Method of treating psoriasis with Anti-il23 specific antibody

Abstract

To provide a method of treating psoriasis in a patient previously treated with and determined to be an inadequate responder to an IL-12 / 23p40 antibody.SOLUTION: The present invention provides a method comprising: measuring whether a patient treated with an IL-12 / 23p40 antibody is an inadequate responder; determining that a patient is an inadequate responder to IL-12 / 23p40 antibody treatment from the measuring step; and administering, to the patient determined to be an inadequate responder to IL-12 / 23p40 antibody treatment, an anti-IL-23 specific antibody in a safe and effective amount.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for treating psoriasis with an antibody that binds to human IL-23 protein. Specifically, the present invention relates to an anti-IL-23 specific antibody and a method for treating psoriasis in a patient. Certain pharmaceutical compositions of antibodies, such as guselkumab, that are safe and effective for IL- The present invention relates to a method of administering the compound to patients who are inadequate responders to 12 / 23p40 antibody therapy. [Background technology]

[0002] Interleukin (IL)-12 is a glycosyltransferase that binds two disulfide bonds. The oligomerized protein subunits (denoted p35 and p40 because of their approximate molecular weight) IL-12 is a secreted heterodimeric cytokine composed of the IL-12 complex (IL-13) and IL-14 (IL-15). It is mainly produced by antigen-presenting cells, and is activated by T cells or natural killer (N K) Stimulates cell-mediated immunity by binding to a two-chain receptor complex expressed on the surface of cells. The IL-12 receptor β-1 (IL-12Rβ1) chain promotes the expression of the p40 subunit of IL-12. However, IL-12 binds to the mitochondrial nucleus, providing the primary interaction between IL-12 and its receptor. These results suggest that the IL-1 receptor signaling pathway is essential for the activation of receptor-bearing cells. It confers IL-12p35 ligation of the second receptor chain, IL-12Rβ2. (Presky et al., 1996). IL-12 signaling in parallel with antigen presentation Th1 expression is a phenotype characterized by interferon-γ (IFNγ) production. It is thought to induce T cell differentiation toward the present type (Trinchieri, 2003) γTh1 cells promote immunity against some intracellular pathogens and complement antibody isotypes. IL-12 is thought to play a key role in host defense by generating IL-12 receptors and contributing to tumor immune surveillance. It is thought to be an important component of the immune system.

[0003] The p40 protein subunit of IL-12 also binds to a separate protein designated p19. It has been discovered that IL-23 can associate with protein subunits to form a novel cytokine, IL-23. (Oppman et al., 2000). IL-23 also acts via a two-chain receptor complex. Signal transduction. The p40 subunit is shared between IL-12 and IL-23 Therefore, the IL-12Rβ1 chain is also shared between IL-12 and IL-23. reported that IL-23-specific intracellular signaling (e.g., STAT3 phosphorylation) and subsequent The first step in the IL-23 receptor complex, IL-23R, confers IL-17 production by T cells. The IL-23p19 ligation of the two components (Parham et al., 2 002; Aggarwal et al. 2003). Recent studies have demonstrated that IL-23 is a The metabolic and biological functions of IL-12 are due to the structural similarities between these two cytokines. Nevertheless, they showed differences (Langrish et al, 2005).

[0004] Neutralization of IL-12 by antibodies has been shown to be effective in treating psoriasis, multiple sclerosis (MS), and Rheumatoid arthritis, inflammatory bowel disease, insulin-dependent (type 1) diabetes mellitus, and uveitis Abnormal regulation of IL-12 and Th1 cell populations for therapeutic benefit in animal models It has been associated with many immune-mediated diseases (Leonard et al., 1999). 5, Hong et al, 1999, Malfait et al, 1998, Dav However, these studies did not identify a shared p40 subunit. By targeting mitogens, both IL-12 and IL-23 were neutralized in vivo. Therefore, it is unclear whether IL-12 or IL-23 mediated the disease or suppressed it. It is unclear whether both cytokines need to be inhibited to achieve inhibition. Studies suggest that IL-23 inhibition may offer benefits comparable to anti-IL-12p40 strategies. The results were confirmed by IL-23p19-deficient mice or specific antibody neutralization of IL-23 (Cua e t al,2003, Murphy et al,2003, Benson et al 2004). Thus, the specific role of IL-23 in immune-mediated diseases is unclear. There is growing evidence that neutralizing IL-23 without inhibiting the IL-12 pathway may be Providing an effective therapy for immune-mediated diseases that have limited impact on important host defense immune mechanisms This would represent a significant improvement over current treatment options.

[0005] Psoriasis is associated with a number of health problems, including psoriatic arthritis (PsA), depression, cardiovascular disease, and hypertension. Common chronic conditions with significant comorbidities such as hypertension, obesity, diabetes, metabolic syndrome, and Crohn's disease It is an immune-mediated skin disease. Plaque psoriasis is the most common form of the disease and is characterized by silvery white spots. The lesions are pruritic, painful, and disfiguring. Psoriasis is often disabling and disabling, with a significant proportion of people with psoriasis experiencing damage to the hands / nails, face, feet, and genitals. Therefore, psoriasis significantly affects health-related quality of life (HRQoL). The physical and psychological effects of the condition go beyond the physical skin symptoms and can affect your daily activities to a great extent. For example, psoriasis can impose significant social burdens on family, spouses, social, and work relationships. It has adverse effects and is associated with high rates of depression and increased suicidal tendencies.

[0006] Histological characterization of psoriatic lesions reveals psoriasis caused by abnormal keratinocyte proliferation and differentiation. Skin thickening and dermal infiltration and colocalization of CD3+ T lymphocytes and dendritic cells were evident. The epidemiology of psoriasis is not well defined, but genetic and protein analyses have demonstrated that IL-1 IL-12, IL-23, and their downstream molecules are overexpressed in psoriatic lesions, and some Several therapies used to treat psoriasis have been shown to correlate with the severity of the disease. They regulate the levels of IL-12 and IL-23, which are suspected to contribute to their efficacy. Th1 and Th17 cells are involved in the production of vasodilators, chemoattractants, and adhesion to endothelial cells. They can produce effector cytokines that induce the expression of molecules that, in turn, activate monocytes. and neutrophil recruitment, T cell infiltration, angiogenesis, and keratinocyte activation and hyperplasia. Activated keratinocytes promote the trafficking of neutrophils, monocytes, T cells, and dendritic cells. They can produce chemoattractant factors that stimulate inflammation and hyperproliferation of keratinocytes. A reproductive cycle is established.

[0007] The etiology of psoriasis is based on tumor necrosis factor-α (TNF-α), interleukin (IL-1), and Targeting both IL-12 and IL-23, and more recently IL-17 and IL-23 alone , which has led to effective biological treatment (Phase 1 and 2 clinical trials using guselkumab The IL-12 / 23 antibody ustekinumab is used to treat moderate to severe plaque psoriasis. It has been approved in the United States, Europe, Japan, and many other countries around the world. Ustekinumab, administered by subcutaneous injection once every 12 weeks, is a validated treatment for psoriasis. The efficacy tool Psoriasis Area and Severity Index (PSI) was x) demonstrated rapid and durable clinical responses. A phase 3 trial comparing ustekinumab with the F antagonist etanercept showed that the efficacy of ustekinumab was higher in patients with moderate to severe bronchitis. than etanercept over a 12-week period in patients with mild to severe psoriasis In addition, the adverse events reported were relatively mild, and the incidence of these events was Most include susceptibility to minor infections such as nasopharyngitis and upper respiratory tract infections. 12 weeks in ustekinumab-treated patients compared with placebo-treated patients across treatment intervals The infection rate was not high and the higher vs. lower ustekinumab doses There was no increased risk of serious infections, cardiovascular events, injection site reactions, or malignancies. The tumor rate was low.

[0008] Guselkumab (also known as CNTO1959) inhibits the p19 subunit of IL-23. IL-23 binds to IL-13 and is required for terminal differentiation of T helper (Th) 17 cells It is a fully human IgG1 lambda monoclonal antibody that inhibits intracellular and downstream signaling. Summary of the Invention [Means for solving the problem]

[0009] The present invention relates to a method for treating IL-12 / 23p40-related disorders using antibodies against IL-12 / 23p40 (e.g., ustekinumab). In patients who were determined to be inadequate responders to IL-12 / 23p40 antibody treatment, The present invention relates to a method for treating psoriasis in a patient receiving treatment with an IL-12 / 23p40 antibody, the method comprising the steps of: The present invention is directed to determining whether a patient is a partial responder, and determining whether the patient is a partial responder or not by the measurement process. To determine whether patients are inadequate responders to IL-12 / 23p40 antibody therapy and whether they have IL-12 / 23p40 antibodies Patients who were determined to be inadequate responders to systemic therapy were treated with anti-IL-23 specific antibody (IL-23). -23p19 antibody), such as guselkumab, in a safe and effective amount to and subcutaneously administering to said patient a therapeutically effective amount of said compound.

[0010] Furthermore, the method of the present invention can be used to determine the degree of pulmonary circulation by measuring the IGA or PASI score in a patient. to determine whether patients treated with IL-12 / 23p40 antibodies are inadequate responders by an IGA score (or PGA score) of 2 or more, or by a baseline Patients were evaluated for PASI score improvement of <75% compared to baseline PASI score. or, Inadequate responders to IL-12 / 23p40 antibody therapy may have had psoriasis that was not eliminated or are patients who are almost not excluded, and excluded or almost excluded patients are The PGA / IGA score is 0 or 1. In another embodiment of the method of the present invention, The different antibodies will be administered at the first dose, 4 weeks after the first dose, and every 8 weeks after the week 4 dose. However, the patient was a responder to an antibody specific for IL-23 and had a 100% success rate after initial treatment. Or, measured after 28 weeks, PASI 75 or higher, PASI 90 or higher, PASI 100 or higher, or as having a PGA score of 0 or 1, or an improvement of at least 2 in the IGA In this method, an antibody specific for IL-23 (e.g., gseclumab) is administered to the skin. The compound is administered subcutaneously and is safe and effective for treating psoriasis in areas of the patient's scalp, nails, hands, and and the foot, and administering an antibody specific to IL-23 at a dose of 25 mg to 200 mg. , 50 mg or 100 mg doses.

[0011] In another embodiment, the composition used in the method of the present invention has a concentration of from about 1.0 μg / ml to about 1000 A pharmaceutical composition comprising an anti-IL-23 specific antibody in an amount of 50 mg / ml, in particular 50 mg or 100 mg. In a preferred embodiment, the anti-IL-23 specific antibody is present in an amount of 100 ml of the pharmaceutical composition. g / mL guselkumab, 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, 0.053% (w / v) polysorbate The pH was 80 and the diluent was water at standard conditions.

[0012] In another aspect of the invention, the pharmaceutical composition comprises: (i) a peptide comprising a sequence selected from the group consisting of SEQ ID NO:5, SEQ ID NO:20, and SEQ ID NO: (ii) the heavy chain CDR amino acid sequence of SEQ ID NO:50, SEQ ID NO:56, and SEQ ID NO: and the light chain CDR amino acid sequence of No. 73. The pharmaceutical composition comprises 100 mg / mL of an anti-IL23 specific antibody and 7.9% (w / v) of sucrose. cellulose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, It contains 0.053% (w / v) polysorbate 80 and the diluent is water at standard conditions.

[0013] Another aspect of the method of the present invention includes administering a pharmaceutical composition, the pharmaceutical composition comprising SEQ ID NO: The guselkumab heavy chain variable region amino acid sequence of SEQ ID NO: 106 and the guselkumab light chain variable region amino acid sequence of SEQ ID NO: 116 and an isolated pharmaceutical composition having an antibody having an antibody variable region amino acid sequence of IL-23 specific antibody, 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate and 0.053% (w / v) polysorbate The diluent is water at standard conditions. [Brief description of the drawings]

[0014] [Figure 1] Patient breakdown from the adverse event (AE) flow chart is shown. [Diagram 2] A-D show the proportion of randomized patients who achieved an IGA of 0 or 1 from Week 16 to Week 52, and an IGA ≥ 2 grade improvement compared to Week 16 (Figure 2A), PASI75 (Figure 2B), PASI90 (Figure 2C), and PASI100 (Figure 2D) response. IGA = Investigator's Global Assessment, PASI75 / 90 / 100, ≥ 75% / 90% / 100% improvement in measured psoriasis area and severity index. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] As used herein, the method of treating psoriasis includes administering isolated, recombinant and / or synthetic anti-I L-23 specific human antibodies and diagnostic and therapeutic compositions, methods, and devices for administration .

[0016] As used herein, "anti-IL-23 specific antibody," "anti-IL-23 antibody," "anti The term "antibody fragment" and / or "antibody variant" are incorporated into the antibody of the present invention. At least one complementarity determining region (CDR) or a complementarity determining region (CDR) of the heavy or light chain that can be embedded in the or a ligand-binding portion thereof, a heavy or light chain variable region, a heavy or light chain constant region, A framework region, or any portion thereof, or an IL-23 receptor or binding protein A small amount of an immunoglobulin molecule, such as, but not limited to, at least a portion of a protein. Such antibodies include any protein or peptide-containing molecule that contains at least a portion of the Optionally, further specific ligands may be affected, including but not limited to, Such antibodies can be characterized in vitro, in situ and / or in vivo by at least one Modulating, reducing, or inhibiting IL-23 activity or binding, or IL-23 receptor activity or binding. augment, antagonize, promote, reduce, mitigate, block, inhibit, neutralize, and / or interfere. As such, preferred anti-IL-23 antibodies, specified portions or variants of the invention comprise at least one IL-23 or a specified portion, variant or domain thereof. Suitable anti-IL-23 antibodies, specific portions, or variants may also be optionally administered in the form of RNA. A, DNA or protein synthesis, IL-23 release, IL-23 receptor signaling, thin These include membrane IL-23 cleavage, IL-23 activity, and IL-23 production and / or synthesis. It can also affect at least one IL-23 activity or function, including but not limited to. do.

[0017] The term "antibody" is further intended to include antibodies, fragments, specified portions and variants thereof. This includes antibody mimetics, or those that mimic the structure and / or function of an antibody. The antibody includes a portion of the antibody having the structure, or a specific fragment or part thereof, and includes single chain antibodies and fragments thereof. The functional fragments include antigen-binding fragments that bind to mammalian IL-23. For example, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial by chemical reduction), and F(ab')2 (e.g., by pepsin digestion), facb (e.g., pFc' (e.g., by pepsin or plasmin digestion) , Fd (e.g., by pepsin digestion, partial reduction, and reassembly), Fv or scFv ( For example, fragments of IL-2 Antibody fragments capable of binding to 3 or portions thereof are encompassed by the present invention (see, e.g., Collins et al., supra). igan, Immunology).

[0018] Such fragments may be used in any manner known in the art and / or as described herein. The antibody may be produced by enzymatic cleavage, synthetic or recombinant techniques, such as those described above. Using an antibody gene in which a stop codon for For example, the combination of genes encoding the F(ab')2 heavy chain portion can be , C for heavy chain H Designed to contain DNA sequences encoding one or more domains and / or hinge regions The various portions of the antibody can be conjugated chemically or genetically by conventional techniques. Using engineering techniques, they can be prepared as contiguous proteins.

[0019] As used herein, the term "human antibody" refers to an antibody in which substantially all portions of the protein (e.g., For example, CDR, framework, C L , C H Domain (e.g., C H 1. C H 2. C H 3 ), Hinge (V L , V H )) is substantially non-human in nature with only minor sequence changes or mutations. "Human antibody" also refers to an antibody that is derived from human germline immunoglobulin sequences. Human antibodies may be derived from or closely matched to germline immunoglobulins. Amino acid residues not encoded by the gene sequence (e.g., random or in vitro are introduced by site-directed mutagenesis or by in vivo somatic mutation. In many cases, this is because a human antibody may contain mutations that are substantially different from those found in humans. Human antibodies are made based on the similarity of their amino acid sequences. Therefore, sequence similarity searches can be used to identify similar linear sequences. An antibody having the nucleotide sequence 1101 can be selected as a template for generating a human antibody. (monkeys, baboons, chimpanzees, etc.), rodents (mice, rats, rabbits, guinea pigs, Antibodies designated for mammals such as hamsters, hamsters, etc., and other mammals, including those designated for such species, subgenera, genus, subfamily, and family, In addition, chimeric antibodies may include any combination of the above. Such changes or mutations optionally, and preferably, result in a more specific, human or other specific, antibody, as compared to an unmodified antibody. Thus, human antibodies, also known as chimeric or is different from a humanized antibody.

[0020] A human antibody is a functionally rearranged human immunoglobulin (e.g., a heavy and / or light chain ) produced by a non-human animal, or a prokaryotic or eukaryotic cell capable of expressing the gene Moreover, when a human antibody is a single-chain antibody, it is possible to obtain a single chain of a single-chain antibody that is not found in natural human antibodies. For example, Fv can be composed of a heavy chain variable region and a light chain variable region. A linker peptide, such as 2 to about 8 glycine or other amino acid residues, that connects the domains Such linker peptides are considered to be of human origin.

[0021] Also preferred are monoclonal antibodies having binding specificities for at least two different antigens. or human or humanized antibodies, bispecific, heterospecific, heterobinding, or similar antibodies. In this case, one of the binding specificities is linked to at least one IL-23 tag. One is directed against a protein and the other against any other antigen. Methods for producing bispecific antibodies are known in the art. The synthesis is based on the co-expression of two immunoglobulin heavy-light chain pairs, where the two heavy chains are different. (Milstein and Cuello, Nature, 305: 537 (1983)). Due to the random assortment of immunoglobulin heavy and light chains, These hybridomas (quadromas) produce a possible mixture of 10 different antibody molecules. Only one of these has the correct bispecific structure. The affinity chromatography step is quite laborious and the yield of the product is low. Similar procedures are described, for example, in WO 93 / 08829 and U.S. Pat. No. 10,668, No. 6,193,967, No. 6,132,992, No. 6,10 No. 6,833, No. 6,060,285, No. 6,037,453, No. 6,010 , No. 902, No. 5,989,530, No. 5,959,084, No. 5,959, No. 083, No. 5,932,448, No. 5,833,985, No. 5,821,3 No. 33, No. 5,807,706, No. 5,643,759, No. 5,601,81 No. 9, No. 5,582,996, No. 5,496,549, No. 4,676,980 No. 91 / 00360, No. 92 / 00373, European Patent No. 030 No. 89, Traunecker et al., EMBO J.10:3655(199 1), Suresh et al.,Methods in Enzymology 1 21:210 (1986), each of which is incorporated herein by reference in its entirety. is incorporated into the book.

[0022] Anti-IL-23 specific antibodies (IL-23 specific) that are useful in the methods and compositions of the invention Antibodies against IL-23 (also referred to as specific antibodies) have high affinity binding to IL-23. , and optionally and preferably, having low toxicity. Specifically, individual components such as variable regions, constant regions, and frameworks are individually and / or collectively, the antibodies of the invention, optionally and preferably having low immunogenicity. , and specified fragments or variants thereof are useful in the present invention. Antibodies capable of this can, optionally, provide measurable alleviation of symptoms and low and / or tolerable Characterized by the ability to treat patients for long periods of time with low or well tolerated toxicity. The immunogenicity and / or high affinity of the compound, as well as other favorable properties, may contribute to the therapeutic outcome obtained. "Low immunogenicity" as used herein refers to approximately 75% of patients treated. %, or preferably less than about 50% significantly HAHA, HACA, or HAMA Increased response and / or lower titers in treated patients (double antigen enzyme immunoassay is defined as an increase of less than about 300, preferably less than about 100, as measured by sieving (Elliott et al., Lancet 344:1125-1127 ( 1994), which is incorporated herein by reference in its entirety. During the entire course of recommended therapy, fewer than 25% of patients treated at the recommended dose should receive Anti-IL-23 antibody treatment in patients with IL-23 occurs in <10% of patients. It can also be defined as the incidence of titer levels of antibodies to the -23 antibody.

[0023] The terms "efficacious" and "effective" are used in the context of a dose, administration regimen, treatment, or method. As used herein, the term refers to the effectiveness of a particular dosage, administration, or treatment regimen. The efficacy can be measured based on changes in the course of the disease in response to an agent of the invention. For example, The anti-IL-23 specific antibodies of the present invention (e.g., the anti-IL-23 specific antibody guselkumab) are useful in treating and (b) improving, preferably sustained, at least one index reflecting the severity of the disorder being treated. The therapeutic amount and duration of the treatment are sufficient to cause a satisfactory improvement in the subject. To determine whether the time and date are sufficient, a Various indicators can be assessed. Such indicators include, for example, disease severity, symptoms, or response. These include clinically recognized measures of the manifestation of the disorder being treated. The diagnosis is made entirely by the physician, who bases this decision on signs, symptoms, biopsy, or other test results. The results can be based on questionnaires administered to subjects, e.g. questions about a given disease. For example, a quality of life questionnaire developed in accordance with the present invention may be used. The anti-IL-23 specific antibody of the present invention is administered to achieve improvement in the condition of patients associated with psoriasis. The improvement may be an improvement in disease activity indicators, amelioration of clinical symptoms, or any other measure of disease activity. Several such indicators of disease can be demonstrated by the investigator. Patient Global Assessment (IGA), Physician Global Assessment (PGA), or psoriasis area and severity The PASI score is the PASI score of the IGA, PGA, or PASI score. The disease activity index for psoriasis was validated. Additional measures included scalp-specific IGA (ss-IG) A), fingernail physician global assessment (f-PGA), and index of area and severity of nail psoriasis (N These are the APSI, and the hand / foot PGA (hf-PGA).

[0024] The term "safe" refers to a compound that is an anti-IL-23 specific antibody of the invention (e.g., an anti-IL-23 specific Regarding the dosage, administration regimen, treatment or method using the specific antibody guselkumab, The therapeutic importance of the drug compared to standard of care or other comparators based on the stage of the trial, e.g., phase 3 trials Acceptable frequency and / or severity of acute adverse events (called AEs or TEAEs) Adverse events refer to the adverse events that occur in patients administered a medicinal product. In particular, the anti-IL-23 specific antibody of the present invention is an undesirable medical event. Dose, dosing regimen or treatment-related safety is unclear. Adverse events may be related to the efficacy and safety of the anti-IL-23 specific antibody. Administration of antibodies if the risk is considered possible, likely, or very high due to use This refers to the acceptable frequency and / or acceptable severity of adverse events associated with

[0025] usefulness The isolated nucleic acids of the present invention comprise at least one anti-IL-23 antibody or a specific variant thereof. The invention can be used to produce a therapeutically effective amount of psoriasis inhibitors, which can be used to diagnose, monitor, regulate, treat, alleviate, or treat the symptoms of psoriasis. To prevent or help reduce the incidence of such diseases, cells, tissues, organs or animals (mammals) The present invention can be used to measure or act on various organs, organisms, and humans.

[0026] Such methods include those for modulating, treating, ameliorating, preventing, or reducing symptoms, effects, or mechanisms. The present invention relates to a method for treating a cell, tissue, organ, animal or patient in need thereof, comprising administering at least one anti-IL-23 antibody to said cell, tissue, organ, animal or patient in need thereof. The method may include administering an effective amount of a composition or pharmaceutical composition comprising the compound. When performed and determined using known methods, as described in the literature or as known in the relevant art. Approximately 0.001 to 500 ml per single (e.g., bolus), multiple, or continuous administration. g / kg or serum concentration of 0.01 to 500 per single, multiple, or continuous dose 0 μg / mL, or any effective range or value therein. good.

[0027] quotation All publications or patents cited herein, whether or not specifically named, are incorporated herein by reference in their entirety. , which is incorporated herein by reference in its entirety and represents the state of the art at the time of the present invention; and The publication may be any scientific publication or patent application Ser. No. 09 / 2009,313, filed on 23 December 2009, which is hereby incorporated by reference in its entirety, and / or which provides a description and enablement of the present invention. Available in any media format, including any published or recorded electronic or printed form. The following documents are incorporated herein by reference in their entirety: :Ausubel,et al.,ed.,Current Protocols in Molecular Biology,John Wiley&Sons,Inc., NY, NY (1987-2001), Sambrook, et al., Molecule ar Cloning:A Laboratory Manual,2nd Editi on, Cold Spring Harbor, NY (1989), Harlow an d Lane,antibodies,a Laboratory Manual,Co ld Spring Harbor, NY (1989), Colligan, et al. .,eds.,Current Protocols in Immunology,J ohn Wiley&Sons, Inc., NY (1994-2001), Collig an et al.,Current Protocols in Protein S science,John Wiley&Sons,NY,NY,(1997-2001) .

[0028] Antibodies of the Invention - Production and Preparation The at least one anti-IL-23 used in the methods of the invention is optionally a compound known in the art. Any cell line, mixed cell line, immortalized cell, or clonal population of immortalized cells known in the art. For example, Ausubel, et al., ed., Cur rent Protocols in Molecular Biology,John Wiley & Sons, Inc., NY, NY (1987-2001), Sambro ok,et al.,Molecular Cloning:A Laboratory Manual,2nd Edition,Cold Spring Harbor,N Y (1989), Harlow and Lane, antibodies, a Lab. oratory Manual,Cold Spring Harbor,NY(198 9), Colligan,et al.,eds.,Current Protocol s in Immunology,John Wiley&Sons,Inc.,NY( 1994-2001), Colligan et al.,Current Proto cols in Protein Science,John Wiley&Sons, NY, NY, (1997-2001), each of which is incorporated herein by reference in its entirety. is incorporated into the book.

