The Experts below are selected from a list of 72 Experts worldwide ranked by ideXlab platform
Vanitha Ramakrishnan - One of the best experts on this subject based on the ideXlab platform.
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A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth -1
2011Co-Authors: Vinay Bhaskar, Melvin Fox, Melanie H-l Wong, Pauline E. Wales, Robert B. Dubridge, Pui Seto, Debra T Chao, Dong Zhang, David Powers, Vanitha RamakrishnanAbstract:Copyright information:Taken from "A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth "http://www.translational-medicine.com/content/5/1/61Journal of Translational Medicine 2007;5():61-61.Published online 27 Nov 2007PMCID:PMC2235829. Fc fusion proteins, (A). A subset of competitive antibodies cross-reacted with human integrin. Antibodies were tested by immunohistochemistry for staining of sections from C32 melanoma (α5β1 negative) or MDA-MB-231 breast carcinoma (α5β1 positive) xenografts, (B). The majority of antibodies tested stained murine α5β1 on tumor vasculature, but only antibodies found to cross-react with human α5β1 by ELISA specifically stained MDA-MB-231 xenograft cells as well. IIA1, the mouse parent antibody of Volociximab, which recognizes only human integrin, anti-mouse CD31, which stains mouse vessels, and pooled rat IgG are shown as controls
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Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits
Investigational New Drugs, 2008Co-Authors: Vinay Bhaskar, Melvin Fox, Danna Breinberg, Melanie H-l Wong, Pauline E. Wales, Susan Rhodes, Robert B. Dubridge, Vanitha RamakrishnanAbstract: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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a function blocking anti mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth in vivo
Journal of Translational Medicine, 2007Co-Authors: Vinay Bhaskar, Melvin Fox, Melanie H-l Wong, Robert B. Dubridge, Dongping Zhang, Pui Seto, Pauline Wales, David M W Powers, Debra T Chao, Vanitha RamakrishnanAbstract:Background: Integrins are important adhesion molecules that regulate tumor and endothelial cell survival, proliferation and migration. The integrin α5β1 has been shown to play a critical role during angiogenesis. An inhibitor of this integrin, Volociximab (M200), inhibits endothelial cell growth and movement in vitro, independent of the growth factor milieu, and inhibits tumor growth in vivo in the rabbit VX2 carcinoma model. Although Volociximab has already been tested in open label, pilot phase II clinical trials in melanoma, pancreatic and renal cell cancer, evaluation of the mechanism of action of Volociximab has been limited because this antibody does not cross-react with murine α5β1, precluding its use in standard mouse xenograft models. Methods: We generated a panel of rat-anti-mouse α5β1 antibodies, with the intent of identifying an antibody that recapitulated the properties of Volociximab. Hybridoma clones were screened for analogous function to Volociximab, including specificity for α5β1 heterodimer and blocking of integrin binding to fibronectin. A subset of antibodies that met these criteria were further characterized for their capacities to bind to mouse endothelial cells, inhibit cell migration and block angiogenesis in vitro. One antibody that encompassed all of these attributes, 339.1, was selected from this panel and tested in xenograft models. Results: A panel of antibodies was characterized for specificity and potency. The affinity of antibody 339.1 for mouse integrin α5β1 was determined to be 0.59 nM, as measured by BIAcore. This antibody does not significantly cross-react with human integrin, however 339.1 inhibits murine endothelial cell migration and tube formation and elicits cell death in these cells (EC 50 = 5.3 nM). In multiple xenograft models, 339.1 inhibited the growth of established tumors by 40–60% (p < 0.05) and this inhibition correlates with a concomitant decrease in vessel density.
Vinay Bhaskar - One of the best experts on this subject based on the ideXlab platform.
