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(12) United States Patent (10) Patent No.: US 8,092,998 B2 Stuhlmiller Et Al USO08092998B2 (12) United States Patent (10) Patent No.: US 8,092,998 B2 Stuhlmiller et al. (45) Date of Patent: Jan. 10, 2012 (54) BOMARKERS PREDCTIVE OF THE 2007/0172475 A1 7/2007 Matheus et al. RESPONSIVENESS TO TNFO INHIBITORS IN 2007/0172897 A1 7/2007 Maksymowych et al. 2007. O184045 A1 8, 2007 Doctor et al. AUTOIMMUNE DISORDERS 2007/0202051 A1 8/2007 Schusching 2007/0202104 A1 8/2007 Banerjee et al. (75) Inventors: Bruno Stuhlmiller, Berlin (DE): 2007/0237831 A1 10/2007 Sung et al. 2007,0269.463 A1 11/2007 Donavan Gerd-Reudiger Burmester, Berlin (DE) 2007,0292442 A1 12/2007 Wan et al. 2008.0118496 A1 5/2008 Medich et al. (73) Assignee: Abbott Laboratories, Abbott Park, IL 2008. O1313.74 A1 6/2008 Medich et al. (US) 2008. O166348 A1 7/2008 Kupper et al. 2008.0193466 A1 8/2008 Banerjee et al. 2008/0227136 A1 9, 2008 Pla et al. (*) Notice: Subject to any disclaimer, the term of this 2008/0311043 A1 12/2008 Hoffman et al. patent is extended or adjusted under 35 2009/0028794 A1 1/2009 Medich et al. U.S.C. 154(b) by 5 days. 2009/0110679 A1 4/2009 Li et al. 2009/O123378 A1 5/2009 Wong et al. (21) Appl. No.: 12/130,373 2009, O1485.13 A1 6/2009 Fraunhofer et al. (Continued) (22) Filed: May 30, 2008 FOREIGN PATENT DOCUMENTS (65) Prior Publication Data EP 1795610 A1 * 6, 2007 US 2009/OO17472 A1 Jan. 15, 2009 (Continued) Related U.S. Application Data OTHER PUBLICATIONS (60) Provisional application No. 60/932,888, filed on May Asli, Bouchira et al., “Inhibition of Tumor Necrosis Factor O and 31, 2007. Ankylosing Spondyiltis.” N. Engl. J. Med., vol. 348(4):359-361 (2003). Int. C. Boeger, C.A. et al., “Treatment of ankylosing spondylitis with (51) infliximab.” Ann. Rheum. Dis... vol. 60(12): 1159-1160 (2001). CI2O I/68 (2006.01) Brandt, Janet al., “Successful Short Term Treatment of Severe Undif GOIN33/53 (2006.01) ferentiated Spondyloarthropathy with the Anti-Tumor Necrosis Fac (52) U.S. Cl. .......................................... 435/6.1; 435/7.1 tor-O. Monoclonal Antibody lnfliximab.” The Journal of Rheumatol Field of Classification Search ........................ None ogy, vol. 29(1):118-122 (2002). (58) Brandt, Jan et al., “Successful Treatment of Active Ankylosing See application file for complete search history. Spondylitis with the Anti-tumor Necrosis Factor O. Monoclonal Anti body lnfliximab.” Arthritis & Rheumatism, vol. 43(6): 1346-1352 (56) References Cited (2000). Braun, J. et al., “Anti-TNFO: a new dimension in the U.S. PATENT DOCUMENTS pharmacotherapy of the spondyloarthropathies?” Ann. Rheum. Dis. 6,090,382 A 7/2000 Salfeld et al. vol. 59(6):404–407 (2000). 6,258,562 B1 7/2001 Salfeld et al. 6,506,607 B1 1/2003 Shyjan (Continued) 6,509,015 B1 1/2003 Salfeld et al. 6,607,879 B1 8, 2003 Cocks et al. Primary Examiner — James Martinell 7,223,394 B2 5, 2007 Salfeld et al. (74) Attorney, Agent, or Firm — McCarter & English, LLP: 7,541,031 B2 6, 2009 Salfeld et al. Cristin Howley Cowles; Deborah L. Nagle 7,588,761 B2 9, 2009 Salfeld et al. 2003, OO12786 A1 1/2003 Teoh et al. (57) ABSTRACT 2003.0161828 A1 8/2003 Abdelghany et al. 2003/0206898 A1 11/2003 Fischkoff et