CN118401550A - Methods of treating ulcerative colitis with anti-IL 23 specific antibodies - Google Patents

Abstract

The present invention relates to a method of treating ulcerative colitis in a patient by administering an IL-23 specific antibody, such as Gu Saiku mab, at an initial dose and at a subsequent dose so that the patient responds to the antibody and meets one or more of the clinical endpoints.

Description

Methods of treating ulcerative colitis with anti-IL 23 specific antibodies

Electronically submitted reference sequence listing

The present application comprises a Sequence listing submitted electronically via the U.S. patent and trademark center patent center as an XML formatted Sequence listing having the file name "JBI6672USNP1 Sequence listing. XML" and a creation date of 2022, 11, 21 days and a size of 11Kb. This sequence listing, which is filed via the patent center, is part of the present specification and is incorporated by reference herein in its entirety.

Technical Field

The present invention relates to methods of treating ulcerative colitis with antibodies that bind to human IL 23. In particular, the invention relates to dosing regimens for administration of anti-IL 23 specific antibodies and specific pharmaceutical compositions of the antibodies.

Background

Interleukin (IL) -12 is a secreted heterodimeric cytokine consisting of 2 disulfide-linked glycosylated protein subunits, designated p35 and p40 according to their approximate molecular weights. IL-12 is produced primarily by antigen presenting cells and drives cell-mediated immunity by binding to double-stranded receptor complexes expressed on the surface of T cells or Natural Killer (NK) cells. The IL-12 receptor beta-1 (IL-12Rbeta 1) chain binds to the p40 subunit of IL-12, thereby providing the primary interaction between IL-12 and its receptor. However, the IL-12p35 linkage, which is the second receptor chain IL-12Rβ2, confers intracellular signaling (e.g., STAT4 phosphorylation) and activation of receptor-bearing cells (Presky et al, 1996). IL-12 signaling concurrent with antigen presentation is thought to cause T-cell differentiation to the T helper 1 (Th 1) phenotype, characterized by the production of interferon gamma (IFNγ) (TRINCHIERI, 2003). Th1 cells are believed to promote immunity to some intracellular pathogens, produce complement fixing antibody isoforms, and aid in tumor immune monitoring. Thus, IL-12 is considered an important component of host defensive immune mechanisms.

It was found that the p40 protein subunit of IL-12 can also be associated with a separate protein subunit designated p19 to form the novel cytokine IL-23 (Oppman et al, 2000). IL-23 also signals through double-stranded receptor complexes. Since the p40 subunit is shared between IL-12 and IL-23, the IL-12Rβ1 chain is also shared between IL-12 and IL-23. However, IL-23p19 ligation of the second component of the IL-23 receptor complex, IL-23R, confers IL-23-specific intracellular signaling (e.g., STAT3 phosphorylation) and subsequent production of IL-17 by T cells (Parham et al, 2002; aggarwal et al, 2003). Recent studies have demonstrated that the biological function of IL-23 differs from that of IL-12, although there is a structural similarity between these two cytokines (Langerish et al 2005).

Dysregulation of IL-12 and Th1 cell populations has been associated with a number of immune-mediated diseases, as neutralization of IL-12 with antibodies is effective in treating animal models of psoriasis, multiple Sclerosis (MS), rheumatoid arthritis, inflammatory bowel disease, insulin-dependent (type 1) diabetes and uveitis (Leonard et al, 1995; hong et al, 1999; malfait et al, 1998; davidson et al, 1998). However, since these studies target the common p40 subunit, both IL-12 and IL-23 are neutralized in vivo. Thus, it is not clear whether IL-12 or IL-23 mediates disease, or whether inhibition of both cytokines is required to achieve disease suppression. Recent studies have confirmed that IL-23 inhibition can provide an equivalent benefit to the anti-IL-12 p40 strategy by neutralization of specific antibodies to IL-23p19 deficient mice or IL-23 (Cua et al, 2003, murphy et al, 2003, benson et al, 2004).

Ulcerative colitis is a chronic inflammatory bowel disease of unknown etiology involving the superficial mucosa, crypt epithelium and submucosa of the colon. Ulcerative colitis is most often diagnosed in late adolescence and early adulthood, but diagnosis may occur at any age. Clinically, UC patients develop diarrhea, rectal bleeding, weight loss, abdominal pain, fever, and may also exhibit significant extra-intestinal manifestations, most commonly arthritis. Ulcerative colitis is characterized by life-long remission and exacerbation, with 15% of patients suffering from an acute episode at some time during the course of the disease requiring hospitalization. In severe UC, the intestinal wall may become extremely thin, the mucosa is stripped off, and inflammation may extend to the serosa, leading to distension, toxic megacolon and subsequent perforation. It is reported that approximately 20% of UC adults have undergone colectomy within 10 years after diagnosis. There is a highly unmet need for a safe and effective new UC treatment regimen, particularly a new therapy that can provide improved long-term efficacy (i.e., sustained relief) compared to currently available therapies.

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

IL-23 has been demonstrated in several mouse models to promote intestinal inflammation, with reduced colitis in mice treated with neutralizing anti-IL-23 p19 antibodies or in mice with gene deletion of the p19 subunit of IL-23. Whole genome association studies (GWAS) have identified polymorphisms in the IL-23 receptor gene (IL 23R) that are associated with both risk and protection of IBD.

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

Biological therapies such as anti-TNFα, IL-12/23 antagonists and anti-integrins have completely altered the clinical management of IBD over the past 20 years. Most of these classes of agents are approved for the treatment of UC. In the anti-TNF-alpha class, infliximab, adalimumab and golimumab are approved for UC. Both Utility mab (an IL-12/23 antagonist) and vedolizumab (an anti-integrin) were approved for the treatment of UC. Various anti-IL-23 agents are currently being evaluated in the stage 3 program of UC. In addition, there are currently two types of oral small molecule therapies approved in UC, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate (S1P) receptor modulators.

However, despite substantial progress in advanced therapies as monotherapy, there remains a significant unmet need in the treatment of UC. Even with the best approved therapies, more than half of patients fail to achieve clinical relief after 1 year. Of the clinically asymptomatic UC patients, approximately 25% still suffer from endoscopically active disease (Colombel JF et al Discrepancies between patient-reported outcomes,and endoscopic and histological appearance in UC.Gut2017;66:2063–2068). and therefore the long-term colectomy rate is not declining within 10 years, which is not surprising (Fumery M et al ,Natural history of adult ulcerative colitis in population-based cohorts:A systematic review.Clin Gastroenterol Hepatol 2018;16:343-56.e3),, which highlights the need for more effective therapies and treatment paradigms.

In summary, there remains a great unmet medical need for new IBD and ulcerative colitis treatment regimens, particularly therapies with new mechanisms of action that potentially increase the efficacy criteria and maximize the proportion of patients who achieve and maintain clinical remission.

Disclosure of Invention

In a first aspect, the invention relates to a method of treating a subject (patient) suffering from ulcerative colitis, the method comprising administering to the patient an anti-IL-23 specific antibody (also referred to as IL23p19 or IL23p19 subunit antibody), e.g. Gu Saiku mab, at an initial induction dose, for 4 weeks from the start of treatment to the start of treatment, and then administering to the patient an anti-IL-23 specific antibody once every 4 weeks, e.g. at a dose for 0 week, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks or 48 weeks. In addition, in another embodiment, treatment is continued after initiation of treatment until 96 weeks or more.

In one embodiment, the subject receives an anti-IL 23 specific antibody: (i) Initially, 4 weeks after initial intravenous administration, 8 weeks after initial intravenous administration, and 12 weeks after initial intravenous administration at a dose of 200mg, and continuing treatment with anti-IL 23 specific antibody, or (ii) initially, 4 weeks after initial intravenous administration, 8 weeks after initial intravenous administration, and 12 weeks after initial intravenous administration at a dose of 400mg, and continuing treatment with anti-IL 23 specific antibody, possibly for more than 12 weeks to 24 weeks, 48 weeks, 96 weeks, and longer.

In another aspect, the composition for use in the methods of the invention comprises a pharmaceutical composition comprising: anti-IL 23 specific antibodies.

In one embodiment, the patient with ulcerative colitis achieves a significant improvement in a clinical endpoint selected from the group consisting of:

(i) Clinical response, defined as a 30% or more and 2% or more decrease in improved Mayo score over the induction baseline,

Wherein the rectal bleeding subdivision is more than or equal to 1 minute or 0 or 1 minute compared with the baseline;

(ii) Clinical remission at week 12, defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopy sub-divided into 0 or 1, and no fragility in endoscopy, wherein stool frequency sub-divided is not increased over induction baseline;

(iii) Symptomatic relief at week 12, defined as a stool frequency sub-division of 0 or 1 and a rectal bleeding sub-division of 0, wherein the stool frequency sub-division is not increased from the induction baseline;

(iv) Endoscopic healing at week 12, defined as endoscopy sub-division 0 or 1, and no fragility of endoscopy;

(v) Histological-endoscopic mucosal healing at week 12, defined as the combination of achieving histological healing and endoscopic healing, wherein histological healing is defined as neutrophil infiltration of <5% of crypt, no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes classification system;

(vi) At week 12, endoscopy was normalized, defined as an endoscopic subdivision into 0 (which requires no brittleness).

In one embodiment of the invention, will have received anti IL23 specific antibodies and at week 12 is judged not to be in clinical response of patients in the extended induction period of time in week 12, 16 and 20 weeks received subcutaneous anti IL23 specific antibodies for treatment, and at week 24 evaluation of clinical response and other clinical end point.

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

Another aspect of the methods of the invention comprises administering a pharmaceutical composition comprising an isolated anti-IL-23 specific antibody having the heavy chain variable region amino acid sequence of SEQ ID No. 7 and the light chain variable region amino acid sequence of SEQ ID No. 8, optionally in a composition comprising: 7.9% (w/v) sucrose, 4.0mM histidine, 6.9mM L-histidine monohydrochloride monohydrate; 0.053% (w/v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water in a standard state.

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

In yet another embodiment, the methods of the invention comprise administering a pharmaceutical composition comprising an antibody, antikumamab (by Janssen Biotech, incSold), optionally in a composition comprising: 7.9% (w/v) sucrose, 4.0mM histidine, 6.9mM L-histidine monohydrochloride monohydrate; 0.053% (w/v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water in a standard state.

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

Drawings

In the drawings:

Figure 1 shows the clinical response at week 12 in the complete analysis set in the study described herein.

Figure 2 shows clinical remission at week 12 in the complete analysis set in the study described herein.

Figure 3 shows the proportion of patients with symptomatic relief at different time points in the study described herein.

Fig. 4 shows the dosing regimen for the treatment phase and how the study intervention is administered.

Detailed Description

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

As used herein, "anti-IL-23 specific antibody," "anti-IL-23 antibody," "antibody portion," or "antibody fragment" and/or "antibody variant" and the like include any protein or peptide comprising: the molecule comprises at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one Complementarity Determining Region (CDR) of a heavy or light chain or a ligand-binding portion thereof, a heavy or light chain variable region, a heavy or light chain constant region, a framework region, or any portion thereof, or a portion of an IL-23 receptor or binding protein that can bind to an antibody of the invention. Such antibodies optionally further affect specific ligands, such as, but not limited to, such antibodies modulate, decrease, increase, antagonize, agonize, alleviate, mitigate, block, inhibit, eliminate, and/or interfere with at least one IL-23 activity or binding, or IL-23 receptor activity or binding, in vitro, in situ, and/or in vivo. As one non-limiting example, a suitable anti-IL-23 antibody, designated portion or variant of the invention may bind to at least one IL-23 molecule, or designated portion, variant or domain thereof. Suitable anti-IL-23 antibodies, designated portions or variants may also optionally affect at least one of IL-23 activity or function, such as, but not limited to, RNA, DNA, or protein synthesis, IL-23 release, IL-23 receptor signaling, membrane IL-23 cleavage, IL-23 activity, IL-23 production, and/or synthesis.

The term "antibody" is also intended to encompass antibodies, digested fragments, specific portions and variants thereof, including antibody mimics or antibody portions comprising the structure and/or function of a mimetic antibody or specific fragment or portion thereof, including single chain antibodies and fragments thereof. Functional fragments include antigen-binding fragments that bind to mammalian IL-23. For example, the invention encompasses antibody fragments capable of binding to IL-23 or a portion thereof, including but not limited to Fab fragments (e.g., obtained by papain digestion), fab ' fragments (e.g., obtained by pepsin digestion and partial reduction), and F (ab ') ₂ fragments (e.g., obtained by pepsin digestion), facb fragments (e.g., obtained by plasmin digestion), pFc ' fragments (e.g., obtained by pepsin or plasmin digestion), fd fragments (e.g., obtained by pepsin digestion, partial reduction, and reaggregation), fv or scFv fragments (e.g., obtained by molecular biology techniques) (see, e.g., colligan, immunology, supra).

Such fragments may be produced by enzymatic cleavage, synthetic or recombinant techniques, as known in the art and/or as 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 combinatorial gene encoding the F (ab') ₂ heavy chain portion can be designed to include DNA sequences encoding the C _H 1 domain and/or hinge region of the heavy chain. The individual portions of the antibodies may be chemically linked together by conventional techniques, or may be prepared as contiguous proteins using genetic engineering techniques.

As used herein, the term "human antibody" refers to an antibody that: wherein substantially each portion of the protein (e.g., CDR, framework, C _L、C_H domain (e.g., C _H1、C_H2、C_H), hinge (V _L、V_H)) is substantially non-immunogenic in humans with only small sequence changes or alterations. A "human antibody" may also be an antibody derived from or closely matching human germline immunoglobulin sequences. Human antibodies may include amino acid residues not encoded by germline immunoglobulin sequences (e.g., mutations introduced in vitro by random mutagenesis or site-specific mutagenesis, or mutations introduced in vivo by somatic mutation). Typically, this means that human antibodies are substantially non-immune in humans. Human antibodies have been classified into groups based on their amino acid sequence similarity. Thus, using a sequence similarity search, antibodies with similar linear sequences can be selected as templates to produce human antibodies. Similarly, antibodies designating genus primate (monkey, baboon, chimpanzee, etc.), rodent (mouse, rat, rabbit, guinea pig, hamster, etc.), and other mammals represent specific antibodies of these species, subgenera, genus, subfamily, family. Furthermore, chimeric antibodies may include any combination of the above antibodies. Such changes or alterations optionally and preferably maintain or reduce immunogenicity in humans or other species relative to unmodified antibodies. Thus, human antibodies are different from chimeric or humanized antibodies.

It should be noted that human antibodies may 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 may comprise a linking peptide that is not present in the native human antibody. For example, fv may comprise a connecting peptide, such as two to about eight glycine or other amino acid residues, connecting the heavy and light chain variable regions. Such connecting peptides are considered to be of human origin.

Bispecific antibodies, xenogenous specific antibodies, xenogenous conjugated antibodies or similar antibodies, which are monoclonal antibodies, preferably human antibodies or humanized antibodies, having binding specificities for at least two different antigens, may also be used. In this case, one of the binding specificities is for at least one IL-23 protein and the other is for any other antigen. Methods for preparing bispecific antibodies are known in the art. Typically, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, nature 305:537 (1983)). Due to the random distribution of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a mixture of potentially 10 different antibody molecules, only one of which has the correct bispecific structure. Purification of the correct molecule (usually by affinity chromatography steps) is quite cumbersome and the yield of the product is low. Similar procedures are disclosed in, for example, the following documents: WO 93/08829, U.S. patent 6210668、6193967、6132992、6106833、6060285、6037453、6010902、5989530、5959084、5959083、5932448、5833985、5821333、5807706、5643759、5601819、5582996、5496549、4676980、WO 91/00360、WO 92/00373、EP 03089、Traunecker et al, EMBO J.10:3655 (1991), suresh et al, methods in Enzymology 121:121 (1986), each of which is incorporated herein by reference in its entirety.

Anti-IL-23 specific antibodies (also referred to as IL-23 specific antibodies) (or anti-IL-23 antibodies) useful in the methods and compositions of the invention may optionally have the following characteristics: binds with high affinity to IL-23 and optionally and preferably has low toxicity. In particular, antibodies, specific fragments or variants of the invention (wherein the individual components, such as the variable, constant and framework regions, are individually and/or collectively optionally and preferably have low immunogenicity) may be used in the invention. Antibodies useful in the present invention are optionally characterized in that they can be used for long periods of time in the treatment of patients, measurably alleviating symptoms and have low and/or acceptable toxicity. Low or acceptable immunogenicity and/or high affinity, as well as other suitable properties, may help achieve therapeutic results. "Low immunogenicity" is defined herein as eliciting a significant HAHA, HACA or HAMA response in less than about 75%, or preferably less than about 50% of the treated patients, and/or eliciting a low titer (less than about 300, preferably less than about 100, as measured by a double antigen enzyme immunoassay) in the treated patients (Elliott et al, lancet 344:1125-1127 (1994), which is incorporated herein by reference in its entirety). "hypoimmunogenicity" may also be defined as the occurrence of titratable levels of antibody against IL-23 in patients treated with anti-IL-23 antibody during the treatment period occurring in less than 25% of patients treated with recommended doses of the recommended course of therapy, preferably in less than 10% of patients treated with recommended doses of the recommended course of therapy.

The term "safe" when it relates to a dose, dosage regimen, treatment, or method of treatment with an anti-IL-23 antibody of the invention (e.g., anti-IL-23 antibody antique-ku mab) refers to a relatively low or reduced frequency, and/or low or reduced severity, of adverse events (termed AE or TEAE) occurring during treatment from a clinical trial performed (e.g., phase 2 clinical trial and earlier clinical trial) as compared to a standard of care or another comparator. An adverse event is an adverse medical event that occurs in a patient administered a drug. In particular, when referring to a dose, dosage regimen, or treatment with an anti-IL-23 antibody of the invention, "safe" refers to a relatively low or reduced frequency, and/or a low or reduced severity of adverse events associated with administration of the anti-IL-23 antibody if attribution is considered likely, or very likely due to use of the antibody.

Utility program

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

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

Citation(s)

All publications or patents cited herein, whether or not specifically indicated, are incorporated herein by reference in their entirety as they show the state of the art upon which this invention pertains and/or provide a description and practice of the invention. Publication refers to any scientific publication or patent publication, or any other information that may be obtained in any media format, including all record formats, electronic formats, or print formats. The following references are incorporated by reference herein in their entirety: ausubel et al, eds. "Current Protocols in Molecular Biology", john Wiley & Sons, inc., NY, NY (1987-2001); sambrook et al, "Molecular Cloning: A Laboratory Manual", 2 nd edition, cold Spring Harbor, NY (1989); harlow and Lane, "anti-bodies, a Laboratory Manual", cold Spring Harbor, NY (1989); colligan et al, "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).

Antibody of the invention-preparation and production

The at least one anti-IL-23 antibody used in the methods of the invention may optionally be prepared by a cell line, a mixed cell line, immortalized cells, or clonal populations of immortalized cells, as is well known in the art. See, e.g., ausubel et al, edit 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, "anti-bodies, a Laboratory Manual", cold Spring Harbor, NY (1989); colligan et al, "Current Protocols in Immunology", john Wiley & Sons, inc., NY (1994-2001); colligan et al, "Current Protocols in Protein Science", john Wiley & Sons, NY, NY (1997-2001), each of which is incorporated herein by reference in its entirety.

A preferred anti-IL-23 antibody is a Costuzumab (also known as CNTO 1959) having the heavy chain variable region amino acid sequence of SEQ ID NO. 7 and the light chain variable region amino acid sequence of SEQ ID NO. 8, and having the heavy chain CDR amino acid sequences of SEQ ID NO. 1, SEQ ID NO. 2 and SEQ ID NO. 3; and the light chain CDR amino acid sequences of SEQ ID NO. 4, SEQ ID NO. 5 and SEQ ID NO. 6. Other anti-IL-23 antibodies have the sequences listed herein and are described in U.S. patent 7,935,344, the entire contents of which are incorporated herein by reference.

Human antibodies specific for human IL-23 protein or fragments thereof, such as isolated IL-23 protein and/or portions thereof (including synthetic molecules such as synthetic peptides), may be produced against suitable immunogenic antigens. Other specific or general mammalian antibodies can be similarly produced. The preparation of the immunogenic antigen and the generation of monoclonal antibodies may be performed using any suitable technique.

In one approach, hybridomas are produced by fusing a suitable immortal cell line (e.g., a myeloma cell line, such as but not limited to Sp2/0、Sp2/0-AG14、NSO、NS1、NS2、AE-1、L.5、L243、P3X63Ag8.653、Sp2 SA3、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 2A, etc., or heteromyeloma, fusion products thereof, or any cell or fusion cell derived therefrom, or any other suitable cell line known in the art) (see, e.g., www.atcc.org, www.lifetech.com., etc.) with an antibody-producing cell, such as but not limited to an isolated or cloned spleen, peripheral blood, lymph, tonsil, or other immune or B-cell-containing cell, or any other cell expressing a constant or variable heavy or variable framework or CDR sequence, as an endogenous or heterologous nucleic acid, such as recombinant or endogenous, virus, bacterium, algae, prokaryote, amphibian, insect, reptile, fish, mammal, rodent, horse, sheep, goat, sheep, primate, eukaryote, genome DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single-chain, double-or triplex, hybrid, etc., or any combination thereof. See, e.g., ausubel, supra, and Colligan, immunology, supra, chapter 2, incorporated by reference in its entirety.

Antibody-producing cells may also be obtained from peripheral blood, or preferably spleen or lymph nodes, of a human or other suitable animal that has been immunized with the antigen of interest. Any other suitable host cell may also be used to express a heterologous or endogenous nucleic acid encoding an antibody, specific fragment or variant thereof of the invention. The 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 of the desired specificity may be selected by a suitable assay (e.g., ELISA).

