Pharmaprojects R&D Pipeline News Feed
Scientists suggest how TeGenero's cytokine storm brewed
5th Feb 2007
Scientists from Imperial College in London have revealed a possible explanation for the devastating outcome of TeGenero's TGN-1412 clinical trial last March.
The drug was designed to activate T-cells via the CD28 receptor and was intended to treat autoimmune diseases and cancers, but despite having no adverse effects in monkey tests, it provoked a cytokine storm in six Phase I volunteers.
The new research suggests that this discrepancy was due to differences in the T-cell population between the animals and humans. It shows that stimulating the CD28 receptor on T-cells could have an adverse effect if these cells have been previously activated and altered by a past infection - around 50% of adult human T-cells are memory cells, having already been activated in this way.
However, the animal models used to test the product do not have many memory T-cells because they are deliberately kept in a sterile environment where they are shielded from infections, the researchers say.
The scientists injected memory T-cells in which CD28 had been previously stimulated into healthy mice and saw that they immediately migrated from the blood into organs such as the kidney, heart and gut, where they would not normally be found except in the event of an infection, where they caused significant organ damage.
"Our research suggests that [the side-effects were seen] because the human subjects' memory T-cells lost their sense of direction and started migrating into several areas of the body where they were not supposed to go, and caused damage," said lead researcher Dr Frederica Marelli-Berg. The findings were presented at the Club de la Transplantation meeting in Paris last week.
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