Paper

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

Troyer, Matthew D., Solanoy, Hilda, Gunasekaran, Kannan, Duque, Joseph, Damo, Lorna A., Pizzo, Michelle E., Chau, Roni, Ullman, Julie C., Wang, Junhua, Shan, Lu, Liang, Nicholas, Diaz, Dolores, Thomsen, Elliot R., Dugas, Jason C., Fang, Meng, Lewcock, Joseph W., Henry, Anastasia G., Watts, Ryan J., Chan, Darren, Nguyen, Hoang N., Scearce-Levie, Kimberly, Kariolis, Mihalis S., Thorne, Robert G., Calvert, Meredith E. K., Arguello, Annie, Kim, Do Jin, Tsogtbaatar, Buyankhishig, Henne, Kirk R., Harris, Jeffrey M., Dennis, Mark S., Sanchez, Pascal E., Lopez, Isabel A., Giese, Tina, Mahon, Cathal S., Earr, Timothy

2021

Overview

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. Brain delivery, biodistribution and pharmacodynamics of a lysosomal enzyme fused to a moderate-affinity transferrin receptor-directed blood-brain barrier enzyme transport vehicle are superior to a traditional high-affinity anti-TfR monoclonal antibody fusion.

• Publisher: Cold Spring Harbor Laboratory
• Subject: Neuroscience