Methods of Treating Crohn's Disease with Anti-IL23 Specific Antibodies

Abstract

A method of treating Crohn's disease in a patient comprises administering an initial intravenous dose followed by subcutaneous administration of an IL-23 specific antibody, e.g., guselkumab, such that the patient responds to the antibody and meets one or more of the clinical endpoints.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to methods for treating Crohn's disease with antibodies that bind to human IL23. In particular, the present invention relates to anti-IL-23 specific antibodies and methods involving specific administration and dosing regimens for administering specific pharmaceutical compositions of antibodies, e.g., guselkumab.

[0002] (Reference to electronically submitted sequence listing) This application includes a sequence listing, which has been submitted electronically through the United States Patent and Trademark Office Patent Center as an XML format sequence listing, with the file name "JBI6656WOPCT1 Sequence Listing.xml", created at and having a size of Kb. The sequence listing submitted through the Patent Center is a part of this specification and is incorporated herein by reference in its entirety.

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

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

[0005] Abnormal regulation of IL-12 and Th1 cell populations has been implicated in many immune-mediated diseases, as neutralization of IL-12 with antibodies has been effective in treating animal models of psoriasis, multiple sclerosis (MS), rheumatoid arthritis, inflammatory bowel disease, insulin-dependent (type 1) diabetes mellitus, and uveitis (Leonard et al., 1995; Hong et al., 1999; Malfait et al., 1998; Davidson et al., 1998). However, these studies neutralized both IL-12 and IL-23 in vivo, as they targeted the common p40 subunit. Thus, it is unclear whether IL-12 or IL-23 mediated the disease, or whether both cytokines need to be inhibited to achieve disease suppression. Recent studies have confirmed that IL-23 inhibition can provide benefits comparable to anti-IL-12p40 strategies using IL-23p19-deficient mice or specific antibody neutralization of IL-23 (Cua et al., 2003; Murphy et al., 2003; Benson et al., 2004). Thus, there is growing evidence for a specific role of IL-23 in immune-mediated diseases. Neutralizing IL-23 without inhibiting the IL-12 pathway could provide an effective treatment for immune-mediated diseases with limited impact on important host defense immune mechanisms. This could provide a significant improvement over current therapeutic options.

[0006] Currently, there are three classes of biologic agents approved for the treatment of moderately to severely active Crohn's disease: tumor necrosis factor (TNF) antagonist therapies (infliximab, adalimumab, certolizumab), integrin inhibitors (natalizumab and vedolizumab), and IL-12 / 23 inhibitors (ustekinumab). Although the introduction of biologic agents has significantly improved the clinical management of patients with moderately to severely active Crohn's disease, a significant proportion of the study patient population does not respond or loses response over time. A review of the available data for the approved biologic agents highlights an unmet need in achieving and maintaining long-term remission, especially among patients who have previously failed biologic agents. In all treated patients (i.e., all patients randomized at week 0 of the study evaluated), the estimated rate of clinical remission at 1 year in the biologic non-responder or intolerant (BIO non-responder) population is approximately 20% and ranges from 20% to 50% in the conventional therapy non-responder or intolerant (CON non-responder) population.

[0007] In summary, there remains a significant unmet medical need for new treatment options, particularly therapies with novel mechanisms of action that have the potential to raise the efficacy bar and maximize the proportion of patients who achieve and maintain clinical remission.

[0008] (Summary of the invention) In a first aspect, the present invention relates to a method for a subject suffering from Crohn's disease comprising administering to the patient an anti-IL-23 specific antibody (also referred to as an IL-23p19 antibody), e.g., guselkumab, as an initial intravenous induction dose from the start of treatment until week 8, followed by subcutaneous administration of the anti-IL-23 specific antibody once every 4 weeks or every 8 weeks, e.g., at weeks 0, 4, 8, 12 or 16, 20 or 24, 28 or 32, 36 or 40, 44 or 48. Moreover, in another embodiment, the subcutaneous treatment continues for 140 weeks after the start of treatment.

[0009] In one embodiment, the subject receives an anti-IL-23 specific antibody intravenously at doses of 1200, 600, or 200 mg initially, 4 weeks after the first dose, and 8 weeks after the first dose, and continues to receive anti-IL-23 specific antibody subcutaneously at 100 or 200 mg every 4 weeks through 44 weeks after the first treatment.

[0010] In another aspect, the composition used in the method of the invention comprises a pharmaceutical composition comprising an anti-IL-23 specific antibody. In a preferred embodiment, the anti-IL-23 specific antibody is comprised in a pharmaceutical composition comprising the following composition: 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) polysorbate 80, and the diluent is water at normal conditions.

[0011] In one embodiment, the Crohn's disease patient achieved a significant improvement in one or more clinical endpoints selected from the following: (i) Change from baseline in Crohn's Disease Activity Index (CDAI) score at week 48. The CDAI score is assessed by collecting information on eight different Crohn's disease-related variables, with scores ranging from 0 to approximately 600. A reduction over time indicates improvement in disease activity. (ii) clinical remission at week 48, defined as a CDAI of less than (<) 150 points; (iii) Clinical response at Week 48, defined as a reduction from baseline in CDAI score of 100 points or more (≥) or a CDAI score of less than (<) 150. (iv) Patient-Reported Outcome (PRO)-2 remission at week 48, defined based on mean daily stool frequency (SF) and mean daily abdominal pain (AP) scores. (v) Clinical biomarker response at week 48, defined using clinical response based on CDAI score and reduction from baseline in C-reactive protein (CRP) or fecal calprotectin. (vi) endoscopic response at week 48, as measured by the Simplified Endoscopic Score for Crohn's Disease (SES-CD). The SES-CD is based on the assessment of four endoscopic components across five ileocolonic segments, with a total score ranging from 0 to 56. (vii) endoscopic remission at week 48 as measured by Simplified Endoscopic Score for Crohn's Disease (SES-CD), SES-CD ≤ 2. (viii) sustained clinical remission at week 48, defined as a CDAI <150 at the majority of all visits between weeks 12 and 48. (ix) Corticosteroid-free clinical remission at Week 48, defined as a CDAI score of less than 150 at Week 48 and no corticosteroids at Week 48. (x) Fatigue response at week 48 based on the Patient-Reported Outcomes Measurement Information System (PROMIS). The Fatigue Short Form 7a includes seven items assessing the severity of fatigue, with higher scores indicating greater fatigue.

[0012] In another aspect of the invention, a pharmaceutical composition comprises an isolated anti-IL23 specific antibody having guselkumab 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, 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 the diluent is standard water.

[0013] Another embodiment of the method of the invention comprises administering a pharmaceutical composition comprising an isolated anti-IL-23 specific antibody having the guselkumab heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the guselkumab light chain variable region amino acid sequence of SEQ ID NO: 8, contained in a composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, 0.053% (w / v) polysorbate 80, and the diluent is water at normal conditions.

[0014] A further embodiment of the method of the invention comprises administering a pharmaceutical composition comprising an isolated anti-IL-23 specific antibody having the guselkumab heavy chain amino acid sequence of SEQ ID NO: 9 and the guselkumab light chain amino acid sequence of SEQ ID NO: 10, contained in a composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, 0.053% (w / v) polysorbate 80, and the diluent is water at normal conditions.

[0015] The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages will become apparent from the following detailed description, the drawings, and the appended claims. [Brief description of the drawings]

[0016] [Figure 1] The mean change from baseline in CDAI scores through 24 weeks in the entire population is shown. [Diagram 2] 1 shows the mean change from baseline in CDAI scores through 24 weeks in the BIO non-responder population. [Diagram 3] 1 shows the mean change from baseline in CDAI scores through 24 weeks in the CON non-responder population. [Figure 4] Patient clinical responses and clinical remissions up to 24 weeks are shown. [Diagram 5] Patients are shown to be in clinical remission by 96 weeks. [Figure 6] Patients are shown to be in clinical remission by 96 weeks.

[0017] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS As used herein, methods of treating a subject suffering from Crohn's disease include administering isolated, recombinant, and / or synthetic anti-IL-23 specific human antibodies, as well as diagnostic and therapeutic compositions, methods, and devices.

[0018] As used herein, "anti-IL-23 specific antibodies," "anti-IL-23 antibodies," "antibody portions," or "antibody fragments," and / or "antibody variants," and the like, include any protein or peptide-containing molecule comprising at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one complementarity determining region (CDR) of a heavy or light chain, or 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 be incorporated into an antibody of the invention. Such antibodies optionally further affect a specific ligand, for example, but not limited to, such antibodies modulate, reduce, enhance, antagonize, stimulate, reduce, ameliorate, block, inhibit, abrogate, and / or prevent at least one IL-23 activity or binding, or IL-23 receptor activity or binding, in vitro, in situ, and / or in vivo. As non-limiting examples, suitable anti-IL-23 antibodies, specified portions, or variants of the invention can bind to at least one IL-23 molecule or specified portions, variants, or domains thereof. Suitable anti-IL-23 antibodies, specified portions, or variants can also optionally affect at least one IL-23 activity or function, including, but not limited to, RNA, DNA, or protein synthesis, IL-23 release, IL-23 receptor signaling, membrane IL-23 cleavage, IL-23 activity, IL-23 production and / or synthesis, etc.

[0019] The term "antibody" is further intended to encompass antibodies, digested fragments thereof, specific portions, and variants thereof, including antibody mimetics or portions of antibodies that mimic the structure and / or function of antibodies, such as single chain antibodies and fragments thereof, or specific fragments or portions thereof. Functional fragments include antigen-binding fragments that bind to mammalian IL-23. For example, antibody fragments capable of binding to IL-23 or portions thereof, including but not limited to Fab (e.g., by papain digestion), Fab' (e.g., by pepsin digestion and partial reduction), and F(ab')2 (e.g., by pepsin digestion), Facb (e.g., by plasmin digestion), pFc' (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction, and reaggregation), Fv, or scFv (e.g., by molecular biology techniques) fragments are encompassed by the present invention (see, e.g., Colligan, Immunology, supra).

[0020] Such fragments can be produced by enzymatic cleavage, synthetic, or recombinant techniques known in the art and / or described herein. Antibodies can also be produced in a variety of truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. For example, a combination of genes encoding a F(ab')2 heavy chain portion can be used to encode a C(ab')2 heavy chain portion. H The antibody can be designed to contain DNA sequences encoding one or more of the antibody domains and / or hinge regions. The various portions of the antibody can be joined chemically by conventional techniques, or can be prepared as a contiguous protein using genetic engineering techniques.

[0021] As used herein, the term "human antibody" refers to an antibody that is human and contains substantially all parts of the protein (e.g., CDRs, frameworks, C L , C H Domain (e.g., C H 1. C H 2. C H 3), Hinge (V L , V Hs)) refers to an antibody that is substantially non-immunogenic in humans with only minor sequence changes or mutations. A "human antibody" may be an antibody derived from or closely corresponding to a human germline immunoglobulin sequence. A human antibody may contain amino acid residues not encoded by a germline immunoglobulin sequence (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). In many cases, this means that the human antibody is substantially non-immunogenic in humans. Human antibodies have been classified into groups based on the similarity of their amino acid sequences. Thus, using sequence similarity searches, antibodies with similar linear sequences can be selected as templates for creating human antibodies. Similarly, antibodies with names including primates (monkeys, baboons, chimpanzees, etc.), rodents (mouse, rats, rabbits, guinea pigs, hamsters, etc.), and other mammals designate antibodies specific for such species, subgenus, genus, subfamily, and family. Furthermore, chimeric antibodies can include any combination of the above. Such changes or mutations optionally and preferably retain or reduce immunogenicity in humans or other species compared to the unmodified antibody. Thus, a human antibody is distinct from a chimeric antibody or a humanized antibody.

[0022] It is noted that human antibodies can be produced by non-human animals or prokaryotic or eukaryotic cells capable of expressing functionally rearranged human immunoglobulin (e.g., heavy and / or light chain) genes. Furthermore, when the human antibody is a single-chain antibody, it can contain a linker peptide not found in naturally occurring human antibodies. For example, Fv can contain a linker peptide, such as 2 to about 8 glycine or other amino acid residues, connecting the variable region of the heavy chain and the variable region of the light chain. Such a linker peptide is considered to be of human origin.

[0023] Bispecific, heterospecific, heterobinding or similar antibodies may also be used, which are monoclonal, preferably human or humanized, antibodies with binding specificities for at least two different antigens, one of which is for at least one IL-23 protein and the other for any other antigen. Methods for producing bispecific antibodies are known in the art. Traditionally, recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-light chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature 305:537 (1983)). Due to the random combination of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a possible mixture of 10 different antibody molecules, of which only one has the correct bispecific structure. Purification of the correct molecule (usually done by affinity chromatography steps) is quite laborious and the product yield is low. Similar procedures are described, for example, in WO 93 / 08829, U.S. Pat. Nos. 6,210,668, 6,193,967, 6,132,992, 6,106,833, 6,060,285, 6,037,453, 6,010,902, 5,989,530, 5,959,084, 5,959,083, 5,989,530, 5,959,084, 5,959,083, 5,989,530, 5,959,084, 5,959,085, 5,989,530 ...89,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,530, 5,989,5 Nos. 32448, 5833985, 5821333, 5807706, 5643759, 5601819, 5582996, 5496549, 4676980, WO 91 / 00360, WO 92 / 00373, EP 03089, Traunecker et al., EMBO J. 10:3655 (1991), and Suresh et al., Methods in Enzymology 121:210 (1986), each of which is incorporated herein by reference in its entirety.

[0024] Anti-IL-23 specific antibodies (also referred to as IL-23 specific antibodies) (or antibodies against IL-23) useful in the methods and compositions of the invention may optionally be characterized by high affinity binding to IL-23, and optionally and preferably low toxicity. In particular, antibodies of the invention, specific fragments or variants thereof, in which the individual components, such as the variable region, constant region and framework, individually and / or collectively, optionally and preferably have low immunogenicity, are useful in the present invention. Antibodies that can be used in the present invention are optionally characterized by the ability to treat patients for extended periods of time with measurable alleviation of symptoms and low and / or acceptable toxicity. Low or acceptable immunogenicity and / or high affinity, as well as other favorable properties, can contribute to the therapeutic results obtained. "Low immunogenicity" is defined herein as raising a significant HAHA, HACA, or HAMA response in less than about 75% of treated patients, or preferably less than about 50%, and / or raising low titers (less than about 300, preferably less than about 100, as measured by double antigen enzyme immunoassay) in treated patients (Elliott et al., Lancet 344:1125-1127 (1994), incorporated herein by reference in its entirety). "Low immunogenicity" can also be defined as the incidence of titratable levels of antibodies to anti-IL-23 antibodies in patients treated with anti-IL-23 antibodies occurring in less than 25% of treated patients, preferably less than 10% of treated patients, at the recommended dose over the recommended course of treatment during the treatment period.

[0025] The term "clinically proven safety" refers to a relatively low or reduced frequency and / or a low or reduced severity of treatment-emergent adverse events (also called AEs or TEAEs) in relation to an administration, dosing regimen, treatment or method with an anti-IL-23 antibody of the present invention (e.g., the anti-IL-23 antibody guselkumab), e.g., from a clinical trial conducted, e.g., a Phase 2 clinical trial, and earlier clinical trials, compared to a standard of care or another comparison standard. An adverse event is an untoward medical occurrence in a patient administered a medicinal product. In particular, when relating to an administration, dosing regimen or treatment with an anti-IL-23 antibody of the present invention, clinically proven safety refers to a relatively low or reduced frequency and / or a low or reduced severity of adverse events associated with administration of the antibody, when the cause is considered possible, probable, or highly likely to be due to the use of the anti-IL-23 antibody.

[0026] usefulness The isolated nucleic acids of the present invention can be used to produce at least one anti-IL-23 antibody or specific variants thereof, which can be used to measure or act on cells, tissues, organs, or animals (including mammals and humans) to diagnose, monitor, regulate, treat, alleviate, help prevent the occurrence of, or reduce the symptoms of Crohn's disease.

[0027] Such methods may include administering an effective amount of a composition or pharmaceutical composition comprising at least one anti-IL-23 antibody to a cell, tissue, organ, animal, or patient in need thereof to modulate, treat, alleviate, prevent, or ameliorate a symptom, effect, or mechanism. An effective amount may include an amount of about 0.001-500 mg / kg per single (e.g., bolus), multiple, or continuous administration, or an amount that achieves a serum concentration of 0.01-5000 μg / ml per single, multiple, or continuous administration, or any effective range or value therein, performed and determined using known methods described herein or known in the relevant art.

[0028] References All publications or patents cited herein, whether specifically stated or not, are incorporated herein by reference in their entirety, indicating the prior art at the time of the invention and / or providing a description and enabling of the invention. A publication refers to any scientific publication or patent publication or any other information available in any media format, including all recorded in electronic or printed form. The following documents are incorporated herein by reference in their entirety: Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2 nd Edition, Cold Spring Harbor, NY(1989), Harlow and Lane, antibodies, a Laboratory Manual, Cold Spring Harbor, NY(1989), Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY(1994-2001), Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2001).

[0029] Antibodies of the Invention - Production and Purification At least one anti-IL-23 used in the methods of the invention can optionally be produced by a cell line, mixed cell line, immortalized cell, or clonal population of immortalized cells, as known in the art, see, for example, Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2002; and U.S. Pat. No. 6,333,311, each of which is incorporated herein by reference in its entirety. nd Edition, Cold Spring Harbor, NY (1989), Harlow and Lane, antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989), Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994-2001), Colligan et al., Current Protocols in Protein Science, John Wiley & See Sons, NY, NY, (1997-2001).

[0030] 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 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.

[0031] Human antibodies specific for human IL-23 protein or fragments thereof can be raised against suitable immunogenic antigens, such as isolated IL-23 protein and / or portions thereof (including synthetic molecules such as synthetic peptides). Other specific or general mammalian antibodies can be similarly produced. Preparation of immunogenic antigens and production of monoclonal antibodies can be carried out using any suitable technique.

[0032] In one approach, a suitable immortal cell line (e.g., but not limited to, Sp2 / 0, Sp2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, L243, P3X63Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5, U937, MLA 144, ACT IV, MOLT4, DA-1, JURKAT, WEHI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA 144, NAMALWA, NEURO Myeloma cell lines such as 2A, or heteromyelomas, fusion products thereof, or any cells or fusion cells derived therefrom, or any other suitable cell line known in the art) (see, for example, www.atcc.org, www.lifetech.com, etc.), antibody producing cells such as isolated or cloned spleen, peripheral blood, lymph, tonsil, or other immune or B cell containing cells, or recombinant or endogenous, viral, bacterial, or other nucleic acids, either as endogenous or heterologous. With any other cell expressing the heavy or light chain constant or variable, or framework or CDR sequences, either as algae, prokaryote, amphibian, insect, reptile, fish, mammal, rodent, horse, ovine, caprine, ovine, primate, eukaryote, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single, double or triple stranded, hybridized, etc., or as any combination thereof, to produce a hybridoma. See, e.g., Ausubel, supra, and Colligan, Immunology, supra, Chapter 2, both of which are incorporated herein by reference in their entireties.

[0033] Antibody producing cells can also be obtained from the peripheral blood, or preferably the spleen or lymph nodes, of humans or other suitable animals immunized with the antigen of interest. Any other suitable host cells can also be used to express heterologous or endogenous nucleic acid encoding the antibody of the invention, specific fragments or variants thereof. Fused cells (hybridomas) or recombinant cells can be isolated using selective culture conditions or other suitable known methods and cloned by limiting dilution or cell sorting or other known methods. Cells producing antibodies with the desired specificity can be selected by a suitable assay (e.g., ELISA).

[0034] Other suitable methods for producing or isolating antibodies with the required specificity can be used, including, but not limited to, recombinant antibody selection from peptide or protein libraries (e.g., but not limited to, bacteriophage, ribosomal, oligonucleotide, RNA, cDNA, etc. display libraries, available, for example, from Cambridge Antibody Technologies, Cambridgeshire, UK; MorphoSys, Martinsreid / Planegg, DE; Biovation, Aberdeen, Scotland, UK; BioInvent, Lund, Sweden; Dyax Corp., Enzon, Affymax / Biosite, Xoma, Berkeley, CA, Ixsys.).For example, European Patent No. 368,684, International Application No. GB91 / 01134, International Application No. GB92 / 01755, International Application No. GB92 / 002240, International Application No. GB92 / 00883, International Application No. GB93 / 00605, U.S. Patent Application No. 08 / 350260 (5 / 12 / 94), International Application No. GB94 / 01422, International Application No. GB94 / 02662, International Application No. GB97 / 01835, (CAT / MRC), WO 90 / 14443, WO 90 / 14424, WO 90 / 14430, International Application No. US94 / 1234, WO 92 / 18619, WO 96 / 07754 (Scripps), WO 96 / 13583, WO 97 / 08320 (MorphoSys), WO 97 / 08320 (MorphoSys), WO 98 / 01835 (MorphoSys), WO 99 / 0203 (MorphoSys), WO 91 / 01835 (MorphoSys), WO 92 / 01836 (MorphoSys), WO 93 / 01837 (MorphoSys), WO 94 / 01838 (MorphoSys), WO 95 / 01839 (MorphoSys), WO 96 / 01839 (MorphoSys), WO 97 / 01839 (MorphoSys), WO 98 / 01839 (MorphoSys), WO 99 / 01836 (MorphoSys), WO 99 / 01839 ... 95 / 16027 (BioInvent), WO 88 / 06630, WO 90 / 3809 (Dyax), U.S. Pat. No. 4,704,692 (Enzon), International Application No. US91 / 02989 (Affymax), WO 89 / 06283, EP 371998, EP 550400, (Xoma), EP 229046, International Application No. US91 / 07149 (Ixsys), or stochastically generated peptides or proteins - U.S. Pat. Nos. 5,723,323, 5,763,192, 5,814,476, 5,817,483, 5,824,514, 5,976,862, WO 86 / 05803, EP 590689 (Ixsys), Applied Molecular Evolution (Applied These techniques include those based on the National Institute of Molecular Evolution (AME), a predecessor of the American Association for Clinical Molecular Evolution (ACME), each of which is incorporated herein by reference in its entirety), or rely on the immunization of transgenic animals capable of producing a repertoire of human antibodies as known in the art and / or described herein (e.g., SCID mice, each of which is incorporated herein by reference in its entirety; Nguyen et al., Microbiol. Immunol. 41:901-907 (1997); Sandhu et al., Crit. Rev. Biotechnol. 16:95-118 (1996); Eren et al., Immunol. 93:154-161 (1998), and related patents and applications).Such techniques include ribosome display (Hanes et al., Proc. Natl. Acad. Sci. USA, 94:4937-4942 (May 1997); Hanes et al., Proc. Natl. Acad. Sci. USA, 95:14130-14135 (Nov. 1998)), single cell antibody production techniques (e.g., the selected lymphocyte antibody method, "SLAM") (U.S. Pat. No. 5,627,052; Wen et al., J. Immunol. 17:887-892 (1987); Babcook et al., Proc. Natl. Acad. Sci. USA 93:7843-7848 (1996)), gel microdroplets and flow cytometry (Powell et al., J. Immunol. 1999, 11:111-111 (1996)). al., Biotechnol. 8:333-337 (1990); One Cell Systems, Cambridge, MA; Gray et al., J. Imm. Meth. 182:155-163 (1995); Kenny et al., Bio / Technol. 13:787-790 (1995)), B cell selectors (Steenbakkers et al., Molec. Biol. Reports 19:125-134 (1994); Jonak et al., Progress Biotech, Vol. 5, In Vitro Immunization in Hybridoma Technology, Borrebaeck, ed., Elsevier Science Publishers BV, Amsterdam, Netherlands (1988)).

[0035] Methods for engineering or humanizing non-human or human antibodies can also be used and are known in the art. Generally, a humanized or modified antibody will have one or more amino acid residues derived from a non-human source, such as, but not limited to, mouse, rat, rabbit, non-human primate, or other mammalian source. These non-human amino acid residues are often replaced by residues referred to as "import" residues, which are typically taken from an "import" variable, constant, or other domain of a known human sequence.

[0036] Available online at: www.ncbi.nlm.nih.gov / entrez / quer y.fcgi, www.ncbi.nih.gov / igblast, www.atcc.org / phage / hdb.html, www w.mrc-cpe.cam.ac.uk / ALIGNMENTS.php, www.kabatdatabase.com / top.html, ftp.ncbi.nih.gov / repository / kabat;www.sciquest.com, www.abc am.com, www.antibodyresource.com / onlinecomp.html, www.public.iastate.edu / ~pedro / research_tools.html, www.whfreeman.com / immunology gy / CH05 / kuby05.htm、www.hhmi.org / grants / lectures / 1996 / vlab、www.path.cam.ac.uk / ~mrc7 / mikeimages.html、mcb.harvard.edu / BioLinks / I mmunology.html;www.immunologylink.com、pathbox.wustl.edu / ~hcenter / index.html;www.appliedbiosystems.com、www.nal.usda.gov / awic / pubs / antibody www.m.ehime-u.ac.jp / ~yasuhito / Elisa.html www.biodesign.com www.cancerresearch.org www.biotech.ufl.edu www.is ac-net.org、baserv.uci.kun.nl / ~jraats / links1.html;www.recab.uni-hd.de / immuno.bme.nwu.edu、www.mrc-cpe.cam.ac.uk、www.ibt.unam.m x / vir / V_mice.html, http: / / www.bioinf.org.uk / abs, antibody.bath.ac.uk; www.unizh.ch, www.cryst.bbk.ac.uk / ~ubcg07s, www.nimr.mrc.ac.uk / CC / ccaewg / ccaewg.html, www.path.cam.ac.uk / ~mrc7 / humanisation / TAHHP.html, www.ibt.unam.mx / vir / structure / stat_aim.html, www.biosci.missouri.edu / smithgp / index.html, www.jerini.de, Kabat et al., Sequences of Proteins of Immunological Interest,USDept.Health(1983). .

[0037] Such imported sequences can be used to reduce immunogenicity, or to reduce, enhance, or modify binding, affinity, binding rate constant, dissociation rate constant, avidity, specificity, half-life, or any other suitable property, as known in the art. Generally, CDR residues directly and most substantially affect antigen binding. Thus, non-human sequences in variable and constant regions can be replaced with human or other amino acids, while maintaining some or all of the non-human or human CDR sequences.

[0038] Antibodies may optionally be humanized, or human antibodies may be modified while retaining high affinity for the antigen and other favorable biological properties. To this end, humanized (or human) antibodies may optionally be prepared by a process of analyzing the parental sequences and various theoretical humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformations of selected candidate immunoglobulin sequences. Inspection of these displays allows analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., analysis of residues that influence the antigen-binding ability of the candidate immunoglobulin. In this way, framework (FR) residues can be selected and combined from the consensus and import sequences such that desired antibody properties, such as enhanced affinity for the target antigen, are achieved.

[0039] In addition, human IL-23 specific antibodies used in the methods of the invention may comprise a human germline light chain framework. In certain embodiments, the light chain germline sequence is selected from a human VK sequence, including, but not limited to, A1, A10, A11, A14, A17, A18, A19, A2, A20, A23, A26, A27, A3, A30, A5, A7, B2, B3, L1, L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23, L24, L25, L4 / 18a, L5, L6, L8, L9, O1, O11, O12, O14, O18, O2, O4, and O8. In certain embodiments, the light chain human germline framework is selected from V1-11, V1-13, V1-16, V1-17, V1-18, V1-19, V1-2, V1-20, V1-22, V1-3, V1-4, V1-5, V1-7, V1-9, V2-1, V2-11, V2-13, V2-14, V2-15, V2-17, V2-19, V2-6, V2-7, V2-8, V3-2, V3-3, V3-4, V4-1, V4-2, V4-3, V4-4, V4-6, V5-1, V5-2, V5-4, and V5-6.

[0040] In other embodiments, the human IL-23 specific antibodies used in the methods of the invention may comprise a human germline heavy chain framework. In certain embodiments, the heavy chain human germline framework is selected from the group consisting of VH1-18, VH1-2, VH1-24, VH1-3, VH1-45, VH1-46, VH1-58, VH1-69, VH1-8, VH2-26, VH2-5, VH2-70, VH3-11, VH3-13, VH3-15, VH3-16, VH3-20, VH3-21, VH3-23, VH3-30, VH3- 33, VH3-35, VH3-38, VH3-43, VH3-48, VH3-49, VH3-53, VH3-64, VH3-66, VH3-7, VH3-72, VH3-73, VH3-74, VH3-9, VH4-28, VH4-31, VH4-34, VH4-39, VH4-4, VH4-59, VH4-61, VH5-51, VH6-1, and VH7-81.

[0041] In certain embodiments, the light chain variable region and / or the heavy chain variable region comprises a framework region, or at least a portion of a framework region (e.g., comprising two or three subregions, such as FR2 and FR3). In certain embodiments, at least FRL1, FRL2, FRL3, or FRL4 is fully human. In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is fully human. In some embodiments, at least FRL1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., human germline) or comprises a human consensus sequence for a particular framework (which are readily available at the sources of known human Ig sequences mentioned above). In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., human germline) or comprises a human consensus sequence for a particular framework. In preferred embodiments, the framework regions are fully human framework regions.

[0042] Humanization or engineering of the antibodies of the present invention may be carried out in accordance with the methods described by Winter (Jones et al., Nature 321:522 (1986); Riechmann et al., Nature 332:323 (1988); Verhoeyen et al., Science 239:1534 (1988)), Sims et al., J. Immunol. 151:2296 (1993), Chothia and Lesk, J. Mol. Biol. 196:901 (1987), Carter et al., Proc. Natl. Acad. Sci. USA 89:4285 (1992), Presta et al. al., J.Immunol.151:2623 (1993), U.S. Patent No. 5723323, U.S. Patent No. 5976862, U.S. Patent No. 5824514, U.S. Patent No. 5817483, U.S. Patent No. 5814476, U.S. Patent No. 5763192, U.S. Patent No. 5723323, U.S. Patent No. 5,76 6886, 5714352, 6204023, 6180370, 5693762, 5530101, 5585089, 5225539, 4816567, International Application No. US98 / 16280, US9 This can be done using any known method, such as, but not limited to, those described in US91 / 09630, US91 / 05939, US94 / 01234, International Application Nos. GB89 / 01334, GB91 / 01134, GB92 / 01755, International Publication Nos. WO 90 / 14443, WO 90 / 14424, WO 90 / 14430, and European Patent No. 229246 (each of which is incorporated by reference in its entirety, including the references cited therein).