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A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth -1
2011Co-Authors: Vinay Bhaskar, Melvin Fox, Melanie H-l Wong, Pauline E. Wales, Robert B. Dubridge, Pui Seto, Debra T Chao, Dong Zhang, David Powers, Vanitha RamakrishnanAbstract:Copyright information:Taken from "A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth "http://www.translational-medicine.com/content/5/1/61Journal of Translational Medicine 2007;5():61-61.Published online 27 Nov 2007PMCID:PMC2235829. Fc fusion proteins, (A). A subset of competitive antibodies cross-reacted with human integrin. Antibodies were tested by immunohistochemistry for staining of sections from C32 melanoma (α5β1 negative) or MDA-MB-231 breast carcinoma (α5β1 positive) xenografts, (B). The majority of antibodies tested stained murine α5β1 on tumor vasculature, but only antibodies found to cross-react with human α5β1 by ELISA specifically stained MDA-MB-231 xenograft cells as well. IIA1, the mouse parent antibody of Volociximab, which recognizes only human integrin, anti-mouse CD31, which stains mouse vessels, and pooled rat IgG are shown as controls
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Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits
Investigational New Drugs, 2008Co-Authors: Vinay Bhaskar, Melvin Fox, Danna Breinberg, Melanie H-l Wong, Pauline E. Wales, Susan Rhodes, Robert B. Dubridge, Vanitha RamakrishnanAbstract: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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a function blocking anti mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth in vivo
Journal of Translational Medicine, 2007Co-Authors: Vinay Bhaskar, Melvin Fox, Melanie H-l Wong, Robert B. Dubridge, Dongping Zhang, Pui Seto, Pauline Wales, David M W Powers, Debra T Chao, Vanitha RamakrishnanAbstract:Background: Integrins are important adhesion molecules that regulate tumor and endothelial cell survival, proliferation and migration. The integrin α5β1 has been shown to play a critical role during angiogenesis. An inhibitor of this integrin, Volociximab (M200), inhibits endothelial cell growth and movement in vitro, independent of the growth factor milieu, and inhibits tumor growth in vivo in the rabbit VX2 carcinoma model. Although Volociximab has already been tested in open label, pilot phase II clinical trials in melanoma, pancreatic and renal cell cancer, evaluation of the mechanism of action of Volociximab has been limited because this antibody does not cross-react with murine α5β1, precluding its use in standard mouse xenograft models. Methods: We generated a panel of rat-anti-mouse α5β1 antibodies, with the intent of identifying an antibody that recapitulated the properties of Volociximab. Hybridoma clones were screened for analogous function to Volociximab, including specificity for α5β1 heterodimer and blocking of integrin binding to fibronectin. A subset of antibodies that met these criteria were further characterized for their capacities to bind to mouse endothelial cells, inhibit cell migration and block angiogenesis in vitro. One antibody that encompassed all of these attributes, 339.1, was selected from this panel and tested in xenograft models. Results: A panel of antibodies was characterized for specificity and potency. The affinity of antibody 339.1 for mouse integrin α5β1 was determined to be 0.59 nM, as measured by BIAcore. This antibody does not significantly cross-react with human integrin, however 339.1 inhibits murine endothelial cell migration and tube formation and elicits cell death in these cells (EC 50 = 5.3 nM). In multiple xenograft models, 339.1 inhibited the growth of established tumors by 40–60% (p < 0.05) and this inhibition correlates with a concomitant decrease in vessel density.
