Abstract 1085: PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, demonstrates robust anti-tumor activity in mouse carcinoma models

Abstract

Abstract PRO1184 is an antibody-drug conjugate (ADC) directed toward folate receptor alpha (FOLR1), a glycosyl phosphatidylinositol anchored membrane protein. FOLR1 is overexpressed in many cancers with unmet medical need, including ovarian, lung, and breast cancers, while normal tissue expression is limited. PRO1184 is comprised of a 1) human monoclonal antibody that selectively binds to FOLR1, 2) a cleavable, hydrophilic linker, and 3) exatecan, a topoisomerase 1 inhibitor. Upon binding to FOLR1 on the surface of malignant cells, PRO1184 is internalized and exatecan released through enzymatic cleavage of the linker. Exatecan blocks the ligation step of the cell cycle and generates DNA single- and double-strand breaks, which leads to cell death. The mechanism of action and clinical potential of PRO1184 was tested in a series of studies. PRO1184 bound selectively and specifically to FOLR1 with nM affinity. PRO1184 was efficiently internalized and demonstrated cytotoxicity against multiple cell lines, in vitro. In mouse carcinoma models, PRO1184 demonstrated robust anti-tumor activity across multiple tumor types that represent ovarian, non-small cell lung, and breast cancer. In addition, PRO1184 was more potent with greater tumor growth inhibition than that of a DM4-conjugated ADC. PRO1184 was tolerated at the 60 mg/kg dose level in cynomolgus monkeys and the safety profile was generally more favorable than that for a DXd-based ADC. The pharmacokinetics (PK) of PRO1184 were similar to that of the unconjugated parent antibody in rats. PRO1184 has the potential for a meaningful therapeutic window to provide an appropriate benefit to risk profile for patients with FOLR1-expressing cancers. Citation Format: Baiteng Zhao, Lei Wang, Haidong Liu, Suping Huang, Xiao Shang, Tae Han. PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, demonstrates robust anti-tumor activity in mouse carcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1085.