Safe and effective method of treating psoriasis with Anti-il23 specific antibody

Abstract

A method of treating psoriasis in a patient by administering an IL-23 specific antibody, e.g., guselkumab, in a safe and effective amount and the patient achieves PASI90, PASI100 or IGA 0 or 1 score as measured 16, 24, 32, 40 and 48 weeks after initial treatment.

Description

(19) *EP004714504A2* (11) EP 4 714 504 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 25.03.2026 Bulletin 2026 / 13 (21) Application number: 25219877.5 (22) Date of filing: 29.09.2017 (51) International Patent Classification (IPC): A61P 37 / 00 (2006.01) (52) Cooperative Patent Classification (CPC): C07K 16 / 244; A61K 45 / 06; A61P 17 / 06; C07K 16 / 241; A61K 2039 / 505; A61K 2039 / 54; A61K 2039 / 545; C07K 2317 / 21 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR Designated Extension States: BA ME Designated Validation States: MA MD (30) Priority: 30.09.2016 US 201662402403 P 13.07.2017 US 201762532068 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 17857471.1 / 3 519 049 (71) Applicant: Janssen Biotech, Inc. Horsham, PA 19044 (US) (72) Inventors: • RANDAZZO, Bruce Spring House, 19477 (US) • WASFI, Yasmine Spring House, 19477 (US) (74) Representative: Carpmaels & Ransford LLP One Southampton Row London WC1B 5HA (GB) Remarks: •This application was filed on 01‑12‑2025 as a divisional application to the application mentioned under INID code 62. •Claims filed after the date of receipt of the divisional application (Rule 68(4) EPC). (54) SAFE AND EFFECTIVE METHOD OF TREATING PSORIASIS WITH ANTI‑IL23 SPECIFIC ANTIBODY (57) A method of treating psoriasis in a patient by administering an IL‑23 specific antibody, e.g., guselku- mab, in a safe and effective amount and the patient achieves PASI90, PASI100 or IGA 0 or 1 score as mea- sured 16, 24, 32, 40 and 48 weeks after initial treatment. EP 4 71 4 50 4 A 2 Processed by Luminess, 75001 PARIS (FR) Description SEQUENCE LISTING

[0001] The instant application contains aSequenceListingwhich has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on September 20, 2017, is named WOPCTSeqlist.txt and is 79,744 bytes in size. FIELD OF THE INVENTION

[0002] The present invention concerns methods for treating psoriasis with an antibody that binds the human IL‑23 protein. In particular, it relates to a method of administering an anti-IL‑23 specific antibody and specific pharmaceutical compositions of an antibody, e.g., guselkumab, which is safe and effective for patients suffering from psoriasis. BACKGROUND OF THE INVENTION

[0003] Interleukin (IL)‑ 12 is a secreted heterodimeric cytokine comprised of 2 disulfide-linked glycosylated protein subunits, designated p35 and p40 for their approximate molecular weights. IL‑12 is produced primarily by antigen- presenting cells and drives cell-mediated immunity by binding to a two-chain receptor complex that is expressed on the surface of Tcells or natural killer (NK) cells. The IL‑12 receptor beta‑1 (IL‑12Rβ1) chain binds to the p40 subunit of IL‑12, providing the primary interaction between IL‑12 and its receptor. However, it is IL‑12p35 ligation of the second receptor chain, IL‑12Rβ2, that confers intracellular signaling (e.g. STAT4 phosphorylation) and activation of the receptor-bearing cell (Presky et al, 1996). IL‑12 signaling concurrent with antigen presentation is thought to invoke T cell differentiation towards theThelper 1 (Th1) phenotype, characterized by interferongamma (IFNγ) production (Trinchieri, 2003). Th1 cells are believed to promote immunity to some intracellular pathogens, generate complement-fixing antibody isotypes, and contribute to tumor immunosurveillance. Thus, IL‑12 is thought to be a significant component to host defense immune mechanisms.

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

[0005] Abnormal regulation of IL‑12 and Th1 cell populations has been associated with many immune-mediated diseases since neutralization of IL‑12 by antibodies is effective in treating animal models of psoriasis, multiple sclerosis (MS), rheumatoidarthritis, inflammatorybowel disease, insulin-dependent (type1) diabetesmellitus, anduveitis (Leonard et al, 1995; Hong et al, 1999; Malfait et al, 1998; Davidson et al, 1998). However, since these studies targeted the shared p40 subunit, both IL‑12 and IL‑23were neutralized in vivo.Therefore, it was unclear whether IL‑12 or IL‑23wasmediating disease, or if both cytokines needed to be inhibited to achieve disease suppression. Recent studies have confirmed through IL‑23p19 deficient mice or specific antibody neutralization of IL‑23 that IL‑23 inhibition can provide equivalent benefit as anti-IL‑12p40 strategies (Cua et al, 2003,Murphy et al, 2003, Benson et al 2004). Therefore, there is increasing evidence for the specific role of IL‑23 in immune-mediated disease. Neutralization of IL‑23 without inhibition of IL‑12 pathways could then provide effective therapy of immune-mediated diseasewith limited impact on important host defense immune mechanism. This would represent a significant improvement over current therapeutic options.

[0006] Psoriasis is a common, chronic immune-mediated skin disorder with significant co-morbidities, such as psoriatic arthritis (PsA), depression, cardiovascular disease, hypertension, obesity, diabetes, metabolic syndrome, and Crohn’s disease.Plaquepsoriasis is themost common formof thediseaseandmanifests inwell demarcatederythematous lesions toppedwith white silver scales. Plaques are pruritic, painful, often disfiguring and disabling, and a significant proportion of psoriatic patients have plaques on hands / nails face, feet and genitalia. As such, psoriasis negatively impacts health- related quality of life (HRQoL) to a significant extent, including imposing physical and psychosocial burdens that extend beyond the physical dermatological symptoms and interfere with everyday activities. For example, psoriasis negatively impacts familial, spousal, social, and work relationships, and is associated with a higher incidence of depression and increased suicidal tendencies.

[0007] Histologic characterization of psoriasis lesions reveals a thickened epidermis resulting from aberrant keratino- cyte proliferation and differentiation as well as dermal infiltration and co-localization of CD3+ T lymphocytes and dendritic cells. While the etiology of psoriasis is not well defined, gene and protein analysis have shown that IL‑12, IL‑23 and their downstreammolecules are over-expressed in psoriatic lesions, and some may correlate with psoriasis disease severity. 2 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 Some therapies used in the treatment of psoriasis modulate IL‑12 and IL‑23 levels, which is speculated to contribute to their efficacy. Th1 and Th17 cells can produce effector cytokines that induce the production of vasodilators, chemoat- tractants and expression of adhesion molecules on endothelial cells which in turn, promote monocyte and neutrophil recruitment, Tcell infiltration, neovascularizationand keratinocyte activationandhyperplasia. Activated keratinocytes can produce chemoattractant factors that promote neutrophil, monocyte, Tcell, and dendritic cell trafficking, thus establishing a cycle of inflammation and keratinocyte hyperproliferation.

[0008] Elucidation of the pathogenesis of psoriasis has led to effective biologic treatments targeting tumor necrosis factor-alpha (TNF-α), both interleukin (IL)‑12and IL‑23and,most recently, IL‑17aswell as IL‑23alone (including inPhase 1 and 2 clinical trials using guselkumab). Guselkumab (also known as CNTO 1959) is a fully human IgG1 lambda monoclonal antibody that binds to the p19 subunit of IL‑23 and inhibits the intracellular and downstreamsignaling of IL‑23, required for terminal differentiation of T helper (Th)17 cells. SUMMARY OF THE INVENTION

[0009] In a first aspect, the invention concerns a method of treating psoriasis in a patient comprising subcutaneously administering an anti-IL‑23 specific antibody (also referred to as IL‑23p19 antibody), e.g., guselkumab, to the patient, wherein the anti-IL‑23 specific antibody is administered at an initial dose, a dose 4 weeks thereafter, and at a dosing interval of once every 8 weeks thereafter, e,g., a dose at 0, 4, 8, 16, 24, 32, 40 and 48 weeks.

[0010] In another aspect, the composition used in themethod of the invention comprises a pharmaceutical composition comprising: ananti-IL‑23specific antibody in anamount fromabout 1.0µg / ml to about 1000mg / ml, specifically at 50mgor 100 mg. In a preferred embodiment the anti-IL‑23 specific antibody is guselkumab at 100 mg / mL; 7.9% (w / v) sucrose, 4.0mM Histidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the pharma- ceutical composition; wherein the diluent is water at standard state.

[0011] In an embodiment, the psoriasis patient achieved the endpoints of achieving an IGA score of cleared or minimal disease (IGA 0 / 1) and 90% improvement in PASI response (PASI 90) or 100% improvement in PASI response (PASI 100) at week 16.

[0012] In another aspect of the invention the pharmaceutical composition comprises an isolated anti-IL23 specific antibody having the guselkumab CDR sequences comprising (i) the heavy chain CDR amino acid sequences of SEQ ID NO: 5, SEQ IDNO: 20, and SEQ IDNO: 44; and (ii) the light chain CDR amino acid sequences of SEQ IDNO: 50, SEQ ID NO: 56, and SEQ IDNO: 73 at 100mg / mL; 7.9% (w / v) sucrose, 4.0mMHistidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the pharmaceutical composition; wherein the diluent is water at standard state.

[0013] Another aspect of the method of the invention comprises administering a pharmaceutical composition compris- ing an isolated anti-IL‑23 specific antibody having the guselkumab heavy chain variable region amino acid sequence of SEQ ID NO: 106 and the guselkumab light chain variable region amino acid sequence of SEQ ID NO: 116 at 100 mg / mL: 7.9% (w / v) sucrose, 4.0mMHistidine, 6.9mML-Histidinemonohydrochloridemonohydrate: 0.053% (w / v) Polysorbate 80 of the pharmaceutical composition; wherein the diluent is water at standard state. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] As used herein the method of treatment of psoriasis comprises administering isolated, recombinant and / or synthetic anti-IL‑ 23 specific human antibodies and diagnostic and therapeutic compositions, methods and devices.

[0015] Asused herein, an "anti-IL‑23 specific antibody," "anti-IL‑23antibody," "antibody portion," or "antibody fragment" and / or "antibody variant" and the like includeanyproteinor peptide containingmolecule that comprisesat least aportionof an immunoglobulinmolecule, suchasbut not limited to, at least one complementarity determining region (CDR)of aheavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework region, or any portion thereof, or at least one portion of an IL‑23 receptor or binding protein, which can be incorporated into an antibody of the present invention. Such antibody optionally further affects a specific ligand, such as but not limited to, where such antibody modulates, decreases, increases, antagonizes, agonizes, mitigates, alleviates, blocks, inhibits, abrogates and / or interferes with at least one IL‑23 activity or binding, or with IL‑23 receptor activity or binding, in vitro, in situ and / or in vivo. As a non-limiting example, a suitable anti-IL‑23 antibody, specified portion or variant of the present invention can bind at least one IL‑23molecule, or specified portions, variants or domains thereof. A suitable anti-IL‑23 antibody, specified portion, or variant can 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.

[0016] The term "antibody" is further intended to encompass antibodies, digestion fragments, specified portions and variants thereof, including antibodymimetics or comprising portions of antibodies thatmimic the structure and / or function of anantibodyor specified fragment or portion thereof, including single chain antibodiesand fragments thereof. Functional 3 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 fragments includeantigen-binding fragments that bind toamammalian IL‑23.For example, antibody fragments capable of binding to IL‑23 or portions thereof, including, but not limited to, Fab (e.g., by papain digestion), Fab’ (e.g., by pepsin digestion and partial reduction) and F(ab’)2 (e.g., by pepsin digestion), facb (e.g., by plasmin digestion), pFc’ (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction and reaggregation), Fv or scFv (e.g., by molecular biology techniques) fragments, are encompassed by the invention (see, e.g., Colligan, Immunology, supra).

[0017] Such fragments can 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 ormore stop codons have been introduced upstream of the natural stop site. For example, a combination gene encodingaF(ab’)2 heavychainportioncanbedesigned to includeDNAsequencesencoding theCH1domainand / orhinge region of the heavy chain. The various portions of antibodies can be joined together chemically by conventional techniques, or can be prepared as a contiguous protein using genetic engineering techniques.

[0018] As used herein, the term "human antibody" refers to an antibody in which substantially every part of the protein (e.g., CDR, framework, CL, CH domains (e.g., CH1, CH2, CH3), hinge, (VL, VH)) is substantially non-immunogenic in humans,withonlyminor sequencechangesor variations.A "humanantibody"mayalsobeanantibody that is derived from or closely matches human germline immunoglobulin sequences. Human antibodiesmay include amino acid residues not encoded by germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). Often, this means that the human antibody is substantially non-immunogenic in humans. Human antibodies have been classified into groupings based on their amino acid sequence similarities. Accordingly, using a sequence similarity search, an antibody with a similar linear sequence can be chosen as a template tocreateahumanantibody.Similarly, antibodiesdesignatedprimate (monkey,baboon, chimpanzee,etc.), rodent (mouse, rat, rabbit, guinea pig, hamster, and the like) and other mammals designate such species, sub-genus, genus, sub-family, and family specific antibodies. Further, chimeric antibodies can include any combination of the above. Such changes or variations optionally and preferably retain or reduce the immunogenicity in humans or other species relative to non- modified antibodies. Thus, a human antibody is distinct from a chimeric or humanized antibody.

[0019] It is pointed out that a human antibody can be produced by a non-human animal or prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and / or light chain) genes. Further,whenahumanantibody is a single chainantibody, it cancomprisea linker peptide that is not found innativehuman antibodies. For example, an Fv can comprise a linker peptide, such as two to about eight glycine or other amino acid residues, which connects the variable region of the heavy chain and the variable region of the light chain. Such linker peptides are considered to be of human origin.

[0020] Bispecific, heterospecific, heteroconjugate or similar antibodies can also be used that are monoclonal, pre- ferably, human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for at least one IL‑23 protein, the other one is for any other antigen. Methods for making bispecific antibodies are known in the art. Traditionally, 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 andCuello, Nature 305:537 (1983)). Because of the randomassortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of 10 different antibodymolecules, of whichonly onehas the correct bispecific structure. Thepurificationof the correctmolecule,which is usually donebyaffinity chromatography steps, is rather cumbersome, and the product yields are low. Similar procedures are disclosed, e.g., in WO93 / 08829,USPatentNos, 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 121:210 (1986), each entirely incorporated herein by reference.

[0021] Anti-IL‑23 specific (also termed IL‑23 specific antibodies) (or antibodies to IL‑23) useful in the methods and compositions of the present invention can optionally be characterized by high affinity binding to IL‑23 and, optionally and preferably, having low toxicity. In particular, an antibody, specified fragment or variant of the invention.where the individual components, such as the variable region, constant region and framework, individually and / or collectively, optionally and preferably possess low immunogenicity, is useful in the present invention. The antibodies that can be used in the invention are optionally characterized by their ability to treat patients for extended periods withmeasurable alleviation of symptoms and low and / or acceptable toxicity. Low or acceptable immunogenicity and / or high affinity, as well as other suitable properties, cancontribute to the therapeutic resultsachieved. "Low immunogenicity" isdefinedhereinas raisingsignificant HAHA,HACAorHAMA responses in less than about 75%, or preferably less thanabout 50%of the patients treated and / or raising low titres in thepatient treated (less thanabout 300, preferably less thanabout 100measuredwith adouble antigen enzyme immunoassay) (Elliott et al., Lancet 344:1125‑1127 (1994), entirely incorporated herein by reference). "Low immunogenicity" can also be defined as the incidence of titrable levels of antibodies to the anti-IL‑23 antibody in patients treated with anti-IL‑23 antibody as occurring in less than 25% of patients treated, preferably, in less than 10% of patients treated with the recommended dose for the recommended course of therapy during the treatment period. 4 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 Utility

[0022] The isolatednucleicacidsof thepresent inventioncanbeused forproductionofat least oneanti-IL‑23antibodyor specifiedvariant thereof,whichcanbeused tomeasureoreffect inancell, tissue, organoranimal (includingmammalsand humans), to diagnose, monitor, modulate, treat, alleviate, help prevent the incidence of, or reduce the symptoms of psoriasis.

[0023] Such a method can comprise administering an effective amount of a composition or a pharmaceutical composition comprising at least one anti-IL‑23 antibody to a cell, tissue, organ, animal or patient in need of such modulation, treatment, alleviation, prevention, or reduction in symptoms, effects or mechanisms. The effective amount can comprise an amount of about 0.001 to 500 mg / kg per single (e.g., bolus), multiple or continuous administration, or to achievea serumconcentration of 0.01‑5000µg / ml serumconcentration per single,multiple, or continuousadministration, or anyeffective rangeor value therein, asdoneanddeterminedusing knownmethods, asdescribedherein or known in the relevant arts. Citations

[0024] All publicationsor patents citedherein,whether or not specifically designated, are entirely incorporatedherein by referenceas theyshow thestateof theart at the timeof thepresent inventionand / or toprovidedescriptionandenablement of the present invention. Publications refer to any scientific or patent publications, or any other information available in any media format, including all recorded, electronic or printed formats. The following references are entirely incorporated herein by reference: Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987‑2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor, NY (1989); HarlowandLane,antibodies, aLaboratoryManual,ColdSpringHarbor,NY (1989);Colligan, et al., eds.,CurrentProtocols in Immunology, JohnWiley&Sons, Inc., NY (1994‑2001); Colligan et al., Current Protocols in Protein Science, JohnWiley & Sons, NY, NY, (1997‑2001). Antibodies of the Present Invention ‑ Production and Generation

[0025] At least one anti-IL‑23 antibody used in themethod of the present invention can be optionally produced by a cell line, a mixed cell line, an immortalized cell or clonal population of immortalized cells, as well known in the art. See, e.g., Ausubel, et al., ed.,CurrentProtocols inMolecularBiology, JohnWiley&Sons, Inc.,NY,NY(1987‑2001);Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor, NY (1989); Harlow and Lane, antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989); Colligan, et al., eds., Current Protocols in Immunology, JohnWiley & Sons, Inc.,NY (1994‑2001),Colliganet al.,CurrentProtocols inProteinScience, JohnWiley&Sons,NY,NY, (1997‑2001), each entirely incorporated herein by reference.

[0026] A preferred anti-IL‑23 antibody is guselkumab (also referred to as CNTO1959) having the heavy chain variable regionaminoacidsequenceofSEQIDNO:106and the light chainvariable regionaminoacidsequenceofSEQIDNO:116 andhaving theheavychainCDRaminoacidsequencesofSEQIDNO:5,SEQIDNO:20, andSEQIDNO:44; and the light chain CDR amino acid sequences of SEQ ID NO: 50, SEQ ID NO: 56, and SEQ ID NO: 73. Other anti‑1L‑23 antibodies have sequences listed herein and are described in U.S. Patent No. 7,935,344, the entire contents of which are incorporated herein by reference).

[0027] Human antibodies that are specific for human IL‑23 proteins or fragments thereof can be raised against an appropriate immunogenic antigen, such as an isolated IL‑23 protein and / or a portion thereof (including synthetic molecules, such as synthetic peptides). Other specific or general mammalian antibodies can be similarly raised. Preparation of immunogenic antigens, and monoclonal antibody production can be performed using any suitable technique.

