Abstract

Folate receptor α (FRα) is overexpressed in a range of solid tumors with limited expression in normal tissues, hence an attractive target for an antibody-drug conjugate (ADC). PRO1184 is comprised of a human monoclonal antibody that selectively binds FRα, a novel cleavable hydrophilic linker, and a topoisomerase 1 inhibitor payload, exatecan. Previous studies established that a) PRO1184 exerts potent antitumor activity in cell-derived xenograft (CDX) models representing ovarian, non-small cell lung, and breast cancer, b) with pharmacokinetics (PK) akin to that of the unconjugated parent antibody in rats, and c) with a preliminary safety profile that was more favorable than a DXd-based ADC in cynomolgus monkeys. Further characterization of the activity and safety of PRO1184 is reported here. PRO1184 displays strong binding affinity, rapid internalization, and potent cytotoxicity with the HCC1954 (breast cancer), JEG-3 (choriocarcinoma), and HEC-1-A (endometrial cancer) cells, in vitro. PRO1184 at a single dose of 5 mg/kg produced marked tumor growth inhibition in CDX models with all three cell lines. In 14 patient-derived xenograft (PDX) models encompassing ovarian, gastric, breast, and non-small cell lung cancer, PRO1184 at a single dose of 5 mg/kg elicited robust antitumor activity in all four tumor types, with ORR and CR accomplished in 10 and 3 out of the 14 models, respectively. Antitumor activity was observed in xenografts with both high and low FRα expression, suggesting that PRO1184 may benefit patients with a wide range of FRα expression. Two DM4-based benchmarking ADCs produced modest to negligible tumor growth inhibition in head-to-head comparisons in the CDX and PDX studies. In a GLP cynomolgus monkey toxicity study for PRO1184, main treatment-related findings were consistent with those associated with exatecan and included reversible gastrointestinal and hematologic toxicities. There were no toxicity findings in lungs, which may translate to a lower risk of interstitial lung disease (ILD) compared to DXd-based ADCs in the clinic. In summary, PRO1184 is a promising development candidate for the treatment of FRα-expressing solid tumors. A first in human phase 1/2 study in patients with advanced solid tumors is currently recruiting (NCT 05579366).

Citation Format: Lei Wang, Haidong Liu, Chang Zhou, Tae Han, Baiteng Zhao, Zhu Chen. Novel folate receptor alpha-directed antibody-drug conjugate PRO1184 demonstrates broad antitumor activity with a promising safety profile in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2637.