Abstract
Radioimmunotherapy (RIT) is currently limited by toxicity to normal tissues as a result of prolonged circulating radioantibody in the blood. In this study, the use of a clearing antibody was investigated (second antibody) in an attempt to reduce blood background levels of [90Y]A5B7 immunoglobulin G (IgG) activity, and, therefore, improve the therapeutic tumour-blood ratio in nude mice bearing human colorectal tumour xenografts. The second antibody was raised against the 12N4 macrocycle group used for chelation of 90Y, and is, thus, applicable to any anti-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 improvement in tumour-blood ratios. This has the advantage of reducing the risk of myelotoxicity caused by prolonged retention of activity in the blood. For all normal tissues, there was a similar or slightly lower uptake of [90Y]IgG with second antibody clearance, apart from a transient rise in liver activity due to complexes of primary and secondary antibody clearing via the liver. As a result of clearance of [90Y]IgG from the blood pool, there was an associated fall in the amount of antibody at the tumour site (up to 3.3-fold) at later time points for mice injected with second antibody. However, despite this, tumour-blood ratios remained superior to the control group at these later time points. 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 estimated tumour-blood dose ratio over the time period studied. This was probably because the majority of the dose was delivered to both the blood and tumour within the first 24 h after administration of [90Y]IgG, so that giving the clearing agent after this time did not produce a large difference in total estimated dose. The anti-macrocycle second antibody proved to be a successful clearing agent and could potentially be applied to any anti-tumour antibody coupled with the 12N4 macrocycle. In the light of the estimated dosimetry results described here, it would 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 higher levels of activity to be administered for RIT, and repeated dosing regimens.
Highlights
The second antibody was raised against the 1 2N4 macrocycle group used for chelation of 90Y. and is, applicable to any anti-tumour antibody labelled with this methodology
As a result of clearance of [90Y]lgG from the blood pool, there was an associated fall in the amount of antibody at the tumour site at later time points for mice injected with second antibody
Estimated dosimetry evaluation revealed that total dose to normal tissues, blood and tumour was lower than for the non-clearance group
Summary
AntibodiesThe 12N4 DOTA macrocvcle %vas conjugated to bovine serum albumin for immunizations. usinc the method previouslI described by Turner et al ( 1994). The mouse IgG 1 anti-macrocycle antibody (1CC) -as raised using conventional hybridoma techniques and shown to be specific for the 12N4 macrocycle (Chaplin et al in preparation). The mouse IgG1 anti-CEA antibody A5B7 was conjucated to the 1 2N4 macrocyvcle group for 'Y labelling, as described previously (Casev et al 1996). B. A5B7 IgG was radiolabelled A-ith +'Y to a specific activity of 74 kBq g1-'. All the MF1 nude mice bearing LS174T human colorectal carcinoma xenografts (Pedlev et al 1993) were injected by the tail v-ein intravenously (i.s-.) w-ith approximately 10 MBq of [90Y]IgG. Test animals s-ere subsequently injected intraperitoneally (i.p.) swith clearing antibody 1C2 at a fivefold molar excess (approximately 25 pa) oser the amount of labelled antibody oriainallv administered. Test and control animals %vere bled and tissues removed for radioactivity assessment at various time inters als after injection. The Mann-Whitnev nonparametric statistical test was used to compare data and results were considered to be sienificant w-hen P < 0.05
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