Anti-HER2 Cancer-Specific mAb, H2Mab-250-hG1, Possesses Higher Complement-Dependent Cytotoxicity than Trastuzumab

Cancer-specific monoclonal antibodies (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy are innovative therapeutic strategies for minimizing adverse effects. We previously established a cancer-specific anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody (mAb), H(2)Mab-250/H(2)CasMab-2. In flow cytometry and immunohistochemistry, H(2)Mab-250 reacted with HER2-positive breast cancer cells but did not show reactivity to normal epithelial cells. In contrast, a clinically approved anti-HER2 mAb, trastuzumab, strongly recognizes both breast cancer and normal epithelial cells in flow cytometry. The human IgG(1) version of H(2)Mab-250 (H(2)Mab-250-hG(1)) possesses compatible in vivo antitumor effects against breast cancer xenografts to trastuzumab despite the lower affinity and effector activation than trastuzumab in vitro. This study compared the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cellular cytotoxicity (CDC) between H(2)Mab-250-hG(1) and trastuzumab. Both H(2)Mab-250-hG(1) and trastuzumab showed ADCC activity against HER2-overexpressed Chinese hamster ovary -K1 and breast cancer cell lines (BT-474 and SK-BR-3) in the presence of human natural killer cells. Some tendency was observed where trastuzumab showed a more significant ADCC effect compared to H(2)Mab-250-hG(1). Importantly, H(2)Mab-250-hG(1) exhibited superior CDC activity in these cells compared to trastuzumab. Similar results were obtained in the mouse IgG(2a) types of both H(2)Mab-250 and trastuzumab. These results suggest the different contributions of ADCC and CDC activities to the antitumor effects of H(2)Mab-250-hG(1) and trastuzumab, and indicate a future direction for the clinical development of H(2)Mab-250-hG(1) against HER2-positive tumors.