Preclinical assessment of broadly neutralizing HIV-1 antibody BNT351 with optimized pharmacokinetics and potent antiviral activity.

Broadly neutralizing antibody (bNAb) 1-18 is a promising tool for future clinical strategies against HIV-1 infection. To enhance 1-18's clinical potential, we introduced half-life-extending LS mutations and evaluated the resulting investigational bNAb candidate, BNT351. LS mutations increased the affinity of BNT351 to human neonatal Fc receptor by 20-fold, resulting in a long half-life of 10-14 days in Tg32 mice and 18 days in non-human primates, with a predicted human half-life of ∼50 days. BNT351 retained 1-18's exceptional neutralization potency and breadth against a 119 multiclade panel, and neutralized a pseudovirus panel of circulating HIV-1 clade C strains with high potency. BNT351 fully suppressed viremia in HIV-1-infected humanized CD34+ NSG mice without eliciting resistant viral variants. Additionally, we observed no off-target binding of BNT351 to a panel of ∼6,500 human proteins, and no developability concerns. This favorable preclinical evaluation supported initiation of a phase 1 clinical trial with BNT351 (NCT07392372).