Methods of treating inflammatory diseases

Abstract

This invention generally relates to methods for the treatment of IL-23 related diseases, in particular inflammatory diseases, such as Crohn's Disease, utilizing anti-IL-23A antibodies.

Description

(19) *EP004752158A2* (11) EP 4 752 158 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 03.06.2026 Bulletin 2026 / 23 (21) Application number: 26166103.7 (22) Date of filing: 15.09.2016 (51) International Patent Classification (IPC): C07K 16 / 24 (2006.01) (52) Cooperative Patent Classification (CPC): C07K 16 / 244; A61P 1 / 00; A61P 1 / 04; A61K 2039 / 505; A61K 2039 / 54; A61K 2039 / 545; C07K 2317 / 70; C07K 2317 / 76; C07K 2317 / 90 (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 (30) Priority: 18.09.2015 US 201562220410 P 01.10.2015 US 201562235654 P 16.02.2016 US 201662295643 P 28.04.2016 US 201662328863 P 12.05.2016 US 201662335242 P 20.05.2016 US 201662339192 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 16771052.4 / 3 350 221 (71) Applicant: Boehringer Ingelheim International GmbH 55216 Ingelheim am Rhein (DE) (72) Inventors: • BOECHER, Wulf Otto 55216 Ingelheim am Rhein (DE) • GALLER, Annette Bettina 55216 Ingelheim am Rhein (DE) • LALOVIC, Bojan Ridgefield, Connecticut, 06877‑0368 (US) • PADULA, Steven John Ridgefield, Connecticut, 06877‑0368 (US) • SCHOLL, Paul Ridgefield, Connecticut, 06877‑0368 (US) • VISVANATHAN, Sudha Ridgefield, Connecticut, 06877‑0368 (US) (74) Representative: Hoffmann Eitle Patent‑ und Rechtsanwälte PartmbB Arabellastraße 30 81925 München (DE) Remarks: •The complete document including Reference Table(s) and the Sequence Listing(s) can be downloaded from the EPO website •This application was filed on 19‑03‑2026 as divisional application to the application mentioned under INID code 62. (54) METHODS OF TREATING INFLAMMATORY DISEASES (57) This invention generally relates to methods for the treatment of IL‑23 related diseases, in particular inflammatory diseases, such as Crohn’s Disease, utiliz- ing anti-IL‑23A antibodies. EP 4 75 2 15 8 A 2 Processed by Luminess, 75001 PARIS (FR) Description Technical Field of the Invention

[0001] This invention generally relates tomethod of treating inflammatory diseases, for exampleCrohn’sDisease (CD), utilizing anti-IL‑23A antibodies. Background of the Invention

[0002] Crohn’s Disease (CD) is a chronic relapsing, remitting inflammatory disease of the gastrointestinal tract characterizedbyabdominal pain, fever, andbloodyormucus-containingdiarrhea. Thediseaseaffects thegastrointestinal tract discontinuously frommouth to anus, butmost commonly the ileumand colon (40%), followed by the small bowel only (30%), and the colon only (25%). It occurs in a relatively young population and there is no marked sex difference.

[0003] The incidence of CD seems to be increasingwithmore recent estimates varying from7.9 to 20.2 cases / 100,000, and a prevalence of 161 to 319 cases / 100,000 in North America and Europe. Mucosal lesions may be complicated by perforation and fistula formation, which may require hospitalization for medical or surgical management. There is a need for treatment options for inflammatory diseases, in particular Crohn’s Disease, that lead to favorable outcomes for patients, for example in terms of efficacy, safety and / or tolerability of the treatment. Summary of the Invention

[0004] The present invention addresses the above needs and provides methods for treating inflammatory diseases, in particular methods comprising administering an anti-IL‑23A antibody to a patient in certain amounts and / or at certain intervals. In one aspect, amethod of the present invention is for the treament of Crohn’sDisease. In one aspect, amethod of the present invention is for the treament of ulcerative colitis.

[0005] The methods of the present invention provide the advantage of enabling patients to experience clinical improvement while receiving fewer administrations of the anti-IL‑23A antibody.

[0006] In one embodiment, the present invention provides amethod for treating an inflammatory disease, in one aspect for treatingCrohn’sDisease, comprising (a) administering to a patient a doseof ananti-IL‑23Aantibody atweek0, atweek 4 and at week 8 by intravenous infusion, wherein the doses of the anti-IL‑23A antibody comprise 200mg or 600mg of the antibody. In one embodiment, themethod further comprises (b) administering to the patient three doses of the anti-IL‑23A antibody, for example at week 14, at week 18 and at week 22 by intravenous infusion, wherein the doses of the anti-IL‑23A antibody comprise 600 mg of the antibody. In one embodiment, the method further comprises (c) administering to the patient one or more doses of the anti-IL‑23A antibody at 8 weeks intervals by subcutaneous injection, for example four doses of the anti-IL‑23A antibody at 8 weeks intervals by subcutaneous injection, for example at week 26, at week 34, at week 42 and at week 50, wherein the one or more doses of the anti-IL‑23A antibody comprise 180 mg of the antibody.

[0007] In one embodiment, at week 12, a patient is evaluated for deep remission, for example defined as reaching clinical remission (CDAI score <150) and endoscopic remission (CDEIS ≤ 4). In one, aspect, for a patient with initial isolated ileitis endoscopic remission is defined by CDEIS ≤ 2.

[0008] In one embodiment, the present invention provides amethod for treating an inflammatory disease, in one aspect for treatingCrohn’sDisease, comprising (a) administering to a patient a doseof ananti-IL‑23Aantibody atweek0, atweek 4 and at week 8 by intravenous infusion, wherein the doses of the anti-IL‑23A antibody comprise 200mg or 600mg of the antibody. In one embodiment, themethod further comprises (b) administering to the patient one ormore doses of the anti- IL‑23A antibody at 8 weeks intervals by subcutaneous injection, for example four doses of the anti-IL‑23A antibody at 8 weeks intervals by subcutaneous injection, for example at week 26, at week 34, at week 42 and at week 50, wherein the one or more doses of the anti-IL‑23A antibody comprise 180 mg of the antibody.

[0009] In one embodiment, at week 12, a patient is evaluated for deep remission, for example defined as reaching clinical remission (CDAI score <150) and endoscopic remission (CDEIS ≤ 4). In one, aspect, for a patient with initial isolated ileitis endoscopic remission is defined by CDEIS ≤ 2.

[0010] In one embodiment, the present invention provides amethod for treating an inflammatory disease, in one aspect for treatingCrohn’sDisease, comprising administering to a patient 180mgof the anti-IL‑23Aantibody at 8weeks intervals by subcutaneous injection.

[0011] In one embodiment, the present invention provides amethod for treating an inflammatory disease, in one aspect for treating Crohn’s Disease, comprising administering to a patient an anti-IL‑23A antibody, said method comprising administering at least one induction doseof the anti-IL‑23Aantibody to the patient, wherein said induction dose comprises 200 to 1,200 mg of the anti-IL‑23A antibody, for example 450 to 1,200 mg of the anti-IL‑23A antibody. In one aspect, the inductiondose comprises200mg, 450mg, 600mg, 900mgor1,200mgof theanti-IL‑23Aantibody. In oneaspect, 1, 2 or 3 induction doses are administered to the patient. In one aspect, 2 or 3 inductions doses are administered, for example at 4 2 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 weeks intervals. In one aspect, the induction dose(s) is administered by intravenous infusion.

[0012] In oneembodiment, the inductiondoses comprise200mgof theanti-IL‑23Aantibodyand three inductionsdoses are administered to the patient at 4 weeks intervals.

[0013] In oneembodiment, the inductiondoses comprise450mgof theanti-IL‑23Aantibodyand three inductionsdoses are administered to the patient at 4 weeks intervals.

[0014] In oneembodiment, the inductiondoses comprise600mgof theanti-IL‑23Aantibodyand three inductionsdoses are administered to the patient at 4 weeks intervals.

[0015] In oneembodiment, the inductiondoses comprise900mgof theanti-IL‑23Aantibodyand three inductionsdoses are administered to the patient at 4 weeks intervals.

[0016] In one embodiment, the induction doses comprise 1,200 mg of the anti-IL‑23A antibody and three inductions doses are administered to the patient at 4 weeks intervals.

[0017] In one embodiment, at least one additional induction dose of the anti-IL‑23A antibody is administered to the patient after the last induction dose above. In one aspect, an additional induction dose comprises 200 to 1,200 mg of the anti-IL‑23A antibody, for example 450 to 1,200mg of the anti-IL‑23A antibody. In one aspect, an additional induction dose comprises 200 mg, 450 mg, 600 mg, 900 mg or 1,200 mg of the anti-IL‑23A antibody. In one aspect, 1, 2 or 3 additional induction doses are administered to the patient. In one aspect, 2 or 3 additional inductions doses are administered, for example at 4 weeks intervals. In one aspect, the additional induction dose(s) is administered by intravenous infusion.

[0018] In one embodiment, the patient has aCDAI score of 220‑450 before the administration of the first induction dose.

[0019] In one embodiment, the patient achieves clinical remission after the administration of the one or more induction doses. In one embodiment, the patient achieves a CDAI score of less than 150 after the administration of the one or more inductiondoses. Inoneembodiment, thepatient achievesaPRO‑2scoreequal toor less than75after theadministrationof the one or more induction doses. In one embodiment, the patient achieves a CDAI score of less than 150 and a PRO‑2 score equal to or less than 75 after the administration of the one or more induction doses.

[0020] In one embodiment, the present invention further provides a method for inducing clinical remission of Crohn’s Disease in a patient comprising administering to the patient an anti-IL‑23 antibody as described above or herein.

[0021] In one embodiment, the present invention further provides a method for inducing clinical response to Crohn’s Disease in a patient comprising administering to the patient an anti-IL‑23 antibody as described above or herein.

[0022] In one ambodiment, the method further comprises administering a first maintenance dose of the anti-IL‑23A antibody to the patient after the last induction dose is administered and administering at least one additional maintenance dose to the patient 4 to 12 weeks after said first maintenance dose is administered. In one aspect, the first maintenance dose is administered 2 to 8 weeks, for example 4 to 6 weeks, for example 2 weeks, 4 weeks, 6 weeks or 8 weeks, after the last induction dose is administered. In one aspect, the at least one additional maintenance dose is administered to the patient 4, 8 or 12 weeks after the first maintenance dose is administered.

[0023] In one embodiment, the first maintenance dose comprises 150 to 300 mg of the anti-IL‑23A antibody. In one aspect, the firstmaintenancedosecomprises150mg,225mgor300mgof theanti-IL‑23Aantibody. Inoneaspect, thefirst maintenance dose comprises 180 mg or 270 mg of the anti-IL‑23A antibody.

[0024] In oneaspect, the at least oneadditionalmaintenancedose comprises150 to 300mgof the anti-IL‑23Aantibody. In one aspect, the at least one additional maintenance dose comprises 150 mg, 225 mg or 300 mg of the anti-IL‑23A antibody. In one aspect, the at least one additional maintenance dose comprises 180 mg or 270 mg of the anti-IL‑23A antibody.

[0025] In one aspect, the first maintenance dose and the at least one additionalmaintenance dose comprise 150 to 300 mgof the anti-IL‑23Aantibody. In oneaspect, the firstmaintenancedoseand theat least oneadditionalmaintenancedose comprise 150mg, 225mgor300mgof saidanti-IL‑23Aantibody. In oneaspect, the firstmaintenancedoseand theat least one additional maintenance dose comprise 180 mg or 270 mg of said anti-IL‑23A antibody.

[0026] In one aspect, a maintenance dose is administered by subcutaneous injection.

[0027] In one embodiment, the maintenance doses comprise 150mg of the anti-IL‑23A antibody and are administered to the patient at 4 weeks intervals.

[0028] In one embodiment, the maintenance doses comprise 150mg of the anti-IL‑23A antibody and are administered to the patient at 8 weeks intervals.

[0029] In one embodiment, the maintenance doses comprise 225mg of the anti-IL‑23A antibody and are administered to the patient at 8 weeks intervals.

[0030] In one embodiment, the maintenance doses comprise 225mg of the anti-IL‑23A antibody and are administered to the patient at 12 weeks intervals.

[0031] In one embodiment, the maintenance doses comprise 300mg of the anti-IL‑23A antibody and are administered to the patient at 8 weeks intervals.

[0032] In one embodiment, the maintenance doses comprise 300mg of the anti-IL‑23A antibody and are administered to the patient at 12 weeks intervals.

[0033] In one embodiment, the patient maintains clinical remission after the administration of the one or more 3 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 maintenancedoses. Inoneembodiment, thepatientmaintainsaCDAI scoreof less than150after theadministrationof the oneormoremaintenancedoses. Inoneembodiment, thepatientmaintainsaPRO‑2scoreequal toor less than75after the administration of the oneormoremaintenance doses. In one embodiment, the patientmaintains aCDAI score of less than 150 and a PRO‑2 score equal to or less than 75 after the administration of the one or more maintenance doses.

[0034] In one embodiment, the present invention further provides amethod formaintaining clinical remission of Crohn’s Disease in a patient comprising administering to the patient an anti-IL‑23 antibody as described above or herein.

[0035] In one embodiment, the present invention further provides amethod formaintaining clinical response to Crohn’s Disease in a patient comprising administering to the patient an anti-IL‑23 antibody as described above or herein.

[0036] In oneembodiment, thepresent invention further providesamethod for treatingCrohn’sDiseaseby inducingand maintaining clinical remission in a patient comprising administering to the patient an anti-IL‑23 antibody as described above or herein.

[0037] In one embodiment, the present invention further provides a method for maintaining endoscopic remission of Crohn’s Disease in a patient comprising administering to the patient an anti-IL‑23 antibody as described above or herein.

[0038] In one embodiment,the present invention provides a method for inducing clinical remission of Crohn’s Disease comprisingadministering toapatient ananti-IL‑23Aantibody, saidmethodcomprisingadministeringat least one induction doseof saidanti-IL‑23Aantibody to thepatient, wherein said inductiondose comprises200 to1,200mgof said anti-IL‑23A antibody. In one embbodiment, the induction dose comprises 450 to 1,200 mg of said anti-IL‑23A antibody. In one embodiment, the induction dose comprises 200mg, 450mg, 600mg, 900mg or 1,200mg of said anti-IL‑23A antibody. In one embodiment, 1, 2 or 3 induction doses are administered to the patient. In one embodiment, 2 or 3 inductions doses are administered at 4 weeks intervals. In one embodiment, the induction dose(s) is / are administered by intravenous infusion. In one embodiment, the patient has a CDAI score of 220‑450 before said administration. In one embodiment, the patient achieves aCDAI score of less than 150. In one embodiment, the patient achieves a PRO‑2 score equal to or less than 75.

[0039] Inoneembodiment, themethod further comprisesmaintainingclinical remissionofCrohn’sdisease, saidmethod further comprising administering a firstmaintenance doseof said anti-IL‑23Aantibody to thepatient after the last induction dose is administered, and administering at least one additional maintenance dose to the patient 4 to 12 weeks after said first maintenance dose is administered. In one embodiment, the first maintenance dose is administered 2 to 8 weeks, for example 4 to 6 weeks, for example 2 weeks, 4 weeks, 6 weeks or 8 weeks, after the last induction dose is administered. In one embodiment, the at least one additional maintenance dose is administered to the patient 4, 8 or 12 weeks after after said first maintenance dose is administered. In one embodiment, the first maintenance dose comprises 150 to 300 mg of said anti-IL‑23A antibody. In one embodiment, the first maintenance dose comprises 150 mg, 225 mg or 300 mg of said anti-IL‑23A antibody. In one embodiment, the first maintenance dose comprises 180 mg or 270 mg of said anti-IL‑23A antibody. In one embodiment, the at least one additional maintenance dose comprises 150 to 300 mg of said anti-IL‑23A antibody. In one embodiment, the at least one additional maintenance dose comprises 150mg, 225mg or 300mg of said anti-IL‑23A antibody. In one embodiment, the at least one additional maintenance dose comprises 180 mg or 270 mg of said anti-IL‑23A antibody. In one embodiment, the first maintenance dose and said at least one additional maintenance dosecomprise150 to300mgof saidanti-IL‑23Aantibody. Inoneembodiment, the firstmaintenancedoseandsaidat least one additional maintenance dose comprise 150 mg, 225 mg or 300 mg of said anti-IL‑23A antibody. In one embodiment, the first maintenance dose and said at least one additional maintenance dose comprise 180 mg or 270 mg of said anti- IL‑23A antibody. In one embodiment, the maintenance dose is administered by subcutaneous injection. In one embodi- ment, the patientmaintains aCDAI score of less than 150. In one embodiment, the patientmaintains aPRO‑2 score equal to or less than 75.

[0040] In one embodiment, the present invention provides amethod for treating an inflammatory disease, in one aspect for treating Crohn’s Disease, comprising administering to a patient 150 to 1,200 mg of an anti-IL‑23A antibody. In one aspect, themethodcomprisesadministering to apatient 200mg to1,200mgof ananti-IL‑23Aantibody, for example450 to 1,200mgof an anti-IL‑23A antibody. In one aspect, themethod comprises administering to a patient 200mg, 450mg, 600 mg, 900mg or 1,200mg of an anti-IL‑23A antibody. In one aspect, themethod comprises administering to a patient 150 to 300mg of an anti-IL‑23A antibody. In one aspect, themethod comprises administering to a patient 150mg, 225mg or 300 mgof ananti-IL‑23Aantibody. In oneaspect, themethodcomprises administering to a patient 180mgor 270mgof ananti- IL‑23A antibody.

[0041] In one embodiment, in any one of the methods above, the anti-IL‑23A antibody is Antibody A, Antibody B, Antibody C or Antibody D.

[0042] In one embodiment, in any one of the methods above, the method is for treating Crohn’s Disease, for example moderately to severely activeCrohn’sDisease. In one aspect, in the context of amethod of the present invention a patient is naïve to, or was previously treated with anti-TNF therapy. In one aspect, in the context of a method of the present invention a patient was previously treated with one, two, three ormore TNF antagonist(s). In one embodiment, the patient is a patient who had an inadequate response with, was intolerant to, or demonstrated dependence on corticosteroids. In one embodiment, the patient is a patient who had an inadequate response with, lost response, or was intolerant to an immunomodulator, a TNFα inhibitor (or TNF antagonist) or an integrin inhibitor. In one embodiment, the treatment is by 4 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 inducing and maintaining clinical remission, corticosteroid-free remission, endoscopic remission and mucosal healing.

[0043] In one embodiment, a patient to be treated by a method according ot the present invention has a CDAI score of 220‑450.

[0044] In one embodiment, in any one of the methods above, the patient is an adult patient.

[0045] In one embodiment, in any one of the methods above, the method is for treating ulcerative colitis.

[0046] In one aspect, the present invention provides an anti-IL‑23A antibody for use in the treament of a disease, for example an inflammatory disease, for example Crohn’s Disease, by administration in certain amounts and / or at certain intervals as described herein. In one aspect, the inflammatory disease is ulcerative colitis.

[0047] In one aspect, the present invention provides for the use of an anti-IL‑23A antibody for the preparation of a medicament for the treatment of a disease, for example an inflammatory disease, for example Crohn’s Disease, by administration in certain amounts and / or at certain intervals as described herein. In one aspect, the inflammatory disease is ulcerative colitis.

[0048] In one embodiment, in any one of the methods or uses above, the anti-IL‑23A antibody is disclosed below.

[0049] In one embodiment, the anti-IL‑23A antibody comprises a light chain variable region comprising the amino acid sequenceofSEQIDNO:1 (CDR1-L); theaminoacidsequenceofSEQIDNO:2 (CDR2-L);and theaminoacidsequenceof SEQ IDNO:3 (CDR3-L); and a heavy chain variable region comprising the amino acid sequence of SEQ IDNO: 4, 7, 8 or 9 (CDR1-H); theaminoacid sequenceofSEQ IDNO:5 (CDR2-H); and theaminoacid sequenceofSEQ IDNO:6 (CDR3-H).

[0050] In one embodiment, the anti-IL‑23A antibody comprises a light chain variable region comprising the amino acid sequenceofSEQIDNO:1 (CDR1-L); theaminoacidsequenceofSEQIDNO:2 (CDR2-L);and theaminoacidsequenceof SEQ IDNO:3 (CDR3-L); and a heavy chain variable region comprising the amino acid sequence of SEQ IDNO:4 (CDR1- H); the amino acid sequence of SEQ ID NO:5 (CDR2-H); and the amino acid sequence of SEQ ID NO:6 (CDR3-H).

