An Anti-HER2 Monoclonal Antibody H <sub>2</sub> Mab-41 Exerts Antitumor Activities in Mouse Xenograft Model Using Dog HER2-Overexpressed Cells
Nami Tateyama, Teizo Asano, Tomokazu Ohishi, Junko Takei, Hideki Hosono, Ren Nanamiya, Tomohiro Tanaka, Masato Sano, Masaki Saito, Manabu Kawada, Mika K. Kaneko, Yukinari Kato
Abstract
Overexpression of human epidermal growth factor receptor 2 (HER2) has been reported in a variety of cancer types, including breast, lung, gastric, pancreatic, and colorectal cancers. Trastuzumab, a humanized anti-HER2 monoclonal antibody (mAb), has been shown to provide significant survival benefits in HER2-overexpressing breast cancer and gastric cancer patients. Previously, an anti-HER2 mAb, H 2 Mab-41 (IgG 2b , kappa), was developed in our laboratory and its antitumor activity was demonstrated in mouse xenograft models of human colon cancer. The present study aimed to investigate the ability of H 2 Mab-41 to induce antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in dog HER2 (dHER2)-overexpressed cell lines, and thus exert its antitumor activity against dHER2-overexpressed tumors in vivo . Flow cytometry results demonstrated the cross-reactivity of H 2 Mab-41 with dHER2. Further evaluation of interaction between H 2 Mab-41 and dHER2-overexpressed CHO-K1 (CHO/dHER2) cells indicated moderate binding affinity of H 2 Mab-41 toward dHER2, with a dissociation constant ( K D ) of 2.6 × 10 −8 M. In vitro analysis revealed that the administration of H 2 Mab-41 induced high levels of ADCC and CDC in CHO/dHER2 cells. Furthermore, intraperitoneal administration of H 2 Mab-41 in mouse xenograft models of CHO/dHER2 resulted in significant inhibition of tumor development compared to the control mouse IgG. Thus, the findings of the present study demonstrated the in vivo safety and efficacy of H 2 Mab-41, highlighting its suitability to be included as a part of a therapeutic regimen for dHER2-expressing canine cancers.