[0028] In one approach, a hybridoma is 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,Sp2SA3,Sp2MAI,Sp2SS1, Sp2 SAS, U937, MLA 144, ACT IV, MOLT4, DA‑1, JURKAT, WEHI, K‑562, COS, RAJI, NIH 3T3, HL‑60, MLA 144, NAMALWA,NEURO2A, or the like, or heteromylomas, fusionproducts thereof, or any cell or fusion cell derived therefrom, or any other suitable cell line as known in the art) (see, e.g., www.atcc.org, www.lifetech.com., and the like), with antibody producing cells, such as, but not limited to, isolated or cloned spleen, peripheral blood, lymph, tonsil, or other immune or B cell containing cells, or any other cells expressing heavy or light chain constant or variable or framework or CDR sequences, either as endogenous or heterologous nucleic acid, as recombinant or endogenous, viral, bacterial, algal, prokaryotic, amphibian, insect, reptilian, fish, mammalian, rodent, equine, ovine, goat, sheep, primate, eukaryotic, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single, double or triple stranded, hybridized, and the like or any combination thereof. See, e.g., Ausubel, supra, and Colligan, Immunology, supra, chapter 2, entirely incorporated herein by reference. 5 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55

[0029] Antibody producing cells can also be obtained from the peripheral blood or, preferably, the spleen or lymph nodes, of humans or other suitable animals that have been immunizedwith the antigen of interest. Any other suitable host cell canalsobeused for expressing heterologousor endogenousnucleic acid encoding anantibody, specified fragment or variant thereof, of the present invention. The fused cells (hybridomas) or recombinant cells can be isolated using selective culture conditions or other suitable knownmethods, and cloned by limiting dilution or cell sorting, or other knownmethods. Cells which produce antibodies with the desired specificity can be selected by a suitable assay (e.g., ELISA).

[0030] Other suitablemethods of producing or isolating antibodies of the requisite specificity can be used, including, but not limited to, methods that select recombinant antibody from a peptide or protein library (e.g., but not limited to, a bacteriophage, ribosome, oligonucleotide, RNA, cDNA, or the like, display library; e.g., as available from Cambridge antibody Technologies, Cambridgeshire, UK; MorphoSys, Martinsreid / Planegg. DE; Biovation, Aberdeen, Scotland, UK; BioInvent, Lund, Sweden; Dyax Corp., Enzon, Affymax / Biosite; Xoma, Berkeley, CA; Ixsys. See, e.g., EP 368,684, 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 stochastically 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 entirely incorporated herein by reference)) or that rely upon immunizationof transgenicanimals (e.g.,SCIDmice,Nguyenetal.,Microbiol. Immunol. 41:901‑907 (1997);Sandhuetal., Crit. Rev. Biotechnol. 16:95‑118 (1996); Eren et al., Immunol. 93:154‑161 (1998), each entirely incorporated by reference aswell as relatedpatents andapplications) that are capableof producinga repertoireof humanantibodies, asknown 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 (May1997); Hanes et al., Proc.Natl. Acad. Sci. USA, 95:14130‑14135 (Nov. 1998)); single cell antibody producing technologies (e.g., selected lymphocyte antibodymethod ("SLAM") (US 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, MA; Gray et al., J. Imm. Meth. 182:155‑163 (1995); Kenny et al., Bio / Technol. 13:787‑790 (1995)); B-cell selection (Steenbakkers et al., Molec. Biol. Reports 19:125‑134 (1994); Jonak et al., Progress Biotech, Vol. 5, In Vitro Immunization in Hybridoma Technology, Borrebaeck, ed., Elsevier Science Publishers B.V., Amsterdam, Netherlands (1988)).

[0031] Methods for engineering or humanizing non-human or humanantibodies can also be used and arewell known in the art. Generally, a humanized or engineered antibody has one or more amino acid residues from a source that is non- human, e.g., but not limited to, mouse, rat, rabbit, non-human primate or other mammal. These non-human amino acid residuesare replacedby residuesoften referred toas "import" residues,whichare typically taken froman "import" variable, constant or other domain of a known human sequence.

[0032] Known human Ig sequences are disclosed, e.g., www.nebi.nlm.nih.gov / entrez / query.fcgi; www.ncbi.nih.gov / ig- blast; 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 / Im- munology.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.cancer- researchuk.org; www.biotech.ufl.edu; www.isac-net.org; baserv.uci.kun.nl / ~jraats / linksl.html; www.recab.uni-hd.de / im- muno.bme.nwu.edu; www.mrc-cpe.cam.ac.uk; www.ibt.unam.mx / vir / V_mice.html; http: / / www.bioinf.org.uk / abs; antibo- dy.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.mis- souri.edu / smithgp / index.html; www.jerini.de; Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Dept. Health (1983), each entirely incorporated herein by reference.

[0033] Such imported sequences can be used to reduce immunogenicity or reduce, enhance ormodify binding, affinity, on-rate, off-rate, avidity, specificity, half-life, or any other suitable characteristic, as known in the art. In general, the CDR residues are directly and most substantially involved in influencing antigen binding. Accordingly, part or all of the non- human or human CDR sequences are maintained while the non-human sequences of the variable and constant regions may be replaced with human or other amino acids.

[0034] Antibodiescanalsooptionally behumanizedorhumanantibodiesengineeredwith retentionof highaffinity for the antigenandother favorable biological properties. Toachieve this goal, humanized (or human) antibodies canbeoptionally prepared by a process of analysis of the parental sequences and various conceptual humanized products using three- dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are com- monly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of 6 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, framework (FR) residues can be selected and combined from the consensus and import sequences so that the desired antibody characteristic, such as increased affinity for the target antigen(s), is achieved.

[0035] In addition, thehuman IL‑23specificantibodyused in themethodof thepresent inventionmaycompriseahuman germline light chain framework. In particular embodiments, the light chain germline sequence is selected from human VK sequences including, but not limited to, A1, A10, A11, A14, A17, A18, A19, A2, A20, A23, A26, A27, A3, A30, A5, A7, B2, B3, L1, L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23, L24, L25, L4 / 18a, L5, L6, L8, L9,O1,O11, 012, 014, 018, O2,O4, andO8. In certain embodiments, this light chain humangermline framework is selected fromV1‑11,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.

[0036] In other embodiments, the human IL‑23 specific antibody used in the method of the present invention may comprise a human germline heavy chain framework. In particular embodiments, this heavy chain human germline framework is selected fromVH1‑18, 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.

[0037] In particular embodiments, the light chain variable region and / or heavy chain variable region comprises a framework region or at least a portion of a framework region (e.g., containing 2 or 3 subregions, such as FR2 and FR3). In certain embodiments, at least FRL1, FRL2, FRL3, or FRL4 is fully human. In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is fully human. In some embodiments, at least FRL1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., humangermline) or compriseshumanconsensus sequences for theparticular framework (readily available at the sources of 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 comprises human consensus sequences for the particular framework. In preferred embodiments, the framework region is a fully human framework region.

[0038] Humanization or engineering of antibodies of the present invention can be performed using any knownmethod, such as but not limited to those described in, Winter (Jones et al., Nature 321:522 (1986); Riechmann et al., Nature 332:323 (1988); Verhoeyenet al., Science239:1534 (1988)), Simset 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), US Patent Nos: 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, each entirely incorporated herein by reference, included references cited therein.

[0039] In certain embodiments, the antibody comprises an altered (e.g., mutated) Fc region. For example, in some embodiments, the Fc region has been altered to reduce or enhance the effector functions of the antibody. In some embodiments, the Fc region is an isotype selected from IgM, IgA, IgG, IgE, or other isotype. Alternatively or additionally, it maybeuseful to combineaminoacidmodificationswithoneormore further aminoacidmodifications that alterC1qbinding and / or the complement dependent cytotoxicity function of the Fc region of an IL‑23 binding molecule. The starting polypeptide of particular interest may be one that binds to C1q and displays complement dependent cytotoxicity (CDC). Polypeptides with pre-existing C1q binding activity, optionally further having the ability to mediate CDCmay be modified such that one or both of these activities are enhanced. Amino acid modifications that alter C1q and / or modify its complement dependent cytotoxicity function are described, for example, in WO0042072, which is hereby incorporated by reference.

[0040] As disclosed above, one can design an Fc region of the human IL‑23 specific antibody of the present invention with altered effector function, e.g., by modifying C1q binding and / or FcγR binding and thereby changing complement dependent cytotoxicity (CDC) activity and / or antibody-dependent cell-mediated cytotoxicity (ADCC) activity. "Effector functions" are responsible for activating or diminishing 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 receptor; BCR), etc. Such effector functions may require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays (e.g., Fc binding assays, ADCC assays, CDC assays, etc.).

[0041] For example, one cangenerate a variant Fc region of the human IL‑23 (or anti-IL‑23) antibodywith improvedC1q bindingand improvedFcγRIIIbinding (e.g., having both improvedADCCactivity and improvedCDCactivity). Alternatively, if it is desired that effector function be reduced or ablated, a variant Fc region can be engineeredwith reducedCDCactivity and / or reduced ADCC activity. In other embodiments, only one of these activities may be increased, and, optionally, also theotheractivity reduced (e.g., togenerateanFc regionvariantwith improvedADCCactivity, but reducedCDCactivityand vice versa).

[0042] Fcmutations canalsobe introduced in engineer to alter their interactionwith theneonatal Fc receptor (FcRn)and 7 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 improve their pharmacokinetic properties. A collection of human Fc variants with improved binding to the FcRn have been described (Shields et al., (2001).High resolutionmappingof the binding site onhuman IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FcγR, J. Biol. Chem. 276:6591‑6604).

[0043] Another type of amino acid substitution serves to alter the glycosylation pattern of the Fc region of the human IL‑23 specific antibody. Glycosylation of an Fc region is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars N-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. The recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain peptide sequences are asparagine-X- serine and asparagine-X-threonine, where X is any amino acid except proline. Thus, the presence of either of these peptide sequences in a polypeptide creates a potential glycosylation site.

[0044] The glycosylation patternmay be altered, for example, by deleting one or more glycosylation site(s) found in the polypeptide, and / or addingoneormoreglycosylation sites that arenot present in thepolypeptide.Additionof glycosylation sites to theFc regionof a human IL‑23specific antibody is conveniently accomplishedbyaltering theaminoacid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). An exemplary glycosylation variant has an amino acid substitution of residue Asn 297 of the heavy chain. The alterationmay also bemade by the addition of, or substitution by, one ormore serine or threonine residues to the sequence of the original polypeptide (forO-linked glycosylation sites). Additionally, a change of Asn 297 toAla can remove oneof the glycosylation sites.

[0045] In certain embodiments, the human IL‑23 specific antibody of the present invention is expressed in cells that express beta (1,4)‑N-acetylglucosaminyltransferase III (GnT III), such that GnT III adds GlcNAc to the human IL‑23 antibody. Methods for producing antibodies in such a fashion are provided in WO / 9954342, WO / 03011878, patent publication 20030003097A1, and Umana et al., Nature Biotechnology, 17:176‑180, Feb. 1999; all of which are herein specifically incorporated by reference in their entireties.

[0046] The anti-IL‑23 antibody can also be optionally generated by immunization of a transgenic animal (e.g., mouse, rat, hamster, non-humanprimate, and the like) capableof producinga repertoire of humanantibodies, as describedherein and / or as known in the art. Cells that produce a human anti-IL‑23 antibody can be isolated from such animals and immortalized using suitable methods, such as the methods described herein.

[0047] Transgenicmice that canproducea repertoire of humanantibodies that bind to humanantigens canbeproduced by known methods (e.g., but not limited to, U.S. Pat. Nos: 5,770,428, 5,569,825, 5,545,806, 5,625,126, 5,625,825, 5,633,425, 5,661,016 and 5,789,650 issued to Lonberg et al.; Jakobovits et al. WO 98 / 50433, Jakobovits et al. WO 98 / 24893, Lonberget al.WO98 / 24884, Lonberget al.WO97 / 13852, Lonberget al.WO94 / 25585,Kucherlapateet al.WO 96 / 34096, Kucherlapate et al. EP 0463 151 B1, Kucherlapate et al. EP 0710 719 A1, Surani et al. US. Pat. No. 5,545,807, Bruggemann et al.WO90 / 04036, Bruggemann et al. EP 0438 474B1, Lonberg et al. EP 0814 259A2, Lonberg et al. GB2 272 440 A, Lonberg et al. Nature 368:856‑859 (1994), Taylor et al., Int. Immunol. 6(4)579‑591 (1994), Green et al, Nature Genetics 7:13‑21 (1994), Mendez et al., Nature Genetics 15:146‑156 (1997), Taylor et al., Nucleic Acids Research 20(23):6287‑6295 (1992), Tuaillon et al., ProcNatl AcadSci USA90(8)3720‑3724 (1993), Lonberg et al., Int Rev Immunol 13(1):65‑93 (1995) and Fishwald et al., Nat Biotechnol 14(7):845‑851 (1996), which are each entirely incorporated herein by reference). Generally, these mice comprise at least one transgene comprising DNA from at least one human immunoglobulin locus that is functionally rearranged, or which can undergo functional rearrangement. The endogenous immunoglobulin loci in suchmice can be disrupted or deleted to eliminate the capacity of the animal to produce antibodies encoded by endogenous genes.

[0048] Screening antibodies for specific binding to similar proteins or fragments can be conveniently achieved using peptidedisplay libraries. Thismethod involves the screeningof largecollectionsof peptides for individualmembershaving the desired function or structure. Antibody screening of peptide display libraries is well known in the art. The displayed peptide sequences canbe from3 to 5000ormoreamino acids in length, frequently from5‑100aminoacids long, and often from about 8 to 25 amino acids long. In addition to direct chemical synthetic methods for generating peptide libraries, several recombinant DNA methods have been described. One type involves the display of a peptide sequence on the surface of a bacteriophage or cell. Each bacteriophage or cell contains the nucleotide sequence encoding the particular displayedpeptidesequence.Suchmethodsaredescribed inPCTPatentPublicationNos.91 / 17271,91 / 18980,91 / 19818, and 93 / 08278.

[0049] Other systems for generating libraries of peptides have aspects of both in vitro chemical synthesis and recombinant methods. See, PCT Patent Publication Nos. 92 / 05258, 92 / 14843, and 96 / 19256. See also, U.S. Patent Nos. 5,658,754; and 5,643,768. Peptide display libraries, vector, and screening kits are commercially available from such suppliers as Invitrogen (Carlsbad,CA), andCambridge antibodyTechnologies (Cambridgeshire,UK). See, e.g., U.S. Pat. Nos. 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, 8 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 5576195, 5698435, 5693493, 5698417, assigned to Xoma, Colligan, supra; Ausubel, supra; or Sambrook, supra, each of the above patents and publications entirely incorporated herein by reference.

[0050] Antibodies used in themethodof the present invention canalsobepreparedusing at least oneanti-IL23antibody encoding nucleic acid to provide transgenic animals or mammals, such as goats, cows, horses, sheep, rabbits, and the like, that produce such antibodies in their milk. Such animals can be provided using known methods. See, e.g., but not limited to, US Patent Nos. 5,827,690; 5,849,992; 4,873,316; 5,849,992; 5,994,616; 5,565,362; 5,304,489, and the like, each of which is entirely incorporated herein by reference.

[0051] Antibodies used in themethod of the present invention can additionally be prepared using at least one anti-IL23 antibody encoding nucleic acid to provide transgenic plants and cultured plant cells (e.g., but not limited to, tobacco and maize) that produce such antibodies, specified portions or variants in the plant parts or in cells cultured therefrom. As a non-limitingexample, transgenic tobacco leavesexpressing recombinantproteinshavebeensuccessfullyused toprovide large amounts of recombinant proteins, e.g., using an inducible promoter. See, e.g., Cramer et al., Curr. Top. Microbol. Immunol. 240:95‑118 (1999) and references cited therein. Also, transgenicmaize have been used to expressmammalian proteins at commercial production levels, 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 have also been produced in large amounts from transgenic plant seeds including antibody fragments, such as single chain antibodies (scFv’s), including tobacco seeds and potato tubers. See, e.g., Conrad et al., Plant Mol. Biol. 38:101‑109 (1998) and references cited therein. Thus, antibodies of the present invention can also be produced using transgenic plants, according to knownmethods. See also, e.g., Fischer et al., Biotechnol. Appl. Biochem. 30:99‑108 (Oct., 1999), Ma et al., Trends Biotechnol. 13:522‑7 (1995); Ma et al., Plant Physiol. 109:341‑6 (1995); Whitelam et al., Biochem. Soc. Trans. 22:940‑944 (1994); and references cited therein. Each of the above references is entirely incorporated herein by reference.

[0052] The antibodies used in themethod of the invention can bind human IL‑23with a wide range of affinities (KD). In a preferred embodiment, a humanmAb can optionally bind human IL‑23 with high affinity. For example, a humanmAb can bind human IL‑23 with a KD 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) X 10‑7, 10‑8, 10‑9, 10‑10, 10‑11, 10‑12, 10‑13 or any range or value therein.

[0053] The affinity or avidity of an antibody for an antigen can be determined experimentally using any suitablemethod. (See, for example,Berzofsky,et al., "Antibody-Antigen Interactions," InFundamental Immunology,Paul,W.E.,Ed.,Raven Press: NewYork, NY (1984); Kuby, Janis Immunology,W.H. Freeman andCompany: NewYork, NY (1992); andmethods described herein). The measured affinity of a particular antibody-antigen interaction can vary if measured under different conditions (e.g., salt concentration, pH). Thus, measurements of affinity and other antigen-binding parameters (e.g., KD, Ka, Kd) are preferably made with standardized solutions of antibody and antigen, and a standardized buffer, such as the buffer described herein. Nucleic Acid Molecules

[0054] Using the information provided herein, for example, the nucleotide sequences encoding at least 70‑100% of the contiguous amino acids of at least one of the light or heavy chain variable or CDR regions described herein, among other sequences disclosed herein, specified fragments, variants or consensus sequences thereof, or a deposited vector comprising at least one of these sequences, a nucleic acid molecule of the present invention encoding at least one anti- IL‑23 antibody can be obtained using methods described herein or as known in the art.

[0055] Nucleic acid molecules of the present invention can be in the form of RNA, such asmRNA, hnRNA, tRNA or any other form, or in the form of DNA, including, but not limited to, cDNA and genomic DNA obtained by cloning or produced synthetically, or any combinations thereof. The DNA can be triple-stranded, double-stranded or single-stranded, or any combination thereof. Any portion of at least one strand of the DNA or RNA can be the coding strand, also known as the sense strand, or it can be the non-coding strand, also referred to as the anti-sense strand.

[0056] Isolated nucleic acid molecules used in the method of the present invention can include nucleic acid molecules comprising an open reading frame (ORF), optionally, with oneormore introns, e.g., but not limited to, at least one specified portion of at least one CDR, such as CDR1, CDR2 and / or CDR3 of at least one heavy chain or light chain; nucleic acid molecules comprising the coding sequence for ananti-IL‑23antibody or variable region; andnucleic acidmoleculeswhich comprise a nucleotide sequence substantially different from those described above but which, due to the degeneracy of thegenetic code, still encodeat least oneanti-IL‑23antibodyasdescribedherein and / or as known in theart.Of course, the genetic code iswell known in the art. Thus, it would be routine for one skilled in the art to generate such degenerate nucleic acid variants that code for specific anti-IL‑23 antibodies used in themethod of the present invention. See, e.g., Ausubel, et al., supra, and such nucleic acid variants are included in the present invention. Non-limiting examples of isolated nucleic acid molecules include nucleic acids encoding HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, respectively.