[0051] In one embodiment, the anti-IL‑23A antibody comprises a light chain variable region comprising the amino acid sequenceofSEQIDNO:1 (CDR1-L); theaminoacidsequenceofSEQIDNO:2 (CDR2-L);and theaminoacidsequenceof SEQ IDNO:3 (CDR3-L); and a heavy chain variable region comprising the amino acid sequence of SEQ IDNO:7 (CDR1- H); the amino acid sequence of SEQ ID NO:5 (CDR2-H); and the amino acid sequence of SEQ ID NO:6 (CDR3-H).

[0052] In one embodiment, the anti-IL‑23A antibody comprises a light chain variable region comprising the amino acid sequenceofSEQIDNO:1 (CDR1-L); theaminoacidsequenceofSEQIDNO:2 (CDR2-L);and theaminoacidsequenceof SEQ IDNO:3 (CDR3-L); and a heavy chain variable region comprising the amino acid sequence of SEQ IDNO:8 (CDR1- H); the amino acid sequence of SEQ ID NO:5 (CDR2-H); and the amino acid sequence of SEQ ID NO:6 (CDR3-H).

[0053] In one embodiment, the anti-IL‑23A antibody comprises a light chain variable region comprising the amino acid sequenceofSEQIDNO:1 (CDR1-L); theaminoacidsequenceofSEQIDNO:2 (CDR2-L);and theaminoacidsequenceof SEQ IDNO:3 (CDR3-L); and a heavy chain variable region comprising the amino acid sequence of SEQ IDNO:9 (CDR1- H); the amino acid sequence of SEQ ID NO:5 (CDR2-H); and the amino acid sequence of SEQ ID NO:6 (CDR3-H).

[0054] In one embodiment, the anti-IL‑23A antibody comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NO:10, 11, 12 or 13; and a heavy chain variable region comprising the amino acid sequence any one of SEQ ID NO:14, 15, 16 or 17.

[0055] In one embodiment, the anti-IL‑23A antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:11 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO:14.

[0056] In one embodiment, the anti-IL‑23A antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:11 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO:15.

[0057] In one embodiment, the anti-IL‑23A antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:10 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO:14.

[0058] In one embodiment, the anti-IL‑23A antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:10 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO:15.

[0059] In oneembodiment, the anti-IL‑23Aantibodycomprises theaminoacid sequenceSEQ IDNO:14or 15 linked toa human IgG1, IgG2, IgG3, IgG4, IgM, IgA or IgE heavy chain constant region. In one embodiment, the anti-IL‑23Aantibody comprises the amino acid sequence of SEQ ID NO: 14 or 15 linked to a human IgG1 heavy chain constant region.

[0060] Inoneembodiment, theanti-IL‑23Aantibodycomprises theaminoacidsequenceofSEQIDNO:10or11 linked to a human kappa or lambda light chain constant region.

[0061] In oneembodiment, In oneembodiment, the anti-IL‑23Aantibody comprises theaminoacid sequenceofSEQ ID NO:14 or 15 linked to a human IgG1 heavy chain constant region; and the amino acid sequence of SEQ ID NO: 10 or 11 linked to a human kappa light chain constant region.

[0062] In one embodiment, the anti-IL‑23A antibody is a humanized monoclonal antibody comprising a light chain variable region comprising the amino acid sequence selected from the group consisting of any one of SEQ ID NO:10, 11, 12and13andaheavychainvariable regioncomprising theaminoacidsequenceselected from thegroupconsistingofany one of SEQ ID NO:14, 15, 16 and 17.

[0063] In one embodiment, the anti-IL‑23A antibody is a humanized monoclonal antibody comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO:11 and a heavy chain variable region comprising the 5 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 amino acid sequence SEQ ID NO:14.

[0064] In one embodiment, the anti-IL‑23A antibody is a humanized monoclonal antibody comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO:11 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO:15.

[0065] In one embodiment, the anti-IL‑23A antibody is a humanized monoclonal antibody comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO:10 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO:14.

[0066] In one embodiment, the anti-IL‑23A antibody is a humanized monoclonal antibody comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO:10 and a heavy chain variable region comprising the amino acid sequence SEQ ID NO:15.

[0067] In one embodiment, the anti-IL‑23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:18 or 21 and a heavy chain comprising the amino acid sequence of SEQ ID NO:19 or 20.

[0068] In one embodiment, the anti-IL‑23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:18 and a heavy chain comprising the amino acid sequence of SEQ ID NO:19.

[0069] In one embodiment, the anti-IL‑23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:18 and a heavy chain comprising the amino acid sequence of SEQ ID NO:20.

[0070] In one embodiment, the anti-IL‑23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:21 and a heavy chain comprising the amino acid sequence of SEQ ID NO:19.

[0071] In one embodiment, the anti-IL‑23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 21 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 20.

[0072] In one embodiment, the anti-IL‑23A antibody is Antibody A, Antibody B, Antibody C or Antibody D.

[0073] In one embodiment, the anti-IL‑23A antibody is as disclosed in WO2007 / 005955, WO2007 / 024846, WO2007 / 027714, WO2007 / 076524, WO2008 / 103432 or WO2012 / 061448.

[0074] In one embodiment, the present invention provides a method for detecting the presence or absence of a beneficial response in a patient after administration of an IL‑23A antagonist, comprising: a) obtaining a biological sample from the patient; b) measuring in said sample the level of expression of one or more genes; c) comparing the level in b) to the level of expression of the one or more genes in a control; and d) determining whether or not the difference in levels between the sample and the control reflects a beneficial response in the patient, wherein the one or more genes is one or moregenesdescribedherein. Inoneaspect, thepatient suffers fromCrohns’Disease. Inoneaspect, thebiological sample is a colon tissue or a ileum tissue. In one aspect, the biological sample is taken from the upper gatrointestinal (GI) tract, for example the stomach or the esophagus. In one aspect, the IL‑23A antagonist is an anti-IL‑23A antibody or an antigen binding fragment thereof, for example Antibody A, Antibody B, Antibody C or Antibody D. Brief Description of the Figures

[0075] Figure 1: Trial Design. Deep remission, defined as achieving clinical remission (CDAI score < 150) and CDEIS remission (CDEIS score ≤ 4 or 2 or less in patients with initial isolated ileitis). Figure 2Aand2B:Proportion of patientswith clinical remission (A) or clinical response (B) atweek4,week8andweek 12. Clinical remission is defined as a CDAI score <150. Clinical response is either a CDAI score <150 or a CDAI reduction from baseline of ≥100 points. Patients in which prohibited concomitant medication to treat Crohn’s disease was used prior to Week 12 were considered as treatment failures. Full analysis set was used for these analyses. *p<0.05 versus placebo, **p<0.005 versus placebo, ***p<0.001 versus placebo. Figure 3A-D: Median CDAI scores over time (A), median CRP over time (B), median percent change in FCP from baseline (C), median percent change in IL‑22 from baseline (D). *p <0.001, Bonferroni adjusted p-value for 600 mg Antibody A versus placebo. **p <0.05, Bonferroni adjusted p-value for 600 mg Antibody A versus placebo. CDAI (Crohn’s Disease Activity Index); CRP (C-reactive protein); FCP (fecal calprotectin). Detailed Description

[0076] The p19 subunit of IL‑23 (also referred to herein as "IL‑23A", "IL‑23p19" and "p19 subunit") is a 189 amino acid polypeptide containing a21 aa leader sequence (Oppmannet al. Immunity 13:715 (2000), SEQ IDNO: 22). The biological activity of themolecule is only detectedwhen it is partneredwith the IL‑12p40 subunit to form IL‑23. IL‑23 is predominantly expressed by activated dendritic cells (DCs) and phagocytic cells. The receptor for IL‑23was found to be composed of the IL‑12Rβ1 subunit of IL‑12 receptor partnered with a unique subunit called IL‑23R (Parham et al. J. Immunol. 168:5699 6 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 (2002)). Expression of the receptor is detected primarily on memory T cells and NK cells. Thus, expression of this cytokine:receptor pair appears to be restricted to specific populations of immune cells.While it was first thought that IL‑12 and IL‑23 would share many functions, the data has shown the picture to be different. Whereas IL‑12 has a predominant role in the production of Th1 cells, IL‑23was found to be critically involved in the production andmaintenance of a recently recognizedThcell subset termedTh17 (Kiklyetal.Curr.Opin. Immunol. 18:670 (2006),Kasteleinet al.Ann.Rev. Immunol. 25:221 (2007)). These cells produce IL‑17A, IL‑17F, IL‑22 and other pro-inflammatory cytokines such as IL‑6 and TNF-α. Asdescribedbelow,animalmodel studieson the roleof theseTh17cells show their importanceasadriving force inchronic inflammation and autoimmunity.

[0077] In oneaspect, thepresent inventionprovidesmethods for the treament of IL‑23A relateddiseases. In oneaspect, the present invention providesmethods for treating a disease, for example an inflammatory disease, in particularmethods comprising administering an anti-IL‑23A antibody to a patient in certain amounts and / or at certain intervals. In one aspect, a method of the present invention is for the treament of Crohn’s Disease.

[0078] In one aspect, the present invention provides an anti-IL‑23A antibody for use in the treament of a disease, for example an inflammatory disease, for example Crohn’s Disease, by administration in certain amounts and / or at certain intervals as described herein.

[0079] In one aspect, the present invention provides for the use of an anti-IL‑23A antibody for the preparation of a medicament for the treatment of a disease, for example an inflammatory disease, for example Crohn’s Disease, by administration in certain amounts and / or at certain intervals as described herein.

[0080] In one embodiment, in the context of the present invention, the treatment of a patient comprises an induction phaseandamaintenancephase. In the inductionphase, oneormoredosesof ananti-IL‑23antibody, for example referred to herein as induction doses, are administered to the patient, for example by intravenous infusion. In the maintenance phase, a first dose of the anti-IL‑23 antibody, for example referred to herein as maintenance dose, is administered to the patient followed by at least one additional dose of the anti-IL‑23 antibody, for example referred to herein as maintenance dose. The maintenance doses are for example administered by subcutaneous injection. Examples of induction phases and maintenance phases are described herein.

[0081] In oneaspect, a certain therapeutic result is achievedby thepatient duringor at theendof the inductionphase, for example clinical remission. In one aspect, a patient achieves a CDAI score of less than 150 during or at the end of the induction phase. In one aspect, a patient achieves a PRO‑2 score equal to or less than 75 during or at the end of the inductionphase. Inoneaspect, apatientachievesaCDAIscoreof less than150andaPRO‑2scoreequal toor less than75 during or at the end of the induction phase.

[0082] Accordingly, in one embodiment, in amethodof the present invention, a patient is evaluated for clinical remission during or at the end of the induction phase.

[0083] In one aspect, if a patient is not responsive in the induction phase, the induction phase is repeated before the maintenance phase is initiated (also referred herein as re-induction phase). In one aspect, in a method of the present invention, apatient is reevaluated for clinical remissionduringorat theendof the re-inductionphase, for exampleasduring or after the induction phase.

[0084] Inoneaspect, a certain therapeutic result ismaintainedby thepatientduring themaintenancephase, for example clinical remission. In one aspect, a patient maintains a CDAI score of less than 150 during themaintenance phase. In one aspect, a patientmaintians aPRO‑2 score equal to or less than 75 during themaintenance phase. In one aspect, a patient maintains a CDAI score of less than 150 and a PRO‑2 score equal to or less than 75 during the maintenance phase.

[0085] Accordingly, in one embodiment, in amethodof the present invention, a patient is evaluated for clinical remission during the maintenance phase.

[0086] In one embodiment, the present invention provides amethod for treating an inflammatory disease, in one aspect for treatingCrohn’sDisease, comprising (a) administering to a patient a doseof ananti-IL‑23Aantibody atweek0, atweek 4 and at week 8 by intravenous infusion, wherein the doses of the anti-IL‑23A antibody comprise 200mg or 600mg of the antibody. In one embodiment, themethod further comprises (b) administering to the patient three doses of the anti-IL‑23A antibody, for example at week 14, at week 18 and at week 22 by intravenous infusion, wherein the doses of the anti-IL‑23A antibody comprise 600 mg of the antibody. In one embodiment, the method further comprises (c) administering to the 7 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 patient one or more doses of the anti-IL‑23A antibody at 8 weeks intervals by subcutaneous injection, for example four doses of the anti-IL‑23A antibody at 8 weeks intervals by subcutaneous injection, for example at week 26, at week 34, at week 42 and at week 50, wherein the one or more doses of the anti-IL‑23A antibody comprise 180 mg of the antibody.

[0087] In one embodiment, at week 12, a patient is evaluated for deep remission, for example defined as reaching clinical remission (CDAI score <150) and endoscopic remission (CDEIS ≤ 4). In one, aspect, for a patient with initial isolated ileitis endoscopic remission is defined by CDEIS ≤ 2.

[0088] In one embodiment, the present invention provides amethod for treating an inflammatory disease, in one aspect for treatingCrohn’sDisease, comprising (a) administering to a patient a doseof ananti-IL‑23Aantibody atweek0, atweek 4 and at week 8 by intravenous infusion, wherein the doses of the anti-IL‑23A antibody comprise 200mg or 600mg of the antibody. In one embodiment, themethod further comprises (b) administering to the patient one ormore doses of the anti- IL‑23A antibody at 8 weeks intervals by subcutaneous injection, for example four doses of the anti-IL‑23A antibody at 8 weeks intervals by subcutaneous injection, for example at week 26, at week 34, at week 42 and at week 50, wherein the one or more doses of the anti-IL‑23A antibody comprise 180 mg of the antibody.

[0089] In one embodiment, at week 12, a patient is evaluated for deep remission, for example defined as reaching clinical remission (CDAI score <150) and endoscopic remission (CDEIS ≤ 4). In one, aspect, for a patient with initial isolated ileitis endoscopic remission is defined by CDEIS ≤ 2.

[0090] In one embodiment, the present invention provides amethod for treating an inflammatory disease, in one aspect for treatingCrohn’sDisease, comprising administering to a patient 180mgof the anti-IL‑23Aantibody at 8weeks intervals by subcutaneous injection.

[0091] In one embodiment, the administration of an anti‑23A antibody according to the present invention is further described in the Examples hereinbelow or in Figure 1.

[0092] In one embodiment, the present invention provides amethod for treating an inflammatory disease, in one aspect for treating Crohn’s Disease, comprising administering to a patient an anti-IL‑23A antibody, said method comprising administering at least one induction doseof the anti-IL‑23Aantibody to the patient, wherein said induction dose comprises 200 to 1,200 mg of the anti-IL‑23A antibody, for example 450 to 1,200 mg of the anti-IL‑23A antibody. In one aspect, the inductiondose comprises200mg, 450mg, 600mg, 900mgor1,200mgof theanti-IL‑23Aantibody. In oneaspect, 1, 2 or 3 induction doses are administered to the patient. In one aspect, 2 or 3 inductions doses are administered, for example at 4 weeks intervals. In one aspect, the induction dose(s) is administered by intravenous infusion.

[0093] In one embodiment, the induction doses comprise 200mg of the anti-IL‑23A antibody and three inductions does are administered to the patient at 4 weeks intervals.

[0094] In one embodiment, the induction doses comprise 450mg of the anti-IL‑23A antibody and three inductions does are administered to the patient at 4 weeks intervals.

[0095] In one embodiment, the induction doses comprise 600mg of the anti-IL‑23A antibody and three inductions does are administered to the patient at 4 weeks intervals.

[0096] In one embodiment, the induction doses comprise 900mg of the anti-IL‑23A antibody and three inductions does are administered to the patient at 4 weeks intervals.

[0097] In one embodiment, the induction doses comprise 1,200 mg of the anti-IL‑23A antibody and three inductions does are administered to the patient at 4 weeks intervals.

[0098] In one aspect, if a patient is not responsive in the induction phase, the induction phase is repeated before the maintenance phase is initiated. For example, if the first induction phase included three induction doses, three additional induction doses are administered to the patient (re-induction phase), leading to a total of six induction doses. The additional inductiondose(s) comprise(s) forexampleanamountof theanti-IL‑23antibodydescribedherein.Theadditional induction doses are for example administered at an interval described herein.

[0099] In one ambodiment, the method further comprises administering a first maintenance dose of the anti-IL‑23A antibody to the patient after the last induction dose is administered; and administering at least one additionalmaintenance dose to the patient 4 to 12 weeks after said first maintenance dose is administered. In one aspect, the first maintenance dose is administered 2 to 8 weeks, for example 4 to 6 weeks, for example 2 weeks, 4 weeks, 6 weeks or 8 weeks, after the last induction dose is administered. In one aspect, the at least one additional maintenance dose is administered to the patient 4, 8 or 12 weeks after the first maintenance dose is administered.

[0100] In one embodiment, the first maintenance dose comprises 150 to 300 mg of the anti-IL‑23A antibody. In one aspect, the firstmaintenancedosecomprises150mg,225mgor300mgof theanti-IL‑23Aantibody. Inoneaspect, thefirst maintenance dose comprises 180 mg or 270 mg of the anti-IL‑23A antibody.

[0101] In oneaspect, the at least oneadditionalmaintenancedose comprises150 to 300mgof the anti-IL‑23Aantibody. In one aspect, the at least one additional maintenance dose comprises 150 mg, 225 mg or 300 mg of the anti-IL‑23A antibody. In one aspect, the at least one additional maintenance dose comprises 180 mg or 270 mg of the anti-IL‑23A antibody.

[0102] In one aspect, the first maintenance dose and the at least one additionalmaintenance dose comprise 150 to 300 mgof the anti-IL‑23Aantibody. In oneaspect, the firstmaintenancedoseand theat least oneadditionalmaintenancedose 8 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 comprise 150mg, 225mgor300mgof saidanti-IL‑23Aantibody. In oneaspect, the firstmaintenancedoseand theat least one additional maintenance dose comprise 180 mg or 270 mg of said anti-IL‑23A antibody.

[0103] In one aspect, the maintenance dose is administered by subcutaneous injection.

[0104] In one embodiment, the maintenance doses comprise 150mg of the anti-IL‑23A antibody and are administered to the patient at 4 weeks intervals.

[0105] In one embodiment, the maintenance doses comprise 150mg of the anti-IL‑23A antibody and are administered to the patient at 8 weeks intervals.

[0106] In one embodiment, the maintenance doses comprise 225mg of the anti-IL‑23A antibody and are administered to the patient at 8 weeks intervals.

[0107] In one embodiment, the maintenance doses comprise 225mg of the anti-IL‑23A antibody and are administered to the patient at 12 weeks intervals.

[0108] In one embodiment, the maintenance doses comprise 300mg of the anti-IL‑23A antibody and are administered to the patient at 8 weeks intervals.

[0109] In one embodiment, the maintenance doses comprise 300mg of the anti-IL‑23A antibody and are administered to the patient at 12 weeks intervals.

[0110] In one embodiment, the present invention provides amethod for treating an inflammatory disease, in one aspect for treating Crohn’s Disease, comprising administering to a patient 150 to 1,200 mg of an anti-IL‑23A antibody. In one aspect, the method comprises administering to a patient 200 to 1,200 mg of an anti-IL‑23A antibody, for example 450 to 1,200mgof an anti-IL‑23A antibody. In one aspect, themethod comprises administering to a patient 200mg, 450mg, 600 mg, 900mg or 1,200mg of an anti-IL‑23A antibody. In one aspect, themethod comprises administering to a patient 150 to 300mg of an anti-IL‑23A antibody. In one aspect, themethod comprises administering to a patient 150mg, 225mg or 300 mgof ananti-IL‑23Aantibody. In oneaspect, themethodcomprises administering to a patient 180mgor 270mgof ananti- IL‑23A antibody.

[0111] In one embodiment, the present invention further provides a method for inducing clinical remission of Crohn’s Disease in a patient, said method comprising administering to the patient at least one induction dose of an anti-IL‑23 antibody as described above or herein. In one embodiment, themethod further comprisingmaintaining clinical remission of Crohn’s disease, saidmethod further comprising administering a first maintenance dose of said anti-IL‑23A antibody to the patient after the last induction dose is administered and administering at least one additional maintenance dose to the patient as described above or herein.

[0112] In one embodiment, the present invention further provides a method for inducing clinical response to Crohn’s Disease in a patient, said method comprising administering to the patient at least one induction dose of an anti-IL‑23 antibodyasdescribedaboveorherein. Inoneembodiment, themethod further comprisingmaintainingclinical response to Crohn’sdisease, saidmethod further comprisingadministeringafirstmaintenancedoseof saidanti-IL‑23Aantibody to the patient after the last induction dose is administered and administering at least one additional maintenance dose to the patient as described above or herein.

