Effector Function Does Not Contribute To Protection From Virus Challenge By A Highly Potent Hiv Broadly Neutralizing Antibody In Nonhuman Primates

Protection from immunodeficiency virus challenge in nonhuman primates (NHPs) by a first-generation HIV broadly neutralizing antibody (bnAb) b12 has previously been shown to benefit from interaction between the bnAb and Fc gamma receptors (Fc gamma Rs) on immune cells. To investigate the mechanism of protection for a more potent second-generation bnAb currently in clinical trials, PGT121, we carried out a series of NHP studies. These studies included treating with PGT121 at a concentration at which only half of the animals were protected to avoid potential masking of Fc gamma R effector function benefits by dominant neutralization and using a new variant that more completely eliminated all rhesus Fc gamma R binding than earlier variants. In contrast to b12, which required Fc gamma R binding for optimal protection, we concluded that PGT121-mediated protection is not augmented by Fc gamma R interaction. Thus, for HIV-passive antibody prophylaxis, these results, together with existing literature, emphasize the importance of neutralization potency for clinical antibodies, with effector function requiring evaluation for individual antibodies.