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 of the clinical endpoints.

Description

[Technical field]

[0001] (Reference to electronically submitted sequence listing) This application contains a sequence listing submitted electronically via the United States Patent and Trademark Office as a sequence listing in XML format with the file name "JBI6672USNP1 Sequence Listing.xml" and a size of 11 Kb created on November 21, 2022. The sequence listing submitted via the Patent Center is a part of the present specification and is incorporated by reference in its entirety herein.

[0002] FIELD OF THEINVENTION The present invention relates to methods of treating ulcerative colitis using antibodies that bind to human IL23. In particular, the present invention relates to anti-IL-23 specific antibodies and regimens for administering certain pharmaceutical compositions of the antibodies.

[0003] BACKGROUND OF THEINVENTION 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 is produced primarily by antigen-presenting cells and promotes cellular immunity by binding to a two-chain receptor complex expressed on the surface of T cells or natural killer (NK) cells. The IL-12 receptor 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, concomitant with antigen presentation, is believed to trigger T cell differentiation towards the T helper 1 (Th1) phenotype, characterized by interferon gamma (IFNγ) production (Trinchieri, 2003). Th1 cells are believed to promote immunity against several intracellular pathogens, generate complementary antibody isotypes, and contribute to tumor immunosurveillance. Therefore, IL-12 is believed to be a critical component of the host defense immune mechanism.

[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. As the p40 subunit is shared between IL-12 and IL-23, it follows that 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 shown 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 neutralization of IL-12 with antibodies has been effective in treating animal models of psoriasis, multiple sclerosis (MS), rheumatoid arthritis, inflammatory bowel disease, insulin-dependent (type 1) diabetes mellitus, 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, as they targeted the common p40 subunit. Thus, it is unclear whether IL-12 or IL-23 mediated the disease, or whether both cytokines need to be inhibited to achieve disease suppression. Recent studies have confirmed that IL-23 inhibition may offer 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 surface mucosa, crypt epithelium, and submucosa of the colon. 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, 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 having acute attacks requiring hospitalization at some point during their illness. In severe UC, the intestinal wall becomes very thin, the mucosa delaminates, and inflammation spreads to the serosa, which can lead to dilatation, toxic megacolon, and subsequent perforation. It has been reported that within 10 years of diagnosis, approximately 20% of adults with UC have undergone 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 controlling symptoms, reducing the need for long-term corticosteroids, preventing recurrences 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 showing 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 increasing evidence of the specific role of IL-23 in immune-mediated diseases. Neutralizing IL-23 without inhibiting the IL-12 pathway can provide an effective treatment for immune-mediated diseases with limited impact on important host defense immune mechanisms. This could provide 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-integrins have revolutionized the clinical management of IBD. Most agents in these classes have been approved for the treatment of UC. Within the anti-TNF-α class, infliximab, adalimumab, and golimumab are approved for UC. Ustekinumab, an IL-12 / 23 antagonist, and vedolizumab, an anti-integrin, 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 in UC.

[0011] However, despite substantial advances made by advanced therapies as monotherapy, there remains a large unmet need in the treatment of UC. Even with the best available approved therapies, more than half of patients fail to achieve clinical remission after one year. Of 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). It is therefore 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-term 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-IL23 specific antibody (also called IL23p19 or IL23p19 subunit antibody), e.g., guselkumab, at an initial induction dose from the start of treatment up to 4 weeks after initiation of treatment, followed by administration of an anti-IL-23 specific antibody once every 4 weeks, e.g., at weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 or 48. Moreover, in another embodiment, the 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 4 weeks after the first dose, 8 weeks after the first dose, and 12 weeks after the first dose, and continues with anti-IL23 specific antibody treatment, or (ii) intravenously at an initial dose of 400 mg, followed by 4 weeks after the first dose, 8 weeks after the first dose, and 12 weeks after the first dose, and continues with anti-IL23 specific antibody treatment, optionally continuing for more than 12 weeks, such as 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 anti-IL23 specific antibody.

[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 baseline in the derived modified Mayo score, with a ≥ 1 point reduction from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1; (ii) Clinical remission at Week 12, 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, with the stool frequency subscore not increasing 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 the stool frequency subscore not increasing from induction baseline. (iv) endoscopic cure at week 12, defined as an endoscopy subscore of 0 or 1 with no bleeding tendency 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 invention, patients who have received anti-IL23 specific antibody and are determined to have no clinical response at week 12 are treated with an extended induction period receiving subcutaneous anti-IL23 specific antibody at weeks 12, 16 and 20 and 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-IL23 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 pharmaceutical composition of composition 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) polysorbate 80, and diluent is water at normal conditions.

[0019] Another embodiment of the method of the invention is an isolated anti-IL-23 specific antibody having a heavy chain variable region amino acid sequence of SEQ ID NO:7 and a light chain variable region amino acid sequence of SEQ ID NO:8, optionally 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 diluent is water at normal conditions.

[0020] A further aspect of the method of the invention is the administration of 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 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 diluent is water at normal conditions.

[0021] In yet a further embodiment, the method of the invention involves the administration of the antibody guselkumab (sold as Tremfya® by Janssen Biotech Inc) in an optionally 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 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 become apparent from the following detailed description, the drawings, and the appended claims. [Brief description of the drawings]

[0023] [Figure 1] FIG. 1 shows the clinical response at 12 weeks in the full analysis set in the study described herein. [Diagram 2] FIG. 2 shows clinical remission at week 12 in the full analysis set in the study described herein. [Diagram 3] FIG. 3 shows the percentage of patients in symptom remission at various time points in the studies described herein. [Figure 4] FIG. 4 shows the dosing regimens for the treatment phase and how the study interventions were administered.

[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 antibodies," "anti-IL-23 antibodies," "antibody portions," or "antibody fragments," and / or "antibody variants," and the like, 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, that 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, reduce, ameliorate, 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 non-limiting examples, suitable anti-IL-23 antibodies, specified portions, or variants of the invention can bind to at least one IL-23 molecule or specified portions, variants, or domains thereof. Suitable anti-IL-23 antibodies, specified portions, or variants 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, etc.

[0026] The term "antibody" is further intended to encompass antibodies, digested fragments thereof, specific portions, and variants thereof, including antibody mimetics, or portions of antibodies that mimic the structure and / or function of antibodies, such as single chain antibodies and fragments thereof, or specific fragments or portions thereof. Functional fragments include antigen-binding fragments that bind to mammalian IL-23. For example, Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab') 2Antibody fragments capable of binding IL-23 or a portion thereof, including, but not limited to, Fc' (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 a variety of truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, F(ab') 2 The combination of genes encoding the heavy chain portion is 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 joined chemically 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 an antibody that is human and contains substantially all parts of the protein (e.g., CDRs, frameworks, C L , C H Domain (e.g., C H 1. C H 2. C H 3), Hinge (V L , V H)) that are substantially non-immunogenic in humans with only minor sequence changes or mutations. A "human antibody" may be an antibody derived from or closely corresponding to a human germline immunoglobulin sequence. A human antibody may contain amino acid residues not encoded by a germline immunoglobulin sequence (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). In many cases, 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, using sequence similarity searches, antibodies with similar linear sequences can be selected as templates for creating human antibodies. Similarly, antibodies with names including primates (monkeys, baboons, chimpanzees, etc.), rodents (mouse, rats, rabbits, guinea pigs, hamsters, etc.), and other mammals designate antibodies specific for such 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 compared to the unmodified antibody. Thus, a human antibody is distinct from a chimeric antibody or a 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 the 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 2 to about 8 glycine or other amino acid residues, connecting the variable region of the heavy chain and the variable region of the light chain. Such a linker peptide is considered to be of human origin.

[0030] Bispecific, heterospecific, heterobinding or similar antibodies may also be used, which are monoclonal, preferably human or humanized, antibodies with binding specificities for at least two different antigens, one of which is for at least one IL-23 protein and the other for any other antigen. Methods for producing bispecific antibodies are known in the art. Traditionally, recombinant production of bispecific antibodies is based on the co-expression 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 done by affinity chromatography steps) is quite laborious and the product yield is 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, 5,959,085, 5,989,530 ...89,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,5 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 may optionally be characterized by high affinity binding to IL-23, and optionally and preferably low toxicity. In particular, antibodies of the invention, specific fragments or variants thereof, in which the 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 present invention. Antibodies that can be used in the present invention are optionally characterized by the ability to treat patients for extended periods 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 obtained. "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" can also be defined as the incidence of titrable levels of antibodies to an anti-IL-23 antibody in patients treated with an anti-IL-23 antibody when occurring in less than 25% of treated patients, preferably less than 10% of treated patients, at the recommended dose over the recommended course of treatment during the treatment period.

[0032] The term "clinically proven safety" refers to a relatively low or reduced frequency and / or a low or reduced severity of treatment-emergent adverse events (also called AEs or TEAEs) in relation to a dose, dosing regimen, treatment or method with an anti-IL-23 antibody of the invention (e.g., the anti-IL-23 antibody guselkumab), e.g., from a clinical trial conducted, e.g., a Phase 2 clinical trial, and earlier clinical trials, compared to a standard of care or another comparison standard. An adverse event is an untoward medical occurrence in a patient administered a medicinal product. In particular, when relating to a dose, dosing regimen or treatment with an anti-IL-23 antibody of the 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 variants 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 can include administering an effective amount of a composition or pharmaceutical composition comprising at least one anti-IL-23 antibody to a cell, tissue, organ, animal, or patient in need thereof to modulate, treat, alleviate, prevent, or ameliorate a symptom, effect, or mechanism. An effective amount can include an amount of about 0.001-500 mg / kg per single (e.g., bolus), multiple, or continuous administration, or an amount that achieves a serum concentration of 0.01-5000 μg / ml per single, multiple, or continuous administration, or any effective range or value therein, performed 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 invention and / or providing a description and enabling of the invention. A publication refers to any scientific publication or patent publication or any other information available in any media format, including all recorded in electronic or printed form. The following documents are incorporated herein by reference in their entirety: Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2 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 purification At least one anti-IL-23 used in the methods of the 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; and, 2003, Immunotherapy and Immunotherapy, 1999, 144:1311-1320, 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 suitable 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 NO:1, SEQ ID NO:2, and SEQ ID NO:3, and the light chain CDR amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6. 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 Myeloma cell lines such as 2A, or heteromyelomas, fusion products thereof, 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.), including, but not limited to, antibody producing cells, such as 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 acid. , 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 as any combination thereof, to produce hybridomas. 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 the antibody of the invention, specific fragments or variants 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 suitable methods for producing or isolating antibodies with the required specificity can be used, including, but not limited to, recombinant antibody selection from peptide or protein libraries (e.g., but not limited to, bacteriophage, ribosomal, oligonucleotide, RNA, cDNA, etc. display libraries, available, for example, from 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.).For example, European Patent No. 368,684, International Application No. GB91 / 01134, International Application No. GB92 / 01755, International Application No. GB92 / 002240, International Application No. GB92 / 00883, International Application No. GB93 / 00605, U.S. Patent Application No. 08 / 350260 (5 / 12 / 94), International Application No. GB94 / 01422, International Application No. GB94 / 02662, International Application No. GB97 / 01835, (CAT / MRC), WO 90 / 14443, WO 90 / 14424, WO 90 / 14430, International Application No. US94 / 1234, WO 92 / 18619, WO 96 / 07754 (Scripps), WO 96 / 13583, WO 97 / 08320 (MorphoSys), WO 97 / 08320 (MorphoSys), WO 98 / 01835 (MorphoSys), WO 99 / 0203 (MorphoSys), WO 91 / 01835 (MorphoSys), WO 92 / 01836 (MorphoSys), WO 93 / 01837 (MorphoSys), WO 94 / 01838 (MorphoSys), WO 95 / 01839 (MorphoSys), WO 96 / 01839 (MorphoSys), WO 97 / 01839 (MorphoSys), WO 98 / 01839 (MorphoSys), WO 99 / 01836 (MorphoSys), WO 99 / 01839 ... 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 techniques include those based on the National Institute of Molecular Evolution (AME), a predecessor of the American Association for Clinical Molecular Evolution (ACME), each of which is incorporated herein by reference in its entirety), or rely on the immunization of transgenic animals capable of producing a repertoire of human antibodies as known in the art and / or described herein (e.g., SCID mice, each of which is incorporated herein 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., Immunol. 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., the selected lymphocyte antibody method, "SLAM") (U.S. Pat. No. 5,627,052; Wen et al., J. Immunol. 17:887-892 (1987); Babcook et al., Proc. Natl. Acad. Sci. USA 93:7843-7848 (1996)), gel microdroplets and flow cytometry (Powell et al., J. Immunol. 1999, 11:111-111 (1998)). 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 can also be used and are known in the art. Generally, a humanized or modified antibody will 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 often replaced by residues referred to as "import" residues, which are typically taken from an "import" variable, constant, or other domain of a known human sequence.

[0043] Available online at: www.ncbi.nlm.nih.gov / entrez / quer y.fcgi, www.ncbi.nih.gov / igblast, www.atcc.org / phage / hdb.html, www w.mrc-cpe.cam.ac.uk / ALIGNMENTS.php, www.kabatdatabase.com / top.html, ftp.ncbi.nih.gov / repository / kabat;www.sciquest.com, www.abc am.com, www.antibodyresource.com / onlinecomp.html, www.public.iastate.edu / ~pedro / research_tools.html, www.whfreeman.com / immunology gy / CH05 / kuby05.htm、www.hhmi.org / grants / lectures / 1996 / vlab、www.path.cam.ac.uk / ~mrc7 / mikeimages.html、mcb.harvard.edu / BioLinks / I mmunology.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.cancerresearch.org www.biotech.ufl.edu www.is ac-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.m x / 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, binding rate constant, dissociation rate constant, avidity, specificity, half-life, or any other suitable property, as known in the art. Generally, CDR residues directly and most substantially affect antigen binding. Thus, non-human sequences in 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 may optionally be humanized, or human antibodies may be modified while retaining high affinity for the antigen and other favorable biological properties. To this end, humanized (or human) antibodies may 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 are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformations of selected candidate immunoglobulin sequences. Inspection of these displays allows analysis of the likely role of the residues in the functioning 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 such that desired antibody properties, such as enhanced affinity for the target antigen, are achieved.

