Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2.
Angiopoietin-2 (Ang2) exhibits broad expression in the remodeling vasculature of human tumors but very limited expression in normal tissues, making it an attractive candidate target for antiangiogenic cancer therapy. To investigate the functional consequences of blocking Ang2 activity, we generated antibodies and peptide-Fc fusion proteins that potently and selectively neutralize the interaction between Ang2 and its receptor, Tie2. Systemic treatment of tumor-bearing mice with these Ang2-blocking agents resulted in tumor stasis, followed by elimination of all measurable tumor in a subset of animals. These effects were accompanied by reduced endothelial cell proliferation, consistent with an antiangiogenic therapeutic mechanism. Anti-Ang2 therapy also prevented VEGF-stimulated neovascularization in a rat corneal model of angiogenesis. These results imply that specific Ang2 inhibition may represent an effective antiangiogenic strategy for treating patients with solid tumors.
Oliner
Jonathan
J
Amgen, Thousand Oaks, California 91320, USA. joliner@amgen.com
Min
Hosung
H
Leal
Juan
J
Yu
Dongyin
D
Rao
Shashirekha
S
You
Edward
E
Tang
Xiu
X
Kim
Haejin
H
Meyer
Susanne
S
Han
Seog Joon
SJ
Hawkins
Nessa
N
Rosenfeld
Robert
R
Davy
Elyse
E
Graham
Kevin
K
Jacobsen
Frederick
F
Stevenson
Shirley
S
Ho
Joanne
J
Chen
Qing
Q
Hartmann
Thomas
T
Michaels
Mark
M
Kelley
Michael
M
Li
Luke
L
Sitney
Karen
K
Martin
Frank
F
Sun
Ji-Rong
JR
Zhang
Nancy
N
Lu
John
J
Estrada
Juan
J
Kumar
Rakesh
R
Coxon
Angela
A
Kaufman
Stephen
S
Pretorius
James
J
Scully
Sheila
S
Cattley
Russ
R
Payton
Marc
M
Coats
Steve
S
Nguyen
Linh
L
Desilva
Binodh
B
Ndifor
Anthony
A
Hayward
Isaac
I
Radinsky
Robert
R
Boone
Tom
T
Kendall
Richard
R
D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003315:Cornea / Q000098:blood supply; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009500:Neutralization Tests; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D042702:Angiopoietin-2; D000906:Antibodies; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins