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

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 PrasadStephen Williams, Robert Kerbel, John Ebos, Anthony Mutsaers, John D. Mendlein, Alan S. Harris, Eric S. Furfine

Research output: Contribution to journalArticle

49 Scopus citations

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 languageEnglish (US)
Pages (from-to)199-208
Number of pages10
JournalmAbs
Volume2
Issue number2
DOIs
StatePublished - Mar 2010

Keywords

  • Adnectin
  • Angiogenesis inhibitor
  • Biologics
  • CT-322
  • Targeted therapy
  • Tumor angiogenesis
  • VEGFR-2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Mamluk, R., Carvajal, I. M., Morse, B. A., Wong, H., Abramowitz, J., Aslanian, S., Lim, A. C., Gokemeijer, J., Storek, M. J., Lee, J., Gosselin, M., Wright, M. C., Camphausen, R. T., Wang, J., Chen, Y., Miller, K., Sanders, K., Short, S., Sperinde, J., ... Furfine, E. S. (2010). Anti-tumor effect of CT-322 as an adnectin inhibitor of vascular endothelial growth factor receptor-2. mAbs, 2(2), 199-208. https://doi.org/10.4161/mabs.2.2.11304