Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis.
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.
Devy
Laetitia
L
Dyax Corp, Cambridge, Massachusetts 02139, USA. ldevy@dyax.com
Huang
Lili
L
Naa
Laurent
L
Yanamandra
Niranjan
N
Pieters
Henk
H
Frans
Nicolas
N
Chang
Edward
E
Tao
Qingfeng
Q
Vanhove
Marc
M
Lejeune
Annabelle
A
van Gool
Reinoud
R
Sexton
Daniel J
DJ
Kuang
Guannan
G
Rank
Douglas
D
Hogan
Shannon
S
Pazmany
Csaba
C
Ma
Yu Lu
YL
Schoonbroodt
Sonia
S
Nixon
Andrew E
AE
Ladner
Robert C
RC
Hoet
Rene
R
Henderikx
Paula
P
Tenhoor
Chris
C
Rabbani
Shafaat A
SA
Valentino
Maria Luisa
ML
Wood
Clive R
CR
Dransfield
Daniel T
DT
D000818:Animals; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000473:pathology; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D014162:Transfection; D014183:Transplantation, Heterologous; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C000608273:DX-2400; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors