Abstract 747: A new class of DNA alkylating indolino-benzodiazepine agents (BIAs) linked with a DNA binding moiety for use with antibody-drug conjugates (ADCs)

We have previously disclosed antibody-drug conjugates (ADCs) that incorporate our highly potent novel DNA alkylating indolino-benzodiazepine (termed IGN) pseudo 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 DNA crosslinking IGNs (Miller, et al., AACR 2017 #53). In our ongoing effort to further explore DNA alkylating effector molecules for ADCs, we disclose here a new class of IGNs (termed BIAs) in which one IGN monomer subunit is connected to a bis-aryl moiety with affinity for the DNA binding pocket. Our initial structure activity relationship (SAR) studies around a series of BIAs identified a set of scaffolds that met our requirement for high in vitro potency. These scaffolds were subsequently modified to incorporate functionalities that allow linkage to an antibody using various linker chemistries. These linkable BIAs displayed high in vitro potency across a panel of cell lines, indicating that the incorporation of a linker was not detrimental to their overall potency. Furthermore, we found that the potency of these linkable BIAs could be modulated by careful selection of substituents on the bis-aryl moiety providing enhanced binding affinity with DNA. Upon identification of lead BIA molecules, conjugates with a folate receptor-α (FRα)-binding antibody were prepared. These ADCs displayed potent, antigen-specific in vitro activity across a panel of FRα-expressing cell lines. In vivo, these ADCs demonstrated potent efficacy in xenograft models at doses well below the maximum tolerated dose. In light of these findings, BIA ADCs represent a promising new class of DNA alkylating effector molecules for use in the development of ADCs. Citation Format: Michael L. Miller, Emily E. Reid, Katie E. Archer, Manami Shizuka, Molly A. McShea, Erin K. Maloney, Olga Ab, Leanne Lanieri, Alan J. Wilhelm, Jose F. Ponte, Nicholas C. Yoder, Ravi V. Chari. A new class of DNA alkylating indolino-benzodiazepine agents (BIAs) linked with a DNA binding moiety for use with antibody-drug conjugates (ADCs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 747.