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Novel affinity binders for neutralization of vascular endothelial growth factor (VEGF) signaling
KTH, School of Biotechnology (BIO), Protein Technology.
KTH, School of Biotechnology (BIO), Protein Technology.ORCID iD: 0000-0002-9747-1399
KTH, School of Biotechnology (BIO), Protein Technology.ORCID iD: 0000-0002-9282-0174
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2016 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 73, no 8, 1671-1683 p.Article in journal (Refereed) PublishedText
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.

Place, publisher, year, edition, pages
Birkhauser Verlag , 2016. Vol. 73, no 8, 1671-1683 p.
Keyword [en]
Affibody molecules, Angiogenesis, Biparatopic affinity protein, Bispecific, VEGF, VEGFR2
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-185609DOI: 10.1007/s00018-015-2088-7ISI: 000373141700010PubMedID: 26552422ScopusID: 2-s2.0-84962247651OAI: oai:DiVA.org:kth-185609DiVA: diva2:924274
Funder
Swedish Research Council, 621-2012-5236Swedish Cancer SocietyWenner-Gren Foundations
Note

QC 20160428

Available from: 2016-04-28 Created: 2016-04-25 Last updated: 2016-04-28Bibliographically approved

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Fleetwood, FilippaGüler, RezanStåhl, StefanLöfblom, John
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