Methods of treating ulcerative colitis with anti-IL23 specific antibodies

Abstract

A method of treating ulcerative colitis in a patient by administering an IL-23-specific antibody, e.g., a coumarin, in an initial dose and a subsequent dose so that the patient responds to the antibody and satisfies one or more of the clinical endpoints.

Description

[0001] Reference sequence listing submitted electronically

[0002] The sequence listing of this application is submitted electronically via the United States Patent and Trademark Center Patent Center as an XML formatted sequence listing with a file name of "JBI6766WOPCT1SEQLIST.xml", a creation date of November 21, 2023, and a size of 11 kilobytes (KB). This submitted sequence listing is part of this specification and is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention relates to methods for treating ulcerative colitis with antibodies that bind to human IL23. Specifically, the present invention relates to dosing regimens for administering anti-IL23 specific antibodies and specific pharmaceutical compositions of the antibodies. Background Art

[0004] Interleukin (IL) -12 is a secreted heterodimeric cytokine composed of two disulfide-linked glycosylated protein subunits, named p35 and p40 according to their approximate molecular weight. IL-12 is primarily produced by antigen-presenting cells and drives cell-mediated immunity by binding to a two-chain receptor complex expressed on the surface of T cells or natural killer (NK) cells. The IL-12 receptor β-1 (IL-12Rβ1) chain binds to the p40 subunit of IL-12, providing the primary interaction between IL-12 and its receptor. However, it is the IL-12p35 connection 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, which occurs simultaneously with antigen presentation, is thought to cause T cells to differentiate into a T helper cell 1 (Th1) phenotype, characterized by the production of interferon gamma (IFNγ) (Trinchieri, 2003). Th1 cells are believed to promote immunity to some intracellular pathogens, produce complement-fixing antibody isotypes, and contribute to tumor immune surveillance. Therefore, IL-12 is considered an important component of the host defense immune mechanism.

[0005] It has been found that the p40 protein subunit of IL-12 can also associate with a separate protein subunit named p19 to form a new cytokine IL-23 (Oppman et al., 2000). IL-23 also signals through a two-chain receptor complex. Since the p40 subunit is shared between IL-12 and IL-23, the IL-12Rβ1 chain is also shared between IL-12 and IL-23. However, it is the IL-23p19 connection of the second component IL-23R of the IL-23 receptor complex that gives IL-23 specific intracellular signaling (e.g., STAT3 phosphorylation) and subsequent production of IL-17 by T cells (Parham et al., 2002; Aggarwal et al., 2003). Recent studies have confirmed that the biological functions of IL-23 are different from those of IL-12, despite the structural similarity between the two cytokines (Langrish et al., 2005).

[0006] Abnormal regulation of IL-12 and Th1 cell populations has been associated with many immune-mediated diseases, as neutralization of IL-12 with antibodies can effectively treat animal models of psoriasis, multiple sclerosis (MS), rheumatoid arthritis, inflammatory bowel disease, insulin-dependent (type 1) diabetes, and uveitis (Leonard et al., 1995; Hong et al., 1999; Malfait et al., 1998; Davidson et al., 1998). However, since these studies target the common p40 subunit, both IL-12 and IL-23 are neutralized in vivo. Therefore, it is unclear whether IL-12 or IL-23 mediates the disease, or whether inhibition of both cytokines is required to achieve disease suppression. Recent studies have confirmed that IL-23 inhibition can provide equivalent beneficial effects to anti-IL-12p40 strategies using IL-23p19-deficient mice or IL-23-specific antibody neutralization (Cua et al., 2003, Murphy et al., 2003, Benson et al., 2004).

[0007] Ulcerative colitis is a chronic inflammatory bowel disease of unknown etiology that affects the surface mucosa, crypt epithelium, and submucosa of the colon. Ulcerative colitis is most often diagnosed in late adolescence and early adulthood, but diagnosis may occur at any age. Clinically, patients with UC present with diarrhea, rectal bleeding, weight loss, abdominal pain, fever, and may also exhibit significant extraintestinal manifestations, most commonly arthritis. Ulcerative colitis is characterized by lifelong remissions and exacerbations, with 15% of patients experiencing acute exacerbations requiring hospitalization at some time during their illness. In severe UC, the intestinal wall may become extremely thin, the mucosa may become denuded, and inflammation may extend to the serosa, leading to dilatation, toxic megacolon, and subsequent perforation. Approximately 20% of adults with UC reportedly undergo colectomy within 10 years of diagnosis. 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) compared to currently available therapies.

[0008] The pathophysiology of inflammatory bowel disease (IBD), including UC, is complex and is considered to be multifactorial. The main purpose of drug therapy is to inhibit the inflammatory response, thereby relieving symptoms and promoting mucosal healing. The specific goals of IBD treatment include symptom control, reduction in long-term corticosteroid requirements, prevention of relapse and complications, and minimization of cancer risk (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. Erratumin: Am J Gastroenterol. 2010; 105(3):500.EDMS-ERI-156811382).

[0009] The role of IL-23 in promoting intestinal inflammation has been demonstrated in several mouse models, with attenuated colitis observed in mice treated with a neutralizing anti-IL-23p19 antibody or in mice with a genetic deletion of the p19 subunit of IL-23. Genome-wide association studies (GWAS) have identified polymorphisms in the IL-23 receptor gene (IL23R) that are associated with both risk and protection against IBD.

[0010] Therefore, there is growing evidence that IL-23 has a specific role in immune-mediated diseases. Therefore, neutralizing IL-23 without inhibiting the IL-12 pathway could provide an effective therapy for immune-mediated diseases with limited impact on important host defense immune mechanisms. This would represent a significant improvement over other treatment options.

[0011] Over the past 20 years, 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 are approved for the treatment of UC. Within the anti-TNFα 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 are currently approved for UC: Janus kinase (JAK) inhibitors and sphingosine-1-phosphate (S1P) receptor modulators.

[0012] However, despite substantial progress in advanced therapies as monotherapy, significant unmet needs remain in the treatment of UC. Even with the best approved therapy, more than half of patients fail to achieve clinical remission after 1 year. Among clinically asymptomatic UC patients, approximately 25% still have endoscopically active disease (Colombel JF et al., Discrepancies between patient-reported outcomes, and endoscopic and histological appearance in UC. Gut 2017; 66: 2063–2068). Therefore, it is not surprising that long-term colectomy rates have not decreased over 10 years (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), which highlights the need for more effective therapies and treatment paradigms. The efficacy platforms observed with monotherapy suggest the need for improved treatments to achieve higher long-term symptomatic and objective remission rates.

[0013] In summary, there remains a significant unmet medical need for new IBD and ulcerative colitis treatment options, particularly therapies with novel mechanisms of action that have the potential to raise the bar for efficacy and maximize the proportion of patients who achieve and maintain clinical remission. Summary of the Invention

[0014] In a first aspect, the present invention relates to a method of treating a subject (patient) suffering from ulcerative colitis, comprising administering to the patient an anti-IL-23 specific antibody (also referred to as IL23p19 or IL23p19 subunit antibody), such as guselkumab, at an initial induction dose from the start of treatment to 4 weeks after the start of treatment, and thereafter administering to the patient the anti-IL-23 specific antibody once every 4 weeks, for example, at a dose administered at week 0, week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 32, week 36, week 40, week 44, or week 48. In addition, in another embodiment, treatment is continued for up to 96 weeks or more after the start of treatment.

[0015] In one embodiment, the subject receives the anti-IL23-specific antibody as follows: (i) at a dose of 200 mg initially, 4 weeks after the initial intravenous administration, 8 weeks after the initial intravenous administration, and 12 weeks after the initial intravenous administration, and continues treatment with the anti-IL23-specific antibody, or (ii) at a dose of 400 mg initially, 4 weeks after the initial intravenous administration, 8 weeks after the initial intravenous administration, and 12 weeks after the initial intravenous administration, and continues treatment with the anti-IL23-specific antibody for potentially more than 12 weeks up to 24 weeks, 48 ​​weeks, 96 weeks, and longer.

[0016] In another aspect, the compositions for use in the methods of the present invention include pharmaceutical compositions comprising: an anti-IL23 specific antibody.

[0017] In one embodiment, the ulcerative colitis patient achieves a significant improvement in a clinical endpoint selected from:

[0018] (i) clinical response, defined as a decrease of ≥30% and ≥2 points in the modified Mayo Clinic score from the induction baseline,

[0019] Among them, the rectal bleeding subscore decreased by ≥1 point compared with the baseline or the rectal bleeding subscore was 0 or 1;

[0020] (ii) clinical remission at week 12, defined as stool frequency sub-scored as 0 or 1, rectal bleeding sub-scored as 0, and endoscopy sub-scored as 0 or 1 with absence of friability on endoscopy,

[0021] Among them, the defecation frequency subscore did not increase compared with the induction baseline;

[0022] (iii) symptom remission at week 12, defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, with no increase in the stool frequency subscore from induction baseline;

[0023] (iv) endoscopic healing at week 12, defined as an endoscopic subscore of 0 or 1 and the absence of endoscopic friability;

[0024] (v) histologic-endoscopic mucosal healing at week 12, defined as the achievement of a combination of histologic and endoscopic healing, where histologic healing was defined as neutrophil infiltration of <5% of crypts according to the Geboes grading system, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue;

[0025] (vi) Endoscopic normalization at week 12, defined as an endoscopic subscore of 0 (which requires the absence of friability).

[0026] In one embodiment of the present invention, patients who have received an anti-IL23-specific antibody and are judged not to be in clinical response at week 12 are treated with subcutaneous anti-IL23-specific antibody at weeks 12, 16, and 20 during an extended induction period, and the clinical response and other clinical endpoints are evaluated at week 24.

[0027] 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 composition comprising: 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; and 0.053% (w / v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water under standard conditions.

[0028] Another aspect of the method of the present invention comprises administering a pharmaceutical composition comprising 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 composition comprising: 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; and 0.053% (w / v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water under standard conditions.

[0029] Another aspect of the method of the present invention comprises administering a pharmaceutical composition comprising an isolated anti-IL-23-specific antibody having a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10, optionally in a composition comprising: 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; and 0.053% (w / v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water under standard conditions.

[0030] In yet another embodiment, the methods of the present invention comprise administering a pharmaceutical composition comprising the antibody guselkumab (available as a The antibody guselkumab is optionally in a composition comprising: 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; and 0.053% (w / v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water under standard conditions.

[0031] The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages will be apparent from the following detailed description, the accompanying drawings, and the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In the attached figure:

[0033] Figure 1 Schematic diagram of the Phase 2b / 3 clinical development program for guselkumab in ulcerative colitis.

[0034] Figure 2 are graphs showing clinical responses at week 12 and / or week 24.

[0035] Figure 3 is a graph showing the primary endpoint of clinical remission at week 44.

[0036] Figure 4 is a graph showing the primary and important secondary endpoints assessed at Week 44.

[0037] Figure 5 is a graph showing the proportion of participants with symptom remission by week 44.

[0038] Figure 6 A summary of the statistical significance of the primary and important secondary endpoints for each US testing procedure is shown.

[0039] Detailed Description of the Preferred Embodiments

[0040] As used herein, methods of treating a subject having ulcerative colitis comprise administering isolated, recombinant and / or synthetic anti-IL-23-specific human antibodies, as well as diagnostic and therapeutic compositions, methods and devices.

[0041] As used herein, "anti-IL-23 specific antibodies," "anti-IL-23 antibodies," "antibody portions," "antibody fragments," and / or "antibody variants" include any protein or peptide comprising at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one complementarity determining region (CDR) of a heavy or light chain, or a ligand-binding portion thereof, a heavy or light chain variable region, a heavy or light chain constant region, a framework region, or any portion thereof, or at least a portion of an IL-23 receptor or binding protein that can bind to an antibody of the invention. Such antibodies optionally further affect specific ligands, such as, but not limited to, such antibodies modulate, decrease, increase, antagonize, agonize, moderate, mitigate, block, inhibit, abrogate, and / or interfere with at least one IL-23 activity or binding, or IL-23 receptor activity or binding, in vitro, in situ, and / or in vivo. As a non-limiting example, 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 may also optionally affect at least one of IL-23 activities or functions, such as, 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.

[0042] The term "antibody" is also intended to encompass antibodies, digested fragments, specified portions, and variants thereof, including antibody mimetics or portions of antibodies comprising structures and / or functions that mimic an antibody or specified fragments or portions thereof, including single-chain antibodies and fragments thereof. Functional fragments include antigen-binding fragments that bind to mammalian IL-23. For example, the present invention encompasses antibody fragments capable of binding to IL-23 or a portion thereof, including but not limited to Fab fragments (e.g., obtained by papain digestion), Fab' fragments (e.g., obtained by pepsin digestion and partial reduction), and F(ab')2 fragments (e.g., obtained by pepsin digestion), facb fragments (e.g., obtained by plasmin digestion), pFc' fragments (e.g., obtained by pepsin or plasmin digestion), Fd fragments (e.g., obtained by pepsin digestion, partial reduction, and reaggregation), Fv or scFv fragments (e.g., obtained by molecular biology techniques) (see, e.g., Colligan, Immunology, supra).

[0043] Such fragments can be produced by enzymatic cleavage, synthesis or recombinant techniques, as known in the art and / or as described herein. Antibodies can also be produced in various truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, a combination gene encoding a F(ab')2 heavy chain portion can be designed to include a C sequence encoding a heavy chain. H The various portions of the antibody can be chemically linked together using conventional techniques, or can be prepared as a contiguous protein using genetic engineering techniques.

[0044] As used herein, the term "human antibody" refers to antibodies in which substantially every portion of the protein (e.g., CDRs, framework, C L 、C H Domain (e.g. C H 1. C H 2. C H 3) Hinge (V L 、V H )) is essentially non-immunogenic in humans, with only small sequence changes or alterations. "Human antibodies" can also be antibodies derived from human germline immunoglobulin sequences or closely matched thereto. Human antibodies can include amino acid residues that are not encoded by germline immunoglobulin sequences (e.g., mutations introduced in vitro by random mutagenesis or site-specific mutagenesis, or mutations introduced in vivo by somatic mutation). Generally, this means that human antibodies are essentially non-immunogenic in humans. Human antibodies have been classified into groups based on their amino acid sequence similarity. Therefore, using sequence similarity searches, antibodies with similar linear sequences can be selected as templates to produce human antibodies. Similarly, antibodies designated as primates (monkeys, baboons, chimpanzees, etc.), rodents (mice, rats, rabbits, guinea pigs, hamsters, etc.) and other mammals represent specific antibodies of these species, subgenus, genus, subfamily, and family. In addition, chimeric antibodies can include any combination of the above antibodies. Such changes or alterations optionally and preferably maintain or reduce immunogenicity in humans or other species relative to unmodified antibodies. Thus, human antibodies are distinguished from chimeric or humanized antibodies.

[0045] It should be noted that human antibodies can be produced by non-human animals or prokaryotic or eukaryotic cells that can express functionally rearranged human immunoglobulin (e.g., heavy chain and / or light chain) genes. In addition, when the human antibody is a single-chain antibody, it may include a connecting peptide that is not present in natural human antibodies. For example, Fv may include a connecting peptide that connects the heavy chain variable region and the light chain variable region, such as two to about eight glycine or other amino acid residues. Such connecting peptides are considered to be human.

[0046] Bispecific antibodies, heterospecific antibodies, heterogeneous conjugated antibodies or similar antibodies can also be used, which are monoclonal antibodies with binding specificity for at least two different antigens, preferably human antibodies or humanized antibodies. In this case, one of the binding specificities is directed against at least one IL-23 protein and the other is directed against any other antigen. Methods for preparing bispecific antibodies are known in the art. Generally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, wherein the two heavy chains have different specificities (Milstein and Cuello, Nature 305:537 (1983)). Due to the random distribution of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a mixture of 10 possible different antibody molecules, only one of which has the correct bispecific structure. Purification of the correct molecule (usually performed by affinity chromatography steps) is quite tedious, and the product yield is low. Similar procedures are disclosed in, for example, WO 93 / 08829, U.S. Patents 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, 5,932,448, 5,833,985, 5,821,333, 5,807,706, 5,643,759, 5,601,819, 5,582,996, 5,496,549, 4,676,980, WO 91 / 00360, WO 92 / 00373, EP 03089, Traunecker et al., EMBO J. 10:3655 (1991), Suresh et al., Methods in Enzymology 121:210 (1986), each of which is herein incorporated by reference in its entirety.

[0047] Anti-IL-23-specific antibodies (also referred to as IL-23-specific antibodies) (or anti-IL-23 antibodies) useful in the methods and compositions of the present invention may optionally have the following characteristics: they bind to IL-23 with high affinity and optionally and preferably have low toxicity. Specifically, the antibodies, specified fragments, or variants of the present invention (in which the individual components, such as the variable region, constant region, and framework region, individually and / or collectively, optionally and preferably have low immunogenicity) may be used in the present invention. The antibodies useful in the present invention may optionally be characterized by their ability to treat patients long-term, measurably reduce symptoms, and have low and / or acceptable toxicity. Low or acceptable immunogenicity and / or high affinity, as well as other suitable properties, may contribute to achieving therapeutic outcomes. "Low immunogenicity" is defined herein as eliciting a significant HAHA, HACA, or HAMA response in less than about 75%, or preferably less than about 50%, of treated patients, and / or eliciting a low titer in treated patients (less than about 300, preferably less than about 100, as measured by a dual antigen enzyme immunoassay) (Elliott et al., Lancet 344: 1125-1127 (1994), which is incorporated herein by reference in its entirety). "Low immunogenicity" can also be defined as the incidence of titratable levels of anti-IL-23 antibodies in patients treated with anti-IL-23 antibodies during the treatment period occurring in less than 25% of patients treated with the recommended dose for the recommended course of therapy, preferably in less than 10% of patients treated with the recommended dose for the recommended course of therapy.

[0048] The term "safety," when used in connection with a dose, dosage regimen, treatment, or method of use of an anti-IL-23 antibody of the present invention (e.g., the anti-IL-23 antibody guselkumab), refers to a relatively low or reduced frequency and / or low or reduced severity of adverse events (referred to as AEs or TEAEs) occurring during treatment in a clinical trial conducted (e.g., a Phase 2 clinical trial and earlier clinical trials) compared to a standard of care or another comparator. An adverse event is an untoward medical occurrence in a patient administered a pharmaceutical product. Specifically, when used in connection with a dose, dosage regimen, or treatment of an anti-IL-23 antibody of the present invention, "safety" refers to a relatively low or reduced frequency and / or low or reduced severity of adverse events associated with the administration of the antibody if the cause is considered possibly, probably, or very likely to be due to the use of the anti-IL-23 antibody.

[0049] Utilities

[0050] The isolated nucleic acids of the present invention can be used to produce at least one anti-IL-23 antibody or a specified variant thereof, which can be used to measure or affect cells, tissues, organs, or animals (including mammals and humans) to diagnose, monitor, regulate, treat, alleviate, help prevent the occurrence of ulcerative colitis, or alleviate the symptoms of ulcerative colitis.

[0051] Such methods may comprise administering to a cell, tissue, organ, animal, or patient in need of such modulation, treatment, alleviation, prevention, or reduction of a symptom, effect, or mechanism, an effective amount of a composition or pharmaceutical composition comprising at least one anti-IL-23 antibody, The effective amount may comprise an amount of about 0.001 mg / kg to 500 mg / kg per single administration (e.g., bolus), multiple administrations, or continuous administration, or to achieve a serum concentration of 0.01 μg / ml to 5000 μg / ml per single administration, multiple administrations, or continuous administration, or any effective range or value therein, the effective amount being administered and determined using known methods as described herein or known in the relevant art.

[0052] Citation

[0053] All publications or patents cited herein, whether expressly stated or not, are hereby incorporated by reference in their entirety as they demonstrate the state of the art at the time of the present invention and / or provide a description and enablement of the present invention. A publication is any scientific publication or patent publication, or any other information available in any media format, including all recorded, electronic, or printed formats. The following references are incorporated herein by reference in their entirety: Ausubel et al., eds., "Current Protocols in Molecular Biology", John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook et al., "Molecular Cloning: A Laboratory Manual", 2nd ed., 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).

[0054] Antibodies of the invention—production and generation

[0055] As is well known in the art, the at least one anti-IL-23 antibody used in the methods of the present invention can optionally be produced by a cell line, a mixed cell line, an immortalized cell, or a clonal population of immortalized cells. See, for example, Ausubel et al., eds., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook et al., "Molecular Cloning: A Laboratory Manual," 2nd ed., Cold Spring Harbor, NY (1989); Harlow and Lane, "Antibodies, a Laboratory Manual," Cold Spring Harbor, NY (1989); Colligan et al., eds., "Current Protocols in Immunology," John Wiley & Sons, Inc., NY (1994-2001); Colligan et al., "Current Protocols in Protein Science," John Wiley & Sons, NY, NY (1997-2001), each of which is incorporated herein by reference in its entirety.

[0056] A preferred anti-IL-23 antibody is guselkumab (also known as CNTO1959), which has 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, and has heavy chain CDR amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3; and 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.

[0057] Human antibodies specific for human IL-23 protein or fragments thereof, such as isolated IL-23 protein and / or portions thereof (including synthetic molecules such as synthetic peptides), can be generated against appropriate immunogenic antigens. Other specific or general mammalian antibodies can be similarly generated. Preparation of immunogenic antigens and generation of monoclonal antibodies can be performed using any suitable technique.

[0058] In one approach, hybridomas are generated by fusion with a suitable immortalized cell line (e.g., a myeloma cell line such as, but not limited to, Sp2 / 0, Sp2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, L243, P3X63Ag8.653, Sp2 SA3, Sp2MAI, 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 2A, etc., or heteromyeloma, its fusion products, or any cell or fusion cell derived therefrom, or any other suitable cell line known in the art) (see, e.g., www.atcc.org, www.lifetech.com., etc.) and antibody-producing cells, such as but not limited to isolated or cloned spleen, peripheral blood, lymphoid, tonsil or other immune or B cell-containing cells, or any other cell expressing heavy or light chain constant or variable or framework or CDR sequences, as endogenous or heterologous nucleic acid, such as recombinant or endogenous, viral, bacterial, algae, prokaryotic, amphibian, insect, reptile, fish, mammal, rodent, horse, sheep, goat, sheep, primate, eukaryotic, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single-stranded, double-stranded or triple-stranded, hybrids, etc., or any combination thereof. See, e.g., Ausubel, supra, and Colligan, Immunology, supra, Chapter 2, which are incorporated herein by reference in their entireties.

[0059] Antibody-producing cells can also be obtained from the peripheral blood of people or other suitable animals immunized with the antigen of interest, or preferably spleen or lymph node. Any other suitable host cell can also be used for expressing heterologous or endogenous nucleic acids encoding the antibody of the present invention, its specific fragment or variant. Fusion cells (hybridomas) or recombinant cells can be separated using selective culture conditions or other suitable known methods, and can be cloned by limiting dilution or cell sorting or other known methods. The cell producing the antibody with required specificity can be selected by suitable assay method (e.g., ELISA).

[0060] Other suitable methods for producing or isolating antibodies with the requisite specificity may be used, including, but not limited to, methods for selecting recombinant antibodies from peptide or protein libraries (e.g., but not limited to, phage, ribosome, oligonucleotide, RNA, cDNA, etc. display libraries; e.g., available from Cambridge Antibody Technologies, Cambridgeshire, UK; MorphoSys, Martinsreid / Planegg, DE; Biovation, Aberdeen, Scotland, UK; BioInvent, Lund, Sweden; Dyax, Enzon, Affymax / Biosite; Xoma, Berkeley, CA; Ixsys).See e.g. EP 368,684, PCT / GB91 / 01134; PCT / GB92 / 01755; PCT / GB92 / 002240; PCT / GB92 / 00883; PCT / GB93 / 00 605; US08 / 350260(5 / 12 / 94); PCT / GB94 / 01422; PCT / GB94 / 02662; PCT / GB97 / 01835; (CAT / MRC); W O90 / 14443; WO90 / 14424; WO90 / 14430; PCT / US94 / 1234; WO92 / 18619; WO96 / 07754; (Scripps); WO9 6 / 13583, WO97 / 08320 (MorphoSys); WO95 / 16027 (BioInvent); WO88 / 06630; WO90 / 3809 (Dyax); US 4,704,692 (Enzon); PCT / US91 / 02989 (Affymax); WO89 / 06283; EP 371998; EP 550 400 (Xoma); EP 229 046; PCT / US91 / 07149 (Ixsys); or randomly generated peptides or proteins - US 5723323, 5763192, 5814476, 5817483, 5824514, 5976862, WO 86 / 05803, EP 590 689 (Ixsys, predecessor of Applied Molecular Biology Evolution (AME), each of which is incorporated herein by reference in its entirety)) or relying on immunization of transgenic animals (e.g., SCID mice, Nguyen et al., Microbiol. Immunol., 41:901-907 (1997); Sandhu et al., Crit. Rev. Biotechnol. 16:95-118 (1996); Eren et al., Immunol. 93:154-161 (1998), each of which is incorporated herein by reference in its entirety and related patents and applications) can produce a full repertoire of human antibodies, as known in the art and / or as described herein.Such techniques include, but are not limited to, 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 (November 1998)); single cell antibody generation 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 droplet and flow cytometry (Powell et al., Biotechnol. 8:333-337 (1990); One Cell Systems, Cambridge, MA; Gray et al., J. Imm. Meth. 182: 155-163 (1995); Kenny et al., Bio / Technol. 13: 787-790 (1995)); B cell selection (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)).

[0061] Also can be used for non-human or human antibody is carried out engineering or humanization method, these methods are well known in the art.Generally speaking, humanized or engineered antibody has one or more amino acid residues from non-human source, and this non-human source is for example but not limited to mouse, rat, rabbit, non-human primate or other mammal.They are generally taken from the "input" variable domain, constant domain or other domain of known human sequence.These non-human amino acid residues are replaced by the residue that is commonly referred to as "input" residue, and described residue is generally taken from the "input" variation, constant or other domain of known human sequence.

[0062] Known human Ig sequences are publicly available, for example, at www.ncbi.nlm.nih.gov / entrez / query.fcgi; www.ncbi.nih.gov / igblast; www.atcc.org / phage / hdb.html; www.mrc-cpe.cam.ac.uk / ALIGNMENTS.php; www.kabatdatabase.com / top.html; ftp.ncbi.nih.gov / repository / kabat; www.sciquest.com; www.abcam.com; www.antib odyresource.com / onlinecomp.html; www.public.iastate.edu / ~pedro / research_tools.html; www.whfreeman.com / immunology / CH05 / kuby05.htm; www.hhmi.org / grants / lectures / 1996 / vlab; www.path.cam.ac.uk / ~mrc7 / mikeimages.html; mcb.harvard.edu / BioLinks / Immunology.html; ww w.immunologylink.com; pathbox.wustl.edu / ~hcenter / index.html; www.appliedbiosystems.com; www.nal.usda.gov / awic / pubs / antibody; www. m.ehime-u.ac.jp / ~yasuhito / Elisa.html; www.biodesign.com; www.cancerresearchuk.org; www.biotech.ufl.edu; www.isac-net.org; baserv.u ci.kun.nl / ~jraats / links1.html; www.recab.uni-hd.de / immuno.bme.nwu.edu; www.mrc-cpe.cam.ac.uk; www.ibt.unam.mx / vir / V_mice.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,” U. S. Dept. Health (1983), each of which is incorporated herein by reference in its entirety.

[0063] Such imported sequences can be used to reduce immunogenicity or reduce, enhance or modify binding, affinity, on-rate, off-rate, avidity, specificity, half-life or any other suitable characteristic, as known in the art. Typically, the CDR residues are directly and substantially mostly involved in influencing antigen binding. Thus, some or all of the non-human CDR sequences or human CDR sequences are retained, while the non-human sequences of the variable and constant regions can be replaced with human amino acids or other amino acids.

[0064] Antibody can also optionally be designed to be retained to the humanization or people's antibody of high affinity and other favorable biological properties to antigen.In order to achieve this goal, humanized (or people) antibody can also optionally use the three-dimensional model of parent and humanized sequence to prepare by the analytical process of parental sequence and various conceptual humanized products.Three-dimensional immunoglobulin model is normally available and is familiar to those skilled in the art. The computer program that illustrates and shows the possible three-dimensional conformational structure of selected candidate immunoglobulin sequence is available. The detection of these displays makes it possible to analyze the possible effect of residue in the function performance of candidate immunoglobulin sequence, i.e., analyzes the residue that affects the ability of candidate immunoglobulin and its antigen combination. In this way, framework (FR) residues can be selected and combined from total and input sequence, thereby can realize required antibody characteristics, such as the affinity to the increase of target antigen.

