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( 12 ) United States Patent US010392438B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 ,392 ,438 B2 Bennett et al. ( 45 ) Date of Patent : Aug . 27 , 2019 ( 54 ) BISPECIFIC ANTIBODIES 2002/ 0039995 Al 4 / 2002 Gao 2008 /0269466 Al 10 /2008 Humphreys 2010 /0150914 A1 6 /2010 Wang et al . ( 71 ) Applicant: Pfizer Inc. , New York , NY (US ) 2010 /0256340 A1 10 /2010 Brinkmann 2012 /0009621 A11 /2012 Yamasaki ( 72 ) Inventors : Eric M . Bennett, Arlington , MA (US ) ; 2014 /0200331 A1 * 7 /2014 Corper . .. .. .. .. .. CO7K 16 / 36 Nathan Higginson - Scott, Boston , MA 530 / 387 . 3 (US ) ; Lioudmila Tchistiakova , Stoneham , MA (US ) ; Kimberly A . FOREIGN PATENT DOCUMENTS Marquette , Somerville , MA (US ) ; WO 199852976 11 / 1998 Janet E . Paulsen , Londonderry , NH WO 200034317 6 / 2000 (US ) ; Ruth E . Gimeno , Carmel , IN WO 2009089004 7 / 2009 (US ) wo 20110117653 9 / 2011 WO 2011143545 11 / 2011 ( 73 ) Assignee : PFIZER INC ., New York , NY (US ) WO 20130096291 6 / 2013 wo 2014081955 Al 5 / 2014 ( * ) Notice : Subject to any disclaimer, the term of this WO 2014150973 9 / 2014 patent is extended or adjusted under 35 WO 2015173756 A2 11/ 2015 U . S . C . 154 (b ) by 0 days . OTHER PUBLICATIONS ( 21) Appl . No. : 15 / 309, 879 Davies et al : “ Fab Assembly : An analysis of different Ch1 :CL May 13, 2015 combinations ” , Progress in Immunology VI : Sixth International (22 ) PCT Filed : Congress of Immunology, pp . 145 - 149 , 1986 . ( 86 ) PCT No. : PCT/ IB2015 / 053537 Klein et al: “ Progress in overcoming the chain association issue in bispecific heterodimeric IgG antibodies " , MABS , vol. 4 , No . 6 , pp . $ 371 (c )( 1 ), 653 -663 , 2012 . ( 2 ) Date : Nov . 9 , 2016 Lewis et al : “Generation of bispecific IgG antibodies by structure based design of an orthogonal Fab interface ” , Nature Biotechnol ( 87 ) PCT Pub . No. : W02015 /173756 ogy , vol. 32 , No. 2 , pp . 191 - 198 , 2014 . Lewis et al : “ Supplemental Information : Generation of bispecific PCT Pub. Date : Nov . 19 , 2015 IgG antibodies by structure -based design of an orthogonal Fab interface ” , Nature Biotechnology , vol . 32 , No . 2 , 2014 doi: 10 . 1038 / (65 ) Prior Publication Data nbt. 2797 . US 2018 /0179285 A1 Jun. 28 , 2018 Liu et al: “ A Novel Antibody Engineering Strategy for Making Monovalent Bispecific Heterodimeric IgG Antibodies by Electro Related U . S . Application Data static Steering Mechanism ” , Journal of Biological Chemistry , vol . 290 , No. 12 , pp . 7535 - 7562 , 2015 . (60 ) Provisional application No .62 /159 , 201 , filed on May Liu et al : “ Disulfide bond structures of IgG molecules: Structural 8 , 2015 , provisional application No . 62 / 150 ,680 , filed variations, chemical modifications and possible impacts to stability on Apr. 21 , 2015 , provisional application No . and biological function ” , MABS , vol . 4 , No . 1 , pp . 17 -23 , 2012 . 61/ 994 ,720 , filed on May 16 , 2014 . Luo et al: “ Design and Applications of Bispecific Heterodimers : Molecular Imaging and beyond ” Molecular Pharmacuetics, vol . 11 , (51 ) Int. CI. No . 6 , pp . 1750 - 1761, 2014 . CO7K 16 / 00 ( 2006 .01 ) Muller et al: “ The first constant domain ( CH1 and CL ) of an CO7K 16 / 28 ( 2006 .01 ) antibody used as heterodimerization domain for bispecific miniantibod COOK 16 / 24 ( 2006 .01 ) ies ” , FEBS Letters, vol . 422 , No . 2 , pp . 259 - 264 , 1998 . A61P 27 / 16 ( 2006 .01 ) International Search Report and the Written Opinion , PCT/ IB2015 / (52 ) U . S . CI. 053537 , dated Dec . 2 , 2015 ; 23 pages. CPC . .. CO7K 16 / 2863 ( 2013 .01 ) ; A61P 27 / 16 ( Continued ) ( 2018 . 01 ) ; CO7K 16 /00 (2013 . 01 ) ; CO7K 16 / 24 ( 2013 . 01 ) ; C07K 16 / 244 (2013 . 01 ) ; COZK Primary Examiner - Sean E Aeder 2317 / 24 ( 2013 .01 ) ; CO7K 2317/ 31 ( 2013 . 01 ) ; CO7K 2317/ 35 (2013 .01 ) ; CO7K 2317/ 522 (57 ) ABSTRACT ( 2013 .01 ) ; COZK 2317 / 55 (2013 .01 ) ; COOK The present invention relates to engineered heteromultim eric proteins , and more specifically , to methods for produc 2317/ 75 ( 2013 .01 ); CO7K 2317/ 92 (2013 . 01 ) ing and purifying heterodimeric proteins, such as bispecific (58 ) Field of Classification Search antibodies and . Methods for producing and purifying such None engineered heterodimeric proteins and their use in diagnos See application file for complete search history. tics and therapeutics are also provided . The present inven References Cited tion also relates to a humanized antibody that specifically (56 ) binds human TrkB and methods for producing and using the U . S . PATENT DOCUMENTS antibody to , inter alia , treat a hearing loss disorder . 