One of the primary challenges in therapeutic development for brain diseases has been the need for penetration across the blood-brain barrier (BBB). Until recently, clinical trials have focused exclusively on small molecule drugs capable of freely crossing cellular membranes and entering the brain parenchyma. Because of the widespread penetration of these agents, defining their tissue pharmacokinetics (PK) is challenging and frequently complicated by interaction of these drugs with multiple enzymatic, metabolic, and signaling cascades. Moreover, in the absence of well validated biomarkers to ensure target engagement, adequate dosing can be difficult to determine, and clinical trials may be conducted without certainty that intended therapeutic mechanisms have been tested.
In contrast, monoclonal antibodies (mAbs), with their extreme specificity, well-defined plasma PK, and potential for molecular imaging to define tissue concentrations, offer the potential to intervene on specific mechanisms with well-defined dosing and duration of target engagement. While these characteristics have helped make mAbs the fastest growing drug class in terms of both new clinical trials and approvals, they have been largely excluded from TBI research due to their inability to cross the BBB. In collaboration with the Tessier laboratory, we are working to develop and optimize novel BBB shuttles, which bind to targets on the cerebrovascular endothelium and transport full length mAbs into the brain parenchyma.