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

• DOI: 10.1084/jem.20211057
• Publication Date: 2022-02-28T14:32:22Z
• Authors: Annie Arguello; Cathal S. Mahon; Meredith E.K. Cal...; Darren Chan; Jason C. Dugas; Michelle E. Pizzo; Elliot R. Thomsen; Roni Chau; Lorna A. Damo; Joseph Duque; Meng Fang; Tina Giese; Do Jin Kim; Nicholas Liang; Hoang N. Nguyen; Hilda Solanoy; Buyankhishig Tsog...; Julie C. Ullman; Junhua Wang; Mark S. Dennis; Dolores Diaz; Kannan Gunasekaran; Kirk R. Henne; Joseph W. Lewcock; Pascal E. Sanchez; Matthew D. Troyer; Jeffrey M. Harris; Kimberly Scearce-...; Lu Shan; Ryan J. Watts; Robert G. Thorne; Anastasia G. Henry; Mihalis S. Kariolis
• Keywords: 0303 health sciences; Recombinant Fusion Proteins; Brief Definitive Report; Brain; Endothelial Cells; Iduronate Sulfatase; Disease Models, Animal; Mice; 03 medical and health sciences; Blood-Brain Barrier; Receptors, Transferrin; Animals; Tissue Distribution; Lysosomes; Mucopolysaccharidosis II

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.