Clinical Trial, UK
New assay predicts TGN1412 side effects
British immunologists claim they have developed a lab test, which for the first time replicates the unexpected side-effects seen in six patients, that received the experimental ‘superantibody‘ drug TGN1412 of the now defunct German TeGenero AG. At the time of the announcement, the British drug authority MHRA published its final report on the disastrous clinical trial that led to a systemic inflammation in all volunteers. Dr. Stephen Inglis, a member of the MHRA panel, announced “a publication on the new assay is in preparation”.
In contrast to all existing in vitro tests, which measure the immune effects of free TGN1412, the novel assay works with the immobilised antibody. “Effectively, we immobilise the antibody in a particular way, and that is the trick that stimulates the immune response”, says Inglis, who is director of the London-based National Institute for Biological Standards and Control (NIBSC). “The effect causes particular CD4 cells to release large amounts of cytokines and to begin to divide dramatically.” Every time, Inglis’ team immobilised TGN1412 either by dry coating to the wells of 96 well plates, or by capturing its Fc part by an anti-human Fc antibody to a surface or endothel cells, the researchers measured a strong proliferative response as well as a stimulated cytokine release by the immune cells. Concentrations ranging from 1-10 µg dry-coated TGN1412 per well boosted the production of interleukin 8 (IL-8), tumour necrosis factor (TNF) and IL-6 in vitro. On top of this, dry-coating of only 2µg TGN1412 per well led to a strong polyclonal proliferative response. With higher concentrations (100 or 1,000 µg/µl), equivalent to doses tested in cynomolgous macaques, either a low or no proliferation of immune cells was observed. Immobilisation of TGN1412 “appears to be a more effective way of presenting the drug to the cells”, concludes the MHRA, “possibly due to cross-linking” of the antibodies’ Fc part, as proposed ealier last year (see EuroBiotechNews 5-6/2006). Inglis said, he believes that the test, once it has been validated, might be useful for screening immunmodulatory drug candidates.
“Binding antibodies to plastic surfaces seems to me a very artificial approach,” disagrees TeGenero’s founder Prof. Dr. Thomas Hünig. “But, if the results with the endothel cells are confirmed, they might point to an unexpected co-activating effect of these cells in vivo.” However, one cannot rely on an immuno assay alone, according to the researcher. Instead, future trials with immunomodulators similar to TGN1412 would require microdosing to avoid unexpected side effects, said Hünig. The expert doubts that the concept of Treg activation will be given a second chance by the regulatory authorities.
Ongoing compensation claims
Martyn Day, the solicitor of 4 of the 6 victims of the TGN1412 trial told EuroBiotechNews that he will continue to receive compensation, either from Tegenero’s CRO Parexel or from the legal successor of the bankrupt TeGenero AG. The firm’s liquidator, Frank Hanselmann, claimed that the company assets were sold as a whole “to a firm outside Germany”, but due to a non-disclosure agreement neither he nor the paid creditors or Tegenero’s ex-management can give any details on the purchase price or the company’s identity. However, Day told EuroBiotechNews that he will try to get access to the insolvency proceedings (reference number 1 IN 389/06 at Amtsgericht Würzburg) to find out, which company bought TeGenero. It remains open if the identity of TeGenero’s buyer will ever become public.