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.

Broadly neutralizing plasma antibodies effective against autologous circulating viruses in infants with multivariant HIV-1 infection

“…The study was approved by institute ethics committee of All India Institute of Medical Sciences (IECPG-307/07.09.2017). The median age for infected infants was 12-months (IQR, [8][9][10][11][12][13][14][15][16][17][18][19], the median CD4 count was 1731 cells/mm 3-(IQR, 1498-2562) and the median viral load on log scale was 5.804 RNA copies/ml (IQR, 5.331-6.301).…”

Durable protection against repeated penile exposures to simian-human immunodeficiency virus by broadly neutralizing antibodies

“…Some of the most clinically advanced among these are 10-1074, which targets the base of the third variable loop and surrounding glycans on the HIV envelope protein (Env), and 3BNC117, which targets the CD4 binding site 15,16 . Both have been shown to be safe and well tolerated in HIV-infected and uninfected individuals, and capable of suppressing HIV viremia in viremic subjects 12,[17][18][19][20] .…”

Neutralizing activity of broadly neutralizing anti-HIV-1 antibodies against primary African isolates

“…The following bNAbs were tested for neutralizing activity against the PBMC isolates in TZM-bl assays: 3BNC117-LS, VRC01, VRC07-523LS, and 1-18, all of which are CD4 binding sitespecific (CD4bs), (Scheid et al, 2011;Wu et al, 2010;Rudicell et al, 2014;Schommers et al, 2020); 10-1074-LS, and BG18, which target base of the V3 loop and surrounding glycans (Mouquet et al, 2012;Freund et al, 2017); and PGDM1400 and CAP256-VRC25.26, which are specific for the V2 loop (Sok et al, 2014;Doria-Rose et al, 2016). We also tested the combination of 3BNC117-LS and 10-1074-LS, which is currently in clinical development (Mendoza et al, 2018; Bar-On et al, 2018;Cohen et al, 2019) (clinicaltrials.gov/ct2/show/NCT03254277, clinicaltrials.gov/ct2/show/NCT03554408, clinicaltrials.gov/ct2/show/NCT04250636, and clinicaltrials.gov/ct2/show/NCT04173819).…”

“…The development of broadly neutralizing antibodies (bNAbs) against HIV has matured in the past few years as several bNAbs were evaluated in clinical trials. VRC01 (Wu et al, 2010), 3BNC117 (Scheid et al, 2011) and 10-1074 (Mouquet et al, 2012) have been the most extensively evaluated to date, in healthy volunteers (Cohen et al, 2019;Mayer et al, 2017), viremic people living with HIV (Caskey et al, 2015(Caskey et al, , 2017Lynch et al, 2015; Bar-On et al, 2018), and in the setting of analytical treatment interruption (Scheid et al, 2016;Cohen et al, 2018a;Mendoza et al, 2018;Bar et al, 2016), with encouraging results. These trials were restricted to patients living in the United States and Europe, limiting the assessment of the global utility of these antibodies, since the majority of the individuals in the regions in question were infected with clade B HIV-1 (Bbosa et al, 2019).…”