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

Author:

,Ledgerwood J E1,Coates E E1,Yamshchikov G1,Saunders J G1,Holman L1,Enama M E1,DeZure A1,Lynch R M1,Gordon I1,Plummer S1,Hendel C S1,Pegu A1,Conan-Cibotti M1,Sitar S1,Bailer R T1,Narpala S1,McDermott A1,Louder M1,O'Dell S1,Mohan S2,Pandey J P2,Schwartz R M1,Hu Z3,Koup R A1,Capparelli E4,Mascola J R1,Graham B S1

Affiliation:

1. Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

2. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA

3. Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

4. School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, CA, USA

Abstract

Summary VRC-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 μg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28-day trough concentrations after the second infusion were 56 and 89 μg/ml for the same two doses. Over the 5–40 mg/kg i.v. dose range (n = 18), the clearance was 0·016 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.

Funder

Division of Intramural Research, National Institute of Allergy and Infectious Diseases

Publisher

Oxford University Press (OUP)

Subject

Immunology,Immunology and Allergy

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