ImmunoPET Probes for the Imaging of Lyme Disease

用于莱姆病成像的免疫PET探针

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要莱姆病是一种由蜱传疾病，由螺旋体伯氏疏螺旋体 (Bbsl) 引起，美国最流行的蜱传疾病。 CDC最新监测报告显示在美国，莱姆病每年影响超过 475,000 人，比 2015 年增加了近 50%。此外，该疾病正在从东北部、大西洋中部和上游地区的流行地区扩大。中西部。与该疾病相关的公共卫生风险迅速增加，医疗费用不断上涨围绕其诊断和治疗的争议加剧了这一问题。虽然莱姆病诊断不足疾病导致治疗不足，对病情的误诊、误治导致了严重的后果发病率也是如此。简而言之，我们目前对诊断、病理生理学和莱姆病缺乏治疗方法。总而言之，数据表明，工具的开发莱姆病的非侵入性分子成像是迫切的科学和临床需求。该 R01 提案重点关注一流药物的合成、表征和体内验证用于莱姆病 PET 成像的放射性药物。这些药物的目标是 VlsE，一种蛋白质在其脊椎动物宿主体内，Bbsl 的表面始终大量表达。具体目标 1 （SA1）将重点关注89Zr-的合成、化学表征和体外生物学评价标记的单克隆抗体和 68Ga 标记的单域抗体能够以高浓度结合 VlsE 特异性、选择性和亲和力。具体目标 2 (SA2) 将集中于询问体内这些 VLSE 靶向放射性药物在两种莱姆病小鼠模型中的性能。首先，我们将使用皮下接种培养的 Bbsl 的小鼠来询问其敏感性和特异性放射免疫缀合物并评估显像剂作为监测反应工具的能力抗生素治疗。随后，我们将更深入地探讨 VlsE 靶向 PET 探针的性能。莱姆病的高级小鼠模型：小鼠通过肩胛硬蜱感染多种 Bbsl 菌株。在对于这两种模型，纵向 PET 数据将与一系列离体分析技术一起使用来评估放射性示踪剂描绘活动感染部位的能力。最终，我们认为，针对 Bbsl 的放射性示踪剂可能会对莱姆病的基础科学和临床研究。在实验室中，VlsE 靶向放射免疫结合物可能是研究 Bbsl 传播、病理生理学和治疗的有价值的非侵入性工具小鼠疾病模型中的感染。在临床上，Bbsl 靶向放射性药物可能是一种支持新型疫苗、治疗方法和药物的临床开发不可或缺的研究工具诊断以及有效的显像剂来监测患者的治疗反应特别持续或严重的 Bbsl 感染。