α-particle radioimmunotherapy of disseminated peritoneal disease using a 212Pb-labeled radioimmunoconjugate targeting HER2

These studies demonstrate the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using Pb-212-labeled Herceptin as an in vivo generator of Bi-212. In vitro studies compare the potential of the bismuth radioisotopes, Bi-213 and Bi-212, to that of Pb-212. Overall, Pb-212 results in a higher therapeutic index than either bismuth radioisotope, requiring lower radioactivity (mu Ci) for effective cytotoxic response. A pilot radioimmunotherapy (RIT) experiment treating mice bearing 5 d LS-174T intraperitoneally (i.p.) xenogrqfts determined a maximum tolerated dose (MTD) of 20-40 mu Ci with i.p. administration. A specific dose response was observed and 10 mu Ci was selected as the effective operating dose for future experiments. Median survival of tumor-bearing mice receiving 10 mu Ci increased from 19 to 56 days (p = 0.008). The efficacy of Pb-212-Herceptin was also assessed in a human pancreatic carcinoma xenograft (Shaw; i.p.) animal model previously reported as unresponsive to Bi-213-Herceptin (p = 0.002). Multiple dosing of Pb-212-Herceptin was evaluated in both animal models. The median survival of mice bearing 3 d LS-174T i.p. xenografts increased to 110 days, with tip to 3 doses of Pb-212-Herceptin given at approximately. monthly intervals; however, there was no evidence of a correlation with the second and third doses (p = 0.98). No improvement in median. survival was noted with a similar regimen in the Shaw xenograft model.