[0065] In addition, the human IL-23-specific antibodies used in the methods of the present invention may include human germline light chain frameworks. In specific embodiments, the light chain germline sequences are selected from human VK sequences including, but not limited to, A1, A10, A11, A14, A17, A18, A19, A2, A20, A23, A26, A27, A3, A30, A5, A7, B2, B3, L1, L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23, L24, L25, L4 / 18a, L5, L6, L8, L9, O1, O11, O12, O14, O18, O2, O4, and O8. In certain embodiments, the light chain human germline framework is selected from the group consisting of: 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.

[0066] In other embodiments, the human IL-23-specific antibodies used in the methods of the present invention may include a human germline heavy chain framework. In specific embodiments, the heavy chain human germline framework is selected from VH1-18, VH1-2, VH1-24, VH1-3, VH1-45, VH1-46, VH1-58, VH1-69, VH1-8, VH2-26, VH2-5, VH2-70, VH3-11, VH3-13, VH3-15, VH3-16, VH3-20, VH3-21, VH3-23, VH3-30, VH3 -33, VH3-35, VH3-38, VH3-43, VH3-48, VH3-49, VH3-53, VH3-64, VH3-66, VH3-7, VH3-72, VH3-73, VH3-74, VH3-9, VH4-28, VH4-31, VH4-34, VH4-39, VH4-4, VH4-59, VH4-61, VH5-51, VH6-1 and VH7-81.

[0067] In specific embodiments, the light chain variable region and / or the heavy chain variable region include a framework region or at least a portion of a framework region (e.g., comprising 2 or 3 subregions, such as FR2 and FR3). In certain embodiments, at least FRL1, FRL2, FRL3, or FRL4 is completely human. In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is completely human. In some embodiments, at least FRL1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., human germline) or a human consensus sequence comprising a specific framework (easily available at the source of the known human Ig sequences described above). In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., human germline) or a human consensus sequence comprising a specific framework. In preferred embodiments, the framework region is a completely human framework region.

[0068] Humanization or engineering of the antibodies of the invention can be performed using any known method, such as, but not limited to, those described in Winter (Jones et al., Nature 321:522 (1986); Riechmann et al., Nature 332:323 (1988); Verhoeyen et al., Science 239:1534 (1988); Sims et al., J. Immunol. 151:2296 (1993); Chothia and Lesk, J. Mol. Biol. 196:901 (1987); Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285 (1992); Presta et al., J. Immunol. 151:2623 (1993); U.S. Patents 5723323, 5976862, 5824514, 5817483, 5814476, 576 98 / 16280, US96 / 18978, US91 / 09630, US91 / 05939, US94 / 01234, GB89 / 01334, GB91 / 01134, GB92 / 01755; WO90 / 14443, WO90 / 14424, WO90 / 14430, EP 229246, each of which is incorporated herein by reference in its entirety, including the references cited therein.

[0069] In certain embodiments, the antibody comprises an altered (e.g., mutated) Fc region. For example, in some embodiments, the Fc region has been 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 thereto, it may be useful to combine amino acid modifications with one or more additional amino acid modifications that alter the C1q binding and / or complement dependent cytotoxicity function of the Fc region of the IL-23 binding molecule. The starting polypeptide of particular interest may be a polypeptide that binds to C1q and exhibits complement dependent cytotoxicity (CDC). A polypeptide having pre-existing C1q binding activity, optionally also having the ability to mediate CDC, may be modified so that one or both of these activities are enhanced. Amino acid modifications that alter C1q and / or modify its complement dependent cytotoxicity function are described in, for example, WO0042072, which is hereby incorporated by reference.

[0070] As disclosed above, one can design the Fc region of the human IL-23-specific antibodies of the present invention 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. "Effector function" is responsible for activating or reducing 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), etc. Such effector functions may require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays (e.g., Fc binding assays, ADCC assays, CDC assays, etc.).

[0071] For example, one can generate a variant Fc region of a human IL-23 (or anti-IL-23) antibody that has improved C1q binding and improved FcγRIII binding (e.g., having both improved ADCC activity and improved CDC activity). Alternatively, if it is desired to reduce or eliminate effector function, a variant Fc region with reduced CDC activity and / or reduced ADCC activity can be designed. In other embodiments, only one of these activities can be increased, and optionally, the other activity can also be reduced (e.g., to generate an Fc region variant with improved ADCC activity but reduced CDC activity (or vice versa)).

[0072] Fc mutations can also be introduced into the design to alter their interaction 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).

[0073] Another type of amino acid substitution is used to alter the glycosylation pattern of the Fc region of human IL-23-specific antibodies. Glycosylation in 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 the 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 creates a potential glycosylation site.

[0074] The glycosylation pattern can be altered, for example, by deleting one or more glycosylation sites found in the polypeptide and / or adding one or more glycosylation sites not present in the polypeptide. Addition of glycosylation sites to the Fc region of a human IL-23-specific antibody can be conveniently accomplished by altering the amino acid sequence to contain one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). An exemplary glycosylation variant comprises an amino acid substitution at heavy chain residue Asn 297. The alteration can also be accomplished by adding or substituting one or more serine or threonine residues to the sequence of the original polypeptide (for O-linked glycosylation sites). Alternatively, a glycosylation site can be removed by converting Asn 297 to Ala.

[0075] In certain embodiments, the human IL-23-specific antibodies of the present invention are expressed in cells expressing β(1,4)-N-acetylglucosaminyltransferase III (GnT III), such that GnT III adds GlcNAc to the human IL-23 antibody. Methods for producing antibodies in this manner are provided in WO / 9954342, WO / 03011878, Patent Publication 20030003097A1, and Umana et al., Nature Biotechnology, 17:176-180, February 1999; all of which are specifically incorporated herein by reference in their entirety.

[0076] As described herein and / or as known in the art, anti-IL-23 antibodies can also be optionally produced by immunizing transgenic animals capable of producing a full repertoire of human antibodies (e.g., mice, rats, hamsters, non-human primates, etc.) Human anti-IL-23 antibody-producing cells can be isolated from such animals and immortalized using suitable methods, such as those described herein.

[0077] Transgenic mice that can produce a full repertoire of human antibodies that bind to human antigens can be generated by known methods (e.g., but not limited to, U.S. Patents: 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.; Jakobovits et al., WO 98 / 50433; Jakobovits et al., WO 98 / 24893; Lonberg et al., WO 98 / 24884; Lonberg et al., WO 97 / 13852; Lonberg et al., WO 94 / 25585; Kucherlapate et al., WO 96 / 34096; Kucherlapate et al., EP 0 463 151 B1; Kucherlapate et al., EP 0 710 0710). 719A1; Surani et al., U.S. Patent 5,545,807; Bruggemann et al., WO90 / 04036; Bruggemann et al., EP 0438474B1; Lonberg et al., EP 0814 259A2; Lonberg et al., GB 2 272 440 A; Lonberg et al., Nature 368:856-859 (1994); Taylor et al., Int. Immunol. 6(4):579-591 (1994); Green et al., Nature Genetics 7:13-21 (1994); Mendez et al., Nature Genetics 15:146-156 (1997); Taylor et al., Nucleic Acids Research 20(23):6287-6295 (1992); Tuaillon et al., Proc Natl Acad Sci USA 90 (8) 3720-3724 (1993); Lonberg et al., Int Rev Immunol 13 (1): 65-93 (1995) and Fishwald et al., Nat Biotechnol 14 (7): 845-851 (1996), each of which is incorporated herein by reference in its entirety). Generally, these mice contain at least one transgene comprising DNA from at least one human immunoglobulin locus that has undergone or is capable of undergoing functional rearrangement. The endogenous immunoglobulin loci in such mice can be disrupted or deleted to eliminate the ability of the animal to produce antibodies encoded by the endogenous genes.

[0078] Peptide display libraries can be used to easily screen for antibodies that specifically bind to similar proteins or fragments. This method involves screening for individual members with desired functions or structures from a large number of peptides. Antibody screening using peptide display libraries is well known in the art. The length of the displayed peptide sequence can be 3 to 5000 or more amino acids, often 5 to 100 amino acids long, and generally about 8 to 25 amino acids long. In addition to direct chemical synthesis methods for producing peptide libraries, several recombinant DNA methods have also been described. One type involves displaying peptide sequences on the surface of phages or cells. Each phage or cell contains a nucleotide sequence encoding the specifically displayed peptide sequence. This type of method is described in PCT patent publications 91 / 17271, 91 / 18980, 91 / 19818, and 93 / 08278.

[0079] Other systems for generating peptide libraries have aspects of both in vitro chemical synthesis methods and recombinant methods. See PCT Patent Publications 92 / 05258, 92 / 14843, and 96 / 19256. See also U.S. Patents 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. Patents 4,704,692, 4,939,666, 4,946,778, 5,260,203, 5,455,030, 5,518,889, 5,534,621, 5,656,730, 5,763,733, 5,767,260, 5,856,456, assigned to Enzon; ​​5,223,409, 5,403,484, 5,571,698, 5,837,500, assigned to Dyax; 5,427,908, 5,580,717, assigned to Affymax; 5,885,793, assigned to Cambridge antibody Technologies; 5750373, assigned to Genentech, 5618920, 5595898, 5576195, 5698435, 5693493, 5698417, assigned to Xoma, Colligan, supra; Ausubel, supra; or Sambrook, supra, each of which is incorporated herein by reference in its entirety.

[0080] Antibodies used in the methods of the present invention can also be prepared by providing transgenic animals or mammals, such as goats, cows, horses, sheep, rabbits, etc., using at least one anti-IL23 antibody-encoding nucleic acid, which are capable of producing such antibodies in their milk. Such animals can be provided using known methods. See, for example, but not limited to, U.S. Patents 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.

[0081] The antibodies used in the methods of the present invention can also be prepared by using at least one anti-IL23 antibody encoding nucleic acid to provide transgenic plants and cultured plant cells (such as, but not limited to, tobacco and corn) that produce such antibodies, specified portions or variants thereof in their plant parts or cells cultured from plant parts. As a non-limiting example, transgenic tobacco leaves expressing recombinant proteins have been successfully used to provide large quantities of recombinant proteins, for example, using inducible promoters. See, for example, Cramer et al., Curr. Top. Microbol. Immunol., 240:95-118 (1999), and references cited therein. Similarly, transgenic corn has been used to express mammalian proteins on a commercial scale with biological activities equivalent to those produced in other recombinant systems or purified from natural sources. See, for example, Hood et al., Adv. Exp. Med., Biol. 464:127-147 (1999), and references cited therein. Antibodies, including antibody fragments such as single-chain antibodies (scFv), can also be produced in large quantities from transgenic plant seeds (including tobacco seeds and potato tubers). See, for example, 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 also, for example, Fischer et al., Biotechnol. Appl. Biochem., 30: 99-108 (Oct., 1999); Ma et al., Trends Biotechnol. 13: 522-7 (1995); Ma et al., Plant Physiol. 109: 341-6 (1995); Whitelam et al., Biochem. Soc. Trans. 22: 940-944 (1994); and references cited therein. Each of the above references is incorporated herein by reference in its entirety.

[0082] The antibodies used in the methods of the present invention can be of a wide range of affinities (K D ) binds to human IL-23. In a preferred embodiment, the human mAb can optionally bind to human IL-23 with high affinity. For example, the human mAb can be equal to or less than about 10 - 7 M, such as but not limited to 0.1-9.9 (or any range or value thereof)×10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 or any range or value thereof D Binds human IL-23.

[0083] The affinity or avidity of an antibody for an antigen can be determined experimentally using any suitable method. (See, for example, Berzofsky et al., "Antibody-Antigen Interactions", In Fundamental Immunology, Paul, WE, ed., Raven Press: New York, NY (1984); Kuby, Janis Immunology, WH Freeman and Company: New York, NY (1992); and methods described herein). The affinity of a particular antibody-antigen interaction measured will be different if measured under different conditions (e.g., salt concentration, pH). Therefore, affinity and other antigen binding parameters (e.g., K D , K a , K d ) is preferably measured using standard solutions of antibody and antigen and a standard buffer (such as the buffer described herein).

[0084] Nucleic acid molecules

[0085] Using the information provided herein, for example, a nucleotide sequence encoding at least 70% to 100% of the contiguous amino acids of at least one of the light or heavy chain variable regions or CDR regions described herein, as well as other sequences disclosed herein, specific fragments, variants, or consensus sequences thereof, or a deposited vector comprising at least one of these sequences, nucleic acid molecules of the present invention encoding at least one anti-IL-23 antibody can be obtained using methods described herein or as known in the art.

[0086] Nucleic acid molecules of the present invention can be the form of RNA, such as mRNA, hnRNA, tRNA or any other form, or be the form of DNA, including but not limited to, by cloning or synthetic cDNA and genomic DNA, or their any combination.DNA can be triple-stranded, double-stranded or single-stranded or their any combination.Any part of at least one chain of DNA or RNA can be coding strand, also referred to as sense strand, or it can be non-coding strand, also referred to as antisense strand.

[0087] The isolated nucleic acid molecules used in the methods of the present invention can include the following: nucleic acid molecules comprising an open reading frame (ORF), optionally with one or more introns, for example, but not limited to, at least a specific portion of at least one CDR, such as CDR1, CDR2, and / or CDR3 of at least one heavy or light chain; nucleic acid molecules comprising coding sequences for anti-IL-23 antibodies or variable regions; and nucleic acid molecules comprising nucleotide sequences that differ significantly from those described above, but still encode at least one anti-IL-23 antibody as 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. Therefore, it should be routine for one skilled in the art to generate such degenerate nucleic acid variants encoding the specific anti-IL-23 antibodies used in the methods of the present invention. See, for example, Ausubel et al., supra, and 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.

[0088] As indicated herein, nucleic acid molecules comprising nucleic acids encoding anti-IL-23 antibodies may include, but are not limited to, those encoding the amino acid sequence of an antibody fragment alone; the coding sequence for the entire antibody or a portion thereof; the coding sequence for an antibody, fragment, or portion, and additional sequences, such as the coding sequence for at least one signal leader peptide or fusion peptide, such as at least one intron, with or without the aforementioned additional coding sequences, as well as additional non-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 stabilization of mRNA); additional coding sequences encoding additional amino acids, such as those that provide additional functions. Thus, the sequence encoding the antibody may be fused to a marker sequence, such as a sequence encoding a peptide that facilitates purification of the fusion antibody comprising the antibody fragment or portion.

[0089] Polynucleotides that selectively hybridize to a polynucleotide as described herein

[0090] The methods of the present invention use isolated nucleic acids that hybridize to the polynucleotides disclosed herein under selective hybridization conditions. Thus, the polynucleotides of the present embodiment can be used to separate, detect, and / or quantify nucleic acids comprising 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 polynucleotide is an isolated genomic sequence or cDNA sequence, or is complementary to a cDNA from a human or mammalian nucleic acid library.

[0091] Preferably, the cDNA library comprises at least 80% full-length sequences, preferably at least 85% or 90% full-length sequences, and more preferably at least 95% full-length sequences. The cDNA library can be standardized to increase the representation of rare sequences. Low or medium stringency hybridization conditions are generally, but not exclusively, used for sequences with reduced sequence identity relative to the complementary sequence. Medium and high stringency conditions can optionally be used for sequences with greater identity. Low stringency conditions allow sequences with approximately 70% sequence identity to perform selective hybridization and can be used to identify orthologous or paralogous sequences.

[0092] Optionally, the polynucleotide will encode at least a portion of an antibody. The polynucleotide comprises a nucleic acid sequence that can be used to selectively hybridize with a polynucleotide encoding an antibody of the invention. See, for example, Ausubel (supra); Colligan (supra), each of which is incorporated herein by reference in its entirety.

[0093] Nucleic acid construction

[0094] Isolated nucleic acid can be prepared using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques and / or (d) combinations thereof, as are well known in the art.

[0095] The nucleic acid can conveniently comprise sequences other than the polynucleotides of the present invention. For example, a multiple cloning site comprising one or more endonuclease restriction sites can be inserted into the nucleic acid to assist in the isolation of the polynucleotides. In addition, a translatable sequence can be inserted to assist in the isolation of the polynucleotides of the present invention. For example, a hexahistidine tag sequence provides a convenient means for purifying the protein of the present invention. The nucleic acids of the present invention (excluding the coding sequence) are optionally vectors, adapters, or joints for cloning and / or expressing the polynucleotides of the present invention.

[0096] 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 the polynucleotide, or to improve the introduction of the polynucleotide 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).

[0097] Recombinant methods for constructing nucleic acids

[0098] Isolated nucleic acid compositions (such as RNA, cDNA, genomic DNA or any combination thereof) can be obtained from biological sources using a variety of cloning methods known to those skilled in the art. In some embodiments, oligonucleotide probes that selectively hybridize to the polynucleotides of the present invention under stringent conditions are used to identify the desired sequence in a cDNA or genomic DNA library. The isolation of RNA, and the construction of cDNA and genomic libraries are well known to those of ordinary skill in the art. (See, for example, Ausubel, supra; or Sambrook, supra).

[0099] Nucleic acid screening and isolation methods

[0100] cDNA or genomic libraries can be screened using probes based on the sequences of the polynucleotides used in the methods of the present invention, such as those disclosed herein. The probes can be used to hybridize to genomic DNA or cDNA sequences to isolate homologous genes from the same or different organisms. Those skilled in the art will appreciate that various degrees of hybridization stringency can be employed in an assay; and that the hybridization or wash medium can be stringent. As the conditions for hybridization become more stringent, a higher degree of complementarity must exist between the probe and target for duplex formation to occur. The degree of stringency can be controlled by one or more of temperature, ionic strength, pH, and the presence of a partially denaturing solvent such as formamide. For example, the stringency of hybridization can be conveniently varied by manipulating the concentration of formamide, for example, within a range of 0% to 50%, thereby varying the polarity of the reactant solution. The degree of complementarity (sequence identity) required for detectable binding will vary depending on the stringency of the hybridization and / or wash medium. The degree of complementarity will optimally be 100% or 70% to 100%, or any range or value therein. However, it will be appreciated that minor sequence variations in probes and primers can be compensated for by reducing the stringency of the hybridization and / or wash media.

[0101] Methods of amplifying RNA or DNA are well known in the art and can be used in accordance with the present invention without undue experimentation based on the teachings and guidance presented herein.

[0102] Known methods for amplifying DNA or RNA include, but are not limited to, polymerase chain reaction (PCR) and related amplification methods (see, e.g., U.S. Patents 4,683,195, 4,683,202, 4,800,159, 4,965,188 to Mullis et al.; 4,795,699 and 4,921,794 to Tabor et al.; 5,142,033 to Innis; 5,122,464 to Wilson et al.; 5,091,310 to Innis; 5,133,033 to Gyll et al.; 5,122,464 to Wilson et al.; 5,091,310 to Innis; 5,133,033 to Gyll et al.

[0013] The present invention relates to a method for amplifying a DNA sequence using RNA as a template for double-stranded DNA synthesis (U.S. Pat. No. 5,066,584 to Pensten et al.; U.S. Pat. No. 4,889,818 to Gelfand et al.; U.S. Pat. No. 4,994,370 to Silver et al.; U.S. Pat. No. 4,766,067 to Biswas; and U.S. Pat. No. 4,656,134 to Ringold), and RNA-mediated amplification using antisense RNA to a target sequence as a template for double-stranded DNA synthesis (U.S. Pat. No. 5,130,238 to Malek et al., tradenamed NASBA), the entire contents of which are incorporated herein by reference. (See, e.g., Ausubel, supra; or Sambrook, supra.)

[0103] For example, the sequence of the polynucleotides and related genes used in the method of the present invention can be amplified directly from genomic DNA or cDNA libraries using polymerase chain reaction (PCR) technology. For example, PCR and other in vitro amplification methods can also be used to clone nucleic acid sequences encoding proteins to be expressed, prepare nucleic acids to be used as probes to detect the presence of desired mRNA in samples, for nucleic acid sequencing, or for other purposes. Examples of techniques sufficient to guide technicians throughout the in vitro amplification method can be found in Berger (supra), Sambrook (supra) and Ausubel (supra), and U.S. Patent No. 4,683,202 (1987) by Mullis et al.; and Innis et al., PCR Protocols A Guide to Methods and Applications, Eds., Academic Press Inc., San Diego, CA (1990). Commercially available kits for genomic PCR amplification are known in the art. See, for example, Advantage-GC Genomic PCR Kit (Clontech). In addition, for example, T4 gene 32 protein (Boehringer Mannheim) can be used to increase the yield of long PCR products.

[0104] Synthetic methods for constructing nucleic acids

[0105] The isolated nucleic acids used in the methods 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 single-stranded oligonucleotides, which 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 although chemical synthesis of DNA may be limited to sequences of about 100 or more bases, longer sequences can be obtained by ligating shorter sequences.

[0106] Recombinant expression cassette

[0107] The present invention uses a recombinant expression cassette comprising a nucleic acid. Nucleic acid sequences, such as cDNA or genomic sequences encoding the antibodies used in the methods of the present invention, can be used to construct a recombinant expression cassette that can be introduced into at least one desired host cell. The recombinant expression cassette will typically comprise a polynucleotide operably linked to a transcription initiation regulatory sequence that directs transcription of the polynucleotide in the desired host cell. Both heterologous and non-heterologous (i.e., endogenous) promoters can be used to direct expression of the nucleic acid.

[0108] In some embodiments, an isolated nucleic acid serving as a promoter, enhancer, or other element can be introduced into a non-heterologous form of a polynucleotide of the present invention at an appropriate position (upstream, downstream, or in an intron) to up-regulate or down-regulate the expression of the polynucleotide. For example, an endogenous promoter can be altered in vivo or in vitro by mutation, deletion, and / or substitution.

[0109] Vectors and host cells

[0110] The present invention also relates to vectors comprising the isolated nucleic acid molecules, host cells genetically engineered with the recombinant vectors, and methods for producing at least one anti-IL-23 antibody by recombinant techniques well known in the art, see, for example, Sambrook et al. (supra); Ausubel et al. (supra), each of which is incorporated herein by reference in its entirety.

[0111] The polynucleotide can be optionally linked to a vector including a selectable marker for propagation in a host. Generally, plasmid vectors are introduced in a precipitate such as a calcium phosphate precipitate, or in 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 a host cell.

[0112] The DNA insert should be operably connected to a suitable promoter. The expression construct also can contain a transcription initiation site, a termination site and a ribosome bind site for translation in the transcription region. The coding portion of the mature transcript expressed by this construct will preferably be included in the translation initiation at the beginning of mRNA to be translated and a terminator codon (for example, UAA, UGA or UAG) at the appropriate position of the mRNA end, preferably UAA and UAG for mammalian or eukaryotic cell expression.

[0113] The expression vector will preferably but optionally include at least one selectable marker. Such markers include, for example, but are not limited to, for eukaryotic cell culture, resistance genes for 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 (GS, U.S. Pat. Nos. 5,122,464; 5,770,359; 5,827,739); and for E. coli and other bacterial or prokaryotic cultures, tetracycline or Ampicillin resistance gene (the above patent is incorporated herein by reference in its entirety). Appropriate culture media and conditions for the above host cells are known in the art. Suitable vectors will be apparent to those skilled in the art. The introduction of vector constructs into host cells can be achieved by calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection or other known methods. Such methods have been described in the art, such as Sambrook, supra, Chapters 1-4 and 16-18; Ausubel, supra, Chapter 1, Chapter 9, Chapter 13, Chapter 15, Chapter 16.

[0114] At least one antibody used in the method of the present invention can be expressed in a modified form (such as a fusion protein) and can include not only a secretion signal but also additional heterologous functional regions. For example, a region of additional amino acids (especially charged amino acids) can be added to the N-terminus of the antibody to improve stability and persistence in the host cell during purification or subsequent processing and storage. Similarly, a peptide portion can be added to the antibody of the present invention to help purification. Such regions can be removed before the final preparation of the antibody or at least one fragment thereof. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, chapters 17.29-17.42 and 18.1-18.74; Ausubel, supra, chapters 16, 17 and 18.

[0115] Those skilled in the art will recognize that many expression systems can be used to express nucleic acids encoding proteins used in the methods of the present invention. Alternatively, the nucleic acid can be expressed in a host cell by turning on (by manipulation) endogenous DNA encoding the antibody in a host cell. Such methods are well known in the art, for example, as described in U.S. Patents 5,580,734, 5,641,670, 5,733,746, and 5,733,761, which are incorporated herein by reference in their entirety.

[0116] The exemplary cell culture that can be used for producing antibody, its specific part or variant is mammalian cell.Mammalian cell system will generally be the form of cell monolayer, but mammalian cell suspension or bioreactor can also be used.Many suitable host cell lines that can express complete glycosylated protein have been developed in the art, including COS-1 (such as ATCC CRL 1650), COS-7 (such as ATCC CRL-1651), HEK293, BHK21 (such as ATCC CRL-10), CHO (such as ATCC CRL 1610) and BSC-1 (such as ATCC CRL-26) cell lines, Cos-7 cell, CHO cell, hep G2 cell, P3X63Ag8.653, SP2 / 0-Ag14, 293 cell, HeLa cell etc., they can easily obtain from such as American Type Culture Collection (Manassas, Va (www.atcc.org)). Preferred host cells include cells of lymphoid origin, such as myeloma cells and lymphoma cells. Particularly preferred host cells are P3X63Ag8.653 cells (ATCC Accession No. CRL-1580) and SP2 / 0-Ag14 cells (ATCC Accession No. CRL-1851). In particularly preferred embodiments, the recombinant cell is a P3X63Ab8.653 or SP2 / 0-Ag14 cell.

[0117] Expression vectors for these cells may include one or more of the following expression control sequences, such as, but not limited to: an origin of replication; a promoter (e.g., the late or early SV40 promoter, the CMV promoter (U.S. Pat. Nos. 5,168,062; 5,385,839), the HSV tk promoter, the pgk (phosphoglycerate kinase) promoter, the EF-1α 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 poly A addition site), and a transcription terminator sequence. See, e.g., Ausubel et al. (supra); Sambrook et al. (supra). Other cells that can be used to produce the nucleic acids or proteins of the invention are also known and / or can be obtained, for example, from the American Type Culture Collection Cell Line and Hybridoma Catalog (www.atcc.org) or other known or commercial sources.

[0118] When using eukaryotic host cells, polyadenylation or transcription termination sequences are typically incorporated into the vector. An example of a termination sequence is the polyadenylation sequence from the bovine growth hormone gene. Sequences for accurate splicing of transcripts may also be included. An example of a splicing sequence is the VP1 intron from SV40 (Sprague et al., J. Virol. 45:773-781 (1983)). In addition, as is known in the art, gene sequences that control replication in the host cell may be incorporated into the vector.

[0119] Antibody purification

[0120] 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, hydroxyapatite 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.

[0121] The antibodies used in the methods of the present invention include naturally purified products, products of chemical synthesis operations, and products produced by recombinant technology from eukaryotic hosts, such as yeast, higher plants, insects, and mammalian cells. Depending on the host used in the recombinant production method, the antibodies may be glycosylated or non-glycosylated, with glycosylated being 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.

[0122] Anti-IL-23 antibodies

[0123] The anti-IL-23 antibodies according to the present invention include any protein or peptide comprising a molecule comprising 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 complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof), a heavy or light chain variable region, a framework region (e.g., FR1, FR2, FR3, FR4, or fragments thereof, optionally further comprising at least one substitution, insertion, or deletion), a heavy or light chain constant region (e.g., comprising at least one CDR), or a heavy or light chain constant region. H 1. Hinge 1, Hinge 2, Hinge 3, Hinge 4, C H 2 or C H 3 or fragments thereof, optionally further comprising at least one substitution, insertion or deletion), or any portion thereof that may be incorporated into an antibody. The antibody may comprise or be derived from any mammal, such as, but not limited to, humans, mice, rabbits, rats, rodents, primates, or any combination thereof.

[0124] The isolated antibodies used in the methods of the present invention comprise an antibody amino acid sequence encoded by any suitable polynucleotide disclosed herein, or any isolated or prepared antibody. Preferably, the human antibody or antigen-binding fragment binds to human IL-23, thereby partially or substantially neutralizing at least one biological activity of the protein. 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 by binding of IL-23 to an IL-23 receptor or by 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% to 120%, preferably at least about 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 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 as described herein and / or known in the art. The human antibody can be of any type (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and can comprise a kappa or lambda light chain. In one embodiment, the human antibody comprises an IgG heavy chain or a defined fragment, e.g., at least one of the isotypes IgG1, IgG2, IgG3, or IgG4 (e.g., γ1, δγ2, γ3, γ4). Antibodies of this type can be prepared as described herein and / or as known in the art by using transgenic mice or other transgenic non-human mammals comprising at least one human light chain (e.g., IgG, IgA, and IgM) transgene. In another embodiment, the anti-IL-23 human antibody comprises an IgG1 heavy chain and an IgG1 light chain.

