Abstract 1782: Discovery and activity of STRO-002, a novel ADC targeting folate receptor alpha for ovarian and endometrial cancer

Abstract

Abstract Folate receptor alpha (FolRα) is a glycosylphosphatidylinositol linked cell-surface glycoprotein that is widely expressed in serous and epithelial ovarian cancer, endometrial adenocarcinoma, non-small cell lung cancer and triple negative breast cancer. In contrast, FolRα expression is highly restricted on normal tissues, making it a highly promising target for cancer therapy using antibody drug conjugates (ADCs). We have designed a novel, FolRα-targeting ADC, STRO-002, with potent cytotoxic activity on FolRα expressing tumors in vitro and in vivo, including in cells with low expression levels (~0.2 million copies/cell) of FolRα. STRO-002 contains the anti-FolRa human IgG1 antibody (SP8166) conjugated to a proprietary cleavable drug-linker (SC239). SC239 contains a tubulin-targeting 3-aminophenyl hemiasterlin warhead, SC209, which has potent cytotoxic activity and is a weak substrate for efflux pumps. SP8166 was discovered and optimized using a Fab ribosome display selection and screening platform based on Sutro's Xpress CF+TM system. Four non-natural amino acid p-azidomethyl phenylalanine (pAMF) residues are incorporated into SP8166 at two defined sites on each heavy chain. These sites were selected based on optimal stability and activity in vitro and in vivo. The SC239 drug-linker is conjugated via a cleavable valine citrulline p-aminobenzyl carbamate linker functionalized with dibenzocyclooctyne (DBCO). The rapid and selective reaction of DBCO and pAMF results in a well-defined, homogeneous ADC with a drug-antibody ratio (DAR) of ~4. STRO-002 has potent cytotoxic activity (0.1-3 nM) on multiple FolRα-positive ovarian cancer cell lines in vitro and demonstrates strong anti-tumor response in KB, Igrov1 and OvCAR3 xenograft models in vivo. On Igrov1 xenografts, STRO-002 exhibits dose-dependent tumor growth inhibition starting at a single dose as low as 2.5 mg/kg. Evaluation of in vivo activity of STRO-002 in additional xenograft and PDX models, as well as in combination studies with chemotherapeutic agents is ongoing. Data from exploratory safety studies of STRO-002 in cynomolgus monkey and SC209 (active catabolite) in rats show a favorable safety profile. Our data suggests that STRO-002 is a promising clinical candidate for ovarian cancer, including tumors with low expression levels of FolRα, and IND enabling studies are currently being conducted. Citation Format: Xiaofan Li, Cristina Abrahams, Sihong Zhou, Stellanie Krimm, Robert Henningsen, Heather Stephenson, Jeffrey Hanson, Mary Rose Masikat, Krishna Bajjuri, Tyler Heibeck, Cuong Tran, Gang Yin, James Zawada, Ganapathy Sarma, Joy Chen, Maureen Bruhns, Willy Solis, Alexander Steiner, Adam Galan, Toni Kline, Ryan Stafford, Alice Yam, Venita I. De Almeida, Mark Lupher, Trevor Hallam. Discovery and activity of STRO-002, a novel ADC targeting folate receptor alpha for ovarian and endometrial cancer [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 1782.