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 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.
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Authors | Roni Mamluk, Irvith M Carvajal, Brent A Morse, Henry Wong, Janette Abramowitz, Sharon Aslanian, Ai-Ching Lim, Jochem Gokemeijer, Michael J Storek, Joonsoo Lee, Michael Gosselin, Martin C Wright, Ray T Camphausen, Jack Wang, Yan Chen, Kathy Miller, Kerry Sanders, Sarah Short, Jeff Sperinde, Gargi Prasad, Stephen Williams, Robert Kerbel, John Ebos, Anthony Mutsaers, John D Mendlein, Alan S Harris, Eric S Furfine |
Journal | mAbs
(MAbs)
2010 Mar-Apr
Vol. 2
Issue 2
Pg. 199-208
ISSN: 1942-0870 [Electronic] United States |
PMID | 20190562
(Publication Type: Journal Article)
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Chemical References |
- Angiogenesis Inhibitors
- Antineoplastic Agents
- Fibronectins
- Vascular Endothelial Growth Factor A
- Vascular Endothelial Growth Factor Receptor-2
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Topics |
- Angiogenesis Inhibitors
(pharmacology)
- Animals
- Antineoplastic Agents
(pharmacology)
- Carcinoma
(drug therapy, pathology)
- Cell Line, Tumor
- Colonic Neoplasms
(drug therapy, pathology)
- Combinatorial Chemistry Techniques
- Endothelium, Vascular
(drug effects, metabolism, pathology)
- Fibronectins
(genetics, metabolism, pharmacology)
- Glioblastoma
(drug therapy, pathology)
- Humans
- Mice
- Protein Binding
(drug effects)
- Protein Engineering
- Surface Plasmon Resonance
- Vascular Endothelial Growth Factor A
(metabolism)
- Vascular Endothelial Growth Factor Receptor-2
(antagonists & inhibitors)
- Xenograft Model Antitumor Assays
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