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J.H.W. (Jeanette) Leusen, PhD

Tuesday 23 October 2012

Dr. J. (Jeanette) Leusen
Laboratory for Immunotherapy
Department of Immunology, UMC Utrecht

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 cetuximab (erbitux) 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 rituxan.

At present, all antibody therapeutics are of the IgG isotype. The immunotherapy group investigates IgA as a novel therapeutic antibody. IgA recruits diffent effectorcells than IgG, i.e. neutrophils. In vitro, it has been demonstrated that IgA is superior in killing tumorcells. In vivo, IgA was not tested until recently, because it is difficult to produce and purify enough recombinant IgA, and mouse do not have the receptor for IgA. In the immunotherapy lab we have solved both issues, and tested for the first time the efficacy of human IgA against solid tumors in an FcαR transgenic mouse, developed within the immunotherapy lab. As it turned out, IgA is also in vivo very effective as a therapeutic antibody. Surprisingly, macrophages were the most important effectorcells in these studies. In the near future, we would like to address 2 challenges for the IgA work: 1) how to extend the half-life of IgA in vivo 2) what is the underlying mechanism of superior tumorkill by IgA? These questions will be answered in new projects within the Immunotherapy group.

Group members
• Toine ten Broeke, Post doc
• Arianne Brandsma, PhD student
• Saskia Meyer, PhD student
• Shamir Jacobino, PhD student
• Marco Jansen, technician
• Maaike Nederend, technician
• Petra Moerer, technician
• Mojtaba Amini, technician
• Evelien van Dueren den Hollander, master-student
• Frederiek Reijneveld, master-student

Key papers
Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer.
Meyer S, Leusen JHW, Boross P.
MAbs. 2014 Sep 3;6(5):1133-44. doi: 10.4161/mabs.29670. Epub 2014 Oct 30.

FcRγ-chain ITAM signaling is critically required for cross-presentation of soluble antibody-antigen complexes by dendritic cells.
Boross P, van Montfoort N, Stapels DA, van der Poel CE, Bertens C, Meeldijk J, Jansen JH, Verbeek JS, Ossendorp F, Wubbolts R, Leusen JH.
J Immunol. 2014 Dec 1;193(11):5506-14. doi: 10.4049/jimmunol.1302012. Epub 2014 Oct 29.

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, Leusen JH.
EMBO Mol Med. 2013 Aug;5(8):1213-26. doi: 10.1002/emmm.201201929.
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. 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
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. Leusen
J Immunol. 2008 Sep 15;181(6):4080-8

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