Effect of dose escalation of a monoclonal anti-CEA IgG on tumour localisation and tissue distribution in nude mice xenografted with human colon carcinoma

Abstract

A monoclonal anti-CEA antibody (1H12) has been examined for the effect of dosage on tumour localisation in immunodeprived mice xenografted with human colon carcinoma. Increased doses produced a linear rise in the absolute concentration found in the tumour but this was found to depend on tumour size, with the smaller tumours (mean weight 44 mg) accumulating significantly more antibody compared to larger tumours (mean weight 146 mg). With the smallest tumour (18 mg), in which saturation was achieved, a 500 micrograms dose produced a concentration in tumour of 60 micrograms/g. In the larger tumours a dose of 256 micrograms produced a mean concentration of 5.2 micrograms/g. Prolonged retention of 1H12 by tumour up to 8 days, observed at doses of 4, 128 and 256 micrograms, indicated that the dynamics of localisation is unaffected by dosage. Increased doses of 125I-1H12 caused an increase in the levels of radioactivity associated with all normal tissues studied. Thus at 8 days after injection an increase from 4 to 128 micrograms produced 50% and 42% declines in the tumour to blood and liver ratios, respectively. Cumulative localisation of 1H12 in tumour, from 4 h to 8 days, relative to normal tissue clearance was diminished on increasing dosage. This study shows that attempted therapy with escalated amounts of intact antibody is likely to be limited by a protracted excretory process and measures aimed at accelerating circulatory clearance are necessary.