Improved efficacy of α‐particle–targeted radiation therapy

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 213 Bi or 212 Pb. 213 Bi‐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 213 Bi administered through an intraperitoneal route. The sequence of administration also was examined. RESULTS: Before combining the 2 monoclonal antibodies, the effective doses of 213 Bi‐CC49ΔCH2 and 213 Bi‐trastuzumab for the treatment of peritoneal disease were determined to be 500 μCi for each labeled antibody. Treatment with 213 Bi‐HuCC49ΔCH2 resulted in a median survival of 45 days and was comparable to the median survival achieved with 213 Bi‐trastuzumab. Each combination provided greater therapeutic efficacy than either of the agents given alone. However, the greatest therapeutic benefit was achieved when 213 Bi‐HuCC49ΔCH2 and 213 Bi‐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. Cancer 2010;116(4 suppl):1059–66. Published 2010 by the American Cancer Society.