[0057] As indicated herein, nucleic acid molecules which comprise a nucleic acid encoding an anti-IL‑23 antibody can 9 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 include, but are not limited to, those encoding the amino acid sequence of an antibody fragment, by itself; the coding sequence for the entire antibody or a portion thereof; the coding sequence for an antibody, fragment or portion, as well as additional sequences, such as the coding sequence of at least one signal leader or fusion peptide, with or without the aforementionedadditional codingsequences, suchasat least one intron, togetherwithadditional, non-codingsequences, including but not limited to, non-coding 5’ and3’ sequences, suchas the transcribed, non-translated sequences that play a role in transcription,mRNAprocessing, including splicingandpolyadenylation signals (for example, ribosomebindingand stability of mRNA); an additional coding sequence that codes for additional amino acids, such as those that provide additional functionalities. Thus, the sequence encoding an antibody can be fused to a marker sequence, such as a sequence encoding a peptide that facilitates purification of the fused antibody comprising an antibody fragment or portion. Polynucleotides Selectively Hybridizing to a Polynucleotide as Described Herein

[0058] The method of the present invention uses isolated nucleic acids that hybridize under selective hybridization conditions to a polynucleotide disclosed herein. Thus, the polynucleotides of this embodiment can be used for isolating, detecting, and / or quantifying nucleic acids comprising such polynucleotides. For example, polynucleotides of the present invention can be used to identify, isolate, or amplify partial or full-length clones in a deposited library. In some embodi- ments, the polynucleotides are genomic or cDNA sequences isolated, or otherwise complementary to, a cDNA from a human or mammalian nucleic acid library.

[0059] Preferably, the cDNA library comprises at least 80% full-length sequences, preferably, at least 85% or 90% full- length sequences, and, more preferably, at least 95% full-length sequences. The cDNA libraries can be normalized to increase the representation of rare sequences. Low or moderate stringency hybridization conditions are typically, but not exclusively, employed with sequences having a reduced sequence identity relative to complementary sequences. Moderate and high stringency conditions can optionally be employed for sequences of greater identity. Low stringency conditionsallowselectivehybridizationof sequenceshavingabout70%sequence identity andcanbeemployed to identify orthologous or paralogous sequences.

[0060] Optionally, polynucleotides will encode at least a portion of an antibody. The polynucleotides embrace nucleic acid sequences that can be employed for selective hybridization to a polynucleotide encoding an antibody of the present invention. See, e.g., Ausubel, supra, Colligan, supra, each entirely incorporated herein by reference. Construction of Nucleic Acids

[0061] The isolated nucleic acids can bemade using (a) recombinantmethods, (b) synthetic techniques, (c) purification techniques, and / or (d) combinations thereof, as well-known in the art.

[0062] The nucleic acids can conveniently comprise sequences in addition to a polynucleotide of the present invention. For example, a multi-cloning site comprising one or more endonuclease restriction sites can be inserted into the nucleic acid to aid in isolation of the polynucleotide. Also, translatable sequences can be inserted to aid in the isolation of the translated polynucleotide of the present invention. For example, a hexa-histidinemarker sequence provides a convenient means to purify the proteins of the present invention. The nucleic acid of the present invention, excluding the coding sequence, is optionally a vector, adapter, or linker for cloning and / or expression of a polynucleotide of the present invention.

[0063] Additional sequences can be added to such cloning and / or expression sequences to optimize their function in cloningand / orexpression, toaid in isolationof thepolynucleotide, or to improve the introductionof thepolynucleotide intoa cell.Useof cloning vectors, expressionvectors, adapters, and linkers iswell known in theart. (See, e.g.,Ausubel, supra;or Sambrook, supra) Recombinant Methods for Constructing Nucleic Acids

[0064] The isolated nucleic acid compositions, such as RNA, cDNA, genomic DNA, or any combination thereof, can be obtained from biological sources using any number of cloning methodologies known to those of skill in the art. In some embodiments, oligonucleotide probes that selectively hybridize, under stringent conditions, to the polynucleotides of the present invention are used to identify the desired sequence in a cDNA or genomic DNA library. The isolation of RNA, and constructionof cDNAandgenomic libraries, arewell known to thoseofordinaryskill in theart. (See,e.g.,Ausubel,supra:or Sambrook, supra) Nucleic Acid Screening and Isolation Methods

[0065] A cDNA or genomic library can be screened using a probe based upon the sequence of a polynucleotide used in themethodof thepresent invention, suchas thosedisclosedherein. Probes canbeused tohybridizewith genomicDNAor 10 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 cDNA sequences to isolate homologous genes in the same or different organisms. Those of skill in the art will appreciate that various degrees of stringency of hybridization can be employed in the assay; and either the hybridization or the wash medium can be stringent. As the conditions for hybridization become more stringent, there must be a greater degree of complementarity between the probe and the target for duplex formation to occur. The degree of stringency can be controlled by one or more of temperature, ionic strength, pH and the presence of a partially denaturing solvent, such as formamide. For example, the stringency of hybridization is conveniently varied by changing the polarity of the reactant solution through, for example, manipulation of the concentration of formamide within the range of 0% to 50%. The degree of complementarity (sequence identity) required for detectable binding will vary in accordance with the stringency of the hybridization medium and / or wash medium. The degree of complementarity will optimally be 100%, or 70‑100%, or any range or value therein. However, it should be understood thatminor sequence variations in the probes and primers can be compensated for by reducing the stringency of the hybridization and / or wash medium.

[0066] Methods of amplification of RNA or DNA are well known in the art and can be used according to the present invention without undue experimentation, based on the teaching and guidance presented herein.

[0067] Known methods of DNA or RNA amplification include, but are not limited to, polymerase chain reaction (PCR) and related amplification processes (see, e.g., U.S. Patent Nos. 4,683,195, 4,683,202, 4,800,159, 4,965,188, toMullis, et al.; 4,795,699and4,921,794 to Tabor, et al; 5,142,033 to Innis; 5,122,464 toWilson, et al.,5,091,310 to Innis; 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 Biswas; 4,656,134 to Ringold) and RNA mediated amplification that uses anti-sense RNA to the target sequence as a template for double-stranded DNA synthesis (U.S. Patent No. 5,130,238 toMalek, et al, with the tradenameNASBA), the entire contents of which references are incorporated herein by reference. (See, e.g., Ausubel, supra; or Sambrook, supra.)

[0068] For instance, polymerase chain reaction (PCR) technology can be used to amplify the sequences of poly- nucleotides used in the method of the present invention and related genes directly from genomic DNA or cDNA libraries. PCRandother in vitro amplificationmethodscanalsobeuseful, for example, to clonenucleic acid sequences that code for proteins to be expressed, to make nucleic acids to use as probes for detecting the presence of the desired mRNA in samples, for nucleic acid sequencing, or for other purposes. Examples of techniques sufficient to direct persons of skill through in vitro amplificationmethods are found in Berger, supra, Sambrook, supra, andAusubel, supra, aswell asMullis, et al., U.S. Patent No. 4,683,202 (1987); and Innis, et al., PCR Protocols A Guide to Methods and Applications, Eds., Academic Press Inc., San Diego, CA (1990). Commercially available kits for genomic PCR amplification are known in the art. See, e.g., Advantage-GC Genomic PCR Kit (Clontech). Additionally, e.g., the T4 gene 32 protein (Boehringer Mannheim) can be used to improve yield of long PCR products. Synthetic Methods for Constructing Nucleic Acids

[0069] The isolated nucleic acids used in the method of the present invention can also be prepared by direct chemical synthesis by knownmethods (see, e.g., Ausubel, et al., supra). Chemical synthesis generally produces a single-stranded oligonucleotide, which can be converted into double-stranded DNA by hybridization with a complementary sequence, or by polymerization with a DNA polymerase using the single strand as a template. One of skill in the art will recognize that while chemical synthesis of DNA can be limited to sequences of about 100 or more bases, longer sequences can be obtained by the ligation of shorter sequences. Recombinant Expression Cassettes

[0070] The present invention uses recombinant expression cassettes comprising a nucleic acid. A nucleic acid sequence, for example, a cDNA or a genomic sequence encoding an antibody used in the method of the present invention, canbeused to construct a recombinant expressioncassette that canbe introduced intoat least onedesiredhost cell. A recombinant expression cassettewill typically comprise a polynucleotide operably linked to transcriptional initiation regulatory sequences thatwill direct the transcriptionof thepolynucleotide in the intendedhost cell. Bothheterologousand non-heterologous (i.e., endogenous) promoters can be employed to direct expression of the nucleic acids.

[0071] In some embodiments, isolated nucleic acids that serve as promoter, enhancer, or other elements can be introduced in the appropriate position (upstream, downstream or in the intron) of a non-heterologous form of a polynucleotide of the present invention so as to up or down regulate expression of a polynucleotide. For example, endogenous promoters can be altered in vivo or in vitro by mutation, deletion and / or substitution. Vectors and Host Cells

[0072] The present invention also relates to vectors that include isolated nucleic acid molecules, host cells that are genetically engineeredwith the recombinant vectors, and theproductionof at least oneanti-IL‑23antibodyby recombinant techniques, as iswell known in the art. See, e.g., Sambrook, et al., supra; Ausubel, et al., supra, eachentirely incorporated 11 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 herein by reference.

[0073] The polynucleotides can optionally be joined to a vector containing a selectablemarker for propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.

[0074] The DNA insert should be operatively linked to an appropriate promoter. The expression constructs will further contain sites for transcription initiation, termination and, in the transcribed region, a ribosome binding site for translation. Thecodingportionof themature transcriptsexpressedby theconstructswill preferably includea translation initiatingat the beginning and a termination codon (e.g., UAA, UGA or UAG) appropriately positioned at the end of the mRNA to be translated, with UAA and UAG preferred for mammalian or eukaryotic cell expression.

[0075] Expression vectors will preferably but optionally include at least one selectable marker. Such markers include, e.g., but are not limited to, methotrexate (MTX), dihydrofolate reductase (DHFR, US Pat.Nos. 4,399,216; 4,634,665; 4,656,134, 4,956,288; 5,149,636; 5,179,017, ampicillin, neomycin (G418), mycophenolic acid, or glutamine synthetase (GS, US Pat.Nos. 5,122,464; 5,770,359; 5,827,739) resistance for eukaryotic cell culture, and tetracycline or ampicillin resistance genes for culturing in E. coli and other bacteria or prokaryotics (the above patents are entirely incorporated hereby by reference). Appropriate culturemediumsand conditions for the above-described host cells are known in the art. Suitable vectors will be readily apparent to the skilled artisan. Introduction of a vector construct into a host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection or other known methods. Such methods are described in the art, such as Sambrook, supra, Chapters 1‑4 and 16‑18; Ausubel, supra, Chapters 1, 9, 13, 15, 16.

[0076] At least one antibody used in themethod of the present invention can be expressed in amodified form, such as a fusion protein, and can include not only secretion signals, but also additional heterologous functional regions. For instance, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of an antibody to improve stability and persistence in the host cell, during purification, or during subsequent handling and storage. Also, peptidemoieties can be added to an antibody of the present invention to facilitate purification. Such regions can be removed prior to final preparation of an antibody or at least one fragment thereof. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Chapters 17.29‑17.42 and 18.1‑18.74; Ausubel, supra, Chapters 16, 17 and 18.

[0077] Thoseof ordinary skill in the art are knowledgeable in the numerousexpression systemsavailable for expression of a nucleic acid encoding a protein used in the method of the present invention. Alternatively, nucleic acids can be expressed in ahost cell by turningon (bymanipulation) in ahost cell that contains endogenousDNAencodinganantibody. Such methods are well known in the art, e.g., as described in US patent Nos. 5,580,734, 5,641,670, 5,733,746, and 5,733,761, entirely incorporated herein by reference.

[0078] Illustrative of cell cultures useful for the production of the antibodies, specified portions or variants thereof, are mammalian cells. Mammalian cell systems often will be in the form of monolayers of cells although mammalian cell suspensionsor bioreactors canalsobeused.Anumberof suitablehost cell lines capableof expressing intact glycosylated proteins have been developed in the art, and include the COS‑1 (e.g., ATCCCRL 1650), COS‑7 (e.g., ATCCCRL‑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, CHOcells, hepG2 cells, P3X63Ag8.653, SP2 / 0-Ag14, 293 cells, HeLa cells and the like, which are readily available from, for example, American Type Culture Collection, Manassas, Va (www.atcc.org). Preferred host cells include cells of lymphoid origin, such as myeloma 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 a SP2 / 0-Ag14 cell.

[0079] Expression vectors for these cells can include one or more of the following expression control sequences, such as, but not limited to, an origin of replication; a promoter (e.g., late or early SV40 promoters, the CMV promoter (US Pat.Nos. 5,168,062; 5,385,839), anHSV tk promoter, a pgk (phosphoglycerate kinase) promoter, anEF‑1 alpha promoter (USPat.No. 5,266,491), at least one human immunoglobulin promoter; an enhancer, and / or processing information sites, such as ribosomebinding sites, RNAsplice sites, polyadenylation sites (e.g., anSV40 large TAgpoly A addition site), and transcriptional terminator sequences. See, e.g., Ausubel et al., supra; Sambrook, et al., supra. Other cells useful for productionof nucleic acidsor proteins of the present inventionare knownand / or available, for instance, from theAmerican Type Culture Collection Catalogue of Cell Lines and Hybridomas (www.atcc.org) or other known or commercial sources.

[0080] When eukaryotic host cells are employed, polyadenlyation or transcription terminator sequences are typically incorporated into thevector.Anexampleof a terminator sequence is thepolyadenlyationsequence from thebovinegrowth hormone gene. Sequences for accurate splicing of the transcript can also be included. An example of a splicing sequence is the VP1 intron from SV40 (Sprague, et al., J. Virol. 45:773‑781 (1983)). Additionally, gene sequences to control replication in the host cell can be incorporated into the vector, as known in the art. 12 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 Purification of an Antibody

[0081] An anti-IL‑23 antibody can be recovered and purified from recombinant cell cultures by well-known methods including, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. High performance liquid chromatography ("HPLC") canalsobeemployed for purification. See, e.g., Colligan,Current Protocols in Immunology, orCurrentProtocols in Protein Science, John Wiley & Sons, NY, NY, (1997‑2001), e.g., Chapters 1, 4, 6, 8, 9, 10, each entirely incorporated herein by reference.

[0082] Antibodies used in the method of the present invention include naturally purified products, products of chemical synthetic procedures, and products produced by recombinant techniques from a eukaryotic host, including, for example, yeast, higher plant, insect and mammalian cells. Depending upon the host employed in a recombinant production procedure, the antibody can be glycosylated or can be non-glycosylated, with glycosylated preferred. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Sections 17.37‑17.42; Ausubel, supra, Chapters 10, 12, 13, 16, 18 and 20, Colligan, Protein Science, supra, Chapters 12‑14, all entirely incorporated herein by reference. Anti-IL‑23 Antibodies.

[0083] Ananti-IL‑23antibodyaccording to thepresent invention includesanyproteinorpeptidecontainingmolecule that 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 chain or light chain variable region, a framework region (e.g., FR1, FR2, FR3, FR4 or fragment thereof, further optionally comprising at least one substitution, insertion or deletion), a heavy chain or light chain constant region, (e.g., comprising at least one CH1, hinge1, hinge2, hinge3, hinge4, CH2, or CH3 or fragment thereof, further optionally comprisingat least onesubstitution, insertionordeletion), oranyportion thereof, that canbe incorporated intoan antibody.Anantibody can includeor bederived fromanymammal, suchasbut not limited to, a human, amouse, a rabbit, a rat, a rodent, a primate, or any combination thereof, and the like.

[0084] The isolatedantibodiesused in themethodof thepresent inventioncomprise theantibodyaminoacid 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 and, thereby, partially or substantially neutralizes at least one biological activity of the protein. Anantibody, or specified portion or variant thereof, that partially or preferably substantially neutralizes at least one biological activity of at least one IL‑23 protein or fragment can bind the protein or fragment and thereby inhibit activities mediated through the binding of IL‑23 to the IL‑23 receptor or through other IL‑23-dependent or mediated mechanisms. As used herein, the term "neutralizing antibody" refers to an antibody that can inhibit an IL‑23- dependent activity by about 20‑120%, preferably by 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%ormore depending on the assay. The capacity of an anti-IL‑23 antibody to inhibit an 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 theart. Ahumanantibody canbeof any class (IgG, IgA, IgM, IgE, IgD, etc.) or isotypeand cancomprise akappaor lambda light chain. Inoneembodiment, thehumanantibodycomprisesan IgGheavychainordefined fragment, for example, at least one of isotypes, IgG1, IgG2, IgG3or IgG4 (e.g., γ1, γ2, γ3, γ4). Antibodies of this type can be prepared by employing a transgenicmouse or other trangenic non-humanmammal comprising at least one human light chain (e.g., IgG, IgA, and IgM) transgenes as described herein and / or as known in the art. In another embodiment, the anti-IL‑23 human antibody comprises an IgG1 heavy chain and an IgG1 light chain.

[0085] Anantibodybindsat least onespecifiedepitopespecific toat least one IL‑23protein, subunit, fragment, portionor anycombination thereof. Theat least oneepitopecancompriseat least oneantibodybinding region that comprisesat least oneportion of the protein,which epitope is preferably comprised of at least oneextracellular, soluble, hydrophillic, external or cytoplasmic portion of the protein.

[0086] Generally, the human antibody or antigen-binding fragment will comprise an antigen-binding region that comprises at least one human complementarity determining region (CDR1, CDR2 and CDR3) or variant of at least oneheavy chain variable regionandat least onehumancomplementarity determining region (CDR1,CDR2andCDR3) or variant of at least one light chain variable region. TheCDRsequencesmaybederived fromhumangermline sequences or closely match the germline sequences. For example, the CDRs from a synthetic library derived from the original non- human CDRs can be used. These CDRs may be formed by incorporation of conservative substitutions from the original non-human sequence. In another particular embodiment, the antibody or antigen-binding portion or variant can have an antigen-binding region that comprises at least a portion of at least one light chain CDR (i.e., CDR1, CDR2 and / or CDR3) having the amino acid sequence of the corresponding CDRs 1, 2 and / or 3.

[0087] Such antibodies can be prepared by chemically joining together the various portions (e.g., CDRs, framework) of 13 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 the antibody using conventional techniques, by preparing and expressing a (i.e., one or more) nucleic acid molecule that encodes the antibody using conventional techniques of recombinant DNA technology or by using any other suitable method.

[0088] The anti-IL‑23 specific antibody can comprise at least one of a heavy or light chain variable region having a definedaminoacidsequence.Forexample, inapreferredembodiment, theanti-IL‑23antibodycomprisesat leastoneofat least one heavy chain variable region, optionally having the amino acid sequence of SEQ ID NO: 106 and / or at least one light chain variable region, optionally having the amino acid sequence of SEQ ID NO:116. Antibodies that bind to human IL‑23 and that comprise a defined heavy or light chain variable region can be prepared using suitable methods, such as phage display (Katsube. Y., et al., Int J Mol. Med, 1(5):863‑868 (1998)) or methods that employ transgenic animals, as known in the art and / or as described herein. For example, a transgenic mouse, comprising a functionally rearranged human immunoglobulin heavy chain transgene and a transgene comprising DNA from a human immunoglobulin light chain locus that can undergo functional rearrangement, can be immunizedwith human IL‑23 or a fragment thereof to elicit the production of antibodies. If desired, the antibody producing cells canbe isolatedandhybridomasor other immortalized antibody-producing cells can be prepared as described herein and / or as known in the art. Alternatively, the antibody, specified portion or variant can be expressed using the encoding nucleic acid or portion thereof in a suitable host cell.

