HIV treatment and prevention using broadly neutralizing antibodies

Unmet Need

For over 40 years, the HIV pandemic has affected millions, reducing life expectancy and quality of life. As of 2021, 38.4 million people globally are living with HIV, with about 1.5 million new cases each year. While 28.7 million are on antiretroviral therapy (ART) to suppress the virus, ART requires strict adherence to a daily regimen of multiple drugs. This places a burden on the patient to have a constant supply of medications and be monitored for treatment escape by the virus, which is especially challenging in communities with limited healthcare access. Further, the use of current standard of care antiretrovirals causes many short- and long-term side effects, such as nausea, rash, dyslipidemia, and bone density loss among others which affect long-term health and quality of life. There is a need for an alternative treatment and preventative for HIV that does not require a strict daily regimen and has minimal side effects.

Technology

Duke inventors, collaborating with the Vaccine Research Center (NIAID, NIH), have developed novel broadly neutralizing antibody variants with best-in-class neutralization breadth and potency for HIV-1. Broadly neutralizing antibodies (bNAbs) can be dosed infrequently and limit the virus’s ability to escape by mutation because they neutralize multiple viral strains. This is intended to be used as a treatment or prophylaxis for HIV-1, with less stringent compliance requirements and fewer side effects than existing options. Specifically, these novel variants improve neutralization breadth from 39% to 54% at clinically relevant concentrations and improve median potency by up to 4-fold over a cross-clade panel of 208 strains (Cell Reports, Holt et al., 2023). Potency was increased over 100-fold against some resistant viruses. This was accomplished using OSPREY, a suite of free and open-source protein design programs developed by Dr. Bruce Donald, to predict mutations for improved antibody affinity. These significant gains in bNAb efficacy were attained in the PGT145 and PG9RSH antibody classes, which are already among the broadest and most potent HIV-1 antibodies thus far identified. Significantly, this has been demonstrated in live HEK and HeLa cells derived from human patients. These same assays have previously been shown to predict bNAb efficacy against viral infection in live monkeys (Rudicell et al., 2014). Additionally, high resolution structural analysis by cryo-EM revealed target engagement, mechanism of action, and unique post-translational modifications via sulfonated tyrosines in the mABs complementarity determining regions.

Advantages

• More potent and broadly neutralizing than existing bNAbs.
• Provides another modality of prophylaxis and treatment for HIV.
• Can be used in combination with other bNAbs (e.g. VRC07-523LS).