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TGN1412 (also known as CD28-SuperMAB and TAB08) was the working name of an immunomodulatory drug which was withdrawn from development after inducing severe inflammatory reactions in the first-in-man study in London in March 2006.〔Goldacre, Ben. ''Bad Pharma''. Fourth Estate, 2012, pp. 8–10, 104–105.〕 The developing company, TeGenero Immuno Therapeutics, went bankrupt later that year. The commercial rights were then acquired by a Russian investor. The drug was renamed TAB08. The Russian biotechnology company TheraMAB conducted Phase I trials with a much lower dose (0.1%) of the antibody than was used in the London study, and they are planning Phase II trials in June 2015. 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 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. 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. ==Description of the drug== Mice of the inbred strain BALB/c were immunized with recombinant human CD28-Fc fusion proteins and boosted with a B lymphoma cell line transfected to express human CD28. Hybridomas were obtained by fusing B cells with the hybridoma partner X63Ag8.653 and screened for reactivity with human CD28 and TCR-independent mitogenic activity. Two monoclonals called 5.11A1 and 9D7 were identified. The more active of the two, 5.11A1, is a mouse IgG1 immunoglobulin. The complementarity determining regions of 5.11A1 were cloned into the framework of human IgG and combined with IgG1 (TGN1112) or IgG4 (TGN1412) constant regions. According to the company's Investigator Brochure, "TGN1412 is a humanised monoclonal antibody directed against the human CD28 antigen. The molecule was genetically engineered by transfer of the complementarity determining regions (CDRs) from heavy and light chain variable region sequences of a monoclonal mouse anti-humanC28 () antibody (5.11A1, Luhder et al., 2003) into human heavy and light chain variable frameworks. Humanised variable regions were subsequently recombined with a human gene coding for the IgG4 gamma chain and with a human gene coding for a human kappa chain, respectively."〔(Investigator's Brochure ), Circare.org, 19 December 2005〕 The recombinant genes were transfected into Chinese hamster ovary cells and the recombinant antibody harvested from culture supernatant. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「TGN1412」の詳細全文を読む スポンサード リンク
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