[0125] The antibody binds to at least one specific epitope that is specific for at least one IL-23 protein, subunit, fragment, portion, or any combination thereof. The at least one epitope may comprise at least one antibody binding region that comprises at least a portion of the protein, preferably at least one extracellular, soluble, hydrophilic, external, or cytoplasmic portion of the protein.

[0126] In general, human antibodies or antigen-binding fragments will comprise an antigen-binding region comprising at least one human complementary determining region (CDR1, CDR2, and CDR3) or a variant of at least one heavy chain variable region and at least one human complementary determining region (CDR1, CDR2, and CDR3) or a variant of at least one light chain variable region. The CDR sequences can be derived from human germline sequences or closely matched to these germline sequences. For example, CDRs derived from a synthetic library of original non-human CDRs can be used. These CDRs can be formed by incorporating conservative substitutions from original non-human sequences. In another specific embodiment, an antibody or antigen-binding portion thereof or variant can have an antigen-binding region comprising at least a portion of at least one light chain CDR (i.e., CDR1, CDR2, and / or CDR3) having the amino acid sequence of corresponding CDR1, CDR2, and / or CDR3.

[0127] Such antibodies can be made by chemically linking together the various portions of the antibody (e.g., CDRs, frameworks) using conventional techniques, by making and expressing nucleic acid molecules encoding the antibody (i.e., one or more) using conventional techniques of recombinant DNA technology, or by using any other suitable method.

[0128] Anti-IL-23 specific antibodies may comprise at least one of a heavy chain variable region or a light chain variable region having a defined amino acid sequence. For example, in one preferred embodiment, the anti-IL-23 antibody comprises at least one heavy chain variable region and / or at least one light chain variable region, wherein the at least one heavy chain variable region optionally has the amino acid sequence of SEQ ID NO: 7, and the at least one light chain variable region optionally has the amino acid sequence of SEQ ID NO: 8. For example, in another preferred embodiment, the anti-IL-23 antibody comprises at least one heavy chain and / or at least one light chain, wherein the at least one heavy chain optionally has the amino acid sequence of SEQ ID NO: 9, and the at least one light chain optionally has the amino acid sequence of SEQ ID NO: 10. Antibodies that bind to human IL-23 and comprise a defined heavy chain or light chain variable region can be prepared using suitable methods such as phage display (Katsube, Y. et al., Int J Mol. Med, 1(5): 863-868 (1998)) or methods using transgenic animals, as known in the art and / or as described herein. For example, human IL-23 or its fragment can be used to immunize transgenic mice containing a human immunoglobulin heavy chain transgene that is functionally rearranged and a transgenic DNA from a human immunoglobulin light chain locus that may undergo functional rearrangement to induce the production of antibodies. If necessary, cells producing antibodies can be isolated and hybridomas or other immortalized antibody-producing cells can be prepared as described herein and / or as known in the art. Alternatively, encoding nucleic acids or portions thereof can be used to express antibodies, specific parts or variants in suitable host cells.

[0129] The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs comprising amino acid sequences substantially identical to those described herein. Preferably, such antibodies or antigen-binding fragments and antibodies comprising such chains or CDRs can bind with high affinity (e.g., less than or equal to about 10 -9 M's K D) binds to human IL-23. Amino acid sequences substantially identical to the sequences described herein include sequences with 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 similar chemical and / or physical properties (e.g., charge, structure, polarity, hydrophobicity / hydrophilicity) as the first amino acid. Conservative substitutions include, but are not limited to, replacing one amino acid with another in the following groups: lysine (K), arginine (R), and histidine (H); aspartic acid (D) and glutamic acid (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.

[0130] Amino acid code

[0131] The amino acids that make up the anti-IL-23 antibodies of the present invention are generally abbreviated. Amino acids can be represented by their single-letter codes, three-letter codes, names, or trinucleotide codons, thereby indicating the amino acid names, as is well known in the art (see Alberts, B. et al., "Molecular Biology of the Cell," 3rd ed., Garland Publishing, Inc., New York, 1994):

[0132]

[0133]

[0134] As described herein, the anti-IL-23 antibodies used in the methods of the invention may include one or more amino acid substitutions, deletions, or additions resulting from natural mutations or from human manipulation.

[0135] The number of amino acid substitutions that a skilled artisan can make depends on many factors, including those described above. As described herein, generally, the number of amino acid substitutions, insertions, or deletions in any given anti-IL-23 antibody, fragment, or variant will not exceed 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, such as 1 to 30, or any range or value therein.

[0136] Amino acids essential for function in anti-IL-23 specific antibodies can be identified by methods known in the art, such as site-directed mutagenesis or alanine scanning mutagenesis (e.g., Ausubel, supra, Chapters 8 and 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, such as, but not limited to, at least one IL-23 neutralization 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)).

[0137] The anti-IL-23 antibody may include, but is not limited to, at least a portion, sequence, or combination of 5 to all contiguous amino acids selected from at least one of SEQ ID NOs: 1, 2, 3, 4, 5, and 6.

[0138] The IL-23 antibody or specified portion or variant may include, but is not limited to, at least one portion, sequence, or combination selected from the group consisting of: at least 3 to 5 contiguous amino acids of the aforementioned SEQ ID NO; 5 to 17 contiguous amino acids of the aforementioned SEQ ID NO; 5 to 10 contiguous amino acids of the aforementioned SEQ ID NO; 5 to 11 contiguous amino acids of the aforementioned SEQ ID NO; 5 to 7 contiguous amino acids of the aforementioned SEQ ID NO; 5 to 9 contiguous amino acids of the aforementioned SEQ ID NO.

[0139] The anti-IL-23 antibody may also optionally comprise a polypeptide comprising 70% to 100% of at least one of the 5, 17, 10, 11, 7, 9, 119, or 108 contiguous amino acids of the aforementioned SEQ ID NOs. In one embodiment, the amino acid sequence of an immunoglobulin chain or portion thereof (e.g., a variable region, a CDR) is about 70%-100% identical (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 thereof) to the amino acid sequence of the corresponding chain of at least one of the aforementioned SEQ ID NOs. For example, the amino acid sequence of the light chain variable region can be compared with the sequence of the above SEQ ID NO, or the amino acid sequence of the heavy chain CDR3 can be compared with the above SEQ ID NO. Preferably, 70% to 100% amino acid identity (i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any range or value therein) is determined using a suitable computer algorithm as known in the art.

[0140] As known in the art, "identity" 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", edited by AM, Oxford University Press, New York, 1988; "Biocomputing: Informatics and Genome Projects", edited by Smith, DW, Academic Press, New York, 1993; "Computer Analysis of Sequence Data", Part I, edited by Griffin, AM and Griffin, HG, Humana Press, New Jersey, 1994; "Sequence Analysis in Molecular Biology", von Heinje, G., Academic Press, 1987; and "Sequence Analysis Primer", edited by Gribskov, M. and Devereux, J., 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 the AlignX component of Vector NTI Suite 8.0 (Informax, Frederick, MD) using default settings.

[0141] Preferred methods for determining identity are designed to give the largest match between test sequences. Methods for determining identity and similarity are codified in publicly available computer programs. Preferred computer program methods for determining 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)). The BLAST X program is available from NCBI and other sources (BLAST Manual, Altschul, S. et al., NCBINLMNIH Bethesda, Md. 20894: Altschul, S. et al., J. Mol. Biol. 215:403-410 (1990)). The well-known Smith-Waterman algorithm can also be used to determine identity.

[0142] Preferred parameters for polypeptide sequence comparisons include the following:

[0143] (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443-453 (1970) Comparison matrix:

[0144] BLOSSUM62 from Hentikoff and Hentikoff,Proc.Natl.Acad.Sci,USA.89:10915-10919(1992)

[0145] Open Shot Penalty: 12

[0146] Gap length penalty: 4

[0147] A program that can be used with these parameters is publicly available as the "gap" program from Genetics Computer Group, Madison, Wis. The foregoing parameters are the default parameters for peptide sequence comparisons (along with no terminal gap penalty).

[0148] Preferred parameters for polynucleotide comparisons include the following:

[0149] (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48: 443-453 (1970)

[0150] Comparison matrix: match = +10, mismatch = 0

[0151] Open Shot Penalty: 50

[0152] Gap length penalty: 3

[0153] Available as the "gap" program from Genetics Computer Group, Madison Wis. These parameters are the default parameters for nucleic acid sequence comparisons.

[0154] By way of example, a polynucleotide sequence can be identical to another sequence, i.e., 100% identical, or it can include up to a certain integer number of nucleotide changes compared to a reference sequence. Such changes are selected from the group consisting of at least one nucleotide deletion, substitution (including conversion and transversion) or insertion, and wherein the changes can occur at the 5' or 3' terminal position of the reference nucleotide sequence or at any position between these terminal positions, interspersed individually among the nucleotides of the reference sequence, or interspersed among one or more adjacent groups within the reference sequence. The number of nucleotide changes is 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 this product from the total number of nucleotides in the sequence, or:

[0155] n.sub.n.ltorsim.x.sub.n-(x.sub.ny),

[0156] where n.sub.n is the number of nucleotide changes, 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 where any non-integer product of x.sub.n and y is rounded to the nearest integer before being subtracted from x.sub.n.

[0157] Alterations in the polynucleotide sequence encoding the above-mentioned SEQ ID NO may produce nonsense mutations, missense mutations or frameshift mutations in the coding sequence, thereby altering the polypeptide encoded by the polynucleotide following such alterations. Similarly, a polypeptide sequence may be identical to the reference sequence of the above-mentioned SEQ ID NO, i.e., 100% identical, or the polypeptide sequence may include up to a certain integer number of amino acid alterations compared to the reference sequence such that the percent identity is less than 100%. Such alterations are selected from the group consisting of at least one amino acid deletion, substitution (including conservative and non-conservative substitutions), or insertion, and wherein the alterations may occur at the amino-terminal position or carboxyl-terminal position of the reference polypeptide sequence, or at any position between these terminal positions, interspersed individually among the amino acids of the reference sequence, or interspersed in one or more contiguous groups within the reference sequence. For a given % identity, the number of amino acid alterations is determined by multiplying the total number of amino acids in the above-mentioned SEQ ID NO by the numerical percentage of the corresponding percent identity (divided by 100), and then subtracting this product from the total number of amino acids in the above-mentioned SEQ ID NO, or:

[0158] n.sub.a.ltorsim.x.sub.a-(x.sub.ay),

[0159] wherein n.sub.a is the number of amino acid changes, x.sub.a is the total number of amino acids in the above SEQ ID NO, and y is, for example, 0.70 (corresponding to 70%), 0.80 (corresponding to 80%), 0.85 (corresponding to 85%), etc., and wherein any non-integer product of x.sub.a and y is rounded to the nearest integer before being subtracted from x.sub.a.

[0160] Exemplary heavy and light chain variable region sequences and portions thereof are provided in the above-mentioned SEQ ID NOs. The antibodies of the present invention, or specific variants thereof, may comprise any number of contiguous amino acid residues from an antibody of the present invention, wherein the number is selected from an integer between 10% and 100% of the number of contiguous residues in the anti-IL-23 antibody. Optionally, the contiguous amino acid subsequence is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 or more amino acids in length, or any range or value therein. Furthermore, the number of such subsequences may be any integer selected from the group consisting of 1 to 20, such as at least 2, 3, 4, or 5.

[0161] The skilled artisan will appreciate that the present invention includes at least one biologically active antibody of the present invention. The specific activity of the biologically active antibody is at least 20%, 30%, or 40%, and preferably at least 50%, 60%, or 70%, and most preferably at least 80%, 90%, or 95% to 100% or more (including, but not limited to, up to 10 times its specific activity) of a natural (non-synthetic), endogenous, or related and known antibody. Methods for determining and quantifying enzymatic activity and substrate specificity are well known to those skilled in the art.

[0162] On the other hand, the present invention relates to human antibodies and Fabs as described herein that are modified by covalently linked organic moieties.Such modifications can produce antibodies or Fabs with improved pharmacokinetic properties (such as increased serum half-life in vivo).The organic moiety can be a linear or branched hydrophilic polymeric group, a fatty acid group or a fatty acid ester group.In a specific embodiment, the hydrophilic polymeric group can have a molecular weight of approximately 800 to approximately 120,000 daltons, and can be a polyalkanediol (such as polyethylene glycol (PEG), polypropylene glycol (PPG)), a carbohydrate polymer, an amino acid polymer or polyvinylpyrrolidone, and the fatty acid or fatty acid ester group can include approximately eight to approximately 40 carbon atoms.

[0163] Modified antibodies and antigen-binding fragments may comprise one or more organic moieties that are directly or indirectly covalently bonded to the antibody. Each organic moiety bonded to the antibody or antigen-binding fragment of the present invention may independently be a hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. As used herein, the term "fatty acid" encompasses monocarboxylic acids and dicarboxylic acids. "Hydrophilic polymer group," as the term is used herein, refers to an organic polymer that is more soluble in water than in octane. For example, polylysine is more soluble in water than in octane. Therefore, antibodies modified by covalently linking polylysine are included in the present invention. Hydrophilic polymers suitable for modifying the antibodies of the present invention may be linear or branched, and include, for example, polyalkanediols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG, etc.), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides, etc.), hydrophilic amino acid polymers (e.g., polylysine, polyarginine, polyaspartic acid, etc.), polyalkylene oxides (e.g., polyethylene oxide, polypropylene oxide, etc.), and polyvinylpyrrolidone. Preferably, the hydrophilic polymer that modifies the antibody of the invention has a molecular weight of about 800 to about 150,000 Daltons as a single molecular entity. For example, PEG 5000 and PEG 20,000, wherein the subscript is the average molecular weight of the polymer (in daltons). The hydrophilic polymer group can be substituted with one to about six alkyl, fatty acid or fatty acid ester groups. The hydrophilic polymer substituted with fatty acid or fatty acid ester groups can be prepared by adopting a suitable method. For example, the polymer comprising an amine group can be coupled to the carboxylate radical of a fatty acid or fatty acid ester, and the activated carboxylate radical on the fatty acid or fatty acid ester (for example, activated with N,N-carbonyldiimidazole) can be coupled to the hydroxyl group on the polymer.

[0164] Fatty acids and fatty acid esters suitable for modifying the antibodies of the present invention may be saturated or may contain one or more unsaturated units. Suitable fatty acids for modifying the antibodies of the present invention include, for example, n-dodecanoate (C 12 , laurate), n-tetradecanoate (C 14 , myristate), n-octadecanoate (C 18 , stearate), n-eicosanoate (C 20 , arachidate), n-docosanoate (C 22 , behenate), n-triacontanoate (C 30 ), n-tetradecanoate (C 40 ), cis-Δ9-octadecanoate (C 18 oleate), all-cis-Δ5,8,11,14-eicosatetraenoate (C 20 Suitable fatty acid esters include monoesters of dicarboxylic acids containing straight or branched lower alkyl groups. The lower alkyl group may contain one to about twelve, preferably one to about six, carbon atoms.

[0165] The human antibodies and Fab of modification can be prepared using a suitable method, such as by reacting with one or more modifiers. As used herein, the term "modifier" refers to a suitable organic group (such as a hydrophilic polymer, a fatty acid, a fatty acid ester) comprising an activating group. "Activating group" is a chemical moiety or functional group that can react with a second chemical group under appropriate conditions to form a covalent bond between the modifier and the second chemical group. For example, amine reactive activating groups include electrophilic groups such as tosylate, mesylate, halogen (chlorine, bromine, fluorine, iodine), N-hydroxysuccinimide ester (NHS) etc. The activating group that can react with thiol includes, for example, maleimide, iodoacetyl, acryloyl, pyridyl disulfide, 5-thiol-2-nitrobenzoic acid thiol (TNB-thiol) etc. The aldehyde functional group can be coupled to a molecule containing amine or hydrazide, and an azide group can be reacted with a trivalent phosphorus group to form a phosphoramidate or phosphoramidite bond. 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)). The activating group can be bonded directly to the organic group (e.g., a hydrophilic polymer, a fatty acid, a fatty acid ester) or through a linking moiety, such as a divalent C1-C 12 In some embodiments, the present invention provides the modification of the present invention.In some embodiments, the present invention provides the modification of the present invention.In some embodiments, the present invention provides the modification of the present invention.In some embodiments, the present invention provides the modification of the present invention.In some embodiments, the present invention provides the modification of the present invention.In some embodiments, the present invention provides the modification of the present invention.In some embodiments, the present invention provides the modification of the present invention.In some embodiments, the present invention provides the modification of the present invention.In some embodiments, the present invention provides the modification of the present invention.In some embodiments, the present invention provides the modification of the present invention. (See, e.g., Thompson et al., WO 92 / 16221, the entire teachings of which are incorporated herein by reference.)

[0166] 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 conjugated to an antibody in a non-site-specific manner using an amine-reactive modifier (e.g., 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 the antibody or antigen-binding fragment. The reduced antibody or antigen-binding fragment can then be reacted with a thiol-reactive modifier to produce a modified antibody of the present invention. Modified human antibodies and antigen-binding fragments containing organic moieties bonded 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 the methods described in Hermanson, GT, Bioconjugate Techniques, Academic Press: San Diego, CA (1996).

[0167] The methods of the present invention also utilize 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 the anti-IL-23 antibodies described herein and / or known in the art, provided in a non-naturally occurring composition, mixture, or form. Such compositions include non-naturally occurring compositions comprising at least one or two full-length sequences, C-terminal and / or N-terminal deleted variants, domains, fragments, or specific variants of an anti-IL-23 antibody amino acid sequence selected from the group consisting of 70% to 100% of the contiguous amino acids of the aforementioned SEQ ID NO, or specific fragments, domains, or variants thereof. Preferred anti-IL-23 antibody compositions comprise at least one or two full-length, fragments, domains, or variants as at least one CDR or LBP comprising a portion of an anti-IL-23 antibody sequence described herein, for example, 70% to 100% of the aforementioned SEQ ID NO, or specific fragments, domains, or variants thereof. More preferred compositions comprise, for example, 70% to 100% of the above SEQ ID NOs or 40% to 99% of at least one of their specified fragments, domains, or variants. Such composition percentages are calculated by weight, volume, concentration, molarity, or molality of the liquid or anhydrous solution, mixture, suspension, emulsion, granule, powder, or colloid, as known in the art or as described herein.

[0168] Antibody compositions comprising additional therapeutically active ingredients

[0169] The compositions used in the methods of the present invention may also optionally comprise an effective amount of at least one compound or protein selected from at least one of the following: anti-infective drugs, cardiovascular (CV) system drugs, central nervous system (CNS) drugs, autonomic nervous system (ANS) drugs, respiratory tract drugs, gastrointestinal (GI) tract drugs, hormonal drugs, drugs for fluid or electrolyte balance, hematological drugs, anti-tumor drugs, immunomodulatory drugs, ophthalmic drugs, otic drugs or nasal drugs, topical drugs, nutritional drugs, statins, etc. Such drugs are well known in the art, including the formulations, indications, dosing, and administration of each drug given herein (see, e.g., “Nursing 2001 Handbook of Drugs,” 21st ed., Springhouse Corp., Springhouse, PA, 2001; “Health Professional's Drug Guide 2001,” ed. Shannon, Wilson, Stang, Prentice-Hall, Inc., Upper Saddle River, NJ; “Pharmcotherapy Handbook,” ed. Wells et al., Appleton & Lange, Stamford, CT, each of which is incorporated herein by reference in its entirety).

[0170] As examples of drugs that can be combined with the antibodies used in the methods of the present invention, anti-infective drugs can be at least one selected from the following: anti-amoebic drugs or antiprotozoal drugs, anti-helminthic drugs, antifungal drugs, antimalarial drugs, anti-tuberculosis drugs or at least one anti-leprosy drug, aminoglycosides, penicillins, cephalosporins, tetracyclines, sulfonamides, fluoroquinolones, antivirals, macrolide anti-infective drugs and other anti-infective drugs. Hormonal drugs can be at least one selected from the following: corticosteroids, androgens or at least one anabolic steroid, estrogens or at least one progesterone, gonadotropins, antidiabetic drugs or at least one glucagon, thyroid hormones, thyroid hormone antagonists, pituitary hormones and parathyroid hormone-like drugs. The at least one cephalosporin may be at least one selected from the group consisting of cefaclor, cefdroxil, cefazolin sodium, cefdinir, cefepime hydrochloride, cefixime, cefmetazole sodium, cefonicid sodium, cefoperazone sodium, ceftriaxone sodium, cefotetan disodium, cefxitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime, ceftibuten, cefizoxime sodium, ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cephalexin hydrochloride, cephalexin monohydrate, cephradine, and loracarbef.

[0171] The at least one corticosteroid can be at least one selected from the group consisting of 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 tert-butyl ethyl ester, prednisone, triamcinolone, triamcinolone acetonide and triamcinolone diacetate. The at least one androgen or anabolic steroid may be at least one selected from the group consisting of danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate, nandrolone phenylpropionate, testosterone, testosterone cypionate, testosterone enanthate, testosterone propionate, and a testosterone transdermal system.

[0172] The at least one immunosuppressant may be at least one selected from the group consisting of azathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immunoglobulin, muromonab-CD3, mycophenolate mofetil, mycophenolate mofetil hydrochloride, sirolimus, and tacrolimus.

[0173] The at least one topical anti-infective agent may be at least one selected from the group consisting of 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 may be at least one selected from the group consisting of crotamiton, lindane, permethrin, and pyrethroids. The at least one topical corticosteroid may be at least one selected from the group consisting of betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, diflorasone acetate, fluocinonide, fluocinolone acetonide, flurandrenolide, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, and triamcinolone acetonide. (See, e.g., pages 1098-1136 of Nursing 2001 Drug Handbook.)

[0174] The anti-IL-23 antibody composition may also comprise any suitable and effective amount of at least one of a composition or pharmaceutical composition comprising at least one anti-IL-23 antibody contacted or administered to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy, and optionally further comprising at least one agent selected from the group consisting of: at least one TNF antagonist (e.g., but not limited to, a chemical or protein antagonist of TNF, a monoclonal or polyclonal antibody or fragment of TNF, a soluble TNF receptor (e.g., p55, p70 or p85) or a fragment thereof, a fusion polypeptide, or a small molecule TNF antagonist). F antagonists, such as TNF binding protein I or II (TBP-1 or TBP-II), nerelimonmab, infliximab, etanercept, CDP-571, CDP-870, afelimomab, lenafcept, etc.), antirheumatic drugs (such as methotrexate, auranofin, gold thioglucose, azathioprine, etanercept, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), immune, immunoglobulin, immunosuppressant (such as basiliximab, cyclosporine, daclizumab), cytokine or cytokine antagonist. Non-limiting examples of such cytokines include, but are not limited to, any one of IL-1 to IL-40, etc. (such as IL-1, IL-2, etc.). Suitable dosages are well known in the art. See, e.g., Wells et al., eds., "Pharmacotherapy Handbook," 2nd ed., Appleton and Lange, Stamford, CT (2000); "PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000," Deluxe ed., Tarascon Publishing, LomaLinda, CA (2000), each of which is incorporated herein by reference in its entirety.

[0175] The anti-IL-23 antibody compounds, compositions, or combinations used in the methods of the present invention may further comprise at least one of any suitable adjuvants, such as, but not limited to, diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, and the like. Pharmaceutically acceptable adjuvants are preferred. Non-limiting examples and methods for preparing such sterile solutions are well known in the art, such as, but not limited to, Gennaro, ed., Remington's Pharmaceutical Sciences, 18th ed., 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 composition can be selected in a conventional manner, as is known in the art or as described herein.

[0176] Pharmaceutical excipients and additives for the compositions of the present invention include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides; derivatized sugars, such as sugar alcohols, aldonic acids, esterified sugars, and the like; and polysaccharides or sugar polymers). Pharmaceutical excipients and additives may be present alone or in combination, each alone or in combination, in an amount of 1-99.99% by weight or volume. Exemplary protein excipients include serum albumin, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid / antibody components that can also function in terms of buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. A preferred amino acid is glycine.

[0177] 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, starch, etc.; and sugar alcohols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), inositol, etc. Preferred carbohydrate excipients for use in the present invention are mannitol, trehalose, and raffinose.

[0178] Anti-IL-23 antibody compositions may also contain a buffer or pH adjuster; typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; tris or phosphate buffers. Preferred buffers for use in the compositions of the present invention are organic acid salts such as citrate.

[0179] In addition, anti-IL-23 antibody compositions may include polymeric excipients / additives such as polyvinyl pyrrolidone, polysucrose (polymeric sugar), dextrose binders (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).

[0180] These and additional known pharmaceutical excipients and / or additives suitable for use in the anti-IL-23 antibody, portion, or variant compositions according to the present invention are known in the art, for example, as listed in: "Remington: The Science & Practice of Pharmacy," 19th ed., Williams & Williams, (1995), and "Physician's Desk Reference," 52nd ed., Medical Economics, Montvale, NJ (1998), the disclosures of which are incorporated herein by reference in their entirety. Preferred carrier or excipient materials are carbohydrates (e.g., sugars and aldehydes) and buffers (e.g., citrate) or polymeric agents. An exemplary carrier molecule is the mucopolysaccharide hyaluronic acid, which can be used for intra-articular delivery.

[0181] preparation

[0182] As noted above, the present invention provides stable formulations suitable for pharmaceutical or veterinary use, preferably comprising a phosphate buffered saline or selected salts, and preservative solutions and formulations containing preservatives, as well as multi-purpose preservative formulations, comprising at least one anti-IL-23 antibody in a pharmaceutically acceptable formulation. The preservative formulation comprises at least one known preservative or optionally selected from the group consisting of at least one phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl benzoates (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof, dissolved in an aqueous diluent. Any suitable concentration or mixture as known in the art may be used, for example, 0.001% to 5% or any range or value therein, such as, but not limited to, 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, 1.6, 1.7, 1.8, 1.9, 2.10, 2.20, 2.30, 2.40, 2.50, 2.60, 2.70, 2.80, 2.90, 3.11, 3.12, 3.13, 3.14, 3.15, 3.16, 3.17, 3.18, 3.19, 3.20, 3.21 4.5, 4.6, 4.7, 4.8, 4.9, or any range or value therein. Non-limiting examples include: no preservatives, 0.1% to 2% m-cresol (e.g., 0.2%, 0.3%, 0.4%, 0.5%, 0.9%, 1.0%), 0.1% to 3% benzyl alcohol (e.g., 0.5%, 0.9%, 1.1%, 1.5%, 1.9%, 2.0%, 2.5%), 0.001% to 0.5% thimerosal (e.g., 0.005%, 0.01%), 0.001% to 2.0% phenol (e.g., 0.05%, 0.25%, 0.05%). .28%, 0.5%, 0.9%, 1.0%), 0.0005% to 1.0% alkyl paraben (e.g., 0.00075%, 0.0009%, 0.001%, 0.002%, 0.005%, 0.0075%, 0.009%, 0.01%, 0.02%, 0.05%, 0.075%, 0.09%, 0.1%, 0.2%, 0.3%, 0.5%, 0.75%, 0.9%, 1.0%), and the like.

[0183] As noted above, the methods of the present invention utilize an article of manufacture comprising packaging material and at least one vial containing a solution of at least one anti-IL-23-specific antibody with a specified buffer and / or preservative (optionally dissolved in an aqueous diluent), wherein the packaging material comprises a label indicating that the solution can be stored for a period of 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 18 hours, 20 hours, 24 hours, 30 hours, 36 hours, 40 hours, 48 ​​hours, 54 hours, 60 hours, 66 hours, 72 hours, or longer. The present invention also utilizes an article of manufacture comprising packaging material, a first vial, and a second vial, wherein the first vial contains a lyophilized anti-IL-23-specific antibody and the second vial contains an aqueous diluent with a specified buffer or preservative, wherein the packaging material comprises a label instructing the patient to reconstitute the anti-IL-23-specific antibody in the aqueous diluent to form a solution that can be stored for a period of 24 hours or longer.

[0184] The anti-IL-23-specific antibodies used according to the present invention can be produced by recombinant means, including production from mammalian cells or transgenic preparations, or can be purified from other biological sources, as described herein or as known in the art.

