as EDTA and EGTA can be optionally added to the formulation or composition to reduce aggregation. (®)These additives are particularly useful when a pump or plastic container is used for administering the formulation. The presence of a pharmaceutically acceptable surfactant reduces the tendency of the protein to aggregate.

[0208] The formulation can be prepared by a process comprising mixing at least one anti-IL-12 / IL-23p40 or IL-23 antibody with a preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (such as methyl, ethyl, propyl, butyl), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal or mixtures thereof in an aqueous diluent. The mixing of at least one anti-IL-12 / IL-23p40 or IL-23 specific antibody with the preservative in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a quantity of at least one anti-IL-12 / IL-23p40 or IL-23 antibody in a buffer solution is combined with the desired preservative in a quantity of buffer solution sufficient to provide the desired concentrations of protein and preservative. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, the presence or absence of additional additives, the temperature and pH during formulation preparation are all factors that can be optimized with respect to the dosage concentration and means of administration used.

[0209] The formulation can be provided to a patient as a dual vial containing a vial of lyophilized anti-IL-12 / IL-23p40 or IL-23 specific antibody that is reconstituted as a clear solution or in a second vial containing water, a preservative and / or excipient, preferably a phosphate buffer and / or saline, and a selected salt in an aqueous diluent. Either a single solution vial or a dual vial requiring reconstitution can be reused multiple times and can fulfill single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0210] The product is useful for administration over a period ranging from immediately up to 24 hours or more. Accordingly, the products claimed by the present invention provide a great benefit to patients. The formulations of the present invention can optionally be safely stored at a temperature of about 2°C to about 40°C and retain the biological activity of the protein for an extended period of time, and thus the packaging label can indicate that the solution can be held and / or used for a period of 6, 12, 18, 24, 36, 48, 72, or 96 hours or more. When using a stored diluent, such labels can include use up to 1 to 12 months, six months, one and a half years, and / or two years.

[0211] Solutions of anti-IL-12 / IL-23p40 or IL-23 specific antibodies can be prepared by a process that includes mixing at least one antibody in an aqueous diluent. Mixing is carried out using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, a quantity of at least one antibody in water or buffer is combined in an amount sufficient to provide the desired concentration of protein and optionally a preservative or buffer. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of components, the use or non-use of additional additives, the temperature and pH during formulation preparation are all factors that can be optimized with respect to the dosing concentration and means of administration used.

[0212] The claimed product can be provided to a patient as a combination vial comprising a vial of at least one lyophilized anti-IL-12 / IL-23p40 or IL-23 specific antibody, either as a transparent solution or reconstituted in a second vial containing an aqueous diluent. Either a single solution vial or a combination vial requiring reconstitution can be reused multiple times and can satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0213] The claimed product can be indirectly provided to a patient by providing a combination vial comprising a vial of at least one lyophilized anti-IL-12 / IL-23p40 or IL-23 specific antibody, either as a transparent solution or reconstituted in a second vial containing an aqueous diluent, to a pharmacy, clinic, or other such institution and facility. The transparent solution in this case can be of a volume of up to 1 liter or even more, and smaller amounts of at least one antibody solution can be removed one or more times from this large container and transferred to smaller vials and provided to customers and / or patients by the pharmacy or clinic.

[0214] Approved devices that include a single vial system include pen-type injector devices for solution delivery such as BD Pens, BD Autojector®, Humaject®, NovoPen®, B-D® Pen, AutoPen®, and OptiPen®, GenotropinPen®, Genotronorm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®, Iject®, J-tip Needle-Free Injector®, Intraject®, Medi-Ject®, Smartject® (e.g., manufactured or developed by Becton Dickensen (Franklin Lakes, NJ, www.bectondickenson.com), Disetronic (Burgdorf, Switzerland, www.disetronic.com), Bioject, Portland, Oregon (www.bioject.com); National Medical Products, Weston Medical (Peterborough, UK, www.weston-medical.com), Medi-Ject Corp (Minneapolis, MN, www.mediject.com)), and similar suitable devices. Approved devices that include a combination vial system include pen-type injector systems for reconstituting a freeze-dried drug within a cartridge for delivering the reconstituted solution such as HumatroPen®. Examples of other suitable devices include prefilled syringes, autoinjectors, needle-free injectors, and needle-free IV infusion sets.

[0215] The product may include a packaging material. The packaging material provides the conditions under which the product can be used, in addition to the information required by the regulatory authorities. The packaging material of the present invention, where applicable, provides the patient with instructions to reconstitute at least one anti-IL-12 / IL-23p40 or IL-23 antibody with an aqueous diluent to form a solution and use this solution in a two-vial wet / dry product for a period of 2 to 24 hours or more. In the case of a single-vial solution product, a pre-filled syringe, or an auto-injector, the label indicates that such a solution can be used for a period of 2 to 24 hours or more. The product is useful for human pharmaceutical product applications.

[0216] The formulation used in the method of the present invention can be prepared by a process that includes mixing an anti-IL-12 / IL-23p40 or IL-23 antibody and a selected buffer, preferably a phosphate buffer containing physiological saline or a selected salt. The mixing of the anti-23 antibody and the buffer in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a certain amount of at least one antibody in water or a buffer is combined with the desired buffer in an amount of water sufficient to provide the desired concentration of protein and buffer. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, the use or non-use of additional additives, the temperature and pH during formulation preparation are all factors that can be optimized with respect to the dosing concentration and dosing means used.

[0217] The method of the present invention provides a pharmaceutical composition that includes various formulations useful and acceptable for administration to human or animal patients. Such pharmaceutical compositions are prepared using "standard state" water as a diluent and conventional methods well known to those skilled in the art. For example, buffer components such as histidine and histidine monohydrochloride monohydrate can be provided first, followed by the addition of an appropriate non-final volume of "standard state" water diluent, sucrose, and polysorbate 80. Then, the isolated antibody can be added. Finally, the volume of the pharmaceutical composition is adjusted to the desired final volume under "standard state" conditions using water as the diluent. Those skilled in the art will recognize several other methods suitable for the preparation of pharmaceutical compositions.

[0218] The pharmaceutical composition may contain each component in the indicated mass per unit volume of water, or may be an aqueous solution or suspension having the indicated pH in the "standard state". As used herein, the term "standard state" means a temperature of 25 °C + / - 2 °C and a pressure of 1 atmosphere. The term "standard state" is not used in the art to refer to a series of temperatures or pressures recognized by a single technical field, but instead is a reference state that specifies the temperature and pressure used to describe a solution or suspension containing a particular composition under the reference "standard state" conditions. This is because the volume of the solution is a function of temperature and pressure in part. One of ordinary skill in the art will recognize that pharmaceutical compositions equivalent to those disclosed herein can be manufactured at other temperatures and pressures. Whether such a pharmaceutical composition is equivalent to those disclosed herein should be determined under the "standard state" conditions defined above (e.g., 25 °C + / - 2 °C and a pressure of 1 atmosphere).

[0219] Importantly, such a pharmaceutical composition may contain a component mass of "about" a particular value (e.g., "about 0.53 mg of L-histidine") per unit volume of the pharmaceutical composition, or may have a pH value of about a particular value. The component mass or pH value present in the pharmaceutical composition is an "about" given numerical value when the isolated antibody can bind to the peptide chain, whether the isolated antibody is present in the pharmaceutical composition or after the isolated antibody has been removed from the pharmaceutical composition (e.g., by dilution). That is, a value such as the component mass value or pH value is an "about" predetermined numerical value when the binding activity of the isolated antibody is maintained and detectable after the isolated antibody is placed in the pharmaceutical composition.

[0220] Perform competitive binding analysis to determine whether the anti-IL-12 / IL-23p40 or IL-23 specific mAbs bind to similar or different epitopes and / or compete with each other. Individually coat the Abs on ELISA plates. Add the competing mAbs, followed by biotinylated hrIL-12 or IL-23. For the positive control, the same mAb used for coating may be used as the competing mAb ("self-competition"). IL-12 / IL-23p40 or IL-23 binding is detected using streptavidin. These results indicate whether the mAbs recognize similar or partially overlapping epitopes on IL-12 / IL-23p40 or IL-23.

[0221] One aspect of the method of the present invention is to administer a pharmaceutical composition to a patient.

[0222] In one embodiment of the pharmaceutical composition, the concentration of the isolated antibody is about 77 to about 104 mg per 1 ml of the pharmaceutical composition. In another embodiment of the pharmaceutical composition, the pH is about 5.5 to about 6.5.

[0223] The stable or preservative formulation can be provided to the patient as a combination vial containing a vial of at least one anti-IL-23 antibody that is lyophilized and reconstituted as a clear solution or in a second vial containing a preservative or buffer and excipient in an aqueous diluent. Either the single solution vial or the combination vial that requires reconstitution can be reused multiple times and can meet single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than currently available.

[0224] Other formulations or methods for stabilizing anti-IL-23 antibodies may be other than clear solutions of lyophilized powders containing the antibody. Non-clear solutions include formulations containing particulate suspensions, and such particles are compositions containing the anti-IL-23 antibody within structures of various sizes variously known as microspheres, microparticles, nanoparticles, nanospheres, or liposomes. Such relatively homogeneous, essentially spherical particulate formulations containing the active agent can be formed, as taught in U.S. Patent No. 4,589,330, by contacting an aqueous phase and a non-aqueous phase containing the active agent and a polymer, and then evaporating the non-aqueous phase to cause aggregation of the particles from the aqueous phase. Porous microparticles can be prepared, as taught in U.S. Patent No. 4,818,542, using a first phase containing the active agent and a polymer dispersed in a continuous solvent and removing this solvent from the suspension by lyophilization or dilution-extraction-precipitation. Polymers preferred for such preparations are natural or synthetic copolymers or polymers selected from the group consisting of gelatin agar, starch, arabinogalactan, albumin, collagen, polyglycolic acid, polylactic acid, glycolide-L(-)lactide poly(epsilon-caprolactone), poly(epsilon-caprolactone-CO-lactic acid), poly(epsilon-caprolactone-CO-glycolic acid), poly(beta-hydroxybutyric acid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate), poly(hydroxyethyl methacrylate), polyamide, poly(amino acid), poly(2-hydroxyethyl DL-aspartoamide), poly(ester urea), poly(L-phenylalanine / ethylene glycol / 1,6-diisocyanatohexane), and poly(methyl methacrylate). Particularly preferred polymers are polyesters such as polyglycolic acid, polylactic acid, glycolide-L(-)lactide poly(epsilon-caprolactone), poly(epsilon-caprolactone-CO-lactic acid), and poly(epsilon-caprolactone-CO-glycolic acid). Solvents useful for dissolving the polymer and / or the active substance include water, hexafluoroisopropanol, methylene chloride, tetrahydrofuran, hexane, benzene, or hexafluoroacetone sesquihydrate.The process of dispersing the phase containing the active substance in the second phase can include the step of forcing this first phase to pass through an orifice in a nozzle under pressure to act on droplet formation.

[0225] Dry powder formulations can be obtained as a result of processes other than lyophilization, such as spray drying, or solvent extraction by evaporation, or solvent extraction by precipitation of a crystalline composition followed by one or more steps to remove an aqueous or non-aqueous solvent. The preparation of spray-dried antibody formulations is taught in U.S. Patent No. 6,019,968. Antibody-based dry powder compositions can be produced by spray drying a solution or slurry of the antibody and, optionally, an excipient in a solvent under conditions to provide a respirable dry powder. Solvents include polar compounds that can be readily dried, such as water and ethanol. The stability of the antibody can be enhanced by performing the spray drying procedure in the absence of oxygen, such as under a nitrogen blanket, or by using nitrogen as the drying gas. Another relatively dry formulation is a dispersion of a plurality of porous microstructures dispersed in a suspension medium typically containing a hydrofluoroalkane propellant, as taught in International Publication No. 9916419. The stabilized dispersion can be administered to a patient's lungs using a metered dose inhaler. Equipment useful in the commercial manufacture of spray-dried pharmaceuticals is manufactured by Buchi Ltd. or Niro Corp.

[0226] Any anti-IL-23 antibody of a stable or preservative formulation or solution described herein can be administered to a patient according to the present invention via various delivery methods such as SC or IM injection, transdermal, transpulmonary, transmucosal, implantation, osmotic pump, cartridge, micropump, or other means well known in the art and understood by those skilled in the art.

[0227] Therapeutic applications The present invention also provides a method for modulating or treating lupus in a cell, tissue, organ, animal, or patient by administering or contacting the cell, tissue, organ, animal, or patient with a therapeutically effective amount of IL-12 / IL-23p40 or an IL-23-specific antibody, using at least one IL-23 antibody of the present invention, which is known in the art or as described herein.

