CD98 (SLC3A2) as a novel target for receptor-mediated transcytosis at the BBB

Biological drugs over the last decade or so have revolutionised treatment options for a number of diseases. This revolution in treatments means that for new molecular entities that are licensed for use in humans in one given year, over 50% are now biological drugs. However the blood-brain barrier (BBB) has restricted their use in CNS disorders. This is due to the fact that the BBB restricts the penetration of the biological drug due to the tight physical barrier that it forms, thus separating the brain from the blood stream. An example biological entity that has this issue are monoclonal antibodies. For example the concentration that is able to penetrate to the brain is ~0.1 to 0.3% compared to the blood. This restricts their application for CNS disorders.

A number of ways round this major problem are being investigated by lab groups around the world. A recent study by the Watts lab group has been published in the Journal Neuron and is entitled “Discovery of Novel Blood-Brain Barrier Targets to Enhance Brain Uptake of Therapeutic Antibodies”1. Using a transcriptomic and proteomic approaches they identify three new novel targets for bispecific antibodies that are able to get through the BBB by a receptor-mediated transcytosis pathway. The best of these three is CD98 (SLC3A2) that forms a heterodimer with LAT1 (SLC7A5) at the BBB. LAT1 is a transporter of neutral amino acids and a number of pharmaceutical drugs (gabapentin, L-DOPA). This is a very interesting finding for CD98 and in the long term with additional validation it could be a novel way for getting monoclonal antibodies through the BBB and into the brain.

References 1 Zuchero, Y. J. et al. Discovery of Novel Blood-Brain Barrier Targets to Enhance Brain Uptake of Therapeutic Antibodies. Neuron 89, 70-82, doi:10.1016/j.neuron.2015.11.024 (2016).