[0046] In addition, human IL-23 specific antibodies 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, the human IL-23 specific antibodies 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- 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 at the sources of known human Ig sequences mentioned 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 framework regions.

[0049] Humanization or engineering of the antibodies of the present invention may be carried out in accordance with the methods 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. WO 90 / 14443, WO 90 / 14424, WO 90 / 14430, and European Patent No. 229246 (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 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 further amino acid modifications that alter the C1q binding and / or complement dependent cytotoxicity function of the Fc region of the IL-23 binding molecule. 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 further with the ability to mediate CDC, may be modified to enhance one or both of these activities. Amino acid modifications that alter C1q and / or modify its complement dependent cytotoxicity function are described, for example, in WO 0042072, which is incorporated herein by reference.

[0051] As disclosed above, the Fc region of the human IL-23 specific antibody 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) activity 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 receptor, BCR), 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 test methods (e.g., Fc binding assays, ADCC assays, CDC assays, and the like).

[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., have both improved ADCC activity and improved CDC activity). Alternatively, where it is desired to reduce or eliminate effector function, variant Fc regions can be modified to have 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 and reduced CDC activity, and vice versa).

[0053] Fc mutations can also be engineered and introduced 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 (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 modify the glycosylation pattern of the Fc region of a human IL-23 specific antibody. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars, N-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. The recognition sequences for 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 modified, for example, by deleting one or more glycosylation sites found in the polypeptide and / or adding one or more glycosylation sites not present in the polypeptide. Addition of glycosylation sites to the Fc region of a human IL-23-specific antibody is conveniently accomplished by modifying the amino acid sequence to include one or more of the above tripeptide sequences (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 performed by the addition of, or substitution by, one or more serine or threonine residues to the original polypeptide sequence (for O-linked glycosylation sites). In addition, changing Asn 297 to Ala can remove one of the glycosylation sites.

[0056] In certain embodiments, the human IL-23 specific antibodies 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, Patent Publication 2003 / 0003097(A1), and Umana et al., Nature Biotechnology, 17:176-180, Feb. 1999, all of which are expressly incorporated herein 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 may 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 (such as, 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 / 2491 to Lonberg et al., each of which is incorporated herein by reference in its entirety). No. 884 to Lonberg et al., International Publication No. WO 97 / 13852 to Lonberg et al., International Publication No. WO 94 / 25585 to Lonberg et al., International Publication No. WO 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. Pat. No. 5,545,807 to Surani et al., International Publication No. WO 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., 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 that comprises 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 of antibodies for specific binding to similar proteins or fragments can be successfully accomplished using peptide display libraries. The method involves screening a large collection of peptides for individual members with the desired function or structure. Antibody screening of peptide display libraries is well known in the art. The displayed peptide sequences can be 3-5000 or more amino acids long, frequently 5-100 amino acids long, and often about 8-25 amino acids long. In addition to direct chemical synthesis methods for creating peptide libraries, several recombinant DNA methods have also been described. One type involves the display of peptide sequences on the surface of bacteriophages or cells. Each bacteriophage or cell contains a nucleotide sequence that codes for 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 International Application Nos. 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, e.g., 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 all assigned to Enzon; ​​U.S. Patent Nos. 5,223,409, 5,403,484, 5,571,698, and 5,837,500 all assigned to Dyax; U.S. Patent Nos. 5,427,908 and 5,580,717 all assigned to Affymax; Cambridge antibody See U.S. Patent No. 5,885,793 assigned to Eppendorf Technologies, 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] The antibodies used 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, rabbits, etc., 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; 5,304,489, etc., each of which is incorporated herein by reference in its entirety.

[0062] The antibodies used in the methods of the invention can further be prepared using at least one anti-IL23 antibody encoding nucleic acid 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, for example, 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 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 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, 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, e.g., 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 performed using standardized solutions of antibody and antigen, and standardized buffers, such as those described herein.

[0065] nucleic acid molecule Using the information provided herein, such as, 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, a nucleic acid molecule 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 may be the non-coding strand, called the antisense strand.

[0067] The isolated nucleic acid molecules used in the methods of the present invention can include nucleic acid molecules that include an open reading frame (ORF) with at least one particular portion of at least one CDR, such as, but not limited to, at least one heavy or light chain CDR1, CDR2, and / or CDR3, optionally including one or more introns, nucleic acid molecules that include coding sequences for anti-IL-23 antibodies or variable regions, and nucleic acid molecules that include nucleotide sequences that are substantially different from those described above, but that still encode at least one anti-IL-23 antibody described herein and / or known in the art due to the degeneracy of the genetic code. Of course, the genetic code is well known in the art. Thus, it would be routine for a person skilled in the art to generate such degenerate nucleic acid variants that encode the specific anti-IL-23 antibodies used in the methods of the present invention. See, for example, 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 full length of an antibody or a portion of an antibody, coding sequences for an antibody, fragment or portion, and additional sequences, such as at least one intron, with or without the aforementioned additional coding sequences, including, but not limited to, non-coding 5' and 3' sequences, such as transcribed non-translated sequences that play a role in transcription, mRNA processing, including splicing and polyadenylation signals (e.g., ribosome binding and stability of mRNA), as well as 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 functions. Thus, the antibody coding sequence can be fused to a marker sequence, e.g., a marker sequence is a sequence that encodes a peptide that facilitates purification of an antibody comprising the antibody fragment or portion to which it is fused.

[0069] Polynucleotides that selectively hybridize to the polynucleotides described herein The method of the present invention uses isolated nucleic acids that hybridize under selective hybridization conditions to the polynucleotides disclosed herein. Thus, the polynucleotides of the present embodiment can be used to isolate, detect, and / or quantify nucleic acids that contain 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 that are 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, 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 limited to, using sequences with low sequence identity to the complementary sequence. Optionally, medium and high stringency conditions can be used for sequences with higher identity. Low stringency conditions allow selective hybridization of sequences with about 70% sequence identity and can be used to 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 present invention. See, e.g., Ausubel, supra; Colligan, supra, each of which is incorporated herein by reference in its entirety.

[0072] Nucleic acid construction An isolated nucleic acid 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] The nucleic acid may conveniently contain sequences in addition to the polynucleotide of the invention. For example, a multiple cloning site containing one or more endonuclease restriction sites may be inserted into the nucleic acid to aid in the isolation of the polynucleotide. Also, a translatable sequence may be inserted to aid in the isolation of the translated polynucleotide of the invention. For example, a hexahistidine marker sequence provides a convenient means for purifying the protein of the invention. The nucleic acid of the invention (excluding the coding sequence) is optionally a vector, adapter, or linker for cloning and / or expression of the polynucleotide 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 a cDNA or genomic DNA library. Isolation of RNA and 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 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 in the same or different organisms. Those skilled in the art will appreciate that various degrees of hybridization stringency can be used in the assay, and that either the hybridization or the wash medium can be made more stringent. The more stringent the hybridization conditions, the greater the degree of complementarity between the probe and the target at which duplex formation occurs. The degree of stringency can be controlled by one or more of temperature, ionic strength, pH, and the presence of a partially denaturing solvent, such as formamide. For example, the stringency of hybridization is successfully altered by changing the polarity of the reaction solution, for example, by manipulating the formamide concentration in the range of 0% to 50%. The degree of complementarity (sequence identity) required for detectable binding varies depending on the stringency of the hybridization medium and / or the 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 differences in sequence in the probe and primers 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., U.S. Pat. No. 5,122,464 to Innis, U.S. Pat. No. 5,091,310 ...122 No. 4,889,818 to nd et al., U.S. Patent No. 4,994,370 to Silver et al., U.S. Patent No. 4,766,067 to Biswas, and U.S. Patent No. 4,656,134 to Ringold), and RNA-mediated amplification (U.S. Patent No. 5,130,238 to Malek et al., under the 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) technology can be used to amplify the sequences of polynucleotides and related genes used in the methods of the present invention 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 sequencing nucleic acids, or for other purposes. Examples of techniques sufficient to guide the skilled artisan through in vitro amplification methods can be found in Berger, Sambrook, and Ausubel, supra, as well as U.S. Patent 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). Commercial kits for genomic PCR amplification are known in the art. See, for example, Advantage-GC Genomic PCR Kit (Clontech). In addition, for example, the T4 gene 32 protein (Boehringer Mannheim) can be used to improve yields of long PCR products.

[0080] Synthetic methods for constructing nucleic acids The isolated nucleic acid used in the method of the present invention can also be prepared by direct chemical synthesis by known methods (see, for example, Ausubel et al., supra). Chemical synthesis generally 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 longer sequences can be obtained by ligation of shorter sequences.

[0081] Recombinant Expression Cassettes The present invention employs recombinant expression cassettes comprising nucleic acids. Nucleic acid sequences, such as cDNA or genomic sequences encoding an antibody 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 comprise a polynucleotide that is 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 suitable location (upstream, downstream, or within an intron) of a non-heterologous form of a polynucleotide of the invention 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 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 of which is incorporated herein by reference in its entirety).

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

[0085] The DNA insert should be operably linked to a suitable promoter. The expression construct further comprises 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 comprises 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 includes at least one selectable marker. Such markers include, for example, methotrexate (MTX), dihydrofolate reductase (DHFR, U.S. Pat. Nos. 4,399,216; 4,634,665; 4,656,134; 4,956,288; 5,149,636; 5,179,017), ampicillin, neomycin (G418), mycophenolic acid, or glutamine synthetase for eukaryotic cell culture. synthetase, GS, U.S. Patent Nos. 5,122,464; 5,770,359; 5,827,739) resistance genes, and tetracycline or ampicillin resistance genes for culture in E. coli and other bacteria or prokaryotes (the above patents are incorporated herein by reference in their entireties). Appropriate culture media and conditions for the above host cells are known in the art. Suitable vectors will be readily apparent to those of ordinary skill in the art. Introduction of the vector construct into the host cell can be accomplished 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, 16.

[0087] At least one antibody used in the method of the invention may be expressed in modified form, such as a fusion protein, and may contain not only secretion signals, but also additional heterologous functional regions. For example, a region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the antibody to improve stability and persistence in the host cell during purification or during subsequent processing and storage. Peptide moieties may also be added to the antibody of the invention to facilitate purification. Such regions may 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, Ausubel, supra, Chapters 16, 17, and 18.

[0088] Those skilled in the art are familiar with the many expression systems available for expressing the nucleic acid encoding the protein used in the method of the present invention. Alternatively, the nucleic acid can be expressed in a host cell by switching on (by manipulation) in the host cell containing the endogenous DNA encoding the antibody. 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, which are incorporated herein by reference in their entirety.

[0089] An example of a cell culture useful for the production of an antibody, specified portion or variant thereof is a mammalian cell. Mammalian cell lines often take the form of a monolayer of cells, although suspensions or bioreactors of mammalian cells can also be used. A number of 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 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 cell is P3X63Ab8.653 or SP2 / 0-Ag14 cell.

[0090] Expression vectors for these cells can include one or more of the following expression control sequences, including, 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 These are available from Hybridomas (www.atcc.org) or other known or commercial sources.

[0091] When eukaryotic host cells are used, typically polyadenylation or transcription termination sequences are 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 (Sprague, et al., J. Virol. 45:773-781 (1983)). In addition, gene sequences for controlling 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, for example, 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, 10, each of which is incorporated herein by reference in its entirety.

[0093] Antibodies for use in the methods of the invention include naturally purified products, products of chemical synthetic processes, and products produced by recombinant techniques from eukaryotic hosts, including, for example, yeast, higher plants, insect, and mammalian cells. Depending on the host utilized in a recombinant production process, the antibodies 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; Colligan, Protein Science, supra, Chapters 12-14, all of which are incorporated herein by reference in their entirety.

[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, and optionally, including at least one substitution, insertion, or deletion), a heavy or light chain constant region (e.g., at least one CDR, FR5, FR6, FR7, FR8, FR9, FR10, FR11, FR12, FR13, FR14, FR15, FR16, FR17, FR18, FR19, FR19, FR119, FR120, FR130, FR140, FR151, FR161, FR172, FR183, FR194, FR195, FR196, FR197, FR198, FR19 ... H 1, Hinge 1, Hinge 2, Hinge 3, Hinge 4, C H 2 or C H 3, or a fragment thereof, and optionally further comprising 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] The isolated antibodies used 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 antibodies or antigen-binding fragments bind to human IL-23, thereby partially or substantially neutralizing at least one biological activity of the protein. Antibodies, or specified portions or variants thereof, that partially or preferably substantially neutralize at least one biological activity of at least one IL-23 protein or fragment, can bind to the protein or fragment, thereby inhibiting 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 (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and may include a kappa or lambda light chain. In one embodiment, the human antibody comprises an IgG heavy chain or defined fragment, e.g., at least one of the following isotypes: IgG1, IgG2, IgG3, or IgG4 (e.g., γ1, γ2, γ3, γ4). Antibodies of this type can be prepared by utilizing transgenic mice or other non-human transgenic mammals that contain at least one human light chain (e.g., IgG, IgA, and 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, which may comprise at least one antibody binding region that comprises at least a portion of the protein, preferably comprising at least one extracellular, soluble, hydrophilic, exoportion, or cytoplasmic portion of the protein.