[0043] In certain embodiments, the antibody comprises an altered (e.g., mutated) Fc region. For example, in some embodiments, the Fc region is altered to reduce or enhance the effector function of the antibody. In some embodiments, the Fc region is an isotype selected from IgM, IgA, IgG, IgE, or other isotypes. Alternatively, or in addition, it may be useful to combine the amino acid modification with one or more further amino acid modifications that alter the C1q binding and / or complement dependent cytotoxicity function of the Fc region of the IL-23 binding molecule. Starting polypeptides of particular interest may be those that bind C1q and exhibit complement dependent cytotoxicity (CDC). Polypeptides with existing C1q binding activity, and optionally further with the ability to mediate CDC, may be modified to enhance one or both of these activities. Amino acid modifications that alter C1q and / or modify its complement dependent cytotoxicity function are described, for example, in WO 0042072, which is incorporated herein by reference.

[0044] As disclosed above, the Fc region of the human IL-23 specific antibody of the present invention can be engineered with altered effector functions, for example, by modifying C1q binding and / or FcγR binding, thereby altering complement-dependent cytotoxicity (CDC) activity and / or antibody-dependent cell-mediated cytotoxicity (ADCC) activity. An "effector function" serves to activate or reduce a biological activity (e.g., in a subject). Examples of effector functions include, but are not limited to, C1q binding, CDC, Fc receptor binding, ADCC, phagocytosis, downregulation of cell surface receptors (e.g., B cell receptor, BCR), and the like. Such effector functions may require the Fc region to bind to a binding domain (e.g., an antibody variable domain) and can be assessed using a wide variety of test methods (e.g., Fc binding assays, ADCC assays, CDC assays, and the like).

[0045] For example, variant Fc regions of human IL-23 (or anti-IL-23) antibodies can be generated that have improved C1q binding and improved FcγRIII binding (e.g., have both improved ADCC activity and improved CDC activity). Alternatively, where it is desired to reduce or eliminate effector function, variant Fc regions can be modified to have reduced CDC activity and / or reduced ADCC activity. In other embodiments, only one of these activities may be enhanced, optionally with the other activity reduced at the same time (e.g., to generate Fc region variants with improved ADCC activity and reduced CDC activity, and vice versa).

[0046] Fc mutations can also be engineered and introduced to alter interactions with the neonatal Fc receptor (FcRn) and improve their pharmacokinetic properties. A collection of human Fc variants with improved binding to FcRn has been described (Shields et al., (2001). High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FcγR, J. Biol. Chem. 276:6591-6604).

[0047] Another type of amino acid substitution serves to modify the glycosylation pattern of the Fc region of a human IL-23 specific antibody. Glycosylation of the Fc region is typically either N-linked or O-linked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars, N-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. The recognition sequences for enzymatic attachment of a carbohydrate moiety to the asparagine side chain peptide sequence are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline. Thus, the presence of either of these peptide sequences in a polypeptide provides a potential glycosylation site.

[0048] The glycosylation pattern can be modified, for example, by deleting one or more glycosylation sites found in the polypeptide and / or adding one or more glycosylation sites that are not present in the polypeptide. Addition of glycosylation sites to the Fc region of a human IL-23-specific antibody is conveniently accomplished by modifying the amino acid sequence to include one or more of the tripeptide sequences described above (for N-linked glycosylation sites). A representative glycosylation variant has an amino acid substitution of residue Asn297 of the heavy chain. This modification may also be performed by the addition of, or substitution by, one or more serine or threonine residues to the original polypeptide sequence (for O-linked glycosylation sites). In addition, changing Asn 297 to Ala can remove one of the glycosylation sites.

[0049] In certain embodiments, the human IL-23 specific antibodies of the invention are expressed in cells expressing beta(1,4)-N-acetylglucosaminyltransferase III (GnT III), such that GnT III adds GlcNAc to the human IL-23 antibody. Methods for producing antibodies in such a manner are provided in WO 9954342, WO 03011878, Patent Publication 2003 / 0003097(A1), and Umana et al., Nature Biotechnology, 17:176-180, Feb. 1999, all of which are expressly incorporated herein by reference in their entirety.

[0050] Anti-IL-23 antibodies may also optionally be generated by immunization of transgenic animals (e.g., mice, rats, hamsters, non-human primates, etc.) capable of producing a repertoire of human antibodies, as described herein and / or known in the art. Cells producing human anti-IL-23 antibodies may be isolated and immortalized from such animals using suitable methods, such as those described herein.

[0051] Transgenic mice capable of producing a repertoire of human antibodies that bind to human antigens can be produced using known methods (such as, but not limited to, U.S. Pat. Nos. 5,770,428, 5,569,825, 5,545,806, 5,625,126, 5,625,825, 5,633,425, 5,661,016, and 5,789,650 issued to Lonberg et al., WO 98 / 50433 to Jakobovits et al., WO 98 / 24893 to Jakobovits et al., WO 98 / 2491 to Lonberg et al., each of which is incorporated herein by reference in its entirety). No. 884 to Lonberg et al., International Publication No. WO 97 / 13852 to Lonberg et al., International Publication No. WO 94 / 25585 to Lonberg et al., International Publication No. WO 96 / 34096 to Kucherlapate et al., European Patent No. 0463151(B1) to Kucherlapate et al., European Patent No. 0710719(A1) to Kucherlapate et al., U.S. Pat. No. 5,545,807 to Surani et al., International Publication No. WO 90 / 04036 to Bruggemann et al., European Patent No. 0438474(B1) to Bruggemann et al., European Patent No. 0814259(A2) to Lonberg et al., UK Patent No. 2272440(A) to Lonberg et al., et al.Nature 368:856-859(1994),Taylor et al.,Int.Immunol.6(4)579-591(1994),Green et al,Nature Genetics 7:13-21(1994),Mendez et al.,Nature Genetics 15:146-156(1997),Taylor et al. al., Nucleic Acids Research 20(23):6287-6295(1992), Tuaillon et al., Proc Natl Acad Sci USA 90(8)3720-3724(1993), Lonberg et al., Int Rev Immunol 13(1):65-93(1995), and Fishwald et al., Nat. Biotechnol 14(7):845-851(1996)).Generally, these mice contain at least one transgene that comprises DNA derived from at least one human immunoglobulin locus that has been functionally rearranged, or is capable of undergoing functional rearrangement. The endogenous immunoglobulin loci of such mice can be disrupted or deleted to eliminate the ability of the mice to produce antibodies encoded by endogenous genes.

[0052] Screening of antibodies for specific binding to similar proteins or fragments can be successfully accomplished using peptide display libraries. The method involves screening a large collection of peptides for individual members with the desired function or structure. Antibody screening of peptide display libraries is well known in the art. The displayed peptide sequences can be 3-5000 or more amino acids long, frequently 5-100 amino acids long, and often about 8-25 amino acids long. In addition to direct chemical synthesis methods for generating peptide libraries, several recombinant DNA methods have also been described. One type involves the display of peptide sequences on the surface of bacteriophages or cells. Each bacteriophage or cell contains a nucleotide sequence that codes for a particular displayed peptide sequence. Such methods are described in International Patent Applications WO 91 / 17271, WO 91 / 18980, WO 91 / 19818, and WO 93 / 08278.

[0053] Other systems for generating peptide libraries include aspects of both in vitro chemical synthesis and recombinant methods. See International Application Nos. WO 92 / 05258, WO 92 / 14843, and WO 96 / 19256. See also U.S. Patent Nos. 5,658,754 and 5,643,768. Peptide display libraries, vectors, and screening kits are commercially available from suppliers such as Invitrogen (Carlsbad, CA) and Cambridge antibody Technologies (Cambridgeshire, UK). See, e.g., U.S. Patent Nos. 4,704,692, 4,939,666, 4,946,778, 5,260,203, 5,455,030, 5,518,889, 5,534,621, 5,656,730, 5,763,733, 5,767,260, and 5,856,456 all assigned to Enzon; ​​U.S. Patent Nos. 5,223,409, 5,403,484, 5,571,698, and 5,837,500 all assigned to Dyax; U.S. Patent Nos. 5,427,908 and 5,580,717 all assigned to Affymax; Cambridge antibody See U.S. Patent No. 5,885,793 assigned to Eppendorf Technologies, U.S. Patent No. 5,750,373 assigned to Genentech, U.S. Patent Nos. 5,618,920, 5,595,898, 5,576,195, 5,698,435, 5,693,493, 5,698,417 assigned to Xoma, Colligan, supra, Ausubel, supra, or Sambrook, supra. Each of the above patents and publications is incorporated herein by reference in its entirety.

[0054] The antibodies used in the methods of the invention can also be prepared using nucleic acids encoding at least one anti-IL23 antibody to provide transgenic animals or mammals, such as goats, cows, horses, sheep, rabbits, etc., that produce such antibodies in their milk. Such animals can be provided using known methods. See, for example, but not limited to, U.S. Patent Nos. 5,827,690, 5,849,992, 4,873,316, 5,849,992, 5,994,616, 5,565,362, 5,304,489, etc., each of which is incorporated herein by reference in its entirety.

[0055] The antibodies used in the methods of the invention can further be prepared using at least one anti-IL23 antibody encoding nucleic acid to provide transgenic plants and cultured plant cells (e.g., but not limited to, tobacco and corn) that produce such antibodies, specific portions, or variants in plant parts or cells cultured therefrom. As a non-limiting example, transgenic tobacco leaves expressing recombinant proteins, for example, using an inducible promoter, have been successfully used to provide large quantities of recombinant proteins. See, e.g., Cramer et al., Curr. Top. Microbol. Immunol. 240:95-118 (1999) and references cited therein. Transgenic corn has also been used to express mammalian proteins at commercial production levels with biological activity equivalent to proteins produced in other recombinant systems or purified from natural sources. See, e.g., Hood et al., Adv. Exp. Med. Biol. 464:127-147 (1999) and references cited therein. Antibodies have also been produced in large quantities from transgenic plant seeds containing antibody fragments, such as single chain antibodies (scFv), including tobacco seeds and potato tubers. See, e.g., Conrad et al., Plant Mol. Biol. 38:101-109 (1998) and references cited therein. Thus, the antibodies of the present invention can also be produced using transgenic plants according to known methods. See, e.g., Fischer et al., Biotechnol. Appl. Biochem. 30:99-108 (Oct., 1999); Ma et al., Trends Biotechnol. 13:522-7 (1995); Ma et al., Plant Physiol. 109:341-6 (1995); Whitelam et al., Biochem. Soc. Trans. 22:940-944 (1994) and references cited therein. Each of the above documents is incorporated herein by reference in its entirety.

[0056] The antibodies used in the methods of the present invention have a wide range of affinities (K D ) can bind human IL-23. In a preferred embodiment, the human mAb can optionally bind human IL-23 with high affinity. For example, the human mAb can bind human IL-23 at about 10 -7 M or less, for example, but not limited to, 0.1 to 9.9 (or any range or value therein) x 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 K, or any range or value therein D can be combined with

[0057] The affinity or avidity of an antibody for an antigen can be determined experimentally using any suitable method. (See, e.g., Berzofsky, et al., "Antibody-Antigen Interactions," Fundamental Immunology, Paul, WE, Ed., Raven Press: New York, NY (1984); Kuby, Janis Immunology, WH Freeman and Company: New York, NY (1992), and methods described therein.) The affinity measured for a particular antibody-antigen interaction can be different when measured under different conditions (e.g., salt concentration, pH). Thus, affinity and other antigen binding parameters (e.g., K D , K a , K d Measurements of ) are preferably performed using standardized solutions of antibody and antigen, and standardized buffers, such as those described herein.

[0058] nucleic acid molecule Using the information provided herein, such as, for example, a nucleotide sequence encoding at least 70-100% of the contiguous amino acids of at least one of the light or heavy chain variable or CDR regions described herein, a particular fragment, variant, or consensus sequence thereof, or a deposited vector containing at least one of these sequences, among other sequences disclosed herein, a nucleic acid molecule of the invention encoding at least one anti-IL-23 antibody can be obtained using methods described herein or known in the art.

[0059] The nucleic acid molecules of the present invention may be in the form of RNA, such as mRNA, hnRNA, tRNA, or any other form, or in the form of DNA, including but not limited to cDNA and genomic DNA obtained by cloning or produced synthetically, or any combination thereof. The DNA may be triple-stranded, double-stranded, or single-stranded, or any combination thereof. Any portion of at least one strand of the DNA or RNA may be the coding strand, also known as the sense strand, or the non-coding strand, called the antisense strand.

[0060] The isolated nucleic acid molecules used in the methods of the present invention may include nucleic acid molecules comprising an open reading frame (ORF), optionally with one or more introns, for example, but not limited to, at least one particular 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 of anti-IL-23 antibodies or variable regions, and nucleic acid molecules comprising nucleotide sequences substantially different from those described above, but still encoding at least one anti-IL-23 antibody described herein and / or known in the art due to the degeneracy of the genetic code. Of course, the genetic code is well known in the art. Thus, it would be routine for a person skilled in the art to generate such degenerate nucleic acid variants that code for a specific anti-IL-23 antibody used in the methods of the present invention. See, for example, Ausubel et al., supra. Such nucleic acid variants are encompassed by the present invention. Non-limiting examples of isolated nucleic acid molecules include nucleic acids encoding HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, respectively.

[0061] As described herein, nucleic acid molecules comprising nucleic acids encoding anti-IL-23 antibodies can include those that themselves encode the amino acid sequence of an antibody fragment, sequences encoding the full length of an antibody or a portion of an antibody, coding sequences for an antibody, fragment or portion, and additional sequences, such as at least one intron, with or without the aforementioned additional coding sequences, including, but not limited to, non-coding 5' and 3' sequences, e.g., transcribed non-translated sequences that play a role in transcription, mRNA processing, including splicing and polyadenylation signals (e.g., ribosome binding and stability of mRNA), as well as additional non-coding sequences, including, but not limited to, coding sequences for at least one signal leader or fusion peptide, additional coding sequences encoding additional amino acids, e.g., amino acids that provide additional functions. Thus, the antibody coding sequence can be fused to a marker sequence, e.g., a marker sequence is a sequence that encodes a peptide that facilitates purification of an antibody comprising the antibody fragment or portion to which it is fused.

[0062] Polynucleotides that selectively hybridize to the polynucleotides described herein The method of the present invention uses isolated nucleic acids that hybridize under selective hybridization conditions to the polynucleotides disclosed herein. Thus, the polynucleotides of the present embodiment can be used to isolate, detect, and / or quantify nucleic acids that contain such polynucleotides. For example, the polynucleotides of the present invention can be used to identify, isolate, or amplify partial or full-length clones in a deposited library. In some embodiments, the polynucleotides are genomic or cDNA sequences that are isolated or otherwise complementary to cDNAs in a human or mammalian nucleic acid library.

[0063] Preferably, the cDNA library contains at least 80% of the full-length sequences, preferably at least 85% or 90% of the full-length sequences, more preferably at least 95% of the full-length sequences. The cDNA library can be normalized to increase the representation of rare sequences. Low or medium stringency hybridization conditions are typical, but not limited to, using sequences with low sequence identity to the complementary sequence. Optionally, medium and high stringency conditions can be used for sequences with higher identity. Low stringency conditions allow selective hybridization of sequences with about 70% sequence identity and can be used to identify orthologous or paralogous sequences.

[0064] Optionally, the polynucleotide encodes at least a portion of an antibody. The polynucleotide comprises a nucleic acid sequence that can be used for selective hybridization to a polynucleotide encoding an antibody of the present invention. See, e.g., Ausubel, supra; Colligan, supra, each of which is incorporated herein by reference in its entirety.

[0065] Nucleic acid construction An isolated nucleic acid can be produced using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, and / or (d) combinations thereof, as are well known in the art.

[0066] The nucleic acid may conveniently contain sequences in addition to the polynucleotide of the invention. For example, a multiple cloning site containing one or more endonuclease restriction sites may be inserted into the nucleic acid to aid in the isolation of the polynucleotide. Also, a translatable sequence may be inserted to aid in the isolation of the translated polynucleotide of the invention. For example, a hexahistidine marker sequence provides a convenient means for purifying the protein of the invention. The nucleic acid of the invention (excluding the coding sequence) is optionally a vector, adapter, or linker for the cloning and / or expression of the polynucleotide of the invention.

[0067] Additional sequences can be added to such cloning and / or expression sequences to optimize their function in cloning and / or expression, to aid in the isolation of polynucleotides, or to improve the introduction of polynucleotides into cells. The use of cloning vectors, expression vectors, adapters, and linkers is well known in the art. (See, e.g., Ausubel, supra, or Sambrook, supra.)

[0068] Recombinant methods for constructing nucleic acids Isolated nucleic acid compositions, such as RNA, cDNA, genomic DNA, or any combination thereof, can be obtained from biological sources using any number of cloning methods known to those of skill in the art. In some embodiments, oligonucleotide probes that selectively hybridize under stringent conditions to the polynucleotides of the present invention are used to identify desired sequences in a cDNA or genomic DNA library. Isolation of RNA and construction of cDNA and genomic libraries are well known to those of skill in the art. (See, e.g., Ausubel, supra, or Sambrook, supra).

[0069] Nucleic Acid Screening and Isolation Methods Probes based on the sequences of the polynucleotides used in the methods of the invention, such as those disclosed herein, can be used to screen cDNA or genomic libraries. Probes can be used to hybridize to genomic DNA or cDNA sequences to isolate homologous genes in the same or different organisms. Those skilled in the art will appreciate that assays can be used with varying degrees of hybridization stringency, and that either the hybridization or wash medium can be made more stringent. The more stringent the hybridization conditions, the greater the degree of complementarity between the probe and target at which duplex formation occurs. The degree of stringency can be controlled by one or more of temperature, ionic strength, pH, and the presence of a partially denaturing solvent, such as formamide. For example, hybridization stringency is successfully altered by changing the polarity of the reaction solution, for example, by manipulation of formamide concentration in the range of 0% to 50%. The degree of complementarity (sequence identity) required for detectable binding varies with the stringency of the hybridization medium and / or wash medium. The degree of complementarity is optimally 100%, or 70-100%, or any range or value therein, however, it should be understood that minor differences in sequence in the probe and primers can be compensated for by reducing the stringency of the hybridization and / or wash medium.

[0070] Methods for amplifying RNA or DNA are well known in the art and can be used in accordance with the present invention without undue experimentation, based on the teachings and guidance provided herein.

[0071] Known methods of DNA or RNA amplification include the polymerase chain reaction (PCR) and related amplification processes (e.g., U.S. Pat. Nos. 4,683,195, 4,683,202, 4,800,159, and 4,965,188 to Mullis et al., U.S. Pat. Nos. 4,795,699 and 4,921,794 to Tabor et al., U.S. Pat. No. 5,142,033 to Innis, U.S. Pat. No. 5,122,464 to Wilson et al., U.S. Pat. No. 5,091,310 to Innis, U.S. Pat. No. 5,066,584 to Gyllensten et al., U.S. Pat. No. 5,066,584 to Gelfa et al., U.S. Pat. No. 5,122,464 to Innis, U.S. Pat. No. 5,091,310 ...122 No. 4,889,818 to nd et al., U.S. Patent No. 4,994,370 to Silver et al., U.S. Patent No. 4,766,067 to Biswas, and U.S. Patent No. 4,656,134 to Ringold), and RNA-mediated amplification (U.S. Patent No. 5,130,238 to Malek et al., trade name NASBA), which uses antisense RNA to a target sequence as a template for double-stranded DNA synthesis, the entire contents of which are incorporated herein by reference. (See, e.g., Ausubel, supra, or Sambrook, supra.)

[0072] For example, polymerase chain reaction (PCR) technology can be used to amplify the sequences of polynucleotides and related genes used in the methods of the present invention directly from genomic DNA or cDNA libraries. PCR and other in vitro amplification methods can also be useful, for example, for cloning nucleic acid sequences encoding proteins to be expressed, for generating nucleic acids to be used as probes for detecting the presence of desired mRNA in a sample, for sequencing nucleic acids, or for other purposes. Examples of techniques sufficient to guide the skilled artisan through in vitro amplification methods can be found in Berger, Sambrook, and Ausubel, supra, as well as U.S. Patent No. 4,683,202 to Mullis et al. (1987), and Innis, et al., PCR Protocols A Guide to Methods and Applications, Eds., Academic Press Inc., San Diego, CA (1990). Commercial kits for genomic PCR amplification are known in the art. See, for example, Advantage-GC Genomic PCR Kit (Clontech). In addition, for example, the T4 gene 32 protein (Boehringer Mannheim) can be used to improve yields of long PCR products.

[0073] Synthetic methods for constructing nucleic acids The isolated nucleic acid used in the method of the present invention can also be prepared by direct chemical synthesis by known methods (see, for example, Ausubel et al., supra). Chemical synthesis generally produces a single-stranded oligonucleotide that can be converted into double-stranded DNA by hybridization with a complementary sequence or by polymerization with a DNA polymerase using the single strand as a template. Those skilled in the art will recognize that chemical synthesis of DNA can be limited to sequences of about 100 or more bases, but longer sequences can be obtained by ligation of shorter sequences.

[0074] Recombinant Expression Cassettes The present invention employs recombinant expression cassettes comprising nucleic acids. Nucleic acid sequences, such as cDNA or genomic sequences encoding an antibody used in the methods of the present invention, can be used to construct recombinant expression cassettes that can be introduced into at least one desired host cell. Recombinant expression cassettes typically comprise a polynucleotide that is operably linked to a transcription initiation regulatory sequence that directs transcription of the polynucleotide in the intended host cell. Both heterologous and non-heterologous (i.e., endogenous) promoters can be utilized to direct expression of the nucleic acid.

[0075] In some embodiments, isolated nucleic acids that function as promoters, enhancers, or other elements can be introduced into a suitable location (upstream, downstream, or within an intron) of a non-heterologous form of a polynucleotide of the invention to up- or down-regulate expression of the polynucleotide. For example, endogenous promoters can be altered in vivo or in vitro by mutation, deletion, and / or substitution.

[0076] Vectors and host cells The present invention also relates to vectors containing the isolated nucleic acid molecules, host cells engineered with the recombinant vectors, and the production of at least one anti-IL-23 antibody by recombinant techniques that are well known in the art (see, e.g., Sambrook et al., supra; Ausubel et al., supra, each of which is incorporated herein by reference in its entirety).

[0077] The polynucleotide can be linked to a vector, which optionally contains a selection marker for propagation in the host. Generally, the plasmid vector is introduced into a precipitate, such as a calcium phosphate precipitate, or into a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into a host cell.

[0078] The DNA insert should be operably linked to a suitable promoter. The expression construct further comprises a transcription initiation site, a transcription termination site, and, within the transcribed region, a ribosome binding site for translation. The coding portion of the mature transcript expressed by the construct preferably comprises translation beginning with a start and stop codon (e.g., UAA, UGA, or UAG) appropriately positioned at the end of the mRNA to be translated, with UAA and UAG being preferred for expression in mammalian or eukaryotic cells.

[0079] It is preferred, but optional, that the expression vector includes at least one selectable marker. Such markers include, for example, methotrexate (MTX), dihydrofolate reductase (DHFR, U.S. Pat. Nos. 4,399,216, 4,634,665, 4,656,134, 4,956,288, 5,149,636, and 5,179,017, ampicillin, neomycin (G418), mycophenolic acid, or glutamine synthetase for eukaryotic cell culture. Synthetase, GS, U.S. Patent Nos. 5,122,464, 5,770,359, 5,827,739) resistance genes, and tetracycline or ampicillin resistance genes for culture in E. coli and other bacteria or prokaryotes (the above patents are incorporated herein by reference in their entireties). Appropriate culture media and conditions for the above host cells are known in the art. Suitable vectors will be readily apparent to those of ordinary skill in the art. Introduction of the vector construct into the host cell can be accomplished by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid mediated transfection, electroporation, transduction, infection, or other known methods. Such methods are described in the art, such as Sambrook, supra, Chapters 1-4 and 16-18, and Ausubel, supra, Chapters 1, 9, 13, 15, 16.

[0080] At least one antibody used in the method of the invention may be expressed in modified form, such as a fusion protein, and may contain not only secretion signals, but also additional heterologous functional regions. For example, a region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the antibody to improve stability and persistence in the host cell during purification or during subsequent processing and storage. Peptide moieties may also be added to the antibody of the invention to facilitate purification. Such regions may be removed prior to final preparation of the antibody or at least one fragment thereof. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Chapters 17.29-17.42 and 18.1-18.74, Ausubel, supra, Chapters 16, 17, and 18.

[0081] Those skilled in the art are familiar with the many expression systems available for expressing the nucleic acid encoding the protein used in the method of the present invention. Alternatively, the nucleic acid can be expressed in a host cell by switching on (by manipulation) in the host cell containing the endogenous DNA encoding the antibody. Such methods are well known in the art, as described in U.S. Patent Nos. 5,580,734, 5,641,670, 5,733,746, and 5,733,761, which are incorporated herein by reference in their entirety.

[0082] An example of a cell culture useful for the production of an antibody, specified portion or variant thereof is a mammalian cell. Mammalian cell lines often take the form of a monolayer of cells, although suspensions or bioreactors of mammalian cells can also be used. A number of suitable host cell lines capable of expressing intact glycosylated proteins have been developed in the art, including COS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-1651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., ATCC CRL1610) and BSC-1 (e.g., ATCC CRL-26) cell lines, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2 / 0-Ag14, 293 cells, HeLa cells, and the like, which are readily available, for example, from the American Type Culture Collection (Manassas, Va.) (www.atcc.org). Preferred host cells include cells derived from lymphatic system, such as myeloma and lymphoma cells. Particularly preferred host cells are P3X63Ag8.653 cells (ATCC deposit number CRL-1580) and SP2 / 0-Ag14 cells (ATCC deposit number CRL-1851). In a particularly preferred embodiment, the recombinant cell is P3X63Ab8.653 or SP2 / 0-Ag14 cell.

[0083] Expression vectors for these cells can include one or more expression control sequences, such as, but not limited to, an origin of replication, a promoter (e.g., the late or early SV40 promoter, a CMV promoter (U.S. Pat. Nos. 5,168,062, 5,385,839), an HSV tk promoter, a pgk (phosphoglycerate kinase) promoter, an EF-1 alpha promoter (U.S. Pat. No. 5,266,491), at least one human immunoglobulin promoter, an enhancer, and / or processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites (e.g., the SV40 large T Ag polyaddition site), and transcription termination sequences. See, e.g., Ausubel et al., supra; Sambrook et al., supra. Other cells useful for producing the nucleic acids or proteins of the invention are known and / or can be found, for example, in the American Type Culture Collection Catalogue of Cell Lines and These are available from Hybridomas (www.atcc.org) or other known or commercial sources.

[0084] When eukaryotic host cells are used, typically polyadenylation or transcription termination sequences are incorporated into the vector. An example of a termination sequence is the polyadenylation sequence from the bovine growth hormone gene. Sequences for accurate splicing of the transcript can also be included. An example of a splicing sequence is the VP1 intron from SV40 (Sprague, et al., J. Virol. 45:773-781 (1983)). In addition, gene sequences for controlling replication in host cells can be incorporated into the vector, as is known in the art.

[0085] Antibody purification Anti-IL-23 antibodies can be recovered and purified from recombinant cell cultures by well-known methods, including, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, and lectin chromatography. High performance liquid chromatography ("HPLC") can also be used for purification. See, for example, Colligan, Current Protocols in Immunology or Current Protocols in Protein Science, John Wiley & Sons, NY, NY (1997-2001), e.g., chapters 1, 4, 6, 8, 9, 10, each of which is incorporated herein by reference in its entirety.

[0086] Antibodies for use in the methods of the invention include naturally purified products, products of chemical synthetic processes, and products produced by recombinant techniques from eukaryotic hosts, including, for example, yeast, higher plants, insect, and mammalian cells. Depending on the host utilized in a recombinant production process, the antibodies may be glycosylated or non-glycosylated, although glycosylated is preferred. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Sections 17.37-17.42; Ausubel, supra, Chapters 10, 12, 13, 16, 18, and 20; Colligan, Protein Science, supra, Chapters 12-14, all of which are incorporated herein by reference in their entirety.

[0087] Anti-IL-23 antibody. The anti-IL-23 antibodies of the present invention comprise at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one ligand binding portion (LBP), such as, but not limited to, a heavy or light chain complementarity determining region (CDR) or a ligand binding portion thereof, a heavy or light chain variable region, a framework region (e.g., FR1, FR2, FR3, FR4, or a fragment thereof, optionally including at least one substitution, insertion, or deletion), a heavy or light chain constant region (e.g., at least one CDR, FR5, FR6, FR7, FR8, FR9, FR10, FR11, FR12, FR13, FR14, FR15, FR16, FR17, FR18, FR19, FR19a, FR19b, FR19c, FR19d, FR19e, FR19f, FR19g, FR19g, FR19g, FR19h, FR19i, FR19m, FR19n ... H 1, Hinge 1, Hinge 2, Hinge 3, Hinge 4, C H 2 or C H 3, or a fragment thereof, and optionally further including at least one substitution, insertion, or deletion), or any portion thereof. The antibody can include or be derived from any mammal, such as, but not limited to, human, mouse, rabbit, rat, rodent, primate, or any combination thereof.

[0088] The isolated antibodies used in the methods of the invention include the amino acid sequences of the antibodies disclosed herein encoded by any suitable polynucleotide, or any isolated or prepared antibody. Preferably, the human antibodies or antigen-binding fragments bind to human IL-23, thereby partially or substantially neutralizing at least one biological activity of the protein. Antibodies, or specified portions or variants thereof, that partially or preferably substantially neutralize at least one biological activity of at least one IL-23 protein or fragment, can bind to the protein or fragment, thereby inhibiting an activity mediated through binding of IL-23 to the IL-23 receptor, or through other IL-23-dependent or mediated mechanisms. As used herein, the term "neutralizing antibody" refers to an antibody that can inhibit IL-23-dependent activity by about 20-120%, preferably at least about 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% or more, depending on the assay. The ability of an anti-IL-23 antibody to inhibit IL-23-dependent activity is preferably assessed by at least one suitable IL-23 protein or receptor assay described herein and / or known in the art. Human antibodies may be of any class (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and may include a kappa or lambda light chain. In one embodiment, the human antibody comprises an IgG heavy chain or a defined fragment, such as at least one isotype of IgG1, IgG2, IgG3, or IgG4 (e.g., γ1, γ2, γ3, γ4). Antibodies of this type can be prepared by utilizing transgenic mice or other non-human transgenic mammals that contain at least one human light chain (e.g., IgG, IgA, and IgM) transgene as described herein and / or known in the art. In another embodiment, the anti-IL-23 human antibody comprises an IgG1 heavy chain and an IgG1 light chain.

