CD98hc is a target for brain delivery of biotherapeutics
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Published:2023-08-19
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Chew Kylie S., Wells Robert C., Moshkforoush Arash, Chan Darren, Lechtenberg Kendra J., Tran Hai L.ORCID, Chow JohannORCID, Kim Do Jin, Robles-Colmenares Yaneth, Srivastava Devendra B., Tong Raymond K., Tong Mabel, Xa Kaitlin, Yang Alexander, Zhou Yinhan, Akkapeddi Padma, Annamalai Lakshman, Bajc Kaja, Blanchette Marie, Cherf Gerald Maxwell, Earr Timothy K., Gill Audrey, Huynh David, Joy DavidORCID, Knight Kristen N., Lac Diana, Leung Amy Wing-Sze, Lexa Katrina W., Liau Nicholas P. D., Becerra Isabel, Malfavon Mario, McInnes Joseph, Nguyen Hoang N.ORCID, Lozano Edwin I., Pizzo Michelle E.ORCID, Roche Elysia, Sacayon Patricia, Calvert Meredith E. K., Daneman Richard, Dennis Mark S., Duque Joseph, Gadkar Kapil, Lewcock Joseph W.ORCID, Mahon Cathal S., Meisner René, Solanoy Hilda, Thorne Robert G., Watts Ryan J., Zuchero Y. Joy Yu, Kariolis Mihalis S.ORCID
Abstract
AbstractBrain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATVCD98hc that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference71 articles.
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