In vivo Cytotoxicity of Type I CD20 Antibodies Critically Depends on Fc Receptor ITAM Signaling

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BlankCancer Research 70, 3209, April 15, 2010. Published Online First March 30,

2010;

doi: 10.1158/0008-5472.CAN-09-4109

In vivo Cytotoxicity of Type I CD20 Antibodies Critically Depends on Fc Receptor

ITAM Signaling

Simone de Haij1,2, J.H. Marco Jansen2, Boross2, J. Beurskens1,

Jantine E. Bakema2, L. Bos2, Anton Martens2, J. Sjef Verbeek3,

W.H.I. Parren1, Jan G.J. van de Winkel1 and Jeanette H.W. Leusen2

Authors' Affiliations: 1 Genmab; 2 Immunotherapy Laboratory, Department of

Immunology, University Medical Center, Utrecht, the Netherlands and 3 Department

of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

Corresponding Author: Jeanette H.W. Leusen, Immunotherapy Laboratory KC

02.085.2, Department of Immunology, University Medical Center, Lundlaan 6, 3584

EA Utrecht, the Netherlands. Phone: 31-88-7554268; Fax: 31-88-7554305; E-mail:

jleusen@... .

Antibody–Fc receptor (FcR) interactions play an important role in the mechanism

of action of most therapeutic antibodies against cancer. Effector cell

activation through FcR triggering may induce tumor cell killing via

antibody-dependent cellular cytotoxicity (ADCC). Reciprocally, FcR cross-linking

of antibody may lead to the induction of apoptotic signaling in tumor cells. The

relative importance of these bisecting pathways to in vivo antibody activity is

unknown. To unravel these roles, we developed a novel mouse model with normal

FcR expression but in which FcR signaling was inactivated by mutation of the

associated gamma-chain. Transgenic mice showed similar immune complex binding

compared with wild-type mice. In contrast, ADCC of cells expressing frequently

used cancer targets, such as CD20, epidermal growth factor receptor, Her2, and

gp75, was abrogated. Using the therapeutic CD20 antibodies ofatumumab and

rituximab, we show that FcR cross-linking of antibody-antigen immune complexes

in the absence of gamma-chain signaling is insufficient for their therapeutic

activity in vivo. ADCC therefore represents an essential mechanism of action for

immunotherapy of lymphoid tumors. Cancer Res; 70(8); 3209–17. ©2010 AACR.

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