Tegenero’s CD28 Antibody tragedy — web findings, and some understanding

BBC News
Six men remain in intensive care after being taken ill during a clinical drugs trial in north-west London.
March 15, 2006.


After 6 volunteers were hospitalized, with 4 having major organ failure, after doses of the CD28 super-agonist antibody TGN1412, the British health agency MHRA concluded “UK drug trial illnesses not due to errors” (Reuters May 25th headline). The traditional news sources left me wanting more.
Wikipedia, the free web encyclopedia, had an excellent article (http://en.wikipedia.org/wiki/TGN1412 ). The 5 minute interval between each volunteer being dosed was clearly a problem.
But why had the animal studies not indicated a need for caution with an antibody aimed at the T cell co-stimulatory pathway? News@Nature.com reported that in the animal study (Beyersdorf, N.et al. J. Exp. Med. 202, 445-455; 2005), TGN1412 had activated only the anti-inflammatory regulatory T cells and not helper T cells that could have released a toxic cytokine storm. Was the T cell activation broader in humans?
The article also suggested that the Fc portion of the humanized antibody may have amplified the toxicity in the volunteers. Were there human versus primate differences in Fc receptor responses or were the animal studies inadequate?
Another great web posting (http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2006/04/tgn1412_a_cauti.html) suggested assuming that regulatory T cells play only an anti-inflammatory role may have been an overly simplistic concept of regulatory T cell biology.
Still more learning to be done!