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Nanobodies as Immunotherapy for Invasive Fungal Infections

Award Number: R21AI195369
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/30/2028

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Nanobodies as Immunotherapy for Invasive Fungal Infections - PROJECT SUMMARY Invasive aspergillosis is a devastating infection for those with a vulnerable immune system, chronic lung disease, or preceding respiratory viral infection. Despite the current three classes of antifungal drugs (polyenes, azoles, echinocandins), mortality rates surpass 50% for these high-risk populations and have not improved over time with the introduction of newer antifungals. Furthering the issue is drug resistance in Aspergillus spp., which continues to rise, highlighting the critical need for the development of new therapeutic strategies. The use of antibodies as immunotherapy has emerged as a powerful strategy to combat human diseases, including cancer and infectious diseases. Nanobodies are small, monomeric, and comprise the variable antigen-binding portion of camelid heavy-chain-only antibodies. Their size enables advantages to circumvent the major limitations of conventional monoclonal antibodies, highlighting their value as potential therapeutics. The development of nanobodies has led to clinical trials for diseases, including infections. Limited information is known about the therapeutic potential of nanobodies against Aspergillus fumigatus. We leveraged a Saccharomyces cerevisiae library expressing every mathematically possible nanobody and identified a collection of nanobodies with substantial binding to the surface of A. fumigatus. Furthermore, we revealed reduced fungal viability in a subset of nanobodies using a FLARE strain upon binding, suggesting that some nanobodies effectively killed the Af conidia. Our major goal is to examine if nanobodies that bind to cell surface antigens on the A. fumigatus surface can be developed as immunotherapy against invasive aspergillosis. To address our primary objective, we propose the following five specific aims: [1] perform four iterative rounds of selection to define positive nanobody clones that bind to A. fumigatus, [2] identify subsets of clones that either kill A. fumigatus or bind and inhibit growth, [3] define antigen specificity of selected nanobodies, [4] characterize nanobody binding using purified A. fumigatus proteins and in vivo pharmacokinetics and toxicity, and [5] test 10 nanobodies in a mouse model of invasive aspergillosis to determine whether they inhibit pathogenesis. The first two aims will be the focus of the R21 phase of the grant, while the last three aims will be covered during the R33 phase. Our work will identify nanobodies for development into novel therapeutics for invasive aspergillosis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $214,906 )
2026	2026	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	5/8/2026	NEW	$214,906
														Subtotal = $214,906

Grand Total All Awards = $214,906

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Nanobodies as Immunotherapy for Invasive Fungal Infections

Award Number: R21AI195369

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/30/2028

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