Interaction between Bevacizumab and Murine VEGF-A: A Reassessment

Yu, Lanlan; Wu, Xiumin; Cheng, Zhiyong; Lee, Chingwei V.; LeCouter, Jennifer; Campa, Claudio; Fuh, Germaine; Lowman, Henry B.; Ferrara, Napoleone

doi:10.1167/iovs.07-1175

Cited by 152 publications

(125 citation statements)

References 24 publications

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“…This can at least partially be explained by the fact that bevacizumab targets only human VEGF, which is produced by the implanted human tumor cells. In the human xenograft tumor models, murine VEGF also plays a role, but bevacizumab does not bind or neutralize murine VEGF (21,22). This assumption is supported by the finding that the radioactive bevacizumab tracer showed a lower tumor uptake in the preclinical setting than in patients (6,7).…”

Section: Discussionmentioning

confidence: 94%

Intraoperative Near-Infrared Fluorescence Tumor Imaging with Vascular Endothelial Growth Factor and Human Epidermal Growth Factor Receptor 2 Targeting Antibodies

Scheltinga¹,

Dam²,

Nagengast³

et al. 2011

J Nucl Med

177

141

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Fluorescence imaging is currently attracting much interest as a method for intraoperative tumor detection, but most current tracers lack tumor specificity. Therefore, this technique can be further improved by tumor-specific detection. With tumortargeted antibodies bound to a radioactive label, tumor-specific SPECT or PET is feasible in the clinical setting. The aim of the present study was to apply antibody-based tumor detection to intraoperative optical imaging, using preclinical in vivo mouse models. Methods: Anti-vascular endothelial growth factor (VEGF) antibody bevacizumab and anti-human epidermal growth factor receptor (HER) 2 antibody trastuzumab were labeled with the near-infrared (NIR) fluorescence dye IRDye 800CW. Tumor uptake of the fluorescent tracers and their 89 Zr-labeled radioactive counterparts for PET was determined in human xenograft-bearing athymic mice during 1 wk after tracer injection, followed by ex vivo biodistribution and pathologic examination. Intraoperative imaging of fluorescent VEGF-or HER2-positive tumor lesions was performed in subcutaneous tumors and in intraperitoneal dissemination tumor models. Results: Tumorto-background ratios, with fluorescent imaging, were 1.93 6 0.40 for bevacizumab and 2.92 6 0.29 for trastuzumab on day 6 after tracer injection. Real-time intraoperative imaging detected tumor lesions at even the submillimeter level in intraperitoneal dissemination tumor models. These results were supported by standard histology, immunohistochemistry, and fluorescence microscopy analyses. Conclusion: NIR fluorescence-labeled antibodies targeting VEGF or HER2 can be used for highly specific and sensitive detection of tumor lesions in vivo. These preclinical findings encourage future clinical studies with NIR fluorescence-labeled tumor-specific antibodies for intraoperative-guided surgery in cancer patients.

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Section: Discussionmentioning

confidence: 94%

Intraoperative Near-Infrared Fluorescence Tumor Imaging with Vascular Endothelial Growth Factor and Human Epidermal Growth Factor Receptor 2 Targeting Antibodies

Scheltinga¹,

Dam²,

Nagengast³

et al. 2011

J Nucl Med

177

141

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“…Therefore, the effects seen with this drug in preclinical in vivo models in various tumors cannot be attributed to the blocking of murine VEGF but rather blocking the effects of tumor-secreted VEGF on the murine vasculature (41). That this could well be the case in our model system is supported by the observation that recombinant human VEGF as well as conditioned medium from melanoma cells did stimulate the growth of murine endothelial cells in vitro, supporting a species-independent angiogenic effect of human VEGF, which has also been observed in a previous publication (42).…”

