Theralizumab
It was withdrawn from development after inducing severe inflammatory reactions as well as chronic organ failure in the first-in-human study by Parexel in London in March 2006.
[1] The developing company, TeGenero Immuno Therapeutics (TeGenero), a spin-off of the University of Würzburg around immunologist Thomas Hünig, co-founder and chief scientific officer (CSO) Thomas Hanke and chief executive officer (CEO) Benedikte Hatz went bankrupt later that year.
The drug, which was designated as an orphan medical product by the European Medicines Agency in March 2005, was developed by TeGenero, tested by Parexel and manufactured by Boehringer Ingelheim.
[8][9] 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.
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 [sic] antibody (5.11A1, Luhder et al., 2003) into human heavy and light chain variable frameworks.
On its website, the company wrote: "A pronounced T-cell activation and expansion mediated by CD28-SuperMAB in animal models is accompanied by the expression of anti-inflammatory cytokines, like IL-10, rather than by the severe cytokine release syndrome of pro-inflammatory mediators induced by other agents that address the TCR complex.".
Pillai et al. found that all T cells that get activated using conventional TCR-mediated stimulation become regulatory for a brief time and express FOXP3.
[17] Roughly fifty minutes after the first participant received his dose, he complained of a headache, and soon afterwards fever and pain.
Shortly after, the remaining participants who received the actual drug also became ill, vomiting and complaining of severe pain.
Paradoxically, some kinds of the men's white blood cells (lymphocytes and monocytes, involved in immune responses) had vanished almost completely several hours after administration of TGN1412.
[22] The US patent application states "it could be shown in a pilot study that an in vitro administration of anti-human CD28-SuperMAB induces in a rhesus monkey in vivo a profound activation of T cells, without clinically visible side effects" and goes on to say "This antibody—in spite of its strong T cell-stimulatory properties—is very well tolerated in vivo, in contrast to all other known T cell activating substances.
"[23] TeGenero apologised to the families involved soon after the events, insisting that the effects were completely unexpected, and that all protocols were followed.
[24] In an initial review of pre-clinical data and the protocol, the MHRA stated there was nothing to cause concern, and that the trial was correctly authorised.
Parexel's records and processes appeared in order, including dose measurement and administration, and no deficiencies were found that may have led to contamination or overdose.
German regulatory authorities inspected the production of the material by Boehringer Ingelheim, looking at the manufacture, testing, storage and distribution of the TGN1412, but no deficiencies were identified which could have contributed to the serious adverse effects.
[28] The MHRA concluded that the most likely cause of the reaction in trial subjects was an unpredicted biological action of the drug in humans.
The UK Secretary of State for Health agreed to establish a group of leading international experts to consider those issues and to provide a report on the future authorization of such trials with an interim report at three months, with Gordon Duff, Professor of Molecular Medicine at Sheffield University, as Chair of the group.
It made 22 recommendations, including the need for independent expert advice before a high-risk study was allowed, testing only one volunteer at a time (sequential inclusion of participants) in case there were rapid ill effects, and administering drugs slowly by infusion rather than as an injection.
In 2007, immunologists from the Paul Ehrlich Institute, the German Federal Agency for Sera and Vaccines, reviewed Germany's regulatory requirements in the aftermath of the TGN1412 trial.
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.
In vitro data revealed that the CD4+ effector memory T-cells of Macaca fascicularis, the species of primate used for pre-clinical safety testing of TGN1412, lack CD28 expression.
[43] Experiments with another drug affecting the CD28 receptor (but to a lesser extent than TGN1412) had also shown side effects in human trials.
