Exit pathways of therapeutic antibodies from the brain and retention strategies

Treating brain diseases requires therapeutics to pass the blood-brain barrier (BBB) which is nearly impermeable for large biologics such as antibodies. Several methods now facilitate crossing or circumventing the BBB for antibody therapeutics. Some of these exploit receptor-mediated transcytosis, others use direct delivery bypassing the BBB. However, successful delivery into the brain does not preclude exit back to the systemic circulation. Various mechanisms are implicated in the active and passive export of antibodies from the central nervous system. Here we review findings on active export via transcytosis of therapeutic antibodies -in particular, the role of the neonatal Fc receptor (FcRn) -and discuss a possible contribution of passive efflux pathways such as lymphatic and perivascular drainage. We point out open questions and how to address these experimentally. In addition, we suggest how emerging findings could aid the design of the next generation of therapeutic antibodies for neurologic diseases.