title: TGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model.
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.
authors.affiliation: Junior Research Group "Novel Vaccination Strategies and Early Immune Responses", Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Weißmüller
authors.affiliation: Junior Research Group "Novel Vaccination Strategies and Early Immune Responses", Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kronhart
authors.affiliation: Division of Immunology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Kreuz
authors.affiliation: Division of Virology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schnierle
authors.affiliation: Institute of Experimental Infection Research, TWINCORE, Centre of Experimental and Clinical Infection Research-a joint venture between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.affiliation: Division of Immunology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kirberg
authors.affiliation: Division of Biostatistics, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Kay-Martin
authors.initials: KM
authors.lastname: Hanschmann
authors.affiliation: Junior Research Group "Novel Vaccination Strategies and Early Immune Responses", Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Waibler
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D015703:Antigens, CD / Q000378:metabolism; D016207:Cytokines / Q000097:blood*; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D008231:Lymphopenia / Q000097:blood* / Q000139:chemically induced*; D051379:Mice; D023421:Models, Animal; D016853:Muromonab-CD3 / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D016207:Cytokines; D016853:Muromonab-CD3; C509303:TGN-1412