Anti-tumor effect of CT-322 as an adnectin inhibitor of vascular endothelial growth factor receptor-2.
CT-322 is a new anti-angiogenic therapeutic agent based on an engineered variant of the tenth type III domain of human fibronectin, i.e., an Adnectin™, designed to inhibit vascular endothelial growth factor receptor (VEGFR)-2. This PE Gylated Adnectin was developed using an mRNA display technology. CT-322 bound human VEGFR-2 with high affinity (K(D), 11 nM), but did not bind VEGFR-1 or VEGFR-3 at concentrations up to 100 nM, as determined by surface plasmon resonance studies. Western blot analysis showed that CT-322 blocked VEGF-induced phosphorylation of VEGFR-2 and mitogen-activated protein kinase in human umbilical vascular endothelial cells. CT-322 significantly inhibited the growth of human tumor xenograft models of colon carcinoma and glioblastoma at doses of 15-60 mg/kg administered 3 times/week. Anti-tumor effects of CT-322 were comparable to those of sorafenib or sunitinib, which inhibit multiple kinases, in a colon carcinoma xenograft model, although CT-322 caused less overt adverse effects than the kinase inhibitors. CT-322 also enhanced the anti-tumor activity of the chemotherapeutic agent temsirolimus in the colon carcinoma model. The high affinity and specificity of CT-322 binding to VEGFR-2 and its anti-tumor activities establish CT-322 as a promising anti-angiogenic therapeutic agent. Our results further suggest that Adnectins are an important new class of targeted biologics that can be developed as potential treatments for a wide variety of diseases.
Mamluk
Roni
R
Adnexus, A Bristol Myers Squibb R&D Company, Waltham, MA, USA.
Carvajal
Irvith M
IM
Morse
Brent A
BA
Wong
Henry
H
Abramowitz
Janette
J
Aslanian
Sharon
S
Lim
Ai-Ching
AC
Gokemeijer
Jochem
J
Storek
Michael J
MJ
Lee
Joonsoo
J
Gosselin
Michael
M
Wright
Martin C
MC
Camphausen
Ray T
RT
Wang
Jack
J
Chen
Yan
Y
Miller
Kathy
K
Sanders
Kerry
K
Short
Sarah
S
Sperinde
Jeff
J
Prasad
Gargi
G
Williams
Stephen
S
Kerbel
Robert
R
Ebos
John
J
Mutsaers
Anthony
A
Mendlein
John D
JD
Harris
Alan S
AS
Furfine
Eric S
ES
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020650:Combinatorial Chemistry Techniques; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D015202:Protein Engineering; D020349:Surface Plasmon Resonance; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D005353:Fibronectins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2