Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits

被引:0
作者
Vinay Bhaskar
Melvin Fox
Danna Breinberg
Melanie H-L Wong
Pauline E. Wales
Susan Rhodes
Robert B. DuBridge
Vanitha Ramakrishnan
机构
[1] PDL Biopharma,
[2] Inc.,undefined
来源
Investigational New Drugs | 2008年 / 26卷
关键词
Integrin; Alpha5; Beta1; Angiogenesis; Volociximab; VX2 tumor;
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学科分类号
摘要
Angiogenesis, the process by which new blood vessels form from existing vasculature, is critical for tumor growth and invasion. Growth factors, such as VEGF, initiate signaling cascades resulting in the proliferation of resting endothelial cells. Blockade of growth factor pathways has proven effective in inhibiting angiogenesis and tumor growth in vivo. Integrins, including the integrin α5β1, are also important mediators of angiogenesis and these adhesion molecules also regulate cancer cell growth and migration in vitro. Volociximab is a high affinity, function-blocking antibody against integrin α5β1 that is currently in multiple Phase II oncology clinical trials. Volociximab displays potent anti-angiogenic activity in a monkey model of choroidal neovascularization. In this study, we explored the consequences of integrin α5β1 blockade on tumorigenesis. Because volociximab does not cross-react with rodent α5β1, the syngeneic rabbit VX2 carcinoma model was utilized as an alternative to standard mouse xenograft models for the assessment of anti-tumor activity of volociximab. Volociximab administered intravenously to rabbits bearing VX2 tumors is detectable on tumor cells and vasculature 45 min post-administration. Volociximab was found to significantly inhibit the growth of tumors growing subcutaneously or intramuscularly, despite a 20-fold lower affinity for rabbit integrin, relative to human. This effect was found to correlate with decreased blood vessel density within these tumors. These results support the use of volociximab in the intervention of malignant disease.
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页码:7 / 12
页数:5
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共 120 条
[1]  
Folkman J(2003)Fundamental concepts of the angiogenic process Curr Mol Med 3 643-651
[2]  
Hynes RO(2002)Integrins: bidirectional, allosteric signaling machines Cell 110 673-687
[3]  
Stromblad S(1996)Integrins, angiogenesis and vascular cell survival Chem Biol 3 881-885
[4]  
Cheresh DA(1999)Integrin signaling Science 285 1028-1032
[5]  
Giancotti FG(2002)The diverse roles of integrins and their ligands in angiogenesis Cold Spring Harbor Symp Quant Biol 67 143-153
[6]  
Ruoslahti E(2005)alpha5beta1 integrin stimulates Bcl-2 expression and cell survival through Akt, focal adhesion kinase, and Ca2+/calmodulin-dependent protein kinase IV J Cell Biochem 95 1214-1223
[7]  
Hynes RO(2006)A non-RGD-based integrin binding peptide (ATN-161) blocks breast cancer growth and metastasis in vivo Mol Cancer Ther 5 2271-2280
[8]  
Lively JC(2002)Inhibition of endothelial cell survival and angiogenesis by protein kinase A J Clin Invest 110 933-941
[9]  
McCarty JH(2006)The small alpha5beta1 integrin antagonist, SJ749, reduces proliferation and clonogenicity of human astrocytoma cells Cancer Res 66 6002-6007
[10]  
Taverna D(2003)Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins Proc Natl Acad Sci USA 100 4766-4771