A PET Radiotracer for Diagnostic and Theranostics Imaging in Lyme Disease

用于莱姆病诊断和治疗成像的 PET 放射性示踪剂

• 批准号: 10041529
• 负责人: WEIGANG QIU
• 金额: $ 19.5万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10041529
• 关键词: Affect; Aftercare; Area; Bacteria; Basic Science; Biochemical; Biological Assay; Biological Markers; Borrelia; Centers for Disease Control and Prevention (U.S.); Characteristics; Chronic; Clinic; Clinical; Clinical Management; Consensus; Consensus Sequence; Conserved Sequence; Data; Development; Diagnosis; Diagnostic; Disease; Disease model; Escherichia coli; Evaluation; Fab Immunoglobulins; Flow Cytometry; Gallium; Generations; Genes; Genome; Goals; Gram-Positive Bacteria; Health Care Costs; Image; Immune Sera; Immunoglobulin Fragments; In Vitro; Infection; Label; Laboratories; Lead; Length; Libraries; Lyme Disease; Midwestern United States; Molecular Biology; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Order Spirochaetales; Patient Care; Patient imaging; Patients; Peptide Synthesis; Peptides; Phase; Physicians; Positron; Positron-Emission Tomography; Property; Protein Biosynthesis; Proteins; Protocols documentation; Public Health; Radioimmunoconjugate; Radiolabeled; Radiopharmaceuticals; Reference Standards; Reporting; Research; Risk; Sampling; Sequence Analysis; Solid; Structure; Surface; Surface Antigens; Surface Plasmon Resonance; Syndrome; System; Technology; Testing; Tick-Borne Diseases; Tick-Borne Infections; Time; United States; Variant; Vector-transmitted infectious disease; Zirconium; base; clinical care; comparative; comparative genomics; design; diagnostic biomarker; immunoreactivity; in vitro testing; in vivo; lead candidate; maltreatment; member; mouse model; new technology; non-invasive monitor; novel diagnostics; nuclear imaging; patient response; radiotracer; targeted treatment; theranostics; tool

Project Summary/Abstract Lyme disease is a tick-borne infection caused by the spirochete Borrelia burgdorgeri sensu lato (Bbsl) and is the most prevalent vector-borne disease in the United States. The latest surveillance from the Centers for Disease Control reported 40,000 new cases of Lyme disease in 2017 alone. Alarmingly, the disease is expanding from its endemic areas in the Northeast, mid-Atlantic, and Upper Midwest to neighboring states. The rapidly increasing public health risks and rising healthcare costs associated with the disease are exacerbated by controversies surrounding its diagnosis and treatment, especially in cases of `post-treatment Lyme disease syndrome' and `chronic Lyme disease'. In these cases, there are no definitive consensus diagnostic markers that are both sensitive and specific for the infection. While the under-diagnosis of Lyme disease has naturally lead to under-treatment, the mis-diagnosis and mis-treatment of the condition has led to serious morbidity as well. Taken together, the data make it clear that the development of new diagnostic and theranostic tools for Lyme disease is an urgent, unmet clinical need. This R21 proposal is focused on the design, synthesis, and in vitro evaluation of sensitive and specific radiotracers for the diagnostic and theranostic positron emission tomography (PET) of patients with Lyme disease. The target for these radiopharmaceuticals 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 identification of broadly reactive VlsE-based biomarkers via the comparative analysis of BBsl genomes, with an overall goal designing 15 candidate targets (10 variants of VlsE and 5 vls-based peptides) based on consensus and conserved sequences. Specific Aim 2 (SA2) will be centered on the expression of the candidate VlsE proteins, the synthesis of the vls-encoded peptides, and the in vitro testing of the antigenicity of these biomolecules with patient antisera in order to identify the most broadly reactive target molecules. Specific Aim 3 (SA3) will focus on the generation of a VlsE-specific monoclonal antibody and F(ab) fragment as well as the radiosynthesis of the corresponding radioimmunoconjugates labeled with positron-emitting radiometals zirconium-89 (89Zr) and gallium-68 (68Ga). The in vitro immunoreactivity of these radioimmunoconjugates will be interrogated with several strains of VlsE-expressing BBsl as well as control gram-negative and gram-positive bacteria. Ultimately, we believe that this proposal could have a transformational impact on both the basic science and clinical management of Lyme disease. In the laboratory, a Lyme-targeted radiotracer could be a valuable research tool during the development of murine models of the disease and the evaluation of Bbsl-targeted therapeutics. Even more importantly, in the clinic, a VlsE-targeted radiopharmaceutical could prove to be both a useful diagnostic tool to help identify patients with active infections and a valuable theranostic tool to monitor the response of patients to therapy.

项目总结/摘要 莱姆病是由螺旋体伯氏疏螺旋体引起的蜱传播感染， 是美国最流行的病媒传播疾病。从中心的最新监测， 疾病控制中心仅在2017年就报告了4万例莱姆病新病例。令人担忧的是，这种疾病 从东北部、大西洋中部和上中西部的地方病流行区扩展到邻近各州。 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， 由于围绕其诊断和治疗的争议，特别是在“治疗后”的情况下， 莱姆病综合征和慢性莱姆病。在这些情况下， 对感染既敏感又特异的诊断标志物。虽然莱姆病的诊断不足 疾病自然会导致治疗不足，误诊和错误治疗的条件，导致 也有严重的发病率。总的来说，数据清楚地表明，新的诊断和 莱姆病的治疗诊断工具是一个迫切的，未满足的临床需求。 该R21提案集中于敏感性和特异性的药物的设计、合成和体外评价。 用于莱姆病患者诊断和治疗诊断的放射性示踪剂正电子发射断层扫描（PET） 疾病这些放射性药物的靶点是VlsE，这是一种在细胞膜上大量表达的蛋白质。 Bbsl在其脊椎动物宿主中的整个时间内的表面。具体目标1（SA 1）将侧重于 通过BBsl基因组的比较分析鉴定广泛反应性的基于VlsE的生物标志物， 总体目标设计15个候选靶标（VlsE的10个变体和5个基于vls的肽）， 共有序列和保守序列。具体目标2（SA 2）将集中在表达 候选VlsE蛋白、Vls编码肽的合成以及VlsE蛋白的抗原性的体外测试。 将这些生物分子与患者抗血清进行比较，以鉴定最广泛反应的靶分子。 特异性目标3（SA 3）将集中于产生VIgE特异性单克隆抗体和F（ab）片段 以及用正电子发射标记的相应放射免疫缀合物的放射合成 放射性金属锆-89（89 Zr）和镓-68（68 Ga）。这些细胞的体外免疫反应性 放射免疫缀合物将用几种表达VlsE的BBs 1菌株以及对照菌株进行研究 革兰氏阴性和革兰氏阳性细菌。最终，我们认为，这一建议可能会有一个 对莱姆病的基础科学和临床管理产生了变革性影响。在实验室里， 莱姆靶向放射性示踪剂可能是一个有价值的研究工具，在小鼠模型的发展， 疾病和Bbsl靶向治疗剂的评价。更重要的是，在临床上， 放射性药物可以证明是一个有用的诊断工具，以帮助确定患者的活动 感染和一个有价值的治疗诊断工具，以监测病人的反应治疗。