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

Abstract

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, 111In and 177Lu, respectively.MethodsWe designed F(ab′)2-fragments of cetuximab radiolabeled with 111In and 177Lu. 111In-F(ab′)2-cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111In-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 177Lu-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. 111In-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 111In-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, 177Lu-DOTAGA-F(ab′)2-cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses.Conclusions111In-DOTAGA-F(ab′)2-cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177Lu-DOTAGA-F(ab′)2-cetuximab is an interesting theranostic tool allowing therapy and imaging.Electronic supplementary materialThe online version of this article (10.1007/s12094-018-1886-4) contains supplementary material, which is available to authorized users.

Evaluation of nimotuzumab Fab2 as an optical imaging agent in EGFR positive cancers

“…Cetuximab, another anti-EGFR antibody was digested to a Fab 2 and labeled with 111 In in two different studies and tested for theranostic properties. Imaging with 111 In-labeled Fab 2 showed accumulation in the tumor that peaked at 24 h post injection 17 , 18 . Two other studies using 64 Cu-cetuximab Fab 2 only reported images at 24 h and showed the ability of the Fab 2 imaging probe to monitor treatment 19 , 20 .…”

Carrier systems of radiopharmaceuticals and the application in cancer therapy

“…Approved radiolabeled mAbs and their derivatives Currently, two radiolabeled anti-CD20 murine mAbs, 90 Y-ibritumomab tiuxetan (Zevalin) and 131 I-tositumomab (Bexxar) have been approved by the United States Food and Drug Administration (FDA) for the treatment of relapsed or refractory, low-grade or follicular B cell Non-Hodgkin lymphoma (NHL), including rituximab refractory follicular NHL in 2002 and 2003, respectively [28]. 131 I-Metuximab for the treatment of hepatocellular carcinoma (HCC) and 131 I-chTNT for the treatment of lung cancer have been approved by the China National Medical Products Administration [29,30]. Clinical translation of radiolabeled antibodies therapy began with the approval of Zevalin and Bexxar.…”

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

“…TKIs, mAb and SMI have previously been radiolabeled for diagnostic purposes, some also for use in TRT, with progress in the field of epidermal growth factor receptor (EGFR) radio-immunotherapy (RIT) [ 23 , 27 , 28 , 49 , 50 , 51 , 52 ]. For instance [ 188 Re]Re-nimotuzumab and [ 125 I]iodo-mAb 425 are in a clinical stage for GB and [ 177 Lu]Lu]-/[ 211 At]At-L8A4 (EGFRIII) mAb and [ 177 Lu]Lu-cetuximab are in a preclinical stage for GB [ 37 , 53 , 54 , 55 , 56 , 57 , 58 ]. In addition, RTK signaling is affected by ionizing radiation and hence the combination of TKI and RT (external beam radiation therapy or TRT) could have synergistic effects [ 59 ].…”