Inhibition of vascular endothelial growth factor induced mitogenesis of human endothelial cells by a chimeric anti-kinase insert domain-containing receptor antibody.
The kinase insert domain-containing receptor (KDR) is the human vascular endothelial growth factor (VEGF) receptor responsible for the mitogenic and angiogenic effects of VEGF. There is much experimental evidence to suggest that the VEGF/KDR pathway plays an important role in tumor angiogenesis, a process essential for tumor growth and metastasis. Here we produced a chimeric anti-KDR antibody (IgG1), c-p1C11, from a single chain (scFv) antibody isolated from a phage display library. C-p1C11 binds specifically to the extracellular domain of soluble as well as cell-surface expressed KDR. It effectively blocks VEGF-KDR interaction and inhibits VEGF-stimulated activation of KDR and MAP kinases p44/p42 of human endothelial cells. Furthermore, c-p1C11 efficiently neutralizes VEGF-induced mitogenesis of human endothelial cells. Our results suggest that antibodies against KDR have potential clinical applications in the treatment of cancer and other diseases where pathological angiogenesis is involved.
Zhu
Z
Z
Department of Molecular and Cell Biology, ImClone Systems Inc., New York, NY 10014, USA. zhenping@imclone.com
Lu
D
D
Kotanides
H
H
Santiago
A
A
Jimenez
X
X
Simcox
T
T
Hicklin
D J
DJ
Bohlen
P
P
Witte
L
L
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D001667:Binding, Competitive; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008938:Mitosis / Q000187:drug effects*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D007074:Immunoglobulin G; D008222:Lymphokines; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases