Fc-engineered Large Molecules Targeting Blood-brain Barrier Transferrin Receptor and CD98hc Have Distinct Central Nervous System and Peripheral Biodistribution

Overview

Journal Nat Commun

Specialty Biology

Date 2025 Feb 20

PMID 39979268

Authors

Nathalie Khoury

Michelle E Pizzo

Claire B Discenza

David Joy

David Tatarakis

Mihail Ivilinov Todorov

Moritz Negwer

Connie Ha

Gabrielly L De 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 Erturk

Robert G Thorne

Meredith E K Calvert

Y Joy Yu Zuchero

Affiliations

Soon will be listed here.

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 (ATV and ATV) compared to control IgG. Mouse whole-body tissue clearing reveals distinct organ localization for each molecule. In the brain, ATV and ATV 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, ATV and ATV exhibit broad and unique parenchymal cell-type distribution. Finally, we profile in detail brain region-specific biodistribution of ATV in cynomolgus monkey brain and spinal cord. Taken together, this in-depth multiscale characterization will guide platform selection for therapeutic targets of interest.

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