This article is commented on by Pallardy and Hünig, pp. 509–511 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00925.x
Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells
Article first published online: 17 JUN 2010
© 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society
British Journal of Pharmacology
Volume 161, Issue 3, pages 512–526, October 2010
How to Cite
Eastwood, D., Findlay, L., Poole, S., Bird, C., Wadhwa, M., Moore, M., Burns, C., Thorpe, R. and Stebbings, R. (2010), Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells. British Journal of Pharmacology, 161: 512–526. doi: 10.1111/j.1476-5381.2010.00922.x
- Issue published online: 3 SEP 2010
- Article first published online: 17 JUN 2010
- Received19 January 2010Revised26 March 2010Accepted30 March 2010
- cytokine storm;
- monoclonal antibody;
- effector memory T-cells;
- pre-clinical safety testing;
- pro-inflammatory cytokines
BACKGROUND AND PURPOSE In 2006, a life-threatening ‘cytokine storm’, not predicted by pre-clinical safety testing, rapidly occurred in all six healthy volunteers during the phase I clinical trial of the CD28 superagonist monoclonal antibody (mAb) TGN1412. To date, no unequivocal explanation for the failure of TGN1412 to stimulate profound cytokine release in vitro or in vivo in species used for pre-clinical safety testing has been established. Here, we have identified a species difference almost certainly responsible for this disparate immunopharmacology.
EXPERIMENTAL APPROACH Polychromatic flow cytometry and intracellular cytokine staining were employed to dissect the in vitro immunopharmacology of TGN1412 and other therapeutic mAbs at the cellular level to identify differences between humans and species used for pre-clinical safety testing.
KEY RESULTSIn vitro IL-2 and IFN-γ release from CD4+ effector memory T-cells were key indicators of a TGN1412-type response. This mechanism of cytokine release differed from that of other therapeutic mAbs, which can cause adverse reactions, because these other mAbs stimulate cytokine release primarily from natural killer cells. In contrast to humans, CD28 is not expressed on the CD4+ effector memory T-cells of all species used for pre-clinical safety testing, so cannot be stimulated by TGN1412.
CONCLUSIONS AND IMPLICATIONS It is likely that activation of CD4+ effector memory T-cells by TGN1412 was responsible for the cytokine storm. Lack of CD28 expression on the CD4+ effector memory T-cells of species used for pre-clinical safety testing of TGN1412 offers an explanation for the failure to predict a ‘cytokine storm’ in humans.