Severity of the TGN1412 trial disaster cytokine storm correlated with IL-2 release.
Br J Clin Pharmacol
; 76(2): 299-315, 2013 Aug.
Article
em En
| MEDLINE
| ID: mdl-23701319
ABSTRACT
AIM:
To determine if cytokine release with a solid phase assay is predictive of adverse responses for a range of therapeutic mAbs.METHODS:
Cytokine ELISAs and a multi-array system were used to compare responses generated by different therapeutic mAbs using a solid phase assay. Flow cytometry was employed to determine the cellular source of those cytokines.RESULTS:
Only TGN1412 and muromonab-CD3 stimulated CD4+ T-cell mediated cytokine release characterized by significant (all P < 0.0001) IFNγ, TNFα, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17 and IL-22 release, comparable with T-cell mitogen. Significantly greater (P < 0.0001) IL-2 release with TGN1412 (2894-6051 pg ml⻹) compared with muromonab-CD3 (62-262 pg ml⻹) differentiated otherwise comparable cytokine responses. Likewise, TGN1412 stimulated significantly more (P = 0.0001) IL-2 producing CD4+ T-cells than muromonab-CD3 and induced Th1, Th2, Th17 and Th22 subsets that co-release this cytokine. Significant TNFα release was observed with bevacizumab (P = 0.0001), trastuzumab (P = 0.0031) and alemtuzumab (P = 0.0177), but no significant IL-2 release. TGN1412 and muromonab-CD3 caused pro-inflammatory cytokine release despite significantly (both P < 0.0001) increasing numbers of T-cells with a regulatory phenotype.CONCLUSIONS:
The severity of the adverse response to TGN1412 compared with muromonab-CD3 and other therapeutic mAbs correlates with the level of IL-2 release.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Projetos de Pesquisa
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Citocinas
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Interleucina-2
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Muromonab-CD3
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Anticorpos Monoclonais Humanizados
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Anticorpos Monoclonais
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article