[0029] A preferred anti-IL-23 antibody has the heavy chain variable region amino acid sequence of SEQ ID NO: 106 and the heavy chain variable region amino acid sequence of SEQ ID NO: and the light chain variable region amino acid sequence of SEQ ID NO:5, SEQ ID NO:20, and SEQ ID NO:116. The heavy chain CDR amino acid sequence of sequence number 44 and SEQ ID NO:50, SEQ ID NO:56, and SEQ ID NO:7 and guselkumab (also referred to as CNTO1959), having the light chain CDR amino acid sequence of Other anti-IL-23 antibodies have the sequences listed herein, the entire contents of which are incorporated by reference. No. 7,935,344, incorporated herein by reference.

[0030] Human antibodies specific for human IL-23 protein or fragments thereof are isolated IL-23 Suitable molecules such as proteins and / or portions thereof (including synthetic molecules such as synthetic peptides) Other specific or general mammalian antibodies may be raised against the immunogenic antigen. Preparation of immunogenic antigens and generation of monoclonal antibodies may be performed using any suitable technique. It is possible.

[0031] In one approach, a suitable immortal cell line (e.g., but not limited to, Sp2 / 0, S p2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, L243, P3X6 3Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5 , U937, MLA144, ACT IV, MOLT4, DA-1, JURKAT, WE HI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA144, N Myeloma cell lines such as AMALWA and NEURO 2A, or heteromyelomas, or fusions thereof The product, or any cell or fusion cell derived therefrom, or any other known in the art. any other suitable cell line from the ech.com), including, but not limited to, isolated or cloned Antibody-producing tissues such as spleen, peripheral blood, lymph, tonsils, or other immune or B cell-containing cells Viable cells, or endogenous or heterologous nucleic acids, whether recombinant or endogenous, viral, bacterial, Algae, prokaryotes, amphibians, insects, reptiles, fish, mammals, rodents, horses, sheep, goats, hogs Azalea, primates, eukaryotes, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single, Either as duplex or triplex, hybridized, etc., or any combination thereof. Either the heavy or light chain constant or variable, or framework or CDR sequences are generated. Hybridomas are produced by fusing the cells with any other cells expressing the same gene. For example, See Ausubel and Colligan, Immunology chapter 2. No. 6,393,945, which is incorporated herein by reference in its entirety.

[0032] Antibody producing cells can also be isolated from the peripheral blood of humans or other suitable animals immunized with an antigen of interest, or The cells may be preferably obtained from the spleen or lymph nodes. The cells also include heterologous or endogenous antibodies encoding the antibodies, specified fragments, or variants thereof of the invention. The fusion cells (hybridomas) or recombinant cells can be used to express the nucleic acid of The cells are isolated using selective culture conditions or other suitable known methods and grown by limiting dilution or cell culture. Antibodies having the desired specificity can be cloned by cell sorting or other known methods. The cells giving rise to the body can be selected by a suitable assay (e.g., ELISA). do.

[0033] Selecting recombinant antibodies from a peptide or protein library (e.g., bacteriophage Display live phage, ribosomes, oligonucleotides, RNA, cDNA, etc. Examples of antibodies include, but are not limited to, Cambridge antibody T echnologies,Cambridgeshire,UK,MorphoSys, Martinsreid / Planegg, DE, Biovation, Aberdee n,Scotland,UK,BioInvent,Lund,Sweden,Dyax Corp., Enzon, Affymax / Biosite, Xoma, Berkel ey,CA, Ixsys. For example, European Patent No. 368,684, International Application PCT / GB 91 / 01134, International Application No. PCT / GB92 / 01755, International Application No. PCT / GB 92 / 002240, International Application No. PCT / GB92 / 00883, International Application No. PCT / G B93 / 00605, U.S. Patent Application Publication No. 08 / 350260 (5 / 12 / 94), International Application No. PCT / GB94 / 01422, International Application No. PCT / GB94 / 02662, International Application No. PCT / GB97 / 01835, (CAT / MRC), International Publication No. 90 / 14 443, International Publication No. 90 / 14424, International Publication No. 90 / 14430, International Application P CT / US94 / 1234, WO 92 / 18619, WO 96 / 077 54, (Scripps), WO 96 / 13583, WO 97 / 083 No. 20 (MorphoSys), WO 95 / 16027 (BioInvent) , WO 88 / 06630, WO 90 / 3809 (Dyax), U.S. Pat. No. 4,704,692 (Enzon), International Application No. PCT / US91 / 02989, International Publication No. 89 / 06283, European Patent No. 371 998, European Patent No. 550 400 No., (Xoma), European Patent No. 229 046, International Application PCT / US91 / 0714 No. 9, or stochastically generated peptides or proteins - U.S. Pat. No. 572,332 No. 3, No. 5763192, No. 5814476, No. 5817483, No. 58 24514, 5976862, WO 86 / 05803, EP 59 0 No. 689 (Ixsys, Applied Molecular Evolution (AME), each of which is incorporated herein by reference in its entirety), or A repertoire of human antibodies as known in the art and / or as described herein. The method relies on immunization of transgenic animals capable of producing Mouse, Nguyen et al.,Microbiol.Immunol.41:9 01-907(1997), Sandhu et al.,Crit.Rev.Biot echnol.16:95-118(1996), Eren et al., Immun. ol.93:154-161(1998), each of which is incorporated by reference in its entirety, and related patents and applications (including, but not limited to, methods for producing antibodies of the required specificity). Other suitable methods for producing or isolating ribosomes can be used. Display (Hanese et al., Proc. Natl. Acad. Sci. US A,94:4937-4942(May 1997), Hanes et al.,Pr. oc.Natl.Acad.Sci.USA,95:14130-14135(Nov. 1998), single cell antibody generation techniques (e.g., Selected Lymphocyte Antibody Method ("SLAM") (U.S. Pat. No. 5,627,052, Wen et al., J. Immunol. 17 :887-892(1987), Babcook et al., Proc. Natl. Acad.Sci.USA 93:7843-7848(1996)), gel microd gel microdroplets, and flow cytometry (Powell et al. al.,Biotechnol.8:333-337(1990), One Cell Systems, Cambridge, MA, Gray et al., J.Imm.M. eth.182:155-163(1995), Kenny et al.,Bio / T echnol.13:787-790(1995), B cell selection (Steenbakk ers et al.,Molec.Biol.Reports 19:125-134 (1994), Jonak et al., Progress Biotech, Vol. .5, In Vitro Immunization in Hybridoma Te chnology,Borrebaeck,ed.,Elsevier Science Publishers BV,Amsterdam,Netherlands(1 988)), but are not limited to these.

[0034] Methods for engineering or humanizing non-human or human antibodies can also be used, Generally, a humanized or engineered antibody is an antibody that is produced by recombining a non-human, For example, but not limited to, mice, rats, rabbits, non-human primates, or other mammals. These non-human amino acid residues are often These are called "import" residues, and are typically "import" variable, constant residues of known human sequences. , or replaced with residues taken from other domains.

[0035] Known human Ig sequences are disclosed, for example, at www.ncbi.nlm.nih. gov / entrez / query.fcgi, www.ncbi.nih.gov / i gblast, www.atcc.org / phage / hdb.html, www.m rc-cpe.cam.ac.uk / ALIGNMENTS.php, www.kaba tdatabase.com / top.html, ftp.ncbi.nih.gov / repository / kabat, www.sciquest.com / , www.a bcam.com / , www.antibodyresource.com / online ecomp.html、www.public.iastate.edu / ~pedro / research_tools.html、www.whfreeman.com / i mmunology / CH05 / kuby05.htm、www.hhmi.org / g rants / lectures / 1996 / vlab / 、www.path.cam.a c.uk / ~mrc7 / mikeimages.html、mcb.harvard.e du / BioLinks / Immunology.html、www.immunolo gylink.com、pathbox.wustl.edu / ~hcenter / in dex.html、www.appliedbiosystems.com、www.n al.usda.gov / awic / pubs / antibody、www.m.ehi me-u.ac.jp / ~yasuhito / Elisa.html、www.biod esign.com、www.cancerresearchuk.org、www.b iotech.ufl.edu、www.isac-net.org、baserv.u ci.kun.nl / ~jraats / links1.html、www.recab. uni-hd.de / immuno.bme.nwu.edu、www.mrc-cpe .cam.ac.uk、www.ibt.unam.mx / vir / V_mice.ht ml、http: / / www.bioinf.org.uk / abs、antibody .bath.ac.uk、www.unizh.ch、www.cryst.bbk.a c.uk / ~ubcg07s、www.nimr.mrc.ac.uk / CC / ccae wg / ccaewg.html、www.path.cam.ac.uk / ~mrc7 / humanisation / TAHHP.html, www.ibt.unam.mx / vir / structure / stat_aim.html, www.biosci.m issouri.edu / smithgp / index.html, www.jerin i.de, Kabat et al., Sequences of Proteins of Immunological Interest,USDept.Healt h (1983), each of which is incorporated herein by reference in its entirety.

[0036] Such imported sequences may be used to reduce immunogenicity or to improve the efficacy and safety of recombinant proteins. As known in the art, the terms binding, affinity, on-rate, off-rate, avidity, specificity, affinity, etc. may be used. The compounds may be used to reduce, enhance or modify the shelf life, or any other suitable property. Generally, the CDR residues are directly and most substantially involved in influencing antigen binding. Therefore, the non-human sequences in the variable and constant regions are replaced with human or other amino acids. While some or all of the non-human or human CDR sequences can be maintained.

[0037] The antibodies are optionally humanized or human, and have high affinity for the antigen and To this end, they can be engineered while retaining their biological and other beneficial properties. Optionally, humanized (or human) antibodies are generated using three-dimensional models of the parental and humanized sequences. These can be prepared by a process of analysis of the parent sequences and various conceptual humanized products. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. The probable three-dimensional conformations of selected candidate immunoglobulin sequences are illustrated. Computer programs are available to display and interpret these displays. and an analysis of the likely roles of residues in the function of the candidate immunoglobulin sequences. i.e., analysis of residues that affect the ability of a candidate immunoglobulin to bind its antigen. In this way, desirable antibody properties, such as increased affinity for the target antigen(s), can be achieved. To achieve this, the framework (FR) is extracted from the consensus and import sequences. ) residues can be selected and combined.

[0038] In addition, the human IL-23 specific antibodies used in the methods of the present invention contain human germline light chain fragments. In certain embodiments, the light chain germline sequence may include the following: A1, A10, A 11, A14, A17, A18, A19, A2, A20, A23, A26, A27, A3 , A30, A5, A7, B2, B3, L1, L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23, L24, L25, L4 / 18 a, L5, L6, L8, L9, O1, O11, O12, O14, O18, O2, O4, and The VK sequences are selected from human VK sequences, including, but not limited to, O8 and O9. In this embodiment, the light chain human germline frameworks are V1-11, V1-13, V1-16, V 1-17, V1-18, V1-19, V1-2, V1-20, V1-22, V1-3, V 1-4, V1-5, V1-7, V1-9, V2-1, V2-11, V2-13, V2-1 4, V2-15, V2-17, V2-19, V2-6, V2-7, V2-8, V3-2, V3-3, V3-4, V4-1, V4-2, V4-3, V4-4, V4-6, V5-1, Selected from V5-2, V5-4, and V5-6.

[0039] In another embodiment, the human IL-23 specific antibody used in the methods of the invention is a human genotype. In certain embodiments, the heavy chain human germline framework may comprise a human germline heavy chain framework. Frameworks are VH1-18, VH1-2, VH1-24, VH1-3, VH1-45 , VH1-46, VH1-58, VH1-69, VH1-8, VH2-26, VH2-5 , VH2-70, VH3-11, VH3-13, VH3-15, VH3-16, VH3- 20, VH3-21, VH3-23, VH3-30, VH3-33, VH3-35, VH 3-38, VH3-43, VH3-48, VH3-49, VH3-53, VH3-64, VH3-66, VH3-7, VH3-72, VH3-73, VH3-74, VH3-9, VH4-28, VH4-31, VH4-34, VH4-39, VH4-4, VH4-59 , VH4-61, VH5-51, VH6-1, and VH7-81.

[0040] In certain embodiments, the light chain variable region and / or the heavy chain variable region comprises a framework region: or at least a portion of a framework region (e.g., two or three, such as FR2 and FR3) In certain embodiments, the FRL1, FRL2, FRL3, and / or FRL4 subregions are included. In other embodiments, at least FRH1, FRH2, or FRL4 are fully human. In some embodiments, at least FRL, FRH3, or FRH4 is fully human. 1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., human germline). or a human consensus sequence for a particular framework (as described above for known human Ig In another embodiment, the sequence includes at least FRH1. , FRH2, FRH3, or FRH4 are germline sequences (e.g., human germline). or a human consensus sequence for a particular framework. In the above, the framework regions are fully human framework regions.

[0041] The humanization or engineering of the antibodies of the present invention can be carried out according to the methods described in Winter (Jones et al., Nature 321:522(1986), Riechmann et al.,Na ture 332:323 (1988), Verhoeyen et al. nce 239:1534(1988)), Sims et al., J. Immuno l.151:2296(1993), Chothia and Lesk, J. Mol. Biol.196:901(1987), Carter et al., Proc.Na tl.Acad.Sci.USA89:4285(1992), Presta e t al., J. Immunol. 151:2623 (1993), U.S. Patent No. 5723 No. 323, No. 5976862, No. 5824514, No. 5817483, No. No. 5814476, No. 5763192, No. 5723323, No. 5,76688 No. 6, No. 5714352, No. 6204023, No. 6180370, No. 56 No. 93762, No. 5530101, No. 5585089, No. 5225539, No. 4,816,567, International Application PCT / :US98 / 16280, US96 / 189 No. 78, US91 / 09630, US91 / 05939, US94 / 01234, No. GB89 / 01334, GB91 / 01134, GB92 / 01755, International Publication No. 90 / 14443, WO 90 / 14424, WO 90 / 14430 and European Patent No. 229246 (each of which is incorporated herein by reference in its entirety). Any known method, including but not limited to those described in the literature (including those described in the literature used in the literature) may be used. This can be done using the method of

[0042] In certain embodiments, the antibody comprises an altered (eg, mutated) Fc region. For example, in some embodiments, the Fc region reduces or enhances the effector functions of an antibody. In some embodiments, the Fc region is modified to enhance IgM, I The isotype is selected from the group consisting of IgG, IgG, IgE, or other isotypes. Alternatively or additionally, amino acid modifications and C1q binding and / or C2q binding properties of the Fc region of the IL-23 binding molecule. or in combination with one or more additional amino acid modifications that alter complement dependent cytotoxicity function. It may be useful to use a starting polypeptide of particular interest that binds C1q. and exhibits complement-dependent cytotoxicity (CDC). A polypeptide having the ability to mediate CDC further comprises one or more of these activities. It may be modified to enhance both. Amino acid modifications that modify the cytotoxic function are described, for example, in WO 0042072. and is incorporated by reference.

[0043] As disclosed above, for example, C1q binding and / or FcγR binding may be modified, Complement-dependent cytotoxicity (CDC) activity and / or antibody-dependent cell-mediated cytotoxicity ( By altering antibody-dependent cell-mediated cytotoxicity (ADCC) activity, Thus, the Fc of the human IL-23 specific antibody of the present invention having altered effector functions A γ "effector function" can be designed to enhance bioactivity (e.g., in a subject). Examples of effector functions include, but are not limited to, These 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) Such effector functions are achieved by the Fc region acting as a binding domain (e.g., an antibody variable domain). A variety of assays (e.g., Fc binding assays) may be required. The antibody can be evaluated using an antibody-specific antibody binding assay (e.g., ADCC assay, CDC assay, etc.).

[0044] For example, having improved C1q binding and improved FcγRIII binding (e.g., Human IL-23 (also known as IL-23A) with both improved ADCC activity and improved CDC activity It is possible to generate mutant Fc regions of anti-IL-23 antibodies. When it is desired to reduce or eliminate target function, the mutated Fc region may have reduced CDC activity. The gene can be engineered with reduced activity and / or reduced ADCC activity. In the method, only one of these activities may be increased, optionally with the other activity being increased at the same time. may be reduced (e.g., have improved ADCC activity and reduced CDC activity (to generate Fc region variants, and vice versa).

[0045] Fc mutations alter interactions with the neonatal Fc receptor (FcRn) and their pharmacokinetics Genes can also be engineered and introduced to improve properties. A collection of improved human Fc variants has been described (Shields et al., 2003). 001).High resolution mapping of the bind ing site on human IgG1 for FcγRI,FcγRII, FcγRIII,and FcRn and design of IgG1 vari ants with improved binding to the FCγR,J .Biol.Chem.276:6591-6604).

[0046] Another type of amino acid substitution is to modify the glycosylation paclitaxel of the Fc region of a human IL-23 specific antibody. Glycosylation of the Fc region is typically N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation can also use 5-hydroxyproline or 5-hydroxylysine. Although it is possible that , N-acetylgalactosamine, galactose, or xylose. The recognition sequence for enzymatic attachment of the carbohydrate moiety to the asparagine side chain peptide sequence is Asparagine-X-serine and Asparagine-X-threonine, where X is other than proline Therefore, any of these peptide sequences in a polypeptide The presence of provides a potential glycosylation site.

[0047] A glycosylation pattern can refer to, for example, one or more glycosylations found on a polypeptide. Deleting a site(s) and / or removing one or more glycosylation sites that are not present in the polypeptide. The Fc region of the human IL-23 specific antibody can be modified by adding cosylation sites. The addition of glycosylation sites to the amino acid sequence can be modified to include one or more of the above tripeptide sequences. This is successfully achieved by modifying the amino acid sequence (in the case of N-linked glycosylation sites). An exemplary glycosylation variant has an amino acid substitution at residue Asn297 of the heavy chain. The modification may be, for example, the addition of one or more serine or threonine residues to the sequence of the native polypeptide; or by substitution (for O-linked glycosylation sites). Changing 297 to Ala can eliminate one of the glycosylation sites.

[0048] In certain embodiments, the human IL-23 specific antibodies of the invention bind to GnT III. To add 1cNAc to the human IL-23 antibody, beta(1,4)-N-acetylglucosamine was synthesized. Expressed in cells expressing glucosaminyltransferase III (GnT III) Methods for producing antibodies in such a manner are described in WO 9954342, WO 9954343, WO 995434 ... Publication No. 03011878, Patent Publication No. 20030003097A1, and Umana e t al.,Nature Biotechnology,17:176-180,Fe b.1999, all of which are expressly incorporated herein by reference in their entireties. are incorporated into the system.

[0049] Anti-IL-23 antibodies also optionally include those described herein and / or in the art. As is known in the art, transgenic mice capable of producing a repertoire of human antibodies have been developed. Produced by immunization of a control animal (e.g., mouse, rat, hamster, non-human primate, etc.) Cells producing human anti-IL-23 antibodies may be produced as described herein. They may be isolated from such animals and immortalized using any suitable method.

[0050] Transgenic mice capable of generating a repertoire of human antibodies that bind to human antigens The cuminoids can be produced by known methods, including, but not limited to, However, U.S. Patents 5,770,428 and 5,569, issued to Lonberg et al. No. 825, No. 5,545,806, No. 5,625,126, No. 5,625,8 25, 5,633,425, 5,661,016, and 5,789, No. 650, WO 98 / 50433 by Jakobovits et al. ts et al., International Publication No. 98 / 24893; Lonberg et al., International Publication No. 98 / 2488 No. 4, International Publication No. 97 / 13852 by Lonberg et al. No. 94 / 25585, Kucherlapate et al., International Publication No. 96 / 34096, European Patent No. 0463 151(B1) to Kucherlapate et al. European Patent No. 0710 719(A1) to Apate et al., U.S. Pat. No. 5,313,233 to Surani et al. ,545,807, Bruggemann et al., International Publication No. 90 / 04036, Bru European Patent No. 0438 474(B1) to Ggemann et al., European Patent No. 0438 474(B1) to Lonberg et al. No. 0814 259(A2), Lonberg et al., UK Patent No. 2 272 44 No. 0(A), Lonberg et al. Nature 368:856-859(1 994), Taylor et al., Int. Immunol. 6(4)579-5 91 (1994), Green et al, Nature Genetics 7:1 3-21 (1994), Mendez et al., Nature Genetics 15:146-156 (1997), Taylor et al., Nucleic Acids Research 20(23):6287-6295(1992), Tu aillon et al., Proc Natl Acad Sci USA 90( 8) 3720-3724 (1993), Lonberg et al., Int Rev. Immunol 13(1):65-93(1995), and Fishwald et al. al., Nat Biotechnol 14(7):845-851(1996), (Each of which is incorporated herein by reference in its entirety.) In general, these mouse The sequence comprises at least one functionally rearranged or functionally rearrangeable gene. at least one transgene comprising DNA from a human immunoglobulin locus The endogenous immunoglobulin loci of such mice can be disrupted or deleted to produce endogenous genes. This can eliminate the ability of the animal to produce the antibody encoded by the offspring.

[0051] Screening of antibodies for specific binding to similar proteins or fragments can be performed using peptide This can be successfully achieved using a display library. Screening large collections of peptides for individual components with novel functions or structures Antibody screening of peptide display libraries is well known in the art. The length of the displayed peptide sequence is 3 to 5,000 or more. Amino acids, frequently 5-100 amino acids long, usually about 8-25 amino acids long In addition to direct chemical synthesis methods for generating peptide libraries, several combination methods are available. Recombinant DNA methods have also been described. One type involves the transfer of bacteriophages or cells, Each bacteriophage or cell is involved in the display of peptide sequences on its surface. , which contain a nucleotide sequence that encodes a particular displayed peptide sequence. Such methods are described in WO 91 / 17271, WO 91 / 18980, WO 91 / 1997, WO 91 / 2003, WO 91 / 2006, WO 91 / 2009, WO 91 / 2008, WO 91 / 2009 ... / 19818 and / 93 / 08278.

[0052] Other systems for generating libraries of peptides include in vitro chemical synthesis and recombinant peptide synthesis. The present invention has both aspects of a method for producing a pharmaceutical composition and a method for producing the same. See U.S. Pat. Nos. 5,658,754 and 96 / 19256. and 5,643,768. The target and screening kit were purchased from Invitrogen (Carlsbad, CA). and Cambridge Antibody Technologies (Cambridge These are commercially available from sources such as Enzon (Edgeshire, UK). Passed U.S. Patent Nos. 4,704,692, 4,939,666, and 4,946,778; Same No. 5260203, Same No. 5455030, Same No. 5518889, Same No. 55346 No. 21, No. 5656730, No. 5763733, No. 5767260, No. 5 No. 856456, No. 5223409 and No. 5403484 assigned to Dyax, Nos. 5,571,698, 5,837,500, and No. 542 assigned to Affymax No. 7908, No. 5580717, Cambridge antibody Tech No. 5,885,793 assigned to Nologies, and assigned to Genentech No. 5750373, No. 5618920 and No. 559589 assigned to Xoma No. 8, No. 5576195, No. 5698435, No. 5693493, No. 56 No. 98417, Colligan, supra, Ausubel, supra, or Samb, supra. see, e.g., U.S. Pat. No. 6,399,343, each of which is incorporated herein by reference in its entirety. Be absorbed.

[0053] The antibodies used in the methods of the present invention may also be derived from goats, cows, horses, and other animals that produce such antibodies in their milk. The nucleic acid can be used to provide a transgenic animal or mammal, such as a mouse, sheep, rabbit, etc. It may also be prepared using at least one anti-IL-23 antibody encoding the same. The animal can be provided using known methods, including, but not limited to, However, U.S. Patent Nos. 5,827,690, 5,849,992, and 4,873,3 No. 16, No. 5,849,992, No. 5,994,616, No. 5,565,36 2, 5,304,489, etc. (each of which is incorporated by reference in its entirety). is incorporated herein).

[0054] The antibodies used in the method of the present invention may be used in plant parts or cells cultured therefrom. Transgenic plants and cultured plants that produce such antibodies, specified portions, or variants. providing plant cells (e.g., but not limited to, tobacco and corn) The method further comprises using at least one anti-IL-23 antibody-encoding nucleic acid to prepare a As a non-limiting example, recombinant proteins can be expressed, for example, using an inducible promoter. Transgenic tobacco leaves expressing the protein have been successfully used to produce large amounts of recombinant protein. For example, Cramer et al., Curr. Top. Micro BoImmunol.240:95-118(1999) and references therein Transgenic maize has also been shown to be viable in other recombinant systems. A commercially available protein with biological activity equivalent to that of a protein synthesized or purified from a natural source. It has been used to express mammalian proteins at production levels. For example, Hood et al. t al.,Adv.Exp.Med.Biol.464:127-147(1999) and the references cited therein. Antibodies have also been used to infect tobacco seeds and potato tubers. and from transgenic plant seeds containing antibody fragments such as single chain antibodies (scFv). It has been produced in large quantities. For example, Conrad et al., Plant Mol. iol.38:101-109 (1998) and the references cited therein. Thus, the antibodies of the present invention can also be produced using transgenic plants according to known methods. For example, Fischer et al., Biotech nol.Appl.Biochem.30:99-108(Oct.,1999),Ma et al.,Trends Biotechnol.13:522-7(1995) , Ma et al., Plant Physiol.109:341-6(1995) , Whitelam et al.,Biochem.Soc.Trans.22:94 0-944(1994), and the references cited therein. is incorporated herein by reference in its entirety.

