Abstract
Therapeutic 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.
Highlights
Therapeutic monoclonal antibodies are approved for many clinical indications including cancer, immunological disorders, transplant rejection, and infectious diseases
Percentages refer to all cells in the peripheral blood of humanized mice since analyses using counting beads indicated that the absolute number of murine cells in the peripheral blood of NOD-RAG1-/-Aβ-/-HLADQ(tg+ or tg-)IL-2Rγc-/- (NRG) mice did not change with Human peripheral blood mononuclear cells (hPBMCs) and/or antibody injection and can serve as an internal reference
HPBMC-reconstituted NRG mice fulfill all requirements for testing of T cell-specific monoclonal antibodies (mAbs) in vivo
Summary
Therapeutic monoclonal antibodies (mAbs) are approved for many clinical indications including cancer, immunological disorders, transplant rejection, and infectious diseases. All 6 volunteers experienced severe adverse effects such as fever, headache, hypotension, and lymphopenia, and all suffered from a multi-organ-failure. These severe adverse events could be attributed to the induction of a cytokine release syndrome (CRS), a life-threatening systemic release of cytokines [2]. Another mAb for which the induction of CRS has been reported, upon first-dose administration, is muromonab-CD3 (Orthoclone OKT31), a murine IgG2a used to treat acute organ rejection [3]. Manufacturing of this antibody was discontinued since other treatment options with comparable efficacy but fewer side effects became available [1]
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