Journal
ONCOTARGETS AND THERAPY
Volume 7, Issue -, Pages 535-541Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/OTT.S59346
Keywords
ADEPT; immunogenicity; integrin alpha(v)beta(3)
Categories
Funding
- National Natural Science Foundation of China [81301983]
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences [SF1305]
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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 beta-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 beta-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 alpha(v)beta(3), to the beta-lactamase variant for use in ADEPT. Biological function studies revealed that RGD4C-beta 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 beta-lactamase had little effect on immunogenicity compared with beta-lactamase in the proliferation of peripheral blood mononuclear cells. The ability of this fusion protein to both target the central region of alpha(v)beta(3) and induce toxicity in the non-small-cell lung cancer cell NCI-H460 makes it a promising therapeutic approach in the treatment of cancer.
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