Abstract
Abstract Experimental systems to effectively evaluate therapeutic antibodies are urgently needed. One of the mechanisms used by antibodies to kill tumor cells is antibody-dependent cellular cytotoxicity (ADCC) in which natural killer cells (NK) are the main mediator. The generation of humanized mice as immunodeficient mice (such as NOG) engrafted with hematopoietic stem cells (HSC) demonstrated their usefulness for studying the human immune system. Nevertheless, one issue of this humanized model is the incomplete maturation of NK cells. To circumvent this lack of functionality the Central Institute for Experimental Animals (CIEA) has developed the second generation of transgenic NOG mice expressing human IL2 or IL15 (NK-NOG). hIL-2 and hIL-15 NOG mice were generated by microinjection of DNA fragments containing human IL-2 cDNA or human IL-15 cDNA replaced with a hIL-2 signal peptide, under the control of a CMV-promoter, into fertilized eggs of NOD-IL-2Rgnull mice. The serum levels of hIL-2 and hIL-15 in mice were 1-2 and 0.1-0.2 ng/mL, respectively. Humanization of NK-NOG mice was validated using freshly collected or frozen hematopoietic stem cells (HSCs) in transgenic NK-NOG mice. The characterization of the reconstituted NK-NOG mice was done in peripheral blood as well as central lymphoid organs such as bone marrow and spleen using flow cytometry. Moreover, the human NK cell function was evidenced using an ex vivo 51Cr assay demonstrating lysis properties of NK cells from collected spleen. Finally in vivo NK-mediated ADCC was evaluated in IL2-NOG mice simultaneously engrafted with human immune system and human Burkitt's lymphoma. Reconstituted mice were treated with Rituximab to examine immune system-related antitumor activity. Genetic manipulation of the host continue to improve the ability of humanized mice to more accurately recapitulate the in vivo function of human immune cells such as NK cells. Prediction of ADCC-mediated antitumor activity of humanized antibodies is now routinely feasible for preclinical evaluation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B11. Citation Format: Caroline Mignard, Olivier Duchamp, Jean-François Mirjolet, Yasuyuki Ohnishi, Ikumi KATANO, Mamoru ITO. In vivo ADCC-mediated antitumor activity study with new preclinical humanized models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B11.
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