Section: Discussionmentioning

confidence: 99%

Erlotinib and Bevacizumab Have Synergistic Activity against Melanoma

Schicher

Paulitschke

Swoboda

et al. 2009

Clinical Cancer Research

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Purpose: Melanoma is one of the most aggressive types of cancer with currently no chance of cure once the disease has spread to distant sites. Therapeutic options for advanced stage III and IV are very limited, mainly palliative, and show response in only ∼20% of all cases. The presented preclinical study was done to investigate the influence of a combined treatment of the epidermal growth factor receptor inhibitor erlotinib and the vascular endothelial growth factor monoclonal antibody bevacizumab in melanoma. Experimental Design and Results: The epidermal growth factor receptor was expressed in all cell lines tested, and treatment with erlotinib did inhibit the activation of the MEK/ extracellular signal-regulated kinase and AKT signaling pathways. Whereas in vitro no influence on tumor cell proliferation was seen with erlotinib or bevacizumab monotherapy, a decreased invasive potential on erlotinib treatment in a three-dimensional Matrigel assay was observed. Furthermore, both drugs inhibited proliferation and sprouting of endothelial cells. In vivo, in a severe combined immunodeficient mouse xenotransplantation model, reduction in tumor volume under combined treatment with erlotinib and bevacizumab was superior to the additive effect of both single agents. This was associated with reduced cell proliferation, increased apoptosis, and a reduction in tumor angiogenesis compared with control or single treatment groups. Likewise, the reduction in the extent of lymph node and lung metastasis was most pronounced in animals treated with both drugs. Conclusion: The presented data strongly support the use of a combination of erlotinib and bevacizumab as a novel treatment regimen for metastatic melanoma.Malignant melanoma is the most aggressive type of skin cancer. It accounts for 3% of all skin cancers but is responsible for at least 80% of skin cancer-related deaths (1). The incidence of melanoma, especially among Caucasians, has been rapidly increasing within the last decades. The disease outcome of melanoma patients depends on depth of invasion of the primary tumor, tumor burden, ulceration, and sites of metastasis. Wide excision of malignant melanoma in early stages leads to complete cure and a 5-year survival rate of 95%. Involvement of the regional lymph node basin reduces the 5-year survival rates to as low as 26% and spreading to distant sites (lung, liver, and brain) decreases the 1-year survival to 41% and the 5-year survival rates to 14% (2). Despite many efforts to find improved therapeutic regimens, none was proven to be superior to cytostatic therapy with dacarbazine, which itself is associated with response rates of only 10% to 15% and rarely leads to complete remissions.Recently, novel targeted drugs directed against the epidermal growth factor (EGF) receptor (EGFR; erbB1) or the vascular endothelial growth factor (VEGF) have been shown to have significant clinical activity in different types of cancer (3-7).Signaling through the EGFR affects cellular functions from proliferation to differenti...

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“…We showed, in a separate experiment, that topical bevacizumab had no observable effect on inflammatory sprouting angiogenesis in our model. In the literature there are some controversy concerning the effect of bevacizumab on murine VEGF-A [16,25,27,28,31,32,35]. The effect of bevacizumab on murine VEGF, is possibly route and species dependent [16,22,25,28,31,32].…”

Section: In Vivo Imaging Of Human Corneal Capillary Regression: Repormentioning

confidence: 99%

Cellular level characterization of capillary regression in inflammatory angiogenesis using an in vivo corneal model

2011

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Abstract:In this study, we introduce a technique for repeated, microscopic observation of single regressing capillaries in vivo in inflamed murine corneas. Natural capillary regression was initiated by removal of inflammatory stimulus during an active pro-angiogenic phase, while the additional impact of anti-angiogenic treatment with triamcinolone or bevazicumab was investigated. Capillaries regressed naturally within one week and treatments did not further enhance the natural regression. Morphologically, early-phase regression was characterized by significant lumen narrowing and a significant reduction in CD11b+ myeloid cell infiltration of the extracellular matrix. By one week, vascular remodeling occurred concomitant with CD11b+CD68+KiM2R+ mature macrophage localization on capillary walls. Empty conduits without blood flow, positive for collagen IV and devoid of vascular endothelium and pericytes, were apparent in vivo and by three weeks were more numerous than perfused capillaries. By three weeks, macrophages aggregated around remaining perfused capillaries and were observed in apposition with degrading capillary segments. Abrupt termination of capillary sprouting in our regression model further revealed vascular endothelial abandonment of sprout tips and perfused capillary loop formation within a single angiogenic sprout, possibly as an intussusceptive response to cessation of the stimulus. Finally, we observed lumen constriction and macrophage localization on capillary walls in vivo in a clinical case of corneal capillary regression that paralleled findings in our murine model.

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Interaction between Bevacizumab and Murine VEGF-A: A Reassessment

Abstract: Bevacizumab has an extremely weak interaction with mVEGF-A, which fails to result in immunoneutralization as assessed by several bioassays.

Cited by 152 publications

References 24 publications

Intraoperative Near-Infrared Fluorescence Tumor Imaging with Vascular Endothelial Growth Factor and Human Epidermal Growth Factor Receptor 2 Targeting Antibodies

Intraoperative Near-Infrared Fluorescence Tumor Imaging with Vascular Endothelial Growth Factor and Human Epidermal Growth Factor Receptor 2 Targeting Antibodies

Erlotinib and Bevacizumab Have Synergistic Activity against Melanoma

Cellular level characterization of capillary regression in inflammatory angiogenesis using an in vivo corneal model

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