RGX-019-MMAE, a novel MERTK-targeting antibody-drug conjugate (ADC) with robust anti-tumor efficacy in both solid and liquid tumors.
Authors: Takeda Shugaku , Lo PuiChi , Schefer Daniel , Andreu-Agullo Celia , Battula Venkata Lokesh , Maiti Abhishek , Tavazoie Masoud , Darst David Martin , Kurth Isabel 
Published: June 2023

e15103

Background: MERTK, a member of the TAM family of receptor tyrosine kinases, is overexpressed in numerous solid and hematologic cancers. MERTK expression has been implicated in promoting cellular proliferation, survival and drug resistance. MERTK is also expressed on innate immune cells, predominantly on immune-suppressive M2 macrophages, where it mediates phagocytosis of apoptotic cells and regulates expression of immunosuppressive cytokines. Development of MERTK inhibitors has been hampered by observance of retinal degeneration due to inhibition of MERTK signaling in retinal pigment epithelium (RPE). We previously reported that our monoclonal antibody RGX-019 triggers transient activation of MERTK, followed by MERTK receptor internalization and degradation. RGX-019 also reduces colony formation of MERTK-expressing cancer cells. Methods: RGX-019-MMAE is a humanized IgG1-MMAE ADC with high specificity and affinity for human and cynomolgus monkey MERTK that induces efficient internalization of MERTK. These characteristics and the limited expression of MERTK in normal tissue make RGX-019 an ideal candidate for an ADC approach. In addition, MMAE selectively targets actively dividing cells such as tumor cells, while sparing macrophages and RPE, both of which represent terminally-differentiated non-dividing cells. Results: We have observed various degrees of MERTK expression on cancer cells within solid tumors and on primary AML samples. In AML, significantly higher expression was noted in M5 subtype, those with PTPN11 mutation or t(9;11) translocation and higher expression correlated with significantly inferior survival. In contrast, in normal tissue, MERTK expression was almost exclusively limited to macrophages, with virtually no expression on healthy epithelial tissue, except for the retina. Twenty-eight-day treatment with RGX-019-MMAE caused no retinal degeneration in a transgenic mouse model expressing a human version of MERTK. RGX-019-MMAE induced cytotoxicity in MERTK-expressing cancer cells and in xenografts, RGX-019-MMAE demonstrated anti-tumor efficacy including complete tumor regressions in various solid cancers such as TNBC as well as AML and MM. Anti-tumor efficacy was associated with increased overall survival. Notably, even tumors with low and heterogenous MERTK expression responded to RGX-019-MMAE treatment. In vitro studies demonstrated that RGX-019-MMAE can kill MERTK non-expressing cancer cells through bystander effects when co-cultured with MERTK-positive cells, consistent with the activity we observed in MERTK heterogenous tumors. Conclusions: Collectively, RGX-019-MMAE’s robust anti-tumor efficacy in multiple aggressive tumors, and MERTK’s expression profile on cancer cells and normal tissue support further advancement of RGX-019-MMAE as a drug candidate for development in solid and liquid cancers.