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J Biol Chem, Vol. 273, Issue 32, 20556-20567, August 7, 1998

2'-Fluoropyrimidine RNA-based Aptamers to the 165-Amino Acid Form of Vascular Endothelial Growth Factor (VEGF₁₆₅)
INHIBITION OF RECEPTOR BINDING AND VEGF-INDUCED VASCULAR PERMEABILITY THROUGH INTERACTIONS REQUIRING THE EXON 7-ENCODED DOMAIN

Judy Ruckman, Louis S. Green, Jim Beeson, Sheela Waugh, Wendy L. Gillette, Dwight D. Henninger, Lena Claesson-Welsh^¶, and Neboja Janji

From  NeXstar Pharmaceuticals, Inc., Boulder, Colorado 80301 and the ^¶ Department of Medicinal and Physical Chemistry, Biomedical Center, Box 575, S-751 23 Uppsala, Sweden

Vascular endothelial growth factor (VEGF) has been implicated in the pathological induction of new blood vessel growth in a variety of proliferative disorders. Using the SELEX process (systematic evolution of ligands by exponential enrichment), we have isolated 2'-F-pyrimidine RNA oligonucleotide ligands (aptamers) to human VEGF₁₆₅. Representative aptamers from three distinct sequence families were truncated to the minimal sequence capable of high affinity binding to VEGF (23-29 nucleotides) and were further modified by replacement of 2'-O-methyl for 2'-OH at all ribopurine positions where the substitution was tolerated. Equilibrium dissociation constants for the interaction of VEGF with the truncated, 2'-O-methyl-modified aptamers range between 49 and 130 pM. These aptamers bind equally well to murine VEGF₁₆₄, do not bind to VEGF₁₂₁ or the smaller isoform of placenta growth factor (PlGF₁₂₉), and show reduced, but significant affinity for the VEGF₁₆₅/PlGF₁₂₉ heterodimer. Cysteine 137 in the exon 7-encoded domain of VEGF₁₆₅ forms a photo-inducible cross-link to a single uridine residue in each of the three aptamers. The aptamers potently inhibit the binding of VEGF to the human VEGF receptors, KDR and Flt-1, expressed by transfected porcine aortic endothelial cells. Furthermore, one of the aptamers is able to significantly reduce intradermal VEGF-induced vascular permeability in vivo.

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