Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections

Abstract

There is great interest in passive transfer of broadly neutralizing antibodies (bnAbs) and engineered bispecific antibodies (Abs) for prevention of HIV-1 infections due to their in vitro neutralization breadth and potency against global isolates and long in vivo half-lives. We compared the potential of eight bnAbs and two bispecific Abs currently under clinical development, and their 2 Ab combinations, to prevent infection by dominant HIV-1 subtypes in sub-Saharan Africa. Using in vitro neutralization data for Abs against 25 subtype A, 100 C, and 20 D pseudoviruses, we modeled neutralization by single Abs and 2 Ab combinations assuming realistic target concentrations of 10μg/ml total for bnAbs and combinations, and 5μg/ml for bispecifics. We used IC80 breadth-potency, completeness of neutralization, and simultaneous coverage by both Abs in the combination as metrics to characterize prevention potential. Additionally, we predicted in vivo protection by Abs and combinations by modeling protection as a function of in vitro neutralization based on data from a macaque simian-human immunodeficiency virus (SHIV) challenge study. Our model suggests that nearly complete neutralization of a given virus is needed for in vivo protection (~98% neutralization for 50% relative protection). Using the above metrics, we found that bnAb combinations should outperform single bnAbs, as expected; however, different combinations are optimal for different subtypes. Remarkably, a single bispecific 10E8-iMAb, which targets HIV Env and host-cell CD4, outperformed all combinations of two conventional bnAbs, with 95–97% predicted relative protection across subtypes. Combinations that included 10E8-iMAb substantially improved protection over use of 10E8-iMAb alone. Our results highlight the promise of 10E8-iMAb and its combinations to prevent HIV-1 infections in sub-Saharan Africa.

An antigenic atlas of HIV-1 escape from broadly neutralizing antibodies

“…We also examined how our maps of escape from individual antibodies compared to those generated using a pool of antibodies-an important question since combinations of bnAbs are a clear future direction in antibody immunotherapy (Wagh et al, , 2018. We mapped escape from one such clinically relevant pool of two bnAbs, 3BNC117 and 10-1074.…”

Protection of rhesus macaques against vaginal SHIV challenges by VRC01 and an anti-α4β7antibody

“…Combinations of more bNAbs or bi-or tri-specific molecules need to be employed to achieve better and more durable protection from HIV acquisition 32,[41][42][43] . Moreover, recent data suggest that bNAbs treatment may impact immune responses to infection [44][45][46] .…”

Ongoing Vaccine and Monoclonal Antibody HIV Prevention Efficacy Trials and Considerations for Sequel Efficacy Trial Designs

“…Such variants could potentially break through with similar efficiency as VRC01-sensitive variants, a problem that could be theoretically circumvented by a cocktail or bispecific/trispecific bnAb regimen. This model for potential failure of a single bnAb that could be repaired by a cocktail or bispecific/trispecific is referred to as the "overwhelming swarm hypothesis," a hypothesis suggested by the Julg et al andXu et al studies (Julg et al 2017, Xu et al 2017) as noted above, as well as by theoretical modeling studies (Wagh et al 2016, Wagh et al 2018.…”