[0185] Ranges for anti-IL-23 specific antibodies include amounts resulting after reconstitution, if in a wet / dry system, from about 1.0 μg / ml to about 1000 mg / ml concentrations, although lower and higher concentrations are possible and depend on the intended delivery vehicle, e.g., solution formulations will vary from transdermal patches, pulmonary, transmucosal, or osmotic or micropump approaches.

[0186] Preferably, the aqueous diluent also optionally comprises a pharmaceutically acceptable preservative.Preferred preservative comprises those preservatives selected from the group consisting of the following: phenol, meta-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parahydroxybenzoate (methyl ester, ethyl ester, propyl ester, butyl ester etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal or their mixture.The concentration of the preservative used in the preparation is the concentration that is enough to produce antimicrobial action.This concentration depends on selected preservative and is easily determined by technical staff.

[0187] Other excipients such as isotonic agents, buffers, antioxidants and preservatives can be optionally and preferably added to the diluent. Isotonic agents such as glycerol are often used at known concentrations. Preferably, a physiologically tolerated buffer is added to provide improved pH control. The preparation can cover a wide pH range, such as about pH 4 to about pH 10, with a preferred range being about pH 5 to about pH 9, and a most preferred range being about 6.0 to about 8.0. Preferably, the preparation of the present invention has a pH between about 6.8 and about 7.8. Preferred buffers include phosphate buffers, most preferably sodium phosphate, particularly phosphate buffered saline (PBS).

[0188] Other additives, such as pharmaceutically acceptable solubilizers, such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymer) and PEG (polyethylene glycol) or nonionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, Polyols, other block copolymers, and chelates such as EDTA and EGTA can optionally be added to the formulation or composition to reduce aggregation. These additives are particularly useful if a pump or plastic container is used to administer the formulation. The presence of a pharmaceutically acceptable surfactant reduces the tendency of the protein to aggregate.

[0189] The formulation can be prepared by a method comprising mixing at least one anti-IL-23-specific antibody and 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. The at least one anti-IL-23-specific antibody and preservative are mixed in the aqueous diluent using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a measured amount of the at least one anti-IL-23-specific antibody in a buffer solution is combined with the desired preservative in a buffer solution in an amount sufficient to provide the desired concentration of protein and preservative. Variations of this method will be recognized by those of ordinary skill in the art. For example, the order of addition of the ingredients, whether additional additives are used, and the temperature and pH during formulation preparation are all factors that can be optimized based on the concentration and mode of administration used.

[0190] These formulations can be provided to patients as clear solutions or as dual vials comprising one vial of lyophilized anti-IL-23-specific antibody reconstituted with a second vial containing water, a preservative, and / or an excipient in an aqueous diluent, preferably a phosphate buffer and / or saline and selected salts. Both the single solution vial and the dual vial requiring reconstitution can be reused multiple times and can satisfy single or multiple cycles of patient treatment, and thus can provide a more convenient treatment regimen than currently available treatment regimens.

[0191] The articles of manufacture of the present invention can be used for administration from immediately to 24 hours or longer. Thus, the articles of manufacture of the present invention provide significant advantages for patients. The formulations of the present invention can optionally be safely stored at temperatures of about 2°C to about 40°C and maintain the biological activity of the protein for extended periods of time, thereby allowing package labels to indicate that the solution can be kept and / or used within a period of 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 96 hours or longer. If a preservative diluent is used, such labeling can include a shelf life of up to 1-12 months, six months, one and a half years, and / or two years.

[0192] Solutions of anti-IL-23 specific antibodies can be prepared by a method comprising mixing at least one antibody in an aqueous diluent. Mixing is performed using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, a measured amount of at least one antibody in water or a buffer is combined in an amount sufficient to provide the protein and optional preservative or buffer to the desired concentration. Variations of this method will be recognized by those of ordinary skill in the art. For example, the order in which the ingredients are added, whether additional additives are used, and the temperature and pH during formulation preparation are all factors that can be optimized based on the concentration and mode of administration used.

[0193] The claimed product can be provided to patients as a clear solution or as a dual vial comprising one vial of lyophilized at least one anti-IL-23 specific antibody reconstituted with a second vial of an aqueous diluent. Both the single solution vial and the dual vial requiring reconstitution can be reused multiple times and can satisfy single or multiple cycles of patient treatment, thereby providing a more convenient treatment regimen than currently available treatment options.

[0194] The claimed product can be provided indirectly to patients by providing a clear solution or dual vials to pharmacies, clinics, or other such institutions and facilities, wherein the dual vials include one vial of lyophilized at least one anti-IL-23-specific antibody that is reconstituted with a second vial of an aqueous diluent. In this case, the volume of the clear solution can be up to one liter or even larger, thereby providing a large reservoir from which smaller portions of the at least one antibody solution can be withdrawn one or more times for transfer to smaller vials and provided to their customers and / or patients by the pharmacy or clinic.

[0195] Recognized devices that include a single vial system include pen-type injector devices for delivering solutions, such as the BD Pen, BD Pen, and Genotronorm Humatro Reco- Roferon J-tip Needle-Free Suitable devices are manufactured or developed, for example, by Becton Dickensen (Franklin Lakes, NJ, www.bectondickenson.com); Disetronic (Burgdorf, Switzerland, www.disetronic.com); Bioject, Portland, Oregon (www.bioject.com); National Medical Products, Weston Medical (Peterborough, UK, www.weston-medical.com); Medi-Ject Corp (Minneapolis, MN, www.mediject.com), and similar suitable devices. Recognized devices that include dual-vial systems include those pen-type injector systems for reconstituting a lyophilized drug in a cartridge that delivers the reconstituted solution, such as Examples of other suitable devices include pre-filled syringes, autoinjectors, needle-free syringes, and needle-free IV infusion sets.

[0196] These products may include packaging materials. In addition to providing information required by regulatory agencies, the packaging materials also provide information on the conditions under which the product may be used. For dual-vial, wet / dry products, the packaging materials of the present invention provide instructions to the patient: where applicable, reconstitute the at least one anti-IL-23 antibody in an aqueous diluent to form a solution and use the solution within a period of 2 to 24 hours or longer. For single-vial, solution products, prefilled syringes, or autoinjectors, the label indicates that the solution can be used within 2 to 24 hours or longer. The products are suitable for use as human pharmaceutical products.

[0197] The formulations used in the methods of the present invention can be prepared by the following method: the method comprises mixing the anti-IL-23 antibody with a selected buffer, preferably a phosphate buffer containing saline or a selected salt. The anti-IL-23 antibody and buffer are mixed in an aqueous diluent using conventional dissolution and mixing procedures. For example, to prepare a suitable formulation, a measured amount of at least one antibody in water or buffer is mixed with the desired buffer in an amount of water sufficient to provide the desired concentrations of protein and buffer. Variations on this method will be recognized by those of ordinary skill in the art. For example, the order in which the ingredients are added, whether additional additives are used, and the temperature and pH during formulation preparation are all factors that can be optimized based on the concentration and mode of administration used.

[0198] The method of the present invention provides pharmaceutical compositions, and these pharmaceutical compositions include various preparations useful and acceptable for administering to human or animal patients. Use "standard state" water as diluent and conventional methods well known to those of ordinary skill in the art to prepare such pharmaceutical compositions. For example, a buffer component (such as histidine and histidine monohydrochloride hydrate) can be first provided, and then a suitable non-final volume of water diluent, sucrose and polysorbate 80 can be added under "standard state". The separated antibody can then be added. Finally, using water as diluent, the volume of the pharmaceutical composition is adjusted to the required final volume under "standard state" conditions. Those skilled in the art will recognize that many other methods are applicable to the preparation of pharmaceutical compositions.

[0199] These pharmaceutical compositions can be aqueous solutions or suspensions, which contain each component of a specified mass per unit volume of water or have a specified pH under "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 represent a single art-recognized temperature or pressure, but rather a reference state, which is specified to describe the temperature and pressure of a solution or suspension with a specific composition under reference to the "standard conditions". This is because the volume fraction of a solution is a function of temperature and pressure. Those skilled in the art will recognize that pharmaceutical compositions comparable to those disclosed herein can be produced at other temperatures and pressures. Whether such pharmaceutical compositions are identical to those disclosed herein should be determined under the "standard conditions" conditions determined above (e.g., 25°C + / - 2°C and a pressure of 1 atmosphere).

[0200] Importantly, such pharmaceutical compositions can contain a component mass of "about" a certain value (e.g., "about 0.53 mg L-histidine") per unit volume of the pharmaceutical composition or have a pH value of about a certain value. If the separated antibody present in the pharmaceutical composition is able to bind to the peptide chain while the separated antibody is present in the pharmaceutical composition or after the separated antibody is removed from the pharmaceutical composition (e.g., by dilution), then the component mass or pH value present in the pharmaceutical composition is "about" a given value. In other words, a value such as a component mass value or pH value is "about" a given value when the binding activity of the separated antibody is maintained and detectable after the separated antibody is placed in the pharmaceutical composition.

[0201] Competitive binding assays were performed to determine whether IL-23-specific mAbs bind to similar or different epitopes and / or compete with each other. Abs were individually coated on ELISA plates. Competing mAbs were added, followed by biotinylated hrIL-23. For a positive control, the same mAb was coated as a competing mAb ("self-competition"). IL-23 binding was detected using streptavidin. These results demonstrate whether the mAbs recognize similar or partially overlapping epitopes on IL-23.

[0202] In one embodiment of the pharmaceutical composition, the isolated antibody is present at a concentration of about 77 mg to about 104 mg per ml of the pharmaceutical composition. In another embodiment of the pharmaceutical composition, the pH is about 5.5 to about 6.5.

[0203] The stable or preserved formulation can be provided to patients as a clear solution or as a dual vial comprising one vial of lyophilized at least one anti-IL-23 antibody reconstituted with a second vial containing a preservative or buffer and excipients in an aqueous diluent. Either the single solution vial or the dual vial requiring reconstitution can be reused multiple times and can satisfy single or multiple cycles of patient treatment, thereby providing a more convenient treatment regimen than currently available treatment regimens.

[0204] Other formulations or methods for stabilizing anti-IL-23 antibodies can produce solutions other than clear solutions containing a lyophilized powder of the antibody. Among the non-clear solutions are formulations containing suspensions of particles, which are compositions containing anti-IL-23 antibodies having structures of varying sizes and are each referred to as microspheres, microparticles, nanoparticles, nanospheres, or liposomes. Such relatively uniform, substantially spherical particle formulations containing the active agent can be formed by contacting an aqueous phase containing the active agent and polymer with a non-aqueous phase, followed by evaporation of the non-aqueous phase to allow the particles to coalesce from the aqueous phase, as taught in U.S. Patent No. 4,589,330. Porous microparticles can be prepared using a first phase containing the active agent and polymer dispersed in a continuous solvent and removing the solvent from the suspension by freeze drying or dilution-extraction-precipitation, as taught in U.S. Patent No. 4,818,542. Preferred polymers for such preparations are natural or synthetic copolymers or polymers selected from the group consisting of gelatin agar, starch, arabinogalactan, albumin, collagen, polyglycolic acid, polylactic acid, glycolide-L(-)lactide, poly(ε-caprolactone), poly(ε-caprolactone-co-lactic acid), poly(ε-caprolactone-co-glycolic acid), poly(β-hydroxybutyric acid), polyethylene oxide, polyethylene, poly(2-alkyl cyanoacrylate), poly(hydroxyethyl methacrylate), polyamide, poly(amino acid), poly(2-hydroxyethyl DL-asparagine), poly(ester urea), poly(L-phenylalanine / ethylene glycol / 1,6-diisocyanatohexane) and poly(methyl methacrylate). Particularly preferred polymers are polyesters such as polyglycolic acid, polylactic acid, glycolide-L(-)lactide, poly(ε-caprolactone), poly(ε-caprolactone-co-lactic acid), and poly(ε-caprolactone-co-glycolic acid). Solvents that can be used to dissolve the polymer and / or active agent include water, hexafluoroisopropanol, methylene chloride, tetrahydrofuran, hexane, benzene, or hexafluoroacetone sesquihydrate. Dispersing the active agent-containing phase with the second phase can involve applying pressure to force the first phase through an orifice in a nozzle to achieve droplet formation.

[0205] Dry powder formulations can be produced by methods other than freeze drying, such as by 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 preparations is taught in U.S. Patent No. 6,019,968. Antibody-based dry powder compositions can be prepared by spray-drying a solution or slurry of the antibody and optional excipients in a solvent under conditions that provide an inhalable dry powder. The solvent can include polar compounds that can be easily dried, such as water and ethanol. The stability of the antibody can be enhanced by performing the spray drying procedure in the absence of oxygen, such as under a nitrogen blanket or by using nitrogen as a drying gas. Another relatively dry formulation is a dispersion of multiple perforated microstructures dispersed in a suspending medium, the suspending medium typically containing a hydrofluorocarbon propellant, as taught in WO 9916419. The stabilized dispersion can be administered to the patient's lungs using a metered dose inhaler. Equipment that can be used in the commercial preparation of spray-dried drugs is manufactured by Buchi Ltd. or Niro Corp.

[0206] The anti-IL-23 antibodies in the stable or preserved formulations or solutions described herein can be administered to patients according to the present invention via a variety of delivery methods, including SC or IM injection; transdermal, pulmonary, transmucosal, implants, osmotic pumps, cartridges, minipumps, or other means known to those skilled in the art, as are well known in the art.

[0207] Therapeutic applications

[0208] The present invention also provides methods of using at least one IL-23 antibody of the present invention to modulate or treat ulcerative colitis in a cell, tissue, organ, animal, or patient as known in the art or as described herein, e.g., administering a therapeutically effective amount of an IL-23-specific antibody to the cell, tissue, organ, animal, or patient, or contacting the cell, tissue, organ, animal, or patient with the therapeutically effective amount of the antibody.

[0209] Any of the methods of the present invention may comprise administering an effective amount of a composition or pharmaceutical composition comprising an anti-IL-23 antibody to a cell, tissue, organ, animal, or patient in need of such modulation, treatment, or therapy. Such methods may optionally further comprise co-administration or combination therapy for treating such diseases or disorders, wherein administration of the at least one anti-IL-23 antibody, specified portion, or variant thereof further comprises prior to, concurrently with, and / or subsequent to the administration of at least one agent selected from the group consisting of: at least one TNF antagonist (e.g., a chemical or protein antagonist of TNF, a monoclonal or polyclonal antibody or fragment of TNF, a soluble TNF receptor (e.g., p55, p70, or p85) or a fragment thereof, a fusion polypeptide, or a small molecule TNF antagonist such as TNF binding protein I or II (TBP-1 or TBP-II), nerimumab, infliximab, etanercept (Enbrel), TM ), adalimumab (Humira TM), CDP-571, CDP-870, afelimomab, lenafemab, etc.), antirheumatic drugs (e.g., methotrexate, auranofin, gold thioglucosinolate, azathioprine, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxants, narcotics, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blockers, antimicrobial agents (e.g., aminoglycosides, antifungals, antiparasitics, antivirals, carbapenems, cephalosporins, fluoroquinolones, macrolides, penicillins, sulfonamides, tetracyclines, other antimicrobial agents), antipsoriatic agents, corticosteroids, anabolic steroids, diabetes-related medications, minerals, nutrients, thyroid agents, vitamins, calcium-related hormones, antidiarrheals, antitussives, antiemetics The present invention relates to an agent that is administered orally. The present invention relates to an agent that is administered orally. The present invention relates to an agent that is administered orally. The present invention relates to an agent that is administered orally. The present invention relates to an agent that is administered orally. The present invention relates to an agent that is administered orally. The present invention relates to an agent that is administered orally. See, e.g., Wells et al., eds., “Pharmacotherapy Handbook,” 2nd ed., 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, 21st ed.,” Springhouse Corp., Springhouse, PA, 2001; “Health Professional's Drug Guide 2001,” Shannon, Wilson, Stang, eds., Prentice-Hall, Inc, Upper Saddle River, NJ, each of which is incorporated herein by reference in its entirety.

[0210] Medical treatment

[0211] Typically, treatment of ulcerative colitis is achieved 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, amounts in the range of at least about 0.01 mg to 500 mg of anti-IL-23 antibody per kg of patient per dose, preferably at least about 0.1 mg to 100 mg of antibody per kg of patient per single or multiple administrations. Alternatively, effective serum concentrations may include serum concentrations of 0.1 μg / ml to 5000 μg / ml per single or multiple administrations. Appropriate dosages are known to medical practitioners and, of course, depend on the specific disease state, the specific activity of the composition to be administered, and the specific patient undergoing treatment. In some cases, to achieve the desired therapeutic amount, it may be necessary to provide repeated administrations, i.e., repeated single administrations of a specific monitoring dose or metered dose, wherein the single administrations may be repeated until the desired daily dose or effect is achieved.

[0212] Preferred dosages may optionally include 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22mg / kg, 23mg / kg, 24mg / kg, 25mg / kg, 26mg / kg, 27mg / kg, 28mg / kg, 29mg / kg, 30mg / kg, 31mg / kg, 32mg / kg, 33mg / kg, 34mg / kg, 35mg / kg, 36mg / kg, 37mg / kg, 38mg / kg, 39mg / kg, 40mg / kg, 41mg / kg, 42mg / kg, 43mg / kg, 44mg / kg, 45mg / kg, 46mg / kg, 47mg / kg, 48mg / kg, 49mg / kg, 50mg / kg, 51mg / kg, 52mg / kg, 53mg / kg, 54mg / kg, 55mg / kg, 56mg / kg, 57mg / kg, 58mg / kg, 59mg / kg, 60mg / kg, 62mg / kg, 63mg / kg, 64mg / kg, 65mg / kg, 66mg / kg, 67mg / kg, 68mg / kg, 6 9mg / kg, 70mg / kg, 71mg / kg, 72mg / kg, 73mg / kg, 74mg / kg, 75mg / kg, 76mg / kg, 77mg / kg, 78mg / kg, 79mg / kg, 80mg / kg, 81mg / kg, 82mg / kg, 83mg / kg, 84mg / kg, 85 mg / kg, 86 mg / kg, 87 mg / kg, 88 mg / kg, 89 mg / kg, 90 mg / kg, 91 mg / kg, 92 mg / kg, 93 mg / kg, 94 mg / kg, 95 mg / kg, 96 mg / kg, 97 mg / kg, 98 mg / kg, 99 mg / kg and / or 100 mg / kg to 500 mg / kg / administration, or any range, value or fraction thereof, or for achieving the following serum concentrations: 0.1 μg / ml, 0.5 μg / ml, 0.9 μg / ml, 1.0 μg / ml, 1.1 μg / ml, 1.2 μg / ml, 1.5 μg / ml, 1.9 μg / ml, 2.0μg / ml、2.5μg / ml、2.9μg / ml、3.0μg / ml、3.5μg / ml、3.9μg / ml、4.0μg / ml、4.5μg / ml、4.9μg / ml、5.0μg / ml、5.5μg / ml、5.9μg / ml、6.0μg / ml、6.5μg / ml、6.9μg / ml、7.0μg / ml、7.5μg / ml、7.9μg / ml、8.0μg / ml、8.5μg / ml、8.9μg / ml、9.0μg / ml、9.5μg / ml、9.9μg / ml、10μg / ml、10.5μg / ml、10.9μg / ml、11μg / ml、11.5μg / ml、11.9μg / ml、20μg / ml、12.5μg / ml、12.9μg / ml、13.0μg / ml、13.5μg / ml、13.9μg / ml、14.0μg / ml、14.5μg / ml、4.9μg / ml、5.0μg / ml、5.5μg / ml、5.9μg / ml、6.0μg / ml、6.5μg / ml、6.9μg / ml、7.0μg / ml、7.5μg / ml、7.9μg / ml、8.0μg / ml、8.5μg / ml、8.9μg / ml、9.0μg / ml、9.5μg / ml、9.9μg / ml、10μg / ml、10.5μg / ml、10.9μg / ml、11μg / ml、11.5μg / ml、11.9μg / ml、12μg / ml、12.5μg / ml、12.9μg / ml、13.0μg / ml、13.5μg / ml、13.9μg / ml、14μg / ml、14.5μg / ml、15μg / ml、15.5μg / ml、15.9μg / ml、16μg / ml、16.5μg / ml、16.9μg / ml、17μg / ml、17.5μg / ml、17.9μg / ml、18μg / ml、18.5μg / ml、18.9μg / ml、19μg / ml、19.5μg / ml、19.9μg / ml、20μg / ml、20.5μg / ml、20.9μg / ml, 21μg / ml, 22μg / ml, 23μg / ml, 24μg / ml, 25μg / ml, 26μg / ml, 27μg / ml, 28μg / ml, 29μg / ml, 30μg / ml, 35μg / ml, 40μ g / ml, 45μg / ml, 50μg / ml, 55μg / ml, 60μg / ml, 65μg / ml, 70μg / ml, 75μg / ml, 80μg / ml, 85μg / ml, 90μg / ml, 96μg / ml, 100μg / ml, 200 μg / ml, 300 μg / ml, 400 μg / ml, 500 μg / ml, 600 μg / ml, 700 μg / ml, 800 μg / ml, 900 μg / ml, 1000 μg / ml, 1500 μg / ml, 2000 μg / ml, 2500 μg / ml, 3000 μg / ml, 3500 μg / ml, 4000 μg / ml, 4500 μg / ml and / or 5000 μg / ml serum concentration per single or multiple administrations, or any range, value or fraction thereof.

[0213] Alternatively, the dosage administered may vary depending on known factors, such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the age, health, and weight of the recipient; the nature and extent of symptoms, the type of concurrent treatment, the frequency of treatment, and the desired effect. Typically, the dosage of the active ingredient may be about 0.1 mg / kg to 100 mg / kg body weight. Typically, 0.1 mg / kg to 50 mg / kg, preferably 0.1 mg / kg to 10 mg / kg, per administration or in sustained-release form is effective to achieve the desired results.

[0214] As a non-limiting example, the treatment of a human or animal may be on at least one of days 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, or alternatively or in addition thereto, in sections 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, 49 100 mg / kg (such as 0.5, 0.9, 1.5, 2.5, 3.5, 4.5, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0, or 20.0 mg / kg daily, or any combination thereof, for at least one of weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or alternatively or additionally, for at least one of 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, using a single dose, an infusion dose, or repeated doses of 0.1 mg / kg to 100 mg / kg (such as 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / kg) of at least one antibody of the invention.

[0215] Dosage forms (compositions) suitable for internal administration typically contain from about 0.001 mg to about 500 mg of active ingredient per unit or container. In these pharmaceutical compositions, based on the total weight of the composition, the active ingredient generally will be present in an amount of from about 0.5% by weight to 99.999% by weight.

[0216] For parenteral administration, the antibody can be formulated as a solution, suspension, emulsion, granule, powder or lyophilized powder, which is provided in combination or separately with a pharmaceutically acceptable parenteral medium. Examples of such media are water, saline, Ringer's solution, dextrose solution and 1% to 10% human serum albumin. Liposomes and non-aqueous media such as fixed oils can also be used. The medium or lyophilized powder may contain additives to maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives). The formulation can be sterilized by known or suitable techniques.

[0217] Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in the field.

[0218] Alternative administration

[0219] Numerous known and developing modes of administration can be used according to the present invention to administer a pharmaceutically effective amount of an anti-IL-23 antibody. Although pulmonary administration is used in the description below, other modes of administration can also be used according to the present invention with suitable results. The IL-23-specific antibodies of the present invention can be delivered as a solution, emulsion, colloid, or suspension in a carrier, or as a dry powder, using any of a variety of devices and methods suitable for administration by inhalation or other modes described herein or known in the art.

[0220] Parenteral preparations and administration

[0221] Preparations for parenteral administration may contain sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of plant origin, hydronaphthalene, etc. as common excipients. Aqueous or oily suspensions for injection can be prepared according to known methods using appropriate emulsifiers or wetting agents and suspending agents. Injectable medicaments can be non-toxic, non-orally administrable diluents such as aqueous solutions, sterile injection solutions, or suspensions in solvents. As available media or solvents, water, Ringer's solution, isotonic saline, etc. are permitted; as common solvents or suspending solvents, sterile fixed oils can be used. For these purposes, any type of fixed oil and fatty acid can be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids; natural or synthetic or semi-synthetic monoglycerides, diglycerides, or triglycerides. Parenteral administration is known in the art and includes, but is not limited to, conventional forms of injection, pneumatic needle-free injection devices as described in US Pat. No. 5,851,198, and laser perforator devices as described in US Pat. No. 5,839,446, which are incorporated herein by reference in their entirety.

[0222] Alternative delivery

[0223] The present invention also contemplates administration of an anti-IL-23 antibody by parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraperitoneal, intracapsular, intracartilaginous, intracavitary, intracavitary, intracerebellar, intracerebroventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, vaginal, rectal, oral, sublingual, intranasal, or transdermal routes. Anti-IL-23 antibody compositions can be prepared for parenteral (subcutaneous, intramuscular or intravenous) or any other administration, particularly in the form of liquid solutions or suspensions; for vaginal or rectal administration, particularly in semisolid form, such as, but not limited to, creams and suppositories; for oral or sublingual administration, such as, but not limited to, tablet or capsule form; or intranasal, such as, but not limited to, powders, nasal drops or aerosols or certain medicament forms; or transdermal, such as, but not limited to, gels, ointments, emulsions, suspensions or patch delivery systems containing chemical enhancers such as dimethyl sulfoxide to alter skin structure or increase drug concentration in transdermal patches (Junginger et al., "Drug Permeation Enhancement", Hsieh, DS, ed., pp. 59-90, (Marcel Dekker, Inc. New York 1994, incorporated herein by reference in its entirety), or containing oxidizing agents that enable the application of formulations containing proteins and peptides to the skin (WO 98 / 53847), or applying an electric field to create a transient transport pathway, such as electroporation, or increasing the mobility of charged drugs through the skin, such as iontophoresis, or applying ultrasound, such as transdermal absorption of ultrasound (U.S. Pat. Nos. 4,309,989 and 4,767,402) (the above publications and patents are incorporated herein by reference in their entirety).

[0224] Having generally described the present invention, the present invention will be more readily understood by reference to the following examples, which are given by way of illustration only 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 in this specification are expressly incorporated herein by reference.

[0225] Example 1 - QUASARUC Study

[0226] Title: A Phase 2b / 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Guselkumab in Participants with Moderately to Severely Active Ulcerative Colitis

[0227] Main objectives :

[0228] The primary objective was to evaluate the clinical efficacy and safety of guselkumab as induction therapy in participants with moderately to severely active UC.

[0229] 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). A schematic diagram of the program is shown in Figure 1 middle.

[0230] Phase 2b Induction Study Design :

[0231] The Phase 2b induction study was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study.

[0232] The target population consists of participants with moderately to severely active ulcerative colitis (UC) who have demonstrated an inadequate response or intolerance failure to conventional therapy (i.e., 6-MP, AZA, or corticosteroids) or advanced therapy (i.e., TNFα antagonists, vedolizumab, or tofacitinib). At Week 1-0, participants must have moderately to severely active UC, defined as a modified Mayo score of 5 to 9 (inclusive), a Mayo rectal bleeding subscore ≥1, and a Mayo endoscopy subscore ≥2, using the Mayo endoscopy subscore obtained during a central visit with videoendoscopy. Note that the program also allows for the inclusion of participants with a modified Mayo score of 4, with an upper limit of ≤5% of the total population. The protocol was modified based on recent feedback from health authorities such that the target population will be based solely on participants with a modified Mayo score of 5 to 9.

[0233] Treatment Allocation: At Week 1-0, participants were randomly assigned in a 1:1:1 ratio to 1 of 3 treatment groups 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 corticosteroid use at baseline (yes / no) as stratification variables:

[0234] Group 1: Placebo IV (Weeks 1-0, 1-4, and 1-8)

[0235] Group 2: Guselkumab 200 mg IV (Weeks 1-0, 1-4, and 1-8)

[0236] Group 3: Guselkumab 400 mg IV (Weeks 1-0, 1-4, and 1-8)

[0237] Duration of Treatment: The main part of this study is 12 weeks.

[0238] Primary endpoint: The primary endpoint was clinical response at Weeks 1-12, defined as a ≥30% decrease in the modified Mayo Clinic score from induction baseline and ≥2 points, with a ≥1-point decrease in the rectal bleeding subscore from baseline or a rectal bleeding subscore of 0 or 1.