[0089] The invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains andCDRs compris- ingaminoacids ina sequence that is substantially the sameasanaminoacid sequencedescribedherein.Preferably, such antibodies or antigen-binding fragments and antibodies comprising such chains or CDRs can bind human IL‑23 with high affinity (e.g., KD less than or equal to about 10‑9 M). Amino acid sequences that are substantially the same as the sequences described herein include sequences comprising conservative amino acid substitutions, as well as amino acid deletions and / or insertions. A conservative amino acid substitution refers to the replacement of a first amino acid by a second amino acid that has chemical and / or physical properties (e.g., charge, structure, polarity, hydrophobicity / hydro- philicity) that are similar to those of the first amino acid. Conservative substitutions include, without limitation, replacement of one amino acid by another within the following groups: lysine (K), arginine (R) and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D and E; alanine (A), valine (V), leucine (L), isoleucine (1), proline (P), phenylalanine (F), tryptophan (W),methionine (M), cysteine (C)andglycine (G); F, W and Y; C, S and T. Amino Acid Codes

[0090] The amino acids that make up anti‑1L‑23 antibodies of the present invention are often abbreviated. The amino acid designations can be indicated by designating the amino acid by its single letter code, its three letter code, name, or three nucleotide codon(s) as is well understood in the art (see Alberts, B., et al., Molecular Biology of The Cell, Third Ed., Garland Publishing, Inc., New York, 1994): SINGLE LETTER CODE THREE LETTER CODE NAME THREE NUCLEOTIDE CODON(S) A Ala Alanine GCA, GCC, GCG, GCU C Cys Cysteine UGC, UGU D Asp Aspartic acid GAC, GAU E Glu Glutamic acid GAA, GAG F Phe Phenylanine UUC, UUU G Gly Glycine GGA, GGC, GGG, GGU H His Histidine CAC, CAU I Ile Isoleucine AUA, AUC, AUU K Lys Lysine AAA, AAG L Leu Leucine UUA, UUG, CUA, CUC, CUG, CUU M Met Methionine AUG N Asn Asparagine AAC, AAU P Pro Proline CCA, CCC, CCG, CCU Q Gln Glutamine CAA, CAG R Arg Arginine AGA, AGG, CGA, CGC, CGG, CGU 14 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) SINGLE LETTER CODE THREE LETTER CODE NAME THREE NUCLEOTIDE CODON(S) S Ser Serine AGC, AGU, UCA, UCC, UCG, UCU T Thr Threonine ACA, ACC, ACG, ACU V Val Valine GUA, GUC, GUG, GUU W Trp Tryptophan UGG Y Tyr Tyrosine UAC, UAU An anti-IL‑23 antibody used in the method of the present invention can include one or more amino acid substitutions, deletions or additions, either from natural mutations or human manipulation, as specified herein.

[0091] The number of amino acid substitutions a skilled artisan would make depends on many factors, including those described above. Generally speaking, the number of amino acid substitutions, insertions or deletions for any given anti- IL‑23 antibody, fragment or variant will not bemore than 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, such as 1‑30 or any range or value therein, as specified herein.

[0092] Aminoacids inananti-IL‑23specificantibody thatareessential for functioncanbe identifiedbymethodsknown in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (e.g., Ausubel, supra, Chapters 8, 15; Cunningham and Wells, Science 244:1081‑1085 (1989)). The latter procedure introduces single alanine mutations at every residue in themolecule. The resultingmutantmoleculesare then tested for biological activity, suchas, but not limited to, at least one IL‑23 neutralizing activity. Sites that are critical for antibody binding can also be identified by structural analysis, such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith, et al., J. Mol. Biol. 224:899‑904 (1992) and de Vos, et al., Science 255:306‑312 (1992)).

[0093] Anti-IL‑23 antibodies can include, but are not limited to, at least one portion, sequence or combination selected from 5 to all of the contiguous amino acids of at least one of SEQ ID NOS: 5, 20, 44, 50, 56, and 73.

[0094] IL‑23antibodies or specifiedportions or variants can include, but arenot limited to, at least oneportion, sequence or combination selected fromat least 3‑5 contiguous amino acids of the SEQ IDNOs above; 5‑17 contiguous amino acids of theSEQIDNOsabove, 5‑10contiguousaminoacidsof theSEQ IDNOsabove, 5‑11contiguousaminoacidsof theSEQ ID NOs above, 5‑7 contiguous amino acids of the SEQ ID NOs above; 5‑9 contiguous amino acids of the SEQ ID NOs above.

[0095] Ananti-IL‑23 antibody can further optionally comprise a polypeptide of at least one of 70‑100%of 5, 17, 10, 11, 7, 9, 119, or 108 contiguous amino acids of the SEQ ID NOs above. In one embodiment, the amino acid sequence of an immunoglobulin chain, or portion thereof (e.g., variable region, CDR) has about 70‑100% identity (e.g., 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any range or value therein) to the amino acid sequence of the corresponding chain of at least one of theSEQ IDNOsabove. For example, the amino acid sequence of a light chain variable region can be comparedwith the sequence of the SEQ IDNOs above, or the amino acid sequence of a heavy chain CDR3 can be compared with the SEQ ID NOs above. Preferably, 70‑100% amino acid identity (i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any range or value therein) is determined using a suitable computer algorithm, as known in the art.

[0096] "Identity," as known in the art, is a relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by comparing the sequences. In the art, "identity" also means the degree of sequence relatedness between polypeptide or polynucleotide sequences, as determined by thematch between strings of such sequences. "Identity" and "similarity" can be readily calculated by knownmethods, including, but not limited to, those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; and Carillo, H., and Lipman, D., Siam J. Applied Math., 48:1073 (1988). In addition, values for percentage identity can be obtained from amino acid and nucleotide sequence alignments generated using the default settings for the AlignX component of Vector NTI Suite 8.0 (Informax, Frederick, MD).

[0097] Preferred methods to determine identity are designed to give the largest match between the sequences tested. Methods to determine identity and similarity are codified in publicly available computer programs. Preferred computer program methods to determine identity and similarity between two sequences include, but are not limited to, the GCG program package (Devereux, J., et al., Nucleic Acids Research 12(1): 387 (1984)), BLASTP, BLASTN, and FASTA (Atschul, S. F. et al., J. Molec. Biol. 215:403‑410 (1990)). The BLASTX program is publicly available fromNCBI and other sources (BLAST Manual, Altschul, S., et al., NCBINLM NIH Bethesda, Md. 20894: Altschul, S., et al., J. Mol. Biol. 215:403‑410 (1990). The well-known Smith Waterman algorithm may also be used to determine identity. 15 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55

[0098] Preferred parameters for polypeptide sequence comparison include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443‑453 (1970) Comparison matrix: BLOSSUM62 from Hentikoff and Hentikoff, Proc. Natl. Acad. Sci. USA. 89:10915‑10919 (1992) Gap Penalty: 12 Gap Length Penalty: 4 A program useful with these parameters is publicly available as the "gap" program from Genetics Computer Group, MadisonWis. The aforementioned parameters are the default parameters for peptide sequence comparisons (along with no penalty for end gaps).

[0099] Preferred parameters for polynucleotide comparison include the following: (1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443‑453 (1970) Comparison matrix: matches=+10, mismatch=0 Gap Penalty: 50 Gap Length Penalty: 3 Available as: The "gap" program fromGenetics Computer Group,MadisonWis. These are the default parameters for nucleic acid sequence comparisons.

[0100] Byway of example, a polynucleotide sequencemaybe identical to another sequence, that is 100% identical, or it may include up to a certain integer number of nucleotide alterations as compared to the reference sequence. Such alterations are selected from the group consisting of at least one nucleotide deletion, substitution, including transition and transversion, or insertion, and wherein the alterations may occur at the 5’ or 3’ terminal positions of the reference nucleotide sequence or anywhere between those terminal positions, interspersed either individually among the nucleo- tides in the reference sequence or in one or more contiguous groups within the reference sequence. The number of nucleotide alterations is determined by multiplying the total number of nucleotides in the sequence by the numerical percent of the respectivepercent identity (dividedby100)andsubtracting that product from the total numberof nucleotides in the sequence, or: n.sub.n.ltorsim.x.sub.n ‑(x.sub.n.y), wherein n.sub.n is the number of nucleotide alterations, x.sub.n is the total number of nucleotides in sequence, and y is, for instance, 0.70 for 70%,0.80 for80%,0.85 for85%,0.90 for 90%,0.95 for95%,etc., andwhereinanynon-integer product of x.sub.n and y is rounded down to the nearest integer prior to subtracting from x.sub.n.

[0101] Alterations of a polynucleotide sequence encoding the the SEQ IDNOs abovemay create nonsense, missense or frameshiftmutations in this coding sequence and thereby alter the polypeptide encoded by the polynucleotide following such alterations. Similarly, a polypeptide sequencemay be identical to the reference sequence of the SEQ IDNOsabove, that is be 100% identical, or it may include up to a certain integer number of amino acid alterations as compared to the reference sequence such that the percentage identity is less than 100%. Such alterations are selected from the group consisting of at least one amino acid deletion, substitution, including conservative and non-conservative substitution, or insertion, and wherein the alterations may occur at the amino‑ or carboxy-terminal positions of the reference polypeptide sequence or anywhere between those terminal positions, interspersed either individually among the amino acids in the reference sequence or in one or more contiguous groups within the reference sequence. The number of amino acid alterations for a given% identity is determined bymultiplying the total number of amino acids in the SEQ IDNOs above by the numerical percent of the respective percent identity (divided by 100) and then subtracting that product from the total number of amino acids in the SEQ ID NOs above, or: n.sub.a.ltorsim.x.sub.a ‑(x.sub.a.y), wherein n.sub.a is the number of amino acid alterations, x.sub.a is the total number of amino acids in the SEQ IDNOs above, and y is, for instance 0.70 for 70%, 0.80 for 80%, 0.85 for 85% etc., and wherein any non-integer produce of x.sub.a and y is rounded down to the nearest integer prior to subtracting it from x.sub.a.

[0102] Exemplary heavy chain and light chain variable regions sequences and portions thereof are provided in theSEQ ID NOs above. The antibodies of the present invention, or specified variants thereof, can comprise any number of 16 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 contiguous amino acid residues froman antibody of the present invention, wherein that number is selected from the group of integers consisting of from 10‑100% of the number of contiguous residues in an anti-IL‑23 antibody. Optionally, this subsequence of contiguous amino acids is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 ormore amino acids in length, or any range or value therein. Further, the numberof suchsubsequencescanbeany integer selected from thegroupconsistingof from1 to20, suchasat least 2, 3, 4, or 5.

[0103] As those of skill will appreciate, the present invention includes at least one biologically active antibody of the present invention.Biologically activeantibodies haveaspecific activity at least 20%,30%, or 40%, and, preferably, at least 50%, 60%, or 70%, and, most preferably, at least 80%, 90%, or 95%‑100% or more (including, without limitation, up to 10 times the specific activity) of that of the native (non-synthetic), endogenous or related and known antibody. Methods of assaying andquantifyingmeasures of enzymatic activity and substrate specificity arewell known to those of skill in the art.

[0104] Inanotheraspect, the invention relates tohumanantibodiesandantigen-binding fragments,asdescribedherein, which are modified by the covalent attachment of an organic moiety. Such modification can produce an antibody or antigen-binding fragment with improved pharmacokinetic properties (e.g., increased in vivo serum half-life). The organic moiety can be a linear or branched hydrophilic polymeric group, fatty acid group, or fatty acid ester group. In particular embodiments, the hydrophilic polymeric group can have a molecular weight of about 800 to about 120,000 Daltons and can be a polyalkane glycol (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymer, amino acidpolymer or polyvinyl pyrolidone, and the fatty acidor fatty acid ester groupcancomprise fromabout eight toabout forty carbon atoms.

[0105] The modified antibodies and antigen-binding fragments can comprise one or more organic moieties that are covalently bonded, directly or indirectly, to the antibody. Each organic moiety that is bonded to an antibody or antigen- binding fragment of the inventioncan independently beahydrophilic polymeric group,a fattyacidgroupor a fatty acidester group. As used herein, the term "fatty acid" encompasses mono-carboxylic acids and di-carboxylic acids. A "hydrophilic polymeric group," as the term is used herein, refers to an organic polymer that is more soluble in water than in octane. For example, polylysine is more soluble in water than in octane. Thus, an antibody modified by the covalent attachment of polylysine is encompassedby the invention.Hydrophilic polymers suitable formodifyingantibodies of the invention canbe linear or branched and include, for example, polyalkane glycols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG and the like), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides and the like), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, polyaspartate and the like), polyalkane oxides (e.g., polyethylene oxide, polypropylene oxide and the like) and polyvinyl pyrolidone. Preferably, the hydrophilic polymer that modifies the antibody of the invention has amolecularweight of about 800 to about 150,000Daltons asa separatemolecular entity. For example,PEG5000 andPEG20.000.wherein the subscript is the averagemolecularweight of the polymer inDaltons, canbe used. The hydrophilic polymeric group can be substituted with one to about six alkyl, fatty acid or fatty acid ester groups. Hydrophilic polymers that are substituted with a fatty acid or fatty acid ester group can be prepared by employing suitable methods. For example, a polymer comprising an amine group can be coupled to a carboxylate of the fatty acid or fatty acid ester, and an activated carboxylate (e.g., activatedwithN,N-carbonyl diimidazole) on a fatty acid or fatty acid ester can be coupled to a hydroxyl group on a polymer.

[0106] Fatty acids and fatty acid esters suitable formodifying antibodies of the invention can be saturated or can contain one or more units of unsaturation. Fatty acids that are suitable for modifying antibodies of the invention include, for example, n-dodecanoate (C12, laurate), n-tetradecanoate (C14, myristate), n-octadecanoate (C18, stearate), n-eicosano- ate (C20, arachidate), n-docosanoate (C22, behenate), n-triacontanoate (C30), n-tetracontanoate (C40), cis-Δ9-octade- canoate (Cis, oleate), all cis-Δ5,8,11,14-eicosatetraenoate (C20, arachidonate), octanedioic acid, tetradecanedioic acid, octadecanedioicacid,docosanedioicacid,and the like.Suitable fattyacidesters includemono-estersof dicarboxylicacids that comprise a linear or branched lower alkyl group. The lower alkyl group can comprise from one to about twelve, preferably, one to about six, carbon atoms.

[0107] Themodifiedhumanantibodiesandantigen-binding fragments canbepreparedusingsuitablemethods, suchas by reaction with one ormoremodifying agents. A "modifying agent" as the term is used herein, refers to a suitable organic group (e.g., hydrophilic polymer, a fatty acid, a fatty acid ester) that comprises an activating group. An "activating group" is a chemical moiety or functional group that can, under appropriate conditions, react with a second chemical group thereby forming a covalent bond between the modifying agent and the second chemical group. For example, amine-reactive activating groups include electrophilic groups, such as tosylate, mesylate, halo (chloro, bromo, fluoro, iodo), N-hydro- xysuccinimidyl esters (NHS), and the like. Activating groups that can react with thiols include, for example, maleimide, iodoacetyl, acrylolyl, pyridyl disulfides, 5-thiol‑2-nitrobenzoic acid thiol (TNB-thiol), and the like. An aldehyde functional group can be coupled to amine‑ or hydrazide-containing molecules, and an azide group can react with a trivalent phosphorousgroup to formphosphoramidateor phosphorimide linkages.Suitablemethods to introduceactivatinggroups into molecules are known in the art (see for example, Hermanson, G. T., Bioconjugate Techniques, Academic Press: San Diego, CA (1996)). An activating group can be bonded directly to the organic group (e.g., hydrophilic polymer, fatty acid, fatty acid ester), or througha linkermoiety, for example, a divalentC1‑C12 groupwherein oneormore carbonatomscanbe 17 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 replaced by a heteroatom, such as oxygen, nitrogen or sulfur. Suitable linker moieties include, for example, tetraethylene glycol, ‑(CH2)3‑, ‑NH‑(CH2)6‑NH‑, ‑(CH2)2-NH‑ and ‑CH2‑O-CH2‑CH2‑O-CH2‑CH2‑O-CH-NH‑. Modifying agents that comprise a linker moiety can be produced, for example, by reacting a mono-Boc-alkyldiamine (e.g., mono-Boc-ethyle- nediamine, mono-Boc-diaminohexane) with a fatty acid in the presence of 1-ethyl‑3‑(3-dimethylaminopropyl) carbodii- mide (EDC) to formanamidebondbetween the freeamineand the fatty acid carboxylate. TheBocprotectinggroupcanbe removed from the product by treatment with trifluoroacetic acid (TFA) to expose a primary amine that can be coupled to another carboxylate, as described, or can be reacted with maleic anhydride and the resulting product cyclized to produce anactivatedmaleimidoderivativeof the fattyacid. (See, for example,Thompson, et al.,WO92 / 16221, theentire teachings of which are incorporated herein by reference.)

[0108] The modified antibodies can be produced by reacting a human antibody or antigen-binding fragment with a modifying agent. For example, the organic moieties can be bonded to the antibody in a non-site specific manner by employing an amine-reactivemodifying agent, for example, anNHSester of PEG.Modified human antibodies or antigen- binding fragments can also be prepared by reducing disulfide bonds (e.g., intra-chain disulfide bonds) of an antibody or antigen-binding fragment. The reduced antibody or antigen-binding fragment can then be reacted with a thiol-reactive modifying agent to produce the modified antibody of the invention. Modified human antibodies and antigen-binding fragments comprising an organic moiety that is bonded to specific sites of an antibody of the present invention can be prepared using suitable methods, such as reverse proteolysis (Fisch et al., Bioconjugate Chem., 3:147‑153 (1992); Werlen et al., Bioconjugate Chem., 5:411‑417 (1994); Kumaran et al., Protein Sci. 6(10):2233‑2241 (1997); Itoh et al., Bioorg. Chem., 24(1): 59‑68 (1996); Capellas et al., Biotechnol. Bioeng., 56(4):456‑463 (1997)), and the methods described in Hermanson, G. T., Bioconjugate Techniques, Academic Press: San Diego, CA (1996).

[0109] The method of the present invention also uses 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 anti-IL‑23 antibodies thereof, as described herein and / or as known in the art that are provided in a non-naturally occurring composition, mixture or form. Such compositions comprise non-naturally occurring compositions comprising at least one or two full length, C‑ and / or N-terminally deleted variants, domains, fragments, or specified variants, of the anti-IL‑23 antibody amino acid sequence selected from the group consisting of 70‑1 00%of the contiguous amino acids of theSEQ IDNOsabove, or specified fragments, domains or variants thereof. Preferred anti-IL‑23 antibody compositions include at least one or two full length, fragments, domains or variantsasat least oneCDRorLBPcontainingportionsof theanti-IL‑23antibodysequencedescribedherein, for example, 70‑100% of the SEQ ID NOs above, or specified fragments, domains or variants thereof. Further preferred compositions comprise, for example, 40‑99%of at least oneof 70‑100%of theSEQ IDNOsabove, etc., or specified fragments, domains or variants thereof. Such composition percentages are by weight, volume, concentration, molarity, or molality as liquid or dry solutions, mixtures, suspension, emulsions, particles, powder, or colloids, as known in the art or as described herein. Antibody Compositions Comprising Further Therapeutically Active Ingredients

[0110] The antibody compositions used in the method of the invention can optionally further comprise an effective amount of at least one compound or protein selected from at least one of an anti-infective drug, a cardiovascular (CV) system drug, a central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid or electrolyte balance, a hematologic drug, an antineoplastic, an immunomodulation drug, an ophthalmic, otic or nasal drug, a topical drug, a nutritional drug or the like.Suchdrugsarewell known in theart, including formulations, indications, dosingandadministration foreachpresented herein (see, e.g., Nursing 2001 Handbook of Drugs, 21st edition, Springhouse Corp., Springhouse, PA, 2001. Health Professional’s DrugGuide 2001, ed., Shannon,Wilson, Stang, Prentice-Hall, Inc, Upper Saddle River, NJ; Pharmcother- apy Handbook, Wells et al., ed., Appleton & Lange, Stamford, CT, each entirely incorporated herein by reference).

