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Journal of Immunology Research
Volume 2015 (2015), Article ID 482089, 13 pages
http://dx.doi.org/10.1155/2015/482089
Research Article

In Vitro and In Vivo Comparison of Lymphocytes Transduced with a Human CD16 or with a Chimeric Antigen Receptor Reveals Potential Off-Target Interactions due to the IgG2 CH2-CH3 CAR-Spacer

1UMR INSERM U892, 8 Quai Moncousu, 44007 Nantes Cedex, France
2Centre Hospitalier Universitaire de Nantes, 1 Place Ricordeau, 44000 Nantes, France
3UMR INSERM 1052, Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France
4Genenthec Inc., South San Francisco, CA 94080, USA

Received 18 September 2015; Accepted 22 October 2015

Academic Editor: Roberta Castriconi

Copyright © 2015 Béatrice Clémenceau et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The present work was designed to compare two mechanisms of cellular recognition based on Ab specificity: firstly, when the anti-HER2 mAb trastuzumab bridges target cells and cytotoxic lymphocytes armed with a Fc receptor (ADCC) and, secondly, when HER2 positive target cells are directly recognized by cytotoxic lymphocytes armed with a chimeric antigen receptor (CAR). To compare these two mechanisms, we used the same cellular effector (NK-92) and the same signaling domain (FcεRIγ). The NK-92 cytotoxic cell line was transfected with either a FcγRIIIa-FcεRIγ () or a trastuzumab-based scFv-FcεRIγ chimeric receptor (). In vitro, the cytotoxic activity against HER2 positive target cells after indirect recognition by was always inferior to that observed after direct recognition by . In contrast, and somehow unexpectedly, in vivo, adoptive transfer of + trastuzumab but not of induced tumor regression. Analysis of the in vivo xenogeneic system suggested that the human CH2-CH3 IgG2 used as a spacer in our construct was able to interact with the FcR present at the cell surface of the few NSG-FcR+ remaining immune cells. This interaction, leading to blockage of the in the periphery of the engrafted tumor cells, stresses the critical role of the composition of the spacer domain.