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

• Published in: Cell chemical biology Vol. 31; no. 2; pp. 361 - 372.e8
• Main Authors: Pornnoppadol, Ghasidit, Bond, Layne G., Lucas, Michael J., Zupancic, Jennifer M., Kuo, Yun-Huai, Zhang, Boya, Greineder, Colin F., Tessier, Peter M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 15.02.2024
• Subjects: 4F2; Antibodies, Bispecific - metabolism; astrocyte; Astrocytes - metabolism; BBB; BDNF; Biological Transport; blood-brain barrier; Blood-Brain Barrier - metabolism; Brain - metabolism; neuron; neurotrophin; SLC3A2; transferrin receptor; TrkB; 4F2; blood-brain barrier; TrkB; BBB; BDNF; neuron; transferrin receptor; SLC3A2; neurotrophin; astrocyte
• ISSN: 2451-9456; 2451-9448; 2451-9456
• DOI: 10.1016/j.chembiol.2023.09.008

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. [Display omitted] •Bispecific antibody shuttles targeting CD98hc result in extended brain retention•CD98hc shuttles delivering untargeted IgGs remain localized to blood vessels•CD98hc shuttles targeting neurons and astrocytes display cell-type specificity•TrkB/CD98hc agonist shuttles demonstrate extended TrkB receptor activation Although the blood-brain barrier largely inhibits brain entry of biologics, Pornnoppadol et al. demonstrated a bispecific antibody shuttle targeting CD98hc for transport of IgGs into the brain and showed that it displays much longer-lived brain retention than transferrin receptor shuttles while selectively targeting different brain cell types.