A humanized CD3ε-knock-in mouse model for pre-clinical testing of anti-human CD3 therapy

Pre-clinical murine models are critical for translating drug candidates from the bench to the bedside. There is interest in better understanding how anti-human CD3 therapy works based on recent longitudinal studies of short-term administration. Although several models have been created in this pursu...

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Veröffentlicht in:PloS one 2021-02, Vol.16 (2), p.e0245917-e0245917
Hauptverfasser: Crespo, Joel, Koh, Yi Ting, Hu, Ningjie, Moore, Paul A, Bonvini, Ezio, Glasebrook, Andrew L, Martin, Andrea P, Benschop, Robert J
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Sprache:eng
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Zusammenfassung:Pre-clinical murine models are critical for translating drug candidates from the bench to the bedside. There is interest in better understanding how anti-human CD3 therapy works based on recent longitudinal studies of short-term administration. Although several models have been created in this pursuit, each have their own advantages and disadvantages in Type-1 diabetes. In this study, we report a murine genetic knock-in model which expresses both a murine and a humanized-CD3ε-exon, rendering it sensitive to manipulation with anti-human CD3. These huCD3εHET mice are viable and display no gross abnormalities. Specifically, thymocyte development and T cell peripheral homeostasis is unaffected. We tested immune functionality of these mice by immunizing them with T cell-dependent antigens and no differences in antibody titers compared to wild type mice were recorded. Finally, we performed a graft-vs-host disease model that is driven by effector T cell responses and observed a wasting disease upon transfer of huCD3εHET T cells. Our results show a viable humanized CD3 murine model that develops normally, is functionally engaged by anti-human CD3 and can instruct on pre-clinical tests of anti-human CD3 antibodies.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0245917