[0097] Generally, a human antibody or antigen-binding fragment comprises an antigen-binding region that comprises at least one human complementarity determining region (CDR1, CDR2, and CDR3) or variant of at least one heavy chain variable region, and at least one human complementarity determining region (CDR1, CDR2, and CDR3) or variant of at least one light chain variable region. The CDR sequences can be derived from human germline sequences or can match exactly to germline sequences. For example, CDRs from a synthetic library derived from the original non-human CDRs can be used. These CDRs can be formed by incorporation of conservative substitutions from the original non-human sequence. In another specific embodiment, the antibody or antigen-binding portion or variant can have an antigen-binding region that comprises at least a portion of at least one light chain CDR (i.e., CDR1, CDR2, and / or CDR3) 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 encoding the antibody (i.e., one or more) using conventional techniques involving recombinant DNA technology, or by chemically linking together the various portions of the antibody (e.g., CDRs, framework) using conventional techniques, or by using any other suitable method.

[0099] An anti-IL-23 specific antibody can comprise at least one of a heavy or light chain variable region having a defined amino acid sequence. For example, in a preferred embodiment, an anti-IL-23 antibody comprises at least one of a heavy chain variable region, optionally having the amino acid sequence of SEQ ID NO: 7, and / or at least one of a light chain variable region, optionally having the amino acid sequence of SEQ ID NO: 8. For example, in a preferred embodiment, an anti-IL-23 antibody comprises at least one of a heavy chain variable region, optionally having the amino acid sequence of SEQ ID NO: 9, and / or at least one of a light chain variable region, optionally having the amino acid sequence of SEQ ID NO: 10. Antibodies that bind to human IL-23 and comprise a defined heavy or light chain variable region can be prepared using suitable methods, such as those 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, a transgenic mouse containing a functionally rearranged human immunoglobulin heavy chain transgene and a transgene containing 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 induce 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, particular portions or variants can be expressed using the encoding nucleic acid or a portion thereof in a suitable host cell.

[0100] The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs that contain 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 that contain 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 replacement 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 within the following groups: lysine (K), arginine (R), and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D, and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine ​​(C), and glycine (G); F, W, and Y; C, S, and T.

[0101] Amino acid code The amino acids constituting the anti-IL-23 antibodies of the present invention are often abbreviated. Amino acid notation can be indicated by representing the amino acid by its one-letter code, its three-letter code, name, or three-nucleotide codon, and is well understood in the art (see Alberts, B. et al., Molecular Biology of The Cell, 3rd Edition, Garland Publishing, Inc., New York (1994)).

[0102] [Table 1]

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

[0104] The number of amino acid substitutions that one of skill in the art may make will depend on many factors, including those described above. Generally speaking, the number of amino acid substitutions, insertions, or deletions in a given anti-IL-23 antibody, fragment, or variant, as specified herein, is 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or less, e.g., 1 to 30, or any range or value therein.

[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] An 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 of the contiguous amino acids 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 can further optionally comprise at least one polypeptide of 70-100% of 5, 17, 10, 11, 7, 9, 119, or 108 contiguous amino acids of SEQ ID NO: above. 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) with the amino acid sequence of the corresponding chain of at least one of the SEQ ID NO: above. For example, the amino acid sequence of the light chain variable region can be compared to the sequence of the SEQ ID NO: above, or the amino acid sequence of the heavy chain CDR3 can be compared to the sequence of the SEQ ID NO: above. 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 for determining identity are designed to obtain the highest degree of correspondence between the sequences tested. Methods for determining 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, SF et al., J. Molec. Biol. 215:403-410(1990)). BLAST X programs are publicly available from NCBI and other sources (BLAST Manual, Altschul, S. et al., NCBINLM NIH Bethesda, Md. 20894: Altschul, S. et al., J. Mol. Biol. 215:403-410 (1990). The well-known Smith Waterman algorithm may also be used to determine identity.

[0111] Preferred parameters for polypeptide sequence comparisons include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48: 443-453 (1970) Comparison matrix: BLOSSUM62 from Hentikoff and Hentikoff, Proc. Natl. Acad. Sci, USA. 89: 10915-10919 (1992), Gap penalty: 12 Gap length penalty: 4 A program useful with these parameters is publicly available as the "Gap" program from the Genetics Computer Group, Madison Wis. The aforementioned parameters are the default parameters for peptide sequence comparisons (as well as no penalty for end gaps).

[0112] Preferred parameters for polynucleotide comparisons include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443-453 (1970) Comparison matrix: match = +10, mismatch = 0 Gap penalty: 50 Gap length penalty: 3 Available as the "Gap" program from the Genetics Computer Group, Madison Wis. These are the default parameters for nucleic acid sequence comparisons.

[0113] By way of example, a polynucleotide sequence may be identical to another sequence, i.e., 100% identical, or may contain up to a certain integer number of nucleotide alterations compared to a reference sequence. Such alterations may be selected from the group consisting of deletion, substitution (including transitions and transversions), or insertion 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 distributed either individually among the nucleotides of the reference sequence, or in one or more adjacent groups within the reference sequence. The number of nucleotide alterations may be determined by multiplying the total number of nucleotides in the sequence by the numerical percentage of the corresponding percent identity (divided by 100) and subtracting the 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.

[0114] Modification of a polynucleotide sequence encoding the above SEQ ID NO may create nonsense, missense, or frameshift mutations in the coding sequence, thereby modifying 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 NO, 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 distributed either individually between 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 calculated by multiplying the total number of amino acids in the above SEQ ID NO by the numerical percent of the respective percent identity (divided by 100) and subtracting the product from the total number of amino acids in the above SEQ ID NO, 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 sequence ID, 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 subtraction from x.sub.a.

[0115] Exemplary heavy and light chain variable region sequences, and portions thereof, are set forth in the SEQ ID NOs. An antibody of the invention, or a particular variant 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. Additionally, 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.

[0116] As will be appreciated by those of skill in the art, 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 of skill in the art.

[0117] 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 serum half-life in vivo). 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.

[0118] The modified antibodies and antigen-binding fragments can include one or more organic moieties that are directly or indirectly covalently attached to the antibody. Each organic moiety attached to the antibody or antigen-binding fragment of the present invention can be independently 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 the antibodies of the present invention may 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 that modify the antibodies of the present invention have a molecular weight of about 800 to about 150,000 daltons as individual molecular entities. For example, PEG 5000 and PEG 20,000 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 a suitable method. For example, a polymer containing an amine group can be linked to a carboxylate of a fatty acid or fatty acid ester, and an activated carboxylate on the fatty acid or fatty acid ester (e.g., activated with N,N-carbonyldiimidazole) can be linked to a hydroxyl group on the polymer.

[0119] 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 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.

[0120] 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., hydrophilic polymer, fatty acid, fatty acid ester) that contains 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 esters (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 activating groups into molecules are known in the art (see, for example, Hermanson, GT, Bioconjugate Techniques, Academic Press: San Diego, CA (1996)). Activating groups can be attached directly to organic groups (e.g., hydrophilic polymers, fatty acids, fatty acid esters) or to linker moieties, such as divalent C 1 ~C 12 The linker moiety can be, for example, tetraethylene glycol, -(CH 2 ) 3 -, -NH-(CH 2 ) 6 -NH-, -(CH 2 ) 2 -NH- and -CH 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2-O-CH-NH-. Modifiers containing a linker moiety can be produced, for example, by reacting mono-Boc-alkyldiamines (e.g., mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with fatty acids in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to form amide bonds 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 linked to another carboxylate as described, or it can be reacted with maleic anhydride and the resulting product cyclized to produce an activated maleimide derivative of the fatty acid. (See, for example, WO 92 / 16221 (Thompson et al.), the entire teachings of which are incorporated herein by reference).

[0121] Modified antibodies can be produced by reacting a human antibody or antigen-binding fragment with a modifying agent. For example, an organic moiety can be attached to the antibody 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 antibody of the invention. Modified human antibodies and antigen-binding fragments containing organic moieties attached to specific sites of 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, GT, Bioconjugate Techniques, Academic Press: San Diego, CA (1996).

[0122] The methods of the 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 said 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 SEQ ID NOs. above, or specific fragments, domains, or variants thereof. A preferred anti-IL-23 antibody composition comprises 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 SEQ ID NOs. above, 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 specific 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.

[0123] Antibody compositions containing further therapeutically active ingredients The antibody compositions used in the methods of the 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) agents, central nervous system (CNS) agents, autonomic nervous system (ANS) agents, respiratory agents, gastrointestinal (GI) tract agents, hormonal agents, fluid or electrolyte balancing agents, hemodynamic agents, antineoplastic agents, immunomodulatory agents, ophthalmic, otic or nasal agents, topical agents, nutritional agents, and the like. Such drugs are well known in the art, including the formulations, indications, dosages, and administration of each as set forth herein (see, e.g., Nursing 2001 Handbook of Drugs, 21st Edition, 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; Pharmacotherapy Handbook, Wells et al., Appleton & Lange, Stamford, CT).

[0124] As examples of drugs that can be combined with the antibodies of the method of the present invention, the anti-infective drug can be at least one selected from amebicide or at least one antiprotozoal drug, anthelmintic drug, antifungal drug, antimalarial drug, antituberculous drug or at least one antilepromycotic drug, aminoglycoside, penicillin, cephalosporin, tetracycline, sulfonamide, fluoroquinolone, antiviral drug, macrolide anti-infective drug, and miscellaneous anti-infective drugs. The hormonal drug can be at least one selected from corticosteroid, androgen, or at least one anabolic steroid, estrogen, or at least one progestin, gonadotropin, antidiabetic drug, or at least one glucagon, thyroid hormone, thyroid hormone antagonist, pituitary hormone, and parathyroid mimetic 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.

[0125] 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 diacetate. 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.

[0126] 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.

[0127] 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, halcionide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, and triamcinolone acetonide. (See, e.g., pages 1098-1136 of Nursing 2001 Drug Handbook.)

[0128] Anti-IL-23 antibody compositions comprise at least one anti-IL-23 antibody that is contacted or administered to a cell, tissue, organ, animal, or subject in need of such modulation, treatment, or therapy, and optionally further comprise 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, a fusion polypeptide thereof, or a small molecule TNF antagonist, such as TNF binding protein I or II (TBP-1 or TBP-II), nerelimonmab, infliximab, The composition may further include at least one of any suitable and effective amount of compositions or pharmaceutical compositions comprising at least one selected from the group consisting of antirheumatic drugs (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, sodium aurothiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), immunizing agents, immunoglobulins, immunosuppressants (e.g., azathioprine, basiliximab, cyclosporine, daclizumab), cytokines, or cytokine antagonists. Non-limiting examples of such cytokines include, but are not limited to, any of IL-1 to IL-40, etc. (e.g., IL-1, IL-2, etc.). Suitable dosages are well known in the art. For example, see 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.

[0129] The anti-IL-23 antibody compound, composition, or mixture used in the method of the present invention may further comprise at least one of any suitable auxiliary agent, such as, but not limited to, a diluent, a binder, a stabilizer, a buffer, a salt, a lipophilic solvent, a preservative, an adjuvant, 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, 1896, 1999, 1998, 19 ... 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 well known in the art or described herein can be routinely selected.

[0130] 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 1-99.99% by weight or volume, alone or in combination. Exemplary protein excipients include serum albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Exemplary amino acids / antibody components that may also function in a 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.

[0131] Carbohydrate excipients suitable 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.

[0132] The anti-IL-23 antibody composition may also include a buffer or pH adjusting agent, typically 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. A preferred buffer for use in the composition is an organic acid salt such as citric acid.

[0133] 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).

[0134] These and additional known pharmaceutical additives and / or excipients suitable for use in the anti-IL-23 antibody, portion or variant compositions according to 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 excipient materials are carbohydrates (e.g., monosaccharides and alditols) and buffers (e.g., citric acid) or polymeric agents. Exemplary carrier molecules are mucopolysaccharides, hyaluronic acid, which may be useful for intra-articular delivery.

[0135] formulation As mentioned 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 preservative formulations suitable for pharmaceutical or veterinary use comprising at least one anti-IL-23 antibody in a pharma- ceutically acceptable formulation. The preservative formulations include at least one known preservative, optionally selected from the group consisting of at least one phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or 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, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.7, 3.8, 3.9, 3.1, 3.2 ...3, 3.4, 3.5, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, Any suitable concentration or mixture may 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 no preservatives, 0.1-2% m-cresol (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (e.g., 0.005, 0.01), 0.001-2.0% phenol (e.g., For example, 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005 to 1.0% alkyl paraben (for example, 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.

[0136] As discussed above, the methods of the invention employ 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 indicating that such solution can be maintained for 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72 hours or more. The invention further employs articles of manufacture comprising packaging and a first vial containing a lyophilized anti-IL-23 specific antibody and a second vial containing an aqueous diluent of the formulated buffer or preservative, 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 maintained for 24 hours or more.

[0137] The anti-IL-23 specific antibodies used in accordance with the present invention may be produced by recombinant means, including production from mammalian cells or transgenic preparations, or may be purified from other biological sources, as described herein or known in the art.

[0138] Ranges of anti-IL-23 specific antibodies include those amounts that will give a concentration 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., for solution formulations, as opposed to transdermal patch, pulmonary, transmucosal, or osmotic or micropump methods.