[0111] Byway of example of the drugs that can be combinedwith the antibodies for themethod of the present invention, the anti-infective drug can be at least one selected from amebicides or at least one antiprotozoals, anthelmintics, antifungals, antimalarials, antituberculotics or at least one antileprotics, aminoglycosides, penicillins, cephalosporins, tetracyclines, sulfonamides, fluoroquinolones, antivirals,macrolideanti-infectives, andmiscellaneousanti-infectives.The hormonal drug can be at least one selected fromcorticosteroids, androgens or at least one anabolic steroid, estrogen or at least one progestin, gonadotropin, antidiabetic drug or at least one glucagon, thyroid hormone, thyroid hormone antagonist, pituitary hormone, and parathyroid-like drug. The at least one cephalosporin can be at least one selected from cefaclor, cefadroxil, cefazolin sodium, cefdinir, cefepime hydrochloride, cefixime, cefmetazole sodium, cefonicid sodium, cefoperazone sodium, cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoximeproxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime sodium, ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cephalexin hydrochloride, cephalexin monohydrate, cephradine, and loracarbef.

[0112] The at least one coricosteroid can be at least one selected from betamethasone, betamethasone acetate or betamethasone sodiumphosphate, betamethasone sodiumphosphate, cortisone acetate, dexamethasone, dexametha- sone acetate, dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone acetate, 18 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, triamcinolone, triamcinolone acetonide, and triamcinolone diacetate. The at least one androgen or anabolic steroid can be at least one selected from danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate, nandrolone phenpropionate, testosterone, testosterone cypionate, testos- terone enanthate, testosterone propionate, and testosterone transdermal system.

[0113] The at least one immunosuppressant can be at least one selected from azathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immune globulin, muromonab-CD3, mycophenolate mofetil, mycophenolate mofetil hydro- chloride, sirolimus, and tacrolimus.

[0114] The at least one local anti-infective can be at least one selected from acyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazole nitrate, clindamycin phosphate, clotrimazole, econazole nitrate, erythromycin, genta- micin sulfate, ketoconazole, mafenide acetate, metronidazole (topical), miconazole nitrate, mupirocin, naftifine hydro- chloride, neomycin sulfate, nitrofurazone, nystatin, silver sulfadiazine, terbinafinehydrochloride, terconazole, tetracycline hydrochloride, tioconazole, and tolnaftate. The at least one scabicide or pediculicide can be at least one selected from crotamiton, lindane, permethrin, and pyrethrins. The at least one topical corticosteroid can be at least one selected from betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desonide, desoximetasone, dexametha- sone, dexamethasone sodium phosphate, diflorasone diacetate, fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasone propionate, halcionide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocorisone valerate,mometasone furoate, and triamcinolone acetonide. (See, e.g., pp. 1098‑1136 of Nursing 2001DrugHandbook.)

[0115] Anti-IL‑23 antibody compositions can further comprise at least one of any suitable and effective amount of a composition or pharmaceutical composition comprising at least one anti-IL‑23 antibody contacted or administered to a cell, tissue, organ, animal or patient in needof suchmodulation, treatment or therapy, optionally further comprising at least one selected from at least one TNF antagonist (e.g., but not limited to a TNF chemical or protein antagonist, TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70 or p85) or fragment, fusion polypeptides thereof, or a small molecule TNF antagonist, e.g., TNF binding protein I or II (TBP‑1 or TBP-II), nereli- monmab, infliximab, eternacept, CDP‑571, CDP‑870, afelimomab, lenercept, and the like), an antirheumatic (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalzine), an immunization, an immunoglobulin, an immunosuppressive (e.g., basiliximab, cyclosporine, daclizumab), a cytokine or a cytokine antagonist. Non-limiting examples of such cytokines include, but are not limited to, any of IL‑1 to IL‑23 et al. (e.g., IL‑1, IL‑2, etc.). Suitable dosages are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, CT (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000,DeluxeEdition, TarasconPublishing, LomaLinda,CA (2000), eachofwhich references are entirely incorporated herein by reference.

[0116] Anti-IL‑23 antibody compounds, compositions or combinations used in the method of the present invention can further comprise at least one of any suitable auxiliary, such as, but not limited to, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like. Pharmaceutically acceptable auxiliaries are preferred. Non-limiting examples of, and methods of preparing such sterile solutions are well known in the art, such as, but limited to, Gennaro, Ed., Remington’s Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (Easton, PA) 1990. Pharmaceutically acceptable carriers can be routinely selected that are suitable for the mode of administration, solubility and / or stability of the anti-IL‑23 antibody, fragment or variant composition as well known in the art or as described herein.

[0117] Pharmaceutical excipients and additives useful in the present composition include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di‑, tri‑, tetra‑, and oligosaccharides: derivatized sugars, such as alditols, aldonic acids, esterified sugars and the like; and polysacchar- ides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1‑99.99% by weight or volume. Exemplary protein excipients include serum albumin, such as human serum albumin (HSA), recombi- nant humanalbumin (rHA), gelatin, casein, and the like. Representative amino acid / antibody components, which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. One preferred amino acid is glycine.

[0118] Carbohydrate excipients suitable for use in the 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, dextrans, starches, and the like; and alditols, such asmannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), myoinositol and the like. Preferred carbohydrate excipients for use in the present invention are mannitol, trehalose, and raffinose.

[0119] Anti-IL‑23 antibody compositions can also include a buffer or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts, such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers. Preferred buffers for use in the present compositions are organic acid salts, such as 19 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 citrate.

[0120] Additionally, anti-IL‑23 antibody compositions can include polymeric excipients / additives, such as polyvinyl- pyrrolidones, ficolls (a polymeric sugar), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin), poly- ethylene glycols, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates, such as "TWEEN20" and "TWEEN80"), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA).

[0121] These and additional known pharmaceutical excipients and / or additives suitable for use in the anti-IL‑23 antibody, portion or variant compositions according to the invention are known in the art, e.g., as listed in "Remington: The Science & Practice of Pharmacy," 19th ed., Williams & Williams, (1995), and in the "Physician’s Desk Reference," 52nded.,MedicalEconomics,Montvale,NJ (1998), thedisclosuresofwhichareentirely incorporatedhereinby reference. Preferred carrier or excipient materials are carbohydrates (e.g., saccharides and alditols) and buffers (e.g., citrate) or polymeric agents. An exemplary carrier molecule is the mucopolysaccharide, hyaluronic acid, which may be useful for intraarticular delivery. Formulations

[0122] As noted above, the invention provides for stable formulations, which preferably comprise a phosphate buffer with saline or a chosen salt, aswell as preserved solutions and formulations containing a preservative aswell asmulti-use preserved formulations suitable for pharmaceutical or veterinary use, comprising at least one anti‑1L‑23 antibody in a pharmaceutically acceptable formulation. Preserved formulations contain at least one known preservative or optionally selected from the group consisting of at least one phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylpar- aben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof in an aqueous diluent. Any suitable concentration or mixture can be used as known in the art, such as 0.001‑5%, 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, no preservative, 0.1‑2% m-cresol (e.g., 0.2, 0.3. 0.4, 0.5, 0.9, 1.0%), 0.1‑3% benzyl alcohol (e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001‑0.5% thimerosal (e.g., 0.005, 0.01), 0.001‑2.0%phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005‑1.0%alkylparaben(s) (e.g., 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%), and the like.

[0123] As noted above, the method of the invention uses an article of manufacture, comprising packagingmaterial and at least one vial comprising a solution of at least one anti-IL‑23 specific antibody with the prescribed buffers and / or preservatives, optionally in anaqueousdiluent,wherein said packagingmaterial comprisesa label that indicates that such solution can be held over a period of 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72 hours or greater. The invention further uses an article of manufacture, comprising packaging material, a first vial comprising lyophilized anti- IL‑23 specific antibody, andasecond vial comprisinganaqueous diluent of prescribed buffer or preservative,wherein said packagingmaterial comprises a label that instructs a patient to reconstitute the anti-IL‑23 specific antibody in the aqueous diluent to form a solution that can be held over a period of twenty-four hours or greater.

[0124] The anti-IL‑23 specific antibody used in accordance with the present invention can be produced by recombinant means, including from mammalian cell or transgenic preparations, or can be purified from other biological sources, as described herein or as known in the art.

[0125] The rangeof theanti-IL‑23specificantibody includesamounts yieldingupon reconstitution, if inawet / drysystem, concentrations fromabout 1.0µg / ml to about 1000mg / ml, although lower and higher concentrations are operable and are dependent on the intended delivery vehicle, e.g., solution formulations will differ from transdermal patch, pulmonary, transmucosal, or osmotic or micro pump methods.

[0126] Preferably, the aqueous diluent optionally further 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, alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkoniumchloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof. The concentration of preservative used in the formulation is a concentration sufficient to yield an anti-microbial effect. Such concentrations are dependent on the preservative selected and are readily determined by the skilled artisan.

[0127] Other excipients, e.g., isotonicity agents, buffers, antioxidants, and preservative enhancers, can be optionally and preferably added to the diluent. An isotonicity agent, such as glycerin, is commonly used at known concentrations. A physiologically tolerated buffer is preferably added to provide improved pH control. The formulations can cover a wide range of pHs, such as from about pH 4 to about pH 10, and preferred ranges from about pH 5 to about pH 9, and a most preferred range of about 6.0 to about 8.0. Preferably, the formulations of the present invention have a pH between about 6.8 and about 7.8. Preferred buffers include phosphate buffers, most preferably, sodium phosphate, particularly, 20 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 phosphate buffered saline (PBS).

[0128] Otheradditives, suchasapharmaceutically acceptablesolubilizers likeTween20 (polyoxyethylene (20)sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymers), and PEG (polyethylene glycol) or nonionic surfactants, suchaspolysorbate20or80orpoloxamer184or188,Pluronic®polyls, otherblockco-polymers, and chelators, such as EDTA and EGTA, can optionally be added to the formulations or compositions to reduce aggregation. These additives are particularly useful if a pumpor plastic container is used to administer the formulation. The presence of pharmaceutically acceptable surfactant mitigates the propensity for the protein to aggregate.

[0129] The formulations can be prepared by a process which comprisesmixing at least one anti-IL‑23 specific antibody andapreservative selected from thegroupconsistingof phenol,m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben, (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehy- droacetate and thimerosal or mixtures thereof in an aqueous diluent. Mixing the at least one anti-IL‑23 specific antibody and preservative in an aqueous diluent is carried out using conventional dissolution andmixing procedures. To prepare a suitable formulation, for example, a measured amount of at least one anti-IL‑23 specific antibody in buffered solution is combinedwith thedesiredpreservative in abuffered solution in quantities sufficient to provide theprotein andpreservative at the desired concentrations. Variations of this process would be recognized by one of ordinary skill in the art. For example, theorder thecomponentsareadded,whetheradditional additivesareused, the temperatureandpHatwhich the formulation is prepared, are all factors that can be optimized for the concentration and means of administration used.

[0130] The formulations can be provided to patients as clear solutions or as dual vials comprising a vial of lyophilized anti-IL‑23 specific antibody that is reconstituted with a second vial containing water, a preservative and / or excipients, preferably, a phosphate buffer and / or saline and a chosen salt, in an aqueous diluent. Either a single solution vial or dual vial requiring reconstitution can be reusedmultiple times and can suffice for a single ormultiple cycles of patient treatment and thus can provide a more convenient treatment regimen than currently available.

[0131] Thepresent articles ofmanufacture are useful for administration over a period ranging from immediate to twenty- four hours or greater. Accordingly, the presently claimedarticlesofmanufacture offer significant advantages to thepatient. Formulations of the invention can optionally be safely stored at temperatures of from about 2°C to about 40°C and retain the biologically activity of the protein for extendedperiods of time, thus allowing apackage label indicating that the solution can be held and / or used over a period of 6, 12, 18, 24, 36, 48, 72, or 96 hours or greater. If preserved diluent is used, such label can include use up to 1‑12 months, one-half, one and a half, and / or two years.

[0132] The solutions of anti-IL‑23 specific antibody can be prepared by a process that comprises mixing at least one antibody in an aqueous diluent. Mixing is carried out using conventional dissolution and mixing procedures. To prepare a suitable diluent, for example, a measured amount of at least one antibody in water or buffer is combined in quantities sufficient to provide the protein and, optionally, a preservative or buffer at the desired concentrations. Variations of this processwould be recognizedbyoneof ordinary skill in the art. For example, the order the components are added,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 means of administration used.

[0133] Theclaimedproductscanbeprovided topatientsasclear solutionsorasdual vials comprisingavial of lyophilized at least one anti-IL‑23 specific antibody that is reconstituted with a second vial containing the aqueous diluent. Either a single solution vial or dual vial requiring reconstitution can be reusedmultiple times and can suffice for a single or multiple cycles of patient treatment and thus provides a more convenient treatment regimen than currently available.

[0134] The claimed products can be provided indirectly to patients by providing to pharmacies, clinics, or other such institutions and facilities, clear solutions or dual vials comprising a vial of lyophilized at least one anti-IL‑23 specific antibody that is reconstitutedwith a second vial containing the aqueous diluent. The clear solution in this case can be up to one liter or even larger in size, providing a large reservoir fromwhich smaller portions of the at least one antibody solution can be retrieved one or multiple times for transfer into smaller vials and provided by the pharmacy or clinic to their customers and / or patients.

[0135] Recognized devices comprising single vial systems include pen-injector devices for delivery of a solution, such as BD Pens, BD Autojector®, Humaject®, NovoPen®, B-D®Pen, AutoPen®, and OptiPen®, GenotropinPen®, Genotro- norm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®, Iject®, J-tip Needle-Free Injector®, Intraject®, Medi- Ject®, Smartject® e.g., as made or developed by Becton Dickensen (Franklin Lakes, NJ, www.bectondickenson.com), Disetronic (Burgdorf, Switzerland, www.disetronic.com; Bioject, Portland, Oregon (www.bioject.com), National Medical Products, WestonMedical (Peterborough, UK, www.weston-medical.com), Medi-Ject Corp (Minneapolis, MN, www.me- diject.com), and similary suitable devices. Recognized devices comprising a dual vial system include those pen-injector systems for reconstituting a lyophilized drug in a cartridge for delivery of the reconstituted solution, such as the HumatroPen®. Examples of other devices suitable include pre-filled syringes, auto-injectors, needle free injectors, and needle free IV infusion sets.

[0136] The products may include packaging material. The packaging material provides, in addition to the information required by the regulatory agencies, the conditions under which the product can be used. The packaging material of the 21 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 present invention provides instructions to the patient, as applicable, to reconstitute the at least one anti‑1L‑23 antibody in the aqueous diluent to forma solution and to use the solution over a period of 2‑24 hours or greater for the two vial, wet / dry, product. For the single vial, solution product, pre-filled syringe or auto-injector, the label indicates that such solution canbe used over a period of 2‑24 hours or greater. The products are useful for human pharmaceutical product use.

[0137] The formulationsused in themethodof thepresent inventioncanbepreparedbyaprocess that comprisesmixing an anti-IL‑23 antibody and a selected buffer, preferably, a phosphate buffer containing saline or a chosen salt. Mixing the anti-IL‑23 antibody and buffer in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, for example, ameasured amount of at least one antibody in water or buffer is combined with the desired buffering agent in water in quantities sufficient to provide the protein and buffer at the desired concentrations. Variations of this process would be recognized by one of ordinary skill in the art. For example, the order the components are added, 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 means of administration used.

[0138] Themethod of the invention provides pharmaceutical compositions comprising various formulations useful and acceptable for administration to a human or animal patient. Such pharmaceutical compositions are prepared using water at "standard state" as the diluent and routinemethodswell known to thoseof ordinary skill in the art. For example, buffering components such as histidine and histidine monohydrochloride hydrate, may be provided first followed by the addition of an appropriate, non-final volume of water diluent, sucrose and polysorbate 80 at "standard state." Isolated antibody may thenbeadded. Last, the volumeof the pharmaceutical composition is adjusted to thedesired final volumeunder "standard state" conditions using water as the diluent. Those skilled in the art will recognize a number of other methods suitable for the preparation of the pharmaceutical compositions.

[0139] The pharmaceutical compositions may be aqueous solutions or suspensions comprising the indicated mass of each constituent per unit ofwater volumeor having an indicated pHat "standard state." As used herein, the term "standard state"meansa temperatureof25°C+ / ‑2°Candapressureof 1atmosphere.The term "standardstate" is not used in theart to refer to a single art recognized set of temperatures or pressure, but is instead a reference state that specifies temperatures and pressure to be used to describe a solution or suspension with a particular composition under the reference "standard state" conditions. This is because the volume of a solution is, in part, a function of temperature and pressure. Those skilled in the art will recognize that pharmaceutical compositions equivalent to those disclosed here can be produced at other temperatures and pressures. Whether such pharmaceutical compositions are equivalent to those disclosed here should be determined under the "standard state" conditions defined above (e.g. 25°C + / ‑ 2°C and a pressure of 1 atmosphere).

[0140] Importantly, such pharmaceutical compositions may contain component masses "about" a certain value (e.g. "about 0.53mgL-histidine") per unit volumeof the pharmaceutical composition or have pH values about a certain value. A component mass present in a pharmaceutical composition or pH value is "about" a given numerical value if the isolated antibody present in the pharmaceutical composition is able to bind a peptide chainwhile the isolated antibody is present in the pharmaceutical composition or after the isolated antibody has been removed from the pharmaceutical composition (e.g., by dilution). Stated differently, a value, such as a component mass value or pH value, is "about" a given numerical value when the binding activity of the isolated antibody is maintained and detectable after placing the isolated antibody in the pharmaceutical composition.

[0141] Competition binding analysis is performed to determine if the IL‑23 specific mAbs bind to similar or different epitopes and / or compete with each other. Abs are individually coated on ELISA plates. Competing mAbs are added, followed by the addition of biotinylated hrlL‑23. For positive control, the same mAb for coating may be used as the competingmAb ("self-competition"). IL‑23 binding is detected using streptavidin. These results demonstrate whether the mAbs recognize similar or partially overlapping epitopes on IL‑23.

[0142] One aspect of the method of the invention administers to a patient a pharmaceutical composition comprising In one embodiment of the pharmaceutical compositions, the isolated antibody concentration is fromabout 77 to about 104 mg per ml of the pharmaceutical composition. In another embodiment of the pharmaceutical compositions the pH is from about 5.5 to about 6.5. The stable or preserved formulations can be provided to patients as clear solutions or as dual vials comprising a vial of lyophilized at least one anti-IL‑23 antibody that is reconstituted with a second vial containing a preservative or buffer and excipients in an aqueous diluent. Either a single solution vial or dual vial requiring reconstitution can be reused multiple times and can suffice for a single or multiple cycles of patient treatment and thus provides a more convenient treatment regimen than currently available.

[0143] Other formulations or methods of stabilizing the anti-IL‑23 antibody may result in other than a clear solution of lyophilized powder comprising the antibody. Among non-clear solutions are formulations comprising particulate suspen- sions, said particulates being a composition containing the anti-IL‑23 antibody in a structure of variable dimension and known variously as a microsphere, microparticle, nanoparticle, nanosphere, or liposome. Such relatively homogenous, essentially spherical, particulate formulations containing an active agent can be formed by contacting an aqueous phase containing the active agent and a polymer and a nonaqueous phase followed by evaporation of the nonaqueous phase to cause the coalescence of particles from the aqueous phase as taught in U.S. 4,589,330. Porous microparticles can be 22 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 prepared using a first phase containing active agent and a polymer dispersed in a continuous solvent and removing said solvent from the suspension by freeze-drying or dilution-extraction-precipitation as taught in U.S. 4,818,542. Preferred polymers for such preparations are natural or synthetic copolymers or polymers selected from the group consisting of gleatin agar, starch, arabinogalactan, albumin, collagen, polyglycolic acid, polylactic aced, glycolide-L(‑) lactide poly(e- pisilon-caprolactone, poly(epsilon-caprolactone-CO-lactic acid), poly(epsilon-caprolactone-CO-glycolic acid), poly(B- hydroxy butyric acid), polyethylene oxide, polyethylene, poly(alkyl‑2-cyanoacrylate), poly(hydroxyethyl methacrylate), polyamides, poly(amino acids), poly(2-hydroxyethyl DL-aspartamide), 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 aced, glycolide-L(‑) lactide poly(episilon-caprolactone, poly(epsilon-caprolactone-CO-lactic acid), and poly(epsilon-caprolactone-CO-glycolic acid. Solvents useful for dissolving the polymer and / or the active include: water, hexafluoroisopropanol, methylenechloride, tetrahydrofuran, hexane, benzene, or hexafluoroacetone sesquihydrate. The process of dispersing the active containing phase with a second phase may include pressure forcing said first phase through an orifice in a nozzle to affect droplet formation.

