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

<div><p>Background</p><p>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.</p><p>Methods and findings</p><p>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 (<i>n</i> = 7) and 326 ± 35 μg/mL (<i>n</i> = 5), respectively. The mean (±SD) serum concentration 12 weeks after one IV and SC administration of 5 mg/kg were 40 ± 3 μg/mL (<i>n</i> = 2) and 25 ± 5 μg/mL (<i>n</i> = 9), respectively. Over the 5–40 mg/kg IV dose range (<i>n</i> = 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.</p><p>Conclusions</p><p>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.</p><p>Trial registration</p><p>ClinicalTrials.gov <a target="_blank">NCT02599896</a></p></div

CONSORT flow diagram of the VRC 606 trial.

<p>Thirty-seven volunteers were allocated to 6 groups. All volunteers who received at least one VRC01LS administration were analyzed for safety and reactogenicity. All volunteers who completed the per-protocol dosing schedule by the time of manuscript submission (<i>n</i> = 25) were additionally analyzed for pharmacokinetic parameters, serum neutralization activity, anti-drug antibodies, and IgG1 GM allotype. These 25 volunteers were all the volunteers in groups 1–4, the first six volunteers in group 5, and the first five volunteers in group 6. GM, genetic marker; IgG1, immunoglobulin G subclass 1; IV, intravenous; SC, subcutaneous; VRC, Vaccine Research Center.</p

Self-reported systemic reactogenicity up to 3 days after VRC01LS administration^*.

<p>Self-reported systemic reactogenicity up to 3 days after VRC01LS administration^{<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002493#t003fn001" target="_blank">*</a>}.</p

Measurement of antibody serum concentration (μg/mL).

<p>(A) Serum VRC01LS concentrations (colored plots) are shown from first measurement through week 24 after a single administration. The infusion dose and route are as specified in the legend. All values are the mean of duplicate samples run in different wells within the same plate. Previously published VRC01 concentrations based on historical data (black plots) after administration at weeks 0 and 4 are shown for comparison. (B) Geometric mean serum VRC01LS concentrations per group over time. The dotted line at 10 μg/mL on each graph is shown as a reference value. IV, intravenous; SC, subcutaneous.</p

Maximum local reactogenicity up to day 7 after VRC01LS administration^*.

<p>Maximum local reactogenicity up to day 7 after VRC01LS administration^{<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002493#t002fn001" target="_blank">*</a>}.</p

Neutralizing ability of VRC01LS is maintained in serum after infusion.

<p>(A) Serum inhibitory neutralization titers (ID₈₀) after VRC01LS infusion. Solid lines and closed squares indicate the reciprocal serum dilution that produces 80% virus neutralization for three viral strains. Dashed lines and open squares indicate predicted ID₈₀ based on the measured amount of VRC01LS in the serum and the known inhibitory concentration (IC₈₀) of VRC01LS for the viruses tested: MW965.26, 0.128 μg/mL; Q23.17, 0.298 μg/mL; and PVO.04, 1.66 μg/mL. All final time points were assessed 12 weeks after the final dose was administered. Values are the mean of duplicate wells run in the same plate. (B) Examples of serum and VRC01LS neutralization curves. Serum from day 2 and week 36 samples (closed circles) were used to generate neutralization curves (solid lines) that are compared to neutralization curves generated with uninfused VRC01LS IgG antibody (open circles and dashed lines) at different dilutions. The x-axis displays both the VRC01LS concentration acquired from serum and in vitro dilutions of uninfused antibody. IC₈₀, 80% inhibitory concentration; ID₈₀, dilution that produced 80% neutralization; IgG, immunoglobulin G; IV, intravenous; SC, subcutaneous.</p

Post infusion serum antibody concentrations and PK parameters by dose and route.

<p>(A) C_max (top panel) showing expected dose-dependent increases of VRC01LS, t_1/2β (middle panel), and antibody clearance (bottom panel), showing similar values for doses and routes. Bars show mean values, with error bars indicating s.d. Previously published VRC01 data following 40 mg/kg infusion are shown for comparison. (B) VRC01LS and VRC01 serum concentrations 4 weeks after a single administration, as indicated on the x-axis. Each value is the mean of duplicate wells in the same plate. VRC01 data (black dots) were derived from historical data. C_max, maximal concentration; IV, intravenous; PK, pharmacokinetic; SC, subcutaneous; s.d., standard deviation; t_1/2β, elimination half-life.</p

Demographic characteristics of study participants.

<p>Demographic characteristics of study participants.</p

VRC01LS mean PK parameter values.

<p>VRC01LS mean PK parameter values.</p