[0139] Preferably, the aqueous diluent further comprises a pharma- ceutically acceptable preservative, optionally. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof. The concentration of the preservative used in the formulation is sufficient to produce an antimicrobial effect. Such concentration will vary depending on the preservative selected, and can be easily determined by those skilled in the art.

[0140] Other excipients, such as isotonicity agents, buffers, antioxidants, and preservative enhancers, can be optionally and preferably 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 range of pH, such as from about pH 4 to about pH 10, and preferably from about pH 5 to about pH 9, and most preferably from about 6.0 to about 8.0. Preferably, the formulations of the present invention have a pH of about 6.8 to about 7.8. Suitable buffers include phosphate buffers, most preferably sodium phosphate, especially phosphate buffered saline (PBS).

[0141] Other additives, such as pharma- ceutically 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 non-ionic 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 be optionally added to the formulation or composition to reduce aggregation. These additives are particularly useful when pumps or plastic containers are used to administer the formulation. The presence of pharma-ceutically acceptable surfactants reduces the tendency of proteins to aggregate.

[0142] The formulations can be prepared by a process that includes 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 (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof, in an aqueous diluent. Mixing at least one anti-IL-23 specific antibody with a preservative in an aqueous diluent is performed 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 a desired preservative in a sufficient amount of buffer solution to provide the desired concentration of protein and preservative. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, the use or non-use of additional additives, the temperature and pH during preparation of the formulation are all factors that can be optimized for the administration concentration and administration means used.

[0143] The formulations can be provided to patients as clear solutions or as dual vials 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 the selected salt 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.

[0144] 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 of time, and thus the packaging label can indicate that the solution may be stored and / or used for 6, 12, 18, 24, 36, 48, 72, or 96 hours or more. When using a preserved diluent, such labeling can include use up to 1-12 months, half a year, one and a half years, and / or up to two years.

[0145] A solution of anti-IL-23 specific antibody can be prepared by a process that includes mixing at least one antibody in an aqueous diluent. The mixing is carried out using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, a certain amount 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 the components, whether or not additional additives are used, the temperature and pH at which the formulation is prepared are all factors that can be optimized for the administration concentration and administration means used.

[0146] The claimed products can be provided to patients as clear solutions or as combination 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.

[0147] The claimed products can be provided indirectly to patients by providing a pharmacy, clinic, or other such institution or facility with a combination vial containing a clear solution or a vial of at least one lyophilized anti-IL-23 specific antibody reconstituted with a second vial containing an aqueous diluent, where the clear solution can be up to a liter or even more in volume, from which smaller amounts of the at least one antibody solution can be removed one or more times from the larger container and transferred to smaller vials and provided to customers and / or patients by the pharmacy or clinic.

[0148] Approved devices that include single vial systems include pen-type injection 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 Dickensen (Franklin Suitable devices include those manufactured or developed by National Medical Products, Weston Medical (Peterborough, UK, www.weston-medical.com), Medi-Ject Corp (Minneapolis, MN, www.mediject.com), and similar suitable devices. Recognized devices that include dual vial systems include pen-type syringe systems such as the HumatroPen® for reconstituting lyophilized medications in a cartridge to deliver the reconstituted solution. Examples of other suitable devices include pre-filled syringes, auto-injectors, needleless syringes, and needleless IV infusion sets.

[0149] The product may include packaging. The packaging provides the conditions under which the product may be used, as well as any information required by regulatory agencies. The packaging of the present invention, when 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 the solution for a period of 2-24 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 may be used for a period of 2-24 hours or more. The product is useful for human pharmaceutical product applications.

[0150] The formulations used in the methods of the present invention can be prepared by a process that includes 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 the buffer in an aqueous diluent is performed 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 a desired buffer in a sufficient amount of water to provide the desired concentration of protein and buffer. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, whether or not additional additives are used, the temperature and pH at which the formulation is prepared are all factors that can be optimized for the administration concentration and administration means used.

[0151] The method of the present invention provides pharmaceutical compositions including various formulations that are useful and acceptable for administration to human or animal patients. Such pharmaceutical compositions are prepared using "standard" water as a diluent and routine methods well known to those skilled in the art. For example, buffer components such as histidine and histidine monohydrochloride hydrate may be provided first, followed by the addition of an appropriate non-final volume of "standard" 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 the preparation of pharmaceutical compositions.

[0152] 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 set of art-recognized temperatures or pressures, but is instead a reference condition that specifies 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 "standard conditions" conditions defined above (e.g., 25°C ± 2°C and a pressure of 1 atmosphere).

[0153] Importantly, such a pharmaceutical composition 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 the pharmaceutical composition is "about" a given numerical value when the isolated antibody is present in the pharmaceutical composition or when the isolated antibody is present in the pharmaceutical composition after it is removed from the pharmaceutical composition (e.g., by dilution) and can bind to a peptide chain. That is, 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 the isolated antibody is placed in the pharmaceutical composition.

[0154] Competitive binding analysis is performed to determine whether IL-23 specific mAbs bind 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 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.

[0155] One aspect of the methods of the invention involves administering a pharmaceutical composition to a patient.

[0156] 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.

[0157] 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.

[0158] Other formulations or methods of stabilizing anti-IL-23 antibodies may be other than clear solutions of lyophilized powders containing the antibodies. Non-clear solutions include formulations containing particulate suspensions, which are compositions containing anti-IL-23 antibodies in structures of various sizes known variously as microspheres, microparticles, nanoparticles, nanospheres, or liposomes. Such relatively homogeneous essentially spherical particulate formulations containing active agents can be formed by contacting an aqueous phase containing active agents and polymers with a non-aqueous phase, as taught in U.S. Pat. No. 4,589,330, and then evaporating the non-aqueous phase to cause coalescence of particles from the aqueous phase. Porous microparticles can be prepared by using a first phase containing active agents and polymers 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), poly(L-phenylalanine / ethylene glycol), poly( ... The preferred polymers are natural or synthetic copolymers or polymers selected from the group consisting of poly(methyl methacrylate), poly(glycol / 1,6-diisocyanatohexane), and poly(methyl methacrylate). Particularly preferred polymers are polyesters such as polyglycolic acid, polylactic acid, glycolide-L(-)lactide poly(epsilon-caprolactone, poly(epsilon-caprolactone-co-lactic acid), and poly(epsilon-caprolactone-co-glycolic acid). Solvents useful for dissolving the polymer and / or active agent include water, hexafluoroisopropanol, methylene chloride, tetrahydrofuran, hexane, benzene, or hexafluoroacetone sesquihydrate.The process of dispersing the active-containing phase into the second phase can include forcing the first phase through orifices in a nozzle under pressure to affect droplet formation.

[0159] Dry powder formulations may also result from processes other than freeze-drying, such as, for example, 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 polar compounds, such as water and ethanol, that are easily dried. 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 that typically includes a hydrofluoroalkane propellant, as taught in WO 9916419. The stabilized dispersion can be administered to the lungs of a patient using a metered dose inhaler. Equipment useful in the commercial production of spray dried drugs is manufactured by Buchi Ltd. or Niro Corp.

[0160] Anti-IL-23 antibodies, either in the stable or preserved formulations or in solution described herein, can be administered to a patient 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.

[0161] Therapeutic Applications The 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.

[0162] Any of the methods of the 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 in combination with at least one TNF antagonist (such as, 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, such as 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, sodium aurothiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxants, narcotics, non-steroidal anti-inflammatory drugsdrugs, NSAIDs), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blockers, antibacterials (e.g., aminoglycosides, antifungals, antiparasitics, antivirals, carbapenams, cephalosporins, fluoroquinolones, macrolides, penicillins, sulfonamides, tetracyclines, other antibacterials), psoriasis medications, corticosteroids, anabolic steroids, diabetes medications, minerals, nutritional drugs, thyroid medications, vitamins, calcium-related hormones, antidiarrheals, antitussives, antiemetics, antineoplastics, laxatives, anticoagulants, erythropoietin (e.g., epoetin alfa), filgrastim (e.g., G-CSF, Neupogen), sargramostim (GM-CSF, Leukine), The method further comprises administering, before, simultaneously, and / or after at least one selected from an immunological 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 drug, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma drug, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or an analogue, 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, 2 nd Edition, Appleton and Lange, Stamford, CT (2000), PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), Nursing 2001 Handbook of Drugs, 21 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 is incorporated herein by reference in its entirety.

[0163] Treatment Typically, the treatment of ulcerative colitis is effected by administering an effective amount or dose of an anti-IL-23 antibody composition, which, depending on the specific activity of the active agent contained in the composition, ranges from at least about 0.01 to 500 milligrams of anti-IL-23 antibody per kilogram of patient, in total, on average, per dose, and preferably at least about 0.1 to 100 milligrams of antibody per kilogram of patient, per dose, per single or multiple doses. Alternatively, an effective serum concentration may include a serum concentration of 0.1 to 5000 μg / mL, per single or multiple doses. Suitable dosages are known to medical practitioners and will, of course, depend on the specific disease state, the specific activity of the composition administered, and the specific patient undergoing treatment. In some cases, it may be necessary to provide repeated administrations, i.e., repeated individual administrations of a particular monitored or metered dose, to achieve the desired therapeutic dose, where the individual administrations are repeated until the desired daily dosage or effect is obtained.

[0164] Preferred doses are optionally 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 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 , 17, 17.5, 17.9, 18, 18.5, 18.9, 19, 19.5, 19.9, 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, and / or 5000 μg / mL, or any range, value or fraction thereof.

[0165] Alternatively, the dose administered 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 the symptoms, type of concurrent treatment, frequency of treatment, and the desired effect. The dosage of active ingredient may typically be about 0.1 to 100 milligrams per kilogram of body weight. Usually, 0.1 to 50, preferably 0.1 to 10 milligrams per kilogram per administration, or in sustained release form, is effective to obtain the desired results.

[0166] As non-limiting examples, treatment of humans or animals may be performed using a single dose, intravenous administration, or multiple doses 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. or additionally, on at least one day of eyes 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, for example, 0.5, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 1.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years, or any combination thereof, for at least one of the following: weeks 48, 49, 50, 51, or 52, or, additionally, for at least one of the following years 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or any combination thereof. 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.

[0167] 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.

[0168] For parenteral administration, the antibody may be formulated as a solution, suspension, emulsion, particle, powder, or lyophilized powder, provided together with or separately from a pharma- ceutical acceptable parenteral vehicle. Examples of such vehicles are 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 for isotonicity, mannitol, buffers and preservatives for chemical stability). The formulation is sterilized by known or suitable techniques.

[0169] Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

[0170] Alternative Administration Many known and developed modes can be used in accordance with the present invention to administer a pharma- ceutical effective amount of an anti-IL-23 antibody. Although pulmonary administration is used in the following description, other modes of administration may 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.

[0171] Parenteral Formulation and Administration Preparations for parenteral administration may contain sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydrogenated naphthalenes, etc. as common excipients. Aqueous or oily suspensions for injection can be prepared by using appropriate emulsifiers or wetting agents and suspending agents according to known methods. Injections can be non-toxic parenterally administrable diluents such as aqueous solutions, sterile injections, or suspensions in solvents. Usable vehicles or solvents include water, Ringer's solution, isotonic saline, etc., and sterile fixed oils can be used as normal solvents or suspension solvents. For these purposes, any kind of fixed oils and fatty acids, including natural, synthetic, or semi-synthetic fatty oils or fatty acids, natural, synthetic, or semi-synthetic 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.

[0172] alternative delivery The invention further relates to 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 IL-23 antibody compositions can be formulated for use parenterally (subcutaneously, intramuscularly, or intravenously) or for any other administration, particularly in the form of liquid solutions or suspensions, particularly in semi-solid forms such as, but not limited to, creams and suppositories, for use in vaginal or rectal administration, in forms such as, but not limited to, tablets or capsules, for buccal or sublingual administration, or intranasally, in forms such as, but not limited to, powders, nasal drops or aerosols, or certain drugs, or with chemical enhancers such as dimethylsulfoxide to either modify the skin structure or increase the drug concentration in transdermal patches (Junginger, et al. In "Drug Permeation Enhancement;" Hsieh, DS, Eds., pp. 59-90 (Marcel Dekker, Inc. New York, 1999), which are incorporated herein by reference in their 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 a charged drug 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, such as, but not limited to, gels, ointments, lotions, suspensions, or patch delivery systems (the above publications and patents are incorporated herein by reference in their entireties).

[0173] 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 are expressly incorporated herein by reference.

[0174] Example 1 - Phase 2b (QUASAR) Induction Study Week I-12 Results (CNTO1959UCO3001 (QUASAR)) 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

[0175] Main purpose: The primary objective is to evaluate the clinical efficacy and safety of guselkumab as induction therapy in participants with moderately to severely 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).

[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 moderate to severe active ulcerative colitis (UC) who have responded inadequately to or lacked tolerance to conventional (i.e., 6-MP, AZA, or corticosteroids) or advanced therapies (i.e., TNFα antagonists, vedolizumab, or tofacitinib). At week I-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. Note that 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 has been amended following recent feedback from health authorities that the target population will be based only 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) Arm 2: Guselkumab 200 mg IV (weeks I-0, I-4, and I-8) Arm 3: Guselkumab 400 mg IV (weeks I-0, I-4, and I-8) Treatment Duration: The main portion of this study was 12 weeks.

[0180] With the intention to select a single induction dose for confirmatory evaluation in the Phase 3 induction study (Induction Study 2), an interim analysis was performed when the first 150 randomized participants completed the Week I-12 visit or terminated study participation prior to Week I-12. This interim analysis does not affect the overall type I error rate (α=0.05, two-sided) for the primary endpoint analysis because the study was not planned to be stopped for positive efficacy.

