TGN1412 (also known as CD28-SuperMAB) is the working name of an immunomodulatory drug which was withdrawn from development after inducing severe inflammatory reactions in the first-in-man study in London in March 2006.[1] The developing company, TeGenero Immuno Therapeutics, entered into insolvency proceedings later that year.
Originally intended for the treatment of B cell chronic lymphocytic leukemia (B-CLL) and rheumatoid arthritis,[2] 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.[3] 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 failure 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.[4] 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 animals 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.[5] However this is a misunderstanding of the research: the research says that non-human 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.[6]