Renal Molecular Imaging of Mesangial Cell Function with Tc-99m-Tilmanocept

使用 Tc-99m-Tilmanocept 对系膜细胞功能进行肾脏分子成像

• 批准号: 10375348
• 负责人: CHARLES GINSBERG
• 金额: $ 62.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375348
• 关键词: Adverse event; Albuminuria; Binding; Biodistribution; Biological Markers; Bladder; Blood; Cell physiology; Cell surface; Chemicals; Chronic Kidney Failure; Clinical; Clinical Trials; Clinical Trials Design; Clinical trial protocol document; Creatinine; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Diagnosis; Diagnostic; Diagnostic tests; Discipline of Nuclear Medicine; Disease; Disease model; Dose; Drug Kinetics; Early Diagnosis; Early treatment; Effective Renal Plasma Flow; European; Evaluation; Future; Glomerular Filtration Rate; Glomerular Mesangial Cell; Half-Life; Heart; Hepatocyte; Histologic; Human; Hypertension; Image; Individual; International; Intervention Trial; Intravenous; Journals; Kidney; Kidney Diseases; Kinetics; Laboratories; Laboratory Study; Liver; Molecular; Motivation; Pathology; Patients; Periodicity; Persons; Phase I Clinical Trials; Plasma; Positron-Emission Tomography; Prevalence; Protocols documentation; Publishing; Radiolabeled; Radiopharmaceuticals; Rattus; Renal Hypertension; Risk; Safety; Sampling; Scanning; Serum; Specificity; Surface; Technetium 99m; Testing; Therapeutic Intervention; Time; Urine; base; db/db mouse; design; diabetic; diabetic patient; drug development; first-in-human; glomerular filtration; high risk; imaging agent; imaging biomarker; kidney cortex; kidney imaging; kidney medulla; macrophage; mesangial cell; microPET; molecular imaging; nuclear imaging; open label; phase I trial; radiation absorbed dose; research clinical testing; single photon emission computed tomography; standard of care; tool

In 2017 the International Diabetes Federation estimated that the worldwide prevalence of diabetes would increase from 415 million in 2015 to 642 million in 2040. Approximately 40% of individuals with diabetes develop diabetic nephropathy (DN). Twenty percent of these individuals do not follow the typical path toward chronic kidney disease, which is a slow multi-decade increase in albuminuria and serum creatinine, the current standard-of-care for surveillance of chronic kidney disease (KD). Consequently, there is an unmet clinical need for routine surveillance during the first decade of chronic KD. We propose external imaging of mesangial cell function as a biomarker for diabetic nephropathy. Our reasoning is based on the following. Mesangial cell matrix (MCM) expansion is a histologic hallmark of diabetic nephropathy, which precedes the reduction of a patient’s glomerular filtration rate or increase in albuminuria. Additionally, all the clinical manifestations of diabetic nephropathy are highly correlated with MCM expansion. There currently does not exist an imaging, serum, or urine biomarker that is sensitive to mesangial cell function. Current imaging agents and biomarkers are only sensitive to glomerular filtration, effective renal plasma flow, or albuminuria, which are altered late in the disease when therapeutic intervention is not effective. We propose a Phase 1 clinical trial of Tc-99m-tilmanocept, which accumulates in the liver and kidneys. The molecular mechanism is binding to CD206, which resides on the cell surface of fixed macrophages within the liver and mesangial cells within the kidney. We present preliminary data consisting of human SPECT/CT and rat microPET images of renal cortex. Additionally, we present evidence of sensitivity to MCM expansion via Tc- 99m-tilmanocept dynamic imaging of db/db mice, an accepted disease model of diabetic nephropathy. We propose an open-label study to investigate the biodistribution at two dose levels (2.0 & 20 nmol) of Tc- 99m-tilmanocept. We will study 5 groups at each dose (10 subjects each): 1) Advance DN, 2) early DN, 3) diabetes with no kidney disease, 4) advanced hypertension (HTN) with KD, and 5) HTN without KD. The study will include a 30-min dynamic followed be a 30-min kidney SPECT/CT, and periodic blood and urine sampling. Dynamic imaging will yield plasma clearance half-lifes, and liver and kidney accumulation rates; SPECT/CT will yield SUVs for the heart, liver, renal cortex, renal medulla. We will also calculate urinary bladder accumulation. We expect the renograms and biodistribution data to reflect the following pathology: Group 1, severe MCM expansion; G2, mild MCM expansion; G3 & G5, no MCM expansion; and G4, low MCM expansion. This study is the necessary first step toward FDA-approval of Tc-99m-tilmancoept as a kidney imaging agent. The study will also provide evidence of imaging sensitivity to MCM expansion in DN patients, and insensitivity to patients with HTN. This senerio will be required if Tc-99m-tilmanocept renograms as “first-line” diagnostic test for diabetic patients.

