Afucosylated broadly neutralizing antibodies targeting the HIV envelope elicit enhanced NK-cell-mediated cytotoxicity against HIV-infected CD4+ T-cell and macrophage targets.

Enhancement of antibody-dependent cellular cytotoxicity is a promising adjunct approach to achieve HIV control in the absence of antiretroviral therapy but requires the development of potent antibody-dependent cellular cytotoxicity-eliciting antibodies that can recognize diverse HIV-infected cell types. A panel of broadly neutralizing antibodies targeting the HIV envelope was identified that specifically binds both HIV-infected CD4+ T cells and monocyte-derived macrophages. Afucosylated versions of these broadly neutralizing antibodies containing ≈30% less core fucose were generated and elicited a significant increase in antibody-dependent cellular cytotoxicity responses from natural killer cells against HIV-infected T-cell and monocyte-derived macrophage targets. Afucosylation did not alter virus neutralization or cell-binding activity of these broadly neutralizing antibodies. Afucosylation modification of broadly neutralizing antibody Fc regions is thus a promising strategy to enhance Fc-mediated activity against both T-cell and macrophage targets in vivo, which may be employed to heighten the therapeutic potential of antibody-based immunotherapy approaches for drug-free HIV control.