Severity of the TGN1412 trial disaster cytokine storm correlated with IL-2 release
Article first published online: 23 JUL 2013
© 2013 Medicines and Healthcare products Regulatory Agency MHRA. The British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
British Journal of Clinical Pharmacology
Special Issue: Biological Products
Volume 76, Issue 2, pages 299–315, August 2013
How to Cite
Eastwood, D., Bird, C., Dilger, P., Hockley, J., Findlay, L., Poole, S., Thorpe, S. J., Wadhwa, M., Thorpe, R. and Stebbings, R. (2013), Severity of the TGN1412 trial disaster cytokine storm correlated with IL-2 release. British Journal of Clinical Pharmacology, 76: 299–315. doi: 10.1111/bcp.12165
- Issue published online: 23 JUL 2013
- Article first published online: 23 JUL 2013
- Accepted manuscript online: 23 MAY 2013 06:16AM EST
- Manuscript Accepted: 21 APR 2013
- Manuscript Received: 21 AUG 2012
- National Institute for Health Research Funding
- cytokine release assays;
- preclinical safety testing;
- therapeutic monoclonal antibodies
To determine if cytokine release with a solid phase assay is predictive of adverse responses for a range of therapeutic mAbs.
Cytokine ELISAs and a multi-array system were used to compare responses generated by different therapeutic mAbs using a solid phase assay. Flow cytometry was employed to determine the cellular source of those cytokines.
Only TGN1412 and muromonab-CD3 stimulated CD4+ T-cell mediated cytokine release characterized by significant (all P < 0.0001) IFNγ, TNFα, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17 and IL-22 release, comparable with T-cell mitogen. Significantly greater (P < 0.0001) IL-2 release with TGN1412 (2894–6051 pg ml−1) compared with muromonab-CD3 (62–262 pg ml−1) differentiated otherwise comparable cytokine responses. Likewise, TGN1412 stimulated significantly more (P = 0.0001) IL-2 producing CD4+ T-cells than muromonab-CD3 and induced Th1, Th2, Th17 and Th22 subsets that co-release this cytokine. Significant TNFα release was observed with bevacizumab (P = 0.0001), trastuzumab (P = 0.0031) and alemtuzumab (P = 0.0177), but no significant IL-2 release. TGN1412 and muromonab-CD3 caused pro-inflammatory cytokine release despite significantly (both P < 0.0001) increasing numbers of T-cells with a regulatory phenotype.
The severity of the adverse response to TGN1412 compared with muromonab-CD3 and other therapeutic mAbs correlates with the level of IL-2 release.