Abstract
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 AdnectintM, designed to inhibit vascular endothelial growth factor receptor (VeGFR)-2. this peGylated Adnectin was developed using an mRNA display technology. Ct-322 bound human VeGFR-2 with high affi nity (KD, 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 mitogenactivated 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 affi nity 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.
| Original language | English |
|---|---|
| Pages (from-to) | 199-208 |
| Number of pages | 10 |
| Journal | mAbs |
| Volume | 2 |
| Issue number | 2 |
| DOIs | |
| State | Published - Mar 2010 |
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Keywords
- Adnectin
- Angiogenesis inhibitor
- Biologics
- CT-322
- Targeted therapy
- Tumor angiogenesis
- VEGFR-2
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
Anti-tumor effect of CT-322 as an adnectin inhibitor of vascular endothelial growth factor receptor-2. / Mamluk, Roni; Carvajal, Irvith M.; Morse, Brent A.; Wong, Henry; Abramowitz, Janette; Aslanian, Sharon; Lim, Ai Ching; Gokemeijer, Jochem; Storek, Michael J.; Lee, Joonsoo; Gosselin, Michael; Wright, Martin C.; Camphausen, Ray T.; Wang, Jack; Chen, Yan; Miller, Kathy; Sanders, Kerry; Short, Sarah; Sperinde, Jeff; Prasad, Gargi; Williams, Stephen; Kerbel, Robert; Ebos, John; Mutsaers, Anthony; Mendlein, John D.; Harris, Alan S.; Furfine, Eric S.
In: mAbs, Vol. 2, No. 2, 03.2010, p. 199-208.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Anti-tumor effect of CT-322 as an adnectin inhibitor of vascular endothelial growth factor receptor-2
AU - Mamluk, Roni
AU - Carvajal, Irvith M.
AU - Morse, Brent A.
AU - Wong, Henry
AU - Abramowitz, Janette
AU - Aslanian, Sharon
AU - Lim, Ai Ching
AU - Gokemeijer, Jochem
AU - Storek, Michael J.
AU - Lee, Joonsoo
AU - Gosselin, Michael
AU - Wright, Martin C.
AU - Camphausen, Ray T.
AU - Wang, Jack
AU - Chen, Yan
AU - Miller, Kathy
AU - Sanders, Kerry
AU - Short, Sarah
AU - Sperinde, Jeff
AU - Prasad, Gargi
AU - Williams, Stephen
AU - Kerbel, Robert
AU - Ebos, John
AU - Mutsaers, Anthony
AU - Mendlein, John D.
AU - Harris, Alan S.
AU - Furfine, Eric S.
PY - 2010/3
Y1 - 2010/3
N2 - 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 AdnectintM, designed to inhibit vascular endothelial growth factor receptor (VeGFR)-2. this peGylated Adnectin was developed using an mRNA display technology. Ct-322 bound human VeGFR-2 with high affi nity (KD, 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 mitogenactivated 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 affi nity 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.
AB - 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 AdnectintM, designed to inhibit vascular endothelial growth factor receptor (VeGFR)-2. this peGylated Adnectin was developed using an mRNA display technology. Ct-322 bound human VeGFR-2 with high affi nity (KD, 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 mitogenactivated 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 affi nity 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.
KW - Adnectin
KW - Angiogenesis inhibitor
KW - Biologics
KW - CT-322
KW - Targeted therapy
KW - Tumor angiogenesis
KW - VEGFR-2
UR - http://www.scopus.com/inward/record.url?scp=77951544346&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77951544346&partnerID=8YFLogxK
U2 - 10.4161/mabs.2.2.11304
DO - 10.4161/mabs.2.2.11304
M3 - Article
VL - 2
SP - 199
EP - 208
JO - mAbs
JF - mAbs
SN - 1942-0862
IS - 2
ER -