Details

Autor(en) / Beteiligte

• Mamluk, Roni
• Carvajal, Irvith M.
• Morse, Brent A.
• Wong, Henry K
• 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 S.
• Ebos, John
• Mutsaers, Anthony
• Mendlein, John D.
• Harris, Alan S.
• Furfine, Eric S.

Titel

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

Ist Teil von

• mAbs, 2010-03, Vol.2 (2), p.199-208

Ort / Verlag

United States: Taylor & Francis

Erscheinungsjahr

2010

Quelle

Taylor & Francis Journals Auto-Holdings Collection

Beschreibungen/Notizen

• 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 affinity (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 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.