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Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical trial.
- Source :
-
The lancet. HIV [Lancet HIV] 2019 Oct; Vol. 6 (10), pp. e667-e679. Date of Electronic Publication: 2019 Aug 28. - Publication Year :
- 2019
-
Abstract
- Background: Human monoclonal antibodies that potently and broadly neutralise HIV-1 are under development to prevent and treat HIV-1 infection. In this phase 1 clinical trial we aimed to determine the safety, tolerability, and pharmacokinetic profile of the broadly neutralising monoclonal antibody VRC07-523LS, an engineered variant of VRC01 that targets the CD4 binding site of the HIV-1 envelope protein.<br />Methods: This phase 1, open-label, dose-escalation clinical trial was done at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Individuals were recruited from the greater Washington, DC, area by IRB-approved written and electronic media. We enrolled healthy, HIV-1-negative adults aged 18-50 years. Inclusion criteria were good general health, measured through clinical laboratory tests, medical history, and physical examination. Participants self-selected into one of seven open groups during enrolment without randomisation. Four groups received a single intravenous dose of 1, 5, 20, or 40 mg/kg of VRC07-523LS, and one group received a single 5 mg/kg subcutaneous dose. Two groups received three doses of either 20 mg/kg intravenous VRC07-523LS, or 5 mg/kg subcutaneous VRC07-523LS at 12-week intervals. The primary outcome was the safety and tolerability of VRC07-523LS, assessed by dose, route, and number of administrations. This study is registered with ClinicalTrials.gov, NCT03015181.<br />Findings: Between Feb 21, 2017, and September 13, 2017, we enrolled 26 participants, including 11 (42%) men and 15 (58%) women. Two (8%) participants withdrew from the study early: one participant in group 1 enrolled in the study but never received VRC07-523LS, and one participant in group 6 chose to withdraw after a single administration. One (4%) participant in group 7 received only one of the three scheduled administrations. 17 participants received intravenous administrations and 8 participants received subcutaneous administrations. VRC07-523LS was safe and well tolerated, we observed no serious adverse events or dose-limiting toxic effects. All reported local and systemic reactogenicity was mild to moderate in severity. The most commonly reported symptoms following intravenous administration were malaise or myalgia in three (18%) participants and headache or chills in two (12%) participants. The most commonly reported symptoms following subcutaneous administration were pain and tenderness in four participants (50%) and malaise or headache in three (38%) participants.<br />Interpretation: Safe and well tolerated, VRC07-523LS is a strong and practical candidate for inclusion in HIV-1 prevention and therapeutic strategies. The results from this trial also indicate that an HIV-1 broadly neutralising monoclonal antibody engineered for improved pharmacokinetic and neutralisation properties can be safe for clinical use.<br />Funding: National Institutes of Health.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Subjects :
- Administration, Cutaneous
Administration, Intravenous
Adult
Antibodies, Monoclonal administration & dosage
Antibodies, Monoclonal adverse effects
Antibodies, Neutralizing administration & dosage
Antibodies, Neutralizing adverse effects
Female
Healthy Volunteers
Humans
Male
Middle Aged
Young Adult
Antibodies, Monoclonal pharmacokinetics
HIV Infections drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 2352-3018
- Volume :
- 6
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The lancet. HIV
- Publication Type :
- Academic Journal
- Accession number :
- 31473167
- Full Text :
- https://doi.org/10.1016/S2352-3018(19)30181-X