[0181] This report provides results for the primary and key secondary endpoints at weeks I-12, as well as safety through weeks I-12.

[0182] Primary Endpoint: The primary endpoint is clinical response at Weeks I-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.

[0183] Primary secondary endpoints: Clinical remission at weeks I-12, defined as absence of easy bleeding on endoscopy, stool frequency subscore of 0 or 1, rectal bleeding subscore of 0, and endoscopy subscore of 0 or 1, with the stool frequency subscore not increasing from induction baseline. o Symptomatic remission at weeks I-12, defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, with the stool frequency subscore not increasing from induction baseline. Endoscopic cure at weeks I-12, defined as an endoscopy subscore of 0 or 1 with no easy bleeding at endoscopy. o Histologic-endoscopic mucosal healing at weeks I-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 at weeks I-12 defined as an endoscopy subscore of 0 (requiring the absence of easy bleeding). ○ IBDQ remission during weeks I-12. Fatigue response at weeks I-12.

[0184] Expected effect size and planned sample size: The minimum sample size for this study is 150 participants required for the interim analysis. Participants continued to be randomized into this Phase 2b induction study while data from the interim analysis were being evaluated. By the time dose determination was made and performed, 313 participants (approximately 104 per treatment group) with a modified Mayo score of 5-9 (i.e., primary analysis population) had been enrolled and treated in the study. Assuming a clinical response rate of 30% in the placebo group and 60% in each guselkumab group (assumed rates were based on data from the ustekinumab UC induction study [CNTO1275UCO3001] and the mirikizumab Phase 2 UC study), 104 participants per treatment group would provide >99% power for the primary endpoint of clinical response at Weeks I-12 for each guselkumab group compared to placebo.

[0185] 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 study intervention. Participants were analyzed according to the study intervention to which they were randomized, regardless of the study intervention they actually received.

[0186] Safety analysis set: The safety analysis set included all randomized participants with a modified Mayo score of 5-9 who received at least one (partial or complete) dose of study intervention. Results based on the all-treatment analysis set, which included all randomized participants who received at least one dose (partial or complete) of study intervention (regardless of modified Mayo score), are also provided. Participants were analyzed according to the study intervention actually received.

[0187] Intercurrent events (ICEs) were used for the analysis of efficacy endpoints. In particular, participants who were prohibited from changing UC medication, underwent UC-related surgery (ostomy or colectomy), or discontinued study drug due to lack of efficacy or UC worsening AEs before the analysis time point were considered not to have met the binary endpoint endpoint. For participants who discontinued study drug for COVID-19-related reasons (excluding COVID-19 infection) before the analysis time point, post-discontinuation data were not used. For participants who discontinued study drug for any other reason, observational data were used, if available.

[0188] Comparisons were based on each guselkumab group versus placebo. For the primary and key secondary endpoints, p values ​​were based on Cochran-Mantel-Haenszel (CMH) chi-square test (two-sided) stratified by ADT failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no). 95% confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. For these endpoints, participants who were missing data at the time of analysis (after accounting for intercurrent events) were considered non-responders at that time.

[0189] Overall type I error was controlled at a significance level of 0.05 for the primary endpoint of clinical response at weeks I-12. Other endpoints were not controlled. Testing of the primary endpoint used a step-up Hochberg multiple testing procedure across two comparisons of guselkumab versus placebo. If the p-value for both guselkumab treatment groups was <0.05, it was concluded that both guselkumab treatment groups were effective compared to placebo. Otherwise, the smaller of the two p-values ​​was compared with α=0.025. If the p-value was <0.025, it was concluded that the guselkumab treatment group with the smaller p-value was effective compared to placebo. For endpoints that were not multiplicity controlled, nominal p-values ​​are presented.

[0190] At Weeks I-12, all participants will be evaluated for clinical response. Administration of further study interventions will be determined by the participant's clinical response status at Weeks I-12 (using Mayo endoscopy subscores assigned by the local endoscopist) as follows:

[0191] Guselkumab Clinical Responders and Placebo Clinical Responders at Weeks I-12 will enter a maintenance study.

[0192] Participants initially randomized to placebo who lack a clinical response at week I-12 will then cross over to guselkumab and receive three doses of 200 mg guselkumab IV at weeks I-12, I-16, and I-20.

[0193] Participants initially randomized to guselkumab who have no 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.

[0194] To maintain blinding, both IV and SC doses will be administered to all participants without clinical response at weeks I-12.

[0195] At Week I-24, participants without a clinical response at Week I-12 will be re-evaluated for clinical response (clinical response status is based on Mayo endoscopy subscores 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 1 will enter the Maintenance Study:

[0196] Placebo crossover responders: Participants were initially randomized to placebo, had no clinical response at Week I-12, then crossed over to 200 mg guselkumab induction IV treatment and achieved a clinical response at Week I-24.

[0197] Guselkumab Week 24 Responders: Participants initially randomized to guselkumab with no clinical response at Week I-12, then received 3 doses of 200 mg guselkumab SC and achieved a clinical response at Week I-24.

[0198] Participants without a clinical response at Weeks I-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.

[0199] 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 judgment 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.

[0200] An interim analysis of the first 150 randomized participants who complete the Week I-12 visit or terminate study participation prior to Week I-12 will be performed. 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 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 be enrolled 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.

[0201] In Induction Study 2, participants will be randomized in a 3:2 ratio to guselkumab or placebo administered 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. Selection of the guselkumab induction dose for Induction Study 2 will be based on an 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., insufficient response or lack of tolerance 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, administration of further study interventions will be determined by the participant's clinical response status (using Mayo endoscopy subscores assigned by the local endoscopist) at weeks I-12, as follows:

[0202] Guselkumab Clinical Responders and Placebo Clinical Responders at Weeks I-12 will enter a maintenance study.

[0203] Initially, participants randomized to placebo who lack a clinical response at week I-12 will then cross over to guselkumab and receive three doses of IV guselkumab treatment (i.e., the induction doses selected based on the interim analysis of Induction Study 1) at weeks I-12, I-16, and I-20.

[0204] Participants initially randomized to guselkumab who have no 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.

[0205] To maintain blinding, both IV and SC doses will be administered to all participants without clinical response at weeks I-12.

[0206] At Week I-24, participants without a clinical response at Week I-12 will be re-evaluated for clinical response (clinical response status is based on Mayo endoscopy subscores 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 enter the Maintenance Study:

[0207] Placebo crossover responder: Participants were initially randomized to placebo, had no clinical response at Week I-12, then crossed over to guselkumab induction IV dose treatment and achieved a clinical response at Week I-24.

[0208] Guselkumab Week 24 Responders: Participants initially randomized to guselkumab with no clinical response at Week I-12, then received 3 doses of 200 mg guselkumab SC and achieved a clinical response at Week I-24.

[0209] Participants without a clinical response at Weeks I-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.

[0210] 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 Investigator judgment due to toxicity or medical necessity. Initiation or dose increase of UC-specific therapy (or any restricted / prohibited medication or therapy) during Induction Study 2 will prohibit the participant from participating in the Maintenance Study.

[0211] result Most important results summary 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.

[0212] 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).

[0213] Disposition and baseline characteristics of the full analysis set (n=313): Overall, nine (2.9%) participants discontinued study treatment before week I-12. There were five (4.8%) discontinuations in the placebo group, three (3.0%) in the 200 mg IV guselkumab group, and one (0.9%) in the 400 mg IV guselkumab group. In the placebo group, four of the five discontinuations were for 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 discontinuation (1.0%). No participants discontinued study drug before week I-12 for reasons related to COVID-19.

[0214] The majority of participants were white (71.6%), and 59.1% of participants were male. The mean age was 41.6 years (range 18-84 years). A total of 147 (47.0%) participants had a history of advanced treatment (ADT) failure. 166 (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.

[0215] The population in this study represents a population with moderate to severe 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 was 1564.0 mg / kg, and the median C-reactive protein (CRP) concentration was 4.6 mg / L. At baseline, 48.9% of participants had extensive disease, 82.4% of participants had moderate UC (i.e., Mayo score ≥6 and ≤10), 17.6% had severe disease (Mayo score >10), 30% of participants had an endoscopy subscore of 2 (i.e., moderate disease), and 70% of participants had an endoscopy subscore of 3 (i.e., severe disease).

[0216] 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%).

[0217] Summary of efficacy endpoints: Guselkumab induction treatment (at both doses evaluated) resulted in significantly higher rates of clinical responses at weeks I-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 I-12.

[0218] Primary Endpoint Based on the primary analysis of clinical response at Weeks I-12, a significantly higher percentage of participants in the 200 mg IV and 400 mg IV guselkumab groups had a clinical response at Weeks I-12 compared to the placebo group. The study is considered a positive study (Figure 1).

[0219] Primary secondary endpoint 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 I-12 (Figure 2, Table 1).

[0220] Separation between the guselkumab treatment groups and placebo for symptom remission was observed as early as 4 weeks after the first dose and continued through weeks I-12 (Figure 3).

[0221] [Table 2]

[0222] Subgroup analysis by ADT failure status: Greater efficacy was observed in both guselkumab arms compared with placebo for the primary and all key secondary endpoints for both the ADT failure and non-ADT failure subgroups, with the exception of endoscopic normalization, which was greater in both guselkumab arms versus placebo in the non-ADT failure subgroup but not in either guselkumab arm versus placebo in the ADT failure subgroup. Generally, 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, the treatment effect (vs. placebo) was greater in the ADT non-failure subgroup compared with the ADT failure subgroup.

[0223] Of note, these subgroup analyses were based on relatively small numbers of participants per group and should be interpreted with caution.

[0224] [Table 3] a Adverse events assessed by the investigator as possibly, probably, or very likely related to the study drug, or unrelated to the study drug. b Infectious diseases assessed by the investigator.

[0225] Safety data from Weeks I-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 guselkumab group was not higher than in the placebo group, and no clinically meaningful differences in AE rates were observed between the guselkumab groups. The most frequently reported system organ classes (SOCs) with 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 system 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 similar between treatment groups (9.5% in the placebo group, 6.9% in the 200 mg guselkumab IV group, and 7.5% in the 400 mg guselkumab IV group). The proportion of participants reporting one or more serious AEs was not higher in the guselkumab-treated groups compared with the placebo group. The majority of 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 guselkumab IV group, and 0 in the 400 mg guselkumab IV 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 guselkumab IV group, and 8.4% in the 400 mg guselkumab IV group). - Two serious infections were observed, both of which occurred in the placebo group. - No cases of active TB were reported. - No opportunistic infections were reported. - There were no cases of malignancy. - Liver tests were similar between treatment groups through weeks I-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).

[0226] The incidence of total WBC count decline was higher in the guselkumab-treated groups compared with placebo through weeks I-12. All total WBC abnormalities were CTCAE grade 1 or 2.

[0227] 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 or intolerance to conventional therapy (i.e., thiopurines or corticosteroids) or advanced therapies (i.e., tumor necrosis factor alpha antagonists, vedolizumab, or tofacitinib). Patients who had a clinical response at week 12 after IV induction entered a maintenance study, while patients without clinical responses were treated in an extended induction period.

[0228] method: Included patients had moderate to severe active UC (modified Mayo score of 5-9 with Mayo rectal bleeding subscore ≥1 and Mayo endoscopy subscore ≥2). Patients were randomized 1:1:1 to receive GUS 200 mg, 400 mg, or placebo (PBO) IV at weeks 0, 4, and 8. At week 12, patients with no clinical response to IV induction 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.

[0229] 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 previous inadequate response or intolerance to advanced UC treatment.

[0230] 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. A clinical response at weeks 12 or 24 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.

[0231] conclusion Patients who did not achieve a clinical response to GUS IV induction at week 12 demonstrated benefit at week 24 after receiving 3 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.

[0232] The following table shows various baseline patient characteristics and efficacy measures of the study.

[0233] [Table 4] Legend: ADT=advanced therapy, TNF=tumor necrosis factor, UC=ulcerative colitis. Note: Includes adalimumab, golimumab, infliximab, tofacitinib, vedolizumab, and biosimilars.

[0234] [Table 5] Legend: UC = ulcerative colitis.

[0235] [Table 6] Legend: 6-MP = 6-mercaptopurine, ADT = advanced therapy, AZA = azathioprine, UC = ulcerative colitis.

[0236] [Table 7-1]

[0237] [Table 7-2]

[0238] [Table 7-3] Legend: CRP=C-reactive protein, IQ=interquartile, SD=standard deviation.

