CD98hc is a target for brain delivery of biotherapeutics

Kylie S. Chew, Robert C. Wells, Arash Moshkforoush, Darren Chan, Kendra J. Lechtenberg, Hai L. Tran, Johann Chow, Do Jin Kim, Yaneth Robles-Colmenares, Devendra B. Srivastava, Raymond K. Tong, Mabel Tong, Kaitlin Xa, Alexander Yang, Yinhan Zhou, Padma Akkapeddi, Lakshman Annamalai, Kaja Bajc, Marie Blanchette, Gerald Maxwell Cherf, Timothy K. Earr, Audrey Gill, David Huynh, David Joy, Kristen N. Knight, Diana Lac, Amy Wing-Sze Leung, Katrina W. Lexa, Nicholas P. D. Liau, Isabel Becerra, Mario Malfavon, Joseph McInnes, Hoang N. Nguyen, Edwin I. Lozano, Michelle E. Pizzo, Elysia Roche, Patricia Sacayon, Meredith E. K. Calvert, Richard Daneman, Mark S. Dennis, Joseph Duque, Kapil Gadkar, Joseph W. Lewcock, Cathal S. Mahon, René Meisner, Hilda Solanoy, Robert G. Thorne, Ryan J. Watts, Y. Joy Yu Zuchero () and Mihalis S. Kariolis ()
Additional contact information
Kylie S. Chew: Denali Therapeutics, Inc.
Robert C. Wells: Denali Therapeutics, Inc.
Arash Moshkforoush: Denali Therapeutics, Inc.
Darren Chan: Denali Therapeutics, Inc.
Kendra J. Lechtenberg: Denali Therapeutics, Inc.
Hai L. Tran: Denali Therapeutics, Inc.
Johann Chow: Denali Therapeutics, Inc.
Do Jin Kim: Denali Therapeutics, Inc.
Yaneth Robles-Colmenares: Denali Therapeutics, Inc.
Devendra B. Srivastava: Denali Therapeutics, Inc.
Raymond K. Tong: Denali Therapeutics, Inc.
Mabel Tong: Denali Therapeutics, Inc.
Kaitlin Xa: Denali Therapeutics, Inc.
Alexander Yang: Denali Therapeutics, Inc.
Yinhan Zhou: Denali Therapeutics, Inc.
Padma Akkapeddi: Denali Therapeutics, Inc.
Lakshman Annamalai: Denali Therapeutics, Inc.
Kaja Bajc: University of California San Diego
Marie Blanchette: University of California San Diego
Gerald Maxwell Cherf: Denali Therapeutics, Inc.
Timothy K. Earr: Denali Therapeutics, Inc.
Audrey Gill: Denali Therapeutics, Inc.
David Huynh: Denali Therapeutics, Inc.
David Joy: Denali Therapeutics, Inc.
Kristen N. Knight: Denali Therapeutics, Inc.
Diana Lac: Denali Therapeutics, Inc.
Amy Wing-Sze Leung: Denali Therapeutics, Inc.
Katrina W. Lexa: Denali Therapeutics, Inc.
Nicholas P. D. Liau: Denali Therapeutics, Inc.
Isabel Becerra: Denali Therapeutics, Inc.
Mario Malfavon: University of California San Diego
Joseph McInnes: Denali Therapeutics, Inc.
Hoang N. Nguyen: Denali Therapeutics, Inc.
Edwin I. Lozano: Denali Therapeutics, Inc.
Michelle E. Pizzo: Denali Therapeutics, Inc.
Elysia Roche: Denali Therapeutics, Inc.
Patricia Sacayon: Denali Therapeutics, Inc.
Meredith E. K. Calvert: Denali Therapeutics, Inc.
Richard Daneman: University of California San Diego
Mark S. Dennis: Denali Therapeutics, Inc.
Joseph Duque: Denali Therapeutics, Inc.
Kapil Gadkar: Denali Therapeutics, Inc.
Joseph W. Lewcock: Denali Therapeutics, Inc.
Cathal S. Mahon: Denali Therapeutics, Inc.
René Meisner: Denali Therapeutics, Inc.
Hilda Solanoy: Denali Therapeutics, Inc.
Robert G. Thorne: Denali Therapeutics, Inc.
Ryan J. Watts: Denali Therapeutics, Inc.
Y. Joy Yu Zuchero: Denali Therapeutics, Inc.
Mihalis S. Kariolis: Denali Therapeutics, Inc.

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Brain 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.

Date: 2023
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Citations: View citations in EconPapers (1)

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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40681-4

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DOI: 10.1038/s41467-023-40681-4

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