[0089] The antibody binds to at least one particular epitope specific for at least one IL-23 protein, subunit, fragment, portion, or any combination thereof, which may comprise at least one antibody binding region that comprises at least a portion of the protein, preferably comprising at least one extracellular, soluble, hydrophilic, exoportion, or cytoplasmic portion of the protein.

[0090] Generally, a human antibody or antigen-binding fragment comprises an antigen-binding region that comprises at least one human complementarity determining region (CDR1, CDR2, and CDR3) or variant of at least one heavy chain variable region, and at least one human complementarity determining region (CDR1, CDR2, and CDR3) or variant of at least one light chain variable region. The CDR sequences can be derived from human germline sequences or can closely match germline sequences. For example, CDRs from a synthetic library derived from the original non-human CDRs can be used. These CDRs can be formed by incorporation of conservative substitutions from the original non-human sequence. In another specific embodiment, the antibody or antigen-binding portion or variant can have an antigen-binding region that comprises at least a portion of at least one light chain CDR (i.e., CDR1, CDR2, and / or CDR3) with the corresponding CDR1, 2, and / or 3 amino acid sequence.

[0091] Such antibodies can be prepared by preparing and expressing a nucleic acid molecule(s) encoding the antibody using conventional techniques involving recombinant DNA technology, or by chemically linking together the various portions of the antibody (e.g., CDRs, framework) using conventional techniques, or by using any other suitable methods.

[0092] An anti-IL-23 specific antibody can comprise at least one of a heavy or light chain variable region having a defined amino acid sequence. For example, in a preferred embodiment, an anti-IL-23 antibody optionally comprises at least one heavy chain variable region having the amino acid sequence of SEQ ID NO: 7, and / or optionally at least one light chain variable region having the amino acid sequence of SEQ ID NO: 8. For example, in an additional preferred embodiment, an anti-IL-23 antibody optionally comprises at least one heavy chain having the amino acid sequence of SEQ ID NO: 9, and / or optionally at least one light chain having the amino acid sequence of SEQ ID NO: 10. Antibodies that bind human IL-23 and comprise a defined heavy or light chain variable region can be prepared using suitable methods, such as those employing phage display (Katsube, Y., et al., Int J Mol. Med, 1(5):863-868 (1998)) or transgenic animals, as known in the art and / or described herein. For example, a transgenic mouse containing a functionally rearranged human immunoglobulin heavy chain transgene and a transgene containing DNA from a human immunoglobulin light chain locus capable of undergoing functional rearrangement can be immunized with human IL-23 or a fragment thereof to induce the production of antibodies. If desired, antibody-producing cells can be isolated and hybridomas or other immortalized antibody-producing cells can be prepared as described herein and / or known in the art. Alternatively, antibodies, particular portions or variants can be expressed using the encoding nucleic acid or a portion thereof in a suitable host cell.

[0093] The present invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs that contain amino acids in sequences that are substantially the same as the amino acid sequences described herein. Preferably, such antibodies or antigen-binding fragments, and antibodies containing such chains or CDRs, have high affinity (e.g., about 10 -9 K below M D) can bind to human IL-23. Amino acid sequences that are substantially the same as the sequences described herein include sequences containing conservative amino acid substitutions as well as amino acid deletions and / or insertions. A conservative amino acid substitution refers to the replacement of a first amino acid with a second amino acid that has chemical and / or physical properties (e.g., charge, structure, polarity, hydrophobicity / hydrophilicity) similar to those of the first amino acid. Conservative substitutions include, but are not limited to, replacing one amino acid with another within the following groups: lysine (K), arginine (R), and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D, and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine ​​(C), and glycine (G); F, W, and Y; C, S, and T.

[0094] Amino acid code The amino acids constituting the anti-IL-23 antibodies of the present invention are often abbreviated. Amino acid notation can be indicated by representing the amino acid by its one-letter code, its three-letter code, name, or three-nucleotide codon, and is well understood in the art (see Alberts, B. et al., Molecular Biology of The Cell, 3rd Edition, Garland Publishing, Inc., New York (1994)).

[0095] [Table 1]

[0096] The IL-23 antibodies used in the methods of the invention may contain one or more amino acid substitutions, deletions, or additions, either due to natural mutations or human manipulation, as specified herein.

[0097] The number of amino acid substitutions that one of skill in the art may make will depend on many factors, including those described above. Generally speaking, the number of amino acid substitutions, insertions, or deletions in a given anti-IL-23 antibody, fragment, or variant, as specified herein, is 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or less, e.g., 1 to 30, or any range or value therein.

[0098] Amino acids within an anti-IL-23 specific antibody that are essential for function can be identified by methods known in the art, such as site-directed mutagenesis or alanine scanning mutagenesis (e.g., Ausubel, supra, Chapters 8, 15; Cunningham and Wells, Science 244:1081-1085 (1989)). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity, including, but not limited to, at least one IL-23 neutralizing activity. Sites critical for antibody binding can also be identified by structural analysis, such as crystallization, nuclear magnetic resonance, or photoaffinity labeling (Smith et al., J. Mol. Biol. 224:899-904 (1992) and de Vos et al., Science 255:306-312 (1992)).

[0099] An anti-IL-23 antibody can include, but is not limited to, at least a portion, sequence, or combination selected from all five of at least one of the contiguous amino acids of SEQ ID NOs: 1, 2, 3, 4, 5, and 6.

[0100] Examples of IL-23 antibodies or specific portions or variants thereof may include, but are not limited to, at least a portion, sequence, or combination selected from at least 3 to 5 contiguous amino acids of the above SEQ ID NO:, 5 to 17 contiguous amino acids of the above SEQ ID NO:, 5 to 10 contiguous amino acids of the above SEQ ID NO:, 5 to 11 contiguous amino acids of the above SEQ ID NO:, 5 to 7 contiguous amino acids of the above SEQ ID NO:, or 5 to 9 contiguous amino acids of the above SEQ ID NO:.

[0101] The IL-23 antibody can further optionally comprise at least one polypeptide that is 70-100% of 5, 17, 10, 11, 7, 9, 119, or 108 contiguous amino acids of SEQ ID NO: above. In one embodiment, the amino acid sequence of an immunoglobulin chain or portion thereof (e.g., variable region, CDR) has about 70-100% identity (e.g., 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or any range or value therein) with the amino acid sequence of at least one corresponding chain of SEQ ID NO: above. For example, the amino acid sequence of the light chain variable region can be compared to the sequence of SEQ ID NO: above, or the amino acid sequence of the heavy chain CDR3 can be compared to the sequence of SEQ ID NO: above. Preferably, 70-100% amino acid identity (i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or any range or value therein) is determined using a suitable computer algorithm known in the art.

[0102] "Identity," as known in the art, is a relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by comparing the sequences. In the art, "identity" also means the degree of sequence relatedness between polypeptide or polynucleotide sequences, as determined by the match between strings of such sequences. "Identity" and "similarity" can be readily calculated by known methods, including, but not limited to, those described in Computational Molecular Biology, Lesk, AM, ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, DW, ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, AM, and Griffin, HG, eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; and Carillo, H., and Lipman, D., Siam J. Applied Math., 48:1073 (1988). In addition, percent identity values ​​can be obtained from amino acid and nucleotide sequence alignments generated using default settings in AlignX, a component of Vector NTI Suite 8.0 (Informax, Frederick, MD).

[0103] Preferred methods for determining identity are designed to obtain the greatest match between the sequences tested. Methods for determining identity and similarity have been codified in publicly available computer programs. Preferred computer program methods for determining identity and similarity between two sequences include, but are not limited to, the GCG program package (Devereux, J. et al., Nucleic Acids Research 12(1):387 (1984)), BLASTP, BLASTN, and FASTA (Atschul, SF et al., J. Molec. Biol. 215:403-410 (1990)). BLAST X programs are publicly available from NCBI and other sources (BLAST Manual, Altschul, S. et al., NCBINLM NIH Bethesda, Md. 20894: Altschul, S. et al., J. Mol. Biol. 215:403-410 (1990). The well-known Smith Waterman algorithm may also be used to determine identity.

[0104] Preferred parameters for polypeptide sequence comparison include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48: 443-453 (1970) Comparison matrix: BLOSSUM62 from Hentikoff and Hentikoff, Proc. Natl. Acad. Sci, USA. 89: 10915-10919 (1992) Gap penalty: 12 Gap length penalty: 4 A program useful with these parameters is publicly available as the "Gap" program from the Genetics Computer Group, Madison Wis. The aforementioned parameters are the default parameters for peptide sequence comparisons (as well as no penalty for end gaps).

[0105] Preferred parameters for polynucleotide comparisons include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48: 443-453 (1970) Comparison matrix: match = +10, mismatch = 0 Gap penalty: 50 Gap length penalty: 3 Available as the "Gap" program from the Genetics Computer Group, Madison Wis. These are the default parameters for nucleic acid sequence comparisons.

[0106] By way of example, a polynucleotide sequence may be identical to another sequence, i.e., 100% identical, or may contain up to a certain integer number of nucleotide alterations compared to a reference sequence. Such alterations may be selected from the group consisting of deletion, substitution (including transitions and transversions), or insertion of at least one nucleotide, which may occur at the 5' or 3' terminal position of the reference nucleotide sequence, or anywhere between these terminal positions, and may be distributed either individually among the nucleotides of the reference sequence, or in one or more adjacent groups within the reference sequence. The number of nucleotide alterations may be determined by multiplying the total number of nucleotides in the sequence by the numerical percentage of the corresponding percent identity (divided by 100) and subtracting the product from the total number of nucleotides in the sequence, or is determined by n.sub.n.ltorsim.x.sub.n-(x.sub.ny), where n.sub.n is the number of nucleotide alterations, x.sub.n is the total number of nucleotides in the sequence, and y is, for example, 0.70 for 70%, 0.80 for 80%, 0.85 for 85%, 0.90 for 90%, 0.95 for 95%, etc., and any non-integer product of x.sub.n and y is rounded down to the nearest integer before subtraction from x.sub.n.

[0107] Modification of a polynucleotide sequence encoding the above SEQ ID NO may create nonsense, missense, or frameshift mutations in the coding sequence, thereby modifying the polypeptide encoded by the polynucleotide after such modification. Similarly, the polypeptide sequence may be identical to the reference sequence of the above SEQ ID NO, i.e., 100% identical, or may contain up to a certain integer number of amino acid changes compared to the reference sequence such that the percent identity is less than 100%. Such modifications are selected from the group consisting of deletion, substitution (including conservative and non-conservative substitution), or insertion of at least one amino acid, which may occur at the amino or carboxy terminal position of the reference polypeptide sequence or anywhere between these terminal positions, and may be distributed either individually among the amino acids of the reference sequence, or in one or more adjacent groups within the reference sequence. The number of amino acid changes for a given percent identity may be calculated by multiplying the total number of amino acids in the above SEQ ID NO by the numerical percent of the respective percent identity (divided by 100) and subtracting the product from the total number of amino acids in the above SEQ ID NO, or is determined by n.sub.a.ltorsim.x.sub.a-(x.sub.ay), where n.sub.a is the number of amino acid changes, x.sub.a is the total number of amino acids in the sequence ID, and y is, for example, 0.70 for 70%, 0.80 for 80%, 0.85 for 85%, etc., and any non-integer product of x.sub.a and y is rounded down to the nearest integer before subtraction from x.sub.a.

[0108] Exemplary heavy and light chain variable region sequences, and portions thereof, are set forth in the SEQ ID NOs. An antibody of the invention, or a particular variant thereof, can include any number of contiguous amino acid residues from an antibody of the invention, the number being selected from the group of integers consisting of 10-100% of the number of contiguous residues in an anti-IL-23 antibody. Optionally, this subsequence of contiguous amino acids is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, or more amino acids in length, or any range or value therein. Additionally, the number of such subsequences can be any integer selected from the group consisting of 1-20, such as at least 2, 3, 4, or 5.

[0109] As will be appreciated by those of skill in the art, the present invention includes at least one biologically active antibody of the invention. A biologically active antibody has a specific activity that is at least 20%, 30%, or 40%, preferably at least 50%, 60%, or 70%, and most preferably at least 80%, 90%, or 95% to 100% or more (including but not limited to up to 10-fold the specific activity) of that of a natural (non-synthetic), endogenous, or related and known antibody. Methods for assaying and quantitatively measuring enzymatic activity and substrate specificity are well known to those of skill in the art.

[0110] In another aspect, the invention relates to human antibodies and antigen-binding fragments described herein that are modified by the covalent attachment of an organic moiety. Such modifications can produce antibodies or antigen-binding fragments with improved pharmacokinetic properties (e.g., increased serum half-life in vivo). The organic moiety can be a linear or branched hydrophilic polymeric group, a fatty acid group, or a fatty acid ester group. In certain embodiments, the hydrophilic polymeric group has a molecular weight of about 800 to about 120,000 daltons and can be a polyalkane glycol (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)), a carbohydrate polymer, an amino acid polymer, or polyvinylpyrrolidone, and the fatty acid group or fatty acid ester group can contain about 8 to about 40 carbon atoms.

[0111] The modified antibodies and antigen-binding fragments can include one or more organic moieties that are directly or indirectly covalently attached to the antibody. Each organic moiety attached to the antibody or antigen-binding fragment of the present invention can be independently a hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. As used herein, the term "fatty acid" includes monocarboxylic and dicarboxylic acids. As used herein, the term "hydrophilic polymer group" refers to an organic polymer that is more soluble in water than octane. For example, polylysine is more soluble in water than octane. Thus, antibodies modified by the covalent attachment of polylysine are encompassed by the present invention. Hydrophilic polymers suitable for modifying the antibodies of the present invention may be linear or branched, and include, for example, polyalkane glycols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG, etc.), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides, etc.), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, polyaspartic acid, etc.), polyalkane oxides (e.g., polyethylene oxide, polypropylene oxide, etc.), and polyvinylpyrrolidone. Preferably, the hydrophilic polymers that modify the antibodies of the present invention have a molecular weight of about 800 to about 150,000 daltons as individual molecular entities. For example, PEG 5000 and PEG 20,000 can be used, where the subscript is the average molecular weight of the polymer in Daltons. The hydrophilic polymer group can be substituted with 1 to about 6 alkyl groups, fatty acid groups, or fatty acid ester groups. Hydrophilic polymers substituted with fatty acid or fatty acid ester groups can be prepared by utilizing a suitable method. For example, a polymer containing an amine group can be attached to a carboxylate of a fatty acid or fatty acid ester, and an activated carboxylate (e.g., activated with N,N-carbonyldiimidazole) on the fatty acid or fatty acid ester can be attached to a hydroxyl group on the polymer.

[0112] Fatty acids and fatty acid esters suitable for modifying antibodies of the invention may be saturated or may contain one or more units of unsaturation. Fatty acids suitable for modifying antibodies of the invention include, for example, n-dodecanoate (C 12 , laurate), n-tetradecanoate (C 14 , myristate), n-octadecanoate (C 18 , stearate), n-eicosanoate (C 20 , arachidate), n-docosanoate (C 22 , behenic acid), n-triacontanoate (C 30 ), n-tetracontanoate (C 40 ), cis-Δ9-octadecanoate (C 18 oleate), all cis-Δ5,8,11,14-eicosatetraenoate (C 20 , arachidonate), octanedioic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, and the like. Suitable fatty acid esters include monoesters of dicarboxylic acids containing a straight or branched chain lower alkyl group. The lower alkyl group can contain from 1 to about 12, preferably from 1 to about 6, carbon atoms.

[0113] Modified human antibodies and antigen-binding fragments can be prepared using suitable methods, such as by reacting with one or more modifying agents. As used herein, the term "modifying agent" refers to a suitable organic group (e.g., hydrophilic polymer, fatty acid, fatty acid ester) that contains an activating group. An "activating group" is a chemical moiety or functional group that can react with a second chemical group under appropriate conditions, thereby forming a covalent bond between the modifying agent and the second chemical group. For example, amine-reactive activating groups include electrophilic groups such as tosylate, mesylate, halo (chloro, bromo, fluoro, iodo), N-hydroxysuccinimidyl esters (NHS), and the like. Activating groups that can react with thiols include, for example, maleimide, iodoacetyl, acrylolyl, pyridyl disulfide, 5-thiol-2-nitrobenzoic acid thiol (TNB-thiol), and the like. Aldehyde functional groups can be linked to amine- or hydrazide-containing molecules, and azide groups can react with trivalent phosphorus groups to form phosphoramidate or phosphorimide bonds. Suitable methods for introducing activating groups into molecules are known in the art (see, for example, Hermanson, GT, Bioconjugate Techniques, Academic Press: San Diego, CA (1996)). Activating groups can be attached directly to organic groups (e.g., hydrophilic polymers, fatty acids, fatty acid esters) or to linker moieties, such as divalent C1-C 12The linker moiety may be linked via a group (wherein one or more carbon atoms may be replaced by a heteroatom such as oxygen, nitrogen, or sulfur). Suitable linker moieties include, for example, tetraethylene glycol, -(CH2)3-, -NH-(CH2)6-NH-, -(CH2)2-NH-, and -CH2-O-CH2-CH2-O-CH2-CH2-O-CH-NH-. A modifying agent containing a linker moiety may be produced, for example, by reacting a mono-Boc-alkyldiamine (e.g., mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to form an amide bond between the free amine and the fatty acid carboxylate. The Boc protecting group can be removed from the product by treatment with trifluoroacetic acid (TFA) to expose a primary amine that can be coupled to another carboxylate as described, or it can be reacted with maleic anhydride and the resulting product cyclized to produce an activated maleimide derivative of a fatty acid. (See, e.g., WO 92 / 16221 (Thompson et al.), the entire teachings of which are incorporated herein by reference.)

[0114] Modified antibodies can be produced by reacting a human antibody or antigen-binding fragment with a modifying agent. For example, organic moieties can be attached to the antibody in a non-site specific manner using an amine-reactive modifying agent, e.g., an NHS ester of PEG. Modified human antibodies or antigen-binding fragments can also be prepared by reducing disulfide bonds (e.g., intrachain disulfide bonds) of the antibody or antigen-binding fragment. The reduced antibody or antigen-binding fragment can then be reacted with a thiol-reactive modifying agent to produce the modified antibody of the invention. Modified human antibodies and antigen-binding fragments containing organic moieties attached to specific sites of the antibodies of the invention can be prepared using suitable methods, such as reverse proteolysis (Fisch et al., Bioconjugate Chem., 3:147-153 (1992); Werlen et al., Bioconjugate Chem., 5:411-417 (1994); Kumaran et al., Protein Sci. 6(10):2233-2241 (1997); Itoh et al., Bioorg. Chem., 24(no. 1):59-68 (1996); Capellas et al., Biotechnol. Bioeng., 56(4):456-463 (1997)), and methods described in Hermanson, GT, Bioconjugate Techniques, Academic Press: San Diego, CA (1996).

[0115] The methods of the invention also employ 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 thereof, provided in a non-naturally occurring composition, mixture, or form, as described herein and / or known in the art. Such compositions include non-naturally occurring compositions comprising at least one or two full-length, C- and / or N-terminal deletion mutants, domains, fragments, or specific variants of an anti-IL-23 antibody amino acid sequence selected from the group consisting of 70-100% of the contiguous amino acids of the SEQ ID NOs. above, or specific fragments, domains, or variants thereof. A preferred anti-IL-23 antibody composition comprises at least one or two full-length, fragments, domains, or variants as at least one CDR- or LBP-containing portion of an anti-IL-23 antibody sequence described herein, e.g., 70-100% of the SEQ ID NOs. above, or specific fragments, domains, or variants thereof. More preferred compositions comprise, for example, 70-100% of at least one of the above SEQ ID NOs, or specific fragments, domains, or variants thereof, 40-99%. Such composition percentages may be by weight, volume, concentration, molarity, or molar concentration as a liquid or dry solution, mixture, suspension, emulsion, particle, powder, or colloid, as known in the art or as described herein.

[0116] Antibody compositions containing further therapeutically active ingredients The antibody compositions used in the methods of the present invention can optionally further comprise an effective amount of at least one compound or protein selected from at least one of anti-infective agents, cardiovascular (CV) agents, central nervous system (CNS) agents, autonomic nervous system (ANS) agents, respiratory agents, gastrointestinal (GI) tract agents, hormonal agents, fluid or electrolyte balancing agents, hemodynamic agents, anti-neoplastic agents, immunomodulatory agents, ophthalmic, otic or nasal agents, topical agents, nutritional agents, etc. Such agents are well known in the art, including the formulations, indications, dosages, and administration of each as set forth herein (see, e.g., Nursing 2001 Handbook of Drugs, 21st Edition, each of which is incorporated herein by reference in its entirety). st edition, Springhouse Corp., Springhouse, PA, 2001; Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc., Upper Saddle River, NJ; Pharmacotherapy Handbook, Wells et al., Appleton & Lange, Stamford, CT).

[0117] As examples of drugs that can be combined with the antibodies of the method of the present invention, the anti-infective drug can be at least one selected from amebicide or at least one antiprotozoal drug, anthelmintic drug, antifungal drug, antimalarial drug, antituberculous drug or at least one antilepromatous drug, aminoglycoside, penicillin, cephalosporin, tetracycline, sulfonamide, fluoroquinolone, antiviral drug, macrolide anti-infective drug, and miscellaneous anti-infective drugs. The hormonal drug can be at least one selected from corticosteroid, androgen, or at least one anabolic steroid, estrogen, or at least one progestin, gonadotropin, antidiabetic drug, or at least one glucagon, thyroid hormone, thyroid hormone antagonist, pituitary hormone, and parathyroid mimetic drug. The at least one cephalosporin can be at least one selected from cefaclor, cefadroxil, cefazolin sodium, cefdinir, cefepime hydrochloride, cefixime, cefmetazole sodium, cefonicid sodium, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime sodium, ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cephalexin hydrochloride, cephalexin monohydrate, cephradine, and loracarbef.

[0118] The at least one corticosteroid can be at least one selected from betamethasone, betamethasone acetate or betamethasone sodium phosphate, betamethasone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, triamcinolone, triamcinolone acetonide, and triamcinolone diacetate. The at least one androgenic or anabolic steroid can be at least one selected from danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate, nandrolone phenpropionate, testosterone, testosterone cypionate, testosterone enanthate, testosterone propionate, and a testosterone transdermal system.

[0119] The at least one immunosuppressant can be at least one selected from azathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immunoglobulin, muromonab-CD3, mycophenolate mofetil, mycophenolate mofetil hydrochloride, sirolimus, and tacrolimus.

[0120] The at least one topical anti-infective can be at least one selected from acyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole, econazole nitrate, erythromycin, gentamicin sulfate, ketoconazole, mafenide acetate, metronidazole (topical), miconazole nitrate, mupirocin, naftifine hydrochloride, neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, terbinafine hydrochloride, terconazole, tetracycline hydrochloride, tioconazole, and tolnaftate. The at least one scabicide or pediculicide can be at least one selected from crotamiton, lindane, permethrin, and pyrethrins. The at least one topical corticosteroid can be at least one selected from betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate, fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasone propionate, halcionide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, and triamcinolone acetonide. (See, e.g., pages 1098-1136 of Nursing 2001 Drug Handbook.)

[0121] Anti-IL-23 antibody compositions comprise at least one anti-IL-23 antibody that is contacted or administered to a cell, tissue, organ, animal, or patient in need of such modulation, treatment, or therapy, and optionally further comprise at least one TNF antagonist (such as, but not limited to, a TNF chemical or protein antagonist, a TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70, or p85) or fragment, a fusion polypeptide thereof, or a small molecule TNF antagonist, such as TNF binding protein I or II (TBP-1 or TBP-II), nerelimonmab, infliximab, The composition may further include at least one of any suitable and effective amount of compositions or pharmaceutical compositions including at least one selected from the group consisting of antirheumatic drugs (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, sodium aurothiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), immunizing agents, immunoglobulins, immunosuppressants (e.g., azathioprine, basiliximab, cyclosporine, daclizumab), cytokines, or cytokine antagonists. Non-limiting examples of such cytokines include, but are not limited to, any of IL-1 to IL-40, etc. (e.g., IL-1, IL-2, etc.). Suitable dosages are well known in the art. For example, see Wells et al., eds., Pharmacotherapy Handbook, 2 nd Edition, Appleton and Lange, Stamford, CT (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), each of which is incorporated herein by reference in its entirety.

[0122] The anti-IL-23 antibody compound, composition, or mixture used in the method of the present invention may further comprise at least one of any suitable auxiliary agent, such as, but not limited to, a diluent, a binder, a stabilizer, a buffer, a salt, a lipophilic solvent, a preservative, an adjuvant, etc. Pharmaceutically acceptable auxiliary agents are preferred. Methods for preparing such sterile solutions and non-limiting examples thereof are well known in the art and are described, for example, in Gennaro, Ed., Remington's Pharmaceutical Sciences, 1896, 1999, 1998, 19 ... th Edition, Mack Publishing Co. (Easton, PA) 1990. Pharmaceutically acceptable carriers suitable for the mode of administration, solubility, and / or stability of the anti-IL-23 antibody, fragment, or variant compositions well known in the art or described herein can be routinely selected.

[0123] Pharmaceutical excipients and additives useful in the present compositions include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., saccharides including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides, derivatized sugars such as alditols, aldonic acids, esterified sugars, and polysaccharides or sugar polymers), which may be present alone or in combination and comprise 1-99.99% by weight or volume, alone or in combination. Exemplary protein excipients include serum albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Exemplary amino acids / antibody components that may also function in a buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. One preferred amino acid is glycine.

[0124] Carbohydrate excipients suitable for use in the present invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, etc., disaccharides such as lactose, sucrose, trehalose, cellobiose, etc., polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starches, etc., alditols such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), myo-inositol, etc. Preferred carbohydrate additives for use in the present invention are mannitol, trehalose, and raffinose.

[0125] The anti-IL-23 antibody composition may also include a buffer or pH adjusting agent, typically a salt prepared from an organic acid or base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, or phosphate buffers. A preferred buffer for use in the composition is an organic acid salt such as citric acid.

[0126] Additionally, anti-IL-23 antibody compositions may include polymeric excipients / additives, such as polyvinylpyrrolidone, Ficoll (a polymeric sugar), dextrates (e.g., cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin), polyethylene glycol, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN 20" and "TWEEN 80"), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA).

[0127] 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 invention are known in the art and are described, for example, in "Remington: The Science & Practice of Pharmacy," 1999. thed., Williams & Williams, (1995), and “Physician's Desk Reference,” 52 nd ed., Medical Economics, Montvale, NJ (1998), the disclosures of which are incorporated herein by reference in their entireties. Preferred carrier or excipient materials are carbohydrates (e.g., monosaccharides and alditols) and buffers (e.g., citric acid) or polymeric agents. Exemplary carrier molecules are mucopolysaccharides, hyaluronic acid, which may be useful for intra-articular delivery.

[0128] formulation As mentioned above, the present invention provides stable formulations, preferably saline or phosphate buffer with selected salts, as well as preservative-containing preservative solutions and formulations, and versatile preserved formulations suitable for pharmaceutical or veterinary use, comprising at least one anti-IL-23 antibody in a pharma- ceutically acceptable formulation. The preserved formulations include at least one known preservative, optionally selected from the group consisting of at least one phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof, in an aqueous diluent. As known in the art, the range may be from 0.001 to 5%, or any range or value therein, for example, 0.001, 0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, 3.7, 3.8, 3.9, 3.1, 3.2 ...3, 3.4, 3.5, 3.8, 3.9, 3.1, 3.2, 3.3, 3.4, 3.5, Any suitable concentration or mixture may be used, such as 0.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, etc., or any range or value therein.Non-limiting examples include no preservatives, 0.1-2% m-cresol (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (e.g., 0.005, 0.01), 0.001-2.0% phenol (e.g., For example, 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005 to 1.0% alkyl paraben (for example, 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%), and the like.

[0129] As discussed above, the methods of the invention employ articles of manufacture comprising packaging and at least one vial containing a solution of at least one anti-IL-23 specific antibody, optionally in an aqueous diluent, with a formulated buffer and / or preservative, the packaging comprising a label indicating that such solution can be stored for 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72 hours or more. The invention further employs articles of manufacture comprising packaging and a first vial containing a lyophilized anti-IL-23 specific antibody and a second vial containing an aqueous diluent of the formulated buffer or preservative, the packaging comprising a label instructing a patient to reconstitute the anti-IL-23 specific antibody with the aqueous diluent to form a solution that can be stored for 24 hours or more.

[0130] The anti-IL-23 specific antibodies used in accordance with the present invention may be produced by recombinant means, including production from mammalian cells or transgenic preparations, or may be purified from other biological sources, as described herein or known in the art.

[0131] Ranges of anti-IL-23 specific antibodies include those amounts that will give a concentration of about 1.0 μg / ml to about 1000 mg / ml upon reconstitution for wet / dry systems, although lower and higher concentrations are workable and depend on the intended delivery vehicle, e.g., for solution formulations, as opposed to transdermal patch, pulmonary, transmucosal, or osmotic or micropump methods.

[0132] Preferably, the aqueous diluent further comprises a pharma- ceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof. The concentration of the preservative used in the formulation is sufficient to produce an antimicrobial effect. Such concentration will vary depending on the preservative selected and can be easily determined by those skilled in the art.

[0133] Other excipients, such as isotonicity agents, buffers, antioxidants, and preservative enhancers, can be optionally and preferably added to the diluent. An isotonicity agent, such as glycerin, is generally used at a known concentration. A physiologically tolerable buffer is preferably added to provide improved pH control. The formulations can cover a wide range of pH, such as from about pH 4 to about pH 10, and preferably from about pH 5 to about pH 9, and most preferably from about 6.0 to about 8.0. Preferably, the formulations of the present invention have a pH of about 6.8 to about 7.8. Suitable buffers include phosphate buffers, most preferably sodium phosphate, especially phosphate buffered saline (PBS).

[0134] Other additives, such as pharma- ceutically acceptable solubilizers, such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymer), and PEG (polyethylene glycol), or non-ionic surfactants, such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polyl, other block copolymers, and chelating agents, such as EDTA and EGTA, can be optionally added to the formulation or composition to reduce aggregation. These additives are particularly useful when pumps or plastic containers are used to administer the formulation. The presence of pharma-ceutically acceptable surfactants reduces the tendency of proteins to aggregate.

