Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis

Abstract

Inhibition of specific matrix metalloproteinases (MMP) is an attractive noncytotoxic approach to cancer therapy. MMP-14, a membrane-bound zinc endopeptidase, has been proposed to play a central role in tumor growth, invasion, and neovascularization. Besides cleavingmatrix proteins, MMP-14 activates proMMP-2 leadingto an amplification of pericellular proteolytic activity. To examine the contribution of MMP-14 to tumor growth and angiogenesis, we used DX-2400, a highly selective fully human MMP-14 inhibitory antibody discovered usingphage display technology. DX-2400 blocked proMMP-2 processingon tumor and endothelial cells, inhibited angio-genesis, and slowed tumor progression and formation of metastatic lesions. The combination of potency, selectivity, and robust in vivo activity shows the potential of a selective MMP-14 inhibitor for the treatment of solid tumors. © 2009 American Association tor Cancer Research.