In:
Journal of Experimental Medicine, Rockefeller University Press, Vol. 219, No. 3 ( 2022-03-07)
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.
Type of Medium:
Online Resource
ISSN:
0022-1007
,
1540-9538
DOI:
10.1084/jem.20211057
Language:
English
Publisher:
Rockefeller University Press
Publication Date:
2022
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218343-2
detail.hit.zdb_id:
1477240-1