Melisa Benard Valle

Project title: Establishing mRNA-based oligoclonal antivenom for coral snake venom neutralization

Host Institution: Technical University of Denmark (DTU)

Host Supervisor: Dr. Andreas Hougaard Laustsen-Kiel

Co-host Institution: Eindhoven University of Technology (TU/e)

Co-host Supervisor: Dr. Roy Van der Meel

Summary project: Coral snake bites account for around 4% of approximately 60,000 snakebites that occur yearly in the Americas and can cause a fatal neurotoxic clinical syndrome if left untreated. The only currently available specific treatments for snakebite envenomation are polyclonal antivenoms made from sera of hyperimmunized animals. These antivenoms have several disadvantages including limited cross-neutralization between snake species, high production costs, and a propensity to cause immunological adverse reactions. Generating neutralizing antibodies (by immunization) against coral snake venoms is complicated by the low proportion and limited immunogenicity of medically important toxins in the venoms. Here, I suggest a novel approach to overcome these limitations, which could rely on using messenger RNA (mRNA) encoding nanobodies as a treatment for
envenomation.
This proposal’s key objectives are: First, I will discover a panel of 5 to 10 recombinant monoclonal nanobodies (VHH) with broadly-neutralizing properties against coral snake venoms. I will generate monoclonal nanobodies linked to an Fc domain (VHH-Fcs) and screen them in vitro and in vivo to identify the most potent candidates. This will represent an important step towards producing a safer oligoclonal antivenom, overcoming the need for venoms during antivenom production. Second, I will evaluate nanobody-encoding mRNAs as envenomation treatment. I will formulate mRNAs encoding the most potent monoclonal VHH-Fcs in lipid nanoparticles (LNPmRNA) and evaluate these as treatment for snakebite envenomation in a mouse model. The knowledge and methods hereby developed will provide the basis for a new generation of mRNAbased treatments which could also have several applications beyond envenomation.