BACKGROUND: 3BNC117 and 10-1074 are potent broadly neutralizing antibodies (bNAbs) against HIV envelope glycoproteins isolated and cloned from people with HIV (PWH). Teropavimab (3BNC117-LS) and zinlirvimab (10-1074-LS) are recombinant, fully human monoclonal antibodies derived from 3BNC117 and 10-1074, respectively, with two amino acid substitutions in the Fc domain to prolong their half-lives. 3BNC117/teropavimab and 10-1074/zinlirvimab have been shown to induce rapid decline in viremia in PWH, as well as delay the time-to-viral rebound in suppressed PWH during analytical treatment interruption (ATI). The purpose of this study is to evaluate the therapeutic concentrations of the bNAbs through pharmacokinetic-dynamic (PK-PD) modeling.
METHODS: Population PK-PD models were developed based on concentration and/or viral dynamic data from 6 studies that evaluated their antiviral activity in 45 viremic and 49 suppressed PWH during ATI, and 3 PK studies of 3BNC117/teropavimab and 10-1074/zinlirvimab. The PK of the bNAbs were modeled by two-compartment linear PK models. The PD model describes viral replication using logistic growth function, and viral elimination by the bNAbs using first-order kinetics, with a saturable nonlinear relationship between bNAb concentrations and viral elimination rates. Distinct viral populations sensitive or resistant to each bNAb were modeled to capture the mechanism of resistance selection in treated participants. Simulations were performed to evaluate different washout durations of teropavimab and zinlirvimab to predict time-to-viral rebound during ATI.
RESULTS: The PK-PD models adequately described the PK and viral dynamic data from all studies analyzed. The estimated half-lives of teropavimab and zinlirvimab in suppressed PWH are ~62 and 77 days, respectively. The estimated mean (95% CI) serum concentrations corresponding to 20% maximum drug effect of 3BNC117/teropavimab and 10-1074/zinlirvimab were 6.3 (4.9-8.2) and 8.1 (2.5-26) µg/mL, respectively. Simulations predicted that after a washout period of =48 weeks following single dose combination of 30 mg/kg teropavimab and 10 or 30 mg/kg zinlirvirmab, these bNAbs would have minimal effects on the time-to-viral rebound during ATI.
CONCLUSIONS: The PK-PD modeling analyses provided insights to the minimal therapeutic serum concentrations and washout durations of the long acting bNAbs to help define their efficacy in HIV cure studies.