5 , 731, 168 A 3 / 1998 Carter et al . 7 , 183 ,076 B2 2 / 2007 Arathoon et al . 24 Claims, 62 Drawing Sheets 7 , 750 , 122 B2 7 / 2010 Cho et al . Specification includes a Sequence Listing . US 10 ,392 ,438 B2 Page 2 ( 56 ) References Cited Schimmang et al: “ Lack of Bdnf and TrkB signalling in the postnatal cochlea leads to a spatial reshaping of innervation along the tonotopic axis and hearing loss ,” Development, vol . 130, pp . OTHER PUBLICATIONS 4741- 4750 , 2003 . Abhinandan et al: “ Analysis and prediction of VH /VL packing in Smith et al : " Predicting the Tolerated Sequences for Proteins and antibodies ” , Protein Engineering, Design & Selection , vol. 23 , No . Protein Interfaces Using RosettaBackrub Flexible Backbone Design ,” 9 , pp . 689 -697 , 2010 . PLoS One , vol. 6 , No . 7 , e20451 ,. Corrada et al : “ Energetic and Dynamic Aspects of the Affinity Songsivilai et al: “ Bispecific antibody: a tool for diagnosis and Maturation Process: Characterizing Improved Variants from the treatment of disease , " Clinical Exp Immunology , vol. 79 , pp . Bevacizumab Antibody with Molecular Simulations, ” Journal of 315 - 321 , 1990 . Chemical Information and Modeling , vol. 53 , pp . 2937 - 2950 , 2013 . Wise et al: “ Resprouting and Survival of Guinea Pig Cochlear Dani et al: “MODIP revisited : re -evaluation and refinement of an Neurons in Response to the Administration of the Neurotrophins automated procedure for modeling of disulfide bonds in proteins, " Brain - Derived Neurotrophic Factor and Neurotrophin - 3 , ” Journal of Protein Engineering , vol . 16 , No. 3 , pp . 187 - 193 , 2003 . 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Secretion of IgG Antibodies , ” Molecular Cell, vol. 34 , pp . 569 -579 , Kleywegt et al: “ Detection , delineation , measurement and display of 2009 . cavities in macromolecular structures, " ACTA Crystallographica Friedman et al : “ Neurotrophin Signaling via Trks and p75 , " Experi Section D , vol. 50 , No . 2 , pp . 178 - 185 , 1994 . mental Cell Research , vol. 253 , pp . 131 - 142 , 1999 . Lewis et al . “ Generation of bispecific IgG antibodies by structure Kostelny et al: “ Formation of a bispecific antibody by the use of based design of an orthogonal Fab interface” 2014 , vol. 32 , No . 2 , leucine zippers , ” Journal of Immunology , vol. 148 , pp . 1547 - 1553 , pp . 191- 202 . 1992 . Mazor et al. “ Improving target cell specificity using a novel Krivov et al: “ Improved prediction of protein side -chain conforma monovalent bispecific IgG design ” MAbs. 2015 ; 7 ( 2 ) :377 -89 . tions with SCWRL4 , ” Proteins, vol . 77 , pp . 778 -795 , 2009 . Regula et al . " Variable heavy - variable light domain and Fab -arm Laskowski: “ PDBsum : summaries and analyses of PDB structures ,” CrossMabs with charged residue exchanges to enforce correct light Nucleic Acids Research , vol. 29 , No . 1 , pp . 221 - 222 , 2001 . chain assembly .” Protein Engineering, Design and Selection , 2018 , Liberman and Kujawa : “ Adding Insult to Injury : Cochlear Nerve vol. 31 , No. 7 - 8 , pp . 289 - 299 . Degeneration after “ Temporary 'Noise - Induced Hearing Loss, ” Jour Schaefer et al. “ Immunoglobulin domain crossover as a generic nal of Neuroscience , vol . 29 , No . 45 , pp . 14077 - 14085 , 2009 . approach for the production of bispecific IgG antibodies. ” PNAS , Meltser et al : “ TrkB -Mediated Protection against Circadian Sensi 2011, vol. 108 , No. 27 , pp . 11187 - 11192. tivity to Noise Trauma in the Murine Cochlea, ” Current Biology , Shen et al. “ Conjugation site modulates the in vivo stability and vol. 24 , pp . 658 -663 , 2014 . therapeutic activity of antibody -drug conjugates .” Nature Biotech Qian et al: “Novel Agonist Monoclonal Antibodies Activate TrkB nology , 2012 , vol. 30 . No . 2 , pp . 184 - 189 . Receptors and Demonstrate Potent Neurotrophic Activities , ” Jour Strop et al . "Generating Bispecific Human IgG1 and IgG2 Anti nal of Neuroscience , vol . 26 , No. 37 , pp . 9394 - 9403 , 2006 . bodies from Any Antibody Pair” J . Mole . Biol. , 2012 , vol. 420 , pp . Saphire et al: " Crystal Structure of a Neutralizing Human IgG 204 - 219 . Against HIV - 1 : A Template for Vaccine Design , ” Science , vol. 293 , pp . 1155 - 1159 , 2001. * cited by examiner U . S .
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