[0135] The formulations can be prepared by a process that includes mixing at least one anti-IL-23 antibody with a preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl parabens (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof, in an aqueous diluent. Mixing at least one anti-IL-23 specific antibody with a preservative in an aqueous diluent is performed using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a quantity of at least one anti-IL-23 specific antibody in a buffer solution is combined with a desired preservative in a sufficient amount of buffer solution to provide the desired concentration of protein and preservative. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, the use or non-use of additional additives, the temperature and pH during preparation of the formulation are all factors that can be optimized for the administration concentration and administration means used.

[0136] The formulations can be provided to patients as clear solutions or as dual vials containing a vial of lyophilized anti-IL-23 specific antibody reconstituted with a second vial containing water, preservatives and / or excipients, preferably phosphate buffer and / or saline, and the selected salt in an aqueous diluent. Either the single solution vial or the dual vial requiring reconstitution can be reused multiple times to satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0137] The product is useful for administration over a period ranging from immediate to 24 hours or more. Thus, the products claimed by the present invention provide significant benefits to patients. The formulations of the present invention can optionally be safely stored at temperatures between about 2° C. and about 40° C. and retain the biological activity of the protein for extended periods of time, and thus the packaging label can indicate that the solution may be stored and / or used for 6, 12, 18, 24, 36, 48, 72, or 96 hours or more. When using a preserved diluent, such labeling can include use up to 1-12 months, half a year, one and a half years, and / or up to two years.

[0138] A solution of anti-IL-23 specific antibody can be prepared by a process that includes mixing at least one antibody in an aqueous diluent. The mixing is carried out using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, a certain amount of at least one antibody in water or a buffer is combined in an amount sufficient to provide the desired concentration of protein, and optionally a preservative or buffer. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, whether or not additional additives are used, the temperature and pH at which the formulation is prepared are all factors that can be optimized for the administration concentration and administration means used.

[0139] The claimed products can be provided to patients as clear solutions or as dual vials containing at least one lyophilized vial of an anti-IL-23 specific antibody that is reconstituted with a second vial containing an aqueous diluent. Either the single solution vial or the dual vial requiring reconstitution can be reused multiple times to satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0140] The claimed products can be provided indirectly to patients by providing a pharmacy, clinic, or other such institution or facility with a dual vial containing a clear solution or a vial of at least one lyophilized anti-IL-23 specific antibody reconstituted with a second vial containing an aqueous diluent, where the clear solution can be up to a liter or even more in volume, from which smaller amounts of the at least one antibody solution can be removed one or more times from the larger container and transferred to smaller vials and provided to customers and / or patients by the pharmacy or clinic.

[0141] Recognized devices that include single vial systems include pen-type injection devices for delivering solutions, such as BD Pens, BD Autojector®, Humaject®, NovoPen®, BD® Pen, AutoPen®, and OptiPen®, GenotropinPen®, Genotronorm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®, Iject®, J-tip Needle-Free Injector®, Intraject®, Medi-Ject®, Smartject®, and the like, manufactured by Becton Dickensen (Franklin Suitable devices include those manufactured or developed by National Medical Products, Weston Medical (Peterborough, UK, www.weston-medical.com), Medi-Ject Corp (Minneapolis, MN, www.mediject.com), and similar suitable devices. Recognized devices that include dual vial systems include pen-type syringe systems, such as the HumatroPen®, for reconstituting lyophilized medication in a cartridge to deliver the reconstituted solution. Examples of suitable other devices include pre-filled syringes, auto-injectors, needleless syringes, and needleless IV infusion sets.

[0142] The product may include packaging. The packaging provides the conditions under which the product may be used, as well as any information required by regulatory agencies. The packaging of the present invention, when applicable, provides instructions to the patient to reconstitute at least one anti-IL-23 antibody with an aqueous diluent to form a solution and use the solution for a period of 2-24 hours or more in a wet / dry two vial product. In the case of a single vial solution product, pre-filled syringe, or autoinjector, the label indicates that such solution may be used for a period of 2-24 hours or more. The product is useful for human pharmaceutical product applications.

[0143] The formulations used in the methods of the present invention can be prepared by a process that includes mixing an anti-IL-23 antibody and a selected buffer, preferably saline or a phosphate buffer containing a selected salt. Mixing the anti-IL-23 antibody and the buffer in an aqueous diluent is performed using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a quantity of at least one antibody in water or buffer is combined with a desired buffer in a sufficient amount of water to provide the desired concentration of protein and buffer. Variations of this process will be recognized by those skilled in the art. For example, the order of addition of the components, whether or not additional additives are used, the temperature and pH at which the formulation is prepared are all factors that can be optimized for the administration concentration and administration means used.

[0144] The method of the present invention provides pharmaceutical compositions including various formulations that are useful and acceptable for administration to human or animal patients. Such pharmaceutical compositions are prepared using "standard" water as a diluent and routine methods well known to those skilled in the art. For example, buffer components such as histidine and histidine monohydrochloride hydrate may be provided first, followed by the addition of an appropriate non-final volume of "standard" water diluent, sucrose, and polysorbate 80. The isolated antibody may then be added. Finally, the volume of the pharmaceutical composition is adjusted to the desired final volume under "standard" conditions using water as a diluent. Those skilled in the art will recognize several other methods suitable for the preparation of pharmaceutical compositions.

[0145] A pharmaceutical composition may be an aqueous solution or suspension containing the indicated mass of each component per volume unit of water or having the indicated pH at "standard conditions". As used herein, the term "standard conditions" refers to a temperature of 25°C ± 2°C and a pressure of 1 atmosphere. The term "standard conditions" is not used in the art to refer to a single set of art-recognized temperatures or pressures, but instead is a reference condition that specifies the temperature and pressure used to describe a solution or suspension containing a particular composition under reference "standard conditions" conditions. This is because the volume of a solution is, in part, a function of temperature and pressure. Those skilled in the art will recognize that pharmaceutical compositions equivalent to those disclosed herein can be produced at other temperatures and pressures. The equivalence of such pharmaceutical compositions to those disclosed herein should be determined under "standard conditions" conditions defined above (e.g., 25°C ± 2°C and a pressure of 1 atmosphere).

[0146] Importantly, such a pharmaceutical composition may contain "about" a certain value of the mass of a component (e.g., "about 0.53 mg of L-histidine") or have a certain value of the pH value per unit volume of the pharmaceutical composition. The mass or pH value of a component present in the pharmaceutical composition is "about" a given numerical value when the isolated antibody is present in the pharmaceutical composition or when the isolated antibody is present in the pharmaceutical composition after it is removed from the pharmaceutical composition (e.g., by dilution) and can bind to a peptide chain. That is, the mass value or pH value or other value of a component is "about" a given numerical value when the binding activity of the isolated antibody is maintained and detectable after the isolated antibody is placed in the pharmaceutical composition.

[0147] Competitive binding analysis is performed to determine whether IL-23 specific mAbs bind similar or different epitopes and / or compete with each other. Abs are individually coated onto ELISA plates. Competing mAbs are added, followed by biotinylated hrIL-23. For a positive control, the same mAb for coating can be used as a competing mAb ("self-competition"). IL-23 binding is detected using streptavidin. These results indicate whether the mAbs recognize similar or partially overlapping epitopes on IL-23.

[0148] In one embodiment of the pharmaceutical composition, the isolated antibody concentration is about 77 to about 104 mg per mL of pharmaceutical composition. In another embodiment of the pharmaceutical composition, the pH is about 5.5 to about 6.5.

[0149] The stable or preserved formulations can be provided to patients as clear solutions or as dual vials containing a vial of at least one lyophilized anti-IL-23 antibody reconstituted in an aqueous diluent with a second vial containing preservatives or buffers and additives. Either the single solution vial or the dual vial requiring reconstitution can be reused multiple times to satisfy single or multiple patient treatment cycles, thus providing a more convenient treatment regimen than is currently available.

[0150] Other formulations or methods of stabilizing anti-IL-23 antibodies may result in other than a clear solution of lyophilized powder containing the antibody. Non-clear solutions include formulations containing particulate suspensions, which are compositions containing anti-IL-23 antibodies in structures of various sizes known variously as microspheres, microparticles, nanoparticles, nanospheres, or liposomes. Such relatively homogeneous essentially spherical particulate formulations containing active agents can be formed by contacting an aqueous phase containing active agents and polymers with a non-aqueous phase, as taught in U.S. Pat. No. 4,589,330, and then evaporating the non-aqueous phase to cause coalescence of particles from the aqueous phase. Porous microparticles can be prepared using a first phase containing active agents and polymers dispersed in a continuous solvent, and removing the solvent from the suspension by lyophilization or dilution-extraction-precipitation, as taught in U.S. Pat. No. 4,818,542. Preferred polymers for such preparations are gelatin agar, starch, arabinogalactan, albumin, collagen, polyglycolic acid, polylactic acid, glycolide-L(-)lactide, poly(epsilon-caprolactone, poly(epsilon-caprolactone-co-lactic acid), poly(epsilon-caprolactone-co-glycolic acid), poly(β-hydroxybutyric acid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate), poly(hydroxyethyl methacrylate), polyamide, poly(amino acids), poly(2-hydroxyethyl DL-aspartamide), poly(ester urea), poly(L-phenylalanine / ethylene glycol), poly( ... The preferred polymers are natural or synthetic copolymers or polymers selected from the group consisting of poly(methyl methacrylate), poly(glycol / 1,6-diisocyanatohexane), and poly(methyl methacrylate). Particularly preferred polymers are polyesters such as polyglycolic acid, polylactic acid, glycolide-L(-)lactide poly(epsilon-caprolactone, poly(epsilon-caprolactone-co-lactic acid), and poly(epsilon-caprolactone-co-glycolic acid). Solvents useful for dissolving the polymer and / or active agent include water, hexafluoroisopropanol, methylene chloride, tetrahydrofuran, hexane, benzene, or hexafluoroacetone sesquihydrate.The process of dispersing the active-containing phase into the second phase can include forcing the first phase through orifices in a nozzle under pressure to affect droplet formation.

[0151] Dry powder formulations may also result from processes other than freeze-drying, such as, for example, spray drying, or solvent extraction by evaporation or precipitation of a crystalline composition followed by one or more steps to remove the aqueous or non-aqueous solvent. The preparation of spray-dried antibody formulations is taught in U.S. Pat. No. 6,019,968. Antibody-based dry powder compositions can be produced by spray drying a solution or slurry of the antibody, optionally with excipients in a solvent, under conditions to provide a respirable dry powder. Solvents include polar compounds, such as water and ethanol, that are easily dried. Antibody stability can be enhanced by performing the spray-drying procedure in the absence of oxygen, for example under a nitrogen blanket, or by using nitrogen as the drying gas. Another relatively dry formulation is a dispersion of multiple porous microstructures dispersed in a suspension medium that typically includes a hydrofluoroalkane propellant, as taught in WO 9916419. The stabilized dispersion can be administered to the lungs of a patient using a metered dose inhaler. Equipment useful in the commercial production of spray dried drugs is manufactured by Buchi Ltd. or Niro Corp.

[0152] Anti-IL-23 antibodies, either in a stable or preserved formulation or solution as described herein, can be administered to a patient in accordance with the present invention via a variety of delivery methods, as are well known in the art, such as SC or IM injection, transdermal, transpulmonary, transmucosal, implants, osmotic pumps, cartridges, micropumps, or other means understood by those of skill in the art.

[0153] Therapeutic Applications The present invention also provides methods for modulating or treating Crohn's disease in a cell, tissue, organ, animal, or patient using at least one IL-23 antibody of the present invention, e.g., by administering or contacting the cell, tissue, organ, animal, or patient with a therapeutically effective amount of an IL-23 specific antibody, as known in the art or described herein.

[0154] Any of the methods of the invention may comprise administering to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy an effective amount of a composition or pharmaceutical composition comprising an anti-IL-23 antibody. Such methods may optionally further comprise co-administration or combination therapy for the treatment of such disease or disorder, wherein administering said at least one anti-IL-23 antibody, specified portion or variant thereof, is administered in combination with at least one TNF antagonist (such as, but not limited to, a chemical or proteinaceous TNF antagonist, a TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70, or p85) or fragment, a fusion polypeptide thereof, or a small molecule TNF antagonist, such as a TNF binding protein. TBP-1 or TBP-II, nerelimonumab, infliximab, etanercept (Enbrel™), adalimumab (Humira™), CDP-571, CDP-870, afelimomab, lenercept, etc.), antirheumatic drugs (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, sodium aurothiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxants, narcotics, non-steroidal anti-inflammatory drugsdrugs, NSAIDs), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blockers, antibacterials (e.g., aminoglycosides, antifungals, antiparasitics, antivirals, carbapenams, cephalosporins, fluoroquinolones, macrolides, penicillins, sulfonamides, tetracyclines, other antibacterials), drugs for treating psoriasis, corticosteroids, anabolic steroids, drugs for diabetes, minerals, nutritional drugs, thyroid drugs, vitamins, calcium-related hormones, antidiarrheals, antitussives, antiemetics, antineoplastic drugs, laxatives, anticoagulants, erythropoietin (e.g., epoetin alfa), filgrastim (e.g., G-CSF, Neupogen), sargramostim (GM-CSF, Leukine), The method further comprises administering, before, simultaneously and / or after at least one selected from an immunizing agent, an immunoglobulin, an immunosuppressant (e.g., basiliximab, cyclosporine, daclizumab), a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, an antimanic, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma treatment, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or an analogue, dornase alfa (Pulmozyme), a cytokine or a cytokine antagonist. Suitable dosages are well known in the art. See, for example, Wells et al., eds., Pharmacotherapy Handbook, 2 nd Edition, Appleton and Lange, Stamford, CT (2000), PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), Nursing 2001 Handbook of Drugs, 21 stedition, Springhouse Corp., Springhouse, PA, 2001, Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc., Upper Saddle River, NJ, each of which is incorporated herein by reference in its entirety.

[0155] Therapeutic Treatment Typically, treatment of Crohn's disease is effected by administering an effective amount or dose of an anti-IL-23 antibody composition, which, on average, ranges from at least about 0.01 to 500 milligrams of anti-IL-23 antibody per kilogram of patient per dose, depending on the specific activity of the active agent contained in the composition, in total, and preferably at least about 0.1 to 100 milligrams of antibody per kilogram of patient per dose, in single or multiple doses. Alternatively, an effective serum concentration may include a serum concentration of 0.1 to 5000 g / mL, in single or multiple doses. Suitable dosages are known to medical practitioners and will, of course, depend on the specific disease state, the specific activity of the composition administered, and the specific patient undergoing treatment. In some cases, it may be necessary to provide repeated doses, i.e., repeated individual doses of a particular monitored or metered dose, to achieve the desired therapeutic dose, where the individual doses are repeated until the desired daily dose or effect is obtained.

[0156] Preferred dosages are optionally 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70 , 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and / or 100-500 mg / kg / dose, or any range, value, or fraction thereof, or 0.1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9, 2.0, 2.5, 2.9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 9.9, 9.1, 9.2, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 9.9, 9.1, .5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 20, 12.5, 12.9, 13.0, 13.5, 13.9, 14.0, 14.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 12, 12.5, 12.9, 13.0, 13.5, 13.9, 14, 14.5, 15, 15.5, 15.9, 16, 16.5, 16.9, In some embodiments, the method may comprise administering to the subject a serum concentration of 17, 17.5, 17.9, 18, 18.5, 18.9, 19, 19.5, 19.9, 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, and / or 5000 g / mL, or any range, value or fraction thereof.

[0157] Alternatively, the dose administered may vary depending on known factors such as the pharmacodynamic characteristics of the particular agent and its method and route of administration, the age, health and weight of the recipient, the nature and extent of the condition, type of concurrent treatment, frequency of treatment, and the desired effect. The dose of active ingredient may typically be about 0.1 to 100 milligrams per kilogram of body weight. Typically, 0.1 to 50, preferably 0.1 to 10 milligrams per kilogram per dose, or in sustained release form, is effective to obtain the desired results.

[0158] As non-limiting examples, treatment of humans or animals may be performed using a single dose, intravenous administration, or multiple doses for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 days. or additionally, on at least one day of eyes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 11 0.1 to 100 mg / kg per day, for example, 0.5, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 1.9, 1.10, 1.20, 1.40, 1.65, 1.80, 1.95, 1.99, 1.99, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 14, 15, 16, 17, 18, 19, or 20 years, or any combination thereof. The antibody may be provided as a single or periodic dose of 0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90, or 100 mg / kg of at least one antibody of the invention.

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

[0160] For parenteral administration, the antibody may be formulated as a solution, suspension, emulsion, particle, powder, or lyophilized powder, provided together with or separately from a pharma- ceutical acceptable parenteral vehicle. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and 1-10% human serum albumin. Non-aqueous vehicles such as liposomes and fixed oils can also be used. The vehicle or lyophilized powder can contain additives that maintain isotonicity and chemical stability (e.g., sodium chloride for isotonicity, mannitol, buffers and preservatives for chemical stability). The formulation is sterilized by known or suitable techniques.

[0161] Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

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

[0163] Parenteral Formulation and Administration Preparations for parenteral administration may contain sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydrogenated naphthalenes, etc. as common excipients. Aqueous or oily suspensions for injection can be prepared by using appropriate emulsifiers or wetting agents and suspending agents according to known methods. Injections may be non-toxic parenterally administrable diluents, such as aqueous solutions, sterile injections, or suspensions in solvents. Usable vehicles or solvents include water, Ringer's solution, isotonic saline, etc., and sterile fixed oils can be used as normal solvents or suspension solvents. For these purposes, any kind of fixed oils and fatty acids, including natural, synthetic, or semi-synthetic fatty oils or fatty acids, natural, synthetic, or semi-synthetic monoglycerides, diglycerides, or triglycerides, can be used. Parenteral administration is known in the art and includes, but is not limited to, conventional injection means, the gas pressurized needleless injection device described in U.S. Pat. No. 5,851,198, and the laser perforator device described in U.S. Pat. No. 5,839,446, which are incorporated herein by reference in their entireties.

[0164] alternative delivery The invention further relates to administration of anti-IL-23 antibodies by parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intrabronchial, intraabdominal, intracapsular, intrachondral, intrasinus, intracavity, intracerebellar, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, intravaginal, rectal, buccal, sublingual, intranasal, or transdermal means. The IL-23 antibody compositions can be formulated for use parenterally (subcutaneously, intramuscularly, or intravenously) or for any other administration, particularly in the form of liquid solutions or suspensions, particularly in semi-solid forms such as, but not limited to, creams and suppositories, for use in vaginal or rectal administration, in forms such as, but not limited to, tablets or capsules, for buccal or sublingual administration, or intranasally, in forms such as, but not limited to, powders, nasal drops or aerosols, or certain drugs, or with chemical enhancers such as dimethylsulfoxide to either modify the skin structure or increase the drug concentration in transdermal patches (Junginger, et al. In "Drug Permeation Enhancement;" Hsieh, DS, Eds., pp. 59-90 (Marcel Dekker, Inc. New York, 1999), which are incorporated herein by reference in their entirety). 1994), or application of protein and peptide containing formulations to the skin (WO 98 / 53847), or application of an electric field to create a transient transport pathway, such as electroporation, or to increase the mobility of a charged drug through the skin, such as iontophoresis, or application of ultrasound, such as sonophoresis (U.S. Pat. Nos. 4,309,989 and 4,767,402), can be formulated for transdermal use, such as, but not limited to, gels, ointments, lotions, suspensions, or patch delivery systems (the above publications and patents are incorporated herein by reference in their entireties).

[0165] Having generally described the present invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting. Further details of the present invention are illustrated by the following non-limiting examples. The disclosures of all citations herein are expressly incorporated herein by reference.

[0166] Embodiment The present invention provides the following non-limiting embodiments. 1. A method of treating Crohn's disease in a patient, comprising administering to the patient an antibody against IL-23: an initial dose, a dose 4 weeks after the initial treatment, a dose 8 weeks after the initial treatment, and a dose every 4 weeks or every 8 weeks after the 8th week dose, 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 comprising the CDRL3 amino acid sequence of SEQ ID NO:6, The heavy chain variable region is Complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO:1; the CDRH2 amino acid sequence of SEQ ID NO:2, and The method comprises the CDRH3 amino acid sequence of SEQ ID NO:3, and the patient is a responder to the antibody. 2. The method of embodiment 1, wherein the patient is identified as meeting one or more clinical endpoints selected from the group consisting of: (i) change from baseline in Crohn's Disease Activity Index (CDAI) score at 48 weeks after first treatment ("Week 48"); (ii) clinical remission at week 48, defined as a CDAI of less than (<) 150 points; (iii) clinical response at week 48, defined as a reduction from baseline in the CDAI score of 100 or more points (≥) or a CDAI score of less than (<) 150; (iv) Patient-Reported Outcome (PRO)-2 remission at week 48, defined based on mean daily stool frequency (SF) and mean daily abdominal pain (AP) scores; (v) clinical biomarker response at week 48, defined using clinical response based on CDAI score and reduction from baseline in C-reactive protein (CRP) or fecal calprotectin; (vi) endoscopic remission at week 48, as measured by the Simplified Crohn's Endoscopic Score for Crohn's Disease (SES-CD), defined as an SES-CD of 2 or less (≤2); (viii) endoscopic response at week 48 as measured by the Simplified Endoscopic Score for Crohn's Disease (SES-CD). (viii) corticosteroid-free clinical remission at week 48, defined as a CDAI score of less than 150 at week 48 and no corticosteroids at week 48; and (ix) fatigue response at week 48 based on Patient-Reported Outcomes Measurement Information System (PROMIS). 3. The method of embodiment 1, wherein the first dose, and the doses 4 weeks after the first treatment and 8 weeks after the first treatment are administered intravenously at doses selected from the group consisting of 1200 mg, 600 mg, and 200 mg, and the doses every 4 weeks or every 8 weeks after the 8th week dose are administered subcutaneously at 100 mg, or 200 mg. 4. The method of embodiment 3, wherein the intravenous dose is 1200 mg and the subcutaneous dose is 200 mg administered every 4 weeks beginning with the 8th week dose. 5. The method of embodiment 3, wherein the intravenous dose is 600 mg and the subcutaneous dose is 200 mg administered every 4 weeks after the 8th week dose. 6. The method of embodiment 3, wherein the intravenous dose is 200 mg and the subcutaneous dose is 100 mg administered every 8 weeks after the 8th week dose. 7. The method of embodiment 3, wherein the antibody is contained in a pharmaceutical composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate; 0.053% (w / v) polysorbate 80, and the diluent is water at standard conditions. 8. The method of embodiment 3, further comprising administering to the patient one or more additional agents used to treat Crohn's disease. 9. The method of embodiment 8, wherein the additional agent is selected from the group consisting of an immunosuppressant, a nonsteroidal anti-inflammatory drug (NSAID), methotrexate (MTX), an anti-B cell surface marker antibody, an anti-CD20 antibody, rituximab, a TNF inhibitor, a corticosteroid, and a costimulatory modulator. 10. The method of embodiment 1, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO:8, and the heavy chain variable region amino acid sequence of SEQ ID NO:7. 11. The method of embodiment 1, wherein the antibody comprises a light chain amino acid sequence of SEQ ID NO:10, and a heavy chain amino acid sequence of SEQ ID NO:9. 12. The method of embodiment 1, wherein the patient is considered a biologic therapy non-responder or intolerant (Bio non-responder) for Crohn's disease. 13. The method of embodiment 1, wherein the patient is considered conventional therapy non-responsive or intolerant (Con non-responsive) for Crohn's disease. EXAMPLES

[0167] Example 1 Preclinical evidence implicating IL-23 as a target in Crohn's disease Genetic and animal model studies have investigated the contribution of IL-12 and IL-23 in the pathophysiology of Crohn's disease. Results indicate that IL-23 plays a major role in inflammatory bowel disease (IBD), and emerging evidence suggests that blocking IL-23 alone may be a more effective strategy than blocking both IL-12 and IL-23.

[0168] Initial observations from genetic and animal model data suggest that Crohn's disease is potentially mediated by IL-12 and / or IL-23, potentially via the Th1 and Th17 pathways induced by IL-12 and / or IL-23, respectively. However, growing evidence suggests that IL-23 in Crohn's disease plays a major role. Genome-wide association studies have identified polymorphisms in the IL-23R gene that are associated with Crohn's disease. The role of IL-23 in driving intestinal inflammation has been shown in several mouse models. Mice treated with anti-IL-23 antibodies show attenuated inflammation, and mice with genetic deletion of the p19 subunit of IL-23 are protected in several models of intestinal inflammation.

[0169] Clinical evidence establishing proof of concept for targeting IL-23 in Crohn's disease The potential therapeutic role of IL-23 in Crohn's disease was first established by clinical trials of IL-12 / 23p40 antagonists (briakinumab and ustekinumab). Ustekinumab (STELARA®) was recently approved for the treatment of moderately to severely active Crohn's disease. Although these programs have shown that blockade of both IL-12 and IL-23 is effective in treating Crohn's disease, they have not been able to ascertain the relative contributions of the two cytokines.

[0170] More recent studies of two anti-IL-23 antagonists, risankizumab (formerly BI-655066) and brazikumab (formerly MEDI2070, AMG139), have reported phase 2 results demonstrating efficacy of IL-23 blockade in participants with moderately to severely active Crohn's disease. The magnitude of efficacy observed in each of these studies indicates the potential for improved efficacy compared to ustekinumab (anti-IL-12 / 23), acknowledging the limitations of crossover comparisons and the relatively small size of the IL-23 phase 2 studies.

[0171] Clinical experience with IL-12 / 23-targeted therapy (ustekinumab) in Crohn's disease The phase 3 program for ustekinumab in Crohn's disease included two 8-week studies evaluating the efficacy and safety of intravenous (IV) induction of ustekinumab, and one maintenance study evaluating the efficacy and safety of subcutaneous (SC) maintenance of ustekinumab over a total treatment period of 52 weeks. Ustekinumab was evaluated in the full spectrum of biologically eligible patients with Crohn's disease, i.e., those who were conventional therapy non-responders and those who were biologic therapy non-responders. After a single IV induction dose of ustekinumab 6 mg / kg at week 0, approximately 21% and 40% of BIO non-responders and CON non-responders, respectively (versus approximately 7% and 20%, respectively, of placebo-treated participants) achieved clinical remission at week 8 (as assessed by the Crohn's Disease Activity Index [CDAI]). Among participants who responded to ustekinumab IV induction and were re-randomized to receive ustekinumab SC maintenance 90 mg every 8 weeks (q8w) or 90 mg every 12 weeks (q12w), approximately 53% and 49% of participants, respectively, were in clinical remission at week 52 compared with 36% of participants who received placebo maintenance.

[0172] Clinical experience with IL-23 targeted therapy in Crohn's disease Recent phase 2 trials of two IL-23 mAbs, risankizumab and brazikumab, have shown efficacy in improving clinical signs and symptoms, reducing inflammatory biomarkers, and improving endoscopic findings primarily in participants with biologically refractory Crohn's disease.

[0173] Crossover study comparisons of clinical remission rates with IL-23 blockade suggest the possibility of improved efficacy compared to ustekinumab. It is noteworthy that the induction doses used in both studies of risankizumab (200 and 600 mg IV at weeks 0, 4, and 8) and brazikumab (700 mg IV at weeks 0 and 4) were substantially higher than the approved ustekinumab dose (approximately 6 mg / kg IV at week 0). Crossover meta-analysis of compounds suggests that the endpoint of the dose-response curve may be higher, especially with risankizumab.

[0174] Furthermore, phase 2 trials with risankizumab also suggested that response rates may not reach their maximum until 6 months after treatment.Using a dose of 600 mg IV every 4 weeks (q4w) for up to 6 months, clinical remission rates of approximately 50% were observed in all treated patients, substantially higher than remission rates previously reported with other agents, including ustekinumab, in similar study populations at similar follow-up time points.Of participants who achieved remission at 6 months and continued on risankizumab maintenance treatment (180 mg SC q8w), approximately 70% were in remission at 1 year.

[0175] Comprehensive Rationale for Guselkumab in Crohn's Disease In summary, genetic and preclinical evidence together suggest a major role for selectively targeting IL-23 in regulating the underlying pathophysiology of IBD. Available clinical experience with two IL-23 antagonists and established evidence from an approved IL-12 / 23 antagonist (ustekinumab) demonstrate proof of mechanism and proof of concept, respectively, for targeting IL-23 in the treatment of Crohn's disease. Together, the available evidence provides support for the clinical trial of guselkumab in the treatment of Crohn's disease.

[0176] Primary Endpoint The primary endpoint is clinical remission (defined as a CDAI score <150) at week 12. For this endpoint, each guselkumab arm will be compared with placebo.

[0177] Key secondary endpoints The primary secondary endpoints are described below. Clinical remission (defined as CDAI<150) at week 48 Sustained clinical remission at week 48 (defined as CDAI < 150 at 80% or more of all visits [i.e., at least 8 of 10 visits] from weeks 12 through 48 (must include week 48)) Corticosteroid-free clinical remission at week 48 (defined as CDAI score <150 at week 48 and not receiving corticosteroids at week 48) PRO-2 remission at week 12 (defined as a mean daily AP score of 1 or less and a mean daily SF score of 3 or less, i.e., AP≦1 and SF≦3) PRO-2 remission at 48 weeks Endoscopic response at week 12 (defined as at least 50% improvement from baseline in SES-CD score or an SES-CD score ≤ 2) Endoscopic response at 48 weeks Fatigue response at week 12 (based on PROMIS Fatigue Short Form 7a, as defined by SAP).

[0178] The short-term endpoint at 12 weeks was based on a comparison of each guselkumab group with the placebo group, and the long-term endpoint at 48 weeks was based on a comparison of each guselkumab group with the ustekinumab group.

