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After TGN1412: Recent developments in cytokine release assays.
- Source :
- Journal of Immunotoxicology; Jan-Mar2013, Vol. 10 Issue 1, p75-82, 8p, 1 Color Photograph, 4 Graphs
- Publication Year :
- 2013
-
Abstract
- The failure of regulatory science to keep pace with and support the development of new biological medicines was very publically highlighted in March 2006 when the first-in-man Phase I clinical trial of the immunomodulatory CD28-specific monoclonal antibody (mAb) TGN1412 ended in disaster when all six volunteers suffered a life-threatening adverse reaction termed a 'Cytokine Storm'. The poor predictive value of standard pre-clinical safety tests and animal models applied to TGN1412 demonstrated the need for a new generation of immunotoxicity assays and animal models that are both sensitive and predictive of clinical outcome in man. The non-predictive result obtained from pre-clinical safety testing in cynomolgus macaques has now been attributed to a lack of CD28 expression on CD4<superscript>+</superscript> effector memory T-cells that therefore cannot be stimulated by TGN1412. In contrast, high levels of CD28 are expressed on human CD4<superscript>+</superscript> effector memory T-cells, the source of most TGN1412-stimulated pro-inflammatory cytokines. Standard in vitro safety tests with human cells were also non-predictive as they did not replicate in vivo presentation of TGN1412. It was subsequently shown that, if an immobilized therapeutic mAb-based assay or endothelial cell co-culture assay was used to evaluate TGN1412, then these would have predicted a pro-inflammatory response in man. New in vitro assays based on these approaches are now being applied to emerging therapeutics to hopefully prevent a repeat of the TGN1412 incident. It has emerged that the mechanism of pro-inflammatory cytokine release stimulated by TGN1412 is different to that of other therapeutic mAbs, such that standard pro-inflammatory markers such as TNF α and IL-8 are not discriminatory. Rather, IL-2 release and lymphoproliferation are optimal readouts of a TGN1412-like pro-inflammatory response. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 1547691X
- Volume :
- 10
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Journal of Immunotoxicology
- Publication Type :
- Academic Journal
- Accession number :
- 85716884
- Full Text :
- https://doi.org/10.3109/1547691X.2012.711783