Other suitable methods of producing or isolating antibodies with the requisite specificity may be used, including, but not limited to, methods of selecting recombinant antibodies from peptide or protein libraries (e.g., without limitation, phage, ribosomes, oligonucleotides, RNA, cDNA, etc. display libraries; For example, commercially available from Cambridge antibody Technologies,Cambridgeshire,UK;MorphoSys,Martinsreid/Planegg,DE;Biovation,Aberdeen,Scotland,UK;BioInvent,Lund,Sweden;Dyax,Enzon,Affymax/Biosite;Xoma,Berkeley,CA;Ixsys., see, e.g., EP368,684、PCT/GB91/01134;PCT/GB92/01755;PCT/GB92/002240;PCT/GB92/00883;PCT/GB93/00605;US 08/350260(5/12/94);PCT/GB94/01422;PCT/GB94/02662;PCT/GB97/01835;(CAT/MRC);WO90/14443;WO90/14424;WO90/14430;PCT/US94/1234;WO92/18619;WO96/07754;(Scripps);WO96/13583、WO97/08320(MorphoSys);WO95/16027(BioInvent);WO88/06630;WO90/3809(Dyax);US 4,704,692(Enzon);PCT/US91/02989(Affymax);WO89/06283;EP 371 998;EP 550 400(Xoma);EP 229 046;PCT/US91/07149(Ixsys); or randomly generated peptides or proteins —US 5723323、5763192、5814476、5817483、5824514、5976862、WO 86/05803、EP 590 689(Ixsys,predecessor of Applied Molecular Evolution(AME), each incorporated herein by reference in their entirety)) or dependent on immunization of transgenic animals (e.g., SCID mice, nguyen et al, microbiol. Immunol.41:901-907 (1997); Sandhu et al, crit.Rev.Biotechnol.16:95-118 (1996); eren et al, immunol.93:154-161 (1998), each incorporated herein by reference and related patents and applications in their entirety) are capable of producing a complete set of human antibodies, as known in the art and/or as described herein. Such techniques include, but are not limited to, ribosome display (Hanes et al, proc. Natl. Acad. Sci. USA,94:4937-4942 (month 5 1997); hanes et al, proc. Natl. Acad. Sci. USA,95:14130-14135 (month 11 1998)); Single cell antibody production techniques (e.g., selected lymphocyte antibody methods ("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 microdroplet and flow cytometry (Powell et al, biotechnol.8:333-337 (1990); one CELL SYSTEMS, cambridge, mass.; Gray et al, J.Imm.Meth.182:155-163 (1995); kenny et al, bio/technology.13:787-790 (1995)); b cell selection (Steenbakkers et al, molecular biol., reports 19:125-134 (1994); jonak et al, progress Biotech, vol.5, "In Vitro Immunization in Hybridoma Technology", borrebaeck, eds., ELSEVIER SCIENCE Publishers B.V., amsterdam, netherlands (1988)).

Methods for engineering or humanizing non-human or human antibodies may also be used, and are well known in the art. Generally, humanized or engineered antibodies have one or more amino acid residues from a non-human source such as, but not limited to, mice, rats, rabbits, non-human primates, or other mammals. They are typically taken from the "input" variable, constant, or other domains of a known human sequence. These non-human amino acid residues are substituted with residues commonly referred to as "import" residues, which are typically taken from "import" varying, constant or other domains of known human sequences.

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

Such input sequences may be used to reduce immunogenicity or to reduce, enhance or modify binding, affinity, binding rate, dissociation rate, avidity, specificity, half-life, or any other suitable feature, as known in the art. Generally, CDR residues are directly and substantially mostly involved in influencing antigen binding. Thus, non-human CDR sequences or portions or all of human CDR sequences are retained, while non-human sequences of the variable and constant regions may be replaced with human amino acids or other amino acids.

Antibodies may also optionally be humanized or human antibodies designed to retain high affinity for the antigen and other advantageous biological properties. To achieve this goal, humanized (or human) antibodies can also optionally be prepared by analysis of the parent sequence and various conceptual humanized products using three-dimensional models of the parent and humanized sequences. Three-dimensional immunoglobulin models are generally available and familiar to those skilled in the art. Computer programs are available that illustrate and display the possible three-dimensional conformational structures of selected candidate immunoglobulin sequences. These displayed assays allow for analysis of the likely role of the residues in the functional functioning of the candidate immunoglobulin sequence, i.e., analysis of residues that affect the ability of the candidate immunoglobulin to bind to its antigen. In this way, framework (FR) residues can be selected and combined from consensus and input sequences to enable desired antibody characteristics, such as increased affinity for the target antigen.

In addition, the human IL-23 specific antibodies used in the methods of the invention may include a human germline light chain framework. In particular embodiments, the light chain germline sequence is selected from the group consisting of sequences of human VK 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.

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

In particular 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 2 or 3 sub-regions, such as FR2 and FR 3). 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 a human consensus sequence comprising a particular framework (readily available at the source of the known human Ig sequences described above). In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., human germline) or a human consensus sequence comprising a particular framework. In a preferred embodiment, the framework region is a fully human framework region.

Humanization or engineering of the antibodies of the invention may be performed using any known method, such as, but not limited to, those described below, 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.U.S. A.,89:4285 (1992); presta et al, J.Immunol.151:2623 (1993); U.S. patent 5723323、5976862、5824514、5817483、5814476、5763192、5723323、5,766886、5714352、6204023、6180370、5693762、5530101、5585089、5225539、4816567;PCT/：US98/16280、US96/18978、US91/09630、US91/05939、US94/01234、GB89/01334、GB91/01134、GB92/01755;WO90/14443、WO90/14424、WO90/14430、EP 229246, is each incorporated by reference herein in its entirety, including the references cited therein.

In certain embodiments, the antibody comprises an altered (e.g., mutated) Fc region. For example, in some embodiments, the Fc region has been altered to reduce or enhance effector function of an antibody. In some embodiments, the Fc region is of the isotype selected from IgM, igA, igG, igE or other isotype. Alternatively or in addition, it may be useful to combine amino acid modifications with one or more additional amino acid modifications that alter the C1q binding and/or complement dependent cytotoxicity functions of the Fc region of the IL-23 binding molecule. The specific starting polypeptide of interest may be a polypeptide that binds to C1q and exhibits Complement Dependent Cytotoxicity (CDC). Polypeptides having pre-existing C1q binding activity, optionally also having the ability to mediate CDC, may be modified such that one or both of these activities are enhanced. Amino acid modifications that alter C1q and/or modify its complement dependent cytotoxic function are described, for example, in WO0042072, hereby incorporated by reference.

As disclosed above, one can design the Fc region of the human IL-23 specific antibodies of the invention with altered effector function, e.g., 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" is responsible for activating or reducing a biological activity (e.g., in a subject). Examples of effector functions include, but are not limited to: c1q binding; CDC; fc receptor binding; ADCC; phagocytosis; down-regulation of cell surface receptors (e.g., B cell receptors; BCR), and the like. Such effector functions may require the Fc region to be combined with a binding domain (e.g., an antibody variable domain), and may be assessed using various assays (e.g., fc binding assays, ADCC assays, CDC assays, etc.).

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

Fc mutations can also be introduced in the design to alter their interactions with neonatal Fc receptors (FcRn) and improve their pharmacokinetic properties. A collection of human Fc variants with improved binding to FcRn has been described (thields 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).

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

Glycosylation patterns can be altered, for example, by deleting one or more glycosylation sites found in the polypeptide, and/or adding one or more glycosylation sites not present in the polypeptide. The addition of glycosylation sites to the Fc region of a human IL-23-specific antibody can conveniently be accomplished by altering the amino acid sequence to contain one or more of the tripeptide sequences described above (for N-linked glycosylation sites). An exemplary glycosylation variant has an amino acid substitution of heavy chain residue Asn 297. Alterations (for O-linked glycosylation sites) may also be made by adding or substituting one or more serine or threonine residues to the sequence of the original polypeptide. In addition, one glycosylation site can be removed to change Asn 297 to Ala.

In certain embodiments, the human IL-23 specific antibodies of the invention are expressed in cells that express β (1, 4) -N-acetylglucosamine transferase III (GnT III), such that GnT III adds GlcNAc to the human IL-23 antibody. Methods of producing antibodies in this manner are provided in WO/9954342, WO/03011878, patent publication 20030003097A1 and Umana et al Nature Biotechnology,17:176-180, 1999 month 2; all of these documents are specifically incorporated by reference herein in their entirety.

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

Transgenic mice that can produce a full set of human antibodies that bind to human antigens can be produced by known methods (e.g., without limitation, 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 to Lonberg et al; jakobovits et al, WO 98/50433; jakobovits et al, WO 98/24893; lonberg et al, WO 98/24884; lonberg et al, WO 97/13852; lonberg et al, WO 94/25585; kucherlinate et al, WO 96/34096; kucherlinate et al, EP 0463 151B1;Kucherlapate et al, EP 0710 719A1;Surani et al, and patents 5,545,807; bruggemann et al, WO 90/04036; bruggemann et al, EP 0438 474B1;Lonberg et al, EP 0814 259A2;Lonberg et al, GB 2272 440A;Lonberg et al, nature 368:856-859 (1994); taylor et al, int.Immunol.6 (4) 579-591 (1994), green et al, nature Genetics 7:13-21 (1994), mendez et al, nature Genetics 15:146-156 (1997), taylor et al, nucleic ACIDS RESEARCH (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 Biohnol 14 (7): 845-851 (1996), each of which is incorporated herein by reference in its entirety). Generally, these mice comprise at least one transgene comprising DNA from at least one human immunoglobulin locus that has undergone a functional rearrangement or that may undergo a functional rearrangement. Endogenous immunoglobulin loci in such mice can be disrupted or deleted to eliminate the ability of the animal to produce antibodies encoded by the endogenous genes.

Screening for antibodies that specifically bind to similar proteins or fragments can be conveniently accomplished using peptide display libraries. This method involves screening a large collection of peptides for individual members having a desired function or structure. Antibody screening of peptide display libraries is well known in the art. The peptide sequences displayed may be 3 to 5000 or more amino acids in length, often 5 to 100 amino acids in length, and typically about 8 to 25 amino acids in length. In addition to the direct chemical synthesis methods used to generate peptide libraries, several recombinant DNA methods have been described. One type involves displaying peptide sequences on the surface of phage or cells. Each phage or cell contains a nucleotide sequence encoding a specific displayed peptide sequence. Such methods are described in PCT patent publications 91/17271, 91/18980, 91/19818 and 93/08278.

Other systems for generating peptide libraries have aspects of both in vitro chemical synthesis methods and recombinant methods. See PCT patent publications 92/05258, 92/14843 and 96/19256. See also U.S. patent 5,658,754 and 5,643,768. Peptide display libraries, vectors and screening kits are commercially available from suppliers such as Invitrogen (Carlsbad, calif.) and Cambridge antibody Technologies (Cambridgeshire, UK). See, for example, U.S. patent 4704692, 4939666, 4946778, 5260203, 5455030, 5518889, 5534621, 5656730, 5763733, 5767260, 5856456, assigned to Enzon;5223409, 5403484, 5571698, 5837500, assigned to Dyax,5427908, 5580717, assigned to Affymax;5885793, assigned to Cambridge antibody Technologies;5750373, assigned to Genentech,5618920, 5595898, 5576195, 5698435, 5693493, 5698417, assigned to Xoma, colligan, supra; ausubel, supra; or Sambrook, supra, each of the above patents and publications are incorporated by reference herein in their entirety.

The use of at least one anti-IL 23 antibody encoding nucleic acid to provide transgenic animals or mammals, such as goats, cows, horses, sheep, rabbits, etc., may also produce antibodies for use in the methods of the invention, which transgenic animals or mammals are capable of producing such antibodies in their milk. Such animals may be provided using known methods. See, for example, but not limited to, U.S. patent 5,827,690;5,849,992;4,873,316;5,849,992;5,994,616;5,565,362;5,304,489, et al, each of which is incorporated herein by reference in its entirety.

Antibodies useful in the methods of the invention may also be prepared using at least one anti-IL 23 antibody encoding nucleic acid to provide transgenic plants and cultured plant cells (such as, but not limited to, tobacco and maize) that produce such antibodies, specific parts or variants thereof in plant parts thereof or cells cultured from plant parts. As a non-limiting example, transgenic tobacco leaves expressing recombinant proteins have been successfully used to provide large amounts of recombinant proteins, for example using inducible promoters. See, e.g., cramer et al, curr. Top. Microbol. Immunol.240:95-118 (1999), and references cited therein. Likewise, transgenic maize has also been used to express mammalian proteins on a commercial production scale, with biological activities equivalent to those 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, including antibody fragments, such as single chain antibodies (scFv), can also be produced in large quantities from transgenic plant seeds, including tobacco seeds and potato tubers. See, e.g., conrad et al, plant mol. Biol.,38:101-109 (1998), and references cited therein. Thus, the antibodies of the invention can also be produced using transgenic plants according to known methods. See, for example, fischer et al, biotechnol. Appl. Biochem.30:99-108 (Oct., 1999); ma et al, trends Biotechnol.13:522-7 (1995); ma et al Plant Physiol.109:341-6 (1995); whitelam et al biochem. Soc. Trans.22:940-944 (1994); and references cited therein. Each of the above references is incorporated by reference herein in its entirety.

Antibodies used in the methods of the invention can bind human IL-23 with a wide range of affinities (K _D). In a preferred embodiment, the human mAb optionally binds human IL-23 with high affinity. For example, the human mAb may be equal to or less than about 10 ^{- 7} M, such as, but not limited to, 0.1-9.9 (or any range or value therein) ×10 ^-7、10^-8、10^-9、10^-10、10^-11、10^-12、10^-13 or K _D of any range or value therein binds human IL-23.

The affinity or avidity of an antibody for an antigen can be determined experimentally using any suitable method. (see, e.g., berzofsky et al, "anti-Antigen Interactions", in Fundamental Immunology, paul, W.E. editions RAVEN PRESS: new York, NY (1984); kuby, janis Immunology, W.H. Freeman and Company: new York, NY (1992); and methods described herein). If measured under different conditions (e.g., salt concentration, pH), the affinity of the particular antibody-antigen interaction measured will be different. Thus, measurements of affinity and other antigen binding parameters (e.g., K _D、K_a、K_d) are preferably made with standard solutions of antibodies and antigens, as well as standard buffers (e.g., buffers as described herein).

Nucleic acid molecules

Using the information provided herein, e.g., nucleotide sequences encoding at least 70% to 100% of the contiguous amino acids of at least one of the light or heavy chain variable or CDR regions described herein, as well as other sequences disclosed herein, designated fragments, variants, or consensus sequences thereof, or preservation vectors comprising at least one of these sequences, nucleic acid molecules of the invention encoding at least one anti-IL-23 antibody can be obtained using methods described herein or as known in the art.

The nucleic acid molecules of the 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 produced by cloning or synthesis, or any combination thereof. The DNA may be triplex, double stranded or single stranded or any combination thereof. Any portion of at least one strand of DNA or RNA may be the coding strand, also referred to as the sense strand, or it may be the non-coding strand, also referred to as the antisense strand.

The isolated nucleic acid molecules used in the methods of the invention may include the following: a nucleic acid molecule comprising an Open Reading Frame (ORF), optionally having one or more introns, for example, but not limited to, at least one designated 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 a variable region for use in an anti-IL-23 antibody; and nucleic acid molecules comprising nucleotide sequences that are significantly different from those described above, but which, due to the degeneracy of the genetic code, still encode at least one anti-IL-23 antibody as described herein and/or as known in the art. Of course, the genetic code is well known in the art. Thus, it should be routinely possible for one of skill in the art to produce such degenerate nucleic acid variants that encode specific anti-IL-23 antibodies for use in the methods of the present invention. See, e.g., ausubel et al, supra, and such nucleic acid variants are included in the 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.

As noted herein, nucleic acid molecules comprising nucleic acids encoding anti-IL-23 antibodies may include, but are not limited to, those nucleic acids encoding the amino acid sequences of antibody fragments alone; a coding sequence for the whole antibody or a portion thereof; the coding sequence of the antibody, fragment or portion, and additional sequences, such as the coding sequence of at least one signal leader peptide or fusion peptide with or without the aforementioned additional coding sequences, such as at least one intron, along with additional non-coding sequences, including but not limited to non-coding 5 'sequences and 3' sequences, such as transcribed, non-translated sequences that function in transcription, mRNA processing, including splicing and polyadenylation signals (e.g., ribosome binding and stabilization of mRNA); additional coding sequences that encode additional amino acids, such as those that provide additional functions. Thus, the sequences encoding the antibodies may be fused to a marker sequence, such as a sequence encoding a peptide that may facilitate purification of the fused antibody comprising the antibody fragment or portion.

Polynucleotides that selectively hybridize to polynucleotides as described herein

The methods of the invention use isolated nucleic acids that hybridize under selective hybridization conditions to the polynucleotides disclosed herein. Thus, the polynucleotides of the present embodiments can be used to isolate, detect, and/or quantify nucleic acids comprising such polynucleotides. For example, polynucleotides of the invention may be used to identify, isolate or amplify partial or full length clones in a registered library. In some embodiments, the polynucleotide is an isolated genomic sequence or a cDNA sequence, or is complementary to a cDNA from a human or mammalian nucleic acid library.

Preferably, the cDNA library comprises at least 80% of the full length sequence, preferably at least 85% or 90% of the full length sequence, and more preferably at least 95% of the full length sequence. cDNA libraries can be normalized to increase the expression of rare sequences. Low or medium stringency hybridization conditions are generally, but not exclusively, used for sequences having reduced sequence identity relative to the complementary sequence. Medium and high stringency conditions can optionally be used for sequences of greater identity. Low stringency conditions allow for selective hybridization of sequences having about 70% sequence identity, and can be used to identify orthologous or paralogous sequences.

Optionally, the polynucleotide will encode at least a portion of an antibody. The polynucleotides comprise nucleic acid sequences that can be used for selective hybridization with polynucleotides encoding antibodies of the invention. See, for example, ausubel (supra); colligan (supra), each incorporated by reference herein in its entirety.

Construction of nucleic acids

The isolated nucleic acids can be prepared using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, and/or (d) combinations thereof, as is well known in the art.

The nucleic acid may conveniently comprise a sequence other than a polynucleotide of the invention. For example, multiple cloning sites comprising one or more endonuclease restriction sites may be inserted into the nucleic acid to aid in the isolation of the polynucleotide. In addition, translatable sequences may be inserted to aid in the isolation of translated polynucleotides of the invention. For example, the hexahistidine tag sequences provide a convenient means for purifying the proteins of the present invention. The nucleic acids of the invention (except for the coding sequences) are optionally vectors, adaptors or linkers for cloning and/or expressing the polynucleotides of the invention.

Additional sequences may be added to such cloning and/or expression sequences to optimize their function in cloning and/or expression to aid in isolation of the polynucleotide or to improve its introduction into a cell. The use of cloning vectors, expression vectors, adaptors and linkers is well known in the art. (see, e.g., ausubel, supra; or Sambrook, supra).

Recombinant methods for constructing nucleic acids

The isolated nucleic acid composition (such as RNA, cDNA, genomic DNA, or any combination thereof) can be obtained from a biological source using a variety of cloning methods known to those of skill in the art. In some embodiments, oligonucleotide probes that selectively hybridize under stringent conditions to polynucleotides of the invention are used to identify a desired sequence in a cDNA or genomic DNA library. Isolation of RNA, and construction of cDNA and genomic libraries are well known to those of ordinary skill in the art. (see, e.g., ausubel, supra; or Sambrook, supra).

Nucleic acid screening and separation methods

CDNA or genomic libraries can be screened using probes based on the sequences of polynucleotides used in the methods of the invention, such as those disclosed herein. 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 hybridization of various degrees of stringency can be employed in the assay; and the hybridization or washing medium may be stringent. As the conditions for hybridization become more stringent, a higher degree of complementarity must exist between the probe and target to allow duplex formation to occur. The degree of stringency can be controlled by one or more of temperature, ionic strength, pH, and the presence of partially denaturing solvents (such as formamide). For example, the polarity of the reactant solution is varied by manipulating the concentration of formamide, for example, in the range of 0% to 50%, to thereby conveniently vary the stringency of hybridization. The degree of complementarity (sequence identity) required for detectable binding will vary depending upon the stringency of the hybridization medium and/or the wash medium. The degree of complementarity will optimally be 100% or 70% to 100% or any range or value therein. It will be appreciated, however, that minor sequence variations in the probes and primers can be compensated for by reducing the stringency of the hybridization and/or wash medium.

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

Known DNA or RNA amplification methods include, but are not limited to, polymerase Chain Reaction (PCR) and related amplification methods (see, e.g., U.S. Pat. nos. 4,683,195, 4,683,202, 4,800,159, 4,965,188 to Mullis et al, 4,795,699 and 4,921,794 to Tabor et al, 5,142,033 to inis, 5,122,464 to Wilson et al, 5,091,310 to inis, 5,066,584 to GYLLENSTEN et al, 4,889,818 to Gelfand et al, 4,994,370 to Silver et al, 4,766,067 to biswans, 4,656,134 to Ringold) and RNA-mediated amplification using antisense RNA of the target sequence as a template for double stranded DNA synthesis (U.S. Pat. No. 5,130,238 to Malek et al, under the name NASBA), the entire contents of these references being incorporated herein by reference. ( See, e.g., ausubel, supra; or Sambrook, supra. )

For example, the sequences of polynucleotides and related genes used in the methods of the invention can be amplified directly from genomic DNA or cDNA libraries using Polymerase Chain Reaction (PCR) techniques. For example, PCR and other in vitro amplification methods can also be used to clone nucleic acid sequences encoding the proteins to be expressed, prepare nucleic acids for use as probes to detect the presence of a desired mRNA in a sample, for nucleic acid sequencing, or for other purposes. Examples of techniques sufficient to guide the skilled artisan throughout the in vitro amplification method can be found in Berger (supra), sambrook (supra), and Ausubel (supra), and U.S. Pat. No. 4,683,202 (1987) to Mullis et al; and Innis et al PCR Protocols A Guide to Methods and Applications, eds., ACADEMIC PRESS Inc., san Diego, calif. (1990). Commercially available kits for genomic PCR amplification are known in the art. See, for example, advantage-GC Genomic PCR Kit (Clontech). In addition, for example, the T4 gene 32 protein (Boehringer Mannheim) can be used to increase the yield of long PCR products.

Synthetic methods for constructing nucleic acids

The isolated nucleic acids used in the methods of the invention may also be prepared by direct chemical synthesis by known methods (see, e.g., ausubel et al, supra). Chemical synthesis typically results in single stranded oligonucleotides that can be converted into double stranded DNA by hybridization to complementary sequences, or by polymerization with a DNA polymerase using the single strand as a template. Those skilled in the art will recognize that while chemical synthesis of DNA may be limited to sequences of about 100 bases or more, longer sequences may be obtained by ligating shorter sequences.

