USOO8435523B2 (12) United States Patent (10) Patent No.: US 8,435,523 B2 POWell et al. (45) Date of Patent: May 7, 2013 (54) ANTIBODIES AGAINST NERVE GROWTH 2008, OO63635 A1 3/2008 Takahashi et al. 2008/0081040 A1 4/2008 Shelton et al. FACTOR (NGF) WITH ENHANCED IN VIVO 2008. O107658 A1 5/2008 Franks et al. STABILITY 2008. O182978 A1 7/2008 Rosenthal et al. 2008, 0213282 A1 9, 2008 Jacob et al. (75) Inventors: John Powell, Cambridgeshire (GB); 2009/004 1717 A1 2/2009 MacDonald et al. Duncan Casson, Royston (GB); Mark 2009. O155274 A1 6/2009 Wild, Jr. et al. 2009, 0208490 A1 8, 2009 Pavone et al. Maginn, Wilburton (GB); Wei Liu, 2009/0300780 A1 12/2009 Cattaneo et al. Mundelein (IL); Sandeep Dutta, Gurnee 2010.0034.818 A1 2/2010 Wild, Jr. et al. (IL); Andrea Best, Lake Forest (IL); 2010.005.5097 A1 3/2010 Kaisheva et al. Jerry A. Hall, Gurnee (IL) 2010/01 11970 A1 5, 2010 Pons et al. 2010.0143355 A1 6, 2010 Shelton et al. (73) Assignee: Abbott Research B.V. Zwolle (NL) 2010/0240582 A1 9/2010 Boone et al. 2010/026O775 A1 10/2010 Mills et al. 2010/0267934 A1 10/2010 Van De Winkel et al. (*) Notice: Subject to any disclaimer, the term of this 2011 OO14208 A1 1/2011 Macdonald et al. patent is extended or adjusted under 35 2011 OO33447 A1 2/2011 Rosenthal et al. U.S.C. 154(b) by 438 days. 2011/0091476 A1 4/2011 Wild, Jr. et al. 2011 0104164 A1 5/2011 Cattaneo et al. (21) Appl. No.: 12/773,488 2011/0105728 A1 5/2011 Cattaneo et al. 2011 019 1872 A1 8/2011 Cattaneo et al. 2011/0243961 A1 10/2011 Shelton et al. (22) Filed: May 4, 2010 2011/O256587 A1 10/2011 Macdonald et al. (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2010/0278839 A1 Nov. 4, 2010 EP O578515 1, 1994 EP 059.2106 4f1994 EP 1891966 2, 2008 Related U.S. Application Data EP 2100902 9, 2009 (60) Provisional application No. 61/175.228, filed on May EP 219 1846 6, 2010 4, 2009, provisional application No. 61/227,251, filed (Continued) on Jul. 21, 2009, provisional application No. 61/238, OTHER PUBLICATIONS 813, filed on Sep. 1, 2009, provisional application No. Berardi et al., “Monoclonal antibodies to nerve growth factor affect 61/252,314, filed on Oct. 16, 2009. the postnatal development of the visual system.” Proc. Natl. Acad. Sci. USA,91:684-688 (1994). (51) Int. Cl. Boss et al., Immunol. Today, 6:12-13 (1985). A 6LX39/395 (2006.01) Bothwell, “p75NTR: a receptor after all.” Science, 272(5261):506 C07K 6/22 (2006.01) 507 (1996). Cattaneo et al., “Functional Blockade of Tyrosine Kinasea in the Rat (52) U.S. Cl. Basal Forebrain in a Novel Antagonistic Anti Receptor Monoclonal USPC ................... 424/145.1: 514/17.7:530/388.24 Antibody.” J. Neurosci., 19(22):9687-9697 (1999). (58) Field of Classification Search ........................ None Graziano et al., "Construction and characterization of a humanized See application file for complete search history. anti-gamma-Ig receptor type I (Fc gamma RI) monoclonal antibody.” J. Immunol., 155(10):4996-5002 (1995). (56) References Cited Harding et al., "Class Switching in human immunoglobulin transgenic mice.” Ann. NY Acad. Sci., 764:536-546 (1995). Hinton et al., “An engineered human IgG1 antibody with longer U.S. PATENT DOCUMENTS serum half-life.” J. Immunol., 176(1):346-356 (2006). 4,230,691 A 10/1980 Young Hinton et al., “Engineered human IgG antibodies with longer serum 6,017,878 A 1/2000 Saragoviet al. half-lives in primates.” J. Biol. Chem., 279 (8):6213-6216 (2004). 6,919,426 B2 7/2005 Boone et al. Morrison, “Transfectomas provide novel chimeric antibodies.” Sci 7,252,822 B2 8, 2007 Shelton et al. ence, 229(4719): 1202-1207 (1985). 7,255,860 B2 8, 2007 Shelton et al. 7,371,559 B2 5, 2008 Boone et al. (Continued) 7,425,329 B2 9, 2008 Shelton et al. 7,449,616 B2 11/2008 Pons et al. Primary Examiner — Robert C Hayes 7,569,364 B2 8, 2009 Rosenthal et al. (74) Attorney, Agent, or Firm — McAndrews, Held & 7,601,818 B2 10/2009 Wild, Jr. et al. 7,655,231 B2 2/2010 Shelton et al. Malloy, Ltd. 7,655,232 B2 2/2010 Pons et al. (57) ABSTRACT 7.727,527 B2 6, 2010 Shelton 7,795,413 B2 9/2010 Wild, Jr. et al. The present invention provides anti-nerve growth factor 7,988,967 B2 8/2011 MacDonald et al. (NGF) antibodies that contain an IgG4 constant region com 8,007,800 B2 8, 2011 Shelton et al. prising a stabilizing hinge region mutation and wherein the 2001/004.6959 A1 11/2001 Buchkovich et al. antibodies exhibit an unexpectedly long serum half life in 2004f0071701 A1 4/2004 Delafoy et al. 2004/O131615 A1 7/2004 Shelton et al. cynomolgus monkeys. Pharmaceutical compositions com 2004/0228862 A1 11/2004 Shelton et al. prising the anti-NGF antibodies, nucleic acids encoding the 2004/0237124 A1 11/2004 Pons et al. NGF antibodies, host cells for expressing the NGF antibodies 2005, OO74821 A1 4, 2005 Wild et al. and methods of using the antibodies for treating NGF-related 2006, O147450 A1 7/2006 Shelton 2007/0264195 A1 1 1/2007 Nykiaer et al. diseases or conditions are also provided. 