TGN1412

From Ganfyd

An experimental therapeutic antibody sponsored by TeGenero AG a German pharmaceutical startup company, produced by Boehringer Ingelheim and used in trials coordinated by Parexel International. It was designed with the intention of modulating the immune system by targetting CD28, a receptor on T lymphocytes. The underlying rationale was that some autoimmune disorders are characterised by a relative deficiency in regulatory T-cells and that by CD28 agonism could expand this population of cells with corresponding therapeutic effects on the autoimmune disorder.^[1][2]

However, during the Phase 1 Trials, administration of the drug in 6 healthy volunteers resulted in a severe reaction from about 1-2 hours after administration, resulting in all 6 being admitted to intensive care with multi-organ failure. A severe cytokine storm resulted and its clinical consequences, including the therapies that may have been a factor in the survival of all 6 have been described. All patients were empirically treated for 3 days with an anti-interleukin-2 receptor antagonist antibody daclizumab as well as high dose corticosteroids, ranitidine and chlorpheniramine.^[3]. The serious clinical condition that resulted has been discussed in several medical journals and will help understanding of cytokine storm in man. ^{[4] [5]}

It is unclear if the adverse reactions were due to a manufacturing error, contamination or wrong dosage. Unlike many other therapeutic antibodies, it appears that TGN1412 was designed to activate the CD28 receptor as a super-agonist rather than act as an antagonist. Some speculate that hyperactivation of the T-cells may have caused a cytokine storm that may have led to the adverse symptoms. Such matters are complex.

The incident prompted an investigation by the MHRA (see interim report ^[6]) as well as an further independent Expert Scientific Group report.^[7]

References