[0113] Representative examples of doses and dose regimens according to the present invention are disclosed in Table A. Table A: doses and dose regimens Induction dose (mg) Frequency of induction doses Maintenance dose (mg) Frequency of maintenance doses 450 Every 4 weeks 150 Every 4 weeks 450 Every 4 weeks 150 Every 8 weeks 450 Every 4 weeks 180 Every 4 weeks 450 Every 4 weeks 180 Every 8 weeks 450 Every 4 weeks 225 Every 8 weeks 450 Every 4 weeks 225 Every 12 weeks 450 Every 4 weeks 270 Every 8 weeks 450 Every 4 weeks 270 Every 12 weeks 450 Every 4 weeks 300 Every 8 weeks 450 Every 4 weeks 300 Every 12 weeks 600 Every 4 weeks 150 Every 4 weeks 600 Every 4 weeks 150 Every 8 weeks 9 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Induction dose (mg) Frequency of induction doses Maintenance dose (mg) Frequency of maintenance doses 600 Every 4 weeks 180 Every 4 weeks 600 Every 4 weeks 180 Every 8 weeks 600 Every 4 weeks 225 Every 8 weeks 600 Every 4 weeks 225 Every 12 weeks 600 Every 4 weeks 270 Every 8 weeks 600 Every 4 weeks 270 Every 12 weeks 600 Every 4 weeks 300 Every 8 weeks 600 Every 4 weeks 300 Every 12 weeks 900 Every 4 weeks 150 Every 4 weeks 900 Every 4 weeks 150 Every 8 weeks 900 Every 4 weeks 180 Every 4 weeks 900 Every 4 weeks 180 Every 8 weeks 900 Every 4 weeks 225 Every 8 weeks 900 Every 4 weeks 225 Every 12 weeks 900 Every 4 weeks 270 Every 8 weeks 900 Every 4 weeks 270 Every 12 weeks 900 Every 4 weeks 300 Every 8 weeks 900 Every 4 weeks 300 Every 12 weeks 1,200 Every 4 weeks 150 Every 4 weeks 1,200 Every 4 weeks 150 Every 8 weeks 1,200 Every 4 weeks 180 Every 4 weeks 1,200 Every 4 weeks 180 Every 8 weeks 1,200 Every 4 weeks 225 Every 8 weeks 1,200 Every 4 weeks 225 Every 12 weeks 1,200 Every 4 weeks 270 Every 8 weeks 1,200 Every 4 weeks 270 Every 12 weeks 1,200 Every 4 weeks 300 Every 8 weeks 1,200 Every 4 weeks 300 Every 12 weeks

[0114] In oneaspect, 1, 2or 3 inductiondose(s) is / areadministered to thepatient in adose regimendescribed inTableA.

[0115] Additional representative examples of doses and dose regimens according to the present invention are described below. In these examples, the first maintenance dose is administered is administered to the patient 4 weeks after the last induction dose. It is also contemplated in the present invention to administer the first maintenance dose 2 weeks, 6 weeks or 8 weeks after the last induction dose.

[0116] For example, in the context of the present invention, inductions doses are administered to the patient at week 0, week 4 and week 8, followed by a first maintenance dose at week 12, a second maintenance dose at week 16, a third maintenancedoseatweek20and soonat dosing intervals of 4weeksbetween themaintenancedoses. In oneaspect, the inductions doses comprise 200 mg, 450 mg, 600 mg, 900 mg or 1,200 mg of the anti-IL‑23A antibody. In one aspect, the maintenance doses comprise 150 mg of the anti-IL‑23A antibody.

[0117] For example, in the context of the present invention, inductions doses are administered to the patient at week 0, week 4 and week 8, followed by a first maintenance dose at week 12, a second maintenance dose at week 20, a third maintenancedoseatweek28and soonat dosing intervals of 8weeksbetween themaintenancedoses. In oneaspect, the inductions doses comprise 200 mg, 450 mg, 600 mg, 900 mg or 1,200 mg of the anti-IL‑23A antibody. In one aspect, the maintenance doses comprise 150 mg, 225 mg or 300 mg of the anti-IL‑23A antibody. 10 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55

[0118] For example, in the context of the present invention, inductions doses are administered to the patient at week 0, week 4 and week 8, followed by a first maintenance dose at week 12, a second maintenance dose at week 24, a third maintenance dose at week 36 and so on at dosing intervals of 12 weeks between the maintenance doses. In one aspect, the inductionsdosescomprise200mg,450mg,600mg,900mgor1,200mgof theanti-IL‑23Aantibody. Inoneaspect, the maintenance doses comprise 225 mg or 300 mg of the anti-IL‑23A antibody.

[0119] In one embodiment, in a method of the present invention, a patient is evaluated for deep remission, for example defined as reaching clinical remission (CDAI score <150) and endoscopic remission (CDEIS ≤ 4). In one aspect, for a patient with initial isolated ileitis endoscopic remission is defined by CDEIS ≤ 2. In one aspect, the PRO response of the patient is assessed, for example defined by either a PRO‑2 score of <8 or a reduction from baseline of at least 8 points (PRO‑2: Patient reported outcome‑2).

[0120] In one embodiment, in a method of the present invention, a patient is evaluated for clinical remission, clinical response, endoscopic remission, endoscopic response or mucosal healing, for example as defined herein,

[0121] In one embodiment, an anti-IL‑23A antibody in any one of the methods above is disclosed herein. In one embodiment, an anti-IL‑23A antibody in any one of the methods above is Antibody A. In one embodiment, an anti-IL‑23A antibody in any one of the methods above is Antibody B. In one embodiment, an anti-IL‑23A antibody in any one of the methods above is AntibodyC. In one embodiment, an anti-IL‑23Aantibody in any oneof themethodsabove is AntibodyD.

[0122] In one aspect, in any one of the methods above, a pharmaceutical composition comprising an anti-IL‑23A antibody is administered to the patient. In one aspect, formulation 2 disclosed in Example 2 comprising an anti-IL‑23A antibody, for example Antibody A, Antibody B, Antibody C or Antibody D is administered to the patient. In one aspect, formulation 3 disclosed in Example 2 comprising an anti-IL‑23A antibody, for example Antibody A, Antibody B, AntibodyC orAntibodyD is administered to the patient. In oneaspect, formulation 1 disclosed inExample 2 comprising ananti-IL‑23A antibody, for example Antibody A, Antibody B, Antibody C or Antibody D is administered to the patient.

[0123] In one aspect, the anti-IL‑23A antibody is a humanized antibody. In one aspect, the anti-IL‑23A antibody is a monoclonal antibody. In one aspect, the anti-IL‑23A antibody is a full length antibody. In one aspect, the anti-IL‑23A antibody is a humanized monoclonal antibody, for example a full length humanized monoclonal antibody.

[0124] An antibody described herein recognizes specific "IL‑23A antigen epitope" or " IL‑23A epitope". As used herein these terms refer to a molecule (e.g., a peptide) or a fragment of a molecule capable of immunoreactivity with an anti- IL‑23A antibody and, for example, include an IL‑23A antigenic determinant recognized by any of the antibodies having a light chain / heavy chain sequence combination of SEQ ID NO:11 / 14, 11 / 15, 10 / 14 or 10 / 15.

[0125] The generalized structure of antibodies or immunoglobulin is well known to those of skill in the art. These molecules are heterotetrameric glycoproteins, typically of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains and are typically referred to as full length antibodies. Each light chain is covalently linked to a heavy chain by one disulfide bond to form a heterodimer, and the heterotramericmolecule is formed through a covalent disulfide linkage between the two identical heavy chains of the heterodimers. Although the light and heavy chains are linked together by one disulfide bond, the number of disulfide linkages between the two heavy chains varies by immunoglobulin isotype. Eachheavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at the amino-terminus a variable domain (VH), followed by three or four constant domains (CH1,CH2,CH3, and CH4), as well as a hinge region between CH1 and CH2. Each light chain has two domains, an amino-terminal variable domain (VL) and a carboxy-terminal constant domain (CL). The VL domain associates non-covalently with the VH domain, whereas the CL domain is commonly covalently linked to the CH1 domain via a disulfide bond. Particular amino acid residuesarebelieved to forman interfacebetween the light andheavy chain variable domains (Chothia et al., 1985, J.Mol. Biol. 186:651‑663). Variable domains are also referred herein as variable regions.

[0126] Certain domains within the variable domains differ extensively between different antibodies i.e., are "hypervari- able." These hypervariable domains contain residues that are directly involved in the binding and specificity of each particular antibody for its specific antigenic determinant. Hypervariability, both in the light chain and the heavy chain variable domains, is concentrated in three segments known as complementarity determining regions (CDRs) or hypervariable loops (HVLs). CDRs are defined by sequence comparison in Kabat et al., 1991, In: Sequences of Proteins of Immunological Interest, 5thEd.PublicHealthService,National InstitutesofHealth,Bethesda,Md.,whereasHVLs (also referred herein as CDRs) are structurally defined according to the three-dimensional structure of the variable domain, as described by Chothia and Lesk, 1987, J. Mol. Biol. 196: 901‑917. These two methods result in slightly different identifications of a CDR. As defined by Kabat, CDR-L1 is positioned at about residues 24‑34, CDR-L2, at about residues 50‑56, and CDR-L3, at about residues 89‑97 in the light chain variable domain; CDR-H1 is positioned at about residues 31‑35, CDR-H2 at about residues 50‑65, and CDR-H3 at about residues 95‑102 in the heavy chain variable domain. The exact residue numbers that encompass aparticularCDRwill vary depending on the sequence and size of theCDR.Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody. The CDR1, CDR2, CDR3 of the heavy and light chains therefore define the unique and functional properties specific for a given antibody.

[0127] The three CDRs within each of the heavy and light chains are separated by framework regions (FR), which 11 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 contain sequences that tend to be less variable. From the amino terminus to the carboxy terminus of the heavy and light chain variable domains, theFRsandCDRsarearranged in theorder: FR1,CDR1, FR2,CDR2, FR3,CDR3, andFR4. The largelyβ-sheet configurationof theFRsbrings theCDRswithin eachof the chains into closeproximity to eachother aswell as to the CDRs from the other chain. The resulting conformation contributes to the antigen binding site (see Kabat et al., 1991, NIH Publ. No. 91‑3242, Vol. I, pages 647‑669), although not all CDR residues are necessarily directly involved in antigen binding.

[0128] FRresiduesand Igconstant domainsarenot directly involved inantigenbinding, but contribute toantigenbinding and / or mediate antibody effector function. SomeFR residues are thought to have a significant effect on antigen binding in at least three ways: by noncovalently binding directly to an epitope, by interacting with one or more CDR residues, and by affecting the interface between the heavy and light chains. The constant domains are not directly involved in antigen binding but mediate various Ig effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC) and antibody dependent cellular phagocytosis (ADCP).

[0129] The light chains of vertebrate immunoglobulins are assigned to one of two clearly distinct classes, kappa (κ) and lambda (λ), based on the amino acid sequence of the constant domain. By comparison, the heavy chains of mammalian immunoglobulins are assigned to one of fivemajor classes, according to the sequence of the constant domains: IgA, IgD, IgE, IgG, and IgM. IgG and IgA are further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are calledα, δ, ε, γ, andµ, respectively. The subunit structures and three-dimensional configurations of the classes of native immunoglobulins are well known.

[0130] The terms, "antibody", "anti-IL‑23A antibody", "anti-IL‑23p19 antibody", "humanized anti-IL‑23A antibody", "humanized anti-IL‑23p19 antibody", "humanized anti-IL‑23A epitope antibody", humanized anti-IL‑2319 epitope anti- body", "variant humanized anti-IL‑23A epitope antibody" and "variant humanized anti-IL‑23p19 epitope antibody" specifically encompass monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, and antibody fragments such as variable domains and other portions of antibodies that exhibit a desired biological activity, e.g., IL‑23A binding. The term "monoclonal antibody" (mAb) refers to an antibody that is highly specific, being directed against a single antigenic determinant, an "epitope". Therefore, the modifier "monoclonal" is indicative of antibodies directed to the identical epitope and is not to be construed as requiring production of the antibody by any particular method. It should be understood that monoclonal antibodies can be made by any technique or methodology known in theart; includinge.g., thehybridomamethod (Kohler et al., 1975,Nature256:495), or recombinantDNAmethods known in the art (see, e.g., U.S. Pat. No. 4,816,567), ormethods of isolation ofmonoclonal recombinantly produced using phageantibody libraries, using techniquesdescribed inClacksonetal., 1991,Nature352: 624‑628,andMarksetal., 1991, J. Mol. Biol. 222: 581‑597.

[0131] The term "monomer" refers to a homogenous form of an antibody. For example, for a full-length antibody, monomer means a monomeric antibody having two identical heavy chains and two identical light chains.

[0132] Chimeric antibodies consist of the heavy and light chain variable regions of an antibody fromone species (e.g., a non-human mammal such as a mouse) and the heavy and light chain constant regions of another species (e.g., human) antibody and can be obtained by linking the DNA sequences encoding the variable regions of the antibody from the first species (e.g.,mouse) to theDNAsequences for theconstant regionsof theantibody from thesecond (e.g. human) species and transforming a host with an expression vector containing the linked sequences to allow it to produce a chimeric antibody. Alternatively, the chimeric antibody also could be one in which one or more regions or domains of the heavy and / or light chain is identical with, homologous to, or a variant of the corresponding sequence in a monoclonal antibody from another immunoglobulin class or isotype, or from a consensus or germline sequence. Chimeric antibodies can include fragments of such antibodies, provided that the antibody fragment exhibits the desired biological activity of its parent antibody, for example binding to the same epitope (see, e.g., U.S. Pat. No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81: 6851‑6855).

[0133] The terms, "antibody fragment", "anti-IL‑23A antibody fragment", "anti-IL‑23A epitope antibody fragment", "humanized anti-IL‑23A antibody fragment", "humanized anti-IL‑23A epitope antibody fragment", "variant humanized anti-IL‑23Aepitope antibody fragment" refer to a portion of a full length anti-IL‑23Aantibody, inwhich a variable region or a functional capability is retained, for example, specific IL‑23Aepitopebinding.Examplesof antibody fragments include, but are not limited to, a Fab, Fab’, F(ab’)2, Fd, Fv, scFv and scFv-Fc fragment.

[0134] Full length antibodies can be treated with enzymes such as papain or pepsin to generate useful antibody fragments. Papain digestion is used to produces two identical antigen-binding antibody fragments called "Fab" fragments, eachwith a single antigen-binding site, and a residual "Fc" fragment. TheFab fragment also contains the constant domain of the light chain and the CH1 domain of the heavy chain. Pepsin treatment yields a F(ab’)2 fragment that has two antigen- binding sites and is still capable of crosslinking antigen.

[0135] Fab’ fragments differ fromFab fragments by the presence of additional residues including one ormore cysteines from theantibodyhinge regionat theC-terminusof theCH1domain.F(ab’)2 antibody fragmentsarepairs of Fab’ fragments linked by cysteine residues in the hinge region. Other chemical couplings of antibody fragments are also known. 12 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55

[0136] "Fv" fragment contains a complete antigen-recognition and binding site consisting of a dimer of one heavy and one light chain variable domain in tight, non-covalent association. In this configuration, the three CDRs of each variable domain interact to define an antigen-biding site on the surface of the VH‑VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody.

[0137] A "single-chain Fv" or "scFv" antibody fragment is a single chain Fv variant comprising the VH and VL domains of anantibodywhere thedomainsarepresent ina single polypeptide chain. Thesingle chainFv is capableof recognizingand binding antigen. The scFv polypeptidemay optionally also contain a polypeptide linker positioned between the VH and VL domains in order to facilitate formation of a desired three-dimensional structure for antigen binding by the scFv (see, e.g., Pluckthun, 1994, In The Pharmacology of monoclonal Antibodies, Vol. 113, Rosenburg andMoore eds., Springer-Verlag, New York, pp. 269‑315).

[0138] A "humanized antibody" or a "humanized antibody fragment" is a specific type of chimeric antibody which includes an immunoglobulin amino acid sequence variant, or fragment thereof, which is capable of binding to a predetermined antigen and which, comprises one or more FRs having substantially the amino acid sequence of a human immunoglobulin and one or more CDRs having substantially the amino acid sequence of a non-human immunoglobulin. This non-human amino acid sequence often referred to as an "import" sequence is typically taken from an "import" antibody domain, particularly a variable domain. In general, a humanizedantibody includes at least theCDRsorHVLsof a non-human antibody, inserted between the FRs of a human heavy or light chain variable domain. The present invention describes specific humanized anti-IL‑23Aantibodieswhich containCDRs derived from themousemonoclonal antibodies or humanizedCDRsshown inTables1and2 insertedbetween theFRsof humangermlinesequenceheavyand light chain variable domains. It will be understood that certainmouse FR residuesmay be important to the function of the humanized antibodies and therefore certain of the human germline sequence heavy and light chain variable domains residues are modified to be the same as those of the corresponding mouse sequence.

[0139] In another aspect, a humanizedanti-IL‑23Aantibody comprises substantially all of at least one, and typically two, variable domains (such as contained, for example, in Fab, Fab’, F(ab’)2, Fabc, and Fv fragments) in which all, or substantially all, of theCDRscorrespond to thoseof anon-human immunoglobulin, and specifically herein, all of theCDRs aremouse or humanized sequences as detailed in Tables 1 and 2 herein below and all, or substantially all, of the FRs are thoseof ahuman immunoglobulin consensusor germlinesequence. Inanother aspect, ahumanizedanti‑ IL‑23Aantibody also includes at least a portion of an immunoglobulin Fc region, typically that of a human immunoglobulin. Ordinarily, the antibody will contain both the light chain as well as at least the variable domain of a heavy chain. The antibody also may include one or more of the CH1, hinge, CH2, CH3, and / or CH4 regions of the heavy chain, as appropriate.

[0140] A humanized anti-IL‑23A antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. For example, the constant domain can be a complement fixing constant domain where it is desired that the humanized antibody exhibit cytotoxic activity, and the isotype is typically IgG1.Wheresuchcytotoxicactivity is notdesirable, theconstant domainmaybeofanother isotype,e.g., IgG2. An alternative humanized anti-IL‑23A antibody can comprise sequences frommore than one immunoglobulin class or isotype, and selecting particular constant domains to optimize desired effector functions iswithin the ordinary skill in the art. In specific embodiments, the present invention provides antibodies that are IgG1 antibodies andmore particularly, are IgG1 antibodies in which there is a knock-out of effector functions.

[0141] TheFRsandCDRs, orHVLs, of a humanized anti-IL‑23Aantibody neednot correspondprecisely to the parental sequences.Forexample, oneormore residues in the importCDR,orHVL,or theconsensusorgermlineFRsequencemay be altered (e.g., mutagenized) by substitution, insertion or deletion such that the resulting amino acid residue is no longer identical to the original residue in the corresponding position in either parental sequence but the antibody nevertheless retains the function of binding to IL‑23A. Such alteration typically will not be extensive andwill be conservative alterations. Usually, at least 75% of the humanized antibody residues will correspond to those of the parental consensus or germline FR and import CDR sequences, more often at least 90%, and most frequently greater than 95%, or greater than 98% or greater than 99%.

[0142] Immunoglobulin residues that affect the interface between heavy and light chain variable regions ("the VL‑VH interface") are those that affect the proximity or orientation of the two chains with respect to one another. Certain residues thatmaybe involved in interchain interactions includeVL residues34, 36, 38, 44, 46, 87, 89, 91, 96, and98andVH residues 35,37,39,45,47,91,93,95,100, and103 (utilizing thenumberingsystemset forth inKabat etal., SequencesofProteinsof Immunological Interest (National Institutes of Health, Bethesda, Md., 1987)). U.S. Pat. No. 6,407,213 also discusses that residues such as VL residues 43 and 85, and VH residues 43 and 60 also may be involved in this interaction. While these residues are indicated for human IgG only, they are applicable across species. Important antibody residues that are reasonably expected to be involved in interchain interactions are selected for substitution into the consensus sequence.