2008.OO33157 A1 2/2008 Wild et al. 9 Claims, 7 Drawing Sheets US 8,435,523 B2 Page 2 FOREIGN PATENT DOCUMENTS Ro et al., “Effect of NGF and anti-NGF on neuropathic pain in rats EP 22O6728 T 2010 following chronic constriction injury of the Sciatic nerve.” Pain, EP 2263692 12/2010 79:265-274 (1999). EP 227OO48 1, 2011 Ruberti et al., “Phenotypic knockout of nerve growth factor in adult WO 92.09631 6, 1992 transgenic mice reveals severe deficits in basal forebrain cholinergic WO 90, 10644 9, 1999 neurons, cell death in the spleen, and skeletal muscle dystrophy.” J. WO OOf73344 12/2000 WO O1 10203 2, 2001 Neurosci., 2007):2589-2601 (2000). WO 01.64247 9, 2001 Ruberti et al., “The use of the RACE method to clone hybridoma WO O1 (78698 10, 2001 cDNA when V region primers fail.” J. Immunol. Methods, 173:33-39 WO O2/O964.58 12/2002 (1994). WO 2004/026329 4/2004 Rudikoff et al., “Single amino acid Substitution altering antigen WO 2004/032852 4/2004 binding specificity.” Proc. Natl. Acad. Sci. Usa, 79 (6):1979-1983 WO 2004/032870 4/2004 (1982). WO 2004/056385 T 2004 Saragoviet al., “Development of pharmacological agents for target WO 2004/0581.84 T 2004 ing neurotrophins and their receptors. Trends Pharmacol. Sci., WO 2004/065560 8, 2004 WO 2004/0736.53 9, 2004 21(3):93-98 (2000). WO 2005/OOO194 1, 2005 Shields et al., “High resolution mapping of the binding site on human WO 2005/O19266 3, 2005 IgG1 for Fc gamma RI. Fc gamma RII, Fc gamma RIII, and FcRn and WO 2005/044.293 5, 2005 design of IgG1 variants with improved binding to the Fc gamma R. WO 2005/061540 7/2005 J. Biol. Chem., 276 (9):6591-6604 (2001). WO 2005/061540 A2 * T 2005 Stephens et al., “Comprehensive pharmacokinetics of a humanized WO 2005,105847 11, 2005 antibody and analysis of residual anti-idiotypic responses.” Immu WO 2005,111077 11, 2005 nology, 85(4):668-674 (1995). WO 2006/077441 T 2006 Tripathy et al., “TrkAkinase inhibitors from a library of modified and WO 2006, 110883 10, 2006 isosteric Staurosporine aglycone.” Bioorg. Med. Chem. Lett. WO 2006,131951 12/2006 WO 2006,131952 12/2006 18(12):3551-3555 (2008). WO 2006,137106 12/2006 Angal et al., “A Single Amino Acid Substitution Abolishes the Het WO 2008. 145142 12/2008 erogeneity of Chimeric Mouse/Human (IgG4) Antibody.” Mol. WO 2009/023540 2, 2009 Immunol. 30(1) 105-108 (1993). WO 2009 O77993 6, 2009 Cattaneo et al., “Three Distinct Types of Monoclonal Antibodies WO 2010, 128398 11, 2010 After Long-Term Immunization of Rats with Mouse Nerve Growth WO 2011 116090 9, 2011 Factor.” J. Neurochem, 50:1003-1010 (1988). Correia, "Stability of IgG isotypes in serum.” mAbs, 2(3):1-12 OTHER PUBLICATIONS (2010). Myers et al., “Optimal alignments in linear space.” Comput. Appl. International Preliminary Report on Patentability in PCT/IB2010/ Biosci., 4(1): 11-17 (1988). 00.1210 dated Nov. 9, 2011. Needleman et al., “A general method applicable to the search for International Search Report in PCT/IB2010/001210 dated Sep. 10, similarities in the amino acid sequence of two proteins. J. Mol. Biol. 2010. 48(3):443-453 (1970). Ruberti et al., “Cloning and Expression of an Anti-Nerve Growth Petkova et al., “Enhanced half-life of genetically engineered human Factor (NGF) Antibody for Studies Using the Neuroantibody IgG1 antibodies in a humanized FeRn mouse model: potential appli Approach.” Cell. Mol. Neurobiol. 13(5):559-568 (1993). cation in humorally mediated autoimmune disease.” Itn. Immunol. 18(12): 1759-1769 (2006). * cited by examiner U.S. Patent May 7, 2013 Sheet 1 of 7 US 8,435,523 B2 torescece its : & 8 F dig Figure U.S. Patent May 7, 2013 Sheet 2 of 7 US 8,435,523 B2 % Cottro; 3isting X : & : : *: Figure 2A U.S. Patent May 7, 2013 Sheet 3 of 7 US 8,435,523 B2 % controi Biciing i Figure 28 U.S. Patent May 7, 2013 Sheet 4 of 7 US 8,435,523 B2 % controi response g Figure 3A U.S.