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A whole blood in vitro cytokine release assay with aqueous monoclonal antibody presentation for the prediction of therapeutic protein induced cytokine release syndrome in humans

Wolf, Babette and Morgan, Hannah and Gani, Zaahira and Milicov, Adriana and Warncke, Max and Jones, Stewart and Krieg, Jennifer and Sims, Jennifer and Kiessling, Andrea and Brennan, Frank (2012) A whole blood in vitro cytokine release assay with aqueous monoclonal antibody presentation for the prediction of therapeutic protein induced cytokine release syndrome in humans. Cytokine. ISSN 1063-4666

Abstract

The administration of several monoclonal antibodies (mAbs) to humans has been associated with acute adverse events characterized by clinically significant release of cytokines in the blood. The limited predictive value of toxicology species in this field has triggered intensive research to establish human in vitro assays using peripheral blood mononuclear cells or blood to predict cytokine release in humans. A thorough characterization of these assays is required to understand their predictive value for hazard identification and risk assessment in an optimal manner, and to highlight potential limitations of individual assay formats.
We have characterized a whole human blood cytokine release assay with only minimal dilution by the test antibodies (95% v/v blood) in aqueous presentation format, an assay which so far received less attention in the scientific world with respect to evaluation of its suitability to predict cytokine release in humans. This format was compared with a human PBMC assay with immobilized mAbs presentation already well-characterized by others. The test mAbs were anti-CD28 superagonist TGN1412-like material (TGN1412L), another anti-CD28 superagonistic mAb (ANC28.1), a T-cell depleting mAb (Orthoclone™), and a TGN1412 isotype-matched control (Tysabri™) not associated with clinically-relevant cytokine release. The whole blood assay was found suitable for hazard identification due to the production of the expected clinical cytokine signature for the tested mAbs and showed markedly lower assay background and cytokine release with the isotype-matched control mAb Tysabri™. However, lower donor response rates to TGN1412L for most tested cytokines were observed when compared to the PBMC assay. Importantly, quantitative and qualitative differences in the relative cytokine responses to the individual mAbs, in the concentration-response relationships and the prominent cytokine signatures for individual mAbs in the two formats reflect diverging mechanisms of cytokine release and different levels of dependency on high density coating even for two anti-CD28 superagonistic antibodies. These results clearly show that one generic approach to assessment of cytokine release using in vitro assays is not sufficient, but rather the assay format needs to be optimized considering the target characteristics and the mechanistic features of the therapeutic mAbs being evaluated.

Item Type: Article
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Keywords: cytokine release; whole blood assay; monoclonal antibody; TGN1412
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/7412

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