TY - JOUR
T1 - Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults
T2 - a phase 1 dose-escalation clinical trial
AU - VRC 605 study team
AU - Gaudinski, Martin R.
AU - Houser, Katherine V.
AU - Doria-Rose, Nicole A.
AU - Chen, Grace L.
AU - Rothwell, Ro Shauna S.
AU - Berkowitz, Nina
AU - Costner, Pamela
AU - Holman, La Sonji A.
AU - Gordon, Ingelise J.
AU - Hendel, Cynthia S.
AU - Kaltovich, Florence
AU - Conan-Cibotti, Michelle
AU - Gomez Lorenzo, Margarita
AU - Carter, Cristina
AU - Sitar, Sandra
AU - Carlton, Kevin
AU - Gall, Jason
AU - Laurencot, Carolyn
AU - Lin, Bob C.
AU - Bailer, Robert T.
AU - McDermott, Adrian B.
AU - Ko, Sung Youl
AU - Pegu, Amarendra
AU - Kwon, Young D.
AU - Kwong, Peter D.
AU - Namboodiri, Aryan M.
AU - Pandey, Janardan P.
AU - Schwartz, Richard
AU - Arnold, Frank
AU - Hu, Zonghui
AU - Zhang, Lily
AU - Huang, Yunda
AU - Koup, Richard A.
AU - Capparelli, Edmund V.
AU - Graham, Barney S.
AU - Mascola, John R.
AU - Ledgerwood, Julie E.
AU - Mendoza, Floreliz
AU - Novik, Laura
AU - Zephir, Kathy
AU - Whalen, William
AU - Larkin, Brenda
AU - Saunders, Jamie
AU - Cunningham, Jennifer
AU - Levinson, Carol
AU - Wang, Xiaolin
AU - Plummer, Sarah
AU - Victorino, Milalynn
AU - Ola, Abidemi
AU - Gama, Lucio
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/10
Y1 - 2019/10
N2 - 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. 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. 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. 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. Funding: National Institutes of Health.
AB - 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. 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. 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. 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. Funding: National Institutes of Health.
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U2 - 10.1016/S2352-3018(19)30181-X
DO - 10.1016/S2352-3018(19)30181-X
M3 - Article
C2 - 31473167
AN - SCOPUS:85072659478
SN - 2352-3018
VL - 6
SP - e667-e679
JO - The Lancet HIV
JF - The Lancet HIV
IS - 10
ER -