Darren Veach

Fully human monoclonal antibody targeting the cysteine-rich substrate-interacting region of ADAM17 on cancer cells

Characterization of the D8P1C1 Anti-ADAM17 Inhibitory Monoclonal Antibody and Generation of Its Bispecific T-Cell Engager Derivative

EGFR signaling, which requires ligand shedding by ADAM proteases, drives the progression of a variety of cancers, including breast, ovarian and lung. We previously reported the generation and characterization of a fully human, affinity-matured anti-ADAM17 monoclonal antibody, D8P1C1, which inhibits both the proliferation of an array of cancer cell lines in vitro as well as breast cancer growth in a mouse xenograft model. Here, we show that the mAb inhibits the shedding of EGFR ligands and EGFR phosphorylation in cancer cell lines, thus explaining its anti-tumor effects. In a xenograft model with a high-grade serous ovarian cancer (HGSOC) cell line, D8P1C1 showed only modest therapeutic effect, without any discernible toxicity. These results suggest that ovarian cancers are less susceptible than breast cancers to therapeutic targeting of ADAM17- or EGFR-dependent signaling. Radioimmuno PET imaging with 89Zr-DFO-D8P1C1 confirmed tumoral accumulation of the mAb in high-grade and non-high-grade serous ovarian tumor xenografts. Furthermore, we report the generation and preliminary characterization of a bispecific T cell engager derivative of D8P1C1 with improved anti-tumor efficacy in vitro.