A human monoclonal antibody drug conjugate against EphA2 inhibits tumor growth in vivo through the induction of apoptosis

5744 The EphA2 receptor tyrosine kinase is selectively expressed on the surface of many human cancers, including prostate and breast cancers. We have generated a human monoclonal antibody that selectively binds to human and rodent EphA2 receptor. Upon antibody binding to the EphA2 receptor, the receptor is phosphorylated and is subsequently internalized. We now report data from our preclinical evaluation of an ADC that specifically inhibits the growth of EphA2 expressing tumor cells. We have conjugated the microtubulin inhibitor monomethylauristatin F (MMAF) to a human monoclonal antibody against the EphA2 receptor using the maleimidocaproyl (mc) linker. The EphA2-mcMMAF antibody conjugate is internalized resulting in the intracellular release of MMAF and the inhibition of cell growth through the induction of caspase dependent apoptosis. The EphA2-mcMMAF antibody conjugate inhibits the growth of EphA2 expressing tumors with an IC50 between 1- 90 ng/ml where the IC50 values for cells that do not express the EphA2 receptor are in the 2 - 3 μg/ml range. In vivo tumor efficacy studies using the EphA2-mcMMAF conjugate antibody resulted in significant inhibition of EphA2 expressing tumor growth when the mice were treated with 1 mg/kg of the antibody. The isotype matched control antibody drug conjugate and the unconjugated EphA2 antibody did not inhibit tumor growth. Our data support the use of an antibody drug conjugate approach to target and inhibit the growth of EphA2 expressing tumors in vivo.