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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.4; Kwok H.F.4; Terp M.G.5; Karatt-Vellatt A.2; Santamaria S.6; McCafferty J.2; Andreasen P.A.1; Itoh Y.6; Ditzel H.J.5; Murphy G.4
2016-03-29
Source PublicationOncotarget
ISSN19492553
Volume7Issue:13Pages:16773-16792
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 substantially upregulated in various cancers and rheumatoid arthritis, and has been considered as a potential therapeutic target. Here, we report the identification of antibody fragments to MT1-MMP that potently and specifically inhibit its cell surface functions. Lead antibody clones displayed inhibitory activity towards pro-MMP-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 antibody fragments with dissociation constants down to 0.11 nM, corresponding to an improved affinity of 332-fold with the ability to interfere with cell-surface MT1-MMP functions, displaying IC50 values down to 5 nM. 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 during tumorigenesis and metastasis.

KeywordAntibody In Vivo targetIng Metastasis Mt1-mmp Non-catalytic Sites
DOI10.18632/oncotarget.7780
URLView the original
Indexed BySCI
Language英语
WOS Research AreaOncology ; Cell Biology
WOS SubjectOncology ; Cell Biology
WOS IDWOS:000375692900112
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Citation statistics
Cited Times [WOS]:21   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Aarhus Universitet
2.IONTAS Ltd
3.Universidade de Macau
4.University of Cambridge
5.Syddansk Universitet
6.Kennedy Institute of Rheumatology
7.Odense Universitetshospital
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,2016,7(13):16773-16792.
APA Botkjaer K.A..,Kwok H.F..,Terp M.G..,Karatt-Vellatt A..,Santamaria S..,...&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,7(13),16773-16792.
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 7.13(2016):16773-16792.
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