Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Storm forecasting: additional lessons from the CD28 superagonist TGN1412 trial

A Corrigendum to this article was published on 07 September 2012

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

References

  1. Hünig, T. The storm has cleared: lessons from the CD28 superagonist TGN1412 trial. Nature Rev. Immunol. 12, 317–318 (2012).

    Article  Google Scholar 

  2. Proft, T. & Fraser, J. D. Bacterial superantigens. Clin. Exp. Immunol. 133, 299–306 (2003).

    Article  CAS  Google Scholar 

  3. Horvath, C. J. & Milton, M. N. The TeGenero incident and the Duff Report conclusions: a series of unfortunate events or an avoidable event? Toxicol. Pathol. 37, 372–383 (2009).

    Google Scholar 

  4. Suntharalingam, G. et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355, 1018–1028 (2006).

    Article  CAS  Google Scholar 

  5. Medicines and Healthcare Products Regulatory Agency. Clinical trial suspension: latest findings. MHRA [online], (2006).

  6. Lühder, F . et al. Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists. J. Exp. Med. 197, 955–966 (2003).

    Article  Google Scholar 

  7. Tacke, M., Hanke, G., Hanke, T. & Hünig, T. CD28-mediated induction of proliferation in resting T cells in vitro and in vivo without engagement of the T cell receptor: evidence for functionally distinct forms of CD28. Eur. J. Immunol. 27, 239–247 (1997).

    Article  CAS  Google Scholar 

  8. Lin, C. H. & Hünig, T. Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist. J. Immunol. 33, 626–638 (2003).

    CAS  Google Scholar 

  9. Stebbings, R. et al. “Cytokine storm” in the phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics. J. Immunol. 179, 3325–3331 (2007).

    Article  CAS  Google Scholar 

  10. Legrand, N. et al. Transient accumulation of human mature thymocytes and regulatory T cells with CD28 superagonist in “human immune system” Rag2−/−γc−/− mice. Blood 108, 238–245 (2006).

    Article  CAS  Google Scholar 

  11. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonized tripartite guideline S6: preclinical safety evaluation of biotechnology-derived pharmaceuticals (ICH, 1997).

  12. US Food and Drug Administration Center for Drug Evaluation and Research. Guidance for industry. Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers (FDA, 2005).

  13. Association of the British Pharmaceutical Industry/BioIndustry Association. Guideline for preclinical and clinical testing of new medicinal products. Parts 1 & 2 (ABPI, 1977).

  14. Sims, J. & ABPI/BIA Early Stage Clinical Trials Task Force. Calculation of the minimum anticipated biological effect level (MABEL) and 1st dose in humans. EMA [online], (2007).

  15. Lowe, P. J. et al. On the anticipation of the human dose in first-in-man trials from preclinical and prior clinical information in early drug development. Xenobiotica 37, 1331–1354 (2007).

    Article  CAS  Google Scholar 

  16. Lowe, P. J., Tannenbaum, S., Wu, K., Lloyd, P. & Sims, J. On setting the first dose in man: quantitating biotherapeutic drug-target binding through pharmacokinetic and pharmacodynamic models. Basic Clin. Pharmacol. Toxicol. 106, 195–209 (2010).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Christopher Horvath or James D. Green.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Citizens for Responsible Care and Research

Rights and permissions

Reprints and permissions

About this article

Cite this article

Horvath, C., Andrews, L., Baumann, A. et al. Storm forecasting: additional lessons from the CD28 superagonist TGN1412 trial. Nat Rev Immunol 12, 740 (2012). https://doi.org/10.1038/nri3192-c1

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nri3192-c1

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing