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.

项目概要/摘要 莱姆病是一种蜱传感染，由螺旋体伯氏疏螺旋体 (Bbsl) 和 是美国最流行的媒介传播疾病。中心最新监控 疾病控制中心报告称，仅 2017 年就有 40,000 例莱姆病新病例。令人担忧的是，这种疾病是 从东北部、大西洋中部和中西部北部的流行区扩展到邻近各州。 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，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，尚无明确的共识 对感染既敏感又特异的诊断标记物。虽然莱姆病诊断不足 疾病自然导致治疗不足，对病情的误诊和误治导致了 也有严重的发病情况。总而言之，这些数据清楚地表明，新的诊断和治疗方法的开发 莱姆病的治疗诊断工具是一项紧迫的、未得到满足的临床需求。 该 R21 提案重点关注敏感和特异的药物的设计、合成和体外评估 用于莱姆病患者诊断和治疗正电子发射断层扫描 (PET) 的放射性示踪剂 疾病。这些放射性药物的目标将是 VlsE，一种在细胞上大量表达的蛋白质。 Bbsl 在其脊椎动物宿主体内的整个过程中都存在于其表面。具体目标 1 (SA1) 将重点关注 通过 BBsl 基因组的比较分析，鉴定基于 VlsE 的广泛反应性生物标志物 总体目标设计 15 个候选靶标（10 个 VLSE 变体和 5 个基于 VLS 的肽） 共有序列和保守序列。具体目标 2 (SA2) 将集中于表达 候选VlsE蛋白、VLS编码肽的合成以及抗原性的体外测试 将这些生物分子与患者抗血清进行分析，以确定最广泛反应的目标分子。 具体目标 3 (SA3) 将重点关注 VlsE 特异性单克隆抗体和 F(ab) 片段的生成 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 (89Zr) 和镓 68 (68Ga)。这些物质的体外免疫反应性 将用表达 VlsE 的 BBsl 以及对照的几种菌株来检测放射免疫缀合物 革兰氏阴性菌和革兰氏阳性菌。最终，我们相信该提案可能会产生 对莱姆病的基础科学和临床治疗产生变革性影响。在实验室里， 在莱姆病小鼠模型的开发过程中，针对莱姆病的放射性示踪剂可能是一种有价值的研究工具。 疾病和 Bbsl 靶向治疗的评估。更重要的是，在临床上，针对 VlsE 的 放射性药物可能被证明是一种有用的诊断工具，可以帮助识别患有活动性放射性药物的患者 感染和监测患者对治疗反应的宝贵治疗诊断工具。