Platelets take up the monoclonal antibody bevacizumab

Henk M W Verheul, Martijn P J Lolkema, David Z. Qian, Yvonne H A Hilkes, Eleni Liapi, Jan Willem N Akkerman, Roberto Pili, Emile E. Voest

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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.

Original languageEnglish (US)
Pages (from-to)5341-5347
Number of pages7
JournalClinical Cancer Research
Volume13
Issue number18
DOIs
StatePublished - Sep 15 2007
Externally publishedYes

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Blood Platelets
Monoclonal Antibodies
Vascular Endothelial Growth Factor A
Fluorescein-5-isothiocyanate
Bevacizumab
P-Selectin
Angiogenesis Inducing Agents
Platelet Activation
Endocytosis
Fluorescence Microscopy
Wound Healing
Fluorescent Antibody Technique
Immunoglobulins
Blood Proteins
Neoplasms
Intercellular Signaling Peptides and Proteins
Flow Cytometry
Research Design
Endothelial Cells
Western Blotting

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Verheul, H. M. W., Lolkema, M. P. J., Qian, D. Z., Hilkes, Y. H. A., Liapi, E., Akkerman, J. W. N., ... Voest, E. E. (2007). Platelets take up the monoclonal antibody bevacizumab. Clinical Cancer Research, 13(18), 5341-5347. https://doi.org/10.1158/1078-0432.CCR-07-0847

Platelets take up the monoclonal antibody bevacizumab. / Verheul, Henk M W; Lolkema, Martijn P J; Qian, David Z.; Hilkes, Yvonne H A; Liapi, Eleni; Akkerman, Jan Willem N; Pili, Roberto; Voest, Emile E.

In: Clinical Cancer Research, Vol. 13, No. 18, 15.09.2007, p. 5341-5347.

Research output: Contribution to journalArticle

Verheul, HMW, Lolkema, MPJ, Qian, DZ, Hilkes, YHA, Liapi, E, Akkerman, JWN, Pili, R & Voest, EE 2007, 'Platelets take up the monoclonal antibody bevacizumab', Clinical Cancer Research, vol. 13, no. 18, pp. 5341-5347. https://doi.org/10.1158/1078-0432.CCR-07-0847
Verheul HMW, Lolkema MPJ, Qian DZ, Hilkes YHA, Liapi E, Akkerman JWN et al. Platelets take up the monoclonal antibody bevacizumab. Clinical Cancer Research. 2007 Sep 15;13(18):5341-5347. https://doi.org/10.1158/1078-0432.CCR-07-0847
Verheul, Henk M W ; Lolkema, Martijn P J ; Qian, David Z. ; Hilkes, Yvonne H A ; Liapi, Eleni ; Akkerman, Jan Willem N ; Pili, Roberto ; Voest, Emile E. / Platelets take up the monoclonal antibody bevacizumab. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 18. pp. 5341-5347.
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AU - Qian, David Z.

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AU - Liapi, Eleni

AU - Akkerman, Jan Willem N

AU - Pili, Roberto

AU - Voest, Emile E.

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