[0143] The terms "consensus sequence" and "consensus antibody" refer to an amino acid sequence which comprises themost frequently occurring aminoacid residueat each location in all immunoglobulins of any particular class, isotype, or subunit structure, e.g., a human immunoglobulin variable domain. The consensus sequence may be based on immu- noglobulins of a particular species or of many species. A "consensus" sequence, structure, or antibody is understood to 13 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 encompass a consensus human sequence as described in certain embodiments, and to refer to an amino acid sequence which comprises themost frequently occurring amino acid residues at each location in all human immunoglobulins of any particular class, isotype, or subunit structure. Thus, the consensus sequence contains an amino acid sequence having at eachpositionanaminoacid that is present inoneormoreknown immunoglobulins, butwhichmaynot exactly duplicate the entire amino acid sequence of any single immunoglobulin. The variable region consensus sequence is not obtained from any naturally produced antibody or immunoglobulin. Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., and variants thereof. The FRs of heavy and light chain consensus sequences, and variants thereof, provide useful sequences for the preparation of humanized anti- IL‑23p19 antibodies. See, for example, U.S. Pat. Nos. 6,037,454 and 6,054,297.

[0144] Humangermline sequencesare foundnaturally in thehumanpopulation. Acombination of thosegermline genes generatesantibodydiversity.Germlineantibodysequences for the light chainof theantibodycome fromconservedhuman germline kappa or lambda v-genes and j-genes. Similarly the heavy chain sequences come from germline v‑, d‑ and j- genes (LeFranc, M-P, and LeFranc, G, "The Immunoglobulin Facts Book" Academic Press, 2001).

[0145] As used herein, "variant", "anti‑ IL‑23A variant", "humanized anti‑ IL‑23A variant", or "variant humanized anti‑ IL‑23A" each refers to a humanized anti-IL‑23A antibody having at least a light chain variablemurine CDR from any of the sequences as shown in Table 1 or a heavy chainmurine CDR sequence derived from themurinemonoclonal antibody as shown in Table 2. Variants include those having one or more amino acid changes in one or both light chain or heavy chain variable domains, provided that the amino acid change does not substantially impair binding of the antibody to IL‑23A. Exemplary antibodies produced herein include those designated as Antibody A, Antibody B, Antibody C and Antibody D, and thevarious light chainsandheavy chainsof thesameare shown inSEQ IDNos:18and21, andSEQ IDNos:19and20, respectively.

[0146] An "isolated" antibody is one that has been identified and separated and / or recovered from a component of its natural environment. Contaminant components of the antibody’s natural environment are those materials that may interfere with diagnostic or therapeutic uses of the antibody, and can be enzymes, hormones, or other proteinaceous or nonproteinaceous solutes. In one aspect, the antibody will be purified to at least greater than 95% isolation by weight of antibody.

[0147] An isolated antibody includes an antibody in situ within recombinant cells in which it is produced, since at least one component of the antibody’s natural environment will not be present. Ordinarily however, an isolated antibody will be prepared by at least one purification step in which the recombinant cellular material is removed.

[0148] The term "antibody performance" refers to factors that contribute to antibody recognition of antigen or the effectiveness of an antibody in vivo. Changes in the amino acid sequence of an antibody can affect antibody properties such as folding, and can influence physical factors such as initial rate of antibody binding to antigen (ka), dissociation constant of the antibody from antigen (kd), affinity constant of the antibody for the antigen (Kd), conformation of the antibody, protein stability, and half life of the antibody.

[0149] The term "epitope tagged" when used herein, refers to an anti-IL‑23A antibody fused to an "epitope tag". An "epitope tag" is apolypeptidehavinga sufficient numberof aminoacids toprovideanepitope for antibodyproduction, yet is designed such that it does not interfere with the desired activity of the anti-IL‑23A antibody. The epitope tag is usually sufficiently unique such that an antibody raised against the epitope tag does not substantially cross-react with other epitopes. Suitable tag polypeptides generally contain at least 6 amino acid residues and usually contain about 8 to 50 amino acid residues, or about 9 to 30 residues. Examples of epitope tags and the antibody that binds the epitope include the fluHA tag polypeptide and its antibody 12CA5 (Field et al., 1988Mol. Cell. Biol. 8: 2159‑2165; c-myc tag and 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies thereto (Evan et al., 1985, Mol. Cell. Biol. 5(12):3610‑3616; and Herpes simplex virus glycoprotein D (gD) tag and its antibody (Paborsky et al. 1990, Protein Engineering 3(6): 547‑553). In certain embodi- ments, the epitope tag is a "salvage receptor binding epitope". As usedherein, the term "salvage receptor binding epitope" refers to anepitopeof theFc regionof an IgGmolecule (suchas IgG1, IgG2, IgG3, or IgG4) that is responsible for increasing the in vivo serum half-life of the IgG molecule.

[0150] For diagnostic as well as therapeutic monitoring purposes, the antibodies of the invention also may be conjugated to a label, either a label alone or a label and an additional second agent (prodrug, chemotherapeutic agent and the like). A label, as distinguished from the other second agents refers to an agent that is a detectable compound or composition and it may be conjugated directly or indirectly to a antibody of the present invention. The label may itself be detectable (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition that is detectable. Labeled anti-IL‑23A antibody can be prepared and used in various applications including in vitro and in vivo diagnostics.

[0151] In various aspects of the present invention one or more domains of the antibodies will be recombinantly expressed. Such recombinant expression may employ one or more control sequences, i.e., polynucleotide sequences necessary for expression of an operably linked coding sequence in a particular host organism. The control sequences suitable for use in prokaryotic cells include, for example, promoter, operator, and ribosome binding site sequences. Eukaryotic control sequences include, but are not limited to, promoters, polyadenylation signals, and enhancers. These 14 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 control sequences canbe utilized for expression andproduction of anti-IL‑23Aantibody in prokaryotic and eukaryotic host cells.

[0152] A nucleic acid sequence is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence.Forexample, anucleicacidpresequenceor secretory leader isoperably linked toanucleicacidencodinga polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked toa coding sequence if it is positionedsoas to facilitate translation.Generally, "operably linked"means that theDNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers are optionally contiguous. Linking can be accomplished by ligation at convenient restriction sites. If such sites do not exist, synthetic oligonucleotide adaptors or linkers can be used.

[0153] As used herein, the expressions "cell", "cell line", and "cell culture" are used interchangeably and all such designations include the progeny thereof. Thus, "transformants" and "transformed cells" include the primary subject cell and cultures derived therefrom without regard for the number of transfers.

[0154] The term "mammal" for purposes of treatment refers to any animal classified as a mammal, including humans, domesticatedand farmanimals, andzoo, sports, or pet animals, suchasdogs, horses, cats, cows, and the like.Preferably, the mammal is human.

[0155] A "disorder", as used herein, is any condition that would benefit from treatment with an anti-IL‑23A antibody described herein. This includes chronic and acute disorders or diseases including those pathological conditions that predispose the mammal to the disorder in question.

[0156] As used herein, the term "IL‑23-associated disorder" or "IL‑23-associated disease" refers to a condition in which IL‑23 activity contributes to the disease and typically where IL‑23 is abnormally expressed. An IL‑23-associated disorder includes diseases and disorders of the immune system, such as autoimmune disorders and inflammatory diseases. Such conditions include psoriasis, inflammatory bowel disease, for example ulcerative colitis or Crohn’s disease, and spondyloarthritis, for example ankylosing spondylitis, non-radiographic axial spondyloarthritis, peripheral spondyloar- thritis or psoriatic arthritis.

[0157] The term "intravenous infusion" refers to introduction of an agent into the vein of an animal or human patient over a period of time greater than approximately 15 minutes, generally between approximately 30 to 90 minutes.

[0158] The term "intravenousbolus"or "intravenouspush" refers todrugadministration intoaveinofananimal orhuman such that the body receives the drug in approximately 15 minutes or less, generally 5 minutes or less.

[0159] The term "subcutaneous administration" refers to introduction of an agent under the skin of an animal or human patient, preferable within a pocket between the skin and underlying tissue, by relatively slow, sustained delivery from a drug receptacle. Pinching or drawing the skin up and away from underlying tissue may create the pocket.

[0160] The term "subcutaneous infusion" refers to introduction of a drug under the skin of an animal or human patient, preferably within a pocket between the skin and underlying tissue, by relatively slow, sustained delivery from a drug receptacle for a period of time including, but not limited to, 30minutes or less, or 90minutes or less.Optionally, the infusion may be made by subcutaneous implantation of a drug delivery pump implanted under the skin of the animal or human patient,wherein thepumpdeliversapredeterminedamountofdrug forapredeterminedperiodof time, suchas30minutes, 90 minutes, or a time period spanning the length of the treatment regimen.

[0161] The term "subcutaneous bolus" refers to drug administration beneath the skin of an animal or human patient, wherebolusdrugdelivery is less thanapproximately 15minutes; in another aspect, less than5minutes, and in still another aspect, less than60seconds. In yetevenanotheraspect, administration iswithinapocket between theskinandunderlying tissue, where the pocket may be created by pinching or drawing the skin up and away from underlying tissue.

[0162] The term "therapeutically effective amount" is used to refer to an amount of an active agent that relieves or ameliorates one or more of the symptoms of the disorder being treated. In another aspect, the therapeutically effective amount refers to a target serum concentration that has been shown to be effective in, for example, slowing disease progression. Efficacy can be measured in conventional ways, depending on the condition to be treated.

[0163] The terms "treatment" and "therapy" and the like, as used herein, are meant to include therapeutic as well as prophylactic, or suppressive measures for a disease or disorder leading to any clinically desirable or beneficial effect, including but not limited to alleviation or relief of one ormore symptoms, regression, slowing or cessation of progression of the disease or disorder. Thus, for example, the term treatment includes the administration of an agent prior to or following the onset of a symptom of a disease or disorder thereby preventing or removing one or more signs of the disease or disorder. As another example, the term includes the administration of an agent after clinicalmanifestation of the disease to combat the symptoms of the disease. Further, administration of an agent after onset and after clinical symptoms have developedwhereadministrationaffects clinical parametersof thediseaseor disorder, suchas thedegreeof tissue injuryor the amount or extent of metastasis, whether or not the treatment leads to amelioration of the disease, comprises "treatment" or "therapy" as used herein. Moreover, as long as the compositions of the invention either alone or in combination with another therapeutic agent alleviate or ameliorate at least one symptom of a disorder being treated as compared to that symptom in the absence of use of the anti-IL‑23A antibody composition, the result should be considered 15 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 an effective treatment of the underlying disorder regardless of whether all the symptoms of the disorder are alleviated or not.

[0164] The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, administration, contraindications and / or warnings concerning the use of such therapeutic products. Antibodies

[0165] The CDRs of selected antibodies used in the context of the present invention are shown in Table 1 and 2. The variable regions of selected antibodies used in the context of the present invention are shown in Table 3 and 4. Table 1: LIGHT CHAIN CDR sequences L-CDR1 L-CDR2 L-CDR3 6B8 KASRDVAIAVA (SEQ ID NO:1) WASTRHT (SEQ ID NO:2) HQYSSYPFT (SEQ ID NO:3) Table 2: HEAVY CHAIN CDR sequences H-CDR1 H-CDR2 H-CDR3 6B8 GNTFTDOTIH (SEQ ID NO:4) YIYPRDDSPKYNENFKG (SEQ ID NO:5) PDRSGYAWFIY (SEQ ID NO:6) Hu_6B8‑2 GYTFTDOTIH (SEQ ID NO:7) YIYPRDDSPKYNENFKG (SEQ ID NO:5) PDRSGYAWFIY (SEQ ID NO:6) Hu_6B8‑5 GFTFTDOTIH (SEQ ID NO:8) YIYPRDDSPKYNENFKG (SEQ ID NO:5) PDRSGYAWFIY (SEQ ID NO:6) Hu_6B8‑36 / 65 GGTFTDOTIH (SEQ ID NO:9) YIYPRDDSPKYNENFKG (SEQ ID NO:5) PDRSGYAWFIY (SEQ ID NO:6) Table 3: Humanized 6B8-VK Sequences 6B8CVK‑65 6B8CVK‑66 6B8CVK‑67 6B8CVK‑78 16 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 Table 4: Humanized 6B8-VH Sequence 6B8CVH‑02 6B8CVH‑05 6B8CVH‑36 6B8CVH‑65

[0166] Selected combination of humanized light chain and heavy chain variable regions derived from mouse antibody 6B8 resulted in Antibodies A, B, C and D: Antibody A: 6B8-IgG1KO‑2 with IgK‑66 (heavy chain variable region 6B8CVH‑02 and light chain variable region 6B8CVK‑66); Antibody B: 6B8-lgG1 KO‑5 with IgK‑66 (heavy chain variable region 6B8CVH‑05 and light chain variable region 6B8CVK‑66); Antibody C: 6B8-lgG1 KO‑2 with IgK‑65 (heavy chain variable region 6B8CVH‑02 and light chain variable region 6B8CVK‑65); Antibody D: 6B8-lgG1 KO‑5 with IgK‑65 (heavy chain variable region 6B8CVH‑05 and light chain variable region 6B8CVK‑65).

[0167] Antibodies A, B, C and D have the heavy and light chain sequences shown in Table 5. Table 5: Heavy and Light Chain DNA and Amino Acid Sequences for Antibodies A, B, C, and D Antibody A IgK light Chain #66 17 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) IgG1 KO Heavy Chain #2 Antibody B IgK light Chain #66 (SEQ ID NO:18) IgG1KO Heavy Chain #5 Antibody C IgK light Chain #65 IgG1KO Heavy Chain #2 (SEQ ID NO:19) 18 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Antibody D IgK light Chain #65 (SEQ ID NO:21) IgG1KO Heavy Chain (SEQ ID NO:20) #5

[0168] Light chains and heavy chain variable regions of Antibodies A, B, C, and D are underlined in Table 5 above.

[0169] In one embodiment, an anti-IL‑23Aantibody comprises the light chain sequence of SEQ IDNO:18 and the heavy chainsequenceofSEQ IDNO:19. Inoneembodiment, ananti-IL‑23Aantibodycomprises the light chainsequenceofSEQ IDNO:18and theheavychainsequenceofSEQIDNO:20. Inoneembodiment, ananti-IL‑23Aantibodycomprises the light chain sequence of SEQ ID NO:21 and the heavy chain sequence of SEQ ID NO:19. In one embodiment, an anti-IL‑23A antibody comprises the light chain sequence of SEQ ID NO:21 and the heavy chain sequence of SEQ ID NO:20.

[0170] In one embodiment, an anti-IL‑23Aantibody consists of the light chain sequence ofSEQ IDNO:18 and theheavy chainsequenceofSEQIDNO:19. Inoneembodiment, ananti-IL‑23Aantibodyconsistsof the light chain sequenceofSEQ ID NO:18 and the heavy chain sequence of SEQ ID NO:20. In one embodiment, an anti-IL‑23A antibody consists of the light chain sequence of SEQ ID NO:21 and the heavy chain sequence of SEQ ID NO:19. In one embodiment, an anti- IL‑23A antibody consists of the light chain sequence of SEQ ID NO:21 and the heavy chain sequence of SEQ ID NO:20.

[0171] In a further embodiment, an anti-IL‑23A antibody binds to human IL‑23A at an epitope consisting of amino acid residues 108 to 126 and amino acid residues 137 to 151 of SEQ ID NO: 22.

[0172] In a further embodiment, an anti-IL‑23A antibody competitively binds to human IL‑23A with an antibody of the present invention, for example Antibody A, Antibody B, Antibody C or Antibody D described herein. The ability of an antibody to competitively bind to IL‑23A can be measured using competitive binding assays known in the art.

[0173] In some embodiments, an anti-IL‑23A antibody comprises light chain variable region sequences having the amino acid sequence set forth in of SEQ ID NO:10, 11, 12 or 13.

[0174] In some embodiments, an anti-IL‑23A antibody comprises heavy chain variable region sequences having the amino acid sequence set forth in of SEQ IDNO:14, 15, 16 or 17 (see Tables 3 and 4 above). TheCDR sequences of these antibodies are shown in Tables 1 and 2. For example, anti-IL‑23A antibodies are monoclonal antibodies with the combinations of light chain variable and heavy chain variable regions of SEQ ID NO: 11 / 14, 11 / 15, 10 / 14 or 10 / 15. Such variable regions can be combined with human constant regions. Polynucleotides, Vectors, Host Cells, and Recombinant Methods

[0175] Other embodiments encompass isolated polynucleotides that comprise a sequence encoding an anti-IL‑23A antibody, vectors, and host cells comprising the polynucleotides, and recombinant techniques for production of the humanized antibody. The isolated polynucleotides can encode any desired form of the anti-IL‑23A antibody including, for example, full length monoclonal antibodies, Fab, Fab’, F(ab’)2, and Fv fragments.

[0176] The polynucleotide(s) that comprise a sequence encoding an anti-IL‑23A antibody can be fused to one or more regulatory or control sequence, as known in the art, and can be contained in suitable expression vectors or host cell as known in the art. Each of the polynucleotide molecules encoding the heavy or light chain variable domains can be independently fused to a polynucleotide sequence encoding a constant domain, such as a human constant domain, enabling the production of intact antibodies. Alternatively, polynucleotides, or portions thereof, can be fused together, providing a template for production of a single chain antibody.

[0177] For recombinant production, a polynucleotide encoding the antibody is inserted into a replicable vector for cloning (amplification of the DNA) or for expression. Many suitable vectors for expressing the recombinant antibody are available. The vector components generally include, but are not limited to, one ormore of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence.

[0178] The anti-IL‑23A antibodies can also be produced as fusion polypeptides, in which the antibody is fused with a heterologous polypeptide, such as a signal sequence or other polypeptide having a specific cleavage site at the amino terminus of the mature protein or polypeptide. The heterologous signal sequence selected is typically one that is recognized and processed (i.e., cleaved by a signal peptidase) by the host cell. For prokaryotic host cells that do not recognize and process the anti-IL‑23Aantibody signal sequence, the signal sequence can be substituted by a prokaryotic signal sequence. The signal sequence can be, for example, alkaline phosphatase, penicillinase, lipoprotein, heat-stable enterotoxin II leaders, and the like. For yeast secretion, the native signal sequence can be substituted, for example, with a leader sequence obtained from yeast invertase alpha-factor (including Saccharomyces and Kluyveromyces α-factor leaders), acid phosphatase, C. albicans glucoamylase, or the signal described in WO90 / 13646. In mammalian cells, 19 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 mammalian signal sequences as well as viral secretory leaders, for example, the herpes simplex gD signal, can be used. The DNA for such precursor region is ligated in reading frame to DNA encoding the anti-IL‑23A antibody.

[0179] Expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Generally, in cloning vectors this sequence is one that enables the vector to replicate independently of the host chromosomal DNA, and includes origins of replication or autonomously replicating sequences. Such sequences are well known for a variety of bacteria, yeast, and viruses. The origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2-υ. plasmid origin is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV, and BPV) are useful for cloning vectors in mammalian cells. Generally, the origin of replication component is not needed for mammalian expression vectors (the SV40 origin may typically be used only because it contains the early promoter).

[0180] Expression and cloning vectorsmay contain a gene that encodes a selectablemarker to facilitate identification of expression. Typical selectable marker genes encode proteins that confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, or alternatively, are complement auxotrophic deficiencies, or in other alternatives supply specific nutrients that are not present in complex media, e.g., the gene encoding D-alanine racemase for Bacilli.

[0181] Oneexample of a selection schemeutilizes adrug toarrest growthof a host cell. Those cells that are successfully transformed with a heterologous gene produce a protein conferring drug resistance and thus survive the selection regimen. Examples of such dominant selection use the drugs neomycin, mycophenolic acid, and hygromycin. Common selectablemarkers formammalian cells are those that enable the identification of cells competent to take up anucleic acid encoding an anti-IL‑23A antibody, such as DHFR (dihydrofolate reductase), thymidine kinase, metallothionein-I and ‑II (such as primatemetallothionein genes), adenosine deaminase, ornithine decarboxylase, and the like. Cells transformed with the DHFR selection gene are first identified by culturing all of the transformants in a culture medium that contains methotrexate (Mtx), a competitive antagonist of DHFR. An appropriate host cell when wild-type DHFR is employed is the Chinese hamster ovary (CHO) cell line deficient in DHFR activity (e.g., DG44).

[0182] Alternatively, host cells (particularly wild-type hosts that contain endogenous DHFR) transformed or co- transformed with DNA sequences encoding an anti-IL‑23A antibody, wild-type DHFR protein, and another selectable marker such as aminoglycoside 3’-phosphotransferase (APH), can be selected by cell growth in medium containing a selection agent for the selectablemarker suchasanaminoglycosidic antibiotic, e.g., kanamycin, neomycin, orG418.See, e.g., U.S. Pat. No. 4,965,199.