[0055] The antibodies used in the methods of the present invention have a wide range of affinities (K D ) to human IL-23 In a preferred embodiment, the human mAb is optionally capable of binding to a high affinity For example, a human mAb can bind to human IL-23. about 10 -7 M or less, for example, 0.1 to 9.9 (or any range or value therein) x 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 Or Any range or value in the range, including but not limited to, K D It can be combined with Cut.

[0056] The affinity or avidity of an antibody for an antigen can be determined experimentally using any suitable method. (For example, Berzofsky, et al., "Antibody- Antigen Interactions,” In Fundamental Imm unology, Paul, WE, Ed., Raven Press: New Yo rk, NY (1984), Kuby, Janis Immunology, WHFr Eeman and Company: New York, NY (1992), and Honmei (See methods described in the literature.) The measured affinity of a particular antibody-antigen interaction is , may differ when measured under different conditions (e.g., salt concentration, pH). Affinity and other antigen binding parameters (e.g., K D , K a , K d The measurement of , standardized solutions of antibodies and antigens, and standardized buffers, such as those described herein. This is carried out using

[0057] nucleic acid molecule Among other sequences disclosed herein, for example, the light chain or At least 70 to 10 contiguous amino acids of at least one of the heavy chain variable or CDR regions 0% of the nucleotide sequence encoding the The present invention also relates to a method for the preparation of a nucleic acid sequence comprising the steps of: The present invention provides a method for the production of a compound according to the present invention, which encodes at least one anti-IL-23 antibody, using the information provided in the present application. The disclosed nucleic acid molecules can be synthesized using methods described herein or known in the art. can be obtained.

[0058] The nucleic acid molecules of the present invention may be in the form of mRNA, hnRNA, tRNA or any other suitable form. in the form of RNA, or cDNA obtained by cloning or produced synthetically and genomic DNA, or any of these forms of DNA. The DNA may be triple-stranded, double-stranded, or single-stranded, or any combination thereof. Any portion of at least one strand of DNA or RNA may be It may be the coding strand, also known as the sense strand, or it may be called the antisense strand. It may be a non-coding strand.

[0059] The isolated nucleic acid molecule used in the methods of the invention optionally contains one or more introns. An open reading frame (ORF), for example, At least one heavy or light chain CDR1, CDR2, and / or CDR3 is not included. A nucleic acid molecule comprising at least one specified portion of at least one CDR, such as R3. , a nucleic acid molecule comprising a coding sequence of an anti-IL-23 antibody or a variable region, and Although substantially different, due to the degeneracy of the genetic code, the sequences described herein and / or in the art may be used interchangeably. The nucleic acid sequence encoding at least one anti-IL-23 antibody known in the art is also It will be appreciated that the genetic code may include nucleic acid molecules that contain nucleotide sequences. Therefore, those skilled in the art will be able to easily identify specific anti-I antibodies for use in the methods of the present invention. It is routine to generate such modified nucleic acid variants encoding the L-23 antibody. See, e.g., Ausubel et al., supra, and such nucleic acid variants are within the scope of the present invention. Non-limiting examples of isolated nucleic acid molecules include HC CDR1, HC CDR2, HC CDR3, HC CDR4, HC CDR5, HC CDR6, HC CDR7, HC CDR8, HC CDR9, HC CDR10, HC CDR11, HC CDR12, HC CDR13, HC CDR14, HC CDR15, HC CDR16, HC CDR17, HC CDR18 HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR Nucleic acids encoding 3 are also included.

[0060] As described herein, a nucleic acid molecule comprising a nucleic acid encoding an anti-IL-23 antibody; The antibody fragment may itself encode the amino acid sequence of an antibody fragment, or may encode the amino acid sequence of a whole antibody or a part thereof. The coding sequence for the portion, the coding sequence for the antibody, fragment or portion, as well as additional sequences, e.g. A non-coding sequence, with or without the additional coding sequences described above, such as at least one intron. 5' and 3' sequences, such as splicing and polyadenylation signals (e.g., Plays a role in transcription, mRNA processing, including ribosome binding and stability of mRNA together with additional non-coding sequences, including but not limited to transcribed, non-translated sequences that serve as , at least one signal leader or fusion peptide coding sequence, additional amino acids Additional coding sequences may be used to encode additional amino acids, e.g., amino acids that provide additional functionality. Thus, the antibody encoding sequence can be, but is not limited to, an antibody. A sequence encoding a peptide that facilitates purification of the fused antibody, including a fragment or portion thereof. It can be fused to a marker sequence.

[0061] Polynucleotides that selectively hybridize to the polynucleotides described herein The method of the present invention provides a method for selectively hybridizing to the polynucleotides disclosed herein. The present invention therefore uses isolated nucleic acids that hybridize under hybridization conditions. Polynucleotides of the embodiments are useful for isolating, detecting, and analyzing nucleic acids that contain such polynucleotides. For example, the polynucleotides of the present invention can be used to detect and / or quantify to identify, isolate, or In some embodiments, the polynucleotide is isolated and amplified. or otherwise complementary to cDNA from a human or mammalian nucleic acid library. , a genomic sequence or a cDNA sequence.

[0062] Preferably, the cDNA library contains at least 80% of the full-length sequences, preferably the full-length It is preferred that the nucleic acid sequence contains at least 85% or 90% of the sequence, more preferably at least 95% of the full-length sequence. cDNA libraries may be normalized to increase the representation of rare sequences. Stringency is used with sequences that have reduced sequence identity to a target sequence. Low or moderate hybridization conditions are typical, but not exclusive. The moderate and high integrity conditions are optionally used for sequences with higher identity. Low stringency conditions can be used for clones with approximately 70% sequence identity. It allows selective hybridization of sequences and identifies orthologous or paralogous sequences. can be used to determine

[0063] Optionally, the polynucleotide encodes at least a portion of an antibody. The nucleotides are capable of selectively hybridizing to a polynucleotide encoding an antibody of the present invention. The present invention also includes nucleic acid sequences that can be used for the synthesis of nucleic acids. See Colligan, supra, each of which is incorporated herein by reference in its entirety. can be.

[0064] Nucleic acid construction Isolated nucleic acids can be prepared by any of a number of methods, including (a) recombinant methods, (b) synthetic methods, as are well known in the art. (c) synthesis techniques, (b) purification techniques, and / or combinations thereof. do.

[0065] The nucleic acid may conveniently comprise a sequence in addition to the polynucleotides of the present invention. For example, a multiple cloning site containing one or more endonuclease restriction sites may be inserted into the nucleic acid. It is also possible to insert a translatable sequence into the vector to aid in the isolation of the polynucleotide. can be used to aid in the isolation of translated polynucleotides of the present invention. The hexahistidine marker sequence provides a convenient means for purifying the proteins of the invention. The nucleic acids of the invention (excluding the coding sequences) are optionally referred to as polynucleotides of the invention. The present invention is directed to a vector, adapter, or linker for the cloning and / or expression of the gene.

[0066] Additional sequences may be added to such cloning and / or expression sequences to facilitate cloning and / or expression. or their function in expression can be optimized to aid in the isolation of polynucleotides. It may be possible to improve the introduction of polynucleotides into cells. The use of vectors, adapters, and linkers is well known in the art. (See, for example, Ausubel, supra, or Sambrook, supra.)

[0067] Recombinant methods for constructing nucleic acids Isolated nucleic acids, such as RNA, cDNA, genomic DNA, or any combination thereof. The acid composition may be derived from a biological source using any number of cloning methods known to those of skill in the art. In some embodiments, the polynucleotides of the invention can be subjected to stringent conditions. The oligonucleotide probe selectively hybridizes to cDNA or genomic DNA. A library is used to identify the desired sequence. RNA isolation and cD The construction of NA and genomic libraries is well known to those skilled in the art. bel, or Sambrook, supra.)

[0068] Nucleic Acid Screening and Isolation Methods The sequences of polynucleotides used in the methods of the invention, such as those disclosed herein, Screening a cDNA or genomic library using sequence-based probes Probes can be used to isolate homologous genes in the same or different organisms. , can hybridize to genomic DNA or cDNA sequences. Various degrees of hybridization stringency can be used in the assay. It is clear that either the hybridization or the washing medium may be harsh. As the conditions for hybridization become more stringent, duplex formation occurs. For this to occur, there must be a high degree of complementarity between the probe and the target. The degree of sensitivity is affected by temperature, ionic strength, pH, and the use of partially denaturing solvents such as formamide. The presence or absence of a nucleotide sequence can be controlled by one or more of the following: The stringency of the reaction can be determined, for example, by manipulating the formamide concentration in the range of 0% to 50%. This can be successfully altered by changing the polarity of the reaction solution. The degree of complementarity (sequence identity) required can be determined by the hybridization medium and / or the washing medium. The degree of complementarity is optimally 100%, or 70%. ~100%, or any range or value therein. However, Small sequence variations within the primers may result in variability in the hybridization and / or wash media. It should be understood that this can be compensated for by reducing efficiency.

[0069] Methods for amplifying RNA or DNA are well known in the art and are described herein. Based on the teachings and guidance provided, one can make use of the present invention without undue experimentation.

[0070] Known methods for amplifying DNA or RNA include the polymerase chain reaction (PCR). PCR) and related amplification processes (see, e.g., U.S. Pat. No. 5,333,393, Mullis et al., No. 4,683,195, No. 4,683,202, No. 4,800,159, No. No. 4,965,188 to Tabor et al., No. 4,795,699 to Tabor et al., and No. 4,921, No. 794 to Innis, No. 5,142,033 to Wilson et al., No. 464 to Innis, No. 5,091,310 to Gyllensten et al. No. 066,584 to Gelfand et al., No. 4,889,818 to Silver et al. No. 4,994,370 to Biswas, No. 4,766,067 to Ringold See US Pat. No. 4,656,134), and templates for double-stranded DNA synthesis. RNA-mediated amplification using antisense RNA against a target sequence as a template (Malek et al. No. 5,130,238, which is also known by the trade name NASBA. (the entire contents of which are incorporated herein by reference). See, for example, Ausubel, supra, or Sambrook, supra.)

[0071] For example, genomic DNA or cDNA may be amplified using polymerase chain reaction (PCR) techniques. Polynucleotides and related genes used in the methods of the invention can be isolated directly from the library. Sequences can be amplified. PCR and other in vitro amplification methods can also be used, e.g., Cloning a nucleic acid sequence encoding a protein to be expressed, Probes for detecting the presence of mRNA, for nucleic acid sequencing, or for other purposes It may be useful to generate nucleic acids for use as probes by in vitro amplification methods. Examples of techniques sufficient to guide one of skill in the art are found in Berger, supra, Sambrook and and Ausubel et al., supra, and Mullis et al., U.S. Pat. No. 4,683,202 (198 7), and Innis, et al., PCR Protocols A Guide to Methods and Applications,Eds.,Academi c Press Inc, San Diego, CA (1990). Genome P Commercially available kits for CR amplification are known in the art. See e-GC Genomic PCR Kit (Clontech). For example, the T4 gene 32 protein (Boehringer Mannheim) It can be used to improve the yield of long PCR products.

[0072] Synthetic methods for constructing nucleic acids The isolated nucleic acids used in the methods of the present invention can also be prepared by direct chemical synthesis using known methods. They can also be prepared by chemical synthesis (see, for example, Ausubel et al., supra). Generally, by hybridization with a complementary sequence or by cleaving a single strand of a template A single strand that can be converted into double-stranded DNA by polymerization with a DNA polymerase used as a Those skilled in the art will appreciate that chemical synthesis of DNA has over 100 salts. Although the sequence of the base may be limited, longer sequences can be obtained by ligation of shorter sequences. You will realize that you can.

[0073] Recombinant Expression Cassettes The present invention uses recombinant expression cassettes that contain nucleic acids. At least one site has been identified using cDNA or genomic sequences encoding the antibody to be used. A recombinant expression cassette can be constructed that can be introduced into a desired host cell. An expression cassette typically directs transcription of a polynucleotide in an intended host cell. The term "heterologous" refers to a polynucleotide that is operably linked to a transcription initiation regulatory sequence that directs the transcription of the target gene. Both heterologous (i.e., endogenous) promoters can be used to direct expression of the nucleic acid. do.

[0074] In some embodiments, isolated polypeptides that function as promoters, enhancers, or other elements are provided. The nucleic acid thus obtained can be used in combination with a polynucleotide of the invention to up- or down-regulate expression of the polynucleotide. A non-heterologous version of the nucleotide can be introduced into the appropriate location (upstream, downstream, or within an intron). For example, endogenous modifications can be made by mutation, deletion and / or substitution in vivo or in vitro. The promoter can be altered.

[0075] Vectors and host cells The present invention relates to vectors comprising isolated nucleic acid molecules, recombinant vectors comprising isolated nucleic acid molecules, and expressing at least one antibody by recombinant techniques well known in the art. The production of IL-23 antibodies is also contemplated. See, e.g., Sambrook et al., supra; Ausu et al., supra. See bel et al., each of which is incorporated by reference in its entirety.

[0076] The polynucleotide may optionally be expressed as a vector containing a selectable marker for propagation in a host. Generally, plasmid vectors are prepared by calcium phosphate precipitation. The vector is introduced into a precipitate such as a vesicle or into a complex with a charged lipid. If so, package it in vitro using an appropriate packaging cell line; It can then be transduced into a host cell.

[0077] The DNA insert should be operably linked to a suitable promoter. Lactococci contain transcription initiation sites, transcription termination sites, and, within the transcribed region, ribosomal enzymes for translation. The coding portion of the mature transcript expressed by the construct preferably further comprises a In general, a start and stop codon (e.g., U In mammalian or eukaryotic cell expression, the translation begins with U AA and UAG are preferred.

[0078] The expression vector preferably contains at least one selectable marker, although this is optional. Such markers include, for example, methotrexate for eukaryotic cell culture. (MTX), dihydrofolate reductase (DHFR, US Permit No. 4,399,216, No. 4,634,665, No. 4,656,134, Same No. 4,956,288, No. 5,149,636, No. 5,179,017, Anne Picillin, neomycin (G418), mycophenolic acid or glutamine synthetase (glutamine synthetase, GS, U.S. Patent Nos. 5,122,464 and 5,770,3 59, 5,827,739) resistance genes and E. coli and other bacteria or Contains tetracycline or ampicillin resistance genes for cultivation in prokaryotes and are not limited to, all of which are incorporated herein by reference in their entireties. Appropriate culture mediums and conditions for the above host cells are known in the art. Appropriate vectors will be readily apparent to those skilled in the art. Introduction of constructs into cells was performed using calcium phosphate transfection and DEAE-dextran. mediated transfection, cationic lipid-mediated transfection, electroporation The cells may be affected by injection, transduction, infection or other known methods. See Sambrook, supra, chapters 1-4 and 16-18; Ausubel, supra, These are described in the art, such as in Chapters 1, 9, 13, 15, 16, etc.

[0079] At least one antibody used in the methods of the invention may be a modified antibody, such as a fusion protein. The vector may be expressed in a form that includes not only a secretion signal but also additional heterologous functional regions. For example, A region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the antibody to enhance its affinity for ribozyme during purification or subsequent processing. It can improve the stability and persistence in the host cell during processing and storage. Peptide moieties can also be added to the antibodies of the invention to facilitate purification. Such regions can be removed prior to final preparation of another fragment thereof. Sambrook, supra, Chapters 17.29-17.42 and 18.1-18.74; Many standard laboratory manuals, such as Ausubel, cited above, Chapters 16, 17 and 18 It is described in.

[0080] Those skilled in the art will appreciate that various methods are available to express nucleic acids encoding proteins for use in the methods of the present invention. Alternatively, the nucleic acid may be expressed intracellularly as a nucleic acid encoding an antibody. By switching on (by engineering) the gene in a host cell that contains the gene for the gene, the host cell Such methods can be expressed in cells. Nos. 5,641,670, 5,733,746, and 5,733,761 These methods are well known in the art, as described in This is incorporated herein by reference.

[0081] One example of a cell culture useful for the production of antibodies, specified portions or variants thereof is a mammalian Mammalian cell lines are often in the form of a monolayer of cells, but suspensions of mammalian cells can also be used. Alternatively, a bioreactor can be used. Several suitable host cell lines have been developed in the art, including COS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-165 1), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., A TCC CRL1610) and BSC-1 (e.g. ATCC CRL-26) cell lines, os-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2 / 0 -Ag14, 293 cells, HeLa cells, etc., which are, for example, a Type Culture Collection,Manassas,Va(w Preferred host cells include myeloma and lymphoma cells. Particularly preferred host cells include cells of lymphoid origin, such as lymphoma cells. Ag8.653 cells (ATCC registration number CRL-1580) and SP2 / 0-Ag14 cells In a particularly preferred embodiment, the recombinant cell is The cells were P3X63Ab8.653 or SP2 / 0-Ag14 cells.

[0082] Expression vectors for these cells include an origin of replication, a promoter (e.g., late or early SV 40 promoter, CMV promoter (U.S. Pat. No. 5,168,062, U.S. Pat. No. 5,3 85,839), HSV tk promoter, pgk (phosphoglycerate kinase) Promoter, EF-1α promoter (U.S. Patent No. 5,266,491), at least Another human immunoglobulin promoter, enhancer, and / or ribosome binding site positions, RNA splice sites, polyadenylation sites (e.g., SV40 large T Ag polyadenylation sites, addition sites), as well as processing information sites such as transcription termination sequences, but are not limited to these. The expression control sequences may include one or more of the expression control sequences described in, for example, Ausubel et al., supra. See Sambrook et al., supra. Useful for producing the nucleic acids or proteins of the invention Other such cells are known and / or may be used, for example, in the American Type The Culture Collection's catalog of cell lines and hybridomas (www atcc.org) or other known or commercial sources.

[0083] When eukaryotic host cells are used, polyadenylation or transcription termination sites are typically included in the vector. An example of a termination sequence is the polyadenylation sequence from the bovine growth hormone gene. Sequences for accurate splicing of the transcript can be included as well. An example of a splicing sequence is the VP1 intron from SV40 (Sprague , et al., J. Virol. 45:773-781 (1983)). As is known in the art, gene sequences for controlling replication within a host cell can be used as a vector. It can be incorporated into the controller.

[0084] Antibody purification Anti-IL-23 antibodies were purified using protein A, ammonium sulfate or ethanol precipitated, and extracted with acid. extraction, anion or cation exchange chromatography, phosphocellulose chromatography -, hydrophobic interaction chromatography, affinity chromatography, hydroxy These include luapatite chromatography and lectin chromatography. The polypeptides can be recovered and purified from recombinant cell culture by well-known methods, including but not limited to those described herein. High performance liquid chromatography ("HPLC") can also be used for purification. Colligan, Current Protocols in Immunolo gy or Current Protocols in Protein Science ,John Wiley & Sons, NY, NY (1997-2001), e.g. See Chapters 1, 4, 6, 8, 9 and 10, each of which is incorporated herein by reference in its entirety. is incorporated into.

[0085] Antibodies for use in the methods of the present invention include naturally purified products, products of chemical synthetic procedures, as well as and recombinant techniques from eukaryotic hosts, including, for example, yeast, higher plants, insect, and mammalian cells. Depending on the host utilized in the recombinant production procedure, antibodies may be produced from It may be glycosylated or non-glycosylated, but is preferably glycosylated. Such methods are described in Sambrook, supra, Sections 17.37-17.42, supra, Ausubel, chapters 10, 12, 13, 16, 18, and 20, Colliga supra. Many standard laboratory manuals, such as Protein Science, Chapters 12-14, Manual, all of which are incorporated herein by reference in their entireties.

[0086] Anti-IL-23 antibody The anti-IL-23 antibody of the present invention can be incorporated into an immunoglobulin molecule, At least a portion of, for example, but not limited to, at least one ligand binding portion nd binding portion, LBP), for example, but not limited to, heavy chain or light chain complementarity determination constant drive (CDR) or ligand-binding portion thereof, heavy or light chain variable region, framework region A region (e.g., FR1, FR2, FR3, FR4, or a fragment thereof, and optionally at least one substitution, insertion, or deletion), a heavy or light chain constant region (e.g., At least 1 C H 1, Hinge 1, Hinge 2, Hinge 3, Hinge 4, C H 2 or C H 3 or a fragment thereof, and optionally containing at least one substitution, insertion, or deletion. ), or any portion thereof. may be human, mouse, rabbit, rat, rodent, primate, or any combination thereof. The subject matter may include or be derived from any mammal, including, but not limited to, a mammal such as a mammalian animal.

[0087] The isolated antibodies used in the methods of the present invention may be prepared by any suitable polynucleotide. The encoded amino acid sequence of the antibody disclosed herein, or any isolated or prepared Preferably, the human antibody or antigen-binding fragment binds to human IL-23 and This partially or substantially neutralizes at least one biological activity of the protein. At least one biological activity of at least one IL-23 protein or fragment is retained. The antibodies, or specified portions or variants thereof, are preferably neutralizing, either partially or preferably substantially neutralizing. IL-23 is a cytoplasmic IL-23 molecule that binds to the IL-23 receptor and binds to the IL-23 protein or fragment, thereby mediating the binding of IL-23 to the IL-23 receptor. or through other IL-23-dependent or -mediated mechanisms. As used herein, the term "neutralizing antibody" refers to a neutralizing antibody that can be used to detect a specific antibody, depending on the assay. and about 20 to 120%, preferably at least about 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 9 Refers to antibodies that can inhibit IL-23-dependent activity by 7, 98, 99, 100% or more. The ability of an anti-IL-23 antibody to inhibit IL-23-dependent activity is preferably determined by the methods described herein. At least one suitable IL-23 as described and / or known in the art Human antibodies can be assessed by protein or receptor assays. IgA, IgM, IgE, IgD, etc.) or isotype, In one embodiment, the human antibody may comprise an IgG heavy chain or a defined fragment. fragments, such as IgG1, IgG2, IgG3 or IgG4 (e.g., γ1, γ2, γ3, γ4). Antibodies of this type are described herein. At least one human light chain, as described and / or known in the art (e.g., Transgenic mice or other transgenic mice containing transgenes for IgG, IgA, and IgM. Alternatively, the present invention can be prepared by utilizing a transgenic non-human mammal. In embodiments, the anti-IL-23 human antibody comprises an IgG1 heavy chain and an IgG1 light chain.

[0088] The antibody is an antibody that binds at least one IL-23 protein, subunit, fragment, portion, or the like. It binds to at least one specified epitope specific for any combination of these. The at least one epitope comprises at least one polypeptide that comprises at least a portion of a protein. The epitope may comprise one antibody binding region, and the epitope is preferably located on the It is composed of at least one extracellular, soluble, hydrophilic, external, or cytoplasmic portion.

[0089] Generally, a human antibody or antigen-binding fragment contains at least one human complementarity determining region (CDR 1, CDR2, and CDR3) or at least one heavy chain variable region variant, and at least Each of the complementarity determining regions (CDR1, CDR2, and CDR3) is human, or at least one The CDR sequences are derived from human germline variants of the light chain variable region. The sequence may be derived from a non-human CD40 gene or may correspond exactly to a germline sequence. CDRs from a synthetic library derived from R can be used. These CDRs include It may be formed by the incorporation of conservative substitutions from the original non-human sequence. In the antibody or antigen-binding portion or variant, the corresponding CDR1, 2 and / or 3 amino acids At least one light chain CDR (i.e., CDR1, CDR2, and / or can have an antigen-binding region comprising at least a portion of the CDR3).

[0090] Such antibodies can be produced using conventional techniques of recombinant DNA technology to encode the antibodies (i.e. by preparing and expressing one or more) nucleic acid molecules, or by any other suitable method. By using this method, various portions of the antibody (e.g., CDRs, fragment ... They can be prepared by chemically bonding together the following polymeric components:

[0091] The anti-IL-23 specific antibody has a heavy or light chain variable region having a defined amino acid sequence. For example, in a preferred embodiment, the antibody may include at least one of anti-IL-2 3. The antibody optionally comprises at least one heavy chain polypeptide having the amino acid sequence of SEQ ID NO: 106. Variable region, and / or optionally at least one having the amino acid sequence of SEQ ID NO: 116 The antibody binds to human IL-23 and has a defined heavy chain variable region. The antibodies comprising the light or light chain variable regions can be prepared using any of the methods known in the art and / or described herein. Phage display (Katsube, Y., et al., Int J Mol. Me d,1(5):863-868(1998)) or those who adopt transgenic animals. For example, functionally rearranged human IgG can be prepared using any suitable method, including the use of a method for the preparation of functionally rearranged human IgG. A human immunoglobulin heavy chain transgene capable of functionally rearrangement and a human immunoglobulin heavy chain transgene capable of functionally rearrangement. and a transgenic mouse comprising a transgene comprising DNA from the purine light chain locus. can be immunized with human IL-23 or a fragment thereof to induce the production of antibodies. In this case, antibody-producing cells can be isolated and cultured as described herein and / or As is known in the art, hybridomas or other immortalized antibody producing cells can be used. Alternatively, the antibody, specified portion or variant can be cultured in a suitable host cell. Within the host cell, the encoding nucleic acid or a portion thereof can be used for expression.

