Methods for treating ulcerative colitis with anti-IL23 specific antibodies

Abstract

A method of treating ulcerative colitis in a patient comprises administering an initial dose and subsequent doses of an IL-23 specific antibody, e.g., guselkumab, such that the patient responds to the antibody and meets one or more clinical endpoints.

Description

[Technical Field]

[0001] (Reference to electronically submitted sequence listing) The Sequence Listing for this application is submitted electronically through the United States Patent and Trademark Office Patent Center as an XML format Sequence Listing with the filename "JBI6766WOPCT1SEQLIST.xml," created on November 21, 2023, and 11 kilobytes (KB) in size. This submitted Sequence Listing is a part of the present specification and is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention relates to methods for treating ulcerative colitis using antibodies that bind to human IL-23. Specifically, the present invention relates to anti-IL-23 specific antibodies and regimens for administering certain pharmaceutical compositions of the antibodies.

[0003] BACKGROUND OF THE INVENTION Interleukin (IL)-12 is a secreted heterodimeric cytokine composed of two disulfide-linked glycosylated protein subunits (designated p35 and p40 for their approximate molecular weight). IL-12 promotes cell-mediated immunity by binding to a two-chain receptor complex produced primarily by antigen-presenting cells and expressed on the surface of T cells or natural killer (NK) cells. The IL-12 receptor beta-1 (IL-12Rβ1) chain binds to the p40 subunit of IL-12, providing the primary interaction between IL-12 and its receptor. However, it is IL-12p35 ligation of the second receptor chain, IL-12Rβ2, that confers intracellular signaling (e.g., STAT4 phosphorylation) and activation of receptor-bearing cells (Presky et al., 1996). IL-12 signaling, occurring concomitantly with antigen presentation, is thought to induce T cell differentiation toward the T helper 1 (Th1) phenotype, characterized by interferon gamma (IFNγ) production (Trinchieri, 2003). Th1 cells are thought to promote immunity against several intracellular pathogens, produce complement-fixing antibody isotypes, and contribute to tumor immunosurveillance. Therefore, IL-12 is thought to be an important component of host defense immune mechanisms.

[0004] It was discovered that the p40 protein subunit of IL-12 can also associate with a separate protein subunit designated p19 to form a novel cytokine, IL-23 (Oppman et al., 2000). IL-23 also signals through a two-chain receptor complex. Because the p40 subunit is shared between IL-12 and IL-23, the IL-12Rβ1 chain is also shared between IL-12 and IL-23. However, it is IL-23p19 ligation of the second component of the IL-23 receptor complex, IL-23R, that confers IL-23-specific intracellular signaling (e.g., STAT3 phosphorylation) and subsequent IL-17 production by T cells (Parham et al., 2002; Aggarwal et al., 2003). Recent studies have demonstrated that the biological functions of IL-23 and IL-12 are distinct, despite the structural similarities between these two cytokines (Langrish et al., 2005).

[0005] Abnormal regulation of IL-12 and Th1 cell populations has been implicated in many immune-mediated diseases, as antibody-mediated neutralization of IL-12 has been effective in treating animal models of psoriasis, multiple sclerosis (MS), rheumatoid arthritis, inflammatory bowel disease, insulin-dependent (type 1) diabetes, and uveitis (Leonard et al., 1995; Hong et al., 1999; Malfait et al., 1998; Davidson et al., 1998). However, these studies neutralized both IL-12 and IL-23 in vivo because they targeted the common p40 subunit. Therefore, it is unclear whether IL-12 or IL-23 mediated the disease or whether both cytokines needed to be inhibited to achieve disease suppression. Recent studies have confirmed that IL-23 inhibition can provide benefits comparable to anti-IL-12p40 strategies using IL-23p19-deficient mice or specific antibody neutralization of IL-23 (Cua et al., 2003; Murphy et al., 2003; Benson et al., 2004).

[0006] Ulcerative colitis is a chronic inflammatory bowel disorder of unknown etiology involving the colonic surface mucosa, crypt epithelium, and submucosa. Ulcerative colitis is most commonly diagnosed in late adolescence and early adulthood, but diagnosis can occur at any age. Clinically, patients with UC suffer from diarrhea, rectal bleeding, weight loss, abdominal pain, and fever, and may also exhibit prominent extraintestinal symptoms, most commonly arthritis. Ulcerative colitis is characterized by a lifelong course of remissions and exacerbations, with 15% of patients experiencing acute attacks requiring hospitalization at some point during their illness. In severe UC, the intestinal wall becomes very thin, the mucosa desquamates, and inflammation spreads to the serosa, potentially leading to dilatation, toxic megacolon, and subsequent perforation. It has been reported that within 10 years of diagnosis, approximately 20% of adults with UC undergo colectomy. There is a high unmet need for new safe and effective treatment options for UC, particularly new therapies that can provide improved long-term efficacy (i.e., sustained remission) over currently available therapies.

[0007] The pathophysiology of inflammatory bowel disease (IBD), including UC, is thought to be complex and multifactorial. The primary goal of pharmacotherapy is to attenuate the inflammatory response, thereby alleviating symptoms and promoting mucosal healing. Specific goals of IBD treatment include symptom control, reducing the need for long-term corticosteroids, preventing recurrence and complications, and minimizing the risk of cancer (D'Haens GR et al., Future directions in inflammatory bowel disease management. J Crohns Colitis. 2014;8(8):726-734, EDMS-RIM-476243; Kornbluth A et al., Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105(3):501-523, Erratum in: Am J Gastroenterol. 2010;105(3):500, EDMS-ERI-156811382).

[0008] The role of IL-23 in promoting intestinal inflammation has been demonstrated in several mouse models, with mice treated with a neutralizing anti-IL-23p19 antibody or with a genetic deletion of the p19 subunit of IL-23 exhibiting attenuated colitis. Genome-wide association studies (GWAS) have identified polymorphisms in the IL-23 receptor gene (IL23R) that are associated with both risk and protection for IBD.

[0009] Thus, there is growing evidence for a specific role of IL-23 in immune-mediated diseases. Neutralizing IL-23 without inhibiting the IL-12 pathway could provide an effective treatment for immune-mediated diseases with limited impact on important host defense immune mechanisms. This could represent a significant improvement over other treatment options.

[0010] Over the past two decades, biologic therapies, such as anti-TNFα, IL-12 / 23 antagonists, and anti-integrin drugs, have revolutionized the clinical management of IBD. Most drugs in these classes have been approved for the treatment of UC. Within the anti-TNFα class, infliximab, adalimumab, and golimumab are approved for UC. The IL-12 / 23 antagonist ustekinumab and the anti-integrin vedolizumab are both approved for the treatment of UC. Multiple anti-IL-23 agents are currently being evaluated in phase 3 programs for UC. In addition, two oral small molecule therapies, including a Janus kinase (JAK) inhibitor and a sphingosine-1-phosphate (S1P) receptor modulator, are currently approved for UC.

[0011] Despite substantial advances made by advanced monotherapy, however, significant unmet need remains in the treatment of UC. Even with the best available approved treatments, more than half of patients fail to achieve clinical remission after one year. Among patients with clinically asymptomatic UC, approximately 25% still have endoscopically active disease (Colombel JF et al. Discussions between patient-reported outcomes, and endoscopic and histological appearance in UC. Gut 2017;66:2063-2068). Therefore, it is not surprising that long-term colectomy rates have not declined over a 10-year period (Fumery M et al., Natural history of adult ulcerative colitis in population-based cohorts: A systematic review. Clin Gastroenterol Hepatol 2018;16:343-56.e3), highlighting the need for more effective therapies and treatment paradigms. The efficacy plateau observed with monotherapy suggests the need for improved treatments that achieve higher rates of long-lasting symptomatic and objective remission.

[0012] In summary, there remains a significant unmet medical need for new treatment options for IBD and ulcerative colitis, particularly therapies with novel mechanisms of action that have the potential to raise the efficacy bar and maximize the proportion of patients who achieve and maintain clinical remission.

[0013] (Summary of the Invention) In a first aspect, the invention provides a method of treating a subject (patient) suffering from ulcerative colitis, comprising administering to the patient an anti-IL-23 specific antibody (also called an IL23p19 or IL23p19 subunit antibody), e.g., guselkumab, at an initial induction dose from the start of treatment up to four weeks into treatment initiation, followed by administration of the anti-IL-23 specific antibody once every four weeks, e.g., at weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48. In yet another embodiment, treatment continues for 96 weeks or more after initiation of treatment.

[0014] In one embodiment, the subject is administered an anti-IL23 specific antibody (i) intravenously at an initial dose of 200 mg, followed by intravenous administration 4 weeks after the first dose, 8 weeks after the first dose, and 12 weeks after the first dose, and continues the anti-IL23 specific antibody treatment, or (ii) intravenously at an initial dose of 400 mg, followed by intravenous administration 4 weeks after the first dose, 8 weeks after the first dose, and 12 weeks after the first dose, and continues the anti-IL23 specific antibody treatment, optionally continuing for more than 12 weeks, 24 weeks, 48 ​​weeks, 96 weeks, and beyond.

[0015] In another embodiment, the composition used in the methods of the invention comprises a pharmaceutical composition comprising an antibody specific for anti-IL23.

[0016] In one embodiment, the ulcerative colitis achieves a significant improvement in a clinical endpoint selected from the following: (i) Clinical response defined as a ≥30% and ≥2-point reduction from derived baseline in the modified Mayo score, with a rectal bleeding subscore of ≥1 point reduction from baseline, or a rectal bleeding subscore of 0 or 1; (ii) Clinical remission at week 12, defined as the absence of easy bleeding at endoscopy, a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, with no increase in stool frequency subscore from induction baseline. (iii) Symptomatic remission at Week 12, defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, with no increase in stool frequency subscore from induction baseline. (iv) endoscopic cure at week 12, defined as an endoscopy subscore of 0 or 1 with the absence of easy bleeding at endoscopy. (v) Histologic-endoscopic mucosal healing at 12 weeks, defined as achieving a combination of histologic and endoscopic healing, where histologic healing is defined as neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes grading system. (vi) Endoscopic normalization at week 12 defined as an endoscopy subscore of 0 (requiring the absence of easy bleeding).

[0017] In one embodiment of the present invention, patients who have received an anti-IL23 specific antibody and are determined to have no clinical response at week 12 are treated with an extended induction period in which they receive subcutaneous anti-IL23 specific antibody at weeks 12, 16, and 20, and are assessed for clinical response and other clinical endpoints at week 24.

[0018] In another aspect of the invention, a pharmaceutical composition comprises an isolated anti-IL-23 specific antibody having CDR sequences comprising: (i) heavy chain CDR amino acid sequences of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3; and (ii) light chain CDR amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, optionally in a composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, 0.053% (w / v) polysorbate 80, and the diluent is water at standard conditions.

[0019] A further aspect of the method of the invention comprises administering a pharmaceutical composition comprising an isolated anti-IL-23 specific antibody having a heavy chain amino acid sequence of SEQ ID NO:7 and a light chain amino acid sequence of SEQ ID NO:8, optionally in a composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, 0.053% (w / v) polysorbate 80, and the diluent is water at normal conditions.

[0020] The method of the present invention provides an isolated anti-IL-23 specific antibody having a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10, optionally in a composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, 0.053% (w / v) polysorbate 80, and the diluent is water at normal conditions.

[0021] In yet a further embodiment, the method of the invention comprises administering a pharmaceutical composition comprising the antibody guselkumab (commercially available as Tremfya® from Janssen Biotech, Inc.), optionally in a composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, 0.053% (w / v) polysorbate 80, and the diluent is water at normal conditions.

[0022] The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages will be apparent from the following detailed description, the drawings, and the appended claims. [Brief explanation of the drawings]

[0023] [Figure 1] Figure 1 is a schematic diagram of the guselkumab Phase 2b / 3 clinical development program in ulcerative colitis. [Figure 2] Graph showing clinical response at 12 and / or 24 weeks. [Figure 3]1 is a graph showing the primary endpoint of clinical remission at week 44. [Figure 4] Graph showing the primary and key secondary endpoints assessed at week 44. [Figure 5] is a graph showing the proportion of participants in symptom remission by week 44. [Figure 6] Figure 1 shows a summary of the statistical significance of the primary and key secondary endpoints per US study procedure.

[0024] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS As used herein, methods of treating a subject suffering from ulcerative colitis include administering isolated, recombinant, and / or synthetic anti-IL-23 specific human antibodies, as well as diagnostic and therapeutic compositions, methods, and devices.

[0025] As used herein, "anti-IL-23 specific antibody," "anti-IL-23 antibody," "antibody portion," or "antibody fragment," and / or "antibody variant," etc., include any protein- or peptide-containing molecule comprising at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one complementarity determining region (CDR) or ligand-binding portion thereof of a heavy or light chain, a heavy or light chain variable region, a heavy or light chain constant region, a framework region, or any portion thereof, or at least a portion of an IL-23 receptor or binding protein, which can be incorporated into an antibody of the invention. Such antibodies optionally further affect a specific ligand, for example, but not limited to, such antibodies modulate, reduce, enhance, antagonize, stimulate, alleviate, moderate, block, inhibit, abrogate, and / or prevent at least one IL-23 activity or binding, or IL-23 receptor activity or binding, in vitro, in situ, and / or in vivo. As a non-limiting example, a suitable anti-IL-23 antibody, specified portion, or variant of the invention can bind to at least one IL-23 molecule or a specified portion, variant, or domain thereof. A suitable anti-IL-23 antibody, specified portion, or variant can also, optionally, affect at least one IL-23 activity or function, including, but not limited to, RNA, DNA, or protein synthesis, IL-23 release, IL-23 receptor signaling, membrane IL-23 cleavage, IL-23 activity, IL-23 production, and / or synthesis.

[0026] The term "antibody" is further intended to encompass antibodies, digested fragments thereof, specified portions, and variants, including antibody mimetics or portions of antibodies that mimic the structure and / or function of antibodies or specified fragments or portions thereof, including single-chain antibodies and fragments thereof. Functional fragments include antigen-binding fragments that bind to mammalian IL-23. For example, antibody fragments capable of binding to IL-23 or a portion thereof, including, but not limited to, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab')2 (e.g., by pepsin digestion), facb (e.g., by plasmin digestion), pFc' (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction, and reassembly), Fv, or scFv (e.g., by molecular biology techniques) fragments, are encompassed by the present invention (see, e.g., Colligan, Immunology, supra).

[0027] Such fragments can be produced by enzymatic cleavage, synthetic, or recombinant techniques known in the art and / or described herein. Antibodies can also be produced in various truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, a combination of genes encoding a F(ab')2 heavy chain portion can be produced by inserting the C(ab')2 heavy chain fragment into the C(ab')2 heavy chain fragment. H The antibody can be designed to contain DNA sequences encoding the antibody domain and / or hinge region. The various portions of the antibody can be chemically coupled by conventional techniques, or can be prepared as a contiguous protein using genetic engineering techniques.

[0028] As used herein, the term "human antibody" refers to a human antibody that contains substantially all portions of the protein (e.g., CDRs, framework, C L , C H Domain (e.g., C H 1. C H 2. C H 3), Hinge (V L , V H) refers to an antibody that is substantially non-immunogenic in humans with only minor sequence changes or mutations. A "human antibody" can also be an antibody derived from or closely matched to a human germline immunoglobulin sequence. A human antibody may include amino acid residues not encoded by germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). Often, this means that the human antibody is substantially non-immunogenic in humans. Human antibodies have been classified into groups based on the similarity of their amino acid sequences. Thus, sequence similarity searches can be used to select antibodies with similar linear sequences as templates for generating human antibodies. Similarly, antibodies whose names include primate (e.g., monkey, baboon, chimpanzee), rodent (e.g., mouse, rat, rabbit, guinea pig, hamster), and other mammals designate antibodies specific for that species, subgenus, genus, subfamily, and family. Furthermore, chimeric antibodies can include any combination of the above. Such changes or mutations optionally and preferably retain or reduce immunogenicity in humans or other species relative to the unmodified antibody. Thus, a human antibody is distinct from a chimeric or humanized antibody.

[0029] It is noted that human antibodies can be produced by non-human animals or prokaryotic or eukaryotic cells capable of expressing functionally rearranged human immunoglobulin (e.g., heavy and / or light chain) genes. Furthermore, when a human antibody is a single-chain antibody, it can contain a linker peptide not found in naturally occurring human antibodies. For example, an Fv can contain a linker peptide, such as two to about eight glycine or other amino acid residues, connecting the heavy chain variable region and the light chain variable region. Such a linker peptide is considered to be of human origin.

[0030] Also, bispecific, heterospecific, heterobinding, or similar antibodies can be used, which are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In this case, one of the binding specificities is for at least one IL-23 protein and the other is for any other antigen. Methods for producing bispecific antibodies are known in the art. Traditionally, recombinant production of bispecific antibodies is based on the coexpression of two immunoglobulin heavy-light chain pairs, where the two heavy chains have different specificities (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, of which only one has the correct bispecific structure. Purification of the correct molecule (usually performed by affinity chromatography steps) is quite laborious, and product yields are low. Similar procedures are described, for example, in WO 93 / 08829, U.S. Pat. Nos. 6,210,668, 6,193,967, 6,132,992, 6,106,833, 6,060,285, 6,037,453, 6,010,902, 5,989,530, 5,959,084, 5,959,083, 5,989,530, 5,959,084, 5,959,083, 5,989,530, 5,959,084, 5,959,083, 5,989,530, 5,989,530, 5,959,084, 5,959,083, 5,989,530, 5,989,530, 5,959,084, 5,989,530 ... Nos. 32448, 5833985, 5821333, 5807706, 5643759, 5601819, 5582996, 5496549, 4676980, WO 91 / 00360, WO 92 / 00373, EP 03089, Traunecker et al., EMBO J. 10:3655 (1991), and Suresh et al., Methods in Enzymology 121:210 (1986), each of which is incorporated herein by reference in its entirety.

[0031] Anti-IL-23 specific antibodies (also referred to as IL-23 specific antibodies) (or antibodies against IL-23) useful in the methods and compositions of the invention can optionally be characterized by high affinity binding to IL-23 and, optionally and preferably, low toxicity. Specifically, antibodies of the invention, particular fragments, or variants thereof, in which individual components such as the variable region, constant region, and framework, individually and / or collectively, optionally and preferably, have low immunogenicity, are useful in the invention. Antibodies that can be used in the invention are optionally characterized by the ability to treat patients over an extended period of time with measurable alleviation of symptoms and low and / or acceptable toxicity. Low or acceptable immunogenicity and / or high affinity, as well as other favorable properties, can contribute to the therapeutic results achieved. "Low immunogenicity" is defined herein as raising a significant HAHA, HACA, or HAMA response in less than about 75%, or preferably less than about 50%, of treated patients, and / or raising low titers (less than about 300, preferably less than about 100, as measured by double antigen enzyme immunoassay) in treated patients (Elliott et al., Lancet 344:1125-1127 (1994), incorporated herein by reference in its entirety). "Low immunogenicity" may also be defined as the incidence of titratable levels of antibodies to an anti-IL-23 antibody in patients treated with the anti-IL-23 antibody when it occurs in less than 25% of patients treated at the recommended dose, preferably less than 10% of treated patients, over the recommended course of treatment during the treatment period.

[0032] The term "safety," when referring to an administration, dosing regimen, treatment, or method with an anti-IL-23 antibody of the present invention (e.g., the anti-IL-23 antibody guselkumab), refers to a relatively low or reduced frequency and / or a low or reduced severity of treatment-emergent adverse events (also referred to as AEs or TEAEs), e.g., from an ongoing clinical trial, e.g., a Phase 2 clinical trial, and prior clinical trials, compared to a standard of care or another comparator. An adverse event is an untoward medical occurrence in a patient administered a pharmaceutical product. Particularly when relating to an administration, dosing regimen, or treatment with an anti-IL-23 antibody of the present invention, clinically proven safety refers to a relatively low or reduced frequency and / or a low or reduced severity of adverse events associated with administration of the antibody, when the cause is considered possible, probable, or highly likely to be due to the use of the anti-IL-23 antibody.

[0033] usefulness The isolated nucleic acids of the present invention can be used to produce at least one anti-IL-23 antibody or specific variant thereof, which can be used to measure or affect cells, tissues, organs, or animals (including mammals and humans) to diagnose, monitor, regulate, treat, alleviate, help prevent the occurrence of, or reduce the symptoms of ulcerative colitis.

[0034] Such methods may comprise administering to a cell, tissue, organ, animal, or patient in need of such modulation, treatment, amelioration, prevention, or reduction of a symptom, effect, or mechanism an effective amount of a composition or pharmaceutical composition comprising at least one anti-IL-23 antibody. An effective amount may include an amount of about 0.001 to 500 mg / kg per single (e.g., bolus), multiple, or continuous administration, or an amount that achieves a serum concentration of 0.01 to 5000 μg / mL per single, multiple, or continuous administration, or any effective range or value therein, administered and determined using known methods described herein or known in the relevant art.

[0035] References All publications or patents cited herein, whether specifically stated or not, are incorporated herein by reference in their entirety, indicating the prior art at the time of the present invention and / or providing a description and enabling of the present invention. A publication refers to any scientific publication or patent publication or any other information available in any media format, including all electronic or printed records. 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., Molecular Cloning: A Laboratory Manual, 2002; nd Edition, Cold Spring Harbor, NY(1989), Harlow and Lane, antibodies, a Laboratory Manual, Cold Spring Harbor, NY(1989), Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY(1994-2001), Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2001).

[0036] Antibodies of the invention - production and generation The at least one anti-IL-23 used in the methods of the present invention can optionally be produced by a cell line, mixed cell line, immortalized cell, or clonal population of immortalized cells, as known in the art, see, for example, Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2002, each of which is incorporated herein by reference in its entirety.nd Edition, Cold Spring Harbor, NY(1989), Harlow and Lane, antibodies, a Laboratory Manual, Cold Spring Harbor, NY(1989), Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY(1994-2001), Colligan et al., Current Protocols in Protein Science, John Wiley & See Sons, NY, NY, (1997-2001).

[0037] A preferred anti-IL-23 antibody is guselkumab (also known as CNTO1959), which has the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8, and the heavy chain CDR amino acid sequences of SEQ ID NOs: 1, 2, and 3 and the light chain CDR amino acid sequences of SEQ ID NOs: 4, 5, and 6. Other anti-IL-23 antibodies have the sequences listed herein and are described in U.S. Patent No. 7,935,344, the entire contents of which are incorporated herein by reference.

[0038] Human antibodies specific for human IL-23 protein or fragments thereof can be raised against suitable immunogenic antigens, such as isolated IL-23 protein and / or portions thereof (including synthetic molecules such as synthetic peptides). Other specific or general mammalian antibodies can be similarly produced. Preparation of immunogenic antigens and production of monoclonal antibodies can be carried out using any suitable technique.

[0039] In one approach, a suitable immortal cell line (e.g., but not limited to, Sp2 / 0, Sp2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, L243, P3X63Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5, U937, MLA 144, ACT IV, MOLT4, DA-1, JURKAT, WEHI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA 144, NAMALWA, NEURO) may be used to culture the cells. Myeloma cell lines such as 2A, or heteromyelomas, their fusion products, or any cells or fusion cells derived therefrom, or any other suitable cell line known in the art (see, e.g., www.atcc.org, www.lifetech.com, etc.), antibody-producing cells such as, but not limited to, isolated or cloned spleen, peripheral blood, lymph, tonsil, or other immune or B-cell containing cells, or recombinant or endogenous, viral, bacterial, as endogenous or heterologous nucleic acids. , algae, prokaryote, amphibian, insect, reptile, fish, mammal, rodent, horse, ovine, caprine, sheep, primate, eukaryote, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single-, double-, or triple-stranded, hybridized, etc., or any combination thereof, to produce a hybridoma. See, e.g., Ausubel, supra, and Colligan, Immunology, supra, Chapter 2, both of which are incorporated herein by reference in their entireties.

[0040] Antibody-producing cells can also be obtained from the peripheral blood, or preferably the spleen or lymph nodes, of humans or other suitable animals immunized with the antigen of interest. Any other suitable host cells can also be used to express heterologous or endogenous nucleic acid encoding an antibody of the invention, or specified fragment or variant thereof. Fused cells (hybridomas) or recombinant cells can be isolated using selective culture conditions or other suitable known methods and cloned by limiting dilution or cell sorting or other known methods. Cells producing antibodies with the desired specificity can be selected by a suitable assay (e.g., ELISA).

