CLEARANCE OF YTTRIUM-90-LABELED ANTITUMOR ANTIBODIES WITH ANTIBODIES RAISED AGAINST THE 12N4 DOTA MACROCYCLE

Radioimmunotherapy (RIT) is currently limited by toxicity to normal ti ssues as a result of prolonged circulating radioantibody in the blood. In this study, the use of a clearing antibody was investigated (secon d antibody) in an attempt to reduce blood background levels of [Y-90]A 5B7 immunoglobulin G (IgG) activity, and, therefore, improve the thera peutic tumour-blood ratio in nude mice bearing human colorectal tumour xenografts. The second antibody was raised against the 12N4 macrocycl e group used for chelation of 90Y, and is, thus, applicable to any ant i-tumour antibody labelled with this methodology. Second antibody was administered 18, 24 or 48 h after radiolabelled antibody injection and produced up to a tenfold reduction in blood levels and a tenfold impr ovement in tumour-blood ratios. This has the advantage of reducing the risk of myelotoxicity caused by prolonged retention of activity in th e blood. For all normal tissues, there was a similar or slightly lower uptake of [Y-90]IgG with second antibody clearance, apart from a tran sient rise in liver activity due to complexes of primary and secondary antibody clearing via the liver. As a result of clearance of [Y-90]Ig G from the blood pool, there was an associated fall in the amount of a ntibody at the tumour site (up to 3.3-fold) at later time points for m ice injected with second antibody. However, despite this, tumour-blood ratios remained superior to the control group at these later time poi nts. Estimated dosimetry evaluation revealed that total dose to normal tissues, blood and tumour was lower than for the non-clearance group. Surprisingly, however, there was little improvement in total estimate d tumour-blood dose ratio over the time period studied. This was proba bly because the majority of the dose was delivered to both the blood a nd tumour within the first 24 h after administration of [Y-90]IgG, so that giving the clearing agent after this time did not produce a large difference in total estimated dose. The anti-macrocycle second antibo dy proved to be a successful clearing agent and could potentially be a pplied to any anti-tumour antibody coupled with the 12N4 macrocycle. I n the tight of the estimated dosimetry results described here, it woul d probably be most useful given at earlier time points (i.e. before 18 h after injection of primary antibody) to produce an improved tumour- blood ratio of total dose. Development of this strategy may allow high er levels of activity to be administered for RIT, and repeated dosing regimens.