Development of nanobody-based vectors that cross the blood brain barrier via receptor-mediated transcytosis for brain delivery of imaging or therapeutic agents – NANOVECTOR

Central Nervous System (CNS) diseases are the world’s leading cause of disability and affect over 450 million people, causing disability and suffering. The total annual cost of brain disorders in Europe is in the range of €500-700 billion/year. CNS disease treatments, though essentially palliative, already represent one of the three main therapeutic areas worldwide, close to cardiovascular diseases and oncology.

The brain's blood vessels known as the blood-brain barrier (BBB) limit the delivery of drugs to the CNS. Fewer than 1% of all drugs are pharmacologically active against brain disorders. Most larger therapeutic molecules (peptides, proteins, antibodies, siRNAs) do not cross efficiently the BBB. CNS drug delivery strategies are thus essential to bring drugs and in particular biomolecules to the market. Among these is the development of vector molecules that enhance the delivery of drugs across the BBB via receptor-mediated transport/transcytosis (RMT). Peptides are ideally suited as RMT-based vectors because of their small size, ease and low cost in synthesis. However, they remain sensitive to proteinase cleavage, and high affinity peptides are difficult to develop for some of the target BBB receptors. Antibody- or protein-ligand based vectors have been developed. While endowed with high affinity and prolonged stability, they are bulky, expensive to produce, may be prone to immunogenicity, are often species-specific, which complicates the translational process from pre-clinical to clinical research. There is thus a strong rational to develop alternative vectors that will present the potential, complexity and affinity of natural protein ligands or antibodies, but with minimal size and industrialization cost. In this context, single domain antibodies (nanobodies, Nbs), the smallest recombinant antibody fragments, are emerging as alternatives with a great potential based on their unique structural and functional properties. There is also a clear need for diversification of target receptors at the BBB: none of those targeted to date are specific of brain endothelial cells.

Two Academic Partners (NICN, Partner 1 and CRCM-ATI, Partner 2) and a Biotechnology SME (VECT-HORUS, Partner 3) propose to combine their expertise with the following general objective: build on the grounds of previous consortia supported by the ANR, unique high-level expertise and results already generated by the Partners to develop Nbs that target BBB receptors, in particular BBB specific receptors, involved in RMT, and optimize them as vector shuttles to transport pharmacological agents (imaging and therapeutic agents, notably anticancer drugs) across the BBB into the brain.

The NANOVECTOR project proposes “bio-inspired” technologies in a context of aging population to bring solutions to CNS diseases, biomedical innovation in human health to generate new imaging and therapeutic molecules, with research at the interface between chemistry, molecular and cellular biology, imaging, neurobiology and cancer; it promotes transfer of knowledge between academic and industrial Partners to reinforce French competitiveness in the biomedical sector.

The impact of the NANOVECTOR project is expected at different levels: i) the development of novel vectors with high added value to be patented; ii) improved strategies for CNS targeting and delivery of pharmaceutical agents, in particular biomolecules, opening new avenues for the treatment of CNS diseases; iii) the reinforcement of fruitful scientific and technological interactions between an SME and its academic Partners; iv) the strengthening of a biotechnology company unique in Europe and its position in the competition for CNS drug delivery strategies; v) the local recruitment of young scientists. In summary, the NANOVECTOR project will promote high level multidisciplinary and interdisciplinary interactions between academic and industrial research to challenge major societal and economical needs.