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

作者：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^*

来源：mAbs, 2010, 2(2): 199-208.

DOI：10.4161/mabs.2.2.11304

• CT-322
• adnectin
• VEGFR-2
• tumor angiogenesis
• angiogenesis inhibitor
• biologics
• targeted therapy

CT-322 is a new anti-angiogenic therapeutic agent based on an engineered variant of the tenth type Ill domain of human fibronectin, i.e., an Adnectin (TM), 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 (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.

• 出版日期2010-4