title: LUZ-Y, a novel platform for the mammalian cell production of full-length IgG-bispecific antibodies.
abstract: The ability of bispecific antibodies to simultaneously bind two unique antigens has great clinical potential. However, most approaches utilized to generate bispecific antibodies yield antibody-like structures that diverge significantly from the structure of archetype human IgG, and those that do approach structural similarity to native antibodies are often challenging to engineer and manufacture. Here, we present a novel platform for the mammalian cell production of bispecific antibodies that differ from their parental mAbs by only a single point mutation per heavy chain. Central to this platform is the addition of a leucine zipper to the C terminus of the C(H)3 domain of the antibody that is sufficient to drive the heterodimeric assembly of antibody heavy chains and can be readily removed post-purification. Using this approach, we developed various antibody constructs including one-armed Abs, bispecific antibodies that utilize a common light chain, and bispecific antibodies that pair light chains to their cognate heavy chains via peptide tethers. We have applied this technology to various antibody pairings and will demonstrate the engineering, purification, and biological activity of these antibodies herein.
authors.affiliation: Department of Protein Chemistry, Genentech, South San Francisco, California 94080, USA.
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Wranik
authors.forename: Erin L
authors.initials: EL
authors.lastname: Christensen
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schaefer
authors.forename: Janet K
authors.initials: JK
authors.lastname: Jackman
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Vendel
authors.forename: Dan
authors.initials: D
authors.lastname: Eaton
mesh_terms: D018033:Antibodies, Bispecific / Q000096:biosynthesis / Q000235:genetics; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D017354:Point Mutation; D015202:Protein Engineering / Q000379:methods*
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains