John Mascola (NIAID)
Peter Kwong (NIAID)
Qingbo Liu (NIAID)
Young Do Kwon (NIAID)
Scientists at NIAID have developed broadly neutralizing antibodies (bNAbs) with enhanced neutralizing activity against HIV-1. Specifically, previously unknown gp120 interactions with a newly elucidated quaternary receptor (CD4)-binding site in the HIV-1 envelope have been discovered by engrafting the extended heavy-chain framework region 3 (FR3) loop of VRC03 onto several potent bNAbs (including VRC01, VRC07 and N6). The new antibodies show improved neutralizaton of gp120 binding to CD4 by interacting with both CD4 binding sites and as a result show improved neutralization of various HIV-1 strains. Furthermore, they show reduced autoreactivity and, as a result, have prolonged in vivo half-life.
One of several antibodies that were developed using this technology is VRC01.23. It combines the VRC03 framework 3 alteration, with a G54W mutation in the heavy chain, and a 3 amino acid deletion in the light chain. The modifications improved the potency while reducing the autoreactivity. In particular, VRC01.23 is capable of neutralizing 96% of HIV-1 viruses tested at geometric mean IC50 =0.042 ug/ml, which is ~10-fold more potent than VRC01.
This technology is available for licensing for commercial development in accordance with 35 U.S.C. § 209 and 37 CFR Part 404, as well as for further development and evaluation under a research collaboration.
- Improving human monoclonal antibodies for HIV treatment or prevention
- New candidates for use as a therapeutic or as a prophylactic
- Interaction with multiple CD4 binding sites on gp120
- Reduced autoreactivity when using the VRC03 framework 3 region mutation
- Improved neutralization breadth and potency over existing antibodies
- Extended in vivo half-life