Dual targeting of transferrin receptor and CD98hc enhances brain exposure of large molecules

Robert C. Wells; Padma Akkapeddi; Darren Chan; David A. Joy; Arash Moshkforoush; Roni Chau; Johann Chow; Gerald Maxwell Cherf; Ellen Y. T. Chien; Allisa J. Clemens; Michelle E. Pizzo; Ahlam N. Qerqez; Tiffany M. Tran; Isabel A. Becerra; Jason C. Dugas; Joseph N. Duque; Timothy Earr; David Huynh; Do Jin Kim; Amy Wing-Sze Leung; Eric Liang; Hoang Ngan Nguyen; Yaneth Robles‐Colmenares; Holly Kane; Elysia Roche; Patricia Sacayon; Kaitlin Xa; Hilda O. Solanoy; Mark S. Dennis; Joseph W. Lewcock

doi:10.1016/j.celrep.2025.116038

NeuroscienceCell ReportsJul 22, 2025

Peer-reviewed journal article

Dual targeting of transferrin receptor and CD98hc enhances brain exposure of large molecules

Robert C. Wells iD, Padma Akkapeddi iD, Darren Chan, David A. Joy iD, Arash Moshkforoush iD, Roni Chau iD, Johann Chow iD, Gerald Maxwell Cherf iD, Ellen Y. T. Chien iD, Allisa J. Clemens, Michelle E. Pizzo iD, Ahlam N. Qerqez iD, Tiffany M. Tran iD, Isabel A. Becerra, Jason C. Dugas iD, Joseph N. Duque iD, Timothy Earr iD, David Huynh, Do Jin Kim iD, Amy Wing-Sze Leung, Eric Liang, Hoang Ngan Nguyen iD, Yaneth Robles‐Colmenares iD, Holly Kane, Elysia Roche, , Kylie S. Chew iD

Abstract

Targeting proteins highly expressed at the blood-brain barrier, including transferrin receptor (TfR) and CD98hc, is a transformative approach enabling more effective brain delivery of biotherapeutics for treatment of neurological diseases. TfR-mediated delivery promotes rapid, high brain uptake, while CD98hc-mediated delivery is slower with more prolonged exposure. Here, we engineer a huIgG Fc domain to bind both TfR and CD98hc to create a dual transport vehicle (TV) platform that drives distinct brain delivery properties. Dual TVs achieve significantly higher brain concentrations than TVs targeting either TfR or CD98hc alone. Modulation of TfR and CD98hc affinities shifts dual TV brain exposure kinetics and biodistribution. Stronger TfR affinity drives faster brain uptake and clearance, while stronger CD98hc affinity yields higher, more sustained concentrations, likely due to CD98hc affinity-dependent reduction in TfR-mediated neuronal internalization. This dual targeting strategy leverages the complementary properties of TfR and CD98hc-mediated brain exposure to increase optionality for brain delivery of biotherapeutics.

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