학술논문
A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody-Drug Conjugates (ADCs).
Document Type
Academic Journal
Author
Miller ML; ImmunoGen, Inc., Waltham, Massachusetts.; Shizuka M; ImmunoGen, Inc., Waltham, Massachusetts.; Wilhelm A; ImmunoGen, Inc., Waltham, Massachusetts.; Salomon P; ImmunoGen, Inc., Waltham, Massachusetts.; Reid EE; ImmunoGen, Inc., Waltham, Massachusetts.; Lanieri L; ImmunoGen, Inc., Waltham, Massachusetts.; Sikka S; ImmunoGen, Inc., Waltham, Massachusetts.; Maloney EK; ImmunoGen, Inc., Waltham, Massachusetts.; Harvey L; ImmunoGen, Inc., Waltham, Massachusetts.; Qiu Q; ImmunoGen, Inc., Waltham, Massachusetts.; Archer KE; ImmunoGen, Inc., Waltham, Massachusetts.; Bai C; ImmunoGen, Inc., Waltham, Massachusetts.; Vitharana D; ImmunoGen, Inc., Waltham, Massachusetts.; Harris L; ImmunoGen, Inc., Waltham, Massachusetts.; Singh R; ImmunoGen, Inc., Waltham, Massachusetts.; Ponte JF; ImmunoGen, Inc., Waltham, Massachusetts.; Yoder NC; ImmunoGen, Inc., Waltham, Massachusetts.; Kovtun Y; ImmunoGen, Inc., Waltham, Massachusetts.; Lai KC; ImmunoGen, Inc., Waltham, Massachusetts.; Ab O; ImmunoGen, Inc., Waltham, Massachusetts.; Pinkas J; ImmunoGen, Inc., Waltham, Massachusetts.; Keating TA; ImmunoGen, Inc., Waltham, Massachusetts.; Chari RVJ; ImmunoGen, Inc., Waltham, Massachusetts. ravi.chari@immunogen.com.
Source
Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE
Subject
Language
English
Abstract
Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared with those of the cross-linker. Thus, the improved in vivo tolerability and antitumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment. Mol Cancer Ther; 17(3); 650-60. ©2018 AACR .
(©2018 American Association for Cancer Research.)
(©2018 American Association for Cancer Research.)