Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits.
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 alpha5beta1, 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 alpha5beta1 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 alpha5beta1 blockade on tumorigenesis. Because volociximab does not cross-react with rodent alpha5beta1, 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.
Bhaskar
Vinay
V
PDL Biopharma, Inc., 34801 Campus Drive, Fremont, CA 94555, USA. vinay.bhaskar@pdl.com
Fox
Melvin
M
Breinberg
Danna
D
Wong
Melanie H-L
MH
Wales
Pauline E
PE
Rhodes
Susan
S
DuBridge
Robert B
RB
Ramakrishnan
Vanitha
V
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D000918:Antibody Specificity; D017326:Clinical Trials, Phase III as Topic; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007120:Immunochemistry; D007275:Injections, Intravenous; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011485:Protein Binding; D011817:Rabbits; D013045:Species Specificity; D020349:Surface Plasmon Resonance / Q000379:methods; D047368:Tumor Burden / Q000187:drug effects