Intranasal delivery of antibodies bypasses the blood‐brain barrier and results in significantly higher central nervous system levels than systemic administration
Authors: Boroumand Sam , Kumar Niyanta , Lochhead Jeffrey , Pizzo Michelle , Nehra Geetika , Thorne Robert G. 
Published: June 2021

Passive immunotherapy has become a prominent therapeutic strategy for the treatment of many different neurological disorders. Antibodies can be targeted to the pathogenic proteins of diseases such as Alzheimer's (e.g., beta‐amyloid and phosphorylated tau), Parkinson's (e.g., alpha‐synuclein), and multiple sclerosis (e.g., CD20 marker on B cells). However, delivery of antibodies to the central nervous system (CNS) following systemic administration is significantly impeded as a result of the blood‐brain barrier (BBB) and blood‐cerebrospinal‐fluid barriers (BCSFBs). The intranasal route has been hypothesized to circumvent the BBB and BCSFBs and allow entry into the brain via extracellular pathways along cranial nerves and the perivascular spaces (PVS) of cerebral blood vessels (Thorne et al. Neuroscience 2004 & 2008; Lochhead et al. J. Cereb. Blood Flow & Metab. 2015). Here, we demonstrate the potential of intranasal delivery as a non‐invasive strategy to bypass the BBB and BCSFBs to rapidly target full length immunoglobulin G (IgG) antibodies to the CNS. Quantitative distribution studies of radiolabeled IgG in the CNS of anesthetized rats revealed that intranasal delivery achieved significantly higher antibody levels in both the CNS and CSF compared to systemic delivery at doses resulting in matched blood exposure via either route. Additional experiments exploring the intactness of radiolabeled IgG in the brain following intranasal delivery were conducted to identify the biochemical conditions necessary for IgG intactness in vivo. Finally, by utilizing fluorophore‐labeled IgG, we provide direct evidence of intranasal IgG transport along perineural and perivascular pathways that directly connect the nasal mucosa to CNS target sites. Our results suggest olfactory and trigeminal nerve‐associated perineural channels provide direct pathways to the olfactory bulbs and brainstem, respectively. Once within the brain, further distribution along perivascular spaces of cerebral blood vessels is capable of transporting IgG to widespread regions of the brain. Our findings highlight that the intranasal route can provide a non‐invasive, direct, and rapid method for targeting antibodies to the CNS, bypassing the BBB and BCSFBs in a way that merits further consideration for the treatment of neurological diseases.Support or Funding InformationSupported by the University of Wisconsin‐Madison School of Pharmacy, the Graduate School at the University of Wisconsin, the Michael J. Fox Foundation for Parkinson's Research, the Parkinson's Foundation, the Wisconsin Alzheimer's Disease Research Center (NIH P50‐AG033514), the Wisconsin institute for Clinical and Translational Research (Clinical and Translational Science Award program through the NIH National Center for Advancing Translational Sciences, grant UL1TR000427), and the Wisconsin Alumni Research Foundation grant 135 PRJ82AZ.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.