Recombinant expression cassette

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

In some embodiments, an isolated nucleic acid that is a promoter, enhancer, or other element may be introduced at a suitable location (upstream, downstream, or within an intron) of a polynucleotide of the invention in a non-heterologous form so as to up-regulate 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.

Vectors and host cells

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

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

The DNA insert should be operably linked to an appropriate promoter. The expression construct will also contain a transcription start site, a termination site and a ribosome binding site for translation in the transcribed region. The coding portion of the mature transcript expressed by the construct will preferably include a translation initiation at the beginning of the mRNA to be translated and a stop codon (e.g., UAA, UGA or UAG) at the appropriate position at the end of the mRNA, with UAA and UAG being preferred for mammalian or eukaryotic cell expression.

The expression vector will preferably, but optionally, include at least one selectable marker. Such markers include, for example, but are not limited to: suitable culture media and conditions for the above-described host cells are known in the art, suitable vectors will be apparent to the skilled artisan, the introduction of vector constructs into host cells may be accomplished by transfection of calcium phosphate, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, infection or the like, methods of transfection, electroporation, transfection or the like, and methods of chapters 1-16, chapters 16 and 16 are also known in the art, and in chapters 1-16, and 16-16, for eukaryotic cell cultures, methotrexate (MTX), dihydrofolate reductase (DHFR, U.S. Pat. No. 4,399,216; 4,634,665; 4,656,134; 4,956,288; 5,149,636; 5,179,017, ampicillin, neomycin (G418), mycophenolic acid or glutamine synthetase (GS, U.S. Pat. No. 5,122,464;5,770,359;5,827,739), and for E.coli (E.coli) and other bacteria or prokaryotes, for tetracycline or ampicillin resistance genes (incorporated herein by reference in their entirety).

At least one antibody used in the methods of the invention may be expressed in a modified form (such as a fusion protein) and may include not only secretion signals, but also additional heterologous functional regions. For example, regions 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 handling and storage. Likewise, peptide moieties may be added to the antibodies of the invention to aid in 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 chapters 18.1-18.74; ausubel, supra, chapters 16, 17 and 18.

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

Exemplary cell cultures useful for producing antibodies, specific portions or variants thereof are mammalian cells. The mammalian cell system will typically be in the form of a monolayer of cells, but mammalian cell suspensions or bioreactors may also be used. Many 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 CRL 1610) 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, etc., which are readily available from, for example, the American type culture Collection (Manassas, va (www.atcc.org)). Preferred host cells include cells of lymphoid origin, such as myeloma cells and lymphoma cells. Particularly preferred host cells are P3X63Ag8.653 cells (ATCC accession number CRL-1580) and SP2/0-Ag14 cells (ATCC accession number CRL-1851). In a particularly preferred embodiment, the recombinant cell is a P3X63Ab8.653 or SP2/0-Ag14 cell.

Expression vectors for these cells may include one or more of the following expression control sequences, such as but not limited to: an origin of replication; promoters (e.g., late or early SV40 promoter, CMV promoter (U.S. Pat. No. 5,168,062; U.S. Pat. No. 5,385,839), HSV tk promoter, pgk (phosphoglycerate kinase) promoter, EF-1. Alpha. Promoter (U.S. Pat. No. 5,266,491), at least one human immunoglobulin promoter, enhancers and/or processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites (e.g., SV40 large-T Ag poly A addition sites), and transcription terminator sequences see, e.g., ausubel et al (supra); sambrook et al (supra); other cells useful in producing nucleic acids or proteins of the invention are also known and/or may be obtained, e.g., from the American type culture Collection cell line and hybridoma catalog (www.atcc.org) or other known sources or commercial sources.

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

Purification of antibodies

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

Antibodies useful in the methods of the invention include naturally purified products, products of chemical synthetic procedures, and products produced by recombinant techniques from eukaryotic hosts including, for example, yeast, higher plant, insect, and mammalian cells. Depending on the host employed in the recombinant production method, the antibody may be glycosylated or may be non-glycosylated, with glycosylated being preferred. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, sections 17.37-17.42; ausubel, supra, chapter 10, chapter 12, chapter 13, chapter 16, chapter 18 and chapter 20; colligan, protein Science, supra, chapters 12-14, all of which are incorporated herein by reference in their entirety.

Anti-IL-23 antibodies

Anti-IL-23 antibodies according to the invention include any protein or peptide comprising: the molecule comprises at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one Ligand Binding Portion (LBP), such as, but not limited to, a Complementarity Determining Region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy or light chain variable region, a framework region (e.g., FR1, FR2, FR3, FR4, or fragments thereof, further optionally comprising at least one substitution, insertion, or deletion), a heavy or light chain constant region (e.g., comprising at least one C _H, hinge 1, hinge 2, hinge 3, hinge 4, C _H 2, or C _H, or fragments thereof, further optionally comprising at least one substitution, insertion, or deletion), or any portion thereof, which may be incorporated into an antibody. Antibodies may include or be derived from any mammal, such as, but not limited to, human, mouse, rabbit, rat, rodent, primate, or any combination thereof, and the like.

The isolated antibodies used in the methods of the invention comprise the antibody amino acid sequences disclosed herein encoded by any suitable polynucleotide, or any isolated or prepared antibody. Preferably, the human antibody or antigen-binding fragment binds human IL-23, thereby partially or substantially neutralizing at least one biological activity of the protein. Antibodies, or designated portions or variants thereof, that partially or preferably substantially neutralize at least one biological activity of at least one IL-23 protein or fragment may bind to the protein or fragment, thereby inhibiting activity mediated through binding of IL-23 to 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% to 120%, preferably at least about 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% or more, depending on the assay. The ability of an anti-IL-23 antibody to inhibit IL-23 dependent activity is preferably assessed by at least one suitable IL-23 protein or receptor assay as described herein and/or as known in the art. The human antibody may be of any type (IgG, igA, igM, igE, igD, etc.) or isotype and may comprise a K or lambda light chain. In one embodiment, the human antibody comprises an IgG heavy chain or a defined fragment, e.g., at least one of isotypes IgG1, igG2, igG3, or IgG4 (e.g., γ1, δγ2, γ3, γ4). Antibodies of this type may be prepared as described herein and/or as known in the art by using transgenic mice or other transgenic non-human mammals that contain at least one human light chain (e.g., igG, igA, and IgM) transgene. In another embodiment, the anti-IL-23 human antibody comprises an IgG1 heavy chain and an IgG1 light chain.

The antibodies bind to at least one designated epitope that is specific for at least one IL-23 protein, subunit, fragment, portion, or any combination thereof. The at least one epitope may comprise at least one antibody binding region comprising at least a portion of a protein, the epitope preferably being constituted by at least one extracellular, soluble, hydrophilic, external or cytoplasmic portion of the protein.

Generally, a human antibody or antigen binding fragment will comprise an antigen binding region comprising at least one human complementarity determining region (CDR 1, CDR2, and CDR 3) or a variant of at least one heavy chain variable region and at least one human complementarity determining region (CDR 1, CDR2, and CDR 3) or a variant of at least one light chain variable region. CDR sequences may be derived from human germline sequences or closely match these germline sequences. For example, CDRs from a synthetic library of original non-human CDRs may be used. These CDRs can be formed by incorporating conservative substitutions from the original non-human sequence. In another specific embodiment, an antibody or antigen binding portion or variant may have an antigen binding region comprising at least a portion of at least one light chain CDR (i.e., CDR1, CDR2, and/or CDR 3) having the amino acid sequence of the corresponding CDR1, CDR2, and/or CDR 3.

Such antibodies can be prepared by the following method: the various portions (e.g., CDRs, frameworks) of the antibody are chemically linked together using conventional techniques, using conventional techniques of recombinant DNA technology, or by using any other suitable method to prepare and express the nucleic acid molecule(s) encoding the antibody.

The anti-IL-23 specific antibody may comprise at least one of a heavy chain variable region or a light chain variable region having a defined amino acid sequence. For example, in a preferred embodiment, an anti-IL-23 antibody comprises at least one heavy chain variable region, optionally having the amino acid sequence of SEQ ID NO. 7, and/or at least one light chain variable region, optionally having the amino acid sequence of SEQ ID NO. 8. For example, in another preferred embodiment, an anti-IL-23 antibody comprises at least one heavy chain, optionally having the amino acid sequence of SEQ ID NO. 9, and/or at least one light chain, optionally having the amino acid sequence of SEQ ID NO. 10. Antibodies that bind to human IL-23 and comprise defined heavy or light chain variable regions can be prepared as known in the art and/or as described herein using suitable methods such as phage display (Katsube, y. Et al, int J mol. Med,1 (5): 863-868 (1998)) or using transgenic animals. For example, transgenic mice comprising a functionally rearranged human immunoglobulin heavy chain transgene and comprising DNA from a human immunoglobulin light chain locus that is likely to undergo functional rearrangement may be immunized with human IL-23 or a fragment thereof to elicit antibody production. If desired, the antibody-producing cells may be isolated, and hybridomas or other immortalized antibody-producing cells may be prepared as described herein and/or as known in the art. Alternatively, the antibody, specific portion or variant may be expressed in a suitable host cell using the encoding nucleic acid or portion thereof.

The invention also relates to antibodies, antigen binding fragments, immunoglobulin chains and CDRs comprising an amino acid sequence substantially identical to the amino acid sequences described herein. Preferably, such antibodies or antigen binding fragments and antibodies comprising such chains or CDRs can bind human IL-23 with high affinity (e.g., less than or equal to about 10 ^-9 M of K _D). Amino acid sequences substantially identical to the sequences described herein include sequences having conservative amino acid substitutions, amino acid deletions and/or insertions. Conservative amino acid substitutions refer to the substitution of a first amino acid with a second amino acid that has chemical and/or physical properties (e.g., charge, structure, polarity, hydrophobicity/hydrophilicity) similar to that of the first amino acid. Conservative substitutions include, but are not limited to, substitution of one amino acid for another within the following groups: lysine (K), arginine (R), and histidine (H); aspartic acid (D) and glutamic acid (E); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D, and E; alanine (a), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine (C) and glycine (G); F. w and Y; C. s and T.

Amino acid code

Amino acids constituting the anti-IL-23 antibody of the present invention are generally abbreviated. Amino acids may be represented by single letter codes, three letter codes, names, or trinucleotide codons of the amino acids, thereby indicating the amino acid name, as is well known in the art (see Alberts, b. Et al, "Molecular Biology of The Cell", third edition, garland Publishing, inc., new York, 1994):

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

The number of amino acid substitutions that can be made by the skilled artisan depends on a number of factors, including those described above. As described herein, generally, the number of amino acid substitutions, insertions, or deletions of any given anti-IL-23 antibody, fragment, or variant will not exceed 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3,2, 1, such as1 to 30, or any range or value therein.

Amino acids essential for function in anti-IL-23 specific antibodies can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (e.g., ausubel, supra, chapter 8, 15; cunningham and Wells, science 244:1081-1085 (1989)). The latter procedure introduces a single alanine mutation at each residue of the molecule. The resulting mutant molecules are then tested for biological activity, such as, but not limited to, at least one IL-23 neutralizing activity. Sites of critical 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, science255:306-312 (1992)).

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

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

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

As known in the art, "identity" is a relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by comparing the sequences. In the art, "identity" also means the degree of sequence relatedness between polypeptide or polynucleotide sequences, as determined by the match between strings of such sequences. "identity" and "similarity" can be readily calculated by known methods including, but not limited to, "Computational Molecular Biology, lesk", a.m. edit, oxford University Press, new York,1988; "Biocomputing: informatics and Genome Projects", smith, D.W. edit, ACADEMIC PRESS, new York,1993; "Computer Analysis of Sequence Data", section I, griffin, A.M. and Griffin, H.G. editions ,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. Editions, M Stockton Press, new York,1991; and Carillo, h. and Lipman, d., siam j.applied mate, 48:1073 (1988). Alternatively, the value of percent identity can be obtained from amino acid and nucleotide sequence alignments generated with the default settings of the alignX component of Vector NTI Suite 8.0 (Informax, frederick, MD).

The preferred method of determining identity is designed to give the greatest match between test sequences. Methods of determining identity and similarity are compiled in publicly available computer programs. Preferred computer program methods for determining similarity between two sequences include, but are not limited to, those responsible for the determination of GCG package (Devereux, J. Et al, nucleic ACIDS RESEARCH (1): 387 (1984)), BLASTP, BLASTN and FASTA (Atschul, S.F. Et al, J. Molecular. Biol.,215:403-410 (1990)). BLAST X programs are 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), well-known SMITH WATERMAN algorithms may also be used to determine identity.

Preferred parameters for polypeptide sequence comparison include the following:

(1) Algorithm: needleman and Wunsch, J.mol biol.48:443-453 (1970) comparison matrix: BLOSSUM62, 62 from Hentikoff and Hentikoff, proc.Natl.Acad.Sci, USA.89:10915-10919 (1992)

Gap penalty: 12

Gap length penalty: 4

Programs that can be used with these parameters are publicly available as the "gap" program from GeneticsComputer Group, madison Wis. The foregoing parameters are default parameters for peptide sequence comparison (along with no end gap penalty).

Preferred parameters for polynucleotide comparison include the following:

(1) Algorithm: needleman and Wunsch, J.mol biol.48:443-453 (1970)

Comparison matrix: matching = +10, no matching = 0

Gap penalty: 50

Gap length penalty: 3

Can be used as "gap" from Genetics Computer Group, madison Wis "

The procedure was obtained. These parameters are default parameters for nucleic acid sequence comparison.

By way of example, a polynucleotide sequence may be identical to another sequence, i.e., 100% identical, or it may include up to some integer number of nucleotide changes as compared to a reference sequence. Such alterations are selected from the group consisting of at least one nucleotide deletion, substitution (including transitions and transversions) or insertion, and wherein the alterations may occur at the 5 'or 3' end positions of the reference nucleotide sequence or at any position between these end positions, interspersed individually among nucleotides of the reference sequence, or in one or more contiguous groups within the reference sequence. The number of nucleotide changes is determined by multiplying the total number of nucleotides in the sequence by the digital percentage of the corresponding percent identity (divided by 100) and subtracting the product from the total number of nucleotides in the sequence, or:

n.sub.n.ltorsim.x.sub.n-(x.sub.n.y)，

Where n.sub.n is the number of nucleotide changes, x.sub.n is the total number of nucleotides in the sequence, and y is, for example, 0.70 (for 70%), 0.80 (for 80%), 0.85 (for 85%), 0.90 (for 90%), 0.95 (for 95%), etc., and where any non-integer product of x.sub.n and y is rounded to the nearest integer before subtracting from x.sub.n.

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

n.sub.a.ltorsim.x.sub.a-(x.sub.a.y)，

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

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

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

In another aspect, the invention relates to human antibodies and antigen-binding fragments as described herein that are modified by covalent attachment of an organic moiety. Such modifications may result in antibodies or antigen binding fragments having improved pharmacokinetic properties (e.g., increased serum half-life in vivo). The organic moiety may be a linear or branched hydrophilic polymeric group, a fatty acid group or a fatty acid ester group. In a specific embodiment, the hydrophilic polymer groups may have a molecular weight of about 800 to about 120,000 daltons, and may be polyalkylene glycols (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymers, amino acid polymers, or polyvinylpyrrolidone, and the fatty acid or fatty acid ester groups may contain about eight to about forty carbon atoms.

The modified antibodies and antigen binding fragments may comprise one or more organic moieties covalently bonded directly or indirectly to the antibody. Each organic moiety bound to an antibody or antigen binding fragment of the invention may independently be a hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. As used herein, the term "fatty acid" encompasses both monocarboxylic and dicarboxylic acids. "hydrophilic polymer groups" as that term is used herein refers to organic polymers that are more soluble in water than in octane. For example, polylysine is more soluble in water than octane. Thus, antibodies modified by covalent attachment of polylysine are included in the present invention. Hydrophilic polymers suitable for modifying antibodies of the invention may be linear or branched and include, for example, polyalkylene glycols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG, etc.), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides, etc.), hydrophilic amino acid polymers (e.g., polylysine, polyarginine, polyaspartic acid, etc.), polyalkylene oxides (e.g., polyethylene oxide, polypropylene oxide, etc.), and polyvinylpyrrolidone. Preferably, the hydrophilic polymer modifying the antibodies of the present invention has a molecular weight of about 800 to about 150,000 daltons as a separate molecular entity. For example, PEG ₅₀₀₀ and PEG _20,000 can be used, where the subscript is the average molecular weight (in daltons) of the polymer. The hydrophilic polymer groups may be substituted with one to about six alkyl, fatty acid or fatty acid ester groups. Hydrophilic polymers substituted with fatty acid or fatty acid ester groups can be prepared by employing suitable methods. For example, the polymer comprising amine groups may be coupled to carboxylate groups of a fatty acid or fatty acid ester, and activated carboxylate groups on the fatty acid or fatty acid ester (e.g., activated with N, N-carbonyldiimidazole) may be coupled to hydroxyl groups on the polymer.

Fatty acids and fatty acid esters suitable for modifying antibodies of the invention may be saturated or may contain one or more unsaturated units. 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, eicosanoate), n-docusate (C ₂₂, behenate), n-triacontanoate (C ₃₀), n-tetradecanoate (C ₄₀), cis- Δ9-octadecanoate (C ₁₈, oleate), all cis- Δ5,8,11, 14-eicosatetraenoate (C ₂₀, arachidonate), suberic acid, tetradecanedioic acid, octadecanedioic acid, docusanedioic acid, and the like. Suitable fatty acid esters include monoesters of dicarboxylic acids comprising a straight or branched chain lower alkyl group. The lower alkyl group may contain one to about twelve, preferably one to about six carbon atoms.

Modified human antibodies and antigen binding fragments may be prepared using suitable methods, such as by reaction with one or more modifying agents. The term "modifier" as used herein refers to a suitable organic group (e.g., hydrophilic polymer, fatty acid ester) comprising 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, halogen (chlorine, bromine, fluorine, iodine), N-hydroxysuccinimide ester (NHS), and the like. Activating groups that can be reacted with the thiol include, for example, maleimide, iodoacetyl, acryl, pyridyl disulfide, 5-thiol-2-nitrobenzoic acid thiol (TNB-thiol), and the like. The aldehyde functional group can be coupled to an amine or hydrazide containing molecule and the azide group can be reacted with a trivalent phosphorus group to form a phosphoramidate or a phosphoramide linkage. Suitable methods for introducing activating groups into molecules are known in the art (see, for example, hermannson, G.T., bioconjugate Techniques, ACADEMIC PRESS: san Diego, calif. (1996)). The activating group may be directly bonded to an organic group (e.g., hydrophilic polymer, fatty acid ester) or through a linking moiety, such as a divalent C ₁-C₁₂ group, in which one or more carbon atoms may be substituted with heteroatoms such as oxygen, nitrogen, or sulfur. Suitable linking moieties include, for example, tetraethylene glycol, - (CH ₂)₃-、-NH-(CH₂)₆-NH-、-(CH₂)₂ -NH-and-CH ₂-O-CH₂-CH₂-O-CH₂-CH₂ -O-CH-NH-. Linking moiety-containing modifiers can be produced, for example, by reacting a mono-Boc-alkyldiamine (e.g., mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) to form an amide bond between the free amine and the fatty acid carboxylate, removing the Boc protecting group from the product by treatment with trifluoroacetic acid (TFA) to expose a primary amine, which can be coupled to another carboxylate (as described), or can be reacted with maleic anhydride and the resulting product cyclized to produce an activated maleimide-based derivative of a fatty acid (see, for example, WO 92/16221 to Thompson et al, the entire teachings of which are incorporated herein by reference.)

The modified antibodies may be produced by reacting a human antibody or antigen binding fragment with a modifying agent. For example, the organic moiety may be bound to the antibody in a non-site specific manner by using an amine reactive modifier (e.g., NHS ester of PEG). Modified human antibodies or antigen-binding fragments can also be prepared by reducing disulfide bonds (e.g., intrachain disulfide bonds) of the antibody or antigen-binding fragment. The reduced antibody or antigen binding fragment may then be reacted with a thiol-reactive modifier to produce a modified antibody of the invention. Modified human antibodies and antigen binding fragments comprising an organic moiety that binds to a specific site of an antibody of the invention can be prepared using suitable methods such as reverse proteolysis (Fisch et al, bioconjugate chem.,3:147-153 (1992); werlen et al, bioconjugate chem.,5:411-417 (1994); kumaran et al, protein Sci.6 (10): 2233-2241 (1997); itoh et al, bioorg. Chem.,24 (1): 59-68 (1996); capellas et al, biotechnol. Bioeng.,56 (4): 456-463 (1997)), and the methods described in Hermannson, G.T., bioconjugate Techniques, ACADEMIC PRESS:san Diego, CA (1996).

The methods of the invention also use an anti-IL-23 antibody composition comprising at least one, at least two, at least three, at least four, at least five, at least six, or more of its anti-IL-23 antibodies, as described herein and/or as known in the art, provided in a non-naturally occurring composition, mixture, or form. Such compositions include non-naturally occurring compositions comprising at least one or two full-length sequences, C-terminal and/or N-terminal deleted variants, domains, fragments or specific variants of an anti-IL-23 antibody amino acid sequence selected from the group consisting of 70% to 100% contiguous amino acids of the above-described SEQ ID NOs or specific fragments, domains or variants thereof. Preferred anti-IL-23 antibody compositions comprise at least one or two full length, fragment, domain or variant as at least one CDR or LBP comprising a portion of an anti-IL-23 antibody sequence described herein, e.g., 70% to 100% of the above-described SEQ ID NO or a specific fragment, domain or variant thereof. More preferred compositions comprise, for example, from 70% to 100% of the above-described SEQ ID NOs or from 40% to 99% of at least one of the specific fragments, domains or variants thereof. Such composition percentages are calculated as weight, volume, concentration, molar concentration, or gravimetric molar concentration of liquid or anhydrous solutions, mixtures, suspensions, emulsions, particles, powders, or colloids, as known in the art or as described herein.

