Abstract 226: Optimization of folate receptor alpha-targeting tunable drug conjugates

Abstract

Abstract We have integrated a family of innovative technologies with an aligned set of properties into Tunable Drug Conjugates (TDCs). TDCs are made up of a targeting moiety (e.g. small molecules, peptides, antibodies or antibody fragments), combined with our proprietary Silicon-based linkers (SiLinkers) and novel Payload Cassette (PC) designs which allow for delivery of multiple payloads, preferentially Conditionally Active Payloads (CAPs). CAPs are cytotoxic moieties which cannot readily permeate into normal cells due to their charged state at physiological pH of 7.4; however, at the more acidic pH of the endosome or the tumor microenvironment, the charge is neutralized enabling the CAP to readily permeate into and accumulate within the cancer cells. Our goal is to establish a beneficial Therapeutic Index (TI) and dosing flexibility by creating TDCs around a rapid payload release/rapid systemic clearance approach. Therefore, SiLinker/CAP constructs are designed to concentrate payload in the targeted tumor cell and associated tumor microenvironment while minimizing systemic payload release and rapidly clearing the parent TDC. Folate Receptor alpha (FRα) is overexpressed in multiple cancers, most notably, ovarian, endometrial, and NSCLC. Our optimized FRα-targeting TDCs use folic acid as the ligand and deliver various triple- and hexa-CAP cassettes. The various CAPs were selected from different target classes in order to allow for optimized treatment of different cancer types. We will present comparative cellular data, in vivo xenograft studies in KB, OV90 and IGROV1 models, as well as DMPK parameters of our lead FRα-TDCs. Using our triple- and hexa-PCs, we have achieved cures in in vivo xenograft studies which were durable and lasted even after treatment was stopped. We also demonstrate that in vivo our hexa-PC shows superior efficacy compared to our triple-PC in the moderate FRα expressing models. Based on our data, we believe that the combined properties of our innovative CAP-TDCs and rapid payload release/rapid systemic clearance approach will further increase TI, differentiate from other Drug Conjugates, and ultimately provide a compelling addition to existing Drug Conjugate technologies. Citation Format: Sara C. Sigler, Vinayak Gupta, Hanh N. Nguyen, Michael K. Rood, Jutta Wanner, Doug S. Werner. Optimization of folate receptor alpha-targeting tunable drug conjugates [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 226.