title: Radioimmunotherapy targeting of HER2/neu oncoprotein on ovarian tumor using lead-212-DOTA-AE1.
abstract: The specificity, toxicity and efficacy of lead (212Pb) radioimmunotherapy were evaluated in nude mice bearing the SK-OV-3 human ovarian tumor cell line expressing the HER2/neu proto-oncogene.
  
  
  METHODS
  The therapeutic agent used was the tumor-specific anti-HER2/neu monoclonal antibody AE1 conjugated to 212Pb, 212Bi being the daughter and thus the source of the alpha-particle and beta emissions. A bifunctional derivative of tetraazacyclododecanetetraacetic acid (p-SCN-Bz-DOTA) was used to couple 212Pb to the anti-HER2/neu monoclonal antibody AE1. The chelating agent did not alter the binding affinity to its antigenic target or the pharmacokinetics and tissue distribution of the AE1 antibody. Toxicity and therapeutic efficacy of 212Pb-AE1 were evaluated in nude mouse ascites or solid tumor models, wherein SK-OV-3 cells were administered i.p. or s.c., respectively.
  
  
  RESULTS
  The dose-limiting acute toxicity after i.v. administration of 212Pb-AE1 was bone marrow suppression, which was observed at doses above 25 microCi. Therefore, doses of 10 and 20 microCi were used in efficacy trials. The i.p. administration of 212Pb-AE1 3 days after i.p. tumor inoculation led to a significant (P2 = 0.015) prolongation of tumor-free survival. In a second model, i.v. treatment with 212Pb-AE1 3 days after s.c. tumor inoculation prevented subsequent tumor development in all animals treated with 10 or 20 microCi of 212Pb-AE1 (P2 = 0.002 compared to control groups). This efficacy in the adjuvant setting was antibody specific because treatments with equivalently labeled control antibody or unlabeled AE1 antibody or no treatment were less effective. The rate of growth of small (mean tumor volume, 15 mm3) SK-OV-3 tumors was modestly inhibited. However, tumor growth was not inhibited in mice bearing larger (mean tumor volume, 146 mm3) SK-OV-3 tumors by the administration of a single dose of 10 or 20 microCi of 212Pb-AE1.
  
  
  CONCLUSIONS
  Lead-212-AE1 as an intact radiolabeled monoclonal antibody may be of only modest value in the therapy of bulky solid tumors due to the short physical half-life of 212Pb and time required to achieve a useful tumor-to-normal tissue ratio of radionuclide after administration. However, the radiolabeled monoclonal antibody may be useful in therapy of tumors in the adjuvant setting. Furthermore, 212Pb may be of value in select situations, including treatment of leukemia, intercavitary therapy or strategies that target vascular endothelial cells of tumors.
authors.affiliation: Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: E
authors.initials: E
authors.lastname: Horak
authors.forename: F
authors.initials: F
authors.lastname: Hartmann
authors.forename: K
authors.initials: K
authors.lastname: Garmestani
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.forename: M
authors.initials: M
authors.lastname: Brechbiel
authors.forename: O A
authors.initials: OA
authors.lastname: Gansow
authors.forename: N F
authors.initials: NF
authors.lastname: Landolfi
authors.forename: T A
authors.initials: TA
authors.lastname: Waldmann
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007856:Lead Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D000090063:Proto-Oncogene Mas; D016499:Radioimmunotherapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D007856:Lead Radioisotopes; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; C000715470:MAS1 protein, human