Non-invasive Brain Drug Delivery

The BBB is a bottleneck for the neuropharmaceutical industry as the large majority of brain drugs cannot cross the barrier and enter the brain. Noninvasive drug delivery strategies that consist of antibody targeting of endogenous BBB molecular transport systems hold considerable promise. After conjugation to drug payloads that can include small molecules, proteins, or DNA therapeutics, these antibodies can act as molecular Trojan horses and allow noninvasive transfer of drug cargo from blood into brain. The receptor of choice is one that normally functions in the transport of nutrients from the blood to the brain. Examples include the transferrin and insulin receptors. Like the natural ligand, the antibody triggers transcytosis for drug delivery to the brain. The drug cargo conjugated to the antibody essentially piggybacks across the cellular barrier as an artificial substrate.

In order to find novel antibody-transporter systems that could prove more efficient at mediating drug uptake into the brain, we have developed a novel combinatorial screening strategy that merges yeast antibody surface display technology with BBB endothelial cells for the identification of BBB targeting antibodies. Using this novel high-throughput selection and analysis strategy, we have mined a large nonimmune human antibody library for BBB-binding antibodies. To date, 34 unique antibodies have been identified, and detailed characterization of the recovered antibodies has revealed that these antibodies avidly bind the plasma membranes of brain endothelial cells and in some instances can internalize into the intracellular compartment. These novel internalizing antibodies therefore may have the potential to allow blood-to-brain transfer of a wide range of pharmaceuticals