Molecular Imaging of persistent HIV: CD30

持续性 HIV 的分子影像：CD30

• 批准号: 10328272
• 负责人: Henry F. VanBrocklin
• 金额: $ 28.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-12 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328272
• 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

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：消除HIV的主要障碍是持续存在的感染细胞的存在 尽管抑制抗逆转录病毒疗法（ART）。 HIV在很大程度上居住在外周循环外， 因此，具有携带艾滋病毒能力的许多解剖和淋巴室是 常规抽样无法访问。结果，对HIV的组织燃烧的了解有限 以及HIV转录和翻译活性的解剖分布。小说，无创体体内 方法，例如正电子发射断层扫描（PET）的成像方法可能会提供一种手段 可视化储层。使用放射性标记的SIV抗GP120单克隆的基于宠物的成像方法 抗体（MAB）已应用于猕猴中的主动感染，但是在 人类尚未报告。但是，HIV包膜蛋白特异性mAb的实施是 在抑制艺术的环境中，艾滋病毒蛋白的表达较低，可能会受到挑战。一个 替代方法是为HIV感染细胞的非病毒生物标志物开发和实施示踪剂。 CD30是在各种肿瘤细胞上更新的TNF受体超家族的成员（例如Hodgkin 淋巴瘤），但没有在绝大多数健康细胞上表达。我们最近证明了HIV RNA 高度富含CD30+ CD4+ T细胞在抑制作用上，并使用FDA批准靶向CD30 细胞毒性抗体 - 药物缀合物（ADC）brentuximab-wedotin（BV）体内和离体导致减少 某些个体中的HIV RNA和DNA水平。重要的是，来自组织中的CD30 mRNA表达 在HIV RNA+细胞中仅发现了抗逆转录病毒治疗的参与者。由于缺乏表达 在未感染的细胞上，CD30是转录活性HIV感染细胞的诱人的非病毒标记 坚持目的地抑制艺术。因此，我们建议：（1）合成89ZR-DFO-BV，（2）收集IND 使用µPET/CT启用体外和体内数据，包括在小鼠中估计全身剂量测定法，（3） 开发有效的免疫反应性测定法以支持临床翻译，（4）验证和记录 当前的良好制造实践（CGMP）生产89ZR-DFO-BV和（5）行为首先是人类 使用89ZR-DFO-BV对CD30进行的PET/MR成像，在ART和未感染的对照下进行的受试者 确定药代动力学，剂量法，概念和安全证明。我们假设放射性标记的BV 将具有针对CD30的活性，并具有有利的剂量法和用于人类使用的药代动力学。 最终，表达CD4+ T细胞的CD30的PET/MR成像具有提供整个组织的潜力 HIV转录活性细胞在ART上的解剖分布。我们的小组有一个既定的预先 临床和临床PET-MR成像基础设施，并具有三项涉及成像HIV的人类研究 当前正在进行的持久性。结果，这项试验研究是可行的，并且有能力提供 严格的非侵入性成像方法的基础，以增强艾滋病毒的消除和治疗努力。