Platelets Take Up the Monoclonal Antibody Bevacizumab
- 15 September 2007
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 13 (18), 5341-5347
- https://doi.org/10.1158/1078-0432.ccr-07-0847
Abstract
Purpose: One of the key factors that promotes angiogenesis is vascular endothelial growth factor (VEGF). Platelets are the main source of VEGF in blood and contribute to angiogenesis by release of growth factors, including VEGF, from their α-granules on activation. The monoclonal antibody bevacizumab blocks VEGF in the blood of patients within hours after administration. Platelets are known to endocytose plasma proteins including immunoglobulins. We tested the hypothesis that platelets take up bevacizumab. Experimental Design: Fluorescence-activated cell sorting analysis, immunofluorescence imaging, and Western blotting were used to study uptake and release of bevacizumab by platelets in vitro and in vivo. The angiogenic activity of platelets preincubated with bevacizumab was studied in endothelial proliferation assays. Finally, we determined whether treatment with bevacizumab neutralizes VEGF in platelets from cancer patients. Results: We found that platelets are able to take up bevacizumab. Activation of platelets preincubated with bevacizumab resulted in release of the antibody and release of VEGF neutralized by bevacizumab. Immunofluorescence microscopy revealed that FITC-labeled bevacizumab and P-selectin colocalize, indicating α-granule localization. In addition, bevacizumab uptake inhibited platelet-induced human endothelial cell proliferation. In in vivo rabbit experiments, FITC-labeled bevacizumab was present in platelets after 2 h and up to 2 weeks following i.v. administration. Finally, we found that platelets take up bevacizumab in patients receiving bevacizumab treatment. Within 8 h after bevacizumab administration, platelet VEGF was almost completely neutralized due to this uptake. Conclusion: These studies show that bevacizumab is taken up by platelets and may explain its clinical effect on wound healing and tumor growth.Keywords
This publication has 26 references indexed in Scilit:
- Vascular Endothelial Growth Factor Levels in Immunodepleted Plasma of Cancer Patients As a Possible Pharmacodynamic Marker for Bevacizumab ActivityJournal of Clinical Oncology, 2007
- Angiogenesis as a therapeutic targetNature, 2005
- From the bench to the bedside: ways to improve rituximab efficacyBlood, 2004
- The Histone Deacetylase Inhibitor NVP-LAQ824 Inhibits Angiogenesis and Has a Greater Antitumor Effect in Combination with the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor PTK787/ZK222584Cancer Research, 2004
- Differential role of platelet granular mediators in angiogenesisCardiovascular Research, 2004
- Targeting Vascular Endothelial Growth Factor for Relapsed and Refractory Adult Acute Myelogenous LeukemiasClinical Cancer Research, 2004
- Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancerNature Reviews Drug Discovery, 2004
- Platelets and cancer metastasis: A causal relationship?Cancer and Metastasis Reviews, 1992
- Incorporation of intravenously injected albumin, immunoglobulin G, and fibrinogen in guinea pig megakaryocyte granules.JCI Insight, 1989
- Antimetastatic effects associated with platelet reduction.Proceedings of the National Academy of Sciences, 1968