title: Bispecific antibodies with natural architecture produced by co-culture of bacteria expressing two distinct half-antibodies.
abstract: By enabling the simultaneous engagement of two distinct targets, bispecific antibodies broaden the potential utility of antibody-based therapies. However, bispecific-antibody design and production remain challenging, owing to the need to incorporate two distinct heavy and light chain pairs while maintaining natural nonimmunogenic antibody architecture. Here we present a bispecific-antibody production strategy that relies on co-culture of two bacterial strains, each expressing a half-antibody. Using this approach, we produce 28 unique bispecific antibodies. A bispecific antibody against the receptor tyrosine kinases MET and EGFR binds both targets monovalently, inhibits their signaling, and suppresses MET and EGFR-driven cell and tumor growth. Our strategy allows rapid generation of bispecific antibodies from any two existing antibodies and yields milligram to gram quantities of bispecific antibodies sufficient for a wide range of discovery and preclinical applications.
authors.affiliation: Department of Antibody Engineering, Genentech, Inc., South San Francisco, California, USA. spiess.christoph@gene.com
authors.forename: Christoph
authors.initials: C
authors.lastname: Spiess
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Arthur
authors.initials: A
authors.lastname: Huang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Nai-Ying
authors.initials: NY
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Peng
authors.forename: Diego
authors.initials: D
authors.lastname: Ellerman
authors.forename: Whitney
authors.initials: W
authors.lastname: Shatz
authors.forename: Dorothea
authors.initials: D
authors.lastname: Reilly
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Yansura
authors.forename: Justin M
authors.initials: JM
authors.lastname: Scheer
mesh_terms: D018033:Antibodies, Bispecific / Q000096:biosynthesis* / Q000276:immunology; D000918:Antibody Specificity; D001419:Bacteria / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D066246:ErbB Receptors / Q000235:genetics / Q000276:immunology*; D015964:Gene Expression Regulation, Bacterial / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015202:Protein Engineering; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific; D007074:Immunoglobulin G; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met