Investigations of 99mTc morpholino pretargeting in mice


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Abstract

This 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 μg complementary MORF (cMORF) radiolabelled with 99mTc via MAG3. 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 μg 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.

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