[0183] Where the recombinant production is performed in a yeast cell as a host cell, the TRP1 gene present in the yeast plasmid YRp7 (Stinchcomb et al., 1979, Nature 282: 39) can be used as a selectable marker. The TRP1 gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4‑1 (Jones, 1977, Genetics 85:12). The presence of the trp1 lesion in the yeast host cell genome then provides an effectiveenvironment for detecting transformationbygrowth in theabsenceof tryptophan.Similarly, Leu2p-deficient yeast strains such as ATCC 20,622 and 38,626 are complemented by known plasmids bearing the LEU2 gene.

[0184] In addition, vectors derived from the 1.6 µm circular plasmid pKD1 can be used for transformation of Kluyver- omyces yeasts. Alternatively, an expression system for large-scale production of recombinant calf chymosinwas reported for K. lactis (Van den Berg, 1990, Bio / Technology 8:135). Stable multi-copy expression vectors for secretion of mature recombinant human serum albumin by industrial strains of Kluyveromyces have also been disclosed (Fleer et al., 1991, Bio / Technology 9:968‑975).

[0185] Expression and cloning vectors usually contain a promoter that is recognized by the host organism and is operably linked to the nucleic acid molecule encoding an anti-IL‑23p19 antibody or polypeptide chain thereof. Promoters suitable for use with prokaryotic hosts include phoA promoter, β-lactamase and lactose promoter systems, alkaline phosphatase, tryptophan (trp) promoter system, and hybrid promoters such as the tac promoter. Other known bacterial promoters are also suitable. Promoters for use in bacterial systems also will contain a Shine-Dalgarno (S.D.) sequence operably linked to the DNA encoding the anti-IL‑23A antibody.

[0186] Many eukaryotic promoter sequences are known. Virtually all eukaryotic genes have an AT-rich region located approximately 25 to 30 bases upstream from the site where transcription is initiated. Another sequence found 70 to 80 basesupstream from the start of transcription ofmanygenes is aCNCAATregionwhereNmaybeanynucleotide.At the3’ endofmosteukaryotic genes isanAATAAAsequence thatmaybe thesignal for additionof thepolyA tail to the3’ endof the coding sequence. All of these sequences are suitably inserted into eukaryotic expression vectors.

[0187] Examples of suitable promoting sequences for use with yeast hosts include the promoters for 3-phosphogly- cerate kinase or other glycolytic enzymes, such as enolase, glyceraldehyde‑3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose‑6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase.

[0188] Inducible promoters have the additional advantage of transcription controlled by growth conditions. These include yeast promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, derivative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde‑3-phosphate dehydrogenase, and enzymes 20 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 responsible for maltose and galactose utilization. Suitable vectors and promoters for use in yeast expression are further described in EP 73,657. Yeast enhancers also are advantageously used with yeast promoters.

[0189] Anti-IL‑23A antibody transcription from vectors inmammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40), from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, or from heat-shock promoters, provided such promoters are compatible with the host cell systems.

[0190] The early and late promoters of the SV40 virus are conveniently obtained as an SV40 restriction fragment that also contains the SV40 viral origin of replication. The immediate early promoter of the human cytomegalovirus is conveniently obtained as a Hindlll E restriction fragment. A system for expressing DNA in mammalian hosts using the bovinepapillomavirus asa vector is disclosed inU.S.Pat.No. 4,419,446.Amodification of this system is described inU.S. Pat. No. 4,601,978. See also Reyes et al., 1982, Nature 297:598‑601, disclosing expression of human p-interferon cDNA inmousecells under thecontrol of a thymidinekinasepromoter fromherpessimplex virus.Alternatively, theRoussarcoma virus long terminal repeat can be used as the promoter.

[0191] Another useful element that can be used in a recombinant expression vector is an enhancer sequence, which is used to increase the transcription of a DNA encoding an anti-IL‑23A antibody by higher eukaryotes. Many enhancer sequences are now known frommammalian genes (e.g., globin, elastase, albumin, α-fetoprotein, and insulin). Typically, however, an enhancer from a eukaryotic cell virus is used. Examples include the SV40 enhancer on the late side of the replicationorigin (bp100‑270), thecytomegalovirusearly promoter enhancer, thepolyomaenhancer on the late sideof the replication origin, and adenovirus enhancers. See also Yaniv, 1982, Nature 297:17‑18 for a description of enhancing elements for activationofeukaryoticpromoters. Theenhancermaybespliced into thevectorat aposition5’ or 3’ to theanti- IL‑23A antibody-encoding sequence, but is preferably located at a site 5’ from the promoter.

[0192] Expression vectors used in eukaryotic host cells (yeast, fungi, insect, plant, animal, human, or nucleated cells from other multicellular organisms) can also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5’ and, occasionally 3’, untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of themRNAencoding anti-IL‑23Aantibody.One useful transcription termination component is the bovine growth hormone polyadenylation region. See WO94 / 11026 and the expression vector disclosed therein. In someembodiments, humanized anti-IL‑23p19 antibodies can be expressed using theCHEFsystem. (See, e.g., U.S. Pat. No. 5,888,809; the disclosure of which is incorporated by reference herein.)

[0193] Suitable host cells for cloning or expressing the DNA in the vectors herein are the prokaryote, yeast, or higher eukaryote cells described above. Suitable prokaryotes for this purpose include eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacilli such as B. subtilis and B. licheniformis (e.g., B. licheniformis 41 P disclosed in DD 266,710 published Apr. 12, 1989), Pseudomonas such as P. aeruginosa, and Streptomyces. One preferred E. coli cloning host is E. coli 294 (ATCC 31,446), although other strains such as E. coli B, E. coli X1776 (ATCC 31,537), and E. coli W3110 (ATCC 27,325) are suitable. These examples are illustrative rather than limiting.

[0194] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for anti-IL‑23A antibody-encoding vectors. Saccharomyces cerevisiae, or common baker’s yeast, is the most commonly used among lower eukaryotic host microorganisms. However, a number of other genera, species, and strains are commonly available and useful herein, such as Schizosaccharomyces pombe; Kluyveromyces hosts such as, e.g., K. lactis, K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906), K. thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichia pastors (EP 183,070); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa; Schwanniomyces such as Schwannio- myces occidentalis; and filamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium, and Aspergillus hosts such as A. nidulans and A. niger.

[0195] Suitable host cells for the expression of glycosylated anti-IL‑23A antibody are derived from multicellular organisms. Examples of invertebrate cells include plant and insect cells, including, e.g., numerous baculoviral strains andvariantsandcorrespondingpermissive insecthost cells fromhosts suchasSpodoptera frugiperda (caterpillar),Aedes aegypti (mosquito), Aedes albopictus (mosquito), Drosophila melanogaster (fruitfly), and Bombyx mori (silk worm). A variety of viral strains for transfection are publicly available, e.g., the L‑1 variant of Autographa californica NPV and the Bm‑5 strain of Bombyx mori NPV, and such viruses may be used, particularly for transfection of Spodoptera frugiperda cells.

[0196] Plant cell cultures of cotton, corn, potato, soybean, petunia, tomato, and tobacco can also be utilized as hosts.

[0197] In another aspect, expression of anti-IL‑23A antibodies is carried out in vertebrate cells. The propagation of vertebrate cells in culture (tissue culture) hasbecome routineprocedure and techniquesarewidely available. Examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS‑7, ATCC CRL 1651), human 21 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, (Grahamet al., 1977, J. GenVirol. 36: 59), baby hamster kidney cells (BHK, ATCC CCL 10), Chinese hamster ovary cells / -DHFR1 (CHO, Urlaub et al., 1980, Proc. Natl. Acad. Sci. USA 77: 4216; e.g., DG44), mouse sertoli cells (TM4, Mather, 1980, Biol. Reprod. 23:243‑251), monkey kidney cells (CV1 ATCC CCL 70), African green monkey kidney cells (VERO‑76, ATCC CRL‑1587), human cervical carcinoma cells (HELA, ATCCCCL 2), canine kidney cells (MDCK, ATCCCCL 34), buffalo rat liver cells (BRL 3A, ATCCCRL1442), human lung cells (W138,ATCCCCL75), human liver cells (HepG2,HB8065),mousemammary tumor (MMT 060562, ATCCCCL51), TR1 cells (Mather et al., 1982, Annals N.Y. Acad. Sci. 383: 44‑68), MRC 5 cells, FS4 cells, and human hepatoma line (Hep G2).

[0198] Host cells are transformed with the above-described expression or cloning vectors for anti-IL‑23A antibody production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences.

[0199] The host cells used to produce an anti-IL‑23A antibody described herein may be cultured in a variety of media. Commercially availablemedia suchasHam’sF10 (Sigma-AldrichCo.,St. Louis,Mo.),MinimalEssentialMedium ((MEM), (Sigma-AldrichCo.), RPMI‑1640 (Sigma-AldrichCo.), andDulbecco’sModifiedEagle’sMedium ((DMEM),Sigma-Aldrich Co.) aresuitable for culturing thehost cells. Inaddition, anyof themediadescribed inoneormoreofHametal., 1979,Meth. Enz. 58: 44, Barnes et al., 1980, Anal. Biochem. 102: 255, U.S. Pat. No. 4,767,704, U.S. Pat. No. 4,657,866, U.S. Pat. No. 4,927,762, U.S. Pat. No. 4,560,655, U.S. Pat. No. 5,122,469, WO 90 / 103430, andWO 87 / 00195 may be used as culture media for the host cells. Any of these media may be supplemented as necessary with hormones and / or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, calcium,magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics (such as gentamicin), trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Other supplements may also be included at appropriate concentrations that would be known to those skilled in the art. The culture conditions, such as temperature, pH, and the like, are those previously used with the host cell selected for expression, and will be apparent to the ordinarily skilled artisan.

[0200] When using recombinant techniques, the antibody can be produced intracellularly, in the periplasmic space, or directly secreted into themedium. If theantibody isproduced intracellularly, thecellsmaybedisrupted to releaseproteinas a first step. Particulate debris, either host cells or lysed fragments, can be removed, for example, by centrifugation or ultrafiltration. Carter et al., 1992, Bio / Technology 10:163‑167 describes a procedure for isolating antibodies that are secreted to the periplasmic space of E. coli. Briefly, cell paste is thawed in the presence of sodiumacetate (pH3.5), EDTA, andphenylmethylsulfonylfluoride (PMSF)over about30minutes.Cell debris canbe removedbycentrifugation.Where the antibody is secreted into themedium, supernatants fromsuchexpression systemsare generally first concentratedusing a commercially available protein concentration filter, for example, an Amicon or Millipore Pellicon ultrafiltration unit. A protease inhibitor such asPMSFmay be included in any of the foregoing steps to inhibit proteolysis and antibioticsmaybe included to prevent the growth of adventitious contaminants. A variety ofmethods can be used to isolate the antibody from the host cell.

[0201] The antibody composition prepared from the cells can be purified using, for example, hydroxylapatite chroma- tography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being a typical purifica- tion technique. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain that is present in the antibody. Protein A can be used to purify antibodies that are based on human gamma1, gamma2, or gamma4 heavy chains (see, e.g., Lindmark et al., 1983 J. Immunol. Meth. 62:1‑13). Protein G is recom- mended for all mouse isotypes and for human gamma3 (see, e.g., Guss et al., 1986 EMBO J. 5:1567‑1575). A matrix to which an affinity ligand is attached is most often agarose, but other matrices are available. Mechanically stable matrices such as controlled pore glass or poly(styrenedivinyl)benzene allow for faster flow rates and shorter processing times than can be achieved with agarose. Where the antibody comprises a CH3 domain, the Bakerbond ABX™ resin (J. T. Baker, Phillipsburg, N.J.) is useful for purification. Other techniques for protein purification such as fractionation on an ion- exchange column, ethanol precipitation, reverse phase HPLC, chromatography on silica, chromatography on heparin SEPHAROSE™ chromatography on an anion or cation exchange resin (such as a polyaspartic acid column), chroma- tofocusing, SDS-PAGE, and ammonium sulfate precipitation are also available depending on the antibody to be recovered.

[0202] Following any preliminary purification step(s), the mixture comprising the antibody of interest and contaminants may be subjected to low pH hydrophobic interaction chromatography using an elution buffer at a pH between about 2.5‑4.5, typically performed at low salt concentrations (e.g., from about 0‑0.25M salt). Therapeutic Uses

[0203] In another embodiment, an anti-IL‑23A antibody disclosed herein is useful in the treatment of various disorders associated with the expression of IL‑23p19 as described herein. In one aspect, a method for treating an IL‑23 associated disorder comprises administering a therapeutically effective amount of an anti-IL‑23A antibody to a subject in need 22 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 thereof.

[0204] The anti-IL‑23A antibody is administered by any suitable means, including parenteral, subcutaneous, intraper- itoneal, intrapulmonary, and intranasal, and, if desired for local immunosuppressive treatment, intralesional administration (includingperfusingor otherwisecontacting thegraftwith theantibodybefore transplantation). Theanti-IL‑23Aantibodyor agent can be administered, for example, as an infusion or as a bolus. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In addition, the anti-IL‑23A antibody is suitably administered by pulse infusion, particularly with declining doses of the antibody. In one aspect, the dosing is given by injections, most preferably intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. In one aspect, the dosing of the anti-IL‑23 antibody is given by subcutaneous injections.

[0205] For the prevention or treatment of disease, the appropriate dosage of antibodywill depend on a variety of factors such as the type of disease to be treated, as definedabove, the severity and course of the disease,whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient’s clinical history and response to the antibody, and the discretion of the attending physician. The antibody is suitably administered to the patient at one time or over a series of treatments.

[0206] The term"suppression" is usedherein in thesamecontext as "amelioration" and "alleviation" tomeana lessening of one or more characteristics of the disease.

[0207] The antibody is formulated, dosed, and administered in a fashion consistent with goodmedical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The "therapeutically effective amount" of the antibody to be administered will be governed by such considerations.

[0208] Theantibodymayoptionally be formulatedwith oneormoreagents currently used toprevent or treat thedisorder in question. The effective amount of such other agents depends on the amount of anti-IL‑23A antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. IL‑23-Associated Disorders

[0209] The anti-IL‑23p19 antibodies or agents are useful for treating or preventing an immunological disorder characterized by abnormal expression of IL‑23, e.g., by inappropriate activation of immune cells (e.g., lymphocytes or dendritic cells). Such abnormal expression of IL‑23 can be due to, for example, increased IL‑23 protein levels.

[0210] Immunological diseases that are characterized by inappropriate activation of immune cells and that can be treated or prevented by the methods described herein can be classified, for example, by the type(s) of hypersensitivity reaction(s) that underlie the disorder. These reactions are typically classified into four types: anaphylactic reactions, cytotoxic (cytolytic) reactions, immune complex reactions, or cell-mediated immunity (CMI) reactions (also referred to as delayed-type hypersensitivity (DTH) reactions). (See, e.g., Fundamental Immunology (WilliamE. Paul ed., Raven Press, N.Y., 3rd ed. 1993). Immunological diseases include inflammatory diseases and autoimmune diseases.

[0211] Examples of immunological diseases include the following: psoriasis, inflammatory bowel disease, for example ulcerative colitis or Crohn’s disease, and spondyloarthritis, for example ankylosing spondylitis, non-radiographic axial spondyloarthritis, peripheral spondyloarthritis or psoriatic arthritis.

[0212] In one aspect, in the context of the present invention, the immunological disease isCrohn’sDisease, for example moderately to severely active Crohn’s Disease. In one aspect, in the context of the present invention, a patient is naïve to, or was previously treatedwith anti-TNF therapy. In one aspect, in the context of amethod of the present invention apatient waspreviously treatedwith one, two, threeormoreTNFantagonist(s). In oneembodiment, thepatient is a patientwhohad an inadequate responsewith, lost response, orwas intolerant to aTNFantagonist. In oneaspect, a patient to be treatedby a method according ot the present invention has a CDAI score of 220‑450.

[0213] Disease severity for Crohn’s Disease is for examplemeasured using the Crohn’s Disease Activity Index (CDAI). CDAI isacomposite scoreused toquantify symptomsofpatientswithCrohn’sDisease. Inoneaspect, the indexconsistsof eight factors added together after adjusting for a predefined weighting factor (see below in Table B). CDAI scores range from0 to 600. Index valuesof 150 andbeloware associatedwith quiescent disease; valuesabove150are associatedwith active disease, and values above 450 are seen with extremely severe disease. Table B. Format for calculation of the CDAI Clinical or laboratory variable Weighting factor Number of liquid or soft stools each day for 7 days ×2 Abdominal pain (graded from 0 to 3 on severity) each day for 7 days ×5 General wellbeing, subjectively assessed from 0 (well) to 4 (terrible) each day for 7 days ×7 23 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Clinical or laboratory variable Weighting factor Presence of complications ×20 Taking Lomotil or opiates for diarrhoea ×30 Presence of an abdominal mass (0 as none, 2 as questionable, 5 as ×10 definite) Haematocrit of <0.47 in men and <0.42 in women ×6 Percentage deviation from standard weight ×1

[0214] At the mucosal level, the extent of disease is for example graded following ileocolonoscopy according to the Crohn’s Disease Endoscopic Index of Severity (CDEIS). In one aspect, CDEIS is a validated scoring system in which six endoscopic variables (presence of deep ulcers, superficial ulcers, non-ulcerated stenosis, ulcerated stenosis, proportion of ulcerated surface, and proportion of surface affected by disease) are assessed in each of the five segments: rectum, sigmoid and left colon, transverse colon, right colon, and ileum. For these segments, the percentage of ulcerated colonic surface and the percentage of surface affected by any Crohn’s disease lesion are indicated on a 10 cm visual analogue scale. CDEIS scores range from 0 to 44 and higher scores indicate more severe disease.

[0215] Other evaluations of the disease are for example described in theExamples hereinbelow. In one aspect, CDAI or CDEIS, or both, or any one of the evaluations described in theExamples hereinbelow, is / are used to assess the efficacy of an anti-IL‑23A antibody, for example Antibody A, Antibody B, Antibody C or Antibody D, in the treatment of Crohn’s Disease, for example moderately to severely active Crohn’s Disease.

[0216] For example, a patient is evaluated for clinical remission, for example defined as a CDAI score of < 150.

[0217] For example, a patient is evaluated for clinical response, for example defined by either aCDAI score of < 150 or a CDAI reduction from baseline of at least 100 points.

[0218] For example, a patient is evaluated for endoscopic remission, for example defined as CDEIS ≤ 4. For patients with initial isolated ileitis, endoscopic remission is for example defined as CDEIS ≤ 2.

[0219] For example, a patient is evaluated for endoscopic response, for example defined as a >50% CDEIS reduction from baseline.

[0220] For example, a patient is evaluated for deep remission, for example defined as reaching clinical remission (CDAI score <150) and / or endoscopic remission (CDEIS ≤ 4). In one, aspect, for a patient with initial isolated ileitis endoscopic remission is definedbyCDEIS≤2. For example, deep remission is definedasachieving clinical remissionandendoscopic remission.

[0221] In one aspect, thePatient reported outcome (PRO) of a patient is assessed, for example using aPRO‑2 score. In one aspect, PRO‑2 remission is assessed, for example as defined by a PRO‑2 score of ≤75. In one aspect, PRO‑2 response is assessed, for example as defined as a decrease from baseline of 50 points or more.

[0222] In one aspect, PRO‑2 includes only the two CDAI items stool frequency and abdominal pain. In one aspect, the PRO‑2 is calculatedbasedon the sumof theweightedpatient-reported subscores ofCDAI for liquid or soft stool frequency plus abdominal pain in the 7 days prior to the study visit. PRO‑2 is calculated by adding the values of the summed stool frequency scores multiplied by 2 plus the summed abdominal pain scores multiplied by 5.

[0223] In one aspect, Health-related quality of life (HRQoL) is assessed by asking patients to complete the 32 questions of the Inflammatory Bowel Disease Questionnaire (IBDQ), which is a tool to scale the impact of bowel-related symptoms, systemic complaints, social functions, and emotional status on HRQoL, with higher scores indicating better HRQoL. A mean change of 16 points is considered clinically meaningful for this instrument.

[0224] In one aspect, in the context of the present invention, the immunological disease is ulcerative colitis. In one aspect, an anti-IL‑23Aantibody, for exampleAntibodyA,AntibodyB,AntibodyCorAntibodyD, is used for the treatment of patients with moderately to severely active ulcerative colitis, for example patients who have had an inadequate response with, lost response to, or were intolerant to conventional therapy or tumour necrosis factor-alpha (TNFα) antagonist. For example, the treatment is by inducingandmaintaining clinical remission, by inducingandmaintaining clinical response, by improving endoscopic appearance of the mucosa or by achieving corticosteroid-free remission. Pharmaceutical Compositions and Administration Thereof

[0225] A composition comprising an anti-IL‑23A antibody can be administered to a subject having or at risk of having an immunological disorder. The term "subject" as used herein means any mammalian patient to which an anti-IL‑23A antibody can be administered, including, e.g., humans and non-human mammals, such as primates, rodents, and dogs. 24 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 Subjects specifically intended for treatment using the methods described herein include humans. The antibodies can be administered either alone or in combination with other compositions in the prevention or treatment of the immunological disorder.