[0041] Other methods suitable for producing or isolating antibodies with the required specificity can be used, including, but not limited to, methods of selecting recombinant antibodies from peptide or protein libraries (e.g., but not limited to, display libraries of bacteriophage, ribosomal, oligonucleotide, RNA, cDNA, etc., available from, e.g., Cambridge antibody Technologies, Cambridgeshire, UK; MorphoSys, Martinsreid / Planegg, DE; Biovation, Aberdeen, Scotland, UK; BioInvent, Lund, Sweden; Dyax Corp., Enzon; ​​Affymax / Biosite; Xoma, Berkeley, CA; Ixsys.See, for example, European Patent No. 368,684, International Application No. PCT / GB91 / 01134, International Application No. PCT / GB92 / 01755, International Application No. PCT / GB92 / 002240, International Application No. PCT / GB92 / 00883, International Application No. PCT / GB93 / 00605, U.S. Patent Application No. 08 / 350260 (5 / 12 / 94), International Application No. PCT / GB94 / 01422, International Application No. PCT / GB94 / 01422, and International Application No. PCT / GB94 / 01424. CT / GB94 / 02662, International Application No. PCT / GB97 / 01835, (CAT / MRC), International Publication No. WO90 / 14443, International Publication No. WO90 / 14424, International Publication No. WO90 / 14430, International Application No. US94 / 1234, International Publication No. WO92 / 18619, International Publication No. WO96 / 07754, (Scripps), International Publication No. WO96 / 13583, International Publication No. WO97 / 0832 0 (MorphoSys), WO 95 / 16027 (BioInvent), WO 88 / 06630, WO 90 / 3809 (Dyax), U.S. Pat. No. 4,704,692 (Enzon), International Application No. US91 / 02989 (Affymax), WO 89 / 06283, EP 371998, EP 550400, (Xoma), EP 229046, International Application No. US91 / 07149 (Ixsys), or stochastically generated peptides or proteins - U.S. Pat. Nos. 5,723,323, 5,763,192, 5,814,476, 5,817,483, 5,824,514, 5,976,862, WO 86 / 05803, EP 590689 (Ixsys), Applied Molecular Evolution (Applied These include the development of human antibody-producing cells, either through the immunization of transgenic animals capable of producing a repertoire of human antibodies (e.g., SCID mice, each of which is incorporated by reference in its entirety; Nguyen et al., Microbiol. Immunol. 41:901-907 (1997); Sandhu et al., Crit. Rev. Biotechnol. 16:95-118 (1996); Eren et al., ...93:154-161 (1998), and related patents and applications). Such techniques include ribosome display (Hanes et al., Proc. Natl. Acad. Sci. USA, 94:4937-4942 (May 1997); Hanes et al., Proc. Natl. Acad. Sci. USA, 95:14130-14135 (Nov. 1998)), single-cell antibody production techniques (e.g., selected lymphocyte antibody method, "SLAM") (U.S. Patent 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 microdroplets, and flow cytometry (Powell et al. al., Biotechnol. 8:333-337 (1990), One Cell Systems, Cambridge, MA; Gray et al., J. Imm. Meth. 182:155-163 (1995); Kenny et al., Bio / Technol. 13:787-790 (1995)), B cell selectors (Steenbakkers et al., Molec. Biol. Reports 19:125-134 (1994); Jonak et al., Progress Biotech, Vol. 5, In Vitro Immunization in Hybridoma Technology, Borrebaeck, ed., Elsevier Science Publishers BV, Amsterdam, Netherlands (1988)).

[0042] Methods for engineering or humanizing non-human or human antibodies are also available and known in the art. Generally, humanized or engineered antibodies have one or more amino acid residues derived from a non-human source, such as, but not limited to, mouse, rat, rabbit, non-human primate, or other mammalian source. These non-human amino acid residues are replaced by residues often referred to as "import" residues, which are typically taken from an "import" variable, constant, or other domain of a known human sequence.

[0043] Known human Ig sequences are available, e.g., www.ncbi.nlm.nih.gov / entrez / query.fcgi、www.ncbi.nih.gov / igblast、www.atcc.org / phage / hdb.html、www.mrc-cpe.cam.ac.uk / ALIGNMENTS.php、www.kabatdatabase.com / top.html、ftp.ncbi.nih.gov / repository / kabat、www.sciquest.com、www.abcam.com、www.antibodyresource.com / onlinecomp.html、www.public.iastate.edu / ~pedro / research_tools.html、www.whfreeman.com / immunology / CH05 / kuby05.htm、www.hhmi.org / grants / lectures / 1996 / vlab、www.path.cam.ac.uk / ~mrc7 / mikeimages.html、mcb.harvard.edu / BioLinks / Immunology.html、www.immunologylink.com、pathbox.wustl.edu / ~hcenter / index.html、www.appliedbiosystems.com、www.nal.usda.gov / awic / pubs / antibody、www.m.ehime-u.ac.jp / ~yasuhito / Elisa.html、www.biodesign.com、www.cancerresearchuk.org、www.biotech.ufl.edu、www.isac-net.org、baserv.uci.kun.nl / ~jraats / links1.html、www.recab.uni-hd.de / immuno.bme.nwu.edu、www.mrc-cpe.cam.ac.uk、www.ibt.unam.mx / vir / V_mice.html、http: / / www.bioinf.org.uk / abs、antibody.bath.ac.uk、www.unizh.ch、www.cryst.bbk.ac.uk / ~ubcg07s、www.nimr.mrc.ac.uk / CC / ccaewg / ccaewg.html、www.path.cam.ac.uk / ~mrc7 / humanisation / TAHHP.html, www.ibt.unam.mx / vir / structure / stat_aim.html, www.biosci.missouri.edu / smithgp / index.html, www.jerini.de, Kabat et al., Sequences of Proteins of Immunological Interest, USDept. Health (1983).

[0044] Such imported sequences can be used to reduce immunogenicity, or to reduce, enhance, or modify binding, affinity, association rate constant, dissociation rate constant, avidity, specificity, half-life, or any other suitable property, as known in the art. Generally, the CDR residues directly and most substantially influence antigen binding. Thus, non-human sequences in the variable and constant regions can be replaced with human or other amino acids while maintaining some or all of the non-human or human CDR sequences.

[0045] Antibodies can optionally be humanized or human antibodies engineered with retention of high affinity for the antigen and other favorable biological properties. To this end, humanized (or human) antibodies can optionally be prepared by a process of analyzing the parental sequences and various theoretical humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and known to those skilled in the art. Computer programs are available that illustrate and display probable three-dimensional conformations of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of residues in the function of the candidate immunoglobulin sequence, i.e., analysis of residues that influence the antigen-binding ability of the candidate immunoglobulin. In this way, framework (FR) residues can be selected and combined from the consensus and import sequences to achieve desired antibody characteristics, such as enhanced affinity for the target antigen.

[0046] Additionally, antibodies specific for human IL-23 used in the methods of the invention may comprise a human germline light chain framework. In certain embodiments, the light chain germline sequence is selected from a human VK sequence, including, but not limited to, A1, A10, A11, A14, A17, A18, A19, A2, A20, A23, A26, A27, A3, A30, A5, A7, B2, B3, L1, L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23, L24, L25, L4 / 18a, L5, L6, L8, L9, O1, O11, O12, O14, O18, O2, O4, and O8. In certain embodiments, the light chain human germline framework is selected from V1-11, V1-13, V1-16, V1-17, V1-18, V1-19, V1-2, V1-20, V1-22, V1-3, V1-4, V1-5, V1-7, V1-9, V2-1, V2-11, V2-13, V2-14, V2-15, V2-17, V2-19, V2-6, V2-7, V2-8, V3-2, V3-3, V3-4, V4-1, V4-2, V4-3, V4-4, V4-6, V5-1, V5-2, V5-4, and V5-6.

[0047] In other embodiments, antibodies specific for human IL-23 used in the methods of the invention may comprise a human germline heavy chain framework. In certain embodiments, the heavy chain human germline framework is selected from the group consisting of VH1-18, VH1-2, VH1-24, VH1-3, VH1-45, VH1-46, VH1-58, VH1-69, VH1-8, VH2-26, VH2-5, VH2-70, VH3-11, VH3-13, VH3-15, VH3-16, VH3-20, VH3-21, VH3-23, VH3-30, VH3- VH3-33, VH3-35, VH3-38, VH3-43, VH3-48, VH3-49, VH3-53, VH3-64, VH3-66, VH3-7, VH3-72, VH3-73, VH3-74, VH3-9, VH4-28, VH4-31, VH4-34, VH4-39, VH4-4, VH4-59, VH4-61, VH5-51, VH6-1, and VH7-81.

[0048] 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., comprising two or three subregions, such as FR2 and FR3). In certain embodiments, at least FRL1, FRL2, FRL3, or FRL4 is fully human. In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is fully human. In some embodiments, at least FRL1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., human germline) or comprises a human consensus sequence for a particular framework (which are readily available from sources of known human Ig sequences, as discussed above). In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., human germline) or comprises a human consensus sequence for a particular framework. In preferred embodiments, the framework regions are fully human.

[0049] Humanization or engineering of the antibodies of the present invention may be carried out using methods such as those described by Winter (Jones et al., Nature 321:522 (1986); Riechmann et al., Nature 332:323 (1988); Verhoeyen et al., Science 239:1534 (1988)), Sims et al., J. Immunol. 151:2296 (1993), Chothia and Lesk, J. Mol. Biol. 196:901 (1987), Carter et al., Proc. Natl. Acad. Sci. USA 89:4285 (1992), Presta et al. al., J.Immunol.151:2623 (1993), U.S. Patent No. 5723323, U.S. Patent No. 5976862, U.S. Patent No. 5824514, U.S. Patent No. 5817483, U.S. Patent No. 5814476, U.S. Patent No. 5763192, U.S. Patent No. 5723323, U.S. Patent No. 5,76 6886, 5714352, 6204023, 6180370, 5693762, 5530101, 5585089, 5225539, 4816567, International Application No. US98 / 16280, US9 This can be done using any known method, such as, but not limited to, those described in US91 / 09630, US91 / 05939, US94 / 01234, International Application Nos. GB89 / 01334, GB91 / 01134, GB92 / 01755, International Publication Nos. WO90 / 14443, WO90 / 14424, WO90 / 14430, and EP229246 (each of which is incorporated by reference in its entirety, including the references cited therein).

[0050] In certain embodiments, the antibody comprises an altered (e.g., mutated) Fc region. For example, in some embodiments, the Fc region is altered to reduce or enhance the effector function of the antibody. In some embodiments, the Fc region is of an isotype selected from IgM, IgA, IgG, IgE, or other isotypes. Alternatively, or in addition, it may be useful to combine the amino acid modification with one or more additional amino acid modifications that alter the C1q binding and / or complement-dependent cytotoxicity function of the Fc region of the IL-23 binding molecule. Starting polypeptides of particular interest may be those that bind C1q and exhibit complement-dependent cytotoxicity (CDC). Polypeptides with existing C1q-binding activity, and optionally, the additional ability to mediate CDC, may be modified to enhance one or both of these activities. Amino acid modifications that alter C1q and / or its complement-dependent cytotoxicity function are described, for example, in WO 0042072, incorporated herein by reference.

[0051] As disclosed above, the Fc region of the human IL-23-specific antibodies of the present invention can be engineered with altered effector functions, for example, by modifying C1q binding and / or FcγR binding, thereby altering complement-dependent cytotoxicity (CDC) and / or antibody-dependent cell-mediated cytotoxicity (ADCC) activity. An "effector function" serves to activate or reduce a biological activity (e.g., in a subject). Examples of effector functions include, but are not limited to, C1q binding, CDC, Fc receptor binding, ADCC, phagocytosis, downregulation of cell surface receptors (e.g., B cell receptors, BCRs), and the like. Such effector functions may require the Fc region to bind to a binding domain (e.g., an antibody variable domain) and can be assessed using a variety of assays (e.g., Fc binding assays, ADCC assays, CDC assays, etc.).

[0052] For example, variant Fc regions of human IL-23 (or anti-IL-23) antibodies can be generated that have improved C1q binding and improved FcγRIII binding (e.g., both improved ADCC activity and improved CDC activity). Alternatively, if it is desired to reduce or eliminate effector function, variant Fc regions can be engineered with reduced CDC activity and / or reduced ADCC activity. In other embodiments, only one of these activities may be enhanced, optionally with the other activity reduced at the same time (e.g., to generate Fc region variants with improved ADCC activity but reduced CDC activity, and vice versa).

[0053] Fc mutations can also be engineered to alter interactions with the neonatal Fc receptor (FcRn) and improve their pharmacokinetic properties. A collection of human Fc variants with improved binding to FcRn has been described (see Shields et al., (2001). High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FcγR, J. Biol. Chem. 276:6591-6604).

[0054] Another type of amino acid substitution serves to alter the glycosylation pattern of the Fc region of an antibody specific for human IL-23. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars, N-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. The recognition sequences for enzymatic attachment of a carbohydrate moiety to the asparagine side chain peptide sequence are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline. Thus, the presence of either of these peptide sequences in a polypeptide provides a potential glycosylation site.

[0055] The glycosylation pattern can be altered, for example, by deleting one or more glycosylation sites found in the polypeptide and / or adding one or more glycosylation sites that are not present in the polypeptide. Addition of glycosylation sites to the Fc region of an antibody specific for human IL-23 is conveniently achieved by modifying the amino acid sequence to include one or more of the tripeptide sequences described above (for N-linked glycosylation sites). A representative glycosylation variant has an amino acid substitution of residue Asn297 of the heavy chain. This modification may also be made by adding or substituting one or more serine or threonine residues to the original polypeptide sequence (for O-linked glycosylation sites). Additionally, changing Asn297 to Ala can remove one of the glycosylation sites.

[0056] In certain embodiments, antibodies specific for human IL-23 of the invention are expressed in cells expressing beta(1,4)-N-acetylglucosaminyltransferase III (GnT III), such that GnT III adds GlcNAc to the human IL-23 antibody. Methods for producing antibodies in such a manner are provided in WO 9954342, WO 03011878, JP 20030003097(A1), and Umana et al., Nature Biotechnology, 17:176-180, February 1999, all of which are expressly incorporated by reference in their entirety.

[0057] Anti-IL-23 antibodies may also optionally be generated by immunization of transgenic animals (e.g., mice, rats, hamsters, non-human primates, etc.) capable of producing a repertoire of human antibodies, as described herein and / or known in the art. Cells producing human anti-IL-23 antibodies can be isolated and immortalized from such animals using suitable methods, such as those described herein.

[0058] Transgenic mice capable of producing a repertoire of human antibodies that bind to human antigens can be produced using known methods (including, but not limited to, U.S. Pat. Nos. 5,770,428, 5,569,825, 5,545,806, 5,625,126, 5,625,825, 5,633,425, 5,661,016, and 5,789,650 issued to Lonberg et al., WO 98 / 50433 to Jakobovits et al., WO 98 / 24893 to Jakobovits et al., WO 98 / 24993 to Lonberg et al., each of which is incorporated herein by reference in its entirety). 884, International Publication No. 97 / 13852 to Lonberg et al., International Publication No. 94 / 25585 to Lonberg et al., International Publication No. 96 / 34096 to Kucherlapate et al., European Patent No. 0463151(B1) to Kucherlapate et al., European Patent No. 0710719(A1) to Kucherlapate et al., U.S. Patent No. 5,545,807 to Surani et al., International Publication No. 90 / 04036 to Bruggemann et al., European Patent No. 0438474(B1) to Bruggemann et al., European Patent No. 0814259(A2) to Lonberg et al., UK Patent No. 2272440(A) to Lonberg et al., Lonberg et al.Nature 368:856-859(1994),Taylor et al.,Int.Immunol.6(4)579-591(1994),Green et al,Nature Genetics 7:13-21(1994),Mendez et al.,Nature Genetics 15:146-156(1997),Taylor et al. al., Nucleic Acids Research 20(23):6287-6295(1992), Tuaillon et al., Proc Natl Acad Sci USA 90(8)3720-3724(1993), Lonberg et al., Int Rev Immunol 13(1):65-93(1995), and Fishwald et al., Nat Biotechnol 14(7):845-851(1996)).Generally, these mice contain at least one transgene comprising DNA derived from at least one human immunoglobulin locus that has been functionally rearranged, or is capable of undergoing functional rearrangement. The endogenous immunoglobulin loci of such mice can be disrupted or deleted to eliminate the ability of the mice to produce antibodies encoded by endogenous genes.

[0059] Screening antibodies for specific binding to similar proteins or fragments can be successfully accomplished using peptide display libraries. This method involves screening large collections of peptides for individual members with the desired function or structure. Antibody screening of peptide display libraries is well known in the art. Displayed peptide sequences can be 3 to 5,000 or more amino acids in length, frequently 5 to 100 amino acids in length, and often about 8 to 25 amino acids in length. In addition to direct chemical synthesis methods for generating peptide libraries, several recombinant DNA methods have also been described. One type involves displaying peptide sequences on the surface of bacteriophage or cells. Each bacteriophage or cell contains a nucleotide sequence encoding a particular displayed peptide sequence. Such methods are described in WO 91 / 17271, WO 91 / 18980, WO 91 / 19818, and WO 93 / 08278.

[0060] Other systems for generating peptide libraries include aspects of both in vitro chemical synthesis and recombinant methods. See WO 92 / 05258, WO 92 / 14843, and WO 96 / 19256. See also U.S. Patent Nos. 5,658,754 and 5,643,768. Peptide display libraries, vectors, and screening kits are commercially available from suppliers such as Invitrogen (Carlsbad, CA) and Cambridge antibody Technologies (Cambridgeshire, UK). See, for example, U.S. Patent Nos. 4,704,692, 4,939,666, 4,946,778, 5,260,203, 5,455,030, 5,518,889, 5,534,621, 5,656,730, 5,763,733, 5,767,260, and 5,856,456 assigned to Enzon; ​​U.S. Patent Nos. 5,223,409, 5,403,484, 5,571,698, and 5,837,500 assigned to Dyax; U.S. Patent Nos. 5,427,908 and 5,580,717 assigned to Affymax; and Cambridge antibody See U.S. Patent No. 5,885,793 assigned to Genentech, U.S. Patent No. 5,750,373 assigned to Genentech, U.S. Patent Nos. 5,618,920, 5,595,898, 5,576,195, 5,698,435, 5,693,493, 5,698,417 assigned to Xoma, Colligan, supra, Ausubel, supra, or Sambrook, supra. Each of the above patents and publications is incorporated herein by reference in its entirety.

[0061] Antibodies for use in the methods of the invention can also be prepared using nucleic acids encoding at least one anti-IL23 antibody to provide transgenic animals or mammals, such as goats, cows, horses, sheep, or rabbits, that produce such antibodies in their milk. Such animals can be provided using known methods. See, for example, but not limited to, U.S. Patent Nos. 5,827,690, 5,849,992, 4,873,316, 5,849,992, 5,994,616, 5,565,362, and 5,304,489, each of which is incorporated herein by reference in its entirety.

[0062] Antibodies for use in the methods of the present invention can further be prepared using nucleic acids encoding at least one anti-IL23 antibody to provide transgenic plants and cultured plant cells (e.g., but not limited to, tobacco and corn) that produce such antibodies, specific portions, or variants in plant parts or cells cultured therefrom. As a non-limiting example, transgenic tobacco leaves expressing recombinant proteins, e.g., using an inducible promoter, have been successfully used to provide large quantities of recombinant proteins. See, e.g., Cramer et al., Curr. Top. Microbol. Immunol. 240:95-118 (1999) and references cited therein. Transgenic corn has also been used to express mammalian proteins at commercial production levels with biological activity equivalent to proteins produced in other recombinant systems or purified from natural sources. See, e.g., Hood et al., Adv. Exp. Med. Biol. 464:127-147 (1999) and references cited therein. Antibodies have also been produced in large quantities from transgenic plant seeds containing antibody fragments, such as single-chain antibodies (scFv), including tobacco seeds and potato tubers. See, e.g., Conrad et al., Plant Mol. Biol. 38:101-109 (1998) and the references cited therein. Thus, the antibodies of the present invention can also be produced using transgenic plants according to known methods. See, e.g., Fischer et al., Biotechnol. Appl. Biochem. 30:99-108 (Oct., 1999), Ma et al., Trends Biotechnol. 13:522-7 (1995), Ma et al., Plant Physiol. 109:341-6 (1995), Whitelam et al., Biochem. Soc. Trans. 22:940-944 (1994), and the references cited therein. Each of the above documents is incorporated herein by reference in its entirety.

[0063] The antibodies used in the methods of the present invention have a wide range of affinities (K D ) can bind human IL-23. In a preferred embodiment, the human mAb can optionally bind human IL-23 with high affinity. For example, the human mAb can bind human IL-23 at about 10 -7 M or less, for example, but not limited to, 0.1 to 9.9 (or any range or value therein) x 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 K, such as, or any range or value therein D can be combined with

[0064] The affinity or avidity of an antibody for an antigen can be determined experimentally using any suitable method. (See, for example, Berzofsky, et al., "Antibody-Antigen Interactions," Fundamental Immunology, Paul, WE, Ed., Raven Press: New York, NY (1984); Kuby, Janis, Immunology, WH Freeman and Company: New York, NY (1992), and methods described therein.) The affinity measured for a particular antibody-antigen interaction can be different when measured under different conditions (e.g., salt concentration, pH). Thus, affinity and other antigen-binding parameters (e.g., K D , K. a , K. d Measurements of ) are preferably made using standardized solutions of antibody and antigen, and standardized buffers, such as those described herein.

[0065] nucleic acid molecule Using the information provided herein, including, for example, a nucleotide sequence encoding at least 70-100% of the contiguous amino acids of at least one of the light or heavy chain variable or CDR regions described herein, a particular fragment, variant, or consensus sequence thereof, or a deposited vector containing at least one of these sequences, among other sequences disclosed herein, nucleic acid molecules of the invention encoding at least one anti-IL-23 antibody can be obtained using methods described herein or known in the art.

[0066] The nucleic acid molecules of the present invention may be in the form of RNA, such as mRNA, hnRNA, tRNA, or any other form, or in the form of DNA, including, but not limited to, cDNA and genomic DNA obtained by cloning or produced synthetically, or any combination thereof. The DNA may be triple-stranded, double-stranded, or single-stranded, or any combination thereof. Any portion of at least one strand of the DNA or RNA may be the coding strand, also known as the sense strand, or the non-coding strand, also called the antisense strand.

[0067] Isolated nucleic acid molecules for use in the methods of the present invention can include nucleic acid molecules comprising an open reading frame (ORF) optionally containing one or more introns, e.g., a specific portion of at least one CDR, such as, but not limited to, at least one heavy or light chain CDR1, CDR2, and / or CDR3; nucleic acid molecules comprising a coding sequence for an anti-IL-23 antibody or variable region; and nucleic acid molecules comprising a nucleotide sequence substantially different from those described above, but which, due to the degeneracy of the genetic code, still encode at least one anti-IL-23 antibody described herein and / or known in the art. Of course, the genetic code is well known in the art. Therefore, it would be routine for one of skill in the art to generate such degenerate nucleic acid variants encoding specific anti-IL-23 antibodies for use in the methods of the present invention. See, e.g., Ausubel et al., supra. Such nucleic acid variants are encompassed by the present invention. Non-limiting examples of isolated nucleic acid molecules include nucleic acids encoding HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, respectively.

[0068] As described herein, nucleic acid molecules comprising nucleic acids encoding anti-IL-23 antibodies can include those that themselves encode the amino acid sequence of an antibody fragment, sequences encoding the entire antibody or a portion thereof, coding sequences for antibodies, fragments, or portions thereof, and additional sequences, such as at least one intron, along with additional non-coding sequences including, but not limited to, non-coding 5' and 3' sequences, e.g., transcribed, non-translated sequences that play a role in transcription, mRNA processing, including splicing and polyadenylation signals (e.g., mRNA ribosome binding and stability), but also additional non-coding sequences, including, but not limited to, coding sequences for at least one signal leader or fusion peptide, additional coding sequences encoding additional amino acids, e.g., amino acids that provide additional function, with or without the aforementioned additional coding sequences. Thus, the antibody-encoding sequence can be fused to a marker sequence, for example, a sequence encoding a peptide that facilitates purification of the antibody comprising the antibody fragment or portion to which it is fused.

[0069] Polynucleotides that selectively hybridize to the polynucleotides described herein The methods of the present invention use isolated nucleic acids that hybridize under selective hybridization conditions to the polynucleotides disclosed herein. Thus, the polynucleotides of the present embodiments can be used to isolate, detect, and / or quantify nucleic acids containing such polynucleotides. For example, the polynucleotides of the present invention can be used to identify, isolate, or amplify partial or full-length clones in a deposited library. In some embodiments, the polynucleotides are genomic or cDNA sequences isolated or otherwise complementary to cDNAs in a human or mammalian nucleic acid library.

[0070] Preferably, the cDNA library contains at least 80% of the full-length sequences, preferably at least 85% or 90% of the full-length sequences, and more preferably at least 95% of the full-length sequences. The cDNA library can be normalized to increase the representation of rare sequences. Low or medium stringency hybridization conditions are typical, but not limiting, for sequences with low sequence identity to the complementary sequence. Optionally, medium and high stringency conditions can be used for sequences with higher identities. Low stringency conditions allow selective hybridization of sequences with approximately 70% sequence identity and can be used to specifically identify orthologous or paralogous sequences.