[0144] Dry powder formulationsmay result from processes other than lyophilization, such as by spray drying or solvent extraction byevaporation or by precipitation of a crystalline composition followedbyoneormore steps to removeaqueous or nonaqueoussolvent.Preparationofa spray-driedantibodypreparation is taught inU.S. 6,019,968.Theantibody-based dry powder compositionsmay be produced by spray drying solutions or slurries of the antibody and, optionally, excipients, in a solvent under conditions to provide a respirable dry powder. Solvents may include polar compounds, such as water and ethanol, whichmaybe readily dried. Antibody stabilitymay be enhancedby performing the spray drying procedures in the absence of oxygen, such as under a nitrogen blanket or by using nitrogen as the drying gas. Another relatively dry formulation is a dispersion of a plurality of perforated microstructures dispersed in a suspension medium that typically comprises a hydrofluoroalkane propellant as taught in WO 9916419. The stabilized dispersions may be administered to the lung of a patient using a metered dose inhaler. Equipment useful in the commercial manufacture of spray dried medicaments are manufactured by Buchi Ltd. or Niro Corp.

[0145] An anti-IL‑23 antibody in either the stable or preserved formulations or solutions described herein, can be administered to a patient in accordance with the present invention via a variety of delivery methods including SC or IM injection; transdermal, pulmonary, transmucosal, implant, osmotic pump, cartridge, micro pump, or other means appreciated by the skilled artisan, as well-known in the art. Therapeutic Applications

[0146] Thepresent invention also provides amethod formodulating or treating psoriasis, in a cell, tissue, organ, animal, or patient, as known in the art or as described herein, using at least one IL‑23 antibody of the present invention, e.g., administering or contacting the cell, tissue, organ, animal, or patient with a therapeutic effective amount of IL‑23 specific antibody.

[0147] Any method of the present 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 a method can optionally further comprise co-administration or combination therapy for treatingsuchdiseasesor disorders,wherein theadministeringof saidat least oneanti-IL‑23antibody, specified portion or variant thereof, further comprises administering, before concurrently, and / or after, at least one selected from at least one TNF antagonist (e.g., but not limited to, a TNF chemical or protein antagonist, TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70 or p85) or fragment, fusion polypeptides thereof, or a small molecule TNF antagonist, e.g., TNF binding protein I or II (TBP‑1 or TBP-II), nerelimonmab, infliximab, eternacept (Enbrel™), adalimulab (Humira™), CDP‑571, CDP‑870, afelimomab, lenercept, and the like), an antirheumatic (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, gold sodium thiomalate, hydroxychloroquine sulfate, lefluno- mide, sulfasalzine), a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial (e.g., aminoglycoside, an antifungal, an antiparasitic, an antiviral, a carbapenem, cephalosporin, a flurorquinolone, a macrolide, a penicillin, a sulfonamide, a tetracycline, another antimicrobial), an antipsoriatic, a corticosteriod, an anabolic steroid, a diabetes related agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, anantidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropoietin (e.g., epoetin alpha), a filgrastim (e.g., G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), an immunization, an immunoglobulin, an immunosuppressive (e.g., basiliximab, cyclosporine, daclizumab), a growth hormone, ahormone replacement drug, anestrogen receptormodulator, amydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analog, dornase alpha (Pulmozyme), a cytokine or a cytokine antagonist. Suitable dosages are well known in theart. See,e.g.,Wellset al., eds.,PharmacotherapyHandbook, 2ndEdition,AppletonandLange,Stamford,CT 23 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 (2000); PDRPharmacopoeia, TarasconPocket Pharmacopoeia 2000, DeluxeEdition, TarasconPublishing, Loma Linda, CA (2000); Nursing 2001 Handbook of Drugs, 21st edition, Springhouse Corp., Springhouse, PA, 2001; Health Profes- sional’s Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, Upper Saddle River, NJ, each of which references are entirely incorporated herein by reference. Therapeutic Treatments

[0148] Typically, treatment of psoriasis is affected by administering an effective amount or dosage of an anti-IL‑23 antibody composition that total, onaverage, a range fromat least about 0.01 to 500milligramsof ananti-IL‑23antibodyper kilogram of patient per dose, and, preferably, from at least about 0.1 to 100 milligrams antibody / kilogram of patient per single or multiple administration, depending upon the specific activity of the active agent contained in the composition. Alternatively, the effective serum concentration can comprise 0.1‑5000 µg / ml serum concentration per single or multiple administrations. Suitable dosages are known to medical practitioners and will, of course, depend upon the particular disease state, specific activity of the composition being administered, and the particular patient undergoing treatment. In some instances, toachieve thedesired therapeuticamount, it canbenecessary toprovide for repeatedadministration, i.e., repeated individual administrations of a particular monitored or metered dose, where the individual administrations are repeated until the desired daily dose or effect is achieved.

[0149] Preferreddoses canoptionally include0.1, 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 100‑500mg / kg / administration, or any range, value or fraction thereof, or to achieve a serum concentration of 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 / or5000µg / ml serumconcentrationper singleor multiple administration, or any range, value or fraction thereof.

[0150] Alternatively, the dosage administered can 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; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a dosage of active ingredient can be about 0.1 to 100 milligrams per kilogram of body weight. Ordinarily 0.1 to 50, and, preferably, 0.1 to 10 milligrams per kilogram per administration or in sustained release form is effective to obtain desired results.

[0151] Asanon-limitingexample, treatment of humansoranimalscanbeprovidedasaone-timeorperiodicdosageof at least oneantibodyof thepresent invention0.1 to100mg / kg, suchas0.5, 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 100mg / kg, per day, on at least oneof day1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or, alternatively or additionally, at least one ofweek 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, or, alternatively or additionally, at least one of 1, 2, 3, 4, 5, 6,, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years, or any combination thereof, using single, infusion or repeated doses.

[0152] Dosage forms (composition) suitable for internal administration generally contain from about 0.001 milligram to about 500milligrams of active ingredient per unit or container. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5‑99.999% by weight based on the total weight of the composition.

[0153] For parenteral administration, the antibody can be formulated as a solution, suspension, emulsion, particle, powder, or lyophilized powder in association, or separately provided, with a pharmaceutically acceptable parenteral vehicle. Examples of such vehicles are water, saline, Ringer’s solution, dextrose solution, and 1‑10% human serum albumin. Liposomesandnonaqueous vehicles, suchas fixedoils, can also be used. The vehicle or lyophilized powder can contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives). The formulation is sterilized by known or suitable techniques.

[0154] Suitable pharmaceutical carriers are described in the most recent edition of Remington’s Pharmaceutical Sciences, A. Osol, a standard reference text in this field. Alternative Administration

[0155] Many known and developed modes can be used according to the present invention for administering pharma- ceutically effective amounts of an anti-IL‑23 antibody.While pulmonary administration is used in the following description, 24 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 other modes of administration can be used according to the present invention with suitable results. IL‑23 specific antibodies of the present invention can be delivered in a carrier, as a solution, emulsion, colloid, or suspension, or as a dry powder, using any of a variety of devices and methods suitable for administration by inhalation or other modes described here within or known in the art. Parenteral Formulations and Administration

[0156] Formulations for parenteral administration can contain as common excipients sterile water or saline, polyalk- ylene glycols, such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like Aqueous or oily suspensions for injection can be prepared by using an appropriate emulsifier or humidifier and a suspending agent, according to known methods. Agents for injection can be a non-toxic, non-orally administrable diluting agent, such as aqueous solution, a sterile injectable solution or suspension in a solvent. As the usable vehicle or solvent, water, Ringer’s solution, isotonic saline, etc. are allowed; as an ordinary solvent or suspending solvent, sterile involatile oil can be used. For thesepurposes, any kind of involatile oil and fatty acid canbeused, including natural or synthetic or semisynthetic fatty oils or fatty acids; natural or synthetic or semisynthtetic mono‑ or di‑ or tri-glycerides. Parental administration is known in theart and includes, but is not limited to, conventionalmeansof injections, a gaspressured needle-less injection device as described in U.S. Pat. No. 5,851,198, and a laser perforator device as described in U.S. Pat. No. 5,839,446 entirely incorporated herein by reference. Alternative Delivery

[0157] The invention further relates to the administration of an anti-IL‑23 antibody by parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal means. An anti-IL‑23 antibody composition can be prepared for use for parenteral (subcutaneous, intramuscular or intravenous) or any other administration particularly in the form of liquid solutions or suspensions; for use in vaginal or rectal administration particularly in semisolid forms, such as, but not limited to, creams and suppositories: for buccal, or sublingual administration, such as, but not limited to, in the form of tablets or capsules; or intranasally, such as, but not limited to, the form of powders, nasal drops or aerosols or certain agents; or transdermally, such as not limited to a gel, ointment, lotion, suspension or patch delivery system with chemical enhancers such as dimethyl sulfoxide to either modify the skin structure or to increase the drug concentration in the transdermal patch (Junginger, et al. In "Drug Permeation Enhancement;" Hsieh, D. S., Eds., pp. 59‑90 (Marcel Dekker, Inc. New York 1994, entirely incorporated herein by reference), or with oxidizing agents that enable the application of formulations containing proteinsandpeptidesonto the skin (WO98 / 53847), or applicationsof electric fields to create transient transport pathways, suchaselectroporation, or to increase themobility of chargeddrugs through the skin, suchas iontophoresis, or application of ultrasound, such as sonophoresis (U.S. Pat. Nos. 4,309,989 and 4,767,402) (the above publications and patents being entirely incorporated herein by reference).

[0158] Having generally described the invention, the samewill bemore readily understood by reference to the following Examples, which are provided by way of illustration and are not intended as limiting. Further details of the invention are illustrated by the following non-limiting Examples. The disclosures of all citations in the specification are expressly incorporated herein by reference.

[0159] Example 1: Comparison of the efficacy and safety of guselkumab (GUS) with the anti-TNFα antibody adalimumab (ADA) and placebo (PBO) in patients treated through one year.

[0160] To confirm findings from earlier studies, two pivotal, phase III trials were conducted: VOYAGE1 andVOYAGE2. Efficacy, safety, andpatient-reportedoutcome (PRO)findings fromVOYAGE1are reported,whichcomparedguselkumab with adalimumab, a widely used TNF-α inhibitor, and placebo in psoriasis patients treated continuously for one year. In addition, an additional trial, known as VOYAGE 2 (described in Example 2), included a randomized withdrawal period. VOYAGE 1 Materials / Methods Summary: VOYAGE 1 is a phase 3, randomized, double-blind, placebo‑ and active comparator-controlled trial. Eligible patients (age≥18 years) had plaque psoriasis for ≥6 months, an Investigator’s Global Assessment [IGA] score ≥3, a Psoriasis Area and Severity Index [PASI] score ≥12, and body surface area involvement ≥10%, and were candidates for systemic therapy or phototherapy. At baseline, 837 patients were randomized to either PBO at weeks 0 / 4 / 12 then GUS 100 mg at weeks 16 / 20, and q8wk through week 44 (n=174); GUS 100mg at weeks 0 / 4 / 12, and q8wk throughweek 44 (n=329); or ADA 80mg at week 0, 40mg at week 1, and 40 mgq2wk throughweek47 (n=334). Theco-primaryendpointswere theproportionsofGUSvsPBOpatients achieving cleared / minimal disease (IGA 0 / 1) and 90% improvement in PASI score (PASI 90) at week 16. Other endpoints 25 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 included the proportions ofGUSvsADApatients achieving IGA0 / 1, IGA0,PASI 90, andPASI 100 atweeks 16 / 24 / 48, and a Dermatology Life Quality Index score of 0 / 1 (DLQI 0 / 1), indicating no impact of psoriasis on health-related quality of life, at weeks 24 / 48. Safety was monitored through week 48. VOYAGE 1 Summary Results: Significantly higher (p<0.001) proportions of patients in the GUS vs PBO group achieved IGA0 / 1 (85.1%vs 6.9%) andPASI 90 (73.3%vs 2.9%) atweek 16.GUSwas also superior to ADAbased on the proportions of patients achieving IGA 0 / 1 (85.1% vs 65.9%) and PASI 90 (73.3% vs 49.7%) at week 16 (p<0.001). Likewise, significantly higher (p<0.001) proportions of patients achieved responses to GUS vs ADA, respectively, at week 24: IGA 0 (52.6% vs 29.3%), IGA 0 / 1 (84.2% vs 61.7%), PASI 100 (44.4% vs 24.9%), and PASI 90 (80.2% vs 53.0%). Corresponding response rates at week 48 were: IGA 0 (50.5% vs 25.7%), IGA 0 / 1 (80.5% vs 55.4%), PASI 100 (47.4%vs23.4%), andPASI 90 (76.3%vs 47.9%), all p<0.001. Theproportion of patientswith aDLQI score of 0 / 1 among GUS vs ADA patients was 60.9% vs 39.5% at week 24 and 62.5% vs 38.9% at week 48 (both p<0.001). Through week 48, adverse events occurred in 73.9% and 74.5% of GUS and ADA patients, respectively; serious adverse event rateswere also similar for theGUSandADAgroups (4.9%vs 4.5%). Serious infections occurred in two GUS patients and three ADA patients. Two malignancies (prostate and breast) occurred in the GUS group. One myocardial infarction occurred in each active treatment group. VOYAGE 1 Summary Conclusions: GUS was superior to ADA in treating moderate-to-severe psoriasis, and was well tolerated, through one year of treatment. Background: Guselkumab, an interleukin‑23 (IL‑23) blocker, was superior to adalimumab in treating moderate-to- severe psoriasis in a phase II trial. Objectives: To compare efficacy and safety of guselkumab with adalimumab and placebo in psoriasis patients treated for one year. Methods: Patients were randomized to guselkumab 100 mg at week0 / 4 / 12, then q8wk (n=329); placebo at week0 / 4 / 16 followed by guselkumab 100 mg at week‑16 / 20, then q8wk (n=174); or adalimumab 80 mg at week0, 40mgatweek, 40mgq2wk (n=334).Physician-reportedoutcomes (investigatorsGlobalAssessment [IGA],Psoriasis AreaandSeverity Index [PASI]), patient-reported outcomes (PROs;Dermatology LifeQuality Index [DLQI], Psoriasis Symptom and Sign Diary [PSSD]), and safety were evaluated through week48. Results:Guselkumab was superior (p<0.001) to placebo at week 16 (85.1% vs. 6.9% [IGA0 / 1] and 73.3% vs. 2.9%, [PASI90]). Guselkumab was also superior (p<0.001) vs. adalimumab for IGA0 / 1 and PASI90 at week16 (85.1% vs. 65.9%, 73.3% vs. 49.7%); week24 (84.2% vs. 61.7%, 80.2% vs. 53.0%); and week48 (80.5% vs. 55.4%, 76.3% vs. 47.9%). Furthermore, guselkumab significantly improved PROs throughweek48. Adverse event rates were compar- able between treatments through week48. Limitations: Analyses were limited to 48weeks. Conclusions: Guselkumab demonstrated superior efficacy compared with adalimumab and is well-tolerated in psoriasis patients through one year. MATERIALS AND METHODS Patients

[0161] The trial enrolled patients aged ≥18 years with moderate-to-severe plaque psoriasis (i.e., Investigator’s Global Assessment [IGA] ≥3, Psoriasis Area and Severity Index [PASI] ≥12, and body surface area [BSA] involvement 210%) for at least 6monthswhowerecandidates for systemic therapyor phototherapy.Patientswere ineligible if theyhadahistoryor current signs of severe, progressive, or uncontrolled medical conditions or had current or history of malignancy within 5 years, except nonmelanoma skin cancer (NMSC). Patients with history or symptoms of active tuberculosis (TB) were excluded. Patients could not participate if they had received guselkumab or adalimumab previously; other anti-TNF-α therapy within 3 months; other treatment targeting IL‑12 / 23, IL‑17, or IL‑23 within 6 months; or any systemic immuno- suppressants (e.g., methotrexate) or phototherapy within 4 weeks. 26 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 Study design

[0162] VOYAGE 1 was a phase 111, randomized, double-blind, placebo‑ and active comparator-controlled trial conducted at 104 global sites (December 2014 - April 2016). The study comprised an active-comparator period when guselkumab was compared with adalimumab (week 0‑48) and a placebo-controlled period (weeks 0‑16), after which placebo patients crossed over to receive guselkumab through week 48. Patients were randomized at baseline in a 2:1:2 ratio to guselkumab 100 mg at weeks 0, 4, 12, and every‑8-weeks thereafter through week 44; placebo at weeks 0, 4, 12 followedby guselkumab100mgatweeks 16, 20, and every‑8-weeks thereafter throughweek44; or adalimumab80mgat week 0, 40mg at week 1, and 40mg every‑2weeks thereafter through week 47. Tomaintain the blind, matching placebos were utilized. An institutional review board or ethics committee approved the study protocol at participating sites; patients provided written informed consent before study initiation. Assessments

[0163] Efficacy was evaluated using the IGA, PASI, scalp-specific IGA (ss-IGA), fingernail Physician’s Global Assess- ment (f-PGA), Nail Psoriasis Area and Severity Index (NAPSI), and PGA of the hands / feet (hf-PGA). Patient-reported outcomes were assessed utilizing the Dermatology Life Quality Index (DLQI) and Psoriasis Symptom and Sign Diary (PSSD). Safety monitoring included collection of adverse events (AEs) and laboratory testing.

[0164] Antibodies-to-guselkumab were detected using a highly sensitive and drug-tolerent electrochemiluminescence immunoassay: the sensitivity was 3.1 ng / mL in guselkumab-free serum and 15 ng / mL with serum guselkumab con- centrations up to 3.125 µg / mL, which exceeds mean trough serum guselkumab levels. Statistical Analyses

[0165] Co-primaryendpointswere theproportionsofpatientsachievingan IGAscoreof clearedorminimal disease (IGA 0 / 1) and90% improvement inPASI response (PASI90) atweek16 in theguselkumabgroupcomparedwithplacebo.Major secondary endpoints were also measured. All randomized patients were included in the primary and selected secondary efficacy analyses; data were analyzed by randomized treatment group. The primary andmajor secondary analyses were tested in a fixed sequence to control for multiplicity.

[0166] The co-primary endpoints and binary major secondary endpoints were analyzed using a Cochran-Mantel- Haenszel (CMH) chi-square statistical test stratified by pooled investigator site. With a sample size of approximately 750 patients, the power to detect a significant difference was >99% for both co-primary endpoints. Continuous response parameters were compared using an analysis of variancemodel with pooled investigator site as a covariate. All statistical testing was performed 2-sided (α=0.05).

[0167] Patients who discontinued study agent due to lack of efficacy or an AE of psoriasis worsening or who started a protocol-prohibited psoriasis treatment were considered non-responders for binary endpoints, and had baseline values carried over for continuous endpoints. Other patients with missing data were considered non-responders for binary endpoints (non-responder imputation) and had last observation carried forward for continuous endpoints (and all PSSD endpoints).

