BIODISTRIBUTION OF IN-111-LABELED AND Y-90-LABELED DOTA AND MALEIMIDOCYSTEINEAMIDO-DOTA CONJUGATED TO CHIMERIC ANTICARCINOEMBRYONIC ANTIGEN-ANTIBODY IN XENOGRAFT-BEARING NUDE-MICE - COMPARISON OF STABLE AND CHEMICALLY LABILE LINKER SYSTEMS

Biodistributions of two radiometal chelate conjugates of the human/mur ine chimeric anticarcinoembryonic antigen monoclonal antibody cT84.66 were obtained in nude mice bearing LS174T human colorectal carcinoma x enografts. Derivatives of the macrocyclic chelating agent 1,4,7,10-tet raazacyclododecane-N,N',N '',N'''-tetraacetic acid (DOTA) were covalen tly attached to the antibody by a stable amide linkage and by a maleim idocysteineamido side chain (MC-DOTA) that has been shown to be chemic ally labile at physiological temperature and pH. Biodistributions of b oth In-111 and Y-90 labels were obtained in these studies. At common b iodistribution time points, it was found that the In-111 label had gre ater uptake in the liver than Y-90 for both conjugates No significant differences were found with respect to bone uptake of Y-90 using eithe r chelate. Blood curves were generally lower at comparable time points for MC-DOTA, indicative of faster clearance as compared to DOTA. Tumo r uptake was high for both conjugates (57-68% ID/g at 48 h), with a lo nger tumor residence time in the case of the DOTA conjugate, probably a result of its longer blood circulation times. We conclude that bone uptake of Y-90 would be minimal if either DOTA MC-DOTA were used as th e bifunctional chelator. This would imply preference for these macrocy clic ligands if radiation doses to the bone marrow would be considered to be dominated by skeletal uptakes. Alternatively, if bone marrow ra diation dose is dominated by circulating antibody, the chemically labi le linker system employed by the MC-DOTA conjugate offers the advantag e of enhanced blood clearance.