[0092] The present invention also provides amino acids within sequences which are substantially the same as the amino acid sequences described herein. The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs comprising the amino acid. Such antibodies or antigen-binding fragments and antibodies comprising such chains or CDRs have high affinity (e.g. For example, K D About 10 -9 M or less) and can bind to human IL-23. Amino acid sequences that are substantially the same as the sequences set forth in the above may include conservative amino acid substitutions, Conservative amino acid substitutions include sequences containing amino acid deletions and / or insertions. have chemical and / or physical properties (e.g., charge, structure, polarity, It refers to the replacement of a first amino acid with a second amino acid that has a hydrophobic / hydrophilic (or hydrophobic) character. Targeted substitutions include, but are not limited to, replacing one amino acid with another amino acid within the following group: Contains: lysine (K), arginine (R), and histidine (H); aspartic acid salt (D) and glutamate (E); asparagine (N), glutamine (Q), serine ( S), threonine (T), tyrosine (Y), K, R, H, D, and E; alanine (A), Valine (V), Leucine (L), Isoleucine (I), Proline (P), Phenylalanine phosphate (F), tryptophan (W), methionine (M), cysteine ​​(C), and glycine (G); F, W, and Y; C, S, and T.

[0093] Amino acid code The amino acids constituting the anti-IL-23 antibodies of the present invention are often abbreviated. is its one-letter code, its three-letter code, its name, or the codon (compound) of three nucleotides. The amino acid sequence can be represented by a symbol (number or number) and is well known in the art. It is well understood (Alberts, B., et al., Molecular Biol ogy of The Cell,Third Ed.,Garland Publis (see, Fing, Inc., New York, 1994).

[0094] [Table 1]

[0095] The anti-IL-23 antibodies used in the methods of the present invention are natural targeting antibodies, as specified herein. Substitution, deletion, or addition of one or more amino acids, either by natural mutation or by human manipulation. It may include addition.

[0096] The number of amino acid substitutions a skilled artisan would make depends on many factors, including those described above. In other words, the amino acid substitutions, insertions or deletions of a given anti-IL-23 antibody, fragment or variant are The numbers are as specified herein: 40, 30, 20, 19, 18, 17, 16, 15 , 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, e.g., 1~ 30, or any range or value therein.

[0097] Amino acids within the anti-IL-23 specific antibody that are functionally essential were identified by site-directed mutagenesis. or by methods known in the art, such as alanine scanning mutagenesis. can be identified (e.g., Ausubel, supra, Chapters 8, 15; Cunningham and Wells,Science 244:1081-10 85 (1989)). The latter procedure introduces one alanine substitution mutation at each residue in the molecule. The resulting substitution mutant molecule is then subjected to, for example, but not limited to, The antibodies are tested for at least one biological activity, such as IL-23 neutralizing activity. The sites that are crucial for the identification of the target molecule are also subject to structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling. (Smith, et al., J. Mol. Biol. 2002). 24:899-904 (1992) and de Vos, et al., Science 255:306-312(1992)).

[0098] The anti-IL-23 antibody may be selected from the group consisting of SEQ ID NOs: 5, 20, 44, 50, 56, and 73. At least one portion, sequence, selected from 5 to all of one adjacent amino acid The following may include, but are not limited to, a sequence, a column, or a combination.

[0099] The IL-23 antibody or specific portion or variant includes at least 3 of the above SEQ ID NO: 5 to 17 adjacent amino acids of the above SEQ ID NO: 10 adjacent amino acids, 5 to 11 adjacent amino acids of the above SEQ ID NO: 7 adjacent amino acids, at least one selected from 5 to 9 adjacent amino acids of the above sequence number It may include, but is not limited to, a single portion, sequence, or a combination.

[0100] The anti-IL-23 antibody further optionally comprises any one of the above SEQ ID NOs: 5, 17, 10, 11, 7, 9, At least one polypeptide having 70-100% of the adjacent amino acids of In one embodiment, the immunoglobulin chain, or a portion thereof (e.g., The amino acid sequence of the variable region (CDR) corresponds to at least one of the above SEQ ID NOs. The amino acid sequence of the chain has about 70 to 100% identity (e.g., 70, 71, 72, 73, 7 4, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87 , 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 For example, the light chain variable region has the amino acid sequence can be compared to the above SEQ ID NOs, or the amino acid sequence of the heavy chain CDR3 can be compared to the above SEQ ID NOs. Preferably, the amino acid sequence is 70 to 100% identical (i.e. , 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or any of the above Any range or value of the above can be calculated using a suitable computer, as known in the art. The time domain is determined using a data algorithm.

[0101] As known in the art, "identity" is determined by comparing sequences. The relationship between two or more polypeptide sequences or between two or more polynucleotide sequences is In the art, "identity" is also determined by the match between strings of such sequences. "sequence relatedness" refers to the degree of sequence relatedness between polypeptide or polynucleotide sequences, as defined by the nucleotide sequence relatedness test. "Identity" and "similarity" are defined as Biology,Lesk,AM,ed.,Oxford University Press, New York, 1988, Biocomputing:Informa tics and Genome Projects, Smith, DW, ed. Academic Press, New York, 1993, Computer An alysis of Sequence Data,Part I,Griffin,A .M.,and Griffin,HG,eds.,Humana Press,N. ew Jersey,1994, Sequence Analysis in Mole cular Biology,von Heinje,G.,Academic Pre ss, 1987, and Sequence Analysis Primer, Gribs kov, M. and Devereux, J., eds., M Stockton Pr. ess, New York, 1991, and Carillo, H., and Lipm an,D.,Siam J.Applied Math.,48:1073(1988) These can be easily achieved by known methods, including, but not limited to, those described in In addition, the percent identity value can be calculated using the Vector NTI Component of Suite 8.0 (Informax, Frederick, MD) The amino acid and nucleotide sequences are generated using the default AlignX settings. This can be obtained from sequence alignment.

[0102] Preferred methods to determine identity are those that give the largest match between the sequences tested. Methods to determine identity and similarity are publicly available computer-aided methods. To determine identity and similarity between two sequences, A preferred computer program method is that of the GCG program package (Devere ux, J., et al., Nucleic Acids Research 12(1 ):387(1984)), BLASTP, BLASTN, and FASTA (Atsch ul,SFet al.,J.Molec.Biol.215:403-410(1 990)). The BLAST X program is available from NCBI and and other sources (BLAST Manual, Altschul, S., et al., CBINLM 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. It can be used to

[0103] Preferred parameters for polypeptide sequence comparison include the following: (1) Algorithm Mu: Needleman and Wunsch, J. Mol Biol. 48:443 -453(1970)Comparison matrix:BLOSSUM62 fr om Hentikoff and Hentikoff,Proc.Natl.Aca d.Sci,USA.89:10915-10919(1992), Gap penalty: 12 Gap length penalty: 4 A useful program for these parameters is Genetics Computer G Publicly available as the "Gap" program from roup, Madison Wis. The above parameters are the default parameters for peptide sequence comparison (terminal (Just as there is no penalty for caps.)

[0104] Preferred parameters for polynucleotide comparisons include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Bi ol.48:443-453(1970) Comparison matrix: match = +10, mismatch = 0 Gap penalty: 50 Gap length penalty: 3 " from Genetics Computer Group, Madison Wis. These are available as the "Gap" program, which uses the default parameters for nucleic acid sequence comparison. It is.

[0105] By way of example, a polynucleotide sequence can be identical to another sequence, i.e., 100% identical. may contain one or up to a certain integer number of nucleotide changes compared to the reference sequence. Such alterations include at least one nucleotide deletion, substitution (including transitions and transversions), or an insertion, wherein the alteration is at the 5' or 3' end of the reference nucleotide sequence. It may occur at the end positions or anywhere between these end positions and may be between nucleotides of the reference sequence. Nucleotides may be present individually or interspersed in one or more adjacent groups within the reference sequence. The number of nucleotide changes corresponds to the total number of nucleotides in the sequence and the corresponding percent identity number. Multiply by the percentage (divided by 100) and subtract that product from the total number of nucleotides in the sequence. Pulling or By n.sub.n.ltorsim.x.sub.n-(x.sub.ny) It was decided, where n.sub.n is the number of nucleotide changes and x.sub.n is the number of nucleotide changes in the sequence. The total number of leucocytes, y is, for example, 0.70 for 70% and 0 for 80%. .80, 0.85 for 85%, 0.90 for 90%, and 0. 95, and any non-integer product of x.sub.n and y is x.sub.n to y. Round down to the nearest integer before subtracting.

[0106] Alterations in the polynucleotide sequence encoding the above SEQ ID NOs include those that do not include any number of sequences in the coding sequence. Create sense, missense, or frameshift mutations, thereby modifying such The polypeptide encoded by the polynucleotide can then be modified. In addition, the polypeptide sequence may be identical to the reference sequence of the above SEQ ID NO: 100%. A specific sequence is compared to the reference sequence such that it is identical or the percent identity is less than 100%. The amino acid sequence may include up to an integer number of amino acid changes. Such changes include at least one amino acid deletion, The alteration is selected from the group consisting of a substitution (including conservative and non-conservative substitutions), or an insertion. At the amino or carboxy terminal positions of the reference polypeptide sequence, or between these terminal positions The amino acid sequence may occur anywhere in the sequence, either individually between amino acids of the reference sequence, or adjacent to one or more amino acids in the reference sequence. The number of amino acid changes for a given percent identity is , the total number of amino acids in the above sequence, plus the corresponding numerical percent identity (1 00) and subtract the product from the total number of amino acids in the sequence. or By n.sub.a.ltorsim.x.sub.a-(x.sub.ay) It was decided, where n.sub.a is the number of amino acid changes and x.sub.a is the is the total number of amino acids, and y is, for example, 0.70 for 70% and 0 for 80%. .80 for 85%, 0.85 for 85%, etc. for any integers x.sub.a and y. Any missing products are truncated to the nearest integer before being subtracted from x.sub.a.

[0107] Exemplary heavy and light chain variable region sequences, and portions thereof, are set forth in the SEQ ID NOs. The antibodies of the invention or specified variants thereof may be any number of adjacent amino acids from an antibody of the invention. The number of adjacent acid residues may be 10-100% of the number of adjacent residues in the anti-IL-23 antibody. Optionally, the subsequence of contiguous amino acids is selected from the group of integers consisting of at least Also about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 , 130, 140, 150, 160, 170, 180, 190, 200, 210, 220 , 230, 240, 250 or more amino acids in length, or any range therein. Further, the number of such subsequences is at least 1 to 2, such as 2, 3, 4, or 5. It may be any integer selected from the group consisting of 0.

[0108] As will be apparent to one of skill in the art, the present invention includes a method for the preparation of a medicament for the treatment of a cancer, comprising administering to the patient a therapeutically effective amount of at least one biologically active antibody of the present invention. Biologically active antibodies include those derived from natural (non-synthetic), endogenous, or related, known At least 20%, 30%, or 40%, and preferably at least 50% of that of the antibody. %, 60%, or 70%, and most preferably at least 80%, 90%, or 95% to Having a specific activity of 100% or more (including but not limited to up to 10 times the specific activity). Methods for assaying and quantitatively determining activity and substrate specificity are well known to those of skill in the art.

[0109] In another aspect, the present invention provides a method for the preparation of a compound according to any one of the preceding claims, wherein the compound is modified by the covalent attachment of an organic moiety. Such modifications may result in improved pharmacokinetic properties (e.g., In some embodiments, the antibody or antigen-binding fragment has an increased serum half-life in vivo. The organic moiety can be a linear or branched hydrophilic polymeric group, a fatty acid group, or a fatty acid ester. In certain embodiments, the hydrophilic polymer group can be a group having a molecular weight of about 800 to about 5000. Approximately 120,000 daltons, polyalkane glycol (e.g., polyethylene glycol) Polypropylene glycol (PEG), polypropylene glycol (PPG), carbohydrate polymers, amines The copolymer may be a polyvinylpyrrolidone or a polyvinyl acid polymer, and may also be a fatty acid or fatty acid ester group. can contain from about 8 to about 40 carbon atoms.

[0110] The modified antibodies and antigen-binding fragments are covalently attached, directly or indirectly, to an antibody. Each organic moiety attached to an antibody or antigen-binding fragment of the invention may comprise: It can be, independently, a hydrophilic polymeric group, a fatty acid group, or a fatty acid ester group. As used, the term "fatty acid" includes mono- and di-carboxylic acids. As used herein, the term "hydrophilic polymeric group" refers to a polymer that is more soluble in water than in octane. For example, polylysine has a higher affinity for water than octane. Therefore, antibodies modified by covalent attachment of polylysine are included in the present invention. Suitable hydrophilic polymers for modifying the antibodies of the invention can be linear or branched, e.g. For example, polyalkane glycols (e.g., PEG, monomethoxy-polyethylene glycol). (mPEG, PPG, etc.), carbohydrates (e.g., dextran, cellulose, oligo sugars, polysaccharides, etc.), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, poly lyaspartic acid, etc.), polyalkane oxides (e.g., polyethylene oxide, poly propylene oxide, etc.), and polyvinylpyrrolidone. The hydrophilic polymer that modifies the body is about 800 to about 150,000 daltons as individual molecular entities. For example, PEG 5000 and PEG 20,000 Use where the subscript is the average molecular weight of the polymer in Daltons. The hydrophilic polymer group is The fatty acid may be substituted with 1 to about 6 alkyl groups, fatty acid groups, or fatty acid ester groups. Hydrophilic polymers substituted with fatty acid or fatty acid ester groups can be prepared using suitable methods. For example, a polymer containing amine groups can be prepared by reacting a fatty acid or The activation of the fatty acid or fatty acid ester can be linked to the carboxylate of the ester. Carboxylate salts (e.g., activated with N,N-carbonyldiimidazole) are added to poly( The linker can be linked to a hydroxyl group on a mer.

[0111] The fatty acids and fatty acid esters suitable for modifying the antibodies of the invention may be saturated. Suitable lipids for modifying the antibodies of the invention may contain one or more unsaturated units. Examples of fatty acids include n-dodecanoic acid salts (C 12 , laurate), n-tetradecane Acid acid (C 14 , myristate), n-octadecanoate (C 18 , stearates), n-Eicosanoic acid salt (C 20, arachidate), n-docosanoate (C 22 , behenic acid ), n-triacontanoate (C 30 ), n-tetracontanoate (C 40 ), cis-Δ 9-Octadecanoic acid salt (C 18 oleate), all cis-Δ5,8,11,14- Eicosatetraenoic acid salt (C 20 , arachidonate), octanedioic acid, tetradecane Suitable fatty acid esters include ethyl ester, octadecanedioic acid, docosanedioic acid, and the like. The esters include monoesters of dicarboxylic acids containing straight or branched chain lower alkyl groups. The lower alkyl group may contain 1 to about 12, preferably 1 to about 6, carbon atoms.

[0112] The modified human antibodies and antigen-binding fragments can be subjected to a suitable treatment, such as by reacting them with one or more modifying agents. As used herein, the term "modifying agent" refers to a compound that can be prepared using the methods described above. Suitable organic groups containing activating groups (e.g., hydrophilic polymers, fatty acids, fatty acid esters) are intended to be An "activating group" is a group that, under appropriate conditions, reacts with a second chemical group, thereby forming a modifier. A chemical moiety or functional group that is capable of forming a covalent bond with a second chemical group. For example, amine-reactive activating groups include tosylate, mesylate, halo (chloro, bromo, fluoro, etc.) Electrophilic groups such as fluoro, iodo, and N-hydroxysuccinimidyl ester (NHS) Examples of activating groups capable of reacting with thiols include maleimide, iodine, and the like. Triacetyl, acryloyl, pyridyl disulfide, 5-thiol-2-nitrobenzoic acid The aldehyde functional group can be an amine- or Hydrazide-containing molecules can be linked, and the azide group can react with the trivalent phosphorus group to form A phosphoramidate or phosphorimide bond can be formed. Activating groups in the molecule Suitable methods for introducing .alpha.-aminobutyric acid are known in the art (e.g., Herma nson,GT,Bioconjugate Techniques,Academ (See, for example, 1996, J. Chem. Press: San Diego, CA). Activating Groups is bonded directly to an organic group (e.g., hydrophilic polymer, fatty acid, fatty acid ester) or to phosphorus Car moiety, e.g., divalent C1-C 12 A group in which one or more carbon atoms are oxygen, nitrogen, or can be substituted with a heteroatom such as sulfur. The car portion is, for example, tetraethylene glycol, -(CH2)3-, -NH-(CH2 )6-NH-, -(CH2)2-NH- and -CH2-O-CH2-CH2-O-CH2 Modifiers that include a linker moiety include, for example, 1-ethyl- In the presence of 3-(3-dimethylaminopropyl)carbodiimide (EDC), mono-Bo c-Alkyldiamines (e.g., mono-Boc-ethylenediamine, mono-Boc-diamine) By reacting dimethylaminohexane with fatty acids, free amines and fatty acid carboxylates are obtained. The Boc protecting group can be converted to a trifluoromethylphenyl by forming an amide bond between the The product was removed by treatment with trifluoroacetic acid (TFA) and another carboxylic acid was added as described. This exposes a primary amine which can be coupled to a salt or this can be reacted with maleic anhydride and cyclizing the resulting product to form an activated maleimide derivative of the fatty acid. (See, e.g., Thompsoh, et al., the teachings of which are incorporated herein by reference in their entirety). (See WO 92 / 16221 to N. et al.).

[0113] The modified antibodies are produced by reacting a human antibody or antigen-binding fragment with a modifying agent. For example, the organic moiety can be an amine-reactive modifier, such as NHS of PEG. By employing esters, binding to the antibody can be achieved in a non-site specific manner. Reducing disulfide bonds (e.g., intrachain disulfide bonds) of an antibody or antigen-binding fragment A modified human antibody or antigen-binding fragment can also be prepared by: The reduced antibody or antigen-binding fragment is reacted with a thiol-reactive modifying agent to form a modified antibody or antigen-binding fragment of the invention. It is possible to produce antibodies that have been modified to specific sites on the antibodies of the invention. Modified human antibodies and antigen-binding fragments containing the nucleotides 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, al.,Bioconjugate Chem.,3:147-153(1992),W Erlen et al.,Bioconjugate Chem.,5:411-41 7(1994), Kumaran et al., Protein Sci.6(10) :2233-2241(1997), Itoh et al.,Bioorg.Chem .,24(1):59-68(1996),Capellas et al.,Biot echnol. Bioeng., 56(4):456-463(1997)) and Her manson,GT,Bioconjugate Techniques,Acad and methods described in, for example, J. Phys. Chem. Press: San Diego, CA (1996). It can be prepared using any suitable method.

[0114] The methods of the present invention also include those described herein and / or known in the art. At least one of the at least one non-naturally occurring compositions, mixtures, or forms is provided, such as 2, at least 3, at least 4, at least 5, at least 6 or more anti-IL-1 The present invention also provides an anti-IL23 antibody composition comprising an -23 antibody. Such a composition comprises a nucleic acid sequence similar to that described above. From 70-100% of the adjacent amino acids, or a specified fragment, domain, or variant thereof At least one or two complete amino acid sequences of an anti-IL-23 antibody selected from the group consisting of Contains full length, C- and / or N-terminal deletion variants, domains, fragments, or specified variants. Preferred anti-IL23 antibody compositions include non-naturally occurring compositions comprising the sequences of, for example, the sequences of SEQ ID NOs. 70-100% of the anti-IL23 antibody sequence described herein, or a specified fragment thereof. At least one CDR or LBP-containing portion of the polypeptide, domain, or variant may comprise at least one of the CDRs or LBP-containing portions of the polypeptide, domain, or variant. More preferred compositions include at least one or two full-length, fragments, domains, or variants. The substance may be, for example, 70 to 100% of the above sequence numbers, or a specified fragment or domain thereof. or at least one of the variants. The percentage of such a composition is , by weight, volume, as known in the art or as described herein. Amount, concentration, molarity or amount of liquid or dry solution, mixture, suspension, emulsion The molar concentration is determined by the volumetric concentration as a nanoparticle, particle, powder, or colloid.

[0115] Antibody compositions containing further therapeutically active ingredients The antibody compositions used in the methods of the present invention may optionally further comprise an anti-infective agent, a cardiovascular Cardiovascular (CV) drugs, central nervous system (CNS) drugs, Autonomic nervous system (ANS) drugs, respiratory tract drugs, gastrointestinal GI) vascular agonists, hormonal agents, fluid or electrolyte balancing agents, hemodynamic agents, antitumor agents, immunomodulatory agents At least one of the following drugs is selected: medicines, eye, ear or nose medicines, topical drugs, nutritional drugs, etc. Such a drug may comprise an effective amount of at least one compound or protein. The art is well known in the art, including the respective formulations, indications, dosages, and administrations set forth herein. It is well known (e.g., Nursing 2001 Handbook of Drugs ,twenty one st edition,Springhouse Corp.,Springho use,PA,2001,Health Professional's Drug G uide 2001, ed.,Shannon,Wilson,Stang,Prent ice-Hall, Inc., Upper Saddle River, NJ, Pharm Cotherapy Handbook,Wells et al.,Appleton & Lange, Stamford, CT, each of which is incorporated herein by reference. (Incorporated into the book).

[0116] Examples of drugs that can be combined with the antibodies of the methods of the invention include anti-infective drugs, such as ampicillin, or at least one antiprotozoal, anthelmintic, antifungal, antimalarial, antituberculous, or At least one antimycobacterial drug, aminoglycoside, penicillin, cephalosporin, tetracycline Lacyclines, sulfonamides, fluoroquinolones, antivirals, macrolides anti-infectives The hormonal drug may be at least one selected from the group consisting of steroids, anti-inflammatory drugs, and various anti-infective drugs. steroids, androgens, or at least one anabolic steroid, estrogens, or at least one progestin, gonadotropin, antidiabetic agent, or A type of glucagon, thyroid hormone, thyroid hormone antagonist, pituitary hormone, and At least one selected from the group consisting of parathyroid mimetics and at least one cephalosporin. Phosphorus is cefaclor, cefadroxil, cefazolin sodium, cefdinir, hydrochloride Cefepime, cefixime, cefmetazole sodium, cefonicid sodium, cef Operazon sodium, cefotaxime sodium, cefotetan disodium, cefo Cefpodoxime sodium, cefpodoxime proxetil, cefprozil, ceftazidime, cef Thibuten, ceftizoxime sodium, ceftriaxone sodium, cefuroxime aki Cetyl, Cefuroxime Sodium, Cephalexin Hydrochloride, Cephalexin Monohydrate, Cef The active ingredient may be at least one selected from the group consisting of azithromycin and loracarbef.

[0117] At least one corticosteroid is betamethasone, betamethasone acetate, Methasone or betamethasone sodium phosphate, betamethasone sodium phosphate, cholesteryl acetate Tisone, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, acetate Fludrocortisone, Hydrocortisone, Hydrocortisone Acetate, Hydrocortisone Cypionate Hydrocortisone, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate, Methionine Tilprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate um, prednisolone, prednisolone acetate, prednisolone sodium phosphate, tebutol Prednisolone, prednisone, triamcinolone, triamcinolone acetonide, and and triamcinolone diacetate. Androgenic or anabolic steroids include danazol, fluoxymesterone, Methyltestosterone, Nandrolone Decanoate, Nandrolone Phenpropionate, Tes Testosterone, Testosterone Cypionate, Testosterone Enanthate, Testosterone Propionate The testosterone may be at least one selected from the group consisting of testosterone transdermal agents.

[0118] At least one immunosuppressant is selected from the group consisting of azathioprine, basiliximab, cyclosporine, Daclizumab, lymphocyte immunoglobulin, muromonab-CD3, mycophenolate mofetil mycophenolate mofetil, mycophenolate mofetil hydrochloride, sirolimus, and tacrolimus. There can be at least one type.

[0119] At least one topical anti-infective agent is selected from the group consisting of acyclovir, amphotericin B, azelaic acid cyclovir, and the like. Ream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole nitrate, econazole, erythromycin, gentamicin sulfate, ketoconazole, acetate Mafenide, metronidazole (topical), miconazole nitrate, mupirocin, naphthyl hydrochloride , neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, tetrahydrofuran Rubinafine, terconazole, tetracycline hydrochloride, tioconazole, and tolnaf At least one scabicide or at least one tate. The pediculicide is selected from crotamiton, lindane, permethrin, and pyrethrins. The at least one topical corticosteroid may be dipropionate. Betamethasone valerate, clobetasol propionate, desonide, desoxyglucose Ximethasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate , fluocinolone acetonide, fluocinonide, flurandrenolide, flupropionate Ticasonide, halcionide, hydrocortisone, hydrocortisone acetate, butyrate Hydrocortisone valerate, hydrocortisone valerate, mometasone furoate, and triamcinol The at least one selected from the group consisting of acetonides and acetonides (see, for example, Nursing 2 See pages 1098-1136 of the 001 Drug Handbook.)

