Inhibitory monoclonal antibody targeting ADAM17 expressed on cancer cells

Highlights • A novel anti-ADAM17 monoclonal antibody, D8P1C1, has been developed. • D8P1C1 inhibits the proteolysis of peptide substrates by ADAM17. • D8P1C1 inhibits the proliferation of cancer cells and tumor growth inhibition in vivo. • D8P1C1 preferentially recognizes ADAM17 on cancer cells. • Negative stain EM analysis reveals that D8P1C1 binds to the ADAM17 protease domain.
ADAM17 is upregulated in many cancers and in turn activates signaling pathways, including EGFR/ErbB, as well as those underlying resistance to targeted anti-EGFR therapies. Due to its central role in oncogenic pathways and drug resistance mechanisms, specific and efficacious monoclonal antibodies against ADAM17 could be useful for a broad patient population with solid tumors. Hence, we describe here an inhibitory anti-ADAM17 monoclonal antibody, named D8P1C1, that preferentially recognizes ADAM17 on cancer cells. D8P1C1 inhibits the catalytic activity of ADAM17 in a fluorescence-based peptide cleavage assay, as well as the proliferation of a range of cancer cell lines, including breast, ovarian, glioma, colon and the lung adenocarcinoma. In mouse models of triple-negative breast cancer and ovarian cancer, treatment with the mAb results in 78% and 45% tumor growth inhibition, respectively. Negative staining electron microscopy analysis of the ADAM17 ectodomain in complex with D8P1C1 reveals that the mAb binds the ADAM17 protease domain, consistent with its ability to inhibit the ADAM17 catalytic activity. Collectively, our results demonstrate the therapeutic potential of the D8P1C1 mAb to treat solid tumors.