Antibody compositions comprising additional therapeutically active ingredients

The composition used in the method of the invention may optionally further comprise an effective amount of at least one compound or protein selected from at least one of the following: antiinfective agents, cardiovascular (CV) system agents, central Nervous System (CNS) agents, autonomic Nervous System (ANS) agents, respiratory tract agents, gastrointestinal (GI) tract agents, hormonal agents, agents for humoral or electrolyte balance, hematologic agents, antineoplastic agents, immunomodulating agents, ophthalmic, otic or nasal agents, topical agents, nutritional agents, statin agents, and the like. Such drugs are well known in the art and include the formulation, indication, administration and administration of each of the drugs given herein (see, e.g., "Nursing 2001Handbook of Drugs", 21 st edition, springhouse corp., springhouse, PA,2001; "Health Professional's Drug Guide 2001", shannon, wilson, stang's editions, pre-Hall, inc, upper SADDLE RIVER, NJ; "Pharmcotherapy Handbook", wells et al editions, appleton & Lange, stamford, CT, each of which is incorporated herein by reference in its entirety).

As an example of a drug that can be combined with an antibody for use in the method of the present invention, the anti-infective drug may be at least one selected from the group consisting of: antimalarial or antiprotozoal agents, antihelminthic agents, antifungal agents, antimalarial agents, antitubercular agents or at least one antimalarial, aminoglycoside, penicillin, cephalosporin, tetracyclines, sulfonamide agents, fluoroquinolones, antivirals, macrolide antiinfectives and other antiinfectives. The hormonal agent may be at least one selected from the group consisting of: corticosteroids, androgens or at least one anabolic steroid, estrogen or at least one progesterone, gonadotrophin, antidiabetic agent or at least one glucagon, thyroid hormone antagonist, pituitary hormone and parathyroid hormone-like agent. The at least one cephalosporin may be at least one selected from the group consisting of: cefaclor, cefadroxil, cefazolin sodium, cefdinir, cefepime hydrochloride, cefixime, cefmetazole sodium, cefnesium sodium, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime sodium, ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cefprozil hydrochloride, cefalexin, cefprozil monohydrate, and chlorocarbon.

The at least one corticosteroid may be at least one selected from the group consisting of: betamethasone acetate or betamethasone sodium phosphate, betamethasone sodium phosphate cortisone acetate, dexamethasone acetate dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone acetate, hydrocortisone cyclopentanepropionate, hydrocortisone sodium phosphate hydrocortisone sodium succinate, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone acetate, prednisolone sodium phosphate, prednisolone tert-butyl ethyl ester, prednisone, triamcinolone acetonide and triamcinolone diacetate. The at least one androgen or anabolic steroid may be at least one selected from the group consisting of: danazol, fluoxytestosterone, methyltestosterone, nandrolone decanoate, nandrolone phenylpropionate, testosterone cyclopentanepropionate, testosterone heptanoate, testosterone propionate, and testosterone transdermal systems.

The at least one immunosuppressant may be at least one selected from the group consisting of: azathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immunoglobulins, moruzumab-CD 3, mycophenolate mofetil hydrochloride, sirolimus and tacrolimus.

The at least one topical anti-infective agent may be at least one selected from the group consisting of: acyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole, econazole nitrate, erythromycin, gentamicin sulfate, ketoconazole, sulfamilone acetate, metronidazole (topical), miconazole nitrate, mupirocin, naftifine hydrochloride, neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, terbinafine hydrochloride, terconazole, tetracycline hydrochloride, tioconazole, and tolnaftate. The at least one scabicide or pediculicide may be at least one selected from the group consisting of: crotamiton, lindane, plodin and pyrethrin. The at least one topical corticosteroid may be at least one selected from the group consisting of: betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desonide, desoxymethasone, dexamethasone sodium phosphate, diflorasone acetate, fluocinolone acetonide, fludrolide, fluticasone propionate, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate and triamcinolone acetonide. (see, e.g., nursing 2001Drug Handbook, pages 1098-1136.)

The anti-IL-23 antibody composition may further comprise any suitable and effective amount of at least one of a composition or pharmaceutical composition comprising at least one anti-IL-23 antibody in contact with or administered to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy, optionally further comprising at least one agent selected from the group consisting of: at least one TNF antagonist (such as, but not limited to, TNF chemical antagonist or protein antagonist, TNF monoclonal or polyclonal antibody or fragment, soluble TNF receptor (such as p55, p70 or p 85) or fragment thereof, fusion polypeptide, or small molecule TNF antagonist, such as TNF binding protein I or II (TBP-1 or TBP-II), nereimomab (nerelimonmab), infliximab, etanercept, CDP-571, CDP-870, alfomamab, lenacip, etc.), antirheumatic drug (such as methotrexate, auranofin, thioglucogold, azathioprine, etanercept, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), immune, immunoglobulin, immunosuppressant (such as basiliximab, cyclosporine, daclizumab), cytokine or cytokine antagonist. Non-limiting examples of such cytokines include, but are not limited to, any of IL-1 through IL-40, and the like. (e.g., IL-1, IL-2, etc.). Suitable dosages are well known in the art. See, e.g., wells et al, edit, "Pharmacotherapy Handbook", 2 nd edition, appleton and Lange, stamford, CT (2000); "PDR Pharmacopoeia, tarascon Pocket Pharmacopoeia 2000", deluxe, eds., tarascon Publishing, loma Linda, CA (2000), each of these references being incorporated by reference herein in its entirety.

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

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

Carbohydrate excipients suitable for use in the present invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides such as raffinose, melezitose, maltodextrins, glucans, starches, and the like; and sugar alcohols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), inositol and the like. Preferred carbohydrate excipients for use in the present invention are mannitol, trehalose and raffinose.

The anti-IL-23 antibody composition may further comprise a buffer or pH adjuster; typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; tris (hydroxymethyl) aminomethane hydrochloride or phosphate buffers. Preferred buffers for use in the compositions of the present invention are organic acid salts, such as citrate.

In addition, the anti-IL-23 antibody composition may comprise polymeric excipients/additives such as polyvinylpyrrolidone, polysucrose (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 chelators (e.g., EDTA).

These and additional known pharmaceutical excipients and/or additives suitable for use in the anti-IL-23 antibodies, portions or variant compositions according to the invention are known in the art, for example, as listed in the following documents: "Remington: THE SCIENCE & Practice of Pharmacy", 19 th edition, williams & Williams, (1995), and "Physician' S DESK REFERENCE", 52 th edition, medical Economics, montvale, NJ (1998), the disclosures of which are incorporated herein by reference in their entirety. Preferred carrier or excipient materials are carbohydrates (e.g., sugar and alditols) and buffers (e.g., citrate) or polymeric reagents. An exemplary carrier molecule is mucopolysaccharide hyaluronic acid, which may be used for intra-articular delivery.

Formulations

As indicated above, the present invention provides stable formulations suitable for pharmaceutical or veterinary use, preferably comprising phosphate buffer with saline or selected salts, as well as preservative solutions and formulations comprising preservatives, and multi-purpose preservative formulations comprising at least one anti-IL-23 antibody in a pharmaceutically acceptable formulation. The preservative formulation comprises at least one known preservative or is optionally selected from the group consisting of: at least one of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkyl benzoates (methyl, ethyl, propyl, butyl, and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof, dissolved in an aqueous diluent. Any suitable concentration or mixture as known in the art may be used, for example 0.001% to 5% or any range or value therein, such as but not limited to ：0.001、0.003、0.005、0.009、0.01、0.02、0.03、0.05、0.09、0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.3、4.5、4.6、4.7、4.8、4.9 or any range or value therein. Non-limiting examples include: preservative-free, 0.1% to 2% m-cresol (e.g., 0.2%, 0.3%, 0.4%, 0.5%, 0.9%, 1.0%), 0.1% to 3% benzyl alcohol (e.g., 0.5%, 0.9%, 1.1%, 1.5%, 1.9%, 2.0%, 2.5%), 0.001% to 0.5% merthiolate (e.g., 0.005%, 0.01%), 0.001% to 2.0% phenol (e.g., 0.05%, 0.25%, 0.28%, 0.5%, 0.9%, 1.0%), 0.0005% to 1.0% alkyl p-hydroxybenzoate (e.g., 0.00075％、0.0009％、0.001％、0.002％、0.005％、0.0075％、0.009％、0.01％、0.02％、0.05％、0.075％、0.09％、0.1％、0.2％、0.3％、0.5％、0.75％、0.9％、1.0％), etc.).

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

The anti-IL-23 specific antibodies used according to the invention may be prepared by recombinant means, including from mammalian cells or transgenic preparations, or may be purified from other biological sources, as described herein or as known in the art.

The range of anti-IL-23 specific antibodies includes the amount produced upon reconstitution, if in a wet/dry system, from about 1.0 μg/ml to about 1000mg/ml, although lower and higher concentrations are also possible and depending on the intended delivery vehicle, for example, the solution formulation will be different from transdermal patches, pulmonary, transmucosal, or osmotic or micropump methods.

Preferably, the aqueous diluent further optionally comprises a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting of: phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl p-hydroxybenzoates (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal or mixtures thereof. The concentration of preservative used in the formulation is that which is sufficient to produce an antimicrobial effect. This concentration depends on the preservative selected and is readily determined by the skilled artisan.

Other excipients such as isotonic agents, buffers, antioxidants and preservative enhancers may optionally and preferably be added to the diluent. Isotonic agents, such as glycerol, are often used in known concentrations. A physiologically tolerated buffer is preferably added to provide improved pH control. The formulation may cover a wide pH range, such as from about pH 4 to about pH 10, with a preferred range being from about pH 5 to about pH 9, and a most preferred range being from about 6.0 to about 8.0. Preferably, the formulation of the present invention has a pH of between about 6.8 and about 7.8. Preferred buffers include phosphate buffers, most preferably sodium phosphate, especially Phosphate Buffered Saline (PBS).

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

The formulation may be prepared by a method comprising mixing at least one anti-IL-23 specific antibody and a preservative in an aqueous diluent, the preservative selected from the group consisting of: phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl p-hydroxybenzoates (methyl, ethyl, propyl, butyl, etc.), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal or mixtures thereof. The at least one anti-IL-23 specific antibody and preservative are mixed in an aqueous diluent using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, a measured amount of at least one anti-IL-23 specific antibody in a buffer is combined with a desired preservative in the buffer in an amount sufficient to provide the desired concentration of protein and preservative. Variations of this method will be recognized by those of ordinary skill in the art. For example, the order of addition of the ingredients, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that can be optimized for the concentration and manner of application used.

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

The articles of the present invention may be used for applications ranging from immediate to twenty-four hours or more. Thus, the claimed article of the invention provides significant advantages to the patient. The formulations of the present invention may optionally be safely stored at a temperature of about 2 ℃ to about 40 ℃ and retain the biological activity of the protein for a long period of time, allowing the packaging label indicator solution to be maintained and/or used for a period of 6,12, 18, 24, 36, 48, 72 or 96 hours or more. Such labels may include use periods of up to 1-12 months, half a year, and/or two years if a preservative diluent is used.

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

The claimed product may be provided to a patient as a clear solution or as dual vials comprising a vial of lyophilized at least one anti-IL-23 specific antibody reconstituted with a second vial containing an aqueous diluent. A single solution vial or dual vials requiring reconstitution may be reused multiple times and may meet a single or multiple cycles of patient treatment and thus provide a more convenient treatment regimen than currently available.

The claimed product may be indirectly provided to a patient by providing a clarified solution or a dual vial to a pharmacy, clinic, or other such facility or unit, the dual vial comprising a vial of lyophilized at least one anti-IL-23 specific antibody reconstituted with a second vial containing an aqueous diluent. In this case the clear solution may be up to one liter or even more in volume, thereby providing a large reservoir from which smaller portions of at least one antibody solution may be withdrawn one or more times for transfer into smaller vials and provided to their customers and/or patients through a pharmacy or clinic.

Recognized devices including single vial systems include pen injector devices for delivering solutions, such as BD pens,And

J-tip Needle-Free Such as manufactured or developed by company ：Becton Dickensen(Franklin Lakes,NJ,www.bectondickenson.com);Disetronic(Burgdorf,Switzerland,www.disetronic.com);Bioject,Portland,Oregon(www.bioject.com);National Medical Products,Weston Medical(Peterborough,UK,www.weston-medical.com)、Medi-Ject Corp(Minneapolis,MN,www.mediject.com), and similar suitable devices. Recognized devices that include dual vial systems include those pen injector systems for reconstitution of lyophilized drug in a cartridge for delivery of the reconstitution solution, such asExamples of other suitable devices include prefilled syringes, auto-syringes, needleless syringes, and needleless IV infusers.

These products may include packaging materials. The packaging material provides conditions under which the product may be used, in addition to information required by regulatory authorities. For a dual vial, wet/dry product, the packaging material of the present invention provides instructions to the patient: where applicable, at least one anti-IL-23 antibody is reconstituted in an aqueous diluent to form a solution, and the solution is used for a period of 2 hours to 24 hours or more. For single vials, solution products, pre-filled syringes or auto-syringes, the label indicates that such solutions can be used for 2 hours to 24 hours or more. The product can be used for human medicine products.

The formulation used in the method of the invention may be prepared by the following method: the method comprises mixing an anti-IL-23 antibody with a selected buffer, preferably a phosphate buffer containing saline or a selected salt. anti-IL-23 antibodies and buffers were mixed in aqueous diluent using conventional solubilization and mixing procedures. For example, to prepare a suitable formulation, a measured amount of at least one antibody in water or buffer is mixed with the desired buffer in an amount of water sufficient to provide the desired concentration of protein and buffer. Variations of this method will be recognized by those of ordinary skill in the art. For example, the order of addition of the ingredients, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that can be optimized for the concentration and manner of application used.

The methods of the present invention provide pharmaceutical compositions comprising various formulations useful and acceptable for administration to a human or animal patient. Such pharmaceutical compositions are prepared using "standard state" water as a diluent and conventional methods well known to those of ordinary skill in the art. For example, the buffer components (such as histidine and histidine monohydrochloride hydrate) may be provided first, followed by the addition of appropriate non-final volumes of water diluent, sucrose, and polysorbate 80 in the "standard state". The isolated antibody may then be added. Finally, the volume of the pharmaceutical composition is adjusted to the desired final volume under "standard state" conditions using water as diluent. Those skilled in the art will recognize many other methods suitable for preparing pharmaceutical compositions.

These pharmaceutical compositions may be aqueous solutions or suspensions, which in the "standard state" contain each component of a specified mass per unit volume of water or have a specified pH. As used herein, the term "standard state" refers to a temperature of 25 ℃ +/-2 ℃ and a pressure of 1 atmosphere. The term "standard state" is not used in the art to refer to a single art-recognized temperature or pressure, but rather is a reference state that is designated to describe a temperature and pressure of a solution or suspension having a particular composition under the reference "standard state" conditions. This is because the volume of the solution is partially a function of temperature and pressure. Those skilled in the art will recognize that pharmaceutical compositions comparable to those disclosed herein may be produced at other temperatures and pressures. It should be determined whether such pharmaceutical compositions are identical to those disclosed herein under the above-identified "standard state" conditions (e.g., 25c +/-2 c and 1 atmosphere pressure).

Importantly, such pharmaceutical compositions can contain a component mass of "about" a certain value (e.g., "about 0.53mg L-histidine") or a pH value of about a certain value per unit volume of the pharmaceutical composition. An isolated antibody present in a pharmaceutical composition is "about" a given value if it is capable of binding a peptide chain at the same time as the isolated antibody is present in the pharmaceutical composition or after the isolated antibody is removed from the pharmaceutical composition (e.g., by dilution). In other words, when the binding activity of an isolated antibody is maintained and detectable after the isolated antibody is placed in a pharmaceutical composition, a value such as a component mass value or pH value is "about" the given value.

Competition binding assays were performed to determine if IL-23 specific mabs bind to similar or different epitopes and/or compete with each other. Abs were individually coated on ELISA plates. The competing mAb was added followed by biotinylated hrIL-23. For positive controls, the same mAb can be used to coat as a competitive mAb ("self-competitive"). IL-23 binding was detected using streptavidin. These results demonstrate whether mAbs recognize similar or partially overlapping epitopes on IL-23.

One aspect of the methods of the invention is to administer to a patient a pharmaceutical composition comprising:

In one embodiment of the pharmaceutical composition, the concentration of the isolated antibody is about 77mg to about 104mg per milliliter of the pharmaceutical composition. In another embodiment of the pharmaceutical composition, the pH is from about 5.5 to about 6.5.

The stable or preserved formulation may be provided to the patient in the form of a clear solution or in dual vials comprising a vial of lyophilized at least one anti-IL-23 antibody reconstituted with a second vial containing a preservative or buffer and excipients in an aqueous diluent. A single solution vial or dual vials requiring reconstitution may be reused multiple times and may meet a single or multiple cycles of patient treatment and thus provide a more convenient treatment regimen than currently available.

Other formulations or methods of stabilizing an anti-IL-23 antibody may produce solutions other than a clear solution of a lyophilized powder comprising the antibody. Formulations comprising suspensions of particles, which are anti-IL-23 antibody-containing compositions having variable size structures and each referred to as microspheres, microparticles, nanoparticles, nanospheres or liposomes, are included in non-clear solutions. Such relatively uniform, substantially spherical particulate formulations containing the active agent may be formed by contacting an aqueous phase containing the active agent and polymer with a non-aqueous phase and then evaporating the non-aqueous phase to cause the particles to coalesce from the aqueous phase, as taught in U.S. patent 4,589,330. The porous microparticles may be prepared using a first phase comprising the active agent and polymer dispersed in a continuous solvent and removing the solvent from the suspension by freeze-drying or dilution-extraction-precipitation, as taught in U.S. patent 4,818,542. Preferred polymers for such preparation are natural or synthetic copolymers or polymers selected from the group consisting of: gelatin agar, starch, arabinogalactan, albumin, collagen, polyglycolic acid, polylactic acid, glycolide-L (-) lactide, poly (epsilon-caprolactone), poly (epsilon-caprolactone-CO-lactic acid), poly (epsilon-caprolactone-CO-glycolic acid), poly (beta-hydroxybutyric acid), polyethylene oxide, polyethylene, poly (alkyl 2-cyanoacrylate), poly (hydroxyethyl methacrylate), polyamides, poly (amino acids), poly (2-hydroxyethyl DL-asparagine), poly (ester urea), poly (L-phenylalanine/ethylene glycol/1, 6-diisocyanatohexane) and poly (methyl methacrylate). Particularly preferred polymers are polyesters such as polyglycolic acid, polylactic acid, glycolide-L (-) lactide, poly (epsilon-caprolactone), poly (epsilon-caprolactone-CO-lactic acid) and poly (epsilon-caprolactone-CO-glycolic acid). Solvents that may be used to dissolve the polymer and/or active include: water, hexafluoroisopropanol, dichloromethane, tetrahydrofuran, hexane, benzene or hexafluoroacetone sesquihydrate. The method of dispersing the active-containing phase with the second phase may include applying pressure to force the first phase through an orifice in the nozzle to effect droplet formation.

Dry powder formulations may be produced by methods other than lyophilization, such as solvent extraction by spray drying or by evaporation, or by precipitation of a crystalline composition, followed by one or more steps to remove aqueous or non-aqueous solvents. The preparation of spray-dried antibody preparations is taught in U.S. patent 6,019,968. The antibody-based dry powder composition may be prepared by spray drying a solution or slurry of the antibody and optional excipients in a solvent under conditions that provide an inhalable dry powder. The solvent may include polar compounds such as water and ethanol, which may be easily dried. The stability of the antibody may be enhanced by performing the spray drying procedure in the absence of oxygen, such as under a nitrogen blanket or by using nitrogen as a drying gas. Another relatively dry formulation is a dispersion of a plurality of perforated microstructures dispersed in a suspending medium that typically contains a hydrofluoroalkane propellant, as taught in WO 9916419. The stabilized dispersion may be administered to the patient's lungs using a metered dose inhaler. The equipment that can be used in the commercial preparation of spray-dried medicaments is manufactured by Buchi ltd.

Anti-IL-23 antibodies in a stable or preserved formulation or solution described herein may be administered to a patient according to the invention via a variety of delivery methods, including SC or IM injections; transdermal, pulmonary, transmucosal, implant, osmotic pump, cartridge, micropump, or other means known to those skilled in the art.

Therapeutic application

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

Any of the methods of the invention can comprise administering an effective amount of a composition or pharmaceutical composition comprising an anti-IL-23 antibody to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy. Such methods may optionally further comprise co-administration or combination therapy for treating such diseases or disorders, wherein administering the at least one anti-IL-23 antibody, designated portion or variant thereof further comprises administering before, concurrently with, and/or after at least one agent selected from the group consisting of: at least one TNF antagonist (such as but not limited to a TNF chemical antagonist or protein antagonist, a TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (such as p55, p70 or p 85) or fragment thereof, a fusion polypeptide, or a small molecule TNF antagonist such as TNF binding protein I or II (TBP-1 or TBP-II), Nerimab, infliximab, etanercept (Enbrel ^TM), adalimumab (Humira ^TM), CDP-571, CDP-870, african mab, lenacil, etc.), antirheumatic drugs (e.g., methotrexate, aurnofin, thioglucogold, azathioprine, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, Sulfasalazine), muscle relaxants, anesthetics (narcotic), non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, anesthetics (anesthetic), sedatives, local anesthetics, neuromuscular blocking agents, antimicrobial agents (e.g., aminoglycosides antifungal agent, antiparasitic agent, antiviral agent, carbapenems cephalosporins, fluoroquinolones, macrolides, penicillins, sulfa drugs, tetracyclines, other antimicrobial agents), antipsoriatic agents, corticosteroids, anabolic steroids, diabetes-related agents, minerals, nutritional agents, thyroid agents, vitamins, calcium-related hormones, Antidiarrheal agents, antitussives, antiemetics, antiulcer agents, laxatives, anticoagulants, erythropoietin (e.g., erythropoietin alpha), fegrid (e.g., G-CSF, neutropen), sargrid (GM-CSF, leukine), immunizing agents, immunoglobulins, immunosuppressants (e.g., basiliximab, cyclosporine, daclizumab), growth hormone, hormone replacement drugs, estrogen receptor modulators, mydriatic agents, ciliary muscle paralysis agents, alkylating agents, antimetabolites, mitotic inhibitors, radiopharmaceuticals, antidepressants, antimanicals, antipsychotics, anxiolytics, antianxietic agents, Hypnotics, sympathomimetics, stimulants, donepezil, tacrine, asthma drugs, beta agonists, inhaled steroids, leukotriene inhibitors, methylxanthines, cromolyn, epinephrine or analogs, alfa-streptase (Pulmozyme), cytokines or cytokine antagonists. Suitable dosages are well known in the art. See, e.g., wells et al, edit, "Pharmacotherapy Handbook", 2 nd edition, appleton and Lange, stamford, CT (2000); "PDR Pharmacopoeia, tarascon Pocket Pharmacopoeia 2000", luxury version, tarascon Publishing, loma Linda, CA (2000); "Nursing 2001Handbook of Drugs, 21 st edition ",Springhouse Corp.,Springhouse,PA,2001;"Health Professional's Drug Guide 2001",Shannon,Wilson,Stang, eds., prentice-Hall, inc., upper SADDLE RIVER, NJ, each of which is incorporated by reference herein in its entirety.