[0226] Anti-IL‑23A antibodies for use in such pharmaceutical compositions are described herein, for example Antibody A, Antibody B, Antibody C or Antibody D.

[0227] Various delivery systems are known and can be used to administer the anti-IL‑23A antibody. Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The anti-IL‑23A antibody can be administered, for example by infusion, bolus or injection, and can be administered together with other biologically active agents such as chemotherapeutic agents. Administrationcanbesystemicor local. Inoneembodiment, theadministration isbysubcutaneous injection.Formulations for such injections may be prepared in for example prefilled syringes that may be administered once every other week.

[0228] In specific embodiments, the anti-IL‑23Aantibody is administered by injection, bymeans of a catheter, bymeans of a suppository, or bymeans of an implant, the implant being of a porous, non-porous, or gelatinous material, including a membrane, suchasa sialasticmembrane, or a fiber. Typically, whenadministering the composition,materials towhich the anti-IL‑23A antibody or agent does not absorb are used.

[0229] In other embodiments, theanti-IL‑23Aantibody is delivered in a controlled release system. In oneembodiment, a pumpmay be used (see, e.g., Langer, 1990, Science 249:1527‑1533; Sefton, 1989, CRCCrit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321:574). In another embodiment, polymeric materials can be used. (See, e.g., Medical Applications of Controlled Release (Langer andWise eds., CRC Press, Boca Raton, Fla., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., Wiley, New York, 1984); Ranger and Peppas, 1983, Macromol. Sci. Rev. Macromol. Chem. 23:61. See also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105.) Other controlled release systems are discussed, for example, in Langer, supra.

[0230] Ananti-IL‑23p19antibody is typicallyadministeredaspharmaceutical compositionscomprisinga therapeutically effective amount of the antibody and one or more pharmaceutically compatible ingredients.

[0231] In typical embodiments, the pharmaceutical composition is formulated in accordancewith routine procedures as a pharmaceutical composition adapted for intravenous or subcutaneous administration to human beings. Typically, compositions for administration by injection are solutions in sterile isotonic aqueous buffer. Where necessary, the pharmaceutical can also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the pharmaceutical is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the pharmaceutical is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0232] Further, the pharmaceutical composition can be provided as a pharmaceutical kit comprising (a) a container containing an anti-IL‑23A antibody in lyophilized form and (b) a second container containing a pharmaceutically acceptable diluent (e.g., sterilewater) for injection. Thepharmaceutically acceptable diluent canbeused for reconstitution or dilution of the lyophilized anti-IL‑23A antibody. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0233] Examples of pharmaceutical compositions used in the context of the present invention are disclosed in Example 2 hereinbelow.

[0234] The invention is further described in the following examples, which are not intended to limit the scope of the invention. Examples Example 1: Clinical Study

[0235] This trial is a proof of concept, multi-center, randomized, double-blind, placebo-controlled, parallel-group phase 2 dose-ranging study of Antibody A in patients with moderately to severely active CD.

[0236] The trial consist of a screening period of up to a maximum of 4 weeks, a 12-week blinded intravenous therapy period (Period 1), a 14-week open label intravenous therapy / wash-out period (Period 2), a 26-week subcutaneous therapy period (Period 3) and a 15-week follow up period.

[0237] Approximately 240 patients are screened and approximately 120 patients with moderate to severe CD and mucosal ulcers detected on ileocolonoscopy are randomized in a ratio of 1:1:1 to one of the 3 following treatment groups in Period 1: 25 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 • Group 1: Placebo IV (n=40) • Group 2: Antibody A 200 mg IV (n=40) • Group 3: Antibody A 600 mg IV (n=40)

[0238] Randomization is stratified according to previous experience with anti-TNF therapy (naïve vs. experienced). Safety and efficacy evaluations are performed through the end of the study. The end of study is defined as the date the last patient completes the last follow up visit.

[0239] Each treatment group receives the correspondingdoseofAntibodyAorplaceboby IV infusionatweek0,week4, and week 8. At week 12, patients are evaluated for deep remission, defined as reaching clinical remission (CDAI score <150) and endoscopic remission (CDEIS ≤ 4) confirmed by central independent reviewer(s). For patients with initial isolated ileitis endoscopic remission is defined by CDEIS ≤ 2.

[0240] Treatment in Period 2 is determined by the outcome at week 12. • Patients who are in deep remission at week 12 stop medication, and enter a wash-out period until week 26.

[0241] In case of a disease flare during this period (including visit E1), defined as an increase of CDAI score ≥ 70 points compared to week 12 and a CDAI score of 220 or greater, the investigator performs an ileocolonoscopy within 2 weeks; ∘ If the CDEIS score is ≤ 4 (in patients with initial ileitis ≤ 2), patients continue on wash-out until week 26. ∘ If theCDEISscore is >4 (inpatientswith initial ileitis >2), patients receiveopen-label intravenous induction therapy (3 doses separated by 4 week intervals) with 600 mg of Antibody A, as described in Figure 1. • Patients who do not achieve deep remission at week 12 receive open label intravenous induction therapy (3 doses separated by 4-week intervals) with 600 mg of Antibody A, as described in Figure 1.

[0242] Patients who are in clinical remission at visit E1, irrespective of their week 12 outcome and period 2 treatment, enter Period 3 (open label subcutaneous period) and receive 4 injections of Antibody A (180mgSC) separated by 8-week intervals.

[0243] Ileocolonoscopy is performed for all patients at screening, week 12 and 52 to evaluate endoscopic response / r- emission, and to provide mucosal biopsy specimens for molecular pharmacodynamic assessments pre and post treatment. Patients who experienced flare after achieving deep remission at week 12 are also required to undergo ileocolonoscopy and receive open-label re-induction therapy only if their CDEIS is >4 (in patients with initial ileitis >2) confirmed by central independent reviewer(s). All colonoscopies are videotaped with the use of a standard protocol and interpreted by an independent reviewer(s), who is (are) unaware of study-group assignments and the timing of the procedure. Patients participating in the study consent to undergo up to 4 colonoscopies.

[0244] Criteria for efficacy are as follow:

[0245] Primary efficacy endpoint is: Clinical remission, for example at week 12, defined as a CDAI score of < 150. Secondary efficacy endpoints are: • Clinical response, for example at week 12, defined by either a CDAI score of < 150 or a CDAI reduction from baseline of at least 100 points. • PRO response, for example at week 12, defined by either a PRO‑2 score of <8 or a reduction from baseline of at least 8 points (PRO‑2: Patient reported outcome‑2). • CDEIS remission, defined as a score of 4 or less, for example at week 12 (for patients with initial isolated ileitis a score of 2 or less). • CDEIS response, defined as a score of 7 or less, for example at week 12 (for patients with initial isolated ileitis >50% reduction from baseline). • Change in SES-CD score, for example at week 12. • Mucosal healing, defined as the absence of mucosal ulceration, for example at week 12. • Deep remission, defined as clinical remission and endoscopic remission (CDEIS), for example at week 12. Change from baseline in CDAI scores by visit. Other efficacy endpoints are: 26 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 • Change from baseline in CDAI scores by visit. • Change from baseline in PRO‑2 scores by visit. • Reduction of 75% in CDEIS scores from baseline, for example at week 12. • Reduction of 75% in SES-CD scores from baseline, for example at week 12. • Time to flare for those who achieve deep remission and stop medication, for example at Week 12. • Time to flare for those who achieve clinical remission, for example at Week 26. • Change from baseline in stool frequency by visit based on patient diary. • Stool consistency by visit based on patient diary. • Change frombaseline in abdominal pain scoresby visit basedon thepatient diary andscored, onanumeric rating scale from 0 (no pain) to 10 (worst possible pain). • Change from baseline in IBDQ scores by visit. • Change from baseline in CRP (C-reactive protein), calprotectin and lactoferrin profile by visit. • Sustained clinical remission after corticosteroid withdrawal (from week 12). • Reduction in the number of draining fistulas in patients with draining fistulas at baseline. • PRO‑2 remission, for example at week 204 / 206 / 216, defined by a PRO‑2 score of <75. • PRO‑2 response, for example at week 204 / 206 / 216, defined as a decrease from baseline of 50 points or more. • Change in CDEIS by visit. • Change in SES-CD by visit. • CDEIS percentage change from baseline by visit. • SES-CD percentage change from baseline by visit. Methods

[0246] The study comprised three treatment periods: a 12-week double-blinded intravenous (iv) induction period, a 14- week open-label iv re-induction / wash-out period (i.e. re-induction at weeks 14‑26 or wash-out at weeks 12‑26 for patients who do not undergo re-induction), and a 26-week subcutaneous maintenance period. In the induction period, patients (N=121), with clinically active disease (CD Activity Index [CDAI] score ≥220) confirmed by endoscopy (CD Endoscopic Index of Severity [CDEIS] score ≥7; ≥4 for patients with isolated ileitis), who failed either a TNF antagonist or conventional CD therapy,were randomlyassigned to receiveeitherAntibodyA (200mgor600mg) or placebo, atWeeks0, 4, and8.The primary endpoint was clinical remission (CDAI <150) at Week 12. Secondary endpoints at Week 12 included clinical response, endoscopic remission / response and deep remission.

[0247] Eligible patients were aged 18‑75 years. They had had a diagnosis of CD for at least 3 months and at screening had moderate-to-severe CD, defined as a CD Activity Index (CDAI) of 220‑450, with mucosal ulcers in the ileum and / or colon, and a CDEndoscopic Index of Severity (CDEIS) ≥7 (≥4 for patients with isolated ileitis) on ileocolonoscopy scored by a blinded central reader. Patients either naive or experienced to one or more tumor necrosis factor (TNF) antagonists were included (Table C). Some patients had an inadequate response with, lost response, or were intolerant to a TNF antagonist (TableC).Patients previously treatedwith ustekinumabwereexcluded, aswerepatientswhohad receivedany biologic agentwithin8weeksor 5half-livesof thebiologic prior to randomization, i.e. prior to thefirst administrationof study agent.

[0248] Differences betweenAntibodyAand placebowere analyzed using appropriate tests for pairwise comparisons of binomial data. Results for the induction period are reported. Table C. Patients with previous TNF antagonist and outcome Placebo Antibody A 200mg iv Antibody A 600mg iv Total N (%) N (%) N (%) N (%) Number of Patients 39 (100.0) 41 (100.0) 41 (100.0) 121 (100.0) Prior TNF antagonist use, n(%) 39 (100.0) 41 (100.0) 41 (100.0) 121 (100.0) 1 12 ( 30.8) 9 ( 22.0) 9 ( 22.0) 30 ( 24.8) 2 20 ( 51.3) 23 ( 56.1) 24 ( 58.5) 67 ( 55.4) >=3 5 ( 12.8) 7 ( 17.1) 4 (9.8) 16 ( 13.2) Missing 2 ( 5.1) 2 ( 4.9) 4 ( 9.8) 8 ( 6.6) Outcome of >=1 previous TNF antagonist, n(%) 35 ( 89.7) 37 ( 90.2) 36 ( 87.8) 108 ( 89.3) Inadequate 10 ( 25.6) 16 ( 39.0) 11 ( 26.8) 37 ( 30.6) Response 27 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Placebo Antibody A 200mg iv Antibody A 600mg iv Total N (%) N (%) N (%) N (%) Loss of response 21 (53.8) 13 ( 31.7) 17 ( 41.5) 51 (42.1) Unacceptable adverse events 1 (2.6) 2 ( 4.9) 5 ( 12.2) 8 ( 6.6) Others 2 ( 5.1) 3 ( 7.3) 1 (2.4) 6 ( 5.0) Unknown 1 (2.6) 3 ( 7.3) 2 ( 4.9) 6 ( 5.0) Results

[0249] Baseline demographics and disease characteristics were similar between study arms. In total, there were 47 males and 74 females, with a mean age of 38.1 years and mean CDAI and CDEIS scores of 306.8 and 13.4; 94.2% of patients had previously been exposed to ≥1 TNF antagonists. AtWeek 12, clinical remission was achieved by 24.4% and 36.6% of patients with 200 mg and 600 mg Antibody A, respectively, compared with 15.4% of patients with placebo (p=0.308 and p=0.025) (Table 6); clinical response rates were 36.6% and 41.5% in the 200 mg and 600 mg Antibody A arms, compared with 20.5% in the placebo group (p=0.103 and p=0.037). Endoscopic remission was achieved by 14.6% and 19.5% of patients with 200 mg and 600 mg Antibody A, compared with 2.6% of patients with placebo (p=0.056 and p=0.017); endoscopic response was achieved by 26.8% and 36.6% of patients with 200 mg and 600 mg Antibody A, compared with 12.8%of patients with placebo (p=0.117 and p=0.014). Deep remissionwas achieved by 2.4%and 12.2% of patients with 200 mg and 600 mg Antibody A, compared with 0.0% for placebo (p=1.0 and p=0.062). Mucosal healing wasdetected in3.0%,2.9%and7.5%ofpatientswithplacebo,200mgand600mgAntibodyA.Adverseevents (AEs)were similar between Antibody A and placebo with no dose-related increase in AEs. Fewer severe and serious AEs were reported in the 600 mg Antibody A arm. Results are shown in Tables 6 and 7. Tables 6 and 7 include pooled values for Antibody A.

[0250] The clinical remission and clinical response of Antibody A over 12weeks are also shown in Figure 2. In Figure 2, the following are depicted from left to right for week 4, week 8 andweek 12: Placebo, 200mgAntibodyA, 600mgAntibody A, and Pooled Antibody A. Figure 2A, clinical remission over time:

[0251] Week 4: Placebo (3 patients / 7.7% with clinical remission), 200 mg Antibody A (4 patients / 9.8% with clinical remission), 600 mg Antibody A (8 patients / 19.5% with clinical remission), Pooled Antibody A (12 patients / 14.6% with clinical remission).

[0252] Week 8: Placebo (1 patients / 2.6% with clinical remission), 200 mg Antibody A (7 patients / 17.1 % with clinical remission), 600 mg Antibody A (10 patients / 24.4% with clinical remission), Pooled Antibody A (17 patients / 20.7% with clinical remission). Week 12: Placebo (6 patients / 15.4% with clinical remission), 200 mg Antibody A (10 patients / 24.4% with clinical remission), 600 mg Antibody A (15 patients / 36.6% with clinical remission), Pooled Antibody A (25 patients / 30.5% with clinical remission). Figure 2B, clinical response over time:

[0253] Week 4: Placebo (6 patients / 15.4% with clinical response), 200 mg Antibody A (10 patients / 24.4% with clinical response), 600 mg Antibody A (13 patients / 31.7% with clinical response), Pooled Antibody A (23 patients / 28.0% with clinical response).Week 8: Placebo (5 patients / 12.8%with clinical response), 200mgAntibodyA (13 patients / 31.7%with clinical response), 600 mg Antibody A (13 patients / 31.7% with clinical response), Pooled Antibody A (26 patients / 31.7% with clinical response). Week 12: Placebo (8 patients / 20.5% with clinical response), 200 mg Antibody A (15 pa- tients / 36.6% with clinical response), 600 mg Antibody A (17 patients / 41.5% with clinical response), Pooled Antibody A (32 patients / 39.0% with clinical response).

[0254] MedianCDAls over timeare shown in Figure 3AandTable 8A. PRO‑2 response atweek 12 is shown in Table 8B, PRO‑2 remission at week 12 is shown in Table 8C. Safety

[0255] Therewasnodose-related increase inanyof theAEs reportedwithAntibodyA (Table11). Themost frequentAEs were related to thegastrointestinal tract. The incidence of severeAEswashigher in the placebogroup than theAntibodyA 28 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 groups (23%, 15%, and 7%, respectively). AEs leading to discontinuationwere reported for 15%, 12%, and 2%of patients in the placebo, 200mg, and 600mgAntibody A arms (Table 11). SAEswere experienced in 31%, 22%, and 7%of patients in the placebo, 200mg, and 600mgAntibodyAgroups, respectively. Themost commonSAEwasworsening of underlying disease. No deaths occurred, while serious infections were reported in three (abdominal, anal and rectal abscess, and pneumonia), one (pneumonia), and two patients (osteomyelitis and anal abscess) in the placebo, 200 mg, and 600 mg Antibody A arms. Infusion-related reactions were mild or moderate and reported in 5%, 2%, and 2% of patients in the placebo, 200 mg, and 600 mg Antibody A arms.

[0256] Treatment-emergent anti-drug antibodies (ADAs) were detected in 4% of patients receiving Antibody A (3 of 76 patients). ADA titer values were low (≤8) and there were no neutralizing antibodies detected. Pre-existing ADAs were observed in five patients in the Antibody A dose groups and three patients in the placebo group Conclusions

[0257] In patients with active CD, selective blockade of IL‑23 with Antibody A was more effective than placebo for inducing clinical and endoscopic remission at 12 weeks and was well tolerated. Table 6. Efficacy endpoints at Week 12 Placebo (N=39) Antibody A 200 mg (N=41) 600 mg (N=41) Pooled 200 mg + 600 mg (N=82) Clinical remission - n / N (%) Difference vs placebo 6 / 39 (15.4) 10 / 41 (24.4) 15 / 41 (36.6) 25 / 82 (30.5) 9.0 20.9 15.1 p-value n / a 0.308 0.025 0.049 Clinical response - n / N (%) Difference vs placebo 8 / 39 (20.5) 15 / 41 (36.6) 17 / 41 (41.5) 32 / 82 (39.0) 16.0 20.3 18.4 p-value n / a 0.103 0.037 0.027 Endoscopic remission‑ n / N (%) Difference vs placebo 1 / 39 (2.6) 6 / 41 (14.6) 8 / 41 (19.5) 14 / 82 (17.1) 12.0 16.9 14.5 p-value n / a 0.056 0.017 0.024 Endoscopic response - n / N (%) Difference vs placebo 5 / 39 (12.8) 11 / 41 (26.8) 15 / 41 (36.6) 26 / 82 (31.7) 14.0 23.8 18.9 p-value n / a 0.117 0.014 0.026 Deep remission - n / N (%) Difference vs placebo 0 / 39(0.0) 1 / 41 (2.4) 5 / 41 (12.2) 6 / 82 (7.3) 2.4 12.2 7.3 p-value n / a 1.000 0.062 0.182 Clinical remission is defined as a CDAI score <150. Clinical response is either a CDAI score <150 or a CDAI re- duction from baseline of ≥100 points. Endoscopic remission is a CDEIS score of ≤4; for patients with initial isolated ileitis a score of ≤2. Endoscopic response is a score of 7 or less; for patients with initial isolated 29 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Placebo (N=39) Antibody A 200 mg (N=41) 600 mg (N=41) Pooled 200 mg + 600 mg (N=82) ileitis a >50% reduction in CDEIS score from baseline. Deep remis- sion is clinical remission and endoscopic remission. Full analysis set was used for this analysis, using last observation carried forward for missing values and stratified Cochran-Mantel-Haenszel tests for clinical endpoints; for endoscopic endpoints, non-response imputa- tion was used for missing values and analyzed with Pearson’s chi- squared test, using Fisher’s exact test for deep remission. CDAI, Crohn’s Disease Activity Index; CDEIS, Crohn’s Disease Endoscopic Index of Severity. Table 7. Efficacy endpoints at Week 12 Table 7 shows the efficacy endpoints at week 12 with a refined statistical analysis (see also Table 6). Mucosal healing is also shown in Table 7. Antibody A Placebo (N=39) 200 mg (N=41) 600 mg (N=41) Pooled (N=82) Clinical remission - n (%) 6 (15.4) 10 (24.4) 15 (36.6) 25 (30.5) 95% confidence interval 5.9, 30.5 12.4, 40.3 22.1, 53.1 20.8, 41.6 Difference vs. placebo 9.0 20.9 15.1 95% confidence interval ‑8.3, 26.2 2.6, 39.2 0.1, 30.1 P-value 0.31 0.025 0.049 Clinical response - n (%) 8 (20.5) 15 (36.6) 17 (41.5) 32 (39.0) 95% confidence interval 9.3, 36.5 22.1, 53.1 26.3, 57.9 28.4, 50.4 Difference vs. placebo 16.0 20.3 18.4 95% confidence interval ‑3.2, 35.2 1.3, 39.4 2.1, 34.8 P-value 0.10 0.037 0.027 Endoscopic remission - n (%) 1 (2.6) 6 (14.6) 8 (19.5) 14 (17.1) 95% confidence interval 0.1, 13.5 5.6, 29.2 8.8, 34.9 9.7, 27.0 Difference vs. placebo 12.1 16.8 14.5 95% confidence interval 0.8, 23.4 3.9, 29.7 5.5, 23.5 P-value 0.036 0.011 0.002 Endoscopic response - n (%) 5 (12.8) 11 (26.8) 15 (36.6) 26 (31.7) 95% confidence interval 4.3, 27.4 14.2, 42.9 22.1, 53.1 21.9, 42.9 Difference vs. placebo 14.1 23.5 18.7 95% confidence interval ‑2.8, 30.9 5.5, 41.5 4.4, 33.0 P-value 0.10 0.011 0.010 Mucosal healing - n (%) 1 (2.6) 1 (2.4) 3 (7.3) 4 (4.9) 95% confidence interval 0.1, 13.5 0.1, 12.9 1.5, 19.9 1.3, 12.0 Difference vs. placebo ‑0.1 4.9 2.4 95% confidence interval ‑7.0, 6.7 ‑4.6, 14.3 ‑4.5, 9.2 P-value 0.97 0.31 0.50 Deep remission - n (%) 0 1 (2.4) 5 (12.2) 6 (7.3) 95% confidence interval 0.0, 9.0 0.1, 12.9 4.1, 26.2 2.7, 15.2 Difference vs. placebo 2.4 12.4 7.4 30 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Table 7 shows the efficacy endpoints at week 12 with a refined statistical analysis (see also Table 6). Mucosal healing is also shown in Table 7. Antibody A Placebo (N=39) 200 mg (N=41) 600 mg (N=41) Pooled (N=82) 95% confidence interval ‑2.3, 7.1 2.3, 22.5 1.7, 13.0 P-value 0.31 0.016 0.011

[0258] Clinical remission is defined as a CDAI score <150. Clinical response is either a CDAI score <150 or a CDAI reduction of ≥100 from baseline. Endoscopic remission is a CDEIS score of ≤4 at Week 12 (≤2 for patients with initial isolated ileitis). Endoscopic response is a >50% reduction in CDEIS score from baseline to Week 12. Mucosal healing is defined as the absence of mucosal ulceration. Deep remission is clinical remission and endoscopic remission. Full analysis set was used for this analysis, using non-response imputation for missing values and stratified Cochran-Mantel- Haenszel tests.