[0071] Optionally, the polynucleotide encodes at least a portion of an antibody. The polynucleotide comprises a nucleic acid sequence that can be used for selective hybridization to a polynucleotide encoding an antibody of the invention. See, e.g., Ausubel, supra; Colligan, supra, each of which is incorporated herein by reference in its entirety.

[0072] Nucleic acid construction Isolated nucleic acids can be produced using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, and / or (d) combinations thereof, as are well known in the art.

[0073] Nucleic acids can contain convenient sequences in addition to the polynucleotides of the invention. For example, a multiple cloning site containing one or more endonuclease restriction sites can be inserted into the nucleic acid to aid in the isolation of the polynucleotides. Also, translatable sequences can be inserted to aid in the isolation of the translated polynucleotides of the invention. For example, a hexahistidine marker sequence provides a convenient means for purifying the proteins of the invention. The nucleic acids of the invention (excluding coding sequences) are optionally vectors, adapters, or linkers for cloning and / or expression of the polynucleotides of the invention.

[0074] Additional sequences can be added to such cloning and / or expression sequences to optimize their function in cloning and / or expression, to aid in the isolation of polynucleotides, or to improve the introduction of polynucleotides into cells. The use of cloning vectors, expression vectors, adapters, and linkers is well known in the art (see, e.g., Ausubel, supra, or Sambrook, supra).

[0075] Recombinant methods for constructing nucleic acids Isolated nucleic acid compositions, such as RNA, cDNA, genomic DNA, or any combination thereof, can be obtained from biological sources using any number of cloning methods known to those of skill in the art. In some embodiments, oligonucleotide probes that selectively hybridize under stringent conditions to the polynucleotides of the present invention are used to identify desired sequences in cDNA or genomic DNA libraries. The isolation of RNA and the construction of cDNA and genomic libraries are well known to those of skill in the art. (See, e.g., Ausubel, supra, or Sambrook, supra.)

[0076] Nucleic Acid Screening and Isolation Methods Probes based on the sequences of the polynucleotides used in the methods of the present invention, such as those disclosed herein, can be used to screen cDNA or genomic libraries. Probes can be used to hybridize to genomic DNA or cDNA sequences to isolate homologous genes from the same or different organisms. Those skilled in the art will appreciate that assays can be performed using varying degrees of hybridization stringency, and that either the hybridization or wash medium can be made more stringent. The more stringent the hybridization conditions, the greater the degree of complementarity between the probe and target for duplex formation to occur. The degree of stringency can be controlled by one or more of temperature, ionic strength, pH, and the presence of a partially denaturing solvent, such as formamide. For example, hybridization stringency can be successfully altered by changing the polarity of the reaction solution, e.g., by manipulating the formamide concentration within the range of 0% to 50%. The degree of complementarity (sequence identity) required for detectable binding varies depending on the stringency of the hybridization and / or wash medium. The degree of complementarity is optimally 100%, or 70-100%, or any range or value therein, however, it should be understood that minor sequence differences in the probe and primer can be compensated for by reducing the stringency of the hybridization and / or wash medium.

[0077] Methods for amplifying RNA or DNA are well known in the art and can be used in accordance with the present invention without undue experimentation, based on the teachings and guidance provided herein.

[0078] Known methods of DNA or RNA amplification include the polymerase chain reaction (PCR) and related amplification processes (e.g., U.S. Pat. Nos. 4,683,195, 4,683,202, 4,800,159, and 4,965,188 to Mullis et al.; U.S. Pat. Nos. 4,795,699 and 4,921,794 to Tabor et al.; U.S. Pat. No. 5,142,033 to Innis; U.S. Pat. No. 5,122,464 to Wilson et al.; U.S. Pat. No. 5,091,310 to Innis; U.S. Pat. No. 5,066,584 to Gyllensten et al.; U.S. Pat. No. 5,066,584 to Gelfa et al.). No. 4,889,818 to And et al., U.S. Pat. No. 4,994,370 to Silver et al., U.S. Pat. No. 4,766,067 to Biswas, and U.S. Pat. No. 4,656,134 to Ringold), and RNA-mediated amplification (U.S. Pat. No. 5,130,238 to Malek et al., trade name NASBA), which uses antisense RNA to a target sequence as a template for double-stranded DNA synthesis, the entire contents of which are incorporated herein by reference. (See, e.g., Ausubel, supra, or Sambrook, supra.)

[0079] For example, polymerase chain reaction (PCR) techniques can be used to amplify polynucleotides used in the methods of the present invention and related gene sequences directly from genomic DNA or cDNA libraries. PCR and other in vitro amplification methods can also be useful, for example, for cloning nucleic acid sequences encoding proteins to be expressed, for generating nucleic acids to be used as probes for detecting the presence of desired mRNA in a sample, for nucleic acid sequencing, or for other purposes. Examples of techniques sufficient to guide one of skill in the art through in vitro amplification methods can be found in Berger, Sambrook, and Ausubel, supra, as well as U.S. Pat. No. 4,683,202 to Mullis et al. (1987) and Innis et al., PCR Protocols: A Guide to Methods and Applications, Eds., Academic Press Inc., San Diego, CA (1990). Commercially available kits for genomic PCR amplification are known in the art. See, for example, the Advantage-GC Genomic PCR Kit (Clontech). Additionally, the yield of long PCR products can be improved using, for example, T4 gene 32 protein (Boehringer Mannheim).

[0080] 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 (see, for example, Ausubel et al., supra). Chemical synthesis generally produces a single-stranded oligonucleotide that can be converted into double-stranded DNA by hybridization with a complementary sequence or by polymerization with a DNA polymerase using the single strand as a template. Those skilled in the art will recognize that chemical synthesis of DNA can be limited to sequences of about 100 or more bases, but that longer sequences can be obtained by ligating shorter sequences.

[0081] Recombinant Expression Cassette The present invention uses recombinant expression cassettes containing nucleic acids. Nucleic acid sequences, such as cDNA or genomic sequences encoding antibodies used in the methods of the present invention, can be used to construct recombinant expression cassettes that can be introduced into at least one desired host cell. Recombinant expression cassettes typically contain a polynucleotide operably linked to a transcription initiation regulatory sequence that directs transcription of the polynucleotide in the intended host cell. Both heterologous and non-heterologous (i.e., endogenous) promoters can be utilized to direct expression of the nucleic acid.

[0082] In some embodiments, isolated nucleic acids that function as promoters, enhancers, or other elements can be introduced into a non-heterologous form of a polynucleotide of the invention at an appropriate location (upstream, downstream, or within an intron) to up- or down-regulate expression of the polynucleotide. For example, endogenous promoters can be altered in vivo or in vitro by mutation, deletion, and / or substitution.

[0083] Vectors and host cells The present invention also relates to vectors comprising the isolated nucleic acid molecules, host cells genetically engineered with the recombinant vectors, and the production of at least one anti-IL-23 antibody by recombinant techniques well known in the art (see, e.g., Sambrook et al., supra; Ausubel et al., supra, each incorporated herein by reference in its entirety).

[0084] Polynucleotide can be optionally linked to a vector containing a selectable marker for propagation in a host.Generally, plasmid vector is introduced into a precipitate such as calcium phosphate precipitate or in a complex with charged lipid.If vector is virus, it can be packaged in vitro using a suitable packaging cell line, and then transduced into host cell.

[0085] The DNA insert should be operably linked to a suitable promoter. The expression construct further contains a transcription initiation site, a transcription termination site, and, within the transcribed region, a ribosome binding site for translation. The coding portion of the mature transcript expressed by the construct preferably includes translation beginning with a start and stop codon (e.g., UAA, UGA, or UAG) appropriately positioned at the end of the mRNA to be translated, with UAA and UAG being preferred for expression in mammalian or eukaryotic cells.

[0086] It is preferred, but optional, that the expression vector include at least one selectable marker. Such markers include, for example, methotrexate (MTX), dihydrofolate reductase (DHFR; see U.S. Pat. Nos. 4,399,216, 4,634,665, 4,656,134, 4,956,288, 5,149,636, and 5,179,017), ampicillin, neomycin (G418), mycophenolic acid, or glutamine synthetase for eukaryotic cell culture. Examples of suitable host cell vectors include, but are not limited to, ribozyme synthetase, GS, U.S. Patent Nos. 5,122,464, 5,770,359, and 5,827,739 (all of which are incorporated herein by reference in their entireties), and tetracycline or ampicillin resistance genes for culturing in E. coli and other bacteria or prokaryotes. Appropriate culture media and conditions for the above host cells are known in the art. Suitable vectors will be readily apparent to those skilled in the art. Introduction of vector constructs into host cells can be achieved by calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other known methods. Such methods are described in the art, such as Sambrook, supra, Chapters 1-4 and 16-18, and Ausubel, supra, Chapters 1, 9, 13, 15, and 16.

[0087] At least one antibody used in the methods of the present invention can be expressed in a modified form, such as a fusion protein, and can contain not only secretion signals but also additional heterologous functional regions. For example, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of the antibody to improve stability and persistence in host cells during purification or subsequent processing and storage. Peptide moieties can also be added to the antibodies of the present invention to facilitate purification. Such regions can be removed prior to final preparation of the antibody or at least one fragment thereof. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Chapters 17.29-17.42 and 18.1-18.74, and Ausubel, supra, Chapters 16, 17, and 18.

[0088] Those skilled in the art are familiar with the numerous expression systems available for expressing nucleic acids encoding proteins used in the methods of the present invention. Alternatively, nucleic acids can be expressed in host cells by switching on (by manipulation) the nucleic acid encoding the antibody in the host cell containing the endogenous DNA. Such methods are well known in the art, as described in U.S. Patent Nos. 5,580,734, 5,641,670, 5,733,746, and 5,733,761, the entire contents of which are incorporated herein by reference.

[0089] One example of a cell culture useful for producing antibodies, specified portions, or variants thereof is mammalian cells. Mammalian cell lines are often in the form of monolayers of cells, although mammalian cell suspensions or bioreactors can also be used. Several suitable host cell lines capable of expressing intact glycosylated proteins have been developed in the art, including COS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-1651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., ATCC CRL1610), and BSC-1 (e.g., ATCC CRL-26) cell lines, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2 / 0-Ag14, 293 cells, HeLa cells, and the like, which are readily available, for example, from the American Type Culture Collection (Manassas, Va.) (www.atcc.org). Preferred host cells include cells derived from the lymphatic system, such as myeloma and lymphoma cells. Particularly preferred host cells are P3X63Ag8.653 cells (ATCC deposit number CRL-1580) and SP2 / 0-Ag14 cells (ATCC deposit number CRL-1851). In a particularly preferred embodiment, the recombinant cells are P3X63Ab8.653 or SP2 / 0-Ag14 cells.

[0090] Expression vectors for these cells can include one or more expression control sequences, such as, but not limited to, an origin of replication, a promoter (e.g., the late or early SV40 promoter, the CMV promoter (U.S. Pat. Nos. 5,168,062, 5,385,839), the HSV tk promoter, the pgk (phosphoglycerate kinase) promoter, the EF-1 alpha promoter (U.S. Pat. No. 5,266,491), at least one human immunoglobulin promoter, an enhancer, and / or processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites (e.g., the SV40 large T Ag polyaddition site), and transcription termination sequences. See, e.g., Ausubel et al., supra; Sambrook et al., supra. Other cells useful for producing the nucleic acids or proteins of the invention are known and / or can be found, for example, in the American Type Culture Collection Catalogue of Cell Lines and They are available from Hybridomas (www.atcc.org) or other known or commercial sources.

[0091] When eukaryotic host cells are used, polyadenylation or transcription termination sequences are typically incorporated into the vector. An example of a termination sequence is the polyadenylation sequence from the bovine growth hormone gene. Sequences for accurate splicing of the transcript can also be included. An example of a splicing sequence is the VP1 intron from SV40 (see Sprague, et al., J. Virol. 45:773-781 (1983)). Additionally, gene sequences for regulating replication in host cells can be incorporated into the vector, as is known in the art.

[0092] Antibody purification Anti-IL-23 antibodies can be recovered and purified from recombinant cell cultures by well-known methods, including, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, and lectin chromatography. High performance liquid chromatography ("HPLC") can also be used for purification. See, e.g., Colligan, Current Protocols in Immunology or Current Protocols in Protein Science, John Wiley & Sons, NY, NY (1997-2001), e.g., chapters 1, 4, 6, 8, 9, and 10, each of which is incorporated herein by reference in its entirety.

[0093] Antibodies for use in the methods of the present invention include naturally purified products, products of chemical synthetic processes, and products produced by recombinant techniques from eukaryotic hosts, including, for example, yeast, higher plant, insect, and mammalian cells. Depending on the host utilized in a recombinant production process, the antibody may be glycosylated or non-glycosylated, although glycosylated is preferred. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, sections 17.37-17.42; Ausubel, supra, chapters 10, 12, 13, 16, 18, and 20; and Colligan, Protein Science, supra, chapters 12-14, all of which are incorporated herein by reference in their entireties.

[0094] Anti-IL-23 antibody. The anti-IL-23 antibodies of the present invention comprise at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one ligand binding portion (LBP), such as, but not limited to, a heavy or light chain complementarity determining region (CDR) or a ligand binding portion thereof, a heavy or light chain variable region, a framework region (e.g., FR1, FR2, FR3, FR4, or a fragment thereof, optionally containing at least one substitution, insertion, or deletion), a heavy or light chain constant region (e.g., at least one CDR), or a heavy or light chain variable region, which may be incorporated into the antibody. 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. The antibody can include or be derived from any mammal, such as, but not limited to, human, mouse, rabbit, rat, rodent, primate, or any combination thereof.

[0095] Isolated antibodies for use in the methods of the invention include the amino acid sequences of the antibodies disclosed herein encoded by any suitable polynucleotide, or any isolated or prepared antibody. Preferably, the human antibody or antigen-binding fragment binds to human IL-23, thereby partially or substantially neutralizing at least one biological activity of the protein. An antibody, or specified portion or variant thereof, that partially or preferably substantially neutralizes at least one biological activity of at least one IL-23 protein or fragment can bind to the protein or fragment and thereby inhibit an activity mediated through 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 an antibody that can inhibit IL-23-dependent activity by about 20-120%, preferably at least about 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% or more, depending on the assay. The ability of an anti-IL-23 antibody to inhibit IL-23-dependent activity is preferably assessed by at least one suitable IL-23 protein or receptor assay described herein and / or known in the art. Human antibodies may be of any class (e.g., IgG, IgA, IgM, IgE, IgD, etc.) or isotype and may contain a kappa or lambda light chain. In one embodiment, the human antibody comprises an IgG heavy chain or a defined fragment, e.g., at least one isotype of IgG1, IgG2, IgG3, or IgG4 (e.g., γ1, γ2, γ3, γ4). Antibodies of this type can be prepared by using transgenic mice or other transgenic non-human mammals containing at least one human light chain (e.g., IgG, IgA, IgM) transgene as described herein and / or known in the art. In another embodiment, the anti-IL-23 human antibody comprises an IgG1 heavy chain and an IgG1 light chain.

[0096] The antibody binds to at least one particular epitope specific for at least one IL-23 protein, subunit, fragment, portion, or any combination thereof. The at least one epitope can comprise at least one antibody binding region comprising at least a portion of the protein, preferably comprising at least one extracellular, soluble, hydrophilic, exodomain, or cytoplasmic portion of the protein.

[0097] Generally, a human antibody or antigen-binding fragment comprises an antigen-binding region comprising at least one human complementarity-determining region (CDR1, CDR2, and CDR3) or variant of at least one heavy chain variable region, and at least one human complementarity-determining region (CDR1, CDR2, and CDR3) or variant of at least one light chain variable region. The CDR sequences can be derived from human germline sequences or can exactly match germline sequences. For example, CDRs from synthetic libraries derived from original non-human CDRs can be used. These CDRs can be formed by incorporation of conservative substitutions from the original non-human sequence. In another specific embodiment, the antibody or antigen-binding portion or variant can have an antigen-binding region comprising at least a portion of at least one light chain CDR (i.e., CDR1, CDR2, and / or CDR3) with the corresponding CDR1, 2, and / or 3 amino acid sequence.

[0098] Such antibodies can be prepared by preparing and expressing a nucleic acid molecule (i.e., one or more) encoding the antibody using conventional techniques related to recombinant DNA technology, or by chemically linking the various portions of the antibody (e.g., CDRs, framework) together using conventional techniques, or by using any other suitable method.

[0099] Antibodies specific for IL-23 can comprise at least one heavy or light chain variable region having a defined amino acid sequence. For example, in a preferred embodiment, an anti-IL-23 antibody optionally comprises at least one heavy chain variable region having the amino acid sequence of SEQ ID NO:7 and / or optionally comprises at least one light chain variable region having the amino acid sequence of SEQ ID NO:8. For example, in a preferred embodiment, an anti-IL-23 antibody optionally comprises at least one heavy chain variable region having the amino acid sequence of SEQ ID NO:9 and / or optionally comprises at least one light chain variable region having the amino acid sequence of SEQ ID NO:10. Antibodies that bind to human IL-23 and comprise defined heavy or light chain variable regions can be prepared using suitable methods, such as methods employing phage display (Katsube, Y., et al., Int J Mol. Med, 1(5):863-868 (1998)) or transgenic animals, as known in the art and / or described herein. For example, transgenic mice containing a functionally rearranged human immunoglobulin heavy chain transgene and a transgene comprising DNA from a human immunoglobulin light chain locus capable of undergoing functional rearrangement can be immunized with human IL-23 or a fragment thereof to elicit the production of antibodies. If desired, antibody-producing cells can be isolated and hybridomas or other immortalized antibody-producing cells can be prepared as described herein and / or known in the art. Alternatively, antibodies, specified portions, or variants can be expressed using encoding nucleic acids or portions thereof in suitable host cells.

[0100] The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs that comprise amino acids in sequences that are substantially the same as the amino acid sequences described herein. Preferably, such antibodies or antigen-binding fragments and antibodies comprising such chains or CDRs have high affinity (e.g., about 10 -9 K below M D) can bind to human IL-23. Amino acid sequences that are substantially the same as the sequences described herein include sequences containing conservative amino acid substitutions as well as amino acid deletions and / or insertions. A conservative amino acid substitution refers to the substitution of a first amino acid with a second amino acid that has chemical and / or physical properties (e.g., charge, structure, polarity, hydrophobicity / hydrophilicity) similar to those of the first amino acid. Conservative substitutions include, but are not limited to, replacing one amino acid with another amino acid within the following group: lysine (K), arginine (R), and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D, and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine ​​(C), and glycine (G); F, W, and Y; C, S, and T.

[0101] Amino acid code The amino acids that make up the anti-IL-23 antibodies of the present invention are often abbreviated. Amino acid abbreviations can be provided by representing the amino acid by its single-letter code, its three-letter code, name, or three-nucleotide codon, and are well understood in the art (see Alberts, B., et al., Molecular Biology of the Cell, Third Ed., Garland Publishing, Inc., New York, 1994).

[0102] [Table 1]

[0103] The anti-IL-23 antibodies used in the methods of the present invention may contain one or more amino acid substitutions, deletions, or additions, either due to natural mutations or human manipulation, as specified herein.

[0104] The number of amino acid substitutions one skilled in the art may make depends on many factors, including those described above. Generally, the number of amino acid substitutions, insertions, or deletions for any given anti-IL-23 antibody, fragment, or variant will not exceed 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 to 30, or any range or value therein, as specified herein.

[0105] Amino acids within an anti-IL-23 specific antibody that are essential for function can be identified by methods known in the art, such as site-directed mutagenesis or alanine scanning mutagenesis (e.g., Ausubel, supra, Chapters 8, 15; Cunningham and Wells, Science 244:1081-1085 (1989)). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity, including, but not limited to, at least one IL-23 neutralizing activity. Sites critical for antibody binding can also be identified by structural analysis, such as crystallization, nuclear magnetic resonance, or photoaffinity labeling (Smith, et al., J. Mol. Biol. 224:899-904 (1992) and de Vos, et al., Science 255:306-312 (1992)).

[0106] The anti-IL-23 antibody can include, but is not limited to, at least one portion, sequence, or combination selected from all five of at least one contiguous amino acid of SEQ ID NOs: 1, 2, 3, 4, 5, and 6.

[0107] The IL-23 antibody or specific portion or variant may include, but is not limited to, at least one portion, sequence, or combination selected from at least 3 to 5 contiguous amino acids of the above SEQ ID NO:, 5 to 17 contiguous amino acids of the above SEQ ID NO:, 5 to 10 contiguous amino acids of the above SEQ ID NO:, 5 to 11 contiguous amino acids of the above SEQ ID NO:, 5 to 7 contiguous amino acids of the above SEQ ID NO:, or 5 to 9 contiguous amino acids of the above SEQ ID NO:.

[0108] The anti-IL-23 antibody further optionally can comprise at least one polypeptide of 70-100% of 5, 17, 10, 11, 7, 9, 119, or 108 contiguous amino acids of SEQ ID NOs: 1-5. In one embodiment, the amino acid sequence of an immunoglobulin chain or portion thereof (e.g., variable region, CDR) has about 70-100% identity (e.g., 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or any range or value therein) to the amino acid sequence of the corresponding chain of at least one of the above SEQ ID NOs. For example, the amino acid sequence of the light chain variable region can be compared to the sequence of the above SEQ ID NOs, or the amino acid sequence of the heavy chain CDR3 can be compared to the sequence of the above SEQ ID NOs. Preferably, 70-100% amino acid identity (i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or any range or value therein) is determined using a suitable computer algorithm known in the art.

[0109] "Identity," as known in the art, is a relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by comparing the sequences. In the art, "identity" also means the degree of sequence relatedness between polypeptide or polynucleotide sequences, as determined by the match between strings of such sequences. "Identity" and "similarity" can be readily calculated by known methods, including, but not limited to, those described in Computational Molecular Biology, Lesk, AM, ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, DW, ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, AM, and Griffin, HG, eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; and Carillo, H., and Lipman, D., Siam J. Applied Math., 48:1073 (1988). Additionally, percent identity values ​​can be obtained from amino acid and nucleotide sequence alignments generated using default settings in AlignX, a component of Vector NTI Suite 8.0 (Informax, Frederick, MD).

[0110] Preferred methods to determine identity are designed to give the largest match between the sequences tested. Methods to determine identity and similarity are codified in publicly available computer programs. Preferred computer program methods for determining identity and similarity between two sequences include, but are not limited to, the GCG program package (Devereux, J., et al., Nucleic Acids Research 12(1):387 (1984)), BLASTP, BLASTN, and FASTA (Atschul, S. F. et al., J. Molec. Biol. 215:403-410 (1990)). The BLAST X program is publicly available from NCBI and other sources (BLAST Manual, Altschul, S., et al., NCB1NLM NIH Bethesda, Md. 20894; Altschul, S., et al., J. Mol. Biol. 215:403-410 (1990). The well-known Smith Waterman algorithm may also be used to determine identity.

[0111] Preferred parameters for polypeptide sequence comparison include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443-453 (1970) Comparison matrix: BLOSSUM62 from Hentikoff and Hentikoff,Proc.Natl.Acad.Sci,USA.89:10915-10919(1992), Gap penalty: 12 Gap length penalty: 4

[0112] A program useful with these parameters is publicly available as the "Gap" program from Genetics Computer Group, Madison Wis. The aforementioned parameters are the default parameters for peptide sequence comparisons (as well as no penalty for end gaps).

[0113] Preferred parameters for polynucleotide comparison include the following: (1) Algorithm: Needleman and Wunsch, J. Mol. Biol. 48:443-453 (1970) Comparison matrix: match = +10, mismatch = 0 Gap penalty: 50 Gap length penalty: 3

[0114] Available as the "Gap" program from Genetics Computer Group, Madison Wis. These are the default parameters for nucleic acid sequence comparisons.

[0115] By way of example, a polynucleotide sequence can be identical to another sequence, i.e., 100% identical, or can contain up to a certain integer number of nucleotide alterations compared to a reference sequence. Such alterations are selected from the group consisting of deletions, substitutions (including transitions and transversions), or insertions of at least one nucleotide, which may occur at the 5' or 3' terminal position of the reference nucleotide sequence, or anywhere between these terminal positions, and may be dispersed either individually among nucleotides of the reference sequence, or in one or more adjacent groups within the reference sequence. The number of nucleotide alterations can be determined by multiplying the total number of nucleotides in the sequence by the corresponding numerical percent identity (divided by 100) and subtracting that product from the total number of nucleotides in the sequence, or is determined by n.sub.n.ltorsim.x.sub.n-(x.sub.ny), where n.sub.n is the number of nucleotide alterations, x.sub.n is the total number of nucleotides in the sequence, and y is, for example, 0.70 for 70%, 0.80 for 80%, 0.85 for 85%, 0.90 for 90%, 0.95 for 95%, etc., and any non-integer product of x.sub.n and y is rounded down to the nearest integer before subtraction from x.sub.n.

