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

ABSTRACT: 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.

SUBMITTER: Erster O

PROVIDER: S-EPMC3412904 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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

Erster Oran O Thomas Jerry M JM Hamzah Juliana J Jabaiah Abeer M AM Getz Jennifer A JA Schoep Tobias D TD Hall Sejal S SS Ruoslahti Erkki E Daugherty Patrick S PS

Journal of controlled release : official journal of the Controlled Release Society 20120523 3

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 ...[more]

PMID: 22634092

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

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

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