[0239] Important secondary endpoints :

[0240] o Clinical remission at Weeks 1-12, defined as stool frequency sub-scored as 0 or 1, rectal bleeding sub-scored as 0, and endoscopy sub-scored as 0 or 1, with absence of friability on endoscopy,

[0241] Among them, the defecation frequency subscore did not increase compared with the induction baseline.

[0242] o Symptom remission at Weeks 1-12, defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, with no increase in the stool frequency subscore from induction baseline.

[0243] o Endoscopic healing at weeks 1-12, defined as an endoscopic subscore of 0 or 1 and absence of endoscopic fragility.

[0244] o Histologic-endoscopic mucosal healing at Weeks 1-12, defined as the combination of histologic healing and endoscopic healing, where histologic healing is defined as neutrophil infiltration of <5% of crypts according to the Geboes grading system, with no crypt destruction and no erosions, ulcers, or granulation tissue.

[0245] o Endoscopic normalization at Weeks 1-12, defined as an endoscopy subscore of 0 (which requires the absence of friability).

[0246] ○ IBDQ remission from Weeks 1-12.

[0247] o Fatigue response at weeks 1-12.

[0248] All participants will be evaluated for clinical response at Weeks 1-12. Further study intervention administration will be determined by the participant's clinical response status at Weeks 1-12 (using Mayo Endoscopy subscores assigned by local endoscopists) as follows:

[0249] Guselkumab clinical responders and placebo clinical responders at Weeks 1-12 will enter the maintenance study.

[0250] Participants initially randomized to the placebo group who are not in clinical response at Weeks 1-12 will then crossover to the guselkumab group and receive three doses of guselkumab 200 mg IV at Weeks 1-12, 1-16, and 1-20.

[0251] Participants initially randomized to the guselkumab group who are not in clinical response at Weeks 1-12 will then receive three doses of guselkumab 200 mg SC at Weeks 1-12, 1-16, and 1-20.

[0252] To maintain blinding, all participants who were not in clinical response at Weeks 1-12 were given IV and SC administration.

[0253] Participants who were not in clinical response at Week 1-12 will be re-evaluated for clinical response at Week 1-24 (clinical response status will be based on Mayo Endoscopy subscore assigned by the local endoscopist). In addition to guselkumab clinical responders and placebo clinical responders at Week 1-12, the following participants from Induction Study 1 will enter the maintenance study:

[0254] Placebo Crossover Responders: Participants who were initially randomized to the placebo group, were not in clinical response at Weeks 1-12, then crossed over to induction treatment with guselkumab 200 mg IV, and achieved clinical response at Weeks 1-24.

[0255] Guselkumab Week 24 Responders: Participants initially randomized to the guselkumab group who are not in clinical response at Weeks 1-12 will then receive 3 doses of guselkumab 200 mg SC at Weeks 1-24 and achieve clinical response.

[0256] Participants who are not in clinical response at Weeks 1-24 will not receive further study intervention and should undergo a safety follow-up approximately 12 weeks after their last dose of study intervention.

[0257] All UC-specific medical therapies (i.e., oral 5-aminosalicylic acid [5-ASA] compounds, oral corticosteroids, 6-MP, AZA, or MTX) must be maintained at a stable dose until the end of Induction Study 1, and dose interruptions or reductions may be made only if necessary due to toxicity or medical necessity at the investigator's discretion. Initiating or increasing the dose of UC-specific therapy (or any restricted / prohibited medication or therapy) during Induction Study 1 will prohibit participants from entering the maintenance study. Efficacy, PK parameters, biomarkers, and safety will be assessed according to the SoA.

[0258] An interim analysis will be performed on the first 150 randomized participants who completed the 1-12 week visit or terminated the study participation before the 1-12 week. The purpose of this interim analysis is to select a single induction dose for confirmatory evaluation in a Phase 3 induction study (Induction Study 2). A dose selection committee consisting of sponsor management representatives from clinical, safety, biostatistics, and clinical pharmacology (regardless of the study) will be responsible for selecting the induction dose of guselkumab evaluated in Induction Study 2. While evaluating the data from the first 150 randomized participants, participants will continue to be enrolled in Induction Study 1, up to 390 participants. Once induction dose selection occurs, participants will begin randomization to Induction Study 2.

[0259] In induction study 2, participants were randomized to guselkumab or placebo at a ratio of 3:2 at weeks 1-0, 1-4, and 1-8. The sample size of induction study 2 was targeted at a modified Mayo score of 5 to 9 for at least 560 randomized participants. The selection of the guselkumab induction dose for induction study 2 will be based on the interim analysis of induction study 1. Participants were assigned to the intervention group using permuted block randomization by ADT-failure status (i.e., insufficient response or tolerance failure to the following: TNFα antagonists, vedolizumab, or tofacitinib) (yes / no), region (Eastern Europe, Asia, or other parts of the world), and permuted block randomization stratified by the use of corticosteroids (yes / no) at baseline. At week 1-12, the clinical response of all participants was evaluated. Similar to the method outlined in induction study 1, further research intervention administration will be determined as follows by the clinical response status of the participant at week 1-12 (using the Mayo endoscopy subscore assigned by the local endoscopist):

[0260] Guselkumab clinical responders and placebo clinical responders at Weeks 1-12 will enter the maintenance study.

[0261] Participants initially randomized to placebo who are not in clinical response at Weeks 1-12 will then cross over to the guselkumab group and receive three doses of guselkumab IV at Weeks 1-12, 1-16, and 1-20 (i.e., the induction dose selected based on the interim analysis of Induction Study 1).

[0262] Participants initially randomized to the guselkumab group who are not in clinical response at Weeks 1-12 will then receive three doses of guselkumab 200 mg SC at Weeks 1-12, 1-16, and 1-20.

[0263] To maintain blinding, all participants who were not in clinical response at Weeks 1-12 were given IV and SC administration.

[0264] Participants who were not in clinical response at Week 1-12 will be re-evaluated for clinical response at Week 1-24 (clinical response status will be based on Mayo Endoscopy subscore assigned by the local endoscopist). In addition to guselkumab clinical responders and placebo clinical responders at Week 1-12, the following participants from Induction Study 2 will enter the maintenance study:

[0265] Placebo-switching responders: Participants who were initially randomized to placebo, were not in clinical response at Weeks 1-12, then crossed over to the induction IV dose of guselkumab and achieved a clinical response at Weeks 1-24.

[0266] Guselkumab Week 24 Responders: Participants initially randomized to the guselkumab group who are not in clinical response at Weeks 1-12 will then receive 3 doses of guselkumab 200 mg SC at Weeks 1-24 and achieve clinical response.

[0267] Participants who are not in clinical response at Weeks 1-24 will not receive further study intervention and should undergo a safety follow-up approximately 12 weeks after their last dose of study intervention.

[0268] All UC-specific medical therapies (i.e., oral 5-ASA compounds, oral corticosteroids, 6-MP, AZA, or MTX) must be maintained at a stable dose until the end of Induction Study 2, and dose interruptions or reductions may be made only if necessary due to toxicity or medical necessity at the discretion of the investigator. Initiation or increase in the dose of UC-specific therapy (or any restricted / prohibited medication or therapy) during Induction Study 2 will prohibit the participant from entering the maintenance study.

[0269] result

[0270] Summary of Top-Line Phase 2b Results

[0271] A total of 327 participants were randomized and dosed at 141 sites in 27 countries. Most (47.4%) participants were from Eastern Europe, with the remainder located in Asia (23.2%) and elsewhere in the world (29.4%). Of note, one participant was randomized but never received the study intervention.

[0272] Among the randomized and treated participants, 313 (95.7%) had a modified Mayo Clinic score of 5 to 9 (the target population for the following efficacy and safety analyses).

[0273] Disposition and Baseline Characteristics of the Full Analysis Set (n=313) :

[0274] Overall, 9 (2.9%) participants discontinued study treatment before Weeks 1-12. There were 5 discontinuations in the placebo group (4.8%), 3 (3.0%) in the 200 mg IV guselkumab group, and 1 (0.9%) in the 400 mg IV guselkumab group. For the placebo group, 4 of the 5 discontinuations were due to reasons indicated by lack of efficacy. The most common reasons for discontinuation of treatment before Weeks 1-12 were adverse events due to worsening UC (1.0%) and subject withdrawal (1.0%). No participants discontinued study medication before Weeks 1-12 for COVID-19-related reasons.

[0275] Most participants were white (71.6%) and 59.1% were female. The mean age was 41.6 years (range 18 to 84 years). A total of 147 (47.0%) participants had a history of failure of advanced therapy (ADT); 166 (53.0%) failed conventional therapy, but not advanced therapy, and most of these participants (93.4%) were ADT-naive. Approximately 40% of participants received corticosteroids (including budesonide and beclomethasone dipropionate) at baseline, and 21.7% received immunomodulators (6-mercaptopurine, azathioprine, or methotrexate). Approximately 90% of participants had a history of insufficient response, intolerance, or dependence on corticosteroids and / or 6-MP / AZA.

[0276] 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 (ie, Mayo score ≥6 and ≤10), and 17.6% of participants had severe disease (Mayo score>10), and 30% of participants had an endoscopic subclassification of 2 (ie, moderate disease), and 70% of participants had an endoscopic subclassification of 3 (ie, severe disease).

[0277] Baseline demographics (including region), disease characteristics, concomitant UC medications, and UC medication history were generally well balanced across 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%).

[0278] Summary of Efficacy Endpoints :

[0279] o Guselkumab induction therapy (at both doses evaluated) resulted in significantly higher clinical response rates at Weeks 1-12 (primary endpoint).

[0280] o Guselkumab induction therapy (at both doses evaluated) also resulted in higher rates of clinical remission, symptomatic remission, endoscopic healing, and symptomatic remission at Weeks 1-12 compared to placebo.

[0281] Histological-endoscopic mucosal healing and endoscopic normalization.

[0282] Primary End Point :

[0283] Based on a preliminary analysis of clinical responses at Weeks 1 to 12, a significantly greater proportion of participants in the 200 mg IV and 400 mg IV placebo groups had a clinical response at Weeks 1 to 12 compared to the guselkumab group. This study is considered an active study.

[0284] Important secondary endpoints :

[0285] A greater proportion of participants in the 200 mg IV and 400 mg IV guselkumab groups achieved clinical remission, symptom relief, endoscopic healing, and endoscopic normalization at Weeks 1-12 compared with the placebo group.

[0286] For symptom remission, separation between the guselkumab-treated groups and placebo was observed as early as 4 weeks after the first dose and persisted through Weeks 1-12.

[0287] Safety data based on the safety analysis set up to Weeks 1-12 :

[0288] ○ The mean duration of follow-up was similar among treatment groups.

[0289] The proportion of participants reporting 1 or more adverse events (AEs) was not higher in the guselkumab group compared with the placebo group, and no clinically meaningful differences in AE rates were observed in the guselkumab group.

[0290] o The system organ classes (SOCs) with the most frequently reported AEs were infections and infestations (11.5% with guselkumab; 10.5% with placebo), gastrointestinal disorders (9.6% with guselkumab; 17.1% with placebo), and blood and lymphatic system disorders (9.6% with guselkumab; 14.3% with placebo).

[0291] o The most common preferred terms (PT) in the combination guselkumab group were anemia (7.2%), headache (4.3%), and COVID-19 (3.8%).

[0292] o PT for anemia was comparable among treatment groups (9.5% in the placebo group, 6.9% in the guselkumab 200 mg IV group, and 7.5% in the guselkumab 400 mg IV group).

[0293] The proportion of participants who reported one or more serious AEs was not higher in the guselkumab-treated group compared with the placebo group. Most SAEs were exacerbations of UC. No deaths were reported.

[0294] o AEs leading to treatment discontinuation were low and comparable across all treatment groups (2 in the placebo group, 1 in the guselkumab 200 mg IV group, and 0 in the guselkumab 400 mg IV group) (Table 2).

[0295] - The proportion of participants reporting an investigator-identified AE of infection was comparable across treatment groups (11.4% in the placebo group, 12.9% in the guselkumab 200 mg IV group, and 8.4% in the guselkumab 400 mg IV group).

[0296] - Two serious infections were observed, both of which occurred in the placebo group.

[0297] - No active TB cases were reported.

[0298] - No opportunistic infections were reported.

[0299] - There were no cases of malignant tumors.

[0300] - Liver laboratory values ​​were similar across treatment groups through Weeks 1-12. Transaminase elevations were low-grade (Common Terminology Criteria for Adverse Events [CTCAE] Grade 1). No cases met Hy's law criteria (i.e., total bilirubin >2× upper limit of normal [ULN] and aspartate aminotransferase [AST] or ALT ≥3× ULN at the same time point).

[0301] By Weeks 1-12, the incidence of decreased total WBC counts was higher in the guselkumab-treated group compared with placebo. All total WBC abnormalities were CTCAE grade 1 or 2.

[0302] Week 24 Results for Patients Not in Clinical Response at Week 12

[0303] The QUASAR Induction Study 1 (NCT04033445) is a Phase 2b study evaluating guselkumab (GUS) therapy in patients with ulcerative colitis (UC) who have had an inadequate response or are intolerant to conventional therapy (i.e., thiopurines or corticosteroids) or advanced therapy (i.e., tumor necrosis factor alpha antagonists, vedolizumab, or tofacitinib). Patients who had a clinical response at week 12 after IV induction entered the maintenance study, and patients who were not in clinical response were treated for an extended induction period.

[0304] method :

[0305] Included patients had moderately to severely active UC (modified Mayo score of 5 to 9 with a Mayo rectal bleeding subscore ≥1 and a Mayo endoscopy subscore ≥2). Patients were randomized 1:1:1 to IV GUS 200 mg, 400 mg, or placebo (PBO) at weeks 0, 4, and 8. At week 12, patients who were not in clinical response to IV induction received SC treatment (PBO IV → GUS 200 mg IV; GUS 200 mg IV → GUS 200 mg SC at weeks 12, 16, and 20) and were evaluated at week 24.

[0306] Three hundred and thirteen patients underwent randomization at baseline. Demographic and disease characteristics at baseline were similar in the treatment groups (mean age, 41.6 years; 59.1% men; mean UC duration, 7.55 years; mean Mayo Clinic score, 9.2; endoscopic subscore of 3, indicating severe disease, in 70%; and use of oral corticosteroids in 39.9%), with approximately 50% having had an inadequate response or intolerance to prior advanced UC therapy.

[0307] At week 12, at baseline, 27.6% (29 / 105) of patients randomized to PBO IV and 61.4% (62 / 101) and 60.7% (65 / 107) of patients randomized to GUS 200 mg and GUS 400 mg IV, respectively, had a clinical response. Of the patients in the GUS group who were not in clinical response at week 12, 54.3% (19 / 35) of those who received GUS 200 mg IV→200 mg SC and 50.0% (19 / 38) of those who received GUS 400 mg IV→200 mg SC achieved a clinical response at week 24. Tables 16 to 21 show the number of subjects in clinical remission and clinical response at week 24. At Wk 12 or 24, 80.2% of patients who received GUS 200 mg IV→200 mg SC and 78.5% of patients who received GUS 400 mg IV→200 mg SC achieved a clinical response.

[0308] in conclusion

[0309] Patients who did not achieve a clinical response to GUS IV induction at Week 12 showed benefit at Week 24 after receiving three SC doses of GUS, with approximately 80% of patients who received GUS IV or GUS IV→SC achieving a clinical response at Weeks 12 or 24. No new safety concerns were identified with GUS.

[0310] Example 2-3 Phase Study Results

[0311] Phase 3 Induction Study Design :

[0312] The Phase 3 induction study was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study. The target population consisted of participants with moderately to severely active ulcerative colitis (UC) who had demonstrated an inadequate response or intolerance failure to conventional therapy (i.e., 6-mercaptopurine [6-MP], azathioprine [AZA], or corticosteroids) or advanced therapy (ADT; i.e., tumor necrosis factor-α [TNFα] antagonists, vedolizumab, or tofacitinib). At Week 1-0, participants must have moderately to severely active UC, defined as a modified Mayo score of 5 to 9 (inclusive), a Mayo rectal bleeding subscore ≥1, and a Mayo endoscopy subscore ≥2, using the Mayo endoscopy subscore obtained during an in-center videoendoscopy visit. The QUASAR program also allowed enrollment of participants with a modified Mayo score of 4, capped at ≤5% of the total population. The protocol was modified based on feedback from health authorities so that the target population would be based only on participants with a modified Mayo Clinic score of 5 to 9.

[0313] Treatment allocation Participants were randomly assigned in a 3:2 ratio to guselkumab or placebo at Week 1-0 using permuted block randomization with ADT-failure status (i.e., inadequate response or intolerance to a TNFα antagonist, vedolizumab, or tofacitinib) (yes / no), region (Eastern Europe, Asia, or rest of the world), and concomitant corticosteroid use at baseline (yes / no) as stratification variables:

[0314] Group 1: Placebo IV (Weeks 1-0, 1-4, and 1-8)

[0315] Group 2: Guselkumab 200 mg IV (Weeks 1-0, 1-4, and 1-8)

[0316] Duration of treatment : The main part of this study is 12 weeks.

[0317] This report provides results for the primary and key secondary endpoints from Weeks 1-12, as well as safety through Weeks 1-12.

[0318] Primary End Point : The primary endpoint was clinical remission at weeks 1-12, defined as Mayo stool frequency subscore of 0 or 1 with no increase from baseline, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1 with no friability on endoscopy.

[0319] Important secondary endpoints :

[0320] Symptom relief at Weeks 1-12: Stool frequency sub-scored as 0 or 1 and no increase from baseline, and rectal bleeding sub-scored as 0.

[0321] Endoscopic healing at weeks 1-12: Endoscopic subscore of 0 or 1, absence of friability on endoscopy.

[0322] Clinical response at Weeks 1-12: A decrease of ≥30% and ≥2 points in the modified Mayo Clinic score compared with baseline, with a decrease of ≥1 point in the rectal bleeding subscore compared with baseline or a rectal bleeding subscore of 0 or 1 point.

[0323] Symptom relief during weeks 1-4.

[0324] Inflammatory Bowel Disease Questionnaire (IBDQ) remission at Weeks 1-12: Total IBDQ score ≥ 170.

[0325] Histological-endoscopic mucosal healing at Weeks 1-12: A combination of histological and endoscopic healing was achieved, where endoscopic healing was defined above and histological healing was defined as neutrophil infiltration of <5% of crypts according to the Geboes grading system, with no crypt destruction and no erosions, ulcers, or granulation tissue.

[0326] • Fatigue response at Weeks 1-12: ≥7-point improvement on PROMIS-Fatigue Short Form 7a.

[0327] Symptom relief in weeks 1-2.

[0328] Endoscopic normalization at week 1-12: Endoscopic subscore of 0

[0329] All key secondary endpoints were 90% effective, except for the endpoints of symptom relief at Weeks 1-2 and endoscopic normalization at Weeks 1-12.

[0330] Statistical considerations :

[0331] Efficacy Analysis Set: The full analysis set included all randomized participants with a modified Mayo Clinic score of 5 to 9 who received at least one dose (partial or complete) of the study intervention. Participants were analyzed according to their randomization or assigned study intervention, regardless of the study intervention they actually received.

[0332] Safety Analysis Set: The safety analysis set included all randomized participants with a modified Mayo score of 5 to 9 who received at least one dose (partial or complete) of the study intervention. Results based on the safety fully treated analysis set, which included all randomized participants (regardless of modified Mayo score) who received at least one dose (partial or complete) of the study intervention, are also presented.

[0333] Participants were analyzed according to the study intervention they actually received.

[0334] Intercurrent events (ICEs) were used in the analysis of efficacy endpoints. Specifically, participants who underwent the following before the analysis time point were considered not to have reached the binary endpoint (i.e., composite strategy): UC-related surgery (ostomy or colectomy), a contraindicated change in UC medication, or discontinuation of the study intervention due to reasons other than coronavirus 19 (COVID-19)-related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (including AEs of lack of efficacy or worsening of UC). For participants who discontinued the study intervention due to COVID-19-related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine before the analysis time point, their observed values ​​(i.e., treatment strategy) were used if available.

[0335] Comparison was performed based on the guselkumab group and the placebo group. For the primary endpoint and important secondary endpoints, p values ​​were based on Cochran-Mantel-Haenszel (CMH) (2-sided), which was stratified by ADT-failure status (yes / no) and concomitant use of corticosteroids (yes / no) at baseline. The 95% confidence interval was based on Wald statistics with CochranMantel-Haenszel weights. For these endpoints, participants with missing data at the analysis time point (after taking into account the concurrent event strategy) were considered to be non-responders at that time point.

[0336] Top-line results summary

[0337] A total of 735 participants were randomized and dosed at 240 sites in 32 countries. The majority (41.5%) of participants were from Eastern Europe, with the remainder located in Asia (20.5%) and elsewhere in the world (38.0%). Notably, one participant was randomized to placebo but never received the study intervention. Among the randomized and treated participants, 701 (95.4%) had a modified Mayo Clinic score of 5 to 9 (the target population for the following efficacy and safety analyses).

[0338] Disposition and Baseline Characteristics of the Full Analysis Set (n=701) :

[0339] Overall, 42 (6.0%) participants discontinued the study intervention before Weeks 1-12: 24 (8.6%) in the placebo group and 18 (4.3%) in the 200 mg IV guselkumab group. The most common reasons for discontinuation of the study intervention before Weeks 1-12 were adverse events (2.4%; 1.4% due to worsening UC) and participant withdrawal (2.3%).

[0340] Most participants were white (72.5%) and 56.9% were female. The mean age was 40.5 years (range 18 to 79 years). A total of 344 (49.1%) participants had a history of ADT failure; 357 (50.9%) failed conventional therapy but not advanced therapy ("ADT not failed"), and most of these participants (95.0%) were ADT-naive. Approximately 43.1% of participants received corticosteroids (including budesonide and beclomethasone dipropionate) at baseline, and 20.5% received immunomodulators (6-MP, AZA, or methotrexate). A total of 93.2% of participants had a history of insufficient response, intolerance, or dependence on corticosteroids and / or 6-MP / AZA.

[0341] The enrolled population in this study represented a population with moderately to severely active UC. The mean duration of UC was 7.27 years. The median Mayo score was 9.0 (mean = 9.1), the median modified Mayo score was 7.0 (mean = 6.9), the median fecal calprotectin 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 (ie, Mayo score ≥6 and ≤10), and 17.8% of participants had severe disease (Mayo score >10), and 32.1% of participants had an endoscopic subscore of 2 (ie, moderate disease), and 67.9% of participants had an endoscopic subscore of 3 (ie, severe disease).

[0342] Baseline demographics (including region), disease characteristics, concomitant UC medications, and UC medication history were generally well balanced across treatment groups.

[0343] Summary of Efficacy Endpoints :

[0344] Based on a prespecified multiple testing procedure, guselkumab induction treatment resulted in a significantly greater proportion of participants in clinical remission at Weeks 1-12 (primary endpoint; 22.6%) compared with placebo (7.9%; adjusted treatment difference: 14.9% [95% CI: 9.9%, 19.9%]); the result was highly significant (p < 0.001) (Table 1).

[0345] Induction treatment with guselkumab also resulted in a significantly greater proportion of participants achieving the key secondary endpoint relative to placebo (highly significant, p<0.001).

[0346] Primary End Point Based on the primary analysis of clinical remission at Weeks 1-12, a significantly greater proportion of participants in the 200 mg IV guselkumab group (22.6%) were in clinical remission at Weeks 1-12 compared with placebo (7.9%; adjusted treatment difference: 14.9% [95% CI: 9.9%, 19.9%]; Table 1).

[0347] Important secondary endpoints :

[0348] Based on global and U.S.-specific testing procedures, a significantly greater proportion of participants in the 200 mg IV guselkumab group achieved symptomatic remission (also known as clinical remission) (adjusted treatment difference: 29.5% [95% CI: 22.9%, 36.1%]; Table 10), endoscopic healing (adjusted treatment difference: 16.0% [95% CI: 10.5%, 13.6%]; Table 10), and endoscopic healing (adjusted treatment difference: 16.0% [95% CI: 10.5%, 13.6%]; Table 10) compared with the placebo group.

[0349] 21.4%]; Table 4), clinical response (adjusted treatment difference: 34.2% [95% CI:

[0350] 27.3%, 41.1%]; Table 2), histological-endoscopic mucosal healing (adjusted treatment difference: 15.9% [95% CI: 10.9%, 20.9%]; Table 8), fatigue response (adjusted treatment difference: 19.8% [95% CI: 13.1%, 26.4%]; Table 9), all at Weeks 1-12; and symptom relief at Weeks 1-4 (adjusted treatment difference:

[0351] 10.3% [95% CI: 4.8%, 15.7%]) (Table 10).

[0352] Based on global testing procedures, a significantly greater proportion of participants in the 200 mg IV guselkumab group achieved IBDQ remission at Weeks 1-12 (adjusted treatment difference: 22.1% [95% CI, 2.0-3.0]).

[0353] CI: 15.1%, 29.2%]; Table 7). Note that IBDQ remission at Weeks 1-12 was not considered a significant secondary endpoint in the US-specific testing procedure.

[0354] There was no significant difference between the 200 mg IV guselkumab group and the placebo group in symptom relief at Weeks 1-2 (adjusted treatment difference: 3.0% [95% CI: -1.5%, 7.5%]; Table 10).

[0355] Although a greater proportion of participants in the 200 mg IV guselkumab group achieved endoscopic normalization at Weeks 1-12 compared with the placebo group (adjusted treatment difference: 10.1% [95% CI, 2.0-3.0]), the

[0356] CI: 5.9%, 14.3%]; Table 3), no statistical significance could be claimed for this endpoint,

[0357] Because the previous endpoint in the test classification (symptom relief at weeks 1-2) was not significant.

[0358] For symptom remission, separation between the guselkumab and placebo groups was observed as early as 4 weeks after the first dose and persisted through Weeks 1-12 (Table 10).

[0359] Subgroup analysis by ADT failure status :

[0360] For both the ADT-non-failure and ADT-failure subgroups, greater efficacy was observed with guselkumab compared with placebo for the primary endpoint and all important secondary endpoints (except symptom relief at Weeks 1-2).

[0361] In general, within the treatment group, a greater proportion of participants in the ADT non-failure subgroup met the primary and important secondary end points compared with the ADT failure subgroup.

[0362] With the exception of fatigue responses at Weeks 1-12, treatment effects (relative to placebo) were greater in the ADT non-failure subgroup compared with the ADT failure subgroup in the primary and key secondary endpoints.

[0363] Clinical / symptom response As early as week 2 and increasing through week 12, greater symptom improvement was observed in patients treated with GUS compared to PBO (see Table 14). At weeks 2, 4, 8, and 12, the symptom response (clinical response) achieved by GUS versus PBO was 34.0% versus 23.6%, 53.2% versus 30.0%, 66.0% versus 39.6%, and 71.7% versus 35.0%, respectively (all p<0.01). The percentage of patients achieving symptom relief with GUS versus PBO was 12.1% versus 9.3% at week 2 (p=0.210); and 22.6% versus 12.9%, 39.7% versus 20.7%, and 49.9% versus 20.7% at weeks 4, 8, and 12, respectively (all p<0.001). As shown in Table 15, the mean changes from baseline in the absolute number of stools per day at Weeks 2, 4, 8, and 12 were -1.19 vs. -0.61, -2.05 vs. -0.75, -2.75 vs. -1.31, and -3.15 vs. -1.36 (all p<0.01). The percentages of patients with a stool frequency subclassification of 0 or 1 at Weeks 2, 4, 8, and 12 were 26.1% vs. 18.2%, 41.3% vs. 25.4%, 53.4% ​​vs. 29.6%, and 60.1% vs. 31.8%, respectively (all p<0.05). The mean change from baseline in the rectal bleeding subscore at Weeks 2, 4, 8, and 12 was -0.6 vs. -0.5, -0.8 vs. -0.5, -1.1 vs. -0.6, and -1.2 vs. -0.6, respectively (all p<0.01). The percentage of patients with a rectal bleeding subscore of 0 at Week 2 was 24.2% vs. 19.3% (p=0.110); at Weeks 4, 8, and 12, it was 36.8% vs. 22.9%, 55.8% vs. 33.2%, and 64.6% vs. 28.6%, respectively (all p<0.001). At Week 12, treatment differences were achieved for all endpoints evaluated (Table 14).

[0364] SecurityTable 13 provides an overall summary of adverse events from Weeks 1-12 for the safety analysis set (n=701). In summary, guselkumab 200 mg IV was safe and well tolerated by participants during the 12-week treatment period. No new safety concerns were identified based on adverse events and laboratory studies. Adverse events are discussed below; laboratory observations were consistent with those in the QUASAR Induction Study 1. Similar results were observed for the safety full-treatment analysis set.