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m200 Volociximab a chimeric antibody against integrin alpha5 beta1 inhibits tumor growth by multiple mechanisms
Cancer Research, 2005Co-Authors: Vinay Bhaskar, Melvin Fox, Danna Breinberg, Robert B. Dubridge, Pauline Wales, Eric Ibsen, Yuni Fang, Chris Ohara, Melanie Wong, Richard MurrayAbstract:Proc Amer Assoc Cancer Res, Volume 46, 2005 4497 Interactions between cells and extracellular matrix (ECM) proteins in the tumor microenvironment are mediated by heterodimeric integrins. One such integrin, alpha5 beta1, mediates adhesion and migration towards fibronectin via a highly conserved RGD sequence. We have found, through immunohistochemical analysis of human tumor tissue, that integrin alpha5 beta1 is highly expressed on the surface of tumor epithelial cells, as well as endothelial cells that make up the invading neovasculature. In vitro , a high-affinity function-blocking antibody against alpha5 beta1, M200, was found to inhibit the proliferation of human endothelial cells by a mechanism that involves cell death. A significant proportion of cancer cell lines tested retained a high level of surface alpha5 beta1 in vitro . In proliferation assays, a subset of these cell lines was particularly sensitive to M200. In affected cell lines, M200 was found to inhibit proliferation on fibronectin, as well as other ECM proteins, even when added 24 hours after plating. The effects on proliferation were due, at least in part, to the ability of M200 to induce cell death in these cell lines. M200 cross-reacts with rabbit, but not rodent, alpha5 beta1, therefore, a rabbit neovascularization model was chosen to evaluate the potency of M200 in vivo . M200 was found to exert a statistically significant effect in inhibiting angiogenesis in this setting. We are currently assessing possible anti-tumor effects using the rabbit VX2 carcinoma model. These data suggest that M200 inhibits tumor growth by targeting cancer cells directly, in addition to endothelial cells in the tumor neovasculature.
Chandra P Belani - One of the best experts on this subject based on the ideXlab platform.
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phase ib safety and pharmacokinetic study of Volociximab an anti α5β1 integrin antibody in combination with carboplatin and paclitaxel in advanced non small cell lung cancer
Annals of Oncology, 2013Co-Authors: Benjamin Besse, L C Tsao, D T Chao, Y Fang, J C Soria, S Almokadem, Chandra P BelaniAbstract:ABSTRACT Background This phase Ib study evaluated Volociximab, an anti-α5β1 integrin antibody, in combination with carboplatin (Eli Lilly and Co., Indianapolis, IN) and paclitaxel (Taxol) in advanced, untreated non-small-cell lung cancer (NSCLC). Patients and methods Three cohorts were treated with Volociximab (10, 20, or 30 mg/kg) for up to six 3-week cycles in combination with carboplatin–paclitaxel chemotherapy and continued as maintenance therapy for patients with stable disease (SD) or better. Dose-limiting toxic effects, adverse events (AEs), pharmacokinetics, and anti-Volociximab antibodies were assessed. Results A maximum tolerated dose was not reached up to the maximum planned dose of 30 mg/kg. In 29 patients who received Volociximab, the most common grade ≥3 AEs were neutropenia (24%), hyponatremia (17%), and fatigue (10%). Three patients experienced Volociximab-related serious AEs. No hemorrhages were observed. Of 33 patients enrolled, 8 (24%) achieved a partial response and 17 (52%) had SD. The median progression-free survival was 6.3 months (95% confidence interval 5.5–8.1). Levels of potential biomarkers of angiogenesis or metastasis were reduced following six cycles of treatment. Conclusions Volociximab combined with carboplatin and paclitaxel was generally well-tolerated and showed preliminary evidence of efficacy in advanced NSCLC.
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Volociximab in cancer
Expert Opinion on Biological Therapy, 2012Co-Authors: Salah Almokadem, Chandra P BelaniAbstract:Introduction: Volociximab is a first-in-class chimeric monoclonal antibody that targets α5β1 integrin. Preclinical studies have shown the ability of Volociximab to inhibit tumor neoangiogenesis by blocking the interaction between α5β1 and fibronectin. Volociximab's safety profile, pharmacokinetics and pharmacodynamics have been established. Ongoing clinical trials are evaluating its efficacy in the treatment of different types of solid tumors as a single agent or in combination with chemotherapy. In this review we focus on the biological effect of Volociximab and results of completed clinical trials. Areas covered: This review summarizes the structures and functions of integrin α5β1 and its ligand fibronectin, provides an overview of the early development of Volociximab, a targeted monoclonal antibody that specifically binds and inhibits activation of integrin α5β1, and discusses the relevant data from pre-clinical and clinical studies. Expert opinion: Volociximab has been well tolerated as monotherapy or...
