2.50
Hdl Handle:
http://hdl.handle.net/10033/606059
Title:
TGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model.
Authors:
Weißmüller, Sabrina; Kronhart, Stefanie; Kreuz, Dorothea; Schnierle, Barbara; Kalinke, Ulrich ( 0000-0003-0503-9564 ) ; Kirberg, Jörg; Hanschmann, Kay-Martin; Waibler, Zoe
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.
Affiliation:
Helmholtzzentrum für Infektionsforschung
Citation:
TGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model. 2016, 11 (3):e0149093 PLoS ONE
Journal:
PloS one
Issue Date:
2016
URI:
http://hdl.handle.net/10033/606059
DOI:
10.1371/journal.pone.0149093
PubMed ID:
26959227
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
publications of the department of experimental infection research ([TC] EXPI)

Full metadata record

DC FieldValue Language
dc.contributor.authorWeißmüller, Sabrinaen
dc.contributor.authorKronhart, Stefanieen
dc.contributor.authorKreuz, Dorotheaen
dc.contributor.authorSchnierle, Barbaraen
dc.contributor.authorKalinke, Ulrichen
dc.contributor.authorKirberg, Jörgen
dc.contributor.authorHanschmann, Kay-Martinen
dc.contributor.authorWaibler, Zoeen
dc.date.accessioned2016-04-20T10:49:50Zen
dc.date.available2016-04-20T10:49:50Zen
dc.date.issued2016en
dc.identifier.citationTGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model. 2016, 11 (3):e0149093 PLoS ONEen
dc.identifier.issn1932-6203en
dc.identifier.pmid26959227en
dc.identifier.doi10.1371/journal.pone.0149093en
dc.identifier.urihttp://hdl.handle.net/10033/606059en
dc.description.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.en
dc.language.isoenen
dc.titleTGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model.en
dc.typeArticleen
dc.contributor.departmentHelmholtzzentrum für Infektionsforschungen
dc.identifier.journalPloS oneen

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