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The storm has cleared: lessons from the CD28 superagonist TGN1412 trial
1Institute for Virology and Immunobiology, Versbacher Strasse 7, D-97078 Würzburg, Germany. huenig@vim.uni-wuerzburg.de
Nature Reviews. Immunology
|April 11, 2012
Summary
Clinical trial participants experienced severe cytokine-release syndrome after receiving the CD28 superagonist TGN1412. Preclinical studies failed to predict this adverse event, prompting an investigation into the trial
Area of Science:
- Immunology
- Clinical Pharmacology
- Drug Development
Background:
- The CD28 superagonist antibody TGN1412 caused life-threatening cytokine-release syndrome in a Phase I clinical trial.
- Preclinical studies did not predict the severe adverse events observed in human volunteers.
Purpose of the Study:
- Investigate the reasons for the failure of preclinical studies to predict TGN1412 toxicity.
- Identify lessons learned to improve the safety of future clinical trials involving immunomodulatory agents.
Main Methods:
- Review of preclinical data and clinical trial outcomes for TGN1412.
- Analysis of the immunological mechanisms underlying cytokine-release syndrome.
Main Results:
- The study identified critical discrepancies between preclinical predictions and clinical outcomes.
- Specific immunological pathways were implicated in the unexpected toxicity of TGN1412.
Conclusions:
- There is a need for improved preclinical models to better predict the in vivo effects of immunomodulatory drugs.
- Enhanced safety assessments are crucial for novel therapeutic antibodies, particularly those targeting immune checkpoints like CD28.
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