Fc-engineered large molecules targeting blood-brain barrier transferrin receptor and CD98hc have distinct central nervous system and peripheral biodistribution

Nathalie Khoury, Michelle E. Pizzo, Claire B. Discenza, David Joy, David Tatarakis, Mihail Ivilinov Todorov, Moritz Negwer, Connie Ha, Gabrielly L. Melo, Lily Sarrafha, Matthew J. Simon, Darren Chan, Roni Chau, Kylie S. Chew, Johann Chow, Allisa Clemens, Yaneth Robles-Colmenares, Jason C. Dugas, Joseph Duque, Doris Kaltenecker, Holly Kane, Amy Leung, Edwin Lozano, Arash Moshkforoush, Elysia Roche, Thomas Sandmann, Mabel Tong, Kaitlin Xa, Yinhan Zhou, Joseph W. Lewcock, Ali Ertürk, Robert G. Thorne, Meredith E. K. Calvert () and Y. Joy Yu Zuchero ()
Additional contact information
Nathalie Khoury: Denali Therapeutics, Inc.
Michelle E. Pizzo: Denali Therapeutics, Inc.
Claire B. Discenza: Denali Therapeutics, Inc.
David Joy: Denali Therapeutics, Inc.
David Tatarakis: Denali Therapeutics, Inc.
Mihail Ivilinov Todorov: Deep Piction
Moritz Negwer: Deep Piction
Connie Ha: Denali Therapeutics, Inc.
Gabrielly L. Melo: Denali Therapeutics, Inc.
Lily Sarrafha: Denali Therapeutics, Inc.
Matthew J. Simon: Denali Therapeutics, Inc.
Darren Chan: Denali Therapeutics, Inc.
Roni Chau: Denali Therapeutics, Inc.
Kylie S. Chew: Denali Therapeutics, Inc.
Johann Chow: Denali Therapeutics, Inc.
Allisa Clemens: Denali Therapeutics, Inc.
Yaneth Robles-Colmenares: Denali Therapeutics, Inc.
Jason C. Dugas: Denali Therapeutics, Inc.
Joseph Duque: Denali Therapeutics, Inc.
Doris Kaltenecker: Deep Piction
Holly Kane: Denali Therapeutics, Inc.
Amy Leung: Denali Therapeutics, Inc.
Edwin Lozano: Denali Therapeutics, Inc.
Arash Moshkforoush: Denali Therapeutics, Inc.
Elysia Roche: Denali Therapeutics, Inc.
Thomas Sandmann: Denali Therapeutics, Inc.
Mabel Tong: Denali Therapeutics, Inc.
Kaitlin Xa: Denali Therapeutics, Inc.
Yinhan Zhou: Denali Therapeutics, Inc.
Joseph W. Lewcock: Denali Therapeutics, Inc.
Ali Ertürk: Deep Piction
Robert G. Thorne: Denali Therapeutics, Inc.
Meredith E. K. Calvert: Denali Therapeutics, Inc.
Y. Joy Yu Zuchero: Denali Therapeutics, Inc.

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Blood brain barrier-crossing molecules targeting transferrin receptor (TfR) and CD98 heavy chain (CD98hc) are widely reported to promote enhanced brain delivery of therapeutics. Here, we provide a comprehensive and unbiased biodistribution characterization of TfR and CD98hc antibody transport vehicles (ATVTfR and ATVCD98hc) compared to control IgG. Mouse whole-body tissue clearing reveals distinct organ localization for each molecule. In the brain, ATVTfR and ATVCD98hc achieve enhanced exposure and parenchymal distribution even when brain exposures are matched between ATV and control IgG in bulk tissue. Using a combination of cell sorting and single-cell RNAseq, we reveal that control IgG is nearly absent from parenchymal cells and is distributed primarily to brain perivascular and leptomeningeal cells. In contrast, ATVTfR and ATVCD98hc exhibit broad and unique parenchymal cell-type distribution. Finally, we profile in detail brain region-specific biodistribution of ATVTfR in cynomolgus monkey brain and spinal cord. Taken together, this in-depth multiscale characterization will guide platform selection for therapeutic targets of interest.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-57108-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57108-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-57108-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().