[0228] Any method of the present invention may comprise administering to a cell, tissue, organ, animal, or patient in need of such modulation, treatment, or therapy an effective amount of a composition or pharmaceutical composition comprising an anti-IL-23 antibody. Such methods may optionally further comprise co-administration or combination therapy for the treatment of such disease or disorder, wherein administering the at least one anti-IL-23 antibody, a specific portion thereof, or variant comprises at least one TNF antagonist (e.g., but not limited to, a chemical or proteinaceous TNF antagonist, a TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70, or p85) or fragment, a fusion polypeptide thereof, or a small molecule TNF antagonist, e.g., TNF binding protein I or II (TBP-1 or TBP-II), neralimomab, infliximab, etanercept (Enbrel™), adalimumab (Humira™), CDP-571, CDP-870, afelimomab, renercept, etc.), an anti-rheumatic drug (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, sodium aurothiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), a muscle relaxant, an anesthetic, a non-steroid anti-inflammatorydrugs, NSAIDs), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blocking agents, antibacterial agents (e.g., aminoglycosides, antifungal agents, antiparasitic agents, antiviral agents, carbapenems, cephalosporins, fluoroquinolones, macrolides, penicillins, sulfonamides, tetracyclines, other antibacterial agents), psoriasis therapeutic agents, corticosteroids, anabolic steroids, diabetes-related drugs, minerals, nutritional agents, thyroid agents, vitamins, calcium-related hormones, antidiarrheal agents, antitussive agents, antiemetic agents, antineoplastic agents, laxatives, anticoagulants, erythropoietin (e.g., epoetin alfa), filgrastim (e.g., G-CSF, Neupogen), sargramostim (GM-CSF, Leukine), immunopotentiators, immunoglobulins, immunosuppressive agents (e.g., basiliximab, cyclosporine, daclizumab), growth hormones, hormone replacement agents, estrogen receptor modulators, mydriatics, cycloplegics, alkylating agents, antimetabolites, mitotic inhibitors, radiopharmaceuticals, antidepressants, antimanic agents, antipsychotic agents, anxiolytics, hypnotics, sympathomimetics, stimulants, donepezil, tacrine, asthma therapeutic agents, beta-acting agents, inhaled steroids, leukotriene inhibitors, methylxanthines, cromolyn, epinephrine or analogs, dornase alfa (Pulmozyme), cytokines or cytokine antagonists, and further comprising administering at least one selected therefrom before, simultaneously, and / or after. Appropriate dosages are well known in the art. For example, Wells et al., eds., Pharmacotherapy Handbook, 2 nd Edition, Appleton and Lange, Stamford, CT (2000), PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), Nursing 2001 Handbook of Drugs, 21 stFor reference, see Edition, Springhouse Corp., Springhouse, PA, 2001; Health Professional’s Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, Upper Saddle River, NJ. Each of these references is hereby incorporated by reference in its entirety into this specification.

[0229] Treatment Typically, the treatment of lupus is affected by administering an effective amount or dose of an anti-IL-12 / 23p40 or anti-IL-23 antibody composition, which, on average, is in the range of at least about 0.01 to 500 milligrams per kilogram of patient body weight per single administration, and preferably in the range of at least about 0.1 to 100 milligrams per kilogram of patient body weight per single or multiple administrations, depending on the specific activity of the active agent contained in the composition. Alternatively, the effective serum concentration can include a serum concentration of 0.1 to 5000 μg / mL per single or multiple administrations. Appropriate dosages are known to medical practitioners and, of course, depend on the specific disease state, the specific activity of the composition being administered, and the specific patient being treated. In some cases, it may be necessary to provide repeated administrations, i.e., repeated individual administrations of a specific monitored amount or dose, in order to obtain the desired therapeutic amount, in which case the individual administrations are repeated until the desired daily dose or effect is obtained.

[0230] Preferred dosages may optionally include 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and / or 100 - 500 mg / kg / dose, or any range, value or fraction thereof, or 0.1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9, 2.0, 2.5, 2.9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 20, 12.5, 12.9, 13.0, 13.5, 13.9, 14.0, 14.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 12, 12.5, 12.9, 13.0, 13.5, 13.9, 14, 14.5, 15, 15.5, 15.9, 16, 16.5, 16.9, 17, 17.5, 17.9, 18, 18.5, 18.9, 19, 19.5, 19.9, 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, and / or 5000 μg / ml serum concentration, or any range, value or fraction thereof, so as to obtain the same.

[0231] Alternatively, the dosage administered may vary depending on known factors such as the pharmacokinetic characteristics of the particular agent, its method and route of administration, the age, health and weight of the recipient, the nature and degree of the symptoms, the type of co-treatment, the treatment frequency, and the desired effect. The dosage of the active ingredient can usually be about 0.1 to 100 milligrams per kilogram of body weight. Usually, 0.1 to 50, preferably 0.1 to 10 milligrams / kg / dose, or a sustained-release form, is effective to obtain the desired results.

[0232] By way of non-limiting example, treatment of a human or animal may be by single, infusion, or repeated administration, using 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 days, or alternatively or additionally, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 weeks, or alternatively or additionally, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 years, or any combination thereof, at a dose of 0.1 to 100 mg / kg per day, 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, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90, or 100 mg / kg, as a single or periodic dose of at least one antibody of the present invention.

[0233] Dosage forms (compositions) suitable for in vivo administration generally contain from about 0.001 milligram to about 500 milligrams of the active ingredient per unit or container. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.5 to 99.999% by weight, based on the total weight of the composition.

[0234] For parenteral administration, the antibody can be formulated as a solution, suspension, emulsion, particle, powder, or lyophilized powder, provided together with or separately from a pharmaceutically acceptable parenteral vehicle. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and 1 to 10% human serum albumin. Non-aqueous vehicles such as liposomes and fixed oils can also be used. The vehicle or lyophilized powder can contain additives (e.g., sodium chloride, mannitol for isotonicity; buffers and preservatives for chemical stability) to maintain isotonicity and chemical stability. The formulation is sterilized by known or appropriate techniques.

[0235] Suitable pharmaceutical carriers are described in the latest edition of Remington’s Pharmaceutical Sciences, A. Osol, a standard reference text in the field.

[0236] Alternative Administration To administer a pharmaceutically effective amount of the anti-IL-23 antibody, many known and developed modes can be used according to the present invention. Although pulmonary administration is used in the following description, other modes of administration may be used according to the present invention to obtain suitable results. The IL-12 / IL-23p40 or IL-23 antibody of the present invention can be delivered in a carrier as a solution, emulsion, colloid, or suspension, or as a dry powder, by inhalation or using any of a variety of devices and methods suitable for administration by other modes described herein or known in the art.

[0237] Parenteral Formulation and Administration Formulations for parenteral administration may contain, as common excipients, sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydrogenated naphthalene, etc. Aqueous or oily suspensions for injection can be prepared by using appropriate emulsifying or wetting agents and suspending agents according to known methods. Injectables may be non-toxic parenterally administrable diluents such as, for example, aqueous solutions, sterile injectable solutions or suspensions in a solvent. Possible vehicles or solvents that can be used include water, Ringer's solution, isotonic saline, etc., and as normal solvents or suspending solvents, sterile non-volatile oils can be used. For these purposes, all kinds of non-volatile oils and fatty acids can be used, including natural or synthetic or semi-synthetic, fatty oils or fatty acids, and natural or synthetic or semi-synthetic, monoglycerides or diglycerides or triglycerides. Parenteral administration is known in the art and includes, but is not limited to, conventional injection means, gas pressurized needleless injection devices such as those described in U.S. Patent No. 5,851,198, and laser perforator devices such as those described in U.S. Patent No. 5,839,446, which are hereby incorporated by reference in their entirety.

[0238] Alternative Delivery The present invention further relates to the administration of anti-IL-12 / IL-23p40 or IL-23 antibodies by parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intra-bronchial, intra-abdominal, intra-pouch, intra-cartilaginous, intra-cavity, intra-cerebellar, intra-ventricular, intra-colonic, intra-cervical, intra-gastric, intra-hepatic, intra-myocardial, intra-osseous, intra-pelvic, intra-pericardial, intra-abdominal, intra-pleural, intra-prostatic, intra-pulmonary, intra-rectal, intra-renal, intra-retinal, intra-spinal, intra-synovial, intra-thoracic, intra-uterine, intra-vesical, intra-lesional, bolus, intravaginal, rectal, intra-oral, sublingual, intra-nasal, or transdermal means. The anti-IL-12 / IL-23p40 or IL-23 antibody compositions can be prepared for parenteral (subcutaneous, intramuscular, or intravenous) or any other administration, particularly in the form of a liquid solution or suspension, particularly in a semi-solid form such as creams and suppositories but not limited thereto, for use in vaginal or rectal administration, in a form such as tablets or capsules but not limited thereto, for oral or sublingual administration, or in a form such as powders, nasal drops or aerosols, or certain agents but not limited thereto, for intra-nasal administration, or for either modifying the skin structure or increasing the drug concentration in a transdermal patch, using a chemical enhancer such as dimethyl sulfoxide (Junginger, et al. In "Drug Permeation Enhancement;" Hsieh, D.S., Eds., pp. 59-90 (Marcel Dekker, Inc. New York 1994, which is hereby incorporated by reference in its entirety), or the application of formulations containing proteins and peptides to the skin (International Publication No. WO 98 / 53847), or creating a transient transport pathway such as electroporation, or applying an electric field to increase the mobility of charged drugs through the skin such as iontophoresis, or applying ultrasound such as sonophoresis (U.S. Patent Nos. 4,309,989 and 4,767,402), using an oxidizing agent that enables this, in a form such as gels, ointments, lotions, suspensions or patch delivery systems but not limited thereto, transdermally (the above publications and patents are hereby incorporated by reference in their entirety).

[0239] Since the present invention has been generally described, the same will be more readily understood by reference to the following examples, which are provided as examples but not intended to be limiting. Further, the details of the present invention are illustrated by the following non-limiting examples. All cited disclosures in this specification are hereby expressly incorporated herein by reference.

Example

[0240] A multicenter, randomized, double-blind, placebo-controlled proof-of-concept trial of ustekinumab in subjects with active systemic lupus erythematosus Overview STELARA® (ustekinumab) is a fully human IgG1κ monoclonal antibody that binds with high affinity and specificity to the shared p40 subunit of human interleukin (IL)-12 and IL-23 cytokines. Binding of ustekinumab to the IL-12 / 23 p40 subunit blocks the binding of IL-12 or IL-23 to the IL-12Rβ1 receptor on the surface of natural killer and CD4 + T cells, inhibiting IL-12- and IL-23-specific intracellular signaling and subsequent activation and cytokine production. Aberrant regulation of IL-12 and IL-23 is associated with multiple immune-mediated diseases, including systemic lupus erythematosus (SLE). Thus, inhibition of IL-12 and IL-23 has the potential to be effective in the treatment of SLE.

[0241] Objectives and Hypothesis Primary Objective The primary objective is to evaluate the efficacy of ustekinumab as measured by a reduction in disease activity in subjects with active SLE.

[0242] Secondary Objectives The secondary objectives are to evaluate the following. · The safety and tolerability of ustekinumab in subjects with SLE. · The effect of ustekinumab administration on health-related quality of life in subjects with SLE. · The effect of ustekinumab on the skin manifestations of SLE. ·Pharmacokinetics and immunogenicity of ustekinumab in subjects with SLE.

[0243] Exploratory objectives The exploratory objectives are to evaluate the following. ·Safety and efficacy during long-term administration of ustekinumab. ·Reduction of corticosteroids during long-term administration of ustekinumab. ·Additional composite clinical endpoints or methods of calculating clinical responses that may enhance sensitivity to improvement and / or worsening of SLE. ·Biomarkers (genetic, systemic, and skin-related) associated with lupus disease.

[0244] Hypothesis The hypothesis is that administration with ustekinumab is significantly superior to placebo as measured by the 24-week Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) responder index (SRI-4) composite measure.

[0245] Summary of trial design CNTO1275 SLE2001 is a Phase 2a, proof-of-concept, multi-center, randomized, double-blind, placebo-controlled trial of the efficacy and safety of ustekinumab added to standard-of-care background in subjects with active SLE. Subjects to be enrolled must have SLE according to the Systemic Lupus International Collaborating Clinics (SLICC) criteria and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score ≥6, despite conventional therapy (e.g., immunosuppressive agents, antimalarials, corticosteroids, nonsteroidal anti-inflammatory drugs, antihypertensives, and / or topical agents). In addition, subjects must have at least one positive autoantibody test (antinuclear antibody [ANA], anti-double-stranded deoxyribonucleic acid [anti-dsDNA] antibody, and / or anti-Smith antibody) observed during screening, as well as a positive autoantibody test well-documented in the medical history. Subjects must also demonstrate at least one British Isles Lupus Assessment Group (BILAG) A and / or two BILAG B domain scores observed during screening. In addition, subjects must have a clinical SLEDAI-2K score ≥4 (excluding laboratory results) at Week 0 prior to randomization.

[0246] Approximately 100 subjects will be assigned in a 3:2 ratio to receive either ustekinumab or placebo for 24 weeks. After randomization at Week 0, subjects will receive an IV dose based on initial body weight range approximating 6 mg / kg of ustekinumab (ustekinumab 260 mg [body weight ≥35 kg to ≤55 kg]; ustekinumab 390 mg [body weight >55 kg and ≤85 kg]; ustekinumab 520 mg [body weight >85 kg], followed by 90 mg SC every 8 weeks (q8w).

[0247] In the 24th week, the subjects who received placebo will crossover, and all subjects will receive subcutaneous ustekinumab 90 mg at weeks 24, 32, and 40, followed by safety follow-up in a blinded manner for 16 weeks (approximately 5 half-lives) until week 56 after the last subcutaneous administration of the investigational drug.