[0120] The anti-IL-23 antibody composition is intended to be used to administer to cells, tissues, organs, or tissues in need of such modulation, treatment, or therapy. At least one anti-IL-23 antibody is contacted or administered to a physician, animal, or patient. and optionally further comprising at least one TNF antagonist (e.g., but not limited to, T NF chemical or protein antagonists, TNF monoclonal or polyclonal antibodies or fragments thereof, soluble TNF receptors (e.g., p55, p70, or p85) or fragments thereof, Fusion polypeptides, or small molecule TNF antagonists, such as TNF binding protein I or II (TBP-1 or TBP-II), nerelimonmab, infliximab Mab, etanercept, CDP-571, CDP-870, Afelimoma antirheumatic drugs (e.g. methotrexate, auranofin, Aurothioglucose, azathioprine, etanercept, sodium gold thiomalate, Hydroxychloroquine sulfate, leflunomide, sulfasalazine), immunomodulators, immunoglobulins robrin, immunosuppressants (e.g., basiliximab, cyclosporine, daclizumab), Any suitable agent including at least one selected from the group consisting of cytokines and cytokine antagonists. The composition may further comprise at least one of a composition or a pharmaceutical composition in an effective amount. Non-limiting examples of cytokines include IL-1 to IL-23 (e.g., IL-1 The appropriate dose may include, but is not limited to, any of the following: It is well known in the art. For example, see Wells et al., eds., Pha rmacotherapy Handbook, 2nd Edition, Applet on and Lange, Stamford, CT (2000), PDR Pharm. acopoeia, Tarascon Pocket Pharmacopoeia 2 000,Deluxe Edition,Tarascon Publishing,L See, for example, Oma Linda, CA (2000), each of which is incorporated by reference in its entirety. The body is incorporated herein.

[0121] The anti-IL-23 antibody compound, composition, or mixture used in the methods of the present invention may further comprise dilutions. agents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc. The composition may include at least one of any suitable auxiliary agent, including but not limited to, pharmaceutically acceptable Non-limiting examples of and methods for preparing such sterile solutions are described in the art. The method is well known in the art and is described, for example, in Gennaro, Ed., Remington's Pharmaceutical Sciences, 18 th Edition,Ma ck Publishing Co. (Easton, PA), 1990, etc. However, the present invention is not limited to the above. The method of administration, solubility, and / or stability of the anti-IL-23 antibody, fragment, or variant composition. A suitable pharma- ceutically acceptable carrier can be routinely selected.

[0122] Pharmaceutical excipients and additives useful in the present compositions include, but are not limited to, protein Proteins, peptides, amino acids, lipids and carbohydrates (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and Sugars including oligosaccharides, alditols, aldonic acids, esterified sugars, and other derivative sugars, and polysaccharides or sugar polymers), which may be present alone or in combination; Included alone or in combination are 1 to 99.99% by weight or volume. Exemplary Proteins Excipients include serum albumins such as human serum albumin (HSA), recombinant human albumin, and Examples of buffering agents include rHA, gelatin, and casein. Common amino acids / antibody building blocks include alanine, glycine, arginine, betaine, histidine, and arginine. gin, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, Examples of preferred amines include valine, methionine, phenylalanine, and aspartame. One of the amino acids is glycine.

[0123] Carbohydrate excipients suitable for use in the present invention include, for example, fructose, maltose, Monosaccharides such as saccharides like glucose, galactose, D-mannose, and sorbose, lactose, sucrose, and Sugar, trehalose, cellobiose and other disaccharides, raffinose, melezitose, maltodextrose, Polysaccharides such as xylitol, dextran, starches, mannitol, xylitol, malic acid, Lutitol, Lactitol, Xylitol, Sorbitol (Glucitol), Myo-inositol Preferred carbohydrate excipients for use in the present invention include alditols such as glycerol. , mannitol, trehalose, and raffinose.

[0124] The anti-IL-23 antibody composition may also include a buffer or pH adjusting agent, typically The buffer is a salt prepared from an organic acid or base. Representative buffers include citric acid, Acids, such as salts of ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid. The composition may be any organic acid salt, Tris, tromethamine hydrochloride, or phosphate buffer. Suitable buffers for use in are organic acid salts such as citric acid.

[0125] In addition, the anti-IL-23 antibody composition may be prepared by mixing 100% polyvinylpyrrolidone, Ficoll (a polymeric sugar) and 100% polyvinylpyrrolidone. ), dextrates (e.g., 2-hydroxypropyl-β-cyclodextrin, etc. Cyclodextrin), polyethylene glycol, flavoring agent, antibacterial agent, sweetener, antioxidant, Antistatic agents, surfactants (e.g., polyethersulfones such as "TWEEN 20" and "TWEEN 80") resorbates), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol may include polymeric excipients / additives such as chelating agents (e.g., EDTA) . β

[0126] These and other compounds suitable for use in anti-IL-23 antibody, portion or variant compositions according to the invention. and additional known pharmaceutical excipients and / or additives are known in the art, e.g. For example, "Remington: The Science & Practice of Ph "armacy", 19 th ed., Williams & Williams, (1995 ), and Physician's Desk Reference, 52 nd ed , Medical Economics, Montvale, NJ (1998). the disclosures of which are incorporated herein by reference in their entireties. The carrier or excipient materials may include carbohydrates (e.g., monosaccharides and alditols) and buffers (e.g., Exemplary carrier molecules are mucopolysaccharides, hyaluronic acid , which may be useful for intra-articular delivery.

[0127] formulation As mentioned above, the present invention preferably comprises a phosphate salt solution containing saline or a selected salt. Stable formulations that are buffered, as well as storage solutions and formulations that contain preservatives, and pharmaceutical Preferred for pharmaceutical or veterinary use are those comprising at least one anti-IL23 antibody in an acceptable formulation. The present invention provides a versatile and versatile preservative formulation comprising at least one known preservative in an aqueous diluent. , i.e., at least one of phenol, m-cresol, p-cresol, o-cresol Benzyl alcohol, phenylmercuric nitrate, phenoxyethanol Alcohol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), Alkylparaben (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, salt benzethonium chloride, sodium dehydroacetate, and thimerosal, or a mixture thereof As known in the art, the present invention further comprises a preservative selected from the group consisting of: 0.001 to 5%, or 0.001, 0.003, 0.005, 0.009, 0.0 1, 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. Such values ​​include, but are not limited to, 8, 4.9, or any range or value therein. Any suitable concentration or mixture of any range or value within the range may be used. Examples include no preservatives, 0.1-2% m-cresol (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (e.g., 0 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001~0.5% Thimerosal (e.g., 0.005, 0.01), 0.001 to 2.0% phenol ( For example, 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005~ 1.0% alkylparaben(s) (e.g., 0.00075, 0.0009, 0. 001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0 .05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%) etc.

[0128] As mentioned above, the method of the present invention comprises the steps of: (a) providing a packaging material and, optionally, a buffer formulated in an aqueous diluent; A small amount of solution containing at least one anti-IL-23 specific antibody with a buffer and / or preservative. The packaging material contains at least one vial of the solution, and the solution is stored in a container for one, two, three or four days. , 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 6 6. The label includes a description that the composition can be preserved for 72 hours or more. A packaging material, a first vial containing a lyophilized anti-IL-23 specific antibody, and a formulated and a second vial containing an aqueous diluent of the buffer or preservative, The packaging material is designed to preserve the anti-IL-23 specific antibody reconstituted in an aqueous diluent for more than 24 hours. The composition includes a label instructing the patient to form a sustained solution.

[0129] The anti-IL-23 specific antibodies used in accordance with the present invention may be any of those described herein or of the It is known in the art that the polypeptides can be produced from mammalian cells or transgenic preparations. The polypeptides may be produced by recombinant means, including recombinant human polypeptides, or may be purified from other biological sources.

[0130] The range of anti-IL-23 specific antibodies is approximately 1.0 μg / mL when reconstituted in the wet / dry system. It is included in amounts that give a concentration of about 1000 mg / ml to about 1000 mg / ml, but lower and higher concentrations are also available. The drug may be administered at any temperature, depending on the intended delivery vehicle. For example, in a solution formulation, the drug may be administered by transdermal penetration. This is distinct from pulmonary, transmucosal, or osmotic or micropump methods.

[0131] Preferably, the aqueous diluent optionally further comprises a pharma- ceutically acceptable preservative. New preservatives include phenol, m-cresol, p-cresol, o-cresol, and chloroform. Croxysol, benzyl alcohol, alkylparaben (methyl, ethyl, propyl, butyl ethyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and Thimerosal or mixtures thereof. The concentration of preservative used is sufficient to produce an antimicrobial effect. This will vary depending on the preservative selected and is readily determined by one of skill in the art.

[0132] Other excipients, such as isotonicity agents, buffers, antioxidants, and preservative enhancers, are optional. Optionally and preferably, an isotonic agent such as glycerin may be added to the diluent. Preferably, a physiologically tolerable buffer is added to improve the stability. The formulations provide excellent pH control, ranging from about pH 4 to about pH 10, and preferably from about pH 5 to about A wide range of pH, such as a pH range of 9, and most preferably a range of about 6.0 to about 8.0 Preferably, the formulation of the present invention has a pH of about 6.8 to about 7.8. Suitable buffers include phosphate buffers, most preferably sodium phosphate, In particular, phosphate buffered saline (PBS).

[0133] Other additives, such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate) rate), Tween 40 (Polyoxyethylene (20) Sorbitan Monopalmitate) , Tween 80 (Polyoxyethylene (20) Sorbitan Monooleate), Plur onic F68 (polyoxyethylene polyoxypropylene block copolymer), and and PEG (polyethylene glycol), or a pharma- ceutically acceptable solubilizer. Rubate 20 or 80 or Poloxamer 184 or 188, Pluronic ( Nonionic surfactants such as Polyls, other block copolymers, and and chelating agents such as EDTA and EGTA may be optionally added to the formulation or composition. These additives can reduce aggregation. This is particularly useful when a pump or plastic container is used. The presence of a surfactant reduces the tendency of the protein to aggregate.

[0134] The formulation comprises at least one anti-IL-23 specific antibody and phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylpa Raben (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzyl chloride from the group consisting of thimerosal, sodium dehydroacetate, and thimerosal or mixtures thereof and a preservative selected from the group consisting of: The present invention relates to a method for the preparation of a pharmaceutical composition comprising administering to a patient a pharmaceutical composition comprising at least one anti-IL-23 specific antibody and a preservative in an aqueous diluent. Mixing is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation: For example, a quantity of at least one anti-IL-23 specific antibody in a buffer solution is added to a desired concentration. and a desired preservative in a sufficient amount of buffer solution to provide the protein and preservative. Variations on this process will be recognized by those skilled in the art. For example, The order of addition of the ingredients, whether or not additional excipients are used, and the temperature and pH at which the formulation is prepared can all be determined by the These are factors that can be optimized with respect to the dosage concentration and means of administration.

[0135] The formulation may be prepared as a clear solution or in the form of a mixture of water, preservatives and / or excipients, preferably phosphate. Salt buffer and / or saline, and a second solution containing the selected salt in an aqueous diluent. A combination comprising a vial of lyophilized anti-IL-23 specific antibody, reconstituted in a vial of It can be provided to the patient as a single solution vial or as a dual vial. Any combination vial requiring configuration can be reused multiple times and can be used in single or multiple It is possible to meet the patient treatment cycle and therefore provide a more convenient treatment regimen than is currently available. We can provide you with the necessary information.

[0136] The product is useful for administration over periods ranging from immediate to 24 hours or more. Thus, the products claimed in accordance with the present invention provide significant benefits to patients. Optionally, safe storage at temperatures between about 2°C and about 40°C will maintain the biological activity of the protein for a long period of time. The packaging label therefore indicates that the solution can be stored for 6, 12, 18, 24, 36, Demonstrate that the product can be retained and / or used for periods of 48, 72, or 96 hours or more. When using stored diluents, such labels may contain up to 1-1 This may include up to 2 months, 6 months, 1.5 years, and / or 2 years of use.

[0137] Solutions of anti-IL-23 specific antibodies are prepared by mixing at least one antibody in an aqueous diluent. The mixture can be prepared by a process comprising: To prepare a suitable diluent, for example, a small amount of water or buffer may be added. At least one antibody is added to the culture medium at a desired concentration of protein, and optionally a preservative or buffer. Variations of this process will be recognized by those of skill in the art. For example, the order of addition of the components, whether additional excipients are used, and the time and place of preparation of the formulation. The temperature and pH of the above can all be optimized for the dosage concentration and means of administration used. It is a factor.

[0138] The claimed product is available as a clear solution or in a second vial containing an aqueous diluent. The method includes the steps of: (a) administering to a patient a vial of at least one lyophilized anti-IL-23 specific antibody that is reconstituted in a lyophilized solution; It can be provided to patients as a single solution vial or as a combination vial that requires reconstitution. Each required combination vial can be reused multiple times for single or multiple patient treatments. cycles, thus providing a more convenient treatment regimen than is currently available. provide.

[0139] The claimed product is a clear solution or a second vial containing an aqueous diluent. a combination comprising at least one lyophilized vial of an anti-IL-23 specific antibody, By providing the vials to pharmacies, clinics, or other such institutions and facilities; It can be provided indirectly to the patient, in which case the clear solution can be up to 1 liter or more. from the larger container, a smaller amount of at least one antibody may be dispensed. The solution is withdrawn one or more times and transferred to smaller vials and dispensed by the pharmacy or clinic. can be provided to customers and / or patients.

[0140] Approved devices that contain single-vial systems include BD Pens, BD Autoj ector(R), Humaject(R), NovoPen(R) , BD® Pen, AutoPen®, and OptiPen® trademark), GenotropinPen (registered trademark), Genotronorm Pen ( Registered trademark), Humatro Pen (registered trademark), Reco-Pen (registered trademark), R oferon Pen(registered trademark), Biojector(registered trademark), Iject(registered trademark) (registered trademark), J-tip Needle-Free Injector (registered trademark), In traject(registered trademark), Medi-Ject(registered trademark), Smartject( Pen-type injector devices for solution delivery such as Becton D ickensen(Franklin Lakes, NJ, www.bectondic kenson.com), Disetronic (Burgdorf, Switzerl) and, www.disetronic.com), Bioject, Portland ,Oregon(www.bioject.com),National Medica l Products,Weston Medical(Peterborough,U K, www.weston-medical.com), Medi-Ject Corp. Manufactured by (Minneapolis, MN, www.mediject.com) (e.g., 100-mL vial systems have been developed), and similar suitable devices. Approved devices include those that deliver reconstituted solutions, such as the HumatroPen®. A pen-type injector system for reconstituting a drug that has been lyophilized in a cartridge for delivery to a patient. Examples of other suitable devices include pre-filled syringes, autoinjectors, and These include needleless injectors, needleless syringes, and needleless IV infusion sets.

[0141] The product may include packaging material that, in addition to any information required by regulatory authorities, The packaging material of the present invention, if applicable, provides conditions under which the product can be used. The anti-IL-23 antibody is reconstituted in an aqueous diluent to form a solution and incubated for a period of 2 to 24 hours or more. Provide patients with instructions to use this solution for the wet / dry two-vial product. For single vial solution products, prefilled syringes, or auto-injectors, label indicates that such a solution can be used for a period of 2 to 24 hours or more. It is useful for pharmaceutical product applications.

[0142] The formulations used in the methods of the invention comprise an anti-IL-23 antibody and a selected buffer, preferably The process includes mixing saline or a phosphate buffer containing a selected salt. The anti-IL-23 antibody and the buffer can be mixed in an aqueous diluent. This is accomplished using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, , adding a quantity of at least one antibody in water or buffer to a desired concentration of protein and buffer. and the desired buffer in a sufficient amount of water to provide the agent. The manner in which the components are added, the order in which additional additives are added, and the like will be recognized by those of skill in the art. The use of , the temperature and pH during preparation of the formulation are all related to the administration concentration and administration method used. It is a factor that can be optimized by

[0143] The methods of the present invention include a variety of formulations that are useful and acceptable for administration to a human or animal patient. The pharmaceutical composition includes water at "normal" conditions as a diluent, and They can be prepared using routine methods well known to those skilled in the art. For example, histidine and histidine- The buffer components, such as hydrochloride hydrate, are provided first, followed by the appropriate non-final volumes of “standard” A water diluent, sucrose, and polysorbate 80 may then be added. Finally, under "standard" conditions using water as the diluent, The volume of the pharmaceutical composition is then adjusted to the desired final volume. Recognize some other ways.

[0144] The pharmaceutical compositions contain the indicated masses of each component per volume unit of water or are "standardized" in the The aqueous solution may be an aqueous solution or suspension having a pH as indicated in the "state of the art." In this specification, the term "standard conditions" means a temperature of 25°C + / - 2°C and a pressure of 1 atmosphere. The term "standard conditions" is used in the art to refer to a single art recognized set of temperatures or It is not used to refer to pressure, but instead refers to a particular composition under "standard state" conditions. Temperature and pressure are reference conditions used to describe solutions or suspensions, including This is because the volume of the solution is in part a function of temperature and pressure. It will be appreciated that pharmaceutical compositions equivalent to those disclosed may be prepared at other temperatures and pressures. The equivalence of such pharmaceutical compositions to those disclosed herein is determined by the above-defined "standard" should be determined under "quasi-state" conditions (e.g., 25°C + / - 2°C and 1 atmosphere pressure). .

[0145] Importantly, such pharmaceutical compositions have a mass of "about" a certain value per unit volume of the pharmaceutical composition. (e.g., "about 0.53 mg L-histidine") or The pH value of the pharmaceutical composition may be a specific value. The isolated antibody may be present in a pharmaceutical composition or may be removed from a pharmaceutical composition. After being diluted (e.g., by dilution), the isolated antibody present in the pharmaceutical composition may be When the mass of a component or a part can be combined, the numerical value is "about" the mass of the component or part. The pH value and other values ​​are determined based on the binding of the isolated antibody after placing the isolated antibody in a pharmaceutical composition. "About" a given value when activity is maintained and detectable.

[0146] Competitive binding assays were performed to determine whether IL-23-specific mAbs bind to similar or different epitopes. Determine whether Abs bind and / or compete with each other. Competing mAb is added, followed by biotinylated hrIL-23. For positive controls, the same mAb was used as a competitor mAb ("self-competition") for coating. IL-23 binding may be detected using streptavidin. The results will show whether the mAbs recognize similar or overlapping epitopes on IL-23. Indicates whether

[0147] One aspect of the methods of the invention involves administering a pharmaceutical composition to a patient.

[0148] In one embodiment of the pharmaceutical composition, the isolated antibody concentration is about 7 mL per mL of pharmaceutical composition. In another embodiment of the pharmaceutical composition, the pH is about 5.5 to about 6.5. be.

[0149] Stable or preserved formulations may be formulated as clear solutions or in aqueous diluents without preservatives or buffers. and a second vial containing excipients. It may be provided to the patient as a combination vial containing a vial of the L-23 antibody. Any solution vials or combination vials requiring reconstitution may be reused multiple times. can satisfy single or multiple patient treatment cycles and therefore are currently available This provides a more convenient treatment regimen.

[0150] Other formulations or methods for stabilizing anti-IL-23 antibodies include permeation of lyophilized powders containing the antibodies. The solution may be other than a clear solution. Non-clear solutions include formulations that contain particulate suspensions. Such particles may be microspheres, microparticles, nanoparticles, nanospheres, or liposomes. Compositions containing anti-IL-23 antibodies in structures of various sizes known variously as globulins. Such relatively homogeneous essentially spherical microparticle formulations containing an active agent are disclosed in U.S. Pat. As taught in US Pat. No. 4,589,330, a non-aqueous phase containing an active agent and a polymer is by contacting the non-aqueous phase with an aqueous phase and then evaporating the non-aqueous phase to cause coalescence of the particles from the aqueous phase. Porous microparticles can be formed by the method taught in U.S. Pat. No. 4,818,542. As described above, a first phase containing an active agent and a polymer dispersed in a continuous solvent is used. The solution can be prepared by removing the solvent from the suspension by freeze-drying or dilution-extraction-precipitation. Preferred polymers for such preparations are gelatin agar, starch, arabinoga Lactan, Albumin, Collagen, Polyglycolic acid, Polylactic acid, Glycolide-L(- ) lactide poly(epsilon-caprolactone, poly(epsilon-caprolactone-C O-lactic acid), poly(epsilon-caprolactone-co-glycolic acid), poly(β- Hydroxybutyric acid), polyethylene oxide, polyethylene, poly(alkyl-2-cyano) acrylate), poly(hydroxyethyl methacrylate), polyamide, poly(amino acid ), poly(2-hydroxyethyl DL-aspartamide), poly(ester urea), poly (L-phenylalanine / ethylene glycol / 1,6-diisocyanatohexane) and poly(methyl methacrylate), a natural or synthetic copolymer selected from the group consisting of or a polymer. Particularly preferred polymers are polyglycolic acid, polylactic acid, glycolic acid, Do-L(-)lactide Poly(epsilon-caprolactone), Poly(epsilon-caprolactone) lactone-co-lactic acid), and poly(epsilon-caprolactone-co-glycolic acid) Solvents useful for dissolving the polymer and / or the active agent Examples of solvents include water, hexafluoroisopropanol, methylene chloride, tetrahydrofuran, The active substances are hexane, benzene, or hexafluoroacetone sesquihydrate. The process of dispersing the first phase into the second phase involves forcing the first phase through an orifice in a nozzle. The step of passing the liquid through the filter may include the step of affecting droplet formation.

[0151] Dry powder formulations can be prepared, for example, by spray drying, or solvent extraction by evaporation, or aqueous or Solvent extraction by precipitation of the crystalline composition followed by one or more steps to remove the non-aqueous solvent. The antibody formulation may also be obtained as a result of processes other than lyophilization, such as spray drying. Antibody-based dry powder compositions are taught in U.S. Patent No. 6,019,968. under conditions to provide a solution or slurry of the body, and optionally, a respirable dry powder. The excipients in the solvent can be produced by spray drying. The stability of antibodies is affected by oxygen-inhibited compounds, such as polar compounds like water and ethanol. The spray drying procedure may be carried out under, for example, a nitrogen blanket, or in the presence of a drying gas. This can be augmented by using nitrogen as a suction source. Another relatively dry formulation is Typically, hydrofluoroalkanes such as those taught in WO 9916419 are used. The stabilized dispersion is a dispersion of a plurality of porous microstructures dispersed in a suspension medium containing a propellant. The resulting dispersion can be administered to the patient's lungs using a metered dose inhaler. Equipment useful in the manufacture of such products is manufactured by Buchi Ltd. or Niro Corp. It is being done.

[0152] The anti-IL-23 antibodies in any of the stable or preserved formulations or solutions described herein As is well known in the art, the present invention can be administered by SC or IM injection, percutaneous, pulmonary, mucosal, or implantation. The pump may be an osmotic pump, a cartridge, a micropump or any other pump known in the art. The present invention can be used in a variety of delivery methods, including other means as will be appreciated by those of skill in the art. It can be administered to a patient.

[0153] therapeutic application The present invention also provides a method for the preparation of ... medicament for the treatment of a brain tumor comprising administering to the patient a therapeutically effective amount of at least one of the following: The IL-23 antibodies of the present invention can be used to, for example, in a cell, tissue, organ, animal, or patient. A therapeutically effective amount of an IL-23 specific antibody is administered or contacted to a cell, tissue, organ, animal, or The present invention also provides a method for modulating or treating psoriasis in a patient.

[0154] Any of the methods of the present invention may be used to treat a cell, tissue, or organ in need of such modulation, treatment, or therapy. administering to the organ, animal, or patient an effective amount of a composition or pharmaceutical composition comprising an anti-IL-23 antibody; Such methods may optionally include administering to a subject a subject for the treatment of such a disease or disorder. The co-administration or combination therapy may further include administering to a subject the at least one anti-IL-2 3. Administering the antibody, specified portion, or variant thereof may be in combination with at least one TNF antagonist ( For example, but not limited to, chemical or protein TNF antagonists, TNF monoclonal antibodies, monoclonal or polyclonal antibodies or fragments, soluble TNF receptors (e.g., p5 5, p70, or p85) or fragments, fusion polypeptides thereof, or small molecule TNF antagonists Drugs such as TNF binding protein I or II (TBP-1 or TBP-II), Nereli Monomab, infliximab, etanercept (Enbrel (TM), adalimumab (Humira™), CDP-571, CDP-870 , afelimomab, lenercept, etc.), antirheumatic drugs (e.g., methotrexate, -Lanofin, aurothioglucose, azathioprine, sodium gold thiomalate, sulfur Hydroxychloroquine, leflunomide, sulfasalazine), muscle relaxants, narcotics, nonsteroidal anti-inflammatory drugs Non-steroid anti-inflammatory drugs (NSAIDs), analgesics, and anesthetics Medications, sedatives, local anesthetics, neuromuscular blockers, antibacterials (e.g., aminoglycosides, antifungals) , antiparasitic drugs, antiviral drugs, carbapenems, cephalosporins, fluoroquinolones, chloride, penicillin, sulfonamides, tetracyclines, and other antibacterial drugs), psoriasis treatment Therapeutic drugs, corticosteroids, anabolic steroids, diabetes-related drugs, minerals, nutritional drugs , thyroid drugs, vitamins, calcium-related hormones, antidiarrheals, antitussives, antiemetics, antitumor drugs, Laxatives, anticoagulants, erythropoietin (e.g., epoetin alfa), filgrastine (e.g., G-CSF, Neupogen), sargramostim (GM-CSF, Le ukine), immunomodulatory agents, immunoglobulins, immunosuppressants (e.g., basiliximab, cytomegalovirus, cyclosporine, daclizumab), growth hormone, hormone replacement drugs, estrogen receptor modulators Antihypertensives, mydriatics, cycloplegics, alkylating agents, metabolic antagonists, mitotic inhibitors, radiopharmaceuticals , antidepressants, antimanics, antipsychotics, anxiolytics, hypnotics, sympathomimetics, stimulants, donepeptides Zil, tacrine, asthma medications, beta agonists, inhaled steroids, leukotriene inhibitors agents, methylxanthines, cromolyn, epinephrine or analogs, dornase alfa (Pulmozyme), a small amount selected from cytokines or cytokine antagonists It further includes administering at least one of the following before, simultaneously, and / or after the administration of the following: , which are well known in the art. See, for example, Wells et al., eds., P Harmacotherapeutic Handbook, 2 nd Edition,Appl eton and Lange, Stamford, CT (2000), PDR Pha rmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing , Loma Linda, CA(2000), Nursing 2001 Handbo ok of drugs,21 stedition, Springhouse Cor p., Springhouse, PA, 2001, Health Profession. al's Drug Guide 2001, ed., Shannon, Wilson, Stang,Prentice-Hall,Inc,Upper Saddle Riv er, NJ, each of which is incorporated herein by reference in its entirety. Be absorbed.

