Systematic Assessment of Antiviral Potency, Breadth, and Synergy of Triple Broadly Neutralizing Antibody Combinations against Simian-Human Immunodeficiency Viruses

Abstract

Daily burden and clinical toxicities associated with antiretroviral therapy (ART) emphasize the need for alternative strategies to induce long-term HIV remission upon ART cessation. Broadly neutralizing antibodies (bNAbs) can both neutralize free virions and mediate effector functions against infected cells and therefore represent a leading immunotherapeutic approach. To increase potency and breadth as well as to limit the development of resistant virus strains, it is likely that bNAbs will need to be administered in combination. It is therefore critical to identify bNAb combinations that can achieve robust polyfunctional antiviral activity against a high number of HIV strains. In this study, we systematically assessed the ability of single bNAbs and triple bNAb combinations to mediate robust polyfunctional antiviral activity against a large panel of cross-clade simian-human immunodeficiency viruses (SHIVs), commonly used as tools for validation of therapeutic strategies targeting the HIV envelope in nonhuman primate models. We demonstrate that most bNAbs are capable of mediating both neutralizing and non-neutralizing effector functions against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs is highly strain-dependent. Moreover, we observe a strong correlation between the neutralization potencies and non-neutralizing effector functions of bNAbs against the transmitted/founder SHIV CH505. Finally, we identify several triple bNAb combinations comprised of CD4 binding site, V2-glycan, and gp120-gp41 interface targeting bNAbs that are capable of mediating, synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs. IMPORTANCE Optimal bNAb immunotherapeutics will need to mediate multiple antiviral functions against a broad range of HIV strains. Our systematic assessment of triple bNAb combinations against SHIVs will identify bNAbs with synergistic, polyfunctional antiviral activity that will inform the selection of candidate bNAbs for optimal combination designs. The identified combinations can be validated in vivo in future passive immunization studies using the SHIV challenge model.

A novel HIV triple broadly neutralizing antibody (bNAb) combination-based passive immunization of infant rhesus macaques achieves durable protective plasma neutralization levels and mediates anti-viral effector functions

“…Our group previously demonstrated that a combination of 3BNC117, PGDM1400 and PGT151 can mediate potent in vitro antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) effector functions against cross clade SHIVs 24 . Here, we assessed the non-neutralizing effector functions of the plasma obtained from triple bNAb-infused infant RMs.…”

“…In fact, recently, using computational modeling on HIVexposed infants, it was projected that bNAb-based prophylaxis would reduce the cumulative pediatric HIV incidence in Sub Saharan African regions and would be cost-effective when added to the current prevention strategies 32 . By systematic assessment of the neutralizing and nonneutralizing antiviral functions of bNAbs targeting multiple epitopes of the HIV Env, we previously identified a bNAb combination, 3BNC117 21 , PGDM1400 22 , and PGT151 23 to have potent in vitro polyfunctional antiviral potency and breadth against cross-clade SHIVs 24 , making this combination ideal for studies in the infant RM model. In the current study, we passively immunized infant RMs with this triple bNAb regimen and monitored the safety and PK of the antibodies in an infant setting.…”

“…Our group previously demonstrated that a triple bNAb combination consisting of 3BNC117 21 (CD4 binding site-specific), PGDM1400 22 (V2 glycan-specific), and PGT151 23 (gp120-41-specifc) confers robust in vitro neutralization breadth and non-neutralizing Fc-mediated effector functions against cross-clade SHIVs 24 . In the current study, we utilized an infant rhesus macaque (RM) model to assess the safety, PK, and ex vivo antiviral potency of this triple bNAb combination in the pediatric setting.…”

Changes at V2 apex of HIV-1 Clade C trimer enhance elicitation of autologous neutralizing and broad V1V2-scaffold antibodies

“…Antibodies with neutralizing properties can also display Fc-mediated anti-viral effector functions such as ADCC (antibody-dependent cellular cytotoxicity), ADCVI (antibody-dependent cell-mediated viral inhibition), ADCP (antibody-dependent cell-mediated phagocytosis) that help in clearing virus infected cells (Berendam et al, 2021). In addition to the neutralizing Abs, non-neutralizing Abs (non-nAbs) have been reported to contribute significantly towards protection in the RV144 human efficacy trial (Rerks-Ngarm et al, 2009).…”

Prediction of serum HIV-1 neutralization titers of VRC01 in HIV-uninfected Antibody Mediated Prevention (AMP) trial participants

“…These possibilities should be thoroughly investigated, for each considered bnAb combination, in both in vitro and animal models prior to clinical consideration. In vitro studies have already identified a number of double 20 - and triple 21 -bnAb combinations with synergistic neutralization potency; these findings await validation in vivo in passive immunization/SHIV challenge studies. When data become available from ongoing and future trials of other single bnAb or combination bnAb infusions, 22 similar approaches can be adapted to analyze data from such studies.…”