al. The invention provides methods for predicting responsive 2003/0219438 A1 11/2003 Salfeld et al. ness to TNFC. inhibitors in a subject suffering from an autoim 2003/0235585 A1 12/2003 Fischkoff 2004.0009172 A1 1/2004 Fischkoffet al. mune disorder, such as rheumatoid arthritis. The methods 2004/0033228 A1 2, 2004 Krause et al. involve assaying for expression of one or more biomarkers in 2004/O126372 A1 7/2004 Banerjee et al. the subject that are predictive of responsiveness to TNFC. 2004/O126373 A1 7/2004 Banerjee et al. inhibitors. A preferred biomarker of the invention is CD11c. 2004/O131614 A1 7/2004 Banerjee et al. The methods can further comprise selecting a treatment regi 2004/O136989 A1 7/2004 Banerjee et al. men with a TNFC. inhibitor in an autoimmune disorder sub 2004/O136990 A1 7/2004 Banerjee et al. ject based upon expression of the biomarker(s) in the Subject. 2004/O136991 A1 7/2004 Banerjee et al. 2004/O151722 A1 8/2004 Banerjee et al. The methods can further comprise administering a TNFC. 2004O1661 11 A1 8/2004 Kaymakcalan et al. inhibitor to the subject according to the selected treatment 2004/0219142 A1 11/2004 Banerjee et al. regimen. Kits that include means for measuring expression of 2006,0009385 A1 1/2006 Hoffman et al. one or more biomarkers that are predictive of responsiveness 2006, 0083741 A1 4/2006 Hoffman et al. to TNFC. inhibitors for an autoimmune disorder are also pro 2006, O149042 A1 7/2006 Konstantinov vided. Methods of preparing and using databases, and com 2006, O153846 A1 7/2006 Krause et al. 2006/0216707 A1* 9, 2006 Stuhlmuller et al. ............. 435/6 puter program products therefore, for selecting an autoim 2006/02694.79 A1 11, 2006 Colton et al. mune disorder subject for treatment with a TNFC. inhibitor 2007/0041905 A1 2/2007 Hoffman et al. are also provided. 2007/007 1747 A1 3/2007 Hoffman et al. 2007/0081996 A1 4/2007 Hoffman et al. 42 Claims, 3 Drawing Sheets US 8,092.998 B2 Page 2 U.S. PATENT DOCUMENTS Emery, Paul et al., “Changes in PRO-MMP-1 in Relation to Standard 2009. O155205 A1 6, 2009 Salfeld et al. Measures of Disease Activity Over a 6Months Treatment Period with 2009,0280065 A1 11, 2009 Willian et al. Adalimumab (D2E7) in Rheumatoid Arthritis.” Arthritis Rheum., 2010.0034823 A1 2/2010 Borhani et al. vol. 44(Suppl.):S215, No. 976 (2001). 2010.0040604 A1 2/2010 Salfeld et al. Furst, D. et al., “TNF Blockade by the Fully Human Monoclonal 2010, 0160894 A1 6/2010 Julian et al. Antibody Adalimumab (D2E7) in the Armada Trial Results in FOREIGN PATENT DOCUMENTS Decrease in Serum Matrix Metalloproteinase (MMP) Levels Along with Impressive Clinical Improvement in Refractory RA Patients.” WO WO972.91.31 8, 1997 WO WO-2004/O16809 A1 * 2, 2004 Arthritis Rheum., vol. 44(9 Suppl.):S215, No. 975 (2001). WO WO 20060925.30 9, 2006 Garnero, Patrick et al., “Association of Baseline Levels of Urinary WO WO 2008028044 3, 2008 Glucosyl-Galactosyl-Pyridinoline and Type II Collagen C-Telopeptide With Progression of Joint Destruction in Patients With OTHER PUBLICATIONS Early Rheumatoid Arthritis.” Arthritis & Rheumatism, vol. 46(1):21 Braun, J. et al., “Anti-tumour necrosis factor Otherapy for ankylosing 30 (2002). spondylitis: international experience.” Ann. Rheum. Dis... vol. Gorman, Jennifer