Alpha-particle radioimmunotherapy of disseminated peritoneal disease using a (212)Pb-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.

• Authors: Diane E Milenic, Kayhan Garmestani, Erik D Brady, Paul S Albert, Dangshe Ma, Alia Abdulla, Martin W Brechbiel
• Journal: Cancer biotherapy & radiopharmaceuticals (Cancer Biother Radiopharm) Vol. 20 Issue 5 Pg. 557-68 (Oct 2005) ISSN: 1084-9785 [Print] United States
• PMID: 16248771 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Immunoconjugates
• Lead Radioisotopes
• Receptor, ErbB-2
• Trastuzumab

Topics

• Alpha Particles
• Animals
• Antibodies, Monoclonal (chemistry)
• Antibodies, Monoclonal, Humanized
• Cell Line, Tumor
• Flow Cytometry
• Genes, erbB-2
• Humans
• Immunoconjugates (chemistry)
• Lead Radioisotopes
• Maximum Tolerated Dose
• Mice
• Neoplasm Transplantation
• Peritoneal Diseases (therapy)
• Radioimmunoassay
• Radioimmunotherapy (methods)
• Receptor, ErbB-2 (immunology, metabolism)
• Time Factors
• Trastuzumab