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

Abstract

Clinical trials registration: Clinicaltrials.gov NCT01993706. SummaryVRC-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 lg/ml for groups infused with 20 mg/kg (n 5 8) and 40 mg/kg (n 5 5) doses, respectively. Mean 28-day trough concentrations after the second infusion were 56 and 89 lg/ml for the same two doses. Over the 5-40 mg/kg i.v. dose range (n 5 18), the clearance was 0Á016 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.

Progress in HIV vaccine development

“…A recent phase I study in healthy adults found that VRC01 administered intravenously or subcutaneously was safe and well tolerated. 86 The AMP (antibody mediated prevention) study, consisting of 2 phase II protocols, aims to evaluate the safety and efficacy of the VRC01 in reducing HIV-1 acquisition, among 2700 men and transgender persons who have sex with men in the US and South America (HVTN704/HPTN 085, clinicaltrials.gov NCT02716675) and in 1500 women in Sub-Saharan Africa (HVTN 703/HPTN 081, clinicaltrials.gov NCT02568215), is currently underway ( Table 2).…”

Modeling cumulative overall prevention efficacy for the VRC01 phase 2b efficacy trials

“…In sensitivity analysis 1, the VRC01 serum levels at exposure are assumed lower than those observed in the phase 1 trials of VRC01, 15–17 and a lower PE is predicted under each scenario (Figure 9). For the 10 mg/kg regimen, the 5-fold and NHP models predict an overall PE of 32% and 55%, respectively.…”

“…15–17 The simulated AMP trials assume participants received all ten infusions every 8 weeks. Thus far, this assumption seems to be holding close to true for the AMP trials.…”

“…reported that a higher concentration of VRC01 was required to reduce transmission in ectocervical tissue compared to colonic tissue 29 . For (2), assuming independence of S and V such that P ( s , v ) = P ( s ) × P ( v ), where P ( s ) and P ( v ) are the probability distributions for S and V , respectively, pharmacokinetics (PK) data from earlier phase 1 trials of VRC01 15–17 are used to estimate P ( s ) for each of the mAb dose groups, and TZM-bl 18 IC80 data for VRC01 against a panel of 177 HIV-1 Env pseudoviruses across multiple genetic subtypes of the virus are used to estimate P ( v ) that is common across the two mAb groups and the placebo group. The TZM-bl VRC01 IC80 neutralization data were described in more detail in Wu et al.…”

Preventing acquisition of HIV is the only path to an AIDS-free generation

“…There have been major advances in the technology to isolate highly potent, broadly neutralizing antibodies to HIV: modify them so that they are manufacturable in high quantity as well as possessing a pharmokinetic profile that allows subcutaneous injections that may only have to be given at 4-to 6-mo intervals. The levels of neutralizing activity are, to date, far greater than the neutralizing titers seen with any candidate HIV vaccine currently in development (13). This approach of antibody-mediated prevention may emerge as a major technology for primary prevention, one that is likely to be more costly than a traditional vaccine but may be a highly successful tool for the highest risk period for high-risk populations and, as such, a useful and cost-effective strategy until a highly effective vaccine is developed.…”