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

Autor:	Arguello A; Denali Therapeutics Inc., South San Francisco, CA., Mahon CS; Denali Therapeutics Inc., South San Francisco, CA., Calvert MEK; Denali Therapeutics Inc., South San Francisco, CA., Chan D; Denali Therapeutics Inc., South San Francisco, CA., Dugas JC; Denali Therapeutics Inc., South San Francisco, CA., Pizzo ME; Denali Therapeutics Inc., South San Francisco, CA., Thomsen ER; Denali Therapeutics Inc., South San Francisco, CA., Chau R; Denali Therapeutics Inc., South San Francisco, CA., Damo LA; Denali Therapeutics Inc., South San Francisco, CA., Duque J; Denali Therapeutics Inc., South San Francisco, CA., Fang M; Denali Therapeutics Inc., South San Francisco, CA., Giese T; Denali Therapeutics Inc., South San Francisco, CA., Kim DJ; Denali Therapeutics Inc., South San Francisco, CA., Liang N; Denali Therapeutics Inc., South San Francisco, CA., Nguyen HN; Denali Therapeutics Inc., South San Francisco, CA., Solanoy H; Denali Therapeutics Inc., South San Francisco, CA., Tsogtbaatar B; Denali Therapeutics Inc., South San Francisco, CA., Ullman JC; Denali Therapeutics Inc., South San Francisco, CA., Wang J; Denali Therapeutics Inc., South San Francisco, CA., Dennis MS; Denali Therapeutics Inc., South San Francisco, CA., Diaz D; Denali Therapeutics Inc., South San Francisco, CA., Gunasekaran K; Denali Therapeutics Inc., South San Francisco, CA., Henne KR; Denali Therapeutics Inc., South San Francisco, CA., Lewcock JW; Denali Therapeutics Inc., South San Francisco, CA., Sanchez PE; Denali Therapeutics Inc., South San Francisco, CA., Troyer MD; Denali Therapeutics Inc., South San Francisco, CA., Harris JM; Denali Therapeutics Inc., South San Francisco, CA., Scearce-Levie K; Denali Therapeutics Inc., South San Francisco, CA., Shan L; Denali Therapeutics Inc., South San Francisco, CA., Watts RJ; Denali Therapeutics Inc., South San Francisco, CA., Thorne RG; Denali Therapeutics Inc., South San Francisco, CA.; Department of Pharmaceutics, University of Minnesota, Minneapolis, MN., Henry AG; Denali Therapeutics Inc., South San Francisco, CA., Kariolis MS; Denali Therapeutics Inc., South San Francisco, CA.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2022 Mar 07; Vol. 219 (3). Date of Electronic Publication: 2022 Feb 28.
DOI:	10.1084/jem.20211057
Abstrakt:	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. Competing Interests: Disclosures: All authors were paid employees of Denali Therapeutics Inc. during the conduct of the study and may have an equity interest in the company. Denali Therapeutics Inc. has filed patent applications related to the subject matter of this paper. No other disclosures were reported. (© 2022 Denali Therapeutics et al.)
Databáze:	MEDLINE
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