Abstract 3897: Stability and safety evaluation of STRO-002, a site-specific anti-folate receptor alpha antibody-drug conjugate for the potential treatment of ovarian and endometrial cancers

Antibody-drug conjugates (ADCs) constitute an expanding class of therapeutic molecules in preclinical and clinical development for multiple oncology indications. Folate receptor alpha (FolRα) is a glycosylphosphatidylinositol-linked cell-surface glycoprotein that is overexpressed in ovarian, endometrial, lung, and triple negative breast cancers. In contrast, FolRα is minimally expressed on normal tissues, thus, making it an amenable ADC target. STRO-002, a site-specific ADC, is comprised of 3-aminophenyl hemiasterlin cytotoxic drug (SC209) conjugated to an aglycosylated anti-FolRα IgG1 antibody through a protease-cleavable linker at two engineered non-natural amino acids in each heavy chain (DAR ~4). In vitro and in vivo stability studies, showed that STRO-002 is highly stable in circulation, with the warhead SC209 predominantly accumulating in tumor tissue. Toxicology and toxicokinetic studies were conducted to determine the safety profiles for STRO-002 and its metabolite SC209 in cynomolgous monkeys and rats, respectively. In single-dose toxicology studies in rats, SC209 was tolerated up to 0.6 mg/kg with the main toxicity findings predominantly found in hematopoietic/lymphoid tissue, consistent with tubulin targeting chemotherapeutic drugs. In a tissue cross-reactivity study with normal human tissues, STRO-002-specific membranous staining was detected in Fallopian tubes, kidney (tubules), and placenta (trophoblasts). In a definitive safety study in cynomolgus monkeys, pharmacologically relevant model for toxicity testing, STRO-002 was tolerated at up to 9 mg/kg when intravenously administered on days 1 and 22 followed by a 4-week observation period. The most prominent STRO-002-related antigen-independent toxicity finding was dose-related, minimal to marked, and cyclical neutropenia. There were no antigen-dependent toxicity findings and no evidence of ocular toxicity. Toxicokinetic analysis confirmed dose proportional STRO-002 exposures (total antibody, ADC, and SC209 catabolite) at all doses tested. In summary, STRO-002 ADC has a favorable nonclinical safety and pharmacokinetic profiles and a Phase I study of STRO-002 in patients with ovarian and endometrial cancer has been initiated. Citation Format: Willy Solis, Venita De Almeida, Cristina Abrahams, Xiaofan Li, Tyler Heibeck, Maureen Bruhns, Adam Galan, Heidi Hoffman, Robert Kiss, Trevor Hallam, Mark Lupher. Stability and safety evaluation of STRO-002, a site-specific anti-folate receptor alpha antibody-drug conjugate for the potential treatment of ovarian and endometrial cancers [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 3897.