TGN1412

Theralizumab (also known as TGN1412, CD28-SuperMAB, and TAB08) is an immunomodulatory drug developed by Professor Thomas Hünig of the University of Würzburg. Theralizumab (also known as TGN1412, CD28-SuperMAB, and TAB08) is an immunomodulatory drug developed by Professor Thomas Hünig of the University of Würzburg. It was withdrawn from development after inducing severe inflammatory reactions in the first-in-human study by PAREXEL in London in March 2006. The developing company, TeGenero Immuno Therapeutics, went bankrupt later that year. The commercial rights were then acquired by a Russian startup, TheraMAB. The drug was renamed TAB08. Phase I and II clinical trials have been completed for arthritis and clinical trials have been initiated for cancer. Originally intended for the treatment of B cell chronic lymphocytic leukemia (B-CLL) and rheumatoid arthritis, TGN1412 is a humanised monoclonal antibody that not only binds to, but is a strong agonist for, the CD28 receptor of the immune system's T cells. CD28 is the co-receptor for the T cell receptor; It binds to receptors on the interacting partner in the reaction through one of its ligands (B7 family). In its first human clinical trials, it caused catastrophic systemic organ failures in the subjects, despite being administered at a supposed sub-clinical dose of 0.1 mg per kg; some 500 times lower than the dose found safe in animals. Six volunteers were hospitalized on 13 March 2006, at least four of these suffering from multiple organ dysfunction. Tentative opinions from an as-yet uncompleted inquiry suggest that the problems resulted from 'unforeseen biological action in humans', rather than breach of trial protocols, and the case therefore has had important ramifications for future trials of potentially powerful clinical agents. Scientists in early 2007 put forth the theory that the drug acted in a different fashion in humans as compared with the laboratory animals in which the drug was first tried. The severe reactions in humans could have only occurred, they believe, in those with memory T lymphocytes. Animals raised in a sterile lab would presumably have no 'memory' of previous illnesses, thus would not exhibit the severe reactions that occurred in the human subjects. However this is a misunderstanding of the research: the research says that lab animals studied have fewer memory T cells than humans, and that stimulation through the CD28 receptor alone in memory T cells causes them to infiltrate organs and also activates them. The drug, which was designated as an orphan medical product by the European Medicines Agency in March 2005, was developed by TeGenero Immuno Therapeutics, tested by Parexel and manufactured by Boehringer Ingelheim. TeGenero announced the first elucidation of the molecular structure of CD28 almost exactly one year prior to commencement of the TGN1412 phase I clinical trial.