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Novel affinity binders for neutralization of vascular endothelial growth factor (VEGF) signaling
KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
KTH, Skolan för bioteknologi (BIO), Proteinteknologi.ORCID-id: 0000-0002-9747-1399
KTH, Skolan för bioteknologi (BIO), Proteinteknologi.ORCID-id: 0000-0002-9282-0174
Vise andre og tillknytning
2016 (engelsk)Inngår i: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 73, nr 8, s. 1671-1683Artikkel i tidsskrift (Fagfellevurdert) Published
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Text
Abstract [en]

Angiogenesis denotes the formation of new blood vessels from pre-existing vasculature. Progression of diseases such as cancer and several ophthalmological disorders may be promoted by excess angiogenesis. Novel therapeutics to inhibit angiogenesis and diagnostic tools for monitoring angiogenesis during therapy, hold great potential for improving treatment of such diseases. We have previously generated so-called biparatopic Affibody constructs with high affinity for the vascular endothelial growth factor receptor-2 (VEGFR2), which recognize two non-overlapping epitopes in the ligand-binding site on the receptor. Affibody molecules have previously been demonstrated suitable for imaging purposes. Their small size also makes them attractive for applications where an alternative route of administration is beneficial, such as topical delivery using eye drops. In this study, we show that decreasing linker length between the two Affibody domains resulted in even slower dissociation from the receptor. The new variants of the biparatopic Affibody bound to VEGFR2-expressing cells, blocked VEGFA binding, and inhibited VEGFA-induced signaling of VEGFR2 over expressing cells. Moreover, the biparatopic Affibody inhibited sprout formation of endothelial cells in an in vitro angiogenesis assay with similar potency as the bivalent monoclonal antibody ramucirumab. This study demonstrates that the biparatopic Affibody constructs show promise for future therapeutic as well as in vivo imaging applications.

sted, utgiver, år, opplag, sider
Birkhauser Verlag , 2016. Vol. 73, nr 8, s. 1671-1683
Emneord [en]
Affibody molecules, Angiogenesis, Biparatopic affinity protein, Bispecific, VEGF, VEGFR2
HSV kategori
Identifikatorer
URN: urn:nbn:se:kth:diva-185609DOI: 10.1007/s00018-015-2088-7ISI: 000373141700010PubMedID: 26552422Scopus ID: 2-s2.0-84962247651OAI: oai:DiVA.org:kth-185609DiVA, id: diva2:924274
Forskningsfinansiär
Swedish Research Council, 621-2012-5236Swedish Cancer SocietyWenner-Gren Foundations
Merknad

QC 20160428

Tilgjengelig fra: 2016-04-28 Laget: 2016-04-25 Sist oppdatert: 2017-11-30bibliografisk kontrollert

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Güler, RezanStåhl, StefanLöfblom, John

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Fleetwood, FilippaGüler, RezanStåhl, StefanLöfblom, John
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