Safety, pharmacokinetics, and immunogenicity of the combination of the broadly neutralizing anti-HIV-1 antibodies 3BNC117 and 10-1074 in healthy adults: A randomized, phase 1 study

Abstract

Background: Additional forms of pre-exposure prophylaxis are needed to prevent HIV-1 infection. 3BNC117 and 10-1074 are broadly neutralizing anti-HIV-1 antibodies that target non-overlapping epitopes on the HIV-1 envelope. We investigated the safety, tolerability, pharmacokinetics, and immunogenicity of the intravenous administration of the combination of 3BNC117 and 10-1074 in healthy adults.

Methods: This randomized, double-blind, placebo-controlled, single center, phase 1 study enrolled healthy adults aged 18-65 years to receive one infusion of 3BNC117 immediately followed by 10-1074 at 10 mg/kg, three infusions of 3BNC117 followed by 10-1074 at 3 mg/kg or 10 mg/kg every 8 weeks, or placebo infusions. The primary outcomes were safety and pharmacokinetics. This trial is registered with ClinicalTrials.gov, number NCT02824536.

Findings: Twenty-four participants were enrolled in a 3:1 ratio to receive the study products or placebo. The combination of 3BNC117 and 10-1074 was safe and generally well tolerated. There were no serious adverse events considered related to the infusions. The mean elimination half-lives of 3BNC117 and 10-1074 were 16.4 ± 4.6 days and 23.0 ± 5.4 days, respectively, similar to what was observed in previous studies in which each antibody was administered alone. Anti-drug antibody responses were rare and without evidence of related adverse events or impact on elimination kinetics.

Interpretation: Single and repeated doses of the combination of 3BNC117 and 10-1074 were well tolerated in healthy adults. These data support the further development of the combination of 3BNC117 and 10-1074 as a long-acting injectable form of pre-exposure prophylaxis for the prevention of HIV-1 infection.

Fig 1. Participant flow diagram.

Fig 2. Serum concentrations of 3BNC117 and 10–1074 by group.

Serum concentrations (μg/ml) of 3BNC117 (blue) and 10–1074 (red) in participants after a single infusion of 3BNC117 and 10–1074 (10 mg/kg of each antibody) (top panel), and three infusions of 3 mg/kg (middle panel) or 10 mg/kg of each antibody (bottom panel) given every eight weeks. bNAb concentrations were determined by TZM-bl assay (dotted lines) and ELISA (solid lines). Lines indicate arithmetic mean concentration and whiskers indicate standard deviation.

Fig 3. Elimination half-lives of 3BNC117 and 10–1074 when administered alone and in combination.

(Top panel) shows 3BNC117 half-lives in HIV-uninfected participants after single antibody (blue, from ClinicalTrials.gov number NCT02018510 [16]), n = 22) or combination (red, current trial n = 18) administration. (Bottom panel) shows 10–1074 half-lives in HIV-uninfected participants after single antibody (green, from ClinicalTrials.gov number NCT02511990 [17], n = 14) or combination (red, current trial n = 18) administration. Boxes illustrate the interquartile range. Vertical lines inside the boxes represent the median half-lives and whiskers represent minimum and maximum values.

Fig 4. Serum neutralization of diverse pseudoviruses.

Week 2 serum from participants who received the antibodies at 3 mg/kg was tested against 12 pseudoviruses from diverse clades previously found to be sensitive to 3BNC117 and 10–1074. X-axis shows calculated serum ID₅₀ titers for each tested pseudovirus (y-axis). Boxes illustrate the interquartile range. Horizontal lines inside the boxes represent the median half-lives and whiskers represent minimum and maximum values.

Fig 5. Anti-drug antibody responses.

Specific anti-3BNC117 antibody titers (top panel) and anti-10-1074 antibody titers (bottom panel) at selected time points following the administration of 3BNC117 plus 10–1074 are displayed for individuals participants. Each line represents participants enrolled in each of the three study groups: green, group 1 (single dose of 3BNC117 and 10–1074 at 10 mg/kg, IV); blue, group 2 (repeated doses of 3BNC117 and 10–1074 at 3 mg/kg, IV); red, group 3 (repeated doses of 3BNC117 and 10–1074 at 10 mg/kg, IV). For each participant, the time points that were tested for the presence of anti-drug antibodies are shown. Samples for which a specific anti-drug antibody response was not detected are indicated in the shaded grey area.