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, theapeutic 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 FcgRI
and FcaRI
is studied in more detail.
Members
- Peter Boross, Post doc
- Geert Tetering, scientist
- Marco Jansen, technician
- Maaike Nederend, technician
- Jan Meeldijk, technician
- Christian Bertens,
student technician
- Arianne Brandsma, master
student
Functional Characteristics of the High Affinity IgG
Receptor, FcgammaRI.
van der Poel CE, Spaapen RM, van de Winkel JGJ, Leusen
JHW.
J
Immunol. 2011 Mar 1;186(5):2699-704.
Expression of CD64 (FcγRI) in skin of patients with
acute GVHD.
van Royen-Kerkhof A, Walraven V, Sanders EA, de Weger R,
van Wichen DF, de Koning E, Thepen T, van de Winkel JGJ,
Leusen JHW.
Bone Marrow Transplant. 2011 Jan 17
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. Leusen
Blood. 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
Bakema JE, Bakker A, de Haij S, Honing H, Bracke M,
Koenderman L, Vidarsson G, van de Winkel JGJ, Leusen JHW
J 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.
Beekman J.M, Bakema J.E, van de Winkel J.G.J, Leusen
J.H.W
Proc Natl Acad Sci USA 2004 101:10392-7
2006-2011
Genmab
BV, research collaboration
'Contribution of ADCC to tumor therapy in vivo'
'Improved immunization method for antibody production'
2011-2012
IICU Seeding Grant, shared with Dr. R. Wubbolts, DGK UU
‘Fc receptor regulated antigen presentation by dendritic
cells’
2011-2014
AICR grant 11-012
‘IgA as new therapeutic antibody’
2010-2015
Synthon BV, research collaboration
‘Kinetics of antibodies in vivo’
‘Improved therapeutic antibodies’