Abstract 224: Antibody-drug conjugates (ADCs) of a new class of N-10 amino linked DNA alkylating indolino-benzodiazepines (IGNs)

Abstract

Abstract We have previously reported on our antibody-drug conjugates (ADCs) that incorporate a highly potent novel DNA alkylating indolino-benzodiazepine (termed IGN) dimer. ADCs of these DNA alkylating IGNs were found preclinically to demonstrate better tolerability and an improved overall therapeutic index (TI) compared with those of the corresponding DNA crosslinking IGNs (Miller, et al., Mol. Cancer Ther. 2016, 2018). IGN-containing ADCs that have reached the clinical stage bear DNA alkylating IGN compounds linked to the antibody via a cleavable linker, incorporated at the amino group of a centrally located anilino spacer moiety. In our ongoing effort to further explore the structure-activity relationship (SAR) of DNA alkylating effector molecules for ADCs, we disclose here a new class of IGNs possessing a self-immolative peptide linker attached at the N-10 amine of the imine-reduced IGN monomer subunit. We explored the impact of modifying the central spacer group connecting the IGN monomers, and site of linkage on in vitro potency and the interaction with DNA. A set of IGN molecules that met our potency criteria were identified and linkable forms of these compounds were prepared and conjugated to a folate receptor-α (FRα)-binding antibody. These ADCs displayed potent, antigen-specific in vitro activity across a panel of FRα-expressing cell lines. A lead ADC selected for in vivo studies demonstrated high stability in plasma and potent efficacy in various xenograft models, at doses well below the maximum tolerated dose. Thus, IGNs modified with an N-10 self-immolative peptide linker are promising DNA alkylating effector molecules for use in ADCs. Citation Format: Michael L. Miller, Emily E. Reid, Katie E. Archer, Luke Harris, Erin K. Maloney, Laura M. Bartle, Olga Ab, Alan J. Wilhelm, Jose F. Ponte, Rajeeva Singh, Thomas A. Keating, Ravi V. Chari. Antibody-drug conjugates (ADCs) of a new class of N-10 amino linked DNA alkylating indolino-benzodiazepines (IGNs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 224.