[0259] CDAI, Crohn’s Disease Activity Index; CDEIS, Crohn’s Disease Endoscopic Index of Severity; SD, standard deviation. Biomarkers

[0260] Median CRP concentrations declined over time in both Antibody A arms compared with placebo and were significantly reduced compared with placebo at Week 12 (P<0.001; Figure 3B). Treatment with 600 mg Antibody A significantly decreased FCP levels (baseline to Week 12) compared with placebo (P<0.001; Figure 3C). In addition, significantly greater decreases inplasma IL‑22 levels (baseline toWeek12)wereobservedwith600mgAntibodyAversus placebo (P=0.018; Figure 3D). IL‑22 levels were measured in patient plasma using the the Erenna® SMC™ IL‑22 Immunoassay - a quasi-quantitative fluorescent sandwich immunoassay technique. FCPwasmeasured in feces using an enzyme immunoassay by Buhlmann Laboratories AG and tested by Covance Central laboratories.

[0261] Table 8Aalso showsmedianCRP (mg / L) over time,median FCP (µg / g) over time andmedian%change in IL‑22 over time (BL: baseline, IQR:interquartile range). Table 8A Median CDAI over time Median (IQRs) Placebo 200 mg Antibody A 600 mg Antibody A BL 294.8 (236.8, 385.5) 310.9 (247.0, 347.7) 298.1 (259.3, 330.0) Week 4 308 (228.8, 342.4) 238 (186.0, 318.0) 247 (185.4, 304.7) Week 8 277.3 (239.2, 337.0) 264 (169.1, 335.7) 209.4 (138.3, 299.0) Week 12 282.6 (173.2, 397.0) 242.7 (138.0, 348.5) 204.3 (92.1, 284.5) Median CRP (mg / L) over time

[0262] Median (IQRs) Placebo 200 mg Antibody A 600 mg Antibody A BL 14.0 (3.2, 34.3) 10.6 (4.5, 33.6) 7.8 (2.0, 28.9) Week 4 8.3 (3.6, 27.7) 6.9 (3.3, 17.6) 4.2 (1.3, 9.8) Week 8 7.6 (4.6, 18.1) 5.2 (2.1, 11.5) 2.7 (1.6, 11.1) Week 12 12.6 (4.7, 25.4) 5.8 (3.2, 14.7) 2.6 (0.9, 9.3) Median FCP (µg / g) over time

[0263] 31 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 Median (IQRs) Placebo 200 mg Antibody A 600 mg Antibody A BL 1746.5 (672.0, 2792.0) 1364.0 (527.0, 2319.0) 1101.0 (434.0, 3539.0) Week 4 1515.5 (765.0, 2391.0) 765.0 (365.0, 1525.0) 680.5 (199.0, 1658.0) Week 8 1110.0 (526.0, 2360.0) 588.0 (192.0, 940.0) 292.0 (142.0, 1414.0) Week 12 1094.0 (621.0, 2467.0) 590.5 (201.0, 1445.0) 198.0 (62.0, 855.0) Median % change in IL‑22 over time

[0264] Median (IQRs) Placebo 200 mg Antibody A 600 mg Antibody A BL 0 0 0 Week 4 ‑10.5 (‑34.2, 16.3) ‑28.6 (‑39.6, 4.3) ‑40.0 (‑52.7, ‑1.4) Week 8 3.5 (‑36.8, 27.3) ‑36.4 (‑56.6, ‑10.0) ‑34.1 (‑52.9, ‑21.3) Week 12 ‑16.7 (‑39.0, 36.8) ‑34.3 (‑58.3, 4.3) ‑44.2 (‑58.8, ‑14.3) Table 8B. PRO‑2 response at Week 12. PRO‑2 response at Week 12 Placebo Antibody A 200mg iv Antibody A 600mg iv Antibody A 200+600mg iv Number of patients [N (%)] 39 (100.0) 41 (100.0) 41 (100.0) 82 (100.0) Number (%) satisfying PRO‑2 response at Week 12 11 (28.2) 17 (41.5) 19 (46.3) 36 (43.9) 95% confidence interval[1] (15.0, 44.9) (26.3, 57.9) (30.7, 62.6) (33.0, 55.3) Comparison vs. Placebo Estimate of the difference 13.30 17.65 15.37 95% confidence interval[2] (‑6.9, 33.5) (‑2.6, 37.9) (‑2.0, 32.7) p-value[2] 0.1959 0.0873 0.0828 Comparison vs. Antibody A 200mg iv Estimate of the difference 3.43 95% confidence interval[2] (‑17.2, 24.0) p-value[2] 0.7443 [1] Exact 95% CI by Clopper and Pearson [2]Statistics for thedifferencearecalculatedusing theCochran-Mantel-Haenszel risk differencestratifiedbyTNFnaive versus TNF experienced Table 8C. PRO‑2 remission at Week 12. PRO‑2 remission at Week 12 Placebo Antibody A 200mg iv Antibody A 600mg iv Antibody A 200+600mg iv Number of patients [N (%)] 39 (100.0) 41 (100.0) 41 (100.0) 82 (100.0) Number (%) satisfying PRO‑2 remission at Week 12 6 (15.4) 12 (29.3) 15 (36.6) 27 (32.9) 95% confidence interval[1] (5.9, 30.5) (16.1, 45.5) (22.1, 53.1) (22.9, 44.2) Comparison vs. Placebo Estimate of the difference 13.89 20.45 17.24 95% confidence interval[2] (‑4.0, 31.8) (2.6, 38.3) (2.3, 32.2) p-value[2] 0.1276 0.0245 0.0237 32 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) PRO‑2 remission at Week 12 Placebo Antibody A 200mg iv Antibody A 600mg iv Antibody A 200+600mg iv Comparison vs. Antibody A 200mg iv Estimate of the difference 6.11 95% confidence interval[2] (‑13.6, 25.8) p-value[2] 0.5426 [1] Exact 95% CI by Clopper and Pearson [2]Statistics for thedifferencearecalculatedusing theCochran-Mantel-Haenszel riskdifferencestratifiedbyTNFnaive versus TNF experienced Molecular Profile

[0265] Colon tissuewas collected at baseline andWeek 12 froma subset of patients (63%200mgAntibodyA, 66%600 mg Antibody A, and 67% placebo). Significant reductions in the expression of selected genes associated with IL‑23 immune-related pathways were observed in Antibody A-treated patients versus placebo (Table 9). Table 9. Selected Genes Decreased in the Colon by Antibody A at 12 Weeks PostTreatment, as Assessed by RNA Seq Analysis Differentially expressed gene by RNA seq analysis Protein name Antibody A treated (combined dose groups) Log2 Fold Change (vs. baseline) P-value IL‑23 / IL‑17 pathway related IL‑23A Interleukin 23A ‑3.07 0.0004 IL‑26 Interleukin 26 ‑1.16 0.0024 S100 family of calcium-binding proteins S‑100A8 S100 calcium-binding protein A8 ‑2.37 0.0023 S‑100A9 S100 calcium-binding protein A9 ‑1.90 0.0034 S‑100A12 S100 calcium-binding protein A12 ‑2.92 0.0018 Immune-related pathways IL‑6 Interleukin 6 ‑3.07 0.0003 IL‑8 Interleukin 8 ‑2.59 0.0029 IL‑11 Interleukin 11 ‑2.66 0.0015 IL‑18RAP Interleukin 18 RAP ‑0.89 0.0026 IL‑20RB Interleukin 20 RB ‑0.39 0.0028

[0266] The molecular profile in the colon and / or ileum tissue was invertigated in a subset of anti-TNF experienced patientswithCD,who received either 200mg (n=26), 600mg (n=27)AntibodyAor placebo (n=26). Fromeachpatient, 6‑9 biopsy samples were obtained from inflamed lesions in the colon or ileum at baseline and at 12 weeks posttreatment. Biopsysamples from ileumand fromcolonwereseparatelyanalysedby transcriptome-wideRNA-Seqprofiling.Univariate associations were assessed using linear regression. Effect size, p-values and FDRwere calculated for significant genes. CDEIS response (>50% reduction from baseline) and CDEIS remission (≤4; for patients with isolated ileitis of ≤2) were evaluated at Week 12 by an independent blinded reviewer.

[0267] AntibodyA treatment significantly decreased theexpressionof 1146genes frombaseline toWeek12 in the colon tissue of CD patients vs placebo (p<0.05). Of note, significant decreases in the expression of genes associated with the IL‑23 pathway (IL‑23A, IL‑26, IL‑21R, IL‑17A, STAT3), innate immunity (IL6, IL7, IL7R, IL8, ICAM1, IL1, IL11, IL13RA2, IL15RA, IL18R1, TNF), tissue turnover (S‑100A8, A9, A12, MMP1, MMP3, MMP9, MMP12, ADAM8, ADAM12, ADAM33) and solute carrier family (SLC11A1, SLC1A3, SLC2A3, SLC2A6, SLC6A14, SLC7A11, SLC7A5) were observed with Antibody A treatment. These overall changes in gene expression in the Antibody A-treated cohort reflected themolecular changes observed in patients achieving CDEIS response and remission at Week 12. A comparison of gene expression 33 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 changes in the colon significantly modulated by Antibody A at Week 12 vs anti-TNF treatment at Week 14 in a published patient cohort highlighted larger decreases in suppression of pathways associated with epithelial biology (cell-cell adhesion, morphogenesis, intracellular signal transduction, second messenger signalling) following Antibody A treat- ment. In contrast, no significant changes were observed in the molecular profile in the ileum from patients treated with Antibody A vs placebo from baseline to Week 12. Pharmacokinetic / Pharmacodynamic analysis

[0268] The relationship of Antibody A concentrations and CDAI or CDEIS categorical response at Week 12 indicates that the median (95% CI) CDAI and CDEIS response rates increase from 36% (23%, 51%) to 47% (33%, 62%) and 33% (21%, 49%) to 36% (23%, 53%) for the 200 mg to 600 mg median Week 12 concentrations, respectively (Table 10A).

[0269] Antibody A concentrations in plasma were sampled pre-dose and at Weeks 2, 4, 8, 12, 23, and 26, then every 8 weeks through Week 50 and at Weeks 52 and 65 (last visit). Concentrations were determined by a validated enzyme- linked immunosorbent assay. Pharmacokinetics were evaluated using a nonlinear mixed-effects population approach usingNONMEMv7.3. TheR software for statistical computing (package glm)was used for logistic regression analyses to examine the relationship of CDEIS and CDEI response as a dependent, categorical variable and Antibody A concentra- tions at Week 12 as an independent variable. Table 10A. Predicted CDAI and CDEIS Response Probability by Quantile of Antibody A Treatment Group Quantile of Antibody A concentration Concentration at Week 12 Predicted Response Probability 95% Confidence Interval Predicted CDAI response probability by quantile of Antibody A concentrations Placebo 0 0 0.33 (0.18‑0.51) 200 mg min 1000 0.33 (0.19‑0.51) 0.25 5810 0.35 (0.22‑0.51) 0.5 8060 0.36 (0.23‑0.51) 0.75 12100 0.37 (0.25‑0.51) Max 22600 0.41 (0.31‑0.53) 600 mg min 2940 0.34 (0.20‑0.51) 0.25 22425 0.41 (0.31‑0.53) 0.5 36400 0.47 (0.33‑0.62) 0.75 44150 0.50 (0.32‑0.68) Max 68900 0.60 (0.29‑0.85) Predicted CDEIS response probability by quantile of Antibody A concentrations Placebo 0 0 0.33 (0.17‑0.52) 200 mg min 1000 0.33 (0.18‑0.52) 0.25 5810 0.33 (0.20‑0.50) 0.5 8060 0.33 (0.21‑0.49) 0.75 12100 0.34 (0.22‑0.48) Max 22600 0.35 (0.25‑0.47) min 2940 0.33 (0.19‑0.51) 0.25 22425 0.35 (0.24‑0.47) 600 mg 0.5 36400 0.36 (0.23‑0.52) 0.75 44150 0.37 (0.21‑0.56) Max 68900 0.40 (0.14‑0.73) 34 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 Table 10B. Predicted Clinical and Endoscopic Response and Remission Rates by Quartile of Antibody A Concentrations at Week 12. Treatment group Antibody A concentration quartile Median concentration at Week 12 (ng / ml) Predicted response rate 95% confidence interval Clinical response probability Placebo 0 0 0·26 (0·17‑0·37) 200 mg Q1 4680 0·28 (0·20‑0·39) Q2 6470 0·29 (0·21‑0·39) Q3 9510 0·31 (0·23‑0·40) Q4 16200 0·35 (0·26‑0·44) 600 mg Q1 17100 0·35 (0·27‑0·45) Q2 27800 0·42 (0·31‑0·53) Q3 41200 0·50 (0·34‑0·67) Q4 48200 0·55 (0·35‑0·73) Clinical remission probability Placebo 0 0 0·18 (0·11‑0·28) 200 mg Q1 4680 0·20 (0·13‑0·30) Q2 6470 0·21 (0·14‑0·30) Q3 9510 0·22 (0·15‑0·32) Q4 16200 0·26 (0·19‑0·35) 600 mg Q1 17100 0·27 (0·19‑0·36) Q2 27800 0·34 (0·24‑0·45) Q3 41200 0‑43 (0·28‑0·60) Q4 48200 0‑48 (0·29‑0·68) Endoscopic response probability Placebo 0 0 0·23 (0·14‑0·35) 200 mg Q1 4690 0·24 (0·16‑0·35) Q2 6520 0·25 (0·17‑0·36) Q3 10300 0·26 (0·18‑0·36) Q4 17100 0·29 (0·21‑0·38) 600 mg Q1 17000 0·29 (0·21‑0·38) Q2 29700 0·33 (0·23‑0·46) Q3 41200 0·38 (0·23‑0·56) Q4 47700 0·41 (0·23‑0·62) Endoscopic remission probability Placebo 0 0 0·09 (0·04‑0·18) 200 mg Q1 4690 0·10 (0·05‑0·19) Q2 6520 0·10 (0·05‑0·19) Q3 10300 0·11 (0·06‑0·19) Q4 17100 0·13 (0·07‑0·21) 35 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Endoscopic remission probability 600 mg Q1 17000 0·12 (0·07‑0·21) Q2 29700 0·16 (0·09‑0·27) Q3 41200 0·20 (0·10‑0·37) Q4 47700 0·23 (0·10‑0·45)

[0270] Clinical response defined as either CDAI <150 or a CDAI reduction from baseline of ≥100 at Week 12. Clinical remission defined as CDAI <150 at Week 12. Endoscopic response defined as >50% CDEIS reduction from baseline. Endoscopic remission is defined as CDEIS ≤4 at Week 12 (≤2 for patients with initial isolated ileitis). Concentration quartiles correspond to min‑25% (Q1), 25‑50% (Q2), 50‑75% (Q3), and 75%-max (Q4) quantile range. Table 11. Adverse Events Summary (On-Treatment at Week 12) Adverse events - n (%) Antibody A Placebo (N=39) 200 mg (N=41) 600 mg (N=41) Any AE 32 (82) 32 (78) 31 (76) Severe AEs 9 (23) 6 (15) 3 (7) Drug-related AEs 8 (21) 10 (24) 5 (12) AEs leading to discontinuation 6 (15) 5 (12) 1 (2) Serious AEs* 12 (31) 9 (22) 3 (7) Persist or significant 0 1 (2) 0 disability / incapacity 10 (26) 8 (20) 2 (5) Requiring or prolonging hospitalization 4 (10) 1 (2) 1 (2) Other medically important serious event Common AEs† Nausea 4 (10) 8 (20) 3 (7) Worsening of Crohn’s disease 6 (15) 2 (5) 0 Abdominal pain 4 (10) 6 (15) 3 (7) Arthralgia 3 (8) 6 (15) 6 (15) Anemia 4 (10) 0 2 (5) Headache 4 (10) 6 (15) 4 (10) Vomiting 4 (10) 3 (7) 2 (5) Adverse events were coded using MedDRA v18.1. The severity of AEs was graded according to the RCTC v2.0. *A serious AE was defined as any AE that results in death, is immediately life-threatening, results in persistent or significant disability / incapacity, requires or prolongs patient hospitalization, is a congenital anomaly / birth defect, or is an important medical event, based upon appropriate medical judgment that may jeopardize the patient and may require medical or surgical intervention. †Common AEs were reported in at least 10% of patients in any study arm. AE, adverse event; RCTC, Rheumatology Common Toxicity Criteria Inflammatory Bowel Disease Questionnaire (IBDQ) assessment at Week 12

[0271] The IBDQ assessment indicated a reduced HRQoL of the randomized study population at baseline. Treatment with study drug resulted in a dose-dependent increase from baseline to Week 12 by 7.3, 21.7, and 34.7 points in the placebo, 200 mg, and 600 mg dose groups, respectively (Table 12). 36 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 Table 12. Baseline and Change from Baseline at Week 12 in IBDQ Score. Placebo (N=39) Antibody A 200 mg (N=41) 600 mg (N=41) Baseline N 37 37 39 Mean 119.3 110.2 111.5 SD 34.9 30.1 27.8 Min 53.0 53.0 52.0 Median 125.0 108.0 112.0 Max 191.0 167.0 169.0 Change from baseline at Week 12 N 32 35 37 Mean 7.3 21.7 34.7 SD 35.2 27.0 29.9 Min ‑54.0 ‑28.0 ‑20.0 Median ‑0.5 20.0 35.0 Max 108 85.0 118.0 IBDQ, Inflammatory Bowel Disease Questionnaire; SD, standard deviation Re-induction treatment

[0272] AtWeek12, patients enteredPeriod2; here, patients in deep remissionunderwentwashout andall other patients underwent open label intravenous re-induction therapy (600 mg Antibody A at Weeks 14, 18 and 22). Results:

[0273] Baseline demographics anddisease characteristicswere similar between study arms.Meanagewas38.1 years and median CDAI and CDEIS scores were 298 and 12; 94% of patients had previously received ≥1 TNF antagonists. At Week 12, clinical remission was achieved by 24.4% and 36.6% of patients with 200 and 600 mg Antibody A vs 15.4% for placebo (p=0.31 and p=0.025) and deep remission was achieved by 2.4% and 12.2% of patients with 200 and 600 mg AntibodyA vs 0% for placebo (p=0.31 and p=0.016). In patients entering Period 2without clinical remission, open label re- induction of placebo patients induced a rate of clinical remission similar to the 600 mg arm in the blinded Period 1, dose escalation from 200 to 600mg induced a high clinical remission rate, and re-induction treatment in the 600mg arm further increased the clinical remission rate in this group atWeek 26 (Table 13). No patients with deep remission relapsed during the Antibody A washout phase to Week 26. Adverse events were similar between Antibody A and placebo with no dose- related increase in adverse events in Period 1. Antibody A was well tolerated in Period 2. Conclusions:

[0274] Re-induction therapy with 600 mg Antibody A was effective in capturing higher clinical remission rates at Week 26. Overall, Antibody A was well tolerated. Table 13. Period 2: Clinical remission at Week 26 vs Week 12 Placebo 200 mg Antibody A 600 mg Antibody A Number of evaluable patients in Period 2 30 34 34 Patients in clinical remission at Week 12, N 6 8 9 Patients in clinical remission at Week 26, n (%) Yes 6 (100) 6 (75) 9 (100) No 0 2 (25) 0 37 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Patients in clinical remission at Week 26, n (%) Patients not in clinical remission at Week 12, N 24 26 25 Patients in clinical remission at Week 26, n (%) Yes 12 (50) 15 (58) 8 (32) No 12 (50) 11 (42) 17 (68) The proportion of patients in clinical remission at Week 26 after open label intravenous re-induction therapy (600 mg Antibody A at Weeks 14, 18 and 22) in Period 2 are shown by original Period 1 treatment designation and prior Week 12 clinical remission status. All patients who were not in deep remission (clinical remission [CDAI <150] + endoscopic remission [CDEIS ≤4; for patients with initial isolated ileitis a CDEIS ≤2]) at Week 12 underwent Anti- body A re-induction therapy. Example 2: Pharmaceutical compositions

[0275] Examples of formulations suitable for an antibody of the present invention are shown below. Antibodies used in the formulations below are for example Antibody A, Antibody B, Antibody C or Antibody D. Formulation 1:

[0276] Components Concentration [mmol / L] Concentration [g / l] Nominal Amount [mg / vial] V = 10.0 ml Antibody 10.0 100.0 Succinic acid 0.7 0.083 0.8 Disodium succinate hexahydrate 24.3 6.564 65.6 Sodium chloride 125 7.305 73.1 Polysorbat 20 0.16 0.20 0.20 Water for Injection - Ad 1L Ad 1mL

[0277] ThepHof formulation1 is typically in the rangeof pH6.0 to7.0, for examplepH6.5. This formulation is particularly suitable for intravenous administration.

