Exceptionally broad HIV-1 neutralization via bispecific antibody-mediated prepositioning

Area of Science:

• Virology
• Immunology
• Drug Discovery

Background:

• Class I viral fusion proteins utilize conserved intermediates, like the prehairpin intermediate (PHI), for membrane fusion.
• Antibodies targeting the PHI of HIV-1 fusion proteins have historically shown limited neutralization efficacy.
• Previous work developed a bispecific antibody (bsAb) targeting HIV-1 N-heptad repeat (NHR) and CD4, enhancing neutralization.

Purpose of the Study:

• To engineer an optimized bispecific antibody (bsAb) targeting the HIV-1 N-heptad repeat (NHR) and the CCR5 coreceptor.
• To evaluate the neutralization potency and breadth of the novel bsAb against a diverse panel of HIV-1 strains.
• To assess the potential of the redesigned bsAb as a prophylactic agent against HIV-1 infection.

Main Methods:

• Development of a bispecific antibody (bsAb) engineered to bind both the HIV-1 N-heptad repeat (NHR) and the CCR5 coreceptor.
• Testing the bsAb's neutralization potency and breadth against a panel of 119 pseudotyped, multiclade HIV-1 viruses.
• Comparison of neutralization efficacy with a previously developed CD4-binding bsAb (iMab/D5_AR).

Main Results:

• The engineered bsAb targeting NHR and CCR5 achieved 100% neutralization breadth against all 119 tested HIV-1 pseudoviruses.
• This bsAb demonstrated improved neutralization potency compared to the CD4-binding bsAb, including against resistant strains.
• The bsAb effectively neutralized CCR5-tropic viruses, which are responsible for most initial HIV-1 infections.

Conclusions:

• The redesigned bsAb targeting NHR and CCR5 represents a significant advancement in HIV-1 neutralization technology.
• This bsAb exhibits broad and potent activity, supporting the NHR as a viable therapeutic target for HIV-1.
• The findings lay the groundwork for a new class of engineered broadly neutralizing antibodies with potential as prophylactic agents.