Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth.
Neuropilin-1 (NRP1) guides the development of the nervous and vascular systems. Binding to either semaphorins or VEGF, NRP1 acts with plexins to regulate neuronal guidance, or with VEGFR2 to mediate vascular development. We have generated two monoclonal antibodies that bind to the Sema- and VEGF-binding domains of NRP1, respectively. Both antibodies reduce angiogenesis and vascular remodeling, while having little effect on other VEGFR2-mediated events. Importantly, anti-NRP1 antibodies have an additive effect with anti-VEGF therapy in reducing tumor growth. Vessels from tumors treated with anti-VEGF show a close association with pericytes, while tumors treated with both anti-NRP1 and anti-VEGF lack this organization. We propose that blocking NRP1 function inhibits vascular remodeling, rendering vessels more susceptible to anti-VEGF therapy.
Pan
Qi
Q
Tumor Biology and Angiogenesis, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Chanthery
Yvan
Y
Liang
Wei-Ching
WC
Stawicki
Scott
S
Mak
Judy
J
Rathore
Nisha
N
Tong
Raymond K
RK
Kowalski
Joe
J
Yee
Sharon Fong
SF
Pacheco
Glenn
G
Ross
Sarajane
S
Cheng
Zhiyong
Z
Le Couter
Jennifer
J
Plowman
Greg
G
Peale
Franklin
F
Koch
Alexander W
AW
Wu
Yan
Y
Bagri
Anil
A
Tessier-Lavigne
Marc
M
Watts
Ryan J
RJ
D000818:Animals; D000911:Antibodies, Monoclonal; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D039942:Neuropilin-1 / Q000276:immunology*; D051381:Rats; D040121:Semaphorin-3A / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*
D000911:Antibodies, Monoclonal; D040121:Semaphorin-3A; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1