Immunoassay for early diagnosis of mucormycosis

毛霉菌病早期诊断的免疫分析

• 批准号: 9912719
• 负责人: Amanda Burnham-Marusich
• 金额: $ 29.8万
• 依托单位: DXDISCOVERY, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-11 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912719
• 关键词: Address; Alveolar; Antifungal Agents; Antigens; Ascomycota; Aspergillosis; Aspergillus; Binding; Biological Assay; Biological Markers; Biological Specimen Banks; Body Fluids; Candida; Candidiasis; Carbohydrates; Cell Wall; Class Zygomycetes; Clinical; Coupled; Detection; Diabetes Mellitus; Diagnosis; Diagnostic; Diagnostic tests; Differential Diagnosis; Disease; Early Diagnosis; Economics; Enzyme-Linked Immunosorbent Assay; Generations; Goals; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Histoplasma; Histoplasmosis; Human; Immunoassay; Individual; Infection; Laboratories; Lateral; Liquid substance; Literature; Mannans; Monoclonal Antibodies; Mucorales; Mucormycosis; Mycoses; Patients; Pharmaceutical Preparations; Phase; Plant Roots; Plasma; Probability; Reporting; Route; Sampling; Sensitivity and Specificity; Serum; Solid; Specimen; Target Populations; Testing; Tissues; Urine; base; chemotherapy; clinically relevant; commercialization; fungus; galactomannan; improved; innovation; mortality; mouse model; phase 1 study; phase 2 testing; polyglucosan; pre-clinical; prospective; prototype; rapid diagnosis; research clinical testing; success

Mucormycosis is one of the deadliest of the invasive fungal infections. Mucormycosis occurs most often in patients with hematological malignancies undergoing chemotherapy, patients who have received hematopoietic stem cell transplants or patients with diabetes mellitus. Improved diagnosis is the most frequently noted unmet need for management of the mucormycosis patient. Delays in treatment increase the mortality rate from an already high 47% to 83%. Unlike other invasive fungal infections, there has been no known fungal biomarker for diagnosis of mucormycosis. However, in our preliminary studies, a monoclonal antibody (mAb 2DA6) was produced that has high reactivity with cell wall fucomannan of the Mucorales. A first-generation immunoassay produced from mAb 2DA6 found fucomannan in serum, urine, broncho alveolar fluid and infected tissue from clinically relevant mouse models of mucormycosis and in plasma and urine from human cases of mucormycosis. The goal is an immunoassay that uses plasma or urine to rapidly diagnose early-stage mucormycosis. The target population is individuals for whom diabetes mellitus or use of potent immunosuppressive drugs has led to a dramatic increase in the occurrence of mucormycosis. The approach is an immunoassay for the presence of fucomannan, a cell wall carbohydrate that is shared by the many Zygomycetes that produce mucormycosis. The product will be a lateral flow immunoassay (LFIA) that is rapid, inexpensive, and easy to use. There are four Specific Aims. Aim 1 will confirm reactivity of mAb 2DA6 across the various Zygomycetes that produce mucormycosis. Aim 2 will optimize specimen treatment for detection of fucomannan by immunoassay. Aim 3 will identify the immunoassay limit of detection needed for optimal assay sensitivity and specificity using well characterized, prospectively collected samples from patients with mucormycosis or aspergillosis, as well as control, not infected patients. Aim 4 will construct an advanced prototype LFIA that meets assay cutoffs for early and specific diagnosis of mucormycosis. This proposal addresses a critical unmet need for an increasingly common and fatal opportunistic fungal infection. Clinical use and market size for the test would be identical to currently available immunoassays for diagnosis of invasive aspergillosis because mucormycosis is on the differential diagnosis for patients with suspected invasive aspergillosis. The study is the first ever to demonstrate and exploit a secreted fungal biomarker for diagnosis of mucormycosis. Project preliminary results, coupled with the well-accepted clinical use and commercial success of other immunoassays that target cell wall mannans for diagnosis of invasive fungal disease, make the probability for commercial success very high.

毛霉菌病是最致命的侵袭性真菌感染之一。毛霉菌病最常发生在 正在接受化疗的血液系统恶性肿瘤患者、接受过造血治疗的患者 干细胞移植或糖尿病患者。改进诊断是最常被注意到的未满足的问题 需要对毛霉菌病患者进行管理。延误治疗会增加死亡率 已经高达 47% 至 83%。与其他侵袭性真菌感染不同，目前尚无已知的真菌生物标志物 毛霉菌病的诊断。然而，在我们的初步研究中，单克隆抗体（mAb 2DA6） 产生的产物与毛霉目细胞壁岩藻甘露聚糖具有高反应性。第一代免疫分析 由 mAb 2DA6 产生的岩藻甘露聚糖存在于血清、尿液、支气管肺泡液和感染组织中 临床相关的毛霉菌病小鼠模型以及来自人类毛霉菌病病例的血浆和尿液。 目标是使用血浆或尿液进行免疫测定来快速诊断早期毛霉菌病。目标 人群是指患有糖尿病或使用强效免疫抑制药物导致病情恶化的个体 毛霉菌病的发生急剧增加。该方法是一种免疫测定法来检测是否存在 岩藻甘露聚糖是一种细胞壁碳水化合物，是许多产生毛霉菌病的接合菌共有的。这 该产品将是一种快速、廉价且易于使用的侧流免疫分析 (LFIA)。 有四个具体目标。目标 1 将确认 mAb 2DA6 在各种接合菌中的反应性 产生毛霉菌病。目标 2 将优化通过免疫分析检测岩藻甘露聚糖的样本处理。 目标 3 将使用以下方法确定最佳测定灵敏度和特异性所需的免疫测定检测限： 特征明确、前瞻性地从毛霉菌病或曲霉病患者以及 控制，而不是感染患者。目标 4 将构建一个先进的 LFIA 原型，满足早期检测的要求 以及毛霉菌病的具体诊断。 该提案解决了对日益常见和致命的机会性真菌的关键未满足需求 感染。该测试的临床应用和市场规模将与目前可用的免疫测定相同 诊断侵袭性曲霉病，因为毛霉菌病是以下患者的鉴别诊断 疑似侵袭性曲霉病。该研究是有史以来第一个展示和利用分泌真菌的研究 用于诊断毛霉菌病的生物标志物。项目初步结果，加上广泛接受的临床应用 以及其他靶向细胞壁甘露聚糖的免疫测定法在诊断侵入性真菌方面取得的商业成功 疾病，使得商业成功的可能性非常高。