[0179] From a nonclinical perspective, the risk to patients with Crohn's disease is considered low when guselkumab is administered IV at doses up to 1200 mg (approximately 16 mg / kg in humans) once every 4 weeks, followed by the proposed maintenance dose of up to 200 mg SC q4w, based on the lack of adverse findings observed in cynomolgus monkeys after 50 mg / kg weekly subchronic IV dosing for 5 weeks and weekly chronic SC dosing for 24 weeks. As summarized above, the actual exposure data achieved in monkeys (area under the serum concentration versus time curve [AUC]) compared to the expected IV clinical induction dosing interval AUC from weeks 8 to 12, or steady-state SC maintenance interval AUC (both normalized to weekly dosing to compare with the monkey dosing interval), provide an adequate exposure margin for the proposed clinical dosing. This is further supported by the fact that guselkumab is a late-stage biotherapeutic with a favorable clinical safety profile in participants with psoriasis vulgaris, data that has been produced primarily at 100 mg SC but also at up to 300 mg SC and 10 mg / kg IV in a limited number of patients with psoriasis vulgaris and healthy volunteers, respectively, during Phase 1 clinical development. Finally, risankizumab, an IL-23 inhibitor with clinical efficacy comparable to guselkumab, has been tested in patients with Crohn's disease administered up to 600 mg IV q4w for 6 months and reported to be well tolerated.

[0180] Guselkumab has undergone extensive preclinical and clinical development. The combined efficacy and safety results of Phase 1, 2, and 3 clinical trials in healthy volunteers and patients with plaque psoriasis, as well as the recent regulatory approval for plaque psoriasis, have established a favorable benefit-risk profile for guselkumab in the treatment of plaque psoriasis. The clinical trials have provided support for ongoing development of guselkumab in other inflammatory diseases, such as PsA, GPP, EP, and PPP.

[0181] Available animal and human data support an important role for IL-23 in the pathogenesis of Crohn's disease, and studies with other anti-IL-23 mAbs suggest that selective targeting of IL-23 may achieve higher levels of efficacy than observed with other mechanisms of action, including ustekinumab, in patients with moderate to severe active Crohn's disease.

[0182] Clinical data with ustekinumab and other anti-IL-23 mAbs suggest that maximal efficacy in Crohn's disease may require higher dosing and exposure than that used in psoriasis. For example, the initial dosing of ustekinumab in Crohn's disease (approximately 6 mg / kg IV in a 70 kg patient) is approximately 4 times higher than in psoriasis (45 mg SC at weeks 0 and 4). Thus, induction dosing of up to 1200 mg IV given q4w for 3 doses and maintenance dosing of up to 200 mg SC q4w will be tested in the Phase 2 portion of this study to evaluate whether higher dosing and exposure of guselkumab is required to obtain maximal efficacy in Crohn's disease. Nonclinical toxicity study data provide an adequate exposure margin for the clinical dosing proposed in this protocol. Moreover, comparable dosing / exposure was previously evaluated in Phase 2 studies of two other anti-IL-23 mAbs, and no significant safety concerns were reported after 1 year of treatment.

[0183] The approved dosing regimen of guselkumab in psoriasis (100 mg SC in weeks 0 and 4, then q8w) has been shown to have a favorable safety profile, and a higher dose regimen of 200 mg SC q8w has been shown to have a favorable safety profile in a Phase 2 study in rheumatoid arthritis. The primary risk is infection. Other potential safety concerns, described in more detail for guselkumab IB, include malignancies and hypersensitivity, based on guselkumab being an immunomodulatory mAb. As the higher dose regimen of guselkumab (proposed in this protocol) has not been previously tested, safety will be evaluated in an initial cohort of 25 patients by an independent Data Monitoring Committee (DMC).

[0184] Early safety evaluation of initial cohorts will ensure acceptable safety for continued testing of proposed Phase 2 and 3 dosing regimens in larger numbers of patients, and ongoing open-label safety evaluations by the DMC throughout Phase 2 and 3 studies will ensure patient safety across the entire development program.

[0185] Active comparator: ustekinumab Ustekinumab (STELARA) is the active comparator in this protocol. Ustekinumab is a human IgG1 kappa mAb that binds with high affinity and specificity to the p40 subunit common to both human IL-12 and human IL-23. Ustekinumab is an approved treatment for moderately to severely active Crohn's disease in adult patients in several countries, including the United States, Canada, and the EU, and applications for regulatory approval for the Crohn's disease indication are currently under review in many countries around the world. The proposed induction and maintenance dosing for ustekinumab in this protocol is compliant with current national labeling approved worldwide and is consistent with the dosing regimen evaluated in the ustekinumab Phase 3 clinical development program in Crohn's disease, which established the efficacy and safety of ustekinumab in patients with moderately to severely active Crohn's disease.

[0186] Phase 2 dosing study (GALAXI1) the purpose Main purpose -Evaluate the clinical efficacy of guselkumab in participants with Crohn's disease -Evaluate the safety of guselkumab

[0187] secondary purpose Evaluate the dose response of guselkumab to inform dosing selection for the Phase 3 portion of this protocol -Evaluate the efficacy of guselkumab on endoscopic improvement To evaluate the pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of guselkumab therapy, including changes in C-reactive protein (CRP) and fecal calprotectin

[0188] Other purposes To assess the impact of guselkumab on health-related quality of life (HRQOL) and health economics outcome measures -Evaluate the efficacy of guselkumab on histological improvement To evaluate the impact of guselkumab treatment on intestinal mucosal gene expression profiles and cellular composition associated with Crohn's disease

[0189] Endpoints The primary and key secondary endpoints will evaluate the short-term efficacy of guselkumab versus placebo and are described below.

[0190] Primary Endpoint Change from baseline in CDAI score at week 12.

[0191] Key secondary endpoints Clinical remission (defined as a CDAI score <150) at week 12. Clinical response at Week 12 (defined as a reduction from baseline in CDAI score of ≥ 100 points or a CDAI score of < 150). PRO-2 remission at week 12 (defined as an average daily abdominal pain [AP] score of 1 or less and an average daily stool frequency [SF] score of 3 or less, i.e., AP≦1 and SF≦3). Clinical biomarker response at week 12 (clinical response based on CDAI score and ≥50% reduction from baseline in CRP or fecal calprotectin). Endoscopic response at week 12 (defined as at least 50% improvement from baseline in the Simplified Endoscopic Score for Crohn's Disease [SES-CD] or an SES-CD score ≤ 2)

[0192] hypothesis The primary hypothesis for GALAXI1 is that guselkumab will be superior to placebo in inducing a reduction from baseline in CDAI scores in participants with moderately to severely active Crohn's disease.

[0193] Phase 3 treatment confirmation study (GALAXI2 and GALAXI3) GALAXI2 and GALAXI3 are identical studies with the same objectives and endpoints.

[0194] the purpose Main purpose -Evaluate the clinical efficacy of guselkumab in participants with Crohn's disease -Evaluate the safety of guselkumab

[0195] secondary purpose -Evaluate the efficacy of guselkumab on endoscopic improvement -Evaluate the impact of guselkumab on HRQOL To evaluate the PK, immunogenicity, and PD of guselkumab therapy, including changes in CRP and fecal calprotectin

[0196] Other purposes -Evaluate the impact of guselkumab on health economic evaluation indicators -Evaluate the efficacy of guselkumab on histological improvement To evaluate the impact of guselkumab treatment on intestinal mucosal gene expression profiles and cellular composition associated with Crohn's disease

[0197] Endpoints Primary Endpoint The primary endpoint is clinical remission (defined as a CDAI score <150) at week 12. For this endpoint, each guselkumab arm will be compared with placebo.

[0198] Key Secondary Endpoints Key secondary endpoints are described below. Clinical remission (defined as CDAI<150) at week 48 Sustained clinical remission at week 48 (defined as CDAI < 150 at 80% or more of all visits [i.e., at least 8 of 10 visits] from weeks 12 through 48 (must include week 48)) Corticosteroid-free clinical remission at week 48 (defined as CDAI score <150 at week 48 and not receiving corticosteroids at week 48) PRO-2 remission at week 12 (defined as a mean daily AP score of 1 or less and a mean daily SF score of 3 or less, i.e., AP≦1 and SF≦3) PRO-2 remission at 48 weeks Endoscopic response at week 12 (defined as at least 50% improvement from baseline in SES-CD score or an SES-CD score ≤ 2) Endoscopic response at 48 weeks Fatigue response at week 12 (based on PROMIS Fatigue Short Form 7a, as defined by SAP).

[0199] The short-term endpoint at 12 weeks was based on a comparison of each guselkumab group with the placebo group, and the long-term endpoint at 48 weeks was based on a comparison of each guselkumab group with the ustekinumab group.

[0200] hypothesis The primary hypothesis for both GALAXI2 and GALAXI3 is that guselkumab is superior to placebo in achieving clinical remission at week 12 in participants with moderately to severely active Crohn's disease.

[0201] GALAXI2 and GALAXI3 will also evaluate the relative performance of long-term treatment with guselkumab versus ustekinumab. Regarding the primary secondary hypothesis of the comparison with ustekinumab, the ultimate objective is to demonstrate that the efficacy of guselkumab is superior to ustekinumab, although an initial study of non-inferiority will also be performed. This is because the overall profile of guselkumab may be favorable compared to ustekinumab (in terms of overall efficacy and safety) even if the final results only show that the relative efficacy is non-inferior to ustekinumab for a specific endpoint.

[0202] Study design Overall Design The clinical development program for guselkumab in Crohn's disease will be conducted under this single protocol: a Phase 2 / 3, randomized, double-blind, placebo and active controlled (ustekinumab), parallel-group, multicenter protocol to evaluate the safety and efficacy of guselkumab in participants with moderately to severely active Crohn's disease who have had an inadequate response to or who were intolerant to previous conventional or biologic therapy.

[0203] A brief overview of this clinical development program is provided below. Under this protocol, there are three separate studies: a 48-week Phase 2 dose-finding study (i.e., GALAXI1), and two identical 48-week Phase 3 confirmatory studies (i.e., GALAXI2, and GALAXI3). All three studies are conducted using a treat-through study design, i.e., participants are randomized to a treatment regimen at week 0 and maintain that treatment regimen through at least week 48 of each study unless otherwise indicated.

[0204] The Phase 2 dose-finding study (i.e., GALAXI1) will evaluate the safety and efficacy of dosing regimens of guselkumab across a broad induction and maintenance dosing range to aid in the selection of induction and maintenance dosing regimens for confirmatory evaluation in Phase 3. It is estimated that 250-500 participants may be required to select the dosing regimens to be evaluated in Phase 3 (GALAXI2, and GALAXI3). Thus, the first 250 participants in GALAXI1 will be enrolled in the initial dose-determination cohort, and an interim analysis (IA) based primarily on this cohort will be conducted when these participants reach week 12 (or terminate study participation prior to week 12). Because data from a larger number of participants may be required to inform dosing decisions, enrollment will continue while data from the initial dose-determination cohort are collected and analyzed, and newly enrolled participants (i.e., starting with participant number 251) will be randomized into the transition cohort. The purpose of the transition cohort is to continue accumulating data on safety and efficacy at the Phase 2 dosing regimen without interrupting the study, thereby not only increasing the size of the overall safety database, but also, in some cases, contributing additional information when making dosing decisions when there is uncertainty about dosing selection based on results from the initial dosing decision cohort. Up to 500 participants are expected to be enrolled in GALAXI1 prior to the dosing decision (i.e., 250 in the initial dosing decision cohort and up to 250 in the transition cohort). If the Phase 3 dosing decision has not been made by the time 500 patients have been randomized, enrollment will continue until the Phase 3 dosing decision or the decision to terminate the development program is made.

[0205] This is an operationally seamless protocol, i.e., there is no break in enrollment between Phase 2 and Phase 3, where dosing decisions can be made before 500 patients are randomized. The transition from the Phase 2 to Phase 3 portion of the protocol will occur when the Phase 3 dosing decisions are made and implemented. All participants randomized after dosing decisions are made will be part of the Phase 3 trial.

[0206] The Phase 3 dosing confirmatory studies (i.e., GALAXI2 and GALAXI3) will evaluate the safety and efficacy of the selected guselkumab dosing regimens. For a total target sample size of 1,540 participants in the Phase 3 portion of the protocol, a target of 770 participants will be enrolled in each of the Phase 3 studies.

[0207] Participants who complete the 48-week Phase 2 or 3 study may be eligible to enter the LTE and receive approximately two additional years of treatment.

[0208] The entire GALAXI Phase 2 / 3 protocol will enroll approximately 2,000 total participants, with each participant's total duration up to approximately 3 years.

[0209] Target population The target population in all three studies under this protocol will be the same, consisting of men or women aged 18 years or older at the time of providing informed consent for moderate to severe active Crohn's disease (at least 3 months duration). Participants must have previously had radiographically, histologically, and / or endoscopically confirmed colitis, ileitis, or ileocolitis.

[0210] Criteria for Active Disease At baseline, participants must have active Crohn's disease, defined as: Clinically active Crohn's disease a.CDAI score ≥220 but ≤450. And any of the following: b. Average daily number of stools >3 based on the unweighted CDAI component of number of liquid or very loose stools; OR c. Average daily AP score >1 based on the unweighted CDAI component of abdominal pain and 2. Endoscopic evidence of ileocolonic Crohn's disease An SES-CD score of ≥3 as assessed by central endoscopic reading at the time of screening endoscopy, indicating the presence of at least one large ulcer (in the ileum, colon, or both), which results in: a. Minimum score of 2 for the component "ulcer size" and b. Minimum score of 1 for the “ulcerated surface” element.

[0211] Within each study, up to 10% of the total enrolled population will be participants with a baseline score of SES-CD<4 (i.e., for participants with isolated ileal disease) or SES-CD<7 (i.e., for participants with colonic or ileocolonic disease).

[0212] Medication History Standards Additionally, a broad population of participants eligible for systemic therapy will be evaluated in this protocol, including those who have previously responded inadequately to or been intolerant to conventional or biologic therapy.

[0213] Please note that participants with previous exposure to IL-12 / 23 or IL-23 agents are ineligible to participate in this protocol, except for participants who have had limited exposure to ustekinumab and who have not demonstrated non-response or intolerance to ustekinumab.

[0214] - Non-response or intolerance to conventional therapy (CON non-response) Participants must have had an inadequate response to or intolerance to at least one of the following conventional Crohn's disease therapies: oral corticosteroids (including prednisone, budesonide, and beclomethasone dipropionate) or the immunomodulatory agents azathioprine (AZA), 6-mercaptopurine (6-MP), or methotrexate (MTX). Participants who exhibited corticosteroid dependence (i.e., inability to successfully taper corticosteroids without return of Crohn's disease symptoms) are also eligible. Participants may have never received biologic therapy (i.e., TNF antagonists, or vedolizumab or ustekinumab) or may have been exposed to biologic therapy but not had an inadequate response or intolerance.

[0215] Within each study, a minimum of 25% and a maximum of 50% of the total population enrolled will be participants who are CON non-responders.

[0216] Non-response or intolerance to biological therapy (BIO non-response) Participants must have had an inadequate response or intolerance to at least one biologic therapy (i.e., TNF antagonist or vedolizumab) at doses approved for the treatment of Crohn's disease. Inadequate response is defined as primary non-response (i.e., no initial response) or secondary non-response (i.e., initial response followed by loss of response). Participants who had an inadequate response or intolerance to ustekinumab were ineligible.

[0217] Concomitant and prohibited therapies are described below with respect to their usage. In general, concomitant therapies should be maintained at stable doses (except for steroid taper) and new concomitant therapies should not be initiated unless deemed medically necessary by the investigator. Corticosteroids will be tapered beginning at week 12. If prohibited therapy is initiated, the treatment trial will be discontinued (SID). Finally, in the event of sustained inadequate response or clinically significant worsening of Crohn's disease, strong consideration should be given to discontinuing the intervention.

[0218] evaluation Across all three studies, efficacy, PK, biomarkers, and safety will be evaluated as indicated on the appropriate activity schedule.

[0219] Blood samples for pharmacogenetics will be collected from participants who consent to this component of the protocol (if local regulations permit). Participation in pharmacogenetic research is voluntary. Deoxyribonucleic acid (DNA) samples will be analyzed for the identification of genetic factors that may be associated with clinical response.

[0220] An external, independent DMC, with defined roles and responsibilities consistent with the DMC Charter, will evaluate participant safety across the three studies. The initial responsibility of the DMC will be to carefully review the safety data from the first 25 participants randomized and treated with GALAXI1. Thereafter, ongoing review of safety data will continue as specified in the DMC Charter. After each review, the DMC will make a recommendation to the sponsor regarding continuation of the study.

[0221] Phase 2 dosing study (GALAXI1) Overview of Phase 2 Study Design and Phase 3 Dosing Decision At week 0, participants are randomized in a 1:1:1:1:1 ratio to receive one of three dose regimens of guselkumab, ustekinumab, or placebo. Participants are assigned to treatment groups using a permuted block randomization method with baseline CDAI score (≦300 or >300) and previous BIO non-response status (yes / no) as stratification variables. A minimum of 25% and a maximum of 50% of the total enrolled population will be CON non-responders. Additionally, a maximum of 10% of the total enrolled population will have a baseline score of SES-CD<4 (i.e., for participants with isolated ileal disease) or SES-CD<7 (i.e., for participants with colonic or ileocolonic disease). Allocation to treatment groups will be performed by an interactive web response system (IWRS) using a central randomization center.

[0222] Up to 500 participants (i.e., 250 in the initial dosing decision cohort and up to 250 in the transition cohort) are expected to be enrolled in GALAXI1 prior to the Phase 3 dosing decision. If the Phase 3 dosing decision has not been made by the time 500 patients have been randomized, enrollment will occur until the Phase 3 dosing decision or a decision to terminate the development program is made.

[0223] An interim analysis is planned at week 12 (week 24, if appropriate) after all participants in the initial dose determination cohort have completed the week 12 (or week 24) visit or have terminated study participation prior to the week 12 (or week 24) visit to inform Phase 3 dosing decisions. At each IA time point, all available data from both the initial dose determination cohort and transition cohort, including any data beyond week 12, will be analyzed. Additional data transfer and analysis may be performed at other time points if needed to enable Phase 3 dosing decisions. The goal is to select two guselkumab dosing regimens for confirmatory evaluation in Phase 3.

[0224] Treatment Group An overview of the five treatment arms and their corresponding dosing schemes for weeks 0 through 48 of the Phase 2 study is provided below.

[0225] Dosing scheme for the five treatment arms during weeks 0-48 of Phase 2 (i.e., GALAXI1) All participants in the Phase 2 study (i.e., the initial dose determination cohort and transition cohorts) will be randomized into one of five treatment arms, as described below. Participants will maintain their assigned treatment regimen until the end of the 48-week study, except for the placebo arm, which is outlined below.

[0226] Group 1: Guselkuma regimen 1 (1200 mg IV q4w × 3 → 200 mg SC q4w) Participants will receive IV induction (i.e., a total of 3 IV doses) of guselkumab 1200 mg q4w through weeks 0 through 8. At week 12, participants will continue treatment with SC maintenance of guselkumab 200 mg q4w through week 44.

[0227] Group 2: Guselkuma regimen 2 (600 mg IV q4w × 3 → 200 mg SC q4w) Participants will receive IV induction (i.e., a total of 3 IV doses) of guselkumab 600 mg q4w through weeks 0 through 8. At week 12, participants will continue treatment with SC maintenance of guselkumab 200 mg q4w through week 44.

[0228] Group 3: Guselkuma regimen 3 (200 mg IV q4w × 3 → 100 mg SC q8w) Participants will receive IV induction (i.e., a total of 3 IV doses) of guselkumab 200 mg q4w through weeks 0 through 8. At week 16, participants will continue treatment with SC maintenance of guselkumab 100 mg q8w through week 40.

[0229] Group 4: Active control, ustekinumab (approximately 6 mg / kg IV → 90 mg SC q8w) Participants will receive a single ustekinumab IV induction dose (approximately 6 mg / kg weight-based IV dose as outlined below) at week 0. At week 8, participants will receive ustekinumab SC maintenance (90 mg SC q8w) through week 40. Ustekinumab 260mg (body weight ≦55kg) Ustekinumab 390 mg [body weight >55 kg and ≤85 kg]; Ustekinumab 520 mg (body weight > 85 kg).

[0230] Group 5: placebo → placebo or ustekinumab crossover Participants will receive placebo IV q4w from weeks 0 through 8 (i.e., a total of 3 IV doses). At week 12, participants will continue treatment based on clinical response status as follows: Placebo responders: continue placebo treatment q4w through weeks 12-44. Placebo Non-Responders: receive one ustekinumab IV induction dose (approximately 6mg / kg weight-based IV dose as outlined above) at week 12. At week 20, participants receive ustekinumab SC maintenance (90mg SC q8w) through week 44.

[0231] Clinical response is defined as a reduction in CDAI score from baseline (i.e., week 0) of ≥ 100 points or clinical remission (CDAI < 150). To maintain blinding, participants in all treatment groups will be evaluated for clinical response status at week 12. In addition, placebo doses (IV and SC) will be given as needed to maintain blinding throughout the study period. Based on the above clinical response status, no dose adjustments are planned for any of the treatment groups from week 0 to week 48, except for group 5 (placebo) at week 12.

[0232] Concomitant and prohibited therapies are described below with respect to their usage. In general, concomitant therapies should be maintained at stable doses (except for steroid tapers) and new concomitant therapies should not be initiated unless deemed medically necessary by the investigator. Corticosteroids will be tapered beginning at week 12. Initiation of prohibited therapy will result in a SID. Finally, in the event of sustained inadequate response or clinically significant worsening of Crohn's disease, discontinuation of the intervention should be strongly considered.

[0233] All participants who complete the 48-week assessment will be eligible to enter the LTE and continue to receive study intervention for approximately two additional years (weeks 48-156).

[0234] Endpoints and Evaluation The primary endpoint is the change from baseline in CDAI score at week 12. Key secondary endpoints are clinical remission at week 12, clinical response at week 12, PRO-2 remission at week 12, endoscopic response at week 12, and clinical biomarker response at week 12. Analyses of these endpoints are based on a comparison of the guselkumab group to the placebo group, respectively. Further analyses of endpoints at other time points will also be conducted, including a comparison of guselkumab to ustekinumab at week 48.

[0235] Efficacy, PK and PD parameters, biomarkers, and safety will be evaluated.

[0236] Database locks (DBLs) are planned at weeks 12 and 48. Additional DBLs (e.g., at week 24) can be added if needed.

[0237] Phase 3 treatment confirmation study (GALAXI2 and GALAXI3) Phase 3 Design Overview At week 0, a target of 980 participants will be randomized to GALAXI2 (n=490) or GALAXI3 (n=490) using a permuted block randomization design with baseline CDAI score (≦300 or >300), baseline SES-CD score (≦12 or >12), prior BIO non-response status (yes / no), and baseline corticosteroid use (yes / no) as stratification variables. Within each stratum, participants in each study will be randomized in a 2:2:2:1 ratio to receive one of two dosing regimens: guselkumab, ustekinumab, or placebo. Within each study (GALAXI2 and GALAXI3), a minimum of 25% and a maximum of 50% of the total enrolled population will be CON non-responders. Additionally, up to 10% of the total enrolled population will have a baseline score of SES-CD<4 (i.e., for participants with isolated ileal disease) or SES-CD<7 (i.e., for participants with colonic or ileocolonic disease). Allocation to treatment groups will be performed by the IWRS using a central randomization center.

[0238] group The guselkumab dosing regimen in Phase 3 will be selected based on the efficacy and safety of the induction dose range (i.e., 200 mg to 1200 mg IV) and maintenance dose range (i.e., 100 mg SC q8w to 200 mg SC q4w) evaluated in the Phase 2 study.

[0239] Based on the Phase 2 data, two guselkumab dosing regimens (i.e., IV induction → SC maintenance) will be selected for confirmatory evaluation in Phase 3. The same dosing regimens will be evaluated in both Phase 3 studies.

[0240] An overview of the four treatment arms in the two Phase 3 studies and the corresponding dosing schemes from Weeks 0 to 48 are summarized below. Participants will maintain their assigned treatment regimen until the end of the 48-week study, except for the placebo arm, which is outlined below.

[0241] Dosing scheme for the four treatment arms from week 0 to week 48 in the Phase 3 trials (i.e., GALAXI2 and GALAXI3) Group 1: Guselkuma regimen 1 (200 mg IV q4w × 3 → 200 mg SC q4w) Participants will receive IV induction (i.e., a total of 3 IV doses) of guselkumab 200 mg q4w through weeks 0 through 8. At week 12, participants will continue treatment with SC maintenance of guselkumab 200 mg q4w through week 44.

[0242] Group 2: Guselkuma regimen 2 (200 mg IV q4w × 3 → 100 mg SC q8w) Participants will receive IV induction (i.e., a total of 3 IV doses) of guselkumab 200 mg q4w through weeks 0 through 8. At week 16, participants will continue treatment with SC maintenance of guselkumab 100 mg q8w through week 40.

[0243] Group 3: Active control - ustekinumab (approximately 6 mg / kg IV → 90 mg SC q8w) Participants will receive a single ustekinumab IV induction dose (approximately 6 mg / kg weight-based IV dose as outlined below) at week 0. At week 8, participants will receive ustekinumab SC maintenance (90 mg SC q8w) through week 40. Ustekinumab 260mg (body weight ≦55kg) Ustekinumab 390 mg [body weight >55 kg and ≤85 kg]; Ustekinumab 520 mg (body weight > 85 kg).

[0244] Group 4: Placebo → placebo or ustekinumab crossover Participants will receive placebo IV q4w from weeks 0 through 8 (i.e., a total of 3 IV doses). At week 12, participants will continue treatment based on clinical response status as follows: Placebo responders: continue placebo treatment from Weeks 12 through 44. Placebo Non-Responders: receive one ustekinumab IV induction dose (approximately 6mg / kg weight-based IV dose as outlined above) at week 12. At week 20, participants receive ustekinumab SC maintenance (90mg SC q8w) through week 44.

[0245] Clinical response is defined as a reduction from baseline (i.e., Week 0) in CDAI score of ≥ 100 points or clinical remission (CDAI < 150). To maintain blinding, participants in all treatment groups will be assessed for clinical response status at Week 12.

[0246] In addition, placebo doses (IV and SC) will be given as needed to maintain blinding throughout the study period. Based on the clinical response status above, no dose adjustments are planned for any of the treatment arms from Weeks 0 to 48, except for Arm 4 (placebo) at Week 12.

[0247] Concomitant and prohibited therapies are described below with respect to their usage. In general, concomitant therapies should be maintained at stable doses (except for steroid reductions) and new concomitant therapies should not be initiated unless deemed medically necessary by the investigator. Corticosteroids will be tapered beginning at week 12. Initiation of prohibited therapy will result in a SID. Finally, in the event of persistent inadequate response or clinically significant worsening of Crohn's disease, discontinuation of the intervention should be strongly considered.

[0248] All participants who completed the 48-week assessment may be eligible to enter the LTE and continue to receive treatment for approximately two additional years.

[0249] Endpoints and Evaluation Both GALAXI2 and GALAXI3 have the same primary and key secondary endpoints.

[0250] The primary endpoint is clinical remission at week 12, based on a comparison between guselkumab and placebo. The key secondary endpoints of clinical remission at week 48, sustained clinical remission at week 48, corticosteroid-free clinical remission at week 48, PRO-2 remission at week 48, and endoscopic response at week 48 are based on a comparison between guselkumab and ustekinumab. The key secondary endpoints of PRO-2 remission at week 12, endoscopic response at week 12, and fatigue response at week 12 are based on a comparison between each guselkumab treatment group and the placebo group.

[0251] Efficacy, PK and PD parameters, biomarkers, and safety will be evaluated.

[0252] A DBL is planned for week 48. Additional DBLs may be added as needed and will be specified in the SAP.

[0253] long term extension LTE will run for approximately four years, from weeks 48 to 252.

[0254] At Week 48 of GALAXI1, GALAXI2, or GALAXI3, all participants who, in the opinion of the investigator, continue to receive benefit from treatment (i.e., based on clinical and endoscopic assessments at Week 48), will be eligible to enter the LTE to receive approximately 4 additional years of treatment, during which the long-term efficacy and safety of guselkumab will be evaluated. All participants will be evaluated. The final efficacy and safety follow-up (FES) visit in the LTE will occur at approximately Week 248-252 (i.e., approximately 16 weeks after the last study intervention dose, at Week 232 [q8w dosing] or Week 236 [q4w dosing]).

[0255] Participants who are not eligible to enter the LTE at week 48 will return for an FES visit 16 weeks after the last study intervention administration.

[0256] During the LTE, all participants will continue to receive the same treatment regimen (i.e., guselkumab, ustekinumab, or placebo) they were receiving at the end of GALAXI1, GALAXI2, or GALAXI3. The first study intervention administration in the LTE will occur at Week 48 and the last study intervention administration will occur at Week 236. Treatment adjustments for inadequate response will be permitted from Weeks 52 through 80 of the LTE.

[0257] At the discretion of the investigator and participant, after appropriate and documented training, beginning at week 48, participants may self-administer the study intervention at the study site. Caregivers may also be trained to administer the intervention. After receiving training at week 48, participants eligible for self-(or caregiver) administration of the study intervention will be offered the study intervention for home administration and will conduct their first home administration at week 52. Participants who are unable or unwilling to administer the intervention away from the study site will continue with administration at the study site.

[0258] All participants continued to receive active or placebo study intervention in the LTE in a blinded fashion until study unblinding, which occurred after DBL at week 48, when the week 48 analysis was completed for Phase 2 (for participants entering the LTE from GALAXI1) or Phase 3 (for participants entering the LTE from GALAXI2 or GALAXI3).

[0259] After study unblinding, all participants receiving active treatment (i.e., guselkumab or ustekinumab) will continue to receive their assigned active treatment for the remainder of the LTE, through week 236. Placebo participants will discontinue the intervention upon study unblinding and will have an FES visit at that time.

[0260] Endpoints and Evaluation The long-term efficacy and safety of guselkumab will be evaluated through Week 252. In addition, the effects of treatment adjustments will be evaluated based on a descriptive analysis of various efficacy endpoints (as specified in the SAP).

[0261] Database lock is planned at Week 96 and when the last participant completes the final efficacy and safety visit in LTE. Additional DBLs may be added as needed and will be specified in the Phase 3 SAP.

[0262] Use of placebo and active controls The inclusion of both placebo and active controls in the same protocol has several advantages. A short-term placebo-controlled period facilitates the evaluation of the short-term efficacy and safety of a new treatment compared to a placebo within a time frame in which the use of a placebo in participants with active disease is deemed to clinically support scientific investigation. For long-term treatments, the use of an active comparator control can alleviate concerns about the long-term use of placebos and also provide an opportunity to evaluate relative efficacy and safety in a randomized comparative setting. There is great clinical value in determining whether a new treatment option provides similar or greater benefit to patients compared to an approved treatment option.

