Development of an optimal imaging strategy for selection of patients for affibody-based PNA-mediated radionuclide therapy

Affibody molecules are engineered scaffold proteins, which demonstrated excellent binding to selected tumor-associated molecular abnormalities in vivo and highly sensitive and specific radionuclide imaging of Her2-expressing tumors in clinics. Recently, we have shown that peptide nucleic acid (PNA)-mediated affibody-based pretargeted radionuclide therapy using beta-emitting radionuclide (177)Lu extended significantly survival of mice bearing human Her2-expressing tumor xenografts. In this study, we evaluated two approaches to use positron emission tomography (PET) for stratification of patients for affibody-based pretargeting therapy. The primary targeting probe Z(HER2:342)-SR-HP1 and the secondary probe HP2 (both conjugated with DOTA chelator) were labeled with the positron-emitting radionuclide (68)Ga. Biodistribution of both probes was measured in BALB/C nu/nu mice bearing either SKOV-3 xenografts with high Her2 expression or DU-145 xenografts with low Her2 expression. (68)Ga-HP2 was evaluated in the pretargeting setting. Tumor uptake of both probes was compared with the uptake of pretargeted (177)Lu-HP2. The uptake of both (68)Ga-Z(HER2:342)-SR-HP1 and (68)Ga-HP2 depended on Her2-expression level providing clear discrimination of between tumors with high and low Her2 expression. Tumor uptake of (68)Ga-HP2 correlated better with the uptake of (177)Lu-HP2 than the uptake of (68)Ga-Z(HER2:342)-SR-HP1. The use of (68)Ga-HP2 as a theranostics counterpart would be preferable approach for clinical translation.