2017年，国际糖尿病联合会估计，全球糖尿病患病率将 糖尿病患者将从 2015 年的 4.15 亿增加到 2040 年的 6.42 亿。约 40% 的人患有糖尿病 发展为糖尿病肾病（DN）。其中百分之二十的人没有遵循典型的道路 慢性肾脏病是白蛋白尿和血清肌酐数十年来缓慢增加的疾病，目前 慢性肾脏病（KD）监测的护理标准。因此，存在未满足的临床需求 用于慢性川崎病最初十年的常规监测。 我们建议将系膜细胞功能的外部成像作为糖尿病肾病的生物标志物。我们的 推理基于以下内容。系膜细胞基质（MCM）扩张是糖尿病的组织学标志 肾病，先于患者肾小球滤过率降低或蛋白尿增加。 此外，糖尿病肾病的所有临床表现均与MCM扩张高度相关。 目前不存在对系膜细胞敏感的成像、血清或尿液生物标志物 功能。目前的显像剂和生物标志物仅对肾小球滤过敏感，有效肾 血浆流量或白蛋白尿，在疾病晚期当治疗干预无效时发生改变。 我们建议对 Tc-99m-tilmanocept 进行 1 期临床试验，该药物在肝脏和肾脏中积累。这 分子机制是与 CD206 结合，CD206 位于固定巨噬细胞的细胞表面。 肝脏和肾脏内的系膜细胞。我们提供的初步数据包括人类 SPECT/CT 和 大鼠肾皮质的 microPET 图像。此外，我们还提供了通过 Tc- 对 MCM 扩展敏感的证据 db/db 小鼠的 99m-tilmanocept 动态成像，这是一种公认​​的糖尿病肾病疾病模型。 我们提出了一项开放标签研究来调查 Tc- 两个剂量水平（2.0 和 20 nmol）的生物分布 99m-替马诺西普。我们将在每个剂量下研究 5 组（每组 10 名受试者）：1) 晚期 DN，2) 早期 DN，3) 无肾脏疾病的糖尿病，4) 伴有 KD 的晚期高血压 (HTN)，以及 5) 不伴有 KD 的高血压。研究 将包括 30 分钟动态检查、随后 30 分钟肾脏 SPECT/CT 检查以及定期血液和尿液采样。 动态成像将得出血浆清除半衰期以及肝脏和肾脏蓄积率； SPECT/CT 将 产生心脏、肝脏、肾皮质、肾髓质的 SUV。我们还将计算膀胱蓄积量。 我们期望肾图和生物分布数据反映以下病理：第 1 组，严重 MCM 扩张; G2，轻度MCM扩张； G3&G5，无MCM扩展； G4，低MCM扩展。 这项研究是 FDA 批准 Tc-99m-tilmancoept 作为肾脏成像药物的必要的第一步 代理人。该研究还将提供 DN 患者中 MCM 扩张的影像学敏感性证据，以及 对高血压患者不敏感。如果 Tc-99m-tilmanocept 肾图作为“一线”，则需要此高级 糖尿病患者的诊断测试。