[0116] Modification of a polynucleotide sequence encoding the above SEQ ID NOs may create nonsense, missense, or frameshift mutations in the coding sequence, thereby altering the polypeptide encoded by the polynucleotide after such modification. Similarly, a polypeptide sequence may be identical to the reference sequence of the above SEQ ID NOs, i.e., 100% identical, or may contain up to a certain integer number of amino acid modifications compared to the reference sequence such that the percent identity is less than 100%. Such modifications are selected from the group consisting of deletion, substitution (including conservative and non-conservative substitution), or insertion of at least one amino acid, which may occur at the amino- or carboxy-terminal position of the reference polypeptide sequence or anywhere between these terminal positions, and may be dispersed either individually among the amino acids of the reference sequence or in one or more adjacent groups within the reference sequence. The number of amino acid changes for a given percent identity may be determined by multiplying the total number of amino acids in the SEQ ID NO by the numerical percent of each percent identity (divided by 100) and subtracting this product from the total number of amino acids in the SEQ ID NOs, or is determined by n.sub.a.ltorsim.x.sub.a-(x.sub.ay), where n.sub.a is the number of amino acid changes, x.sub.a is the total number of amino acids in the SEQ ID NO: and y is, for example, 0.70 for 70%, 0.80 for 80%, 0.85 for 85%, etc., and any non-integer product of x.sub.a and y is rounded down to the nearest integer before subtracting from x.sub.a.

[0117] Representative heavy and light chain variable region sequences, and portions thereof, are set forth in the SEQ ID NOs: 1 and 2 above. Antibodies of the invention, or specified variants thereof, can include any number of contiguous amino acid residues from an antibody of the invention, the number being selected from the group of integers consisting of 10-100% of the number of contiguous residues in an anti-IL-23 antibody. Optionally, this subsequence of contiguous amino acids is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, or more amino acids in length, or any range or value therein. Furthermore, the number of such subsequences can be any integer selected from the group consisting of 1-20, such as at least 2, 3, 4, or 5.

[0118] As those skilled in the art will recognize, the present invention includes at least one biologically active antibody of the invention. A biologically active antibody has a specific activity that is at least 20%, 30%, or 40%, preferably at least 50%, 60%, or 70%, and most preferably at least 80%, 90%, or 95% to 100% or more (including but not limited to, up to 10-fold the specific activity) of that of a natural (non-synthetic), endogenous, or related and known antibody. Methods for assaying and quantitatively measuring enzymatic activity and substrate specificity are well known to those skilled in the art.

[0119] In another aspect, the invention relates to human antibodies and antigen-binding fragments described herein that are modified by the covalent attachment of an organic moiety. Such modifications can produce antibodies or antigen-binding fragments with improved pharmacokinetic properties (e.g., increased in vivo serum half-life). The organic moiety can be a linear or branched hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. In certain embodiments, the hydrophilic polymer group has a molecular weight of about 800 to about 120,000 daltons and can be a polyalkane glycol (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)), a carbohydrate polymer, an amino acid polymer, or polyvinylpyrrolidone, and the fatty acid group or fatty acid ester group can contain about 8 to about 40 carbon atoms.

[0120] The modified antibodies and antigen-binding fragments can include one or more organic moieties covalently attached directly or indirectly to the antibody. Each organic moiety attached to an antibody or antigen-binding fragment of the present invention can independently be a hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. As used herein, the term "fatty acid" includes monocarboxylic and dicarboxylic acids. As used herein, the term "hydrophilic polymer group" refers to an organic polymer that is more soluble in water than octane. For example, polylysine is more soluble in water than octane. Thus, antibodies modified by the covalent attachment of polylysine are encompassed by the present invention. Hydrophilic polymers suitable for modifying antibodies of the present invention can be linear or branched, and include, for example, polyalkane glycols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG, etc.), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides, etc.), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, polyaspartic acid, etc.), polyalkane oxides (e.g., polyethylene oxide, polypropylene oxide, etc.), and polyvinylpyrrolidone. Preferably, the hydrophilic polymers used to modify antibodies of the present invention have, as individual molecular entities, a molecular weight of about 800 to about 150,000 daltons. For example, PEG 5000 and PEG20,000 can be used, where the subscript is the average molecular weight of the polymer in Daltons. The hydrophilic polymer group can be substituted with 1 to about 6 alkyl groups, fatty acid groups, or fatty acid ester groups. Hydrophilic polymers substituted with fatty acid or fatty acid ester groups can be prepared by utilizing suitable methods. For example, a polymer containing an amine group can be linked to a carboxylate salt of a fatty acid or fatty acid ester, or an activated carboxylate salt on a fatty acid or fatty acid ester (e.g., activated with N,N-carbonyldiimidazole) can be linked to a hydroxyl group on the polymer.

[0121] Fatty acids and fatty acid esters suitable for modifying antibodies of the invention may be saturated or may contain one or more units of unsaturation. Fatty acids suitable for modifying antibodies of the invention include, for example, n-dodecanoate (C 12 , laurate), n-tetradecanoate (C 14 , myristate), n-octadecanoate (C 18 , stearate), n-eicosanoate (C 20 , arachidate), n-docosanoate (C 22 , behenic acid), n-triacontanoate (C 30 ), n-tetracontanoate (C 40 ), cis-Δ9-octadecanoate (C 18 oleate), all cis-Δ5,8,11,14-eicosatetraenoate (C 20 , arachidonate), octanedioic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, and the like. Suitable fatty acid esters include monoesters of dicarboxylic acids containing a straight-chain or branched-chain lower alkyl group. The lower alkyl group can contain from 1 to about 12, preferably from 1 to about 6, carbon atoms.

[0122] Modified human antibodies and antigen-binding fragments can be prepared using suitable methods, such as by reacting with one or more modifying agents. As used herein, the term "modifying agent" refers to a suitable organic group (e.g., a hydrophilic polymer, a fatty acid, a fatty acid ester) containing an activating group. An "activating group" is a chemical moiety or functional group that can react with a second chemical group under appropriate conditions, thereby forming a covalent bond between the modifying agent and the second chemical group. For example, amine-reactive activating groups include electrophilic groups such as tosylate, mesylate, halo (chloro, bromo, fluoro, iodo), N-hydroxysuccinimidyl ester (NHS), and the like. Activating groups that can react with thiols include, for example, maleimide, iodoacetyl, acrylolyl, pyridyl disulfide, 5-thiol-2-nitrobenzoic acid thiol (TNB-thiol), and the like. Aldehyde functional groups can be linked to amine- or hydrazide-containing molecules, and azide groups can react with trivalent phosphorus groups to form phosphoramidate or phosphorimide bonds. Suitable methods for introducing activated groups into molecules are known in the art (see, for example, Hermanson, GT, Bioconjugate Techniques, Academic Press: San Diego, CA (1996)). Activated groups can be attached directly to organic groups (e.g., hydrophilic polymers, fatty acids, fatty acid esters) or to linker moieties, such as divalent C1-C 12The linker moiety can be linked via a group (wherein one or more carbon atoms can be replaced by a heteroatom such as oxygen, nitrogen, or sulfur). Suitable linker moieties include, for example, tetraethylene glycol, -(CH2)3-, -NH-(CH2)6-NH-, -(CH2)2-NH-, and -CH2-O-CH2-CH2-O-CH2-CH2-O-CH-NH-. A modifying agent containing a linker moiety can be produced, for example, by reacting a mono-Boc-alkyldiamine (e.g., mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to form an amide bond between the free amine and the fatty acid carboxylate. The Boc protecting group can be removed from the product by treatment with trifluoroacetic acid (TFA) to expose a primary amine that can be coupled to another carboxylic acid salt as described, or it can be reacted with maleic anhydride and the resulting product cyclized to produce an activated maleimide derivative of a fatty acid (see, e.g., WO 92 / 16221 (Thompson et al.), the entire teachings of which are incorporated herein by reference).

[0123] Modified antibodies can be produced by reacting a human antibody or antigen-binding fragment with a modifying agent. For example, organic moieties can be attached to antibodies in a non-site-specific manner using an amine-reactive modifying agent, e.g., an NHS ester of PEG. Modified human antibodies or antigen-binding fragments can also be prepared by reducing disulfide bonds (e.g., intrachain disulfide bonds) of an antibody or antigen-binding fragment. The reduced antibody or antigen-binding fragment can then be reacted with a thiol-reactive modifying agent to produce the modified antibodies of the invention. Modified human antibodies and antigen-binding fragments containing organic moieties attached to specific sites on the antibodies of the invention can be prepared using suitable methods, such as reverse proteolysis (Fisch et al., Bioconjugate Chem., 3:147-153 (1992); Werlen et al., Bioconjugate Chem., 5:411-417 (1994); Kumaran et al., Protein Sci. 6(10):2233-2241 (1997); Itoh et al., Bioorg. Chem., 24(1):59-68 (1996); Capellas et al., Biotechnol. Bioeng., 56(4):456-463 (1997)), and methods described in Hermanson, G.T., Bioconjugate Techniques, Academic Press: San Diego, CA (1996).

[0124] The methods of the present invention also employ anti-IL-23 antibody compositions comprising at least one, at least two, at least three, at least four, at least five, at least six, or more of such anti-IL-23 antibodies, provided in a non-naturally occurring composition, mixture, or form, as described herein and / or known in the art. Such compositions include non-naturally occurring compositions comprising at least one or two full-length, C- and / or N-terminal deletion mutants, domains, fragments, or specific variants of an anti-IL-23 antibody amino acid sequence selected from the group consisting of 70-100% of the contiguous amino acids of the above SEQ ID NOs, or specific fragments, domains, or variants thereof. Preferred anti-IL-23 antibody compositions comprise at least one or two full-length, fragments, domains, or variants as at least one CDR- or LBP-containing portion of an anti-IL-23 antibody sequence described herein, e.g., 70-100% of the above SEQ ID NOs, or specific fragments, domains, or variants thereof. More preferred compositions comprise, for example, 70-100% of at least one of the above SEQ ID NOs, or specified fragments, domains, or variants thereof, 40-99%. Such composition percentages may be by weight, volume, concentration, molarity, or molar concentration as a liquid or dry solution, mixture, suspension, emulsion, particle, powder, or colloid, as known in the art or as described herein.

[0125] Antibody compositions containing additional therapeutically active ingredients The antibody compositions used in the methods of the present invention can optionally further comprise an effective amount of at least one compound or protein selected from at least one of anti-infective agents, cardiovascular (CV) acting agents, central nervous system (CNS) agents, autonomic nervous system (ANS) agents, respiratory agents, gastrointestinal (GI) tract acting agents, hormonal agents, fluid or electrolyte balancing agents, hemodynamic agents, anti-neoplastic agents, immunomodulatory agents, ophthalmic, otic or nasal agents, topical agents, nutritional agents, etc. Such drugs are well known in the art, including the formulations, indications, dosages, and administration of each set forth herein (see, e.g., Nursing 2001 Handbook of Drugs, 21, each of which is incorporated herein by reference in its entirety). st edition, Springhouse Corp., Springhouse, PA, 2001; Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc., Upper Saddle River, NJ; Pharmacology Handbook, Wells et al., Appleton & Lange, Stamford, CT).

[0126] As examples of drugs that can be combined with the antibodies of the methods of the present invention, the anti-infective drug can be at least one selected from an amebicide or at least one antiprotozoal drug, an anthelmintic, an antifungal, an antimalarial, an antituberculosis drug or at least one antileprosy drug, an aminoglycoside, a penicillin, a cephalosporin, a tetracycline, a sulfonamide, a fluoroquinolone, an antiviral drug, a macrolide anti-infective drug, and miscellaneous anti-infective drugs. The hormonal drug can be at least one selected from a corticosteroid, an androgen, or at least one anabolic steroid, an estrogen, or at least one progestin, a gonadotropin, an antidiabetic drug, or at least one glucagon, a thyroid hormone, a thyroid hormone antagonist, a pituitary hormone, and a parathyroidomimetic drug. The at least one cephalosporin can be at least one selected from cefaclor, cefadroxil, cefazolin sodium, cefdinir, cefepime hydrochloride, cefixime, cefmetazole sodium, cefonicid sodium, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime sodium, ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cephalexin hydrochloride, cephalexin monohydrate, cephradine, and loracarbef.

[0127] The at least one corticosteroid can be at least one selected from betamethasone, betamethasone acetate or betamethasone sodium phosphate, betamethasone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, triamcinolone, triamcinolone acetonide, and triamcinolone acetate. The at least one androgenic or anabolic steroid can be at least one selected from danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate, nandrolone phenpropionate, testosterone, testosterone cypionate, testosterone enanthate, testosterone propionate, and a testosterone transdermal system.

[0128] The at least one immunosuppressant can be at least one selected from azathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immunoglobulin, muromonab-CD3, mycophenolate mofetil, mycophenolate mofetil hydrochloride, sirolimus, and tacrolimus.

[0129] The at least one topical anti-infective can be at least one selected from acyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole, econazole nitrate, erythromycin, gentamicin sulfate, ketoconazole, mafenide acetate, metronidazole (topical), miconazole nitrate, mupirocin, naftifine hydrochloride, neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, terbinafine hydrochloride, terconazole, tetracycline hydrochloride, tioconazole, and tolnaftate. The at least one scabicide or pediculicide can be at least one selected from crotamiton, lindane, permethrin, and pyrethrins. The at least one topical corticosteroid can be at least one selected from betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate, fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, and triamcinolone acetonide. (See, e.g., pages 1098-1136 of the Nursing 2001 Drug Handbook.)

[0130] Anti-IL-23 antibody compositions comprise at least one anti-IL-12 / 23p40 or IL-23 antibody that is contacted with or administered to a cell, tissue, organ, animal, or subject in need of such modulation, treatment, or therapy, and optionally at least one TNF antagonist (such as, but not limited to, a TNF chemical or protein antagonist, a TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70, or p85) or fragment, fusion polypeptide thereof, or a small molecule TNF antagonist, such as TNF binding protein I or II (TBP-1 or TBP-II), nerelimonmab, infliximab, or the like). The composition may further comprise at least one suitable and effective amount of any composition or pharmaceutical composition selected from the group consisting of anti-rheumatic drugs (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), immunizing agents, immunoglobulins, immunosuppressants (e.g., azathioprine, basiliximab, cyclosporine, daclizumab), cytokines, and cytokine antagonists. Non-limiting examples of such cytokines include, but are not limited to, IL-1 to IL-40 (e.g., IL-1, IL-2, etc.). Suitable dosages are well known in the art. For example, Wells et al., eds., Pharmacotherapy Handbook, 2 nd Edition, Appleton and Lange, Stamford, CT (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), each of which is incorporated herein by reference in its entirety.

[0131] The anti-IL-23 antibody compounds, compositions, or mixtures used in the methods of the present invention may further comprise at least one of any suitable auxiliary agent, including, but not limited to, diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc. Pharmaceutically acceptable auxiliary agents are preferred. Methods for preparing such sterile solutions and non-limiting examples thereof are well known in the art and are described, for example, in Gennaro, Ed., Remington's Pharmaceutical Sciences, 1894, pp. 181-184. th Edition, Mack Publishing Co. (Easton, PA) 1990. Pharmaceutically acceptable carriers suitable for the mode of administration, solubility, and / or stability of the anti-IL-23 antibody, fragment, or variant compositions known in the art or described herein can be routinely selected.

[0132] Pharmaceutical excipients and additives useful in the present compositions include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., saccharides including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars, and polysaccharides or sugar polymers), which may be present alone or in combination and comprise 1 to 99.99% by weight or volume, alone or in combination. Representative protein excipients include serum albumins, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acids / antibody components that may also function in buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. One preferred amino acid is glycine.

[0133] Suitable carbohydrate excipients for use in the present invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, etc., disaccharides such as lactose, sucrose, trehalose, cellobiose, etc., polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starches, etc., alditols such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), myo-inositol, etc. Preferred carbohydrate additives for use in the present invention are mannitol, trehalose, and raffinose.

[0134] The anti-IL-23 antibody composition can also contain a buffer or pH adjuster, and typically the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, or phosphate buffers. Preferred buffers for use in the present compositions are organic acid salts such as citric acid.

[0135] Additionally, anti-IL-23 antibody compositions may include polymeric excipients / additives such as polyvinylpyrrolidone, Ficoll (a polymeric sugar), dextrates (e.g., cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin), polyethylene glycol, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN 20" and "TWEEN 80"), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA).

[0136] These and additional known pharmaceutical additives and / or excipients suitable for use in the anti-IL-23 antibody, portion or variant compositions of the invention are known in the art and are described, for example, in "Remington: The Science & Practice of Pharmacy," 1999; thed., 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. Preferred carrier or additive materials are carbohydrates (e.g., monosaccharides and alditols) and buffering agents (e.g., citric acid) or polymeric agents. An exemplary carrier molecule is the mucopolysaccharide, hyaluronic acid, which may be useful for intra-articular delivery.

[0137] formulation As noted above, the present invention provides stable formulations, preferably saline or phosphate buffer with selected salts, as well as preservative-containing preservative solutions and formulations, and versatile preserved formulations suitable for pharmaceutical or veterinary use, comprising at least one anti-IL-23 antibody in a pharmaceutically acceptable formulation, comprising at least one known preservative, optionally selected from the group consisting of at least one of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylparaben (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof, in an aqueous diluent. As known in the art, the range may be from 0.001 to 5%, or any range or value therein, for example, 0.001, 0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.10, 4.11, 4.12, 4.13, 4.14, 4.15, 4.16, 4.17, 4.18, 4.19, 4.20, 4.21, 4.22, 4.23, 4.24, 4.25, 4.26, 4.27, 4.28, 4.29, 4.30, 4.31, 4.32, 4.33, 4.34, 4.35, 4.36, 4.37, 4.38, 4.39, 4.40, 4.41, 4.42, 4.43, 4.44, 4.45, 4.46 Any suitable concentration or mixture can be used, such as 0.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, etc., or any range or value therein.Non-limiting examples include preservative-free, 0.1-2% m-cresol (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (e.g., 0.005, 0.01%), 0.001-2.0% phenol (e.g., Examples include 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005 to 1.0% alkylparabens (e.g., 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%), and the like.

[0138] As described above, the methods of the present invention utilize articles of manufacture comprising packaging and at least one vial containing a solution of at least one anti-IL-23-specific antibody, optionally with a buffer and / or preservative, formulated in an aqueous diluent, the packaging comprising a label stating that such solution can be preserved for 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72, or more hours. The present invention also utilizes articles of manufacture comprising packaging and a first vial containing a lyophilized anti-IL-23-specific antibody and a second vial containing a formulated buffer or preservative aqueous diluent, the packaging comprising a label instructing a patient to reconstitute the anti-IL-23-specific antibody with the aqueous diluent to form a solution that can be preserved for 24 hours or more.

[0139] Antibodies specific for anti-IL-23 used in accordance with the present invention may be produced by recombinant means, including production from mammalian cells or transgenic preparations, or purified from other biological sources, as described herein or known in the art.

[0140] Anti-IL-23 specific antibody ranges include amounts that yield concentrations of about 1.0 μg / mL to about 1000 mg / mL upon reconstitution for wet / dry systems, although lower and higher concentrations are workable and depend on the intended delivery vehicle, e.g., solution formulations, as opposed to transdermal patch, pulmonary, transmucosal, or osmotic or micropump methods.

[0141] Preferably, the aqueous diluent optionally further contains a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof. The concentration of the preservative used in the formulation is sufficient to produce an antibacterial effect. Such a concentration will vary depending on the preservative selected and can be easily determined by one skilled in the art.

[0142] Other excipients, such as isotonicity agents, buffers, antioxidants, and preservative enhancers, can optionally and preferably be added to the diluent. An isotonicity agent, such as glycerin, is generally used at a known concentration. A physiologically tolerable buffer is preferably added to provide improved pH control. The formulations can cover a wide pH range, such as from about pH 4 to about pH 10, preferably from about pH 5 to about pH 9, and most preferably from about pH 6.0 to about pH 8.0. Preferably, the formulations of the present invention have a pH of about 6.8 to about pH 7.8. Suitable buffers include phosphate buffers, most preferably sodium phosphate, particularly phosphate buffered saline (PBS).

[0143] Other additives, such as pharmaceutically acceptable solubilizers such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymer), and PEG (polyethylene glycol), or nonionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polyl, other block copolymers, and chelating agents such as EDTA and EGTA, can optionally be added to the formulation or composition to reduce aggregation. These additives are particularly useful when a pump or plastic container is used to administer the formulation. The presence of a pharmaceutically acceptable surfactant reduces the tendency of proteins to aggregate.

[0144] The formulations can be prepared by a process comprising mixing at least one anti-IL-23 antibody with a preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (e.g., methyl, ethyl, propyl, butyl), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof, in an aqueous diluent. Mixing of the at least one anti-IL-23-specific antibody with the preservative in the aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a quantity of at least one anti-IL-23-specific antibody in a buffer solution is combined with the desired preservative in a sufficient amount of buffer solution to provide the desired concentrations of protein and preservative. Variations on this process will be recognized by those skilled in the art. For example, the order of addition of components, whether or not additional additives are used, and the temperature and pH during formulation preparation are all factors that can be optimized for the dosage concentration and administration means used.

[0145] The formulation can be provided to patients as a clear solution or as a dual vial containing a vial of lyophilized anti-IL-23 specific antibody reconstituted with a second vial containing water, preservatives and / or excipients, preferably phosphate buffer and / or saline, and selected salts in an aqueous diluent. Either the single solution vial or the dual vial requiring reconstitution can be reused multiple times to satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0146] The product is useful for administration over a period ranging from immediate to 24 hours or more. Thus, the products claimed by the present invention provide significant benefits to patients. The formulations of the present invention can optionally be safely stored at temperatures between about 2°C and about 40°C and retain the biological activity of the protein for extended periods; therefore, the packaging label can indicate that the solution can be stored and / or used for 6, 12, 18, 24, 36, 48, 72, or 96 hours or more. When a preserved diluent is used, such labeling can include use periods of up to 1-12 months, 6 months, 1.5 years, and / or 2 years.

[0147] Solutions of antibodies specific for anti-IL-23 can be prepared by a process comprising mixing at least one antibody in an aqueous diluent. Mixing is carried out using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, a quantity of at least one antibody in water or a buffer is combined in an amount sufficient to provide the desired concentration of protein, and optionally, a preservative or buffer. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of components, whether or not additional additives are used, and the temperature and pH during formulation preparation are all factors that can be optimized for the dosage concentration and means of administration used.

[0148] The claimed products can be provided to patients as a clear solution or as dual vials containing a vial of at least one lyophilized anti-IL-23 specific antibody that is reconstituted with a second vial containing an aqueous diluent. Either the single solution vial or the dual vial requiring reconstitution can be reused multiple times to satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0149] The claimed products can be provided indirectly to patients by providing pharmacies, clinics, or other such institutions and facilities with dual vials containing a vial of at least one lyophilized antibody specific to anti-IL-23 reconstituted with a second vial containing a clear solution or aqueous diluent, where the clear solution may be up to one liter or even more in volume, from which smaller amounts of the at least one antibody solution can be withdrawn one or more times from the larger container and transferred to smaller vials and provided by the pharmacy or clinic to customers and / or patients.

[0150] Approved devices that include single-vial systems include pen-type injector devices for delivering solutions, such as BD Pens, BD Autojector®, Humaject®, NovoPen®, B-DPen®, AutoPen®, and OptiPen®, GenotropinPen®, Genotronorm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®, Iject®, J-tip Needle-Free Injector®, Intraject®, Medi-Ject®, Smartject®, and the like (Becton Dickens (Franklin)). Suitable devices include those manufactured or developed by Bioject (Portland, Oregon (www.bioject.com), National Medical Products, Weston Medical (Peterborough, UK (www.weston-medical.com), Medi-Ject Corp (Minneapolis, MN (www.mediject.com)), and similar devices. Recognized devices that include dual vial systems include pen-type injector systems, such as HumatroPen®, for reconstituting lyophilized medication within a cartridge to deliver the reconstituted solution. Examples of other suitable devices include pre-filled syringes, auto-injectors, needleless injectors, and needleless IV infusion sets.

[0151] The product may include packaging. The packaging provides information required by regulatory authorities as well as the conditions under which the product can be used. The packaging of the present invention, if applicable, provides instructions to the patient to reconstitute at least one anti-IL-23 antibody with an aqueous diluent to form a solution and use this solution for a period of 2 to 24 hours or more in a wet / dry two-vial product. In the case of a single-vial solution product, pre-filled syringe, or autoinjector, the label indicates that such solution can be used for a period of 2 to 24 hours or more. The product is useful for human pharmaceutical product applications.

