title: 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.
authors.affiliation: Adnexus, A Bristol Myers Squibb R&D Company, Waltham, MA, USA.
authors.forename: Roni
authors.initials: R
authors.lastname: Mamluk
authors.forename: Irvith M
authors.initials: IM
authors.lastname: Carvajal
authors.forename: Brent A
authors.initials: BA
authors.lastname: Morse
authors.forename: Henry
authors.initials: H
authors.lastname: Wong
authors.forename: Janette
authors.initials: J
authors.lastname: Abramowitz
authors.forename: Sharon
authors.initials: S
authors.lastname: Aslanian
authors.forename: Ai-Ching
authors.initials: AC
authors.lastname: Lim
authors.forename: Jochem
authors.initials: J
authors.lastname: Gokemeijer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Storek
authors.forename: Joonsoo
authors.initials: J
authors.lastname: Lee
authors.forename: Michael
authors.initials: M
authors.lastname: Gosselin
authors.forename: Martin C
authors.initials: MC
authors.lastname: Wright
authors.forename: Ray T
authors.initials: RT
authors.lastname: Camphausen
authors.forename: Jack
authors.initials: J
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Kathy
authors.initials: K
authors.lastname: Miller
authors.forename: Kerry
authors.initials: K
authors.lastname: Sanders
authors.forename: Sarah
authors.initials: S
authors.lastname: Short
authors.forename: Jeff
authors.initials: J
authors.lastname: Sperinde
authors.forename: Gargi
authors.initials: G
authors.lastname: Prasad
authors.forename: Stephen
authors.initials: S
authors.lastname: Williams
authors.forename: Robert
authors.initials: R
authors.lastname: Kerbel
authors.forename: John
authors.initials: J
authors.lastname: Ebos
authors.forename: Anthony
authors.initials: A
authors.lastname: Mutsaers
authors.forename: John D
authors.initials: JD
authors.lastname: Mendlein
authors.forename: Alan S
authors.initials: AS
authors.lastname: Harris
authors.forename: Eric S
authors.initials: ES
authors.lastname: Furfine
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020650:Combinatorial Chemistry Techniques; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D015202:Protein Engineering; D020349:Surface Plasmon Resonance; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D005353:Fibronectins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2