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

Abstract

Purpose: This 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, 111 In and 177 Lu, respectively. Methods: We designed F(ab′) 2 -fragments of cetuximab radiolabeled with 111 In and 177 Lu. 111 In-F(ab′) 2 -cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111 In-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 177 Lu-F(ab′) 2 -cetuximab was evaluated in SWISS nude mice bearing A431 tumors. Results: Radiolabeling procedure did not change F(ab′) 2 -cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111 In-DOTAGA-F(ab′) 2 -cetuximab exhibited a peak tumor uptake at 24 h 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 111 In-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, 177 Lu-DOTAGA-F(ab′) 2 -cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq 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. 177 Lu-DOTAGA-F(ab′) 2 -cetuximab is an interesting theranostic tool allowing therapy and imaging.