[0248] The placebo comparator (added to standard-of-care background therapy) will be used until week 24 for the evaluation of the efficacy and safety of ustekinumab in subjects with SLE. From week 24 to week 40, the placebo group will crossover and receive subcutaneous ustekinumab 90 mg (q8w). This crossover design will enable placebo subjects to receive the investigational drug and provide the experience of using subcutaneous ustekinumab 90 mg without the IV loading dose in subjects with SLE. The 40-week dosing period will be useful for understanding the long-term safety and time-course changes in the potential clinical response of ustekinumab in the SLE population.

[0249] All reasonable efforts should be made to keep the concomitant medications in a stable state as defined in the protocol. All concomitant therapies must be recorded throughout the trial starting from registration for screening, and any changes must be recorded throughout the trial.

[0250] All subjects with skin diseases will be evaluated using the Cutaneous Erythematosus Disease Area and Severity Index (CLASI) scoring. Additionally, subjects with skin diseases who consented to participate in the cutaneous lupus substudy will have additional evaluations including collection of a skin biopsy of the active disease (optional consent) and / or collection of photographs of the skin lesions or areas of the active disease (optional consent). There will be no restrictions on the number of subjects with skin diseases who can enroll in either the main trial or the cutaneous lupus substudy.

[0251] Interim analyses (IAs) will be conducted when approximately one-third and two-thirds of the subjects reach 24 weeks. Only an assessment of significant efficacy will be conducted in the first IA. In the second IA, significant efficacy as well as treatment failure will be analyzed. Database lock (DBL) will be conducted after the 24th week and the 56th week visit of the last subject, or at the visit for the 16-week safety follow-up of the last subject from the main study. In addition, an independent Data Monitoring Ring Committee (DMC) will regularly review the interim safety data, including formal reviews, when approximately one-third and two-thirds of the subjects reach the 24th week, and at the time of the 24-week DBL. The DMC will make recommendations regarding whether the trial should be stopped due to futility or safety concerns, or whether the data meet pre-specified criteria demonstrating significant efficacy. The general content, the role and responsibilities of the DMC, and the general procedures (including communication) will be defined in the DMC charter.

[0252] The corrected study design will continue to provide ustekinumab 90 mg, q8w SC in an open-label manner throughout 104 weeks. Subjects meet the study inclusion criteria (section 4.1.3) including: · Having no permanently discontinued study treatment at or before the visit at week 40, and · Being able to continue the q8-week study treatment at approximately 8 weeks (±2 weeks) after the visit at week 40, or · Being able to restart the study treatment for 16 weeks (±2 weeks) or less after the visit at week 40. If the subject meets these criteria, they will be eligible to continue the study treatment until week 104.

[0253] In addition to the planned DBL after the 56th week visit of the last subject, or at the visit for the 16-week safety follow-up of the last subject, there will be an additional DBL at the end of the follow-up study (after the 16-week safety follow-up of the follow-up study).

[0254] Subject Population Screening of eligible subjects must be performed within 6 weeks prior to the visit for randomization (week 0). The target study population is subjects with SLE according to the SLICC criteria and SLEDAI-2K score ≥ 6, regardless of previous treatment (e.g., immunosuppressants, antimalarials, corticosteroids, non-steroidal anti-inflammatory drugs, antihypertensives, and / or topical agents). In addition, subjects must have at least one positive autoantibody test (ANA, anti-dsDNA antibody, and / or anti-Smith antibody) observed during screening and a positive autoantibody test well-documented in the medical history. Subjects must also have at least one BILAG A and / or two BILAG B domain scores observed during screening prior to the first dose of the investigational agent.

[0255] In addition, to be eligible to participate in the study, subjects must have a clinical SLEDAI-2K score ≥ 4 for clinical characteristics at week 0 (prior to randomization) (excluding laboratory results) and obtain approval for study randomization after review and confirmation by the sponsor and / or an independent reviewer(s) selected by the sponsor.

[0256] SLE subjects enrolled in the main study with active cutaneous lupus (including subjects with discoid lupus erythematosus, subacute cutaneous lupus erythematosus, alopecia, or SLE malar rash, or other SLE skin lesions characterized by erythema and / or scale) will be evaluated using the CLASI scoring. In addition, subjects providing consent will be enrolled in a cutaneous lupus substudy that will evaluate the histology of skin biopsies and / or skin photographs. Subjects participating in the cutaneous lupus substudy will not be required to undergo a biopsy and may be permitted photographs only to demonstrate changes in identified lesions or areas of active disease.

[0257] Dose and Administration All subjects received IV administration based on the body weight range of the study drug (placebo or ustekinumab) at week 0, followed by SC administration of placebo or ustekinumab at weeks 8 and 16, and subsequently all subjects received ustekinumab administration at weeks 24, 32, and 40. As defined in the protocol, in order to maintain the concomitant therapy stably until at least week 28, some adjustments should be made to maintain the drug in a stable state, allowing for safety follow-up at week 8 beyond week 28 or subsequent trials defined in the protocol. All reasonable efforts should be made. The dose of the concomitant drug may be reduced or temporarily interrupted due to abnormal laboratory values, side effects, co-morbidities, or performance of surgical treatment, but the changes and reasons should be clearly documented in the subject's medical record. If the concomitant drug is adjusted after randomization allowed for each protocol, all efforts should be made to return the subject to the baseline (week 0) dose level by the subject's visit at week 12, or an increase in the use of the drug may result in the subject being considered treatment failure.

[0258] Subjects enrolled during the subsequent trial will continue to receive SC administration of 90 mg of ustekinumab every 8 weeks until week 104. Except for corticosteroids, the concomitant drugs should be maintained at a stable dose throughout the subsequent trial.

[0259] From week 0 to a maximum of week 24 (double-blind study drug administration period) Group 1: Subjects received IV administration of ustekinumab based on the body weight range of approximately 6 mg / kg at week 0, followed by SC administration of 90 mg of ustekinumab at weeks 8 and 16.

[0260] Group 2: Subjects received IV administration of placebo based on the body weight range at week 0, followed by SC administration of placebo at weeks 8 and 16.

[0261] Weeks 24 - 40 (crossover administration period) Group 1: Subjects received SC administration of 90 mg of ustekinumab at week 24, followed by q8w administration until week 40.

[0262] Group 2: Subjects in the placebo administration group will crossover to subcutaneous administration of ustekinumab 90 mg at week 24 and subsequently receive administration every 8 weeks until week 40.

[0263] Observation for 16 weeks after 40 weeks (safety follow-up period) Groups 1 and 2: Subjects who do not participate in the subsequent study are expected to return for safety follow-up visits for safety follow-up at week 44 and return for safety follow-up at 8 weeks and 16 weeks.

[0264] Subsequent study (weeks 48 / 56 to 120) Subjects who meet the criteria for inclusion in the subsequent study (Section 4.1.3) will receive an additional 1-year open-label ustekinumab administration for the purpose of expanding the safety experience and maintaining efficacy in lupus patients exposed to ustekinumab 90 mg every 8 weeks. Subjects who continue administration in the subsequent study starting at week 48 or 56 will receive open-label subcutaneous administration of ustekinumab via week 104. If the development of ustekinumab in SLE is terminated, the subsequent study will also be interrupted.

[0265] Evaluation of efficacy The primary efficacy endpoint of this study is to compare the composite SRI-4 response at week 24 in subjects who received ustekinumab with that in subjects who received placebo treatment.

[0266] The following are included as efficacy evaluation and patient-reported quality of life scales. · SLEDAI-2K · S2K RI-50 · BILAG · CLASI · Physician's overall assessment of disease activity · Patient's overall assessment of disease activity · Short Form 36 Questionnaire · Fatigue Severity Scale · Patient's pain assessment

[0267] Pharmacokinetics and Immunogenicity Evaluation Serum samples will be used to evaluate the pharmacokinetics of ustekinumab and the immunogenicity of anti-drug antibodies (antibodies to ustekinumab).

[0268] Biomarker Evaluation and Serological Markers The collection, preparation, storage, and transportation of skin biopsies, blood, serum, and urine are detailed in the laboratory manual. Biomarkers may include, but are not limited to, inflammatory markers, ribonucleic acid (RNA), cell surface markers, autoantibodies, T-cell and B-cell repertoires, target-specific markers, and other categories of biomarkers that may be involved in the onset and progression of lupus.

[0269] Serum Analysis Serum will be analyzed for the levels of specific proteins including, but not limited to, soluble CD40 ligand (sCD154), interleukin (IL)-6, IL-12p40, IL-17, IL-21, IL-22, IL-23p19, C-X-C motif chemokine 10 (CXCL10), B-cell activating factor (BAFF), interferon, autoantibodies, and other inflammation-related molecules.

[0270] Skin Biopsy Analysis Skin biopsies will be utilized for cell, molecular, and gene expression analysis.

[0271] Whole Blood Gene Expression Analysis Whole blood will be collected from all subjects for RNA, flow cytometry, T-cell and B-cell repertoire, and epigenetics analysis (e.g., deoxyribonucleic acid [DNA] methylation).

[0272] Serological Markers Autoantibodies (e.g., ANA, anti-dsDNA, etc.), complement C3 and C4 will be collected as described in the event schedule (Table 1).

[0273] Pharmacogenetic (DNA) Evaluation DNA samples will be used in research related to this study (CNTO1275 SLE2001). Specific genomic tests will be conducted to obtain the consent of the subjects (some of the subjects participating in this study must sign a separate informed consent. This procedure will involve collecting blood samples that can be analyzed for specific target genes that may play a role in lupus. Any genomic evaluation will be carried out in strict compliance with the current subject confidentiality regulations regarding genetic testing. Refusal to participate in the genomic test will not render the subject ineligible to participate in the remainder of the clinical trial).

[0274] Cutaneous lupus sub-study All subjects with cutaneous disease will be evaluated using CLASI scoring. Additionally, subjects with cutaneous disease who consent to participate in the cutaneous lupus sub-study will have additional evaluations including collection of a skin biopsy of the active disease (optional consent) and / or collection of photographs of identified skin lesions or areas of the active disease (optional consent). There will be no restrictions on the number of subjects with cutaneous disease who can enroll in either the main study or the cutaneous lupus study).

[0275] Subjects providing consent will be enrolled in the cutaneous lupus sub-study to evaluate the histology of the skin biopsy and / or skin photographs. Biopsy samples (two samples, 4 mm size) from consenting subjects will be taken from one lesion or area of active cutaneous disease prior to dosing at Week 0 and Week 24. Photographs and skin biopsies can target different areas of the active disease, but follow-up photographs or biopsies should re-evaluate the same area of active disease that was initially evaluated at Week 0. Subjects participating in the cutaneous lupus sub-study may not be required to undergo a biopsy and may be permitted only photographs to demonstrate changes in identified lesions or areas of active disease. Subjects with cutaneous lupus who are considered inappropriate for biopsy (e.g., malar rash or alopecia) may also enroll in the sub-study and be evaluated by photography).

[0276] Regardless of skin biopsy collection, subjects participating in the skin loop sub-study will be asked to consent to having photographs taken from lesions or areas where the active disease has been identified. The photographs are for exploratory purposes only. The photographs will be used to assist in the qualitative assessment of clinical response. The confidentiality of subjects involved in this study will be maintained. Specifically, the photographs of subjects in this study will not be publicly released or otherwise published without obscuring the appropriate parts of the subject's face or body so that the individual cannot be identified.

[0277] Safety Assessment Safety assessments will include vital signs, a full physical examination and skin evaluation, adverse events (AE), serious AEs, concomitant medication investigations, pregnancy tests, acute infusion reactions, chemistry and hematology tests, and antibodies to ustekinumab. Chest X-rays and tests for tuberculosis, human immunodeficiency virus, hepatitis B, and hepatitis C will be required at screening. Any clinically significant abnormalities that persist at the end of the trial will be followed by the principal investigator until resolved or until a clinically stable endpoint is reached. The subject's diary card will be used to capture any drug changes that occur during study visits during the main part of this study. Safety data collected up to 16 weeks after the last dose of the study drug will be evaluated.

[0278] Statistical Methods Sample Size Determination Approximately 100 subjects will be assigned in a 3:2 ratio to receive either ustekinumab or placebo for 24 weeks. Approximately 60 subjects treated with ustekinumab and approximately 40 subjects treated with placebo are estimated to provide approximately 80% power to detect a significant difference in efficacy compared to placebo at a 0.1 alpha level (assuming respective response rates of 35% and 60% in placebo and ustekinumab, which is interpreted as a 25% absolute increase or an odds ratio of 2.79 compared to placebo).

[0279] Efficacy Analysis The primary endpoint of this trial is the proportion of subjects with a composite measure of SLE disease activity at week 24 (SLE Responder Index [SRI]-4 response). The primary analysis is based on the primary endpoint and is conducted for the intent-to-treat (mITT) population according to the modified intention-to-treat principle, which includes all randomized subjects who received at least one dose of the study drug, had at least one measurement before dosing, and had at least one post-baseline SRI-4 measurement.

[0280] If a subject has data for at least one SRI-4 component at week 24, the last observation carried forward (LOCF) procedure is used to impute the missing SRI-4 components. If a subject has no data for any SRI component at week 24, the subject is considered not to have achieved an SRI-4 response.