[0155] Treatment Typically, treatment of psoriasis will take approximately 10 minutes, on average, depending on the specific activity of the active agent contained in the composition. A total of at least about 0.01 to 500 milligrams per kilogram of patient body weight per dose. and preferably at least 100 mg / kg of the patient's body weight per single or multiple dose. Anti-IL-23 antibody compositions in the range of at least about 0.1 to 100 milligrams of antibody per kg. The effective serum concentration is affected by administering an effective amount or dose of the composition. The composition may contain a serum concentration of 0.1 to 5000 μg / ml per single or multiple dose. Suitable dosages are known to medical practitioners and will, of course, depend on the particular disease state, the dosage to be administered, and the dosage regimen. It will depend on the specific activity of the composition being treated, and the particular patient being treated. Repeated administration, i.e., repeated individual doses of specific monitored or metered amounts, may be used to obtain the desired therapeutic dose. It may be necessary to provide doses, in which case individual doses may be provided in accordance with the desired daily dose or is repeated until an effect is achieved.

[0156] Preferred doses are optionally 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 1 3, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 , 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 5 3, 54, 55, 56, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67 , 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 9 4, 95, 96, 97, 98, 99 and / or 100-500 mg / kg / dose, or includes any range, value, or fraction thereof, or 0 per single or multiple dose. .1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9, 2.0, 2.5, 2 .9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6 .0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9 .5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 20, 12.5 , 12.9, 13.0, 13.5, 13.9, 14.0, 14.5, 4.9, 5.0, 5 .5., 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11. 9, 12, 12.5, 12.9, 13.0, 13.5, 13.9, 14, 14.5, 15 , 15.5, 15.9, 16, 16.5, 16.9, 17, 17.5, 17.9, 18, 18.5, 18.9, 19, 19.5, 19.9, 20, 20.5, 20.9, 21, 2 2, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55 , 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400 , 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500 , 3000, 3500, 4000, 4500, and / or 5000 μg / ml of serum The present invention may include obtaining a concentration, or any range, value, or fraction thereof.

[0157] Alternatively, the dose administered may be determined based on the pharmacokinetic characteristics of the particular drug and its method and route of administration. , age, health and weight of the recipient, nature and severity of symptoms, type of concurrent treatment, frequency of treatment The dosage of the active ingredient may vary depending on known factors such as the dosage, the amount of the active ingredient administered, and the desired effect. It may be about 0.1 to 100 milligrams per kilogram of weight. Usually, it is 0.1 to 50, preferably Preferably, 0.1 to 10 milligrams per kilogram per dose, or in sustained release form, is used to obtain desirable results. It is effective to obtain

[0158] As a non-limiting example, human or animal treatment may include the use of single, infusion, or repeated doses: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 1 7, 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 At least one day, or in addition, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 2 4, 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, In at least one of weeks 51 or 52, or in addition, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 1 1 day in at least one of the 9th or 20th years, or any combination of these 0.1 to 100 mg / kg per kg, e.g., 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, 4 0, 45, 50, 60, 70, 80, 90, or 100 mg / kg of at least one of the compounds of the present invention. The antibody may also be provided as a single or periodic dose.

[0159] Dosage forms (compositions) suitable for internal administration generally contain about 0.001 milligrams per unit or container. These pharmaceutical compositions contain from about 1000 mg to about 500 milligrams of active ingredient. is typically present in an amount of about 0.5 to 99.999% by weight, based on the total weight of the composition.

[0160] For parenteral administration, the antibody may be administered either together with a pharma- ceutically acceptable parenteral vehicle or separately. provided as a solution, suspension, emulsion, particle, powder, or lyophilized powder, Examples of such vehicles include water, saline, Ringer's solution, dextrose, etc. The solution is 1-10% human serum albumin. Non-aqueous vehicles such as liposomes and fixed oils A vehicle or lyophilized powder may be used. The vehicle or lyophilized powder must maintain isotonicity and chemical stability. Additives that maintain the stability of the solution (e.g., sodium chloride for isotonicity, mannitol; The formulation may contain various additives (e.g., buffering agents and preservatives, for example). Thus, it is sterilized.

[0161] Suitable pharmaceutical carriers are described in Remington's, a standard reference text in this field. Described in the latest edition of Pharmaceutical Sciences, A. Osol It has been done.

[0162] Alternative Administration In order to administer a pharma- ceutical effective amount of an anti-IL-23 antibody, in accordance with the present invention, a number of known The previously described and developed methods can be used. In the following description, pulmonary administration is used. However, other modes of administration may be used in accordance with the present invention with suitable results. The IL-23 specific antibody may be present in the carrier as a solution, emulsion, colloid or suspension. or as a dry powder, by inhalation, or by administration as described herein or in the art. Any of a variety of devices and methods suitable for administration by other methods known in the art. can be used to deliver.

[0163] Parenteral Formulation and Administration Formulations for parenteral administration contain sterile water or saline, polyethylene glycol, and glycerol as common excipients. It may contain polyalkylene glycols such as ethanol, vegetable oils, hydrogenated naphthalene, etc. Aqueous or oily suspensions for injection may be prepared by adding suitable emulsifying agents or wetting agents and The injection preparation can be prepared by using a suspension. The vehicle may be a non-toxic parenterally administrable diluent, such as a suspension in a solvent. The solvent or the solvent may be water, Ringer's solution, isotonic saline, etc. For these purposes, sterile, fixed oils may be used as a suspending medium. Natural, synthetic or semi-synthetic fatty oils or fatty acids, natural, synthetic or semi-synthetic mono Any type of fixed oil, including glycerides, diglycerides or triglycerides, and Fatty acids may be used. Parenteral administration is known in the art and is conventional. Injection means, gas-pressurized needleless injection as described in U.S. Pat. No. 5,851,198 Devices and laser drilling machines such as those described in U.S. Pat. No. 5,839,446. These include, but are not limited to, devices, which are entirely incorporated herein by reference. To be incorporated.

[0164] alternative delivery The present invention further relates to parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraperitoneal, intracapsular, intrachondral, Intracavitary, intracavity, intracerebellum, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic , intrapericardium, intraperitoneum, intrapleura, intraprostate, intrapulmonary, intrarectum, intrakidney, intraretina, intraspinal cord, bursa Intrathoracic, intrauterine, intravesical, intralesional, bolus, intravaginal, rectal, oral, sublingual, intranasal, The anti-IL-23 antibody composition is administered parenterally or via a transdermal route. Oral (subcutaneous, intramuscular or intravenous) or any other administration, particularly liquid solutions or suspensions In particular, semi-prepared formulations, such as, but not limited to, creams and suppositories, are suitable for use in the form of In solid form, such as tablets or capsules, for use in vaginal or rectal administration. For oral or sublingual administration, or in the form of powder, nasal spray, etc., but not limited to or in the form of, but not limited to, an aerosol or certain medications, either intracavity, or by modifying the skin structure, or by increasing drug concentration in transdermal patches. For either, chemical promoters such as dimethyl sulfoxide (Junging er, et al. In “Drug Permeation Enhancement; "Hsieh, DS, Eds., pp.59-90 (Marcel Dekker, Inc. New York 1994, which is incorporated herein by reference in its entirety), The application of protein and peptide-containing formulations to the skin (WO 98 / 53847 No. 5, or for creating a transient transport pathway, such as by electroporation, or Application of an electric field to increase the mobility of a charged drug through the skin, such as in iontophoresis or application of ultrasound, such as sonophoresis (U.S. Pat. Nos. 4,309,989 and 4,713,621). No. 67,402) by using an oxidizing agent that enables the preparation of a gel, ointment, lotion, suspension or The compositions may be prepared transdermally, such as, but not limited to, a patch delivery system. (The above publications and patents are incorporated herein by reference in their entireties.)

[0165] Having generally described the invention, it is to be understood that the same is offered by way of illustration and not by way of limitation. This will be more readily understood by reference to the following non-exhaustive examples. Further details of the present invention are illustrated by the following non-limiting examples. The disclosures are expressly incorporated herein by reference.

[0166] Example 1: Guselkumab (GUS) and anti-TNF in patients treated over a one-year period Comparison of efficacy and safety with the alpha antibody adalimumab (ADA) and placebo (PBO).

[0167] To confirm findings from previous studies, two pivotal Phase III clinical trials: YAGE1 and VOYAGE2 were conducted. Psoriasis patients who were treated continuously for one year In this study, guselkumab was compared with adalimumab, a widely used TNF-α inhibitor. Efficacy, safety, and patient-reported outcomes from VOYAGE 1 compared with placebo In addition, the results of an additional study known as VOYAGE 2 (Practical Opinion Study) were reported. In Example 2, the efficacy of guselkumab was demonstrated in psoriasis patients treated for 24 consecutive weeks. The study compared adalimumab with adalimumab and placebo, with a randomized withdrawal period beginning after 28 weeks of treatment. This also includes the time.

[0168] Materials / Methods Overview of VOYAGE1: VOYAGE1 is a phase 3, randomized, double-blind This is a placebo-controlled clinical trial. Eligible patients (age 18 years or older) were plaque psoriasis, Investigator Global Assessment [IGA] score of ≥3, psoriasis aspect ratio of ≥12 Patients with Patient Area and Severity Index [PASI] score and ≥10% body surface area disease who were not receiving systemic treatment At baseline, 837 patients were randomized to 0 / 4 / 1 PBO was administered in week 2, then switched to GUS 100mg in weeks 16 / 20, then q8w group (n=174) administered GUS 100mg at weeks 0, 4, and 12 for 44 weeks; 0 weeks, followed by q8wk for 44 weeks (n=329); DA was administered at 80 mg, 40 mg in the first week, and then 40 mg q2wk for 47 weeks. Patients were randomly assigned to receive either 1 mg or 2 mg of nivolumab (n=334). Eliminated / minimal disease (IGA 0 / 1) at 6 weeks and 90% in PASI score The proportion of GUS patients achieving improvement (PASI90) was compared to PBO patients. Evaluation items included IGA0 / 1, IGA0, PASI90, and There was no effect of infection on PASI100 and PASI200 scores, and health-related quality of life at 24 / 48 weeks. Achieved a skin condition questionnaire score of 0 / 1 (DLQI 0 / 1), indicating no The safety profile was assessed over 48 weeks. Monitored.

[0169] Summary of VOYAGE 1 results: At week 16, PBO patients were significantly more likely to receive GUS than PBO patients. A significantly higher (p<0.001) proportion of patients had IGA 0 / 1 (85.1% vs. 6.9%) and and PASI90 (73.3% vs. 2.9%). IGA 0 / 1 was achieved at week 16. and the proportion of patients achieving PASI90 (7 GUS was also superior to ADA on the basis of 3.3% vs. 49.7% (p<0.01). Similarly, a significantly higher proportion (p<0.001) of patients had Responses were achieved for GUS versus ADA: IGA0 (52.6% vs. 29.3%) ), IGA0 / 1 (84.2% vs. 61.7%), PASI100 (44.4% vs. 24.9%) %), and PASI90 (80.2% vs. 53.0%). The corresponding response rates at 48 weeks were IGA0 (50.5% vs. 25.7%), IGA0 / 1 (80.5% vs. 55.4%), PA SI100 (47.4% vs. 23.4%) and PASI90 (76.3% vs. 47.9%) All p<0.001. DLQ of 0 / 1 in patients in the GUS vs. ADA group The proportion of patients with an I score was 60.9% vs. 39.5% at 24 weeks and 62. 5% vs 38.9% (both p<0.001). At 48 weeks, GUS and ADA Adverse events occurred in 73.9% and 74.5% of patients, respectively, with serious adverse events occurring in 73.9% and 74.5% of patients, respectively. The rates were similar for the GUS and ADA groups (4.9% vs. 4.5%). Disease occurred in two GUS patients and three ADA patients. Two malignant tumors (prostate One case of myocardial infarction occurred in each active treatment group. .

[0170] Summary of VOYAGE 1 conclusions: GUS is an effective treatment for moderate to severe psoriasis A and was well tolerated over the course of 1 year of treatment.

[0171] Background: Guselkumab, an interleukin-23 (IL-23) blocker, is a phase II Superior to adalimumab in treating moderate to severe psoriasis in clinical trials .

[0172] Objectives: To assess the efficacy and safety of guselkumab in patients with psoriasis treated over one year. to compare with adalimumab and placebo.

[0173] Methods: Patients were randomized to receive guselkumab 100mg at weeks 0 / 4 / 12, then q8wk (n=329), placebo administered at weeks 0, 4, and 16, and then at weeks 16 and 20. Switch to guselkumab 100 mg q8wk (n=174), or , adalimumab 80 mg at week 0, 40 mg at week 1, then 40 mg q2w Patients were randomly assigned to receive either 100 mg or 100 mg twice daily (n=334). Patient-reported scores were calculated based on the Interpersonal Global Assessment (IGA) score, Psoriasis Area and Severity Index (PASI), and Patient-reported scores. Outcomes (PROs, Skin Profile Questionnaire [DLQI], psoriasis symptoms and signs Patients were randomly assigned to receive a follow-up questionnaire (PSSD) and safety were assessed over 48 weeks.

[0174] Results: Guselkumab was superior to placebo at week 16 (p<0.001) (8 5.1% vs. 6.9% [IGA0 / 1] and 73.3% vs. 2.9% [PASI90]). Selkumab also improved IGA0 / 1 and PASI90 at week 16 (85.1% vs. 65.9%, 73.3% vs. 49.7%) at week 24 (84.2% vs. 61.7%, 80. 2% vs. 53.0%), and at 48 weeks (80.5% vs. 55.4%, 76.3% vs. 47.9%). %), which was superior to adalimumab (p<0.001). The treatment significantly improved PROs over 48 weeks. The incidence of adverse events was significantly higher over 48 weeks. was comparable between treatments.

[0175] LIMITATIONS: Analysis was limited to 48 weeks.

[0176] Conclusion: Guselkumab showed superior efficacy compared with adalimumab in patients with psoriasis. It has been well tolerated for up to one year.

[0177] Materials and Methods patient Clinical trials were conducted in patients with moderate to severe plaque psoriasis (i.e., investigator global assessment [I GA] score ≥ 3, Psoriasis Area and Severity Index [PASI] ≥ 12, and body surface area Patients aged 18 years or older with BSA lesions ≥ 10% for at least 6 months Patients enrolled were those who were candidates for systemic or phototherapy. Patients had severe, progressive, have a history or current symptoms of a medical condition that is uncontrolled or uncontrolled within the last 5 years Patients are ineligible if they have a current or history of malignant disease, except for melanoma skin cancer (NMSC). Patients with a history or symptoms of active tuberculosis (TB) were excluded. If receiving selkuma or adalimumab, received other anti-TNF-α therapy within 3 months If the patient has received other drugs targeting IL-12 / 23, IL-17, or IL-23 within 6 months, If you have been treated with any systemic immunosuppressant (e.g., methotrexate) within the last 4 weeks Patients were ineligible for participation if they had received chemotherapy (e.g., chemotherapy with vitiligo) or phototherapy.

[0178] Experimental design VOYAGE 1 was conducted at 104 centers worldwide (December 2014–2016). (April 2019), a Phase III, randomized, double-blind, placebo- and active-controlled clinical trial. The study will include an active comparison period (0-48 weeks) comparing guselkumab to adalimumab, and Includes a placebo-controlled period (weeks 0-16), followed by crossover of placebo patients to 4 Patients were randomized to receive guselkumab for 8 weeks. Kumab 100 mg was administered at weeks 0, 4, and 12, and then every 8 weeks for 44 weeks. The control group received placebo at weeks 0, 4, and 12, followed by guselkumab 100 mg for 16 , administered at week 20 and then every 8 weeks for 44 weeks, or Adalimumab 80 mg, 40 mg in week 1, then 40 mg every 2 weeks for 47 Patients were randomly assigned in a 2:1:2 ratio to receive either 1 or 2 weekly doses of A matching placebo was used. The study protocol was approved by the National Center for Clinical Trials and patients were required to provide written informed consent before the study began. submitted the following:

[0179] evaluation Efficacy was evaluated using IGA, PASI, scalp-specific IGA (ss-IGA), and fingernail physician evaluation. Global Assessment (f-PGA), Nail Psoriasis Area and Severity Index (NAPSI), and Hand / Foot Psoriasis Patient-reported outcomes were assessed using the human femoral-facet-gastroenterological analysis (hf-GPA). The DLQI questionnaire and the Psoriasis Symptoms and Signs Diary (PSSD) were used. Safety monitoring included the collection of adverse events (AEs) and laboratory tests. Ta.

[0180] A sensitive and drug-tolerant electrochemiluminescence immunoassay was used to identify the antibody versus guselkumab. The sensitivity was 3.1 ng / mL in guselkumab-free serum and 3.1 ng / mL in mean trough blood plasma. In serum, guselkumab concentrations of up to 3.125 μg / mL exceeded serum guselkumab levels. The level was 15ng / mL.

[0181] Statistical analysis: The co-primary endpoint was elimination of gliomas at week 16 in the guselkumab group compared with placebo. or achievement of an IGA score of minimal disease (IGA 0 / 1) and a PASI response of 9 The proportion of patients achieving a PASI90 response rate of 0.0% was also measured. All randomized patients were included in the primary and selected secondary efficacy analyses. The primary and main secondary analyses were performed using a fixed sequence method. Multiplicity was controlled for by testing.

[0182] The composite primary endpoint and binary secondary endpoints were assessed by pooled investigator sites. Cochran-Mantel-Haenszel (CMH) stratified by Analysis was performed using the chi-square test. With a sample size of approximately 750 patients, a significant difference could not be detected. The statistical power to predict the outcome was >99% for both composite outcomes. Continuous response parameters were then compared with investigator site pooled as a covariate. All statistical tests were two-sided (α = 0.05).

[0183] Patients who discontinued study drug due to lack of efficacy or worsening psoriasis AEs or due to protocol Patients who initiated prohibited psoriasis treatments were considered inadequate responders for the dichotomous endpoint. All patients had missing data and had baseline values ​​carried over for the continuous endpoints. Patients were considered inadequate responders for binary endpoints (imputed as inadequate responders) Methods), and for continuous endpoints (and all PSSD endpoints), the last observed value Complemented.

[0184] The safety analysis included all patients who received at least one dose of study drug and included The proportion of patients with antibodies to guselkumab was compared with the proportion of patients with biologics The data were compiled for those who received at least one dose.

[0185] result At baseline, 837 patients were randomly assigned to receive either placebo (n=174), guselkumab ( Patients were randomized to receive either adalimumab (n=329) or adalimumab (n=334). Overall, 4 At 8 weeks, 6.9% of patients in each of the placebo, guselkumab, and adalimumab groups , 8.5%, and 15.6% discontinued treatment. Demographic and disease characteristics were The results were comparable across treatment groups in the study.

[0186] Clinical response Guselkumab was superior to placebo and and / or adalimumab (all p<0.001) compared with placebo. In comparison, a significantly higher proportion of patients in the guselkumab arm achieved an IGA of 0 / 1 at week 16 (6.9% vs. 85.1%) and PASI90 (2.9% vs. 73.3%) achieved PASI At least 75% improvement in PASI score (PASI75) and IGA score 0 and PASI score 100 The achievement rate was significantly higher with guselkumab versus placebo at week 16. At week 16, Mab achieved IGA 0 / 1 (85.1% vs. 65.9%) and PASI90 (73.3%) outcomes. % vs. 49.7%), and the proportion of patients achieving PASI 75 (91.2% vs. 73.1%) was superior to adalimumab as measured by the A significantly better response to selkuma was seen at week 24 (IGA0 [52.6% vs. 29.3% ], IGA0 / 1 [84.2% vs. 61.7%], and PASI90 [80.2% vs. 53. 0%]) and at 48 weeks (50.5% vs. 25.7%, 80.5% vs. 55.4%, respectively). %, and 76.3% vs. 47.9%). A higher proportion of patients achieved a higher PASI response at week 48 compared with adalimumab After starting guselkumab at week 16, patients in the placebo crossover group Responses similar to those observed in the cumab group were achieved.

[0187] Topical Psoriasis Scale Topical psoriasis was classified based on ss-IGA, f-PGA, NAPSI, and hf-PGA assessments. The results were evaluated in the guselkumab group for ss-IGA0 / 1 (absent / very mild scalp psoriasis) The proportion of patients achieving AF was significantly higher compared to placebo at week 16 (83.4% vs. 1 4.5%, p<0.001), with a significantly better response to guselkumab versus adalimumab was observed at weeks 24 (p<0.001) and 48 (p=0.045). The proportion of patients achieving GA 0 / 1 (elimination / minimal) and improvement rate in NAPSI were 16 The effect was significantly higher for guselkumab than for placebo at week 1 (p<0.001). PGA responses were similar at 24 weeks, but guselkumab was superior to adalimumab at 48 weeks. The mean improvement in NAPSI score with guselkumab was superior to that with placebo (p=0.038). was significantly higher than placebo at week 16 (p<0.001) and at weeks 24 and 48 The results were comparable between guselkumab and adalimumab in patients with hf-PGA0 / 1 The proportion of patients who achieved (elimination / near elimination) was 100% with guselkumab versus placebo at week 16 The response to guselkumab was significantly higher than that to adalimumab at weeks 24 and 48. was also superior (p<0.001).

[0188] Health-related quality of life measures At week 16, improvement from baseline in DLQI was 0 / 1 (DLQI 0 / 1; HRQo The proportion of patients achieving psoriasis without any effect on L compared to placebo The difference was significantly greater in the coumab group (mean change, -0.6 vs. -11.2) (both p<0.01). At weeks 24 and 48, improvement from baseline in DLQI and The proportion of patients achieving DLQI 0 / 1 was significantly higher with guselkumab than with adalimumab. was higher (p<0.001).

[0189] At week 16, improvement from baseline in PSSD symptom scores was greater than or equal to placebo The mean change in PSSD symptom score was significantly higher in the guselkumab group (mean change, -3.0 vs. -41.9) The mean change in was similarly favorable for guselkumab (both p<0.001). Similarly, PSSD symptom and sign scores in the guselkumab group at weeks 24 and 48 were The mean change in was significantly greater in the adalimumab group than in the placebo group (p<0.001). Proportion of patients achieving PSSD symptom score = 0 with guselkumab and adalimumab The rates of AF and AF-related adverse events at week 24 were 36.3% and 21.6%, respectively, with a statistically significant difference from guselkumab. The significantly better response was sustained at week 48 (p<0.001). The proportion of patients achieving a PSSD symptom score of 0 at week 8 (p<0.001) Similar results were observed.

[0190] Safety outcomes During the placebo-controlled period (weeks 0 to 16), the proportion of patients with at least one AE was cured. The incidence rates were comparable across treatment groups, with the most commonly reported events occurring in all three groups. The most common adverse events were nasopharyngitis and upper respiratory tract infection. AEs occurred infrequently and in similar proportions of patients with each treatment. The incidence of overall infections and infections requiring antibiotic treatment was similar across treatment groups. Two patients in the adalimumab group experienced serious infections (both cellulitis). One case of NMSC (i.e., basal cell carcinoma [BCC]) was reported in the guselkumab arm and No malignancies occurred in either group. One myocardial infarction (i.e., major myocardial infarction) occurred. Adverse cardiovascular events (MACE) occurred in each active treatment group throughout the 16-week period.

[0191] The types and patterns of AEs reported over the 48-week period were significantly higher than those reported during the placebo-controlled period. The results were similar to those reported in the previous study. The proportion of patients with EGFR was similar in the guselkumab and adalimumab groups. During the 8-week period, serious infections occurred in 2 patients in the guselkumab group (i.e., 1 case of cellulitis and 1 case of bronchitis). and one with a thigh abscess with postoperative wound infection), and two cases in the adalimumab group (i.e. One was an abdominal abscess and the other was a fatal outcome in a patient with abdominal wall cellulitis reported earlier. Overall infection and antibiotic treatment Infections requiring follow-up occurred at similar rates across treatment groups. No active tuberculosis or No suspected infectious AEs were reported. Two additional cases of NMSC (i.e., Gusse One BCC in each of the lucumab and adalimumab groups) and two malignancies (i.e. Prostate and breast cancer in the guselkumab group were reported at 48 weeks. Additional MA was reported after 16 weeks. No CEs occurred. One suicide attempt was reported in an adalimumab patient. The incidence of didiasis and neutropenia was low and similar between the guselkumab and placebo groups. (data not shown), and no Crohn's disease events were reported through 48 weeks.

