Antagonists to human and mouse vascular endothelial growth factor receptor 2 generated by directed protein evolution in vitro

  • Getmanova E
  • Chen Y
  • Bloom L
 et al. 
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Using directed in vitro protein evolution, we generated proteins that bound and antagonized the function of vascular endothelial growth factor receptor 2 (VEGFR2). Binders to human VEGFR2 (KDR) with 10-200 nM affinities were selected by using mRNA display from a library (10(13) variants) based on the tenth human fibronectin type III domain (10Fn3) scaffold. Subsequently, a single KDR binding clone (K(d) = 11 nM) was subjected to affinity maturation. This yielded improved KDR binding molecules with affinities ranging from 0.06 to 2 nM. Molecules with dual binding specificities (human/mouse) were also isolated by using both KDR and Flk-1 (mouse VEGFR2) as targets in selection. Proteins encoded by the selected clones bound VEGFR2-expressing cells and inhibited their VEGF-dependent proliferation. Our results demonstrate the potential of these inhibitors in the development of anti-angiogenesis therapeutics

Author-supplied keywords

  • Flk-1
  • KDR
  • affinity
  • antagonist
  • cell
  • development
  • drug
  • endothelial
  • evolution
  • factor
  • fibronectin
  • growth
  • growth factor
  • library
  • maturation
  • proliferation
  • protein
  • receptor
  • scaffold
  • selection
  • specificity

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  • PMID: 16720276


  • E V Getmanova

  • Y Chen

  • L Bloom

  • J Gokemeijer

  • S Shamah

  • V Warikoo

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