title: A New Class of Antibody-Drug Conjugates with Potent DNA Alkylating Activity.
abstract: The promise of tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADC) has now been realized, evidenced by the approval of two ADCs, both of which incorporate highly cytotoxic tubulin-interacting agents, for cancer therapy. An ongoing challenge remains in identifying potent agents with alternative mechanisms of cell killing that can provide ADCs with high therapeutic indices and favorable tolerability. Here, we describe the development of a new class of potent DNA alkylating agents that meets these objectives. Through chemical design, we changed the mechanism of action of our novel DNA cross-linking agent to a monofunctional DNA alkylator. This modification, coupled with linker optimization, generated ADCs that were well tolerated in mice and demonstrated robust antitumor activity in multiple tumor models at doses 1.5% to 3.5% of maximally tolerated levels. These properties underscore the considerable potential of these purpose-created, unique DNA-interacting conjugates for broadening the clinical application of ADC technology. Mol Cancer Ther; 15(8); 1870-8. ©2016 AACR.
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Miller
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Fishkin
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Whiteman
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Kovtun
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Reid
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Katie E
authors.initials: KE
authors.lastname: Archer
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Erin K
authors.initials: EK
authors.lastname: Maloney
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Charlene A
authors.initials: CA
authors.lastname: Audette
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Michele F
authors.initials: MF
authors.lastname: Mayo
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Alan
authors.initials: A
authors.lastname: Wilhelm
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Modafferi
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Rajeeva
authors.initials: R
authors.lastname: Singh
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Jan
authors.initials: J
authors.lastname: Pinkas
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Victor
authors.initials: V
authors.lastname: Goldmacher
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: John M
authors.initials: JM
authors.lastname: Lambert
authors.affiliation: ImmunoGen, Inc., Waltham, Massachusetts. ravi.chari@immunogen.com.
authors.forename: Ravi V J
authors.initials: RV
authors.lastname: Chari
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000494:pharmacology*; D024201:Bystander Effect; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D018796:Immunoconjugates; D004247:DNA