[0365] Safety data based on the safety analysis set up to Weeks 1-12 :

[0366] The mean duration of follow-up was similar among the treatment groups.

[0367] 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.

[0368] • The most frequently reported system organ classes (SOC) were infections and infestations (15.7% guselkumab; 15.0% placebo) and gastrointestinal disorders (10.7% guselkumab; 16.4% placebo).

[0369] The most common preferred terms (PT) in the 200 mg IV guselkumab group were COVID-19 (5.0% guselkumab; 4.3% placebo), anemia (4.8% guselkumab;

[0370] 6.8% placebo) and headache (2.9% guselkumab; 2.9% placebo).

[0371] 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 study intervention. No anaphylaxis or serum sickness reactions were reported.

[0372] Three deaths were reported (1 in the 200 mg IV guselkumab group and 2 in the placebo group).

[0373] A numerically lower proportion of participants reported one or more serious AEs in the 200 mg IV guselkumab group (2.9%) compared to the placebo group (7.5%). Most SAEs were exacerbations of UC (PT: ulcerative colitis: 1.4% in the 200 mg IV guselkumab group and 5.0% in the placebo group).

[0374] • AEs leading to treatment discontinuation were low in the treatment groups (6 [1.4%] in the 200 mg IV guselkumab group and 12 [4.3%] in the placebo group).

[0375] • The proportion of participants reporting an AE of infection was comparable across treatment groups (66 [15.7%] in the 200 mg IV guselkumab group and 42 [15.0%] in the placebo group).

[0376] Four serious infections were reported (3 [0.7%] in the 200 mg IV guselkumab group,

[0377] and 1 case [0.4%] in the placebo group).

[0378] No active tuberculosis (TB) cases were reported.

[0379] One opportunistic infection (PT Cytomegalovirus infection) was reported in the placebo group.

[0380] Two participants in the 200 mg IV guselkumab group reported treatment-emergent malignancies of non-melanoma skin cancer on study days 23 and 32, respectively.

[0381] Liver laboratory values ​​were similar across treatment groups through Weeks 1-12. Transaminase elevations were low grade (Common Terminology Criteria for Adverse Events [CTCAE] Grade 1). No cases met the Ho's Law biochemistry criteria (i.e., total bilirubin ≥ 2 × upper limit of normal [ULN] and aspartate aminotransferase [AST] or alanine aminotransferase [ALT] ≥ 3 × ULN at the same time points).

[0382] Week 24 efficacy and week 32 safety data - At week 12, a higher percentage of patients treated with GUS achieved a clinical response compared to patients treated with PBO. Figure 2 As shown, among GUS-treated patients who did not have a clinical response at week 12, 55% (66 / 120) achieved a clinical response at week 24. 77.2% of patients randomized to GUS 200 mg IV at baseline achieved a clinical response at week 12 or week 24. Patients with or without prior ADT failure benefited from continued treatment with GUS 200 mg SC through week 24. For patients receiving PBO IV→GUS 200 mg IV, the clinical response at week 24 (69.7%) was similar to the clinical response at week 12 after induction with GUS 200 mg IV (61.5%). Figure 2The analyses included only patients with a modified Mayo score of 5-9 at induction baseline. A clinical response was defined as a decrease of ≥30% and ≥2 points from baseline in the modified Mayo score, with a decrease of ≥1 point from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. Patients who underwent the following before the designated time point were considered not to have achieved a clinical response at the designated time point: a contraindicated change in UC medication, ostomy or colectomy, or discontinuation of study medication due to lack of efficacy or AE of worsening UC or reasons other than COVID-19-related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine. Patients who were missing one or more Mayo subscores associated with clinical response at the designated time point were considered not to have achieved a clinical response. Adjusted treatment differences and confidence intervals are based on Wald statistics with Cochran-Mantel-Haenszel weights. p-values ​​are based on Cochran-Mantel-Haenszel chi-square tests, stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0383] As shown in Table 16, safety findings were consistent with the week 12 results; no new safety issues were noted. The most common adverse events in all GUS-treated patients (n=586) were COVID-19 (7.2%), UC exacerbation (4.6%), and anemia (5.1%).

[0384] More than three-quarters of patients with moderately to severely active UC treated with GUS 200 mg IV induction achieved a clinical response by Week 12 or Week 24. No new safety issues with GUS were identified through Week 32 (deaths were reported in two placebo-treated patients and one GUS-treated patient, all of which were cardiovascular in nature. Patients in the GUS group had extensive cardiovascular risk factors). No AEs within one hour of infusion were considered serious or led to treatment discontinuation. The incidence of anti-drug antibodies (ADA) was low (1.5%, 6 / 409) through Week 12, and no ADA-positive subjects had neutralizing antibodies.

[0385] Effects on histology Colonic biopsies were collected during endoscopy at baseline and week 12 to evaluate treatment effects on histology, as measured by three methods: the Geboes-Robarts Histopathology Index (RHI) and the Nancy Histology Index (NHI). Histological improvement, histological remission, histological-endoscopic mucosal improvement (HEMI), and a combination of histological remission and endoscopic normalization (deep HEMI) were evaluated at week 12.

[0386] Histological activity at baseline was similar in the GUS and PBO groups: mean Geboes total score (11.8 vs. 11.9, respectively), mean RHI (16.6 vs. 16.6), and mean NHI (2.7 vs. 2.8). The proportion of patients achieving histological improvement at week 12 was 44.9% among GUS-treated patients and 21.4% among PBO-treated patients (adjusted Δ: 23.7%; nominal p < 0.001; Table 17). 39.9% and 18.6% of patients treated with GUS and PBO, respectively, achieved histological remission (as defined by Geboes) at week 12 (adjusted Δ: 21.5%; nominal p < 0.001). Identical results were observed in two additional definitions of histological remission (i.e., RHI and NHI; Table 17). The proportion of GUS-treated patients who achieved HEMI at week 12 was significantly greater than that of PBO-treated patients (23.5% vs. 7.5%, respectively; adjusted Δ: 16.2%; p < 0.001). Finally, a greater proportion of patients in the GUS group achieved deep HEMI at week 12 compared with the PBO group (13.5% vs. 3.9%, respectively; adjusted Δ: 16.2%; p < 0.001).

[0387] At week 12, patients experienced clinically meaningful improvements in histological and histo-endoscopic findings.

[0388] biomarkers - C-reactive protein (CRP) and fecal calprotectin (FeCal) are non-invasive inflammatory biomarkers used to assess disease activity in UC. In patients with elevated CRP and / or FeCal, the effects of GUS treatment on CRP and FeCal by week 12 are shown in Table 18 and described below. CRP and FeCal were assessed at baseline, week 4, week 8 (for CRP only), and week 12. A total of 701 patients were evaluated in this study, and approximately 50% of randomized patients had a history of inadequate response / intolerance to prior advanced therapy for UC; 47.4% of these patients had an inadequate response / intolerance to two or more classes of advanced therapy. Median baseline concentrations of CRP and FeCal were similar between the GUS-treated and PBO-treated groups (4.34 mg / L vs. 3.83 mg / L and 1651.00 mg / kg vs. 1606.00 mg / kg, respectively).

[0389] In patients with elevated CRP and / or FeCal at baseline, greater reductions in CRP and FeCal were observed at the earliest time point assessed with GUS (week 4) compared to PBO, and were sustained through week 12 (Table 18). At baseline, 248 GUS-treated patients and 160 PBO-treated patients had elevated CRP (>3 mg / L); the proportions were similar between treatment groups (58.9% vs. 57.1%, respectively). Among these patients, the median change from baseline in CRP concentration (mg / L) at week 12 was -3.99 mg / L and -0.51 mg / L for the GUS and PBO groups, respectively (nominal p<0.001). The proportion of patients achieving a 50% and 75% reduction in CRP levels (or ≤3 mg / L) at week 12 was higher for GUS-treated patients than for those receiving PBO (59.7% vs. 28.1% and 47.2% vs. 19.4%, respectively; nominal p<0.001 for both). Similarly, a higher proportion of GUS-treated patients achieved CRP ≤ 3 mg / L at week 12 compared with PBO-treated patients (40.3% vs. 16.3%, nominal p < 0.001), and 39.1% of GUS-treated patients vs. 25.0% of PBO achieved CRP ≤ 3 mg / L at week 8; 34.3% of GUS-treated patients vs. 21.9% of PBO achieved CRP ≤ 3 mg / L at week 4.

[0390] At baseline, 333 GUS-treated patients and 225 PBO-treated patients had elevated FeCal (>250 mg / kg); the proportions were similar between treatment groups (79.1% vs. 80.4%, respectively). The median change from baseline in FeCal concentration (mg / kg) for patients with elevated FeCal at baseline at Week 12 was -800.00 mg / kg and -86.00 mg / kg for the GUS and PBO groups, respectively (nominal p<0.001); the proportion of patients who achieved a 50% and 75% reduction in FeCal levels (or ≤250 mg / kg) at Week 12 was higher for GUS-treated patients than for those receiving PBO (51.1% vs. 33.8% and 41.4% vs. 23.6%, respectively; both nominal p<0.001). A higher proportion of patients treated with GUS achieved FeCal ≤ ​​250 mg / kg at week 12 compared to patients treated with PBO (29.4% vs. 17.3%, nominal p < 0.001), and 14.1% of GUS-treated patients achieved FeCal ≤ ​​250 mg / kg at week 4 compared to 8.9% of PBO.

[0391] Patients with moderately to severely active UC and elevated inflammatory markers who received induction treatment with GUS 200 mg IV compared with PBO showed greater improvements from baseline in CRP and FeCal levels. Differences were observed as early as the first assessment at week 4 and persisted through week 12.

[0392] Results and analysis of phase 3, weeks 1-12

[0393] Early onset of symptomatic improvement was achieved, as shown in Tables 19-25 below. The primary analysis population included all randomized patients with a modified Mayo score of 5-9 who received at least 1 dose (partial or complete) of the study intervention. Symptomatic relief at Weeks 2, 4, and 12 were important secondary endpoints controlled for type 1 error. P values ​​for all other analyses were nominal. Patients who underwent a prohibited change in UC medication, ostomy, or colectomy before Week 12, or who discontinued study medication due to lack of efficacy or adverse events of UC worsening, or for reasons other than COVID-19 related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine, were considered to have not reached the specified binary endpoint, and baseline observations were carried forward to the specified continuous endpoint. Patients who were missing one or more components related to the specified binary endpoint were considered to have not reached the endpoint.

[0394] Guselkumab 200 mg IV induced effective improvement in symptoms in patients with moderately to severely active UC as early as one week after the first dose. Table 19 shows symptom relief achieved as early as one week after the first dose. Table 20 shows symptom responses achieved as early as one week after the first dose. Table 21 shows a stool frequency subscore of 0 or 1 achieved as early as one week after the first dose. Table 22 shows a rectal bleeding subscore of 0 achieved as early as one week after the first dose. Table 23 shows the change in absolute stool count as early as one week after the first dose. Table 24 shows the change in stool frequency and rectal bleeding subscores as early as one week after the first dose. Table 25 shows symptomatic Mayo score improvements achieved as early as two weeks after the first dose. In addition, symptom improvement continued to increase through week 12 with guselkumab treatment.

[0395] Phase 3 Maintenance Study Design:The Phase 3 maintenance study is a randomized withdrawal, double-blind, placebo-controlled, parallel-group, multicenter study. The target population consists of participants with moderately to severely active UC who have a history of inadequate response or intolerance failure to conventional therapy (i.e., 6-MP, AZA, or corticosteroids) or advanced therapy (i.e., TNFα antagonists, vedolizumab, or tofacitinib) who have a clinical response 12 weeks after receiving guselkumab IV induction therapy. At week 1-0, participants must have moderately to severely active UC, defined as a modified Mayo score of 5 to 9 (including endpoints), a Mayo rectal bleeding subscore ≥1, and a Mayo endoscopy subscore ≥2, using the Mayo endoscopy subscore obtained during a central examination with video endoscopy. The QUASAR program also allows for the enrollment of participants with a modified Mayo score of 4, with an upper limit of ≤5% of the total population of the enrolled program. The protocol was modified based on feedback from health management agencies so that the target population should be based only on participants with a modified Mayo score of 5 to 9.

[0396] Treatment allocation Participants who were in clinical response 12 weeks after receiving IV guselkumab induction therapy (i.e., guselkumab clinical responders at Weeks 1-12 and placebo crossover guselkumab responders at Weeks 1-24 from Induction Study 1 or Induction Study 2) were randomized in a 1:1:1 ratio at Week 24 (Maintenance)-0 to one of three treatment groups: (i) placebo SC every 4 weeks (q4w), (ii) guselkumab 100 mg SC every 8 weeks (q8w), and (iii) guselkumab 200 mg SC q4w.

[0397] Participants were assigned to the intervention group by permuted block randomization with maintenance of clinical remission status at baseline (yes / no), maintenance of concomitant corticosteroid use at baseline (yes / no), and induction therapy (guselkumab 400 mg IV, guselkumab 200 mg IV, and placebo IV→guselkumab 200 mg IV) as stratification variables.

[0398] Randomized participants who lost clinical response (i.e., did not meet clinical response criteria) were eligible for a single blinded dose adjustment to receive guselkumab 200 mg SC q4w starting at a visit between Weeks 24-8 and 24-32. In addition to the randomized populations described above, guselkumab-induced 24-week responders and induction placebo responders from Weeks 1-12 of Induction Study 1 or Induction Study 2 entered the maintenance study but were not randomized and were not included in the key efficacy analyses herein.

[0399] Duration of treatment / duration of trial: For this reporting period, treatment duration was 40 weeks, and trial duration was 44 weeks. This report presents results for the primary and important secondary endpoints based on global and US-specific multiple testing procedures.

[0400] Primary End Point : The primary endpoint was clinical remission at week M-44, defined as Mayo stool frequency subscore of 0 or 1 with no increase from induction baseline, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1 with no friability on endoscopy.

[0401] Important secondary endpoints (ranked by global testing program ):

[0402] Symptom relief at Week 24-44: Mayo stool frequency subscore of 0 or 1 and no increase from induction baseline, and Mayo rectal bleeding subscore of 0.

[0403] Endoscopic healing at week 24-44: Mayo endoscopic subclassification of 0 or 1, absence of friability on endoscopy. Corticosteroid-free (ie, no need for any corticosteroid treatment for at least 8 weeks prior) clinical remission at week 24-44.

[0404] Maintenance of Clinical Response at Week M-44: Among subjects who achieved a clinical response while maintaining baseline, a clinical response at Week M-44 was defined as a ≥30% decrease in the modified Mayo Clinic score from induction baseline and ≥2 points, with a ≥1-point decrease in the rectal bleeding subscore from baseline or a rectal bleeding subscore of 0 or 1.

[0405] Histologic-endoscopic mucosal healing at Week 24-44: Achieve a combination of histologic and endoscopic healing, where histologic healing is defined as neutrophil infiltration of <5% of crypts, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue according to the Geboes grading system (i.e., Geboes score ≤ 3.1).

[0406] IBDQ remission at Week 24-44: Total IBDQ score ≥ 170.

[0407] Fatigue response at Week 24-4: Fatigue response compared to baseline on PROMIS-Fatigue Short Form 7a

[0408] Improvement of ≥7 points.

[0409] Maintenance of clinical remission at Week 24-44: Among participants who achieved clinical remission at baseline, maintenance of clinical remission at Week 24-44 was achieved.

[0410] Endoscopic normalization at week M-44: Mayo endoscopy subscore 0.

[0411] Expected effect size and planned sample size : Assuming a clinical remission rate of 25% in the placebo group and 45% in each guselkumab treatment group at Week 24-44 (the assumed rates were based on data from the ustekinumab UC maintenance study [CNTO1275UCO3001]), 118 participants in each randomized group (354 participants total) provided 90% statistical power at a significance level of 0.05 (2-sided) for the primary endpoint. However, the target number in the primary analysis population was increased to 484 participants in order to have at least 90% power for most important secondary endpoints (note that there was no 90% power for the endpoints of maintenance of clinical remission at Week 24-44 and endoscopic normalization at Week 24-44).

[0412] Statistical considerations :

[0413] Efficacy Analysis Set: The full analysis set for randomization included all participants with a modified Mayo Clinic score of 5 to 9 at Week 1-0 who were randomized in this maintenance study and received at least one dose (partial or full) of the study intervention. Participants were analyzed according to their randomized study intervention, regardless of the study intervention they actually received.

[0414] Safety analysis set: The safety analysis set of randomized groups includes all participants with a modified Mayo score of 5 to 9 at week 1-0 who were randomized in this maintenance study and received at least 1 dose (partial or complete) of the study intervention. There are 2 additional safety settings. The first is a safety analysis set, which includes randomized and non-randomized participants with a modified Mayo score of 5 to 9 at week 1-0 treated in this maintenance study, and the second is an analysis set for all treatments, which includes participants with all treatments with a modified Mayo score of 4 to 9 at week 1-0 in this maintenance study. In general, participants are analyzed according to their designated treatment. However, starting from the first guselkumab administration, participants assigned to placebo who did not correctly receive guselkumab at any time were analyzed in the guselkumab group; participants assigned to guselkumab who only received placebo were analyzed in the placebo group.

[0415] Intercurrent events (ICE) and corresponding strategies were applied to the analysis of efficacy endpoints. Participants who underwent the following before the analysis time point were considered not to have reached the binary endpoint (i.e., composite strategy): ostomy or colectomy (ICE1), dose adjustment (including simulated dose adjustment) (ICE2), prohibited change of UC medication (ICE3), or discontinuation of study medication due to lack of efficacy or AE of worsening UC (ICE4). For participants who discontinued study medication before the analysis time point due to COVID-19 related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (ICE5), their observed values ​​(if any) were used (i.e., treatment policy). Participants who discontinued study medication before the analysis time point for reasons other than those in ICE4 and 5 (ICE6; composite strategy) were considered not to have reached the binary endpoint.

[0416] Compare based on each guselkumab group and placebo group.For primary and important secondary endpoints (except the maintenance of clinical remission), p value is based on Cochran-Mantel-Haenszel (CMH) test (2 sides), it is by maintaining clinical remission state (yes / no) and induction therapy (guselkumab 400mgIV, guselkumab 200mgIV, placebo IV → guselkumab 200mg IV) when baseline and stratification.For the maintenance of clinical remission, use the CMH test (2 sides) stratified by induction therapy.95% confidence interval is based on Wald statistics with Cochran-Mantel-Haenszel weight.For these endpoints, the participant of the missing data of the analysis time point (after considering the concurrent event strategy) is considered to be non-responder at this time point.

[0417] Global Testing Program (Countries outside the U.S. ): A hierarchical testing procedure was used to control the overall type 1 error rate in the primary and important secondary efficacy analyses within the guselkumab dose groups at a 2-sided 0.05 significance level. The primary endpoint was tested using a fixed-order testing procedure, starting with the high maintenance treatment group (200 mg SC q4w). Important secondary endpoints for a dose group were considered significant only if the previous endpoint and the current endpoint for that dose group in the hierarchy tested positive at a 2-sided 0.05 significance level. If the endpoint was not significant, all subsequent tests in the hierarchy for that dose were considered not significant.

[0418] U.S.-Specific Testing Procedures: A hierarchical testing procedure was used to strongly control the overall type 1 error rate of the primary and important secondary endpoints and the two guselkumab treatment groups at the 0.05 level. An endpoint was considered significant only if all previous endpoints and the current endpoint in the hierarchy tested positive at the 2-sided 0.05 significance level. If the endpoint was not significant, all subsequent tests in the hierarchy were considered not significant. Note that due to regional preferences, the rank order of the endpoints was different for the two testing strategies. In addition, IBDQ remission at weeks 24-44 was not included in the US-specific testing procedure.

[0419] Main objectives : The primary objective was to evaluate the clinical efficacy and safety of guselkumab as maintenance therapy in participants with moderately to severely active UC who were in clinical response induced by guselkumab.

[0420] Execution Summary :Based on pre-specified global and U.S.-specific multiple testing procedures, guselkumab maintenance therapy with 200mg SC q4w and 100mg SC q8w resulted in a significantly greater proportion of participants being in clinical remission at week 24-44 (primary endpoint; Table 26). An adjusted treatment difference of ≥25 percentage points was observed, and the results were highly statistically significant (ie, p < 0.001). Relative to placebo, guselkumab maintenance therapy (at the two doses evaluated) also resulted in a significantly greater proportion of participants reaching each important secondary endpoint (Table 27). By week 24-44, the subcutaneous maintenance regimen of guselkumab 200mg SC q4w or guselkumab 100mg SC q8w was well tolerated, and safety data were consistent with the known safety profile of guselkumab. In the treatment of UC, the benefit-risk profile favors GUS.

[0421] Top-line results summary A total of 846 participants entered the maintenance study and were treated at 254 sites in 32 countries: 599 were randomized and 247 were non-randomized. Of the 599 randomized and treated participants, 568 (94.8%) had a modified Mayo Clinic score of 5 to 9 at Week 1-0 (the target population for the following efficacy and safety analyses). Any impact on the study due to COVID-19 or the regional crisis was negligible.

[0422] Disposition and baseline characteristics of the full analysis set of randomized groups (n=568)A total of 12.0% of participants discontinued the study intervention before Weeks 24-44, with comparable rates across treatment groups: 11.6% in the 200 mg guselkumab SC q4w group, 10.6% in the 100 mg guselkumab SC q8w group, and 13.7% in the placebo group. The most common reasons for discontinuing the study intervention before Weeks 24-44 were adverse events due to worsening UC (3.3%) and subject withdrawal (3.3%). Demographics, disease characteristics, UC medication history, and concomitant UC medications were generally well-balanced across treatment groups.

[0423] At baseline, the majority of participants were white (73.2%), and 54.8% were female. The mean age was 40.7 years (range, 18 to 79 years). The mean duration of UC disease was 7.81 years, the median modified Mayo score was 7.0 (mean = 6.9), 63.9% had severe disease as defined by a modified Mayo score of 7 to 9, 66.4% of participants had an endoscopic subscore of 3 (i.e., severe disease), 45.2% of participants had extensive disease, the median fecal calprotectin was 1605.0 mg / kg, and the median C-reactive protein (CRP) concentration was 3.9 mg / L (Table 29).

[0424] At maintenance baseline, the median modified Mayo score was 2.0 (mean = 2.5), the median fecal calprotectin was 303.5 mg / kg, and the median C-reactive protein (CRP) concentration was 1.5 mg / L. At maintenance baseline, 34.2% of participants were in clinical remission and 39.1% had endoscopic healing (Table 30).

[0425] At induction baseline, a total of 240 (42.3%) participants had a history of advanced therapy (ADT) failure (102 of these participants [42.5%] had a history of failure in two or more ADT categories); 328 (57.7%) had failed conventional therapy but not advanced therapy ("ADT-naive"), and the majority of these participants (309) (94.2%) were ADT-naive. A total of 40.0% of participants received corticosteroids at induction baseline, and 22.2% received immunomodulators (6-mercaptopurine, azathioprine, or methotrexate).

[0426] Primary End Point: This study was considered a positive study. A significantly greater proportion of participants in the guselkumab 200 mg SC q4w group (50.0%) and the guselkumab 100 mg SC q8w group (45.2%) were in clinical remission at Weeks M-44 compared with the placebo group (18.9%; adjusted treatment differences 29.5% [95% CI: 20.9%, 38.1%] and 25.2% [95% CI: 16.4%, 33.9%], respectively) ( Figure 3 ; Table 26).

[0427] Important secondary endpoints : Based on the global testing program (Table 27) and the US-specific testing program ( Figure 6 ), significantly greater proportions of participants in the guselkumab 200 mg SC q4w group and the guselkumab 100 mg SC q8w group achieved each of the key secondary endpoints at Weeks 24-44 compared with the placebo group (Table 28). Figure 6 , asterisks indicate the achieved significance level ( * p<0.05; ** p<0.01; *** p < 0.001. p value based on Cochran-Mantel-Haenszel test).

[0428] A significantly higher proportion of patients treated with subcutaneous guselkumab maintenance therapy achieved the primary and key secondary endpoints assessed at Week 44 ( Figure 4 Key secondary endpoints evaluated at Week 44 included symptom relief, corticosteroid-free clinical remission, clinical response, maintenance of clinical remission, endoscopic improvement, histologic-endoscopic mucosal improvement, and endoscopic normalization.

[0429] for Figure 4 : Adjusted treatment differences (Δ) were based on the Wald statistic with Cochran-Mantel-Haenszel (CMH) weights. P values ​​were based on the CMH test stratified by maintenance of clinical remission status at baseline and at induction of therapy. a Clinical remission: Mayo stool frequency subscore of 0 or 1 and no increase from baseline, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1, with no friability. b Symptomatic remission: Stool frequency subscore of 0 or 1 and no increase from baseline, rectal bleeding subscore of 0. c Corticosteroid-free clinical remission: No corticosteroid treatment was required for at least 8 weeks prior to week 44, and the criteria for clinical remission were also met. d Clinical response: A decrease of ≥30% and ≥2 points from baseline in the modified Mayo score, with a decrease of ≥1 point from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. e Maintenance of clinical remission: Clinical remission at week 44 in patients who were in clinical remission at maintenance baseline. f Endoscopic improvement: Endoscopic subscore of 0 or 1, absence of friability on endoscopy. g Histologic-endoscopic mucosal improvement: Achievement of a combination of histologic improvement (neutrophil infiltration of <5% of crypts, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue according to the Geboes grading system) and endoscopic improvement. h Endoscopic normalization: Endoscopic subscore of 0.

[0430] Subgroup analysis by ADT failure status : For the primary endpoint and all important secondary endpoints in the ADT non-failure and ADT failure subgroups, greater efficacy was observed in both guselkumab groups compared to placebo (Table 31 and Table 32). In general, a greater proportion of participants in the ADT non-failure subgroup met the primary endpoint and important secondary endpoints in the treatment group compared to the ADT failure subgroup. For both primary and important secondary endpoints, the treatment effect (relative to placebo) was generally greater in the ADT failure subgroup compared to the ADT non-failure subgroup, and in some cases comparable, for both guselkumab groups.

[0431] Other endpoints : A greater proportion of participants in the guselkumab 200 mg SC q4w group and the guselkumab 100 mg SC q8w group achieved histological healing at Week 24-44 compared to the placebo group (adjusted treatment difference for the guselkumab 200 mg SC q4w group: 32.6% [95% CI: 23.3%, 41.9%], and the guselkumab 100 mg SC q8w group: 33.6% [95% CI: 24.3%, 42.9%]) (Table 33). Over time, the proportion of participants in symptom remission in the guselkumab group continued to Week 24-44, while the proportion of participants in symptom remission in the placebo group decreased. Separation from the placebo group was observed at Week 24-16 and continued to increase to Week 24-44. ( Figure 5 ).

[0432] Security : By week 24-44, the subcutaneous maintenance regimen of guselkumab 200mg SC q4w or guselkumab 100mg SC q8w was well tolerated, and the safety data were consistent with the known safety profile of guselkumab. Table 34 provides an overall summary of adverse events (AEs) for the safety analysis set of randomization to week 24-44 (until dose adjustment). No new safety issues were found based on adverse events and laboratory studies. The total AE rate of the treatment group was similar. In the safety analysis set of randomization, the ratio of serious AEs (SAEs) in the guselkumab 200mg SC q4w group was numerically higher than that in the placebo group, but this trend was less obvious in the safety analysis set and the analysis set of all treatments.

[0433] Safety data from the randomized safety analysis set through Week M-44 The mean duration of follow-up was shorter in the placebo group (34.0 weeks) than in the guselkumab 200 mg SC every 4 weeks group (39.2 weeks) and the guselkumab 100 mg SC every 8 weeks group (40.5 weeks) (Table 34). The proportion of participants who reported one or more AEs in the guselkumab 200 mg SC every 4 weeks and guselkumab 100 mg SC every 8 weeks groups (70.0% and 64.5%) was comparable to that in the placebo group (68.2%) (Table 34). The system organ classes (SOCs) with the most frequently reported AEs were infections and infestations (31.1% guselkumab 200 mg SC q4w; 31.7% guselkumab 100 mg SC q8w; 32.8% placebo) and gastrointestinal disorders (25.8% guselkumab 200 mg SC q4w; 24.7% guselkumab 100 mg SC q8w; 37.0% placebo). The most common preferred terms (PTs) in the guselkumab combination group were COVID-19 (11.2%), ulcerative colitis (11.2%), and arthralgia (6.1%); the PTs in the placebo group were 14.1%, 29.7%, and 6.8%, respectively.

