Project 2: Limiting anti-drug antibodies
Project 2: Limiting anti-drug antibodies
批准号:
10625286
负责人:
Ronald C Desrosiers
金额:
$40.3万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-04-15 至 2025-03-31
关键词:
AccelerationAddressAnimalsAntibodiesAntibody ResponseAntibody TherapyAntigen TargetingAntigensAntiviral AgentsBindingBispecific AntibodiesBlood specimenCapsidCellsCollectionCpG dinucleotideDataDevelopmentDoseEnsureErythrocytesFundingGoalsHIVHIV-1HumanImmune ToleranceImmunityImmunizationImmunoglobulin Constant RegionIndividualInfectionIngestionInjectionsIntramuscular InjectionsLightLiteratureMacacaMacaca mulattaMediatingMonitorMonkeysMonoclonal AntibodiesMusMutationOralPaperPersonsPharmaceutical PreparationsPharmacotherapyProgram Research Project GrantsProphylactic treatmentProtocols documentationPublicationsPublishingRegimenResistanceRhesusSafetyTechnologyTestingTherapy trialTransgenesUnited States National Institutes of HealthViral Load resultVirus Replicationadeno-associated viral vectorarmdesignefficacy evaluationexpectationexperimental studyhuman monoclonal antibodiesimmunogenicoral toleranceoral tolerizationpromotersimian human immunodeficiency virusvector
中文摘要
项目摘要(项目 2 – 限制针对 AAV 传递的 bNAb 的抗药物抗体)
考虑到具有强大中和活性的人类单克隆抗体的显着收集
广泛的 HIV-1 分离株(bNAb),可以预见长期提供
此类抗体的组合作为实现严格、长期病毒学控制的手段
缺乏持续的抗病毒药物治疗。在初步数据和最近发表的论文中
免疫方面,我们证明了 AAV 介导的两种 bNAb 10-1074 和 3BNC117 的持续表达,
在未经治疗的 SHIV-AD8 感染 86 周后引入,导致对
病毒复制超过三年。这只猴子被称为“迈阿密猴”。我们也
尽管如此,表明使用 AAV 持续递送 bNAb 已受到抗药物的严重阻碍
大多数猕猴对 bNAb 产生抗体 (ADA) 反应。尽管广泛的抗体样
免疫粘附素 eCD4-Ig 的免疫原性较低,它还会提高 ADA,这可能会限制其功效或
它对人类的安全性。因此,该项目致力于寻找能够有效且有效的方法
使用免疫原性 bNAb 3BCN117 作为我们的研究,实际上抑制了对抗体的 ADA 反应
主要测试用例。在这个项目中,我们将评估三种方法:(1) 消除 CpG
转基因中的基序,(2) 口服耐受性,以及 (3) 协调双特异性抗体的耐受性
bNAb 与红细胞结合。此外,我们将协助评估来自不同国家的 ADA 回应
衣壳和启动子(项目 1),以及来自 AAV 转基因的衣壳和启动子,其表达已
推迟了四个月(项目 4)。然后我们将使用这些方法和 AAV 的最佳组合-
表达的 bNAb 用于建立和表征经 ART 治疗和未治疗的恒河猴的功能性治愈
猕猴。因此,该项目将解决使用 AAV 表达的 bNAb 的核心挑战
HIV-1 预防和治疗。
英文摘要
PROJECT SUMMARY (Project 2 – Limiting anti-drug antibodies against AAV-delivered bNAbs)
Given the remarkable collection of human monoclonal antibodies with potent neutralizing activity against a
broad range of HIV-1 isolates (bNAbs), it has become possible to envision long-term delivery of a
combination of such antibodies as a means for achieving stringent, long-term virological control in the
absence of continuing antiviral drug therapy. In preliminary data and recently published paper in
Immunity, we shown that sustained AAV-mediated expression of two bNAbs, 10-1074 and 3BNC117,
introduced 86 weeks after an untreated SHIV-AD8 infection resulted in robust long-term suppression of
viral replication for over three years. This monkey has been referred to as “the Miami monkey”. We also
nonetheless show that consistent delivery of bNAbs using AAV has been severely hampered by anti-drug
antibody (ADA) responses to the bNAb in the majority of macaques. Although the broad antibody-like
immunoadhesin eCD4-Ig is less immunogenic, it also raises ADA that could potentially limit its efficacy or
its safety in humans. This project is therefore committed to finding approaches that can effectively and
practically suppress ADA responses to an antibody, using the immunogenic bNAb 3BCN117 as our
primary test case. In this project we will evaluate three approaches for doing so: (1) elimination of CpG
motifs in the transgene, (2) oral tolerization, and (3) tolerization with a bispecific antibody that coordinates
bNAb binding to erythrocytes. In addition, we will assist in evaluating the ADA responses from different
capsids and promoters (Project 1), and those from an AAV transgene whose expression has been
delayed by four months (Project 4). We will then use the best combination of these approaches and AAV-
expressed bNAbs to establish and characterize functional cures in ART-treated and untreated rhesus
macaques. This project will therefore address a central challenge to the use AAV-expressed bNAbs for
HIV-1 prophylaxis and therapy.