[0263] Ustekinumab was selected as the active comparator because it targets an overlapping mechanism of action (i.e., both IL-12 / 23 blockade) and preclinical evidence suggests the potential for improved efficacy with more specific targeting of IL-23. Furthermore, the dose proposed for ustekinumab in this protocol is the maximum currently approved induction-maintenance dosing regimen and was one of the dosing regimens evaluated in the ustekinumab Phase 3 clinical development program in Crohn's disease. Thus, the inclusion of ustekinumab as an active comparator in this program provides a useful and appropriate benchmark for comparison with guselkumab.

[0264] Ustekinumab will be included as the active reference group in the Phase 2 study to collect data that will inform treatment effect size and sample size assumptions for the Phase 3 study. Ustekinumab will be included in the two Phase 3 studies as the active comparator reference group to allow for randomized evaluation of the long-term efficacy and safety of the two guselkumab dosing regimens compared to ustekinumab through approximately one year of treatment (i.e., week 48). An important objective of this development program is to determine whether the efficacy of guselkumab is superior (or at least non-inferior) to ustekinumab in achieving long-term clinical remission.

[0265] Patient-reported outcomes of health-related quality of life Patient-reported outcome (PRO) assessments (i.e., IBDQ, PROMIS-29, PROMIS fatigue 7-item short form, and 5-level EuroQol 5-level [EQ-5D-5L] measure) will be used to assess the benefit of guselkumab treatment with regard to disease-specific and general HRQOL.

[0266] Phase 2 dosing design study (GALAXI1) The following guselkumab dosing regimens will be evaluated through week 48 of GALAXI1: Guselkuma regimen 1 - Induction: 1200 mg IV at weeks 0, 4, and 8, followed by maintenance: 200 mg SC q4w (i.e., weeks 12, 16, 20, 24, 28, 32, 36, 40, and 44) Guselkuma regimen 2 - Induction: 600 mg IV at weeks 0, 4, and 8, followed by maintenance: 200 mg SC q4w (i.e., weeks 12, 16, 20, 24, 28, 32, 36, 40, and 44) Guselkuma regimen 3 - Induction: 200 mg IV at weeks 0, 4, and 8, followed by maintenance: 100 mg SC q8w (i.e., weeks 16, 24, 32, and 40)

[0267] Induction Dosing Regimen A crossover study comparison between phase 2 studies of guselkumab and risankizumab in patients with psoriasis vulgaris suggests that comparable efficacy was obtained with roughly similar dosing regimens. A model-based meta-analysis also suggests comparable clinical efficacy of these two compounds. Furthermore, the PK of guselkumab was found to be similar to that of risankizumab. These dose-response and PK data suggest that similar levels of IL-23 blockade and efficacy may be achieved in Crohn's disease with similar dosing regimens or systemic exposure of these two compounds. Furthermore, the PK / PD model of ustekinumab (an IL-12 / 23 blocker) approved in Crohn's disease was deemed applicable to predict efficacy after administration of different guselkumab dosing regimens.

[0268] A phase 2 study of risankizumab in participants with moderately to severely active Crohn's disease demonstrated dose-dependent efficacy, with a greater proportion of participants on a higher induction dosing regimen of risankizumab (i.e., 600 mg IV q4w) achieving remission at week 12 compared with those receiving a lower dosing regimen (i.e., 200 mg IV q4w). However, it was not clear in this phase 2 study whether maximum efficacy was achieved with the risankizumab 600 mg IV induction dosing regimen. Dose-dependent efficacy was further demonstrated with risankizumab, as shown by an increase in remission rates in patients switched from 200 mg IV to 600 mg IV in the second period of the study (weeks 12-26). Based on these findings, along with the comparable PK and clinical efficacy of guselkumab and risankizumab, and combined with the PK / PD predictions for Crohn's disease, an induction dosing regimen containing guselkumab 600 mg IV and 200 mg IV administered at weeks 0, 4, and 8, respectively, was selected for a Phase 2 dose-finding study.

[0269] Additionally, the potential for a higher dose of guselkumab (1200 mg q4w IV) induction dosing regimen to achieve a higher level of efficacy at week 12 than that observed with the higher risankizumab dosing regimen (i.e., 600 mg IV) tested in Phase 2 will be evaluated. Overall, the three guselkumab IV induction dosing regimens provide a six-fold range of exposure that is likely to provide adequate separation between dose levels, thereby supporting the Phase 3 guselkumab induction dosing selection.

[0270] Regarding the safety of these higher IV induction guselkumab doses, a single dose of 10 mg / kg guselkumab with a maximum single dose of 987 mg has been previously tested in a phase 1 plaque psoriasis study in a limited number of participants. Furthermore, guselkumab IV doses of up to 50 mg / kg once weekly for 5 weeks and guselkumab SC doses of up to 50 mg / kg once weekly for 24 weeks were well tolerated in cynomolgus monkeys and did not result in clinical or anatomical findings. These data suggest an acceptable exposure margin between the expected guselkumab exposure for the 1200 mg IV regimen compared to that observed in the toxicity study. Furthermore, risankizumab was well tolerated at dose regimens of up to six doses of 600 mg IV q4w over a 26-week period, i.e., a total of 3600 mg. Long-term follow-up of these participants through week 52 did not identify any significant safety concerns based on published data. Nevertheless, an external DMC will be appointed to monitor the efficacy-risk of guselkumab.

[0271] Maintenance Dosing Regimen The posology of other biologics for Crohn's disease suggests that as the inflammatory burden of the disease is reduced, the drug exposure required to maintain efficacy may be reduced from that achieved with the initial loading dose.

[0272] In a phase 3 Crohn's disease trial of ustekinumab, among participants who were in remission at week 8 after an IV induction regimen of approximately 6 mg / kg, a 90 mg SC q8w maintenance regimen resulted in 67% of subjects remaining in remission at week 52. In a phase 2 Crohn's disease trial of risankizumab, among participants who were in remission at week 26 after receiving up to 6 months of 600 mg IV q4w induction, long-term uncontrolled data showed that a 180 mg SC q8w regimen resulted in 71% of patients remaining in remission at week 52.

[0273] Therefore, in this protocol, after 12 weeks of IV guselkumab induction treatment, dosing regimens providing lower guselkumab exposure will be evaluated during SC maintenance treatment up to 48 weeks. The selected maintenance dosing regimen provides adequate maintenance, with induction exposure ratios comparable to those of other biologics approved for Crohn's disease.

[0274] Regimen 1 and 2 evaluate guselkumab 1200 mg IV q4w and 600 mg IV q4w induction, respectively. For each of these regimens, a maintenance regimen of 200 mg SC q4w was tested to evaluate whether a higher exposure than was tested in the risankizumab Phase 2 study (i.e., 180 mg SC q8w) was necessary to optimize efficacy in maintenance.

[0275] For regimen 3 evaluating guselkumab 200 mg IV q4w induction, a maintenance regimen of 100 mg SC q8w will be tested. The guselkumab 100 mg SC q8w regimen is expected to provide efficacy at least similar to, or greater than, that observed with ustekinumab 90 mg SC q8w, and the maintenance dosing regimen of the active comparator will be evaluated in this study.

[0276] Overall, the two guselkumab maintenance SC dosing regimens provide a four-fold range of exposure that should support phase 3 dosing selection.

[0277] No treatment adjustments are planned for any of the treatment arms at Weeks 0-48 of GALAXI1, except for IV induction placebo non-responders who will cross over to receive the ustekinumab dosing regimen evaluated in this study (i.e., 6 mg / kg IV at Week 12 followed by 90 mg SC q8w beginning at Week 20). Participants randomized to placebo IV who are responders at Week 12 will continue to receive SC placebo through Week 44.

[0278] Phase 3 treatment confirmation study (GALAXI2 and GALAXI3) Based on the Phase 2 data, two guselkumab dosing regimens (i.e., IV induction → SC maintenance) will be selected for confirmatory evaluation in Phase 3.

[0279] The goal is to select a single induction dosing regimen from the induction dosing range evaluated in the Phase 2 dose-finding study (i.e., 200 mg to 1200 mg IV q4w at weeks 0, 4, and 8) based on the overall efficacy, safety, and exposure-response (ER) data at the time of dosing decision. The selection of the single induction regimen to be evaluated in the Phase 3 dose-finding study will be based on considering that a sufficient amount of information is available to establish the optimal induction dosing regimen. In this scenario, the selected induction dosing regimen will be paired with two maintenance dosing regimens selected from the exposure range obtained from the guselkumab SC dosing regimens evaluated in Phase 2 (i.e., 100 mg q8w to 200 mg q4w).

[0280] It is also possible that Phase 2 data may support the selection of more than one induction dosing regimen for Phase 3 evaluation, in which case each selected induction dosing regimen would be paired with an appropriate maintenance dosing regimen.

[0281] No treatment adjustments are planned for any of the treatment arms in GALAXI2 and GALAXI3 from Weeks 0 to 48, except for IV induction placebo non-responders, who will cross over to receive the ustekinumab dosing regimen evaluated in this study (i.e., approximately 6 mg / kg IV at Week 12, followed by 90 mg SC q8w beginning at Week 20). Participants randomized to placebo IV who are responders at Week 12 will continue to receive SC placebo through Week 44.

[0282] Long-term extension (48th to 240th week) Participants will continue their assigned guselkumab maintenance treatment during LTE in GALAXI1, GALAXI2, and GALAXI3.

[0283] Inclusion criteria Each potential participant must meet all of the following criteria to be enrolled in the study: 1. Be male or female (according to reproductive organs and functions assigned by chromosomal complement) aged 18 years or older. 2. Have Crohn's disease or fistulizing Crohn's disease of at least 3 months duration (defined as a minimum of 12 weeks) with colitis, ileitis, or ileocolitis confirmed by radiography, histology, and / or endoscopy at any time in the past. 3. Have clinically active Crohn's disease defined as a baseline CDAI score ≥ 220 and ≤ 450: a. Average daily number of stools >3 based on the unweighted CDAI component of number of liquid or very loose stools; OR b. Average daily AP score >1 based on the unweighted CDAI component of abdominal pain 4. SES-CD score ≥ 3 as assessed by central endoscopic reading at the time of screening endoscopy, indicating the presence of at least one large ulcer (in the ileum, colon, or both), resulting in: a. Minimum score of 2 for the component "ulcer size" and b. Minimum score of 1 for the “ulcerated surface” element.

[0284] Within each study, up to 10% of the total enrolled population will be participants with a baseline score of SES-CD<4 (i.e., for participants with isolated ileal disease) or SES-CD<7 (i.e., for participants with colonic or ileocolonic disease).

[0285] Concomitant or past drug therapy received 5. Past or current medications for Crohn's disease must include at least one of the following and meet the additional criteria listed in Schedule 2 (Section 10.2), Schedule 3 (Section 10.3), and Schedule 4 (Section 10.4): Current treatment with oral corticosteroids (including budesonide and beclomethasone dipropionate) and / or immunomodulators (including AZA, 6-MP, MTX) OR b. History of failure to respond to or intolerance to at least one of the following therapies: oral corticosteroids (including budesonide and beclomethasone dipropionate) or immunomodulatory agents (AZA, 6-MP, MTX). OR c. History of corticosteroid dependence (i.e., inability to successfully taper corticosteroids without return of Crohn's disease symptoms). OR d. Have previously demonstrated lack of initial response (i.e., primary non-responder), responded initially but lost response with continued therapy (i.e., secondary non-responder), or been intolerant to one or more biologic agents (i.e., infliximab, adalimumab, certolizumab pegol, vedolizumab, or approved biosimilars to these agents) administered approved for the treatment of Crohn's disease. NOTE: Participants who meet criteria 5a-c may not have received biologic therapy (i.e., TNF antagonists or vedolizumab or ustekinumab) or may have been exposed to these biologic therapies but have not demonstrated an inadequate response or intolerance. Participants with previous exposure to IL-12 / 23 or IL-23 agents are not eligible for participation in this protocol, except for participants who have had limited exposure to ustekinumab at the approved label dose and who meet the necessary washout criteria and have not demonstrated non-response or intolerance to ustekinumab. 6. Adhere to the following requirements for concomitant medications for the treatment of Crohn's disease. The following medications are permitted provided that dosing meeting the requirements listed below is stable or has been discontinued prior to baseline within the time frames specified below: a. Oral 5-aminosalicylic acid (5-ASA) compounds on stable dosing for at least 2 weeks, or if recently discontinued, must be discontinued for at least 2 weeks. b. Oral corticosteroids at a prednisone equivalent dose of 40 mg / day or less, or budesonide 9 mg / day, or beclomethasone dipropionate 5 mg / day, and stable therapy for at least 2 weeks; or if recently discontinued, must be discontinued for at least 2 weeks. c. At least 12 weeks of conventional immunomodulatory agents (i.e., AZA, 6-MP, or MTX) and on stable dosing for at least 4 weeks, or if recently discontinued, must be discontinued for at least 4 weeks. d. If antibiotics are being taken as primary treatment for Crohn's disease, administration must be stable for at least 3 weeks; or, if recently discontinued, must be discontinued for at least 3 weeks. e. If receiving enteral nutrition as a primary treatment for Crohn's disease, it must have been taken for at least 2 weeks; or, if recently discontinued, it must be discontinued for at least 2 weeks.

[0286] Laboratory Test Screening 7. Have laboratory screening test results within the following parameter ranges and will be allowed one retest of the laboratory values ​​during the approximately 5 week screening period if one or more of the laboratory parameters are out of range: Hemoglobin ≥ 8.0 g / dL. b. White blood cells (WBC) ≧3.5×103 / μL. c. Neutrophils ≥1.5x103 / μL. d. Platelets ≥100x103 / μL. e. Serum creatinine ≤ 1.5 mg / dL. f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations should be within 2 times the upper limit of the normal range (ULN) for the testing laboratory. g. Direct (conjugated) bilirubin <1.0 mg / dL.

[0287] tuberculosis 8. Be considered eligible according to the following tuberculosis (TB) screening criteria: No history of latent or active TB prior to screening. Exceptions are made for participants with a history of latent TB who meet one of the following criteria: Currently undergoing treatment for latent TB Initiate treatment for latent TB before or at the same time as the first administration of the study intervention OR Documented completion of appropriate treatment for latent TB within 5 years prior to first administration of the intervention. It is the investigator's responsibility to verify the adequacy of prior anti-TB treatment and provide appropriate documentation. b. No signs or symptoms suggestive of active TB upon medical history and / or physical examination. c) Have not had recent close contact with anyone with active TB, in which case they will be referred to a TB specialist for further evaluation and, if confirmed, appropriate treatment for latent TB prior to or at the same time as the first administration of the intervention. d. A negative QuantiFERON®-TB Gold test result within 8 weeks prior to first administration of the study intervention, or a newly identified positive QuantiFERON-TB Gold test result where active TB has been ruled out and appropriate treatment for latent TB has been initiated either prior to or concomitantly with first administration of the study intervention. Note: If the QuantiFERON-TB Gold test is not approved / registered in the country where this protocol is performed, a negative result of tuberculin skin test is additionally required. In Ukraine, the QuantiFERON-TB gold test is not approved / registered but is accepted and an additional tuberculin skin test is not mandatory. The QuantiFERON-TB Gold test and the tuberculin skin test are not required for screening participants with a history of latent TB if active TB has been excluded and appropriate treatment has been started / completed, as described in inclusion criterion 8a above. e. Chest radiograph (both anteroposterior and lateral views, or in accordance with national regulations, if applicable) taken within 12 weeks prior to first administration of the study intervention, read by a competent radiologist and showing no evidence of current active or old inactive TB.

[0288] contraception Contraception (birth control) provided by men or women must be consistent with local regulations regarding acceptable methods of contraception for clinical trial participants. Typical implementation failure rates may differ from those that are implemented consistently and correctly. Implementation must be consistent with local regulations regarding contraception for clinical trial participants. 9. Female participants of childbearing potential must have a negative urine pregnancy test at screening and baseline. 10. Prior to random selection, female participants must be: a.There is no possibility of pregnancy b. There is a possibility of pregnancy, and c. Implement a highly effective method of contraception (<1% non-response rate per year when used consistently and accurately) and agree to maintain a highly effective method while receiving the study intervention and until 16 weeks after the last dose (i.e., end of relevant systemic exposure). However, the method selected must meet local / regional regulations / guidelines for highly effective contraception. Note: If a participant's fertility changes after study initiation (e.g., a premenarcheal woman experiences menarche) or pregnancy risk changes (e.g., a sexually inactive woman becomes sexually active), women must begin using highly effective contraception as described throughout the inclusion and exclusion criteria. 11. Women must agree not to donate eggs (eggs, oocytes) for assisted reproductive purposes during the study and for 16 weeks after the last administration of the study intervention. 12. During the study and for at least 16 weeks after the last administration of the intervention, male participants will: a. If you are sexually active with a woman of childbearing potential, you must agree to use a barrier method of contraception (e.g., condoms with spermicidal foam / gel / film / cream / suppository). b. If you are sexually active with a pregnant woman, you must use a condom. c. You must agree not to donate sperm for reproductive purposes.

[0289] general 13. Willing and able to adhere to the lifestyle restrictions specified in this protocol. 14. Each person must sign an informed consent form (ICF) indicating that they understand the purpose of the study and the procedures involved, and are willing to participate in the study. 15. If each person agrees to voluntarily provide a DNA sample for research, they must sign an individual ICF (if local regulations permit). Refusal to consent to a voluntary DNA research sample will not exclude a participant from participation in the study.

[0290] 5.2. Exclusion criteria Prospective participants who meet any of the following criteria will be excluded from participating in this protocol: 1. The presence of complications of Crohn's disease, such as symptomatic strictures or stenosis, short bowel syndrome, or any other manifestation that may predict the need for surgery, may preclude the use of the CDAI to assess response to treatment, which may otherwise confound the assessment of the effect of treatment with guselkumab or ustekinumab. 2. Current or suspected abscess. Recent skin and anal abscesses will not be excluded if they have been drained and adequately treated at least 3 weeks prior to baseline, or for intra-abdominal abscesses, 8 weeks prior to baseline, unless a need for further surgery is anticipated. Participants with active fistulas may be included if no need for surgery is anticipated and if there are no currently identified abscesses. 3. Has had bowel resection of any kind within 6 months prior to baseline, or any other intra-abdominal or other major surgery (i.e., requiring general anesthesia) within 12 weeks prior to baseline. 4. You have a draining (i.e., functioning) stoma or ostomy. 5. A positive stool culture or other test for an enteric pathogen, including Clostridium difficile toxin, within the past 4 months, unless repeated tests have been negative and there is no evidence of ongoing infection with that pathogen.

[0291] Concomitant or past drug therapy received 6. If you have taken any of the following prescription drugs or therapies within the specified period: a. Receipt of IV corticosteroids within 3 weeks of baseline b. Receipt of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil within 8 weeks of baseline c. Receipt of 6-thioguanine (6-TG) within 4 weeks from baseline d. Biological agents: 1) Received anti-TNF therapy (e.g., infliximab, etanercept, certolizumab pegol, adalimumab, golimumab) within 8 weeks from baseline 2) Received vedolizumab within 16 weeks from baseline 3) Received ustekinumab within 16 weeks from baseline 4) Receipt of another immunomodulatory biologic agent within 12 weeks of baseline or within 5 half-lives of baseline, whichever is longer. e. Received any investigational intervention within 4 weeks of baseline or within 5 half-lives of baseline, whichever is longer. f. Receipt of non-autologous stem cell therapy (e.g., Proximal), natalizumab, efalizumab, or B- or T-cell depleting biologics (e.g., rituximab, alemtuzumab, or visilizumab) within 12 months of baseline. g. Receipt of apheresis treatment (e.g., adalimumab) or total parenteral nutrition for Crohn's disease within 3 weeks of baseline. 7. Previous receipt of IL-12 / 23 or IL-23 targeted biologics including but not limited to briakinumab, brazikumab, guselkumab, mirakizumab (formerly LY2525623), and risankizumab. Exception: Participants who have had limited exposure to the approved labelled dose of ustekinumab and who meet the necessary washout criteria and have not demonstrated non-response or intolerance to ustekinumab will not be excluded from this protocol, provided they meet the other inclusion criteria and do not meet any other exclusion criteria.

[0292] Infectious diseases or susceptibility to infections: 8. Has a history of or ongoing chronic or recurrent infections, including but not limited to chronic kidney infections, chronic chest infections (e.g., bronchiectasis), recurrent urinary tract infections (e.g., recurrent pyelonephritis or chronic persistent cystitis), or open, draining, or infected skin wounds or ulcers. 9. Currently have signs or symptoms of clinically significant infection. Clearly non-serious infections (e.g., acute upper respiratory tract infection, uncomplicated urinary tract infection) need not be considered exclusionary, at the investigator's discretion. 10. History of serious infection (e.g., hepatitis, sepsis, pneumonia, or pyelonephritis) in the 8 weeks prior to baseline, including any infection requiring hospitalization or IV antibiotics. 11. Evidence of herpes zoster infection within 8 weeks prior to baseline. 12. History of latent or active granulomatous infection, including histoplasmosis or coccidioidomycosis, prior to screening. Participants with previous radiographic evidence of possible histoplasmosis or coccidioidomycosis will be excluded. 13. Chest x-ray within 12 weeks prior to first administration of study intervention showing abnormal indications of malignancy or current active infection, including TB. 14.Current or past nontuberculous mycobacterial infection or clinically significant opportunistic infection (e.g., cytomegalovirus colitis, pneumocystiosis, invasive aspergillosis). 15. Participants must be screened for human immunodeficiency virus (HIV). Any participant with a history of positive HIV antibodies or who tests positive for HIV at screening will not be eligible for this study. 16. Participants who are seropositive for antibodies to hepatitis C virus (HCV), unless they have two negative HCV RNA test results at least 6 months apart after completion of antiviral treatment and prior to screening, and a third negative HCV RNA test result at screening. 17. If you test positive for hepatitis B virus (HBV) infection. Note: Participants who do not qualify for this study because of HIV, HCV, HBV, or TB test results are encouraged to consult with a physician with expertise in the treatment of these infections. 18. Has received or is expected to receive any live viral or bacterial vaccination within 12 weeks prior to first administration of the study intervention. For Bacille Calmette-Guerin (BCG) vaccine, see Exclusion Criterion 14. 19. Have received the BCG vaccination within 12 months of screening.

[0293] Malignant tumor or high probability of malignant tumor 20.Currently has a malignancy or has a history of malignancy within 5 years prior to screening (excluding non-melanoma skin cancer that has been adequately treated and has had no evidence of recurrence for at least 3 months [defined as a minimum of 12 weeks] prior to administration of the first study intervention, or cervical intraepithelial neoplasia that has been treated and has had no evidence of recurrence for at least 3 months prior to administration of the first study intervention). 21. Known history of lymphoproliferative disorders, including monoclonal gammopathy of undetermined significance, lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disorders, such as lymphadenopathy, liver enlargement, splenomegaly, or monoclonal gammopathy of undetermined significance.

[0294] Concomitant medical conditions or past medical history 22. Have a history of severe, progressive, or uncontrolled renal, genitourinary, hepatic, hematologic, endocrine, cardiac, vascular, pulmonary, rheumatologic, neurological, psychiatric, or metabolic disorder, or signs and symptoms thereof. 23. Receiving a transplanted organ (excluding corneal transplants performed >12 weeks prior to screening). 24. Unable or unwilling to undergo multiple venipunctures due to poor tolerance or lack of adequate venous access. 25. Known history of drug or alcohol abuse according to Diagnostic and Statistical Manual of Mental Disorders (5th ed.) (DSM-V) criteria within the 12 months prior to baseline. 26. Have unstable suicidal ideation or behavior, which may be defined as a Columbia-Suicide Severity Rating Scale (C-SSRS) screening score of suicidal ideation with intent to carry out (ideation level 4), suicidal ideation with a specific plan and intent (ideation level 5), or suicidal behavior (actual suicide attempt, aborted suicide attempt, unsuccessful suicide attempt, or preparatory behavior to carry out a suicide attempt) in the past 6 months and are deemed at risk by the investigator based on evaluation by a mental health professional. In addition, participants with C-SSRS scores of wishing for death ("ideation level 1"), nonspecific active suicidal thoughts ("ideation level 2"), active suicidal ideation by any method without intent to carry it out (without a plan) ("ideation level 3"), or non-suicidal self-harm behaviors deemed at risk by the investigator may not be randomized. 27. Known allergy, hypersensitivity, or intolerance to guselkumab or ustekinumab or any of their excipients (see guselkumab IB and ustekinumab IB). 28.Women who are pregnant, breastfeeding, or planning to become pregnant during enrollment in this study or within 16 weeks after administration of the last study intervention. 29.A man who plans to father a child during enrollment in this study or within 16 weeks after administration of the last study intervention.

[0295] General 30. Are enrolled in or intend to participate in any other study using an investigational drug or procedure during participation in this study. 31.Has any condition where, in the opinion of the investigator, participation would not be in the participant's best interest (e.g., would compromise their health) or which might prevent, limit, or confound the evaluations specified in the protocol. 32. An employee of the investigator or trial site who is directly involved in the proposed study or other studies at the direction of the investigator or trial site, or a family member of such an employee or principal investigator. NOTE: Investigators should ensure that all study entry criteria are met at screening. If a participant's clinical condition changes after screening but before the first dose of intervention is given (including receipt of any available laboratory results or additional medical records) such that the participant no longer meets all eligibility criteria, the participant should be excluded from participation in the study.

[0296] Interventions implemented In both phases 2 and 3 of the protocol, All participants will receive two IV infusions (either active or placebo) at week 0 and one IV infusion (either active or placebo) at weeks 4, 8, and 12. All participants will receive one SC injection (of either active or placebo) at week 8 and up to three SC injections (of either active or placebo) at each visit from weeks 12 through 140.

[0297] Intravenous study interventions should be performed over a period of at least 1 hour and not more than 2 hours. Infusions should be completed within 6 hours of preparation. Because multiple SC injections may be administered within a dosing visit, each injection of the intervention should be given at a different location on the body.

[0298] Concomitant medications Participants receiving oral 5-ASA compounds, oral corticosteroids, conventional immunomodulators (i.e., AZA, 6-MP, or MTX), antibiotics, and / or enteral nutrition for the treatment of Crohn's disease at baseline should maintain stable dosing for the specified period prior to baseline, as defined in the inclusion criteria.

[0299] In general, participants receiving these medications for Crohn's disease at baseline (i.e., week 0) in all three studies should maintain stable dosing through week 48, with the exception of oral corticosteroids. Therapy may be discontinued or reduced after week 0 only if required by the investigator's discretion due to toxicity or other medical necessity, and such therapy should not be resumed even if toxicity has resolved. Corticosteroids must be maintained at baseline dosing through week 12, and all participants must begin corticosteroid tapering at week 12 unless medically feasible.

[0300] Week 0 to Week 48 During weeks 0 through 48 of each study, enrolled participants should not begin any of the following concurrent Crohn's disease-specific medical therapies: Oral or rectal 5-ASA compounds. Immunomodulatory agents (i.e., AZA, 6-MP, or MTX). · Oral, parenteral, or rectal corticosteroids, including budesonide and beclomethasone dipropionate. ·Antibiotics as first-line treatment for Crohn's disease. Total parenteral or enteral nutrition as a treatment for Crohn's disease.

[0301] If the above medications are initiated or medication is changed based on medical necessity as assessed by the investigator, the participant should continue to participate in all study visits and have all evaluations. This does not represent a deviation from the study protocol, and participants may maintain their assigned therapy (guselkumab, ustekinumab, or placebo), but this may be considered treatment non-response. Treatment non-response is defined in the SAP.

[0302] Week 12 - Week 48 Between weeks 12 and 48 of each study, participants may temporarily (i.e., <4 weeks) increase their corticosteroid dosing for reasons other than loss of response to Crohn's disease treatment (e.g., stress dosing of corticosteroids for surgery, asthma, or adrenal insufficiency).

[0303] During the treatment phase of the LTE (i.e., Weeks 48-240): Concomitant therapy for Crohn's disease, including 5-ASA, corticosteroids, antibiotics, and immunomodulators (i.e., AZA, 6-MP, or MTX), and / or parenteral or enteral nutrition, may be administered and modified at the investigator's discretion.

[0304] Tapering oral corticosteroids At week 12, all participants who received corticosteroids at week 0 must begin tapering their corticosteroids. This tapering is mandatory unless medically feasible and should follow the recommended schedule shown in Table 6. If, during corticosteroid tapering, participants experience a worsening of their disease activity, further dose reductions may be stopped and / or their oral corticosteroid dose may be temporarily increased if deemed necessary by the investigator. However, oral corticosteroid doses should not be increased beyond the week 0 dose unless medically necessary. Subjects whose corticosteroid tapering is interrupted will be encouraged by the investigator to resume tapering within 4 weeks. Tapering may exceed this schedule only if justified by medical necessity (e.g., participants experiencing corticosteroid-related side effects).

[0305] Prohibited Concomitant Medications Participants who began any of the following procedures while participating in the study will have that intervention discontinued: Immunomodulatory agents other than AZA, 6-MP, or MTX (including, but not limited to, 6-TG, cyclosporine, mycophenolate mofetil, tacrolimus, and sirolimus). Immunomodulatory biologic agents (including but not limited to TNF antagonists, natalizumab, ustekinumab, rituximab, vedolizumab). Ustekinumab is permitted in this study only in participants randomized to ustekinumab and only as specified in this protocol. Experimental Crohn's disease agents (including but not limited to upadacitinib, filgotinib, ozanimod, etrolizumab, brazikumab, mirakizumab [formerly LY-3074828], risankizumab, and GS-5745). -Thalidomide or related drugs.

[0306] Efficacy evaluation Efficacy assessment includes the following: ·CDAI PRO-2 (unweighted CDAI components of total liquid or very loose stool count and abdominal pain score) Endoscopic evaluation of the intestinal mucosa based on the presence or absence of mucosal ulceration and histological evaluation based on the SES-CD and the Global Histology Activity Score (GHAS) Inflammatory PD markers including CRP and fecal calprotectin Fistula assessment Patient-reported outcome (PRO) measures to assess HRQOL outcomes (i.e., IBDQ, PROMIS-29, and PROMIS Fatigue 7-item Short Form [7a], and EQ-5D-5L) and health economics outcomes (i.e., WPAI-CD). Preliminary patient-reported symptom measures including the BSFS, AP-NRS, Patient's Global Impression of Severity (PGIS), and Patient's Global Impression of Change (PGIC).