[0281] In addition, subjects who meet any of various treatment failure criteria, such as receiving a higher dose of immunosuppressive agent at week 24 than at baseline, starting a prohibited corticosteroid treatment (dose or timing), or discontinuing the study drug due to lack of efficacy, will be considered not to have achieved the primary endpoint, the SRI-4 response, at week 24.

[0282] Baseline stratification and logistic regression adjusting for baseline SLEDAI will be used to analyze the primary endpoint. The baseline SLEDAI value is defined as the most recent non-missing measurement taken before infusion at week 0. If significant non-normality is observed, appropriate non-parametric tests will be used to evaluate the differences between treatments.

[0283] If the primary analysis achieves statistical significance at a significance level of 0.1 (two-sided) and ustekinumab shows a favorable effect compared to the placebo treatment, the trial will be considered positive.

[0284] Safety analysis Safety is evaluated by analysis of the incidence and type of AE, SAE, reasonably related AE, infection, and acute infusion reactions. Safety assessment also includes analysis of laboratory parameters, changes from baseline in laboratory parameters (hematology and chemistry), and the incidence of abnormal laboratory parameters (hematology and chemistry).

[0285] [Table 2]

[0286] [Table 3]

[0287] [Table 4]

[0288] [Table 5]

[0289] [Table 6]

[0290] [Table 7]

[0291] [Table 8-1]

[0292] [Table 8-2]

[0293] 1. Introduction STELARA® (ustekinumab) is a fully human G1κ monoclonal antibody that binds with high affinity and specificity to the shared p40 subunit of human interleukin (IL)-12 and IL-23 cytokines. Binding of ustekinumab to the IL-12 / 23 p40 subunit blocks the binding of IL-12 or IL-23 to the IL-12Rβ1 receptor on the surface of natural killer and CD4 + T cells, inhibiting IL-12- and IL-23-specific intracellular signaling and subsequent activation and cytokine production. Dysregulation of IL-12 and IL-23 is associated with multiple immune-mediated diseases, including systemic lupus erythematosus (SLE). Thus, inhibition of IL-12 and IL-23 has the potential to be effective in the treatment of SLE.

[0294] Systemic lupus erythematosus is a complex, chronic, heterogeneous autoimmune disease of unknown etiology that can affect almost all organ systems and follows a relapsing and remitting disease course. Systemic lupus erythematosus occurs much more frequently in women than in men, and in some studies, up to nine times more frequently, and often presents in the reproductive age group of 15 to 45 years. This disease is more commonly seen in African-Caribbean, Asian, and Hispanic populations. In SLE, the immune system attacks the body's cells and tissues, resulting in inflammation and tissue damage that can harm the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous system. Approximately half of the subjects diagnosed with SLE who have life-threatening disease may take several years to be diagnosed in subjects without organ involvement. Some of the main symptoms in newly diagnosed lupus patients are arrhythmias (62%) and skin symptoms (new photosensitivity; 20%), persistent fever and fatigue 39 persist. The estimated annual incidence of lupus varies from 1.8 to 7.6 cases per 100,000 people, and the prevalence worldwide ranges from 14 to 172 cases per 100,000 people. 39Patients with mild disease mostly have skin rashes and joint pain and require more aggressive treatment; regimens include non-steroidal anti-inflammatory drugs (NSAIDs), anti-malarial drugs (e.g., hydroxychloroquine, chloroquine, or quinacrine), and / or low-dose corticosteroids. Patients with more severe disease may experience various serious conditions depending on the involved organ systems, including potential renal failure, endocarditis or myocarditis, pneumonia, pregnancy complications, stroke, neurological complications, vasculitis, and cytopenia associated with risks of bleeding or infection. Common treatments for more severe disease include methotrexate (MTX), azathioprine, cyclophosphamide, cyclosporine, high-dose corticosteroids, biological B-cell cytotoxics, or B-cell modulators, and other immunomodulators. Patients with severe SLE have a shortened lifespan of 10 - 30 years, mainly due to complications of the disease, standard care therapies, and / or accelerated atherosclerotic disease. In addition, SLE substantially affects quality of life, work productivity, and medical costs. Existing therapies for SLE are generally either cytotoxic or immunomodulatory and can have significant safety risks. Newer treatments for SLE provide only slightly more benefit than standard care therapies. Thus, there is a major unmet need for new alternative treatments that can provide significant benefit in this disease without incurring high safety risks.

[0295] The long-term outcome for patients with lupus depends on various factors, including whether they have organ lesions, certain laboratory measures (such as anti-phospholipid antibodies), race, gender, age at consent, access to insurance coverage, treatment compliance, education, and the presence of other comorbidities. Only about 5% of patients diagnosed with SLE will show spontaneous remission without treatment. Various new therapeutic agents are being evaluated for the treatment of subjects with refractory lupus, but to date, few have demonstrated significant clinical efficacy beyond these currently considered standard agents for patients with this disease.

[0296] In this study, the target population has systemic lupus erythematosus according to the Systemic Lupus International Collaborating Clinics (SLICC) criteria and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score ≥ 6 despite conventional treatment (e.g., immunomodulatory drugs, antimalarials, corticosteroids, NSAIDs, antihypertensives, and / or topical agents). 11 In addition, subjects must have at least one positive autoantibody test (antinuclear antibody [ANA], anti-double-stranded deoxyribonucleic acid [anti-dsDNA] antibody, and / or anti-Smith antibody) observed during screening and a positive autoantibody test well-documented in the medical history. Subjects must also demonstrate at least one British Isles Lupus Assessment Group (BILAG) 38 A and / or two BILAG B domain scores. In addition, subjects must have an SLEDAI score ≥ 4 at week 0 for clinical features (excluding laboratory results). This disease activity level is consistent with previous studies investigating experimental therapies for systemic lupus 36 erythematosus.

[0297] 1.1. Background To date, ustekinumab has received marketing approval worldwide, including in countries in North America, Europe, South America, and the Asia-Pacific region, for the treatment of adult patients with moderate to severe plaque psoriasis and / or active psoriatic arthritis. Ustekinumab has also been evaluated in a Phase 3 trial for Crohn's disease (CD).

[0298] 1.2. Overall rationale for the study 1.2.1. Scientific rationale for the use of anti-IL-12 / 23p40 therapy in systemic lupus erythematosus Systemic lupus erythematosus is a complex immune-mediated inflammatory disorder characterized by dysregulated B lymphocytes that produce destructive autoantibodies. However, B cell-targeted therapies for SLE (e.g., belimumab) have shown only modest clinical outcomes beyond limited standard of care control22 This suggests that additional immune pathways play important roles in the etiology of SLE. Chronic immune activation in SLE leads to an increase in the production of inflammatory cytokines that actively contribute to local inflammation and processes that mediate tissue damage. For example, many SLE patients have a characteristic type I interferon signature observed in blood cells. 2 The interferon signature has been observed to occur more frequently in lupus families and may be a risk factor for the development of SLE. . 23 Several studies have also reported elevated levels of IL-12, IL-6, and IL-23 in both the sera and tissues of patients, 4、20、24、26、30、44 suggesting that the inflammatory environment in SLE is prone to inducing T helper (Th)1 and Th17 cells. Increased levels of IL-17 in serum have been observed in SLE patients, 3、31、36、44、45、46 but the correlation between IL-17 levels and disease activity is not strong. 37、46 Although a direct genetic link to the IL-12 / IL-23 / Th17 pathway in SLE has not been established, 18、28、29 genome-wide association studies in SLE have identified STAT4, which mediates IL-12 signaling, as a susceptibility gene in both white and Asian ethnic groups.1 2、16 In patients with active SLE, the messenger RNA levels of p19, p40, and p35 were significantly higher compared to levels in patients with inactive SLE. 14 Targeting of IL-12 / 23p40 with ustekinumab has been shown to be associated with significant improvement in cutaneous lupus in three separate case reports. 5、6、43 Collectively, there is accumulating evidence to demonstrate the importance of the IL-12 and IL-23 cytokine pathways in the etiology of SLE, justifying further clinical investigation of ustekinumab as an intervention in this disease.

[0299] In addition, two disease-related groups, the Alliance for Lupus Research and the Lupus Research Institute, independently commissioned a scientific review of a large set of commercially available lupus drug candidates, from which ustekinumab was recommended and evaluated based on its molecular mechanism, which further supports the scientific rationale for placebo-controlled clinical trials to evaluate the efficacy and safety of ustekinumab in subjects with active SLE.

[0300] 1.1.2.1. Subgroup of subjects with active cutaneous manifestations of systemic lupus erythematosus The above-described case reports of patients with refractory cutaneous lupus who respond to ustekinumab therapy prompt an evaluation of the effect of ustekinumab on skin lesions. Considering the relatively common occurrence of cutaneous symptoms in SLE, the feasibility of repeated punch biopsies and / or photographs of identified lesions or areas of active disease, and the availability of disease-specific evaluation tools for cutaneous lupus erythematosus (CLE), this patient population may provide useful data regarding the effect of ustekinumab on the symptoms of SLE and cutaneous disease. All subjects with cutaneous disease will be evaluated using CLASI scoring. In addition, subjects with cutaneous disease who consent to participate in the cutaneous lupus substudy will have additional evaluations including possible collection (with any consent) of skin biopsies of active disease and / or photographs (with any consent) of identified lesions or areas of active disease. For either the main study or the cutaneous lupus substudy, there is no pre-specified number of subjects with cutaneous disease to be enrolled.

[0301] 1.3. Justification of the dosing regimen The dosing regimen for this study was selected based on experience with the use of ustekinumab in the treatment of moderately to severely active CD (C0743T26, CNTO1275 CRD3001, and CNTO1275 CRD3002). Both CD and SLE are immune-mediated inflammatory diseases, which are generally treated with immunosuppressive agents such as methotrexate (MTX), azathioprine, and corticosteroids, and thus this metric serves as a useful model for risk assessment of ustekinumab in lupus. Although the theoretical basis for the dosing has not changed, additional safety and efficacy information has become available from the ustekinumab Phase 3 CD (UNITI) trial, which supports a protocol amendment to continue treatment with ustekinumab 90 mg SC q8w for an additional year. These results from the UNITI CD trial are summarized later in this section.

[0302] Although the theoretical basis for the dosing has not changed, some additional safety and efficacy information has become available from the ustekinumab Phase 3 CD (UNITI) trial, which supports the planned treatment extension in this study. These results from the UNITI CD trial are summarized later in this section (Section 1.3).

[0303] In Study C0743T26 of the 2b phase dose range, a single IV dose of ustekinumab at 6 mg / kg was the maximum loading dose tested in subjects with CD. In this study, the IV dose of 6 mg / kg was shown to be effective in inducing clinical response up to week 8 and was well tolerated with a safety profile generally comparable to that of other treatment groups. Also, results from the ustekinumab CD studies also suggest that an IV loading dose can result in a rapid onset of clinical response following inhibition of IL-12 and IL-23. In the phase 3 studies CNTO1275CRD3001 and CNTO1275CRD3002, a body weight range dosing approach (ustekinumab 260 mg [body weight ≤ 55 kg]; ustekinumab 390 mg (body weight > 55 kg and ≤ 85 kg); ustekinumab 520 mg [body weight > 85 kg]) was used to approximate the IV loading dose of 6 mg / kg. Dosing based on body weight range allows for administration of a full vial to patients to simplify dose calculation and reduce the potential for error during administration. This body weight range dosing is intended to achieve drug exposure similar to that observed at a body weight-adjusted dose of 6 mg / kg. Thus, in this study, a body weight range-based IV loading dose strategy at week 0 was evaluated to assess the ability of the drug to rapidly reduce disease activity without raising significant concerns regarding increased safety risk based on data obtained from previous studies.

[0304] A maintenance dosing regimen of 90 mg SC of ustekinumab every 8 weeks (q8w) was tested in subjects with CD (C0743T26). Results of the C0743T26 study suggest that 90 mg SC of ustekinumab q8w was safe and effective in maintaining subjects in clinical remission. The q8w dosing frequency was chosen to determine whether sufficient ustekinumab exposure could be maintained to provide a sustained clinical response with ustekinumab treatment. In addition, SC administration is considered to be more convenient compared to IV administration. A 16-week follow-up period was selected after the last ustekinumab study dose to allow for a half-life greater than 5 to enable drug elimination and appropriate safety follow-up.

