Abstract B122: 2 for 1: Targeting tumor-associated macrophages and cancer cells with a novel MERTK-targeting antibody-drug conjugate (ADC)
Authors: Takeda Shugaku , Lo PuiChi , Schefer Daniel , Siddiqui Maryam , Tyagi Anudishi , Battula Venkata Lokesh , Maiti Abhishek , Tavazoie Sohail , Tavazoie Masoud , Darst David Martin , Kurth Isabel 
Published: December 2023

MERTK, a member of the TAM family receptor tyrosine kinases, is overexpressed in various solid and hematologic cancers. MERTK signaling drives multiple processes such as proliferation, survival, invasion and drug resistance. Furthermore, MERTK is expressed on M2 tumor-associated macrophages (TAMs), playing a role in the production of immunosuppressive cytokines and efferocytosis. Within normal tissue, MERTK is also expressed in the retinal pigment epithelium (RPE). Our RNA-DRIVErTM platform identified MERTK as a key driver of metastatic progression and thus a potentially potent target for therapeutic intervention. Our MERTK-targeting humanized monoclonal antibody, RGX-019, is internalized by both MERTK-expressing cancer cells and macrophages. In M2 macrophages, RGX-019 induced expression of pro-inflammatory M1 macrophage type cytokines. To effectively target MERTK in both cancer cells and immune-suppressive macrophages, we developed an MMAE antibody drug conjugate (ADC). Here, we assessed the anti-tumor efficacy and retinal safety of RGX-019-MMAE and examined MERTK expression in both solid and hematologic cancers. RGX-019-MMAE induced cytotoxicity against MERTK-expressing cancer cells and mediated bystander anti-tumor efficacy in vitro. In xenograft models, RGX-019-MMAE demonstrated robust anti-tumor efficacy, including complete tumor regressions in various cancers such as TNBC, melanoma, and multiple myeloma. Anti-tumor efficacy of RGX-019-MMAE was associated with improved overall survival. RGX-019-MMAE suppressed syngeneic tumor growth in a mouse model expressing human MERTK extracellular domain, and lacked anti-tumor efficacy in animals not expressing human MERTK. Anti-tumor efficacy was associated with reduced M2 macrophage levels in tumors. Given that RGX-019 only binds human but not murine MERTK, these findings suggest that RGX-019-MMAE targets the host tumor microenvironment to mediate anti-tumor efficacy. Immunohistochemical analysis revealed broad MERTK expression in multiple human cancers with highest expression detected in ovarian, NSCLC, and urothelial cancers. In primary AML samples, significantly higher expression was detected in M5 subtype samples, those with PTPN11 mutations or t(9;11) translocations. Higher MERTK expression in AML correlated with significantly worse patient survival. MERTK in the RPE is involved in maintenance of retinal homeostasis. After a 28-day treatment with RGX-019-MMAE, we observed no signs of retinal degeneration in a transgenic mouse expressing human MERTK extracellular domain. The lack of retinal toxicity can be explained by the partial agonist activity of RGX-019 and absence of MMAE cytotoxicity against non-proliferating RPE cells. The substantial anti-tumor efficacy of RGX-019-MMAE in multiple aggressive tumors, along with the limited expression in normal tissues, reveal MERTK as a promising novel target for an ADC approach. Our findings support the continued advancement of RGX-019-MMAE for the treatment of solid and hematologic cancers through targeting of both TAMs and cancer cells.

Citation Format: Shugaku Takeda, PuiChi Lo, Daniel Schefer, Maryam Siddiqui, Anudishi Tyagi, Venkata Lokesh Battula, Abhishek Maiti, Sohail Tavazoie, Masoud Tavazoie, David Martin Darst, Isabel Kurth. 2 for 1: Targeting tumor-associated macrophages and cancer cells with a novel MERTK-targeting antibody-drug conjugate (ADC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B122.