Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, 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.
Cell Chem Biol. 2024 Feb 15;31(2):361-372.e8. doi: 10.1016/j.chembiol.2023.09.008. Epub 2023 Oct 26.
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.
抗体无法穿透血脑屏障 (BBB)，这是其在各种应用中使用的一个关键限制。一种有前途的策略是使用双特异性 BBB 穿梭物来输送 IgG，这涉及将 IgG 融合到第二个亲和配体上，该配体与脑血管内皮细胞靶标结合，并促进穿过 BBB 的转运。尽管存在固有传递和安全挑战，但几乎所有先前的努力都集中在针对转铁蛋白受体 (TfR-1) 的穿梭物上。在这里，我们报告了与 CD98hc 结合的双特异性抗体穿梭物，CD98hc 是大型中性氨基酸转运蛋白 (LAT1) 的重链，可有效将 IgG 转运到大脑中。值得注意的是，与 TfR-1 穿梭物相比，CD98hc 穿梭物使 IgG 在大脑中的半衰期更长，同时由于 CD98hc 在脑实质中的结合有限，因此能够更特异性地靶向，我们针对在神经元和星形胶质细胞上既激动神经元受体 (TrkB) 又靶向其他内源性细胞表面蛋白的 IgG 证明了这一点。