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会议论文
Project 2: Limiting anti-drug antibodies
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批准号:10381478
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项目类别:
-
资助金额:$31.62万
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财政年份:2020
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负责人:Ronald C Desrosiers
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依托单位:
Functional Role of O-Glycosylation of HIV-1
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批准号:8705821
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项目类别:
-
资助金额:$31.46万
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财政年份:2013
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负责人:Ronald C Desrosiers
-
依托单位:
Functional Role of O-Glycosylation of HIV-1
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批准号:8617796
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项目类别:
-
资助金额:$38.38万
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财政年份:2013
-
负责人:Ronald C Desrosiers
-
依托单位:
Functional Role of O-glycosylation of HIV-1
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批准号:10363617
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项目类别:
-
资助金额:$44.81万
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财政年份:2013
-
负责人:Ronald C Desrosiers
-
依托单位:
Functional Role of O-glycosylation of HIV-1
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批准号:10582533
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项目类别:
-
资助金额:$44.66万
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财政年份:2013
-
负责人:Ronald C Desrosiers
-
依托单位:
Functional Role of O-Glycosylation of HIV-1
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批准号:8534995
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项目类别:
-
资助金额:$5.26万
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财政年份:2013
-
负责人:Ronald C Desrosiers
-
依托单位:
Functional Role of O-Glycosylation of HIV-1
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批准号:9010906
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项目类别:
-
资助金额:$38.38万
-
财政年份:2013
-
负责人:Ronald C Desrosiers
-
依托单位:
Functional Role of O-Glycosylation of HIV-1
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批准号:8792828
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项目类别:
-
资助金额:$38.38万
-
财政年份:2013
-
负责人:Ronald C Desrosiers
-
依托单位:
Functional Role of O-glycosylation of HIV-1
-
批准号:10012154
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项目类别:
-
资助金额:$46.1万
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财政年份:2013
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负责人:Ronald C Desrosiers
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依托单位:
Immunoglobulins Delivered by AAV Vector for the Prevention of SIV Infection
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批准号:8513256
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项目类别:
-
资助金额:$66.79万
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财政年份:2012
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负责人:Ronald C Desrosiers
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依托单位:
Immunoglobulins Delivered by AVV Vector for the Prevention of SIV Infection
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批准号:10061523
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项目类别:
-
资助金额:$73.1万
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财政年份:2012
-
负责人:Ronald C Desrosiers
-
依托单位:
Immunoglobulins Delivered by AAV Vector for the Prevention of SIV Infection
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批准号:8860104
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项目类别:
-
资助金额:$71.06万
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财政年份:2012
-
负责人:Ronald C Desrosiers
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依托单位:
Immunoglobulins Delivered by AVV Vector for the Prevention of SIV Infection
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批准号:9270728
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项目类别:
-
资助金额:$73.1万
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财政年份:2012
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负责人:Ronald C Desrosiers
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依托单位:
Therapuetic effector functions of AAV expressed transgenes
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批准号:8311211
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项目类别:
-
资助金额:$43.67万
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财政年份:2012
-
负责人:Ronald C Desrosiers
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依托单位:
Immunoglobulins Delivered by AAV Vector for the Prevention of SIV Infection
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批准号:8326890
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项目类别:
-
资助金额:$81.01万
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财政年份:2012
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负责人:Ronald C Desrosiers
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依托单位:
MICROBIOLOGICAL REAGENT AND SAMPLE DISTRIBUTION
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批准号:8357910
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项目类别:
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资助金额:$21.06万
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财政年份:2011
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负责人:Ronald C Desrosiers
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依托单位:
MEMBRANE SPANNING REGIONS AS PROTEIN-PROTEIN INTERACTING DOMAINS IN HIV
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批准号:8358009
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项目类别:
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资助金额:$21.06万
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财政年份:2011
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负责人:Ronald C Desrosiers
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依托单位:
STRATEGIES OF IMMUNE EVASION IN AIDS
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批准号:8357951
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项目类别:
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资助金额:$21.06万
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财政年份:2011
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负责人:Ronald C Desrosiers
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依托单位:
Immunoglobulins Delivered by AAV Vector for the Prevention of SIV Infection
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批准号:8198151
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项目类别:
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资助金额:$43.88万
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财政年份:2011
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负责人:Ronald C Desrosiers
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依托单位:
GAMMA-2 HERPESVIRUS AS VACCINE VECTORS FOR AIDS
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批准号:8357981
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项目类别:
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资助金额:$21.06万
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财政年份:2011
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负责人:Ronald C Desrosiers
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依托单位:
海外基金