title: Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index.
abstract: Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display-based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding. When conjugated to monomethyl auristatin E, an antibody against the ovarian cancer antigen MUC16 is as efficacious as a conventional conjugate in mouse xenograft models. Moreover, it is tolerated at higher doses in rats and cynomolgus monkeys than the same conjugate prepared by conventional approaches. The favorable in vivo properties of the near-homogenous composition of this conjugate suggest that our strategy offers a general approach to retaining the antitumor efficacy of antibody-drug conjugates, while minimizing their systemic toxicity.
authors.affiliation: Genentech Inc, South San Francisco, California 94080, USA.
authors.forename: Jagath R
authors.initials: JR
authors.lastname: Junutula
authors.forename: Helga
authors.initials: H
authors.lastname: Raab
authors.forename: Suzanna
authors.initials: S
authors.lastname: Clark
authors.forename: Sunil
authors.initials: S
authors.lastname: Bhakta
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Leipold
authors.forename: Sylvia
authors.initials: S
authors.lastname: Weir
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Chen
authors.forename: Michelle
authors.initials: M
authors.lastname: Simpson
authors.forename: Siao Ping
authors.initials: SP
authors.lastname: Tsai
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dennis
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Lu
authors.forename: Y Gloria
authors.initials: YG
authors.lastname: Meng
authors.forename: Carl
authors.initials: C
authors.lastname: Ng
authors.forename: Jihong
authors.initials: J
authors.lastname: Yang
authors.forename: Chien C
authors.initials: CC
authors.lastname: Lee
authors.forename: Eileen
authors.initials: E
authors.lastname: Duenas
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Gorrell
authors.forename: Viswanatham
authors.initials: V
authors.lastname: Katta
authors.forename: Amy
authors.initials: A
authors.lastname: Kim
authors.forename: Kevin
authors.initials: K
authors.lastname: McDorman
authors.forename: Kelly
authors.initials: K
authors.lastname: Flagella
authors.forename: Rayna
authors.initials: R
authors.lastname: Venook
authors.forename: Sarajane
authors.initials: S
authors.lastname: Ross
authors.forename: Susan D
authors.initials: SD
authors.lastname: Spencer
authors.forename: Wai
authors.initials: W
authors.lastname: Lee Wong
authors.forename: Henry B
authors.initials: HB
authors.lastname: Lowman
authors.forename: Richard
authors.initials: R
authors.lastname: Vandlen
authors.forename: Mark X
authors.initials: MX
authors.lastname: Sliwkowski
authors.forename: Richard H
authors.initials: RH
authors.lastname: Scheller
authors.forename: Paul
authors.initials: P
authors.lastname: Polakis
authors.forename: William
authors.initials: W
authors.lastname: Mallet
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000494:pharmacology; D000912:Antibodies, Neoplasm / Q000235:genetics / Q000494:pharmacology*; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D018394:CA-125 Antigen / Q000276:immunology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003545:Cysteine / Q000235:genetics; D003603:Cytotoxins / Q000494:pharmacology*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009842:Oligopeptides / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D018394:CA-125 Antigen; D003603:Cytotoxins; D000922:Immunotoxins; C451759:MUC16 protein, human; D008565:Membrane Proteins; D009842:Oligopeptides; D013438:Sulfhydryl Compounds; D003545:Cysteine; C495575:monomethyl auristatin E