ImmunoPET Probes for the Imaging of Lyme Disease

用于莱姆病成像的免疫PET探针

• 批准号: 10802275
• 负责人: Maria Gomes-Solecki
• 金额: $ 56.52万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10802275
• 关键词: Active Sites; Affect; Affinity; Aftercare; Antibiotic Therapy; Area; Autoradiography; Bacteria; Basic Science; Binding; Biological; Biological Markers; Biological Testing; Black-legged Tick; Borrelia; Borrelia burgdorferi; Borrelia burgdorferi Group; Centers for Disease Control and Prevention (U.S.); Chemicals; Clinic; Clinical; Clinical Management; Clinical Research; Data; Dedications; Development; Diagnosis; Diagnostic; Disease; Disease model; Doxycycline; Drug Kinetics; Evaluation; Functional disorder; Health Care Costs; Histology; Image; ImmunoPET; Immunoconjugates; Immunohistochemistry; In Vitro; Infection; Investigation; Label; Laboratories; Lyme Disease; Lyme disease diagnosis; Midwestern United States; Modeling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mus; Order Spirochaetales; Performance; Persons; Positron-Emission Tomography; Post Treatment Lyme Disease Syndrome; Proteins; Public Health; Radioimmunoconjugate; Radiopharmaceuticals; Reporting; Research; Risk; Sensitivity and Specificity; Site; Specificity; Sulfhydryl Compounds; Surface; Surface Antigens; Techniques; Therapeutic; Tick-Borne Diseases; Ticks; Time; United States; Vaccination; Vaccine Clinical Trial; Validation; Variant; Vector-transmitted infectious disease; Visualization; Work; clinical development; clinical imaging; efficacy evaluation; fighting; imaging agent; imaging probe; in vivo; longitudinal positron emission tomography; maltreatment; member; molecular imaging; mouse model; nanobodies; new technology; non-invasive imaging; novel; novel therapeutics; novel vaccines; patient response; pre-clinical research; radiotracer; response; subcutaneous; targeted agent; targeted imaging; tick-borne; tool; tool development; trait; transmission process; treatment response

Project Summary/Abstract Lyme disease is a tick-borne disease caused by the spirochete Borrelia burgdorferi sensu lato (Bbsl) and is the most prevalent tick-borne disease in the United States. The latest surveillance from the CDC reported that Lyme disease affects more than ~475,000 people in the U.S. every year, a nearly 50% increase from 2015. Furthermore, the disease is expanding from its endemic areas in the Northeast, mid-Atlantic, and Upper Midwest. The rapidly increasing public health risks and rising healthcare costs associated with the disease are exacerbated by controversies surrounding its diagnosis and treatment. While the under-diagnosis of Lyme disease has led to under-treatment, the mis-diagnosis and mis-treatment of the condition have led to serious morbidity as well. Simply put, our current fundamental understanding of the diagnosis, pathophysiology, and treatment of Lyme disease is lacking. Taken together, the data indicate that the development of tools for the non-invasive molecular imaging of Lyme disease is an urgent scientific and clinical need. This R01 proposal is focused on the synthesis, characterization, and in vivo validation of first-in-class radiopharmaceuticals for the PET imaging of Lyme disease. The target for these agents will be VlsE, a protein that is abundantly expressed on the surface of Bbsl throughout its time in its vertebrate host. Specific Aim 1 (SA1) will be focused on the synthesis, chemical characterization, and in vitro biological evaluation of 89Zr- labeled monoclonal antibodies and 68Ga-labeled single domain antibodies capable of binding VlsE with high specificity, selectivity, and affinity. Specific Aim 2 (SA2) will be centered on interrogating the in vivo performance of these VlsE-targeted radiopharmaceuticals in two murine models of Lyme disease. First, we will use mice subcutaneously inoculated with cultured Bbsl to interrogate the sensitivity and specificity of the radioimmunoconjugates and to assess the power of the imaging agents as tools for monitoring response to antibiotic therapy. Subsequently, we will explore the performance of the VlsE-targeted PET probes in a more advanced murine model of Lyme disease: mice infected multiple strains of Bbsl via Ixodes scapularis ticks. In both models, longitudinal PET data will be used alongside a battery of ex vivo analytical techniques to evaluate the ability of the radiotracers to delineate sites of active infection. Ultimately, we contend that a Bbsl-targeting radiotracer could have a paradigm-shifting impact on both the basic science and clinical study of Lyme disease. In the laboratory, a VlsE-targeted radioimmunoconjugate could be a valuable non-invasive tool for studying the dissemination, pathophysiology, and treatment of Bbsl infections in murine models of disease. In the clinic, a Bbsl-targeted radiopharmaceutical could be an indispensable research tool to support the clinical development of novel vaccines, therapeutics, and diagnostics as well as an effective imaging agent to monitor the therapeutic response of patients with particularly persistent or severe Bbsl infections.

项目摘要/摘要 莱姆病是由Spirochete Borrelia burgdorferi sensu Lato（BBSL）引起的一种tick传播疾病 美国最普遍的壁虱传播疾病。 CDC的最新监视报告称 莱姆病在美国每年影响约47.5万人，比2015年增加了近50％。 此外，该疾病正在从其东北，中大西洋和上部的地方性地区扩展 中西部。与该疾病相关的医疗保健成本的迅速增加是 围绕其诊断和治疗的争议加剧了。而莱姆的诊断不足 疾病导致治疗不足，疾病的错误诊断和错误治疗导致严重 发病也是如此。简而言之，我们目前对诊断，病理生理学和 缺乏治疗莱姆病的治疗。综上所述，数据表明开发了 莱姆病的非侵入性分子成像是紧迫的科学和临床需求。 该R01提案的重点是第一类的综合，表征和体内验证 用于莱姆病的PET成像的放射性药物。这些药物的目标是VLSE，一种蛋白质 在BBSL的整个脊椎动物宿主中，它在BBSL的表面上大量表达。具体目标1 （SA1）将集中于89ZR-的合成，化学表征和体外生物学评估 标记的单克隆抗体和68GA标记的单域抗体，能够结合具有高的VLSE 特异性，选择性和亲和力。特定的目标2（SA2）将以询问体内的审查 这些针对VLSE靶向的放射性药物的性能在莱姆病的两个鼠模型中。首先，我们会的 使用皮下接种培养的BBSL的小鼠询问敏感性和特异性 放射免疫共轭物并评估成像剂的功能，作为监视对响应的工具 抗生素疗法。随后，我们将更多地探讨VLSE靶向PET探针的性能 莱姆病的晚期鼠模型：小鼠通过ixodes肩ca虫感染了多种BBSL菌株。在 这两种模型，纵向PET数据都将与一系列的离体分析技术一起评估 放射性示踪剂描述活性感染部位的能力。 最终，我们认为，靶向BBSL的放射性示例可能会对这两者产生范式转移影响 莱姆病基础科学和临床研究。在实验室中，涉及VLSE靶向的放射膜轭 可能是研究BBSL的传播，病理生理学和治疗的有价值的非侵入性工具 鼠类疾病模型中的感染。在诊所中，靶向BBSL的放射性药物可能是 必不可少的研究工具，以支持新型疫苗，治疗剂和 诊断和有效的成像剂，以监测患者的治疗反应 特别是持续或严重的BBSL感染。