[0278] Molecular weight (MW in g / mol) of used excipients: Disodium succinate hexahydrate = 270.14 g / mol; Succinic acid = 118.09 g / mol; Sodium chloride = 58.44 g / mol.

[0279] The osmolarity of the formulation is 300 + / ‑ 30 mOsmol / kg, as determined using an Osmomat 030 (Gonotec GmbH, Berlin, Germany). The density at 20°C of the formulation is approximately 1.0089 g / cm3, as determined using a measuring unit DMA 4500 (Anton Paar GmbH, Ostfildern-Scharnhausen, Germany). Formulation 2:

[0280] Components Concentration [mmol / L] Concentration [g / l] Nominal Amount [mg / syringe] V = 1.0 ml Antibody 0.6 90.0 90.0 Succinic acid 0.5 0.059 0.059 Disodium succinate hexahydrate 3.9 1.054 1.054 Sorbitol 225 41.00 41.00 38 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 (continued) Components Concentration [mmol / L] Concentration [g / l] Nominal Amount [mg / syringe] V = 1.0 ml Polysorbat 20 0.16 0.20 0.20 Water for Injection - Ad 1L Ad 1mL

[0281] The pH of formulation 2 is typically in the range of pH 5.5 to 6.5, for example 5.5 to 6.1, for example the pH is 5.8. This formulation is particularly suitable for subcutaneous administration.

[0282] Molecular weight (MW in g / mol) of used excipients: MW: Succinic acid (C4H6O4)= 118.09 g / mol MW: Disodium succinate hexahydrate (C4O4Na2H4 x 6H2O) = 270.14 g / mol MW: Sorbitol = 182.17 g / mol MW: Polysorbate 20 = 1227.72 g / mol

[0283] The osmolarity of the formulation is 300 + / ‑ 30 mOsmol / kg, as determined using an Osmomat 030 (Gonotec GmbH, Berlin, Germany). The density at 20°C of the formulation is approximately 1.040 g / cm3, as determined using a measuring unit DMA 4500 (Anton Paar GmbH, Ostfildern-Scharnhausen, Germany). Formulation 3:

[0284] Components Concentration [mmol / L] Concentration [g / l] Nominal Amount [mg / syringe] V = 1.0 ml Antibody 0.6 90.0 90.0 Sorbitol 240 43.733 43.733 Polysorbat 20 0.16 0.20 0.20 Water for Injection - Ad 1L Ad 1mL

[0285] The pH of formulation 3 is typically in the range of pH 5.5 to 6.5, for example 5.5 to 6.1, for example the pH is 5.8. This formulation is particularly suitable for subcutaneous administration.

[0286] Molecular weight (MW in g / mol) of used excipients: MW: Sorbitol = 182.17 g / mol MW: Polysorbate 20 = 1227.72 g / mol.

[0287] The osmolarity of the formulation is 300 + / ‑ 30 mOsmol / kg, as determined using an Osmomat 030 (Gonotec GmbH, Berlin, Germany). Preferred Embodiments

[0288] 1. Amethod for inducing remission of Crohn’s Disease comprising administering to a patient an anti-IL‑23A antibody, said method comprising: a) administering at least one induction dose of said anti-IL‑23A antibody to the patient, wherein said induction dose comprises 200 to 1,200 mg of said anti-IL‑23A antibody. 2. The method according to item 1, wherein said induction dose comprises 450 to 1,200 mg of said anti-IL‑23A antibody. 39 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 3. Themethod according to item1, wherein said induction dose comprises 200mg, 450mg, 600mg, 900mg or 1,200 mg of said anti-IL‑23A antibody. 4. Themethod according to any one of items 1 to 3, wherein 1, 2 or 3 induction doses are administered to the patient. 5. The method according to any one of items 1 to 4, wherein 2 or 3 inductions doses are administered at 4 weeks intervals. 6. The method according to any one of items 1 to 5, wherein said induction dose is administered by intravenous infusion. 7. The method according to anyone of items 1 to 6, wherein said patient has a CDAI score of 220‑450 before said administration in step a). 8. The method according to anyone of items 1 to 7, wherein said patient achieves a CDAI score of less than 150. 9. Themethod according to anyone of items 1 to 8, wherein said patient achieves a PRO‑2 score equal to or less than 75. 10.Themethodaccording toanyoneof items1 to9, further comprisingmaintaining remissionofCrohn’sdisease, said method further comprising: b) administering a firstmaintenancedoseof said anti-IL‑23Aantibody to thepatient after the last induction dose is administered; and c) administering at least oneadditionalmaintenance dose to thepatient 4 to 12weeksafter said firstmaintenance dose is administered. 11.Themethodaccording toanyoneof items10,wherein said firstmaintenancedose isadministered2 to8weeks, for example4 to6weeks, for example2weeks, 4weeks, 6weeksor8weeks, after the last inductiondose isadministered. 12. The method according to any one of items 10 or 11, wherein said at least one additional maintenance dose is administered to the patient 4, 8 or 12 weeks after said first maintenance dose is administered. 13. Themethod according to any one of items 10 to 12, wherein said firstmaintenance dose comprises 150 to 300mg of said anti-IL‑23A antibody. 14. The method according to any one of items 10 to 13, wherein said first maintenance dose comprises 150 mg, 225 mg or 300 mg of said anti-IL‑23A antibody. 15.Themethod according to any one of items 10 to 14, wherein said firstmaintenance dose comprises 180mg or 270 mg of said anti-IL‑23A antibody. 16. The method according to any one of items 10 to 15, wherein said at least one additional maintenance dose comprises 150 to 300 mg of said anti-IL‑23A antibody. 17. The method according to any one of items 10 to 16, wherein said at least one additional maintenance dose comprises 150 mg, 225 mg or 300 mg of said anti-IL‑23A antibody. 18. The method according to any one of items 10 to 17, wherein said at least one additional maintenance dose comprises 180 mg or 270 mg of said anti-IL‑23A antibody. 19. The method according to any one of items 10 to 18, wherein said first maintenance dose and said at least one additional maintenance dose comprise 150 to 300 mg of said anti-IL‑23A antibody. 20. The method according to any one of items 10 to 19, wherein said first maintenance dose and said at least one additional maintenance dose comprise 150 mg, 225 mg or 300 mg of said anti-IL‑23A antibody. 21. The method according to any one of items 10 to 20, wherein said first maintenance dose and said at least one 40 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 additional maintenance dose comprise 180 mg or 270 mg of said anti-IL‑23A antibody. 22. The method according to any one of items 10 to 21, wherein said maintenance dose is administered by subcutaneous injection. 23. Themethod according to anyone of items 10 to 22, wherein said patient maintains a CDAI score of less than 150. 24. Themethod according to anyone of items 10 to 23, wherein said patient maintains a PRO‑2 score equal to or less than 75. 25. A method for treating Crohn’s Disease comprising administering to a patient 150 to 1,200 mg of an anti-IL‑23A antibody. 26.The method according to item 25, said method comprising administering to a patient 200 to 1,200 mg of an anti- IL‑23A antibody. 27. The method according to item 25, said method comprising administering to a patient 450 to 1,200 mg of an anti- IL‑23A antibody. 28. Themethodaccording to item25, saidmethod comprisingadministering to apatient 200mg, 450mg, 600mg, 900 mg or 1,200 mg of an anti-IL‑23A antibody. 29. The method according to item 25, said method comprising administering to a patient 150 to 300 mg of an anti- IL‑23A antibody. 30. Themethod according to item25, saidmethod comprising administering to a patient 150mg, 225mgor 300mg of an anti-IL‑23A antibody. 31. Themethod according to item 25, saidmethod comprising administering to a patient 180mg or 270mg of an anti- IL‑23A antibody. 32. Amethod for treatingCrohn’sDisease comprising administering to a patient an anti-IL‑23Aantibody, saidmethod comprising: a) administering at least one induction dose of said anti-IL‑23A antibody to the patient, wherein said induction dose comprises 200 to 1,200 mg of said anti-IL‑23A antibody. 33. The method according to item 32, further comprising: b) administering a firstmaintenancedoseof said anti-IL‑23Aantibody to thepatient after the last induction dose is administered; and c) administering at least oneadditionalmaintenance dose to thepatient 4 to 12weeksafter said firstmaintenance dose is administered. 34.Themethodaccording to item33,whereinsaidfirstmaintenancedosecomprises150 to300mgof saidanti-IL‑23A antibody. 35. The method according to item 33 or 34, wherein said at least one additional maintenance dose comprises 150 to 300 mg of said anti-IL‑23A antibody. 36. The method according to anyone of items 1 to 35, wherein said anti-IL‑23A antibody is Antibody A, Antibody B, Antibody C or Antibody D. 37. The method according to anyone of items 1 to 36, wherein said method is for treating moderate to severe active Crohn’s Disease. 41 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 Claims 1. An anti-IL‑23A antibody for use in a method of treating an inflammatory bowel disease, wherein the anti-IL‑23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:18 and a heavy chain comprising the amino acid sequence of SEQ ID NO:19, and wherein theusecomprisesadministering three inductiondosesat4weeks intervals,whereineach inductiondose comprises 200 mg to 1200 mg of the anti-IL‑23A antibody. 2. An anti-IL‑23A antibody for use for inducing remission of an inflammatory bowel disease, wherein the anti-IL‑23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:18 and a heavy chain comprising the amino acid sequence of SEQ ID NO:19, and wherein theusecomprisesadministering three inductiondosesat4weeks intervals,whereineach inductiondose comprises 200 mg to 1200 mg of the anti-IL‑23A antibody. 3. Theanti-IL‑23Aantibody for useaccording to claim1or 2,wherein each induction dose comprises450mg to 1200mg of the anti-IL‑23A antibody. 4. Theanti-IL‑23Aantibody for useaccording to claim1or 2,wherein each induction dose comprises600mg to 1200mg of the anti-IL‑23A antibody. 5. The anti-IL‑23A antibody for use according to claim 1 or 2, wherein each induction dose comprises 600mg of the anti- IL‑23A antibody. 6. Theanti-IL‑23Aantibody for useaccording to claim1or2,whereineach inductiondosecomprises1200mgof theanti- IL‑23A antibody. 7. The anti-IL‑23A antibody for use according to any one of the preceding claims, wherein the use comprises administering induction doses at week 0, week 4 and week 8. 8. The anti-IL23A antibody for use according to any one of the preceding claims, wherein the use further comprises administering at least one additional induction dose of the anti-IL‑23A antibody, wherein an additional induction dose comprises 200mg to 1200mg of the anti-IL‑23A antibody, preferably wherein an additional induction dose comprises 450 to 1200 mg of the anti-IL‑23A antibody. 9. The anti-IL‑23A antibody for use according to any one of the preceding claims, wherein a patient to be treated has a CDAI score of 220‑450 before the administration of the first induction dose. 10. The anti-IL‑23A antibody for use according to any one of the preceding claims, wherein the patient is an adult patient. 11. The anti-IL‑23A antibody for use according to any one of the preceding claims, wherein the induction doses are administered by parenteral administration, in particular by intravenous infusion. 12. The anti-IL‑23A antibody for use according to any one of the preceding claims, wherein the use further comprises administering a first maintenance dose of the anti-IL‑23A antibody after the last induction dose is administered and administeringat least oneadditionalmaintenancedose4 to12weeksafter thefirstmaintenancedose isadministered, preferably 8 weeks after the first maintenance dose is administered, and wherein, preferably, the first maintenance dose is administered 2, 4, 6 or 8 weeks after the last induction dose was administered. 13. Theanti-IL‑23Aantibody for useaccording toclaim12,wherein thefirstmaintenancedose isadministeredatweek12, a secondmaintenance dose at week 20, optionally a thirdmaintenance dose at week 28 and so on at dosing intervals of 8 weeks between the maintenance doses. 14. The anti-IL‑23A antibody for use according to claim 12 or 13, wherein the first maintenance dose and the at least one additional maintenance dose are administered parenterally, preferably subcutaneously. 15. The anti-IL‑23A antibody for use according to any one of the preceding claims, wherein the IBD is Crohn’s disease, 42 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 preferably wherein the Crohn’s disease is moderately to severely active Crohn’s disease, and further preferably, wherein the dose during the induction treatment is 600 mg of said antibody. 16. The anti-IL‑23A antibody for use according to any of the preceding claims, wherein the anti-IL‑23A antibody is a full- length anti-IL‑23A antibody, preferably wherein said anti-IL‑23A antibody comprises two light chains each having the aminoacid sequenceofSEQ IDNO:18, and twoheavy chain eachhaving the aminoacid sequence ofSEQ IDNO:19. 17. The anti-IL‑23A antibody for use according to any of claims 12 - 16, wherein the maintenance dose is 180 mg or 270 mg, preferably 180 mg. 18. Theanti-IL‑23Aantibody foruseaccording toanyof theprecedingclaims,wherein thepatientachievescorticosteroid- free remission. 19. The anti-IL‑23A antibody for use according to any of the preceding claims, wherein the patient achieves clinical remission and endoscopic remission. 20. The anti-IL‑23A antibody for use according to any of the preceding claims, wherein the patient achieves mucosal healing. 43 EP 4 752 158 A2 5 10 15 20 25 30 35 40 45 50 55 44 EP 4 752 158 A2 45 EP 4 752 158 A2 46 EP 4 752 158 A2 47 EP 4 752 158 A2 48 EP 4 752 158 A2 49 EP 4 752 158 A2 50 EP 4 752 158 A2 51 EP 4 752 158 A2 REFERENCES CITED IN THE DESCRIPTION This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard. Patent documents cited in the description • WO 2007005955 A

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[0229] 摘要 本发明概括而言涉及使用抗IL-23A抗体治疗IL-23相关疾病、具体 而言炎性疾病、例如克罗恩病(Crohn’s Disease)的方法。

Claims

1. An anti-IL-23A antibody for use in a method of treating an inflammatory bowel disease, wherein the anti-IL-23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:18 and a heavy chain comprising the amino acid sequence of SEQ ID NO:19, and wherein the use comprises administering three induction doses at 4 weeks intervals, wherein each induction dose comprises 200 mg to 1200 mg of the anti-IL-23A antibody.

2. An anti-IL-23A antibody for use for inducing remission of an inflammatory bowel disease, wherein the anti-IL-23A antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:18 and a heavy chain comprising the amino acid sequence of SEQ ID NO:19, and wherein the use comprises administering three induction doses at 4 weeks intervals, wherein each induction dose comprises 200 mg to 1200 mg of the anti-IL-23A antibody.

3. The anti-IL-23A antibody for use according to claim 1 or 2, wherein each induction dose comprises 450 mg to 1200 mg of the anti-IL-23A antibody.

4. The anti-IL-23A antibody for use according to claim 1 or 2, wherein each induction dose comprises 600 mg to 1200 mg of the anti-IL-23A antibody.

5. The anti-IL-23A antibody for use according to claim 1 or 2, wherein each induction dose comprises 600 mg of the anti-IL-23A antibody.

6. The anti-IL-23A antibody for use according to claim 1 or 2, wherein each induction dose comprises 1200 mg of the anti-IL-23A antibody.

7. The anti-IL-23A antibody for use according to any one of the preceding claims, wherein the use comprises administering induction doses at week 0, week 4 and week 8.

8. The anti-IL23A antibody for use according to any one of the preceding claims, wherein the use further comprises administering at least one additional induction dose of the anti-IL-23A antibody, wherein an additional induction dose comprises 200 mg to 1200 mg of the anti-IL-23A antibody, preferably wherein an additional induction dose comprises 450 to 1200 mg of the anti-IL-23A antibody.

9. The anti-IL-23A antibody for use according to any one of the preceding claims, wherein a patient to be treated has a CDAI score of 220-450 before the administration of the first induction dose.

10. The anti-IL-23A antibody for use according to any one of the preceding claims, wherein the patient is an adult patient.

11. The anti-IL-23A antibody for use according to any one of the preceding claims, wherein the induction doses are administered by parenteral administration, in particular by intravenous infusion.

12. The anti-IL-23A antibody for use according to any one of the preceding claims, wherein the use further comprises administering a first maintenance dose of the anti-IL-23A antibody after the last induction dose is administered and administering at least one additional maintenance dose 4 to 12 weeks after the first maintenance dose is administered, preferably 8 weeks after the first maintenance dose is administered, and wherein, preferably, the first maintenance dose is administered 2, 4, 6 or 8 weeks after the last induction dose was administered.

13. The anti-IL-23A antibody for use according to claim 12, wherein the first maintenance dose is administered at week 12, a second maintenance dose at week 20, optionally a third maintenance dose at week 28 and so on at dosing intervals of 8 weeks between the maintenance doses.

14. The anti-IL-23A antibody for use according to claim 12 or 13, wherein the first maintenance dose and the at least one additional maintenance dose are administered parenterally, preferably subcutaneously.

15. The anti-IL-23A antibody for use according to any one of the preceding claims, wherein the IBD is Crohn's disease, preferably wherein the Crohn's disease is moderately to severely active Crohn's disease, and further preferably, wherein the dose during the induction treatment is 600 mg of said antibody.

16. The anti-IL-23A antibody for use according to any of the preceding claims, wherein the anti-IL-23A antibody is a full-length anti-IL-23A antibody, preferably wherein said anti-IL-23A antibody comprises two light chains each having the amino acid sequence of SEQ ID NO:18, and two heavy chain each having the amino acid sequence of SEQ ID NO:19.

17. The anti-IL-23A antibody for use according to any of claims 12 - 16, wherein the maintenance dose is 180 mg or 270 mg, preferably 180 mg.

18. The anti-IL-23A antibody for use according to any of the preceding claims, wherein the patient achieves corticosteroid-free remission.

19. The anti-IL-23A antibody for use according to any of the preceding claims, wherein the patient achieves clinical remission and endoscopic remission.

20. The anti-IL-23A antibody for use according to any of the preceding claims, wherein the patient achieves mucosal healing.

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