Medical treatment

In general, treatment of ulcerative colitis is accomplished by administering an effective amount or dose of an anti-IL-23 antibody composition, which, depending on the specific activity of the active agent contained in the composition, amounts to a range of at least about 0.01 mg to 500 mg of anti-IL-23 antibody per kilogram of patient on average, preferably at least about 0.1 mg to 100mg of antibody per kilogram of patient per single or multiple administrations. Alternatively, the effective serum concentration may comprise a serum concentration of 0.1g/ml to 5000 μg/ml per single or multiple administrations. Suitable dosages are known to the medical practitioner and will of course depend on the particular disease state, the specific activity of the composition to be administered, and the particular patient undergoing treatment. In some cases, in order to achieve a desired therapeutic amount, it may be necessary to provide repeated administrations, i.e., repeated individual administrations of a particular monitored or metered dose, wherein individual administrations may be repeated until a desired daily dose or effect is achieved.

Preferred dosages may optionally include 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 to 500 mg/kg/administration, or any range, value or fraction thereof, or be used to achieve the following serum concentrations ：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、7.5、7.9、8.0、8.5、8.9、9.0、9.5、9.9、10、10.5、10.9、11、11.5、11.9、20、12.5、12.9、13.0、13.5、13.9、14.0、14.5、4.9、5.0、5.5、5.9、6.0、6.5、6.9、7.0、7.5、7.9、8.0、8.5、8.9、9.0、9.5、9.9、10、10.5、10.9、11、11.5、11.9、12、12.5、12.9、13.0、13.5、13.9、14、14.5、15、15.5、15.9、16、16.5、16.9、17、17.5、17.9、18、18.5、18.9、19、19.5、19.9、20、20.5、20.9、21、22、23、24、25、26、27、28、29、30、35、40、45、50、55、60、65、70、75、80、85、90、96、100、200、300、400、500、600、700、800、900、1000、1500、2000、2500、3000、3500、4000、4500 and/or 5000 μg/ml serum concentration/single or multiple administrations, or any range, value or fraction thereof.

Alternatively, the dosage administered may vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; age, health, and weight of the recipient; the nature and extent of the symptoms, the nature of the concurrent treatment, the frequency of treatment, and the desired effect. Typically the dosage of the active ingredient may be about 0.1 to 100 mg/kg body weight. Typically, each administration or administration in a slow release form of from 0.1 mg/kg to 50mg/kg, preferably from 0.1 mg/kg to 10 mg/kg, is effective to achieve the desired result.

As one non-limiting example, treatment of a human or animal may be provided at least one day on days 1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39 or 40, alternatively or in addition to at least one week on weeks 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 or 52, alternatively or in addition to at least one year 1,2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or any combination thereof, using a single dose, infusion dose, or repeat dose, at a disposable dose or periodic dose of 0.1mg/kg to 100mg/kg per day (such as 0.5、0.9、1.0、1.1、1.5、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、40、45、50、60、70、80、90 or 100 mg/kg) of at least one antibody of the invention.

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

For parenteral administration, the antibodies may be formulated as solutions, suspensions, emulsions, granules, powders or lyophilized powders, which are provided in association with or separately from a pharmaceutically acceptable parenteral medium. Examples of such media are water, saline, ringer's solution, dextrose solution, and 1% to 10% human serum albumin. Liposomes and non-aqueous media such as fixed oils can also be used. The medium or lyophilized powder may contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives). The formulation may be sterilized by known or suitable techniques.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, the latest version of a.osol (standard reference text in this field).

Alternative application

Many modes of known and developed are useful for administering pharmaceutically effective amounts of anti-IL-23 antibodies according to the present invention. Although pulmonary administration is used in the following description, other modes of administration may be used in accordance with the present invention with appropriate results. The IL-23 specific antibodies of the 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 other means described herein or known in the art.

Parenteral formulations and administration

Formulations for parenteral administration may contain sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like as conventional excipients. Aqueous or oily suspensions for injection may be prepared according to known methods by using suitable emulsifying or wetting agents and suspending agents. The injectable medicament may be a nontoxic, non-orally administrable diluent such as an aqueous solution, a sterile injectable solution or a suspension in a solvent. As a usable medium or solvent, water, ringer's solution, isotonic saline, or the like is allowed to be used; as the common solvent or suspension solvent, sterile fixed oils may be employed. For these purposes, any type of non-volatile oils and fatty acids may be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids; natural or synthetic or semisynthetic mono-or diglycerides or triglycerides. Parenteral administration is known in the art and includes, but is not limited to, injection in conventional form, pneumatic needle-free injection devices as described in U.S. patent 5,851,198, and laser perforator devices as described in U.S. patent 5,839,446, which are incorporated herein by reference in their entirety.

Alternative delivery

The invention also relates to the administration of an anti-IL-23 antibody by: parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intrabronchial, intra-abdominal, intracapsular, intracartilaginous, intracavity, cerebellar, intracerebroventricular, intracolonic, endocervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intracardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus injection, vaginal, rectal, buccal, sublingual, intranasal, or transdermal modes. anti-IL-23 antibody compositions may be prepared for parenteral (subcutaneous, intramuscular or intravenous) or any other administration, particularly in the form of liquid solutions or suspensions; for vaginal or rectal administration, particularly semi-solid forms such as, but not limited to, creams and suppositories; for oral or sublingual administration, such as but not limited to tablet or capsule form; or intranasally, such as but not limited to in the form of a powder, nasal drops or aerosol or some pharmaceutical agent; or transdermal, such as but not limited to, gels, ointments, emulsions, suspensions, or patch delivery systems containing chemical enhancers such as dimethyl sulfoxide to alter the skin structure or increase the drug concentration in the transdermal patch (Junginger et al, "Drug Permeation Enhancement", hsieh, d.s. Edit, pages 59-90, (MARCEL DEKKER, INC.NEW York 1994, incorporated herein by reference in its entirety), or oxidizing agents that enable the application of protein and peptide-containing formulations to the skin (WO 98/53847), or electric fields to create transient delivery pathways, such as electroporation, or to increase the mobility of charged drugs through the skin, such as iontophoresis, or ultrasound, such as transdermally absorbed ultrasound (us patents 4,309,989 and 4,767,402) (the publications and patents described above are incorporated herein by reference in their entirety).

Having generally described the invention, the same will be more readily understood by reference to the following examples, which are given by way of illustration only and are not intended to be limiting. Further details of the invention are illustrated by the following non-limiting examples. The disclosures of all references in the specification are expressly incorporated herein by reference.

Results of Induction study at weeks I-12 (CNTO 1959UCO3001 (QUASAR)) in examples 1-2b (QUASAR)

Title: evaluation Gu Saiku efficacy and safety of mab in phase 2b/3, randomized group, double-blind, placebo-controlled, parallel group, multicenter regimen in participants with moderate to severe active ulcerative colitis

The main object is:

the main objective was to evaluate Gu Saiku mab as a clinical efficacy and safety of induction therapy in participants with moderate to severe active UC.

The archaebankab phase 2b/3 clinical development program (QUASAR) for ulcerative colitis consisted of 3 separate studies: phase 2b induction dose range study (induction study 1), phase 3 induction study (induction study 2) and phase 3 maintenance study (maintenance study).

Phase 2b induction study trial design:

phase 2b induction studies were randomized, double-blind, placebo-controlled, parallel, multi-center study.

The target population consisted of participants with moderate to severe active Ulcerative Colitis (UC) who have demonstrated inadequate responses or failed tolerance to: conventional therapies (i.e., 6-MP, azo, or corticosteroids) or advanced therapies (i.e., tnfα antagonists, vedolizumab, or tofacitinib). At week I-0, the participants had to have moderate to severe activity UC, defined as a modified Mayo score of 5 to 9 (including 5 and 9), a Mayo rectal bleeding sub-score of ≡1 and a Mayo endoscopic sub-score of ≡2, using the Mayo endoscopic sub-score obtained during the center examination of video endoscopy. Note that this procedure also allowed for enrolling participants with a modified Mayo score of 4, with an upper limit of ∈5% of the total population. The regimen is modified according to the latest feedback of the health authorities, i.e. the target population will only be based on participants with improved Mayo scores of 5 to 9.

Treatment distribution: on weeks I-0, participants were randomly grouped into 1 treatment group of 3 treatment groups at a 1:1:1 ratio using ADT-failure status (i.e., inadequate response or failure to tolerize: TNFα antagonist, vedolizumab, or tofacitinib) (yes/no), regional (east Europe, asia, or elsewhere in the world), and arrangement block with concomitant use of corticosteroid (yes/no) as a stratification variable at baseline with allocation:

Group 1: placebo IV (weeks I-0, I-4 and I-8)

Group 2: 200mg IV of Gu Sai Ku Bian (weeks I-0, I-4 and I-8)

Group 3: gu Sai ku Bian 400mg IV (weeks I-0, weeks I-4 and weeks I-8)

Duration of treatment: the main part of the study was 12 weeks.

When the current 150 randomized participants completed the visit at week I-12 or terminated study participation prior to week I-12, a metaphase analysis was performed in order to select a single induction dose for confirmatory evaluation in the phase 3 induction study (induction study 2). This interim analysis did not affect the overall type I error rate of the primary endpoint analysis (α= 0.05,2 side) because the study was not planned to stop for positive efficacy.

The report provides results for primary and important secondary endpoints at weeks I-12, as well as safety up to week I-12.

The main end point is: the primary endpoint was the following clinical response at weeks I-12, defined as a 30% or more and 2% or more decrease in modified Mayo score than the induced baseline, with a rectal bleeding sub-score of 0 or 1 or more decrease in rectal bleeding sub-score than the baseline.

Important secondary endpoint:

o clinical remission at weeks I-12, defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopic sub-divided into 0 or 1, and no fragility in endoscopic, wherein stool frequency sub-divided is not increased over induction baseline.

O symptom relief at weeks I-12 is defined as a stool frequency sub-divided into 0 or 1 and a rectal bleeding sub-divided into 0, wherein the stool frequency sub-divided is not increased from the induction baseline.

O endoscopic healing at weeks I-12 is defined as endoscopy sub-division 0 or 1 and no fragility exists.

O histological-endoscopic mucosal healing at weeks I-12, defined as the combination of achieving histological healing and endoscopic healing, wherein histological healing is defined as neutrophil infiltration of <5% of crypts, no crypt destruction, and no erosion, ulceration or granulation tissue according to the Geboes classification system.

O endoscope normalization at weeks I-12, defined as endoscopy sub-division 0 (which requires no brittleness).

IBDQ remission at weeks I-12.

Fatigue response at weeks I-12.

Expected effect size and planned sample size:

the minimum sample size for this study was 150 participants required for the interim analysis. While evaluating data from the metaphase analysis, participants continued to be randomized into the phase 2b induction study. In making and conducting the dosing decisions, 313 participants (i.e., the main analysis group) with improved Mayo scores of 5 to 9 were enrolled and treated in the study (approximately 104 per treatment group). Assuming a clinical response rate of 30% in the placebo group and a clinical response rate of 60% in each of the archaebacterium groups (assuming ratios based on data from the you-peck mab UC induction study [ CNTO1275UCO3001] and Mi Jizhu mab (mirikizumab) 2-phase UC study), 104 participants/treatment groups provided >99% efficacy at the primary endpoint of clinical response at weeks I-12 for each of the archaebacterium groups compared to placebo.

Statistical considerations:

Efficacy analysis set: the full analysis set included all randomized group participants with a modified Mayo score of 5 to 9 who received at least 1 (partial or complete) study intervention. Participants were analyzed based on their randomized group study interventions, regardless of the study intervention they actually accepted.

Security analysis set: the safety analysis set included all randomized group participants with a modified Mayo score of 5 to 9 who received at least 1 (partial or complete) study intervention. Results based on the whole treatment analysis set are also provided, including all randomized group participants (without regard to improved Mayo score) who received at least 1 (partial or complete) study intervention. Participants were analyzed according to the study intervention they actually received.

Concurrent Events (ICEs) were used in the analysis of efficacy endpoints. In particular, participants who refrain from altering UC drugs, UC related surgery (ostomy or colectomy), or discontinuing study agents due to lack of efficacy or worsening AE of UC, prior to the analysis time point, are considered not to reach the endpoint of the binary endpoint. For participants who discontinued study the agent prior to the analysis time point for COVID-19 related reasons (excluding COVID-19 infection), no post-discontinuation data was used. Participants who discontinued studying the agent use their observations (if available) for any other reason.

Comparison was made based on each of the archaebankab groups versus placebo group. For primary endpoint and important secondary endpoint, p-values were based on the Cochran-Mantel-Haenszel (CMH) chi-square test (side 2), which was stratified by ADT-failure status (yes/no) and concomitant corticosteroid use at baseline (yes/no). The 95% confidence interval is based on Wald statistics with the Cochran-Mantel-Haenszel weights. For these endpoints, participants who were missing data at the analysis time point (after considering the concurrent event) were considered non-responders at that time point.

At weeks I-12, overall type 1 error was controlled to a significant level of 0.05 for the primary endpoint of the clinical response; the other endpoint is not controlled. In 2 comparisons of the archaebankab to placebo, the primary endpoint test used a stepwise enhanced Hochberg multiplex test procedure. If the p-value of both of the archaebacterium-treated groups was <0.05, it was concluded that both of the archaebacterium-treated groups were effective compared to placebo. Otherwise, the smaller of the 2 p values is compared to α=0.025; if the p-value is <0.025, it is concluded that the treatment group of the archaebankizumab associated with a smaller p-value is effective compared to placebo. For the endpoint of the non-multiplex control, a nominal p-value is presented.

All participants were evaluated for clinical response at weeks I-12. Further study intervention administration will be determined by the participants' clinical response status at weeks I-12 (using Mayo endoscopy subfractions assigned by the local endoscopist) as follows:

The Gu Saiku mab clinical responders and placebo clinical responders at week I-12 will enter a maintenance study.

Participants that were initially randomized to placebo at weeks I-12, who were not in clinical response, will then convert (crospover) to vasomotor and receive 3 doses of vasomotor 200mg IV at weeks I-12, weeks I-16 and weeks I-20.

The participants initially randomized to the coumarone that were not in clinical response at week I-12 will then receive 3 doses of coumarone 200mg SC at weeks I-12, weeks I-16 and weeks I-20.

To maintain blindness, IV and SC administration was given to all participants not in clinical response at weeks I-12.

At weeks I-24, the clinical response of the participants not in clinical response at weeks I-12 will be re-evaluated (the clinical response status will be based on the Mayo endoscopy subfractions assigned by the local endoscopist). In addition to Gu Saiku mab clinical responders and placebo clinical responders at weeks I-12, the following participants from induction study 1 will enter maintenance studies:

Placebo-converted responders: initial randomized group to placebo, no clinical response at week I-12, then conversion to coumarone induced 200mg IV therapy, and participants who achieved clinical response at week I-24.

The responders to the archaebankeid at week 24: participants initially randomized to the coumarone that were not in clinical response at week I-12 will then receive 3 doses of coumarone 200mg SC at week I-24 and achieve a clinical response.

Participants not in clinical response at weeks I-24 will not receive further study intervention and should be followed up for safety approximately 12 weeks after their last dose of study intervention.

All UC-specific medical therapies (i.e. oral 5-aminosalicylic acid [5-ASA ] compound, oral corticosteroid, 6-MP, azo or MTX) must be maintained at a stable dose until the end of induction study 1 and the dose can be discontinued or reduced only if the researcher decides it is needed due to toxicity or medical necessity. Starting or increasing the dose of UC specific therapy (or any limiting/prohibited drug or therapy) during induction study 1 will prohibit participants from entering the maintenance study. Efficacy, PK parameters, biomarkers and safety will be assessed according to SoA.

Metaphase analysis was performed on the first 150 randomized participants who completed the visit at week I-12 or terminated study participation prior to week I-12. The objective of this metaphase analysis was to select a single induction dose for confirmatory evaluation in the phase 3 induction study (induction study 2). The dose selection committee (independent of study progress) constituted by sponsored regulatory representatives from clinical, safety, biometrical and clinical pharmacology will be responsible for selecting the induction dose of the coumarone mab evaluated in induction study 2. While evaluating data from the first 150 randomly grouped participants, the participants will continue to enroll in induction study 1, with a maximum of 390 participants. Once induction dose selection occurred, the participants will begin to group randomly to induction study 2.

In induction study 2, participants were randomized to either administration of either the coumarone or placebo at a 3:2 ratio at weeks I-0, I-4 and I-8. Induction study 2 was targeted to sample sizes of at least 560 randomly grouped participants with improved Mayo scores of 5 to 9. The choice of the induction dose of the coumarone mab of induction study 2 will be based on the metaphase analysis of induction study 1. Participants were assigned to the intervention group using a random grouping of permutation blocks by ADT-failure status (i.e., inadequate response or failure to tolerize tnfα antagonist, vedolizumab, or tofacitinib) (yes/no), regional (eastern europe, asia, or elsewhere in the world), and permutation blocks stratified at baseline with corticosteroid (yes/no). All participants were evaluated for clinical response at weeks I-12. Similar to the method outlined in induction study 1, further study intervention administration will be determined by the participant's clinical response status at weeks I-12 (using the Mayo endoscopy subfractions assigned by the local endoscopist) as follows:

The Gu Saiku mab clinical responders and placebo clinical responders at week I-12 will enter a maintenance study.

Participants who were not initially randomized to placebo at weeks I-12 in clinical response will then switch to the coumarone and receive 3 doses of coumarone IV therapy (i.e., induction doses selected based on mid-term analysis of induction study 1) at weeks I-12, weeks I-16 and weeks I-20.

The participants initially randomized to the coumarone that were not in clinical response at week I-12 will then receive 3 doses of coumarone 200mg SC at weeks I-12, weeks I-16 and weeks I-20.

To maintain blindness, IV and SC administration was given to all participants not in clinical response at weeks I-12.

At weeks I-24, the clinical response of the participants not in clinical response at weeks I-12 will be re-evaluated (the clinical response status will be based on the Mayo endoscopy subfractions assigned by the local endoscopist). In addition to Gu Saiku mab clinical responders and placebo clinical responders at weeks I-12, the following participants from induction study 2 will enter the maintenance study:

placebo-converted responders: initial randomized group to placebo, no clinical response at week I-12, then conversion to coumarone-induced IV dose therapy, and participants who achieved clinical response at week I-24.

The responders to the archaebankeid at week 24: participants initially randomized to the coumarone that were not in clinical response at week I-12 will then receive 3 doses of coumarone 200mg SC at week I-24 and achieve a clinical response.

Participants not in clinical response at weeks I-24 will not receive further study intervention and should be followed up for safety approximately 12 weeks after their last dose of study intervention.

All UC specific medical therapies (i.e. oral 5-ASA compounds, oral corticosteroids, 6-MP, azo or MTX) must be maintained at a stable dose until the end of induction study 2 and the dose can be discontinued or reduced only if the investigator decides that it is needed due to toxicity or medical necessity. Starting or increasing the dose of UC specific therapy (or any limiting/prohibited drug or therapy) during induction study 2 will prohibit participants from entering the maintenance study.

Results

Top line result summarization

A total of 327 participants were randomly grouped and dosed at 141 sites in 27 countries. Most (47.4%) of the participants were from eastern europe, with the remaining participants distributed in asia (23.2%) and elsewhere in the world (29.4%). Notably, 1 participant was randomly grouped but never received study intervention.

Of the randomly grouped and treated participants, 313 (95.7%) had a modified Mayo score of 5 to 9 (target population for the following efficacy and safety analysis).

Treatment and baseline characteristics of the full analysis set (n=313):

overall, 9 (2.9%) participants discontinued study treatment before week I-12. There were 5 (4.8%) interruptions in the placebo group, 3 (3.0%) interruptions in the 200mg IV archaeolizumab group, and 1 (0.9%) interruptions in the 400mg IV archaeolizumab group. For the placebo group, 4 out of 5 interruptions were due to the lack of efficacy indicated. The most common reasons for discontinuing treatment prior to weeks I-12 are adverse events due to worsening UC (1.0%) and subject withdrawal (1.0%). No participants discontinued study medication before week I-12 for COVID-19 related reasons.

Most of the participants were caucasians (71.6%) and 59.1% of the participants were females. The average age was 41.6 years (ranging from 18 to 84 years). A total of 147 (47.0%) participants had a history of advanced therapy (ADT) failure; 166 (53.0%) failed in conventional therapy but not advanced therapy, and most of these participants (93.4%) were untreated with ADT. Approximately 40% of the participants received corticosteroids (including budesonide and beclomethasone dipropionate) at baseline, and 21.7% received immunomodulators (6-mercaptopurine, azathioprine, or methotrexate). About 90% of the participants had a history of inadequate, intolerance or dependence on corticosteroids and/or 6-MP/AZA.

The population in this study represents a population with moderate to severe active UC. The average duration of UC was 7.55 years. Median Mayo score was 9.0 (average=9.2), median modified Mayo score was 7.0 (average=7.0), median fecal calprotectin was 1564.0mg/kg, and median C-reactive protein (CRP) concentration was 4.6mg/L. At baseline, 48.9% of the participants had extensive disease, 82.4% had moderate UC (i.e., mayo score >6 and 10), and 17.6% had severe disease (Mayo score > 10), and endoscopy of 30% of the participants was sub-divided into 2 (i.e., moderate disease), and endoscopy of 70% of the participants was sub-divided into 3 (i.e., severe disease).

Baseline demographics (including regions), disease characteristics, concomitant UC drugs, and UC drug history are typically well balanced in the treatment group. However, a higher proportion of the participants in the 400mg IV Gu Saiku mab group had a broad disease (55.1%) than the placebo group (43.8%) and the 200mg IV archaebankab group (47.5%).

Summary of efficacy endpoints:

o-coumarone induction treatment (at the two doses evaluated) resulted in significantly higher clinical response rates at weeks I-12 (primary endpoint).

