Comparison of various radioactive payloads for a human monoclonal antibody to glycoprotein 41 for elimination of HIV-infected cells

Background: cART has significantly improved the life expectancy of people living with HIV (PLWH). However, it fails to eliminate the long-lived reservoir of latent HIV-infected cells. Radioimmunotherapy (RIT) relies on antigen-specific monoclonal antibodies (mAbs) for targeted delivery of lethal doses of ionizing radiation to cells. Previously, we have demonstrated that human mAb 2556 against HIV gp41 conjugated with ²¹³Bismuth radioisotope (t_1/2 = 46 min, alpha-emitter) selectively killed HIV-infected cells. ²²⁵Actinium (t_1/2 = 9.92 d, alpha-emitter) and ¹⁷⁷Lutetium (t_1/2 = 6.7 d, beta-emitter) are two long-lived clinically proven radioisotopes for cancer treatment which might be more effective in killing infected cells systemically and in CNS. Methods: In this study we have conjugated 2556 mAb with ²¹³Bi, ²²⁵Ac and ¹⁷⁷Lu, and compared their ability to kill HIV-infected human peripheral blood mononuclear cells (PBMCs) and monocytes. PBMCs and monocytes from healthy donors were infected with HIV_p49.5 and treated in vitro with increasing concentrations of ²¹³Bi (4–20 μCi)-, ²²⁵Ac (20–100 nCi)- and ¹⁷⁷Lu (4–50 μCi)-2556 mAb. Results: After three days post-treatment of infected PBMCs and monocytes, ²¹³Bi- and ¹⁷⁷Lu-conjugated 2556 mAb reduced virus production measured by p24 level in a dose-dependent manner, whereas, ²²⁵Ac-2556 showed minimal effect. However, seven days post-treatment all three radioisotopes showed significantly more pronounced reduction of virus replication as compared to control labeled mAb with ²²⁵Ac-2556 showing the least non-specific killing. Conclusion: These results indicate that RIT holds promise as a novel treatment option for the eradication of HIV-infected cells that merits further study in combination with cART and reactivation drugs.