[0305] In addition, three Phase 3 trials in subjects with CD initiated in 2011 also recently provided additional safety and efficacy data; UNITI-1, UNITI 2, and IMUNITI. UNITI-1 and UNITI-2 were 8-week induction trials that were identical in design but tested separate patient populations. UNITI-1 tested subjects who had failed anti-TNF drugs or were intolerant, while UNITI-2 tested subjects who had not failed TNF antagonists but had failed conventional immunomodulators or steroid therapy. The IM-UNITI trial evaluated maintenance therapy in patients enrolled from both the UNITI-1 and UNITI-2 trials. The UNITI trials tested 1,367 subjects randomized to either placebo, 130 mg IV, or approximately 6 mg / kg IV. After 8 weeks of treatment, subjects in both the UNITI-1 and UNITI-2 trials were able to participate in IM-UNITI, which evaluated two maintenance regimens of 90 mg every 8 or 12 weeks compared to placebo in induction responders. The IM-UNITI trial is still ongoing in the long-term follow-up period, but the primary results of all three trials have been published 7 , and these results supported the approval of ustekinumab in patients with moderately to severely active CD. The approved dose for induction was a single IV weight-based dose approximating 6 mg / kg, and the approved maintenance dose was 90 mg every 8 or 12 weeks depending on the approved indication. The results of these trials are particularly relevant to the CNTO1275 SLE2001 SLE trial in that similar doses were evaluated. In addition, similar to the SLE population, approximately one-third of the CD patients enrolled in the UNITI trials used concomitant immunomodulators (e.g., MTX, AZA, 6-MP), and approximately 46% used glucocorticoids concomitantly. The results of these trials were reviewed in detail in the primary literature 7 and the key points are presented below: · In the two UNITI induction trials, the primary endpoint and all major secondary endpoints were met for both doses tested, including the 6 mg / kg dose. · In the IM-UNITI maintenance trial, both the 90 mg regimens every 8 weeks or every 12 weeks were superior to placebo in maintaining response or achieving remission compared to placebo at week 44. · Importantly, the safety profiles of both maintenance doses were comparable to placebo over 44 weeks and no new safety signals were identified. The safety profiles were similar to those seen in psoriasis indicators.

[0306] In summary, these CD trials support the planned dosing regimen of this proof-of-concept SLE trial, which includes an IV loading dose based on body weight range approximating 6 mg / kg, followed by 90 mg SC q8w, to ensure high levels of systemic exposure of ustekinumab to inhibit the action of IL-12 / 23.

[0307] The open-label, 90 mg SC q8w ustekinumab dose will be provided to patients starting at week 24 and up to week 40. According to the amended study plan, after the week 40 visit, subjects can continue the q8w study treatment at approximately week 8 (±2 weeks), or subjects eligible to restart the study treatment within 16 weeks or less (±2 weeks) because the week 40 visit of the subject is eligible to continue the 90 mg SC q8w ustekinumab treatment up to week 104, are followed by a further 16-week follow-up period.

[0308] 2. Objectives and Hypotheses 2.1. Objectives Primary Objective The primary objective is to evaluate the efficacy of ustekinumab as measured by a reduction in disease activity in subjects with active SLE.

[0309] Secondary Objectives The secondary objectives are to evaluate the following. · The safety and tolerability of ustekinumab in subjects with SLE. · The effect of ustekinumab administration on health-related quality of life in subjects with SLE. · The effect of ustekinumab on skin symptoms of SLE. ·Pharmacokinetics and immunogenicity of ustekinumab in subjects with SLE.

[0310] Purpose of the study The exploratory objectives are to evaluate the following. ·Safety and efficacy during long-term administration of ustekinumab. ·Reduction of corticosteroids during long-term administration of ustekinumab. ·Additional composite clinical endpoints or methods to calculate responses that may have the potential to enhance sensitivity to improvement and / or worsening of SLE. ·Biomarkers (genetic, systemic, and skin-related) associated with lupus disease.

[0311] 2.2. Hypothesis The hypothesis is that ustekinumab is significantly superior to placebo as measured by the 24-week Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) responder index (SRI-4) composite measure.

[0312] 3. Study Plan and Rationale A complete list describing all efficacy evaluations and endpoints, and which evaluations are included in the composite endpoint, is provided in Appendix 1. The main study is defined from the original protocol as a screening via hospital visits for safety follow-up at weeks 8 and 16 of the main study. Note that the hospital visits for safety follow-up at weeks 8 and 16 of the main study were previously described in the original protocol as hospital visits at weeks 48 and 56. However, with this amendment, the hospital visits at weeks 48 and 56 will only be used to account for hospital visits for treatment of subjects participating in subsequent studies. The subsequent study (applicable to subjects meeting the inclusion criteria) is defined as from the hospital visit at week 48 or 56 to the hospital visit for safety follow-up at week 16 of the subsequent study.

[0313] 3.1. Overview of the Study Design CNTO1275 SLE2001 is a Phase 2a, proof-of-concept, multi-center, randomized, double-blind, placebo-controlled trial of the efficacy and safety of ustekinumab added to standard-of-care background therapy in subjects with active SLE. Subjects 18 to 75 years of age must have SLE according to SLICC criteria and SLEDAI-2K score ≥6, regardless of prior therapy (e.g., immunosuppressants, antimalarials, corticosteroids, NSAIDs, antihypertensives, and / or topical agents). In addition, subjects must have at least one positive autoantibody test (ANA, anti-dsDNA antibody, and / or anti-Smith antibody) observed during screening, as well as a positive autoantibody test well-documented in their medical history. Subjects must also demonstrate at least one BILAG A and / or two BILAG B domain scores observed during screening. In addition, subjects must have a clinical SLEDAI-2K score ≥4 (excluding laboratory results) at Week 0 prior to randomization.

[0314] Randomization of subjects will be stratified according to consent for skin biopsy collection (y / n), and other characteristics (e.g., presence of lupus nephritis [y / n], baseline SLE medications and SLEDAI score), site / region, and race, or presence of concomitant medications, as described in Section 8.

[0315] Approximately 100 subjects will be randomly assigned in a 3:2 ratio to receive either ustekinumab or placebo for 24 weeks. After randomization at Week 0, subjects will receive an initial IV dose based on initial body weight range approximating 6 mg / kg of ustekinumab (ustekinumab 260 mg [body weight ≥35 kg to ≤55 kg]; ustekinumab 390 mg [body weight >55 kg and ≤85 kg]; ustekinumab 520 mg [body weight >85 kg]), followed by 90 mg of SC q8w (Section 6). At Week 24, subjects who received placebo will crossover, and all subjects will receive 90 mg of SC ustekinumab at Weeks 24, 32, and 40, followed by safety follow-up in a blinded fashion for 16 weeks (approximately 5 half-lives) until Week 56 after the last SC administration of study drug.

[0316] The placebo comparator (added to standard of care background therapy) will be used up to week 24 for the evaluation of the efficacy and safety of ustekinumab in subjects with SLE. From week 24 to week 40, the placebo group will crossover to ustekinumab 90 mg SC q8w. This crossover design will allow placebo subjects to receive the investigational drug and experience the use of ustekinumab 90 mg SC without the IV loading dose in subjects with SLE. The 40-week dosing period will be useful to understand the long-term safety and changes over time in the potential clinical response of ustekinumab in the SLE population.

[0317] All reasonable efforts should be made to keep the concomitant medications in a stable state as defined in the protocol. All concomitant therapies must be recorded throughout the trial starting from registration for screening, and any changes must be recorded throughout the trial.

[0318] All subjects with skin disease will be evaluated using CLASI scoring. Additionally, subjects with skin disease who consent to participate in the skin lupus substudy will have additional evaluations including collection of a skin biopsy of active disease (optional consent) and / or collection of photographs of identified skin lesions or areas of active disease (optional consent). There will be no restrictions on the number of subjects with skin disease who can enroll in either the main study or the skin lupus substudy.

[0319] Interim analyses (IAs) will be conducted when approximately one-third and two-thirds of the subjects reach 24 weeks. In the first IA, only evidence of significant efficacy will be evaluated. In the second IA, evidence of significant efficacy as well as treatment futility will be analyzed. Variations in the placebo effect across regions will be incorporated into the interim analyses. Database lock (DBL) will be conducted after the 24-week visit of the last subject and after the 56-week visit of the last subject or after the 16-week safety follow-up visit of the last subject from the main study. In addition, an independent Data Monitoring Ring Committee (DMC) will regularly review the interim safety data, including a formal review, when approximately one-third and two-thirds of the subjects reach 24 weeks and at the time of the 24-week DBL. The DMC will make recommendations regarding whether the trial should be stopped for futility or safety concerns or whether the data meet pre-specified criteria demonstrating significant efficacy. The general content, the role and responsibilities of the DMC, and the general procedures (including communication) will be defined in the DMC charter.

[0320] The corrected study design will continue to provide non-blind ustekinumab 90 mg, q8w SC until week 104 (the follow-up study). Subjects will be eligible to continue study treatment until week 104 if they meet the following study inclusion criteria (Section 4.13): ·Must not have a permanently discontinued study treatment at or before the week 40 visit, and ·Must be able to continue the q8-week study treatment for approximately 8 weeks (±2 weeks) after the week 40 visit, or ·Must be able to restart the study treatment for 16 weeks (±2 weeks) or less after the week 40 visit. If these criteria are met, subjects will be eligible to continue study treatment until week 104.

[0321] In addition to the planned DBL after the 56-week visit of the last subject and after the visit for the last 16-week safety follow-up, there will be an additional DBL after the 16-week safety follow-up of the follow-up study.

[0322] The diagrams of the main test designs are provided in Figure 1, and the diagrams of the subsequent tests are provided in Figure 2.

[0323] 3.2. Theoretical basis of the test plan Blind test, control, test period / duration, treatment group A placebo control is used to establish the frequency and magnitude of changes in clinical endpoints that can occur in the absence of active treatment. Randomization is used to minimize bias in the assessment of subjects for treatment groups, increase the likelihood that known and unknown subject attributes (e.g., demographic and baseline characteristics) are evenly balanced across treatment groups, and enhance the validity of statistical comparisons across treatment groups. Blind procedures are used to reduce potential bias during data collection and in the assessment of clinical endpoints.

[0324] Collection of DNA and biomarkers Genetic variation is known to potentially be an important factor contributing to individual differences in drug distribution and response, and can serve as a marker for disease susceptibility and prognosis. Pharmacogenetic studies may help explain individual differences in clinical outcomes and may also help identify subpopulations of the parent population that respond differently to drugs. The goal of the pharmacogenetic component is to collect deoxyribonucleic acid (DNA) to identify genetic factors that may affect the pharmacokinetics, pharmacodynamics, efficacy, safety, or tolerability of ustekinumab, and also to identify genetic factors related to SLE.

[0325] Biomarker samples are collected to evaluate the mechanism of action of inter-individual variability in clinical outcomes, which may help identify sub-groups of the population that exhibit different responses to drugs. The purpose of biomarker analysis is to evaluate the pharmacodynamics of ustekinumab and to assist in the evaluation of the drug-clinical response relationship.

[0326] DNA and biomarker samples may also be used to address new problems and to enable the development of safer, more effective, and ultimately individualized therapies.

[0327] 4. Target population The target test population is subjects with SLE according to the SLICC criteria and SLEDAI-2K score ≥ 6, regardless of prior treatment (e.g., immunosuppressants, antimalarials, corticosteroids, NSAIDs, antihypertensives, and / or topical agents). Subjects must have at least one BILAG A and / or two BILAG B domain scores observed during screening. In addition, subjects must have at least one positive autoantibody test (ANA, anti-dsDNA antibody, and / or anti-Smith antibody) observed during screening, as well as a positive autoantibody test well-documented in their medical history, and they must also have a clinical SLEDAI-2K score ≥ 4 (excluding laboratory results) prior to randomization at week 0.

[0328] The inclusion and exclusion criteria for enrolling subjects in this trial are described in the following two subsections. If there are any questions regarding inclusion or exclusion criteria, the principal investigator of the clinical trial must consult with the appropriate sponsor representative before enrolling subjects in this study.

[0329] Subjects with SLE enrolled in the pivotal trial with active cutaneous lupus (including subjects with discoid lupus erythematosus, subacute cutaneous lupus erythematosus, or SLE malar rash, or other SLE skin lesions characterized by erythema and / or scale) will be evaluated using the CLASI scoring. In addition, subjects providing consent will be enrolled in a cutaneous lupus substudy that will evaluate the histology of skin biopsies and / or skin photographs. Biopsy samples (two samples, 4 mm in size) from consenting subjects will be taken from lesions demonstrating active skin disease prior to dosing at Week 0 and Week 24. Subjects participating in the cutaneous lupus substudy may not be required to undergo a biopsy and may be permitted only photographs to demonstrate changes in identified skin lesions or areas of active disease. Subjects with cutaneous lupus considered inappropriate for biopsy (e.g., malar rash or alopecia) may also be enrolled in the substudy and evaluated by photography.

[0330] If a subject fails screening and the PI wishes to re-screen the subject, this should be discussed by the sponsor and / or its designee. Only one re-screening is permitted per subject (see Section 9.1.2).

[0331] The subsequent study population will consist of subjects who have not permanently discontinued the study treatment prior to or at Week 40 of dosing and subjects in whom the PI determines that there is a potential benefit that outweighs the potential risks of continued ustekinumab treatment.

[0332] For discussion of the statistical considerations in subject selection, see Sample Size Determination in Section 11.2.

[0333] 4.1. Inclusion Criteria 4.1.1. Inclusion Criteria Applicable to All Subjects Potential subjects must each meet all of the following criteria to be enrolled in this study. 1. The subjects must be 18 years old (or 18 years old and above according to local requirements) to 75 years old and have a body weight of at least 35 kg. 2. The subjects must have a confirmed medical history to meet the SLICC classification criteria for SLE for at least 3 months at the first dose (Table 3). Eligible subjects for enrollment in this study must be considered to have SLE by meeting the SLICC classification criteria for SLE25 based on one or both of the following: · Meeting four criteria with at least one clinical criterion and at least one immunological criterion, or · Having a diagnosis of lupus nephritis in the presence of at least one of the immunological variables.

