12th Biennial Ovarian Cancer Research Symposium – STRO-002 Abstract
We have employed an E. coli cell-free expression system (Xpress CF+™) and a site-specific conjugation technology, to rapidly optimize the lead ADC by selection of the best antibody, drug-linker, conjugation site and drug-antibody ratio (DAR) to generate STRO-002, a novel, FolRa-targeting ADC.We have conducted preclinical studies to evaluate the stability of STRO-002 and characterize the pharmacological properties of the cytotoxic metabolite SC209. In vitro cytotoxicity assays and in vivo efficacy studies were conducted to evaluate the activity of STRO-002 in multiple ovarian cancer cell lines and xenografts. IND enabling toxicology studies were conducted to determine the safety profiles for STRO-002 and its metabolite SC209 in cynomolgous monkeys and rats, respectively.
Results:Based on optimization studies, the anti-FolRa human IgG1 antibody (SP8166) conjugated to a proprietary cleavable drug-linker (SC239) was selected for the lead ADC STRO-002. SC239 contains a tubulin-targeting 3-aminophenyl hemiasterlin warhead, SC209, which has potent cytotoxic activity and is a weak substrate for efflux pumps. Cytotoxic activity of SP8166 conjugated to SC239 was optimal in ADCs with DAR of ~4 with SC239 incorporated at two positions on each heavy chain, which were selected based on stability and cytotoxic activity.
The drug-linkage in STRO-002 is highly stable and the released warhead, SC209, is a very weak substrate for cellular drug-resistance efflux pumps and is cleared rapidly from plasma. STRO-002 has potent cytotoxic activity (0.1-3 nM) on multipleFolRa-positive ovarian and endometrial cancer cell lines in vitro and anti-tumor activity in ovarian and endometrial xenograft models. STRO-002 exhibits dose-dependent tumor growth inhibition in Igrov-1 tumor xenografts at a single dose and complete regression is achieved in Igrov-1 and OVCAR-3 tumors with a single dose at 10 and 5 mg/kg, respectively. In addition, administration of STRO-002 in combination with carboplatin confers added benefit in efficacy in Igrov-1 tumors. Toxicology studies show favorable safety profiles for STRO-002 and SC209. The main toxicity finding in monkeys dosed up to 9 mg/kg consists of reversible hematopoietic/lymphoid tissue toxicity, which is considered antigen-independent and is consistent with the anti-proliferative effects of SC209 observed in single-dose toxicology studies in rats. No evidence of ocular toxicity due to SC209 were observed in either species.
Conclusions: STRO-002 is an ADC with minimal drug moiety release in circulation and the potential for an improved safety and activity profile, and a reduced risk of tumor drug resistance. Our data supports the advancement of STRO-002 to the clinic as a potential treatment of FolRa expressing malignancies such as ovarian and endometrial cancer.