Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults

Abstract

BackgroundVRC01 is a human broadly neutralizing monoclonal antibody (bnMAb) against the CD4-binding site of the HIV-1 envelope glycoprotein (Env) that is currently being evaluated in a Phase IIb adult HIV-1 prevention efficacy trial. VRC01LS is a modified version of VRC01, designed for extended serum half-life by increased binding affinity to the neonatal Fc receptor.Methods and findingsThis Phase I dose-escalation study of VRC01LS in HIV-negative healthy adults was conducted by the Vaccine Research Center (VRC) at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD). The age range of the study volunteers was 21–50 years; 51% of study volunteers were male and 49% were female. Primary objectives were safety and tolerability of VRC01LS intravenous (IV) infusions at 5, 20, and 40 mg/kg infused once, 20 mg/kg given three times at 12-week intervals, and subcutaneous (SC) delivery at 5 mg/kg delivered once, or three times at 12-week intervals. Secondary objectives were pharmacokinetics (PK), serum neutralization activity, and development of antidrug antibodies. Enrollment began on November 16, 2015, and concluded on August 23, 2017. This report describes the safety data for the first 37 volunteers who received administrations of VRC01LS. There were no serious adverse events (SAEs) or dose-limiting toxicities. Mild malaise and myalgia were the most common adverse events (AEs). There were six AEs assessed as possibly related to VRC01LS administration, and all were mild in severity and resolved during the study. PK data were modeled based on the first dose of VRC01LS in the first 25 volunteers to complete their schedule of evaluations. The mean (±SD) serum concentration 12 weeks after one IV administration of 20 mg/kg or 40 mg/kg were 180 ± 43 μg/mL (n = 7) and 326 ± 35 μg/mL (n = 5), respectively. The mean (±SD) serum concentration 12 weeks after one IV and SC administration of 5 mg/kg were 40 ± 3 μg/mL (n = 2) and 25 ± 5 μg/mL (n = 9), respectively. Over the 5–40 mg/kg IV dose range (n = 16), the clearance was 36 ± 8 mL/d with an elimination half-life of 71 ± 18 days. VRC01LS retained its expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. Potential limitations of this study include the small sample size typical of Phase I trials and the need to further describe the PK properties of VRC01LS administered on multiple occasions.ConclusionsThe human bnMAb VRC01LS was safe and well tolerated when delivered intravenously or subcutaneously. The half-life was more than 4-fold greater when compared to wild-type VRC01 historical data. The reduced clearance and extended half-life may make it possible to achieve therapeutic levels with less frequent and lower-dose administrations. This would potentially lower the costs of manufacturing and improve the practicality of using passively administered monoclonal antibodies (mAbs) for the prevention of HIV-1 infection.Trial registrationClinicalTrials.gov NCT02599896

Vaccine Elicitation of HIV Broadly Neutralizing Antibodies from Engineered B cells

“…1 a ). We chose to use the VRC01 genes because this prototype CD4 binding-site bnAb, which blocks entry of the virus into target CD4 + T cells, has been extensively tested in the clinic for its ability to suppress viremia in patients and prevent infection after administration as a recombinant monoclonal antibody 17–19 (clinicaltrials.gov NCT02568215, NCT02716675).…”

Targeting the Latent Reservoir for HIV-1

“…Another caveat is that passive immunization is currently the only method of delivering bNAbs to HIV + individuals, and the half-lives of bNAbs, which range from 12–20 days in HIV + individuals, will require sequential infusions for improved reservoir reduction (Caskey et al 2016; Scheid et al 2016). However, engineered variants of bNAbs with substantially longer half-lives are currently being tested (Gaudinski et al, 2018). …”

Innovations in HIV-1 Vaccine Design

“…In addition, because of the extended half-life, VRC01-LS could be administered less frequently than VRC01, making this a more feasible tool for HIV prevention. 152 Investigators have isolated several additional bNAbs, including, but not limited to, 3BNC117, 10e1074, and 10E8. 153e155 Multiple antibodies that target different epitopes on HIV-1 Env are likely going to be needed for any widely deployable passive immunotherapy program because, much like combination antiretroviral therapy is required to Clinical Therapeutics successfully suppress HIV-1, it has become clear that a single monoclonal antibody will likely not be sufficient to prevent infection.…”