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safety and early efficacy results from a phase i study of Volociximab v in combination with carboplatin c and paclitaxel p in patients pts with advanced non small cell lung cancer nsclc
Journal of Clinical Oncology, 2009Co-Authors: Benjamin Besse, S Almokadem, David Planchard, I Chico, C Tsao, F Ringeisen, J Soria, Chandra P BelaniAbstract:e13513 Background: Volociximab is a chimeric monoclonal antibody that blocks fibronectin binding to α5β1 and induces apoptosis in proliferating endothelial cells. Its anti-angiogenic actions are in...
Melvin Fox - One of the best experts on this subject based on the ideXlab platform.
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A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth -1
2011Co-Authors: Vinay Bhaskar, Melvin Fox, Melanie H-l Wong, Pauline E. Wales, Robert B. Dubridge, Pui Seto, Debra T Chao, Dong Zhang, David Powers, Vanitha RamakrishnanAbstract:Copyright information:Taken from "A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth "http://www.translational-medicine.com/content/5/1/61Journal of Translational Medicine 2007;5():61-61.Published online 27 Nov 2007PMCID:PMC2235829. Fc fusion proteins, (A). A subset of competitive antibodies cross-reacted with human integrin. Antibodies were tested by immunohistochemistry for staining of sections from C32 melanoma (α5β1 negative) or MDA-MB-231 breast carcinoma (α5β1 positive) xenografts, (B). The majority of antibodies tested stained murine α5β1 on tumor vasculature, but only antibodies found to cross-react with human α5β1 by ELISA specifically stained MDA-MB-231 xenograft cells as well. IIA1, the mouse parent antibody of Volociximab, which recognizes only human integrin, anti-mouse CD31, which stains mouse vessels, and pooled rat IgG are shown as controls
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Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits
Investigational New Drugs, 2008Co-Authors: Vinay Bhaskar, Melvin Fox, Danna Breinberg, Melanie H-l Wong, Pauline E. Wales, Susan Rhodes, Robert B. Dubridge, Vanitha RamakrishnanAbstract: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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a function blocking anti mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth in vivo
Journal of Translational Medicine, 2007Co-Authors: Vinay Bhaskar, Melvin Fox, Melanie H-l Wong, Robert B. Dubridge, Dongping Zhang, Pui Seto, Pauline Wales, David M W Powers, Debra T Chao, Vanitha RamakrishnanAbstract:Background: Integrins are important adhesion molecules that regulate tumor and endothelial cell survival, proliferation and migration. The integrin α5β1 has been shown to play a critical role during angiogenesis. An inhibitor of this integrin, Volociximab (M200), inhibits endothelial cell growth and movement in vitro, independent of the growth factor milieu, and inhibits tumor growth in vivo in the rabbit VX2 carcinoma model. Although Volociximab has already been tested in open label, pilot phase II clinical trials in melanoma, pancreatic and renal cell cancer, evaluation of the mechanism of action of Volociximab has been limited because this antibody does not cross-react with murine α5β1, precluding its use in standard mouse xenograft models. Methods: We generated a panel of rat-anti-mouse α5β1 antibodies, with the intent of identifying an antibody that recapitulated the properties of Volociximab. Hybridoma clones were screened for analogous function to Volociximab, including specificity for α5β1 heterodimer and blocking of integrin binding to fibronectin. A subset of antibodies that met these criteria were further characterized for their capacities to bind to mouse endothelial cells, inhibit cell migration and block angiogenesis in vitro. One antibody that encompassed all of these attributes, 339.1, was selected from this panel and tested in xenograft models. Results: A panel of antibodies was characterized for specificity and potency. The affinity of antibody 339.1 for mouse integrin α5β1 was determined to be 0.59 nM, as measured by BIAcore. This antibody does not significantly cross-react with human integrin, however 339.1 inhibits murine endothelial cell migration and tube formation and elicits cell death in these cells (EC 50 = 5.3 nM). In multiple xenograft models, 339.1 inhibited the growth of established tumors by 40–60% (p < 0.05) and this inhibition correlates with a concomitant decrease in vessel density.
