Immunotherapy

Within the last years, we have developed nanobodies (Nbs) originating from Camelids, murine monoclonal antibodies targeting VAR2CSA and are currently developing Human monoclonal antibodies against VAR2CSA. We are also currently developing Nbs libraries to select Nbs targeting PfEMP1 and conserved proteins present on the surface of asexual and sexual stages of P. falciparum. Nbs are the smallest recombinant antigen-binding domains that can be produced (≈ 15 kDa). They are therefore relatively easy to express in large quantities in bacteria-based heterologous systems. They also present an excellent thermal stability allowing a long shelf life before usage. Furthermore, Nbs have the capability to interact with epitopes present in antigen cavities (cryptic epitopes) that are not accessible by conventional antibodies due to their large size, thus broadening the spectrum of potential parasite-derived molecular targets.

This latter feature is particularly interesting, as P. falciparum antigenic variation considerably restrict the number of relevant targets to design immunotherapeutic tools. Indeed, cryptic epitopes, which are subjected to minor immune pressure, most often display conserved sequences, and could therefore represent exquisite molecular targets for therapeutics. However, since Nbs are devoid of Fc region, they cannot trigger Fc-dependent effector mechanisms, such as antibody-dependent phagocytosis or complement activation (classical pathway).

We conceptualized a novel immunotherapeutic approach aiming at redirecting a pre-existing polyclonal antibody response against Epstein-Barr virus (EBV), which is present in over 95% of the population, towards defined target cells. We recently validated this approach in the oncology field and are currently assessing this technology for a COVID-19 treatment, markedly leading to 2 patents (1 granted, 1 pending). In the context of malaria, the EBV antigen will be coupled to Nbs targeting P. falciparum-derived antigens specifically expressed at the surface of cells infected by asexual or sexual parasite forms.