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.

毛霉病是侵袭性真菌感染中最致命的一种。毛霉病最常发生在 接受化疗的恶性血液病患者，接受过造血治疗的患者 干细胞移植或糖尿病患者。改进的诊断是最常见的未被注意到的问题 毛霉病患者的治疗需要。治疗的延误增加了由癌症引起的死亡率 已经很高了，47%到83%。与其他侵袭性真菌感染不同，目前还没有已知的真菌生物标记物 毛霉病的诊断。然而，在我们的初步研究中，一种单抗(MAb2DA6) 产生的产物与毛霉目的细胞壁的呋喃甘露聚糖具有很高的反应性。第一代免疫测定法 由单抗2DA6产生，在血清、尿液、支气管肺泡液和感染组织中发现呋喃甘露聚糖 毛霉病的临床相关小鼠模型以及人类毛霉病患者的血浆和尿液中的毛霉病。 其目标是一种利用血浆或尿液快速诊断早期毛霉病的免疫分析方法。目标是 人群是指糖尿病或使用有效的免疫抑制药物导致 毛霉病的发病率急剧增加。该方法是一种免疫分析方法，用于检测是否存在 呋喃甘露聚糖，一种细胞壁碳水化合物，由许多产生毛霉病的接合菌所共有。这个 产品将是一种快速、廉价和易于使用的侧向流动免疫分析(LFIA)。 有四个具体目标。目标1将确认mAb2DA6在各种接合菌中的反应性 产生毛霉病。目的优化免疫分析法检测呋喃甘露聚糖的标本处理方法。 目标3将确定最佳检测灵敏度和特异度所需的免疫检测极限 从毛霉病或曲霉病患者身上收集的具有良好特征的前瞻性样本，以及 控制，而不是感染病人。Aim 4将构建一种先进的LFIA原型，以满足早期检测的截止日期 毛霉菌病的特异性诊断。 这项提议解决了对一种日益常见和致命的机会性真菌的严重未得到满足的需求 感染。该检测的临床应用和市场规模将与目前可用的免疫分析方法相同 侵袭性曲霉病的诊断，因为毛霉病是对 疑似侵袭性曲霉病。这项研究是有史以来第一次展示和利用一种分泌真菌 毛霉病诊断的生物标志物。项目初步结果，加上良好接受的临床应用 针对细胞壁甘露聚糖的其他免疫分析在诊断侵袭性真菌方面取得了商业上的成功 疾病，使得商业成功的可能性非常高。