[0334]

Table 9-1

[0335]

Table 9-2

[0336] The levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase must be within 2 times the upper limit of normal (ULN) range for the laboratory where the test is performed. For subjects within the range of 1.5 - 2×ULN, the subject may be included only if the principal investigator of the trial determines that the abnormality or deviation from normal is not clinically significant or is appropriate and reasonable for the population under study. This determination must be promptly reported to the medical monitor of the trial sponsor, recorded in the subject's source document, and initialed and signed in abbreviated form by the principal investigator of the trial.

[0337] Subjects with other marked disease-related laboratory abnormalities may be included only if the principal investigator of the trial determines that the abnormality or deviation from normal is not clinically significant or is appropriate and reasonable for the population during the trial. This determination must be promptly reported to the medical monitor of the trial sponsor, recorded in the subject's source document, and initialed and signed in abbreviated form by the principal investigator of the trial. 16. Subjects must have the intention and be able to abide by the prohibitions and restrictions specified in this protocol. 17. Each subject must sign an informed consent form (ICF) indicating that they understand the purpose of the study and the procedures required for it and have the intention to participate in the study. 18. If consent is given to provide optional DNA samples for the study, each subject must sign a separate informed consent form (if permitted by local regulations). Refusal to give permission for optional DNA study samples will not exclude the subject from participation in this trial.

[0338] 4.1.2. Additional inclusion criteria for the cutaneous lupus substudy To enroll in the cutaneous lupus substudy, SLE subjects must meet all previously listed inclusion criteria (section 4.1.1) in addition to the criteria listed below. 1. Subjects with active CLE at screening and a diagnosis of a cutaneous disease demonstrated prior to trial registration, including discoid lupus erythematosus, subacute cutaneous lupus erythematosus, or SLE malar rash, or other SLE cutaneous lesions characterized by erythema and / or scale are included. 2. Subjects taking systemic, topical, or intralesional agents for CLE must have been on a stable dose or treatment regimen for 4 weeks prior to the first study drug administration. 3. Subjects who consent to participate in the cutaneous lupus substudy will be required to provide biopsies of active CLE target lesions at pre-dose visits at Week 0 and Week 24. Active CLE lesions are characterized by scale and / or erythema, excluding previously scarred tissue. In addition, separate consent will be obtained to collect photographs of cutaneous lesions or areas of active disease according to the schedule defined in Table 1. 4. Subjects with cutaneous lupus that is considered inappropriate for biopsy (e.g., malar rash or alopecia) may also enroll in the substudy and can be evaluated by photography.

[0339] 4.1.3. Inclusion Criteria Applicable to All Subjects Entering Subsequent Trials (Week 48 or Week 56 Visits) Any subject who does not meet the inclusion criteria for the subsequent trial must follow the schedule of times and events for the main study design (Table 1) and must also attend the safety follow-up visits at Week 40 or 8 and 16 weeks after the final study drug administration. 1. The subject must not have had the study treatment permanently discontinued by Week 40 visit or earlier and must be able to continue q8w SC dosing at approximately 8 weeks (±2 weeks) after the Week 40 visit or resume dosing at Week 56 within 16 weeks (±2 weeks) from the Week 40 visit. 2. In the judgment of the study physician, the potential benefits of continuing ustekinumab long-term outweigh the potential risks to the subject. 3. Each subject must sign a revised informed consent indicating agreement to participate in the subsequent trial.

[0340] 4.2. Exclusion Criteria Any potential subject who meets any of the following criteria will be excluded from participation in this study: 1. Having another inflammatory disease that may confound the assessment of efficacy, including but not limited to rheumatoid arthritis (RA), psoriatic arthritis (PsA), RA / lupus overlap, psoriasis, or active Lyme disease. 2. Being pregnant, lactating, or planning to become pregnant during the period of registration in the study or within 4 months after receiving the last dose of the investigational agent. 3. Having received systemic or topical cream / ointment formulations of cyclosporine A or other systemic immunomodulatory agents other than those described in the inclusion criteria within the past 3 months prior to the first dose of the investigational agent (Section 4.1). Corticosteroids are not included in this criterion. See Sections 4.3 and 8.3 regarding corticosteroids. 4. Having received a single B-cell targeting agent within 3 months prior to the first dose of the investigational agent, or having received two or more previous B-cell targeting therapies including belimumab or epratuzumab within 6 months prior to the first dose of the investigational agent, or having received B-cell depletion therapy (e.g., rituximab) within 12 months prior to the first dose of the investigational agent, or having evidence of continued B-cell depletion after such treatment. 5. Having received ustekinumab previously. 6. Having received a previous immunomodulatory biologic therapy for lupus that is not described in Exclusion Criterion #4, including but not limited to tocilizumab, alefacept, efalizumab, natalizumab, abatacept, anakinra, brodalumab, secukinumab, ixekizumab, or inhibitors of the TNF, IL-1, IL-6, IL-17, or interferon pathways, within a period of either less than 5 half-lives or less than 3 months, whichever is longer, prior to the first dose of the investigational agent. 7. If there is a known allergy to human immunoglobulin (Ig) protein (e.g., intravenous Ig). 8. If oral cyclophosphamide was used within 90 days from the start of screening, or IV cyclophosphamide was used within 180 days. 9. There is a history of active granulomatous infection, including histoplasmosis or coccidioidomycosis, prior to screening. For information on the eligibility of a history of latent TB, refer to the inclusion criteria. 10. Had Bacille Calmette Guerin (BCG) vaccination during 12 months of screening. 11. Had a chest X-ray 3 months prior to the first administration of the test agent that shows an abnormal suggestion of a malignant disease or current active infection, including TB. 12. Had a non-tuberculous mycobacterial infection or an opportunistic infection (e.g., cytomegalovirus, pneumocystosis, aspergillosis) within 6 months prior to screening. 13. Received or is expected to receive any live virus or bacterial vaccination within 3 months prior to the first administration of the test agent, during the trial, or within 3 months after the last administration of the test agent. For BCG vaccination criteria, refer to exclusion criterion 10 and prohibition / limitation criterion 8. 14. Has a serious infection (including but not limited to hepatitis, pneumonia, sepsis, or pyelonephritis), or is hospitalized due to an infection, or was treated with intravenous antibiotics for infection within 2 months prior to the first administration of the test agent. In the case of a less severe infection (e.g., acute upper respiratory tract infection, simple urinary tract infection), it is not necessarily considered an exclusion at the discretion of the principal investigator of the clinical trial. 15. Has a history of chronic or recurrent infection, including but not limited to chronic kidney infection, chronic chest infection (e.g., bronchiectasis), sinusitis, recurrent urinary tract infection (e.g., recurrent pyelonephritis), open, draining, or infected skin wounds, or ulcers. 16. The subject is positive for human immunodeficiency virus (HIV) antibodies or has a positive HIV test result at the time of screening. 17. Has hepatitis B infection. The subject must be screened for hepatitis B virus (HBV). At a minimum, this includes testing for HBsAg (HBV surface antigen), anti-HBs (HBV surface antibody), and total anti-HBc (total HBV core antibody). 18. Subjects who are seropositive for antibodies to hepatitis C virus (HCV) must be separated by 6 months prior to screening and have a third negative HCV RNA test result at the time of screening, unless they have had two negative HCV RNA test results prior to screening. 19. Subjects who have experienced a recent episode of single dermatomal herpes zoster within the past 4 months are excluded. Those who have had multiple dermatomal herpes zoster or central nervous system (CNS) herpes zoster within the past 5 years are excluded. 20. Subjects with a history or suspicion of drug-induced lupus. 21. If the subject has urine protein > 4 g / day or protein / creatinine ratio > 4. 22. If the subject has congenital complement deficiency or unclassifiable immunodeficiency. 23. Having end-stage renal disease, or severe or rapidly progressive glomerulonephritis, including severe active lupus nephritis, rapidly increasing creatinine, or other factors suggesting severe or rapidly progressive nephritis reported in recent biopsy and / or other evaluations such as active urine sediment (see also the serum creatinine limit in inclusion criterion #15). 24. Having severe CNS lupus, including but not limited to seizures, psychosis, transverse myelitis, CNS vasculitis, and optic neuritis. 25. Having severe, progressive, or uncontrolled liver, hematological, gastrointestinal, endocrine, pulmonary, cardiac, nervous system / brain, or psychiatric disease, or current signs and symptoms thereof. 26. A history of lymphoproliferative disease, such as lymphoma, or lymphoproliferative disorders of abnormal size or location, clinically significant splenomegaly, or monoclonal gammopathy of undetermined significance, or a history of known lymphoproliferative disease including potential lymphoma or signs and symptoms of lymphoproliferative disease. 27. The subject has a history of malignant disease within 5 years prior to screening (exceptions are surgically cured cervical cancer, squamous cell carcinoma of the skin and basal cell carcinoma treated without evidence of recurrence at least 3 months prior to the first administration of the test agent). 28. Known allergies, hypersensitivities, or intolerance to ustekinumab, its excipients, or latex (see Section 14.1, which is included in the syringe needle cover). 29. Currently receiving bee venom immunotherapy (honey bee, wasp, hornet, or fire ant). 30. Received an investigational agent not previously defined by other exclusion criteria (including the investigational vaccine or other agents specified in Section 4.3, Prohibition / Limitation No. 3) within the longer of 5 half-lives or 3 months, or used an invasive investigational medical device within 3 months of the planned first dose of the test agent, or is currently enrolled in an interventional trial. 31. In the opinion of the principal investigator and / or the sponsor of the trial, participation is not in the best interest of the subject (e.g., detrimental to health), or has any condition that may prevent, limit, or confound the protocol-specified evaluation, including a previous pattern of non-compliance with medical follow-up or a low likelihood of adhering to the study visit schedule. 32. Underwent major surgery (e.g., requiring general anesthesia) within 1 month prior to screening, or has not fully recovered from surgery, or plans to undergo major surgery within the period of planned participation in the trial or within 1 month after the last volume of test agent administration. Note: Subjects with minor surgical procedures planned under local anesthesia are eligible to participate. 33. Has a transplanted organ (except for corneal transplantation performed 3 months prior to the first administration of the test agent). 34. Have or had a drug abuse (drug or alcohol) problem within the past three years. 35. Have a poor tolerance or, due to difficult access to veins, have no intention or are unable to undergo multiple venipunctures. 36. If the subject is directly involved in a proposed trial or other trial based on the instructions of the principal investigator of the clinical trial or an employee of the trial conducting institution (i.e., a staff member to whom the principal investigator has delegated roles or responsibilities for conducting the trial), the principal investigator of the trial, or the trial conducting institution, and is a family member of such an employee or principal investigator. 37. Are a resident of a facility by order of a court or authority, unless permitted by local regulations. Note: The principal investigator of the clinical trial should ensure that all trial registration criteria are met at the time of screening. If, after screening but before the first dose of the investigational drug is administered, the condition of the subject changes (including receipt of test results or additional medical records) such that the first dose of the investigational drug cannot meet all eligibility criteria, the subject should be excluded from participation in the study. The sponsor reserves the right to discontinue the subject for any operational or safety reasons.

[0341] 4.3. Prohibitions and Restrictions Potential subjects must comply with the following prohibitions and restrictions during the course of the trial (including subsequent trials) in order to be eligible for continuous rubbing administration in the trial. 1. If a female is potentially pregnant, she must continue to use a highly effective contraceptive method during the trial and for four months after receiving the last dose of the investigational drug. An exception to this restriction is if the subject or male partner is infertile, in which case contraception is not required. A female should not provide eggs (oocytes, ova) for reproductive assistance purposes during the trial and for four months after receiving the last dose of the investigational drug. 2. Also, in the case of males, an effective contraceptive method should be used during the trial and for four months after receiving the last dose of the test agent, and sperm should not be provided. Exceptions to this restriction are when the subject or female partner is infertile, in which case contraception is not required. 3. The use of additional immunosuppressive or immunomodulatory agents other than those explicitly permitted in the inclusion / exclusion criteria is prohibited and includes, but is not limited to, the following: · Biological agents targeting TNFα reduction (including, but not limited to, infliximab, golimumab, certolizumab pegol, etanercept, yisaipu, CT-P13 [Remsima (registered trademark)], and adalimumab) · B cell depletion agents (known as anti-CD20 [e.g., rituximab], anti-B cell activating factor [BAFF], B lymphocyte stimulator [BLyS] [e.g., belimumab], or anti-CD22 [e.g., epratuzumab]) · Interleukin-1 inhibitors (e.g., canakinumab) · Interferon inhibitors · IL-1ra (e.g., anakinra) · Tocilizumab, or any other biological targeting of IL-6 or the IL-6 receptor · Tofacitinib or any other Janus kinase (JAK) inhibitor · Abatacept · Anti-IL-17 agents (e.g., brodalumab, secukinumab, and ixekizumab) · Leflunomide · Cyclosporine A (oral or topical ointment / cream formulations) · Tacrolimus or pimecrolimus, oral or topical formulations · Toll-like receptor inhibitors · Thalidomide or lenalidomide · Dapsone · Injectable adrenocorticotropic hormone (ACTH) 4. The use of cytotoxic agents, including but not limited to cyclophosphamide, chlorambucil, nitrogen mustard, or other alkylating agents, is prohibited. 5. Multiple administrations of high-dose corticosteroids and initiation of medium- or high-potency topical corticosteroids are prohibited during the trial, as defined in Section 8.3. 6. In addition to ongoing immunomodulatory therapy, initiation of new approved immunomodulatory agents (MTX, azathioprine, 6-mercaptopurine, mycophenolate mofetil / mycophenolic acid) is prohibited. 7. After the first dose of the test article, initiation of new angiotensin II receptor blocker (ARB) or angiotensin-converting enzyme (ACE) inhibitor therapy for the treatment of lupus-related diseases is not permitted until week 28. 8. Subjects must consent not to receive live virus or live bacterial vaccinations during the study. Subjects must also consent not to receive BCG vaccination for 12 months after the last dose of the test article, or any other live vaccine for 3 months after the last dose of the test article. 9. Subjects must consent not to receive investigational medical devices or investigational drugs other than the test article during the study period. 10. Traditional medications (e.g., herbs / use of complementary therapies that can induce lupus activation or relieve SLE symptoms) and traditional medications (e.g., herbs / alternative preparations [e.g., Echinacea], Chinese herbal medicine, acupuncture, ayurvedic) are prohibited until week 40. 11. Subjects should avoid excessive sunlight exposure and must not participate in commercial ultraviolet tanning or ultraviolet phototherapy during the trial. 12. Skin concealers or topical tanning preparations should be avoided as they may obscure the activity of skin diseases. 13. Sulfur-based antibiotics should generally be avoided, even if appropriate.

