Anti-HER2 Cancer-Specific mAb, H 2 Mab-250-hG 1 , 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.