Boris Julg, Victoria E. K. Walker-Sperling, Kshitij Wagh, Malika Aid, Kathryn E. Stephenson, Rebecca Zash, Jinyan Liu, Joseph P. Nkolola, Amelia Hoyt, Mike Castro, Leonid Serebryannyy, Katherine Yanosick, Tessa Speidel, Erica N. Borducchi, Tetyana Murzda, Lori Maxfield, Roberto Arduino, Adrian B. McDermott, Lucio Gama, Elena E. Giorgi, Richard A. Koup, Michael S. Seaman, Charlotte-Paige Rolle, Edwin DeJesus, Wenjun Li, Bette Korber, Dan H. Barouch
{"title":"HIV-1 广泛中和抗体三联疗法的安全性和抗病毒效果:1/2a 期试验","authors":"Boris Julg, Victoria E. K. Walker-Sperling, Kshitij Wagh, Malika Aid, Kathryn E. Stephenson, Rebecca Zash, Jinyan Liu, Joseph P. Nkolola, Amelia Hoyt, Mike Castro, Leonid Serebryannyy, Katherine Yanosick, Tessa Speidel, Erica N. Borducchi, Tetyana Murzda, Lori Maxfield, Roberto Arduino, Adrian B. McDermott, Lucio Gama, Elena E. Giorgi, Richard A. Koup, Michael S. Seaman, Charlotte-Paige Rolle, Edwin DeJesus, Wenjun Li, Bette Korber, Dan H. Barouch","doi":"10.1038/s41591-024-03247-5","DOIUrl":null,"url":null,"abstract":"<p>Human immunodeficiency virus type 1 (HIV-1)-specific broadly neutralizing monoclonal antibodies (bNAbs) have to date shown transient viral suppression when administered as monotherapy or as a cocktail of two antibodies<sup>1,2,3,4</sup>. A combination of three bNAbs provides improved neutralization coverage of global viruses, which may more potently suppress viral escape and rebound<sup>5,6,7</sup>. Here we performed an open-label, two-part study evaluating a single intravenous dose of HIV-1 bNAbs, PGT121, PGDM1400 and VRC07-523LS, in six adults without HIV in part 1 and a multicenter trial of up to six monthly infusions of these three bNAbs in 12 people living with HIV with an antiretroviral therapy (ART) interruption in part 2. The primary endpoints were safety, tolerability and pharmacokinetics, and the secondary endpoints in part 2 were antiviral activity following ART discontinuation, changes in CD4<sup>+</sup> T cell counts and development of HIV-1 sequence mutations associated with bNAb resistance. The trial met its prespecified endpoints. The bNAb treatment was generally safe and well tolerated. In part 2, 83% of participants (10 of 12) maintained virologic suppression for the duration of antibody therapy for at least 28 weeks, and 42% of participants (5 of 12) showed virologic suppression for at least 38–44 weeks, despite the decline of serum bNAb concentrations to low or undetectable levels. In exploratory analyses, early viral rebound in two individuals correlated with baseline resistance to PGT121 and PGDM1400, whereas long-term virologic control in five individuals correlated with reduced immune activation, T cell exhaustion and proinflammatory signaling following bNAb therapy. Our data show the potential of a triple bNAb cocktail to suppress HIV-1 in the absence of ART. ClinicalTrials.gov registration: NCT03721510.</p>","PeriodicalId":58,"journal":{"name":"The Journal of Physical Chemistry ","volume":"149 1","pages":""},"PeriodicalIF":2.7810,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Safety and antiviral effect of a triple combination of HIV-1 broadly neutralizing antibodies: a phase 1/2a trial\",\"authors\":\"Boris Julg, Victoria E. K. Walker-Sperling, Kshitij Wagh, Malika Aid, Kathryn E. Stephenson, Rebecca Zash, Jinyan Liu, Joseph P. Nkolola, Amelia Hoyt, Mike Castro, Leonid Serebryannyy, Katherine Yanosick, Tessa Speidel, Erica N. Borducchi, Tetyana Murzda, Lori Maxfield, Roberto Arduino, Adrian B. McDermott, Lucio Gama, Elena E. Giorgi, Richard A. Koup, Michael S. Seaman, Charlotte-Paige Rolle, Edwin DeJesus, Wenjun Li, Bette Korber, Dan H. Barouch\",\"doi\":\"10.1038/s41591-024-03247-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Human immunodeficiency virus type 1 (HIV-1)-specific broadly neutralizing monoclonal antibodies (bNAbs) have to date shown transient viral suppression when administered as monotherapy or as a cocktail of two antibodies<sup>1,2,3,4</sup>. A combination of three bNAbs provides improved