Investigations of 99mTc morpholino pretargeting in mice.

SUMMARYThis laboratory is exploring the use of morpholinos (MORFs), synthetic DNA analogues, for nuclear medicine applications, including pretargeting. The anti-CEA antibody MN14 was conjugated with an 18 mer MORF and with diethylenetriaminepentaacetic acid (DTPA) for 111In labelling. In a dual label pretargeting study, tumour-bearing nude mice received different doses of (MN14-DTPA-111In+MN14-MORF) followed, at various times after i.v. injection, by 0.15 &mgr;g complementary MORF (cMORF) radiolabelled with 99mTc via MAG(3). Animals were killed 3 h thereafter and tissues were counted for both radionuclides. The 99mTc-cMORF was also administered to tumour bearing mice that, 2 days previously, had received different doses of unlabelled MN14-MORF IgG or, as control, unlabelled Sandoglobulin IgG-MORF (Sandoz-MORF). Tumour uptake was higher at all time points for the labelled antibody itself versus labelled cMORF (8-10 vs 1.3-2.3%ID/g, respectively) in part due to the rapid clearance of cMORF through the kidneys. However, target to non-target ratios were superior for pretargeting at all time points and in all tissue except blood and kidneys. By pretargeting alone, these ratios were highest in all tissues for 15 &mgr;g compared to higher MN14-MORF dosages and in all cases were superior to that of the Sandoz-MORF control. The superior target to non-target ratios for pretargeting can be partially explained through calculations based on both radiolabels: after 24 h, only 0-6% of MORF on MN14 was bound by 99mTc-cMORF in liver and spleen suggesting that the antibody is sequestered in these organs and 'invisible' to labelled MORF. Fortunately, this was not the case in tumours in which 50-60% was bound. It is concluded that pretargeting using MORFs provided encouraging results in one mouse model/anti-tumour antibody system. The advantages of pretargeting in this model were evident in the superior target to non-target ratios obtained over conventional imaging.