188Re Dose escalation in tumored mice by MORF/cMORF pretargeting

Objectives All radiotherapy studies in xenografted animals using ¹⁸⁸Re have thus far shown only tumor growth inhibition, including our earlier proof-of-concept study of MORF/cMORF pretargeting.

Methods Tumor size reduction has now been achieved in TAG-72 positive LS174T tumored mice using the anti TAG-72 CC49 antibody and escalating ¹⁸⁸Re radioactivity. A ¹⁸⁸Re-cMORF tracer study was first performed to estimate the radiation doses achievable in the dose-escalating therapy trial.

Results No loss of ¹⁸⁸Re in tumor was observed over 90 h in mice pretargeted with MORF-CC49 antibody 48 h earlier. Infinite retention was therefore assumed in the subsequent dosimetric calculations. Both necropsy and imaging showed that the whole body radioactivity after 1 h post IV administration of ¹⁸⁸Re was largely restricted to the tumor. These results were used to obtain the areas under the radioactivity curves (AUCs). The tumor to normal organ AUC ratios in all cases were greater than unity and varied from 3 (kidneys) to 48 (muscle). In the dose-escalation trials, sacrifice at fixed tumor size was at 6, 8, 13, 16, and 21 days for doses of 0, 350, 700, 1050, and 1400 µCi and the maximum dose to tumor was estimated at 2200 rads. A dose response was therefore observed both in tumor size and in time to sacrifice and a clear reduction in tumor size to the point of disappearance was evident in animals receiving the highest radiation dose. Histological examination of tissues from animals receiving highest dose showed no evidence of cytotoxicity in any normal tissues but clear evidence of radiation damage in tumor tissue.

Conclusions Effective radiotherapy is achievable by pretargeting using MORF-CC49 and ¹⁸⁸Re-cMORF.