[0342] 5. Treatment Assignment and Blinding 5.1. Randomization Procedure In conducting this trial, dynamic central randomization is implemented. Subjects are assigned to one of two treatment groups based on a minimization randomization algorithm implemented by an Interactive Web Response System (IWRS) prior to the trial. Dynamic central randomization targets the distribution of subjects to balance and obtains a randomization ratio (3:2) within the levels of each individual stratifying factor: skin biopsy (y / n, when n < 16 for y), presence of lupus nephritis (y / n), baseline SLE medications and SLEDAI-2K score (combined factor) * , site, region (approximately 4 categories), and race (3 categories). Based on the algorithm, each subject is assigned to the treatment group that generates the minimum total imbalance score with high probability, where the total imbalance score is the weighted average of the imbalance scores for each stratifying factor and for the entire trial. The IWRS will assign a unique treatment code that determines the treatment assignment for the subject. * The baseline SLE medications and SLEDAI-2K score are calculated as a combined factor that includes the following. · The SLEDAI-2K score (<10 or ≥10) is · Combined with the baseline medications. - High dosing is defined as ≥15 mg / week of MTX, or ≥1.5 mg / kg / day of AZA / 6-MP, or ≥1.5 g / day of MMF / MPA, and / or ≥15 mg / day of prednisone. - Low dosing is defined as <15 mg / week of MTX, or <1.5 mg / kg / day of AZA / 6-MP, or <1.5 g / day of MMF / MPA, and / or <15 mg / day of prednisone.

[0343] 5.2. Blinding The randomization code is not provided to the principal investigator of the trial. This code is maintained within the IWRS. This code has a function that enables the principal investigator of the trial to break the blinding for individual subjects.

[0344] Under normal circumstances, blinding should not be lifted until all subjects have completed the trial by week 56 or until participation in the trial ends and the database is defined. Otherwise, blinding should be lifted only if knowledge of the treatment status of a subject could indicate specific emergency treatment / a series of actions. In such cases, the principal investigator of the clinical trial can determine the details of the treatment by contacting the IWRS in an emergency. Before lifting the blinding, it is recommended that the principal investigator of the clinical trial contact the sponsor or designee, if possible, to discuss the specific situation. Telephone contact with the sponsor or its designee is available 24 hours a day, 7 days a week. If the blinding is lifted, the sponsor must be notified as soon as possible. The date and reason for unblinding must be documented by the IWRS. The document indicating the code release received from the IWRS is kept together with the subject's source document in a secure manner.

[0345] Subjects for whom the treatment assignment was unblinded may be discontinued from further administration of the investigational drug and should return for safety follow-up.

[0346] Generally, the randomization code will be fully disclosed only when the trial is completed and the clinical database is closed. The sponsor is blinded until the 24-week assessment and until the database is cleaned and finalized for the planned analysis. The clinical sites, subjects, principal investigators of the clinical trial, and facility staff will remain blinded until the week 56 data are defined and until the end of the trial. Data that could potentially unblind the treatment assignment will be handled with special care.

[0347] 6. Dosage and Administration 6.1. IV Administration In the case of IV administration, the investigational drug is administered to each subject over a period of more than 1 hour.

[0348] The ustekinumab 5 mg / mL product for final vial (FVP) is supplied as a single-dose strength, sterile solution in a 30 mL vial (i.e., 130 mg in a nominal volume of 26 mL). In addition to ustekinumab, this solution contains 10 mM L-histidine, 8.5% (w / v) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL disodium ethylenediaminetetraacetate (EDTA) dihydrate, at pH 6.0. There is no preservative.

[0349] The placebo for FVP (IV) is supplied as a single-use, sterile solution in a 30 mL vial with a nominal volume of 26 mL. The composition of the placebo is 10 mM L-histidine, 8.5% (w / v) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL disodium EDTA dihydrate, at pH 6.0. There is no preservative.

[0350] Dosing based on weight range will enable administration of a full vial to the patient, to simplify dose calculation and reduce the potential for error during administration. The IV dose based on this weight range is intended to achieve drug exposure similar to that observed at a body weight-adjusted dose of 6 mg / kg. An equal number of vials will be administered to subjects receiving placebo based on that weight range. The weight range dosing is based on the following. · Body weight ≥ 35 kg to ≤ 55 kg: 260 mg of ustekinumab (2 vials) · Body weight > 55 kg to ≤ 85 kg: 390 mg of ustekinumab (3 vials) · Body weight > 85 kg: 520 mg of ustekinumab (4 vials)

[0351] 6.2. SC Administration Ustekinumab is also supplied as a single-use, latex-free prefilled syringe (PFS) with a nominal volume of 1 mL and a strength of 90 mg for SC administration. Each 1 mL solution of ustekinumab in the PFS contains 90 mg of ustekinumab with a nominal excipient concentration of 6.7 mM L-histidine, 7.6% (w / v) sucrose, and 0.004% (w / v) polysorbate 80 at pH 6.0. There is no preservative. The needle cover of the PFS contains dry natural rubber (a derivative of latex), which may cause an allergic reaction in latex-sensitive individuals.

[0352] Placebo administration has the same appearance as each of the ustekinumab administrations. Liquid placebo is also supplied in 1 mL PFS and has 10 mM L-histidine, 8.5% (w / v) sucrose, and 0.004% (w / v) polysorbate 80 at pH 6.0. There is no preservative. The needle cover of the PFS contains dry natural rubber (a derivative of latex), which may cause an allergic reaction in latex-sensitive individuals.

[0353] From week 0 to week 24 at the longest (blinded study drug administration period) Group 1: Subjects receive an IV administration of approximately 6 mg / kg of ustekinumab based on body weight range at week 0, followed by SC administrations of 90 mg of ustekinumab at weeks 8 and 16.

[0354] Group 2: Subjects receive an IV administration of placebo based on body weight range at week 0, followed by SC administrations of placebo at weeks 8 and 16.

[0355] From week 24 to week 40 (crossover administration period) Group 1: Subjects receive an SC administration of 90 mg of ustekinumab at week 24, followed by q8w administrations until week 40.

[0356] Group 2: Subjects crossover to an SC administration of 90 mg of ustekinumab at week 24, followed by q8w administrations until week 40.

[0357] Follow-up observation for 16 weeks starting from 40 weeks (Safety follow-up period) Groups 1 and 2: Subjects who do not participate in the subsequent trial are expected to return for the safety follow-up visit for the safety follow-up observation at week 44 and return for the safety follow-up observations at 8 weeks and 16 weeks.

[0358] Subsequent trial (week 48 / weeks 56 - 120) Subjects who meet the criteria for inclusion in the subsequent trial will receive open-label ustekinumab administration for the purpose of expanding the safety experience and maintaining efficacy in lupus patients continuously exposed to 90 mg of ustekinumab q8w. Subjects who continue administration in the subsequent trial starting at week 48 or 56 will receive open-label ustekinumab SC administration via week 104. If the development of ustekinumab in SLE is terminated, the subsequent trial will also be interrupted.

[0359] 7. Treatment compliance The study personnel will maintain a log of all study drug administrations. The supply of study drug to each subject will be cataloged and reported. All ongoing therapies administered at screening must be recorded.

[0360] Adherence to the treatment schedule is strongly encouraged. It is understood that treatment may be interrupted for health-related or safety reasons. Visits at weeks 0, 24, and 48 are essential for evaluating the efficacy and safety of ustekinumab as treatment for active SLE.

[0361] Therefore, for any reason, if the subject is unable to receive the intended dose of the investigational drug at the scheduled visit, the subject must make all efforts for the intended evaluation. Until the 32nd week visit, the visit and administration of the investigational drug should be conducted within ±7 days of the scheduled visit date (relative to week 0). After the 32nd week visit, the administration of the investigational drug should be conducted within ±2 weeks of the scheduled visit date (relative to week 0). The investigational drug administrations are planned to be conducted approximately 8 weeks apart and cannot be conducted 14 days apart. In case of a delay in the procedure, the subject must resume the normal test schedule relative to the baseline visit (week 0).

[0362] All subjects will be monitored by the monitors designated by the sponsor of the clinical trial. During these monitoring visits, all procedures will be evaluated to comply with the protocol. The subject's chart will be reviewed and compared with the previous data entry to ensure accuracy. The sponsor must notify of any deviation from the above time frame.

[0363] 8. Concomitant Therapy All pre-study therapies administered up to 90 days before entering screening must be recorded at screening. Modifications to effective existing therapies should not be made for the explicit purpose of the subject entering the study. All concomitant therapies must be recorded throughout the study starting from registration for screening, and any changes must be recorded throughout the study.

[0364] All reasonable efforts should be made to maintain the concomitant medications stable until at least week 28, and also, if possible, to maintain stable medications throughout the 8-week safety follow-up of the main trial or until the subsequent trial (if applicable). Except for corticosteroids (see Section 8.3 regarding corticosteroid tapering), all other concomitant medications should be maintained at a stable dose throughout the trial. The concomitant medication dose may be reduced or temporarily discontinued due to abnormal laboratory values, side effects, concurrent illnesses, or performance of surgical treatment, but the changes and the reasons should be clearly documented in the subject's medical record. If the concomitant medication is adjusted after randomization allowed for each protocol, every effort should be made to return the subject to the baseline (week 0) dose level by the subject's visit at week 12, or an increase in the use of the medication (compared to baseline) may be considered a treatment failure for the subject. Corticosteroid adjustments for justifiable reasons are permitted as defined in Section 8.3.

[0365] The sponsor must notify in advance (or as soon as possible thereafter) any case where prohibited therapy is administered.

[0366] All pharmacological therapies different from the investigational product (all prescription or over-the-counter medications including vaccines, vitamins, and herbal supplements) must be recorded. The subject's diary card is used to capture medication changes administered to the subject that occur during the subject's trial visits during the main part of the trial, and these changes must also be recorded.

[0367] 8.1. Immunomodulators When receiving an immunomodulatory agent, the subject should receive stable dosing up to week 28 from screening. The subject can receive MMF / MPA (≤2 g / day), azathioprine / 6-mercaptopurine (≤2 mg / kg / day) and / or folic acid (recommended ≥5 mg / week), MTX (≤25 mg / week) between screening and week 28. Reduction of the immunomodulatory agent from week 12 to week 28 is only permitted if the subject develops unacceptable side effects, which may affect the interpretation of the subject's clinical data. Adding a higher dose of an immunomodulatory agent or a new immunomodulatory agent to the existing treatment regimen between the visit at week 12 and the visit at week 24 will result in the subject being considered a treatment failure for the purpose of the primary endpoint analysis. Permanent interruption of the study treatment must be considered for subjects who have received an increased dose of the immunomodulatory agent (compared to baseline). After week 28, the immunomodulatory agent should remain as stable as possible until the safety follow-up at week 8 or subsequent trial (if applicable). However, dose adjustment is possible for unacceptable side effects.

[0368] 8.2. Antimalarial drugs Stable treatment with hydroxychloroquine, chloroquine, or quinacrine is permitted until the safety follow-up at week 8. After week 28, introduction or adjustment of the antimalarial drug dose is possible. Antimalarial drugs (e.g., quinacrine) manufactured by a licensed pharmacy using pharmaceutical-grade ingredients under national control are permitted.

[0369] 8.3. Corticosteroid treatment Unnecessary dose changes should be suppressed and any dose adjustment should be made incrementally. Changes in corticosteroids up to the safety follow-up at week 8 or subsequent trial (if applicable) are permitted for medical necessity, but the degree and timing of adjustment should be carefully considered as they may affect the test results, especially during the period from week 12 to week 28.