[0192] The proportion of patients with ISR (2.2% vs. 9.0%) and ISR-related The rate of associated injections (0.5% vs. 1.2%) was lower with guselkumab compared with adalimumab. Most ISRs were considered mild. The incidence of laboratory abnormalities was low and there was no significant difference between the groups. No differences were observed (data not shown). Antibodies to guselkumab were administered for 44 weeks. Overall, it was detected in 26 / 492 patients (5.3%), and titers were generally low (8 1% ≤ 1:320). There is a significant correlation between the development of antibodies and either a decrease in efficacy or the development of ISR. No clear associations were observed (data not shown).

[0193] Consideration The findings in the VOYAGE 1 study are described in Example 2 below. Results of the study included two injections of 100 mg guselkumab (at weeks 0 and 4) and one every 8 weeks The study confirmed that maintenance therapy with guselkumab effectively treats moderate to severe infections. The study used two rigorous endpoints (IGA0 / 1 and PASI90) to assess the efficacy and safety of 16-week Guselkumab was superior to placebo by a significant margin in both groups. , with evidence of a significant response as early as week 2 compared with placebo. IG has been shown to be more effective than adalimumab, a widely used and highly effective subcutaneous TNF-α inhibitor. The 16-week endpoints of A0 / 1, PASI90, and PASI75 were also superior. Response rates continued to improve with guselkumab beyond week 16. Weeks 24 and 48 Approximately half of all patients in the guselkumab group achieved complete elimination (IGA0), is associated with optimal HRQoL for patients with psoriasis. Patient reports indicating minimal / no effect on the skin or absence of symptoms or signs of psoriasis The reported outcome measures (PSSD and DLQI) were superior to placebo at 16 weeks. and demonstrated superior responses to guselkumab compared with adalimumab at weeks 24 and 48 .

[0194] The study evaluated multiple hard-to-treat areas of the body for psoriasis, with guselkumab Guselkumab was highly effective in all sites based on rigorous endpoints. Superior to placebo at week 6 and superior to adalimumab at weeks 24 / 48 Complete or near complete resolution of scalp and hand / foot psoriasis in at least 75% of guselkumab-treated patients The proportion of patients with eliminated / minimal fingernail psoriasis (f-PGA0 / 1) and N Based on both the mean improvement in APSI and placebo at week 16, guselkumab was significantly Nail responses were comparable to active treatment at 24 and 48 weeks, with no significant difference in the habit of Lucumab was superior to adalimumab in terms of f-PGA0 / 1 at week 48 (75 % vs. 62%).

[0195] The incidence and types of AEs, SAEs, and laboratory abnormalities were significantly higher with guselkumab than with placebo through 16 weeks. There were approximately 100% significant differences between the guselkumab and placebo groups and between the guselkumab and adalimumab groups through 48 weeks. The incidence of serious infections, malignancies, and MACE was low across treatment groups. No notable differences in the incidence of neutropenia or candidiasis were observed between guselkumab and control. No Crohn's disease AEs were observed between the treatment groups. One suicide attempt was reported in the adalimumab group. Number and percentage of injections in patients with ISR The size and duration of this study Time may not allow for evaluation of rare events or those with long latencies, but Treatment over a period of time will be evaluated in an extension of the ongoing study.

[0196] VOYAGE1 confirms the role of IL-23 in the pathogenesis of psoriasis. TNF-α inhibition The drug is effective in many diseases, and TNF-α inhibits normal systemic inflammatory and immunological processes. Selective targeting of the IL-23 pathway compared with TNF-α blockade , a new anti-psoriasis treatment with higher efficacy, while maintaining a favorable safety profile IL-23 provides differential cytokine inhibition to Th17 cell differentiation and survival. It is a driver and upstream regulator of IL-17A, a central inflammatory enzyme involved in the pathogenesis of psoriasis. Furthermore, IL-23 is an effector cytokine that mediates the expression of other Th17 subunits by other cell types. Stimulates the production of cytokines (e.g., IL-22) in innate lymphoid cells type 3 These include interleukin-3 (ILC3) cells and γδ T cells. Thus, inhibition of IL-23 reduces the Blocks downstream production of IL-17A, IL-22, and other cell types. Because these cells depend on IL-23 for survival, inhibition of IL-23 may abrogate these pathogenic This may explain the long duration of effect and may be due to the anti-TNF-α and anti-IL-1 -17 This may allow for convenient dosing intervals for guselkumab compared with both agents.

[0197] These findings, along with those from VOYAGE 2, compared adalimumab in psoriasis. Superior efficacy of guselkumab, efficacy in localized disease of the scalp, nails, and hands / feet; and Demonstrate a clear safety profile. Related therapies, ustekinumab (IL-12 and To review the long-term safety findings reported for IL-23 (which blocks both IL-1 and IL-23) Given this, the favorable safety profile through one year is not unexpected. The efficacy and safety of guselkumab will continue to be evaluated and long-term outcomes will be evaluated based on the ustekinumab study. This will increase the understanding of IL-23 blockade.

[0198] Example 2: VOYAGE2 Results To confirm the therapeutic potential of guselkumab, Phase 3 trials VOYAGE 1 and VOYAGE The two studies evaluated the efficacy and safety of guselkumab versus placebo and adalimumab. VOYAGE 1 evaluated continued treatment for 1 year, and VOYAGE 2 evaluated continued treatment for 24 weeks. The efficacy and safety of continuous maintenance therapy beyond 28 weeks were also evaluated using a randomized withdrawal approach. In addition, VOYAGE 2 evaluated the efficacy and safety of adalimumab-guselkumab conversion. Evaluate transitions and provide clinically relevant information for patients switching biologics .

[0199] Materials and Methods patient Adults (aged 18 years or older) with moderate to severe plaque psoriasis were eligible. The important inclusion / exclusion criteria are summarized in VOYAGE1 above. The study was approved by the Institutional Review Board at the institution, and written informed consent was obtained. All patients provided.

[0200] Experimental design VOYAGE2 was conducted at 115 facilities around the world between November 2014 and June 2016. A phase 3, multicenter, randomized, double-blind, placebo- and adalimumab-controlled study This study had a placebo-controlled period (weeks 0 to 16 weeks), active control period (weeks 0-28), and randomized withdrawal and retreatment period (weeks 28- The study consisted of 72 weeks of randomized controlled trials. Results from the 48th week of the study are presented here. At baseline, 100 mg of guselkumab was administered at weeks 0, 4, 12, and 20. Placebo was administered at weeks 0, 4, and 12, followed by guselkumab at weeks 16 and 20. or adalimumab 80 mg at week 0 and 40 mg at week 1, followed by Patients were randomized in a 2:1:1 ratio to receive either 100 mg once every 2 weeks (q2W) for 23 weeks. did.

[0201] At week 28, patients were expected to achieve 90% improvement from baseline in psoriasis area and severity measures. Guselkumab-treated patients (PASI90, responders) were randomized to guselkumab or placebo for 1: In this study, inadequate responders were randomized to receive PASI from treatment. Failure to achieve PASI response was defined as failure to achieve 90% at week 28. Patients were re-treated with guselkumab, receiving another dose 4 weeks later, then q8w thereafter Non-responders to guselkumab continued guselkumab treatment. Placebo → Week 28 Non-responders to guselkumab continued on guselkumab q8w, whereas responders were treated with guselkumab q8w from week 28 onwards. Patients received placebo q8w at the start of treatment and upon ≥50% loss of PASI response at 28 weeks , patients were re-treated with guselkumab followed by another dose 4 weeks later, then q8 Non-responders to adlimumab were administered guselkumab at week 28 and 4 weeks later Adalimumab responders received a placebo. Upon loss of ≥ 50% PASI response at 28 weeks, guselkumab was initiated and Another dose was administered q8W thereafter. Both cumab and adalimumab placebo were administered as needed.

[0202] Efficacy and safety evaluation Efficacy was evaluated through 24 weeks, and safety was evaluated through 28 weeks. Key efficacy data, including data on psoriasis, patient-reported outcomes, and safety measures, were collected from the VOYAGE 1 trial. In addition, this study included 36 medical outcome studies. The SF-36 questionnaire was evaluated in this study.

[0203] Study Evaluation Items The co-primary endpoint was eliminated at week 16 in the guselkumab vs. placebo groups. Proportion of patients achieving an IGA score of (0) or a minimum of (1) and PASI at Week 16 The proportion of patients achieving a response of ≥ 90% was included in the study. Key secondary outcomes were also measured. The focal psoriasis endpoints evaluating the nails and hands / feet are described in detail elsewhere.

[0204] statistical analysis All randomized patients were included in the primary analysis and in the randomized control group according to their assigned treatment arm. and several secondary analyses. To evaluate the efficacy and safety of schizophrenia in patients with schizophrenia who underwent a second randomization and underwent a PASI assessment at 28 weeks, Patients were included in the analysis.

[0205] The composite primary endpoint and binary secondary endpoints were stratified by investigator's site. The covariates were analysed using the Cochran-Mantel-Haenszel (CMH) chi-square test (α = An analysis of variance model was used to compare continuous response parameters with site and Time to loss of PASI90 response was compared across sites stratified by locoregional Grank's test was used.

[0206] Patients who discontinued study treatment due to lack of efficacy or AE of worsening psoriasis or AE of improvement of psoriasis Patients who initiated protocol-prohibited medications / therapy were considered treatment failures. Patients who met treatment failure criteria before week 16 and those who did not return for evaluation at week 16 were included in the 1 Patients randomized to placebo were considered non-responders to the primary endpoint at 6 weeks. For patients who cross over to receive guselkumab at week 16 / week 16, Only those patients with ≥ 16 weeks of baseline schizophrenia were included in the efficacy analysis at 16 weeks.

[0207] To control the overall type I error rate, the primary and secondary analyses were performed in a fixed order. The first primary secondary endpoint was studied only if the coprimary endpoint was met. and the subsequent evaluation item(s) are satisfied if the preceding evaluation item(s) in the sequence are satisfied. Only tested.

[0208] Safety analyses included all patients who received at least one dose of study drug. Events and serious adverse events (SAEs) were grouped according to treatment received. Antibodies to cumab were analyzed.

[0209] result Patient demographics and baseline demographic characteristics A total of 1279 patients were screened, and 992 were selected for treatment with guselkumab (n=496); Patients were randomized 2:1:1 to receive placebo (n=248) or adalimumab (n=248). Overall, 9.7% (96 / 992) of patients were randomly assigned to receive the 48-week The study drug was discontinued throughout the study (guselkumab: 7.9%, placebo: 11.7%, adalimumab: 11.7%). Mab: 11.3%). Baseline demographic and disease characteristics were generally comparable between groups. .

[0210] Effectiveness Guselkumab was superior to placebo and and / or adalimumab (all p<0.001).

[0211] Placebo-controlled period (weeks 0-16) At week 16, a significantly greater proportion of guselkumab patients had elimination compared with placebo patients. achieved a median (0) or minimal (1) IGA (84.1% vs. 8.5%, p<0.001 ), and achieved a PASI90 response (70.0% vs. 2.4%, p<0.001) (combined Primary endpoint: A significantly higher PASI improvement rate was observed in patients with guselkumab compared to placebo patients (p=0.001). This was observed as early as week 16 (p<0.001). A significantly higher proportion of guselkumab patients achieved PASI 75 and PASI 1 responses compared with bronchodilator patients. At week 16, guselkumab patients achieved ss-I response rates of 1.00 vs. placebo. All localized psoriasis outcome measures, including GA, f-PGA, NAPSI, and hf-PGA As in VOYAGE 1, guselkumab achieved greater improvements in SF -36 plus the Skin Condition Questionnaire (DLQI) and psoriasis symptoms and signs All patient-reported outcomes, including the patient-reported self-reported diary (PSSD), were significantly higher than placebo at week 16. was better than.

[0212] Comparison period (0-24 weeks) A significantly greater proportion of patients in the guselkumab arm achieved IGA 0 / 1 and PASI 90 responses at week 16. At week 24, patients with adalimumab achieved a 100% response, 95% confidence interval (CI): 1.0 - 1.0; In mab, IGA0 (51.5% vs. 31.5%), IGA0 / 1 (83.5% vs. 64 .9%), PASI90 (75.2% vs. 54.8%), and PASI100 (44.2% Consistent with VOYAGE 1, the response rate was significantly higher in both groups (26.6% vs. 18.1%). With the exception of improvement rates in f-PGA0 / 1 and NAPSI, which were similar, localized psoriasis disease severity was Greater improvements in core were seen in guselkumab patients compared with adalimumab patients (2. At week 24, improvements in DLQI 0 / 1 and PSSD symptom and sign scores were observed. The proportion of patients achieving a mean change of 0, a PSSD symptom score of 0, and a symptom score of 0 The proportion of patients with refractory pulmonary edema was significantly greater in the guselkumab group than in the adalimumab group (p < 0.05). 0.001).

[0213] Randomized withdrawal and retreatment period (28-48 weeks) PASI90 responses were compared with responders re-randomized to placebo (withdrawal group). Guselkumab was maintained better in responders at 28 weeks (maintenance group) who continued on guselkumab The median time to loss of PASI90 response was 1.0% in patients randomized to withdrawal. Among patients who discontinued guselkumab at week 28, PAS The I90 response rate began to diverge from the maintenance group at week 32. Through week 48, 80% of maintenance patients 8.6% maintained a PASI90 response compared with 36.8% of withdrawn patients. At week 48, clinical response (IGA, PASI) was significantly higher in the maintenance group than in the withdrawal group. (p<0.001). DLQI and PSSD symptom or sign scores from baseline Improvement in a was also significantly greater at week 48 in the maintenance group versus the withdrawal group ( Through 48 weeks, a small number of patients (n=16) received guselkumab. Re-treated.

[0214] Switching to guselkumab in adalimumab non-responders Overall, 112 adalimumab non-responders were randomly assigned to Guselkumab was started after 5 weeks of chemotherapy (after 5 weeks of chemotherapy). The response rates for sline and PASI100 increased after switching and were The figures reached 66.1% and 28.6%, respectively.

[0215] safety Placebo-controlled period (weeks 0-16) The proportion of patients with at least one AE, AEs leading to discontinuation, and SAEs was The incidence rates were comparable between the lucumab and placebo groups. The most commonly reported events were nasopharyngitis. The most common side effects were headache, headache, and upper respiratory tract infection. The incidence of infections, infections requiring treatment, and serious Serious infections were similar between groups. Malignancies or nonmelanoma skin cancers (NMSCs) occurred in 16 None were reported throughout the week. One major adverse cardiovascular event (MACE) (myocardial infarction [M I) occurred in the adalimumab group. A higher proportion of adalimumab patients had Limumab patients suffered from injection site reactions (ISR) (6.9% vs. 2.6%) and ISR injection site reactions (1.5% vs. 0.9%). All injection site reactions were mild.

[0216] Comparison period (0-28 weeks) The types of AEs were similar to those reported during the placebo-controlled period. The proportion of patients with AEs, AEs leading to discontinuation, and SAEs was The incidence of infections and infections requiring treatment was also comparable between the guselkumab and guselkumab arms. The clinical outcomes were comparable between the adalimumab and guselkumab groups. Three serious infections occurred in each of the guselkumab and adalimumab groups. There were 2 cases of bronchitis, erythema, and soft tissue infection in the adalimumab group and 2 cases of tuberculosis in the adalimumab group [1 One case of malignancy (prostate cancer) and one case of injection site abscess were reported. Two cases of NMSC (one squamous cell carcinoma [SCC] in the guselkumab arm and one pla Two MACE cases (basal cell carcinoma [BCC] in the sebo → guselkumab group) were reported. One case of MI was reported in each of the guselkumab and adalimumab groups.

[0217] Randomized withdrawal and retreatment period (28-48 weeks) From weeks 28 to 48, no patients discontinued treatment due to AEs, and one serious infection (appendix No additional malignancies, NMSC, or MACE were reported. No AEs were reported among the 16 retreated patients.

[0218] Further safety through 48 weeks Through week 48, 1 additional BCC and 1 additional SCC of the skin occurred in placebo vs placebo-treated patients. One additional M occurred in the guselkumab group (data not shown) between weeks 28 and 48. ACE (MI) was reported in placebo → guselkumab patients. Serious infections, No major tumor or MACE events occurred in the adalimumab → guselkumab group. Death No opportunistic infections, hypersensitivity reactions, or anaphylactic reactions occurred over the 48 weeks. The incidence of laboratory abnormalities was low and similar between treatment arms through 48 weeks. Antibodies against IFN-α were detected in 57 / 869 (6.6%) patients through 48 weeks, with titers of The incidence of antibodies and reduced efficacy or ISR was low overall (88% ≤ 1:160). No clear association was observed between any of the occurrences (data not shown).

[0219] Consideration VOYAGE 2 demonstrates guselkumab's efficacy in treating a broad range of moderate-to-severe psoriasis populations We will review the results of VOYAGE 1, which confirms that guselkumab is highly effective. The 16-week composite primary endpoint of resolved / minimal IGA and PASI90 response was Guselkumab was also superior to Sebo in terms of eliminated / minimal IGA, PASI75 / 90 at 16-week endpoints and through 24-week excluded IGA and PAS Guselkumab was also superior to adalimumab in I90 / 100. Successfully treated difficult localized psoriasis involving the hands / feet. Improvement as assessed by investigator was Patient-reported outcomes assessed in VOYAGE1 (DLQI and PSSD, psoriasis symptoms) Patient-reported outcomes were assessed using a newly validated scale measuring symptoms and In addition, a significant improvement in quality of life (QoL) (SF-36) was observed in the VOY The combined robustness of the data from VOYAGE1 and VOYAGE2 was reported. The overall results showed superiority over both placebo and adalimumab.

[0220] Consistent with findings of other biologics for psoriasis, VOYAGE2 demonstrated that maintenance therapy was more effective than interrupted therapy. and that blocking IL-23 does not reverse the underlying mechanisms of psoriasis. Unlike VOYAGE 1, in which patients continued treatment for 48 weeks, VOY In AGE2, PASI90 responders at week 28 were randomized to continue guselkumab or placebo. Patients treated with guselkumab were randomized to receive either PASI 90 or PASI 100. 100, and maintained responses including eliminated IGA, while in placebo patients, psoriasis slowly progressed. There was frequent relapse and a decline in QoL. Time to loss of PASI90 response for withdrawn patients The median discontinuation rate was 15.2 weeks, which is consistent with the 1-year use of psoriasis biologics. associated with being significant (often >50%).

[0221] Guselkumab is also used to treat adalimumab non-responders (those who did not achieve PASI90). The patient responded at week 28, 5 weeks after the last adalimumab injection. Patients were classified as responders / non-responders. At week 20 after guselkumab treatment, patients were switched to guselkumab. Of the 112 adalimumab non-responders who switched to adalimumab, two-thirds had a PASI90 (baseline To determine the proportion of patients with suboptimal responses who achieve treatment goals This calls for greater elimination as more effective psoriasis therapies continue to enter the market. This could have a significant impact on patient treatment decisions. Although the mechanism of action is unknown, in psoriasis, tumor necrosis factor-α (CD163+ macrophages) IL-17A (released from neutrophils, mast cells, and T h17 cells) is an effector cytokine that acts primarily on keratinocytes. IL-23 promotes the activation of T cells and neutrophils and induces IL-17 production. Therefore, it can be seen as a comprehensive master cytokine for psoriasis. IL-23 induces Th17 and other innate cells and upregulates IL-22, which is involved in the pathogenesis of psoriasis. Therefore, antibodies such as guselkumab can be used to inhibit IL-2 Targeting these three pathways may provide more effective and durable responses. do.

[0222] The safety profile of guselkumab in this study was consistent with that in VOYAGE 1 The incidence and types of AEs, SAEs, and laboratory abnormalities were significantly higher in placebo and placebo-treated patients than in placebo-treated patients through 16 weeks. Throughout the 48-week period, the incidence of serious infections, malignancies, and The incidence of tumors and MACE was low across treatment groups. Overall, there were 2 cases of TB. Both were present in adalimumab-treated patients. There were 13 malignant tumors, 4 of which were NMSC (2 BCC and 2 SCC). e.g., ISR occurred more frequently in patients receiving adalimumab. Safety profile of guselkumab While the use of genomic DNA is preferred, the size and duration of the study may be insufficient to detect rare events. there were.

[0223] There are some other limitations in VOYAGE2. Comparisons of adilimumab with adalimumab were limited to 24 weeks, but VOYAGE 1 showed The comparison with mab was extended to 48 weeks. More importantly, at week 48, the patient was withdrawn from active treatment. In VOYAGE 2 patients, sufficient numbers of patients were enrolled to allow evaluation of the efficacy and safety of treatment. Only a few lost their response; however, these numbers increased at later time points. .

[0224] In conclusion, VOYAGE 2 demonstrated that guselkumab administered as a single dose at weeks 0, 4, and every 8 weeks When administered in a simple 100 mg injection, it showed superior efficacy to adalimumab These results support the results of VOYAGE 1, which showed efficacy and comparable safety in patients with glaucoma. These results suggest that cumab could be an important addition to the treatment options for psoriasis. VOYAGE 2 will continue with guselkumab to maintain the highest level of response. Regarding the need for treatment with guselkumab and the need for successful transition from adalimumab to guselkumab Provide important data.

[0225] [Table 2]

[0226] Secondary efficacy and safety profile of the anti-IL-23 specific antibody guselkumab in patients with moderate to severe plaque psoriasis The efficacy observed in the Phase 1 study was comparable between guselkumab and ustekinumab (SEQ ID NOs: 149-15). 1, the light chain CDR sequences of SEQ ID NOs: 152 to 154, and the heavy chain CDR sequences of SEQ ID NO: 155. and an anti-IL-12 / 23p40 antibody having a light chain variable region of SEQ ID NO: 156. This led to the hypothesis that it may be useful in patients who have an inadequate response to chemotherapy. In NAVIGATE, patients with gucelkoma who had previously responded inadequately to ustekinumab were randomized to receive We evaluated the cutaneous response rate in patients treated with mab. A strengthened experimental design with ustekinumab induction followed by randomization of primary non-responders was used. .

[0227] Methods Summary: In this phase 3 randomized, double-blind study, 871 patients were randomized at weeks 0 and 4. At week 16, patients received open-label ustekinumab (45 mg or 90 mg). 268 patients who had an inadequate response to tekinumab (investigator global assessment [ Patients with IGA ≥ 2, who were not excluded or were nearly excluded, were randomized to 100 mg tetanustine or continued ustekinumab (double-blind), and then IG at week 16 585 / 871 (67%) A0 / 1 patients continued on open-label ustekinumab. The outcome measures were IGA 0 / 1 and IGA 2 in randomized patients from week 28 to week 40. This was the number of visits that achieved ≥2 grade improvement (from week 16 onwards).

[0228] Summary of results: At weeks 28-40, patients showed an average improvement of IGA 0 / 1 and ≥2 grades. The mean number of visits was significantly higher in the guselkumab group compared with the randomized ustekinumab group (1.5 vs. 0.7, P<0.001). Improvement in IGA 0 / 1 and ≥2 grades (week 16) The proportion of patients with PASI75, PASI90, and PASI100 was 52 was greater in the guselkumab arm versus the randomized ustekinumab arm throughout the week. From week 16 onwards, 64.4% of patients in the guselkumab group and 55. 6% of patients had one or more AEs. Patients with one or more serious AEs (SAEs) The rates were 6.7% (n=9) for guselkumab and 4. The rate was 5% (n=6).

[0229] Summary of conclusions: IGA did not achieve "eliminated" or "minimal" response by week 16 Ustekinumab-treated patients with RA derive significant benefit from switching to guselkumab.

[0230] Background: Interleukin (IL)-23 / IL-17 underlie the pathophysiology of psoriasis. Ustekinumab inhibits IL-12 and IL-23, which are major pathways that cause chronic inflammation. is a monoclonal antibody that targets psoriasis vulgaris and is currently approved for patients with psoriasis vulgaris. Guselkumab is a novel anti-IL-23 monoclonal antibody and is a novel treatment for IL-23. In a Phase 3 trial, it showed high efficacy in patients with psoriasis vulgaris.

[0231] Patients and methods Patients: Adults (aged 18 years or older) diagnosed with moderate to severe plaque psoriasis for 6 months or more. Patients with Mycosis Area and Severity Index (PASI) score ≥ 12 and Investigator Global Assessment (I Patients were eligible if they had a GA score of ≥ 3, body surface area (BSA) involvement of ≥ 10%, and had psoriasis were candidates for phototherapy or systemic treatment.

[0232] Patients had a severe, progressive, or uncontrolled medical condition or Patients were classified as having a malignant disease or history of malignant disease within the past year (excluding non-melanoma skin cancer). Patients were ineligible if they had a history or symptoms of active TB or were Patients were excluded if they tested positive or seropositive for antibodies to hepatitis C. Within 6 months of first study drug administration, guselkumab or ustekinumab, (guselkumab and Therapies targeting IL-12, IL-17, or IL-23 (excluding ustekinumab) Prior drug treatment, anti-TNF therapy (within 3 months or 5 half-lives of first dose of study drug) Prior treatment, or systemic immunosuppressant or phototherapy (within 4 weeks of first study drug administration) I couldn't get treatment.