[0239] [Table 8] a Clinical response was defined as a ≧30% and ≧2 point reduction from baseline in the derived modified Mayo score, with a ≧1 point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1. b Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the Week I-12 visit were considered to not be clinical responders. c Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. d Subjects who were missing one or more of the Mayo subscores for this endpoint (stool frequency, rectal bleeding, or endoscopy) at weeks I-12 were considered to be non-clinical responders. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f p values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

[0240] [Table 9] a Clinical remission was 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, where the stool frequency subscore has not increased from the induction baseline. bSubjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the Week I-12 visit were considered not in clinical remission. c Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. d Subjects who were missing one or more Mayo subscores for this endpoint (stool frequency, rectal bleeding, or endoscopy) at weeks I-12 were considered not in clinical remission. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f p values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

[0241] [Table 10] a Symptom remission was defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, where the stool frequency subscore has not increased from the induction baseline. b Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the Week I-12 visit were considered not in symptom remission. c Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. d Subjects who were missing one or more Mayo subscores (stool frequency, rectal bleeding, or endoscopy) for this endpoint at weeks I-12 were considered not in symptom remission. eAdjusted treatment differences and confidence intervals were based on Wald statistics with Cochran-Mantel-Haenszel weights. f p values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

[0242] [Table 11] a Symptom remission was defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, where the stool frequency subscore has not increased from the induction baseline. b Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the designated time points were considered not in symptom remission. c Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. d Subjects who were missing one or more of the Mayo subscores for this endpoint (stool frequency, rectal bleeding, or endoscopy) at the designated time points were considered not in symptom remission. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f p values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

[0243] [Table 12] a Endoscopic cure is defined as an endoscopy subscore of 0 or 1 with no bleeding tendency present at the time of endoscopy. bSubjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the Week I-12 visit were considered to have not achieved endoscopic cure. c Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. d Subjects who were missing an endoscopy subscore at weeks I-12 were considered to have not achieved endoscopic cure. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f p values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

[0244] [Table 13] a Histologic-endoscopic mucosal healing is defined as achieving a combination of histologic and endoscopic healing. b Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the Week I-12 visit were considered to have not achieved histologic-endoscopic mucosal healing. c Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. eSubjects who underwent an unevaluable biopsy at Weeks I-12 (i.e., a biopsy that was taken but could not be evaluated due to sample preparation or technical error) or who lacked either the endoscopic subscore or the histologic component for this endpoint (i.e., assessment of neutrophils, crypt destruction, or erosions or ulceration or granulation tissue in the epithelium) were considered to have not achieved histologic-endoscopic mucosal healing. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f p values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

[0245] [Table 14] a Endoscopic normalization is defined as an endoscopy subscore of 0. b Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the Week I-12 visit were considered to have not achieved endoscopic normalization. c Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. d Subjects who were missing an endoscopy subscore at weeks I-12 were considered to have not achieved endoscopic normalization. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f p values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

[0246] [Table 15] Legend: ADT=Advanced Treatment, IBDQ=Inflammatory Bowel Disease Questionnaire, PROMIS=Patient-Reported Outcomes Measurement Information System. a1 Clinical response was defined as a ≧30% and ≧2 point reduction from baseline in the derived modified Mayo score, with a ≧1 point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1. a2 Clinical remission was 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, where the stool frequency subscore has not increased from the induction baseline. a3 Symptom remission was defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, where the stool frequency subscore has not increased from the induction baseline. a4 Endoscopic cure is defined as an endoscopy subscore of 0 or 1 with no bleeding tendency present at the time of endoscopy. a5 Endoscopic normalization is defined as an endoscopy subscore of 0 or 1. b Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs before the designated time points were considered to have not achieved the indicated critical efficacy endpoint. c Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. d Subjects who were missing one or more of the endpoint-related components at the specified time points were considered to have not achieved the endpoint. Subjects who received non-evaluable biopsies (i.e., biopsies that were taken but could not be evaluated due to sample preparation or technical errors) were considered to have not achieved the histological endpoint. ep values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

[0247] [Table 16] Legend: ADT=Advanced Treatment, IBDQ=Inflammatory Bowel Disease Questionnaire, PROMIS=Patient-Reported Outcomes Measurement Information System. a1 Clinical response was defined as a ≧30% and ≧2 point reduction from baseline in the derived modified Mayo score, with a ≧1 point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1. a2 Clinical remission was 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, where the stool frequency subscore has not increased from the induction baseline. a3 Symptom remission was defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, where the stool frequency subscore has not increased from the induction baseline. a4 Endoscopic cure is defined as an endoscopy subscore of 0 or 1 with no bleeding tendency present at the time of endoscopy. a5 Endoscopic normalization is defined as an endoscopy subscore of 0 or 1. b Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs before the designated time points were considered to have not achieved the indicated critical efficacy endpoint. c Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. dSubjects who were missing one or more of the endpoint-related components at the designated time points were considered to have not achieved the endpoint. Subjects who received non-evaluable biopsies (i.e., biopsies that were taken but could not be evaluated due to sample preparation or technical errors) were considered to have not achieved the histological endpoint. e p values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

[0248] [Table 17] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Subjects who had no clinical response at weeks I-12 as determined by IWRS and received treatment from weeks I-12. b Clinical remission was 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, where the stool frequency subscore has not increased from the induction baseline. c Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the Week I-24 visit were considered not in clinical remission. d Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. e Subjects who were missing one or more Mayo subscores (stool frequency, rectal bleeding, or endoscopy) for this endpoint at Weeks I-24 were considered not in clinical remission.

[0249] [Table 18] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Clinical remission was 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, where the stool frequency subscore has not increased from the induction baseline. b Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the designated time points were considered not in clinical remission. c Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. d Subjects who were missing one or more of the Mayo subscores for this endpoint (stool frequency, rectal bleeding, or endoscopy) at the designated time points were considered not in clinical remission.

[0250] [Table 19] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Clinical remission was 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, where the stool frequency subscore has not increased from the induction baseline. b Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the designated time points were considered not in clinical remission. c Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. dSubjects who were missing one or more of the Mayo subscores for this endpoint (stool frequency, rectal bleeding, or endoscopy) at the designated time points were considered not in clinical remission.

[0251] [Table 20] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Subjects who had no clinical response at weeks I-12 as determined by IWRS and received treatment from weeks I-12. b Clinical response was defined as a ≧30% and ≧2 point reduction from baseline in the derived modified Mayo score, with a ≧1 point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1. c Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the Week I-24 visit were considered to not be clinical responders. d Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. e Subjects who were missing one or more of the Mayo subscores (stool frequency, rectal bleeding, or endoscopy) for this endpoint at Weeks I-24 were considered to be non-clinical responders.

[0252] [Table 21] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Clinical response was defined as a ≧30% and ≧2 point reduction from baseline in the derived modified Mayo score, with a ≧1 point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1. b Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the designated time points were considered to not be clinical responders. c Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. d Subjects who were missing one or more of the Mayo subscores for this endpoint (stool frequency, rectal bleeding, or endoscopy) at the designated time points were considered to be non-clinical responders.

[0253] [Table 22] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Clinical response was defined as a ≧30% and ≧2 point reduction from baseline in the derived modified Mayo score, with a ≧1 point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1. b Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the designated time points were considered to not be clinical responders. c Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. d Subjects who were missing one or more of the Mayo subscores for this endpoint (stool frequency, rectal bleeding, or endoscopy) at the designated time points were considered to be non-clinical responders.

[0254] [Table 23] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Subjects who had no clinical response at weeks I-12 as determined by IWRS and received treatment from weeks I-12. b Endoscopic normalization is defined as an endoscopy subscore of 0. c Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the Week I-24 visit were considered to have not achieved endoscopic normalization. d Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. e Subjects who were missing an endoscopy subscore at weeks I-24 were considered to have not achieved endoscopic normalization.

[0255] [Table 24] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Subjects who had no clinical response at weeks I-12 as determined by IWRS and received treatment from weeks I-12. b Endoscopic cure is defined as an endoscopy subscore of 0 or 1 with no bleeding tendency present at the time of endoscopy. c Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the Week I-24 visit were considered to have not achieved endoscopic cure. d Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. eSubjects who were missing an endoscopy subscore at weeks I-24 were considered to have not achieved endoscopic cure.

[0256] [Table 25] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Subjects who had no clinical response at weeks I-12 as determined by IWRS and received treatment from weeks I-12. b Histologic-endoscopic mucosal healing is defined as achieving a combination of histologic and endoscopic healing. c Subjects who were prohibited from changing UC medication, underwent ostomy or colectomy, or discontinued study drug due to lack of efficacy or UC-worsening AEs prior to the Week I-24 visit were considered to have not achieved histologic-endoscopic mucosal healing. d Data following discontinuation of study medication for reasons related to COVID-19 (excluding COVID-19 infection) were considered missing. e Subjects who had an unevaluable biopsy at Weeks I-24 (i.e., a biopsy that was taken but could not be evaluated due to sample preparation or technical error) or who lacked either the endoscopic subscore or the histologic component for this endpoint (i.e., assessment of neutrophils, crypt destruction, or erosion or ulceration or granulation in the epithelium) were considered to have not achieved histologic-endoscopic mucosal healing.

[0257] [Table 26] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. aIncludes data through Week I-12 for subjects who received treatment during Week I-12. Includes all data through the final safety visit for subjects who did not receive treatment during Week I-12. b Includes data from week I-12 onwards. c After first guselkumab IV dose; for subjects who received guselkumab 200 mg SC during weeks I-12, data through weeks I-12 are included. d After the first dose of guselkumab. e Adverse events assessed by the investigator as possibly, probably, or very likely related to the study drug, or unrelated to the study drug. f Infectious diseases assessed by the investigator. g Injection site reactions assessed by the investigator.

[0258] 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 study. The target population consists of participants with moderately to severely active ulcerative colitis (UC) who have responded inadequately to or been intolerant of conventional treatment (i.e., 6-mercaptopurine [6-MP], azathioprine [AZA], or corticosteroids) or advanced therapies (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 to 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 modified following feedback from health authorities so that the target population should be based only on participants with a modified Mayo score of 5–9.

[0259] Treatment Assignment: Participants were randomized in a 3:2 ratio to guselkumab or placebo at Week I-0 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) Arm 2: Guselkumab 200 mg IV (weeks I-0, I-4, and I-8) Treatment Duration: The main portion of this study was 12 weeks.

[0260] This report provides results for the primary and key secondary endpoints at weeks I-12, as well as safety through weeks I-12.

[0261] 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.

[0262] Primary secondary endpoints: ● Symptom remission at weeks 1-12: stool frequency subscore 0 or 1, no increase from baseline, and rectal bleeding subscore 0. ● Endoscopic healing at weeks I-12: endoscopy subscore of 0 or 1 with no easy bleeding at endoscopy. ● Clinical response at weeks I-12: either ≥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 I-12: total IBDQ score ≥ 170. ● Histological-endoscopic mucosal healing at weeks I-12: achieving a combination of histological and endoscopic healing, where endoscopic healing is defined above and histological 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. ● Fatigue response at weeks I-12: improvement of ≥ 7 points on PROMIS-Fatigue short form 7a. ● Symptoms resolved in week I-2. ● Endoscopic normalization at weeks I-12: endoscopy subscore of 0

[0263] Power of 90% for all major secondary endpoints except for the endpoints of symptomatic resolution at week I-2 and endoscopic normalization at week I-12.

[0264] Statistical considerations: ● Efficacy analysis set: The full analysis set included all randomized participants with a modified Mayo score of 5 to 9 who received at least one (partial or full) dose of 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 included 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 dose (partial or full) of study intervention (irrespective of modified Mayo score), are also provided. Participants were analyzed according to the study intervention they actually received.

[0265] Intercurrent events (ICEs) were used for the analysis of efficacy endpoints. In particular, 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 19 (COVID-19)-related reasons (excluding COVID-19 infection) or experienced the regional crisis with 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 with Russia and Ukraine before the analysis time point, we used their observations, if available (i.e., treatment-directed strategy).

[0266] Comparisons were based on guselkumab versus placebo. For the primary and key secondary endpoints, p-values ​​were based on the Cochran-Mantel-Haenszel (CMH) test (two-sided) stratified by ADT failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no). 95% confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. For these endpoints, participants who were missing data at the time of analysis (after accounting for the intercurrent events strategy) were considered non-responders at that time.

[0267] Most important results summary A total of 735 participants were randomized and dosed 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 who was randomized to the placebo group but never received the study intervention. Of the randomized and treated participants, 701 (95.4%) participants had a modified Mayo score of 5 to 9 (the target population used for the efficacy and safety analyses below).

[0268] Disposition and baseline characteristics of the full analysis set (n=701): Overall, 42 (6.0%) participants discontinued the study intervention before Week I-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 I-12 were adverse events (2.4%; 1.4% due to worsening UC) and participant discontinuation (2.3%).

[0269] The majority of participants were white (72.5%), and 56.9% of participants 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 treatment ("ADT non-failures"), and 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.

[0270] The population enrolled in this study represents a population with moderate to severe 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 was 1641.0 mg / kg, and the median C-reactive protein (CRP) concentration was 4.2 mg / L. At baseline, 47.8% of participants had extensive disease, 82.2% of participants had moderate UC (i.e., Mayo score ≥6 and ≤10), 17.8% had severe disease (Mayo score >10), 32.1% of participants had an endoscopy subscore of 2 (i.e., moderate disease), and 67.9% of participants had an endoscopy subscore of 3 (i.e., severe disease).

[0271] Baseline demographics (including region), disease characteristics, concomitant UC medications, and UC medication history were generally well balanced between treatment groups.

[0272] Summary of efficacy endpoints: Based on multiple prespecified study procedures, guselkumab induction treatment resulted in a significantly higher proportion of participants achieving clinical remission at weeks I-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 26).

[0273] Compared with placebo, guselkumab induction treatment also significantly increased the proportion of participants achieving the primary secondary endpoint (highly significant, p<0.001).

[0274] PRIMARY ENDPOINT: Based on the primary analysis of clinical remission at Weeks I-12, a significantly higher proportion of participants in the 200 mg IV guselkumab group (22.6%) 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 26).

