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TGN1412—a regulator's perspective

Nature Biotechnology volume 24, pages 493–496 (2006)Cite this article

To the editor:

As your editorial in the April issue (Nat. Biotechnol. 24, 368, 2006) highlighted, the tragic and unexpected severe adverse events in the recent phase 1 clinical trial of the agonistic anti-CD28 antibody TGN1412 illustrate the risks inherently associated with first-in-human studies of new monoclonal antibodies (mAbs). For reasons of data reproducibility and better estimation of safety margins, phase 1 trials are often carried out in healthy volunteers. The adverse effects associated with the TGN1412 phase 1 trial indicate that the predictive value of animal models requires re-evaluation and that, in certain cases, standard clinical protocols may need refinement or redesign. As researchers at the Paul-Ehrlich-Institut (PEI) in Langen—the German regulatory authority that had approved a trial protocol similar to the one approved and carried out at London's Northwick Park Hospital in the United Kingdom on March 13—we provide here our perspective on the TGN1412 case and the likely consequences for future regulatory oversight of mAbs. Even though the exact reasons and the underlying mechanisms associated with the severe acute adverse responses to TGN1412 are still under evaluation, it is clear that the scientific and regulatory principles for mAb development and approval of clinical trials require re-evaluation. We propose the introduction of three new definition criteria for mAbs entering the clinic to ensure that the next generation of new and very potent immunomodulatory mAbs is developed at the lowest possible risk to human subjects.

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Figure 1: Antigen-specific activation of T cells requires an antigen-dependent signal 1 and a co-stimulatory signal 2.

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Authors and Affiliations

  1. Division of Immunology, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, Langen, 63225, Germany

    Christian K. Schneider, Ulrich Kalinke & Johannes Löwer

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  1. Christian K. Schneider
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  2. Ulrich Kalinke
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  3. Johannes Löwer
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Schneider, C., Kalinke, U. & Löwer, J. TGN1412—a regulator's perspective. Nat Biotechnol 24, 493–496 (2006). https://doi.org/10.1038/nbt0506-493

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