A MERTK-Targeting Antibody–Drug Conjugate Selectively Depletes M2 Tumor-Associated Macrophages and MERTK-Expressing Cancer Cells

MERTK is a receptor tyrosine kinase predominantly expressed on M2 macrophages that plays a critical role in the clearance of apoptotic cells and the maintenance of an immunosuppressive phenotype. M2 macrophages are highly abundant in the tumor microenvironment, in which they facilitate tumor progression and resistance to immunotherapy. MERTK is also overexpressed in cancer cells, in which it can drive cancer survival and metastasis through the induction of proliferation and antiapoptotic signaling programs. In this study, we developed an antibody-drug conjugate (ADC) that simultaneously targets MERTK-expressing M2 tumor-associated macrophages and cancer cells. The ADC comprised the monoclonal antibody RGX-019 that binds human MERTK, combined with a monomethyl auristatin E (MMAE) toxic payload. The unconjugated antibody had intrinsic activity to suppress M2 cytokine expression by macrophages, block in vitro colony formation of cancer cells, and inhibit in vivo tumor growth and metastasis. When MMAE was conjugated to the antibody, the ADC exhibited superior in vitro cytotoxicity and in vivo antitumor efficacy in MERTK-expressing tumors. Tumor growth inhibition in humanized mice was associated with the depletion of tumor-associated M2 macrophages. Furthermore, unlike other MERTK-targeting small molecules or antibodies, no retinal toxicity of RGX-019-MMAE was observed in vivo. These findings reveal that combined therapeutic targeting of MERTK in cancer cells and M2 macrophages offers enhanced opportunities for antitumor efficacy in a wide range of MERTK-expressing tumors. SIGNIFICANCE: Concomitant targeting of cancer cells and immunosuppressive tumor-associated macrophages with RGX-019-MMAE, a MERTK-targeting antibody-drug conjugate, suppresses tumor growth through direct cancer cell killing and depletion of M2 macrophages.