VEGF-Trap: a VEGF blocker with potent antitumor effects.
Vascular endothelial growth factor (VEGF) plays a critical role during normal embryonic angiogenesis and also in the pathological angiogenesis that occurs in a number of diseases, including cancer. Initial attempts to block VEGF by using a humanized monoclonal antibody are beginning to show promise in human cancer patients, underscoring the importance of optimizing VEGF blockade. Previous studies have found that one of the most effective ways to block the VEGF-signaling pathway is to prevent VEGF from binding to its normal receptors by administering decoy-soluble receptors. The highest-affinity VEGF blocker described to date is a soluble decoy receptor created by fusing the first three Ig domains of VEGF receptor 1 to an Ig constant region; however, this fusion protein has very poor in vivo pharmacokinetic properties. By determining the requirements to maintain high affinity while extending in vivo half life, we were able to engineer a very potent high-affinity VEGF blocker that has markedly enhanced pharmacokinetic properties. This VEGF-Trap effectively suppresses tumor growth and vascularization in vivo, resulting in stunted and almost completely avascular tumors. VEGF-Trap-mediated blockade may be superior to that achieved by other agents, such as monoclonal antibodies targeted against the VEGF receptor.
Holash
Jocelyn
J
Regeneron Pharmaceuticals, Incorporated, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. jocelyn.holash@regeneron.com
Davis
Sam
S
Papadopoulos
Nick
N
Croll
Susan D
SD
Ho
Lillian
L
Russell
Michelle
M
Boland
Patricia
P
Leidich
Ray
R
Hylton
Donna
D
Burova
Elena
E
Ioffe
Ella
E
Huang
Tammy
T
Radziejewski
Czeslaw
C
Bailey
Kevin
K
Fandl
James P
JP
Daly
Tom
T
Wiegand
Stanley J
SJ
Yancopoulos
George D
GD
Rudge
John S
JS
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000098:blood supply / Q000188:drug therapy; D002455:Cell Division; D015195:Drug Design; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D005109:Extracellular Matrix / Q000502:physiology; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D015202:Protein Engineering; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012208:Rhabdomyosarcoma / Q000098:blood supply / Q000188:drug therapy; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1