148 – Bispecific Antibody VRC07/PGT121 Protects Against High-Dose Intravenous SHIV-BG505 Challenge

Background

Non-human primate (NHP) and human clinical studies highlight the utility of broadly neutralizing antibodies (bNAbs) for immunoprophylaxis against HIV-1. Passively delivered bNAbs protect against viral strains susceptible to antibody-mediated neutralization.  To protect against HIV-1 strains resistant to individual antibodies, endeavors to improve bNAb breadth are required.  A key strategy to enhance the neutralization breadth of individual bNAbs is to generate designer bispecific bNAbs.

Methods

We implemented CrossMAb technology to generate a bispecific anti-HIV-1 Env bNAb with antigen-binding arms derived from the VRC07 and PGT121 bNAbs.  We screened the antibody for viral neutralization in a pseudovirus neutralization assay and assessed for in vivo anti-viral activity in humanized NSG mice infected with HIV-1_JRCSF (n=8).  We then implemented an NHP high-dose intravenous viral exposure model to assess antibody-mediated immunoprophylaxis.  This model mimics exposure via a large unscreened blood transfusion but is also relevant to lower-dose intravenous exposures such as through sharing drug injection equipment.  Experimental (n=8) and control (n=8) Indian-origin rhesus macaques were infused with VRC07/PGT121 (30 mg/kg) or an equivalent volume of saline, respectively, one hour before intravenous challenge with SHIV-BG505 (40 X 10⁶ viral RNA copies).  Plasma bNAb concentration was monitored by ELISA. Starting at week eight post-challenge, anti-CD8 alpha antibody (45 mg/kg) was administered in animals lacking evidence of plasma viremia and with VRC07/PGT121 plasma concentrations <1 µg/ml for at least two weeks to reveal possible subclinical infections.      

Results

The VRC07/PGT121 bispecific bNAb neutralized >90% of a panel of 64 global HIV-1 strains (geometric mean IC₅₀=0.64 µg/ml) and reduced viremia in HIV-1-infected humanized mice (average viral load decline ~1.0-1.5 log₁₀ for three weeks). The high-dose intravenous SHIV-BG505 challenge infected all eight control animals (peak log₁₀ viral load range: 6.3-7.3 copies/ml).  We have yet to observe evidence of viral replication in animals pre-treated with VRC07/PGT121 before SHIV-BG505 exposure, including during the post-CD8 depletion period (animals are currently between one- and five-weeks post-depletion).

Conclusions

Bispecific anti-HIV-1 bNAbs are potentially valuable biomedical interventions for ongoing efforts to achieve HIV-1 immunoprophylaxis, as evidenced in this very stringent IV challenge model. 

Table or Figure