After TGN1412: Recent developments in cytokine release assays. (March 2013)

• Record Type: Journal Article
• Authors: Stebbings, R.; Eastwood, D.; Poole, S.; Thorpe, R.
• Is Part Of: Journal of immunotoxicology. Volume 10:Number 1(2013)
• Page Start: 75
• Page End: 82
• Publication Date: 2013-03
• Subjects: Immunotoxicology -- Periodicals; Poisons -- Immunology -- Periodicals; Environmental health -- Periodicals; 616.97
• DOI: 10.3109/1547691X.2012.711783
• Languages: English
• ISSNs: 1547-691X

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <p>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<sup>+</sup> effector memory T-cells that therefore cannot be stimulated by TGN1412. In contrast, high levels of CD28 are expressed on human CD4<sup>+</sup> effector memory T-cells, the source of most TGN1412-stimulated pro-inflammatory cytokines. Standard <italic>in vitro</italic> safety tests with human cells were also non-predictive as they did not replicate <italic>in vivo</italic> 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 <italic>in vitro</italic> 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<italic>α</italic> and IL-8 are not discriminatory. Rather, IL-2 release and lymphoproliferation are optimal readouts of a TGN1412-like pro-inflammatory response.</p> </abstract>