Molecular architecture determines brain delivery of a transferrin receptor-targeted lysosomal enzyme

J Exp Med. 2022 Mar 7;219(3):e20211057. doi: 10.1084/jem.20211057. Epub 2022 Feb 28.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Iduronate Sulfatase* / metabolism
  • Iduronate Sulfatase* / pharmacology
  • Lysosomes / metabolism
  • Mice
  • Mucopolysaccharidosis II* / metabolism
  • Receptors, Transferrin* / metabolism
  • Recombinant Fusion Proteins* / metabolism
  • Recombinant Fusion Proteins* / pharmacology
  • Tissue Distribution

Substances

  • Receptors, Transferrin
  • Recombinant Fusion Proteins
  • Iduronate Sulfatase