First-in-human evaluation of safety and pharmacokinetics of intravenous or subcutaneous infusions of PGT121.141.LS, an anti-V3 HIV-1 broadly neutralizing antibody in healthy volunteers without HIV


BACKGROUND: Multiple broadly neutralizing antibodies (bnAbs) targeting domains of gp120 are in development for prevention of HIV-1. PGT121.414.LS, a modification of the anti-V3 glycan bnAb PGT121, potently neutralizes multiple HIV-1 clades in vitro.
METHODS: The ongoing, phase 1 HVTN 136/HPTN 092 trial assesses the safety, tolerability, and pharmacokinetics (PK) of PGT121.414.LS in 13 healthy adults without HIV. We evaluated IV dose-escalation and SC infusion in four groups: 3 mg/kg IV (group T1, n=3), 10 mg/kg IV (T2, n=4), 30 mg/kg IV (T3, n=3) and 5 mg/kg SC (T4, n=3). Serum concentrations of PGT121.414.LS were measured on days 0, 1, 2, 3, 6, 14, 28, 56 and 112 after a single infusion. Non-compartmental PK analyses were performed.
RESULTS: The median participant age was 30 years; 77% were assigned female sex at birth; 15% Black and 85% White. IV and SC infusions were safe and well-tolerated, with no related serious adverse events or dose-limiting toxicities. Peak concentrations after IV infusions were observed on day 1, increasing linearly with higher doses (median = 525.8 in T3 vs 164.7 µg/mL in T2). Peak concentrations after SC infusion occurred on day 14. On day 112 (trough visit), T1 and T4 concentrations were similar (12.1 and 13.7 µg/mL); T2 concentrations (31.3 µg/mL) were lower than those predicted for T3 (78.8 µg/mL). Day 112 concentrations for T3 are in progress. PGT121.414.LS estimated clearance was 0.06-0.12 liter/day in T1-T4. PGT121.414.LS estimated elimination half-lives were 3 times longer than its precursor, PGT121, with medians of 53.6 -74.3 days in T1-T4. The estimated bioavailability of SC PGT121.414.LS was 70%, twice the bioavailability of its precursor.
CONCLUSIONS: PGT121.414.LS was safe and well-tolerated following IV or SC infusion in healthy US adults. These preliminary safety and pharmacokinetic findings support further development of PGT121.414.LS in combination with other bnAbs for global HIV-1 prevention.

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