title: Mild method for succinimide hydrolysis on ADCs: impact on ADC potency, stability, exposure, and efficacy.
abstract: The stability of the connection between the antibody and the toxin can have a profound impact on ADC safety and efficacy. There has been increasing evidence in recent years that maleimide-based ADCs are prone to payload loss via a retro-Michael type reaction. Herein, we report a mild method for the hydrolysis of the succinimide-thioether ring which results in a "ring-opened" linker. ADCs containing this hydrolyzed succinimide linker show equivalent cytotoxicity, improved in vitro stability, improved PK exposure, and improved efficacy as compared to their nonhydrolyzed counterparts. This method offers a simple way to improve the stability, exposure, and efficacy of maleimide-based ADCs.
authors.affiliation: Worldwide Medicinal Chemistry, ‡Global Biological Technologies, §Pharmacokinetics, Metabolism, and Distribution, and ∥Oncology Research Unit, Pfizer Global R&D , Groton, Connecticut 06340, United States.
authors.forename: L Nathan
authors.initials: LN
authors.lastname: Tumey
authors.forename: Manoj
authors.initials: M
authors.lastname: Charati
authors.forename: Tao
authors.initials: T
authors.lastname: He
authors.forename: Eric
authors.initials: E
authors.lastname: Sousa
authors.forename: Dangshe
authors.initials: D
authors.lastname: Ma
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Han
authors.forename: Tracey
authors.initials: T
authors.lastname: Clark
authors.forename: Jeff
authors.initials: J
authors.lastname: Casavant
authors.forename: Frank
authors.initials: F
authors.lastname: Loganzo
authors.forename: Frank
authors.initials: F
authors.lastname: Barletta
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Edmund I
authors.initials: EI
authors.lastname: Graziani
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D000922:Immunotoxins / Q000097:blood / Q000737:chemistry* / Q000627:therapeutic use; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D055550:Protein Stability; D013388:Succinimides / Q000737:chemistry*; D013440:Sulfides / Q000737:chemistry*
chemical_list: D000922:Immunotoxins; D013388:Succinimides; D013440:Sulfides; C032620:succinimide