O relative to placebo, the archaebankab induction treatment (at the two doses evaluated) also resulted in higher rates of clinical relief, symptomatic relief, endoscopic healing, histological-endoscopic mucosal healing and endoscopic normalization at weeks I-12.

The main end point is:

based on a preliminary analysis of clinical response at weeks I-12, a significantly greater proportion of the participants in the 200mg IV and 400mg IV placebo groups had clinical response at weeks I-12 than the archaebacterium group. This study was considered an active study (fig. 1).

Important secondary endpoint:

a greater proportion of the participants in the 200mg IV and 400mg IV archaebankizumab groups achieved clinical relief, symptomatic relief, endoscopic healing and endoscopic normalization at weeks I-12 compared to the placebo group (fig. 2, table 1).

For symptom relief, separation between the archaebankizumab treated group and placebo was observed as early as 4 weeks after the first dose and continued until weeks I-12 (fig. 3).

Table 1. Summary of important secondary endpoints at weeks I-12; full analysis set

Subgroup analysis by ADT failure status:

o for the primary endpoint and all important secondary endpoints of ADT failed and ADT non-failed subgroups, higher efficacy than placebo was observed in both archaebankizumab groups, except for endoscope normalization. For endoscope normalization, in the ADT non-failing subgroup, higher efficacy than placebo was observed in the two archaebankizumab groups; however, in the ADT failure subgroup, no higher efficacy than placebo was observed in either of the archaebankizumab groups.

In general, the proportion of participants meeting the primary endpoint and important secondary endpoint in the ADT non-failing subgroup is greater in the treatment group than in the ADT failing subgroup.

O the treatment effect (relative to placebo) was greater in the ADT non-failing subgroup compared to the ADT failing subgroup in the primary endpoint and the important secondary endpoint.

Notably, these sub-groups are based on a relatively small number of participants per group, and should be interpreted carefully.

Table 2: a total summary of treatment emergent adverse events by week I-12; security analysis set

^a Adverse events that are likely, likely or highly likely to be related to the study agent or if the relationship to the study agent is missing are assessed by the investigator.

^b Infection assessed by the investigator.

Safety data by week I-12 based on safety analysis set:

the average duration of follow-up in the o-treated group was similar.

The proportion of participants reporting 1 or more Adverse Events (AEs) in the o-coumarone mab group was not higher than in the placebo group, and no clinically significant differences in AE rates were observed in the coumarone mab group.

O the Systemic Organ Category (SOC) with the most frequently reported AEs were infection and infestation (11.5% combined Gu Saiku mab; 10.5% placebo), gastrointestinal disorder (9.6% combined Gu Saiku mab; 17.1% placebo) and blood and lymphatic system disorder (9.6% combined Gu Saiku mab; 14.3% placebo).

The most common Preferred Terms (PT) in the o-combination Gu Saiku mab group are anemia (7.2%), headache (4.3%) and COVID-19 (3.8%).

O the PT of anemia in the treatment group was comparable (9.5% in placebo group, 6.9% in 200mg IV group and 7.5% in 400mg IV group).

The proportion of participants reporting 1 or more severe AEs in the o-guluroumab-treated group was not higher than in the placebo group. Most SAE are exacerbations of UC. Death was not reported.

O the AEs resulting in treatment discontinuation were lower and comparable in all treatment groups (2 in placebo group, 1 in 200mg IV group, and 0 in 400mg IV group of archaebankab) (table 2).

In the treatment group, the proportion of the participants of the AE identified by the researchers reporting the infection was comparable (11.4% in the placebo group, 12.9% in the 200mg IV group and 8.4% in the 400mg IV group).

Two severe infections were observed and both occurred in the placebo group.

No active TB cases are reported.

No opportunistic infections are reported.

No malignancy cases.

Liver laboratory values were similar by week I-12 in the treatment group. Elevation of transaminase is low grade (common term standard for adverse events [ CTCAE ] grade 1). No case meets the Hold's law standard (Hy' S LAW CRITERIA) (i.e., total bilirubin >2 x upper normal value limit [ ULN ]

And aspartate aminotransferase [ AST ] or ALT.gtoreq.3×ULN at the same time point).

By week I-12, the incidence of total WBC count reduction was higher in the archaebankizumab treated group compared to placebo. All total WBC anomalies are CTCAE grade 1 or grade 2.

Week 24 results for patients not in clinical response at week 12

QUASAR induction study 1 (NCT 04033445) is a phase 2b study evaluating Gu Saiku mab (GUS) therapy in patients with Ulcerative Colitis (UC) who are either insufficiently responsive or intolerant to conventional therapies (i.e., thiopurine or corticosteroids) or higher therapies (i.e., tumor necrosis factor alpha antagonists, vedolizumab or tofacitinib). Patients with clinical response at week 12 post IV induction entered the maintenance study, and patients not in clinical response received treatment for an extended induction period.

The method comprises the following steps:

the patients included had moderate to severe active UC (modified Mayo score 5 to 9, with Mayo rectal bleeding sub-score ≡1 and Mayo endoscopic sub-score ≡2). At weeks 0, 4 and 8, patients were randomized 1:1:1 into IV GUS200mg, 400mg or Placebo (PBO). Patients not in clinical response to IV induction received SC treatment at week 12 (PBOIV→GUS200mg IV; GUS200mg IV→GUS200mg SC; GUS400 mg IV→GUS200mg SC at weeks 12, 16 and 20) and were evaluated at week 24.

313 Patients were randomized at baseline. In the treatment group, the demographics and disease characteristics at baseline were similar (average age, 41.6 years; male 59.1%; average UC duration, 7.55 years; average Mayo score, 9.2; endoscopy sub-division 3, indicating severe disease, 70%; oral corticosteroid use 39.9%) and approximately 50% had prior inadequate or intolerance to advanced UC therapy.

At week 12, at baseline, 27.6% (29/105) and 61.4% (62/101) and 60.7% (65/107) of patients randomized to PBO IV and patients randomized to GUS200mg and GUS 400mg IV had clinical responses, respectively. In patients in the GUS group who were not in clinical response at week 12, a clinical response was achieved at week 24 with 54.3% (19/35) of GUS200mg IV to 200mg SC and 50.0% (19/38) of GUS 400mg IV to 200mg SC. Tables 16 to 21 show the number of subjects in clinical remission and clinical response at week 24. At Wk 12 or 24, 80.2% of patients receiving 200mg IV to 200mg SC of GUS and 78.5% of patients receiving 400mg IV to 200mg SC of GUS achieved a clinical response.

Conclusion(s)

Patients who did not achieve a clinical response to GUS IV induction at Wk 12 showed benefits at Wk 24 after receiving three SC doses of GUS, with approximately 80% of patients receiving GUS IV or GUS IV→SC achieving a clinical response at Wk 12 or 24. No new security issues were found with GUS.

The following table shows various baseline patient characteristics and efficacy measurements for this study.

Elements: ADT = advanced therapy, TNF = tumor necrosis factor, UC = ulcerative colitis.

Note that: including adalimumab, golimumab, infliximab, tofacitinib, vedolizumab and biosimilar.

Elements: uc=ulcerative colitis.

Elements: 6-mp=6-mercaptopurine, adt=advanced therapy, azo=azathioprine, uc=ulcerative colitis.

Elements: crp=c reactive protein, iq=quartile, sd=standard deviation.

^a Clinical response is defined as an improvement in Mayo score of greater than or equal to 30% and greater than or equal to 2% less than the induction baseline, wherein the rectal bleeding sub-score is greater than or equal to 1% less than the baseline or the rectal bleeding sub-score is 0 or 1.

^b Subjects who either refrain from altering UC medication, ostomy or colectomy prior to visit I-12 or discontinue study medication due to lack of efficacy or AE with worsening UC are not considered to be in clinical response.

^c Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^d Subjects lacking one or more Mayo subfractions associated with this endpoint (frequency of bowel movement, rectal bleeding, or endoscopy) at weeks I-12 were considered not to be in clinical response.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

^a Clinical relief is defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopic sub-divided into 0 or 1, and no fragility in endoscopic examination, where stool frequency sub-divided is not increased over the induction baseline.

^b Subjects who either refrain from altering UC medication, ostomy or colectomy prior to visit I-12 or discontinue study medication due to lack of efficacy or AE with worsening UC are not considered to be in clinical remission.

^c Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^d Subjects lacking one or more Mayo subfractions associated with this endpoint (frequency of bowel movement, rectal bleeding, or endoscopy) at weeks I-12 were not considered to be in clinical remission.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

^a Symptomatic relief is defined as a sub-division of defecation frequency of 0 or 1 and a sub-division of rectal bleeding of 0, wherein the defecation frequency is not increased from the induction baseline.

^b Subjects who either refrain from altering UC medication, ostomy or colectomy prior to visit I-12 or discontinue study medication due to lack of efficacy or AE with worsening UC are not considered to be in symptomatic relief.

^c Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^d Subjects lacking one or more Mayo subfractions associated with this endpoint (frequency of bowel movement and/or rectal bleeding) at weeks I-12 were not considered to be in symptomatic relief.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

^a Symptomatic relief is defined as a sub-division of defecation frequency of 0 or 1 and a sub-division of rectal bleeding of 0, wherein the defecation frequency is not increased from the induction baseline.

^b Inhibiting alteration of UC drugs, ostomies or colectomy prior to the indicated time point or due to lack of efficacy or AE with worsening UC

Subjects who are not on study of the agent are not considered to be in symptomatic relief.

^c Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^d Subjects lacking one or more Mayo subfractions associated with this endpoint (frequency of bowel movement and/or rectal bleeding) at the indicated time points were considered not to be in symptomatic relief.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

^a Endoscopic healing is defined as endoscopy being sub-divided into 0 or 1 and there is no fragility in endoscopy.

^b Subjects who either refrain from altering UC medication, ostomy or colectomy prior to visit I-12 or discontinue study medication due to lack of efficacy or AE with worsening UC are considered to achieve endoscopic healing.

^c Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^d Subjects lacking endoscopic subfractions at weeks I-12 were considered not to achieve endoscopic healing.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

^a Histological-endoscopic mucosal healing is defined as the combination of achieving histological healing and endoscopic healing.

^b Subjects who either refrain from altering UC drugs, ostomies or colectomy prior to visit I-12 or discontinue study medication due to lack of efficacy or AE with worsening UC are considered to achieve histological-endoscopic mucosal healing.

^c Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^d Subjects with an undesireable biopsy (i.e., a collected biopsy but not assessed due to sample preparation or technical errors) or a lack of an endoscopic subfraction or any histological component associated with this endpoint (i.e., evaluation of neutrophils, crypt destruction, or erosion or ulceration or granulation tissue in the epithelium) at weeks I-12 were considered to have failed histological-endoscopic mucosal healing.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

^a Endoscope normalization is defined as endoscopy sub-division 0.

^b Subjects who either refrain from altering UC medication, ostomy or colectomy prior to visit I-12 or discontinue study medication due to lack of efficacy or AE with worsening UC are considered to achieve endoscopic normalization.

^c Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^d Subjects lacking endoscopic subfractions at weeks I-12 were considered not to achieve endoscopic normalization.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

Elements: ADT = advanced therapy, IBDQ = inflammatory bowel disease questionnaire, PROMO = patient report outcome measure information system.

^a1 Clinical response is defined as an improvement in Mayo score of greater than or equal to 30% and greater than or equal to 2% less than the induction baseline, wherein the rectal bleeding sub-score is greater than or equal to 1% less than the baseline or the rectal bleeding sub-score is 0 or 1.

^a2 Clinical relief is defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopic sub-divided into 0 or 1, and no fragility in endoscopic examination, where stool frequency sub-divided is not increased over the induction baseline.

^a3 Symptomatic relief is defined as a sub-division of defecation frequency of 0 or 1 and a sub-division of rectal bleeding of 0, wherein the defecation frequency is not increased from the induction baseline.

^a4 Endoscopic healing is defined as endoscopy being sub-divided into 0 or 1 and there is no fragility in endoscopy.

^a5 Endoscope normalization is defined as endoscopy sub-division 0.

^b Subjects who either refrain from altering UC drugs, ostomies or colectomy prior to the indicated time point or discontinue study medication due to lack of efficacy or AE with worsening UC are considered not to reach the indicated key efficacy endpoint.

^c Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^d Subjects lacking one or more components associated with an endpoint at a given time point are considered not to reach the endpoint. Subjects with an undesireable biopsy (i.e., a collected biopsy, but not assessed due to sample preparation or technical errors) were considered not to reach a histological endpoint.

^e The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

Elements: ADT = advanced therapy, IBDQ = inflammatory bowel disease questionnaire, PROMO = patient report outcome measure information system.

^a1 Clinical response is defined as an improvement in Mayo score of greater than or equal to 30% and greater than or equal to 2% less than the induction baseline, wherein the rectal bleeding sub-score is greater than or equal to 1% less than the baseline or the rectal bleeding sub-score is 0 or 1.

^a2 Clinical relief is defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopic sub-divided into 0 or 1, and no fragility in endoscopic examination, where stool frequency sub-divided is not increased over the induction baseline.

^a3 Symptomatic relief is defined as a sub-division of defecation frequency of 0 or 1 and a sub-division of rectal bleeding of 0, wherein the defecation frequency is not increased from the induction baseline.

^a4 Endoscopic healing is defined as endoscopy being sub-divided into 0 or 1 and there is no fragility in endoscopy.

^a5 Endoscope normalization is defined as endoscopy sub-division 0.

^b Subjects who either refrain from altering UC drugs, ostomies or colectomy prior to the indicated time point or discontinue study medication due to lack of efficacy or AE with worsening UC are considered not to reach the indicated key efficacy endpoint.

^c Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^d Subjects lacking one or more components associated with an endpoint at a given time point are considered not to reach the endpoint. Subjects with an undesireable biopsy (i.e., a collected biopsy, but not assessed due to sample preparation or technical errors) were considered not to reach a histological endpoint.

^e The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Subjects not in clinical response at week I-12 and receiving treatment from week I-12 were determined by IWRS.

^b Clinical relief is defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopic sub-divided into 0 or 1, and no fragility in endoscopic examination, where stool frequency sub-divided is not increased over the induction baseline.

^c Subjects who either refrain from altering UC medication, ostomy or colectomy prior to visit I-24 weeks or discontinue study medication due to lack of efficacy or AE with worsening UC are not considered to be in clinical remission.

^d Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^e Subjects lacking one or more Mayo subfractions associated with this endpoint (frequency of bowel movement, rectal bleeding, or endoscopy) at weeks I-24 were not considered to be in clinical remission.

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Clinical relief is defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopic sub-divided into 0 or 1, and no fragility in endoscopic examination, where stool frequency sub-divided is not increased over the induction baseline.

^b Subjects who either refrain from altering UC drugs, ostomies or colectomy prior to the indicated time point or discontinue study medication due to lack of efficacy or AE with worsening UC are not considered to be in clinical remission.

^c Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing. ^d Subjects lacking one or more Mayo subfractions associated with this endpoint (frequency of bowel movement, rectal bleeding, or endoscopy) at the indicated time points are not considered to be in clinical remission.

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Clinical relief is defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopic sub-divided into 0 or 1, and no fragility in endoscopic examination, where stool frequency sub-divided is not increased over the induction baseline.

^b Subjects who either refrain from altering UC drugs, ostomies or colectomy prior to the indicated time point or discontinue study medication due to lack of efficacy or AE with worsening UC are not considered to be in clinical remission.

^c Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^d Subjects lacking one or more Mayo subfractions associated with this endpoint (frequency of bowel movement, rectal bleeding, or endoscopy) at the indicated time points are not considered to be in clinical remission.

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Subjects not in clinical response at week I-12 and receiving treatment from week I-12 were determined by IWRS.

^b Clinical response is defined as an improvement in Mayo score of greater than or equal to 30% and greater than or equal to 2% less than the induction baseline, wherein the rectal bleeding sub-score is greater than or equal to 1 score less than the baseline or the rectal bleeding sub-score is 0 or 1 score.

^c Subjects who either refrain from altering UC medication, ostomy or colectomy prior to visit I-24 weeks or discontinued study medication due to lack of efficacy or AE with worsening UC are not considered to be in clinical response.

^d Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^e Subjects lacking one or more Mayo subfractions associated with this endpoint (frequency of bowel movement, rectal bleeding, or endoscopy) at weeks I-24 were considered not to be in clinical response.

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Clinical response is defined as an improvement in Mayo score of greater than or equal to 30% and greater than or equal to 2% less than the induction baseline, wherein the rectal bleeding sub-score is greater than or equal to 1% less than the baseline or the rectal bleeding sub-score is 0 or 1.

^b Subjects who either refrain from altering UC drugs, ostomies or colectomy prior to the indicated time point or discontinue study medication due to lack of efficacy or AE with worsening UC are not considered to be in clinical response.

^c Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^d Subjects lacking one or more Mayo subfractions associated with this endpoint (frequency of bowel movement, rectal bleeding, or endoscopy) at the indicated time points were considered not to be in clinical response.

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Clinical response is defined as an improvement in Mayo score of greater than or equal to 30% and greater than or equal to 2% less than the induction baseline, wherein the rectal bleeding sub-score is greater than or equal to 1% less than the baseline or the rectal bleeding sub-score is 0 or 1.

^b Subjects who either refrain from altering UC drugs, ostomies or colectomy prior to the indicated time point or discontinue study medication due to lack of efficacy or AE with worsening UC are not considered to be in clinical response.

^c Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^d Subjects lacking one or more Mayo subfractions associated with this endpoint (frequency of bowel movement, rectal bleeding, or endoscopy) at the indicated time points were considered not to be in clinical response.

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Subjects not in clinical response at week I-12 and receiving treatment from week I-12 were determined by IWRS.

^b Endoscope normalization is defined as endoscopy sub-division 0.

^c Subjects who either refrain from altering UC medication, ostomy or colectomy prior to visit I-24 weeks or discontinue study medication due to lack of efficacy or AE with worsening UC are considered to achieve endoscopic normalization.

^d Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^e Subjects lacking endoscopic subfractions at weeks I-24 were considered not to achieve endoscopic normalization.

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Subjects not in clinical response at week I-12 and receiving treatment from week I-12 were determined by IWRS.

^b Endoscopic healing is defined as endoscopy being sub-divided into 0 or 1 and there is no fragility in endoscopy.

^c Subjects who either refrain from altering UC medication, ostomy or colectomy prior to visit I-24 weeks or discontinue study medication due to lack of efficacy or AE with worsening UC are considered to achieve endoscopic healing.

^d Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^e Subjects lacking endoscopic subfractions at weeks I-24 were considered not to achieve endoscopic healing.

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Subjects not in clinical response at week I-12 and receiving treatment from week I-12 were determined by IWRS.

^b Histological-endoscopic mucosal healing is defined as the combination of achieving histological healing and endoscopic healing.

^c Subjects who either refrain from altering UC drugs, ostomies or colectomy prior to visit I-24 or discontinue study medication due to lack of efficacy or AE with worsening UC are considered to achieve histological-endoscopic mucosal healing.

^d Data following discontinuation of study dose for COVID-19 related reasons (excluding COVID-19 infection) were considered missing.

^e Subjects with an undesireable biopsy (i.e., a collected biopsy but not assessed due to sample preparation or technical errors) or a lack of an endoscopic subfraction or any histological component associated with this endpoint (i.e., evaluation of neutrophils, crypt destruction, or erosion, or ulcers or granulations in the epithelium) were considered to not achieve histological-endoscopic mucosal healing.

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Including data from subjects receiving treatment at weeks I-12 up to weeks I-12. All data up to the last safety visit for subjects not receiving treatment at weeks I-12 are included.

^b Including data from weeks I-12.

^c Starting from the first dose of the coumarone IV; subjects receiving Gu Saiku mab 200mg at week I-12 SC included data up to week I-12. ^d From the first dose of the antique pessary mab.

^e Adverse events that are likely, likely or highly likely to be related to the study agent or if the relationship to the study agent is missing are assessed by the investigator.

^f Infection assessed by the investigator.

^g Injection site response assessed by the investigator.

EXAMPLES 2-3 phase study results

Phase 3 induction study trial design:

Phase 3 induction studies were randomized, double-blind, placebo-controlled, parallel, multi-center study. The target population consisted of participants with moderate to severe active Ulcerative Colitis (UC) who have demonstrated inadequate responses or failed tolerance to: conventional therapies (i.e., 6-mercaptopurine [6-MP ], azathioprine [ AZA ] or corticosteroids) or advanced therapies (ADT; i.e., tumor necrosis factor-alpha [ TNF alpha ] antagonists, vedolizumab or tofacitinib). At week I-0, the participants had to have moderate to severe activity UC, defined as a modified Mayo score of 5 to 9 (including 5 and 9), a Mayo rectal bleeding sub-score of ≡1 and a Mayo endoscopic sub-score of ≡2, using the Mayo endoscopic sub-score obtained during the center examination of video endoscopy. The QUASAR program also allows for the inclusion of participants with a modified Mayo score of 4, with an upper limit of ∈5% of the total population. The regimen is modified according to health regulatory agency feedback so that the target group should be based solely on participants with improved Mayo scores of 5 to 9.

Treatment distribution: at week I-0, participants were randomly grouped into either tangkuzumab or placebo at a 3:2 ratio using ADT-failure status (i.e., failure to respond or tolerate to either TNFα antagonist, vedolizumab, or tofacitinib) (yes/no), regional (east Europe, asia, or elsewhere in the world), and alignment blocks with concomitant use of corticosteroid (yes/no) as a stratification variable at baseline with allocation:

Group 1: placebo IV (weeks I-0, I-4 and I-8)

Group 2: 200mg IV of Gu Sai Ku Bian (weeks I-0, I-4 and I-8)

Duration of treatment: the main part of the study was 12 weeks.

The report provides results for primary and important secondary endpoints at weeks I-12, as well as safety up to week I-12.

The main end point is: the primary endpoints were clinical remissions at weeks I-12, defined as Mayo bowel frequency sub-divided into 0 or 1 and no increase over baseline, mayo rectal bleeding sub-divided into 0, and Mayo endoscopy sub-divided into 0 or 1, and endoscopy was not brittle.

Important secondary endpoint:

Symptomatic relief at weeks I-12: stool frequency was sub-divided into 0 or 1 and no increase over baseline, and rectal bleeding was sub-divided into 0.

Endoscopic healing at weeks I-12: endoscopy is sub-divided into 0 or 1, and there is no brittleness in endoscopy.

