Development of NPC1-targeting nanobodies against filovirus infections summary filoviruses, including ebola (ebov), sudan (sudv), and marburg (marv) viruses, are highly lethal pathogens with fatality…

The National Institute of Allergy and Infectious Diseases awarded Nanoli Therapeutics LLC $300,000 on August 10, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop NPC1-targeting nanobodies against filovirus infections.

Nanoli will develop small-domain antibodies derived from camelids to treat infections caused by Ebola, Sudan, and Marburg viruses. The work focuses on creating nanobodies that target NPC1, the intracellular receptor that filoviruses use to enter human cells, alongside nanobodies blocking viral glycoprotein. This dual-targeting approach is designed to ensure specificity for virus-infected cells while minimizing effects on uninfected cells. The research objectives include generating and screening NPC1-targeting nanobodies from alpacas, adapting those nanobodies for animal models, and optimizing their structure and potency for human therapeutic use. Nanobodies have been selected as the therapeutic platform because they are highly effective, broadly neutralizing, easy to produce and store, can be administered intranasally, and are safe for human use.

The award addresses a significant public health gap: while one vaccine and two antibody treatments exist for Ebola virus, no approved vaccines or treatments are available for Sudan or Marburg viruses, both of which carry fatality rates between 44 percent and 73 percent.

Performance occurs in Minneapolis, Minnesota from the award date through July 31, 2028.

Development of NPC1-targeting nanobodies against filovirus infections summary filoviruses, including ebola (ebov), sudan (sudv), and marburg (marv) viruses, are highly lethal pathogens with fatality rates ranging from 44% to 73%. With known or potential animal reservoirs, these viruses are likely to persist in human populations long term. While one vaccine and two antibody treatments exist for ebov, their effectiveness, accessibility, and antiviral spectrum remain limited. Currently, no approved vaccines or treatments are available for sudv or marv, highlighting the urgent need for new therapeutics. Our research focuses on developing nanobody-based antiviral treatments for filoviruses. Nanobodies are small, single-domain antibodies derived from camelids. They are highly effective, broadly neutralizing, and easy to produce, store, and transport. They can also be administered intranasally and are safe for human use. Our team has previously developed nanobodies targeting sars-COV-2 and filoviruses and pioneered a rapid, structure-guided adaptation method to optimize nanobodies against emerging viral variants. Filoviruses infect human cells by using their glycoprotein (GP) to bind NPC1 (HNPC1), a receptor inside endosomes. Our current nanobodies block GP to prevent viral entry. In this project, we aim to develop nanobodies that target NPC1 itself. Since NPC1 is intracellular and plays a role in cholesterol metabolism, we will design bispecific nanobodies that target both GP and NPC1. This dual-targeting approach ensures specificity for virus-infected cells while minimizing effects on uninfected cells. Our research has three key objectives: (i) develop and optimize HNPC1-targeting nanobodies. We will generate and screen nanobodies from alpacas, selecting those that most effectively block filovirus GP from binding to HNPC1. (II) adapt NPC1-targeting nanobodies for animal models. Before human trials, treatments must be tested in animals. Using our recently developed structure- guided in vitro evolution approach, we will engineer nanobodies to recognize NPC1 from mice, guinea pigs, and non-human primates for preclinical studies. (III) create bispecific nanobodies targeting both GP and NPC1. By combining NPC1-targeting nanobodies with GP-targeting nanobodies, we aim to enhance selectivity and potency. These bispecific nanobodies will be tested against filovirus pseudoviruses to evaluate their ability to neutralize filovirus GP-mediated viral entry. Beyond this project, the most promising nanobody candidates will be tested against authentic filoviruses and evaluated for safety and efficacy in animal models. In SUM, guided by structural biology and leveraging the unique properties of nanobodies, this project aims to develop potent, broad-spectrum, safe, cost-effective, and accessible treatments for filoviruses. In addition to addressing a critical GAP in global health and national security, this research will advance nanobody technology and potentially lead to new therapies for other viruses and human diseases.