[0168] Safety analyses included all patients who received at least one administration of study agent and were summarized by actual treatment. The proportion of patients with antibodies-to-guselkumab was summarized for those receiving at least one dose of the biologic. RESULTS

[0169] At baseline, 837 patients were randomized to placebo (n=174), guselkumab (n=329), or adalimumab (n=334). Overall, 6.9%, 8.5%, and 15.6%of patients discontinued treatment in the placebo, guselkumab, and adalimumab groups, respectively, through week 48. Demographic and disease characteristics were comparable across treatment groups at baseline ). Clinical responses

[0170] Guselkumabwassuperior to bothplaceboand / or adalimumabwith respect to co-primaryendpoints andallmajor secondary endpoints (all p<0.001). Comparedwith placebo, significantly higher proportions of patients in the guselkumab group achieved IGA 0 / 1 (6.94% vs. 85.1%) and PASI 90 (2.9% vs. 73.3%) at week 16. Additionally, the proportions achieving at least 75% improvement in PASI (PASI 75) as well as IGA 0 and PASI 100 were significantly higher for guselkumab vs. placebo at week 16. Guselkumabwas superior to adalimumab asmeasured by the proportion of patients achieving IGA0 / 1 (85.1%vs.65.9%),PASI90 (73.3%vs. 49.7%), andPASI75 (91.2%vs. 73.1%)atweek16.Significantly 27 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 better responses to guselkumab compared with adalimumab weremaintained at week 24 (IGA 0 [52.6% vs. 29.3%], IGA 0 / 1 [84.2% vs. 61.7%], and PASI 90 [80.2% vs. 53.0%]) and week 48 (50.5% vs. 25.7%, 80.5% vs. 55.4%, and 76.3% vs. 47.9%, respectively). Additionally, higher proportions of patients receiving guselkumab attained response in higher PASI categories compared with adalimumab at week 48. After initiating guselkumab at week 16, patients in the placebo crossover group achieved responses similar to those observed in the guselkumab group. Regional psoriasis measures

[0171] Regional psoriasis was evaluated based on the ss-IGA, f-PGA, NAPSI, and hf-PGA assessments. The proportion of patients achieving ss-IGA 0 / 1 (absent / very mild scalp psoriasis) in the guselkumab group was significantly higher compared with placebo (83.4% vs. 14.5%, p<0.001) at week 16; significantly better responses to guselkumab vs. adalimumabwere observed at week 24 (p<0.001) andweek 48 (p=0.045). The proportion of patients achieving f-PGA0 / 1 (clear / minimal) and percent improvement in NAPSI were significantly higher for guselkumab vs. placebo at week 16 (p<0.001). The f-PGA responseswere comparable at week 24, though guselkumabwas superior to adalimumab byweek 48 (p=0.038).Meanpercent improvement inNAPSIwithguselkumabwassignificantly higher than that for placeboatweek 16 (p<0.001) and comparable between guselkumab and adalimumab at weeks 24 and 48. Finally, the proportion of patients achieving hf-PGA 0 / 1 (clear / almost clear) was significantly higher for guselkumab vs. placebo at week 16, and responses to guselkumab were superior to adalimumab at weeks 24 and 48 (p<0.001). Health-related quality of life measures

[0172] Atweek16, the improvement frombaseline inDLQIwas significantly greater in the guselkumabgroup compared with placebo (mean change, ‑0.6 vs. ‑11.2), aswere the proportions of patients achievingDLQI 0 / 1 (no impact of psoriasis on HRQoL) (both p<0.001). At weeks 24 and 48, both improvements from baseline in DLQI and proportions of patients achieving DLQI 0 / 1were significantly higher for guselkumab vs. adalimumab (p<0.001).

[0173] Atweek16, the improvement frombaseline in thePSSDsymptomscorewassignificantly greater for guselkumab vs. placebo (mean change, ‑3.0 vs. ‑41.9);mean changes in thePSSDsign scorewere similarly favorable for guselkumab (both p<0.001). Likewise, at weeks 24 and 48, mean changes in the PSSD symptom and sign scores in the guselkumab group were significantly greater than those in the adalimumab group (p<0.001). The proportions of patients achieving a PSSD symptom score=0 with guselkumab and adalimumab, respectively, were 36.3% and 21.6% at week 24, and the significantly better response to guselkumab was maintained at week 48 (p<0.001). Similar results were observed for the proportions of patients achieving a PSSD sign score=0 at weeks 24 and 48 (p<0.001). Safety outcomes

[0174] During the placebo-controlled period (weeks 0‑16), the proportion of patients with at least one AE was comparable across treatment groups, and the most commonly reported events were nasopharyngitis and upper respiratory tract infection in all three groups. Serious AEs (SAEs) and AEs leading to study agent discontinuation occurred infrequently and in similar proportions of patients for each treatment. Rates of overall infections and infections requiring antibiotic treatment were comparable across treatment groups. Two patients in the adalimumab group experienced serious infections (both cellulitis). One NMSC (i.e., basal cell carcinoma [BCC]) was reported in the guselkumab group, and no other malignancies occurred in any group. One myocardial infarction (i.e., major adverse cardiovascular event [MACE]) occurred in each active treatment group through week 16.

[0175] The types and patterns of AEs reported through week 48 were similar to those reported during the placebo- controlledperiod.Theproportionsof patientswithat least oneAE,anAE leading todiscontinuation, or anSAEweresimilar in the guselkumab and adalimumab groups. Betweenweeks 16‑48, serious infectionswere reported in two patients in the guselkumab group (i.e., cellulitis in one and thigh abscess with post-operative wound infection in another) and two in the adalimumab group (i.e., one abdominal abscess and one staphylococcal pneumonia with a fatal outcome in the patient with abdominal wall cellulitis reported earlier). Overall infections and infections requiring antibiotic treatment occurred at comparable rates across treatment groups. No AEs of active tuberculosis or opportunistic infection were reported during the study. Two additional NMSCs (i.e., one BCC each in the guselkumab and adalimumab groups) and twomalignancies (i.e., prostate and breast in the guselkumab group) were reported through week 48. No additional MACE occurred after week 16. A single suicide attempt was reported in an adalimumab patient. Incidence rates of candidiasis and neutropenia were low and comparable between the guselkumab and placebo groups (data not shown), and no events of Crohn’s disease were reported through week 48.

[0176] Through week 48, the proportion of patients with an ISR (2.2% vs. 9.0%) and the proportion of injections associatedwith ISRs (0.5%vs 1.2%)were lower for guselkumabcomparedwith adalimumab;most ISRswere considered mild. Laboratory abnormalities rates were low, and no between-group differences were noted (data not shown). 28 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 Antibodies-to-guselkumab were detected in 26 / 492 patients (5.3%) through week 44; titers were generally low (81% ≤1:320). No apparent association was observed between antibody development and either reduced efficacy or ISR occurrence (data not shown). DISCUSSION

[0177] Thefindings inVOYAGE1study, togetherwith theVOYAGE2 results described inExample 2 below, confirm that two injections of guselkumab100mg (weeks 0 and4) and every 8-weekmaintenance therapy effectively treatsmoderate- to-severe psoriasis.Guselkumabwas superior to placebo by substantialmargins atweek 16 using two rigorous endpoints (IGA 0 / 1 and PASI 90). The onset of action of guselkumab was rapid, with significant response evident as early as week 2 compared with placebo. Guselkumab was also superior to adalimumab, which is a widely used and very effective subcutaneous TNF-α inhibitor, at the week‑16 endpoints of IGA 0 / 1, PASI 90, and PASI 75. Response rates continued to improvewith guselkumabbeyondweek16.Atweeks24and48, approximately half of all patients in the guselkumabgroup achievedcompleteclearance (IGA0),which isassociatedwithoptimalHRQoL forpatientswithpsoriasis.Patient-reported outcome endpoints (PSSD andDLQI) based on total change, or indicatingminimal / no impact onHRQoL or no symptoms or signs of psoriasis, demonstrated guselkumab responses that were superior to placebo at week 16 and adalimumab at weeks 24 and 48.

[0178] This study assessed multiple areas of the body where psoriasis is challenging to treat, and guselkumab was highly effective in all regions based on rigorous endpoints Guselkumab was superior to placebo at week 16 and to adalimumab at weeks 24 / 48, indicating complete or nearly complete clearance of scalp and hand / foot psoriasis in at least 75% of guselkumab-treated patients. Based on both the proportion of patients with clear / minimal fingernail psoriasis (f- PGA 0 / 1) and themean percent improvement in NAPSI, guselkumabwas superior to placebo at week 16. Nail responses were comparable between active treatments at weeks 24 and 48, and guselkumab was superior to adalimumab (75% vs. 62%) for f-PGA 0 / 1 at week 48.

[0179] Rates and types of AEs, SAEs, and laboratory abnormalities were generally comparable between the guselk- umab and placebo groups through week 16 and between the guselkumab and adalimumab groups through week 48. Rates of serious infections, malignancies, and MACE were low across treatment groups. No notable differences in the incidence of neutropenia or candidiasis, were observed between the guselkumab and control groups. No AEs of Crohn’s disease occurred in any treatment group, and one suicide attempt was reported in the adalimumab group. The number of injections and proportions of patients with ISRs were higher for adalimumab compared with guselkumab. The size and durationof this studymaynotallow forassessmentof uncommoneventsor thosewitha long latency:however, longer-term treatment will be evaluated in ongoing study extensions.

[0180] VOYAGE 1 confirms the role of IL‑23 in the pathogenesis of psoriasis. TNF-α inhibitors are effective in many diseases, and TNF-α is involved in normal systemic inflammatory and immunologic processes. Selective targeting of the IL‑23 pathway provides more psoriasis-specific cytokine inhibition with a higher degree of efficacy while maintaining a favorable safety profile, when comparedwith TNF-α blockade. IL‑23 is a key driver of Th17 cell differentiation and survival and an upstream regulator of IL‑17A, a central pro-inflammatory effector cytokine implicated in the pathogenesis of psoriasis. Moreover, IL‑23 stimulates the production of other Th17 cytokines (e.g., IL‑22) by other cell types, including innate lymphoid cells type 3 (ILC3) cells and γδ T-cells. Therefore, inhibition of IL‑23 blocks downstream production of IL‑17A, IL‑22, and other cell types. Sincemany IL‑17A-producing cells are dependent upon IL‑23 for survival, inhibition of IL‑23 may reduce the number of these pathogenic cells. This may explain the long duration of effect and allow for the convenient dosing interval of guselkumab compared with both anti-TNF-α and anti‑1L‑17 agents.

[0181] The findings, together with those from VOYAGE 2, demonstrate the superior efficacy of guselkumab compared with adalimumab in psoriasis, efficacy in regional disease of the scalp, nails, and hands / feet, and a positive safety profile. The favorable safety profile through one year is not unexpected, considering the reassuring long-term safety findings reported for a related treatment, ustekinumab, which blocks both IL‑12 and IL‑23. Study extensions will continue to examine theefficacyandsafetyof guselkumabandadd to theunderstandingof long-term IL‑23blockadebasedonstudies of ustekinumab. Example 2: VOYAGE 2 Results

[0182] To confirm the therapeutic potential of guselkumab, the Phase 3 VOYAGE 1 and VOYAGE 2 studies assessed the efficacy and safety of guselkumab versus placebo and adalimumab. VOYAGE 1 assessed continuous 1-year treatment, and VOYAGE 2 evaluated the efficacy and safety of interrupted treatment, as treatment gaps frequently occur in clinical practice. Additionally, VOYAGE 2 assessed the transition from adalimumab to guselkumab, providing clinically-relevant information about patients who switch biologics. MATERIALS AND METHODS 29 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 Patients

[0183] Adults (aged ≥18 years) with moderate-to-severe plaque-type psoriasis were eligible. Major inclusion / exclusion criteria are summarized inVOYAGE1above. The study protocol was approved by an investigational reviewboard at each site, and written informed consent was provided by all patients. Study design

[0184] VOYAGE 2 was a Phase 3, multicenter, randomized, double-blind, placebo‑ and adalimumab comparator- controlled study (NCT02207244) conducted in 115 global sites between November 2014 and June 2016. The study consisted of a placebo-controlled period (weeks 0 to 16), an active comparator-controlled period (weeks 0 to 28), and a randomized withdrawal and retreatment period (weeks 28 to 72). Study results through week 48 are presented here. Patients were randomized at baseline 2:1:1 to guselkumab 100 mg at weeks 0, 4, 12, and 20; placebo at weeks 0, 4, 12, then guselkumab at weeks 16 and 20; or adalimumab 80 mg at week 0, 40 mg at week 1, and every-two-weeks (q2w) thereafter through week 23.

[0185] At week 28, guselkumab-treated patients achieving a 90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90; responders) were re-randomized in a 1:1 ratio to guselkumab or placebo. Upon loss of ≥50% of week‑28 PASI response, patients were retreated with guselkumab, another dose 4 weeks later, then q8w thereafter. Guselkumab nonresponders continued guselkumab treatment. Placebo-guselkumab nonresponders at week 28 con- tinued guselkumab q8w, while responders received placebo q8w beginning at week 28. Upon loss of ≥50% of week 28- PASI response, patients were retreated with guselkumab, followed by another dose 4 weeks later, then q8w thereafter. Adalimumab nonresponders initiated guselkumab at week 28, another dose 4 weeks later, then q8w thereafter. Adalimumab responders received placebo and upon loss of ≥50% of week 28-PASI response, initiated guselkumab, another dose 4 weeks later, then q8w thereafter. Tomaintain the blind, both guselkumab and adalimumab placebos were administered as necessary. Efficacy and safety assessments

[0186] Efficacywasassessed throughweek24andsafety throughweek28.Keyefficacy, includinggeneral and regional psoriasis, patient-reported outcomes, and safety assessments are discussed in detail in theVOYAGE1 study. In addition, the Medical Outcomes Study 36-ltem Short Form (SF‑36) was evaluated in this study. Study Endpoints

[0187] The co-primary endpoints were the proportions of patients achieving an IGAscore of cleared (0) orminimal (1) at week 16 and the proportion of patients achieving aPASI 90 response atweek 16, comparing the guselkumab and placebo groups Major secondary endpoints were also measured. Regional psoriasis endpoints evaluating the scalp, fingernails, and hand / feet were described in detail elsewhere. Statistical analysis

[0188] All randomized patients were included in the primary analysis and some secondary efficacy analyses according to their assigned treatment group. To assess maintenance dosing versus treatment withdrawal for the major secondary endpoints, all patients who underwent the second randomization and had PASI evaluation after week 28 were included in the analyses.

[0189] The co-primary endpoints and binary major secondary endpoints were analyzed using a two-sided Cochran- Mantel-Haenszel (CMH) chi-squared statistical test (α=0.05) stratified by investigator site. Continuous response para- meters were compared using an analysis of variance model with site as a covariate. For the time to loss of PASI 90 response, the log-rank test stratified by site was used.

[0190] Patients who discontinued study treatment due to lack of efficacy or an AE of worsening of psoriasis, or who started a protocol-prohibited medication / therapy that could improve psoriasis were considered treatment failures. Patients who met treatment failure criteria before week 16 and patients not returning for week‑16 evaluation were considered nonresponders for the week‑16 primary endpoint. For patients randomized to placebo, only those who crossed-over to receive guselkumab at / after week 16 were included in the efficacy analyses after week 16.

[0191] To control the overall Type 1 error rate, the primary analysis andmajor secondary analyseswere tested in a fixed sequence, with the first major secondary endpoint being tested only if the co-primary endpoints were met, and the subsequent endpoint(s) tested only if the preceding endpoint in the sequence were met.

[0192] Safety analyses included all patients who received at least one study agent administration. Adverse events and 30 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 serious adverse events (SAEs) were grouped according to the treatment received. Antibodies to guselkumab were analyzed. RESULTS Patient disposition and baseline demographic characteristics

[0193] A total of 1279 patients were screened and 992were randomized 2:1:1 to receive guselkumab (n=496), placebo (n=248), or adalimumab (n=248) (Fig 2). Overall, 9.7% (96 / 992) of patients discontinued the study agent throughweek 48 (guselkumab: 7.9%; placebo: 11.7%; adalimumab: 11.3%). Baseline demographics and disease characteristics were generally comparable among groups. Efficacy

[0194] Guselkumab was superior to both placebo and / or adalimumab with respect to the co-primary endpoints and all major secondary endpoints (all p<0.001). Placebo-controlled period (weeks 0‑16)

[0195] Atweek16, significantly greater proportionsof guselkumabpatientsachievedan IGAof cleared (0)orminimal (1) compared with the placebo patients (84.1% vs. 8.5%; p<0.001), and achieved a PASI 90 response (70.0% vs. 2.4%; p<0.001) (co-primary endpoints). Significantly higher PASI percent improvement was observed as early as week 2 in guselkumab vs. placebo patients (p<0.001). Additionally, at week 16, significantly higher proportions of guselkumab patients achieved PASI 75 and PASI 100 responses compared with placebo patients. Guselkumab patients achieved greater improvement inall regional psoriasis outcomeassessments, comparedwithplaceboatweek16 including: ss-IGA, f-PGA, NAPSI, and hf-PGA. Similar to VOYAGE1, guselkumabwas superior to placebo at week 16 in all patient-reported outcomes including Dermatology Life Quality Index (DLQI) and Psoriasis Symptom and Sign Diary (PSSD), and in addition, SF‑36. Active-comparator period (weeks 0‑24)

[0196] Significantly greater proportions of patients in the guselkumab group achieved IGA 0 / 1, PASI 90, and PASI 75 responsesatweek16.Atweek24, significantlyhigher response ratesweremaintained in theguselkumabvs. adalimumab patients for IGA 0 (51.5% vs. 31.5%), IGA 0 / 1 (83.5% vs. 64.9%), PASI 90 (75.2% vs. 54.8%), and PASI 100 (44.2% vs. 26.6%).ConsistentwithVOYAGE1,greater improvements in regional psoriasis diseasescoreswereobservedatweek24 in guselkumab patients comparedwith adalimumab patients, with the exception of f-PGA0 / 1 and percent improvement in NAPSI, which were comparable. At week 24, the proportions of patients achieving DLQI 0 / 1, mean changes in the PSSD symptom and sign scores, proportions of patients achieving a PSSD symptom score of 0 and a sign score of 0 were significantly greater in the guselkumab group than in the adalimumab group (p<0.001) Randomized withdrawal and retreatment period (weeks 28‑48)

[0197] PASI 90 responses were better maintained in guselkumab week‑28 responders continuing guselkumab (maintenance group) versus responders re-randomized to placebo (withdrawal group). The median time to loss of PASI 90 response was 15.2 weeks for patients randomized to the withdrawal group. Among patients withdrawn from guselkumab at week 28, PASI 90 response rates began to diverge from the maintenance group at week 32. Through week 48, 88.6% of the maintenance patients sustained a PASI 90 response versus 36.8% of withdrawal patients. In addition, atweek48, clinical responses (IGA,PASI)weresignificantly greater inmaintenancegroup thanwithdrawal group (p<0.001). Improvements inDLQIandPSSDsymptomor sign scores frombaselinewerealso significantly greater atweek 48 in the maintenance vs. withdrawal groups (both p<0.001). Through week 48, a small number of patients (n=16) were retreated with guselkumab. Switching adalimumab nonresponders to guselkumab

[0198] Overall, 112 adalimumab nonresponders initiated guselkumab at week 28 (5 weeks after the last adalimumab dose). In these patients, PASI 90 (relative to baseline) and PASI 100 response rates increased after switching, reaching 66.1% and 28.6%, respectively at week 48. 31 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 Safety Placebo-controlled period (weeks 0‑16)

