MERTK-Targeted Therapy with RGX-019-MMAE in Acute Myeloid Leukemia: Enhancing Treatment Outcomes

The myeloid epithelial reproductive tyrosine kinase receptor (MERTK) is a transmembrane receptor that is overexpressed in various cancers, including solid tumors and hematological malignancies. Its overexpression is linked to reduced apoptosis, increased metastasis, and drug resistance in tumor cells. RGX-019-MMAE is a humanized IgG1-MMAE antibody-drug conjugate (ADC) that selectively binds to MERTK, leading to receptor internalization, degradation, and the release of a cytotoxic payload, MMAE, which disrupts mitosis in dividing cells.

In the study, the clinical relevance of MERTK in acute myeloid leukemia (AML) was assessed using gene expression data and protein expression analysis in a large cohort of AML patients. The highest MERTK expression was identified in monocytic AML subtypes, particularly those with specific mutations or translocations, and was associated with poorer survival outcomes. AML cell lines with the highest MERTK expression were treated with RGX-019-MMAE, which demonstrated a significant dose-dependent reduction in cell viability.

The treatment of primary AML cells with RGX-019-MMAE induced substantial cell death, particularly in cells with high MERTK expression. Furthermore, the combination of RGX-019-MMAE with either Venetoclax or 5-Azacytidine showed a synergistic effect, enhancing cytotoxicity in AML cells.

The findings suggest that RGX-019-MMAE effectively targets MERTK-expressing leukemic cells, enhances their susceptibility to chemotherapy, and increases overall cytotoxicity. MERTK appears to be a promising therapeutic target in AML, particularly in patients with monocytic subtypes of the disease. The study supports the potential of RGX-019-MMAE as a novel treatment for AML and warrants further investigation into its use in combination with other therapeutic agents.