Significance of circulatory clearance of tumour-localising IgG and F(ab')2 for potential therapy studied in a CEA-producing xenograft model.
The significance of circulatory clearance of tumour-localising IgG and F(ab')2 for potential cancer therapy has been studied in immunodeprived mice bearing a carcinoembryonic antigen (CEA)-producing colon tumour. Intact radiolabelled anti-CEA (1H12) exhibited a prolonged localisation in tumour up to 8 days with injected doses between 4 and 256 g. Increased dosage caused a rise in the absolute concentration in tumour which, for the highest dose, reached 5.1 micrograms/g at 3 days after injection. A concomitant increase in concentration of 1H12 in blood occurred, which with the highest dose, remained above that in the tumour up to 7 days after injection. With F(ab')2 fragments (prepared from anti-CEA, 1C12) increased doses up to 380 micrograms also resulted in an increased uptake in tumour reaching almost 3 micrograms/g for a 234-micrograms dose. Circulatory clearance of F(ab')2-1C12 was essentially complete by 2 days for all doses up to 234 micrograms. Differences in clearance between 1H12 and F(ab')2-1C12 were reflected in the tumour to blood ratios. For high doses of 1H12 this ratio did not exceed unity up to 8 days. With F(ab')2, however, the tumour to blood ratio remained unaffected by dosage after 2 days. Our data suggest that F(ab')2 fragments clear sufficiently quickly to allow compensation by dosage for their premature escape from tumour. Therapeutic administration of intact antibody, however, appears to be limited by a protracted excretory process.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis* / Q000276:immunology; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism*; D007074:Immunoglobulin G / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013997:Time Factors; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G