Identification of variable lymphocyte receptors that can target therapeutics to pathologically exposed brain extracellular matrix

• Type of Material: Article
• Authors: Benjaimin J. Umlauf, University of Wisconsin; Paul A. Clark, University of Wisconsin; Jason M. Lajoie, University of Wisconsin; Julia V. Georgieva, University of Wisconsin; Samantha Bremner, University of Wisconsin; Brantley Herrin, Emory University; John S. Kuo, University of Wisconsin; Eric V. Shusta, University of Wisconsin
• Language: English
• Date: 2019-05-15
• Publisher: American Association for the Advancement of Science: Science Advances
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2019 The Authors.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.aau4245
• Title of Journal or Parent Work: Science Advances
• ISSN: 2375-2548
• Volume: 5
• Issue: 5
• Start Page: eaau4245
• End Page: eaau4245
• Grant/Funding Information: This work was supported by NIH grants NS091851 (to E.V.S. and B.R.H.) and NS099158 (to E.V.S.), a Falk Medical Research Trust Catalyst award (to E.V.S. and J.S.K.), and a Defense Threat Reduction Agency grant HDTRA1-15-1-0012 (to E.V.S.).
• Keywords: pathology; circulating blood; blood-brain barrier disruption; extracellular matrix; moieties; variable lymphocyte receptors; P1C10
• Research Categories: Biology, Neuroscience; Health Sciences, Medicine and Surgery

Abstract

Diseases that lead to blood-brain barrier (BBB) disruption will pathologically expose normally inaccessible brain extracellular matrix (ECM) to circulating blood components. Therefore, we hypothesized that brain ECM-targeting moieties could specifically target the disrupted BBB and potentially deliver therapies. Variable lymphocyte receptors (VLRs) that preferentially associate with brain ECM were identified from an immune VLR library via yeast surface display biopanning coupled with a moderate throughput ECM screen. Brain ECM binding of VLR clones to murine and human brain tissue sections was confirmed. After systemic administration, P1C10, the lead brain ECM-targeting VLR candidate, specifically accumulated in brains with mannitol-disrupted BBB and at disrupted BBB regions in two different intracranial glioblastoma models. We also demonstrate P1C10’s ability to deliver doxorubicin-loaded liposomes, leading to significantly improved survival in glioblastoma-bearing mice. Thus, VLRs can be used to selectively target pathologically exposed brain ECM and deliver drug payloads.