PMID- 29364886
OWN - NLM
STAT- MEDLINE
DCOM- 20181220
LR  - 20220321
IS  - 1549-1676 (Electronic)
IS  - 1549-1277 (Print)
IS  - 1549-1277 (Linking)
VI  - 15
IP  - 1
DP  - 2018 Jan
TI  - Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody 
      VRC01LS: A Phase 1 open-label clinical trial in healthy adults.
PG  - e1002493
LID - 10.1371/journal.pmed.1002493 [doi]
LID - e1002493
AB  - BACKGROUND: VRC01 is a human broadly neutralizing monoclonal antibody (bnMAb) 
      against the CD4-binding site of the HIV-1 envelope glycoprotein (Env) that is 
      currently being evaluated in a Phase IIb adult HIV-1 prevention efficacy trial. 
      VRC01LS is a modified version of VRC01, designed for extended serum half-life by 
      increased binding affinity to the neonatal Fc receptor. METHODS AND FINDINGS: 
      This Phase I dose-escalation study of VRC01LS in HIV-negative healthy adults was 
      conducted by the Vaccine Research Center (VRC) at the National Institutes of 
      Health (NIH) Clinical Center (Bethesda, MD). The age range of the study 
      volunteers was 21-50 years; 51% of study volunteers were male and 49% were 
      female. Primary objectives were safety and tolerability of VRC01LS intravenous 
      (IV) infusions at 5, 20, and 40 mg/kg infused once, 20 mg/kg given three times at 
      12-week intervals, and subcutaneous (SC) delivery at 5 mg/kg delivered once, or 
      three times at 12-week intervals. Secondary objectives were pharmacokinetics 
      (PK), serum neutralization activity, and development of antidrug antibodies. 
      Enrollment began on November 16, 2015, and concluded on August 23, 2017. This 
      report describes the safety data for the first 37 volunteers who received 
      administrations of VRC01LS. There were no serious adverse events (SAEs) or 
      dose-limiting toxicities. Mild malaise and myalgia were the most common adverse 
      events (AEs). There were six AEs assessed as possibly related to VRC01LS 
      administration, and all were mild in severity and resolved during the study. PK 
      data were modeled based on the first dose of VRC01LS in the first 25 volunteers 
      to complete their schedule of evaluations. The mean (+/-SD) serum concentration 12 
      weeks after one IV administration of 20 mg/kg or 40 mg/kg were 180 +/- 43 mug/mL (n 
      = 7) and 326 +/- 35 mug/mL (n = 5), respectively. The mean (+/-SD) serum concentration 
      12 weeks after one IV and SC administration of 5 mg/kg were 40 +/- 3 mug/mL (n = 2) 
      and 25 +/- 5 mug/mL (n = 9), respectively. Over the 5-40 mg/kg IV dose range (n = 
      16), the clearance was 36 +/- 8 mL/d with an elimination half-life of 71 +/- 18 days. 
      VRC01LS retained its expected neutralizing activity in serum, and anti-VRC01 
      antibody responses were not detected. Potential limitations of this study include 
      the small sample size typical of Phase I trials and the need to further describe 
      the PK properties of VRC01LS administered on multiple occasions. CONCLUSIONS: The 
      human bnMAb VRC01LS was safe and well tolerated when delivered intravenously or 
      subcutaneously. The half-life was more than 4-fold greater when compared to 
      wild-type VRC01 historical data. The reduced clearance and extended half-life may 
      make it possible to achieve therapeutic levels with less frequent and lower-dose 
      administrations. This would potentially lower the costs of manufacturing and 
      improve the practicality of using passively administered monoclonal antibodies 
      (mAbs) for the prevention of HIV-1 infection. TRIAL REGISTRATION: 
      ClinicalTrials.gov NCT02599896.