[0233] Study design: NAVIGATE was conducted in 10 countries between October 2014 and May 2016. This was a 100-center, phase 3, randomized, double-blind study. The study was conducted over a 16-week period. The study included an open-label period, a 28-week randomized active treatment period, and a 16-week follow-up period. All patients received open-label ustekinumab (body weight ≤ 100 kg) at weeks 0 and 4. Patients weighing >100 kg were administered 45 mg / kg and 90 mg / kg, respectively. Patients with A≥2 (i.e., inadequate response to ustekinumab) were randomized to receive 100 mg of guselkumab every 8 weeks thereafter, or at week 16 Patients were randomized to continue ustekinumab every 12 weeks thereafter. Interactive questionnaires were used to assess the efficacy and safety of 100 kg vs. >100 kg patients stratified by study site. Randomization was performed using the Web Response System. Placebo injections were administered to maintain blinding. Patients with IGA 0 or 1 were randomized to receive open-label ustekinumab at week 16 and every 12 weeks thereafter. Ustekinumab and guselkumab injections were administered at weeks 40 and 47, respectively. The patients were administered the drug at weeks 42 and 44. Efficacy was evaluated over a 52-week period and safety was evaluated over a 60-week period. Patients were followed up for gender.

[0234] This study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. The protocol was approved by the Institutional Review Board / Ethics Committee of each site. , and provided written informed consent before undergoing any study-related treatment. .

[0235] Study evaluation: IGA (eliminated [0], minimal [1], mild [2], moderate [3], or severe [4]) and PASI (scale of 0 to 72, with higher scores indicating more severe disease). The primary endpoint was the number of randomized patients (all That is, among patients with inadequate response to ustekinumab at week 16 (IGA ≥ 2) Compared with week 16, between weeks 28 and 40, patients were eliminated (0) or had a minimal (1) IGA score and the number of visits at which an improvement of ≥2 grades was achieved. The key secondary endpoint among patients enrolled was whether patients had an IG of 0 from Week 28 to Week 40. Number of visits where patients achieved an A score, and PASI score ≥ 9 between weeks 28 and 40 Number of visits achieving 0.0% improvement (PASI 90) and at 28 weeks compared with 16 weeks , proportion of patients achieving IGA 0 / 1 and ≥2 grade improvement. The TOCAM assessment included the Skin Condition Questionnaire (DLQI) and the Overall Quality of Life Questionnaire (QoL). A dermatology-specific scale for assessing quality of life (scale 0-30); higher scores indicate Psoriasis Symptoms and Signs Diary (PSSD), which shows a greater impact of the disease on A self-administered questionnaire to measure the severity of psoriasis symptoms (itching, pain, stinging, burning, skin tightness) (0-10), symptoms over the past 7 days (dry, cracked, scaly, peeling or flaking skin, redness, and bleeding), with higher scores indicating greater disease severity.

[0236] Patients were followed up for adverse events (AEs), vital signs, and clinical laboratory values ​​(chemistry and and hematology) were monitored.

[0237] Statistical Analysis: The primary and key secondary analyses were performed on randomized patients at week 16. Data were analyzed by randomized treatment group. Lack of efficacy or worsening of psoriasis was Patients who discontinued study treatment due to AEs or protocol-prohibited AEs that could improve their psoriasis Patients who started the drug / therapy were subsequently considered non-responders. Missing values ​​for patients who were randomized were imputed as non-response for categorical variables. The primary and key secondary endpoints in the treatment groups were baseline body weight (≤100 kg Comparisons were made using the Cochran-Mantel-Haenszel test stratified by age (g, >100 kg). The sample size (130 patients / treatment group) was estimated at a significance level of 0.05 (two-sided). Approximately 98% confidence interval (CI) was established to detect a treatment difference between ustekinumab and guselkumab for the primary endpoint. Selected to have output.

[0238] The safety analysis included all patients who received at least one dose of study drug and assessed AEs based on actual Summarised according to the treatment received.

[0239] result Study population. A total of 872 patients were enrolled, with 871 receiving open-label ustekinumab. A higher proportion of patients in the randomized group had received prior anti-TNF therapy. Baseline demographic and disease characteristics were compared in the randomized and non-randomized treatment groups. The results were generally similar for all groups (Table 1).

[0240] Eighteen patients discontinued ustekinumab by week 16 (Figure 1). Sixty-eight patients had an IGA score of ≥2 and received 100 mg guselkumab (n Patients were randomized to receive 585 / 87 cerebrospinal fluid (n=135) or ustekinumab (n=133). 1 (67.2%) patient had an IGA score of 0 / 1 and was treated with open-label ustekinumab (non-randomized Of the randomized patients, 25 (guselkumab, n=9) continued to receive [6.7%], ustekinumab, n=20 [15.0%]) were studied from weeks 16 to 44 Seventeen patients (2.9%) who continued open-label ustekinumab had a median survival of 16–4 years and discontinued the drug. Treatment was discontinued from week 0.

[0241] Clinical efficacy. During the open-label run-in period, 68.5% (589 / 860) of patients achieved With an IGA score of 0 or 1, 73.7% achieved PASI 75 and 49.0% achieved PASI 90. Ta.

[0242] Among randomized patients, the guselkumab group achieved the following primary endpoint: Compared with the mab group, 0 or 40 patients had ≥ 1 CI from week 28 to week 40 compared with week 16. There were significantly more patients with an IGA score of 1 and mean number of visits with at least 2 grade improvement. (1.5 vs. 0.7, p<0.001) (Table 2). All major secondary endpoints were also achieved. The mean number of visits in which patients had PASI90 compared to baseline was 28 weeks to 4 weeks. At week 0, significantly more patients in the guselkumab group than in the randomized ustekinumab group ( 2.2 vs. 1.1, P<0.001). Patients with an IGA score of 0 at weeks 28-40 were The mean number of visits was significantly greater in patients receiving guselkumab compared with the randomized ustekinumab group. At week 28, compared with week 16, The proportion of patients with an IGA score of 0 or 1 and an improvement of ≥2 grades was Significantly more patients in the guselkumab group (31.1%) than in the kinumab group (14.3%, p=0.001) was higher than that of the control group (Table 2).

[0243] Among randomized patients, IGA scores of 0 or 1 and ≥ Proportion of patients with 2-grade improvement and PASI75 / 90 compared to baseline The proportion of patients who achieved a 100 / 100 response was randomized from Week 20 to Week 52. The results were consistently numerically higher in the guselkumab group than in the numbve group (Figure 2). In randomized patients, response rates increased beginning at week 16 and continued to improve at week 36 (2 weeks after randomization). The response rate in the randomized ustekinumab group increased significantly from week 16 onwards. The response rate increased slightly and reached a plateau at 32 weeks, with periodic loss of response every 12 weeks. Responses were generally maintained through 52 weeks (Figure 2). Separation of responses between groups was observed at week 20. The incidence of pulmonary embolism occurred as early as 4 weeks after randomization and increased over time.

[0244] A total of 585 patients (67.2%) had an IGA score of 0 or 1 at week 16 and were open-label At week 52, 81.1% of these patients maintained their response. and 42.6% had an IGA score of 0. Almost all patients had PASI 75 at week 16, 69.7% had PASI 90, and 2 7.2% had a PASI 100. These levels were maintained through 52 weeks.

[0245] Patient-reported outcome measures. At week 16, 131 patients in each randomized group had a DLQI score of 0.01. Among these patients, the incidence rate was significantly higher in the ustekinumab group than in the control group. A high proportion of patients in the guselkumab group had a DLQI score of 0 or 1 at week 52 (38.8% vs. 19.0%, p=0.002). At week 16, PSSD symptom score >0 or Among randomized patients with a PSSD symptom score >0, A significantly higher proportion of patients in the guselkumab group had a PS of 0 at week 52 compared with the sirolimus group, respectively. had an SD symptom score or a symptom score of 0 (Table 2).

[0246] Adverse events in the open-label ustekinumab induction group (weeks 0 to 16). Initial open-label period Of 871 enrolled patients who received at least one dose of ustekinumab during the study, 254 (29 0.2%) experienced one or more AEs by week 16 (Table 3). The most common AEs were nasal Pharyngitis (5.4%) and upper respiratory tract infection (3.8%). 11 patients (1.3%) 100% had one or more SAEs. Two patients reported serious infections (pneumonia and anal abscess). Malignancies occurred in two patients (both basal cell carcinomas). Opportunistic infections or No cases of active TB, major adverse cardiovascular events or deaths occurred over the 16 weeks .

[0247] Adverse events in the randomized guselkumab and ustekinumab groups (weeks 16 to 60). In one randomized group, between weeks 16 and 60, 64.4% of patients in the guselkumab group and 55.6% of patients in the ustekinumab group had at least one AE (Table 3). Infections were the most common adverse events in both randomized groups (guselkumab, 41.5 %, ustekinumab 35.3%). Overall higher incidence of AEs in the guselkumab group The rate appeared to be associated with a higher incidence of nasopharyngitis and upper respiratory tract infections. However, the rates of infections requiring oral or parenteral antibiotic therapy were similar between the randomized groups. (guselkumab: 15.6%, ustekinumab: 9.8%)

[0248] In the randomized group, 9 (6.7%) guselkumab-treated patients and 6 (4.5%) uterine leukemia patients had bronchitis. SAEs were reported in patients treated with sutekinumab (Table 3). One serious infection occurred. No cases of opportunistic infections or active TB were reported. Two malignancies were reported (transitional cell carcinoma of the bladder in the guselkumab group). cell carcinoma and squamous cell carcinoma of the cervix, of unknown origin). Three patients developed myocardial infarction (Gruselk Mab group: 1 woman, 70 years old, and 1 man, 53 years old, ustekinumab group: 1 man All three patients had at least two known cardiovascular risk factors. Injection site reactions were uncommon and not severe from weeks 16 to 40. There were no anaphylactic or serum sickness-like reactions or Crohn's disease AEs.

[0249] Adverse events in the open-label ustekinumab extension group (Weeks 16 to 60). The most common AEs in the sutekinumab group were nasopharyngitis and upper respiratory tract infection (Table 3 ).

[0250] Twenty patients (3.4%) had one or more SAEs at weeks 16 to 60. Five patients in the group had serious infections after 16 weeks (appendicitis, epididymitis, periodontitis, vertebral Parasalveolar abscess, each occurring in one patient; salpingitis and urinary tract infection, both occurring in the same patient There were no cases of opportunistic infections or active TB. Four malignancies were identified: These included bile duct cancer, fatal metastatic pancreatic cancer, basal cell carcinoma, and squamous cell carcinoma of the skin. The patient had an acute myocardial infarction and a history of multiple known risk factors. One patient died (the metastatic pancreatic cancer patient mentioned above). The incidence of injection site reactions was low (0.3%). ), none of which were severe. Anaphylactic or serum sickness-like reactions or Crohn's disease-related AEs did not exist.

[0251] Consideration This controlled Phase 3 study demonstrated that guselkumab achieved optimal clinical efficacy with ustekinumab. The aim of this study was to verify that ustekinumab is effective in treating patients with moderate to severe psoriasis, for which no previous studies have been reported. is as effective in treating moderate to severe psoriasis as any other treatment, but Not all patients achieve complete or near complete elimination of psoriasis. Guselkumab, a monoclonal antibody that selectively targets -23, is being developed for the treatment of moderate to severe cases of rheumatoid arthritis. had substantial efficacy in adults with psoriasis, and was more effective than ustekinumab It has been established that ustekinumab may be insufficient. The results described herein support the conclusion that ustekinumab If partial responders were randomized to guselkumab versus continued ustekinumab, Mab improved patients' IGA score of 0 / 1 and grade improvement of ≥2 at week 16, The mean number of visits between weeks 28 and 40 with IGA score and PASI90 response was included. The study demonstrated superiority over ustekinumab across all endpoints measured. Over time, guselkumab also significantly increased the proportion of patients who achieved clinical benefit between weeks 16 and 52. The proportion of patients with refractory pulmonary tuberculosis and patient-reported outcomes were also excellent. Given that the patient responded poorly to ustekinumab, a treatment with The results are important and should encourage dermatologists to approach switching from ustekinumab to guselkumab. provide.

[0252] To rigorously demonstrate superiority of guselkumab in inadequate responders to STELARA To establish inadequate responders, an intensification schedule for ustekinumab inadequate responders was used. To assess the efficacy and safety of ustekinumab, we used rigorous endpoints, which are a more robust method than medical history. As partial responders continued to improve after 16 weeks, we decided to continue ustekinumab or Patients were required to be randomized to either receive or start treatment with NAVI. The ustekinumab dosing regimen evaluated in GATE is approved in most regions worldwide. The dosing regimen was consistent with that used in previous studies, and therefore no dose escalation was permitted. The study aimed to achieve a relatively high level of efficacy ( We used IGA 0 / 1, excluded or nearly excluded) to define ustekinumab responders. Two outcome measures were assessed: the number of visits at which patients had a high degree of response and the number of patients with a high degree of response over time. The proportion of patients who achieved the standard PASI and IGA responses was used. To evaluate the consistency of responses across the different dosing regimens of the two biologics This helps address the peak and trough concentrations that occur at a given visit. The percentage of patients with IGA and PASI responses is more intuitive and easier to interpret.

[0253] Endpoints used, number of visits at which a response was achieved, or proportion of patients who achieved a response over time Regardless of the combination, outcomes consistently showed greater efficacy for guselkumab. In the randomized group, PASI75 / 90 / 100 response rates were higher in the guselkumab group Separation between groups was observed at week 20 (4 weeks after the first dose of giselkumab). The response rate was 32. The effect peaked between weeks 30 and 36 and was generally maintained through 52 weeks. This was a patient population that had an inadequate response to effective drugs such as % of guselkumab patients achieved PASI90 compared with 24% of ustekinumab patients Considering the previous data, the response rate was high. Initial responses to ustekinumab were higher than in previous Consistent with the study, responses were generally maintained during the open-label treatment period.

[0254] The safety profiles of guselkumab and ustekinumab were consistent with previous studies. During the randomized controlled period, the incidence of AEs was low, primarily due to a high incidence of nasopharyngitis and upper respiratory tract infections. Survival rates were slightly higher in the guselkumab arm compared with the randomized ustekinumab arm No serious infections, hypersensitivity reactions, or Crohn's disease-related AEs occurred in these groups. The incidence of infections requiring oral or parenteral antibiotics was similar in the randomized groups. Few guselkumab-treated patients had injection site reactions, all of which were considered mild. Despite the use of a guselkumab loading dose, When the drug was transferred to the serogroup, there were no signals for SAEs or hypersensitivity reactions. The favorable safety profile of the drug was consistent with the clear historical safety profile of ustekinumab. Given the narrower MOA of guselkumab compared with rituximab and ustekinumab, That is not the case.

[0255] Efficacy of guselkumab compared with ustekinumab in inadequate responders to ustekinumab The increased expression of IL-23 in psoriasis further confirms the central role of IL-23 in the pathogenesis of psoriasis and is an interleukin-1 (IL-23)-dependent inhibitor of psoriasis. Activation of the proinflammatory Th1 pathway by IFN-12 has previously been implicated in the immunopathogenesis of psoriasis. These results suggest that the effect of guselkumab on CR-positive patients is not as important as previously thought. Potential reasons for the increased efficacy of the antibody include more potent IL-23 blockade, more frequent Administration of guselkumab and / or Th17 in the setting of IL-12 inhibition Enhancement of the response can be achieved.

[0256] Despite the rigorous design of the study, there are several limitations. The primary endpoint of this study was , which does not intuitively translate into clinical response. However, it does (standard evaluation in dermatology studies). Furthermore, the primary endpoint was The study covered a limited period from weeks 28 to 40.

[0257] In conclusion, in controlled enrichment studies, high (or sufficient) responses could be achieved with usekinumab. For patients who have not achieved this, switching to guselkumab is an effective strategy, and this transition is It has been demonstrated that it is not associated with any safety concerns.

[0258] [Table 3-1]

[0259] [Table 3-2]

[0260] [Table 4]

[0261]

Table 5

[0262]

Table 6-1

[0263]

Table 6-2

[0264]

Table 6-3

[0265]

Table 6-4

[0266]

Table 6-5

[0267]

Table 6-6

[0268]

Table 6-7

[0269]

Table 6-8

[0270]

Table 6-9

[0271]

Table 6-10

[0272]

Table 6-11

[0273]

Table 6-12

[0274]

Table 6-13

[0275]

Table 6-14

[0276]

Table 6-15

[0277]

Table 6-16

[0278]

Table 6-17

[0279]

Table 6-18

[0280]

Table 6-19

[0281]

Table 6-20

[0282]

Table 6-21

[0283]

Table 6-22

[0284]

Table 6-23

[0285]

Table 6-24

[0286]

Table 6-25

[0287]

Table 6-26

[0288]

Table 6-27

[0289]

Table 6-28

[0290]

Table 6-29

[0291]

Table 6-30

[0292]

Table 6-31

[0293]

Table 6-32

[0294]

Table 6-33

[0295]

Table 6-34

[0296]

Table 6-35

[0297]

Table 6-36

[0298]

Table 6-37

[0299]

Table 6-38

[0300]

Table 6-39

[0301]

Table 6-40

[0302]

Table 6-41

[0303]

Table 6-42

[0304]

Table 6-43

[0305]

Table 6-44

[0306]

Table 6-45

[0307]

Table 6-46

Claims

1. Treated with antibodies against IL-12 / 23p40, IL-12 / 23p40 antibody therapy 1. A method for treating psoriasis in a patient determined to be an inadequate responder to To determine whether patients treated with IL-12 / 23p40 antibodies are inadequate responders And, The measuring step determines whether the patient is an inadequate responder to IL-12 / 23p40 antibody therapy. Determining that there is The patient is determined to be an inadequate responder to IL-12 / 23p40 antibody treatment. administering a safe and effective amount of an anti-IL-23 specific antibody to the patient, The .23-specific antibody comprises a light chain variable region and a heavy chain variable region, the light chain variable region comprising: a light chain complementarity determining region 1 (CDRL1) amino acid sequence of SEQ ID NO:50; The CDRL2 amino acid sequence of SEQ ID NO:56; and a CDRL3 amino acid sequence of SEQ ID NO:73, The heavy chain variable region The heavy chain complementarity determining region 1 (CDRH1) amino acid sequence of SEQ ID NO:5; a CDRH2 amino acid sequence of SEQ ID NO: 20; and a CDRH3 amino acid sequence of SEQ ID NO:

44.

2. By determining that the psoriasis has not been eliminated or has been almost completely eliminated, and determining that the patient is an inadequate responder to IL-12 / 23p40 antibody therapy. The method of claim 1 .

3. The method of claim 1, wherein the IL-12 / 23p40 antibody is ustekinumab.

4. To determine whether patients treated with IL-12 / 23p40 antibodies are inadequate responders and wherein said step of measuring one or more of an IGA, a PGA, or a PASI score in said patient. The method of claim 1 , comprising measuring

5. by an IGA and / or PGA score of 2 or greater, or a PASI score of less than 75 determining that the patient is an inadequate responder to IL-12 / 23p40 antibody treatment; The method according to claim 4.

6. The anti-IL-23 specific antibody was administered at the first dose, 4 weeks after the first dose, and at the fourth week.

6. The method of claim 5, wherein the dose is administered every 8 weeks after administration.

7. the patient is a responder to the anti-IL-23 specific antibody and has a PASI of 75 or greater; PASI 90 or higher, PASI 100 or higher, or PGA score of 0 or 1, or IG The method of claim 5, wherein the compound is identified as having at least 2 improvements in A.

8. The PASI 90, PASI 100, or IGA score of 0 or 1, or the IGA score of 8. The method of claim 7, wherein the improvement of at least 2 is measured 16, 20, or 28 weeks after the initial treatment. The method described above.

9. 2. The method of claim 1, wherein the anti-IL-23 specific antibody is guselkumab administered subcutaneously. method.

10. The anti-IL-23 specific antibody is selected from the group consisting of scalp, nails, hands, and feet.

10. The method of claim 9, which is safe and effective for treating psoriasis in the area of

11. The anti-IL-23 specific antibody is a pharmaceutical composition having an antibody concentration of 100 mg / mL and 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride salt monohydrate and 0.053% (w / v) polysorbate 80.

10. The method of claim 9, wherein the diluent is water at normal conditions.

12. The method according to claim 11, wherein the anti-IL-23 specific antibody is administered in a dose of 25 mg to 200 mg. The method described.

13. 13. The method of claim 12, wherein the anti-IL-23 specific antibody is administered at a dose of 100 mg. 。

14. and administering to said patient one or more additional agents used to treat psoriasis. The method of claim 13 , comprising:

15. The additional agent is an immunosuppressant, a nonsteroidal anti-inflammatory drug (NSAID), methotrexate, Sirt (MTX), anti-B cell surface marker antibody, anti-CD20 antibody, rituximab, TNF 14. The method of claim 13, wherein the agonist is selected from the group consisting of a vasopressin inhibitor, a corticosteroid, and a costimulatory regulator. The method described above.

16. The anti-IL-23 specific antibody reduces symptoms of psoriasis in the patient or provides clinical relief. Induce a response, induce or maintain clinical remission, inhibit progression of disease, or is effective to inhibit a disease complication in the patient.

17. Treated with antibodies against IL-12 / 23p40, IL-12 / 23p40 antibody therapy 1. A method for treating psoriasis in a patient determined to be an inadequate responder to To determine whether patients treated with IL-12 / 23p40 antibodies are inadequate responders And, The measuring step determines whether the patient is an inadequate responder to IL-12 / 23p40 antibody therapy. Determining that there is The patient is determined to be an inadequate responder to IL-12 / 23p40 antibody treatment. administering a safe and effective amount of an anti-IL-23 specific antibody, said antibody comprising: A light chain variable region of the amino acid sequence of SEQ ID NO: 116 and a heavy chain variable region of the amino acid sequence of SEQ ID NO: 106 and a variable region.

18. By determining that the psoriasis has not been eliminated or has been almost completely eliminated, and determining that the patient is an inadequate responder to IL-12 / 23p40 antibody therapy. The method of claim 17 .

19. The method of claim 17, wherein the IL-12 / 23p40 antibody is ustekinumab.

20. To determine whether patients treated with IL-12 / 23p40 antibodies are inadequate responders and wherein said step of measuring one or more of an IGA, a PGA, or a PASI score in said patient. The method of claim 17, comprising measuring

21. by an IGA and / or PGA score of 2 or greater, or a PASI score of less than 75 determining that the patient is an inadequate responder to IL-12 / 23p40 antibody treatment; The method of claim 20.

22. The anti-IL-23 specific antibody was administered at the first dose, 4 weeks after the first dose, and at the fourth week.

22. The method of claim 21, wherein the dose is administered every 8 weeks.

23. the patient is a responder to the anti-IL-23 specific antibody and has a PASI of 75 or greater; PASI 90 or higher, PASI 100 or higher, or IGA score of 0 or 1, or IG 22. The method of claim 21, wherein the compound is identified as having at least 2 improvements in A.

24. The PASI 90, PASI 100, or IGA 0 or 1, or at least The improvement in the second score is measured 16, 20, or 28 weeks after the initial treatment.

3. The method according to claim 3.

25. The method of claim 17, wherein the anti-IL-23 specific antibody is guselkumab administered subcutaneously. How to.

26. The anti-IL-23 specific antibody is selected from the group consisting of scalp, nails, hands, and feet.

26. The method of claim 25, which is safe and effective for treating psoriasis in the area of

27. The anti-IL-23 specific antibody is a pharmaceutical composition having an antibody concentration of 100 mg / mL and 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride salt monohydrate and 0.053% (w / v) polysorbate 80.

26. The method of claim 25, wherein the diluent is water at normal conditions.

28. 28. The method of claim 27, wherein the anti-IL-23 specific antibody is administered in a dose of 25 mg to 200 mg. The method described.

29. 29. The method of claim 28, wherein the anti-IL-23 specific antibody is administered at a dose of 100 mg. 。

30. and administering to said patient one or more additional agents used to treat psoriasis.

30. The method of claim 29, comprising:

31. The additional agent is an immunosuppressant, a nonsteroidal anti-inflammatory drug (NSAID), methotrexate, Sirt (MTX), anti-B cell surface marker antibody, anti-CD20 antibody, rituximab, TNF 30. The method of claim 30, wherein the therapeutic agent is selected from the group consisting of a vasopressin inhibitor, a corticosteroid, and a costimulatory regulator. The method described above.

32. The anti-IL-23 specific antibody reduces symptoms of psoriasis in the patient or provides clinical relief. Induce a response, induce or maintain clinical remission, inhibit progression of disease, or is effective to inhibit a disease complication in the patient.

33. Treated with antibodies against IL-12 / 23p40, IL-12 / 23p40 antibody therapy 1. A method for treating psoriasis in a patient determined to be an inadequate responder to To determine whether patients treated with IL-12 / 23p40 antibodies are inadequate responders And, The measuring step determines whether the patient is an inadequate responder to IL-12 / 23p40 antibody therapy. Determining that there is The patient is determined to be an inadequate responder to IL-12 / 23p40 antibody treatment. A safe and effective amount of an anti-IL-23 specific antibody is administered at a dose of 100 mg, and administering the same 4 weeks after the first dose and every 8 weeks after the week 4 dose; The anti-IL-23 specific antibody comprises a light chain variable region having the amino acid sequence of SEQ ID NO: 116 and a sequence and a heavy chain variable region of the amino acid sequence of sequence number 106. of antibody, 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.

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