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Anti-tumor effect of CT-322 as an adnectin inhibitor of vascular endothelial growth factor receptor-2.

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.
AuthorsRoni 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
JournalmAbs (MAbs) 2010 Mar-Apr Vol. 2 Issue 2 Pg. 199-208 ISSN: 1942-0870 [Electronic] United States
PMID20190562 (Publication Type: Journal Article)
Chemical References
  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Fibronectins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-2
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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