Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults

Abstract

VRC-HIVMAB060-00-AB (VRC01) is a broadly neutralizing HIV-1 monoclonal antibody (mAb) isolated from the B cells of an HIV-infected patient. It is directed against the HIV-1 CD4 binding site and is capable of potently neutralizing the majority of diverse HIV-1 strains. This Phase I dose-escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose-limiting toxicities. Mean 28-day serum trough concentrations after the first infusion were 35 and 57 μg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28-day trough concentrations after the second infusion were 56 and 89 μg/ml for the same two doses. Over the 5-40 mg/kg i.v. dose range (n = 18), the clearance was 0.016 l/h and terminal half-life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half-life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV-1 prevention efficacy studies.

Trial registration: ClinicalTrials.gov NCT01993706.

Keywords: HIV-1; Phase I clinical trial; monoclonal antibody; passive immunization; pharmacokinetics.

Figure 1

VRC602 Consolidated Standards of Reporting Trials (CONSORT) diagram with study enrolment, VRC-HIVMAB060-00-AB (VRC01) administration, subject follow-up and data analysis for the four study groups.

Figure 2

VRC-HIVMAB060-00-AB (VRC01) concentration (μg/ml) shown per subject over time (days). (a) 5 mg/kg intravenous (i.v.), (b) 5 mg/kg subcutaneous (s.c.), (c) 20 mg/kg i.v., (d) 40 mg/kg i.v., (e) 20 mg/kg i.v. single dose and (f) subject means, all dose groups. A reference level of 10 μg/ml is indicated by the horizontal line on all plots. Doses were administered at days 0 and 28 (a–f) and at day 0 only (e).

Figure 3

Evaluation of anti-VRC-HIVMAB060-00-AB (VRC01) antibodies following VRC01 infusion. The anti-drug antibody analysis (ADA) response is measured using a homogeneous bridging electrochemiluminescence (ECL) format. (a) Typical detection of ECL anti-VRC01 activity from a non-human primate 56 days following infusion with VRC01. The geometric mean values from 30 HIV-negative non-infused subjects demonstrate the negative control for the ECL bridging assay. (b) Longitudinal analyses following either subcutaneously delivered VRC01 at 5 mg/kg or placebo on days 0 and 28 (marked with arrows). (c) Longitudinal analyses following intravenous doses (5, 20 or 40 mg/kg) on days 0 and 28 (marked with arrows). All error bars indicate geometric mean with 95% confidence intervals. The horizontal line on panels a, b and c represents the upper bound of all known negative ADA responses from subjects never exposed to VRC01. No anti-VRC01 antibody was detected post-infusion on days 28, 56 or 112.

Figure 4

Serum neutralization titres after VRC-HIVMAB060-00-AB (VRC01) infusion of 40 mg/kg. Data for five subjects are shown. Solid lines and symbols show measured serum dilution that produced 80% neutralization (ID₈₀) against the virus indicated in the legend. Predicted ID₈₀ values were calculated based on the measured concentration of VRC01 in each sera and the established inhibitory concentration (IC₈₀) of the monoclonal antibody against each virus. Predicted values are graphed as open circles with dotted lines. The viruses tested are Q23.17, clade A (red), PVO, clade B (green) and MW965, clade C (blue) The VRC01 IC₈₀ values against each virus is shown in parenthesis in the legend.