Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial

Boris Julg; Kathryn E. Stephenson; Kshitij Wagh; Sabrina C. Tan; Rebecca Zash; Stephen Walsh; Jessica Ansel; Diane Kanjilal; Joseph Nkolola; Victoria E.K. Walker-Sperling; Jasper Ophel; Katherine Yanosick; Erica N. Borducchi; Lori Maxfield; Peter Abbink; Lauren Peter; Nicole L. Yates; Martina S. Wesley; Tom Hassell; Huub C. Gelderblom; Allen deCamp; Bryan T. Mayer; Alicia Sato; Monica W. Gerber; Elena E. Giorgi; Lucio Gama; Richard A. Koup; John R. Mascola; Ana Monczor; Sofia Lupo; Charlotte Paige Rolle; Roberto Arduino; Edwin DeJesus; Georgia D. Tomaras; Michael S. Seaman; Bette Korber; Dan H. Barouch

doi:10.1038/s41591-022-01815-1

Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial

Boris Julg, Kathryn E. Stephenson, Kshitij Wagh, Sabrina C. Tan, Rebecca Zash, Stephen Walsh, Jessica Ansel, Diane Kanjilal, Joseph Nkolola, Victoria E.K. Walker-Sperling, Jasper Ophel, Katherine Yanosick, Erica N. Borducchi, Lori Maxfield, Peter Abbink, Lauren Peter, Nicole L. Yates, Martina S. Wesley, Tom Hassell, Huub C. GelderblomAllen deCamp, Bryan T. Mayer, Alicia Sato, Monica W. Gerber, Elena E. Giorgi, Lucio Gama, Richard A. Koup, John R. Mascola, Ana Monczor, Sofia Lupo, Charlotte Paige Rolle, Roberto Arduino, Edwin DeJesus, Georgia D. Tomaras, Michael S. Seaman, Bette Korber, Dan H. Barouch

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 (NCT03205917). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4⁺ T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg⁻¹ and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg⁻¹ of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log₁₀ copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml⁻¹. The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control.

Original language	English (US)
Pages (from-to)	1288-1296
Number of pages	9
Journal	Nature medicine
Volume	28
Issue number	6
DOIs	https://doi.org/10.1038/s41591-022-01815-1
State	Published - Jun 2022

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/s41591-022-01815-1

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Julg, B., Stephenson, K. E., Wagh, K., Tan, S. C., Zash, R., Walsh, S., Ansel, J., Kanjilal, D., Nkolola, J., Walker-Sperling, V. E. K., Ophel, J., Yanosick, K., Borducchi, E. N., Maxfield, L., Abbink, P., Peter, L., Yates, N. L., Wesley, M. S., Hassell, T., ... Barouch, D. H. (2022). Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial. Nature medicine, 28(6), 1288-1296. https://doi.org/10.1038/s41591-022-01815-1

Julg, B, Stephenson, KE, Wagh, K, Tan, SC, Zash, R, Walsh, S, Ansel, J, Kanjilal, D, Nkolola, J, Walker-Sperling, VEK, Ophel, J, Yanosick, K, Borducchi, EN, Maxfield, L, Abbink, P, Peter, L, Yates, NL, Wesley, MS, Hassell, T, Gelderblom, HC, deCamp, A, Mayer, BT, Sato, A, Gerber, MW, Giorgi, EE, Gama, L, Koup, RA, Mascola, JR, Monczor, A, Lupo, S, Rolle, CP, Arduino, R, DeJesus, E, Tomaras, GD, Seaman, MS, Korber, B & Barouch, DH 2022, 'Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial', Nature medicine, vol. 28, no. 6, pp. 1288-1296. https://doi.org/10.1038/s41591-022-01815-1

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title = "Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial",

abstract = "HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 (NCT03205917). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4+ T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg−1 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg−1 of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml−1. The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control.",

author = "Boris Julg and Stephenson, {Kathryn E.} and Kshitij Wagh and Tan, {Sabrina C.} and Rebecca Zash and Stephen Walsh and Jessica Ansel and Diane Kanjilal and Joseph Nkolola and Walker-Sperling, {Victoria E.K.} and Jasper Ophel and Katherine Yanosick and Borducchi, {Erica N.} and Lori Maxfield and Peter Abbink and Lauren Peter and Yates, {Nicole L.} and Wesley, {Martina S.} and Tom Hassell and Gelderblom, {Huub C.} and Allen deCamp and Mayer, {Bryan T.} and Alicia Sato and Gerber, {Monica W.} and Giorgi, {Elena E.} and Lucio Gama and Koup, {Richard A.} and Mascola, {John R.} and Ana Monczor and Sofia Lupo and Rolle, {Charlotte Paige} and Roberto Arduino and Edwin DeJesus and Tomaras, {Georgia D.} and Seaman, {Michael S.} and Bette Korber and Barouch, {Dan H.}",

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year = "2022",

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doi = "10.1038/s41591-022-01815-1",

language = "English (US)",

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T1 - Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1

T2 - a phase 1 clinical trial

AU - Julg, Boris

AU - Stephenson, Kathryn E.

AU - Wagh, Kshitij

AU - Tan, Sabrina C.

AU - Zash, Rebecca

AU - Walsh, Stephen

AU - Ansel, Jessica

AU - Kanjilal, Diane

AU - Nkolola, Joseph

AU - Walker-Sperling, Victoria E.K.

AU - Ophel, Jasper

AU - Yanosick, Katherine

AU - Borducchi, Erica N.

AU - Maxfield, Lori

AU - Abbink, Peter

AU - Peter, Lauren

AU - Yates, Nicole L.

AU - Wesley, Martina S.

AU - Hassell, Tom

AU - Gelderblom, Huub C.

AU - deCamp, Allen

AU - Mayer, Bryan T.

AU - Sato, Alicia

AU - Gerber, Monica W.

AU - Giorgi, Elena E.

AU - Gama, Lucio

AU - Koup, Richard A.

AU - Mascola, John R.

AU - Monczor, Ana

AU - Lupo, Sofia

AU - Rolle, Charlotte Paige

AU - Arduino, Roberto

AU - DeJesus, Edwin

AU - Tomaras, Georgia D.

AU - Seaman, Michael S.

AU - Korber, Bette

AU - Barouch, Dan H.

PY - 2022/6

Y1 - 2022/6

N2 - HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 (NCT03205917). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4+ T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg−1 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg−1 of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml−1. The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control.

AB - HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2 (NCT03205917). The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4+ T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg−1 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg−1 of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml−1. The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control.

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Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial

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