title: Astatinated trastuzumab, a putative agent for radionuclide immunotherapy of ErbB2-expressing tumours.
abstract: The anti-ErbB2 antibody trastuzumab is used for the treatment of patients with advanced breast cancer, resulting in a response rate of 40-60%. Coupling with a cytotoxic nuclide, e.g. alpha-emitting 211At, may further increase tumour response. The tumour-targeting properties of trastuzumab, astatinated using N-succinimidyl-para-(tri-n-methylstannyl)-benzoate, were evaluated and compared with those of radioiodinated trastuzumab in this study. We found that astatinated trastuzumab retains high specificity towards ErbB2. While the immunoreactive fraction of radioiodinated trastuzumab was higher than that of astatinated trastuzumab (76+/-9% versus 54+/-28%), both radioconjugates showed high affinity (KD 0.75+/-0.16 nM versus 1.8+/-0.3 nM). A growth inhibition study indicated a dose-dependent cell deactivation, in which approximately 74 cell-associated astatine decays per cell gave a survival fraction of 4.5+/-0.8x10(-4). Results of a comparative animal study on normal mice gave no indication that astatination would have any adverse effects on the biodistribution of the antibody. In conclusion, the results of the study suggest that astatinated trastuzumab is a promising candidate for treating ErbB2-expressing tumours.
authors.affiliation: Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden. mikael.persson@bms.uu.se
authors.forename: M I
authors.initials: MI
authors.lastname: Persson
authors.forename: L
authors.initials: L
authors.lastname: Gedda
authors.forename: H J
authors.initials: HJ
authors.lastname: Jensen
authors.forename: H
authors.initials: H
authors.lastname: Lundqvist
authors.forename: P-U
authors.initials: PU
authors.lastname: Malmström
authors.forename: V
authors.initials: V
authors.lastname: Tolmachev
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001246:Astatine / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D016499:Radioimmunotherapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001246:Astatine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab