Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical trial

VRC 605 study team

Research output: Contribution to journalArticle

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. 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.

Original languageEnglish (US)
Pages (from-to)e667-e679
JournalThe Lancet HIV
Volume6
Issue number10
DOIs
StatePublished - Oct 2019

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HIV-1
Pharmacokinetics
Monoclonal Antibodies
Clinical Trials
Safety
National Institutes of Health (U.S.)
Neutralizing Antibodies
Intravenous Administration
Headache
Chills
Clinical Trials, Phase I
Poisons
Research Ethics Committees
Myalgia
Random Allocation
Physical Examination
HIV Infections
Binding Sites
Pain
Health

ASJC Scopus subject areas

  • Epidemiology
  • Immunology
  • Infectious Diseases
  • Virology

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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. / VRC 605 study team.

In: The Lancet HIV, Vol. 6, No. 10, 10.2019, p. e667-e679.

Research output: Contribution to journalArticle

@article{a9ff608b30074f0cbd2ef9e717ac1306,
title = "Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical trial",
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. 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.",
author = "{VRC 605 study team} and Gaudinski, {Martin R.} and Houser, {Katherine V.} and Doria-Rose, {Nicole A.} and Chen, {Grace L.} and Rothwell, {Ro Shauna S.} and Nina Berkowitz and Pamela Costner and Holman, {La Sonji A.} and Gordon, {Ingelise J.} and Hendel, {Cynthia S.} and Florence Kaltovich and Michelle Conan-Cibotti and {Gomez Lorenzo}, Margarita and Cristina Carter and Sandra Sitar and Kevin Carlton and Jason Gall and Carolyn Laurencot and Lin, {Bob C.} and Bailer, {Robert T.} and McDermott, {Adrian B.} and Ko, {Sung Youl} and Amarendra Pegu and Kwon, {Young D.} and Kwong, {Peter D.} and Namboodiri, {Aryan M.} and Pandey, {Janardan P.} and Richard Schwartz and Frank Arnold and Zonghui Hu and Lily Zhang and Yunda Huang and Koup, {Richard A.} and Capparelli, {Edmund V.} and Graham, {Barney S.} and Mascola, {John R.} and Ledgerwood, {Julie E.} and Floreliz Mendoza and Laura Novik and Kathy Zephir and William Whalen and Brenda Larkin and Jamie Saunders and Jennifer Cunningham and Carol Levinson and Xiaolin Wang and Sarah Plummer and Milalynn Victorino and Abidemi Ola and Lucio Gama",
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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

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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