Bibliographic Details
| Title: |
TGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model. |
| Authors: |
Sabrina Weißmüller, Stefanie Kronhart, Dorothea Kreuz, Barbara Schnierle, Ulrich Kalinke, Jörg Kirberg, Kay-Martin Hanschmann, Zoe Waibler |
| Source: |
PLoS ONE, Vol 11, Iss 3, p e0149093 (2016) |
| Publisher Information: |
Public Library of Science (PLoS), 2016. |
| Publication Year: |
2016 |
| Collection: |
LCC:Medicine
LCC:Science |
| Subject Terms: |
Medicine, Science |
| More Details: |
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. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1932-6203 |
| Relation: |
http://europepmc.org/articles/PMC4784892?pdf=render; https://doaj.org/toc/1932-6203 |
| DOI: |
10.1371/journal.pone.0149093 |
| Access URL: |
https://doaj.org/article/8daa67b39476469498d11bc18fa5b1a4 |
| Accession Number: |
edsdoj.8daa67b39476469498d11bc18fa5b1a4 |
| Database: |
Directory of Open Access Journals |
