Bispecific antibody shuttles targeting CD98hc mediate efficient and long-lived brain delivery of IgGs

Ghasidit Pornnoppadol; Layne G Bond; Michael J Lucas; Jennifer M Zupancic; Yun-Huai Kuo; Boya Zhang; Colin F Greineder; Peter M Tessier

doi:10.1016/j.chembiol.2023.09.008

Bispecific antibody shuttles targeting CD98hc mediate efficient and long-lived brain delivery of IgGs

Cell Chem Biol. 2024 Feb 15;31(2):361-372.e8. doi: 10.1016/j.chembiol.2023.09.008. Epub 2023 Oct 26.

Authors

Ghasidit Pornnoppadol¹, Layne G Bond², Michael J Lucas³, Jennifer M Zupancic⁴, Yun-Huai Kuo¹, Boya Zhang⁵, Colin F Greineder⁶, Peter M Tessier⁷

Affiliations

¹ Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
² Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA; Program in Chemical Biology, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Emergency Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: coling@umich.edu.
⁷ Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA; Program in Chemical Biology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: ptessier@umich.edu.

PMID: 37890480
PMCID: PMC10922565 (available on 2025-02-15)
DOI: 10.1016/j.chembiol.2023.09.008

Abstract

The inability of antibodies to penetrate the blood-brain barrier (BBB) is a key limitation to their use in diverse applications. One promising strategy is to deliver IgGs using a bispecific BBB shuttle, which involves fusing an IgG to a second affinity ligand that engages a cerebrovascular endothelial target and facilitates transport across the BBB. Nearly all prior efforts have focused on shuttles that target transferrin receptor (TfR-1) despite inherent delivery and safety challenges. Here, we report bispecific antibody shuttles that engage CD98hc, the heavy chain of the large neutral amino acid transporter (LAT1), and efficiently transport IgGs into the brain. Notably, CD98hc shuttles lead to much longer-lived brain retention of IgGs than TfR-1 shuttles while enabling more specific targeting due to limited CD98hc engagement in the brain parenchyma, which we demonstrate for IgGs that either agonize a neuronal receptor (TrkB) or target other endogenous cell-surface proteins on neurons and astrocytes.

Keywords: 4F2; BBB; BDNF; SLC3A2; TrkB; astrocyte; blood-brain barrier; neuron; neurotrophin; transferrin receptor.

MeSH terms

Antibodies, Bispecific* / metabolism
Astrocytes / metabolism
Biological Transport
Blood-Brain Barrier / metabolism
Brain* / metabolism

Substances

Antibodies, Bispecific

Abstract

MeSH terms

Substances

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