[0434] The proportion of participants reporting one or more SAEs was 6.3%, 2.7%, and 0.5% in the guselkumab 200 mg SC q4w, guselkumab 100 mg SC q8w, and placebo groups, respectively (Table 34). There was no clear pattern in the SAEs regarding individual PTs or SOCs, and the majority of SAEs were assessed by the investigators as unrelated. The difference in SAE rates between the guselkumab 200 mg SC q4w group and the placebo group was less pronounced in the safety analysis set and the all-treatment analysis set, which included a large number of participants, including non-randomized guselkumab-induced 24-week responders and placebo-induced responders. The proportion of participants with AEs leading to study drug discontinuation was numerically higher in the placebo group than in the guselkumab 100 mg SC q4w and guselkumab 200 mg SC q8w groups, at 6.8%, 3.8%, and 2.6%, respectively (Table 34). The proportion of participants reporting one or more serious intensity AEs was similar across treatment groups (Table 34). The proportion of participants reporting an infection AE was comparable between treatment groups (Table 34). Serious infections were rare (2 [1.1%] in the guselkumab 200 mg SC q4w group [1 participant with moderate bacterial infection at the venipuncture site and 1 participant with gangrenous appendicitis], and 1 [0.5%] in the guselkumab 100 mg SC q8w group [intergluteal abscess]). There were no significant differences in the proportion of participants with a maximum toxicity grade ≥1 in the placebo and guselkumab groups after baseline in chemistry and hematology laboratory results. Grade 3 and 4 chemistry and hematology laboratory values ​​were uncommon. No cases met Ho's rule biochemistry criteria (i.e., total bilirubin ≥2× upper limit of normal [ULN] and aspartate aminotransferase [AST] or alanine aminotransferase [ALT] ≥3×ULN at the same time points).

[0435] AEs of particular interest and other AEs in the maintenance study through Weeks M-44 based on the all-treated analysis set: No deaths were reported. No cases of active tuberculosis were reported. No cases of opportunistic infections were reported based on the Standardized MedDRA Query (SMQ) for Opportunistic Infections. Nine malignancies were reported in eight participants; three participants had four non-melanoma skin cancer malignancies (all in the randomized placebo group). Three participants had breast cancer (two randomized placebo groups and one non-randomized placebo group). One participant had clear cell renal cell carcinoma (non-randomized guselkumab 200 mg SC q4w group), and one participant had rectal adenocarcinoma (non-randomized guselkumab 200 mg SC q4w group). One participant in the randomized guselkumab 200 mg SC q4w group had a reported hemorrhagic stroke, which was considered a major adverse cardiovascular event (MACE). There were no confirmed cases of Hy's Law, no cases of treatment-emergent serious hepatic adverse events, and no treatment-emergent hepatic adverse events leading to study drug discontinuation. Two participants reported venous thromboembolism (VE). One was in the randomized guselkumab 200 mg subcutaneous 4 weeks group, and the other was in the non-randomized guselkumab 200 mg subcutaneous 4 weeks group. Both participants had a history of VTE. No cases of anaphylaxis or serum sickness were reported.

[0436]

[0437]

[0438] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included. a Clinical remission was defined as a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, with no increase in the stool frequency subscore from the induction baseline, and the absence of friability on endoscopy.

[0439] b Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a prohibited change in UC medication (ICE 2), or discontinued study medication due to lack of efficacy or AEs of worsening UC (ICE 3) before Weeks 1-12 were considered not to be in clinical remission at Weeks 1-12. For subjects who discontinued study medication due to COVID-19 related reasons (excluding COVID-19 infection) or regional crises (ICE 4) before Weeks 1-12, their observed values ​​will be used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before Weeks 1-12 were considered not to be in clinical remission at Weeks 1-12.

[0440] cNonresponder Imputation for Missing Data: Subjects missing one or more Mayo subscores related to this endpoint (stool frequency, rectal bleeding, or endoscopy) at Weeks 1-12 were considered not to be in clinical remission after accounting for ICE.

[0441] d Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0442] e Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0443] f P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0444]

[0445]

[0446] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0447] a Clinical response was defined as a decrease of ≥30% and ≥2 points in the modified Mayo Clinic score compared with the induction baseline, with a decrease of ≥1 point in the rectal bleeding subscore compared with the baseline or a rectal bleeding subscore of 0 or 1.

[0448] b Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a prohibited change in UC medication (ICE 2), or discontinued study medication due to lack of efficacy or AEs of worsening UC (ICE 3) before Weeks 1-12 were considered not to be in clinical response at Weeks 1-12. For subjects who discontinued study medication due to COVID-19 related reasons (excluding COVID-19 infection) or regional crises (ICE 4) before Weeks 1-12, their observed values ​​will be used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before Weeks 1-12 were considered not to be in clinical response at Weeks 1-12.

[0449] c Non-responder imputation for missing data: Subjects missing one or more Mayo subscores related to this endpoint (stool frequency, rectal bleeding, or endoscopy) at Weeks 1-12 were considered not to be in clinical response after accounting for ICE.

[0450] d Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0451] e Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0452] f P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0453]

[0454]

[0455] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0456] a Endoscopic normalization was defined as an endoscopic subscore of 0.

[0457] b Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a contraindicated change in UC medication (ICE 2), or discontinued study medication due to lack of efficacy or AEs of worsening UC (ICE 3) before Weeks 1-12 were considered to have not achieved endoscopic normalization at Weeks 1-12. For subjects who discontinued study medication due to COVID-19 related reasons (excluding COVID-19 infection) or regional crises (ICE 4) before Weeks 1-12, their observed values ​​will be used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before Weeks 1-12 were considered to have not achieved endoscopic normalization at Weeks 1-12.

[0458] c Nonresponder Imputation for Missing Data: Subjects with missing endoscopy subscores at Weeks 1-12 were considered not to have achieved endoscopic normalization after accounting for ICE.

[0459] d Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0460] eAdjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0461] f P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0462]

[0463]

[0464] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0465] a Endoscopic healing was defined as an endoscopic subscore of 0 or 1 with no endoscopic fragility present.

[0466] b Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a prohibited change in UC medication (ICE 2), or discontinued study medication due to lack of efficacy or AEs of worsening UC (ICE 3) before Weeks 1-12 were considered to have not achieved endoscopic healing at Weeks 1-12. For subjects who discontinued study medication due to COVID-19 related reasons (excluding COVID-19 infection) or regional crises (ICE 4) before Weeks 1-12, their observed values ​​will be used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before Weeks 1-12 were considered to have not achieved endoscopic healing at Weeks 1-12.

[0467] c Nonresponder Imputation for Missing Data: Subjects with missing endoscopy subscores at Weeks 1-12 were considered not to have achieved endoscopic healing after accounting for ICE.

[0468] d Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0469] e Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0470] f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test, which is analyzed by ADT-failure status (yes /

[0471] No) and concomitant corticosteroid use at baseline (yes / no).

[0472]

[0473]

[0474] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0475] a Histologic healing was defined according to the Geboes grading system as neutrophil infiltration of <5% of crypts, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue.

[0476] b Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a prohibited change in UC medication (ICE 2), or discontinued study medication due to lack of efficacy or AEs of worsening UC (ICE 3) before Weeks 1-12 were considered to have not achieved histological healing at Weeks 1-12. For subjects who discontinued study medication due to COVID-19 related reasons (excluding COVID-19 infection) or regional crises (ICE 4) before Weeks 1-12, their observed values ​​will be used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before Weeks 1-12 were considered to have not achieved histological healing at Weeks 1-12.

[0477] c Nonresponder Imputation for Missing Data: After accounting for ICE, subjects with unevaluable biopsies (i.e., biopsies collected but could not be evaluated due to sample preparation or technical errors) or missing any components related to this endpoint (i.e., assessment of neutrophils in the epithelium, crypt disruption, or erosions or ulcers or granulations) at Weeks 1-12 were considered to have not achieved histologic healing.

[0478] d Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0479] e Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0480] fP values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0481]

[0482]

[0483] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0484] a Histologic remission is defined as the absence of neutrophils from the mucosa (both the lamina propria and epithelium), the absence of crypt destruction, and the absence of erosions, ulcers, or granulation tissue according to the Geboes grading system. This definition is equivalent to a Robarts histopathology index of ≤3, with a subscore of 0 for neutrophils in the lamina propria and epithelium, and the absence of ulcers or erosions.

[0485] b Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a prohibited change in UC medication (ICE 2), or discontinued study medication due to lack of efficacy or AEs of worsening UC (ICE 3) before Weeks 1-12 were considered not to be in histological remission at Weeks 1-12. For subjects who discontinued study medication due to COVID-19 related reasons (excluding COVID-19 infection) or regional crises (ICE 4) before Weeks 1-12, their observed values ​​will be used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before Weeks 1-12 were considered not to be in histological remission at Weeks 1-12.

[0486] c Nonresponder Imputation for Missing Data: Subjects with unevaluable biopsies (i.e., biopsies collected but not assessable due to sample preparation or technical errors) or missing any histologic components relevant to this endpoint (i.e., assessment of neutrophils in the lamina propria or epithelium, crypt disruption, or erosions or ulcers or granulations) at Weeks 1-12 were considered not to be in histologic remission after accounting for ICE.

[0487] d Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0488] eAdjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0489] f P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0490]

[0491]

[0492] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0493] a IBDQ (Inflammatory Bowel Disease Questionnaire) remission was defined as a total IBDQ score ≥170.

[0494] b Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE1), contraindicated change of UC medication (ICE2), or discontinued study medication due to lack of efficacy or AE of UC worsening (ICE3) before Weeks 1-12 were considered not in IBDQ remission at Weeks 1-12. For subjects who discontinued study medication due to COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE4) before Weeks 1-12, their observed values ​​will be used if available. Subjects who experienced ICE5 (discontinuation of study medication due to reasons other than those in ICE3 and 4) before Weeks 1-12 were considered not in IBDQ remission at Weeks 1-12.

[0495] c Non-responder imputation for missing data: Subjects with missing IBDQ total scores at Weeks 1-12 were considered not to be in IBDQ remission after accounting for ICE.

[0496] d Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0497] e Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0498] fP values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0499]

[0500]

[0501] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0502] a Histologic-endoscopic mucosal healing was defined as the combination of histologic and endoscopic healing. Histologic healing was defined as neutrophil infiltration of <5% of crypts, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue, according to the Geboes grading system. Endoscopic healing was defined as an endoscopic subscore of 0 or 1 with the absence of friability on endoscopic examination.

[0503] b Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE1), prohibited change of UC medication (ICE 2), or discontinued study medication due to lack of efficacy or AE of UC worsening (ICE 3) before Week 1-12 were considered to have not achieved histological-endoscopic mucosal healing at Week 1-12. For subjects who discontinued study medication due to COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4) before Week 1-12, their observed values ​​will be used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before Week 1-12 were considered to have not achieved histological-endoscopic mucosal healing at Week 1-12.

[0504] c Nonresponder Imputation for Missing Data: After accounting for ICE, subjects with unevaluable biopsies (i.e., biopsies collected but could not be evaluated due to sample preparation or technical errors) or missing endoscopic subfractions or any histologic components relevant to this endpoint (i.e., assessment of neutrophils in the epithelium, crypt disruption, or erosions or ulcers or granulations) at Weeks 1-12 were considered to have not achieved histologic-endoscopic mucosal healing.

[0505] d Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0506] eAdjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0507] f P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0508]

[0509]

[0510] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0511] a Fatigue response was defined as an improvement of ≥7 points from induction baseline on the PROMIS (Patient-Reported Outcomes Measurement Information System) Fatigue Short Form 7a.

[0512] b Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a prohibited change in UC medication (ICE 2), or discontinued study medication due to lack of efficacy or AEs of worsening UC (ICE 3) before Weeks 1-12 were considered to be out of fatigue response at Weeks 1-12. For subjects who discontinued study medication due to COVID-19 related reasons (excluding COVID-19 infection) or regional crises (ICE 4) before Weeks 1-12, their observed values ​​will be used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before Weeks 1-12 were considered to be out of fatigue response at Weeks 1-12.

[0513] c Non-responder classification for missing data: Subjects missing one or more PROMIS Fatigue Short Form 7a items at induction baseline or Weeks 1-12 were considered non-responders to fatigue after accounting for ICE.

[0514] d Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0515] e Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0516] fP values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0517]

[0518]

[0519] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0520] 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 did not increase from the induction baseline.

[0521] b Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), an inadvertent change in UC medication (ICE 2), or discontinued study medication due to an AE of lack of efficacy or worsening UC (ICE 3) before the designated time point were considered not to be in remission at the designated time point.

[0522] For subjects who discontinued study medication due to COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4) before the designated time point, their observed values ​​will be used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before the designated time point were considered not to be in symptom remission at the designated time point.

[0523] c Nonresponder Imputation for Missing Data: Subjects who were missing one or more Mayo subscores related to this endpoint (stool frequency and / or rectal bleeding) at a given time point were considered not to be in remission after accounting for ICE.

[0524] d Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0525] e Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0526] f P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533] Legend of symbols: ADT = advanced therapy; IBDQ = inflammatory bowel disease questionnaire; PROMIS = patient-reported outcomes measurement information system;

[0534] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0535] a1 Clinical remission was defined as a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, with no increase in the stool frequency subscore from the induction baseline, and the absence of friability on endoscopy.

[0536] 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 did not increase from the induction baseline.

[0537] a3 Endoscopic healing was defined as an endoscopic subscore of 0 or 1 with no endoscopic fragility present.

[0538] a4 Clinical response was defined as a decrease of ≥30% and ≥2 points in the modified Mayo Clinic score compared with the induction baseline, with a decrease of ≥1 point in the rectal bleeding subscore compared with the baseline or a rectal bleeding subscore of 0 or 1.

[0539] a5 IBDQ remission was defined as a total IBDQ score ≥170.

[0540] a6 Histological-endoscopic mucosal healing was defined as the achievement of a combination of histological and endoscopic healing.

[0541] a7 Fatigue response was defined as an improvement of ≥7 points from baseline on the PROMIS Fatigue Short Form 7a.

[0542] a8 Endoscopic normalization was defined as an endoscopic subscore of 0.

[0543] a9 Histologic healing was defined according to the Geboes grading system as neutrophil infiltration of <5% of crypts, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue.

[0544] a10 Histologic remission was defined as the absence of neutrophils from the mucosa (both the lamina propria and epithelium), crypt destruction, and the absence of erosions, ulcers, or granulation tissue according to the Geboes grading system.

[0545] a11 Histologic-endoscopic mucosal healing (alternative definition 1) was defined as the achievement of a combination of histologic remission and endoscopic healing.

[0546] a12 Deep histological-endoscopic mucosal healing was defined as the combination of endoscopic normalization and histological remission.

[0547] b The denominator was subjects who did not fail ADT.

[0548] c Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a prohibited change in UC medication (ICE 2), or discontinued study medication due to an AE of lack of efficacy or worsening UC (ICE 3) before the designated time point were considered to have not achieved any of the displayed key efficacy endpoints at the designated time point. For subjects who discontinued study medication due to COVID-19-related reasons (excluding COVID-19 infection) or regional crises (ICE 4) before the designated time point, their observed values ​​will be used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before the designated time point were considered to have not achieved any of the displayed key efficacy endpoints at the designated time point.

[0549] d Imputation of nonresponders for missing data: Subjects missing one or more components related to an endpoint at a given time point, after accounting for ICE, were considered not to have reached that endpoint. Subjects with unevaluable biopsies (i.e., biopsies collected but not assessable due to sample preparation or technical errors) were considered not to have reached the histological endpoint.

[0550] e Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0551] fAdjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0552] g p values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test, stratified by concomitant corticosteroid use at baseline (yes / no).

[0553]

[0554]

[0555]

[0556]

[0557] Legend of symbols: IBDQ = Inflammatory Bowel Disease Questionnaire; PROMIS = Patient-Reported Outcomes Measurement Information System;

[0558] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0559] a1 Clinical remission was defined as a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, with no increase in the stool frequency subscore from the induction baseline, and the absence of friability on endoscopy.

[0560] 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 did not increase from the induction baseline.

[0561] a3 Endoscopic healing was defined as an endoscopic subscore of 0 or 1 with no endoscopic fragility present.

[0562] a4 Clinical response was defined as a decrease of ≥30% and ≥2 points in the modified Mayo Clinic score compared with the induction baseline, with a decrease of ≥1 point in the rectal bleeding subscore compared with the baseline or a rectal bleeding subscore of 0 or 1.

[0563] a5 IBDQ remission was defined as a total IBDQ score ≥170.

[0564] a6 Histological-endoscopic mucosal healing was defined as the achievement of a combination of histological and endoscopic healing.

[0565] a7 Fatigue response was defined as an improvement of ≥7 points from baseline on the PROMIS Fatigue Short Form 7a.

[0566] a8 Endoscopic normalization was defined as an endoscopic subscore of 0.

[0567] a9 Histologic healing was defined according to the Geboes grading system as neutrophil infiltration of <5% of crypts, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue.

[0568] a10 Histologic remission was defined as the absence of neutrophils from the mucosa (both the lamina propria and epithelium), crypt destruction, and the absence of erosions, ulcers, or granulation tissue according to the Geboes grading system.

[0569] a11 Histologic-endoscopic mucosal healing (alternative definition 1) was defined as the achievement of a combination of histologic remission and endoscopic healing.

[0570] a12 Deep histological-endoscopic mucosal healing was defined as the combination of endoscopic normalization and histological remission.

[0571] b The denominator is the subjects who failed biology.

[0572] c Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a prohibited change in UC medication (ICE 2), or discontinued study medication due to an AE of lack of efficacy or worsening UC (ICE 3) before the designated time point were considered to have not achieved any of the displayed key efficacy endpoints at the designated time point. For subjects who discontinued study medication due to COVID-19-related reasons (excluding COVID-19 infection) or regional crises (ICE 4) before the designated time point, their observed values ​​will be used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before the designated time point were considered to have not achieved any of the displayed key efficacy endpoints at the designated time point.

[0573] d Imputation of nonresponders for missing data: Subjects missing one or more components related to an endpoint at a given time point, after accounting for ICE, were considered not to have reached that endpoint. Subjects with unevaluable biopsies (i.e., biopsies collected but not assessable due to sample preparation or technical errors) were considered not to have reached the histological endpoint.

[0574] e Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0575] f Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0576] g p values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test, stratified by concomitant corticosteroid use at baseline (yes / no).

[0577]

[0578] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0579] a Adverse events assessed by the investigator as possibly, probably, or very probably related to the study drug, or if the relationship to the study drug is absent.

[0580] b Infection was defined as any adverse event coded to the MedDRA system organ class 'infections and infestations'.

[0581]

[0582]

[0583] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0584] a A symptomatic response was defined as a symptomatic Mayo score decrease of ≥30% and ≥1 point from the induction baseline, with the rectal bleeding subscore decreased by ≥1 point from baseline or the rectal bleeding subscore being 0 or 1. The symptomatic Mayo score was defined as the sum of the stool frequency and rectal bleeding subscores.

[0585] b Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a contraindicated change in UC medication (ICE 2), or discontinued study medication due to an AE of lack of efficacy or worsening UC (ICE 3) before the designated time point were considered not to be in symptomatic response at the designated time point. For subjects who discontinued study medication before the designated time point due to COVID-19-related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (ICE 4), their observed values ​​were used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before the designated time point were considered not to be in symptomatic response at the designated time point.

[0586] c Non-responder imputation for missing data: Subjects missing one or more Mayo subscores related to this endpoint (stool frequency and / or rectal bleeding) at a given time point were considered not to be in symptomatic response after accounting for ICE.

[0587] d Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0588] e Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0589] f P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0590] Table 15. Symptom results at week 12

[0591]

[0592] Table 16. Safety Summary up to Final Safety Visit (Week 32)

[0593]

[0594] Note: Only patients with a modified Mayo Clinic score of 5-9 at induction baseline were included. a Includes data up to Week 12 for subjects who received treatment at Week 12. Includes all data up to the last safety visit for subjects who did not receive treatment at Week 12. b Includes data starting from Week 12. c From the first guselkumab IV dose; for subjects who received guselkumab 200 mg subcutaneously at Week 12, data were included up to Week 12. d From the first guselkumab dose. e Infection was defined as any adverse event coded to the MedDRA system organ class "Infections and Infestations." f Injection site reactions assessed by the investigator.

[0595] Table 17. Summary of Histological and Histo-endoscopic Results at Week 12

[0596]

[0597] aThis definition is equivalent to histologic remission using the alternative definition of Robarts Histopathology Index (RHI ≤ 3, with neutrophils in the lamina propria and neutrophil subscore of 0 in the epithelium, and no ulcers or erosions). NOTE: Patients who underwent a prohibited change in UC medication, ostomy, or colectomy before Week 12, or who discontinued study medication due to lack of treatment effect or due to an AE of worsening UC, or for reasons other than COVID-19-related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine were considered not to have reached the endpoint. Patients with an unevaluable biopsy (i.e., a biopsy collected but could not be evaluated due to sample preparation or technical error) or missing endoscopic subscore (if applicable) or any histologic component related to this endpoint (i.e., assessment of neutrophils in the epithelium, crypt disruption, or erosions or ulcers or granulations) at Week 12 were considered not to have reached the endpoint. Adjusted treatment differences and confidence intervals are based on Wald statistics with Cochran-Mantel-Haenszel weights. P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0598] Table 18. Patients with elevated CRP (>3 mg / L) or FeCal (>250 mg / kg) at baseline. Weekly changes in CRP and FeCal compared to baseline

[0599]

[0600] ***Nominal P ≤ 0.001. Patients who underwent a prohibited change in UC medication, ostomy, or colectomy before the designated time point, or discontinued study medication due to an AE of lack of efficacy or worsening UC, or for reasons other than COVID-19-related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine, had their baseline values ​​carried forward from the time of the event. P values ​​for treatment comparisons were based on mixed-effects models with repeated measures, in which CRP and FeCal values ​​were log-transformed.

[0601]

[0602] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0603] 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 did not increase from the induction baseline.

[0604] bIntercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a contraindicated change in UC medication (ICE 2), or discontinued study medication due to an AE of lack of efficacy or worsening UC (ICE 3) before the designated time point were considered not to be in symptom remission at the designated time point. For subjects who discontinued study medication before the designated time point due to COVID-19-related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (ICE 4), their observed values ​​were used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before the designated time point were considered not to be in symptom remission at the designated time point.

[0605] c Nonresponder Imputation for Missing Data: Subjects missing one or more Mayo subscores for this endpoint (stool frequency and / or rectal bleeding) at a given time point were considered not to be in remission after accounting for ICE.

[0606] d Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0607] e Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0608] f P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0609]

[0610]

[0611] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0612] a A symptomatic response was defined as a symptomatic Mayo score decrease of ≥30% and ≥1 point from the induction baseline, with the rectal bleeding subscore decreased by ≥1 point from baseline or the rectal bleeding subscore being 0 or 1. The symptomatic Mayo score was defined as the sum of the stool frequency and rectal bleeding subscores.

[0613] bIntercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a contraindicated change in UC medication (ICE 2), or discontinued study medication due to an AE of lack of efficacy or worsening UC (ICE 3) before the designated time point were considered to be non-symptomatic at the designated time point. For subjects who discontinued study medication before the designated time point due to COVID-19-related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (ICE 4), their observed values ​​were used, if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than ICE 3 and 4) before the designated time point were considered to be non-symptomatic at the designated time point.

[0614] c Non-responder imputation for missing data: Subjects missing one or more Mayo subscores related to this endpoint (stool frequency and / or rectal bleeding) at a given time point were considered not to be in symptomatic response after accounting for ICE.

[0615] d Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0616] e Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0617] f P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0618]

[0619]

[0620] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0621] a Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0622] bIntercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a contraindicated change in UC medication (ICE 2), or discontinued study medication due to an AE of lack of efficacy or worsening UC (ICE 3) before the designated time point were considered not to have a stool frequency subscore of 0 or 1 at the designated time point. For subjects who discontinued study medication before the designated time point due to COVID-19-related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (ICE 4), their observed values ​​were used if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before the designated time point were considered not to have a stool frequency subscore of 0 or 1 at the designated time point.

[0623] c Nonresponder Imputation for Missing Data: After accounting for ICE, subjects with missing stool frequency subscores at a given time point were considered not to have a stool frequency subscore of 0 or 1.

[0624] d Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0625] e P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0626]

[0627]

[0628] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0629] a Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), a contraindicated change in UC medication (ICE 2), or discontinued study medication due to an AE of lack of efficacy or worsening UC (ICE 3) before the designated time point were considered to have a rectal bleeding subscore of 0 at the designated time point. For subjects who discontinued study medication due to COVID-19-related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (ICE 4) before the designated time point, their observed values ​​were used, if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before the designated time point were considered to have a rectal bleeding subscore of 0 at the designated time point.

[0630] b Nonresponder Imputation for Missing Data: Subjects with missing rectal bleeding subscore at a given time point were considered not to have a rectal bleeding subscore of 0 after accounting for ICE.

[0631] c Confidence intervals for the proportion of subjects in each treatment group who met the end point were based on normal approximate confidence limits.

[0632] d Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0633] e P values ​​were based on the Cochran-Mantel-Haenszel (CMH) chi-square test stratified by ADT-failure status (yes / no) and concomitant corticosteroid use at baseline (yes / no).

[0634]

[0635]

[0636]

[0637]

[0638] Keywords: CI = confidence interval; IQ, quartile; SD = standard deviation.

[0639] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0640] a Confidence intervals for the mean for each treatment group were based on normal approximate confidence limits.

[0641] b Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE1), contraindicated change in UC medication (ICE2), or discontinued study medication due to an AE of lack of efficacy or worsening UC (ICE3) before the designated time point had their baseline values ​​carried forward from the start of the event. For subjects who discontinued study medication due to COVID-19 related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (ICE4) before the designated time point, their observed values ​​were used, if available. Subjects who experienced ICE5 (discontinuation of study medication due to reasons other than those in ICE3 and 4) before the designated time point

[0642] Their baseline values ​​were carried forward from the time of the event.

[0643] c Missing data were accounted for using a mixed-effects model with repeated measures (MMRM) under the assumption of missing at random (MAR). In the MMRM, missing data were accounted for by the correlation of repeated measures in the model. The treatment difference between the guselkumab group and the placebo group was estimated by the difference in least-squares means (LS means).

[0644] d The p-values ​​for treatment comparisons were based on MMRM.

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652] Keywords: CI = confidence interval; IQ, quartile; SD = standard deviation.

[0653] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0654] a Confidence intervals for the mean for each treatment group were based on normal approximate confidence limits.

[0655] b Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), an inadvertent change in UC medication (ICE 2), or discontinued study medication due to an AE of lack of efficacy or worsening UC (ICE 3) before the designated time point had their baseline values ​​carried forward from the start of the event. For subjects who discontinued study medication before the designated time point due to COVID-19-related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (ICE 4), their observed values ​​were used, if available. Subjects who experienced ICE 5 (discontinuation of study medication due to reasons other than those in ICE 3 and 4) before the designated time point had their baseline values ​​carried forward from the start of the 12832 event.

[0656] c Missing data were accounted for using a mixed-effects model with repeated measures (MMRM) under the assumption of missing at random (MAR). In the MMRM, missing data were accounted for by the correlation of repeated measures in the model. The treatment difference between the guselkumab group and the placebo group was estimated by the difference in least-squares means (LS means).

[0657] d The p-values ​​for treatment comparisons were based on MMRM.

[0658]

[0659]

[0660]

[0661] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0662] a Symptomatic Mayo score improvement was defined as a decrease of ≥30% and ≥1 point from the induction baseline in the symptomatic Mayo score, with either a decrease of ≥1 point from the baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. The symptomatic Mayo score was defined as the sum of the stool frequency and rectal bleeding subscores.

[0663] b Subjects who underwent a prohibited change in UC medication, ostomy, or colectomy before the designated time point, or discontinued study medication due to lack of efficacy or an AE of worsening UC, were considered not to have achieved symptomatic Mayo score improvement.

[0664] c Data following discontinuation of study medication due to COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

[0665] d Subjects who were missing one or more Mayo subscores related to this endpoint (stool frequency and / or rectal bleeding) at a given time point were considered not to have achieved an improvement in symptomatic Mayo score.

[0666] e Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0667] f Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0668] gValues ​​are based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

[0669]

[0670] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0671] a Subjects who were in clinical response to guselkumab IV induction dosing and were randomized to placebo SC for entry into this maintenance study.

[0672] b Clinical remission was defined as a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, with no increase in the stool frequency subscore from the induction baseline, and the absence of friability on endoscopy.

