Immunoassay for early diagnosis of mucormycosis

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.Mucormycosis is one of the deadliest of the invasive fungal infections. The goal of this study is a rapid and simple diagnostic test that can detect early-stage infection. The results will be improved patient survival due to earlier diagnosis and prompt administration of the appropriate antifungal treatment.