[0307] The CDAI is assessed by collecting information on eight different Crohn's disease-related variables (extraintestinal manifestations, abdominal masses, weight, hematocrit, total number of liquid stools, abdominal pain / cramps, use of antidiarrheal medications, and / or opiate medications, and general health status). The last four variables are scored by participants over a seven-day period on diary cards, which they complete daily. The PRO-2 includes the unweighted CDAI components of total number of liquid or very loose stools and AP score.

[0308] Endoscopic assessment of the intestinal mucosa will be assessed during ileocolonoscopy in all participants. Video ileocolonoscopy will be performed at screening, weeks 12, 48, 96, 144, 192, and 240. Optional substudies, including the week 4 assessment, will be performed for consenting participants in addition to the predefined assessments listed above. Video endoscopy will be assessed by a central site and will be blinded to treatment group and visit. A complete video endoscopy will not require evaluation of the terminal ileum if it cannot be visualized. The SES-CD score will be used to assess endoscopic improvement. The SES-CD score is based on the assessment of four endoscopic elements (presence / size of ulcers, percentage of mucosal surface covered by ulcers, percentage of mucosal surface affected by other lesions, and presence / type of stenosis / stricture) across five ileocolonic segments. Each endoscopic component is scored from 0 to 3 for each segment, giving a maximum total score of 15 for each component, except for the stenosis component, which by definition can only obtain a maximum total score of 11 because the presence of an impassable stenosis can only be observed once. In summary, the total SES-CD score is derived from the sum of all component scores and can range from 0 to 56. Endoscopic healing, conventionally defined as the resolution (absence) of mucosal ulcers in response to therapeutic intervention, is also assessed.

[0309] Histological assessments will be performed using biopsy samples collected during ileocolonoscopy. Biopsy samples will be collected at screening, weeks 12, 48, 96, 144, 192, and 240 from each of three predefined anatomical locations, i.e., terminal ileum, splenic flexure, and rectum. Optional substudies, including the week 4 assessment, will be performed in addition to the specified assessments above for consenting participants. Biopsy samples collected after baseline will be obtained proximal to where the screening biopsy samples were collected from each of the three specified locations. Histological assessments will be performed by a central observer blinded to treatment group and visit. Histological improvement and healing will be assessed using the Global Histology Activity Score (GHAS). Five analyses will be specified in the SAP.

[0310] Fistula assessments will be performed continuously in all participants throughout the study. All participants will be evaluated for fistulas at baseline. Participants with fistula disease will be evaluated for fistula closure during the study. Enterocutaneous fistulas (e.g., perianal and abdominal) will be considered no longer draining (i.e., closed) when there is no drainage despite gentle pressure. Rectovaginal fistulas will be considered closed based on either physical exam or the absence of associated symptoms (e.g., passage of rectal contents, vaginal flatus, etc.).

[0311] Patient-reported outcome measures will be assessed at the visits as indicated in the Schedule of Activities (Section 1.3). The IBDQ is a 32-item self-report questionnaire for subjects with IBD that assesses PROs across four scales: bowel symptoms (loose stools, abdominal pain), systemic symptoms (fatigue, changes in sleep patterns), social functioning (attending work, need to cancel social events), and emotional functioning (anger, depression, irritability). 11 scores range from 32 to 224, with higher scores indicating better outcome. PROMIS-29 is a validated general health profile instrument that is not disease-specific. It is a collection of short forms that include four items for each of seven domains (depression, anxiety, physical functioning, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities). PROMIS-29 also includes an overall mean pain intensity 0-10 numeric rating scale (NRS). The PROMIS Fatigue 7-item Short Form (PROMIS Fatigue Short Form 7a) contains 7 items assessing fatigue-related symptoms (i.e., fatigue, exhaustion, mental fatigue, and lack of energy) and associated impacts on daily activities (i.e., activity limitations related to work, self-care, and exercise). The PROMIS Fatigue Short Form 7a has a recall period of the past 7 days. Compared to the PROMIS-29 fatigue scale, the PROMIS Fatigue Short Form 7a provides additional information to assess fatigue severity. ·EQ-5D-5L is a validated instrument consisting of the EuroQol five dimensions descriptive system (EQ-5D) and the EuroQol visual analog scale (EQ-VAS). The descriptive system includes five dimensions (degree of mobility, self-care, usual activities, pain / discomfort, anxiety / depression). Each dimension has five levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Respondents are asked to indicate their health status by checking the most appropriate statement in each of the five dimensions. The EQ-VAS records the respondent's self-rated health status on a 20 cm vertical visual analog scale with endpoints labeled "best health you can imagine" and "worst health you can imagine". Respondents mark an "X" on the scale to indicate their health status for that day and then write the number marked on the scale within a box. · The WPAI-CD is a validated instrument designed as a patient-reported quantitative assessment of the amount of absenteeism, presenteeism, and interference with daily activities attributable to Crohn's disease. It consists of six questions to determine employment status, time absent from work due to Crohn's disease, time absent from work for other reasons, hours worked, the extent to which Crohn's disease has affected work productivity while at work, and the extent to which Crohn's disease has affected activities outside of work. Four scores are derived: percentage of absenteeism, percentage of sickness attendance (reduced productivity while at work), overall work impairment combining absenteeism and sickness attendance, and percentage of impairment for activities performed outside of work. The higher the score, the greater the impairment.

[0312] Exploratory patient-reported symptom measures will be assessed at visits as indicated in the activity schedule. The BSFS is a medical aid to classify human stool morphology (or consistency) into seven categories. 14 It has been used as a research tool to evaluate the effectiveness of treatments for various intestinal disorders (e.g., irritable bowel syndrome [IBS]). Participants complete the BSFS as daily diary entries from weeks 0 to 48. The AP-NRS is an 11-point (0-10) scale used to rate abdominal pain. A score of 0 represents "no abdominal pain" and a score of 10 represents "the worst abdominal pain possible," with higher scores indicating greater severity and intensity of pain. Participants complete the AP-NRS as a daily diary entry from weeks 0 to 48, selecting only the one number that best reflects their worst pain. · PGIS for Crohn's Disease: Participants rate the activity of their Crohn's disease at baseline and each visit using a 5-point scale (none, mild, moderate, severe, and very severe). The PGIS is used as an anchor to establish and / or validate response criteria for other clinical endpoints. · PGIC for Crohn's Disease Severity: Participants' perceived change (improvement or worsening) in the severity of their Crohn's disease will be assessed using the PGIC. Participants rate how their Crohn's disease has changed since the start of the study using a 7-point scale ranging from "now very good" to "now very bad," including a neutral midpoint ("neither better nor worse"). The PGIC will be used as an anchor to establish and / or validate response criteria for other clinical endpoints.

[0313] Safety assessment Adverse events will be reported and followed up by the investigator. Any clinically relevant changes occurring during the study must be recorded in the adverse events section of the eCRF. Any clinically significant abnormalities persisting at the end of the study / early withdrawal will be followed up by the Investigator until resolution or until a clinically stable endpoint is reached.

[0314] The study included the following assessments of safety and tolerability at specified time points:

[0315] electro-cardiogram A 12-lead electrocardiogram (ECG) will be performed at screening.

[0316] During ECG collection, subjects should be in a quiet environment free of distractions (e.g., television, cell phone). Subjects should be in supine position and resting for at least 5 minutes prior to ECG collection and should refrain from talking or moving their arms or legs. If blood sampling or vital signs measurements are scheduled at the same time as ECG recording, procedures should be performed in the following order: ECG, vital signs, blood draw.

[0317] Physical Examination Physical examinations will be conducted as specified in the Activity Schedule. Participant evaluations for safety and efficacy will require some physical examination by the investigator at all visits, however, more complete detailed physical examinations will be conducted at designated visits.

[0318] Height and weight Height and weight will be measured as specified in the activity schedule. Subjects will be instructed to remove shoes and outdoor clothing and equipment prior to these measurements.

[0319] Vital signs Vital signs (including temperature, pulse / heart rate, respiratory rate, and blood pressure) will be obtained prior to and approximately every 30 minutes during all IV infusions, and at approximately 30 minute intervals after completion of the final IV infusion. Vital signs should be obtained prior to and approximately 30 minutes after the final SC injection.

[0320] infectious disease Intervention administration should not be given to participants with clinically significant active infection. Investigators will be asked to assess participants for any signs or symptoms of infection at scheduled visits (see section 1.3 of the Schedule of Activities). Discontinuation of study treatment (i.e., no further administration of the study intervention) must be considered if a participant develops a severe infection, including, but not limited to, sepsis or pneumonia.

[0321] Tuberculosis evaluation Early Tuberculosis Assessment Participants must be tested for TB, and their medical history assessment must include specific questions regarding history of TB or known occupational or other personal exposure to individuals with active TB. Participants should be asked questions regarding past testing for TB, including chest x-ray results and response to tuberculin skin or other TB tests. Investigators have the option to use both the QuantiFERON-TB Gold test and the tuberculin skin test to screen for latent TB if, based on their judgment, they believe that using both tests is clinically indicated to evaluate participants at high risk for having latent TB. If either the QuantiFERON-TB Gold test or the tuberculin skin test is positive, the participant will be considered to have latent TB infection for purposes of eligibility for this study.

[0322] Participants with a negative QuantiFERON-TB Gold test result (and a negative tuberculin skin test result in countries where the QuantiFERON-TB Gold test is not approved / registered or where the tuberculin skin test is mandated by the local health authority) are eligible to continue with the pre-randomization procedure. Participants with a newly identified positive QuantiFERON-TB Gold (or tuberculin skin) test result must be evaluated to rule out active TB and begin appropriate treatment for latent TB. Appropriate treatment for latent TB is defined according to local national guidelines for immunocompromised patients. In the absence of local national guidelines for immunocompromised patients, US guidelines must be followed or the participant will be excluded from the study.

[0323] Participants with an equivocal first QuantiFERON-TB Gold test result should repeat the study. If the second QuantiFERON-TB Gold test result is also equivocal, participants may be enrolled without treatment for latent TB if latent TB has been ruled out, their chest radiographs show no abnormalities suggestive of TB (active or old inactive TB), and the participant has no further risk factors for TB as determined by the investigator. This determination must be promptly reported to the sponsor or designee medical monitor, recorded on the participant's source documentation, and abbreviated initialed by the investigator.

[0324] Tuberculosis evaluation Early detection of active tuberculosis To aid in the early detection of TB reactivity or new TB infections during study participation, participants must be assessed for signs and symptoms of active TB at scheduled visits or by telephone contact approximately every 8-12 weeks. The following set of questions is suggested for use during the assessment: "Have you had a new cough or a change in your chronic cough in the last 14 days?" Do you have any of the following symptoms? -Continuous fever -Unintentional weight loss - Night sweats · "Have you been in close contact with an individual with active TB?" (If there is uncertainty as to whether a contact should be considered "close", a TB specialist should be consulted).

[0325] If the evaluation raises suspicion that a participant may have TB reactivation or new TB infection, immediate and thorough investigation should occur, including consultation with a TB specialist, if possible. Investigators should be aware that TB reactivation in immunocompromised participants may present as disseminated disease or with extrapulmonary features. Participants with evidence of active TB should be referred for appropriate treatment. Participants who have had close contact with individuals with active TB during the conduct of the study should undergo repeat chest x-rays, repeat QuantiFERON TB Gold tests, repeat tuberculin skin tests in countries where the QuantiFERON-TB Gold test is not approved / registered or where tuberculin skin testing is mandated by the local health authority, and referral to a TB specialist, if possible, to determine the participant's risk of developing active TB and whether treatment of latent TB is warranted.

[0326] Intervention administration should be suspended during the study. A positive result of the QuantiFERON-TB Gold test or tuberculin skin test should be considered as detection of latent TB. If the QuantiFERON-TB Gold test result is indeterminate, the test should be repeated as outlined in Section 5.10.5. Participants should be encouraged to return for all subsequent scheduled study visits according to the protocol. Subjects who prematurely discontinue latent TB or are non-compliant with therapy should be encouraged to immediately discontinue further administration of the study intervention and return for all subsequent scheduled study visits according to the Activity Schedule (Section 1.3).

[0327] Allergic reactions Prior to any SC or IV infusion, appropriately trained personnel and medications must be available to treat allergic reactions, including anaphylaxis. All participants must be closely observed for symptoms of allergic reactions (e.g., hives, pruritus, skin rash). If mild or moderate allergic reactions are observed, acetaminophen, nonsteroidal anti-inflammatory drugs, and / or diphenhydramine may be administered.

[0328] In the event of a severe allergic reaction (e.g., anaphylaxis), SC aqueous epinephrine, corticosteroids, respiratory support, and other appropriate resuscitation measures are essential and must be available at the study site where the injection or infusion is administered.

[0329] Participants who experience a serious adverse reaction related to the injection or infusion should be discontinued from further intervention.

[0330] Participants who experience a reaction after injection or infusion that results in bronchospasm with wheezing and / or dyspnea requiring ventilatory support, or symptomatic hypotension with a fall in systolic blood pressure of more than 40 mm Hg, will not be allowed to receive additional study interventions.

[0331] Participants who experience a reaction suggestive of a serum sickness-like reaction (resulting in symptoms such as myalgia and / or joint pain accompanied by fever and / or rash without signs and symptoms of other recognized clinical syndromes) occurring 1-14 days after infusion of the study intervention should discontinue further study intervention administration. Note that these symptoms may be accompanied by other events including pruritus, swelling of the face, hands, or lips, dysphagia, urticaria, pharyngitis, and / or headache.

[0332] Adverse events related to infusion in time Any AEs (excluding laboratory abnormalities) occurring during or within 1 hour after the IV infusion of the study intervention will be carefully evaluated. Minor AEs related to the infusion may be managed by reducing the rate of IV infusion and / or treating with antihistamines and / or acetaminophen (paracetamol) as clinically indicated. If IV infusion of an intervention is interrupted because of an AE that is not severe or results in a serious adverse event (SAE) in the investigator's opinion, the infusion may be resumed with caution.

[0333] Injection site reactions Injection site reactions are any adverse reactions at the site of SC intervention injection. The injection site will be evaluated for reactions and any injection site reaction will be recorded as an AE.

[0334] Columbia-Suicide Severity Rating Scale (C-SSRS) The C-SSRS defines five subtypes of suicidal ideation and four possible suicidal behaviors, as well as non-suicidal self-injury behaviors and completed suicide. It will be used as a screening tool to prospectively assess suicidal ideation and behaviors in the study as part of a comprehensive safety evaluation. The C-SSRS is an investigator-administered questionnaire. Two versions will be used in the study, the "Baseline / Screening" version of the C-SSRS will be administered during the screening visit and the "Since Last Visit" version of the C-SSRS will be completed at all other visits until the end of the study.

[0335] Investigators or trained study site personnel will interview participants to complete the C-SSRS, which will be delivered in the local language according to local guidelines.

[0336] At screening, the C-SSRS is the first assessment performed before any other study procedures. At all subsequent visits, the C-SSRS will be administered according to the assessment schedule, which should be administered after other PROs but before any other study procedures. Participants will be interviewed by the investigator or trained study site personnel in a private, quiet location.

[0337] At the end of each assessment, trained personnel administering the C-SSRS will determine the level, if any, of suicidal ideation or behavior and will then determine the next course of action if any level of suicidal ideation or behavior is reported. Participants should not be released from the site until the C-SSRS has been reviewed by study personnel, who have assessed the participant's risk and determined follow-up, if necessary.

[0338] Participants with C-SSRS scores of suicidal ideation with intent to carry it out ("ideation level 4"), suicidal ideation with specific plans and intentions ("ideation level 5"), or suicidal behavior (actual suicide attempt, aborted suicide attempt, unsuccessful suicide attempt, or preparatory behavior to make a suicide attempt) at screening (within the last 6 months) and week 0 must be determined by the investigator to be not at risk based on assessment by a mental health professional (e.g. a psychiatrist, psychologist, or appropriately trained social worker or nurse) in order to be randomized.

[0339] Participants with C-SSRS scores of wishing for death ("ideation level 1"), nonspecific active suicidal thoughts ("ideation level 2"), no intention to carry out, active suicidal ideation by any method (no plan) ("ideation level 3"), or nonsuicidal self-harm behaviors must be determined by the investigator to be not at risk in order to be randomized. Any questions regarding the eligibility of such participants should be discussed with the medical monitor or designee.

[0340] For each evaluation after Week 0, the following actions should be taken, if applicable: No suicidal thoughts or behavior (including self-harming behavior without suicidal intent): No further action is required. Suicidal ideation levels 1-3 or non-suicidal self-harm behaviors: Participants' risk will be assessed by the investigator. · Suicidal ideation level 4 or 5 or any suicidal behavior: The participant's risk will be assessed and referred to a mental health professional.

[0341] Interruption or discontinuation of study treatment should be considered for any participant who reports suicidal ideation with intent to act (ideation level 4), suicidal ideation with specific plan and intent (ideation level 5), or suicidal behavior (actual suicide attempt, aborted suicide attempt, unsuccessful suicide attempt, or preparatory behavior to make a suicide attempt) on a post-baseline C-SSRS assessment and who is deemed at risk by the investigator based on evaluation by a mental health professional. If the participant can be appropriately treated with psychiatric and / or pharmacotherapy, the participant may, at the investigator's discretion, continue treatment if consent is obtained from the medical monitor or designee. Discussion of the participant with the medical monitor or designee is required.

[0342] Any C-SSRS finding that, in the opinion of the investigator, is considered to be new or worsening and clinically significant should be reported on the AE eCRF (Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting).

[0343] Clinical Safety Laboratory Evaluation Blood samples for serum chemistry and hematology will be collected. The investigator must review the laboratory results, document this review, and record any clinically relevant changes that occurred during the study in the AE section of the eCRF. Laboratory reports must be submitted with the source documentation.

[0344] The following tests will be performed by the Central Laboratory unless otherwise specified or approved by the Medical Monitor. Hematological evaluations include, but are not limited to: hemoglobin, hematocrit, platelet count, WBC total count, and WBC differential. ·Blood chemistry evaluation will include, but is not limited to, the following: chemistry panel (total and direct bilirubin, ALT, AST, alkaline phosphatase, albumin, total protein, calcium, phosphate, sodium, potassium, chloride, serum urea nitrogen / urea, and creatinine).

[0345] If pre-specified abnormal laboratory values, as defined in the laboratory manual, are identified in any participant during the conduct of the study, the medical monitor or representative and the clinical site will be notified. Serology: HIV antibodies, HBV antibodies and surface antigens, and HCV antibodies Liver function test abnormalities: If laboratory testing for subjects enrolled in the study and receiving the study intervention reveals elevations of serum aminotransferases (ALT or AST) to greater than 3 x ULN and bilirubin to greater than 2 x ULN, study drug should be immediately discontinued. In addition, laboratory tests for ALT, AST, alkaline phosphatase, and total bilirubin should be confirmed by repeat testing within 24 hours, if possible, but no later than 72 hours after notification of study results. Pregnancy testing: Female participants of childbearing potential will undergo a urine pregnancy test at screening prior to each study intervention, at the SID visit, and at the FES visit.

[0346] Immunogenicity assessment (antibodies to guselkumab and ustekinumab) Serum samples will be screened for antibodies that bind guselkumab or ustekinumab, and titers of confirmed positive samples will be reported accordingly. Other analyses may be performed to further characterize the immunogenicity of guselkumab or ustekinumab. Antibodies to guselkumab or ustekinumab will be assessed on blood drawn from all participants. Additionally, samples should also be collected at the final visit for participants who discontinue from the study. These samples will be tested by the sponsor or the sponsor's designee. No genetic analysis will be performed on these serum samples. Participant confidentiality will be maintained.

[0347] evaluation At visits where antibodies to the study intervention are assessed in addition to serum concentrations of the study intervention, one venous blood sample of sufficient volume should be collected. Each serum sample should be split into three aliquots (one each for serum concentration of the study intervention, antibodies to the study intervention, and a backup).

[0348] Analytical procedures Detection and characterization of antibodies to guselkumab and ustekinumab will be performed by or under the sponsor's supervision using validated assays.

[0349] Medication history survey Concomitant medications will be reviewed at each visit.

[0350] Adverse events and serious adverse events Timely, accurate, and complete reporting and analysis of safety information from clinical trials is essential to the protection of participants, investigators, and sponsors, and is mandated by regulatory authorities worldwide. Sponsors have established Standard Operating Procedures in compliance with global regulatory requirements to ensure proper reporting of safety information, and all clinical trials conducted by the Sponsor or its affiliates will be conducted in accordance with these procedures.

[0351] Adverse events will be reported by the participant (or, where appropriate, the caregiver, proxy, or legally authorized representative of the participant) for the duration of the study.

[0352] Anticipated events are recorded and reported.

[0353] Period and frequency of collecting adverse event and serious adverse event information All adverse events All AEs and special reporting circumstances, whether serious or non-serious, will be reported from the time the signed and dated ICF is obtained until the completion of the participant's last study-related procedure, which may include safety follow-up contact. Serious adverse events, including those spontaneously reported to the investigator within 16 weeks after the last dose of study intervention, must be reported using the Serious Adverse Event Form. The sponsor will evaluate all safety information spontaneously reported by investigators beyond the protocol-specified timeframes.

[0354] Serious Adverse Events All serious adverse events occurring during the study must be reported by study site personnel to the appropriate sponsor or designated contact within 24 hours of becoming aware of the event.

[0355] Information regarding SAEs will be sent to the sponsor or designee using the Serious Adverse Event form, which must be completed and reviewed by a study site physician and sent to the sponsor or designee within 24 hours.

[0356] Follow-up of adverse events and serious adverse events Adverse events, including pregnancy, will be followed up by the investigator.

[0357] Regulatory reporting requirements for serious adverse events The sponsor is responsible for appropriate reporting of AEs to regulatory authorities. The sponsor will also report all SUSARs to the investigator (and the site director, if appropriate). The investigator (or sponsor, if appropriate) must report SUSARs to the IEC / IRB unless otherwise required and documented by the appropriate IEC / IRB that approved the protocol. SUSARs will be reported to regulatory authorities in an unblinded manner. Unless otherwise specified, participating investigators and the IEC / IRB will receive a blinded summary of SUSARs.

[0358] pregnancy All early reports of pregnancy in a female participant or the partner of a male participant must be reported to the sponsor or designee within 24 hours of knowledge of the event by study site personnel using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and must be reported using a serious adverse event form. Any participant who becomes pregnant during the study must discontinue further interventions.

[0359] Follow-up information on the outcome of the pregnancy and any postnatal outcomes for the infant is needed.

[0360] Particularly interesting events All newly identified cases of malignancy or active TB occurring after the first intervention in participants enrolled in this clinical study must be reported by the investigator. Investigators are also advised that in the majority of countries, active TB is considered a reportable disease. These events should only be considered serious if they meet the definition of an SAE.

[0361] Treatment of overdosage In this study, any administration of an intervention higher than the highest administration at a single-dose visit specified in this protocol will be considered an overdose. The sponsor does not recommend a specific intervention for overdose.

[0362] In the event of an overdose, the investigator or treating physician should: Contact the medical monitor immediately. Closely monitor participants for AEs / SAEs and laboratory abnormalities. · Document the amount of overdose on the eCRF.

[0363] Decisions regarding interruption or modification of dosing will be made by the Investigator in consultation with the Medical Monitor, based on the participant's clinical evaluation.

[0364] Pharmacokinetics The PK of guselkumab and ustekinumab will be evaluated using serum samples. Samples collected for serum concentration analysis of guselkumab and ustekinumab may be further used to evaluate safety or efficacy aspects to address concerns that may arise during or after the study, or for evaluation of relevant biomarkers. No genetic analysis will be performed on these serum samples. Participant confidentiality will be maintained.

[0365] evaluation At visits assessing only serum concentrations of the study intervention (i.e., not assessing antibodies to the study intervention), one venous blood sample of sufficient volume should be collected and each serum sample should be split into two aliquots (one each for serum concentration of the study intervention, and a backup). At visits assessing serum concentrations of the study intervention and antibodies to the study intervention, one venous blood sample of sufficient volume should be collected. Each serum sample should be split into three aliquots (one each for serum concentration of the study intervention, antibodies to the study intervention, and a backup).

[0366] Analytical procedures Serum samples will be analyzed to determine guselkumab and ustekinumab concentrations using respective validated, specific and sensitive methods by, or under the supervision of, the sponsor's respective assays.

[0367] Pharmacokinetic parameters Serum samples will be used to evaluate various guselkumab PK parameters based on blood drawn from all participants according to the activity schedule.

[0368] Pharmacodynamics Inflammatory PD markers will be assessed using blood samples collected at the visits. Post-baseline PD test results will not be released to investigators by central testing. CRP has been shown to be useful as a marker of inflammation in IBD patients. In Crohn's disease, high CRP concentrations are associated with severe clinical activity, high sedimentation rates, and active disease detected by colonoscopy. Blood samples for measurement of CRP will be collected from all participants. CRP will be assessed using a validated, highly sensitive assay. Fecal calprotectin has been shown to be a sensitive and specific marker in identifying intestinal inflammation and response to treatment in IBD patients. Three stool samples for fecal calprotectin concentration will be collected from all participants. Assays for fecal calprotectin concentration will be performed using validated methods. Additional testing can also be performed on fecal samples for additional markers related to intestinal inflammation and treatment response, such as the microbiome.

[0369] Genetics Pharmacogenetic blood samples will be collected from participants who consent separately to this component of the study to enable pharmacogenetic research, if required and where local regulations permit. Participation in pharmacogenetic research is voluntary.

[0370] Genetic (DNA) variation can be an important contributor to inter-individual variability in drug response and associated clinical outcomes. Genetic factors can also serve as markers for disease susceptibility and prognosis, and can identify subgroups of the population that respond differently to interventions.

[0371] The DNA sample is analyzed to identify genetic factors that may be associated with clinical response. This investigation may consist of analysis of one or more candidate genes for guselkumab or ustekinumab intervention and / or Crohn's disease, evaluation of Single Nucleic Polymorphisms (SNPs), or analysis of the entire genome (if appropriate). For genetic analysis, a whole blood sample of approximately 10 mL is collected.

[0372] Phase 2 dosing study (GALAXI1) The first hypothesis is that guselkumab will be superior to placebo as assessed by reduction from baseline in the CDAI at week 12.

[0373] Phase 3 treatment confirmation study (GALAXI2 and GALAXI3) The first hypothesis is that guselkumab treatment will be superior to placebo, as assessed by the proportion of participants achieving clinical remission at week 12.

[0374] Regarding the second key hypothesis of the comparison with ustekinumab, although the ultimate objective is to demonstrate that the efficacy of guselkumab is superior to ustekinumab, an initial study of non-inferiority is included because the overall profile of guselkumab may be favorable compared to ustekinumab (in terms of overall efficacy and safety) even if the final results only show that the relative efficacy is non-inferior to ustekinumab.

[0375] Sample size determination Assumptions Data from several sources inform the underlying assumptions for sample size determination in Phase 2 and Phase 3, as summarized in the following sections. These include data from the ustekinumab Crohn's disease Phase 3 program, consisting of three studies (i.e., CNTO1275CRD3001, CNTO1275CRD3002, and CNTO1275CRD3003), a program conducted by a clinical trial sponsor in participants with Crohn's disease who were previously non-responding to or intolerant of TNF antagonist therapy (referred to herein as TNF non-responding) or previously non-responding to or intolerant of conventional therapy (referred to herein as CON non-responding), and from the risankizumab Crohn's disease Phase 2 trial, in which the majority of participants were previously non-responding to or intolerant of biologic therapy (referred to herein as BIO non-responding).

[0376] Clinical remission at 12 weeks Assumptions for the BIO non-responder population at week 12 were based on the following: In CNTO1275CRD3001, the proportion of participants in clinical remission (CDAI<150) at week 8 was 7.3% and 20.9% for placebo and ustekinumab 6 mg / kg, respectively, with a treatment difference of 13.6%. Based on a 15% clinical remission rate with placebo at week 12, phase 2 trials of risankizumab suggested an approximately 9% difference in clinical remission between 200 mg IV and placebo, and an approximately 21% difference between 600 mg IV and placebo at week 12.7.

[0377] Based on these data, clinical remission rates are assumed to be 10% for placebo, 20% for guselkumab 200 mg IV, and 30% for guselkumab 600 mg IV at week 12 in the BIO non-responder population.

[0378] Assumptions for the CON non-responder population at week 12 were based on the following: In CNTO1275CRD3002, the proportion of participants in clinical remission at week 8 was 19.6% and 40.2% for placebo and ustekinumab 6 mg / kg, respectively, with a treatment difference of 20.6%. · No data are currently available for guselkumab or other anti-IL-23 agents in the CON non-responder population. Based on data from CNTO1275CRD3002 and previous biologic studies in similar populations, it is reasonable to assume that the difference in treatment effect between active and placebo in the CON non-responder population will be greater compared to that observed in the BIO non-responder population. In addition, dose-response trends in the CON non-responder population are assumed to be similar to those observed in the BIO non-responder population.

[0379] Based on these data and assumptions, clinical remission rates are assumed to be 20% for placebo, 40% for guselkumab 200 mg IV, and 50% for guselkumab 600 mg IV in the CON non-responder population.

[0380] In the absence of data from guselkumab or other anti-IL-23 agents at 1200 mg IV, it is conservatively assumed that clinical remission rates with guselkumab 1200 mg IV are similar to the minimum clinical remission rates of guselkumab 600 mg IV for both the BIO non-responder and CON non-responder populations.

[0381] Taking into account the mixed BIO non-responder / CON non-responder population, assumptions for the entire randomized population at 12 weeks were based on the following: Based on the ratio of minimum 25% and maximum 50% of participants in the CON non-responder population, the percentage of participants in clinical remission at week 12 is expected to be approximately 12%-15% for placebo, approximately 25%-30% for guselkumab 200 mg IV, and approximately 35%-40% for both guselkumab 600 mg IV and guselkumab 1200 mg IV.

[0382] Change in CDAI at 12 weeks Assumptions for the BIO and CON non-responder populations were based on the following: In CNTO1275CRD3001, the mean change from baseline in CDAI at week 8 was -25.1 (SD=91.41) and -78.7 (SD=91.79) for the placebo and ustekinumab 6 mg / kg groups, respectively. In CNTO1275CRD3002, the mean change from baseline in CDAI at week 8 was -66.3 (SD=97.81) and -116.3 (SD=102.88) for placebo and ustekinumab 6 mg / kg groups, respectively.