Clinical response at weeks I-12: the improved Mayo score decreased by more than or equal to 30% and more than or equal to 2 minutes from baseline, wherein the rectal bleeding sub-score decreased by more than or equal to 1 minute from baseline or the rectal bleeding sub-score was 0 or 1 minute.

Symptomatic relief at weeks I-4.

Inflammatory Bowel Disease Questionnaire (IBDQ) alleviation at weeks I-12: the total IBDQ score is more than or equal to 170.

Histological-endoscopic mucosal healing at weeks I-12: a combination of histological healing and endoscopic healing is achieved, wherein endoscopic healing is defined above and histological healing is defined as neutrophil infiltration of <5% of the crypts, no crypt destruction, and no erosion, ulceration or granulation tissue according to the Geboes classification system.

Fatigue response at weeks I-12: an improvement of ≡7 in PROMO-fatigue profile 7 a.

Symptomatic relief at week I-2.

Endoscopic subfractions at week I-12 endoscope normalization: 0

All important secondary endpoints were 90% efficacy except the endpoint of symptomatic relief at weeks I-2 and the endpoint of endoscope normalization at weeks I-12.

Statistical considerations:

Efficacy analysis set: the full analysis set included all randomized group participants with a modified Mayo score of 5 to 9 who received at least 1 (partial or complete) study intervention. Participants analyzed based on their randomized groupings or assignments of study interventions, regardless of the study interventions they actually accepted.

Security analysis set: the safety analysis set included all randomized group participants with a modified Mayo score of 5 to 9 who received at least 1 (partial or complete) study intervention. Results based on a safety whole therapy analysis set are also provided, which include all randomized group participants (without consideration of the modified Mayo score) who received at least 1 (partial or complete) study intervention. Participants were analyzed according to the study intervention they actually received.

Concurrent Events (ICEs) were used in the analysis of efficacy endpoints. In particular, participants who underwent UC-related surgery (ostomy or colectomy) prior to the analysis time point, were prohibited from altering the UC drug, or discontinued study intervention for reasons other than coronavirus 19 (COVID-19) -related reasons (excluding COVID-19 infection) or regional crisis of russia and ukraine (including AEs lacking efficacy or worsening of UC) were considered to not reach the endpoint of the binary endpoint (i.e., compounding strategy). For participants who discontinued study intervention prior to the analysis time point for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis in russia and ukraine, their observations (i.e., treatment guideline strategies) will be used if available.

Comparison was based on the archaebankab group versus the placebo group. For primary endpoint and important secondary endpoint, p-values were based on Cochran-Mantel-Haenszel (CMH) (2-side), which stratified by ADT-failure status (yes/no) and concomitant corticosteroid usage at baseline (yes/no). The 95% confidence interval is based on Wald statistics with CochranMantel-Haenszel weights. For these endpoints, participants who were missing data at the analysis time point (after considering the concurrency event policy) were considered non-responders at that time point.

Top line result summarization

A total of 735 participants were randomly grouped and dosed at 240 sites in 32 countries. Most (41.5%) of the participants were from eastern europe, with the remaining participants distributed in asia (20.5%) and elsewhere in the world (38.0%). Notably, 1 participant was randomized to the placebo group but never received study intervention. Of the randomly grouped and treated participants, 701 (95.4%) had a modified Mayo score of 5 to 9 (target population for the following efficacy and safety analysis).

Treatment and baseline characteristics of the full analysis set (n=701):

In summary, 42 (6.0%) participants discontinued study intervention at week I-12: study intervention was discontinued in 24 (8.6%) of the placebo group and discontinued in 18 (4.3%) of the 200mg IV archaebankab group. The most common reasons for discontinuing study intervention prior to weeks I-12 are adverse events (2.4%; 1.4% due to worsening UC) and participant withdrawal (2.3%).

Most of the participants were caucasians (72.5%) and 56.9% of the participants were females. The average age was 40.5 years (ranging from 18 years to 79 years). A total of 344 (49.1%) participants had a history of ADT failure; 357 (50.9%) failed in conventional therapy, but not advanced therapy ("ADT failed"), and most of these participants (95.0%) were untreated with ADT. Approximately 43.1% of the participants received corticosteroids (including budesonide and beclomethasone dipropionate) at baseline, and 20.5% received immunomodulators (6-MP, azo or methotrexate). A total of 93.2% of the participants had a history of inadequate, intolerance or dependence on the corticosteroid and/or 6-MP/AZA response.

The enrolled population in this study represents a population with moderate to severe active UC. The average duration of UC was 7.27 years. Median Mayo score was 9.0 (average=9.1), median modified Mayo score was 7.0 (average=6.9), median fecal calprotectin was 1641.0mg/kg, and median C-reactive protein (CRP) concentration was 4.2mg/L. At baseline, 47.8% of the participants had extensive disease, 82.2% had moderate UC (i.e., mayo score > 6 and 10), and 17.8% had severe disease (Mayo score > 10), and endoscopy of 32.1% of the participants was sub-divided into 2 (i.e., moderate disease), and endoscopy of 67.9% of the participants was sub-divided into 3 (i.e., severe disease).

Baseline demographics (including regions), disease characteristics, concomitant UC drugs, and UC drug history are typically well balanced in the treatment group.

Summary of efficacy endpoints:

Based on the pre-specified multiplex test procedure, the archaebacteria induced treatment resulted in a significantly greater proportion of participants in clinical remission at weeks I-12 (primary endpoint; 22.6%) than placebo (7.9%; adjusted treatment difference: 14.9% [95% CI:9.9%,19.9% ]); the results were highly pronounced (p < 0.001) (table 26).

The treatment induced by the coumarone also resulted in a significantly greater proportion of participants reaching important secondary endpoints (highly significant, p < 0.001) relative to placebo.

The main end point is: based on a preliminary analysis of clinical remission at weeks I-12, a significantly greater proportion of the participants in the 200mg IV Gu Saiku mab group (22.6%) were in clinical remission at weeks I-12 than placebo (7.9%; adjusted treatment difference: 14.9% [95% CI:9.9%,19.9% ]; table 26).

Important secondary endpoint:

Based on global and us specific test procedures, a significantly greater proportion of participants in the 200mg IV Gu Saiku mab group achieved symptomatic relief (adjusted treatment difference: 29.5% [95% CI:22.9%,36.1% ]; table 35), endoscopic healing (adjusted treatment difference: 16.0% [95% CI:10.5%,21.4% ]; table 29), clinical response (adjusted treatment difference: 34.2% [95% CI:27.3%,41.1% ]; table 27), histological-endoscopic music healing (adjusted treatment difference: 15.9% [95% CI:10.9%,20.9% ]; table 33), fatigue response (adjusted treatment difference: 19.8% [95% CI:13.1%,26.4% ]; table 34), all at weeks I-12; and symptom relief at week I-4 (treatment differences after adjustment: 10.3% [95% CI:4.8%,15.7% ]) (Table 35).

Based on global test procedure, a significantly greater proportion of participants in the 200mg IV Gu Saiku mab group achieved IBDQ remission at weeks I-12 (adjusted treatment differences: 22.1% [95% ci:15.1%,29.2% ]; table 32). Note that IBDQ remission at weeks I-12 is not considered an important secondary endpoint in the us specificity test program.

There was no significant difference in symptom relief at week I-2 in the 200mg IV Gu Saiku mab group versus placebo group (post-adjustment treatment difference: 3.0% [95% CI: -1.5%,7.5% ]; table 35).

Although a greater proportion of the participants in the 200mg IV Gu Saiku mab group achieved endoscope normalization at weeks I-12 than the placebo group (adjusted treatment differences: 10.1% [95% ci:5.9%,14.3% ]; table 28) were not statistically significant for this endpoint, as the previous endpoint in the test grading (symptom relief at weeks I-2) was not significant.

For symptom relief, separation between the archaebankizumab and placebo group was observed as early as 4 weeks after the first dose and continued until weeks I-12 (table 35).

Subgroup analysis by ADT failure status:

For ADT failure and ADT failure subgroups, higher efficacy of the coumarone compared to placebo was observed for the primary endpoint and all important secondary endpoints (except for symptomatic relief at weeks I-2).

Generally, the proportion of participants who met the primary endpoint and important secondary endpoint in the ADT non-failing subgroup is greater in the treatment group than in the ADT failing subgroup.

In addition to the fatigue response at weeks I-12, the therapeutic effect (relative to placebo) was greater in the ADT non-failing subgroup compared to the ADT failing subgroup in the primary and important secondary endpoints.

Safety: table 38 provides a general summary of adverse events up to week I-12 for the safety analysis set (n=701). In summary, 200mg IV of archaebankab was safe during 12 weeks of treatment and well tolerated by the participants. No new safety issues were found based on adverse events and laboratory studies. Adverse events are discussed below; laboratory results observations were consistent with QUASAR induction study 1. Similar results were observed for the safety whole therapy analysis set.

Safety data by week I-12 based on safety analysis set:

The average duration of follow-up in the treatment group was similar.

The proportion of participants reporting 1 or more Adverse Events (AEs) in the 200mg IV archaebankizumab group was similar to the placebo group.

The most frequently reported Systemic Organ Categories (SOCs) are infection and infestation (15.7% of coumarone; 15.0% placebo) and gastrointestinal disorders (10.7% of coumarone; 16.4% placebo).

The most common Preferred Terms (PT) in the 200mg IV group of coumarone are COVID-19 (5.0% coumarone; 4.3% placebo), anemia (4.8% coumarone; 6.8% placebo) and headache (2.9% coumarone; 2.9% placebo).

AE (6 [1.4% ] in the 200mg IV archaebankab group and 1[0.4% ] in the placebo group) were reported by 7 participants within 1 hour of infusion; none of these AEs was severe or resulted in discontinuation of study intervention. No allergic or serological reactions were reported.

Report 3 deaths (1 in 200mg IV archaebankizumab group and 2 in placebo group).

The proportion of participants reporting 1 or more severe AEs in the 200mg IV archaebankizumab group (2.9%) was numerically lower compared to the placebo group (7.5%). Most SAE is a worsening of UC (PT ulcerative colitis: 1.4% in the 200mg IV archaebankab group and 5.0% in the placebo group).

In the treatment group, AEs resulting in discontinuation of treatment were lower (6 [1.4% ] in the 200mg IV archaebankab group and 12[4.3% ] in the placebo group).

The proportion of participants reporting infected AEs was comparable in the treatment group (66 [15.7% ] in the 200mg IV archaebankab group and 42[15.0% ] in the placebo group).

4 Severe infections were reported (3 cases [0.7% ] in the 200mg IV archaebankab group and 1 case [0.4% ] in the placebo group).

No cases of active Tuberculosis (TB) were reported. An opportunistic infection (PT cytomegalovirus infection) was reported in the placebo group.

Two participants in the 200mg IV Gu Saiku mab group reported treatment of bursty malignancy for non-melanoma skin cancers on study day 23 and day 32, respectively.

Liver laboratory values were similar by week I-12 in the treatment group. Elevation of transaminase is low grade (common term standard for adverse events [ CTCAE ] grade 1). No cases met Hold's law biochemical criteria (i.e., total bilirubin. Gtoreq.2×upper normal [ ULN ] and aspartate aminotransferase [ AST ] or alanine aminotransferase [ ALT ]. Gtoreq.3×ULN) at the same time point)

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Clinical relief is defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopic sub-divided into 0 or 1, and no fragility in endoscopic examination, where stool frequency sub-divided is not increased over the induction baseline.

^b Concurrent Event (ICE) policy: subjects who underwent an ostomy or colectomy (ICE 1), prohibited replacement of UC drug (ICE 2), or discontinued study medication due to lack of efficacy or worsening of UC AE (ICE 3) at weeks I-12 were considered not in clinical remission at weeks I-12. For subjects who discontinued study medication prior to week I-12 for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4), their observations will be used if available. Subjects who experienced ICE 5 prior to week I-12 (discontinued study medication for reasons other than those of ICE 3 and 4) were considered not in clinical remission at weeks I-12.

^c Non-respondent attribution to missing data: after considering ICE, subjects lacking one or more Mayo subfractions associated with this endpoint (frequency of bowel movement, rectal bleeding, or endoscopy) at weeks I-12 were not considered to be in clinical remission.

^d The confidence interval for the proportion of subjects meeting the endpoint in each treatment group is based on the approximate confidence limits of the normal.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test, which is stratified by ADT-failure status (yes/no) and concomitant use of corticosteroid at baseline (yes/no).

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Clinical response is defined as an improvement in Mayo score of greater than or equal to 30% and greater than or equal to 2% less than the induction baseline, wherein the rectal bleeding sub-score is greater than or equal to 1% less than the baseline or the rectal bleeding sub-score is 0 or 1.

^b Concurrent Event (ICE) policy: subjects who underwent an ostomy or colectomy (ICE 1), prohibited replacement of UC drug (ICE 2), or discontinued study medication due to lack of efficacy or worsening of UC AE (ICE 3) at weeks I-12 were considered not in clinical response at weeks I-12. For subjects who discontinued study medication prior to week I-12 for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4), their observations will be used if available. Subjects who experienced ICE 5 prior to week I-12 (discontinued study medication for reasons other than those of ICE 3 and 4) were considered not to be in clinical response at weeks I-12.

^c Non-respondent attribution to missing data: after considering ICE, subjects lacking one or more Mayo subfractions associated with this endpoint (frequency of bowel movement, rectal bleeding, or endoscopy) at weeks I-12 were considered not to be in clinical response.

^d The confidence interval for the proportion of subjects meeting the endpoint in each treatment group is based on the approximate confidence limits of the normal.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test, which is stratified by ADT-failure status (yes/no) and concomitant use of corticosteroid at baseline (yes/no).

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Endoscope normalization is defined as endoscopy sub-division 0.

^b Concurrent Event (ICE) policy: subjects who underwent an ostomy or colectomy (ICE 1), prohibited replacement of UC drug (ICE 2), or discontinued study medication due to lack of efficacy or worsening of UC AE (ICE 3) at weeks I-12 were considered not to achieve endoscopic normalization at weeks I-12. For subjects who discontinued study medication prior to week I-12 for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4), their observations will be used if available. Subjects who underwent ICE 5 prior to week I-12 (discontinued study medication for reasons other than those of ICE 3 and 4) were considered not to achieve endoscope normalization at weeks I-12.

^c Non-respondent attribution to missing data: after considering ICE, subjects lacking an endoscopic subfraction at weeks I-12 were considered not to achieve endoscopic normalization.

^d The confidence interval for the proportion of subjects meeting the endpoint in each treatment group is based on the approximate confidence limits of the normal.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test, which is stratified by ADT-failure status (yes/no) and concomitant use of corticosteroid at baseline (yes/no).

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Endoscopic healing is defined as endoscopy being sub-divided into 0 or 1 and there is no fragility in endoscopy.

^b Concurrent Event (ICE) policy: subjects who underwent an ostomy or colectomy (ICE 1), prohibited replacement of UC drug (ICE 2), or discontinued study medication due to lack of efficacy or worsening of UC AE (ICE 3) at weeks I-12 were considered not to achieve endoscopic healing at weeks I-12. For subjects who discontinued study medication prior to week I-12 for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4), their observations will be used if available. Subjects who underwent ICE 5 prior to week I-12 (discontinued study medication for reasons other than those in ICEs 3 and 4) were considered not to achieve endoscopic healing at weeks I-12.

^c Non-respondent attribution to missing data: after considering ICE, subjects lacking an endoscopic subfraction at weeks I-12 were considered not to achieve endoscopic healing.

^d The confidence interval for the proportion of subjects meeting the endpoint in each treatment group is based on the approximate confidence limits of the normal.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test, which is stratified by ADT-failure status (yes/no) and concomitant use of corticosteroid at baseline (yes/no).

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a According to the Geboes classification system, histological healing is defined as neutrophil infiltration of <5% of the crypts, no crypt destruction, and no erosion, ulceration or granulation tissue.

^b Concurrent Event (ICE) policy: subjects who underwent ostomy or colectomy (ICE 1), prohibited replacement of UC drug (ICE 2), or discontinuation of study medication due to lack of efficacy or worsening of UC AE (ICE 3) at weeks I-12 were considered not to achieve histological healing at weeks I-12. For subjects who discontinued study medication prior to week I-12 for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4), their observations will be used if available. Subjects who underwent ICE 5 prior to week I-12 (discontinued study medication for reasons other than those in ICE 3 and 4) were considered not to achieve histological healing at weeks I-12.

^c Non-respondent attribution to missing data: after considering ICE, subjects with an undesireable biopsy (i.e., a collected biopsy but not assessed due to sample preparation or technical errors) or a loss of any component associated with this endpoint (i.e., assessment of neutrophils, crypt destruction, or erosion or ulceration or granulation in the epithelium) were considered to have failed histological healing.

^d The confidence interval for the proportion of subjects meeting the endpoint in each treatment group is based on the approximate confidence limits of the normal.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test, which is stratified by ADT-failure status (yes/no) and concomitant use of corticosteroid at baseline (yes/no).

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Histological remission is defined as the absence of neutrophils from the mucosa (both mucosal lamina propria and epithelium), no crypt destruction, and no erosion, ulceration or granulation tissue according to the Geboes classification system. This definition is equivalent to Robra histopathological indexes +.3, where the mucosal lamina propria neutrophils and neutrophils in the epithelium are sub-divided into 0 and there are no ulcers or erosion.

^b Concurrent Event (ICE) policy: subjects who underwent an ostomy or colectomy (ICE 1), prohibited replacement of UC drug (ICE 2), or discontinued study medication due to lack of efficacy or worsening of UC AE (ICE 3) at weeks I-12 were considered not to be in histological remission at weeks I-12. For subjects who discontinued study medication prior to week I-12 for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4), their observations will be used if available. Subjects who experienced ICE 5 prior to week I-12 (discontinued study medication for reasons other than those of ICE 3 and 4) were considered not to be in histological remission at weeks I-12.

^c Non-respondent attribution to missing data: after considering ICE, subjects with an undesireable biopsy (i.e., a collected biopsy but not assessed due to sample preparation or technical errors) or a lack of any histological component associated with this endpoint (i.e., assessment of neutrophils, crypt destruction, or erosion or ulceration or granulation in the mucosa lamina propria or epithelium) were considered not in histological remission.

^d The confidence interval for the proportion of subjects meeting the endpoint in each treatment group is based on the approximate confidence limits of the normal.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test, which is stratified by ADT-failure status (yes/no) and concomitant use of corticosteroid at baseline (yes/no).

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a IBDQ (inflammatory bowel disease questionnaire) remission is defined as total IBDQ score > 170.

^b Concurrent Event (ICE) policy: subjects who underwent an ostomy or colectomy (ICE 1), prohibited replacement of UC drug (ICE 2), or discontinuation of study medication due to lack of efficacy or worsening of UC AE (ICE 3) at weeks I-12 were considered not in IBDQ remission at weeks I-12. For subjects who discontinued study medication prior to week I-12 for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4), their observations will be used if available. Subjects who experienced ICE 5 prior to week I-12 (discontinued study medication for reasons other than those of ICE 3 and 4) were considered not to be in IBDQ remission at weeks I-12.

^c Non-respondent attribution to missing data: after considering ICE, subjects who had lost the total IBDQ score at weeks I-12 were considered not to be in IBDQ remission.

^d The confidence interval for the proportion of subjects meeting the endpoint in each treatment group is based on the approximate confidence limits of the normal.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test, which is stratified by ADT-failure status (yes/no) and concomitant use of corticosteroid at baseline (yes/no).

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Histological-endoscopic mucosal healing is defined as the combination of achieving histological healing and endoscopic healing. According to the Geboes classification system, histological healing is defined as neutrophil infiltration of <5% of the crypts, no crypt destruction, and no erosion, ulceration or granulation tissue. Endoscopic healing is defined as endoscopy being sub-divided into 0 or 1 and there is no fragility in endoscopy.

^b Concurrent Event (ICE) policy: subjects who underwent ostomy or colectomy (ICE 1), prohibited replacement of UC drug (ICE 2), or discontinuation of study medication due to lack of efficacy or worsening of UC AE (ICE 3) at weeks I-12 were considered not to achieve histological-endoscopic mucosal healing at weeks I-12. For subjects who discontinued study medication prior to week I-12 for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4), their observations will be used if available. Subjects who underwent ICE 5 prior to week I-12 (discontinued study medication for reasons other than those of ICE 3 and 4) were considered not to achieve histological-endoscopic mucosal healing at weeks I-12.

^c Non-respondent attribution to missing data: after considering ICE, subjects with an undesireable biopsy (i.e., a collected biopsy but not assessed due to sample preparation or technical errors) or a missing endoscopic subfraction or any histological component associated with this endpoint (i.e., evaluation of neutrophils, crypt destruction, or erosion or ulcers or granulations in the epithelium) were considered to not achieve histological-endoscopic mucosal healing.

^d Confidence intervals for the proportion of subjects meeting the endpoint in each treatment group are based on the approximate confidence limits of normal

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test, which is stratified by ADT-failure status (yes/no) and concomitant use of corticosteroid at baseline (yes/no).

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Fatigue response is defined as ≡7 score improvement over the induction baseline in PROMIS (patient report outcome measurement information System) fatigue profile 7 a.

^b Concurrent Event (ICE) policy: subjects who underwent an ostomy or colectomy (ICE 1), prohibited replacement of UC drug (ICE 2), or discontinued study medication due to lack of efficacy or worsening of UC AE (ICE 3) at weeks I-12 were considered not to be in fatigue response at weeks I-12. For subjects who discontinued study medication prior to week I-12 for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4), their observations will be used if available. Subjects who experienced ICE 5 prior to week I-12 (discontinued study medication for reasons other than those of ICE 3 and 4) were considered not to be in fatigue response at weeks I-12.

^c Non-respondent attribution to missing data: after considering ICE, subjects lacking one or more of the proci fatigue profile 7a items at induction baseline or weeks I-12 were considered not to be in fatigue response.

^d The confidence interval for the proportion of subjects meeting the endpoint in each treatment group is based on the approximate confidence limits of the normal.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test, which is stratified by ADT-failure status (yes/no) and concomitant use of corticosteroid at baseline (yes/no).

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Symptomatic relief is defined as a sub-division of defecation frequency of 0 or 1 and a sub-division of rectal bleeding of 0, wherein the defecation frequency is not increased from the induction baseline.

^b Concurrent Event (ICE) policy: subjects who underwent an ostomy or colectomy (ICE 1), prohibited replacement of UC drug (ICE 2), or discontinuation of study medication due to lack of efficacy or worsening of UC AE (ICE 3) at the indicated time points were considered not to be in symptomatic relief at the indicated time points.

