In vitro evaluation of anti-HIV radioimmunoconjugates labeled with astatine-211, thorium-227 and actinium-225

We conducted an in vitro investigation of the selective cytotoxicity of alpha-emitting radioimmunoconjugates (α-RICs) directed against cells expressing HIV envelope (Env) proteins. It is well known that monoclonal antibody (mAb)-targeted α-emitting radionuclides can effectively kill antigen-expressing cells; however, the expected low-level expression of HIV antigens on latently infected cells poses an obstacle to all anti-HIV immune-based treatments, including α-RICs. This investigation tested the cytotoxicity of the HIV envelope antigen-binding mAbs, PGT126 (binding gp120) and 7B2 (binding gp41), conjugated with labeling chelators that bind the α-emitters astatine-211 ( 211 At), actinium-225 ( 225 Ac) or thorium-227 ( 227 Th). Methods High specific activity (SA) preparations of the α-RICs were made to increase the proportion of mAb conjugates carrying the α-emitting isotope. RIC cytolytic activity was evaluated against a cell line stably expressing the HIV envelope. Results 211 At-labeled mAb conjugates did not demonstrate specific cell killing, while the longer lived radiometal α-RICs, 227 Th and 225 Ac, efficiently and specifically killed HIV envelope expressing cells. Conclusions Potential explanations for these differential effects include the longer half-lives of 225 Ac and 227 Th compared to 211 At and differences in the decay properties of radiometals compared to radiohalogens. These encouraging in vitro results suggest that in vivo evaluations of α-RIC in depleting the HIV harboring cells are warranted.