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Novel affinity binders for neutralization of vascular endothelial growth factor (VEGF) signaling
AlbaNova Univ Ctr, Royal Inst Technol, Sch Biotechnol, Div Prot Technol,KTH, S-10691 Stockholm, Sweden..
AlbaNova Univ Ctr, Royal Inst Technol, Sch Biotechnol, Div Prot Technol,KTH, S-10691 Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
AlbaNova Univ Ctr, Royal Inst Technol, Sch Biotechnol, Div Prot Technol,KTH, S-10691 Stockholm, Sweden..
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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
2016. Vol. 73, no 8, 1671-1683 p.
Keyword [en]
Affibody molecules, Angiogenesis, Biparatopic affinity protein, Bispecific, VEGF, VEGFR2
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-293008DOI: 10.1007/s00018-015-2088-7ISI: 000373141700010PubMedID: 26552422OAI: oai:DiVA.org:uu-293008DiVA: diva2:927466
Funder
Swedish Research Council, 621-2012-5236Swedish Cancer SocietyVINNOVA, 2009-00179Wenner-Gren Foundations
Available from: 2016-05-12 Created: 2016-05-11 Last updated: 2016-05-12Bibliographically approved

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Gordon, EmmaClaesson-Welsh, Lena
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