[0152] The formulations used in the methods of the present invention can be prepared by a process comprising mixing an anti-IL-23 antibody and a selected buffer, preferably saline or a phosphate buffer containing a selected salt. Mixing the anti-IL-23 antibody and buffer in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a quantity of at least one antibody in water or buffer is combined with the desired buffer in a quantity of water sufficient to provide the desired concentrations of protein and buffer. Variations on this process will be recognized by those skilled in the art. For example, the order of addition of components, whether or not additional additives are used, and the temperature and pH during formulation preparation are all factors that can be optimized for the administration concentration and means used.

[0153] The methods of the present invention provide pharmaceutical compositions, including various formulations, that are useful and acceptable for administration to human or animal patients. Such pharmaceutical compositions are prepared using "standard conditions" water as a diluent and routine methods well known to those skilled in the art. For example, buffering components such as histidine and histidine monohydrochloride hydrate may be provided first, followed by the addition of an appropriate non-final volume of "standard conditions" water diluent, sucrose, and polysorbate 80. The isolated antibody may then be added. Finally, the volume of the pharmaceutical composition is adjusted to the desired final volume under "standard conditions" using water as a diluent. Those skilled in the art will recognize several other methods suitable for preparing pharmaceutical compositions.

[0154] A pharmaceutical composition may be an aqueous solution or suspension containing the indicated mass of each component per volume unit of water or having the indicated pH at "standard conditions." As used herein, the term "standard conditions" refers to a temperature of 25°C ± 2°C and a pressure of 1 atmosphere. The term "standard conditions" is not used in the art to refer to a single art-recognized set of temperatures or pressures, but instead is a reference condition specifying the temperature and pressure used to describe a solution or suspension containing a particular composition under reference "standard conditions" conditions. This is because the volume of a solution is, in part, a function of temperature and pressure. Those skilled in the art will recognize that pharmaceutical compositions equivalent to those disclosed herein can be produced at other temperatures and pressures. The equivalence of such pharmaceutical compositions to those disclosed herein should be determined under the "standard conditions" conditions defined above (e.g., 25°C ± 2°C and a pressure of 1 atmosphere).

[0155] Importantly, such pharmaceutical compositions may contain "about" a certain value of the mass of a component (e.g., "about 0.53 mg of L-histidine") or have a certain value of the pH value per unit volume of the pharmaceutical composition. The mass or pH value of a component present in a pharmaceutical composition is "about" a given numerical value when the isolated antibody is present in the pharmaceutical composition or when the isolated antibody is capable of binding to a peptide chain after it is removed from the pharmaceutical composition (e.g., by dilution). In other words, the mass value or pH value or other value of a component is "about" a given numerical value when the binding activity of the isolated antibody is maintained and detectable after it is placed in a pharmaceutical composition.

[0156] Competitive binding assays are performed to determine whether IL-23-specific mAbs bind to similar or different epitopes and / or compete with each other. Abs are individually coated onto ELISA plates. Competing mAbs are added, followed by biotinylated hrIL-23. For a positive control, the same mAb used for coating can be used as a competing mAb ("self-competition"). IL-23 binding is detected using streptavidin. These results indicate whether the mAbs recognize similar or partially overlapping epitopes on IL-23.

[0157] In one embodiment of the pharmaceutical composition, the isolated antibody concentration is about 77 to about 104 mg per mL of pharmaceutical composition. In another embodiment of the pharmaceutical composition, the pH is about 5.5 to about 6.5.

[0158] The stable or preserved formulations can be provided to patients as clear solutions or as dual vials containing a vial of at least one lyophilized anti-IL-23 antibody that is reconstituted with a second vial containing a preservative or buffer and additives in an aqueous diluent. Either the single solution vial or the dual vial requiring reconstitution can be reused multiple times to satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0159] Other formulations or methods for stabilizing anti-IL-23 antibodies may be other than clear solutions of lyophilized powders containing the antibodies. Non-clear solutions include formulations containing microparticle suspensions, which are compositions containing anti-IL-23 antibodies within structures of various sizes known variously as microspheres, microparticles, nanoparticles, nanospheres, or liposomes. Such relatively homogeneous, essentially spherical microparticle formulations containing active agents can be formed by contacting an aqueous phase containing the active agent and polymer with a non-aqueous phase, followed by evaporation of the non-aqueous phase to cause coalescence of particles from the aqueous phase, as taught in U.S. Pat. No. 4,589,330. Porous microparticles can be prepared using a first phase containing the active agent and polymer dispersed in a continuous solvent and removing the solvent from the suspension by lyophilization or dilution-extraction-precipitation, as taught in U.S. Pat. No. 4,818,542. Preferred polymers for such preparations are gelatin agar, starch, arabinogalactan, albumin, collagen, polyglycolic acid, polylactic acid, glycolide-L(-)lactide, poly(epsilon-caprolactone, poly(epsilon-caprolactone-co-lactic acid), poly(epsilon-caprolactone-co-glycolic acid), poly(β-hydroxybutyric acid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate), poly(hydroxyethyl methacrylate), polyamide, poly(amino acids), poly(2-hydroxyethyl DL-aspartamide), poly(ester urea), The copolymers or polymers are natural or synthetic copolymers or polymers selected from the group consisting of poly(L-phenylalanine / ethylene glycol / 1,6-diisocyanatohexane) and poly(methyl methacrylate). Particularly preferred polymers are polyesters such as polyglycolic acid, polylactic acid, glycolide-L(-)lactide poly(epsilon-caprolactone), poly(epsilon-caprolactone-co-lactic acid), and poly(epsilon-caprolactone-co-glycolic acid).Useful solvents for dissolving the polymer and / or active agent include water, hexafluoroisopropanol, methylene chloride, tetrahydrofuran, hexane, benzene, or hexafluoroacetone sesquihydrate. The process of dispersing the active agent-containing phase into the second phase can include forcing the first phase under pressure through an orifice in a nozzle to affect droplet formation.

[0160] Dry powder formulations may also be obtained as a result of processes other than lyophilization, such as spray drying, or solvent extraction by evaporation, or by precipitation of a crystalline composition followed by one or more steps to remove the aqueous or non-aqueous solvent. The preparation of spray-dried antibody formulations is taught in U.S. Pat. No. 6,019,968. Antibody-based dry powder compositions can be produced by spray-drying a solution or slurry of antibody and, optionally, excipients in a solvent under conditions to provide a respirable dry powder. Solvents include readily driable polar compounds, such as water and ethanol. Antibody stability can be enhanced by performing the spray-drying procedure in the absence of oxygen, for example, under a nitrogen blanket, or by using nitrogen as the drying gas. Another relatively dry formulation is a dispersion of multiple porous microstructures dispersed in a suspension medium, typically containing a hydrofluoroalkane propellant, as taught in WO 9916419. The stabilized dispersion can be administered to the patient's lungs using a metered-dose inhaler. Equipment useful in the commercial production of spray-dried drugs is manufactured by Buchi Ltd. or Niro Corp.

[0161] Anti-IL-23 antibodies, either in the stable or preserved formulations or in solution described herein, can be administered to patients in accordance with the present invention via a variety of delivery methods well known in the art, such as SC or IM injection, transdermal, transpulmonary, transmucosal, implants, osmotic pumps, cartridges, micropumps, or other means understood by those of skill in the art.

[0162] Therapeutic applications The present invention also provides methods for modulating or treating ulcerative colitis in a cell, tissue, organ, animal, or patient using at least one IL-23 antibody of the invention, e.g., by administering or contacting the cell, tissue, organ, animal, or patient with a therapeutically effective amount of an IL-23-specific antibody, as known in the art or described herein.

[0163] Any of the methods of the present invention may comprise administering to a cell, tissue, organ, animal, or patient in need of such modulation, treatment, or therapy an effective amount of a composition or pharmaceutical composition comprising an anti-IL-23 antibody. Such methods may optionally further comprise co-administration or combination therapy for the treatment of such a disease or disorder, wherein administering the at least one anti-IL-23 antibody, specified portion, or variant thereof, is administered in combination with at least one TNF antagonist (e.g., but not limited to, a chemical or proteinaceous TNF antagonist, a TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70, or p85) or fragment, a fusion polypeptide thereof, or a small molecule TNF antagonist, e.g., a TNF binding protein TBP-1 or TBP-II, nerelimonumab, infliximab, etanercept (Enbrel™), adalimumab (Humira™), CDP-571, CDP-870, afelimomab, lenercept, etc.), antirheumatic drugs (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxants, narcotics, non-steroidal anti-inflammatory drugsdrugs, NSAIDs), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blockers, antibiotics (e.g., aminoglycosides, antifungals, antiparasitics, antivirals, carbapenams, cephalosporins, fluoroquinolones, macrolides, penicillins, sulfonamides, tetracyclines, and other antibacterial agents), psoriasis medications, corticosteroids, anabolic steroids, diabetes medications, minerals, nutritional supplements, thyroid medications, vitamins, calcium-related hormones, antidiarrheals, antitussives, antiemetics, antineoplastic agents, laxatives, anticoagulants, erythropoietin (e.g., epoetin alfa), filgrastim (e.g., G-CSF, Neupogen), sargramostim (GM-CSF, Leukine), The method may further comprise administering, before, simultaneously with, and / or after at least one of an immunizing agent, an immunoglobulin, an immunosuppressant (e.g., basiliximab, cyclosporine, daclizumab), a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, an antimanic, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta-agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, cromolyn, epinephrine or an analog, dornase alfa (Pulmozyme), a cytokine, or a cytokine antagonist. Suitable dosages are well known in the art. See, for example, Wells et al., eds., Pharmacotherapy Handbook, 2009, Vol. 2, No. 1, pp. 211-214, 2011. nd Edition, Appleton and Lange, Stamford, CT (2000), PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), Nursing 2001 Handbook of Drugs, 21 stedition, Springhouse Corp., Springhouse, PA, 2001; Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc., Upper Saddle River, NJ, each of which references is incorporated herein by reference in its entirety.

[0164] Treatment Typically, treatment of ulcerative colitis is affected by administering an effective amount, or dose, of an anti-IL-23 antibody composition, which, depending on the specific activity of the active agent(s) contained in the composition, ranges from at least about 0.01 to 500 milligrams of anti-IL-23 antibody per kilogram of patient per dose, in total, on average, and preferably from at least about 0.1 to 100 milligrams of antibody per kilogram of patient per dose, per single or multiple doses. Alternatively, effective serum concentrations may include serum concentrations of 0.1 to 5000 mg / mL per single or multiple doses. Suitable dosages are known to medical professionals and, of course, depend on the specific disease state, the specific activity of the administered composition, and the specific patient receiving treatment. In some cases, achieving the desired therapeutic dose may require providing multiple doses, i.e., repeated individual administrations of a particular monitored or metered dose, where the individual administrations are repeated until the desired daily dose or effect is achieved.

[0165] Preferred dosages 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, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70 , 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and / or 100-500 mg / kg / dose, or any range, value, or fraction thereof, or 0.1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9, 2.0, 2.5, 2.9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5, 6.9, 7.0, 7.0, 7.5 ... .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, The amount of sucrose or sucrose in the serum may be 17, 17.5, 17.9, 18, 18.5, 18.9, 19, 19.5, 19.9, 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, and / or 5000 g / mL, or any range, value, or fraction thereof.

[0166] Alternatively, the administered dose may vary depending on known factors such as the pharmacodynamic characteristics of the particular agent and its method and route of administration, the age, health, and weight of the recipient, the nature and extent of symptoms, the type of concurrent treatment, the frequency of treatment, and the desired effect. The dose of active ingredient may typically be about 0.1 to 100 milligrams per kilogram of body weight. Typically, 0.1 to 50, preferably 0.1 to 10 milligrams per kilogram per dose, or sustained-release forms, are effective to achieve the desired results.

[0167] As a non-limiting example, treatment of humans or animals can be performed over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 days using a single dose, intravenous administration, or multiple doses. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 0.1 to 100 mg / kg per day, e.g., 0.5, 0.9, 1.0, 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, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.8, 5.9, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.24, 5.25, 5.26, 5.27, 5.28, 5.29, 6.30, 6.31, 6.32, 6.33, 6.34, 6.35, 6.36, 6.37, 6.38, 6.39, 6.40, 6.41, 6.42, 6.43, 6.44, 6.45, 6.46, 6.47, 6.48, 6.49, 7.50, 7.51, 7.52, 7.53, 7.54, 7.55, 7.56, 7.57, 7. The antibody may be provided as a single or periodic dose of 0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90, or 100 mg / kg of at least one antibody of the invention.

[0168] Dosage forms (compositions) suitable for internal administration generally contain about 0.001 milligrams to about 500 milligrams of active ingredient per unit or container. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.5 to 99.999% by weight based on the total weight of the composition.

[0169] For parenteral administration, antibodies can be formulated as solutions, suspensions, emulsions, particles, powders, or lyophilized powders, either combined with or provided separately from a pharmaceutically acceptable parenteral vehicle. Examples of such vehicles include water, saline, Ringer's solution, dextrose solution, and 1-10% human serum albumin. Non-aqueous vehicles such as liposomes and fixed oils can also be used. The vehicle or lyophilized powder can contain additives that maintain isotonicity and chemical stability (e.g., sodium chloride or mannitol for isotonicity, buffers and preservatives for chemical stability). The formulation is sterilized by known or suitable techniques.

[0170] Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

[0171] Alternative administration Many known and developed modes can be used in accordance with the present invention to administer a pharmaceutically effective amount of an anti-IL-23 antibody. Although pulmonary administration is used in the following description, other modes of administration can be used in accordance with the present invention with suitable results. The IL-23-specific antibodies of the present invention can be delivered in a carrier, as a solution, emulsion, colloid, or suspension, or as a dry powder, using any of a variety of devices and methods suitable for administration by inhalation or by other methods described herein or known in the art.

[0172] Parenteral Formulation and Administration Preparations for parenteral administration may contain, as common excipients, sterile water or physiological saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydrogenated naphthalenes, etc. Aqueous or oily suspensions for injection can be prepared according to known methods by using appropriate emulsifiers or wetting agents and suspending agents. Injectable preparations can be non-toxic parenterally administrable diluents, such as aqueous solutions, sterile injection solutions, or solvent suspensions. Acceptable vehicles or solvents include water, Ringer's solution, isotonic saline, etc., and sterile fixed oils can be used as common solvents or suspending media. For these purposes, any type of fixed oil or fatty acid, including natural, synthetic, or semisynthetic fatty oils or fatty acids, natural, synthetic, or semisynthetic monoglycerides, diglycerides, or triglycerides, can be used. Parenteral administration is known in the art and includes, but is not limited to, conventional injection means, the gas-pressurized needleless injection device described in U.S. Pat. No. 5,851,198, and the laser perforator device described in U.S. Pat. No. 5,839,446, which are incorporated herein by reference in their entireties.

[0173] alternative delivery The invention further relates to the administration of anti-IL-23 antibodies by parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intrabronchial, intraabdominal, intracapsular, intrachondral, intrasinus, intracavity, intracerebellar, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, intravaginal, rectal, buccal, sublingual, intranasal or transdermal means. The anti-IL-23 antibody compositions may be formulated for parenteral (subcutaneous, intramuscular, or intravenous) or any other administration, particularly in the form of a liquid solution or suspension; for use in vaginal or rectal administration, particularly in semi-solid forms such as, but not limited to, creams and suppositories; for buccal or sublingual administration, such as, but not limited to, tablets or capsules; or for intranasal administration, such as, but not limited to, powders, nasal sprays, or aerosols, or certain medications; or with the use of chemical enhancers such as dimethyl sulfoxide to either modify skin structure or increase drug concentration in transdermal patches (Junginger, et al. In "Drug Permeation Enhancement"; Hsieh, DS, Eds., pp. 59-90 (Marcel Dekker, Inc. New York, NY, incorporated herein by reference in its entirety). 1994), or application of protein and peptide-containing formulations to the skin (WO 98 / 53847), or application of an electric field to create a transient transport pathway, such as electroporation, or to increase the mobility of charged drugs through the skin, such as iontophoresis, or application of ultrasound, such as sonophoresis (U.S. Pat. Nos. 4,309,989 and 4,767,402), can be formulated for transdermal use, including, but not limited to, gels, ointments, lotions, suspensions, or patch delivery systems using oxidizing agents that allow for the application of an electric field to create a transient transport pathway, such as electroporation, or to increase the mobility of charged drugs through the skin, such as iontophoresis (U.S. Pat. Nos. 4,309,989 and 4,767,402) (the above publications and patents are incorporated herein by reference in their entireties).

[0174] Having generally described the present invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting. Further details of the present invention are illustrated by the following non-limiting examples, the disclosures of all citations herein being expressly incorporated herein by reference.

[0175] Example 1 - QUASAR UC Study Title: A Phase 2b / 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Protocol to Evaluate the Efficacy and Safety of Guselkumab in Participants With Moderately to Severely Active Ulcerative Colitis Main purpose: The primary objective is to evaluate the clinical efficacy and safety of guselkumab as induction therapy in participants with moderate to severe active UC.

[0176] The Phase 2b / 3 clinical development program for guselkumab in ulcerative colitis (QUASAR) consists of three separate studies: a Phase 2b induction dose-ranging study (Induction Study 1), a Phase 3 induction study (Induction Study 2), and a Phase 3 maintenance study (Maintenance Study). An overview of the program is shown in Figure 1.

[0177] Phase 2b induction study design: The Phase 2b induction study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study.

[0178] The target population consists of participants with moderately to severely active ulcerative colitis (UC) who have responded inadequately to or are intolerant to conventional treatments (i.e., 6-MP, AZA, or corticosteroids) or advanced treatments (i.e., TNFα antagonists, vedolizumab, or tofacitinib). At week 1-0, participants must have moderately to severely active UC, defined as a modified Mayo score of 5–9 (inclusive), a Mayo rectal bleeding subscore ≥1, and a Mayo endoscopy subscore ≥2, using the Mayo endoscopy subscore obtained during central review of video endoscopy. The program will also allow for enrollment of participants with a modified Mayo score of 4, but this will be capped at ≤5% of the total population. The protocol was amended following recent feedback from health authorities to base the target population solely on participants with a modified Mayo score of 5–9.

[0179] Treatment Assignment: Participants were randomized at Week I-0 in a 1:1:1 ratio to one of three treatment arms using permuted block randomization with ADT failure status (i.e., inadequate response or intolerance to TNFα antagonists, vedolizumab, or tofacitinib) (yes / no), region (Eastern Europe, Asia, or rest of the world), and concomitant use of corticosteroids at baseline (yes / no) as stratification variables: Group 1: Placebo IV (Weeks I-0, I-4, and I-8) Group 2: Guselkumab 200 mg IV (Weeks I-0, I-4, and I-8) Group 3: Guselkumab 400 mg IV (Weeks I-0, I-4, and I-8)

[0180] Treatment duration: The main part of this study is 12 weeks.

[0181] Primary Endpoint: The primary endpoint is clinical response at Weeks 1-12, defined as a ≥ 30% and ≥ 2-point reduction from derived baseline in the modified Mayo score, with a ≥ 1-point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1.

[0182] Key secondary endpoints: Clinical remission at weeks 1-12, defined as absence of easy bleeding on endoscopy, a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, with the stool frequency subscore not increasing from induction baseline. Symptomatic remission, defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0 at weeks 1-12, with the stool frequency subscore not increasing from induction baseline. Endoscopic cure, defined as an endoscopy subscore of 0 or 1 with no easy bleeding at endoscopy, at weeks 1-12. Histologic-endoscopic mucosal healing at weeks 1-12, defined as achieving a combination of histologic and endoscopic healing, where histologic healing is defined as neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes grading system. Endoscopic normalization (requiring the absence of easy bleeding), defined as an endoscopy subscore of 0, at weeks 1-12. 〇 IBDQ remission at weeks 1-12. Fatigue response at weeks 1-12.

[0183] At Weeks I-12, all participants will be assessed for clinical response. Administration of further study intervention will be determined by the participant's clinical response status (using the Mayo endoscopy subscore assigned by the local endoscopist) at Weeks I-12 as follows:

[0184] Guselkumab Clinical Responders and Placebo Clinical Responders at Weeks 1-12 will enter a maintenance study.

[0185] Participants initially randomized to placebo who do not have a clinical response at week I-12 will then cross over to guselkumab and receive three doses of 200 mg IV guselkumab at weeks I-12, I-16, and I-20.

[0186] Participants initially randomized to guselkumab who do not have a clinical response at week I-12 will then receive three doses of 200 mg guselkumab SC at weeks I-12, I-16, and I-20.

[0187] To maintain blinding, both IV and SC doses will be administered to all participants without a clinical response at weeks 1-12.

[0188] At Week I-24, participants who did not have a clinical response at Week I-12 will be re-evaluated for clinical response (clinical response status will be based on the Mayo Endoscopy Subscore assigned by the local endoscopist). In addition to guselkumab clinical responders at Week I-12 and placebo clinical responders, participants from Induction Study 1 will enter the Maintenance Study: Placebo crossover responders: Participants were initially randomized to placebo, had no clinical response at Week 1-12, and then crossed over to 200 mg guselkumab induction IV treatment and achieved a clinical response at Week 1-24.

[0189] Guselkumab 24-week responders: Participants initially randomized to guselkumab with no clinical response at week I-12, then received three doses of 200 mg guselkumab SC and achieved a clinical response at week I-24.

[0190] Participants without a clinical response at Weeks 1-24 should not receive further study intervention and should undergo a safety follow-up visit approximately 12 weeks after the last dose of study intervention.

[0191] All UC-specific medications (i.e., oral 5-aminosalicylic acid [5-ASA] compounds, oral corticosteroids, 6-MP, AZA, or MTX) must be maintained at stable doses through the end of Induction Study 1 and may be discontinued or dose reduced only if required by investigator discretion due to toxicity or medical necessity. Initiation or dose increase of UC-specific therapy (or any restricted / prohibited medication or therapy) during Induction Study 1 will prohibit the participant from participating in the Maintenance Study. Efficacy, PK parameters, biomarkers, and safety will be evaluated according to the SoA.

[0192] An interim analysis will be conducted of the first 150 randomized participants who complete the Week 1-12 visit or terminate study participation before Week 1-12. The purpose of this interim analysis is to select a single induction dose for confirmatory evaluation in the Phase 3 induction study (Induction Study 2). A dose selection committee, composed of sponsor management representatives from clinical, safety, biostatistics, and clinical pharmacology who are not associated with study conduct, will be responsible for selecting the induction dose of guselkumab to be evaluated in Induction Study 2. While data from the first 150 randomized participants are being evaluated, participants will continue to enroll in Induction Study 1, up to a maximum of 390 participants. Once induction dose selection is made, participants will begin randomization into Induction Study 2.

[0193] In Induction Study 2, participants will be randomized in a 3:2 ratio to receive guselkumab or placebo at weeks I-0, I-4, and I-8. Induction Study 2 will target a sample size of at least 560 randomized participants with a modified Mayo score of 5-9. The selection of the guselkumab induction dose for Induction Study 2 will be based on the interim analysis of Induction Study 1. Participants will be assigned to the intervention arm using permuted block randomization stratified by ADT failure status (i.e., inadequate response or intolerance to TNFα antagonists, vedolizumab, or tofacitinib) (yes / no), region (Eastern Europe, Asia, or other regions), and concomitant use of corticosteroids at baseline (yes / no). At week I-12, all participants will be evaluated for clinical response. Similar to the approach outlined in Induction Study 1, further study intervention administration will be determined by the participant's clinical response status (using the Mayo endoscopy subscore, as assigned by the local endoscopist) at Weeks 1-12, as follows: Guselkumab Clinical Responders and Placebo Clinical Responders at Weeks 1-12 will enter a maintenance study.

[0194] Participants initially randomized to placebo who do not have a clinical response at week I-12 will then cross over to guselkumab and receive three doses of IV guselkumab treatment (i.e., induction doses selected based on the interim analysis of Induction Study 1) at weeks I-12, I-16, and I-20.

[0195] Participants initially randomized to guselkumab who do not have a clinical response at week I-12 will then receive three doses of 200 mg guselkumab SC at weeks I-12, I-16, and I-20.

[0196] To maintain blinding, both IV and SC doses will be administered to all participants without a clinical response at weeks 1-12.

[0197] At Week I-24, participants who did not have a clinical response at Week I-12 will be re-evaluated for clinical response (clinical response status is based on the Mayo endoscopy subscore assigned by the local endoscopist). In addition to the guselkumab clinical responders and placebo clinical responders at Week I-12, the following participants from Induction Study 2 will participate in the maintenance study:

[0198] Placebo crossover responder: Participants initially randomized to placebo, had no clinical response at Week 1-12, then crossed over to guselkumab induction IV dose treatment and achieved a clinical response at Week 1-24.

[0199] Guselkumab 24-week responders: Participants initially randomized to guselkumab with no clinical response at week I-12, then received three doses of 200 mg guselkumab SC and achieved a clinical response at week I-24.

[0200] Participants without a clinical response at Weeks 1-24 should not receive further study intervention and should undergo a safety follow-up visit approximately 12 weeks after the last dose of study intervention.

