Radiolabeled F(ab `)(2)-cetuximab for theranostic purposes in colorectal and skin tumor-bearing mice models

PurposeThis study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, In-111 and Lu-177, respectively.MethodsWe designed F(ab)(2)-fragments of cetuximab radiolabeled with In-111 and Lu-177. In-111-F(ab)(2)-cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of In-111-F(ab)(2)-cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on Lu-177-F(ab)(2)-cetuximab was evaluated in SWISS nude mice bearing A431 tumors.ResultsRadiolabeling procedure did not change F(ab)(2)-cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. In-111-DOTAGA-F(ab)(2)-cetuximab exhibited a peak tumor uptake at 24h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab)(2)-cetuximab. SPECT imaging of In-111-DOTAGA-F(ab)(2)-cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, Lu-177-DOTAGA-F(ab)(2)-cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8MBq doses.Conclusions(111)In-DOTAGA-F(ab)(2)-cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. Lu-177-DOTAGA-F(ab)(2)-cetuximab is an interesting theranostic tool allowing therapy and imaging.