[0370] Oral corticosteroids* When using oral corticosteroids, prior to the first administration of the test agent, the subject must have received this agent for at least 6 weeks and at a stable dose equivalent to prednisone ≤20 mg / day for at least 4 weeks. Adjustment (increase or decrease) of corticosteroid dose from prednisone ≤5 mg (equivalent / day) to a maximum of 25 mg / day is allowed up to week 6. From week 6 to week 12, an increase in corticosteroid dose is not recognized, and within this window, only a gradual decrease in adjustment of up to 5.0 mg of prednisone (equivalent / day) towards the baseline dose is allowed until the 12-week visit. Further adjustment of the corticosteroid dose for the treatment of SLE disease is not allowed between week 12 and week 28. After week 28, changes in corticosteroid dosage up to the 8-week safety follow-up are allowed for medical necessity, but the degree and timing of adjustment should be carefully considered as this may affect the trial. An increase in the oral corticosteroid dose above 40 mg / day should be considered in a medical monitor and may result in interruption of test agent administration.

[0371] Subjects may receive a short course (≤2 weeks) of oral corticosteroids for reasons such as preoperative prophylaxis (stress dose of corticosteroids) or treatment of limited infectious diseases, asthma aversion, or treatment of chronic obstructive pulmonary disease.

[0372] Subjects who may require multiple courses of steroids for reasons other than SLE should be excluded from trial participation.

[0373] A gradual reduction in the oral corticosteroid dose in subsequent trials (a recommended reduction to 10 - 20% or less of the initial weekly dose) is encouraged to be initiated after week 48 at the discretion of the trial's principal investigator. Whenever possible, a taper to the lowest possible maintenance dose of corticosteroids, including complete withdrawal, is recommended. During the corticosteroid taper, subjects should be educated and monitored by the trial staff for symptoms of steroid deficiency (e.g., Addisonian symptoms) as needed.

[0374] If a subject experiences a worsening of their disease activity while corticosteroids are being tapered, further dose reductions can be halted and / or their oral corticosteroid dose can be temporarily increased if deemed necessary by the principal investigator. Subjects whose corticosteroid taper has been interrupted should be encouraged by the principal investigator to resume the taper within 4 weeks.

[0375] In the case of an increase in corticosteroid dose, it is recommended that the mean dose not be increased above the baseline dose unless medically necessary. Any increase in corticosteroids should be used with discretion as it may be considered treatment failure or failure of the corticosteroid taper. A sustained oral corticosteroid dose of 40 mg / day or more may result in interruption of the study drug.

[0376] * If necessary, rectal administration of corticosteroids should be short - term and local preparations must be used.

[0377] Epidural, intravenous, intramuscular, intra - articular, and intralesional corticosteroids Epidural, IV, IM, IA, or intralesional administration of corticosteroids should be avoided as much as possible within 4 weeks before the first administration of the test agent and is not permitted for the treatment of SLE until week 28. Drugs that induce the release of endogenous steroids such as ACTH administered by injection are not permitted within 3 months before the first administration of the test agent and throughout the entire study. Short-term (≤2 weeks) epidural, IV, IM, IA, or intralesional corticosteroids used for indications other than SLE should be limited to situations where there are no appropriate alternatives, in the opinion of the treating physician. If clinically necessary, a total of one or two IA injections may be permitted up to the 16th week of dosing, but this renders those joints unevaluable for subsequent assessment. For conditions other than SLE, corticosteroid therapy should be limited to situations where there are no appropriate alternatives, in the opinion of the treating physician. Intravenous corticosteroids at a total of >625 mg of prednisone equivalent per day for more than 2 days during the 24-week period will be evaluated for treatment failure according to the Statistical Analysis Plan (SAP).

[0378] Inhaled corticosteroids Corticosteroids administered by bronchial or nasal inhalation for the treatment of conditions other than SLE may be given as needed.

[0379] Use of corticosteroids in the cutaneous lupus sub-study For subjects in the cutaneous lupus sub-study, the use of potent topical corticosteroids, or the initiation or increase from baseline of intralesional corticosteroid injections is not permitted and should be avoided in the 8-week safety follow-up or subsequent studies.

[0380] 8.4. Non-steroidal anti-inflammatory drugs Subjects treated with an NSAID containing aspirin and a selective cyclooxygenase-2 (COX-2) inhibitor, and other analgesics, should receive the normal commercially available doses approved in the country where the study is conducted. Prescriptions for NSAIDs and other regularly administered analgesics should not be adjusted for at least 2 weeks before the first administration of the test article and m...

Claims

1. A pharmaceutical composition for use in a method of treating a patient with active systemic lupus erythematosus (SLE), said pharmaceutical composition comprising an anti-IL-12 / IL-23p40 antibody, said method comprising administering said antibody to a patient in a clinically proven safe and clinically proven effective amount at an initial intravenous (IV) dose of the antibody of 6.0 (of the antibody) mg / (of the patient) kg ± 1.5 mg / kg, and thereafter at a subcutaneous (SC) dose of 90 mg of the antibody every 8 weeks, said antibody comprising a heavy chain variable region and a light chain variable region, said heavy chain variable region comprising a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1, a CDRH2 amino acid sequence of SEQ ID NO: 2, and a CDRH3 amino acid sequence of SEQ ID NO: 3, and said light chain variable region comprising a complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4, a CDRL2 amino acid sequence of SEQ ID NO: 5, and a CDRL3 amino acid sequence of SEQ ID NO: 6, said antibody being administered at an initial intravenous (IV) dose of the antibody of 6.0 (of the antibody) mg / (of the patient) kg ± 1.5 mg / kg, and thereafter at a subcutaneous (SC) dose of 90 mg of the antibody every 8 weeks, said patient being, (a) having a statistically significant improvement in disease activity determined by a decrease from baseline in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥ 4 by week 24 of treatment with said antibody (SRI-4 response), (b) having a statistically significant reduction defined as ≥ 1 new British Isles Lupus Assessment Group (BILAG) A domain score or ≥ 2 new BILAG B domain scores in the risk of new BILAG flare by week 24 of treatment with said antibody, (c) having a 50% improvement from baseline in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score compared to patients treated with placebo, and (d) having a statistically significant improvement in disease activity, as determined by a 50% improvement from baseline joint disease activity by week 24 of treatment with the antibody A pharmaceutical composition that is a responder to said treatment with said antibody, as identified as at least one selected from the group consisting of.

2. The pharmaceutical composition according to claim 1, wherein the initial IV dose is 260 mg for patients with a body weight of ≧ 35 kg to ≦ 55 kg, 390 mg for patients with a body weight of > 55 kg to ≦ 85 kg, and 520 mg for patients with a body weight of > 85 kg.

3. The pharmaceutical composition according to claim 1 or 2, wherein the patient is a responder to said treatment with said antibody and is identified as having a statistically significant improvement in disease activity that persists throughout one year of treatment by week 24 of treatment.

4. The antibody for use in IV administration is in a pharmaceutical composition containing a solution containing 10 mM L-histidine, 8.5% (w / v) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL disodium EDTA salt, dehydrate, at pH 6.

0. The pharmaceutical composition according to any one of claims 1 to 3.

5. The antibody for use in SC administration is in a pharmaceutical composition containing a solution containing 6.7 mM L-histidine, 7.6% (w / v) sucrose, 0.004% (w / v) polysorbate 80, at pH 6.

0. The pharmaceutical composition according to any one of claims 1 to 3.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the method further comprises administering to the patient one or more additional agents used to treat lupus.

7. The pharmaceutical composition according to claim 6, wherein the additional agent is selected from the group consisting of an immunosuppressant, a non-steroidal anti-inflammatory drug (NSAID), methotrexate (MTX), an anti-B cell surface marker antibody, an angiotensin-converting enzyme inhibitor, an angiotensin receptor blocker, an anti-malarial drug, mycophenolate mofetil, mycophenolic acid, azathioprine, 6-mercaptopurine, belimumab, an anti-CD20 antibody, rituximab, a corticosteroid, and a costimulatory modulator.

8. A pharmaceutical composition for use in a method of treating a patient's active systemic lupus erythematosus (SLE), wherein the pharmaceutical composition comprises an anti-IL-12 / IL-23p40 antibody, wherein the method comprises administering the antibody to the patient in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7 and a light chain variable region of the amino acid sequence of SEQ ID NO: 8, wherein the antibody is administered at an initial intravenous (IV) dose of 6.0 (antibody) mg / (patient) kg ± 1.5 mg / kg, and thereafter at a subcutaneous (SC) dose of 90 mg every 8 weeks, wherein the patient is (a) having a statistically significant improvement in disease activity determined by a decrease from baseline in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≧ 4 by 24 weeks of treatment with the antibody (SRI-4 response), (b) having a statistically significant reduction defined as ≧ 1 new British Isles Lupus Assessment Group (BILAG) A domain score or ≧ 2 new BILAG B domain scores in the risk of a new BILAG flare by 24 weeks of treatment with the antibody, (c) having a 50% improvement from baseline in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score compared to patients treated with placebo, and (d) having a statistically significant improvement in disease activity, as determined by a 50% improvement from baseline joint disease activity by week 24 of treatment with the antibody A pharmaceutical composition that is a responder to the treatment with the antibody, as identified as at least one selected from the group consisting of

9. The pharmaceutical composition according to claim 8, wherein the initial IV dose is 260 mg for patients with a body weight of ≥ 35 kg to ≤ 55 kg, 390 mg for patients with a body weight of > 55 kg to ≤ 85 kg, and 520 mg for patients with a body weight of > 85 kg.

10. The pharmaceutical composition according to claim 8 or 9, wherein the patient is a responder to the treatment with the antibody and is identified as having a statistically significant improvement in disease activity that persists throughout 1 year of treatment by week 24 of treatment.

11. The pharmaceutical composition according to any one of claims 8 to 10, wherein the antibody for use in IV administration is in a pharmaceutical composition containing a solution containing 10 mM L-histidine, 8.5% (w / v) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL disodium EDTA salt, dehydrate, at pH 6.

0.

12. The pharmaceutical composition according to any one of claims 8 to 10, wherein the antibody for use in SC administration is in a pharmaceutical composition containing a solution containing 6.7 mM L-histidine, 7.6% (w / v) sucrose, 0.004% (w / v) polysorbate 80, at pH 6.

0.

13. The pharmaceutical composition according to any one of claims 8 to 12, wherein the method further comprises administering to the patient one or more additional agents used to treat lupus.

14. The pharmaceutical composition according to claim 13, wherein the additional agent is selected from the group consisting of an immunosuppressant, a non-steroidal anti-inflammatory drug (NSAID), methotrexate (MTX), an anti-B cell surface marker antibody, an angiotensin-converting enzyme inhibitor, an angiotensin receptor blocker, an antimalarial drug, mycophenolate mofetil, mycophenolic acid, azathioprine, 6-mercaptopurine, belimumab, an anti-CD20 antibody, rituximab, a corticosteroid, and a costimulatory modulator.

15. A pharmaceutical composition for use in a method of treating a patient's active systemic lupus erythematosus (SLE), wherein the pharmaceutical composition comprises an anti-IL-12 / IL-23p40 antibody, and the method comprises administering the antibody to the patient in a clinically proven safe and clinically proven effective amount, wherein the antibody comprises a heavy chain of the amino acid sequence of SEQ ID NO: 10 and a light chain of the amino acid sequence of SEQ ID NO: 11, and the antibody is administered at an initial intravenous (IV) dose of the antibody at 6.0 (antibody) mg / (patient) kg ± 1.5 mg / kg, and thereafter at a subcutaneous (SC) dose of 90 mg of the antibody every 8 weeks, and the patient is (a) having a statistically significant improvement in disease activity determined by a decrease from baseline in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥ 4 by week 24 of treatment with the antibody (SRI-4 response), (b) having a statistically significant reduction defined as ≥ 1 new BILAG A domain score or ≥ 2 new BILAG B domain scores in the risk of a new British Isles Lupus Assessment Group (BILAG) flare by week 24 of treatment with the antibody, (c) having a 50% improvement from baseline in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score compared to patients treated with placebo, and (d) having a statistically significant improvement in disease activity as determined by a 50% improvement from baseline joint disease activity by week 24 of treatment with the antibody and being identified as at least one selected from the group consisting of the antibody for use in IV administration is in a pharmaceutical composition comprising a solution containing 10 mM L-histidine, 8.5% (w / v) sucrose, 0.04% (w / v) polysorbate 80, 0.4 mg / mL L-methionine, and 20 μg / mL disodium EDTA dihydrate at pH 6.0 the antibody for use in SC administration is in a pharmaceutical composition comprising a solution containing 6.7 mM L-histidine, 7.6% (w / v) sucrose, 0.004% (w / v) polysorbate 80 at pH 6.0

16. The patient is having a 50% improvement from baseline in the cutaneous erythematosus disease area and severity index (CLASI) score by week 24 of treatment with the antibody compared to patients treated with placebo, and having a statistically significant improvement in disease activity as determined by a 50% improvement from baseline joint disease activity by week 24 of treatment with the antibody and being identified as at least one selected from the group consisting of, and being a responder to the treatment with the antibody according to any one of claims 1, 8, and 15

Images