[0673] C Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), dose adjustment (including simulated dose adjustment) (ICE 2), prohibited change of UC medication (ICE 3), or discontinued study medication due to lack of efficacy or AE of worsening UC (ICE 4) before Week 24-44 were considered not to be in clinical remission at Week 24-44. For subjects who discontinued study medication at Week 24-44 due to COVID-19 related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (ICE 5), their observed values ​​(if available) were used. Subjects who experienced ICE 6 (discontinuation of study medication due to reasons other than those in ICE 4 and 5) before Week 24-44 were considered not to be in clinical remission at Week 24-44.

[0674] d Nonresponder Imputation for Missing Data: Subjects missing one or more Mayo subscores related to this endpoint (stool frequency, rectal bleeding, or endoscopy) at Weeks M-44 were considered not to be in clinical remission after accounting for ICE.

[0675] e Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0676] f Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0677] gThe p-values ​​were based on the Cochran-Mantel-Haenszel (CMH) test, stratified by maintenance of clinical remission status at baseline (yes / no) and induction therapy (guselkumab 400 mg IV, guselkumab 200 mg IV, placebo IV crossover to guselkumab 200 mg IV).

[0678] Table 27. Summary of Key Secondary Endpoints at Weeks 24-44; Full Analysis Set of Randomized Groups (Ordered by Global Testing Program) sequence)

[0679]

[0680]

[0681] * p<0.05; ** p<0.01; *** p<0.001. p-value based on Cochran-Mantel-Haenszel test (Appendix 2). The significance of the results based on the US-specific testing procedure is shown in Appendix 4.

[0682] a Adjusted treatment differences (95% CI).

[0683] b The denominator is the number of subjects who remained in clinical remission at baseline.

[0684]

[0685]

[0686]

[0687] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0688] a Subjects who were in clinical response to guselkumab IV induction dosing and were randomized to placebo SC for entry into this maintenance study.

[0689] b1 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 did not increase from the induction baseline.

[0690] b2 Endoscopic healing was defined as an endoscopic subscore of 0 or 1 with no endoscopic fragility present.

[0691] b3Corticosteroid-free clinical remission was defined as not requiring any corticosteroid treatment for at least 8 weeks before week 24-44 and also meeting the criteria for clinical remission at week 24-44.

[0692] b4 Clinical response was defined as a decrease of ≥30% and ≥2 points in the modified Mayo Clinic score compared with the induction baseline, with a decrease of ≥1 point in the rectal bleeding subscore compared with the induction baseline or a rectal bleeding subscore of 0 or 1.

[0693] b5 Histologic-endoscopic mucosal healing was defined as the combination of histologic and endoscopic healing. Histologic healing was defined as neutrophil infiltration of <5% of crypts, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue, according to the Geboes grading system. Endoscopic healing was defined as an endoscopic subscore of 0 or 1 with the absence of friability on endoscopic examination.

[0694] b6 IBDQ (Inflammatory Bowel Disease Questionnaire) remission was defined as a total IBDQ score ≥170.

[0695] b7 Fatigue response was defined as an improvement of ≥7 points from induction baseline on the PROMIS (Patient-Reported Outcomes Measurement Information System) Fatigue Short Form 7a.

[0696] b8 Clinical remission was defined as a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, with no increase in the stool frequency subscore from the induction baseline, and the absence of friability on endoscopy.

[0697] b9 Endoscopic normalization was defined as an endoscopic subscore of 0.

[0698] C Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), dose adjustment (including simulated dose adjustment) (ICE 2), prohibited change of UC medication (ICE 3), or discontinued study medication due to lack of efficacy or AE of worsening UC (ICE 4) before Week 24-44 were considered not to have reached any key efficacy endpoint shown at Week 24-44. For subjects who discontinued study medication at Week 24-44 due to COVID-19 related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (ICE 5), their observed values ​​(if available) were used. Subjects who experienced ICE 6 (discontinuation of study medication due to reasons other than those in ICE 4 and 5) before Week 24-44 were considered not to have reached any key efficacy endpoint shown at Week 24-44.

[0699] d Nonresponder Imputation for Missing Data: Subjects who were missing one or more components related to an endpoint at Weeks 24-44 were considered not to have reached that endpoint. Subjects with unevaluable biopsies (i.e., biopsies collected but could not be evaluated due to sample preparation or technical errors) were considered not to have reached the histological endpoint.

[0700] e Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0701] f Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0702] g The p-values ​​were based on the Cochran-Mantel-Haenszel (CMH) test, stratified by maintenance of clinical remission status at baseline (yes / no) and induction therapy (guselkumab 400 mg IV, guselkumab 200 mg IV, placebo IV crossover to guselkumab 200 mg IV).

[0703] h The denominator was based on subjects who were in clinical remission at baseline.

[0704] i The p-values ​​were based on the Cochran-Mantel-Haenszel (CMH) test stratified by induction treatment (guselkumab 400 mg IV, guselkumab 200 mg IV, placebo IV with crossover to guselkumab 200 mg IV).

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712] Keywords: CRP = C-reactive protein; IQ, quartile; SD = standard deviation.

[0713] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0714] NOTE: At week M-0, subjects appeared in their assigned treatment group.

[0715] a Subjects who were in clinical response to guselkumab IV induction dosing and were randomized to placebo SC for entry into this maintenance study.

[0716] b Subjects who were in clinical response to placebo IV induction dosing and received placebo SC for entry into this maintenance study.

[0717] c Subjects who had no clinical response to guselkumab IV at Weeks 1-12, but had a clinical response at Weeks 1-24 after receiving SC administration of guselkumab starting at Weeks 1-12.

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725] Keywords: CRP = C-reactive protein; IBDQ = Inflammatory Bowel Disease Questionnaire; IQ, quartiles; SD = standard deviation.

[0726] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0727] NOTE: At week M-0, subjects appeared in their assigned treatment group.

[0728] a Subjects who were in clinical response to guselkumab IV induction dosing and were randomized to placebo SC for entry into this maintenance study.

[0729] b Subjects who were in clinical response to placebo IV induction dosing and received placebo SC for entry into this maintenance study.

[0730] cSubjects who had no clinical response to guselkumab IV at Weeks 1-12, but had a clinical response at Weeks 1-24 after receiving SC administration of guselkumab starting at Weeks 1-12.

[0731] d Endoscopic healing was defined as an endoscopic subscore of 0 or 1 with no endoscopic fragility present.

[0732] e Endoscopic normalization was defined as an endoscopic subscore of 0.

[0733] f Clinical remission was defined as a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, with no increase in the stool frequency subscore from the induction baseline, and the absence of friability on endoscopy.

[0734] g IBDQ remission was defined as a total IBDQ score ≥170.

[0735]

[0736]

[0737]

[0738]

[0739] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0740] a Subjects who were in clinical response to guselkumab IV induction dosing and were randomized to placebo SC for entry into this maintenance study.

[0741] b1 Clinical remission was defined as a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, with no increase in the stool frequency subscore from the induction baseline, and the absence of friability on endoscopy.

[0742] b2 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 did not increase from the induction baseline.

[0743] b3 Endoscopic healing was defined as an endoscopic subscore of 0 or 1 with no endoscopic fragility present.

[0744] b4Corticosteroid-free clinical remission was defined as not requiring any corticosteroid treatment for at least 8 weeks before week 24-44 and also meeting the criteria for clinical remission at week 24-44.

[0745] b5 Clinical response was defined as a decrease of ≥30% and ≥2 points in the modified Mayo Clinic score compared with the induction baseline, with a decrease of ≥1 point in the rectal bleeding subscore compared with the induction baseline or a rectal bleeding subscore of 0 or 1.

[0746] b6 Histologic-endoscopic mucosal healing was defined as the combination of histologic and endoscopic healing. Histologic healing was defined as neutrophil infiltration of <5% of crypts, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue, according to the Geboes grading system. Endoscopic healing was defined as an endoscopic subscore of 0 or 1 with the absence of friability on endoscopic examination.

[0747] b7 IBDQ (Inflammatory Bowel Disease Questionnaire) remission was defined as a total IBDQ score ≥170.

[0748] b8 Fatigue response was defined as an improvement of ≥7 points from induction baseline on the PROMIS (Patient-Reported Outcomes Measurement Information System) Fatigue Short Form 7a.

[0749] b9 Endoscopic normalization was defined as an endoscopic subscore of 0.

[0750] b10 Histologic healing was defined according to the Geboes grading system as neutrophil infiltration of <5% of crypts, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue.

[0751] c The denominator is the number of subjects who did not fail ADT.

[0752] dIntercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), dose adjustment (including simulated dose adjustment) (ICE 2), prohibited change of UC medication (ICE 3), or discontinued study medication due to lack of efficacy or AE of worsening UC (ICE 4) before Week 24-44 were considered not to have reached any key efficacy endpoint shown at Week 24-44. For subjects who discontinued study medication at Week 24-44 due to COVID-19 related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (ICE 5), their observed values ​​(if available) were used. Subjects who experienced ICE 6 (discontinuation of study medication due to reasons other than those in ICE 4 and 5) before Week 24-44 were considered not to have reached any key efficacy endpoint shown at Week 24-44.

[0753] e Nonresponder Imputation for Missing Data: Subjects who were missing one or more components related to an endpoint at Weeks 24-44 were considered not to have reached that endpoint. Subjects with unevaluable biopsies (i.e., biopsies collected but could not be evaluated due to sample preparation or technical errors) were considered not to have reached the histological endpoint.

[0754] f Confidence intervals for the proportion of subjects in each treatment group who met the end point were based on normal approximate confidence limits.

[0755] g Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0756] h The p-values ​​were based on the Cochran-Mantel-Haenszel (CMH) test, stratified by maintenance of clinical remission status at baseline (yes / no) and induction therapy (guselkumab 400 mg IV, guselkumab 200 mg IV, placebo IV crossover to guselkumab 200 mg IV).

[0757] i The denominator is the number of subjects who did not fail ADT and were in clinical remission at baseline.

[0758] j The p-values ​​are based on Fisher's exact test. The confidence intervals are based on the exact confidence limits.

[0759] [tefkey610c.rtf][PROD / cnto1959 / uco3001 / dbr_maintenance_w44 / re_w44 / tefkey610c.sas]26OCT2023,16:14

[0760]

[0761]

[0762]

[0763] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0764] a Subjects who were in clinical response to guselkumab IV induction dosing and were randomized to placebo SC for entry into this maintenance study.

[0765] b1 Clinical remission was defined as a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1, with no increase in the stool frequency subscore from the induction baseline, and the absence of friability on endoscopy.

[0766] b2 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 did not increase from the induction baseline.

[0767] b3 Endoscopic healing was defined as an endoscopic subscore of 0 or 1 with no endoscopic fragility present.

[0768] b4 Corticosteroid-free clinical remission was defined as not requiring any corticosteroid treatment for at least 8 weeks before week 24-44 and also meeting the criteria for clinical remission at week 24-44.

[0769] b5 Clinical response was defined as a decrease of ≥30% and ≥2 points in the modified Mayo Clinic score compared with the induction baseline, with a decrease of ≥1 point in the rectal bleeding subscore compared with the induction baseline or a rectal bleeding subscore of 0 or 1.

[0770] b6 Histologic-endoscopic mucosal healing was defined as the combination of histologic and endoscopic healing. Histologic healing was defined as neutrophil infiltration of <5% of crypts, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue, according to the Geboes grading system. Endoscopic healing was defined as an endoscopic subscore of 0 or 1 with the absence of friability on endoscopic examination.

[0771] b7 IBDQ (Inflammatory Bowel Disease Questionnaire) remission was defined as a total IBDQ score ≥170.

[0772] b8 Fatigue response was defined as an improvement of ≥7 points from induction baseline on the PROMIS (Patient-Reported Outcomes Measurement Information System) Fatigue Short Form 7a.

[0773] b9 Endoscopic normalization was defined as an endoscopic subscore of 0.

[0774] b10 Histologic healing was defined according to the Geboes grading system as neutrophil infiltration of <5% of crypts, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue.

[0775] c The denominator was the number of subjects who failed ADT.

[0776] d Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), dose adjustment (including simulated dose adjustment) (ICE 2), prohibited change of UC medication (ICE 3), or discontinued study medication due to lack of efficacy or AE of worsening UC (ICE 4) before Week 24-44 were considered not to have reached any key efficacy endpoint shown at Week 24-44. For subjects who discontinued study medication at Week 24-44 due to COVID-19 related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (ICE 5), their observed values ​​(if available) were used. Subjects who experienced ICE 6 (discontinuation of study medication due to reasons other than those in ICE 4 and 5) before Week 24-44 were considered not to have reached any key efficacy endpoint shown at Week 24-44.

[0777] e Nonresponder Imputation for Missing Data: Subjects who were missing one or more components related to an endpoint at Weeks 24-44 were considered not to have reached that endpoint. Subjects with unevaluable biopsies (i.e., biopsies collected but could not be evaluated due to sample preparation or technical errors) were considered not to have reached the histological endpoint.

[0778] f Confidence intervals for the proportion of subjects in each treatment group who met the end point were based on normal approximate confidence limits.

[0779] g Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0780] h The p-values ​​were based on the Cochran-Mantel-Haenszel (CMH) test, stratified by maintenance of clinical remission status at baseline (yes / no) and induction therapy (guselkumab 400 mg IV, guselkumab 200 mg IV, placebo IV crossover to guselkumab 200 mg IV).

[0781] i The denominator is the number of subjects who failed ADT and were in clinical remission at baseline.

[0782] j The p-values ​​are based on Fisher's exact test. The confidence intervals are based on the exact confidence limits.

[0783]

[0784] Note: Only subjects with a modified Mayo Clinic score of 5-9 at induction baseline were included.

[0785] a Subjects who were in clinical response to guselkumab IV induction dosing and were randomized to placebo SC for entry into this maintenance study.

[0786] b Histologic healing was defined according to the Geboes grading system as neutrophil infiltration of <5% of crypts, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue.

[0787] c Intercurrent Event (ICE) Strategy: Subjects who underwent ostomy or colectomy (ICE 1), dose adjustment (including simulated dose adjustment) (ICE 2), prohibited change of UC medication (ICE 3), or discontinued study medication due to lack of efficacy or AE of worsening UC (ICE 4) before Week 24-44 were considered to have not achieved histological healing at Week 24-44. For subjects who discontinued study medication at Week 24-44 due to COVID-19 related reasons (excluding COVID-19 infection) or the regional crisis in Russia and Ukraine (ICE 5), their observed values ​​(if available) were used. Subjects who experienced ICE 6 (discontinuation of study medication due to reasons other than those in ICE 4 and 5) before Week 24-44 were considered to have not achieved histological healing at Week 24-44.

[0788] dNonresponder Imputation for Missing Data: After accounting for ICE, subjects with an unevaluable biopsy (i.e., a biopsy collected but could not be evaluated due to sample preparation or technical error) or missing any component related to this endpoint (i.e., assessment of neutrophils in the epithelium, crypt disruption, or erosions or ulcers or granulations) at Weeks 24-44 were considered to have not achieved histologic healing.

[0789] e Confidence intervals for the proportion of subjects meeting the end point in each treatment group were based on normal approximate confidence limits.

[0790] f Adjusted treatment differences and confidence intervals were based on Wald statistics with Cochran–Mantel–Haenszel weights.

[0791] g The p-values ​​were based on the Cochran-Mantel-Haenszel (CMH) test, stratified by maintenance of clinical remission status at baseline (yes / no) and induction therapy (guselkumab 400 mg IV, guselkumab 200 mg IV, placebo IV crossover to guselkumab 200 mg IV).

[0792] Table 34: Overall Summary of Treatment-Emergent Adverse Events (Until Dose Modification) through Weeks 24-44; Randomized Security Analysis Set

[0793]

[0794] Two participants randomized to GUS 100 mg q8w SC received only PBO on M-0 (discontinued study treatment before their first scheduled GUS dose at week M-4). They were included in the placebo SC treatment group.

[0795] a Subjects who were in clinical response to guselkumab IV induction dosing and were randomized to placebo SC for entry into the maintenance study.

[0796] b Data on the timing of dose adjustments were included for subjects who had a dose adjustment from Week M-0 or who had no dose adjustment by Week M-44.

[0797] The present invention may be described with reference to the following numbered embodiments:

[0798] 1. Use of an antibody specific for IL23 for treating ulcerative colitis in a patient, wherein the antibody comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region comprises:

[0799] the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:4;

[0800] the CDRL2 amino acid sequence of SEQ ID NO: 5; and

[0801] The CDRL3 amino acid sequence of SEQ ID NO: 6,

[0802] The heavy chain variable region comprises:

[0803] the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1;

[0804] the CDRH2 amino acid sequence of SEQ ID NO: 2; and

[0805] The CDRH3 amino acid sequence of SEQ ID NO: 3, and the use allows the patient to produce a clinical response.

[0806] 2. The use according to embodiment 1, wherein the antibody is administered as an initial dose, a dose about 4 weeks after the initial dose, and a dose about 8 weeks after the initial dose.

[0807] 3. The use according to embodiment 2, wherein the initial dose and the dose about 4 weeks after the initial dose and the dose about 8 weeks after the initial dose are 200 mg or 400 mg of the antibody.

[0808] 4. The use according to embodiment 3, wherein the administration is intravenous.

[0809] 5. The use according to embodiment 1, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is a clinical response defined as a decrease of ≥30% and ≥2 points from the induction baseline in the modified Mayo score, with a decrease of ≥1 point from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.

[0810] 6. The use according to embodiment 1, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is selected from the group consisting of:

[0811] (i) clinical remission, defined as a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability on endoscopy, where the stool frequency subscore has not increased from the induction baseline;

[0812] (ii) symptom remission, defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, wherein the stool frequency subscore did not increase from the induction baseline;

[0813] (iii) endoscopic healing, defined as an endoscopic subscore of 0 or 1, with no friability present on endoscopic examination;

[0814] (iv) histologic-endoscopic mucosal healing, defined as the combination of histologic and endoscopic healing, where histologic healing is defined as neutrophil infiltration of <5% of crypts according to the Geboes grading system, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue; and

[0815] (v) Endoscopic normalization, defined as an endoscopic subscore of 0 (which requires the absence of friability).

[0816] 7. The use according to embodiment 1, wherein the patient is a responder to the antibody and is identified as having biomarkers of CRP ≤ 3 mg / L and / or FeCal ≤ ​​250 mg / kg.

[0817] 8. The use according to embodiment 4, wherein the antibody is administered in a maintenance dose about every 4 weeks or every 8 weeks after the dose administered about 8 weeks after the initial dose.

[0818] 9. The use according to embodiment 8, wherein the maintenance dose is 100 mg or 200 mg of the antibody.

[0819] 10. The use of any one of embodiments 5 to 9, wherein the clinical endpoint is measured at about 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks and / or 48 weeks after initial treatment.

[0820] 11. The use according to embodiment 10, wherein the clinical endpoint is measured about 12 weeks after the initial treatment.

[0821] 12. The use according to embodiment 10, wherein the clinical endpoint is measured about 44 weeks after the initial treatment.

[0822] 13. The use according to 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.

[0823] 14. 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.

[0824] 15. The use according to embodiment 13 or 14, wherein the antibody is in a composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) polysorbate 80 of the pharmaceutical composition; and wherein the diluent is water under standard conditions.

[0825] 16. The use according to embodiment 12 or 12, wherein the antibody is further administered to the patient.

[0826] 15. The use according to embodiment 14, wherein the antibody is administered subcutaneously at a dose of 100 mg or 200 mg.

[0827] 16. The use according to embodiment 1, wherein the patient is not a responder to the antibody and is identified as not meeting a clinical endpoint, wherein the clinical endpoint is a clinical response defined as a ≥30% decrease and ≥2 points from the induction baseline in the modified Mayo score, with a ≥1 point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.

[0828] 17. The use according to embodiment 16, wherein the patient is further administered the antibody specific for IL23.

[0829] 18. The use according to embodiment 17, wherein the antibody is administered 12 weeks after initial treatment.

[0830] 19. The use according to embodiment 18, wherein the antibody is administered 12 weeks after the initial treatment, 16 weeks after the initial treatment, and 20 weeks after the initial treatment.

[0831] 20. The use according to embodiment 19, wherein the antibody is administered subcutaneously at a dose of 200 mg.

[0832] 21. The use according to embodiment 20, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is defined as improved

[0833] A clinical response of ≥30% and ≥2 Mayo Clinic scores compared to the induction baseline, with a rectal bleeding subscore of ≥1 point compared to the baseline or a rectal bleeding subscore of 0 or 1 was considered.

[0834] 22. The use according to embodiment 20, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is selected from the group consisting of

[0835] Groups:

[0836] (i) clinical remission, defined as a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability on endoscopy, where the stool frequency subscore has not increased from the induction baseline;

[0837] (ii) symptom remission, defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, wherein the stool frequency subscore did not increase from the induction baseline;

[0838] (iii) endoscopic healing, defined as an endoscopic subscore of 0 or 1, with no friability present on endoscopic examination;

[0839] (iv) histologic-endoscopic mucosal healing, defined as the combination of histologic and endoscopic healing, where histologic healing is defined as neutrophil infiltration of <5% of crypts according to the Geboes grading system, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue; and

[0840] (v) Endoscopic normalization, defined as an endoscopic subscore of 0 (which requires the absence of friability).

[0841] 23. The use according to embodiment 21 or 22, wherein the clinical endpoint is measured at about 24 weeks or 44 weeks after the initial treatment.

[0842] 24. The use according to embodiment 21 or 22, wherein the patient is further administered the antibody specific for IL23 every 4 weeks or every 8 weeks thereafter.

[0843] 25. The use according to embodiment 16, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO: 8 and the heavy chain variable region amino acid sequence of SEQ ID NO: 7.

[0844] 26. The use according to embodiment 16, wherein the antibody comprises a light chain amino acid sequence of SEQ ID NO: 10 and a heavy chain amino acid sequence of SEQ ID NO: 9.

[0845] 27. The use according to embodiment 25 or 26, wherein the antibody is in a composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) polysorbate 80 of the pharmaceutical composition; and wherein the diluent is water under standard conditions.

[0846] 28. The use according to any one of embodiments 1 to 27, further comprising the use of one or more additional drugs for the treatment of ulcerative colitis.

[0847] 29. The use according to embodiment 28, wherein the additional drug 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 co-stimulatory modulators.

[0848] 30. The use according to embodiment 1, wherein prior to treatment with the antibody specific for IL23, the patient is considered to have failed or is intolerant to biological therapy for ulcerative colitis (Bio-failure).

[0849] 31. The use according to embodiment 1, wherein prior to treatment with the antibody specific for IL23, the patient is considered to have failed or is intolerant to conventional therapy for ulcerative colitis (Con-failure).

[0850] 32. The use according to embodiment 1, wherein the ulcerative colitis is moderately to severely active ulcerative colitis.

[0851] 33. The use according to embodiment 32, wherein prior to administration of the initial dose, the patient has endoscopic evidence of active Crohn's disease.

[0852] 34. The use according to embodiment 33, wherein prior to administration of the initial dose, the patient's modified Mayo score is 5 to 9, inclusive, with a Mayo rectal bleeding subscor...

Claims

1. A method of treating ulcerative colitis in a patient, the method comprising administering to the patient an antibody specific for IL23, wherein the antibody comprises 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 The CDRL3 amino acid sequence of SEQ ID NO: 6, The heavy chain variable region comprises: the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1; the CDRH2 amino acid sequence of SEQ ID NO: 2; and The CDRH3 amino acid sequence of SEQ ID NO: 3, and wherein the patient is considered a responder to the antibody.

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

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

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

5. The method of claim 1 , wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is a clinical response defined as a ≥30% decrease and ≥2 points in the modified Mayo Clinic score from induction baseline, with a ≥1 point decrease in the rectal bleeding subscore from baseline or a rectal bleeding subscore of 0 or 1.

6. The method of claim 1, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is selected from the group consisting of: (i) clinical remission, defined as a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability on endoscopy, where the stool frequency subscore has not increased from the induction baseline; (ii) symptom remission, defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, wherein the stool frequency subscore did not increase from the induction baseline; (iii) endoscopic healing, defined as an endoscopic subscore of 0 or 1, with no endoscopic friability present; (iv) histologic-endoscopic mucosal healing, defined as the combination of histologic and endoscopic healing, where histologic healing is defined as neutrophil infiltration of <5% of crypts according to the Geboes grading system, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue; and (v) Endoscopic normalization, defined as an endoscopic subscore of 0 (which requires the absence of friability).

7. The method of claim 1, wherein the patient is a responder to the antibody and is identified as having a biomarker of CRP ≤ 3 mg / L and / or FeCal ≤ ​​250 mg / kg.

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

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

10. The method of any one of claims 5 to 9, wherein the clinical endpoint is about 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 28 weeks, 32 weeks, Measurements were taken at 36, 40, 44, and / or 48 weeks.

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

12. The method of claim 10, wherein the clinical endpoints and / or biomarkers are measured about 24 weeks after initial treatment.

13. The method of claim 10, wherein the clinical endpoints and / or biomarkers are measured about 44 weeks after initial treatment.

14. The method of claim 4, 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.

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

9.

16. The method of claim 14 or 15, wherein the antibody is in a composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; and 0.053% (w / v) polysorbate 80 of the pharmaceutical composition. The diluent is water under standard conditions.

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

18. The method of claim 1, wherein the patient is not a responder to the antibody and is identified as not meeting a clinical endpoint, wherein the clinical endpoint is a clinical response defined as a ≥30% decrease and ≥2 points from the induction baseline in the modified Mayo score, with a ≥1 point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.

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

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

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

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

23. The method of claim 22, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is a clinical response defined as a ≥30% decrease and ≥2 points in the modified Mayo score from induction baseline, with a ≥1 point decrease in the rectal bleeding subscore from baseline or a rectal bleeding subscore of 0 or 1.

24. The method of claim 14, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is selected from the group consisting of: (i) clinical remission, defined as a stool frequency subscore of 0 or 1, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability on endoscopy, where the stool frequency subscore has not increased from the induction baseline; (ii) symptom remission, defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, wherein the stool frequency subscore did not increase from the induction baseline; (iii) endoscopic healing, defined as an endoscopic subscore of 0 or 1, with no endoscopic friability present; (iv) histologic-endoscopic mucosal healing, defined as the combination of histologic and endoscopic healing, where histologic healing is defined as neutrophil infiltration of <5% of crypts according to the Geboes grading system, absence of crypt destruction, and absence of erosions, ulcers, or granulation tissue; and (v) Endoscopic normalization, defined as an endoscopic subscore of 0 (which requires the absence of friability).

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

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

27. The method according to claim 23 or 24, comprising further subcutaneously administering to the patient the antibody specific for IL23 at a dose of 100 mg or 200 mg of the antibody every 4 weeks or every 8 weeks thereafter.

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

9.

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

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

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

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

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

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

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

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

37. A method of treating moderately to severely active ulcerative colitis in a patient, the method comprising administering to the patient (i) an initial intravenous dose of 200 mg or 400 mg of an antibody specific for IL23, (ii) an intravenous dose of 200 mg or 400 mg of the antibody about 4 weeks after the initial dose, and (iii) an intravenous dose 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, wherein the clinical endpoint is a clinical response defined as a decrease of ≥30% and ≥2 points in the modified Mayo score from induction baseline, with a decrease of ≥1 point from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.

38. The method of claim 37, further comprising administering a maintenance dose of the antibody specific for IL23 at a dose of 100 mg or 200 mg approximately every 4 weeks or every 8 weeks after administering the dose approximately 8 weeks after administering the initial dose.

39. A method of treating moderately to severely active ulcerative colitis in a patient, the method comprising administering to the patient (i) an initial intravenous dose of 200 mg or 400 mg of an antibody specific for IL23, (ii) an intravenous dose of 200 mg or 400 mg of the antibody about 4 weeks after the initial dose, (iii) an intravenous dose of 200 mg or 400 mg of the antibody about 8 weeks after the initial dose, and (iv) a maintenance dose of 100 mg or 200 mg of the antibody specific for IL23 about every 4 weeks or every 8 weeks after the dose 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 light chain variable region amino acid sequence of SEQ ID NO:

9. NO:7, and the patient is a responder to the antibody by being identified as meeting the clinical endpoint at approximately 12 weeks, 24 weeks and / or 44 weeks after the initial dose, wherein the clinical endpoint is a clinical response defined as a decrease of ≥30% and ≥2 points in the modified Mayo score from the induction baseline, wherein the rectal bleeding subscore is decreased by ≥1 point from baseline or the rectal bleeding subscore is 0 or 1.

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