Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults.
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.
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
J E
JE
Ledgerwood
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
E E
EE
Coates
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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G
Yamshchikov
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
J G
JG
Saunders
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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L
Holman
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
M E
ME
Enama
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
A
A
DeZure
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
R M
RM
Lynch
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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I
Gordon
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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S
Plummer
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
C S
CS
Hendel
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
A
A
Pegu
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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M
Conan-Cibotti
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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S
Sitar
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
R T
RT
Bailer
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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S
Narpala
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
A
A
McDermott
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
M
M
Louder
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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S
O'Dell
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
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S
Mohan
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
J P
JP
Pandey
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
R M
RM
Schwartz
Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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Z
Hu
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
R A
RA
Koup
School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, CA, USA.
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E
Capparelli
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
J R
JR
Mascola
Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
B S
BS
Graham
D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000009:adverse effects; D000080908:Broadly Neutralizing Antibodies; D004305:Dose-Response Relationship, Drug; D005260:Female; D015483:HIV Antibodies / Q000008:administration & dosage / Q000009:adverse effects; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy; D015497:HIV-1; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000080908:Broadly Neutralizing Antibodies; D015483:HIV Antibodies; C578595:VRC01 monoclonal antibody
HIV-1; Phase I clinical trial; monoclonal antibody; passive immunization; pharmacokinetics