[0199] The proportions of patients with at least one AE, AEs leading to discontinuation, and SAEs were comparable between theguselkumabandplacebogroups.Themost commonly reportedeventswerenasopharyngitis, headache,and upper respiratory tract infection. Rates of infections, infections requiring treatment, and serious infections were similar among groups. No malignancies or nonmelanoma skin cancers (NMSC) were reported through week 16. One major adverse cardiovascular event (MACE) (myocardial infarction [MI]) occurred in the adalimumab group. A higher proportion of adalimumab patients had injection site reactions (ISR) (6.9% vs 2.6%) and injections resulting in ISRs (1.5% vs. 0.9%) compared with guselkumab patients. All injection site reactions were mild. Active-comparator period (weeks 0‑28)

[0200] The types of AEswere similar to those reported in the placebo-controlled period. The proportions of patientswith at least one AE, AEs leading to discontinuation, and SAEs were comparable between the guselkumab and adalimumab groups. Infections and infections requiring treatment were also comparable between guselkumab and adalimumab groups. Three serious infections each were reported in the guselkumab (bronchitis, erysipelas, and soft tissue infection) and adalimumab groups (two cases of tuberculosis [one disseminated], and one injection site abscess). Onemalignancy (prostate cancer) and two NMSCs (one squamous cell carcinoma [SCC] in the guselkumab group and one basal cell carcinoma [BCC] in the placebo-guselkumab group) were reported. Two MACE (one MI each in guselkumab and adalimumab groups) were reported. Randomized withdrawal and retreatment period (weeks 28‑48)

[0201] Fromweeks 28‑48, no patients discontinued due to AEs; one serious infection (appendicitis) was reported in the maintenance group. No additional malignancies, NMSC, or MACE were reported. No AEs were reported among the 16 retreated patents. Additional safety through week 48

[0202] Throughweek 48, one additional BCCand one additional SCCof the skin occurred in the placebo→gusetkumab group (data not shown). Between weeks 28‑48, one additional MACE (MI) was reported in a placebo→guselkumab patient. No events of serious infections, malignancies, or MACE occurred in the adalimumab→guselkumab group. No deaths, opportunistic infections, hypersensitivity, or anaphylactic reactions occurred throughweek 48. Rates of abnormal labs were low and comparable between the treatment groups through week 48. Antibodies to guselkumab were detected in 57 / 869 patients (6.6%) through week 48; titers were generally low (88% ≤1:160). No apparent associations were observed between antibody development and decreased efficacy or ISR development (data not shown). DISCUSSION

[0203] VOYAGE 2 confirms the results of VOYAGE 1 demonstrating that guselkumab is highly effective in treating a broad moderate-to-severe psoriasis population. Guselkumab was superior to placebo at the week‑16 co-primary end- points of IGA cleared / minimal and PASI 90 response. Guselkumab was also superior to adalimumab at the week‑16 endpoints of IGA cleared / minimal, PASI 75 / 90, and by week 24, IGA cleared and PASI 90 / 100. Guselkumab also successfully treated difficult regional psoriasis, including scalp, nails, and hands / feet. Investigator-assessed improve- ments were mirrored by improvements in the patient-reported outcomes evaluated in VOYAGE 1, (DLQI and PSSD, a newly validated instrument that measures signs and symptoms of psoriasis). In addition, significant improvements in quality of life (QoL) (SF‑36) were reported in VOYAGE2. The combined robust and comprehensive results fromVOYAGE 1 and VOYAGE 2 demonstrated superiority to both placebo and adalimumab.

[0204] Consistentwith findingsof other biologics for psoriasis,VOYAGE2demonstrated thatmaintenance is superior to interrupted therapy, and that blockade of IL‑23 did not reverse the underlyingmechanism of psoriasis. Unlike VOYAGE1, in which patients continued treatment for 48 weeks, in VOYAGE 2, PASI 90-responders were randomized at week 28 to continue guselkumab or receive placebo. Guselkumab-treated patients maintained response, including PASI 90, PASI 100, and IGAcleared,while psoriasis slowly recurredandQoLwas reduced in placebopatients. Themedian time to lossof PASI 90 response for withdrawal patients was 15.2 weeks, which is relevant because discontinuation rates are significant with psoriasis biologics use through 1 year (often >50%).

[0205] Guselkumabwas also effective in treating adalimumab nonresponders (did not achieve PASI 90).Patientswere 32 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 classified as responders / nonresponders at week 28, 5 weeks after the last adalimumab injection. After 20 weeks of guselkumab treatment, 2 / 3 of the 112 adalimumab nonresponders who switched to guselkumab achieved PASI 90 (relative tobaseline).Determining the rateatwhichpatientswhohavehadsub-optimal responsesachieve treatment goals could have a significant impact on treatment decisions for those who seek greater clearance, as more effective psoriasis therapiescontinue toenter themarket.While themechanismofactionof thebroaderefficacyofguselkumab isunknown, in psoriasis, tumor necrosis factor-α (released from CD 163+ macrophages / CD11c+ DCs) and IL‑17A (released from neutrophils,mast cells, and Th17 cells) are effector cytokines primarily acting on keratinocytes. IL‑23 could be seen as the overarching master cytokine for psoriasis because it drives the activation of T cells and neutrophils, and induces IL‑17 production.Moreover, IL‑23 inducesTh17andother innate cells to produce IL‑22, another cytokine implicated in psoriasis pathogenesis. Therefore, targeting the IL‑23 pathway with an antibody such as guselkumab can provide higher efficacy and durable responses.

[0206] The safety profile of guselkumab in this studywas consistentwithVOYAGE1. The rates and types of AEs, SAEs, and laboratory abnormalities were generally comparable to placebo though week 16 and adalimumab through week 28. Through week 48, rates of serious infections, malignancies, andMACEwere low across treatment groups. Overall, there were 2 cases of TB, both in adalimumab patients. There were 5 malignancies in the guselkumab-treated patients, 4 of whichwereNMSCs (2BCCand2SCC). ISRsoccurredmore frequently in adalimumabpatients.While the safety profile of guselkumab is favorable, the size and duration of the study was inadequate to detect rare events.

[0207] Thereare several other limitations ofVOYAGE2.While comparisonof guselkumab toadalimumab inVOYAGE2 was limited to 24 weeks, VOYAGE 1 extended the comparison to adalimumab through 48 weeks. More importantly, at week 48, few VOYAGE 2 patients withdrawn from active therapy had lost adequate response to allow assessment of the efficacy and safety of retreatment. However, these numbers will be augmented at a later timepoint.

[0208] In conclusion, VOYAGE2 confirms the results of VOYAGE1 that guselkumab demonstrated superior efficacy to adalimumab and comparable safety when administered in a convenient dosage regimen of a single 100-mg injection at weeks 0, 4, and every‑8-weeks. These results suggest that guselkumab may be an important addition to psoriasis treatment alternatives. Additionally, VOYAGE 2 provides important data on the need for continuing therapy with guselkumab to maintain the highest level of response, as well as successful transition from adalimumab to guselkumab. ABBREVIATIONS AND ACRONYMS

[0209] AE adverse event BCC basal cell carcinoma BMI body mass index BSA body surface area DLQI Dermatology Life Quality Index f-PGA Fingernail Physician’s Global Assessment hf-PGA Physician’s Global Assessment of Hands and / or Feet HRQoL health-related quality of life IGA Investigator’s Global Assessment IL interleukin NAPSI Nail Psoriasis Area and Severity Index NMSC nonmelanoma skin cancer PASI Psoriasis Area and Severity Index PRO patient-reported outcome 33 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 PSSD Psoriasis Sign and Symptom Diary SAE serious adverse event ss-IGA Scalp-Specific Investigator’s Global Assessment TNFα-inhibitor tumor necrosis factor-α inhibitor US Regulatory Approval

[0210] The anti-IL‑23 specific antibody guselkumab has been approved for marketing in the U.S. by the U.S. Food and Drug Administration for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy by way of a Biologics License Application. The initial approved dosage is 100 mg administered by subcutaneous injection at Week 0, Week 4 and every 8 weeks thereafter. The antibody is at a concentration of 100 mg / mL in a single-dose prefilled syringe. 34 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 35 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 36 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 37 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 38 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 39 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 40 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 41 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 42 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 43 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 44 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 45 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 46 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 47 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 48 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 49 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 50 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 51 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 52 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 53 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 54 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 55 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 56 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 57 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 58 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 59 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 60 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 61 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 62 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 63 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 64 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 65 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 66 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 67 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 68 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 69 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 70 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 71 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 72 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 73 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 74 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 75 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 76 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 77 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 Numbered embodiments:

[0211] 1. Amethod of treating psoriasis in a patient, comprising administering an antibody to IL‑23 to the patient in a safe and effective amount, wherein theantibody comprises a light chain variable region andaheavy chain variable region, said light chain variable region comprising: a complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:50; a CDRL2 amino acid sequence of SEQ ID NO:56; and a CDRL3 amino acid sequence of SEQ ID NO:73, said heavy chain variable region comprising: a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO:5; a CDRH2 amino acid sequence of SEQ ID NO:20; and a CDRH3 amino acid sequence of SEQ ID NO:44. 2. Themethod of embodiment 1, wherein the antibody is administered in an initial dose, 4 weeks after the initial dose and every 8 weeks after the dose at 4 weeks. 3. The method of embodiment 2, wherein the patient is a responder to the antibody and is identified as having a PASI90, PASI100 or IGA 0 or 1 score. 78 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 4. The method of embodiment 3, wherein the PASI90, PASI100 or IGA 0 or 1 score is measured 16, 20 or 28 weeks after initial treatment. 5. The method of embodiment 1, wherein the antibody is guselkumab administered subcutaneously. 6. Themethod of embodiment 5, wherein the anti-IL‑23 antibody is safe and effective treating psoriasis at an area of a patient selected from the group consisting of scalp, nails, hands and feet. 7. The method of embodiment 5, wherein the antibody is in a composition comprising 100 mg / mL of antibody; 7.9% (w / v) sucrose, 4.0mMHistidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the pharmaceutical composition; wherein the diluent is water at standard state. 8. The method of embodiment 7, wherein the antibody is administered at a dose of between 25 mg and 200 mg. 9. The method of embodiment 8, wherein the antibody is administered at a dose of 50 mg or 100 mg. 10. Themethod of embodiment 1, further comprising administering to the patient one ormore additional drugs used to treat psoriasis. 11. The method of embodiment 10, wherein the additional drug is selected from the group consisting of: immuno- suppressive agents, non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B-cell surface marker antibodies, anti-CD20 antibodies, rituximab, TNF-inhibitors, corticosteroids, and co-stimulatory modifiers. 12. The method of embodiment 1, wherein the antibody is effective to reduce a symptom of psoriasis in the patient, induce clinical response, induce or maintain clinical remission, inhibit disease progression, or inhibit a disease complication in the patient. 13.Amethodof treatingpsoriasis inapatient, comprisingadministeringanantibody to IL‑23 to thepatient inasafeand effective amount, wherein the antibody comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 116 and a heavy chain variable region of the amino acid sequence of SEQ ID NO: 106. 14.Themethodofembodiment 13,wherein theantibody isadministered inan initial dose, 4weeksafter the initial dose and every 8 weeks after the dose at 4 weeks. 15. The method of embodiment 14, wherein the patient is a responder to the antibody and is identified as having a PASI90, PASI100 or IGA 0 or 1 score. 16. Themethod of embodiment 15, wherein the PASI90, PASI100 or IGA 0 or 1 score ismeasured 16, 20 or 28weeks after initial treatment. 17. Themethodof embodiment 16,wherein theanti-IL‑23antibody is safeandeffective treating psoriasis at anareaof a patient selected from the group consisting of scalp, nails, hands and feet. 18. Themethod of embodiment 13, wherein the antibody is in a composition comprising 100mg / mL of antibody; 7.9% (w / v) sucrose, 4.0mMHistidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the pharmaceutical composition; wherein the diluent is water at standard state. 19. Themethod of embodiment 13, wherein the antibody is in a composition comprising 50mg / mL of antibody; 7.9% (w / v) sucrose, 4.0mMHistidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the pharmaceutical composition; wherein the diluent is water at standard state. 20. The method of embodiment 19, wherein the antibody is administered subcutaneously. 21. The method of embodiment 13, wherein the antibody is administered at a dose of between 25 mg and 200 mg. 22. The method of embodiment 21, wherein the antibody is administered at a dose of 50 mg or 100 mg. 23. Themethod of embodiment 13, further comprising administering to the patient one ormore additional drugs used 79 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 to treat psoriasis. 24. The method of embodiment 23, wherein the additional drug is selected from the group consisting of: immuno- suppressive agents, non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B-cell surface marker antibodies, anti-CD20 antibodies, rituximab, TNF-inhibitors, corticosteroids, and co-stimulatory modifiers. 25. Amethod of treating psoriasis in a patient that is a non-responder to a TNF inhibitors, comprising administering an antibody to IL‑23 to the patient in a safe and effective amount, wherein the antibody comprises a light chain variable regionof theaminoacid sequenceofSEQ IDNO:116andaheavy chain variable regionof theaminoacid sequenceof SEQ ID NO: 106. 26. The method of embodiment 25, wherein the TNF inhibitor is adalilumab or eternacept. 27. The method of embodiment 25, wherein the patient is determined to be a non-responder to a TNF inhibitors by measuring the PASI and / or IGA score. 28. A method of treating moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy, comprising administering an antibody to IL‑23 to the patient in a safe and effective amount, wherein the antibody comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 116 and a heavy chain variable region of the amino acid sequence of SEQ ID NO: 106, the dosage is 100 mg administered by subcutaneous injection atWeek 0,Week 4 and every 8weeks thereafter and the antibody is at a concentration of 100 mg / mL in a single-dose prefilled syringe comprising 7.9% (w / v) sucrose, 4.0mM Histidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 and the diluent is water at standard state. Claims 1. An IL‑23 antibody for use in a method of treating psoriasis in a patient that is a non-responder to a TNF inhibitor, wherein the method comprises administering the antibody to the patient in a safe and effective amount, wherein the antibody comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 116 and a heavy chain variable region of the amino acid sequence of SEQ ID NO: 106. 2. The antibody for use of claim 1, wherein the antibody is guselkumab. 3. Theantibody for use of claim1or 2,wherein theTNF inhibitor is aTNFmonoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70 or p85) or fragment, fusion polypeptides thereof, or a small molecule TNF antagonist, e.g., TNF binding protein I or II (TBP‑1 or TBP-II), nerelimomab, infliximab, etanercept, CDP‑571, CDP‑870, afelimomab or lenercept. 4. The antibody for use of claim 1, wherein the TNF inhibitor is adalimumab or etanercept. 5. The antibody for use of any one of claims 1‑4, wherein the patient is determined to be a non-responder to the TNF inhibitor by measuring the PASI and / or IGA score. 6. The antibody for use of any one of claims 1‑5, wherein the antibody is administered at a dose of between 25 mg and 200 mg. 7. The antibody for use of claim 6, wherein the antibody is administered at a dose of 50 mg or 100 mg. 8. The antibody for use of any one of claims 1‑7, wherein the antibody is administered subcutaneously. 9. Theantibody foruseof claim8,wherein theanti-IL‑23antibody is safeandeffective for treatingpsoriasisat anareaofa patient selected from the group consisting of scalp, nails, hands and feet. 10. The antibody for use of claim 9, wherein the antibody is in a composition comprising: (a) 100 mg / mL of antibody; 7.9% (w / v) sucrose, 4.0mM Histidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the pharmaceutical composition; wherein the diluent is water 80 EP 4 714 504 A2 5 10 15 20 25 30 35 40 45 50 55 at standard state, or (b) 50 mg / mL of antibody; 7.9% (w / v) sucrose, 4.0mM Histidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the pharmaceutical composition; wherein the diluent is water at standard state. 11. Theantibody for useofanyoneof claims1‑10,wherein theantibody isadministered inan initial dose, 4weeksafter the initial dose and every 8 weeks after the dose at 4 weeks. 12. The antibody for use of any one of claims 1‑11, wherein the patient achieves an IGA score of 0 or 1 and PASI90 or PASI100 at week 16. 13. The antibody for use of claim 12, wherein the PASI90, PASI100 or IGA 0 or 1 score is measured 16, 20 or 28 weeks after initial treatment. 14. The antibody for use of any one of claims 1‑13, further comprising administering to the patient one or more additional drugs used to treat psoriasis, optionally wherein the additional drug is selected from the group consisting of: immunosuppressive agents, non- steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B-cell surface marker antibodies, anti-CD20 antibodies, rituximab, TNF inhibitors, corticosteroids, and co-stimulatory modifiers. 15. 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[0157] 摘要 一種通過安全有效地給予患者 IL-23 特異性抗體（例如古塞庫單抗）來 治療銀屑病的方法。患者在初始治療後 16、24、32、40 和 48 周時，PASI 評分達到 90、100 或 IGA 評分 0 或 1。

Claims

1. An IL-23 antibody for use in a method of treating psoriasis in a patient that is a non-responder to a TNF inhibitor, wherein the method comprises administering the antibody to the patient in a safe and effective amount, wherein the antibody comprises a light chain variable region of the amino acid sequence of SEQ ID NO: 116 and a heavy chain variable region of the amino acid sequence of SEQ ID NO: 106.

2. The antibody for use of claim 1, wherein the antibody is guselkumab.

3. The antibody for use of claim 1 or 2, wherein the TNF inhibitor is a TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70 or p85) or fragment, fusion polypeptides thereof, or a small molecule TNF antagonist, e.g., TNF binding protein I or II (TBP-1 or TBP-II), nerelimomab, infliximab, etanercept, CDP-571, CDP-870, afelimomab or lenercept.

4. The antibody for use of claim 1, wherein the TNF inhibitor is adalimumab or etanercept.

5. The antibody for use of any one of claims 1-4, wherein the patient is determined to be a non-responder to the TNF inhibitor by measuring the PASI and / or IGA score.

6. The antibody for use of any one of claims 1-5, wherein the antibody is administered at a dose of between 25 mg and 200 mg.

7. The antibody for use of claim 6, wherein the antibody is administered at a dose of 50 mg or 100 mg.

8. The antibody for use of any one of claims 1-7, wherein the antibody is administered subcutaneously.

9. The antibody for use of claim 8, wherein the anti-IL-23 antibody is safe and effective for treating psoriasis at an area of a patient selected from the group consisting of scalp, nails, hands and feet.

10. The antibody for use of claim 9, wherein the antibody is in a composition comprising: (a) 100 mg / mL of antibody; 7.9% (w / v) sucrose, 4.0mM Histidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the pharmaceutical composition; wherein the diluent is water at standard state, or (b) 50 mg / mL of antibody; 7.9% (w / v) sucrose, 4.0mM Histidine, 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053% (w / v) Polysorbate 80 of the pharmaceutical composition; wherein the diluent is water at standard state.

11. The antibody for use of any one of claims 1-10, wherein the antibody is administered in an initial dose, 4 weeks after the initial dose and every 8 weeks after the dose at 4 weeks.

12. The antibody for use of any one of claims 1-11, wherein the patient achieves an IGA score of 0 or 1 and PASI90 or PASI100 at week 16.

13. The antibody for use of claim 12, wherein the PASI90, PASI100 or IGA 0 or 1 score is measured 16, 20 or 28 weeks after initial treatment.

14. The antibody for use of any one of claims 1-13, further comprising administering to the patient one or more additional drugs used to treat psoriasis, optionally wherein the additional drug is selected from the group consisting of: immunosuppressive agents, non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), anti-B-cell surface marker antibodies, anti-CD20 antibodies, rituximab, TNF inhibitors, corticosteroids, and co-stimulatory modifiers.

15. The antibody for use of any one of claims 1-14, wherein the antibody is effective to reduce a symptom of psoriasis in the patient, induce clinical response, induce or maintain clinical remission, inhibit disease progression, or inhibit a disease complication in the patient.