TGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model.
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AbstractTherapeutic monoclonal antibodies (mAbs) such as the superagonistic, CD28-specific antibody TGN1412, or OKT3, an anti-CD3 mAb, can cause severe adverse events including cytokine release syndrome. A predictive model for mAb-mediated adverse effects, for which no previous knowledge on severe adverse events to be expected or on molecular mechanisms underlying is prerequisite, is not available yet. We used a humanized mouse model of human peripheral blood mononuclear cell-reconstituted NOD-RAG1-/-Aβ-/-HLADQ(tg+ or tg-)IL-2Rγc-/- mice to evaluate its predictive value for preclinical testing of mAbs. 2-6 hours after TGN1412 treatment, mice showed a loss of human CD45+ cells from the peripheral blood and loss of only human T cells after OKT3 injection, reminiscent of effects observed in mAb-treated humans. Moreover, upon OKT3 injection we detected selective CD3 downmodulation on T cells, a typical effect of OKT3. Importantly, we detected release of human cytokines in humanized mice upon both OKT3 and TGN1412 application. Finally, humanized mice showed severe signs of illness, a rapid drop of body temperature, and succumbed to antibody application 2-6 hours after administration. Hence, the humanized mouse model used here reproduces several effects and adverse events induced in humans upon application of the therapeutic mAbs OKT3 and TGN1412.
CitationTGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model. 2016, 11 (3):e0149093 PLoS ONE
AffiliationHelmholtzzentrum für Infektionsforschung
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- A whole blood in vitro cytokine release assay with aqueous monoclonal antibody presentation for the prediction of therapeutic protein induced cytokine release syndrome in humans.
- Authors: Wolf B, Morgan H, Krieg J, Gani Z, Milicov A, Warncke M, Brennan F, Jones S, Sims J, Kiessling A
- Issue date: 2012 Dec
- A non-activating "humanized" anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo.
- Authors: Alegre ML, Peterson LJ, Xu D, Sattar HA, Jeyarajah DR, Kowalkowski K, Thistlethwaite JR, Zivin RA, Jolliffe L, Bluestone JA
- Issue date: 1994 Jun 15