Background
Broadly neutralizing antibodies (bNAbs) against HIV-1 are in active clinical development. While they exhibit potent antiviral activity, their impact on the autologous HIV immune response remains unclear. The kinetics of autologous functional antibody responses during bNAb therapy have not been studied, as therapeutic and endogenous antibody effects are difficult to separate. To address this, we combined a novel serum bNAb depletion approach with a comprehensive antibody profiling platform to analyze ten T003 trial participants (Julg, Nat Med 2024) who received monthly infusions of PGT121, PGDM1400, and VRC07-523LS during an analytical treatment interruption (ATI).
Methods
Serum was depleted of the 3 bNAbs using anti-idiotype antibodies coupled to magnetic beads and columns. This approach yielded robust, highly specific bNAb depletion to undetectable levels. Undepleted (w bNAbs) and depleted (w/o bNAbs) serum at key timepoints—pre-infusion, during treatment, before HIV RNA rebound, and at the study endpoint if rebound did not occur—was analyzed by Systems Serology to profile IgG subclasses, FcγR binding, and Fc-mediated functions including ADCD, ADNKA, and ADCP against gp120YU2 and SOSIPBJRFL.
Results
As expected, the presence of 3 bNAbs in serum increased FcγR binding activity, as well as functional breadth and magnitude, while the autologous antibody response was not significantly affected and remained stable throughout the observation period. We did not observe changes in IgG3 responses that could have indicated a vaccinal boost of the autologous immune response by IgG1-bNAbs. As 5/10 participants developed viral rebound after >28 weeks of ATI and 5/10 never rebounded during the study, we compared their antibody profiles. Pre-bNAb administration, no difference in antibody profiles between the groups was observed. ADCD activity trended higher in the 5 without rebound and ADCP was significantly increased in this group early on. In contrast, ADNKA, specifically from autologous responses, was more prominent in those with viral rebound, potentially reflecting a response to early low-level viral replication.
Conclusions
Our data suggest that bNAbs, while given for neutralizing activity, also enhance Fc-mediated functions, with ADCD and ADCP enriched in individuals without viral rebound, suggesting a potential role in viral control. The autologous antibody response, however, was not affected, arguing against a vaccinal effect, at least in this small cohort and for the Fc functions measured.