| First Author | Arguello A | Year | 2022 |
| Journal | J Exp Med | Volume | 219 |
| Issue | 3 | PubMed ID | 35226042 |
| Mgi Jnum | J:342207 | Mgi Id | MGI:7257716 |
| Doi | 10.1084/jem.20211057 | Citation | Arguello A, et al. (2022) Molecular architecture determines brain delivery of a transferrin receptor-targeted lysosomal enzyme. J Exp Med 219(3):e20211057 |
| abstractText | Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis across the BBB. Here, we characterized the pharmacological behavior of two distinct TfR-targeted platforms fused to iduronate 2-sulfatase (IDS), a lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared the relative brain exposures and functional activities of both approaches in mouse models. IDS fused to a moderate-affinity, monovalent TfR-binding enzyme transport vehicle (ETV:IDS) resulted in widespread brain exposure, internalization by parenchymal cells, and significant substrate reduction in the CNS of an MPS II mouse model. In contrast, IDS fused to a standard high-affinity bivalent antibody (IgG:IDS) resulted in lower brain uptake, limited biodistribution beyond brain endothelial cells, and reduced brain substrate reduction. These results highlight important features likely to impact the clinical development of TfR-targeting platforms in MPS II and potentially other CNS diseases. |
