Development of a specific affinity-matured exosite inhibitor to MT1-MMP that efficiently inhibits tumor cell invasion in vitro and metastasis in vivo

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Status	已發表Published
	Development of a specific affinity-matured exosite inhibitor to MT1-MMP that efficiently inhibits tumor cell invasion in vitro and metastasis in vivo
	Botkjaer, K.A.; Kwok, H. F.; Terp, M.G.; Karatt-Vellatt, A.; Santamaria, S.; McCafferty, J.; Andreasen, P.A.; Itoh, Y.; Ditzel, H.J.; Murphy, G.
	2016-02-01
Source Publication	Oncotarget
ISSN	1949-2553
Pages	1-20
Abstract	The membrane-associated matrix metalloproteinase-14, MT1-MMP, has been implicated in pericellular proteolysis with an important role in cellular invasion of collagenous tissues. It is highly upregulated in various cancers and rheumatoid arthritis, and has been considered a potential therapeutic target. Here, we report the identification of antibodies to MT1-MMP that potently and specifically inhibit its cell surface functions. Lead antibody clones displayed inhibitory activity towards proMMP-2 activation, collagen-film degradation and gelatin-film degradation, and were shown to bind to the MT1-MMP catalytic domain outside the active site cleft, inhibiting binding to triple helical collagen. Affinity maturation using CDR3 randomization created a second generation of antibodies with dissociation constants down to 0.11nM, corresponding to an improved affinity of 332-fold with the ability to interfere with cell-surface MT1-MMP functions displaying IC50 values down to 5nM. Importantly, the new inhibitors were able to inhibit collagen invasion by tumor-cells in vitro and in vivo primary tumor growth and metastasis of MDA-MB-231 cells in a mouse orthotopic xenograft model. Herein is the first demonstration that an inhibitory antibody targeting sites outside the catalytic cleft of MT1-MMP can effectively abrogate its in vivo activity relative to tumorigenesis and metastasis.
Keyword	MT1-MMP antibody non-catalytic sites in vivo targeting metastasis
URL	View the original
Language	英語English
The Source to Article	PB_Publication
PUB ID	16691
Document Type	Journal article
Collection	DEPARTMENT OF BIOMEDICAL SCIENCES Faculty of Health Sciences Cancer Centre
Corresponding Author	Botkjaer, K.A.; Kwok, H. F.; Murphy, G.
Recommended Citation GB/T 7714	Botkjaer, K.A.,Kwok, H. F.,Terp, M.G.,et al. Development of a specific affinity-matured exosite inhibitor to MT1-MMP that efficiently inhibits tumor cell invasion in vitro and metastasis in vivo[J]. Oncotarget, 2016, 1-20.
APA	Botkjaer, K.A.., Kwok, H. F.., Terp, M.G.., Karatt-Vellatt, A.., Santamaria, S.., McCafferty, J.., Andreasen, P.A.., Itoh, Y.., Ditzel, H.J.., & Murphy, G. (2016). Development of a specific affinity-matured exosite inhibitor to MT1-MMP that efficiently inhibits tumor cell invasion in vitro and metastasis in vivo. Oncotarget, 1-20.
MLA	Botkjaer, K.A.,et al."Development of a specific affinity-matured exosite inhibitor to MT1-MMP that efficiently inhibits tumor cell invasion in vitro and metastasis in vivo".Oncotarget (2016):1-20.

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