Safety, tolerability, pharmacokinetics, and immunological activity of dual-combinations and triple-combinations of anti-HIV monoclonal antibodies PGT121, PGDM1400, 10-1074, and VRC07-523LS administered intravenously to HIV-uninfected adults: a phase 1 randomised trial

Abstract

Background: Preclinical and clinical studies suggest that combinations of broadly neutralising antibodies (bnAbs) targeting different HIV envelope epitopes might be required for sufficient prevention of infection. We aimed to evaluate the dual and triple anti-HIV bnAb combinations of PGDM1400 (V2 Apex), PGT121 (V3 glycan), 10-1074 (V3 glycan), and VRC07-523LS (CD4 binding site).

Methods: In this phase 1 trial (HVTN 130/HPTN 089), adults without HIV were randomly assigned (1:1:1) to three dual-bnAb treatment groups simultaneously, or the triple-bnAb group, receiving 20 mg/kg of each antibody administered intravenously at four centres in the USA. Participants received a single dose of PGT121 + VRC07-523LS (treatment one; n=6), PGDM1400 + VRC07-523LS (treatment two; n=6), or 10-1074 + VRC07-523LS (treatment three; n=6), and two doses of PGDM1400 + PGT121 + VRC07-523LS (treatment four; n=9). Primary outcomes were safety, pharmacokinetics, and neutralising activity. Safety was determined by monitoring for 60 min after infusions and throughout the study by collecting laboratory assessments (ie, blood count, chemistry, urinalysis, and HIV), and solicited and unsolicited adverse events (via case report forms and participant diaries). Serum concentrations of each bnAb were measured by binding antibody assays on days 0, 3, 6, 14, 28, 56, 112, 168, 224, 280, and 336, and by serum neutralisation titres against Env-pseudotyped viruses on days 0, 3, 28, 56, and 112. Pharmacokinetic parameters were estimated by use of two-compartment population pharmacokinetic models; combination bnAb neutralisation titres were directly measured and assessed with different interaction models. This trial is registered with ClinicalTrials.gov, NCT03928821, and has been completed.

Findings: 27 participants were enrolled from July 31, to Dec 20, 2019. The median age was 26 years (range 19-50), 16 (58%) of 27 participants were assigned female sex at birth, and 24 (89%) participants were non-Hispanic White. Infusions were safe and well tolerated. There were no statistically significant differences in pharmacokinetic patterns between the dual and triple combinations of PGT121, PGDM1400, and VRC07-523LS. The median estimated elimination half-lives of PGT121, PGDM1400, 10-1074, and VRC07-523LS were 32·2, 25·4, 27·5, and 52·9 days, respectively. Neutralisation coverage against a panel of 12 viruses was greater in the triple-bnAb versus dual-bnAb groups: area under the magnitude-breadth curve at day 28 was 3·1, 2·9, 3·0, and 3·4 for treatments one to four, respectively. The Bliss-Hill multiplicative interaction model, which assumes complementary neutralisation with no antagonism or synergism among the bnAbs, best described combination bnAb titres in the dual-bnAb and triple-bnAb groups.

Interpretation: No pharmacokinetic interactions among the bnAbs and no loss of complementary neutralisation were observed in the dual and triple combinations. This study lays the foundation for designing future combination bnAb HIV prevention efficacy trials.

Funding: US National Institute of Allergy and Infectious Diseases, US National Institute on Drug Abuse, US National Institute of Mental Health, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Figure 1:. Consort Diagram and specimen collection schedule.

CONSORT, Consolidated Standards of Reporting Trials; IV, intravenous; BAMA, Binding Antibody Multiplex Assay; PK, pharmacokinetic; nAb, neutralizing antibody; SPA, study product administration; FU, follow-up.

Figure 1:. Consort Diagram and specimen collection schedule.

CONSORT, Consolidated Standards of Reporting Trials; IV, intravenous; BAMA, Binding Antibody Multiplex Assay; PK, pharmacokinetic; nAb, neutralizing antibody; SPA, study product administration; FU, follow-up.

Figure 2:. Observed antibody serum concentrations with 90% prediction interval from the population PK model.

Observed (symbol) and predicted (line) concentrations of each bnAb. Serum concentration was measured by BAMA and 10–1074 by ELISA. Shaded areas denote 90% prediction interval. One T3 participant received partial infusion of 10–1074 and no VRC07–523LS.

Figure 3.. Geometric mean ID80 neutralization-effective serum concentrations of each bnAb in dual and triple-bnAb combinations.

x axis: time in days following infusions; y axis: TZM-bl assay derived concentration. Neutralization-effective serum concentrations of each bnAb were calculated by multiplying the ID80 neutralization titer of the serum sample against a bnAb-specific isolate by the IC80 of the clinical lot of the bnAb against the corresponding isolate.

Figure 4.. Individual participant and group-average ID80 neutralization magnitude and breadth against a 12 multi-clade virus panel at 3 (Panel A), 28 (Panel B) and 112 days (Panel C) after product administration.

Participants received all scheduled product administrations. Dashed curves are for individual participant and solid curves are for group average. Area under the curve (AUC) are calculated for the group average magnitude-breadth curve. Env-pseudotyped virus panel includes: 0330.v4.c3; 3426.v5.c17; 377.v4.c09; AC10.0.29; Ce1176_A3; DU156.12; DU172.17; PVO.4; RHPA4259.7; SC422661.8; T263–8; and TRO.11. x-axis: neutralization ID80 titer. Y-axis: fraction of isolates with neutralization ID80 titer great then t.

Figure 5.. Concordance between observed and estimated combination bnAb neutralization ID80 titers against a 12 multi-clade virus panel in T4 participants.

Y-axis: observed neutralization ID80 titer at 3, 28 and 112 days after product administration in serum samples of T4 participants who received the triple bnAb combination PGT121+PGDM1400+VRC07–523LS. X-axis: estimated combination neutralization ID50 titer under the Maximum (red color), Additive (blue) and Bliss-Hill (green) neutralization interaction model. Circles denote individual data points. Solid lines denote the best fit linear regression line. Dashed line denote the identity Y=X line (indicating perfect agreement).