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Characterization of a fusion protein of RGD4C and the ß-lactamase variant for antibody-directed enzyme prodrug therapy

Authors Zhou X, Wang H, Shi P, Meng A

Received 17 December 2013

Accepted for publication 30 January 2014

Published 10 April 2014 Volume 2014:7 Pages 535—541

DOI https://doi.org/10.2147/OTT.S59346

Checked for plagiarism Yes

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Peer reviewer comments 3


Xiaoliang Zhou, Hao Wang, Peiji Shi, Ai-min Meng

Institute of Radiation Medicine, Tianjin Key Laboratory of Molecular Nuclear Medicine, Tianjin, People's Republic of China

Abstract: Antibody-directed enzyme prodrug therapy (ADEPT) delivers chemotherapeutic agents in high concentration to tumor tissue, while minimizing systemic drug exposure. ADEPT has been reported to be an attractive approach for improving the efficacy of cancer therapy. A previously reported β-lactamase was found to contain four cluster of differentiation (CD)4+ T cell epitopes; however, single amino acid changes in the enzyme resulted in significantly reduced proliferative responses, while retaining stability and activity of the enzyme. The β-lactamase variant with reduced immunogenicity is an attractive alternative for constructing the ADEPT fusion protein. In this study, we fused the peptide, RGD4C, known to target integrin αvβ3, to the β-lactamase variant for use in ADEPT. Biological function studies revealed that RGD4C- β-lactamase had a high hydrolytic effect on nitrocefin and cephalosporin–melphalan, and high plasma stability was observed. In addition, fusion of the RGD4C moiety to β-lactamase had little effect on immunogenicity compared with β-lactamase in the proliferation of peripheral blood mononuclear cells. The ability of this fusion protein to both target the central region of αvβ3 and induce toxicity in the non-small-cell lung cancer cell NCI-H460 makes it a promising therapeutic approach in the treatment of cancer.

Keywords: ADEPT, immunogenicity, integrinαvβ3

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