[0275] Primary secondary endpoints: Based on both global and US-specific testing procedures, the 200 mg IV guselkumab group had significantly higher rates of symptomatic remission (adjusted treatment difference: 29.5% [95% CI: 22.9%, 36.1%]; Table 35), endoscopic healing (adjusted treatment difference: 16.0% [95% CI: 10.5%, 21.4%]; Table 29), clinical response (adjusted treatment difference: 34.2% [95% CI: 27.3%, 41.1%]; Table 27), histologic-endoscopic mucosal healing (adjusted treatment difference: 34.2% [95% CI: 27.3%, 41.1%]; Table 27), and histologic-endoscopic mucosal healing (adjusted treatment difference: 34.2% [95% CI: 27.3%, 41.1%]; Table 28). The proportion of participants who achieved a fatigue response (adjusted treatment difference: 19.8% [95% CI: 13.1%, 26.4%]; Table 34), and symptom remission (adjusted treatment difference: 10.3% [95% CI: 4.8%, 15.7%]) at week I-12 and week I-4 were significantly higher in the placebo group compared to the placebo group (Table 35). Based on intent-to-treat procedures, a significantly higher proportion of participants achieved IBDQ remission at weeks I-12 in the 200 mg IV guselkumab group (adjusted treatment difference: 22.1% [95% CI: 15.1%, 29.2%]; Table 32). Note that IBDQ remission at weeks I-12 was not considered a primary secondary endpoint in US-specific testing procedures. ● The 200 mg IV guselkumab group was not significantly different from the placebo group in symptom remission at week I-2 (adjusted treatment difference: 3.0% [95% Cl: -1.5%, 7.5%]; Table 35). ● A higher proportion of participants achieved endoscopic normalization at Week I-12 in the 200 mg IV guselkumab group compared with the placebo group (adjusted treatment difference: 10.1% [95% CI: 5.9%, 14.3%]; Table 28), but statistical significance could not be claimed for this endpoint because the previous endpoint in the study hierarchy (symptomatic remission at Week I-2) was not significant. ● Separation between the guselkumab and placebo groups for symptom remission was observed as early as 4 weeks after the first dose and continued through weeks I-12 (Table 35).

[0276] 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 I-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 I-12, the treatment effect (vs. placebo) was greater in the ADT non-failure subgroup compared with the ADT failure subgroup.

[0277] Safety: Table 38 provides an overall summary of adverse events from Weeks I-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.

[0278] Safety data from Weeks I-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. • 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 (three [0.7%] in the 200 mg IV guselkumab group and one [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 I-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).

[0279] [Table 27] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Clinical remission was 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, where the stool frequency subscore has not increased from the induction baseline. bIntercurrent Event (ICE) Strategy: Subjects who were prohibited from changing UC medication (ICE1), underwent ostomy or colectomy (ICE2), or discontinued study drug due to lack of efficacy or worsening UC AEs (ICE3) before week I-12 were considered not in clinical remission at week I-12. For subjects who discontinued study drug due to COVID-19 related reasons (excluding COVID-19 infection) or local crisis (ICE4) before week I-12, we use those observations if available. Subjects who experienced ICE5 (discontinued study drug for reasons other than ICE3 and 4) before week I-12 were considered not in clinical remission at week I-12. c Non-responder imputation for missing data: After accounting for ICE, subjects who were missing one or more Mayo subscores for this endpoint (stool frequency, rectal bleeding, or endoscopy) at weeks I-12 were considered not in clinical remission. d Confidence intervals for the proportion of subjects meeting the endpoint in each treatment group were based on normal approximation confidence limits. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f P values ​​were based on Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0280] [Table 28] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Clinical response was defined as a ≧30% and ≧2 point reduction from baseline in the derived modified Mayo score, with a ≧1 point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1. bIntercurrent Event (ICE) Strategy: Subjects who were prohibited from changing UC medication (ICE1), underwent ostomy or colectomy (ICE2), or discontinued study drug due to lack of efficacy or worsening UC AEs (ICE3) before week I-12 were considered to be in clinical non-response at week I-12. For subjects who discontinued study drug due to COVID-19 related reasons (excluding COVID-19 infection) or local crisis (ICE4) before week I-12, their observations will be used if available. Subjects who experienced ICE5 (discontinued study drug for reasons other than ICE3 and 4) before week I-12 were considered to be in clinical non-response at week I-12. c Non-responder imputation for missing data: After accounting for ICE, subjects who were missing one or more Mayo subscores for this endpoint (stool frequency, rectal bleeding, or endoscopy) at weeks I-12 were considered to be non-clinical responders. d Confidence intervals for the proportion of subjects meeting the endpoint in each treatment group were based on normal approximation confidence limits. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f P values ​​were based on Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0281] [Table 29] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Endoscopic normalization is defined as an endoscopy subscore of 0. bIntercurrent Event (ICE) Strategy: Subjects who were prohibited from changing UC medication (ICE1), underwent ostomy or colectomy (ICE2), or discontinued study drug due to lack of efficacy or UC worsening AE (ICE3) before week I-12 were considered not to have achieved endoscopic normalization at week I-12. For subjects who discontinued study drug due to COVID-19 related reasons (excluding COVID-19 infection) or local crisis (ICE4) before week I-12, we use those observations if available. Subjects who experienced ICE5 (discontinued study drug for reasons other than ICE3 and 4) before week I-12 were considered not to have achieved endoscopic normalization at week I-12. c Non-responder imputation for missing data: After accounting for ICE, subjects who were missing endoscopy subscores at weeks I-12 were considered to have not achieved endoscopic normalization. d Confidence intervals for the proportion of subjects meeting the endpoint in each treatment group were based on normal approximation confidence limits. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f P values ​​were based on Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0282] [Table 30] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Endoscopic cure is defined as an endoscopy subscore of 0 or 1 with no bleeding tendency present at the time of endoscopy. bIntercurrent Event (ICE) Strategy: Subjects who were prohibited from changing UC medication (ICE1), underwent ostomy or colectomy (ICE2), or discontinued study drug due to lack of efficacy or UC worsening AE (ICE3) before week I-12 were considered not to have achieved endoscopic cure at week I-12. For subjects who discontinued study drug due to COVID-19 related reasons (excluding COVID-19 infection) or local crisis (ICE4) before week I-12, we use those observations if available. Subjects who experienced ICE5 (discontinued study drug for reasons other than ICE3 and 4) before week I-12 were considered not to have achieved endoscopic cure at week I-12. c Non-responder imputation for missing data: After accounting for ICE, subjects who were missing endoscopy subscores at weeks I-12 were considered to have not achieved endoscopic cure. d Confidence intervals for the proportion of subjects meeting the endpoint in each treatment group were based on normal approximation confidence limits. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f P values ​​were based on Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0283] [Table 31] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a 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. bIntercurrent Event (ICE) Strategy: Subjects who were prohibited from changing UC medication (ICE1), underwent ostomy or colectomy (ICE2), or discontinued study drug due to lack of efficacy or UC worsening AEs (ICE3) before week I-12 were considered not to have achieved histologic healing at week I-12. For subjects who discontinued study drug due to COVID-19 related reasons (excluding COVID-19 infection) or local crisis (ICE4) before week I-12, we use those observations if available. Subjects who experienced ICE5 (discontinued study drug for reasons other than ICE3 and 4) before week I-12 were considered not to have achieved histologic healing at week I-12. c Non-responder imputation for missing data: After accounting for ICE, subjects who had an unevaluable biopsy at Weeks I-12 (i.e., a biopsy that was taken but could not be evaluated due to sample preparation or technical error) or who were missing any of the components for this endpoint (i.e., assessment of neutrophils, crypt destruction, or erosion or ulceration or granulation in the epithelium) were considered to have not achieved histologic cure. d Confidence intervals for the proportion of subjects meeting the endpoint in each treatment group were based on normal approximation confidence limits. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f P values ​​were based on Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0284] [Table 32] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. aHistologic remission is defined as disappearance of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes grading system. This definition corresponds to a Robart Histopathology Index ≦3 with subscores of 0 for lamina propria neutrophils and epithelium neutrophils, and no ulceration or erosion. b Intercurrent Event (ICE) Strategy: Subjects who were prohibited from changing UC medication (ICE1), underwent ostomy or colectomy (ICE2), or discontinued study drug due to lack of efficacy or worsening UC AEs (ICE3) before week I-12 were considered not in histologic remission at week I-12. For subjects who discontinued study drug due to COVID-19 related reasons (excluding COVID-19 infection) or local crisis (ICE4) before week I-12, we use those observations if available. Subjects who experienced ICE5 (discontinued study drug for reasons other than ICE3 and 4) before week I-12 were considered not in histologic remission at week I-12. c Non-responder imputation for missing data: After accounting for ICE, subjects who had an unevaluable biopsy at Weeks I-12 (i.e., a biopsy that was taken but could not be evaluated due to sample preparation or technical error) or who lacked any of the histologic components for this endpoint (i.e., assessment of neutrophils, crypt destruction, or erosion or ulceration or granulation in the lamina propria or epithelium) were considered not in histologic response. d Confidence intervals for the proportion of subjects meeting the endpoint in each treatment group were based on normal approximation confidence limits. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f P values ​​were based on Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0285] [Table 33] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a IBDQ (Inflammatory Bowel Disease Questionnaire) remission is defined as a total IBDQ score ≧170. b Intercurrent Event (ICE) Strategy: Subjects who were prohibited from changing UC medication (ICE1), underwent ostomy or colectomy (ICE2), or discontinued study drug due to lack of efficacy or UC worsening AEs (ICE3) before week I-12 were considered not in IBDQ remission at week I-12. For subjects who discontinued study drug due to COVID-19 related reasons (excluding COVID-19 infection) or local crisis (ICE4) before week I-12, we use those observations if available. Subjects who experienced ICE5 (discontinued study drug for reasons other than ICE3 and 4) before week I-12 were considered not in IBDQ remission at week I-12. c Non-responder imputation for missing data: After accounting for ICE, subjects who were missing an IBDQ total score at weeks I-12 were considered not in IBDQ remission. d Confidence intervals for the proportion of subjects meeting the endpoint in each treatment group were based on normal approximation confidence limits. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f P values ​​were based on Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0286] [Table 34] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Histologic-endoscopic mucosal healing is defined as achieving a combination of histologic and endoscopic healing. 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 healing is defined as an endoscopy subscore of 0 or 1 with no bleeding tendency present during endoscopy. b Intercurrent Event (ICE) Strategy: Subjects who were prohibited from changing UC medication (ICE1), underwent ostomy or colectomy (ICE2), or discontinued study drug due to lack of efficacy or UC worsening AEs (ICE3) before week I-12 were considered not to have achieved histologic-endoscopic mucosal healing at week I-12. For subjects who discontinued study drug due to COVID-19 related reasons (excluding COVID-19 infection) or local crisis (ICE4) before week I-12, we use those observations if available. Subjects who experienced ICE5 (discontinued study drug for reasons other than ICE3 and 4) before week I-12 were considered not to have achieved histologic-endoscopic mucosal healing at week I-12. c Non-responder imputation for missing data: After accounting for ICE, subjects who had an unevaluable biopsy at Weeks I-12 (i.e., a biopsy that was taken but could not be evaluated due to sample preparation or technical error) or who were missing either the endoscopic subscore or the histologic component for this endpoint (i.e., assessment of neutrophils, crypt destruction, or erosion or ulceration or granulation in the epithelium) were considered to have not achieved histologic-endoscopic mucosal healing. d Confidence intervals for the proportion of subjects meeting the endpoint in each treatment group were based on normal approximation confidence limits. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. f P values ​​were based on Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0287] [Table 35] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Fatigue response is defined as a ≥ 7-point improvement from baseline on the PROMIS (Patient-Reported Outcomes Measurement Information System) Fatigue Short Form 7a. b Intercurrent Event (ICE) Strategy: Subjects who were prohibited from changing UC medication (ICE1), underwent ostomy or colectomy (ICE2), or discontinued study drug due to lack of efficacy or UC worsening AEs (ICE3) before week I-12 were considered to be non-fatigue responders at week I-12. For subjects who discontinued study drug due to COVID-19 related reasons (excluding COVID-19 infection) or local crisis (ICE4) before week I-12, their observations will be used if available. Subjects who experienced ICE5 (discontinued study drug for reasons other than ICE3 and 4) before week I-12 were considered to be non-fatigue responders at week I-12. c Non-responder imputation for missing data: After accounting for ICE, subjects who were missing one or more of the PROMIS Fatigue Short Form 7a items at either induction baseline or weeks I-12 were considered to be non-fatigue responders. d Confidence intervals for the proportion of subjects meeting the endpoint in each treatment group were based on normal approximation confidence limits. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. fP values ​​were based on Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0288] [Table 36] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a Symptom remission was defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, where the stool frequency subscore has not increased from the induction baseline. b Intercurrent Event (ICE) Strategy: Subjects who were prohibited from changing UC medication (ICE1), underwent ostomy or colectomy (ICE2), or discontinued study drug due to lack of efficacy or UC-worsening AEs (ICE3) prior to the designated time point were considered not in symptom remission at the designated time point. For subjects who discontinued study medication due to COVID-19 related reasons (excluding COVID-19 infection) or community crisis (ICE4) before the designated time point, those observations will be used if available. Subjects who experienced ICE5 (discontinued study medication for reasons other than ICE3 and 4) before the designated time point were considered not in symptom remission at the designated time point. c Non-responder imputation for missing data: After accounting for ICE, subjects who were missing one or more Mayo subscores (stool frequency and / or rectal bleeding) for this endpoint at a specified time point were considered not in symptom remission. d Confidence intervals for the proportion of subjects meeting the endpoint in each treatment group were based on normal approximation confidence limits. e Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. fP values ​​were based on Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0289] [Table 37-1]

[0290] [Table 37-2] Legend: ADT=Advanced Treatment; IBDQ=Inflammatory Bowel Disease Questionnaire; PROMIS=Patient-Reported Outcomes Measurement Information System. NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a1 Clinical remission was 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, where the stool frequency subscore has not increased from the induction baseline. a2 Symptom remission was defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, where the stool frequency subscore has not increased from the induction baseline. a3 Endoscopic cure is defined as an endoscopy subscore of 0 or 1 with no bleeding tendency present at the time of endoscopy. a4 Clinical response was defined as a ≧30% and ≧2 point reduction from baseline in the derived modified Mayo score, with a ≧1 point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1. a5 IBDQ remission is defined as a total IBDQ score ≥ 170. a6 Histologic-endoscopic mucosal healing is defined as achieving a combination of histologic and endoscopic healing. a7Fatigue response is defined as a ≥ 7 point improvement from baseline on the PROMIS Fatigue Short Form 7a. a8 Endoscopic normalization is defined as an endoscopy subscore of 0. a9 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. a10 Histologic response is defined as disappearance of neutrophils from the mucosa (both the lamina propria and epithelium), no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes grading system. a11 Histologic-endoscopic mucosal healing (alternative definition 1) is defined as achieving a combination of histologic resolution and endoscopic healing. a12 Deep histologic-endoscopic mucosal healing is defined as achieving a combination of endoscopic normalization and histologic remission. b The denominator is subjects who did not fail ADT. c Intercurrent Event (ICE) Strategy: Subjects who were prohibited from changing UC medication (ICE1), underwent ostomy or colectomy (ICE2), or discontinued study drug due to lack of efficacy or UC worsening AE (ICE3) before the designated time point were considered not to have achieved any of the key efficacy endpoints indicated at the designated time point. For subjects who discontinued study drug due to COVID-19 related reasons (excluding COVID-19 infection) or local crisis (ICE4) before the designated time point, those observations will be used if available. Subjects who experienced ICE5 (discontinued study drug for reasons other than ICE3 and 4) before the designated time point were considered not to have achieved any of the key efficacy endpoints indicated at the designated time point. dNon-responder imputation for missing data: After accounting for ICE, subjects who were missing one or more of the endpoint-related components at a specified time point were considered to have not achieved the endpoint. Subjects who received non-evaluable biopsies (i.e., biopsies that were taken but could not be evaluated due to sample preparation or technical errors) were considered to have not achieved the histological endpoint. e Confidence intervals for the proportion of subjects meeting the endpoint in each treatment group were based on normal approximation confidence limits. f Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. g P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test and stratified by concomitant corticosteroid use at baseline (yes / no).

