Beta emitters rhenium-188 and lutetium-177 are equally effective in radioimmunotherapy of HPV-positive experimental cervical cancer

Abstract

Cervical cancer caused by the infection with the human papillomavirus (HPV) remains the fourth leading killer of women worldwide. Therefore, more efficacious treatments are needed. We are developing radioimmunotherapy (RIT) of HPV-positive cervical cancers by targeting E6 and E7 viral oncoproteins expressed by the cancer cells with the radiolabeled monoclonal antibodies (mAbs). To investigate the influence of different radionuclides on the RIT efficacy—we performed RIT of experimental cervical cancer with Rhenium-188 (¹⁸⁸Re) and Lutetium-177 (¹⁷⁷Lu)-labeled mAb C1P5 to E6. The biodistribution of ¹⁸⁸Re- and ¹⁷⁷Lu-labeled C1P5 was performed in nude female mice bearing CasKi cervical cancer xenografts and the radiation dosimetry calculations for the tumors and organs were carried out. For RIT the mice were treated with 7.4 MBq of either ¹⁸⁸Re-C1P5 or ¹⁷⁷Lu-C1P5 or left untreated, and observed for their tumor size for 28 days. The levels of ¹⁸⁸Re- and ¹⁷⁷Lu-C1P5 mAbs-induced double-strand breaks in CasKi tumors were compared on days 5 and 10 post treatment by staining with anti-gamma H2AX antibody. The radiation doses to the heart and lungs were similar for both ¹⁷⁷Lu-C1P5 and ¹⁸⁸Re-C1P5. The dose to the liver was five times higher for ¹⁷⁷Lu-C1P5. The doses to the tumor were 259 and 181 cGy for ¹⁷⁷Lu-C1P5 and ¹⁸⁸Re-C1P5, respectively. RIT with either ¹⁷⁷Lu-C1P5 or ¹⁸⁸Re-C1P5 was equally effective in inhibiting tumor growth when each was compared to the untreated controls (P = 0.001). On day 5 there was a pronounced staining for gamma H2AX foci in ¹⁷⁷Lu-C1P5 group only and on day 10 it was observed in both ¹⁷⁷Lu-C1P5 and ¹⁸⁸Re-C1P5 groups. ¹⁸⁸Re- and ¹⁷⁷Lu-labeled mAbs were equally effective in arresting the growth of CasKi cervical tumors. Thus, both of these radionuclides are candidates for the clinical trials of this approach in patients with advanced, recurrent or metastatic cervical cancer.

Our group has been developing an approach of targeting human papilloma virus (HPV) antigens with the radiolabeled antibodies on cancers of viral etiology. We have demonstrated that such approach is specific, effective and safe in several experimental models of cervical and head and neck cancers. In all our previously published studies we have utilized 188Rhenium, a strong beta emitter with a short half-life. In this study, we investigated the influence of different radionuclides on the radioimmunotherapy efficacy by performing side by side comparison of the efficacy and mechanisms of action of the 188Rhenium versus 177Lutetium-labeled antibodies to HPV-16/18 viral oncoprotein E6. This study demonstrated equal efficacy of these two radionuclides for therapy of experimental cervical cancer which makes these radionuclides candidates for clinical translation.

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