Preclinical and phase I studies of monoclonal antibodies in melanoma: application to boron neutron capture therapy of melanoma.
Monoclonal antibodies (MAbs) provide an attractive method of selectively localizing sufficient boron atoms around tumour cells to capture neutrons. Assuming that 10(8)-10(10) 10B atoms are needed for one capture event and that 10(3)-10(4) atoms can be coupled to each antibody molecule, then 10(5)-10(6) antibody molecules gathered on an individual cell will destroy that cell. Binding to normal tissues, on the other hand, would need to be at least 20-fold less than that to tumour tissues to avoid toxic effects of neutrons on surrounding tissues. Preclinical studies in animals show that several MAbs may bind to melanoma cells in sufficient quantities in vitro to localize the required amount of Boron per cell. Whether this will occur in vivo, however, may depend not only on antigen density but a variety of other properties of the tumour cells and MAbs. These include the Ig class and affinity of the antibody and whether the antibody is internalized into the tumour cell. The ratio of uptake between tumour and normal tissue is governed by such factors as the percentage of tumour cells within a tumour expressing the antigen and whether the MAb react with normal tissues. Use of Fab or F(ab)2 preparations of the MAb may increase the uptake ratio by preventing uptake of MAb by cells with Fc receptors. In contrast to preclinical animal studies, tumour/normal tissue uptake ratios in phase I studies in humans have been disappointingly low.(ABSTRACT TRUNCATED AT 250 WORDS)
Hersey
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Immunology and Oncology Unit, Mater Misericordiae Hospital, Royal Newcastle Hospital, N.S.W. Australia.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000032:analysis / Q000276:immunology; D001895:Boron / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000592:standards*; D004341:Drug Evaluation / Q000592:standards*; D006801:Humans; D007554:Isotopes; D008545:Melanoma / Q000032:analysis / Q000188:drug therapy* / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D009502:Neutrons; D012878:Skin Neoplasms / Q000032:analysis / Q000188:drug therapy* / Q000532:radiotherapy; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D007554:Isotopes; D001895:Boron