[0291] [Table 38-1]

[0292] [Table 38-2] Legend: IBDQ = Inflammatory Bowel Disease Questionnaire; PROMIS = Patient-Reported Outcomes Measurement Information System. NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. a1 Clinical remission was 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, where the stool frequency subscore has not increased from the induction baseline. a2 Symptom remission was defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, where the stool frequency subscore has not increased from the induction baseline. a3Endoscopic cure is defined as an endoscopy subscore of 0 or 1 with no bleeding tendency present at the time of endoscopy. a4 Clinical response was defined as a ≧30% and ≧2 point reduction from baseline in the derived modified Mayo score, with a ≧1 point reduction from baseline in the rectal bleeding subscore, or a rectal bleeding subscore of 0 or 1. a5 IBDQ remission is defined as a total IBDQ score ≥ 170. a6 Histologic-endoscopic mucosal healing is defined as achieving a combination of histologic and endoscopic healing. a7 Fatigue response is defined as a ≥ 7 point improvement from baseline on the PROMIS Fatigue Short Form 7a. a8 Endoscopic normalization is defined as an endoscopy subscore of 0. a9 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. a10 Histologic response is defined as disappearance of neutrophils from the mucosa (both the lamina propria and epithelium), no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes grading system. a11 Histologic-endoscopic mucosal healing (alternative definition 1) is defined as achieving a combination of histologic resolution and endoscopic healing. a12 Deep histologic-endoscopic mucosal healing is defined as achieving a combination of endoscopic normalization and histologic remission. b The denominator is subjects who had biological failure. cIntercurrent Event (ICE) Strategy: Subjects who were prohibited from changing UC medication (ICE1), underwent ostomy or colectomy (ICE2), or discontinued study drug due to lack of efficacy or UC worsening AE (ICE3) before the designated time point were considered not to have achieved any of the key efficacy endpoints indicated at the designated time point. For subjects who discontinued study drug due to COVID-19 related reasons (excluding COVID-19 infection) or local crisis (ICE4) before the designated time point, those observations will be used if available. Subjects who experienced ICE5 (discontinued study drug for reasons other than ICE3 and 4) before the designated time point were considered not to have achieved any of the key efficacy endpoints indicated at the designated time point. d Non-responder imputation for missing data: After accounting for ICE, subjects who were missing one or more of the endpoint-related components at a specified time point were considered to have not achieved the endpoint. Subjects who received non-evaluable biopsies (i.e., biopsies that were taken but could not be evaluated due to sample preparation or technical errors) were considered to have not achieved the histological endpoint. e Confidence intervals for the proportion of subjects meeting the endpoint in each treatment group were based on normal approximation confidence limits. f Adjusted treatment differences and confidence intervals were based on the Wald statistic with Cochran-Mantel-Haenszel weights. g P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test and stratified by concomitant corticosteroid use at baseline (yes / no).

[0293] [Table 39] NOTE: Only include subjects with a modified Mayo score of 5–9 at induction baseline. aAdverse events assessed by the investigator as possibly, probably, or very likely related to the study drug, or unrelated to the study drug. b Infections were defined as any adverse event coded to the MedDRA system organ class "infections and infestations."

[0294] 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, 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 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 The method comprises 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 a first dose, at a dose about 4 weeks after the first dose, and at a dose about 8 weeks after the first dose. 3. The use of embodiment 2, wherein the first dose and the dose about 4 weeks after the first dose and about 8 weeks after the first 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, (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, with the stool frequency subscore not increasing from induction baseline; (ii) symptomatic remission, 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; (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) endoscopic normalization, defined as an endoscopy subscore of 0 (requiring the absence of easy bleeding). 7. The use according to embodiment 5 or 6, wherein the clinical endpoint is measured at about 4, 8, 12, 16, 20, 28, 32, 36, 40, 44, and / or 48 weeks after the initial treatment. 8. The use of embodiment 7, wherein the clinical endpoint is measured about 12 weeks after the initial treatment. 9. 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. 10. The use according to 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. 11. The use according to embodiment 9 or 10, wherein the antibody is 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. 12. The use according to embodiment 9 or 10, wherein an antibody is further administered to the patient. 13. The use of embodiment 12, wherein the antibody is administered subcutaneously in a dose of 100 mg or 200 mg. 14. 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 ≧1 point reduction from baseline in rectal bleeding subscore or a ≧30% and ≧2 point reduction from derived baseline in modified Mayo score accompanied by either a rectal bleeding subscore of 0 or 1. 15. The use according to embodiment 14, wherein an antibody specific for IL23 is additionally administered to the patient. 16. The use of embodiment 15, wherein the antibody is administered 12 weeks after the first treatment. 17. The use according to embodiment 16, wherein the antibody is administered 12 weeks after the first treatment, 16 weeks after the first treatment and 20 weeks after the first treatment. 18. The use of embodiment 17, wherein the antibody is administered subcutaneously in a dose of 200 mg. 19. The use of embodiment 18, 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 rectal bleeding subscore or a ≧30% and ≧2 point reduction from derived baseline in modified Mayo score accompanied by either a rectal bleeding subscore of 0 or 1. 20. 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 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; (ii) symptomatic remission, 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; (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) endoscopic normalization, defined as an endoscopy subscore of 0 (requiring the absence of easy bleeding). 21. The use according to embodiment 19 or 20, wherein the clinical endpoint is measured about 24 weeks after the initial treatment. 22. The use according to embodiment 19 or 20, wherein an antibody specific for IL23 is further administered to the patient every 4 weeks or every 8 weeks thereafter. 23. The use of embodiment 14, 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. 24. The use according to embodiment 14, 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. 25. The use according to embodiment 23 or 24, wherein the antibody is 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. 26. The use according to any of embodiments 1 to 25, further comprising the use of one or more additional agents used to treat ulcerative colitis. 27. The use of embodiment 26, wherein the additional agent is selected from the group consisting of immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface marker antibodies, anti-CD20 antibodies, rituximab, TNF inhibitors, corticosteroids, and costimulatory regulators. 28. The use according to embodiment 1, wherein the patient is considered to have failure or intolerance (Bio-Failure) of biological therapy for ulcerative colitis prior to treatment with an antibody specific for IL23. 29. The use according to embodiment 1, wherein the patient is considered to have failed or intolerant (Con-Failure) of conventional treatments for ulcerative colitis prior to treatment with an antibody specific for IL23. 30. The use according to embodiment 1, wherein the ulcerative colitis is moderately to severely active ulcerative colitis. 31. The use according to embodiment 30, wherein the patient has endoscopic evidence of active Crohn's disease prior to administration of the first dose. 32. The use of embodiment 31, 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. 33. Use of an antibody specific for IL23 to treat moderately to severely active ulcerative colitis in a patient, comprising: (i) an initial intravenous dose of 200 mg or 400 mg; (ii) intravenous administration of 200 mg or 400 mg of the antibody about 4 weeks after the initial dose; and (iii) intravenous administration of 200 mg or 400 mg of the antibody about 8 weeks after the initial dose, wherein the antibody comprises 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, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint about 12 weeks after the initial dose, the clinical endpoint being a clinical response defined as a ≧1 point reduction from baseline in 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. 34. The use according to embodiment 33, wherein the administration of the antibody specific for IL23 is a dose of 200 mg or 400 mg administered about 8 weeks after the first dose, followed by administration about every 4 weeks or every 8 weeks.

[0295] Sequence Listing

[0296] JPEG2024543885000045.jpg209132

[0297] JPEG2024543885000046.jpg214132

[0298] JPEG2024543885000047.jpg198159

[0299] JPEG2024543885000048.jpg221132

[0300] JPEG2024543885000049.jpg216132

[0301] JPEG2024543885000050.jpg162132

Claims

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

2. 10. The pharmaceutical composition 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 pharmaceutical composition 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 are 200 mg or 400 mg of the antibody.

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

5. 2. The pharmaceutical composition 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. 6. The pharmaceutical composition of claim 5, wherein the clinical endpoint is measured at about 4, 8, 12, 16, 20, 28, 32, 36, 40, 44, and / or 48 weeks after initial treatment.

8. 8. The pharmaceutical composition of claim 7, wherein the clinical endpoint is measured about 12 weeks after initial treatment.

9. The pharmaceutical composition of claim 7 , 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.

10. The pharmaceutical composition of claim 7 , 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.

11. 10. The pharmaceutical composition of claim 9, 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 normal conditions.

12. The pharmaceutical composition of claim 9, wherein the method further comprises administering to the patient an antibody specific to IL23.

13. 13. The pharmaceutical composition of claim 12, wherein the antibody is further administered subcutaneously in a dose of 100 mg or 200 mg.

14. 2. The pharmaceutical composition of claim 1, wherein the patient is identified as a non-responder to the antibody and does not meet 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.

15. The pharmaceutical composition of claim 14, wherein the method further comprises administering to the patient an antibody specific to IL23.

16. 16. The pharmaceutical composition of claim 15, wherein the antibody is administered 12 weeks after the initial treatment.

17. 17. The pharmaceutical composition of claim 16, wherein the antibody is administered 12 weeks after the initial treatment, 16 weeks after the initial treatment, and 20 weeks after the initial treatment.

18. 18. The pharmaceutical composition of claim 17, wherein the antibody is administered subcutaneously at a dose of 200 mg.

19. 19. The pharmaceutical composition of claim 18, 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.

20. The patient is identified as a responder to the antibody and meets a clinical endpoint, wherein the clinical endpoint is: (vi) 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; (vii) 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 induction baseline; (viii) endoscopic cure, defined as an endoscopy subscore of 0 or 1 with the absence of easy bleeding at endoscopy; (ix) 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 (x) Endoscopy normalized, defined as an endoscopy subscore of 0 (requiring the absence of easy bleeding).

21. 20. The pharmaceutical composition of claim 19, wherein the clinical endpoint is measured about 24 weeks after initial treatment.

22. The pharmaceutical composition of claim 19, wherein the method further comprises administering to the patient an antibody specific for IL23 every four weeks or every eight weeks thereafter.

23. The pharmaceutical composition of claim 14, 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.

24. 15. The pharmaceutical composition of claim 14, 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.

25. 24. The pharmaceutical composition of claim 23, 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 normal conditions.

26. A pharmaceutical composition described in any of claims 1 to 25, wherein the method further comprises administering to the patient one or more additional drugs used to treat ulcerative colitis.

27. 27. The pharmaceutical composition of claim 26, 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.

28. The pharmaceutical composition 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.

29. The pharmaceutical composition 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.

30. The pharmaceutical composition according to claim 1, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.

31. 31. The pharmaceutical composition of claim 30, wherein the patient has endoscopic evidence of active Crohn's disease prior to administration of the first dose.

32. 32. The pharmaceutical composition of claim 31 , 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.

33. 1. A pharmaceutical composition for use in a method for treating moderate to severely active ulcerative colitis in a patient, comprising: The pharmaceutical composition comprises an antibody specific for IL23; The method comprises administering to the patient: (i) an initial intravenous administration of 200 mg or 400 mg of an antibody specific for IL23; (ii) about 4 weeks after the initial administration, an intravenous administration of 200 mg or 400 mg of the antibody; and (iii) about 8 weeks after the initial administration, an intravenous administration of 200 mg or 400 mg of the antibody; the antibody comprises 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; the patient is a responder to the antibody as identified as meeting a clinical endpoint about 12 weeks after the first administration; The pharmaceutical composition, 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.

34. The pharmaceutical composition of claim 33, wherein the method further comprises administering the antibody specific to IL23 at a dose of 200 mg or 400 mg approximately every 4 weeks or 8 weeks thereafter, the dose being administered approximately 8 weeks after the initial dose.

Images