February 18, 2014
In March 2006, clinical trials of the anti-CD28 mAb TGN1412 started. While existing test systems suggested the drug candidate would be safely tolerated, all six healthy volunteers in the study rapidly developed a dangerous so-called cytokine storm. (TRON and TWINCORE and were not involved in the drug development or clinical trial.)
Researchers have now taken important steps to understand the mechanism of this dangerous reaction. Examining gene expression profiling data generated in the TRON laboratories, the team showed that specific T cell populations rapidly generate TGN1412 responses which are massively boosted by FcγR crosslinking in CD32-expressing B cells. While TGN1412 treatment of fresh PBMCs induced only moderate responses, restoration of tissue-like conditions by high-density pre-culture resulted in vigorous cytokine production.
These results help explain the cytokine storm and, by identifying specific cell types and experimental conditions, enable the development of an in vitro system that more completely tests mAbs. Together, the findings and test system will help improve the assessment of novel drug candidates before moving into human clinical trials.
The results were published in January in the Journal of Immunology:
Bartholomaeus, P., Semmler, L.Y., Bukur, T., Boisguerin, V., Römer, P.S., Tabares, P., Chuvpilo, S., Tyrsin, D.Y., Matskevich, A., Hengel, H., Castle, J., Hünig, T., Kalinke, U. (2014) Cell Contact-Dependent Priming and Fc Interaction with CD32+ Immune Cells Contribute to the TGN1412-Triggered Cytokine Response. J Immunol. 2014 Jan 27. [Pubmed; DOI]