[0201] All UC-specific medications (i.e., oral 5-ASA compounds, oral corticosteroids, 6-MP, AZA, or MTX) must be maintained at stable doses through the end of Induction Study 2 and may be discontinued or dose reduced only if required by the investigator's judgment due to toxicity or medical necessity. Initiation of, or dose increase in, a UC-specific therapy (or any restricted / prohibited medication or therapy) during Induction Study 2 will prohibit the participant from participating in the Maintenance Study.

[0202] result Summary of Topline Phase 2b Results A total of 327 participants were randomized and administered at 141 sites across 27 countries. The majority of participants (47.4%) were from Eastern Europe, with the remaining participants distributed across Asia (23.2%) and other regions (29.4%). Of note, there was one participant who was randomized but never received the study intervention.

[0203] Of the randomized and treated participants, 313 (95.7%) participants had a modified Mayo score of 5 to 9 (the target population used for the efficacy and safety analyses below).

[0204] Disposition and baseline characteristics of the full analysis set (n=313): Overall, nine participants (2.9%) discontinued study treatment before Week I-12. There were five discontinuations (4.8%) in the placebo group, three discontinuations (3.0%) in the 200 mg IV guselkumab group, and one discontinuation (0.9%) in the 400 mg IV guselkumab group. In the placebo group, four of the five discontinuations were due to reasons indicating lack of efficacy. The most common reasons for discontinuing treatment before Week I-12 were adverse events due to worsening UC (1.0%) and subject-initiated discontinuation (1.0%). No participants discontinued study drug before Week I-12 for reasons related to COVID-19.

[0205] The majority of participants were Caucasian (71.6%), and 59.1% were male. The mean age was 41.6 years (range 18-84 years). A total of 147 participants (47.0%) had a history of advanced treatment (ADT) failure. 166 participants (53.0%) had failed conventional therapy but not advanced treatment, and the majority of these participants (93.4%) were ADT-naive. Approximately 40% of participants were receiving corticosteroids (including budesonide and beclomethasone dipropionate) at baseline, and 21.7% were receiving immunomodulatory agents (6-mercaptopurine, azathioprine, or methotrexate). Approximately 90% of participants had a history of inadequate response, intolerance, or dependence on corticosteroids and / or 6-MP / AZA.

[0206] The study population represented a population with moderately to severely active UC. The mean duration of UC was 7.55 years. The median Mayo score was 9.0 (mean = 9.2), the median modified Mayo score was 7.0 (mean = 7.0), the median fecal calprotectin level was 1564.0 mg / kg, and the median C-reactive protein (CRP) level was 4.6 mg / L. At baseline, 48.9% of participants had extensive disease, 82.4% had moderate UC (i.e., Mayo score ≥ 6 and ≤ 10), 17.6% had severe disease (Mayo score > 10), 30% had an endoscopy subscore of 2 (i.e., moderate disease), and 70% had an endoscopy subscore of 3 (i.e., severe disease).

[0207] Baseline demographics (including region), disease characteristics, concomitant UC medications, and UC medication history were generally balanced between treatment groups. However, a higher proportion of participants in the 400 mg IV guselkumab group (55.1%) had extensive disease compared with the placebo group (43.8%) and the 200 mg IV guselkumab group (47.5%).

[0208] Summary of efficacy endpoints: Guselkumab induction treatment (at both doses evaluated) resulted in significantly higher rates of clinical response at weeks 1-12 (primary endpoint). Compared with placebo, guselkumab induction treatment (at both doses evaluated) also resulted in higher rates of clinical remission, symptomatic remission, endoscopic healing, histologic-endoscopic mucosal healing, and endoscopic normalization at weeks 1-12.

[0209] Primary endpoint Based on the primary analysis of clinical response at Weeks 1-12, a significantly higher proportion of participants in the 200 mg IV and 400 mg IV guselkumab groups had a clinical response at Weeks 1-12 compared with the placebo group. The study is considered a positive study.

[0210] Key secondary endpoints Compared with the placebo group, a greater proportion of participants in the 200 mg IV and 400 mg IV guselkumab groups achieved clinical remission, symptomatic remission, endoscopic cure, and endoscopic normalization at Weeks 1-12.

[0211] Separation between the guselkumab-treated groups and placebo for symptomatic remission was observed as early as 4 weeks after the first dose and continued through weeks 1-12.

[0212] Safety data from Weeks 1-12 based on the safety analysis population: The mean duration of follow-up was similar between treatment groups. The proportion of participants reporting one or more adverse events (AEs) was not higher in the guselkumab group compared with the placebo group, and no clinically meaningful differences in AE rates were observed between the guselkumab groups. The system organ classes (SOCs) with the most frequently reported AEs were infections and infestations (11.5% concomitant guselkumab; 10.5% placebo), gastrointestinal disorders (9.6% concomitant guselkumab; 17.1% placebo), and blood and lymphatic disorders (9.6% concomitant guselkumab; 14.3% placebo). The most common preferred terms (PTs) in the combination guselkumab group were anemia (7.2%), headache (4.3%), and COVID-19 (3.8%). The PT of anemia was comparable between treatment groups (9.5% in the placebo group, 6.9% in the 200 mg IV guselkumab group, and 7.5% in the 400 mg IV guselkumab group). The proportion of participants reporting one or more serious AEs was not higher in the guselkumab-treated group compared with the placebo group. Most SAEs were exacerbations of UC. No deaths were reported. AEs leading to treatment discontinuation were low and comparable across treatment groups (2 in the placebo group, 1 in the 200 mg IV guselkumab group, and 0 in the 400 mg IV guselkumab group) (Table 2). - The proportion of participants reporting investigator-identified infectious AEs was similar between treatment groups (11.4% in the placebo group, 12.9% in the 200 mg IV guselkumab group, and 8.4% in the 400 mg IV guselkumab group). - Two serious infections were observed, both in the placebo group. - No cases of active TB were reported. - No opportunistic infections were reported. - There were no cases of malignancy. Liver test values ​​were similar between treatment groups through weeks 1-12. Transaminase elevations were low grade (Common Terminology Criteria for Adverse Events [CTCAE] grade 1). No cases met Hy's rule criteria (i.e., total bilirubin >2 × upper limit of normal [ULN] and either aspartate aminotransferase [AST] or ALT ≥3 × ULN at the same time point).

[0213] The incidence of decreased total WBC counts was higher in the guselkumab-treated group compared with placebo through weeks 1-12. All total WBC abnormalities were CTCAE grade 1 or 2.

[0214] Week 12 outcomes in patients without clinical response at week 24 QUASAR Induction Study 1 (NCT04033445) is a Phase 2b study to evaluate guselkumab (GUS) therapy in patients with ulcerative colitis (UC) who had an inadequate response to or intolerance to conventional therapy (i.e., thiopurines or corticosteroids) or advanced therapy (i.e., tumor necrosis factor alpha antagonists, vedolizumab, or tofacitinib). Patients who had a clinical response at 12 weeks after IV induction entered a maintenance study, while patients without clinical responses received treatment in an extended induction period.

[0215] method: Included patients had moderate to severe active UC (modified Mayo score of 5-9 with a Mayo rectal bleeding subscore of ≥1 and a Mayo endoscopy subscore of ≥2). Patients were randomized 1:1:1 to receive IV GUS 200 mg, 400 mg, or placebo (PBO) at weeks 0, 4, and 8. Patients without a clinical response to IV induction at week 12 received SC treatment (PBO IV → GUS 200 mg IV; GUS 200 mg IV → GUS 200 mg SC; GUS 400 mg IV → GUS 200 mg SC at weeks 12, 16, and 20) and were evaluated at week 24.

[0216] 313 patients were randomized at baseline. Baseline demographic and disease characteristics were similar between treatment groups (mean age, 41.6 years; 59.1% male; mean UC duration, 7.55 years; mean Mayo score, 9.2; endoscopy subscore 3 indicating severe disease, 70%; oral corticosteroid use, 39.9%), and approximately 50% had a previous inadequate response or intolerance to advanced UC treatment.

[0217] At Week 12, clinical response was achieved by 27.6% (29 / 105) of patients randomized to PBO IV at baseline and 61.4% (62 / 101) and 60.7% (65 / 107) of patients randomized to GUS 200 mg and GUS 400 mg IV, respectively. Of patients in the GUS group who did not have a clinical response at Week 12, 54.3% (19 / 35) who received GUS 200 mg IV → 200 mg SC and 50.0% (19 / 38) who received GUS 400 mg IV → 200 mg SC achieved a clinical response at Week 24. Tables 16-21 show the number of subjects in clinical remission and clinical response at Week 24. Clinical response at 12 or 24 weeks was achieved by 80.2% of patients receiving GUS 200 mg IV → 200 mg SC and 78.5% of patients receiving GUS 400 mg IV → 200 mg SC.

[0218] conclusion Patients who did not achieve a clinical response to GUS IV induction at week 12 demonstrated benefit at week 24 after receiving three SC doses of GUS, and approximately 80% of patients receiving GUS IV or GUS IV→SC achieved a clinical response at week 12 or 24. No new safety concerns with GUS were identified.

[0219] Example 2 - Phase 3 Study Results Phase 3 Induction Study Design: The Phase 3 induction study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. The target population consists of participants with moderately to severely active ulcerative colitis (UC) who have responded inadequately to or are intolerant of conventional treatment (i.e., 6-mercaptopurine [6-MP], azathioprine [AZA], or corticosteroids) or advanced treatment (ADT; i.e., tumor necrosis factor-alpha [TNFα] antagonists, vedolizumab, or tofacitinib). At week I-0, participants must have moderately to severely active UC, defined as a modified Mayo score of 5–9 (inclusive), a Mayo rectal bleeding subscore ≥1, and a Mayo endoscopy subscore ≥2, using the Mayo endoscopy subscore obtained during central review of video endoscopy. Note that the QUASAR program also allowed for the enrollment of participants with a modified Mayo score of 4, but this was capped at ≤5% of the total population. The protocol was amended following feedback from health authorities so that the target population should be based only on participants with a modified Mayo score of 5–9.

[0220] Treatment Assignment: Participants were randomized at Week 1-0 in a 3:2 ratio to guselkumab or placebo using permuted block randomization with ADT failure status (i.e., inadequate response or intolerance to TNFα antagonists, vedolizumab, or tofacitinib) (yes / no), region (Eastern Europe, Asia, or rest of the world), and concomitant use of corticosteroids at baseline (yes / no) as stratification variables: Group 1: Placebo IV (Weeks I-0, I-4, and I-8) Group 2: Guselkumab 200 mg IV (Weeks I-0, I-4, and I-8) Treatment duration: The main part of this study is 12 weeks.

[0221] This report provides results for the primary and key secondary endpoints at weeks I-12, as well as safety through weeks I-12.

[0222] Primary Endpoint: The primary endpoint was clinical remission at weeks 1-12, defined as a Mayo stool frequency subscore of 0 or 1 not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1 with no easy bleeding on endoscopy.

[0223] Key secondary endpoints: Symptom remission at weeks 1-12: bowel frequency subscore of 0 or 1, no increase from baseline, and rectal bleeding subscore of 0. Endoscopic healing at weeks 1-12: Endoscopy subscore of 0 or 1 with absence of easy bleeding at endoscopy. Clinical response at Weeks 1-12: ≥ 30% and ≥ 2 point reduction from baseline in modified Mayo score, ≥ 1 point reduction from baseline in rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1. Symptoms resolved in week 1-4. Inflammatory Bowel Disease Questionnaire (IBDQ) remission at weeks 1-12: total IBDQ score ≥ 170. Histologic-endoscopic mucosal healing at weeks 1-12: Achieving a combination of histologic and endoscopic healing, where endoscopic healing is defined above and histologic healing is defined according to the Geboes grading system as neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosion, ulceration, or granulation tissue. Fatigue response at weeks 1-12: ≥ 7-point improvement on PROMIS-Fatigue short form 7a. Symptoms resolved by week 1-2. Endoscopic normalization at weeks 1-12: endoscopic subscore of 0

[0224] 90% power for all key secondary endpoints except for the endpoints of symptomatic resolution at week I-2 and endoscopic normalization at week I-12.

[0225] Statistical considerations: Efficacy Analysis Set: The full analysis set included all randomized participants with a modified Mayo score of 5-9 who received at least one (partial or full) dose of the study intervention. Participants were analyzed according to the study intervention to which they were randomized or assigned, regardless of the study intervention they actually received. Safety Analysis Set: The safety analysis set includes all randomized participants with a modified Mayo score of 5-9 who received at least one (partial or full) dose of study intervention. Results based on the Safety All Treated Analysis Set, which includes all randomized participants who received at least one (partial or full) dose of study intervention (regardless of modified Mayo score), are also provided. Participants were analyzed according to the study intervention they actually received.

[0226] Intercurrent events (ICEs) were used in the analysis of efficacy endpoints. Specifically, participants who underwent UC-related surgery (ostomy or colectomy), including AEs of lack of efficacy or worsening UC, were prohibited from changing UC medication, or discontinued the study intervention for reasons other than coronavirus disease 2019 (COVID-19)-related (excluding COVID-19 infection) or experienced the regional crisis between Russia and Ukraine before the analysis time point were considered not to have met the endpoint for the binary endpoint (i.e., combined strategy). For participants who discontinued the study intervention for COVID-19-related reasons (excluding COVID-19 infection) or the regional crisis between Russia and Ukraine before the analysis time point, we used their observations, if available (i.e., treatment-directed strategy).

[0227] Comparisons were based on the guselkumab group versus the placebo group. For the primary and key secondary endpoints, p values ​​were based on a two-sided Cochran-Mantel-Haenszel (CMH) test stratified by ADT failure status (yes / no) and concomitant use of corticosteroids at baseline (yes / no). 95% confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. For these endpoints, participants with missing data at the time of analysis (after accounting for intercurrent event strategies) were considered non-responders at that time.

[0228] Most important results summary A total of 735 participants were randomized and administered at 240 sites across 32 countries. The majority of participants (41.5%) were from Eastern Europe, with the remaining participants distributed across Asia (20.5%) and other regions (38.0%). Of note, there was one participant randomized to the placebo group who never received the study intervention. Of the randomized and treated participants, 701 (95.4%) had a modified Mayo score of 5 to 9 (the target population used for efficacy and safety analyses below).

[0229] Disposition and baseline characteristics of the full analysis set (n=701): Overall, 42 (6.0%) participants discontinued the study intervention before Week 1-12: 24 (8.6%) in the placebo group and 18 (4.3%) in the 200 mg IV guselkumab group. The most common reasons for discontinuing the study intervention before Week 1-12 were adverse events (2.4%; 1.4% due to worsening UC) and participant-initiated discontinuation (2.3%).

[0230] The majority of participants were Caucasian (72.5%), and 56.9% were male. The mean age was 40.5 years (range 18-79 years). A total of 344 participants (49.1%) had a history of ADT failure. 357 participants (50.9%) had failed conventional therapy but not advanced therapy ("ADT non-failures"); the majority of these participants (95.0%) were ADT-naive. Approximately 43.1% of participants were receiving corticosteroids (including budesonide and beclomethasone dipropionate) at baseline, and 20.5% were receiving immunomodulatory agents (6-MP, AZA, or methotrexate). A total of 93.2% of participants had a history of inadequate response, intolerance, or dependence on corticosteroids and / or 6-MP / AZA.

[0231] The population enrolled in this study represents a population with moderately to severely active UC. The mean duration of UC was 7.27 years. The median Mayo score was 9.0 (mean = 9.1), the median modified Mayo score was 7.0 (mean = 6.9), the median fecal calprotectin level was 1641.0 mg / kg, and the median C-reactive protein (CRP) level was 4.2 mg / L. At baseline, 47.8% of participants had extensive disease, 82.2% had moderate UC (i.e., Mayo score ≥ 6 and ≤ 10), 17.8% had severe disease (Mayo score > 10), 32.1% had an endoscopy subscore of 2 (i.e., moderate disease), and 67.9% had an endoscopy subscore of 3 (i.e., severe disease).

[0232] Baseline demographics (including region), disease characteristics, concomitant UC medications, and UC medication history were generally well balanced between treatment groups.

[0233] Summary of efficacy endpoints: Based on prespecified multiple study protocols, guselkumab induction treatment resulted in a significantly higher proportion of participants achieving clinical remission at weeks 1-12 (primary endpoint; 22.6%) compared with placebo (7.9%; adjusted treatment difference: 14.9% [95% CI: 9.9%, 19.9%]), a result that was highly significant (p<0.001) (Table 1).

[0234] Compared with placebo, guselkumab induction treatment also significantly increased the proportion of participants achieving the primary secondary endpoint (highly significant, p<0.001).

[0235] Based on the primary analysis of the primary endpoint: clinical remission at weeks I-12, a significantly higher proportion of participants (22.6%) in the 200 mg IV guselkumab group was in clinical remission at weeks I-12 compared with placebo (7.9%; adjusted treatment difference: 14.9% [95% CI: 9.9%, 19.9%]; Table 1 ).

[0236] Key secondary endpoints: Based on both intent-to-treat and US-specific testing procedures, a significantly greater proportion of participants in the 200 mg IV guselkumab group compared with the placebo group achieved symptomatic remission (also known as clinical remission) (adjusted treatment difference: 29.5% [95% CI: 22.9%, 36.1%]; Table 10), endoscopic cure (adjusted treatment difference: 16.0% [95% CI: 10.5%, 21.4%]; Table 4), and clinical response (adjusted treatment difference: 34.2% [95% CI: 27.2%, 34.2%]; Table 10). 3%, 41.1%]; Table 2), histoendoscopic mucosal healing (adjusted treatment difference: 15.9% [95% CI: 10.9%, 20.9%]; Table 8), fatigue response (adjusted treatment difference: 19.8% [95% CI: 13.1%, 26.4%]; Table 9) (all at I-12 weeks), and symptom remission (adjusted treatment difference: 10.3% [95% CI: 4.8%, 15.7%]) at I-4 weeks were achieved (Table 10). Based on intent-to-treat procedures, a significantly higher proportion of participants in the 200 mg IV guselkumab group achieved IBDQ remission at weeks I-12 (adjusted treatment difference: 22.1% [95% CI: 15.1%, 29.2%]; Table 7). Note that IBDQ remission at weeks I-12 was not considered a primary secondary endpoint in US-specific testing procedures. Symptom remission at week 1-2 in the 200 mg IV guselkumab group was not significantly different from that in the placebo group (adjusted treatment difference: 3.0% [95% Cl: -1.5%, 7.5%]; Table 10). Although a higher proportion of participants in the 200 mg IV guselkumab group achieved endoscopic normalization at week I-12 compared with the placebo group (adjusted treatment difference: 10.1% [95% CI: 5.9%, 14.3%]; Table 3), statistical significance could not be claimed for this endpoint because the previous endpoint in the study strata (symptom resolution at week I-2) was not significant. Separation between the guselkumab and placebo groups for symptomatic remission was observed as early as 4 weeks after the first dose and persisted through weeks 1-12 (Table 10).

[0237] Subgroup analysis by ADT failure status: Greater efficacy was observed with guselkumab compared with placebo for both the ADT-non-failure and ADT-failure subgroups for the primary endpoint and all key secondary endpoints (except symptom resolution at Week 1-2). In general, across treatment groups, the proportion of participants who met the primary and key secondary endpoints was greater in the ADT non-failure subgroup compared with the ADT failure subgroup. Across the primary and key secondary endpoints, with the exception of fatigue response at weeks 1-12, the treatment effect (vs. placebo) was greater in the ADT non-failure subgroup compared with the ADT failure subgroup.

[0238] Clinical / Symptom Response—Greater symptomatic improvement was observed in patients treated with GUS compared with PBO, beginning as early as week 2 and increasing through week 12 (see Table 14). At weeks 2, 4, 8, and 12, GUS vs. PBO-treated patients achieved a symptomatic (clinical) response of 34.0% vs. 23.6%, 53.2% vs. 30.0%, 66.0% vs. 39.6%, and 71.7% vs. 35.0%, respectively (all p<0.01). The proportion of patients achieving symptomatic remission at week 2 with GUS vs. PBO was 12.1% vs. 9.3% (p=0.210). At weeks 4, 8, and 12, the proportions were 22.6% vs. 12.9%, 39.7% vs. 20.7%, and 49.9% vs. 20.7%, respectively (all p<0.001). As shown in Table 15, the mean changes from baseline in the absolute number of stools per day at weeks 2, 4, 8, and 12 were -1.19 vs. -0.61, -2.05 vs. -0.75, -2.75 vs. -1.31, and -3.15 vs. -1.36 (all p<0.01). The proportions of patients with a stool frequency subscore of 0 or 1 at weeks 2, 4, 8, and 12 were 26.1% vs. 18.2%, 41.3% vs. 25.4%, 53.4% ​​vs. 29.6%, and 60.1% vs. 31.8%, respectively (all p<0.05). The mean changes from baseline in the rectal bleeding subscore at weeks 2, 4, 8, and 12 were -0.6 vs. -0.5, -0.8 vs. -0.5, -1.1 vs. -0.6, and -1.2 vs. -0.6, respectively (all p<0.01). At week 2, the proportion of patients with a rectal bleeding subscore of 0 was 24.2% vs. 19.3% (p=0.110). At weeks 4, 8, and 12, the proportions were 36.8% vs. 22.9%, 55.8% vs. 33.2%, and 64.6% vs. 28.6%, respectively (all p<0.001). Treatment differences were achieved at week 12 for all endpoints evaluated (Table 14).

[0239] Safety: Table 13 provides an overall summary of adverse events from Weeks 1-12 for the safety population (n=701). Overall, guselkumab 200 mg IV was safe and well-tolerated by participants throughout the 12-week treatment period. No new safety concerns were identified based on adverse events and laboratory investigations. Adverse events are discussed below. Laboratory observations were consistent with QUASAR Derivation Study 1. Similar results were observed for the safety overall treatment population.

[0240] Safety data from Weeks 1-12 based on the safety analysis population: The mean duration of follow-up was similar between treatment groups. The proportion of participants reporting one or more adverse events (AEs) in the 200 mg IV guselkumab group was similar to that in the placebo group. The most frequently reported system organ classes (SOCs) were infections and infestations (15.7% guselkumab; 15.0% placebo) and gastrointestinal disorders (10.7% guselkumab; 16.4% placebo). The most common preferred terms (PTs) in the 200 mg IV guselkumab group were COVID-19 (5.0% guselkumab; 4.3% placebo), anemia (4.8% guselkumab; 6.8% placebo), and headache (2.9% guselkumab; 2.9% placebo). Seven participants reported AEs within 1 hour of infusion (6 [1.4%] in the 200 mg IV guselkumab group and 1 [0.4%] in the placebo group); none of these AEs were serious or led to discontinuation of the study intervention. No anaphylactic or serum sickness reactions were reported.

[0241] Three deaths were reported (one in the 200 mg IV guselkumab group and two in the placebo group). The proportion of participants reporting one or more serious AEs was numerically lower in the 200 mg IV guselkumab group (2.9%) compared with the placebo group (7.5%). The majority of SAEs were exacerbations of UC (PT ulcerative colitis: 1.4% in the 200 mg IV guselkumab group and 5.0% in the placebo group). AEs leading to treatment discontinuation were low across treatment groups (6 patients [1.4%] in the 200 mg IV guselkumab group and 12 patients [4.3%] in the placebo group). The proportion of participants reporting infectious AEs was similar between treatment groups (66 [15.7%] in the 200 mg IV guselkumab group and 42 [15.0%] in the placebo group). Four serious infections were reported (3 [0.7%] in the 200 mg IV guselkumab group and 1 [0.4%] in the placebo group). No cases of active tuberculosis (TB) were reported. One opportunistic infection (PT cytomegalovirus infection) was reported in the placebo group. Two participants in the 200 mg IV guselkumab group had treatment-emergent malignancies of non-melanoma skin cancer reported on study days 23 and 32, respectively. Liver test values ​​were similar between treatment groups through weeks 1-12. Transaminase elevations were low grade (Common Terminology Criteria for Adverse Events [CTCAE] grade 1). No cases met Hy's law biochemical criteria (i.e., total bilirubin ≥ 2 × upper limit of normal [ULN] and either aspartate aminotransferase [AST] or alanine aminotransferase [ALT] ≥ 3 × ULN at the same time point).