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m200 Volociximab a chimeric antibody against integrin alpha5 beta1 inhibits tumor growth by multiple mechanisms
Cancer Research, 2005Co-Authors: Vinay Bhaskar, Melvin Fox, Danna Breinberg, Robert B. Dubridge, Pauline Wales, Eric Ibsen, Yuni Fang, Chris Ohara, Melanie Wong, Richard MurrayAbstract:Proc Amer Assoc Cancer Res, Volume 46, 2005 4497 Interactions between cells and extracellular matrix (ECM) proteins in the tumor microenvironment are mediated by heterodimeric integrins. One such integrin, alpha5 beta1, mediates adhesion and migration towards fibronectin via a highly conserved RGD sequence. We have found, through immunohistochemical analysis of human tumor tissue, that integrin alpha5 beta1 is highly expressed on the surface of tumor epithelial cells, as well as endothelial cells that make up the invading neovasculature. In vitro , a high-affinity function-blocking antibody against alpha5 beta1, M200, was found to inhibit the proliferation of human endothelial cells by a mechanism that involves cell death. A significant proportion of cancer cell lines tested retained a high level of surface alpha5 beta1 in vitro . In proliferation assays, a subset of these cell lines was particularly sensitive to M200. In affected cell lines, M200 was found to inhibit proliferation on fibronectin, as well as other ECM proteins, even when added 24 hours after plating. The effects on proliferation were due, at least in part, to the ability of M200 to induce cell death in these cell lines. M200 cross-reacts with rabbit, but not rodent, alpha5 beta1, therefore, a rabbit neovascularization model was chosen to evaluate the potency of M200 in vivo . M200 was found to exert a statistically significant effect in inhibiting angiogenesis in this setting. We are currently assessing possible anti-tumor effects using the rabbit VX2 carcinoma model. These data suggest that M200 inhibits tumor growth by targeting cancer cells directly, in addition to endothelial cells in the tumor neovasculature.
Robert B. Dubridge - One of the best experts on this subject based on the ideXlab platform.
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A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth -1
2011Co-Authors: Vinay Bhaskar, Melvin Fox, Melanie H-l Wong, Pauline E. Wales, Robert B. Dubridge, Pui Seto, Debra T Chao, Dong Zhang, David Powers, Vanitha RamakrishnanAbstract:Copyright information:Taken from "A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth "http://www.translational-medicine.com/content/5/1/61Journal of Translational Medicine 2007;5():61-61.Published online 27 Nov 2007PMCID:PMC2235829. Fc fusion proteins, (A). A subset of competitive antibodies cross-reacted with human integrin. Antibodies were tested by immunohistochemistry for staining of sections from C32 melanoma (α5β1 negative) or MDA-MB-231 breast carcinoma (α5β1 positive) xenografts, (B). The majority of antibodies tested stained murine α5β1 on tumor vasculature, but only antibodies found to cross-react with human α5β1 by ELISA specifically stained MDA-MB-231 xenograft cells as well. IIA1, the mouse parent antibody of Volociximab, which recognizes only human integrin, anti-mouse CD31, which stains mouse vessels, and pooled rat IgG are shown as controls
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Volociximab, a chimeric integrin alpha5beta1 antibody, inhibits the growth of VX2 tumors in rabbits
Investigational New Drugs, 2008Co-Authors: Vinay Bhaskar, Melvin Fox, Danna Breinberg, Melanie H-l Wong, Pauline E. Wales, Susan Rhodes, Robert B. Dubridge, Vanitha RamakrishnanAbstract: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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a function blocking anti mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth in vivo
