title: Chemical generation of bispecific antibodies.
abstract: Bispecific antibodies (BsAbs) are regarded as promising therapeutic agents due to their ability to simultaneously bind two different antigens. Several bispecific modalities have been developed, but their utility is limited due to problems with stability and manufacturing complexity. Here we report a versatile technology, based on a scaffold antibody and pharmacophore peptide heterodimers, that enables rapid generation and chemical optimization of bispecific antibodies, which are termed bispecific CovX-Bodies. Two different peptides are joined together using a branched azetidinone linker and fused to the scaffold antibody under mild conditions in a site-specific manner. Whereas the pharmacophores are responsible for functional activities, the antibody scaffold imparts long half-life and Ig-like distribution. The pharmacophores can be chemically optimized or replaced with other pharmacophores to generate optimized or unique bispecific antibodies. As a prototype, we developed a bispecific antibody that binds both vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2) simultaneously, inhibits their function, shows efficacy in tumor xenograft studies, and greatly augments the antitumor effects of standard chemotherapy. This unique antiangiogenic bispecific antibody is in phase-1 clinical trials.
authors.affiliation: CovX Research, Biotherapeutics Division of Pfizer, San Diego, CA 92121, USA. venkata.doppalapudi@pfizer.com
authors.forename: Venkata R
authors.initials: VR
authors.lastname: Doppalapudi
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Dingguo
authors.initials: D
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Jin
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Lingna
authors.initials: L
authors.lastname: Li
authors.forename: Joel
authors.initials: J
authors.lastname: Desharnais
authors.forename: Crystal
authors.initials: C
authors.lastname: Hagen
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Levin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shields
authors.forename: Michelle
authors.initials: M
authors.lastname: Parish
authors.forename: Robert E
authors.initials: RE
authors.lastname: Murphy
authors.forename: Joselyn
authors.initials: J
authors.lastname: Del Rosario
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Oates
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Lai
authors.forename: Marla J
authors.initials: MJ
authors.lastname: Matin
authors.forename: Zemeda
authors.initials: Z
authors.lastname: Ainekulu
authors.forename: Abhijit
authors.initials: A
authors.lastname: Bhat
authors.forename: Curt W
authors.initials: CW
authors.lastname: Bradshaw
authors.forename: Gary
authors.initials: G
authors.lastname: Woodnutt
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lerner
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Lappe
mesh_terms: D000595:Amino Acid Sequence; D042702:Angiopoietin-2 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology*; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology; D001384:Azetidines / Q000737:chemistry; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D020349:Surface Plasmon Resonance; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C116379:2-azetidinone; D042702:Angiopoietin-2; D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D001384:Azetidines; D007155:Immunologic Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2