neutralization coverage of global viruses, which may more potently suppress viral escape and rebound<sup>5,6,7</sup>. Here we performed an open-label, two-part study evaluating a single intravenous dose of HIV-1 bNAbs, PGT121, PGDM1400 and VRC07-523LS, in six adults without HIV in part 1 and a multicenter trial of up to six monthly infusions of these three bNAbs in 12 people living with HIV with an antiretroviral therapy (ART) interruption in part 2. The primary endpoints were safety, tolerability and pharmacokinetics, and the secondary endpoints in part 2 were antiviral activity following ART discontinuation, changes in CD4<sup>+</sup> T cell counts and development of HIV-1 sequence mutations associated with bNAb resistance. The trial met its prespecified endpoints. The bNAb treatment was generally safe and well tolerated. In part 2, 83% of participants (10 of 12) maintained virologic suppression for the duration of antibody therapy for at least 28 weeks, and 42% of participants (5 of 12) showed virologic suppression for at least 38–44 weeks, despite the decline of serum bNAb concentrations to low or undetectable levels. In exploratory analyses, early viral rebound in two individuals correlated with baseline resistance to PGT121 and PGDM1400, whereas long-term virologic control in five individuals correlated with reduced immune activation, T cell exhaustion and proinflammatory signaling following bNAb therapy. Our data show the potential of a triple bNAb cocktail to suppress HIV-1 in the absence of ART. ClinicalTrials.gov registration: NCT03721510.</p>\",\"PeriodicalId\":58,\"journal\":{\"name\":\"The Journal of Physical Chemistry \",\"volume\":\"149 1\",\"pages\":\"\"},\"PeriodicalIF\":2.7810,\"publicationDate\":\"2024-09-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Physical Chemistry \",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41591-024-03247-5\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Physical Chemistry ","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41591-024-03247-5","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Safety and antiviral effect of a triple combination of HIV-1 broadly neutralizing antibodies: a phase 1/2a trial
Human immunodeficiency virus type 1 (HIV-1)-specific broadly neutralizing monoclonal antibodies (bNAbs) have to date shown transient viral suppression when administered as monotherapy or as a cocktail of two antibodies1,2,3,4. A combination of three bNAbs provides improved neutralization coverage of global viruses, which may more potently suppress viral escape and rebound5,6,7. Here we performed an open-label, two-part study evaluating a single intravenous dose of HIV-1 bNAbs, PGT121, PGDM1400 and VRC07-523LS, in six adults without HIV in part 1 and a multicenter trial of up to six monthly infusions of these three bNAbs in 12 people living with HIV with an antiretroviral therapy (ART) interruption in part 2. The primary endpoints were safety, tolerability and pharmacokinetics, and the secondary endpoints in part 2 were antiviral activity following ART discontinuation, changes in CD4+ T cell counts and development of HIV-1 sequence mutations associated with bNAb resistance. The trial met its prespecified endpoints. The bNAb treatment was generally safe and well tolerated. In part 2, 83% of participants (10 of 12) maintained virologic suppression for the duration of antibody therapy for at least 28 weeks, and 42% of participants (5 of 12) showed virologic suppression for at least 38–44 weeks, despite the decline of serum bNAb concentrations to low or undetectable levels. In exploratory analyses, early viral rebound in two individuals correlated with baseline resistance to PGT121 and PGDM1400, whereas long-term virologic control in five individuals correlated with reduced immune activation, T cell exhaustion and proinflammatory signaling following bNAb therapy. Our data show the potential of a triple bNAb cocktail to suppress HIV-1 in the absence of ART. ClinicalTrials.gov registration: NCT03721510.