Antibodies and Fc receptors in autoimmunedisease, infections and cancer
@ Jeanette Leusen
The Immunotherapy group studies the working mechanisms of therapeutic antibodies and the biology of Fc receptors. As therapy for cancer, monoclonal antibodies are used that specifically target tumor cells, leading to disruption of cancer cell activities or to enhancement of the immune response against the cancer. In the clinic, an antibody called rituximab (rituxan) is used for patients with non-Hodgkin's lymphoma, trastuzumab (herceptin) for treatment of certain breast cancers, and bevacizumab (avastin) for colorectal cancer and other metastatic cancers. Although clinical results are promising, therapeutic responses to antibody therapy remain heterogeneous. It is crucial to better understand the in vivo action of therapeutic antibodies.
Previous work showed clinical responses induced by cancer therapeutic antibodies to critically depend on immune cell Fc receptor interaction. Fc receptors bind the constant part or Fc part of antibodies. Fc receptors are expressed on immune cells and induce phagocytosis, cellular cytotoxicity and facilitate antigen presentation: in mice lacking Fc receptors, cancer therapeutic antibodies lose their effect on tumor growth, and in cancer patients FcR polymorphisms directly impact therapeutic responses to antibodies like rituximab.
At present, the immunotherapy group investigates the underlying mechanisms of Fc-mediated therapeutic antibody function on two levels: 1) signaling required from Fc receptors 'outside-in' killer immune cells, and 2) 'inside-out' control of Fc receptors.
We recently developed a unique transgenic mouse, which is selectively deficient in Fc receptor signaling. In a panel of tumormodels we plan to address the first issue. The second issue will be studied with novel tools that we plan to develop to selectively monitor whether Fc receptors are "on" or "off", in vitro, and in vivo in mouse models. The signaling of FcγRI and FcαRI is studied in more detail.
- Laura Meulenbroek, Post doc
- Toine ten Broeke, Post doc
- Gerco den Hartog, Post doc
- Saskia Meyer, PhD student
- Shamir Jacobino, PhD student
- Marco Jansen, technician
- Maaike Nederend, technician
- Petra Moerer, technician
- Mojtaba Amini, technician
- Tamar Grevelink, master-student
- Thierry Noorbergen, master-student
Mechanisms of action of CD20 antibodies.
P. Boross and J.H.W. Leusen. Am J Cancer Res. 2012 2:676-690
Cutting edge: FcγRIII (CD16) and FcγRI (CD64) are responsible for anti-glycoprotein 75 monoclonal antibody TA99 therapy for experimental metastatic B16 melanoma.
M. Albanesi, D.A. Mancardi, L.E. Macdonald, B. Iannascoli, L. Zitvogel, A.J. Murphy, M. Daëron, J.H.W. Leusen, P. Bruhns. J Immunol. 2012 189:5513-5517. Erratum in: J Immunol. 2013 190:1381
Immunoreceptors: evolution, structure and therapeutic applications.
J.H.W. Leusen. EMBO Rep. 2012 13 :1046
Crosstalk between Human IgG Isotypes and Murine Effector Cells.
M.B. Overdijk, S. Verploegen, A. Ortiz Buijsse, T. Vink, J.H.W. Leusen, W.K. Bleeker, P.W. Parren. J Immunol. 2012 189:3430-3438
Boosting antibody therapy with complement.
P. Boross, J.H.W. Leusen. Blood. 2012 119:5945-59457
The in vivo mechanism of action of CD20 monoclonal antibodies depends on local tumor burden.
P. Boross, M.J.H. Jansen, S. de Haij, F.J. Beurskens, C.E. van der Poel, L. Bevaart, M. Nederend, J. Golay, J.G.J. van de Winkel, P.W. Parren, J.H.W. Leusen. Haematologica. 2011 Aug 31
. [Epub ahead of print].
Functional Characteristics of the High Affinity IgG Receptor, FcgammaRI.
C.E. van der Poel, R.M. Spaapen, J.G.J. van de Winkel, J.H.W. Leusen. J Immunol. 2011 Mar 1;186(5):2699-704
Cytokine induced immune complex binding to the high affinity IgG receptor, FcγRI, in the presence of monomeric IgG.
C.E. van der Poel, R.A. Karssemeijer, P. Boross, J.A. van der Linden, M. Blokland, J.G.J. van de Winkel, J.H.W. LeusenBlood. 2010 Dec 9;116(24):5327-33
. Epub 2010 Aug 30.
c-Jun activating binding protein 1 binds to the IgA receptor and modulates protein levels of FcalphaRI and FcRgamma-chain.
J.E. Bakema, I.H.Hiemstra, , J. Bakker, S. de Haij, Y. Kok, G. Adema, M. van Egmond, P.J. Coffer, J.G.J. van de Winkel, and J.H.W. Leusen. Eur. J. Immunol. 2010 40:2035-2040
In vivo cytotoxicity of type I CD20 antibodies critically depends on Fc receptor ITAM signaling.
S. de Haij, J.H.M. Jansen, P. Boross, F.J. Beurskens, J.E. Bakema, D.L. Bos, A. Martens, J. S. Verbeek, P.W.H.I. Parren, J.G.J. van de Winkel and J.H.W. Leusen. Cancer Research. 2010 70:3209-17
Inside-out regulation of Fc alpha RI (CD89) depends on PP2A
J.E. Bakema, A. Bakker, S. de Haij, H. Honing, M. Bracke, L. Koenderman, G. Vidarsson, J.G.J. van de Winkel, J.H.W. LeusenJ Immunol. 2008 Sep 15;181(6):4080-8
Filamin A stabilizes FcgRI surface expression and prevents its lysosomal routing.
J.M. Beekman, C.E. van der Poel, J. van der Linden, D.L.C. van den Berg, P.V.E. van den Berghe, J.M. Griffith, M.J. Kleijmeer, J.G.J. van de Winkel, and J.H.W. Leusen.J. Immunol., 2008 180:3938-45
Signaling through mutants of the IgA receptor, CD89, and consequences for FcR g-chain interaction.
J.E. Bakema, S.de Haij, C.F.den Hartog-Jager, J.Bakker, G.Vidarsson, M. van Egmond, J.G.J. van de Winkel, and J.H.W. Leusen. J. Immunol., 2006 Mar; 176: 3603 - 3610
The high affinity IgG receptor, FcgRI, plays a central role in antibody therapy of experimental melanoma.
L. Bevaart, M.J.H. Jansen, M.J. van Vugt, J.S. Verbeek, J.G.J. van de Winkel, and J.H.W. Leusen. Cancer Research, 2006 Feb 1;66(3):1261-4
Direct interaction between FcgammaRI (CD64) and periplakin controls receptor endocytosis and ligand binding capacity.
J.M. Beekman, J.E. Bakema, J.G.J. van de Winkel, J.H.W. Leusen Proc Natl Acad Sci USA 2004 101:10392-7
Financial support from Genmab
'Contribution of ADCC to tumor therapy in vivo'
'Improved immunization method for antibody production'
AICR grant 11-012
‘IgA as new therapeutic antibody’
UU ERC stimuleringssubsidie
‘Immunoglobulin A as new therapeutic antibody for Influenza’
2011 – 2015
Synthon financial support
‘Improved therapeutic antibodies’
2012 - 2013
Immune regulation by cow's milk
2012 - 2013
ADCC capacity of novel therapeutic antibodies