D. et al., “Treatment of Ankylosing Spondylitis by 61(Suppl. III):iii.51-iii60 (2002). Inhibition of Tumor Necrosis Factor C.” The New England Journal of Braun, J. et al., “Biologic therapies in the spondyloarthritis: new Medicine, vol. 346(18): 1349-1356 (2002). opportunities, new challenges.” Curr: Opin. Rheumatol., vol. 15:394 Hawley, Peter et al., “Evaluation of an ELISA Assay for the Simul 407 (2003). taneous Detection of HIV-1 Antibodies and Hepatitis B Surface Anti Braun, J. et al., “International ASAS consensus statement for the use gen.” VII International Conference on Aids, Abstracts vol. II, p. 345, of anti-tumour necrosis factor agents in patients with ankylosing No. W.C.3196 (1991). spondylitis.” Ann. Rheum. Dis... vol. 62:817-824 (2003). Horneff, G. et al., “TNF-C. antagonists for the treatment of juvenile Braun, Jürgen et al., “New treatment options in onset spondyloarthritides.” Clin. Exp. Rheumatol., vol. 20(Suppl. spondyloarthropathies: increasing evidence for significant efficacy of 28):S137-S142 (2002). anti-tumor necrosis factor therapy,” Current Opinion in Rheumatol Kaiser, M.J. et al., “Efficacy of infliximab (Remicade(R) in the treat ogy, vol. 13:245-249 (2001). ment of spondyloarthropathies. Two case reports.' Joint Bone Spine, Braun, Juergen et al., “Novel approaches in the treatment of ankylos vol. 68:525-527 (2001). ing spondylitis and other spondyloarthritides. Expert Opin. Investig. KeySZer, G. et al., “Circulating levels of matrix metalloproteinases Drugs, vol. 12(7): 1097-1109 (2003). MMP-3 and MMP-1, tissue inhibitor of metalloproteinases 1 (TIMP Braun, J. et al., “Persistent clinical response to the anti-TNFO anti 1), and MMP-1/TIMP-1 complex in rheumatoid disease. Correlation body infliximab in patients with ankylosing spondylitis over 3 years.” with clinical activity of rheumatoid arthritis versus other Surrogate Rheumatology, vol. 44:670-676 (2005). markers.” J. Rheumatol., vol. 26(2):251-258 (1999). Braun, Juergen et al., “Therapy of ankylosing spondylitis and other MacCallum, Robert M. et al., “Antibody-antigen Interactions: Con spondyloarthritides: established medical treatment, anti-TNF-C. tact Analysis and Binding Site Topography.” J. Mol. Biol., vol. therapy and other novel approaches.” Arthritis Res., vol. 4:307-321 262:732-745 (1996). (2002). Maini R et al., “Infliximab (chimeric anti-tumour necrosis factor Braun, J. et al., “Treatment of active ankylosing spondylitis with alpha monoclonal antibody) versus placebo in rheumatoid arthritis infliximab: a randomised controlled multicentre trial.” Lancet, vol. patients receiving concomitant methotrexate: a randomised phase III 359:1187-1193 (2002). trial.” The Lancet, vol. 354: 1932-39 (1999). Breban, M. et al., “Efficacy of infliximab in refractory ankylosing Maksymowych, Walter P. et al., “Canadian Rheumatology Associa spondylitis: results of a six-month open-label study, Rheumatology, tion Consensus on the Use of Anti-Tumor Necrosis Factor-O. Directed vol. 41: 1280-1285 (2002). Therapies in the Treatment of Spondyloarthritis.” The Journal of Briot, K. et al., “Body weight, body composition, and bone turnover Rheumatology, vol.
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