α-Particle Radioimmunotherapy of Disseminated Peritoneal Disease Using a ²¹²Pb-Labeled Radioimmunoconjugate Targeting HER2

Abstract

These studies demonstrate the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using (212)Pb-labeled Herceptin as an in vivo generator of (212)Bi. In vitro studies compare the potential of the bismuth radioisotopes, (213)Bi and (212)Bi, to that of (212)Pb. Overall, (212)Pb results in a higher therapeutic index than either bismuth radioisotope, requiring lower radioactivity (microCi) for effective cytotoxic response. A pilot radioimmunotherapy (RIT) experiment treating mice bearing 5 d LS-174T intraperitoneally (i.p.) xenografts determined a maximum tolerated dose (MTD) of 20-40 microCi with i.p. administration. A specific dose response was observed and 10 microCi was selected as the effective operating dose for future experiments. Median survival of tumor-bearing mice receiving 10 microCi increased from 19 to 56 days (p = 0.008). The efficacy of (212)Pb-Herceptin was also assessed in a human pancreatic carcinoma xenograft (Shaw; i.p.) animal model previously reported as unresponsive to 213Bi-Herceptin (p = 0.002). Multiple dosing of (212)Pb-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 up to 3 doses of (212)Pb-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.

Evaluation of cetuximab as a candidate for targeted α-particle radiation therapy of HER1-positive disseminated intraperitoneal disease

“…tumors by 3-to 4-fold. 1,2 This therapeutic benefit can be potentiated by incorporating chemotherapeutics such as gemcitabine, paclitaxel or carboplatin into the treatment regimen. 3-5 213 Bismuth, a decay product of 225 Ac, has a T 1/2 of 45.7 min whereas 212 Pb is a 10.6 h half-life b ¡ -emitter that decays to 212 Bi, an a-emitter with a T 1/2 of 60.6 min.…”

Pre-clinical evaluation of [111In]-benzyl-DOTA-ZHER2:342, a potential agent for imaging of HER2 expression in malignant tumors

“…According to Milenic and co-authors (32,33), this cell line possesses low but uniform expression of HER2 and may be a good model to demonstrate the sensitivity of Z HER2:342 in detection of lowlevel antigen expression. Female outbred Balb/c nu/nu mice were sc injected with one million LS174T cells in the hind leg 3 weeks before the experiment.…”

Potentiation of High-LET Radiation by Gemcitabine: Targeting HER2 with Trastuzumab to Treat Disseminated Peritoneal Disease

“…This laboratory recently showed the efficacy of two different a-emitting radionuclides in a peritoneal model for ovarian and pancreatic cancer using trastuzumab as the targeting moiety (3,4). HER2 is overexpressed in several epithelial tumors, including 35% to 45% of all pancreatic adenocarcinomas, 25% to 30% ovarian cancers, and 4% to 83% colorectal adenocarcinomas (5 -7).…”

“…A specific dose response was observed when trastuzumab was radiolabeled with either 213 Bi or 212 Pb. Studies that exploited 212 Pb as an in vivo generator of 212 Bi clearly showed the feasibility of this isotope for targeted therapy treating disseminated peritoneal disease (4). Specifically, whereas HER2 was targeted using trastuzumab, the results therein also showed that at the protein doses used, the mAb itself provided no therapeutic benefit (3).…”

“…Its selection was based on the observation of minimal toxicity (weight loss) experienced by the mice that would also permit differences in responses to treatment regimens to be discerned (e.g., when 212 Pb radioimmunotherapy was evaluated with other modalities such as chemotherapy; ref. 4). Median survival of mice bearing LS-174T i.p.…”