title: Radioimmunoconjugates for targeted alpha therapy of malignant melanoma.
abstract: Effective targeted cancer therapy requires high selectivity and cytotoxicity. To this end we have prepared and tested a new alpha-emitting radioimmunoconjugate (RIC) against malignant melanoma. The melanoma antibody 9.2.27 is specific for most melanoma cell lines. This antibody was labelled with an a emitter, bismuth-213 (213Bi), and a positron emitter, terbium-152 (152Tb), which is an analogue of the alpha-emitting radioisotope terbium-149. The chelators cDTPAa (a cyclic anhydride of diethylenetriamine pentacetic acid) and CHX-A" (a 2-(p-SCN-Bz)-cyclohexyl-DTPA ligand) were used in order to obtain high labelling yields for both isotopes with either chelator. The labelling efficiency with 213Bi was found to be 96% and 92% with cDTPAa and CHX-A", respectively. With 152Tb it was 93% and 89%, respectively. Serum stability studies showed 20% leaching with 213Bi over a period of 2.5 half-lives. For 152Tb the leaching was 13%. There was no difference in the melanoma cell binding of the labelled and unlabelled antibodies. DNA synthesis data were compared for both isotopes with either chelator. Based on these results, the therapeutic activity ratio for 213Bi a particles and 152Tb positrons for the same endpoint was calculated to be 120. The stability of the bismuth and terbium RICs, together with the outstanding cytotoxicity of the alpha emitter, provides the basis for a new approach to the potential control of micrometastatic melanoma.
authors.affiliation: Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Kogarah, NSW, Australia.
authors.forename: S M
authors.initials: SM
authors.lastname: Abbas Rizvi
authors.forename: S
authors.initials: S
authors.lastname: Sarkar
authors.forename: G
authors.initials: G
authors.lastname: Goozee
authors.forename: B J
authors.initials: BJ
authors.lastname: Allen
mesh_terms: D000911:Antibodies, Monoclonal; D001729:Bismuth / Q000627:therapeutic use*; D002614:Chelating Agents / Q000627:therapeutic use; D004273:DNA, Neoplasm / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D017879:Isothiocyanates / Q000627:therapeutic use; D008545:Melanoma / Q000532:radiotherapy*; D019384:Nucleic Acid Synthesis Inhibitors; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011868:Radioisotopes / Q000627:therapeutic use*; D013725:Terbium / Q000627:therapeutic use*; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D004273:DNA, Neoplasm; D018796:Immunoconjugates; D017879:Isothiocyanates; D019384:Nucleic Acid Synthesis Inhibitors; D011868:Radioisotopes; D013725:Terbium; C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid; D004369:Pentetic Acid; D001729:Bismuth; D013936:Thymidine