Copper-64-Labeled 1C1m-Fc, a New Tool for TEM-1 PET Imaging and Prediction of Lutetium-177-Labeled 1C1m-Fc Therapy Efficacy and Safety

SIMPLE SUMMARY: The prevalence of TEM-1 in the vasculature and the stroma of solid tumors and in malignant cells of sarcomas suggests that targeting TEM-1 could have therapeutic benefit. In this context, an anti-TEM-1 companion diagnostic may assist in the personalized medicine approach, whereby TEM-1 expression is exploited as a biomarker to select patients that would most benefit from a treatment directed toward the TEM-1 antigen. In our previous works, we have selected 1C1m-Fc, a fusion protein antibody, radiolabeled it with (177)Lu and demonstrated that [(177)Lu]Lu-1C1m-Fc has interesting therapeutic performance. To define a suitable radiopharmaceutical companion for theranostic applications, (64)Cu was chosen to radiolabel the fusion protein antibody. The aim of this work was thus to determine if [(64)Cu]Cu-1C1m-Fc can be considered for TEM-1 PET imaging and to predict the dosimetry of the [(177)Lu]Lu-1C1m-Fc companion therapy. ABSTRACT: 1C1m-Fc, a promising anti-TEM-1 DOTA conjugate, was labeled with (64)Cu to target cancer cells for PET imaging and predicting the efficacy and safety of a previously studied [(177)Lu]Lu-1C1m-Fc companion therapy. DOTA-conjugated 1C1m-Fc was characterized by mass spectrometry, thin layer chromatography and immunoreactivity assessment. PET/CT and biodistribution studies were performed in human neuroblastoma xenografted mice. Absorbed doses were assessed from biodistribution results and extrapolated to (177)Lu based on the [(64)Cu]Cu-1C1m-Fc data. The immunoreactivity was ≥ 70% after 48 h of incubation in serum, and the specificity of [(64)Cu]Cu-1C1m-Fc for the target was validated. High-resolution PET/CT images were obtained, with the best tumor-to-organ ratios reached at 24 or 48 h and correlated with results of the biodistribution study. Healthy organs receiving the highest doses were the liver, the kidneys and the uterus. [(64)Cu]Cu-1C1m-Fc could be of interest to give an indication of (177)Lu dosimetry for parenchymal organs. In the uterus and the tumor, characterized by specific TEM-1 expression, the (177)Lu-extrapolated absorbed doses are overestimated because of the lack of later measurement time points. Nevertheless, 1C1m-Fc radiolabeled with (64)Cu for imaging would appear as an interesting radionuclide companion for therapeutic application with [(177)Lu]Lu-1C1m-Fc.