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* Klinik I für Innere Medizin, Tumorgenetik, Kliniken der Universität zu Köln and Zentrum für Molekulare Medizin Köln, Köln, Germany;
Fraunhofer Institute for Molecular Biology and Applied Ecology, Pharmaceutical Product Development, Aachen, Germany; and
Cancer Research U.K. Department of Medical Oncology, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom
Recombinant TCRs confer specificity to T cells and trigger their activation. Receptors with Ab-derived binding domains have the advantages of MHC-independent Ag recognition and of targeting a variety of chemically different molecules. We explored the impact of the position of a defined epitope within the target molecule on the efficacy of receptor-mediated T cell activation. T cells were grafted with recombinant immunoreceptors that recognize either the membrane distal N or the proximal A3 domain of carcinoembryonic Ag (CEA). Upon binding to isolated, solid-phase immobilized CEA, receptor-mediated T cell activation correlates with the binding efficiency, irrespectively, of the epitope position. Upon binding to CEA expressed on the cell membrane, in contrast, the A3 epitope mediates more efficiently T cell activation than the N epitope, although the N epitope is bound with higher affinity. The CEA N epitope when expressed in a more membrane proximal position, however, activated receptor grafted T cells with higher efficiency than in the distal position. The position of the targeted epitope within the molecule obviously has major impact on the efficacy of T cell activation independently of the binding efficiency of the immunoreceptor.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by grants from the Deutsche Forschungsgemeinschaft, Bonn; Deutsche Krebshilfe, Bonn; Wilhelm Sander-Stiftung, Munich, the Köln Fortune Programm; Cancer Research U.K.; and the ATTACK Programme of the European Union.
2 Current address: Klinik für Hämatologie, Onkologie und Klinische Immunologie, Heinrich Heine Universität, Düsseldorf, Germany.
3 Current address: Dyax s.a. Lead Discovery, Liège, Belgium.
4 Address correspondence and reprint requests to Dr. Hinrich Abken, Klinik I für Innere Medizin, Labor für Tumorgenetik, Universität zu Köln, Josef-Stelzmann Strasse 9, Köln, Germany. E-mail address: hinrich.abken{at}uk-koeln.de
5 Abbreviations used in this paper: scFv, single-chain fragment; MFI, mean fluorescence intensity; XTT, 2,3-bis(2-methoxy-4-nitro-5-sulfonyl)-5[(phenyl-amino)carbonyl]-2H-tetrazolium hydroxide; CEA, carcinoembryonic Ag; BSM, bovine submaxillary mucin.
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