Journal of Translational Medicine, 2007Co-Authors: Vinay Bhaskar, Melvin Fox, Melanie H-l Wong, Robert B. Dubridge, Dongping Zhang, Pui Seto, Pauline Wales, David M W Powers, Debra T Chao, Vanitha RamakrishnanAbstract:Background: Integrins are important adhesion molecules that regulate tumor and endothelial cell survival, proliferation and migration. The integrin α5β1 has been shown to play a critical role during angiogenesis. An inhibitor of this integrin, Volociximab (M200), inhibits endothelial cell growth and movement in vitro, independent of the growth factor milieu, and inhibits tumor growth in vivo in the rabbit VX2 carcinoma model. Although Volociximab has already been tested in open label, pilot phase II clinical trials in melanoma, pancreatic and renal cell cancer, evaluation of the mechanism of action of Volociximab has been limited because this antibody does not cross-react with murine α5β1, precluding its use in standard mouse xenograft models. Methods: We generated a panel of rat-anti-mouse α5β1 antibodies, with the intent of identifying an antibody that recapitulated the properties of Volociximab. Hybridoma clones were screened for analogous function to Volociximab, including specificity for α5β1 heterodimer and blocking of integrin binding to fibronectin. A subset of antibodies that met these criteria were further characterized for their capacities to bind to mouse endothelial cells, inhibit cell migration and block angiogenesis in vitro. One antibody that encompassed all of these attributes, 339.1, was selected from this panel and tested in xenograft models. Results: A panel of antibodies was characterized for specificity and potency. The affinity of antibody 339.1 for mouse integrin α5β1 was determined to be 0.59 nM, as measured by BIAcore. This antibody does not significantly cross-react with human integrin, however 339.1 inhibits murine endothelial cell migration and tube formation and elicits cell death in these cells (EC 50 = 5.3 nM). In multiple xenograft models, 339.1 inhibited the growth of established tumors by 40–60% (p < 0.05) and this inhibition correlates with a concomitant decrease in vessel density.
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m200 Volociximab a chimeric antibody against integrin alpha5 beta1 inhibits tumor growth by multiple mechanisms
Cancer Research, 2005Co-Authors: Vinay Bhaskar, Melvin Fox, Danna Breinberg, Robert B. Dubridge, Pauline Wales, Eric Ibsen, Yuni Fang, Chris Ohara, Melanie Wong, Richard MurrayAbstract:Proc Amer Assoc Cancer Res, Volume 46, 2005 4497 Interactions between cells and extracellular matrix (ECM) proteins in the tumor microenvironment are mediated by heterodimeric integrins. One such integrin, alpha5 beta1, mediates adhesion and migration towards fibronectin via a highly conserved RGD sequence. We have found, through immunohistochemical analysis of human tumor tissue, that integrin alpha5 beta1 is highly expressed on the surface of tumor epithelial cells, as well as endothelial cells that make up the invading neovasculature. In vitro , a high-affinity function-blocking antibody against alpha5 beta1, M200, was found to inhibit the proliferation of human endothelial cells by a mechanism that involves cell death. A significant proportion of cancer cell lines tested retained a high level of surface alpha5 beta1 in vitro . In proliferation assays, a subset of these cell lines was particularly sensitive to M200. In affected cell lines, M200 was found to inhibit proliferation on fibronectin, as well as other ECM proteins, even when added 24 hours after plating. The effects on proliferation were due, at least in part, to the ability of M200 to induce cell death in these cell lines. M200 cross-reacts with rabbit, but not rodent, alpha5 beta1, therefore, a rabbit neovascularization model was chosen to evaluate the potency of M200 in vivo . M200 was found to exert a statistically significant effect in inhibiting angiogenesis in this setting. We are currently assessing possible anti-tumor effects using the rabbit VX2 carcinoma model. These data suggest that M200 inhibits tumor growth by targeting cancer cells directly, in addition to endothelial cells in the tumor neovasculature.
