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Cancer Research 69, 1517, February 15, 2009. Published Online First February 10, 2009;
doi: 10.1158/0008-5472.CAN-08-3255
© 2009 American Association for Cancer Research
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Experimental Therapeutics, Molecular Targets, and Chemical Biology

Selective Inhibition of Matrix Metalloproteinase-14 Blocks Tumor Growth, Invasion, and Angiogenesis

Laetitia Devy1, Lili Huang1, Laurent Naa2, Niranjan Yanamandra1, Henk Pieters2, Nicolas Frans2, Edward Chang1, Qingfeng Tao1, Marc Vanhove2, Annabelle Lejeune2, Reinoud van Gool2, Daniel J. Sexton1, Guannan Kuang1, Douglas Rank1, Shannon Hogan1, Csaba Pazmany1, Yu Lu Ma1, Sonia Schoonbroodt2, Andrew E. Nixon1, Robert C. Ladner1, Rene Hoet2, Paula Henderikx2, Chris TenHoor1, Shafaat A. Rabbani3, Maria Luisa Valentino3, Clive R. Wood1 and Daniel T. Dransfield1

1 Dyax Corp., Cambridge, Massachusetts; 2 Dyax S.A., Liege, Belgium; and 3 Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada

Requests for reprints: Laetitia Devy, Dyax Corp., 300 Technology Square, Cambridge, MA 02139. Phone: 617-250-5531; Fax: 617-225-2501; E-mail: ldevy{at}dyax.com.

Key Words: Matrix metalloproteinase-14 • phage display • antibody inhibitor • anticancer activity • breast cancer

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 cleaving matrix proteins, MMP-14 activates proMMP-2 leading to 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 using phage display technology. DX-2400 blocked proMMP-2 processing on tumor and endothelial cells, inhibited angiogenesis, 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. [Cancer Res 2009;69(4):1517–26]




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Protease-dependent versus -independent cancer cell invasion programs: three-dimensional amoeboid movement revisited
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[Abstract] [Full Text] [PDF]


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