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3BNC117 and 10-1074 to suppress HIV-1 replication and reduce the reservoir

3BNC117 and 10-1074 to suppress HIV-1 replication and reduce the reservoir
3BNC117 和 10-1074 抑制 HIV-1 复制并减少病毒库
批准号:
9897465
负责人:
Marina Caskey
金额:
$81.49万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-04-15 至 2022-03-31

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英文摘要
Project Summary Combination antiretroviral therapy (ART) is highly successful in suppressing viral replication and preventing disease progression, however it cannot eradicate HIV-1 infection, and it does not accelerate the elimination of infected cells. HIV-1 persists in a latent state as integrated proviruses in resting memory CD4+ T cells that are not accessible to ART. Several eradication strategies are currently being evaluated, and broadly neutralizing antibodies (bNAbs) represent a promising new modality, particularly if coupled with latency reversing agents. Antibodies differ from ART in that they can recruit immune effector functions through their Fc domains to accelerate clearance of viruses and infected cells. In addition, immune complexes are potent immunogens that can foster development of host immune responses. Passive administration of earlier anti-HIV-1 bNAbs has been evaluated in humans and found to be generally safe and well tolerated. While these first generation neutralizing antibodies were largely ineffective in preclinical and clinical settings, selected newer generation bNAbs can prevent infection and suppress active infection in humanized mice (hu-mice) and non-human primates (NHP). 3BNC117 and 10-1074 are two of most potent broadly neutralizing antibodies currently available. 3BNC117 targets the CD4 binding site and 10-1074 targets the base of the V3 loop of HIV-1 gp120. In phase 1 clinical studies, 3BNC117 and 10-1074 have been generally safe to date. A single infusion of 3BNC117 suppressed HIV-1 viremia by an average of 1.48 log copies/ml, while 10-1074 suppressed HIV-1 viremia by an average of 1.34 copies/ml when dosed at 30 mg/kg. When evaluated in ART-treated individuals during an analytical interruption of ART (ATI), 3BNC117 effectively delayed rebound of antibody sensitive viruses from the HIV-1 reservoir. Similar to preclinical findings, selection of resistant viral strains occurred when either antibody was administered alone. The combination of 3BNC117 and 10-1074 have additive effects and provide broader coverage of viral strains. We now propose to study whether the administration of 3BNC117 and 10-1074 can suppress replication and reduce the reservoir by engaging the host immune system. The envisioned clinical trial is a phase I, open label, randomized study to evaluate the antiretroviral activity of 6 monthly infusions of 3BNC117 and 10-1074 to HIV-infected subjects who have achieved viral suppression with ART alone, in the presence or absence of ART. We will evaluate the reservoir by quantitative and qualitative methods to determine the genetic composition of the replication-competent viral reservoir. In addition, we will evaluate if 3BNC117 and 10-1074 modulate HIV-1-specific immune responses.
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First-in-human study of a potent anti-HBsAg neutralizing antibody
  • 批准号:
    10550458
  • 项目类别:
  • 资助金额:
    $86.47万
  • 财政年份:
    2023
  • 负责人:
    Marina Caskey
  • 依托单位:
Defining the mechanisms of HIV resistance to bNAbs in humans
  • 批准号:
    10659172
  • 项目类别:
  • 资助金额:
    $156.98万
  • 财政年份:
    2022
  • 负责人:
    Marina Caskey
  • 依托单位:
Defining the mechanisms of HIV resistance to bNAbs in humans
  • 批准号:
    10446159
  • 项目类别:
  • 资助金额:
    $156.98万
  • 财政年份:
    2022
  • 负责人:
    Marina Caskey
  • 依托单位:
REACH: Research Enterprise to Advance a Cure for HIV
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