Findlay, LA; (2012) Development of in vitro procedures that can better predict the safety of therapeutic monoclonal antibodies. Doctoral thesis , UCL (University College London).

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Abstract

Pre-clinical safety testing (in vivo and in vitro) of the therapeutic monoclonal antibody (mAb) TGN1412 (developed for the treatment of autoimmune diseases) failed to predict the life threatening adverse events that occurred during its Phase I Clinical Trial. The treatment of disease using mAb therapy is becoming increasingly common, so, to ensure the safety of mAbs, pre-clinical safety tests that can better predict the toxicity of immunomodulatory mAbs, such as TGN1412, are required. The aim of this study was to investigate the hypothesis that cytokine-driven adverse effects of therapeutic monoclonal antibodies and the mechanisms involved can be better predicted with novel in vitro procedures using human cells, given the failure of animal models to predict the toxicity of TGN1412. Consistent with the results from pre-clinical testing, aqueous phase TGN1412 incubated with human peripheral blood mononuclear cells (PBMC) failed to stimulate the “cytokine storm” suffered by the six recipients of TGN1412. In contrast, TGN1412 immobilised onto polypropylene microtitre plates by “air-drying” stimulated cytokine release from PBMC. This technique was superior to other mAb immobilisation techniques, investigated in terms of predicting cytokine release. Immobilisation of TGN1412 may mimic the immunological synapse formed between this mAb and target cells in vivo. In a more physiologically relevant procedure, TGN1412 incubated in aqueous phase with PBMC over a monolayer of human endothelial cells stimulated cytokine release. Endothelial cell to PBMC contact was crucial to these responses. Furthermore, interactions between lymphocyte function-associated antigen-3 (LFA-3) and intercellular adhesion molecule-1 (ICAM-1) expressed by endothelial cells with their counterstructures CD2 and LFA-1, respectively, expressed by T cells, mediated these TGN1412-stimulated responses. Both procedures developed in this study were capable of distinguishing therapeutic mAbs not associated with a significant incidence of cytokine-driven clinical infusion reactions from mAbs frequently associated with clinical infusion reactions.

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