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.

粘膜菌病是侵入性真菌感染中最致命的一种。粘膜细胞增多最常发生 血液学恶性肿瘤的患者接受化学疗法，接受造血的患者 干细胞移植或糖尿病患者。改进的诊断是最常见的未经诊断 需要治疗粘膜菌病患者。治疗的延迟增加了死亡率 已经很高47％至83％。与其他侵入性真菌感染不同，没有已知的真菌生物标志物 诊断粘膜细胞增多。但是，在我们的初步研究中，单克隆抗体（mAb 2Da6）为 与粘膜的细胞壁fucomannan具有高反应性的产生。第一代免疫测定 由MAB 2DA6产生的发现，在血清，尿液，支气管肺泡液和受感染的组织中发现了Fucomannan 临床相关的粘膜细胞增多小鼠模型，血浆中的血浆和尿液中的肌肉菌病例。 目标是一种免疫测定法，该免疫测定使用血浆或尿液快速诊断早期粘膜菌病。目标 人口是糖尿病或使用有效免疫抑制药物的人 粘膜细胞增多的发生急剧增加。该方法是用于存在的免疫测定 Fucomannan是一种细胞壁碳水化合物，由许多产生粘膜菌病的合子菌共享。这 产品将是横向流量免疫测定（LFIA），快速，廉价且易于使用。 有四个具体目标。 AIM 1将确认MAB 2DA6在各种zygomycetes中的反应性 产生粘膜细胞增多。 AIM 2将通过免疫测定方法优化样品处理以检测Fucomannan。 AIM 3将确定最佳测定敏感性和特异性所需的免疫测定限制 从粘膜菌病或曲霉病患者以及 对照，不是感染的患者。 AIM 4将构建一个高级原型LFIA，该原型符合早期的测定截止 和粘膜病的特定诊断。 该提案解决了对日益普遍和致命的机会真菌的关键需求 感染。测试的临床使用和市场规模与当前可用的免疫测定相同 诊断浸润性曲霉病是由于粘霉菌病在患者的鉴别诊断上 怀疑是侵入性的曲霉病。该研究是有史以来第一个证明和利用分泌的真菌的研究 诊断粘膜菌病的生物标志物。项目初步结果，再加上公认的临床用途 以及其他免疫测定的商业成功，该免疫测定目标细胞壁曼纳斯诊断侵入性真菌 疾病，使商业成功的可能性很高。