Lab Leusen: Immunotherapy

 


Antibodies and Fc receptors in cancer, autoimmunediseases and infection

 

  University Medical Center Utrecht

  Heidelberglaan 100, 3584 CX

  Utrecht, The Netherlands

  E-mail: jleusen@umcutrecht.nl

 

 

Research interest

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

      - Milad Tannazi, student

      - Frederiek Reijneveld, master student

      - Mojtaba Amini, technician

      - Evelien Dueren den Hollander, master student

      - Petra Moerer, technician

      - Maaike Nederend, technician

      - Toine ten Broeke, Post-Doc

      - Saskia Meyer, PhD student

      - Marco Jansen, technician

      - Shamir Jacobino, AIO

      - Laura Meulenbroek, Post-Doc

      - Jeanette Leusen

      - Arianne Brandsma, AIO

 

Key publications

Specificity and effector functions of human RSV-specific IgG from bovine milk.
G. Den Hartog, S. Jacobino, L. Bont, L. Cox, L.H. Ulfman, R.J.J. van Neerven, and J.H.W. Leusen.
Plos one 2014 in press.

IgA EGFR antibodies mediate tumour killing in vivo.
Boross P, Lohse S, Nederend M, Jansen JH, van Tetering G, Dechant M, Peipp M, Royle L, Liew LP, Boon L, van Rooijen N, Bleeker WK, Parren PW, van de Winkel JG, Valerius T, J.H.W. Leusen.
EMBO Mol Med. 2013 Aug;5(8):1213-26

Boosting antibody therapy with complement.
P. Boross, J.H.W. Leusen.
Blood. 2012 Jun 21;119(25):5945-7

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 Dec;96(12):1822-30.

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.


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.

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
 

Current grants

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’

 

2011-2016

UU ERC stimulation grant

'IgA for viral infections'

 

2013-2017

STW grant MIRACLE

 

2014

FrieslandCampina

 

2014-2015

Genmab BV, research collaboration

Genetic polymorphisms