[0242] Efficacy at Week 24 and Safety at Week 32 - At Week 12, a higher proportion of GUS-treated patients achieved a clinical response compared with PBO-treated patients. As shown in Figure 2, among GUS-treated patients who did not achieve a clinical response at Week 12, 55% (66 / 120) achieved a clinical response at Week 24. Clinical response at Week 12 or Week 24 was achieved by 77.2% of patients randomized to GUS 200 mg IV at baseline. Patients with and without prior ADT failure benefited from continued treatment with GUS 200 mg SC through Week 24. For patients who received PBO IV → GUS 200 mg IV, clinical response at Week 24 (69.7%) was similar to clinical response at Week 12 after GUS 200 mg IV induction (61.5%). The analysis in Figure 2 includes only patients with a modified Mayo score of 5–9 at induction baseline. Clinical response was defined as a ≥30% and ≥2-point reduction from the derived baseline in the modified Mayo score, with a ≥1-point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1. Patients who underwent a prohibited change in UC medication, ostomy, or colectomy, or discontinuation of study medication before the designated time point due to lack of efficacy or worsening UC AEs, or for COVID-19-related reasons (excluding COVID-19 infection) or other reasons excluding the local crisis in Russia and Ukraine, were considered not to have achieved a clinical response at the designated time point. Patients who did not have one or more Mayo subscores at the endpoint at the designated time point were considered not to have achieved a clinical response. Adjusted treatment differences and confidence intervals were based on Wald statistics using Cochran-Mantel-Haenszel weights. p-values ​​were based on the Cochran-Mantel-Haenszel chi-square test stratified by ADT failure status (yes / no) and concomitant use of corticosteroids at baseline (yes / no).

[0243] As shown in Table 16, safety findings were consistent with the Week 12 results; no new safety concerns were reported. The most frequent adverse events among all GUS-treated patients (n=586) were COVID-19 (7.2%), worsening UC (4.6%), and anemia (5.1%).

[0244] More than three-quarters of patients with moderately to severely active UC treated with GUS 200 mg IV induction achieved a clinical response at Week 12 or Week 24. No new safety concerns with GUS were identified through Week 32 (deaths were reported in two placebo-treated patients and one GUS-treated patient, all cardiovascular in nature; patients in the GUS group had substantial cardiovascular risk factors). AEs absent within 1 hour of infusion were considered serious or resulted in discontinuation of treatment. The incidence of anti-drug antibodies (ADA) through Week 12 was low (1.5%, 6 / 409), and none of the ADA-positive subjects had neutralizing antibodies.

[0245] Histologic Effect—Colon biopsies were collected during endoscopy at baseline and at week 12 to assess the effect of treatment on histology, measured by three methods: the Geboes and Roberts histopathology index (RHI), and the Nancy histologic index (NHI). Histologic improvement, histologic remission, histoendoscopic mucosal improvement (HEMI), and combined histologic remission and endoscopic normalization (deep HEMI) were assessed at week 12.

[0246] Histologic activity at baseline was similar across the GUS and PBO cohorts: mean Geboes total score (11.8 vs. 11.9, respectively), mean RHI (16.6 vs. 16.6), and mean NHI (2.7 vs. 2.8). The proportion of patients achieving histologic improvement at week 12 was 44.9% among GUS-treated patients and 21.4% among PBO-treated patients (adjusted delta: 23.7%; nominal P<0.001, Table 17). Histologic remission (as defined by Geboes) at week 12 was achieved by 39.9% and 18.6% of patients receiving GUS and PBO, respectively (adjusted delta: 21.5%; nominal P<0.001). Identical results were seen across two additional definitions of histologic remission (i.e., RHI and NHI, Table 17). The proportion of GUS-treated patients who achieved HEMI at week 12 was highly significant compared with PBO-treated patients (23.5% vs. 7.5%, respectively; adjusted delta: 16.2%; p<0.001). Finally, deep HEMI at week 12 was achieved in a greater proportion of GUS-treated patients than in PBO-treated patients (13.5% vs. 3.9%, respectively; adjusted delta: 9.8%; p<0.001). Patients experienced clinically meaningful improvements in histologic and histoendoscopic outcomes at week 12.

[0247] Biomarkers—C-reactive protein (CRP) and fecal calprotectin (FeCal) are noninvasive inflammatory biomarkers used to assess disease activity in UC. The effect of GUS treatment on CRP and FeCal through week 12 in patients with elevated CRP and / or FeCal is shown in Table 18 and described below. CRP and FeCal were assessed at baseline, week 4, week 8 (CRP only), and week 12. A total of 701 patients were evaluated in this study, and approximately 50% of randomized patients had a history of inadequate response / intolerance to prior advanced therapy for UC; 47.4% of these patients had an inadequate response / intolerance to two or more advanced treatment classes. Median baseline concentrations of CRP and FeCal were similar between the GUS- and PBO-treated cohorts (4.34 vs. 3.83 mg / L and 1651.00 vs. 1606.00 mg / kg, respectively).

[0248] Among patients with elevated CRP and / or FeCal at baseline, greater decreases in CRP and FeCal were observed at the earliest time point assessed by GUS (week 4) compared with PBO, and continued through week 12 (Table 18). At baseline, 248 GUS-treated patients and 160 PBO-treated patients had elevated CRP (>3 mg / L), with rates similar between treatment groups (58.9% vs. 57.1%, respectively). Among these patients, the median change from baseline in CRP concentrations (mg / L) at week 12 for the GUS and PBO cohorts was -3.99 and -0.51 mg / L, respectively (nominal p<0.001), and the proportion of patients achieving a 50% and 75% reduction in CRP levels (or ≦3 mg / L) at week 12 was higher in GUS-treated patients than in patients receiving PBO (59.7% vs. 28.1%, and 47.2% vs. 19.4%, respectively; both nominal P<0.0001). Similarly, a higher proportion of GUS-treated patients achieved CRP ≤ 3 mg / L at week 12 than PBO-treated patients (40.3% vs. 16.3%, nominal p < 0.001), 39.1% of GUS-treated patients vs. 25.0% of PBO-treated patients achieved CRP ≤ 3 mg / L at week 8, and 34.3% of GUS-treated patients vs. 21.9% of PBO-treated patients achieved CRP ≤ 3 mg / L at week 4.

[0249] At baseline, 333 GUS-treated patients and 225 PBO-treated patients had elevated FeCal (>250 mg / kg); proportions were similar between treatment groups (79.1% vs. 80.4%, respectively). At week 12, the median change from baseline in FeCal concentrations (mg / kg) among patients with elevated FeCal at baseline was -800.00 and -86.00 mg / kg for the GUS and PBO cohorts, respectively (nominal p<0.001). At week 12, the proportion of patients achieving a 50% and 75% reduction in FeCal levels (or ≤250 mg / kg) was higher among GUS-treated patients than among those receiving PBO (51.1% vs. 33.8%, and 41.4% vs. 23.6%, respectively; both nominal P<0.0001). A greater proportion of patients treated with GUS achieved FeCal ≤ ​​250 mg / kg at week 12 than those treated with PBO (29.4% vs. 17.3%, nominal p < 0.001), and 14.1% of GUS-treated patients vs. 8.9% of PBO achieved FeCal ≤ ​​250 mg / kg at week 4.

[0250] Patients with moderate to severe active UC and elevated inflammatory markers treated with GUS 200 mg IV induction showed greater improvements from baseline in both CRP and FeCal levels compared with PBO, with differences observed as early as the first assessment at week 4 and continuing through week 12.

[0251] Phase 3 Weeks 1-12 Results and Analysis As shown in Tables 19-25 below, early onset of symptom improvement was achieved. The primary analysis population included all randomized patients with a modified Mayo score of 5-9 who received at least one dose of study intervention (partial or complete). Symptom remission at weeks 2, 4, and 12 was the primary secondary endpoint, controlled for type I error. p values ​​for all other analyses were nominal. Patients who underwent a no-change in UC medication, ostomy or colectomy, or discontinuation of study medication due to lack of efficacy or adverse events of UC worsening, or for COVID-19-related reasons (excluding COVID-19 infection) or other reasons excluding the local crisis in Russia and Ukraine prior to week 12, were considered not to have achieved the designated binary endpoint, and baseline observations were carried forward for the designated sequential endpoints. Patients who lacked one or more components associated with the binary endpoint at the designated time point were considered not to have achieved the endpoint.

[0252] Guselkumab 200 mg IV induction was effective in improving symptoms as early as one week after the first dose in patients with moderately to severely active UC. Table 19 shows symptomatic remission achieved as early as one week after the first dose. Table 20 shows symptom response achieved as early as one week after the first dose. Table 21 shows achievement of a bowel frequency subscore of 0 or 1 as early as one week after the first dose. Table 22 shows achievement of a rectal bleeding subscore of 0 as early as one week after the first dose. Table 23 shows change in absolute stool count as early as one week after the first dose. Table 24 shows change in bowel frequency and rectal bleeding subscores as early as one week after the first dose. Table 25 shows achievement of symptomatic Mayo score improvement as early as two weeks after the first dose. Furthermore, guselkumab treatment continued to increase symptomatic improvement through Week 12.

[0253] Phase 3 Maintenance Study Design: The Phase 3 maintenance study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study. The target population consists of participants with moderate to severe active UC who have a history of inadequate response or lack of tolerance to conventional therapy (i.e., 6-MP, AZA, or corticosteroids) or advanced therapy (i.e., TNFα antagonists, vedolizumab, or tofacitinib) and have achieved a clinical response 12 weeks after receiving guselkumab IV induction therapy. At Week 1-0, participants must have moderate to severe active UC, defined as a modified Mayo score of 5–9 (inclusive), a Mayo rectal bleeding subscore ≥1, and a Mayo endoscopy subscore ≥2, using the Mayo endoscopy subscore obtained during central review of video endoscopy. The QUASAR program also allowed for the enrollment of participants with a modified Mayo score of 4, but this was capped at ≤5% of the total population enrolled in the program. The protocol was amended following feedback from health authorities so that the target population should be based only on participants with a modified Mayo score of 5–9.

[0254] Treatment Assignment: Participants who had a clinical response after 12 weeks of receiving guselkumab IV induction treatment, i.e., guselkumab clinical responders at Week I-12 and placebo crossover guselkumab responders at Week I-24 from Induction Study 1 or Induction Study 2, were randomized in a 1:1:1 ratio at Week M (maintenance)-0 to one of three treatment arms: (i) placebo SC every 4 weeks (q4w), (ii) guselkumab 100 mg SC every 8 weeks (q8w), and (iii) guselkumab 200 mg SC q4w.

[0255] Participants were assigned to intervention groups using permuted block randomization with clinical remission status at maintenance baseline (yes / no), concomitant corticosteroid use at maintenance baseline (yes / no), and induction treatment (guselkumab 400 mg IV, guselkumab 200 mg IV, and placebo IV → guselkumab 200 mg IV) as stratification variables.

[0256] Randomized participants who lost clinical response (i.e., did not meet the criteria for clinical response) were eligible for single-blind dose adjustment to receive guselkumab 200 mg SC q4w, beginning at a visit between Weeks M-8 and M-32. In addition to the aforementioned randomized populations, guselkumab induction week 24 responders and induction placebo responders at Week I-12 from Induction Study 1 or Induction Study 2 entered the maintenance study but were not randomized and were not included in the pivotal efficacy analyses herein.

[0257] Treatment / Study Period: For this reporting period, the treatment period was 40 weeks and the study period was 44 weeks. This report provides results for the primary and key secondary endpoints based on global and US-specific multiple study protocols.

[0258] Primary Endpoint: The primary endpoint was clinical remission at week M-44, defined as a Mayo stool frequency subscore of 0 or 1 with no increase from induction baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1 with no easy bleeding on endoscopy.

[0259] Key secondary endpoints (ordered by global study procedures): Symptom remission at Week M-44: Mayo stool frequency subscore of 0 or 1 with no increase from induction baseline and Mayo rectal bleeding subscore of 0. Endoscopic cure at week M-44: absence of easy bleeding at endoscopy, Mayo endoscopy subscore of 0 or 1. Corticosteroid-free (i.e., no need for treatment with corticosteroids for at least 8 weeks prior) clinical remission at week M-44. Maintenance of Clinical Response at M-44: Clinical response at week M-44 among subjects who achieved a clinical response at maintenance baseline. Clinical response is defined as a ≥ 30% and ≥ 2-point reduction from derived baseline in the modified Mayo score, with a ≥ 1-point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1. Histologic-endoscopic mucosal healing at week M-44, defined as achieving a combination of histologic and endoscopic healing, where histologic healing is defined as neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes grading system (i.e., Geboes score ≦3.1). IBDQ remission at week M-44: total IBDQ score ≥ 170. Fatigue response at week M-44: ≥ 7-point improvement from induction baseline on PROMIS-Fatigue Short Form 7a. Maintenance of clinical remission at M-44: Clinical remission at week M-44 among participants who achieved clinical remission at maintenance baseline. Endoscopic normalization at week M-44: Mayo endoscopy subscore was 0.

[0260] Expected effect size and planned sample size: Assuming a clinical remission rate of 25% at week M-44 for placebo and 45% for each of the guselkumab treatment groups (assumed rates were based on data from the ustekinumab UC maintenance trial [CNTO1275UCO3001]), 118 participants in each randomized group (354 participants total) provided 90% statistical power (two-sided) at a significance level of 0.05 for the primary endpoint. However, to have at least 90% power for most of the key secondary endpoints, the target number in the primary analysis population was increased to 484 participants (note that the endpoints of maintenance of clinical remission at week M-44 and endoscopic normalization at week M-44 were not powered at 90%).

[0261] Statistical considerations: Efficacy Analysis Set: The full randomized analysis set included all participants in this maintenance study who received at least one dose of study intervention (partial or full) and had a modified Mayo score of 5-9 at Week 1-0. Participants were analyzed according to their randomized study intervention, regardless of the study intervention they actually received.

[0262] Safety Analysis Set: The randomized safety analysis set included all participants in this maintenance study who received at least one dose of study intervention (partial or full) and had a modified Mayo score of 5 to 9 at Week I-0. There were two additional safety sets. The first set was the safety analysis set, which included both randomized and non-randomized participants treated in this maintenance study who had a modified Mayo score of 5 to 9 at Week I-0. The second set was the all-treated analysis set, which included all treated participants in this maintenance study who had a modified Mayo score of 4 to 9 at Week I-0. In general, participants were analyzed according to their treatment assignment. However, participants assigned to placebo who accidentally received guselkumab at any time point were analyzed in the guselkumab group from the time of their first guselkumab dose onward; participants assigned to guselkumab who received only placebo were analyzed in the placebo group.

[0263] Intercurrent events (ICEs) and corresponding strategies were applied to the analysis of efficacy endpoints. Participants who underwent an ostomy or colectomy (ICE1), a dose adjustment (including sham dose adjustment) (ICE2), a prohibited change in UC medication (ICE3), or discontinued study drug due to AEs of lack of efficacy or worsening UC (ICE4) before the analysis time point were considered not to have achieved the binary endpoint (i.e., composite strategy). For participants who discontinued study drug before the analysis time point due to COVID-19-related reasons (excluding COVID-19 infection) or the local crisis in Russia and Ukraine (ICE5), their observations were used if available (i.e., treatment-directed strategy). Participants who discontinued study drug for reasons other than ICE4 and 5 (ICE6, composite strategy) were considered not to have achieved the binary endpoint.

[0264] Comparisons were based on each guselkumab group versus placebo. For the primary and key secondary endpoints (excluding maintenance of clinical remission), p values ​​were based on a two-sided Cochran-Mantel-Haenszel (CMH) test stratified by clinical remission status at maintenance baseline (yes / no) and induction treatment (guselkumab 400 mg IV, guselkumab 200 mg IV, placebo IV → guselkumab 200 mg IV). For maintenance of clinical remission, a two-sided CMH test stratified by induction treatment was used. 95% confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. For these endpoints, participants with missing data at the time of analysis (after accounting for intercurrent events) were considered non-responders at that time point.

[0265] Global Study Procedures (Countries Outside the United States): A hierarchical testing procedure was used to control the overall Type I error rate across the primary and key secondary efficacy analyses at a two-sided 0.05 significance level within guselkumab dose groups. The primary endpoint was tested using a fixed-sequence testing procedure, starting with the high maintenance treatment group (200 mg SC q4w). A key secondary endpoint for a dose group was considered significant only if the previous endpoint and the current endpoint for that dose group in the stratum tested positive at a two-sided 0.05 significance level. If the endpoint was not significant, all subsequent tests in the stratum for that dose were considered non-significant.

[0266] US-specific study procedures: A hierarchical study procedure was used to strongly control the overall type I error rate at the 0.05 level across the primary and secondary endpoints and across the two guselkumab treatment groups. An endpoint was considered significant only if all previous endpoints within the stratum and the current endpoint tested positive at the two-sided 0.05 level of significance. If an endpoint was not significant, all subsequent tests within the stratum were considered non-significant. Note that the ranking of endpoints differed in the two study strategies due to regional preferences. Additionally, IBDQ remission at week M-44 was not included in the US-specific study procedures.

[0267] Primary Objective(s): The primary objective is to evaluate the clinical efficacy and safety of guselkumab as maintenance therapy in participants with moderately to severely active UC who have achieved a clinical response with guselkumab.

[0268] Execution Summary: Based on pre-specified global and US-specific multiple study protocols, guselkumab maintenance treatment at both 200 mg SC q4w and 100 mg SC q8w resulted in a significantly greater proportion of participants in clinical remission at Week M-44 (primary endpoint, Table 26). An adjusted treatment difference of ≥25 percentage points was observed, and the results were highly statistically significant (i.e., p<0.001). Compared with placebo, guselkumab maintenance treatment (at both doses evaluated) also resulted in a significantly higher proportion of participants achieving each of the primary secondary endpoints (Table 27). Subcutaneous maintenance regimens of guselkumab 200 mg SC q4w or guselkumab 100 mg SC q8w through Week M-44 were well tolerated, and safety data are consistent with the known safety profile of guselkumab. The benefit-risk profile is favorable for GUS in the treatment of UC.

[0269] Topline Results Summary: A total of 846 participants enrolled in the maintenance study and were treated across 254 centers in 32 countries: 599 randomized and 247 not. Of the 599 randomized and treated participants, 568 (94.8%) participants had a modified Mayo score of 5-9 at Week 1-0 (the target population used for efficacy and safety analyses below). The impact of COVID-19 or regional crises on the study was negligible.

[0270] Dispositional and baseline characteristics for the randomized full analysis population (n=568): A total of 12.0% of participants discontinued the study intervention before week M-44, with similar rates across treatment groups: 11.6% in the guselkumab 200 mg SC q4w group, 10.6% in the guselkumab 100 mg SC q8w group, and 13.7% in the placebo group. The most common reasons for discontinuing the intervention before week M-44 were adverse events due to worsening UC (3.3%) and subject-initiated discontinuation (3.3%). Demographics, disease characteristics, UC medication history, and concomitant UC medications were generally well balanced across treatment groups.

[0271] At induction baseline, the majority of participants were white (73.2%), and 54.8% of participants were male. The mean age was 40.7 years (range 18-79 years). The mean duration of UC disease was 7.81 years, the median modified Mayo score was 7.0 (mean = 6.9), 63.9% had severe disease as defined by a modified Mayo score of 7-9, 66.4% of participants had an endoscopy subscore of 3 (i.e., severe disease), 45.2% of participants had extensive disease, the median fecal calprotectin was 1605.0 mg / kg, and the median C-reactive protein (CRP) concentration was 3.9 mg / L (Table 29).

[0272] At maintenance baseline, the median modified Mayo score was 2.0 (mean = 2.5), the median fecal calprotectin was 303.5 mg / kg, and the median C-reactive protein (CRP) concentration was 1.5 mg / L. At maintenance baseline, 34.2% of participants were in clinical remission and 39.1% had endoscopic healing (Table 30).

[0273] At induction baseline, a total of 240 (42.3%) participants had a history of advanced therapy (ADT) failure (102 [42.5%] of these participants had a history of failure of two or more ADT classes), and 328 (57.7%) had failed conventional therapy but not advanced therapy ("ADT non-failures"); the majority of these participants, 309 (94.2%), were ADT-naive. A total of 40.0% of participants were receiving corticosteroids at induction baseline, and 22.2% were receiving immunomodulators (6-mercaptopurine, azathioprine, or methotrexate).

[0274] Primary Endpoint: The study is considered a positive study. A significantly higher proportion of participants in the guselkumab 200 mg SC q4w group (50.0%) and the guselkumab 100 mg SC q8w group (45.2%) were in clinical remission at week M-44 compared with the placebo group (18.9%) (adjusted treatment differences 29.5% [95% CI: 20.9%, 38.1%] and 25.2% [95% CI: 16.4%, 33.9%], respectively) (Figure 3, Table 26).

[0275] Key Secondary Endpoints: Based on both global (Table 27) and US-specific study procedures (Figure 6), significantly greater proportions of participants in the guselkumab 200 mg SC q4w and guselkumab 100 mg SC q8w groups achieved each of the key secondary endpoints at Week M-44 compared to the placebo group (Table 28). For Figure 6, asterisks indicate the level of significance achieved ( * p<0.05, ** p<0.01, *** p<0.001, p-values ​​are based on the Cochran-Mantel-Haenszel test).

[0276] A significantly higher proportion of patients treated with subcutaneous guselkumab maintenance therapy achieved the primary and key secondary endpoints assessed at Week 44 compared with discontinued (placebo) patients (Figure 4). Key secondary endpoints assessed at Week 44 included symptomatic remission, corticosteroid-free clinical remission, clinical response, maintenance of clinical remission, endoscopic improvement, histoendoscopic mucosal improvement, and endoscopic normalization.

[0277] For Figure 4: Adjusted treatment differences (Δ) were based on Wald statistics with Cochran-Mantel-Haenszel (CMH) weighting. P values ​​were based on the CMH study, stratified by clinical remission status at maintenance baseline and induction treatment. a Clinical remission: Mayo stool frequency subscore of 0 or 1 and no increase from baseline, Mayo rectal bleeding subscore of 0 and Mayo endoscopy subscore of 0 or 1, no easy bleeding, bSymptom remission: bowel frequency subscore of 0 or 1 and no increase from baseline, rectal bleeding subscore of 0; c Corticosteroid-free clinical remission: not requiring any treatment with corticosteroids for at least 8 weeks prior to Week 44 and meeting the criteria for clinical remission; d Clinical response: either a ≥ 30% and ≥ 2 point reduction from baseline in the modified Mayo score, a ≥ 1 point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1; e Maintenance of clinical remission: Clinical remission at Week 44 among patients in clinical remission at maintenance baseline. f Endoscopic improvement: Endoscopy subscore of 0 or 1, no easy bleeding present on endoscopy; g Histoendoscopic mucosal improvement: Achieve a combination of histologic improvement (neutrophil infiltration in <5% of crypts according to the Geboes grading system, no crypt destruction, and no erosion, ulceration, or granulation tissue) and endoscopic improvement. h Endoscopic normalization: Endoscopy subscore of 0;

[0278] Subgroup analysis by ADT failure status: For both the ADT non-failure and ADT failure subpopulations, greater efficacy was observed in both the guselkumab group versus placebo for the primary and all key secondary endpoints (Tables 31 and 32). In general, across treatment groups, the proportion of participants who met the primary and key secondary endpoints was greater in the ADT non-failure subgroup compared to the ADT failure subgroup. Across the primary and key secondary endpoints, the treatment effect (vs. placebo) for both guselkumab groups was generally higher, and in some cases similar, in the ADT failure subgroup compared to the ADT non-failure subgroup.

[0279] Other endpoints: A greater proportion of participants in the guselkumab 200 mg SC q4w and guselkumab 100 mg SC q8w groups achieved histologic cure at week M-44 compared with the placebo group (adjusted treatment difference in the guselkumab 200 mg SC q4w group: 32.6% [95% CI: 23.3%, 41.9%], guselkumab 100 mg SC q8w group: 33.6% [95% CI: 24.3%, 42.9%]) (Table 33). Over time, the proportion of participants in symptom remission persisted through week M-44 in the guselkumab group, whereas the proportion of participants in symptom remission decreased in the placebo group. Separation from the placebo group was observed at week M-16 and continued to increase through week M-44 (Figure 5).

[0280] Safety: The subcutaneous maintenance regimen of guselkumab 200 mg SC q4w or guselkumab 100 mg SC q8w through Week M-44 was well tolerated, and safety data are consistent with the known safety profile of guselkumab. Table 34 provides an overall summary of adverse events (AEs) (until dose adjustment) through Week M-44 for the randomized safety population. No new safety concerns were identified based on adverse events and laboratory investigations. Overall AE rates were similar across treatment groups. The rate of serious AEs (SAEs) was numerically higher in the guselkumab 200 mg SC q4w group compared with the placebo group in the randomized safety population, although this trend was less evident in the safety and overall treatment populations.

[0281] Safety data through Week M-44 based on the randomized safety population: The mean follow-up period in the placebo group (34.0 weeks) was shorter than in the guselkumab 200 mg SC q4w group (39.2 weeks) and the guselkumab 100 mg SC q8w group (40.5 weeks) (Table 34). The proportions of participants reporting at least one AE in the guselkumab 200 mg SC q4w group and the guselkumab 100 mg SC q8w group (70.0% and 64.5%, respectively) were similar to those in the placebo group (68.2%) (Table 34). The most frequently reported system organ classes (SOCs) were infections and infestations (31.1% guselkumab 200 mg SC q4w, 31.7% guselkumab 100 mg SC q8w, 32.8% placebo) and gastrointestinal disorders (25.8% guselkumab 200 mg SC q4w, 24.7% guselkumab 100 mg SC q8w, 37.0% placebo). The most common preferred terms (PTs) in the combination guselkumab group were COVID-19 (11.2%), ulcerative colitis (11.2%), and arthralgia (6.1%) compared with 14.1%, 29.7%, and 6.8% in the placebo group.

