Armed nanobodies as antimalarial agents

Malaria, the mosquito-borne disease caused by Plasmodium, preys upon the weakest and poorest in developing countries, with >0.5 million yearly fatalities, especially among children. Absent effective vaccines, drug-resistant parasites are on the rise, raising the alarming prospect of incurable malaria. It is therefore imperative that innovative therapies be developed. Plasmodium parasites excel at hiding from the immune system. They are highly polymorphic, express decoy surface proteins, are only exposed in the bloodstream for a short time and exploit the tolerogenic process of erythrocyte clearance to avoid immune responses. Even if uncomplicated, a single malaria infection does not induce long-term protection, and in endemic areas, individuals are typically infected multiple times a year. Repeated infections are associated with increased risks for vascular and neurological damages, such as strokes or heart disease. These antimalarial ARMs recruit naturally occurring circulating polyclonal immunoglobulin, regardless of specificity or isotype, and redirect them to the parasite. This is accomplished by linking a nanobody against the conserved region of the kappa light chain of immunoglobulins, to a nanobody specific for the parasite. This shall induce potent Fc-mediated effector mechanisms against the parasite and release parasite antigens, which in turn should induce a vaccinal effect against all antigens in the parasites. In this project, Le gall will characterize the ability of these constructs to include antibody-dependent cytotoxicity (ADCC) and phagocytosis (ADCP), as well as complement-mediated phagocytosis (CDC). Le gall will compare targets on the parasite itself and targets on the infected erythrocytes in a human model of malaria. To study the expected vaccinal effect, Le gall will make use of engineered rodent models of malaria to study the fate of antigen-specific immune responses and long-term protection against the parasite. It is expected that this novel immunotherapy will reduce disease burden and induce long-lasting immunity against the parasite. Should ARM treatment lead to an in-situ vaccination, the consequences for public health would be significant.

Immunology

Jan 2025 — Dec 2026

$156,640

United States