De weg naar innovatieve antilichaam therapie: DNA-gebaseerde toediening en halfleven verlenging in de hersenen van antilichamen

This PhD project addresses challenges of conventional antibody therapy in two ways: 1) DNA-based antibody therapy seeks to administer the encoding nucleotide sequence, rather than the antibody protein. This innovative approach can allow the patient's body to produce its own medicine, and presents an alternative to the complex production and frequent administration of conventional antibody protein therapy. Our research group previously obtained therapeutic proof of concept in mice for several plasmid-encoded antibody formats delivered via intramuscular electroporation, and demonstrated clinical translation in sheep. This PhD project takes a step back and focuses on a series of fundamental research questions, based on in-house experimental observations and unmet needs in the field. These include the necessity to attain a more robust antibody production and increase the application potential. In brief, we thereto aim to better characterize the factors that influence in vivo antibody expression, define the expression and efficacy of more complex DNA-based bispecific antibody formats, and evaluate synthetic formulations in mice and sheep as a delivery alternative for electroporation. The generated insights will improve the fundamental understanding of antibody gene transfer, and pave the way for a better design and broader application of DNA-based antibody therapeutics. 2) Antibody therapies to treat neurological disorders often fail to reach therapeutic levels in the brain due to the presence of the blood-brain barrier. While strategies to actively shuttle antibodies over the blood-brain barrier are already heavily investigated, with transferrin recpetor-mediated transcytosis being the most succesfull so far, this project focusses on increasing the half-life of antibodies in the brain. Once antibodies reach the brain after active shuttling, they are rapidly cleared from the brain. In this project we succesfully increased the brain half-life of antibodies by binding to myelin oligodendrocyte glycoprotein, an abundant brain specific protein. We reported the discovery of nanobodies binding to myelin oligodendrocyte glycoprotein, which when fused to antibodies that shuttle the blood-brain barrier through receptor-mediated transcytosis, decrease the brain efflux of the fused antibodies, resulting in significantly increased brain half-life and prolonged therapeutic effects.