Researchers at Memorial Sloan-Kettering Cancer Center and Eureka Therapeutics have shown the therapeutic efficacy of an Fc-enhanced TCR-like antibody to the intracellular WT1 oncoprotein.
ESK1 is a human IgG1 T-cell receptor mimic monoclonal antibody directed to a 9 amino acid sequence of WT1 in the context of cell surface HLA-A*02. ESKM is an Fc-engineered version of ESK1 with enhanced antibody dependent cell-mediated cytotoxicity (ADCC) function due to altered Fc glycosylation. ESK1 mediated ADCC against hematopoietic and solid tumor cells at concentrations below 1µg/ml, but ESKM was about 5-10 fold more potent in vitro against multiple cancer cell lines. ESKM was more potent in vivo against JMN mesothelioma, and effective against SET2 AML and fresh ALL xenografts. At therapeutic doses of ESKM, there was no difference in half-life or biodistribution in HLA-A*02:01+ transgenic mice compared to the parent strain. Importantly, therapeutic doses of ESKM in these mice caused no depletion of total WBCs or hematopoetic stem cells, or pathologic tissue damage.
The data provide proof of concept that an Fc-enhanced mAb can improve efficacy against a low-density, tumor-specific, peptide/MHC target, and support further development of this mAb against an important intracellular oncogenic protein.
The antibody was developed under a collaborative effort between Eureka Therapeutics and Memorial Sloan-Kettering Cancer Center.