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

Abstract

Background

VRC01 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 findings

This 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.

Conclusions

The 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 registration

ClinicalTrials.gov NCT02599896

Abstract

John Mascola and colleagues study the safety and pharmacokinetics of VRC01LS, a broadly neutralizing anti-HIV-1 antibody designed to have an extended half-life in serum, in healthy people.

Author summary

Why was this study done?

• New HIV-1 infections continue to occur despite improvements in traditional prevention strategies. Novel interventions to prevent acquisition of HIV-1 infection may help to turn the tide of the global pandemic.

• Human monoclonal antibodies capable of neutralizing many strains of HIV-1 have been discovered. These antibodies, referred to as broadly neutralizing antibodies (bnAbs), can be produced as biologic medications and their ability to protect people from HIV-1 infection is being investigated.

• This study evaluated a new form of an HIV-1 antibody with the potential to remain in the blood for a longer period of time than traditional antibodies. If the antibodies stay in the blood longer, then people may be protected for longer periods of time and require less frequent dosing.

What did the researchers do and find?

• We modified a promising antibody called VRC01 so that it stays in the blood for a longer period of time. The modified antibody, VRC01LS, works by taking advantage of how the body recycles its own antibodies, so that the body prevents VRC01LS from being broken down.

• We gave VRC01LS to healthy adults for the first time, to see how safe it was and to understand how long it stays in the body compared to unmodified VRC01.

• In this study, VRC01LS was found to be safe. There were no serious health consequences for participants, although some people were bothered by mild muscle aches and feeling tired.

• Compared to historical data for VRC01, VRC01LS stays in the blood more than four times longer than VRC01.

• The VRC01LS in people’s blood retained the ability to neutralize the HIV-1 virus, as it has been shown to do in the laboratory.

What do these findings mean?

• Our findings mean that the modifications made to VRC01 to produce VRC01LS may be useful when incorporated into other, similar antibodies that are being developed in the hope of producing medications to prevent HIV-1 infection.

• Our findings also mean that fewer doses of these HIV-1 antibodies may be required for protection, thus reducing product cost.