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CD98hc is a target for brain delivery of biotherapeutics

Author

Listed:
  • 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
    University of California San Diego)

  • Marie Blanchette

    (University of California San Diego
    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
    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
    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.
    University of Minnesota)

  • Ryan J. Watts

    (Denali Therapeutics, Inc.)

  • Y. Joy Yu Zuchero

    (Denali Therapeutics, Inc.)

  • Mihalis S. Kariolis

    (Denali Therapeutics, Inc.)

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.

Suggested Citation

  • 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. Ton, 2023. "CD98hc is a target for brain delivery of biotherapeutics," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40681-4
    DOI: 10.1038/s41467-023-40681-4
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    Cited by:

    1. Timothy F. Shay & Seongmin Jang & Tyler J. Brittain & Xinhong Chen & Beth Walker & Claire Tebbutt & Yujie Fan & Damien A. Wolfe & Cynthia M. Arokiaraj & Erin E. Sullivan & Xiaozhe Ding & Ting-Yu Wang , 2024. "Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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