title: Site-specific trastuzumab maytansinoid antibody-drug conjugates with improved therapeutic activity through linker and antibody engineering.
abstract: Antibody-drug conjugates (ADCs) have a significant impact toward the treatment of cancer, as evidenced by the clinical activity of the recently approved ADCs, brentuximab vedotin for Hodgkin lymphoma and ado-trastuzumab emtansine (trastuzumab-MCC-DM1) for metastatic HER2+ breast cancer. DM1 is an analog of the natural product maytansine, a microtubule inhibitor that by itself has limited clinical activity and high systemic toxicity. However, by conjugation of DM1 to trastuzumab, the safety was improved and clinical activity was demonstrated. Here, we report that through chemical modification of the linker-drug and antibody engineering, the therapeutic activity of trastuzumab maytansinoid ADCs can be further improved. These improvements include eliminating DM1 release in the plasma and increasing the drug load by engineering four cysteine residues into the antibody. The chemical synthesis of highly stable linker-drugs and the modification of cysteine residues of engineered site-specific antibodies resulted in a homogeneous ADC with increased therapeutic activity compared to the clinically approved ADC, trastuzumab-MCC-DM1.
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Pillow
authors.forename: Janet
authors.initials: J
authors.lastname: Tien
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Parsons-Reponte
authors.forename: Sunil
authors.initials: S
authors.lastname: Bhakta
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.forename: Leanna R
authors.initials: LR
authors.lastname: Staben
authors.forename: Guangmin
authors.initials: G
authors.lastname: Li
authors.forename: Josefa
authors.initials: J
authors.lastname: Chuh
authors.forename: Aimee
authors.initials: A
authors.lastname: Fourie-O'Donohue
authors.forename: Martine
authors.initials: M
authors.lastname: Darwish
authors.forename: Victor
authors.initials: V
authors.lastname: Yip
authors.forename: Luna
authors.initials: L
authors.lastname: Liu
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Leipold
authors.forename: Dian
authors.initials: D
authors.lastname: Su
authors.forename: Elmer
authors.initials: E
authors.lastname: Wu
authors.forename: Susan D
authors.initials: SD
authors.lastname: Spencer
authors.forename: Ben-Quan
authors.initials: BQ
authors.lastname: Shen
authors.forename: Keyang
authors.initials: K
authors.lastname: Xu
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Kozak
authors.forename: Helga
authors.initials: H
authors.lastname: Raab
authors.forename: Richard
authors.initials: R
authors.lastname: Vandlen
authors.forename: Gail D
authors.initials: GD
authors.lastname: Lewis Phillips
authors.forename: Richard H
authors.initials: RH
authors.lastname: Scheller
authors.forename: Paul
authors.initials: P
authors.lastname: Polakis
authors.forename: Mark X
authors.initials: MX
authors.lastname: Sliwkowski
authors.forename: John A
authors.initials: JA
authors.lastname: Flygare
authors.forename: Jagath R
authors.initials: JR
authors.lastname: Junutula
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D008453:Maytansine / Q000031:analogs & derivatives*; D051379:Mice; D015202:Protein Engineering; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D008453:Maytansine; D000068878:Trastuzumab