[0282] The proportions of participants reporting one or more SAEs were 6.3%, 2.7%, and 0.5% in the guselkumab 200 mg SC q4w, guselkumab 100 mg SC q8w, and placebo groups, respectively (Table 34). There was no clear pattern of SAEs with respect to individual PTs or SOCs, and the majority of SAEs were assessed by the investigator as unrelated. Differences in SAE rates between the guselkumab 200 mg SC q4w and placebo groups were less evident in the safety and overall treatment populations, which included a larger number of participants, including non-randomized guselkumab induction 24-week responders and induction placebo responders. The proportion of participants with AEs leading to discontinuation of study drug was numerically higher in the placebo group than in the guselkumab 100 mg SC q4w and guselkumab 200 mg SC q8w groups: 6.8%, 3.8%, and 2.6%, respectively (Table 34). The proportion of participants reporting one or more AEs of severe intensity was similar between treatment groups (Table 34). The proportion of participants reporting infectious AEs was comparable between treatment groups (Table 34). Serious infections were rare (2 [1.1%] in the guselkumab 200 mg SC q4w group [1 participant had a moderate bacterial infection at the venipuncture site and 1 participant had gangrenous appendicitis], and 1 [0.5%] in the guselkumab 100 mg SC q8w group [gluteal abscess]). The proportion of participants with a post-baseline chemistry maximum toxicity grade of ≥1 and hematology laboratory values ​​did not differ significantly between the placebo and each guselkumab group. Grade 3 and Grade 4 chemistry and hematology laboratory values ​​were infrequent. No cases met Hy's law biochemistry criteria (i.e., total bilirubin ≥2 × upper limit of normal [ULN] and either aspartate aminotransferase [AST] or alanine aminotransferase [ALT] ≥3 × ULN at the same time point).

[0283] AEs of special interest and other AEs in the maintenance study through Week M-44 based on the full-treatment population: No deaths were reported. No cases of active tuberculosis were reported. No cases of opportunistic infections were reported based on the standard MedDRA query (SMQ) for opportunistic infections. Eight participants reported nine malignancies, with three participants having four non-melanoma skin cancers (all in the randomized placebo group). Three participants had breast cancer (two in the randomized placebo group and one in the non-randomized placebo group). One participant had clear cell renal cell carcinoma (non-randomized guselkumab 200 mg SC q4w group) and one participant had rectal adenocarcinoma (non-randomized guselkumab 200 mg SC q4w group). One participant in the randomized guselkumab 200 mg SC q4w group reported a hemorrhagic stroke, considered a major adverse cardiovascular event (MACE). There were no confirmed cases of Hy's law, no cases of treatment-emergent serious liver injury adverse events, and no treatment-emergent liver injury adverse events leading to discontinuation of study drug. Two participants reported venous thromboembolic events. One case occurred in the randomized guselkumab 200 mg SC q4w group, and the other in the non-randomized guselkumab 200 mg SC q4w group. Both participants had a history of VTE. No cases of anaphylaxis or serum sickness were reported.

[0284] [Table 2]

[0285] [Table 3]

[0286] [Table 4]

[0287] [Table 5]

[0288] Table 6

[0289] Table 7

[0290] Table 8

[0291] Table 9

[0292] Table 10

[0293] Table 11

[0294] Table 12-1

[0295] Table 12-2

[0296] Table 12-3

[0297] Table 13-1

[0298] [Table 13-2]

[0299] [Table 13-3]

[0300] [Table 14]

[0301] [Table 15]

[0302] [Table 16]

[0303] [Table 17] NOTE: Include only patients with a modified Mayo score of 5–9 at induction baseline. a Includes data through Week 12 for subjects who received treatment at Week 12. Includes all data through the final safety visit for subjects who did not receive treatment at Weeks 1-12. b Includes data from 12 weeks onwards. c From first guselkumab IV dose onwards; for subjects who received guselkumab 200 mg SC on weeks 1-12, data through weeks 1-12 are included. d After the first guselkumab dose. e Infection was defined as any adverse event coded under the MedDRA system organ class "infections and infestations." f Injection site reactions assessed by the investigator.

[0304] [Table 18] aThis definition is equivalent to histologic remission as an alternative definition using the Roberts Histopathology Index (RHI ≤ 3, lamina propria neutrophils and epithelial neutrophils subscores of 0, and no ulcers or erosions). Note: Patients who underwent a prohibited change in UC medication, ostomy or colectomy, or discontinuation of study medication before Week 12 due to lack of treatment effect, AEs of worsening UC, or COVID-19-related reasons (excluding COVID-19 infection) or other reasons excluding the regional crisis in Russia and Ukraine were considered not to have achieved the endpoint. Patients who underwent an unevaluable biopsy (i.e., a biopsy taken but unable to be evaluated due to sample preparation or technical errors) at Week 12 or who lacked any of the endoscopy subscores or histologic components for this endpoint (i.e., assessment of neutrophils, crypt destruction, or erosions, or ulceration, or granulation in the epithelium) were considered not to have achieved the endpoint. Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran-Mantel-Haenszel weights. p-values ​​were based on the Cochran-Mantel-Haenszel chi-square test stratified by ADT failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0305] [Table 19] *** Nominal P ≤ 0.001. Patients who underwent a no-change in UC medication, ostomy or colectomy, or discontinuation of study medication before the specified time point for lack of efficacy or AE of worsening UC, or for COVID-19-related reasons (excluding COVID-19 infection) or other reasons excluding the local crisis in Russia and Ukraine, carried over baseline values ​​from the time of event occurrence. p values ​​for treatment comparisons were based on mixed-effects repeated measures models with log-transformed CRP and FeCal values.

[0306] [Table 20]

[0307] Table 21

[0308] Table 22

[0309] Table 23

[0310] Table 24-1

[0311] Table 24-2

[0312] Table 25-1

[0313] Table 25-2

[0314] Table 25-3

[0315] Table 25-4

[0316] Table 26

[0317] [Table 27]

[0318] [Table 28] * p<0.05; ** p<0.01; *** p<0.001. p-values ​​were based on the Cochran-Mantel-Haenszel test (Appendix 2). The significance of the results based on US-specific test procedures is shown in Appendix 4. a Adjusted treatment difference (95% CI). b The denominator is the number of subjects in clinical remission at the maintenance baseline.

[0319] [Table 29-1]

[0320] [Table 29-2]

[0321] [Table 29-3]

[0322] [Table 30-1]

[0323] [Table 30-2]

[0324] [Table 30-3]

[0325] Table 30-4

[0326] Table 31-1

[0327] Table 31-2

[0328] Table 31-3

[0329] Table 32-1

[0330] Table 32-2

[0331] Table 32-3

[0332] Table 33-1

[0333] Table 33-2

[0334] Table 33-3

[0335] [Table 34]

[0336] [Table 35] † Two participants randomized to GUS 100 mg q8w SC received only PBO on M-0 (they discontinued study treatment before the first scheduled GUS dose on M-4 week). They were included in the placebo SC treatment group. a Subjects who had a clinical response to guselkumab IV induction were randomized to placebo SC upon entry into this maintenance study. b includes data from week M-0 to the time of dose adjustment for subjects who underwent a dose adjustment, or up to week M-44 for subjects who did not undergo a dose adjustment.

[0337] The present invention can be described with reference to the following numbered embodiments. 1. Use of an antibody specific for IL23 for the treatment of ulcerative colitis in a patient, wherein the antibody comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region is the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4; the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRL3 amino acid sequence of SEQ ID NO:6, The heavy chain variable region is the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1; the CDRH2 amino acid sequence of SEQ ID NO: 2, and A use comprising the CDRH3 amino acid sequence of SEQ ID NO: 3, wherein the use results in a clinical response in a patient. 2. The use of embodiment 1, wherein the antibody is administered at an initial dose, at about 4 weeks after the initial dose, and at about 8 weeks after the initial dose. 3. The use of embodiment 2, wherein the initial dose and the dose about 4 weeks after the initial dose and the dose about 8 weeks after the initial dose are 200 mg or 400 mg of antibody. 4. The use of embodiment 3, wherein administration is intravenous. 5. The use of embodiment 1, wherein the patient is identified as a responder to the antibody and meets the clinical endpoint, the clinical endpoint being a clinical response defined as a ≥ 1 point reduction from baseline in the rectal bleeding subscore or a ≥ 30% and ≥ 2 point reduction from derived baseline in the modified Mayo score, accompanied by either a rectal bleeding subscore of 0 or 1. 6. The patient is identified as a responder to the antibody and meets the clinical endpoint, and the clinical endpoint is: (i) Clinical remission defined as the absence of easy bleeding at endoscopy, a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, with no increase in stool frequency subscore from induction baseline; (ii) symptomatic remission defined as a bowel frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, with no increase in bowel frequency subscore from induction baseline; (iii) endoscopic cure, defined as an endoscopy subscore of 0 or 1 with no easy bleeding present at the time of endoscopy; (iv) histologic-endoscopic mucosal healing, defined as achieving a combination of histologic and endoscopic healing, where histologic healing is defined as neutrophil infiltration in <5% of the crypts, no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes grading system; and (v) endoscopy normalization, defined as an endoscopy subscore of 0 (requiring the absence of easy bleeding). 7. The use of embodiment 1, wherein the patient is identified as a responder to the antibody and has biomarkers of CRP ≦3 mg / L and / or FeCal ≦250 mg / kg. 8. The use of embodiment 4, wherein the antibody is administered in maintenance doses administered about 8 weeks after the initial dose, followed by maintenance doses about every 4 weeks or every 8 weeks. 9. The use of embodiment 8, wherein the maintenance dose is 100 mg or 200 mg of the antibody. 10. The use according to any of embodiments 5 to 9, wherein the clinical endpoint(s) are measured at about 1, 2, 4, 8, 12, 16, 20, 28, 32, 36, 40, 44, and / or 48 weeks after initial treatment. 11. The use of embodiment 10, wherein the clinical endpoint(s) are measured about 12 weeks after the initial treatment. 12. The use of embodiment 10, wherein the clinical endpoint(s) are measured about 44 weeks after initial treatment. 13. The use of embodiment 1, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO: 8 and the heavy chain variable region amino acid sequence of SEQ ID NO: 7. 14. The use of embodiment 1, wherein the antibody comprises a light chain amino acid sequence of SEQ ID NO: 10, and a heavy chain amino acid sequence of SEQ ID NO: 9. 15. The use of embodiment 13 or 14, wherein the antibody is in a pharmaceutical composition comprising 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. 16. The use according to embodiment 12 or 12, wherein an antibody is further administered to the patient. 15. The use of embodiment 14, wherein the antibody is administered subcutaneously in a dose of 100 mg or 200 mg. 16. The use of embodiment 1, wherein the patient is identified as a non-responder to the antibody and does not meet the clinical endpoint, the clinical endpoint being a clinical response defined as a ≥ 30% and ≥ 2 point reduction from derived baseline in the modified Mayo score, accompanied by either a ≥ 1 point reduction from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. 17. The use according to embodiment 16, wherein an antibody specific for IL23 is additionally administered to the patient. 18. The use of embodiment 17, wherein the antibody is administered 12 weeks after the initial treatment. 19. The use of embodiment 18, wherein the antibody is administered 12 weeks after the initial treatment, 16 weeks after the initial treatment, and 20 weeks after the initial treatment. 20. The use of embodiment 19, wherein the antibody is administered subcutaneously at a dose of 200 mg. 21. The use of embodiment 20, wherein the patient is identified as a responder to the antibody and meets the clinical endpoint, the clinical endpoint being a clinical response defined as a ≥ 30% and ≥ 2 point reduction from derived baseline in the modified Mayo score, accompanied by either a ≥ 1 point reduction from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. 22. The patient is identified as a responder to the antibody and meets the clinical endpoint, and the clinical endpoint is: (i) Clinical remission defined as the absence of easy bleeding at endoscopy, a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, with no increase in stool frequency subscore from induction baseline; (ii) symptomatic remission defined as a bowel frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, with no increase in bowel frequency subscore from induction baseline; (iii) endoscopic cure, defined as an endoscopy subscore of 0 or 1 with no easy bleeding present at the time of endoscopy; (iv) histologic-endoscopic mucosal healing, defined as achieving a combination of histologic and endoscopic healing, where histologic healing is defined as neutrophil infiltration in <5% of the crypts, no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes grading system; and (v) endoscopy normalization, defined as an endoscopy subscore of 0 (requiring the absence of easy bleeding). 23. The use according to embodiment 21 or 22, wherein the clinical endpoint is measured at about 24 weeks or about 44 weeks after initial treatment. 24. The use according to embodiment 21 or 22, wherein the patient is further administered an antibody specific for IL23 every 4 weeks or every 8 weeks thereafter. 25. The use of embodiment 16, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO: 8, and the heavy chain variable region amino acid sequence of SEQ ID NO: 7. 26. The use of embodiment 16, wherein the antibody comprises a light chain amino acid sequence of SEQ ID NO: 10 and a heavy chain amino acid sequence of SEQ ID NO: 9. 27. The use of embodiment 25 or 26, wherein the antibody is in a pharmaceutical composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, 0.053% (w / v) polysorbate 80, and the diluent is water at standard conditions. 28. The use according to any of embodiments 1 to 27, further comprising the use of one or more additional agents used to treat ulcerative colitis. 29. The use of embodiment 28, wherein the additional agent is selected from the group consisting of an immunosuppressant, a nonsteroidal anti-inflammatory drug (NSAID), methotrexate (MTX), an anti-B cell surface marker antibody, an anti-CD20 antibody, rituximab, a TNF inhibitor, a corticosteroid, and a costimulatory modulator. 30. The use according to embodiment 1, wherein the patient is considered to have failed or intolerant to biological therapy for ulcerative colitis (Bio-Failure) prior to treatment with an antibody specific for IL23. 31. The use according to embodiment 1, wherein the patient is considered to have failed or intolerant of conventional treatments for ulcerative colitis (Con-Failure) prior to treatment with an antibody specific for IL23. 32. The use according to embodiment 1, wherein the ulcerative colitis is moderately to severely active ulcerative colitis. 33. The use of embodiment 32, wherein the patient has endoscopic evidence of active Crohn's disease prior to administration of the first dose. 34. The use of embodiment 33, wherein the patient has a modified Mayo score of 5 to 9, inclusive, a Mayo rectal bleeding subscore of ≧1, and a Mayo endoscopy subscore of ≧2, prior to administration of the first dose. 35. Use of an antibody specific for IL23 to treat moderately to severely active ulcerative colitis in a patient, comprising: (i) an initial intravenous administration of 200 mg or 400 mg; (ii) intravenous administration of 200 mg or 400 mg of the antibody about 4 weeks after the initial administration; and (iii) intravenous administration of 200 mg or 400 mg of the antibody about 8 weeks after the initial administration, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO: 8 and the heavy chain variable region amino acid sequence of SEQ ID NO: 7, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint about 12 weeks or about 44 weeks after the initial administration, wherein the clinical endpoint is a clinical response defined as a ≥ 30% and ≥ 2 point reduction from derived baseline in the modified Mayo score, accompanied by either a ≥ 1 point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1. 36. The use of embodiment 35, wherein the administration of the antibody specific for IL23 is 200 mg or 400 mg administered about 8 weeks after the first administration, followed by administration about every 4 weeks or every 8 weeks. TIFF2025539830000056.tif221132TIFF2025539830000057.tif214132TIFF2025539830000058.tif199140 TIFF2025539830000059.tif221132TIFF2025539830000060.tif217132TIFF2025539830000061.tif162132

Claims

1. 1. A method of treating ulcerative colitis in a patient, comprising administering to the patient an antibody specific for IL-23, the antibody comprising a light chain variable region and a heavy chain variable region, the light chain variable region comprising: the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4; the CDRL2 amino acid sequence of SEQ ID NO:5, and comprising the CDRL3 amino acid sequence of SEQ ID NO:6, the heavy chain variable region the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1; the CDRH2 amino acid sequence of SEQ ID NO: 2, and The method of claim 1, wherein the antibody comprises a CDRH3 amino acid sequence of SEQ ID NO: 3, and the patient is considered a responder to the antibody.

2. 10. The method of claim 1, wherein the antibody is administered at a first dose, at about 4 weeks after the first dose, and at about 8 weeks after the first dose.

3. 3. The method of claim 2, wherein the initial administration and the administration about 4 weeks after the initial administration and about 8 weeks after the initial administration is 200 mg or 400 mg of the antibody.

4. The method of claim 3 , wherein the antibody is administered intravenously.

5. 2. The method of claim 1, wherein the patient is identified as a responder to the antibody and meets a clinical endpoint, the clinical endpoint being a clinical response defined as a ≥ 30% and ≥ 2 point reduction from derived baseline in the modified Mayo score, accompanied by either a ≥ 1 point reduction from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.

6. The patient is identified as a responder to the antibody and meets a clinical endpoint, wherein the clinical endpoint is: (i) Clinical remission defined as the absence of easy bleeding on endoscopy, a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, wherein the stool frequency subscore has not increased from induction baseline; (ii) symptomatic remission, defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, wherein the stool frequency subscore has not increased from the induction baseline; (iii) endoscopic cure, defined as an endoscopy subscore of 0 or 1 with no easy bleeding at endoscopy; (iv) histologic-endoscopic mucosal healing, defined as achieving a combination of histologic and endoscopic healing, where histologic healing is defined as neutrophil infiltration in <5% of the crypts, no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes grading system; and (v) endoscopy normalization, defined as an endoscopy subscore of 0 (requiring the absence of easy bleeding).

7. 10. The method of claim 1, wherein the patient is identified as a responder to the antibody and has a CRP of 3 mg / L or less and / or an FeCal of 250 mg / kg or less.

8. 5. The method of claim 4, wherein the antibody is administered in maintenance doses about every 4 weeks or every 8 weeks following the dose administered about 8 weeks after the initial dose.

9. 9. The method of claim 8, wherein the maintenance dose is 100 mg or 200 mg of antibody.

10. 10. The method of any of claims 5 to 9, wherein the clinical endpoint(s) are measured at about 1, 2, 4, 8, 12, 16, 20, 28, 32, 36, 40, 44, and / or 48 weeks after initial treatment.

11. 11. The method of claim 10, wherein the clinical endpoint(s) and / or biomarkers are measured about 12 weeks after initial treatment.

12. 11. The method of claim 10, wherein the clinical endpoint(s) and / or biomarkers are measured about 24 weeks after initial treatment.

13. 11. The method of claim 10, wherein the clinical endpoint(s) and / or biomarkers are measured about 44 weeks after initial treatment.

14. The method of claim 4 , wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO:8 and the heavy chain variable region amino acid sequence of SEQ ID NO:

7.

15. The method of claim 4, wherein the antibody comprises a light chain amino acid sequence of SEQ ID NO: 10 and a heavy chain amino acid sequence of SEQ ID NO:

9.

16. 16. The method of claim 14 or 15, wherein the antibody is in a pharmaceutical composition comprising 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 normal conditions.

17. 17. The method of claim 16, wherein the antibody is further administered in a subcutaneous maintenance dose about every 4 weeks or every 8 weeks following the dose administered about 8 weeks after the initial dose, wherein the maintenance dose is 100 mg or 200 mg.

18. 2. The method of claim 1, wherein the patient is identified as a non-responder to the antibody and does not meet a clinical endpoint, wherein the clinical endpoint is a clinical response defined as a ≥ 30% and ≥ 2 point reduction from derived baseline in the modified Mayo score accompanied by either a ≥ 1 point reduction from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.

19. 19. The method of claim 18, further comprising administering to the patient an antibody specific for IL23.

20. 20. The method of claim 19, wherein the antibody is administered 12 weeks after the initial treatment.

21. 20. The method of claim 19, wherein the antibody is administered 12 weeks after the initial treatment, 16 weeks after the initial treatment, and 20 weeks after the initial treatment.

22. 22. The method of claim 21, wherein the antibody is administered subcutaneously at a dose of 100 mg or 200 mg of antibody.

23. 23. The method of claim 22, wherein the patient is identified as a responder to the antibody and meets a clinical endpoint, the clinical endpoint being a clinical response defined as a ≥ 30% and ≥ 2 point reduction from derived baseline in the modified Mayo score, accompanied by either a ≥ 1 point reduction from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.

24. The patient is identified as a responder to the antibody and meets a clinical endpoint, wherein the clinical endpoint is: (i) Clinical remission defined as the absence of easy bleeding on endoscopy, a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, wherein the stool frequency subscore has not increased from induction baseline; (ii) symptomatic remission, defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, wherein the stool frequency subscore has not increased from the induction baseline; (iii) endoscopic cure, defined as an endoscopy subscore of 0 or 1 with no easy bleeding at endoscopy; (iv) histologic-endoscopic mucosal healing, defined as achieving a combination of histologic and endoscopic healing, where histologic healing is defined as neutrophil infiltration in <5% of the crypts, no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes grading system; and (v) endoscopy normalization, defined as an endoscopy subscore of 0 (requiring the absence of easy bleeding).

25. 25. The method of claim 23 or 24, wherein the clinical endpoint is measured about 24 weeks after initial treatment.

26. 25. The method of claim 23 or 24, wherein the clinical endpoint is measured about 44 weeks after initial treatment.

27. 25. The method of claim 23 or 24, comprising further administering to the patient subcutaneously an antibody specific for IL23 every four weeks thereafter or every eight weeks thereafter at a dose of 100 mg or 200 mg of antibody.

28. 28. The method of claim 27, wherein the antibody comprises a light chain amino acid sequence of SEQ ID NO: 10 and a heavy chain amino acid sequence of SEQ ID NO:

9.

29. 29. The method of claim 27 or 28, wherein the antibody is in a pharmaceutical composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, 0.053% (w / v) polysorbate 80, and the diluent is water at standard conditions.

30. 16. The method of claim 15, further comprising administering to the patient one or more additional drugs used to treat ulcerative colitis.

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

32. The method of claim 1, wherein the patient is considered to have failed or intolerant to biological therapy (Bio-Failure) for ulcerative colitis prior to treatment with the antibody specific for IL23.

33. The method of claim 1, wherein the patient is considered to have failed or intolerant to conventional treatments for ulcerative colitis (Con-Failure) prior to treatment with the antibody specific for IL23.

34. 2. The method of claim 1, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.

35. 35. The method of claim 34, wherein the patient has endoscopic evidence of active Crohn's disease prior to administration of the first dose.

36. 36. The method of claim 35, wherein the patient has a modified Mayo score of 5 to 9, inclusive, a Mayo rectal bleeding subscore of ≧1, and a Mayo endoscopy subscore of ≧2, prior to administration of the first dose.

37. 1. A method of treating moderately to severely active ulcerative colitis in a patient, comprising administering to the patient: (i) an initial intravenous administration of 200 mg or 400 mg of an antibody specific for IL23; (ii) an intravenous administration of 200 mg or 400 mg of the antibody about 4 weeks after the initial administration; and (iii) an intravenous administration of 200 mg or 400 mg of the antibody about 8 weeks after the initial administration, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO: 8 and the heavy chain variable region amino acid sequence of SEQ ID NO: 7; and the patient is a responder to the antibody by being identified as meeting a clinical endpoint about 12 weeks after the initial administration, wherein the clinical endpoint is a clinical response defined as a ≥ 1 point reduction from baseline in the rectal bleeding subscore, or a ≥ 30% and ≥ 2 point reduction from derived baseline in the modified Mayo score, accompanied by either a rectal bleeding subscore of 0 or 1.

38. 38. The method of claim 37, further comprising administering the antibody specific for IL23 at a dose of 100 mg or 200 mg about every 4 weeks or 8 weeks thereafter, said administration occurring about 8 weeks after said first administration.

39. 1. A method of treating moderately to severely active ulcerative colitis in a patient, comprising administering to the patient: (i) an initial intravenous administration of 200 mg or 400 mg of an antibody specific for IL23; (ii) an intravenous administration of 200 mg or 400 mg of the antibody about 4 weeks after the initial administration; (iii) an intravenous administration of 200 mg or 400 mg of the antibody about 8 weeks after the initial administration; and (iv) a maintenance administration of the antibody specific for IL23 at 100 mg or 200 mg doses about every 4 or 8 weeks thereafter, wherein the antibody 8, a light chain variable region amino acid sequence of SEQ ID NO: 8, and a heavy chain variable region amino acid sequence of SEQ ID NO: 7, wherein the patient is a responder to the antibody by being identified as meeting a clinical endpoint at about 12, 24, and / or 44 weeks after the first administration, wherein the clinical endpoint is a clinical response defined as a ≥ 1 point reduction from baseline in a rectal bleeding subscore, or a ≥ 30% and ≥ 2 point reduction from derived baseline in a modified Mayo score, accompanied by either a rectal bleeding subscore of 0 or 1.

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