Molecular Imaging of persistent HIV: CD30

持续性 HIV 的分子影像：CD30

基本信息

批准号：
10159653
负责人：
Henry F. VanBrocklin
金额：
$ 16.15万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-12 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159653
关键词：
Anatomy Anti-Retroviral Agents Antibody-drug conjugates Biological Biological Assay Biological Markers Blood Circulation Budgets CD4 Positive T Lymphocytes Cells Clinical DNA Data Development Drug Kinetics Evaluation FDA approved Foundations Genetic Transcription Goals HIV HIV Envelope Protein gp120 HIV Infections HIV envelope protein Hodgkin Disease Hour Human Image In Vitro Individual Infection Infrastructure Investigational Drugs Investigational New Drug Application Lymphoid Macaca Magnetic Resonance Imaging Measurement Methods Monoclonal Antibodies Mus Organ Participant Patients Peripheral Phase Pilot Projects Positron-Emission Tomography Process Production Proteins RNA Radiation exposure Radiolabeled Reporting SIV Safety Sampling Surrogate Markers TNFRSF8 gene Therapeutic Tissues Tracer Tumor Necrosis Factor Receptor United States Food and Drug Administration antiretroviral therapy clinical translation cohort cytotoxic dosimetry experience first-in-human healthy volunteer human study imaging approach imaging modality immunoreactivity in vivo in vivo evaluation mRNA Expression member molecular imaging neoplastic cell non-invasive imaging novel pre-clinical radiotracer

项目摘要

PROJECT SUMMARY: A major hurdle to HIV eradication is the presence of infected cells that persist despite suppressive antiretroviral therapy (ART). HIV largely resides outside of the peripheral circulation, and thus, numerous anatomical and lymphoid compartments that have the capacity to harbor HIV are inaccessible to routine sampling. As a result, there is a limited understanding of the tissue burden of HIV and the anatomical distribution of HIV transcriptional and translational activity. Novel, non-invasive, in vivo methods, such as positron emission tomography (PET)-based imaging approaches may provide a means to visualize the reservoir. A PET-based imaging approach using a radiolabeled SIV anti-gp120 monoclonal antibody (mAb) has been applied to assess active infection in macaques, but similar approaches in humans have not been reported. However, the implementation of HIV envelope protein specific mAbs is likely to be challenging due to low expression of HIV proteins in the setting of suppressive ART. An alternative approach is to develop and implement tracers for non-viral biomarkers of HIV infected cells. CD30 is a member of the TNF receptor superfamily that is upregulated on various tumor cells (e.g. Hodgkin lymphoma) but not expressed on a vast majority of healthy cells. We recently demonstrated that HIV RNA is highly enriched in CD30+CD4+ T cells on suppressive ART, and targeting CD30 using the FDA approved cytotoxic antibody-drug conjugate (ADC) brentuximab-vedotin (BV) in vivo and ex vivo leads to reduced HIV RNA and DNA levels in some individuals. Importantly, CD30 mRNA expression in tissues from antiretroviral treated participants is found exclusively in HIV RNA+ cells. Because of the lack of expression on uninfected cells, CD30 is an enticing non-viral marker of transcriptionally active HIV-infected cells that persist despite suppressive ART. Therefore, we propose to: (1) Synthesize 89Zr-DFO-BV, (2) Collect IND enabling in vitro and in vivo data including estimate whole-body dosimetry in mice using µPET/CT, (3) Develop an efficient immunoreactivity assay to support clinical translation, (4) Validate and document the current Good Manufacturing Practice (cGMP) production of 89Zr-DFO-BV and (5) Conduct first-in-human PET/MR imaging of CD30 using 89Zr-DFO-BV in viremic, subjects under ART and uninfected controls to determine pharmacokinetics, dosimetry, proof of concept and safety. We hypothesize that radiolabeled BV will have activity against CD30 and have favorable dosimetry and pharmacokinetics for human use. Ultimately, PET/MR imaging of CD30 expressing CD4+ T cells has the potential to provide tissue-wide anatomical distribution of HIV transcriptionally active cells on ART. Our group has an established pre- clinical and clinical PET-MR imaging infrastructure and have three human studies involving imaging HIV persistence currently in process. As a result, this pilot study is feasible and has the capacity to provide a rigorous foundation for non-invasive imaging methods to enhance HIV eradication and therapeutic efforts.

项目摘要：根除艾滋病毒的一个主要障碍是持续存在的受感染细胞尽管进行了抗逆转录病毒治疗（ART），HIV仍处于抑制状态，HIV主要存在于外周循环之外。因此，许多具有藏匿艾滋病毒能力的解剖学和淋巴室因此，人们对 HIV 的组织负担了解有限。以及 HIV 转录和翻译活性的解剖分布新颖、非侵入性、体内。方法，例如基于正电子发射断层扫描（PET）的成像方法可以提供一种手段使用放射性标记的 SIV 抗 gp120 单克隆抗体对储层进行可视化。抗体（mAb）已被用于评估猕猴的活动性感染，但在然而，HIV 包膜蛋白特异性单克隆抗体的实施尚未见报道。由于在抑制性 ART 环境中 HIV 蛋白表达低，因此可能具有挑战性。另一种方法是开发和实施 HIV 感染细胞非病毒生物标志物的示踪剂。 CD30 是 TNF 受体超家族的成员，在多种肿瘤细胞（例如霍奇金细胞）上表达上调淋巴瘤），但在绝大多数健康细胞中不表达，我们最近证明了 HIV RNA。在抑制性 ART 中高度富集 CD30+CD4+ T 细胞，并使用 FDA 批准的靶向 CD30 细胞毒性抗体-药物偶联物 (ADC) brentuximab-vedotin (BV) 体内和离体导致减少重要的是，某些个体中的 HIV RNA 和 DNA 水平是组织中 CD30 mRNA 的表达。由于缺乏表达，接受抗逆转录病毒治疗的参与者仅在 HIV RNA+ 细胞中发现。在未感染的细胞上，CD30 是转录活跃的 HIV 感染细胞的一种诱人的非病毒标记，尽管有抑制性 ART，但仍持续存在，因此，我们建议：(1) 合成 89Zr-DFO-BV，(2) 收集 IND。实现体外和体内数据，包括使用 µPET/CT 估计小鼠全身剂量测定，(3) 开发有效的免疫反应测定以支持临床转化，(4) 验证并记录 89Zr-DFO-BV 的现行良好生产规范 (cGMP) 生产以及 (5) 进行首次人体试验使用 89Zr-DFO-BV 对病毒血症、接受 ART 的受试者和未感染对照进行 CD30 的 PET/MR 成像确定药代动力学、剂量测定、概念验证和安全性。将具有针对 CD30 的活性，并具有适合人类使用的剂量测定和药代动力学。最终，表达 CD30 的 CD4+ T 细胞的 PET/MR 成像有可能提供组织范围内的我们小组已经确定了 ART 上 HIV 转录活性细胞的解剖分布。临床和临床 PET-MR 成像基础设施，并进行了三项涉及 HIV 成像的人体研究因此，目前正在进行的试点研究是可行的，并且有能力提供参考。为非侵入性成像方法加强艾滋病毒根除和治疗工作奠定了坚实的基础。