>>Published online before print August 12, 2002, 10.1073/pnas.172398299;
Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 17, 11393-11398, August 20, 2002
Medical Sciences
VEGF-Trap: A VEGF blocker with potent antitumor effects
Jocelyn Holash*, Sam Davis, Nick Papadopoulos, Susan D. Croll, Lillian Ho, Michelle Russell, Patricia Boland, Ray Leidich, Donna Hylton, Elena Burova, Ella Ioffe, Tammy Huang, Czeslaw Radziejewski, Kevin Bailey, James P. Fandl, Tom Daly, Stanley J. Wiegand, George D. Yancopoulos, and John S. Rudge
Regeneron Pharmaceuticals, Incorporated, 777 Old Saw Mill River Road, Tarrytown, NY 10591
Communicated by P. Roy Vagelos, Merck & Co., Inc., Bedminster, NJ, July 2, 2002 (received for review April 19, 2002)
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.<<
>>Published online before print August 12, 2002, 10.1073/pnas.172398399;
Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 17, 11399-11404, August 20, 2002
Medical Sciences
Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma
Eugene S. Kim*, Anna Serur*, Jianzhong Huang*, Christina A. Manley, Kimberly W. McCrudden*, Jason S. Frischer*, Samuel Z. Soffer*, Laurence Ring, Tamara New, Stephanie Zabski, John S. Rudge, Jocelyn Holash, George D. Yancopoulos, Jessica J. Kandel*, and Darrell J. Yamashiro*,,§
Divisions of * Pediatric Surgery and Pediatric Oncology, College of Physicians and Surgeons of Columbia University, New York, NY 10032; and Regeneron Pharmaceuticals, Incorporated, 777 Old Saw Mill River Road, Tarrytown, NY 10591
Communicated by P. Roy Vagelos, Merck & Co., Inc., Bedminster, NJ, July 5, 2002 (received for review April 19, 2002)
Vascular endothelial growth factor (VEGF) plays a key role in human tumor angiogenesis. We compared the effects of inhibitors of VEGF with different specificities in a xenograft model of neuroblastoma. Cultured human neuroblastoma NGP-GFP cells were implanted intrarenally in nude mice. Three anti-VEGF agents were tested: an anti-human VEGF165 RNA-based fluoropyrimidine aptamer; a monoclonal anti-human VEGF antibody; and VEGF-Trap, a composite decoy receptor based on VEGFR-1 and VEGFR-2 fused to an Fc segment of IgG1. A wide range of efficacy was observed, with high-dose VEGF-Trap causing the greatest inhibition of tumor growth (81% compared with controls). We examined tumor angiogenesis and found that early in tumor formation, cooption of host vasculature occurs. We postulate that this coopted vasculature serves as a source of blood supply during the initial phase of tumor growth. Subsequently, control tumors undergo vigorous growth and remodeling of vascular networks, which results in disappearance of the coopted vessels. However, if VEGF function is blocked, cooption of host vessels may persist. Persistent cooption, therefore, may represent a novel mechanism by which neuroblastoma can partly evade antiangiogenic therapy and may explain why experimental neuroblastoma is less susceptible to VEGF blockade than a parallel model of Wilms tumor. However, more effective VEGF blockade, as achieved by high doses of VEGF-Trap, can lead to regression of coopted vascular structures. These results demonstrate that cooption of host vasculature is an early event in tumor formation, and that persistence of this effect is related to the degree of blockade of VEGF activity.<<
Cheers, Tuck |
