Site-specific targeting of antibody activity in vivo mediated by disease-associated proteases.

Autor: Erster O; Department of Chemical Engineering, University of California, Santa Barbara, CA 93106, USA., Thomas JM, Hamzah J, Jabaiah AM, Getz JA, Schoep TD, Hall SS, Ruoslahti E, Daugherty PS
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2012 Aug 10; Vol. 161 (3), pp. 804-12. Date of Electronic Publication: 2012 May 23.
DOI: 10.1016/j.jconrel.2012.05.035
Abstrakt: As a general strategy to selectively target antibody activity in vivo, a molecular architecture was designed to render binding activity dependent upon proteases in disease tissues. A protease-activated antibody (pro-antibody) targeting vascular cell adhesion molecule 1 (VCAM-1), a marker of atherosclerotic plaques, was constructed by tethering a binding site-masking peptide to the antibody via a matrix metalloprotease (MMP) susceptible linker. Pro-antibody activation in vitro by MMP-1 yielded a 200-fold increase in binding affinity and restored anti-VCAM-1 binding in tissue sections from ApoE⁻/⁻ mice ex vivo. The pro-antibody was efficiently activated by native proteases in aorta tissue extracts from ApoE⁻/⁻, but not from normal mice, and accumulated in aortic plaques in vivo with enhanced selectivity when compared to the unmodified antibody. Pro-antibody accumulation in aortic plaques was MMP-dependent, and significantly inhibited by a broad-spectrum MMP inhibitor. These results demonstrate that the activity of disease-associated proteases can be exploited to site-specifically target antibody activity in vivo.
(Published by Elsevier B.V.)
Databáze: MEDLINE
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