FAU - Gaudinski, Martin R
AU  - Gaudinski MR
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Coates, Emily E
AU  - Coates EE
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Houser, Katherine V
AU  - Houser KV
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Chen, Grace L
AU  - Chen GL
AUID- ORCID: 0000-0001-9236-3180
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Yamshchikov, Galina
AU  - Yamshchikov G
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Saunders, Jamie G
AU  - Saunders JG
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Holman, LaSonji A
AU  - Holman LA
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Gordon, Ingelise
AU  - Gordon I
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Plummer, Sarah
AU  - Plummer S
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Hendel, Cynthia S
AU  - Hendel CS
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Conan-Cibotti, Michelle
AU  - Conan-Cibotti M
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Lorenzo, Margarita Gomez
AU  - Lorenzo MG
AD  - Vaccine Clinical Research Branch, Division of AIDS, National Institute of Allergy 
      and Infectious Diseases, National Institutes of Health, Rockville, Maryland, 
      United States of America.
FAU - Sitar, Sandra
AU  - Sitar S
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Carlton, Kevin
AU  - Carlton K
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Laurencot, Carolyn
AU  - Laurencot C
AUID- ORCID: 0000-0001-9117-1064
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Bailer, Robert T
AU  - Bailer RT
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Narpala, Sandeep
AU  - Narpala S
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - McDermott, Adrian B
AU  - McDermott AB
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Namboodiri, Aryan M
AU  - Namboodiri AM
AD  - Department of Microbiology and Immunology, Medical University of South Carolina, 
      Charleston, South Carolina, United States of America.
FAU - Pandey, Janardan P
AU  - Pandey JP
AUID- ORCID: 0000-0001-9992-4737
AD  - Department of Microbiology and Immunology, Medical University of South Carolina, 
      Charleston, South Carolina, United States of America.
FAU - Schwartz, Richard M
AU  - Schwartz RM
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Hu, Zonghui
AU  - Hu Z
AUID- ORCID: 0000-0001-5496-0611
AD  - Biostatistics Research Branch, Division of Clinical Research, National Institute 
      of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 
      Maryland, United States of America.
FAU - Koup, Richard A
AU  - Koup RA
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Capparelli, Edmund
AU  - Capparelli E
AUID- ORCID: 0000-0002-1630-0505
AD  - School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, 
      University of California San Diego, San Diego, California, United States of 
      America.
FAU - Graham, Barney S
AU  - Graham BS
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Mascola, John R
AU  - Mascola JR
AUID- ORCID: 0000-0002-5293-4695
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
FAU - Ledgerwood, Julie E
AU  - Ledgerwood JE
AD  - Vaccine Research Center, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Bethesda, Maryland, United States of America.
CN  - VRC 606 Study Team
LA  - eng
SI  - ClinicalTrials.gov/NCT02599896
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20180124
PL  - United States
TA  - PLoS Med
JT  - PLoS medicine
JID - 101231360
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Broadly Neutralizing Antibodies)
RN  - 0 (HIV Antibodies)
RN  - 0 (VRC01 monoclonal antibody)
SB  - IM
MH  - Adult
MH  - Antibodies, Monoclonal/*adverse effects/*pharmacokinetics
MH  - Antibodies, Neutralizing/immunology
MH  - Antibody Formation
MH  - Broadly Neutralizing Antibodies
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - HIV Antibodies/*immunology
MH  - Half-Life
MH  - Humans
MH  - Infusions, Intravenous
MH  - Infusions, Subcutaneous
MH  - Male
MH  - Middle Aged
MH  - Young Adult
PMC - PMC5783347
COIS- The authors have declared that no competing interests exist.
EDAT- 2018/01/25 06:00
MHDA- 2018/12/21 06:00
PMCR- 2018/01/24
CRDT- 2018/01/25 06:00
PHST- 2017/09/06 00:00 [received]
PHST- 2017/12/14 00:00 [accepted]
PHST- 2018/01/25 06:00 [entrez]
PHST- 2018/01/25 06:00 [pubmed]
PHST- 2018/12/21 06:00 [medline]
PHST- 2018/01/24 00:00 [pmc-release]
AID - PMEDICINE-D-17-03122 [pii]
AID - 10.1371/journal.pmed.1002493 [doi]
PST - epublish
SO  - PLoS Med. 2018 Jan 24;15(1):e1002493. doi: 10.1371/journal.pmed.1002493. 
      eCollection 2018 Jan.