Broadly neutralizing monoclonal antibodies (bNAbs) suppress HIV-1 RNA and may deplete viral reservoir. Before evaluating dual bNAbs as a treatment alternative in children, we evaluated the safety and pharmacokinetics (PK) of intravenous VRC01LS and 10-1074 in early-treated children with HIV on suppressive antiretroviral treatment (ART).
Eligible children had received ART from <7 days through ?96 weeks of life, and had HIV-1 RNA <40 copies/mL for ?24 weeks prior to enrollment. The initial PK phase (A) (previously presented) evaluated safety and PK of each bNAb separately in two groups of 6 participants for 12 weeks. In the second phase (B), we evaluated safety and PK of the two bNAbs in combination, and with a higher VRC01LS maintenance dose based on review of Phase A. Six participants received IV infusions every 4 weeks of both 10-1074 (30 mg/kg) and VRC01LS (30mg/kg first dose followed by 15mg/kg maintenance). PK samples were collected over 8 weeks and safety evaluated through 32 weeks. PK concentrations were measured by ELISA. Results were combined from both phases for analysis by noncompartmental (first dose Cmax, Cave and trough) and population PK (PopPK) methods. For the PopPK analysis, a two-compartment model was developed for each bNAb using NONMEM and 5000 virtual participants were simulated to predict steady-state concentrations.
There were no infusion reactions, no expedited adverse events, and no grade 3 or 4 events related to dual bNAb administration through 32 weeks. The first dose median (range) Cmax and trough for VRC01LS were 776 (559-846) mcg/mL and 230 (158-294) mcg/mL, and first dose median (range) Cmax and trough for 10-1074 were 1405 (876-1999) mcg/mL and 133 (84-319) mcg/mL. All participants’ average concentrations following the first dose were >245 mcg/mL for VRC01LS and 290 mcg/mL for 10-1074. The population t1/2 was 38 days for VRC01LS and 16 days for 10-1074; in contrast, VRC01LS t1/2 in healthy adults has previously been reported as 71 days (Gaudiniski 2018). VRC01LS and 10-1074 elimination were similar when administered alone or in combination. The predicted median steady-state troughs with Phase B dosing were 269 mcg/mL (VRC01LS) and 211 mcg/mL (10-1074).
IV infusions of VRC01LS and 10-1074 were well tolerated as dual therapy in children, and generated concentrations similar to those following single bNAb administration. Monthly dosing of VRC01LS at 15mg/kg and 10-1074 at 30 mg/kg achieve target concentrations at steady state.