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.

项目总结/摘要 莱姆病是由螺旋体伯氏疏螺旋体（Borrelia burgdorferi sensu lato，Bbsl）引起的蜱传播疾病， 这是美国最流行的蜱传疾病疾控中心的最新监测报告说， 莱姆病每年影响美国超过475，000人，比2015年增加近50%。 此外，该疾病正在从东北部、大西洋中部和上大西洋的地方病流行区扩大。 中西部。与这种疾病相关的公共卫生风险迅速增加，医疗费用不断上升， 围绕其诊断和治疗的争议加剧了这一问题。虽然莱姆病的诊断不足 疾病导致治疗不足，误诊和错误治疗的条件，导致严重的 发病率也是。简单地说，我们目前对诊断、病理生理学和 缺乏对莱姆病的治疗。总的来说，数据表明， 莱姆病的非侵入性分子成像是迫切的科学和临床需要。 该R 01提案的重点是合成、表征和体内验证一流的 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 其在脊椎动物宿主中的整个时间内在Bbs 1的表面上大量表达。具体目标1 (SA1)将集中在合成，化学表征，并在体外生物学评价的89锆- 标记的单克隆抗体和68 Ga标记的单结构域抗体，其能够以高亲和力结合VlsE， 特异性、选择性和亲和力。特定目标2（SA 2）将集中于询问体内 这些VlsE靶向放射性药物在两种莱姆病鼠模型中的性能。一是 使用皮下接种培养的Bbsl的小鼠来询问检测的灵敏度和特异性。 放射性免疫缀合物，并评估成像剂作为监测对放射性免疫缀合物反应的工具的能力。 抗生素治疗随后，我们将进一步探索VlsE靶向PET探针的性能 莱姆病的晚期鼠模型：小鼠通过肩突硬蜱感染多个Bbsl菌株。在 这两种模型，纵向PET数据将与一组离体分析技术一起使用，以评估 放射性示踪剂描绘活动性感染部位的能力。 最终，我们认为，BBSL靶向放射性示踪剂可能会对两个方面产生范式转变的影响。 莱姆病的基础科学和临床研究。在实验室中，VlsE靶向放射免疫缀合物 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 感染的小鼠疾病模型。在临床上，靶向Bbsl的放射性药物可能是一种 不可或缺的研究工具，以支持新型疫苗，治疗剂和 诊断以及有效的成像剂，以监测患者的治疗反应， 特别是持续或严重的Bbsl感染。