[0383] Considering the mixed BIO non-responder / CON non-responder population, the mean CDAI reduction from baseline at week 12 is expected to be approximately 45-50 for placebo, approximately 85-95 for guselkumab 200 mg IV, and approximately 105-115 for guselkumab 600 mg IV and guselkumab 1200 mg IV at week 12, with a typical SD of 100 (accounting for the increased variability of relatively small phase 2 trials).

[0384] Clinical remission at 48 weeks The rate of clinical remission at week 48 obtained by combining randomized and non-randomized populations in CNTO1275CRD3003 results in a clinical remission rate of 23% in TNF non-responders and 50% in CON non-responders for ustekinumab. Thus, the full randomized population with a minimum of 25% and a maximum of 50% participants from the CON non-responder population is expected to achieve approximately 30%-36% clinical remission at week 48 for ustekinumab. A significant difference of 15% in clinical remission between guselkumab and ustekinumab is anticipated at week 48.

[0385] Power and sample size calculations Phase 2 dosing study (GALAXI1) Power for Phase 2 was assessed for the two analysis populations described below using a 2-sample t-test (at the 0.05 level of significance) to detect significant differences in change from baseline in CDAI scores at Week 12 between guselkumab high IV induction dose and placebo.

[0386] We expect the mean CDAI reduction from baseline at week 12 in the guselkumab high IV induction group to be approximately 105-115, compared with approximately 45-50 in the placebo group with a common SD of 100.

[0387] For the initial dose determination cohort: 50 participants in the guselkumab high IV induction dose group and 50 participants in the placebo group will provide >80% power to detect a treatment difference between guselkumab and placebo with a type 1 error rate controlled at α=0.05 (2-sided) (Table 8). With 5 dose groups, the total sample size for the initial dose determination cohort is 250 subjects.

[0388] For the total Phase 2 population: By the time dosing decisions are made for Phase 3, 100-250 participants are expected to be enrolled in the transition cohort. Thus, the total Phase 2 study sample size is expected to range from a maximum of 350 participants (70 per dose arm) to a maximum of 500 participants (100 per dose arm). Power based on the minimum number of participants is greater than 90% for change from baseline in CDAI score at week 12 and greater than 85% for clinical remission at week 12 (Table 8).

[0389] Safety analysis Adverse events The reporter verbatim terms used to identify the AE in the eCRF by the investigator will be coded using the Medical Dictionary for Regulatory Activities. Treatment-emergent AEs are those that begin during the intervention period or are the result of a pre-existing condition that worsens from baseline. All reported treatment-emergent AEs will be included in the analysis. For each AE, the proportion of subjects experiencing at least one occurrence of the specific event will be summarized by intervention group.

[0390] The following analyses of AEs will be used to assess participant safety: · Frequency and type of AEs. · Frequency and type of SAE. The frequency and type of reasonably relevant AEs as assessed by the investigator. -The frequency and type of AEs leading to discontinuation of the intervention. · Frequency and type of infection. -The frequency and type of AEs temporally associated with the infusion. -The frequency and type of injection site reactions.

[0391] Summaries, lists, data sets, or participant narratives of participants who died, discontinued the intervention due to an AE, or experienced a serious AE may be provided, as appropriate.

[0392] Lab Test The following outline of clinical laboratory tests will be used to assess participant safety. ·Laboratory parameters and changes from baseline in laboratory parameters (haematological and chemical). Summary of maximum NCI-CTCAE toxicity grades for post-baseline laboratory values ​​(hematology and chemistry).

[0393] A list of participants with any abnormal post-baseline laboratory values ​​of NCI-CTCAE grade 2 or greater will also be provided.

[0394] Suicidal thoughts and behavior Suicidal thoughts and behaviors based on the C-SSRS and AEs will be summarized narratively.

[0395] Further analysis Pharmacokinetic analysis Descriptive statistics will be calculated for serum guselkumab and ustekinumab concentrations at each sampling time point. These concentrations will be summarized over time by treatment group.

[0396] All concentrations below the lowest quantifiable concentration or missing data will be labeled as such in the concentration database or data presentation. Concentrations below the lowest quantifiable concentration will be treated as zero in summary statistics.

[0397] A population PK analysis approach using nonlinear mixed-effects modeling will be used to evaluate the PK parameters of guselkumab. The effects of important covariates on the population PK parameter estimates will be evaluated. Details will be provided in the population PK analysis plan, and the results of the population PK analysis will be presented in a separate technical report.

[0398] Participants will be excluded from the PK analysis if their data do not allow for an accurate assessment of PK (e.g., incomplete dosing of the intervention; missed time to intervention administration). Detailed rules for the analysis will be specified in the SAP.

[0399] Immunogenicity analysis The incidence and titers of antibodies to guselkumab and ustekinumab will be summarized for all participants who received guselkumab or ustekinumab and had a sample adequate for detection of antibodies to guselkumab or ustekinumab, respectively (i.e., participants with at least one sample obtained after the first dose of guselkumab or ustekinumab).

[0400] A list of participants testing positive for antibodies to guselkumab or ustekinumab will be provided. The maximum titers of antibodies to guselkumab or ustekinumab will be provided for participants testing positive for antibodies to guselkumab or ustekinumab.

[0401] The incidence of neutralizing antibodies (NAb) to guselkumab or ustekinumab will be summarized for participants who tested positive for antibodies to guselkumab or ustekinumab and had samples evaluable for NAb to guselkumab or ustekinumab.

[0402] Biomarker Analysis Planned biomarker analyses may be postponed if the new study data show no potential to provide useful scientific information. Any biomarker samples received by the contract supplier or sponsor after the cut-off date will not be analyzed and therefore will be excluded from the biomarker analyses.

[0403] Changes in serum protein samples and whole blood RNA obtained over time will be summarized by treatment group. Associations between baseline values ​​and changes from baseline in selected markers and response to treatment will be explored. RNA analyses will be summarized in a separate technical report.

[0404] Biomarker analysis will characterize the impact of guselkumab to identify treatment-associated biomarkers and determine whether these biomarkers can predict response to guselkumab. Results of serum, whole blood, fecal, and mucosal biopsy analyses will be reported in separate technical reports.

[0405] Pharmacokinetic / pharmacodynamic analysis The relationship between serum guselkumab concentrations and efficacy measures will be analyzed graphically. If any visual trends are observed, suitable population PK / PD models can be developed to explain the ER relationships. Details will be provided in the population PK / PD analysis plan and the results of the population PK / PD analysis will be presented in a separate technical report.

[0406] Healthcare resource utilization and health economics analysis Health resource utilization, including labor productivity, and health economics will be summarized by treatment group.

[0407] Example 2 - Results of the Phase 2 GALAXI1 Study at Week 12 result 250 patients were included in the primary analysis population. Approximately 50% were biologic therapy failures and approximately 50% were conventional therapy failures. Baseline demographic and disease characteristics were generally similar between treatment groups (mean age, 39.4 years; mean weight, 70.0 kg; mean CD time, 8.8 years; mean CDAI, 306.6; median PRO-2, 141.0; median SES-CD, 11.0).

[0408] Significantly greater reductions from baseline in CDAI were observed for the GUS 200, 600, and 1200 mg IV groups vs. placebo at week 12 (LS mean: -154.1, -144.3, -149.5 vs. -36.0, respectively), with a higher percentage of patients with GUS achieving clinical remission (CDAI<150) at 54.0%, 56.0%, 50.0%, vs. 15.7%, respectively (Table 1). Similarly, a higher percentage of GUS-treated patients achieved clinical response, PRO-2 remission, clinical biomarker response, and endoscopic response at week 12 vs. placebo-treated patients. Among biononresponders, 45.5% (35 / 77) treated with GUS and 12.5% ​​(3 / 24) treated with placebo achieved clinical remission at week 12. Among conventional therapy non-responders, 61.6% (45 / 73) treated with GUS and 18.5% (5 / 27) treated with placebo achieved clinical remission at 12 weeks.

[0409] At week 12, the overall discontinuation rate was low (3.6%) and safety event rates were generally balanced across treatment groups. There were similar rates of patient-reported AEs (40.0%, 52.0%, 46.0%, and 56.9%), serious AEs (4.0%, 4.0%, 2.0%, and 3.9%), infections (10.0%, 14.0%, 14.0%, and 17.6%), and serious infections (2.0%, 0%, 0%, and 0%) in the GUS 200, 600, 1200 mg IV, and placebo treatment groups, respectively. No cases of active TB, serious hypersensitivity reactions, or malignancies were reported at week 12.

[0410] Biomarkers Non-invasive inflammatory markers, specifically C-reactive protein (CRP) and fecal calprotectin (FeCal), are useful tools for the clinical management of patients with Crohn's disease, and these concentrations were measured among Galaxi patients. For the placebo and GUS combination groups, the median baseline (BL) CRP concentrations were 4.18 (n=51) and 5.81 mg / L (n=150), respectively, and the median BL FeCal was 433.50 (n=50) and 626.50 μg / g (n=146), respectively. Through week 12, patients treated with GUS had a greater reduction in CRP and FeCal concentrations compared to placebo. The median change from BL in CRP (mg / L) was -2.17 in the combined GUS group versus 0.00 for placebo at week 12. The median change in BL in FeCal (μg / g) was -176.00 in the combined GUS group versus 20.00 in the placebo group at week 12. At week 12, the proportion of patients with normalized CRP (≦3 mg / L) among patients with abnormal CRP in BL was 35.4% versus 19.4% for the combined GUS group versus placebo, respectively. The proportion of patients with normalized FeCal (≦250 μg / g) among patients with abnormal FeCal (>250 μg / g) in BL was 33.3% versus 27.3% for the combined GUS group versus placebo, respectively (Table 9).

[0411] Clinical biomarker responses were achieved in a higher proportion of patients treated with GUS compared with placebo (48.0% (72 / 150) vs. 7.8% (4 / 51), respectively) at week 12. Similar results were achieved between the BIO non-responder cohort (46.1% [35 / 76] vs. 8.7% [2 / 23]) and CON non-responder cohorts (50.0% [37 / 74] vs. 7.1% [2 / 28]) at week 12.

[0412] Patients with moderately to severely active CD treated with GUS IV induction therapy had greater reductions in CRP and FeCal concentrations at week 12 compared to those receiving placebo. A higher percentage of patients treated with GUS achieved clinical biomarker responses and normalized CRP or FeCal at week 12 compared to placebo. These patterns of improvement were also observed in a subanalysis of patients who were biologic or conventional therapy nonresponders.

[0413] conclusion All three GUS doses (200, 600, and 1200 mg IV) consistently induced significantly greater improvements versus placebo in prespecified clinical and endoscopic efficacy measures at week 12 in patients with moderately to severely active CD who had previously failed biologic or conventional therapy. At week 12, GUS demonstrated a safety profile consistent with that established from clinical trials for the investigated and approved indications. Furthermore, at week 4, clinical remission was achieved in 20.0% of GUS-treated patients compared with 11.8% of placebo-treated patients. A greater proportion of GUS-treated patients achieved clinical remission compared with placebo-treated patients at week 8 (42.0% vs. 15.7%) and at week 12 (54.0% vs. 15.7%). Similarly, within each subgroup of BIO or CON non-responders, GUS-treated patients achieved higher clinical remission rates at weeks 4, 8, and 12 compared to placebo. The proportion of patients achieving clinical and clinical biomarker responses was also higher among GUS-treated patients at weeks 4, 8, and 12 compared to placebo-treated patients. From week 4 to weeks 8-12, the proportion of GUS-treated patients achieving clinical responses increased from 44.0% to 56.0%-66.0%, and the proportion of clinical biomarker responses increased from 26.0% to 43.3%-48.0%, respectively. In contrast, the proportion of placebo-treated patients achieving clinical and clinical biomarker responses remained stable or decreased from week 4 to weeks 8-12, from 25.5% to 25.5%-23.5%, and from 13.7% to 9.8%-7.8%, respectively.

[0414] [Table 2]

[0415] [Table 3-1]

[0416] [Table 3-2]

[0417] [Table 4]

[0418] Phase 2 GALAXI1 Study Results Through Week 24 Table 4 (below) shows the treatment disposition of patients prior to week 24. Figure 1 shows the mean change from baseline in CDAI scores through week 24 in the entire population. All guselkumab treatment groups showed early-onset significant improvement compared to placebo, even 4 weeks after treatment. This translates to similar observations of clinical response and remission in the entire population and subpopulations. Figures 2 and 3 show the mean change from baseline in CDAI scores through week 24 (BIO non-response in Figure 2 and CON non-response in Figure 3). Figure 4 shows the clinical response (measured by CDAI) and clinical remission (measured by CDAI) of patients in the different treatment groups through week 24. Tables 5 and 6 (below) show the safety of guselkumab and ustekinumab versus placebo at weeks 12 (Table 5) and 24 (Table 6).

[0419] [Table 5]

[0420] [Table 6] a UST approx. 6mg / kg IV → 90mg SC b Investigator-assessed infections

[0421] [Table 7] a Placebo included all participants who received placebo and crossed over to UST at week 12 bUST approx. 6mg / kg IV → 90mg SC c Investigator-assessed infections

[0422] Fatigue is a common and debilitating symptom frequently experienced by patients with Crohn's disease. Accurate assessment of patient fatigue is important because fatigue correlates with disease activity and can negatively impact health-related quality of life. This study evaluated the psychometric properties of the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue Short Form 7a (SF-7a) and 4a (SF-4a) scales, which assessed the frequency and severity of fatigue, respectively, in patients with Crohn's disease.

[0423] At baseline, the mean ± standard deviation values ​​of PROMIS-Fatigue SF-7a (fatigue frequency) and SF-4a (fatigue severity) were 58.8 ± 8.29 and 56.9 ± 9.26, respectively. At week 12, the mean values ​​of PROMIS-Fatigue SF-7a and SF-4a correlated with an increasing trend of disease severity at week 12 in PGIS categories and CDAI quartiles (worse health), but a decreasing trend in IBDQ total score quartiles (better health). The PROMIS-Fatigue scale was reliable (intraclass coefficient ≥ 0.77) and was able to detect changes in disease severity assessed by PGIS or PGIC at week 12. The PROMIS-Fatigue scale also showed a strong correlation (r = -0.81) with the IBDQ "feeling fatigued" item and a weak correlation (r = -0.25) with the IBDQ "rectal bleeding" item, further confirming convergent and discriminant validity. Using the PGIC as an anchor variable to assess clinically important improvement from baseline through week 12, a 1-level change (improvement) in feeling "a little better" at week 12 was associated with a 4.2-point and 3.4-point reduction in the PROMIS-Fatigue SF-7a and SF-4a scores, respectively. Similarly, a 2-level change in feeling "moderately better" at week 12 was associated with a 5.5-point and 6.2-point reduction in the PROMIS-Fatigue SF-7a and SF-4a scores, respectively.

[0424] This psychometric analysis demonstrated that the PROMIS-Fatigue SF-7a and SF-4a scales are valid, reliable, and sensitive assessments of fatigue in patients with moderate to severe active Crohn's disease. A change in mean PROMIS-Fatigue scale score of 4 to 6 points indicated a clinically important improvement in clinical response.

[0425] The IBDQ is a 32-item questionnaire with four dimensions: bowel symptoms, emotional function, general symptoms, and social function. IBDQ scores range from 32 to 224, with higher scores indicating better quality of life. IBDQ scores were assessed at weeks 8 and 12 for change from baseline, IBDQ response (defined as ≥16-point improvement from baseline), and IBDQ remission (defined as an IBDQ score ≥170) for the GUS combination and placebo treatment groups. UST was the reference group.

[0426] 250 patients were evaluated. Approximately 50% had prior biologic therapy failure. Baseline demographic and disease characteristics were generally similar between treatment groups. However, some differences were observed between groups, most notably a slightly lower disease time in the GUS 1200 mg IV group (6.2 years) compared with the GUS 200 mg IV group (11.7 years) and a higher mean baseline IBDQ total score in the GUS 600 mg IV group (131.4) compared with placebo (117.3). Changes in IBDQ scores from baseline at weeks 8 and 12 are shown in Table 7. The mean changes from baseline in total IBDQ and each of the four IBDQ domains were greater among patients in the combined GUS groups compared with the placebo group.

[0427] The proportion of patients who achieved an IBDQ response at weeks 8 and 12 was higher in the combined GUS treatment group compared with placebo: 66.0% (99 / 150) and 73.3% (110 / 150) vs. 37.3% (19 / 51) and 41.2% (21 / 51). A similar trend was seen for IBDQ remission: 44.7% (67 / 150) and 52.7% (79 / 150) of patients in the combined GUS treatment group achieved IBDQ remission at weeks 8 and 12, respectively, compared with 17.6% (9 / 51) and 21.6% (11 / 51) of placebo-treated patients. For UST-treated patients at weeks 8 and 12, 85.7% (42 / 49) and 81.6% (40 / 49) achieved IBDQ response and 55.1% (27 / 49) and 46.9% (23 / 49) achieved IBDQ remission.

[0428] In patients with moderate to severe active Crohn's disease, patients treated with GUS (combination) induction therapy reported greater improvement in IBDQ scores as early as week 8 compared to placebo. A higher proportion of patients treated with GUS compared to placebo achieved IBDQ response and remission at weeks 8 and 12, and this treatment effect (as delta) increased throughout weeks 8-12.

[0429] [Table 8] * Nominal p-values, all <0.001 Note: LS means (CI) for each treatment group and p-values ​​for comparison of GUS with placebo are based on MMRM analyses including change from baseline in IBDQ total or perspective score as response: treatment group, visit, baseline IBDQ total or perspective score, BIO non-response status (yes, no), baseline CDAI stratification (≦300, >300), interaction term of visit with treatment group, and interaction term of visit with baseline IBDQ perspective score as explanatory variables.

[0430] PRO-2 symptom remission is a measure of efficacy based on the mean daily patient-reported abdominal pain symptoms (none, mild, moderate, and severe) and the number of liquid or very loose stools (stool frequency). Reported herein are the changes from baseline in abdominal pain (AP), and bowel frequency (SF) and PRO-2 remission after induction with GUS versus PBO in the interim analysis cohort. AP, SF, and PRO-2 symptom remission (mean daily AP score of 1 or less, and mean daily SF score of 3 or less, i.e., AP≦1 and SF≦3, and no worsening of AP or SF from baseline) were assessed for the pooled GUS versus PBO groups through weeks 4-12. UST was the reference group. Mean baseline AP for PBO and GUS was 2.04 and 2.02, respectively. Mean baseline SF for PBO and GUS was 5.51 and 5.27, respectively. Other baseline demographic and disease characteristics were generally similar between treatment groups.

[0431] Patients treated with GUS had greater reductions in AP and SF through week 12 compared to PBO. The mean changes from baseline in AP at weeks 4, 8, and 12 for GUS-treated patients were -0.63, -0.91, and -1.07, respectively, and for PBO-treated patients were -0.37, -0.41, and -0.32. The mean changes from baseline in SF at weeks 4, 8, and 12 for GUS-treated patients were -1.83, -2.46, and -2.77, respectively, and for PBO were -0.82, -0.65, and -0.94. At weeks 4, 8, and 12, a higher proportion of GUS-treated patients achieved PRO-2 remission compared to PBO: 11.8%, 15.7%, and 17.6% compared to 18.0%, 37.3%, and 44.0%. Similarly, within each subgroup of patients who were biologic therapy non-responders (BIO non-responders) or conventional therapy non-responders (CON non-responders), a higher proportion of GUS-treated patients achieved PRO-2 remission at weeks 4, 8, and 12 compared with PBO (Table 8). The proportion of GUS-treated patients in PRO-2 remission at week 12 by serum GUS concentration quartiles for GUS combination administration was 44.8% (<9.40 μg / mL) for Q1, 34.5% (9.40-<24.72 μg / mL) for Q2, 55.2% (24.72-<44.30 μg / mL) for Q3, and 46.7% (>=44.30 μg / mL) for Q4, thus not demonstrating an exposure-response relationship.

[0432] GUS-treated patients had greater reductions in AP and SF at all post-baseline visits. Furthermore, a higher proportion of patients achieved PRO-2 remission during the induction dose compared with PBO. For the total population, as well as the BIO non-responder and CON non-responder subgroups, the differences between GUS- and PBO-treated patients increased over time with a greater proportion of GUS-treated patients achieving PRO-2 remission earlier. Small sample sizes limit overall conclusions for subgroups. No exposure-response relationship was observed for PRO-2 remission at week 12.

[0433] [Table 9]

[0434] [Table 10-1]

[0435] [Table 10-2]

[0436] Example 3 - Results of the Phase 2 GALAXI1 Study at Week 48 result Clinical remission rates achieved at week 12 (Crohn's Disease Activity Index [CDAI] <150) increased at week 48. At week 48, 65% of patients had a CDAI score <150, indicating clinical remission. In this relatively small, treatment-throughout Phase 2b study that included a UST reference arm, patients initiated with IV GUS followed by SC maintenance achieved high levels of clinical efficacy at week 48. Safety results were consistent with the well-established safety profile of each treatment in the approved indications.

[0437] The mean change and clinically meaningful improvement from baseline to week 48 were assessed for each of the PROMIS-29 domains. For the pain intensity domain, clinically meaningful improvement was defined as a ≥ 3 point improvement in the pain numerical rating score. For the other PROMIS-29 domains, clinically meaningful improvement was defined as a ≥ 5 point improvement in the T-score. The mean change and clinically meaningful improvement from baseline to week 48 were assessed for each of the PROMIS-29 domains. For the pain intensity domain, clinically meaningful improvement was defined as a ≥ 3 point improvement in the pain numerical rating score. For the other PROMIS-29 domains, clinically meaningful improvement was defined as a ≥ 5 point improvement in the T-score. Induction and maintenance treatment with GUS was effective in improving health-related quality of life, as measured by the PROMIS-29 domains, in patients with moderate to severe active CD at week 48 (see Table 10).

[0438] [Table 11-1]

[0439] [Table 11-2] a Patients who made prohibited changes to Crohn's disease concomitant medications, underwent Crohn's disease-related surgery, or discontinued study drug due to lack of efficacy or worsening Crohn's disease AEs before the designated analysis time point had baseline values ​​carried forward from that time point. Patients who discontinued study drug for any other reason before the designated analysis time point had observed data used from that time point, if available. b Patients who had insufficient data to calculate PROMIS-29 domain scores at the designated analysis time points did not have missing data imputed.

[0440] [Table 12] a Patients who made prohibited changes to Crohn's disease concomitant medications, underwent Crohn's disease-related surgery, or discontinued study drug due to lack of efficacy or worsening Crohn's disease AEs prior to the designated analysis time point were considered to have not achieved a clinically meaningful improvement in PROMIS-29 domain scores from that time point. Patients who discontinued study drug for any other reason prior to the designated analysis time point had observed data used, if available, to determine responder and non-responder status from that time point. b Patients who had insufficient data to calculate PROMIS-29 domain scores at a designated analysis time point were considered to have not achieved a clinically meaningful improvement in PROMIS-29 domain score at that time point. c Among patients in the primary efficacy analysis set who had a pain intensity numeric rating score of ≥ 3 at baseline:

[0441] Study drug discontinuation was low prior to week 48. No dose response was observed across clinical efficacy assessments (Table 12). The proportion of patients achieving clinical remission at week 48 ranged from 57.4 to 73.0% among the GUS groups. The majority of patients in clinical remission were also in corticosteroid-free remission. Corticosteroid-free remission rates at week 48 ranged from 55.7 to 71.4% among the GUS groups. PRO-2 remission rates ranged from 50.8 to 69.8%, and the proportion of patients achieving a clinical response ranged from 67.2 to 84.1% among the GUS groups. The proportion of patients achieving an abdominal pain score of ≦1 or a mean number of liquid or very loose stools per day of ≦3 is shown in Table 12. Outcomes in the UST group are also shown in Table 12 for reference.

[0442] Table 13 shows additional measures of efficacy (clinical endpoints) at 48 weeks.

[0443] [Table 13] CDAI, Crohn's Disease Activity Index; CI, confidence interval; PRO-2, patient-reported outcome; AP, abdominal pain; a Patients who made prohibited changes to Crohn's disease concomitant medications, underwent Crohn's disease-related surgery, or discontinued study drug due to lack of efficacy or worsening Crohn's disease AEs prior to the designated analysis time point were considered to be in clinical remission, corticosteroid-free clinical remission, PRO-2 remission, or no clinical response from that time point. Patients who discontinued study drug for any other reason prior to the designated analysis time point had observed data used, if available, to determine responder and non-responder status from that time point. b Patients who had insufficient data to calculate CDAI scores, stool frequency, or abdominal pain scores at a designated analysis time point were considered to be in clinical remission, corticosteroid-free remission, PRO-2 remission, or no clinical response at that time point. c CIs were based on Wald statistics. d Patients who had insufficient data to calculate an abdominal pain score at a designated analysis time point were considered to have no abdominal pain score ≦1 at that time point. e Patients who had insufficient data to calculate the mean daily number of liquid or very loose stools at the designated analysis time point were considered to have no mean daily number of liquid or very loose stools ≦3.

[0444] [Table 14-1]

[0445] [Table 14-2]

[0446] Through week 48, rates of significant safety events were similar between the GUS treatment groups (Table 14). No opportunistic infections, cases of tuberculosis, or deaths were reported.

[0447] [Table 15]

[0448] Example 4 - Results of the Phase 2 GALAXI1 Study at Week 96 result The rate of clinical remission achieved at week 48 (Crohn's Disease Activity Index [CDAI] <150) decreased by 7.7% at week 96. At week 96, 57.3% of patients had a CDAI score <150, indicating clinical remission. In this relatively small, treatment-throughout Phase 2b study that included a UST reference arm, patients initiated with IV GUS followed by SC maintenance achieved high levels of clinical efficacy at week 96. Safety results were consistent with the well-established safety profile of each treatment in the approved indications.

[0449] Mean changes and clinically meaningful improvements from baseline to week 96 were assessed for each of the PROMIS-29 domains. For the pain intensity domain, clinically meaningful improvement was defined as a ≥ 3 point improvement in the Numeric Pain Rating Score. For the other PROSMIS-29 domains, clinically meaningful improv...

Claims

1. 1. A pharmaceutical composition for use in a method of treating Crohn's disease in a patient, the pharmaceutical composition comprising an antibody against IL-23, the method comprising administering the antibody against IL-23 to the patient in the following doses: an initial dose, an administration 4 weeks after the initial treatment, an administration 8 weeks after the initial treatment, and an administration every 4 weeks or every 8 weeks thereafter; the antibody comprising a light chain variable region and a heavy chain variable region, the light chain variable region comprising: the complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO: 4; the CDRL2 amino acid sequence of SEQ ID NO:5, and comprising the CDRL3 amino acid sequence of SEQ ID NO:6, the heavy chain variable region the complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO: 1; the CDRH2 amino acid sequence of SEQ ID NO: 2, and A pharmaceutical composition comprising the CDRH3 amino acid sequence of SEQ ID NO: 3, wherein the patient is a responder to the antibody.

2. 10. The pharmaceutical composition of claim 1, wherein the patient is identified as meeting one or more clinical endpoints selected from the group consisting of: (i) Change from baseline in Crohn's Disease Activity Index (CDAI) score at 48 weeks after initial treatment ("Week 48"); (ii) clinical remission at week 48, defined as a CDAI of less than (<) 150 points; (iii) clinical response at Week 48, defined as a reduction from baseline in the CDAI score of 100 points or more (≧) or a CDAI score of less than (<) 150; (iv) Patient-Reported Outcome (PRO)-2 remission at week 48, defined based on mean daily stool frequency (SF) and mean daily abdominal pain (AP) scores; (v) clinical biomarker response at week 48, defined using the clinical response based on the CDAI score and the reduction from baseline in C-reactive protein (CRP) or fecal calprotectin; (vi) endoscopic remission at week 48, as measured by the Simplified Endoscopic Score for Crohn's Disease (SES-CD), defined as an SES-CD of 2 or less (≦); (vii) endoscopic response at week 48 as measured by the Simplified Endoscopic Score for Crohn's Disease (SES-CD); (viii) corticosteroid-free clinical remission at Week 48, defined as a CDAI score of less than 150 at Week 48 and no corticosteroids at Week 48; and (ix) Fatigue response at Week 48 based on Patient-Reported Outcomes Measurement Information System (PROMIS).

3. 2. The pharmaceutical composition of claim 1, wherein the initial administration, and the administrations 4 weeks after the initial treatment and 8 weeks after the initial treatment are intravenous administrations selected from the group consisting of 1200 mg, 600 mg, and 200 mg, and the administrations every 4 weeks or every 8 weeks after the 8th week administration are subcutaneous administrations of 100 mg or 200 mg.

4. 4. The pharmaceutical composition of claim 3, wherein the intravenous administration is 1200 mg and the subcutaneous administration is 200 mg administered every four weeks after the administration at week 8.

5. 4. The pharmaceutical composition of claim 3, wherein the intravenous administration is 200 mg and the subcutaneous administration is 200 mg administered every four weeks after the administration at week 8.

6. 4. The pharmaceutical composition of claim 3, wherein the intravenous administration is 200 mg and the subcutaneous administration is 100 mg administered every 8 weeks after the administration at week 8.

7. 4. The pharmaceutical composition of claim 3, wherein the antibody is contained in a pharmaceutical composition comprising 7.9% (w / v) sucrose, 4.0 mM histidine, 6.9 mM L-histidine monohydrochloride monohydrate, 0.053% (w / v) polysorbate 80, and the diluent is water at standard conditions.

8. The pharmaceutical composition of claim 3, wherein the method further comprises administering to the patient one or more additional drugs used to treat Crohn's disease.

9. 9. The pharmaceutical composition of claim 8, wherein the additional agent is selected from the group consisting of an immunosuppressant, a nonsteroidal anti-inflammatory drug (NSAID), methotrexate (MTX), an anti-B cell surface marker antibody, an anti-CD20 antibody, rituximab, a TNF inhibitor, a corticosteroid, and a costimulatory modulator.

10. The pharmaceutical composition of claim 1 , 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.

11. 2. The pharmaceutical composition of claim 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.

12. 10. The pharmaceutical composition of claim 1, wherein the patient is considered a biotherapy non-responder or intolerant (Bio-non-responder) for Crohn's disease.

13. 2. The pharmaceutical composition of claim 1, wherein the patient is considered conventional therapy non-responsive or intolerant (Con non-responsive) for Crohn's disease.

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