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The Journal of Immunology, 2007, 179: 3325-3331.
Copyright © 2007 by The American Association of Immunologists, Inc.
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"Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics

Richard Stebbings, Lucy Findlay, Cherry Edwards1, David Eastwood, Chris Bird, David North, Yogesh Mistry, Paula Dilger, Emily Liefooghe, Isabelle Cludts, Bernard Fox, Gill Tarrant, Jane Robinson, Tony Meager, Carl Dolman, Susan J. Thorpe, Adrian Bristow, Meenu Wadhwa, Robin Thorpe and Stephen Poole2

Biotherapeutics Group, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, United Kingdom

The CD28-specific mAb TGN1412 rapidly caused a life-threatening "cytokine storm" in all six healthy volunteers in the Phase I clinical trial of this superagonist, signaling a failure of preclinical safety testing. We report novel in vitro procedures in which TGN1412, immobilized in various ways, is presented to human white blood cells in a manner that stimulates the striking release of cytokines and profound lymphocyte proliferation that occurred in vivo in humans. The novel procedures would have predicted the toxicity of this superagonist and are now being applied to emerging immunotherapeutics and to other therapeutics that have the potential to act upon the immune system. Data from these novel procedures, along with data from in vitro and in vivo studies in nonhuman primates, suggest that the dose of TGN1412 given to human volunteers was close to the maximum immunostimulatory dose and that TGN1412 is not a superagonist in nonhuman primates.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 The contribution of C.E. was to regenerate and analyze flow cytometry data using human white blood cells.

2 Address correspondence and reprint requests to Dr. Stephen Poole, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, U.K. E-mail address: spoole{at}nibsc.ac.uk


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The JI 2007 179: 2665-2666. [Full Text]  



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