Improved efficacy of alpha-particle-targeted radiation therapy: dual targeting of human epidermal growth factor receptor-2 and tumor-associated glycoprotein 72. Cancer 116(4 Suppl):1059-1066

BACKGROUND: Human epidermal growth factor receptor–2 (HER-2) and tumor-associated glycoprotein 72 (TAG-72) have proven to be excellent molecular targets for cancer imaging and therapy. Trastuzumab, which binds to HER-2, is effective in the treatment of disseminated intraperitoneal disease when labeled with 213Bi or 212Pb. 213Bi-humanized CC49 monoclonal antibody (HuCC49ΔCH2), which binds to TAG-72, inhibits the growth of subcutaneous xenografts. A next logical step to improve therapeutic benefit would be to target tumors with both molecules simultaneously. METHODS: Athymic mice bearing intraperitoneal human colon carcinoma xenografts were treated with a combination of trastuzumab and HuCC49ΔCH2 labeled with 213Bi administered through an intraperitoneal route. The sequence of administration also was examined. RESULTS: Before combining the 2 monoclonal antibodies, the effective doses of 213Bi-CC49ΔCH2 and 213Bi-trastuzumab for the treatment of peritoneal disease were determined to be 500 μCi for each labeled antibody. Treatment with 213Bi-HuCC49ΔCH2 resulted in a median survival of 45 days and was comparable to the median survival achieved with 213Bi-trastuzumab. Each combination provided greater therapeutic efficacy than either of the agents given alone. However, the greatest therapeutic benefit was achieved when 213Bi-HuCC49ΔCH2 and 213Bi-trastuzumab were coinjected, and a median survival of 147 days was obtained. CONCLUSIONS: Dual targeting of 2 distinct molecules in tumors such as TAG-72 and HER-2 with α-particle radiation resulted in an enhanced, additive, therapeutic benefit. The authors also observed that this radioimmunotherapeutic strategy was well tolerated.