For subjects who discontinued study medication prior to the indicated time point for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4), their observations will be used if available. Subjects who experienced ICE 5 (discontinued study medication for reasons other than those of ICEs 3 and 4) prior to the indicated time point were considered not to be in symptomatic relief at the indicated time point.

^c Non-respondent attribution to missing data: after considering ICE, subjects lacking one or more Mayo subfractions associated with this endpoint (frequency of bowel movement and/or rectal bleeding) at the indicated time points were considered not to be in symptomatic relief.

^d The confidence interval for the proportion of subjects meeting the endpoint in each treatment group is based on the approximate confidence limits of the normal.

^e The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^f The p-value is based on the Cochran-Mantel-Haenszel (CMH) chi-square test, which is stratified by ADT-failure status (yes/no) and concomitant use of corticosteroid at baseline (yes/no).

Elements: ADT = advanced therapy; IBDQ = inflammatory bowel disease questionnaire; proci = patient report outcome measurement information system;

note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a1 Clinical relief is defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopic sub-divided into 0 or 1, and no fragility in endoscopic examination, where stool frequency sub-divided is not increased over the induction baseline.

^a2 Symptomatic relief is defined as a sub-division of defecation frequency of 0 or 1 and a sub-division of rectal bleeding of 0, wherein the defecation frequency is not increased from the induction baseline.

^a3 Endoscopic healing is defined as endoscopy being sub-divided into 0 or 1 and there is no fragility in endoscopy.

^a4 Clinical response is defined as an improvement in Mayo score of greater than or equal to 30% and greater than or equal to 2% less than the induction baseline, wherein the rectal bleeding sub-score is greater than or equal to 1% less than the baseline or the rectal bleeding sub-score is 0 or 1.

^a5 IBDQ remission is defined as total IBDQ score > 170.

^a6 Histological-endoscopic mucosal healing is defined as the combination of achieving histological healing and endoscopic healing.

^a7 Fatigue response is defined as ≡7 score improvement over baseline in PROMIS fatigue profile 7 a.

^a8 Endoscope normalization is defined as endoscopy sub-division 0.

^a9 According to the Geboes classification system, histological healing is defined as neutrophil infiltration of <5% of the crypts, no crypt destruction, and no erosion, ulceration or granulation tissue.

^a10 Histological remission is defined as the absence of neutrophils from the mucosa (both mucosal lamina propria and epithelium), no crypt destruction, and no erosion, ulceration or granulation tissue according to the Geboes classification system.

^a11 Histological-endoscopic mucosal healing (alternative definition 1) is defined as the combination of achieving histological remission and endoscopic healing.

^a12 Deep histology-endoscopic mucosal healing is defined as the combination of achieving endoscopic normalization and histological remission.

^b The denominator is the subject who did not fail ADT.

^c Concurrent Event (ICE) policy: subjects who underwent an ostomy or colectomy (ICE 1), prohibited replacement of UC drug (ICE 2), or discontinuation of study medication due to lack of efficacy or worsening of UC AE (ICE 3) at the indicated time points were considered to not achieve any displayed key efficacy endpoint at the indicated time points. For subjects who discontinued study medication prior to the indicated time point for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4), their observations will be used if available. Subjects who experienced ICE 5 prior to the indicated time point (discontinued study medication for reasons other than those of ICE 3 and 4) were considered not to achieve any displayed key efficacy endpoint at the indicated time point.

^d Non-respondent attribution to missing data: after considering ICE, subjects lacking one or more components associated with an endpoint at a given time point are considered not to reach the endpoint. Subjects with an undesireable biopsy (i.e., a collected biopsy, but not assessed due to sample preparation or technical errors) were considered not to reach a histological endpoint.

^e The confidence interval for the proportion of subjects meeting the endpoint in each treatment group is based on the approximate confidence limits of the normal.

^f The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^g The p-value was based on the Cochran-Mantel-Haenszel (CMH) chi-square test, stratified by concomitant use of corticosteroid (yes/no) at baseline.

Elements: IBDQ = inflammatory bowel disease questionnaire; proci = patient report outcome measurement information system;

note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a1 Clinical relief is defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopic sub-divided into 0 or 1, and no fragility in endoscopic examination, where stool frequency sub-divided is not increased over the induction baseline.

^a2 Symptomatic relief is defined as a sub-division of defecation frequency of 0 or 1 and a sub-division of rectal bleeding of 0, wherein the defecation frequency is not increased from the induction baseline.

^a3 Endoscopic healing is defined as endoscopy being sub-divided into 0 or 1 and there is no fragility in endoscopy.

^a4 Clinical response is defined as an improvement in Mayo score of greater than or equal to 30% and greater than or equal to 2% less than the induction baseline, wherein the rectal bleeding sub-score is greater than or equal to 1% less than the baseline or the rectal bleeding sub-score is 0 or 1.

^a5 IBDQ remission is defined as total IBDQ score > 170.

^a6 Histological-endoscopic mucosal healing is defined as the combination of achieving histological healing and endoscopic healing.

^a7 Fatigue response is defined as ≡7 score improvement over baseline in PROMIS fatigue profile 7 a.

^a8 Endoscope normalization is defined as endoscopy sub-division 0.

^a9 According to the Geboes classification system, histological healing is defined as neutrophil infiltration of <5% of the crypts, no crypt destruction, and no erosion, ulceration or granulation tissue.

^a10 Histological remission is defined as the absence of neutrophils from the mucosa (both mucosal lamina propria and epithelium), no crypt destruction, and no erosion, ulceration or granulation tissue according to the Geboes classification system.

^a11 Histological-endoscopic mucosal healing (alternative definition 1) is defined as the combination of achieving histological remission and endoscopic healing.

^a12 Deep histology-endoscopic mucosal healing is defined as the combination of achieving endoscopic normalization and histological remission.

^b The denominator is the subject with biological failure.

^c Concurrent Event (ICE) policy: subjects who underwent an ostomy or colectomy (ICE 1), prohibited replacement of UC drug (ICE 2), or discontinuation of study medication due to lack of efficacy or worsening of UC AE (ICE 3) at the indicated time points were considered to not achieve any displayed key efficacy endpoint at the indicated time points. For subjects who discontinued study medication prior to the indicated time point for COVID-19 related reasons (excluding COVID-19 infection) or regional crisis (ICE 4), their observations will be used if available. Subjects who experienced ICE 5 prior to the indicated time point (discontinued study medication for reasons other than those of ICE 3 and 4) were considered not to achieve any displayed key efficacy endpoint at the indicated time point.

^d Non-respondent attribution to missing data: after considering ICE, subjects lacking one or more components associated with an endpoint at a given time point are considered not to reach the endpoint. Subjects with an undesireable biopsy (i.e., a collected biopsy, but not assessed due to sample preparation or technical errors) were considered not to reach a histological endpoint.

^e The confidence interval for the proportion of subjects meeting the endpoint in each treatment group is based on the approximate confidence limits of the normal.

^f The adjusted treatment differences and confidence intervals are Wald statistics based on the Cochran-Mantel-Haenszel weights.

^g The p-value was based on the Cochran-Mantel-Haenszel (CMH) chi-square test, stratified by concomitant use of corticosteroid (yes/no) at baseline.

Note that: only subjects with a modified Mayo score of 5-9 at the induction baseline were included.

^a Adverse events that are likely, likely or highly likely to be related to the study agent or if the relationship to the study agent is missing are assessed by the investigator.

^b Infection is defined as any adverse event encoded as the MedDRA system organ category 'infection and infestation'.

The invention may be described in connection with the following numbered embodiments:

1. use of an antibody specific for IL23 for treating ulcerative colitis in a patient, wherein the antibody comprises a light chain variable region comprising:

the complementarity determining region light chain 1 (CDRL 1) amino acid sequence of SEQ ID NO. 4;

CDRL2 amino acid sequence of SEQ ID NO. 5; and

CDRL3 amino acid sequence of SEQ ID NO. 6,

The heavy chain variable region comprises:

the complementarity determining region heavy chain 1 (CDRH 1) amino acid sequence of SEQ ID NO. 1;

CDRH2 amino acid sequence of SEQ ID NO. 2; and

The CDRH3 amino acid sequence of SEQ ID No. 3 and the use is such that the patient produces a clinical response.

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

3. The use of embodiment 2, wherein the initial dose, and the dose about 4 weeks after the initial dose, and the dose about 8 weeks after the initial dose, is 200mg or 400mg of the antibody.

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

5. The use of embodiment 1, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is defined as a clinical response that improves Mayo score by ≡30% and ≡2 score over the induction baseline, wherein rectal bleeding sub-score is ≡1 score over the baseline decrease or rectal bleeding sub-score is 0 or 1.

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

(i) Clinical remission, defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopy sub-divided into 0 or 1, and no fragility in endoscopy, wherein the stool frequency sub-divided is not increased from the induction baseline;

(ii) Symptomatic relief, defined as a stool frequency sub-division of 0 or 1 and a rectal bleeding sub-division of 0, wherein the stool frequency sub-division is not increased from the induction baseline;

(iii) Endoscopic healing, defined as endoscopy sub-division 0 or 1, and no fragility of endoscopy;

(iv) Histological-endoscopic mucosal healing, defined as the combination of achieving histological healing and endoscopic healing, wherein histological healing is defined as neutrophil infiltration of <5% of the crypt, no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes classification system; and

(V) Endoscope normalization is defined as an endoscopic subdivision into 0 (which requires no brittleness).

7. The use according to embodiments 5 or 6, wherein the clinical endpoint is measured about 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks and/or 48 weeks after the initial treatment.

8. The use of embodiment 7, wherein the clinical endpoint is measured about 12 weeks after initial treatment.

9. The use according to embodiment 1, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO. 8 and the heavy chain variable region amino acid sequence of SEQ ID NO. 7.

10. The use according to embodiment 1, wherein the antibody comprises the light chain amino acid sequence of SEQ ID NO. 10 and the heavy chain amino acid sequence of SEQ ID NO. 9.

11. The use according to embodiment 9 or 10, wherein the antibody is in a composition comprising 7.9% (w/v) sucrose, 4.0mM histidine, 6.9mM L-histidine monohydrochloride monohydrate; 0.053% (w/v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water in a standard state.

12. The use of embodiment 9 or 10, wherein the patient is further administered the antibody.

13. The use of embodiment 12, wherein the antibody is administered subcutaneously at a dose of 100mg or 200 mg.

14. The use of embodiment 1, wherein the patient is not a responder to the antibody and is identified as not meeting a clinical endpoint, wherein the clinical endpoint is a clinical response defined as a decrease in modified Mayo score of ≡30% and ≡2 score over the induction baseline, wherein the rectal bleeding sub-score is ≡1 score over the baseline decrease or the rectal bleeding sub-score is 0 or 1.

15. The use of embodiment 14, wherein the patient is further administered the antibody specific for IL 23.

16. The use of embodiment 15, wherein the antibody is administered 12 weeks after initial treatment.

17. The use of embodiment 16, wherein the antibody is administered 12 weeks after initial treatment, 16 weeks after initial treatment, and 20 weeks after initial treatment.

18. The use of embodiment 17, wherein the antibody is administered subcutaneously at a dose of 200 mg.

19. The use of embodiment 18, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is defined as a clinical response that improves Mayo score by ≡30% and ≡2 score over the induction of baseline decrease, wherein rectal bleeding sub-score is ≡1 score over the baseline decrease or rectal bleeding sub-score is 0 or 1.

20. The use of embodiment 18, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is selected from the group consisting of:

(i) Clinical remission, defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopy sub-divided into 0 or 1, and no fragility in endoscopy, wherein the stool frequency sub-divided is not increased from the induction baseline;

(ii) Symptomatic relief, defined as a stool frequency sub-division of 0 or 1 and a rectal bleeding sub-division of 0, wherein the stool frequency sub-division is not increased from the induction baseline;

(iii) Endoscopic healing, defined as endoscopy sub-division 0 or 1, and no fragility of endoscopy;

(iv) Histological-endoscopic mucosal healing, defined as the combination of achieving histological healing and endoscopic healing, wherein histological healing is defined as neutrophil infiltration of <5% of the crypt, no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes classification system; and

(V) Endoscope normalization is defined as an endoscopic subdivision into 0 (which requires no brittleness).

21. The use according to embodiment 19 or 20, wherein the clinical endpoint is measured about 24 weeks after initial treatment.

22. The use of embodiment 19 or 20, wherein the antibody specific for IL23 is further administered to the patient every 4 weeks or every 8 weeks thereafter.

23. The use according to embodiment 14, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO. 8 and the heavy chain variable region amino acid sequence of SEQ ID NO. 7.

24. The use according to embodiment 14, wherein the antibody comprises the light chain amino acid sequence of SEQ ID NO. 10 and the heavy chain amino acid sequence of SEQ ID NO. 9.

25. The use of embodiment 23 or 24, wherein the antibody is in a composition comprising 7.9% (w/v) sucrose, 4.0mM histidine, 6.9mM L-histidine monohydrochloride monohydrate; 0.053% (w/v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water in a standard state.

26. The use according to any one of embodiments 1 to 25, further comprising the use of one or more additional medicaments for the treatment of ulcerative colitis.

27. The use of embodiment 26, wherein the additional drug is selected from the group consisting of: immunosuppressants, non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface marker antibodies, anti-CD 20 antibodies, rituximab, TNF inhibitors, corticosteroids, and co-stimulatory modulators.

28. The use of embodiment 1, wherein the patient is considered to be failed or intolerant to biotherapy (Bio-failure) for ulcerative colitis prior to treatment with the antibody specific for IL 23.

29. The use of embodiment 1, wherein the patient is considered to have failed or failed conventional therapy for ulcerative colitis (Con-failure) prior to treatment with the antibody specific for IL 23.

30. The use of embodiment 1, wherein the ulcerative colitis is moderate to severe active ulcerative colitis.

31. The use of embodiment 30, wherein the patient has endoscopic evidence of active crohn's disease prior to administration of the initial dose.

32. The use of embodiment 31, wherein the patient has a modified Mayo score of 5 to 9, including 5 and 9, a Mayo rectal bleeding sub-score of ≡1 and a Mayo endoscopic sub-score of ≡2, prior to administration of the initial dose.

33. Use of an antibody specific for IL23 for treating moderate to severe active ulcerative colitis in a patient at a dose of: (i) an initial intravenous dose of 200mg or 400mg, (ii) an intravenous dose of 200mg or 400mg about 4 weeks after the initial dose, and (iii) an intravenous dose of 200mg or 400mg about 8 weeks after the initial dose of the antibody, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID NO:8 and the heavy chain variable region amino acid sequence of SEQ ID NO:7, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint about 12 weeks after the initial dose, wherein the clinical endpoint is defined as a clinical response that improves Mayo score by ∈30% and ∈2% over the induction of a baseline decrease, wherein rectal bleeding sub-score ∈1 or rectal bleeding sub-score 0 or 1.

34. The use of embodiment 33, wherein the administration of the antibody specific for IL23 is at a dose of 200mg or 400mg about every 4 weeks or every 8 weeks after the dose of about 8 weeks after administration of the initial dose.

Claims (34)

1. A method of treating ulcerative colitis in a patient, the method comprising administering to the patient an antibody specific for IL23, wherein the antibody comprises a light chain variable region and a heavy chain variable region, the light chain variable region comprising:

the complementarity determining region light chain 1 (CDRL 1) amino acid sequence of SEQ ID NO. 4;

CDRL2 amino acid sequence of SEQ ID NO. 5; and

CDRL3 amino acid sequence of SEQ ID NO. 6,

The heavy chain variable region comprises:

the complementarity determining region heavy chain 1 (CDRH 1) amino acid sequence of SEQ ID NO. 1;

CDRH2 amino acid sequence of SEQ ID NO. 2; and

The CDRH3 amino acid sequence of SEQ ID No. 3, and wherein said patient is considered a responder to said antibody.

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

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

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

5. The method of claim 1, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is a clinical response defined as a modified Mayo score that decreases by ≡30% and ≡2 score over the induction baseline, wherein rectal bleeding sub-score decreases by ≡1 score over the baseline or rectal bleeding sub-score is 0 or 1.

6. The method of claim 1, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is selected from the group consisting of:

(i) Clinical remission, defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopy sub-divided into 0 or 1, and no fragility in endoscopy, wherein the stool frequency sub-divided is not increased from the induction baseline;

(ii) Symptomatic relief, defined as a stool frequency sub-division of 0 or 1 and a rectal bleeding sub-division of 0, wherein the stool frequency sub-division is not increased from the induction baseline;

(iii) Endoscopic healing, defined as endoscopy sub-division 0 or 1, and no fragility of endoscopy;

(iv) Histological-endoscopic mucosal healing, defined as the combination of achieving histological healing and endoscopic healing, wherein histological healing is defined as neutrophil infiltration of <5% of the crypt, no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes classification system; and

(V) Endoscope normalization is defined as an endoscopic subdivision into 0 (which requires no brittleness).

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

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

9. The method of claim 7, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID No. 8 and the heavy chain variable region amino acid sequence of SEQ ID No. 7.

10. The method of claim 7, wherein the antibody comprises the light chain amino acid sequence of SEQ ID No. 10 and the heavy chain amino acid sequence of SEQ ID No. 9.

11. The method of claim 9 or 10, wherein the antibody is in a composition comprising 7.9% (w/v) sucrose, 4.0mM histidine, 6.9mM L-histidine monohydrochloride monohydrate; 0.053% (w/v) polysorbate 80 of the pharmaceutical composition; wherein the diluent is water in a standard state.

12. The method of claim 9 or 10, further comprising administering the antibody specific for IL23 to the patient.

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

14. The method of claim 1, wherein the patient is not a responder to the antibody and is identified as not meeting a clinical endpoint, wherein the clinical endpoint is a clinical response defined as a decrease in modified Mayo score of ≡30% and ≡2 score over the induction baseline, wherein the rectal bleeding sub-score is ≡1 score over the baseline decrease or the rectal bleeding sub-score is 0 or 1.

15. The method of claim 14, further comprising administering the antibody specific for IL23 to the patient.

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

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

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

19. The method of claim 18, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is a clinical response defined as a modified Mayo score that decreases by ≡30% and ≡2 score over the induction baseline, wherein rectal bleeding sub-score decreases by ≡1 score over the baseline or rectal bleeding sub-score is 0 or 1.

20. The method of claim 18, wherein the patient is a responder to the antibody and is identified as meeting a clinical endpoint, wherein the clinical endpoint is selected from the group consisting of:

(vi) Clinical remission, defined as a stool frequency sub-divided into 0 or 1, rectal bleeding sub-divided into 0, and endoscopy sub-divided into 0 or 1, and no fragility in endoscopy, wherein the stool frequency sub-divided is not increased from the induction baseline;

(vii) Symptomatic relief, defined as a stool frequency sub-division of 0 or 1 and a rectal bleeding sub-division of 0, wherein the stool frequency sub-division is not increased from the induction baseline;

(viii) Endoscopic healing, defined as endoscopy sub-division 0 or 1, and no fragility of endoscopy;

(ix) Histological-endoscopic mucosal healing, defined as the combination of achieving histological healing and endoscopic healing, wherein histological healing is defined as neutrophil infiltration of <5% of the crypt, no crypt destruction, and no erosion, ulceration, or granulation tissue according to the Geboes classification system; and

(X) Endoscope normalization is defined as an endoscopic subdivision into 0 (which requires no brittleness).

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

22. The method of claim 19 or 20, further comprising thereafter administering the antibody specific for IL23 to the patient every 4 weeks or every 8 weeks.

23. The method of claim 14, wherein the antibody comprises the light chain variable region amino acid sequence of SEQ ID No. 8 and the heavy chain variable region amino acid sequence of SEQ ID No. 7.

24. The method of claim 14, wherein the antibody comprises the light chain amino acid sequence of SEQ ID No. 10 and the heavy chain amino acid sequence of SEQ ID No. 9.

25. The method of claim 23 or 24, wherein the antibody is in a composition comprising 7.9% (w/v) sucrose, 4.0mM histidine, 6.9mM L-histidine monohydrochloride monohydrate; 0.053% (w/v) polysorbate 80 of the pharmaceutical composition;

Wherein the diluent is water in a standard state.

26. The method of any one of claims 1-25, further comprising administering to the patient one or more additional drugs for treating ulcerative colitis.

27. The method of claim 26, wherein the additional drug is selected from the group consisting of: immunosuppressants, non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B cell surface marker antibodies, anti-CD 20 antibodies, rituximab, TNF inhibitors, corticosteroids, and co-stimulatory modulators.

28. The method of claim 1, wherein the patient is considered to be failed or intolerant of biological therapy to ulcerative colitis (Bio-failure) prior to treatment with the antibody specific for IL 23.

29. The method of claim 1, wherein the patient is considered to have failed or failed conventional therapy for ulcerative colitis (Con-failure) prior to treatment with the antibody specific for IL 23.

30. The method of claim 1, wherein the ulcerative colitis is moderate to severe active ulcerative colitis.

31. The method of claim 30, wherein the patient has endoscopic evidence of active crohn's disease prior to administration of the initial dose.

32. The method of claim 31, wherein the patient has a modified Mayo score of 5 to 9, including 5 and 9, a Mayo rectal bleeding sub-score of ≡1 and a Mayo endoscopic sub-score of ≡2, prior to administration of the initial dose.

33. A method of treating moderate to severe active ulcerative colitis in a patient, the method comprising administering to the patient (i) an initial intravenous dose of 200mg or 400mg of an antibody specific for IL23, (ii) an intravenous dose of the antibody about 4 weeks after the initial dose, and (iii) an intravenous dose of 200mg or 400mg of the antibody about 8 weeks after the initial dose, wherein the antibody comprises a light chain variable region amino acid sequence of SEQ ID NO:8 and a heavy chain variable region amino acid sequence of SEQ ID NO:7, and the patient is a responder to the antibody by being identified as meeting a clinical endpoint about 12 weeks after the initial dose, wherein the clinical endpoint is defined as a clinical response that improves Mayo score by more inducing a decrease of ≡30% and ≡2 score, wherein rectal bleeding subfraction is ≡1 score or rectal subfraction is 0 or 1.

34. The method of claim 33, further comprising administering the antibody specific for IL23 at a dose of 200mg or 400mg about every 4 weeks or every 8 weeks after administration of the dose about 8 weeks after administration of the initial dose.