Bi-modular fusion proteins for re-directing a pre-existing Epstein-Barr virus antibody response towards Plasmodium falciparum-infected red blood cells – ARTIC

Despite a significant decrease in number of Plasmodium falciparum-related deaths in recent years, malaria remains a major public health problem. Resistance of parasites to anti-malarial drugs could soon lead to a resurgence of the disease and calls for the need of developing new interventional strategies. We recently conceptualized a novel immunotherapeutic approach aiming at redirecting a pre-existing polyclonal antibody response against Epstein-Barr virus (EBV), which chronically infects over 95% of the population, towards defined target cells to mediate their clearance by immune effectors. As a proof-of-concept, we established that this strategy is efficient against cancer cells. We will here generate bi-modular fusion proteins (BMFPs) able to recruit polyclonal endogenous high-affinity antibodies (anti-EBV) towards P. falciparum-infected erythrocytes. BMFPs will be designed based on an EBV antigen coupled to nanobody-derived binding moieties targeting P. falciparum antigens specifically expressed at the surface of cells infected by asexual or sexual parasite forms. Following generation and screening of nanobody libraries specifically targeting parasite-derived proteins, best binders will be fused to the EBV antigen. The efficacy of the resulting BMFP candidates to recruit immune effector mechanisms and mediate infected erythrocytes’ clearance will be evaluated both in vitro and in vivo. The development of BMFP therapeutics, interfering with parasite pathogenicity and/or transmission, could offer new malaria control alternatives and allow a broader therapy access to individuals infected by P. falciparum in sub-Saharan Africa.