title: Modulating Therapeutic Activity and Toxicity of Pyrrolobenzodiazepine Antibody-Drug Conjugates with Self-Immolative Disulfide Linkers.
abstract: A novel disulfide linker was designed to enable a direct connection between cytotoxic pyrrolobenzodiazepine (PBD) drugs and the cysteine on a targeting antibody for use in antibody-drug conjugates (ADCs). ADCs composed of a cysteine-engineered antibody were armed with a PBD using a self-immolative disulfide linker. Both the chemical linker and the antibody site were optimized for this new bioconjugation strategy to provide a highly stable and efficacious ADC. This novel disulfide ADC was compared with a conjugate containing the same PBD drug, but attached to the antibody via a peptide linker. Both ADCs had similar efficacy in mice bearing human tumor xenografts. Safety studies in rats revealed that the disulfide-linked ADC had a higher MTD than the peptide-linked ADC. Overall, these data suggest that the novel self-immolative disulfide linker represents a valuable way to construct ADCs with equivalent efficacy and improved safety.Mol Cancer Ther; 16(5); 871-8. ©2017 AACR.
authors.affiliation: Genentech, Inc., South San Francisco, California. thomashp@gene.com.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Pillow
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Melissa
authors.initials: M
authors.lastname: Schutten
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Shang-Fan
authors.initials: SF
authors.lastname: Yu
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Rachana
authors.initials: R
authors.lastname: Ohri
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Jack
authors.initials: J
authors.lastname: Sadowsky
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Kirsten Achilles
authors.initials: KA
authors.lastname: Poon
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Willy
authors.initials: W
authors.lastname: Solis
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Fiona
authors.initials: F
authors.lastname: Zhong
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Del Rosario
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Mary Ann T
authors.initials: MAT
authors.lastname: Go
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lau
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Sharon
authors.initials: S
authors.lastname: Yee
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Jintang
authors.initials: J
authors.lastname: He
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Luna
authors.initials: L
authors.lastname: Liu
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Carl
authors.initials: C
authors.lastname: Ng
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Keyang
authors.initials: K
authors.lastname: Xu
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Leipold
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Amrita V
authors.initials: AV
authors.lastname: Kamath
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Donglu
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Spirogen Ltd., QMB Innovation Centre, London, United Kingdom.
authors.forename: Luke
authors.initials: L
authors.lastname: Masterson
authors.affiliation: Spirogen Ltd., QMB Innovation Centre, London, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gregson
authors.affiliation: Spirogen Ltd., QMB Innovation Centre, London, United Kingdom.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Howard
authors.affiliation: WuXi AppTec Co., Ltd., Shanghai, P.R. China.
authors.forename: Fan
authors.initials: F
authors.lastname: Fang
authors.affiliation: WuXi AppTec Co., Ltd., Shanghai, P.R. China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Chen
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Janet
authors.initials: J
authors.lastname: Gunzner-Toste
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Kozak
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Susan
authors.initials: S
authors.lastname: Spencer
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Polakis
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Polson
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: John A
authors.initials: JA
authors.lastname: Flygare
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: Jagath R
authors.initials: JR
authors.lastname: Junutula
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004220:Disulfides / Q000737:chemistry / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D004220:Disulfides; D018796:Immunoconjugates; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines