TGN1412

from Wikipedia, the free encyclopedia

TGN1412 is an agonistic monoclonal antibody directed against the CD28 antigen on T lymphocytes and was used to treat multiple sclerosis , blood cancer and rheumatism . The antibody was developed by the Würzburg company Tegenero Immuno Therapeutics and manufactured on behalf of Boehringer Ingelheim . It was the first active ingredient that TeGenero wanted to develop to market . According to the manufacturer, the benefit of the antibody should be to therapeutically balance an immune system that reacts too strongly or too weakly in autoimmune diseases and blood cancer .

TGN1412 also became known in non-specialist media when serious incidents (so-called serious adverse events ) occurred in healthy volunteers during a clinical study .

Phase I study

After corresponding tests on cell cultures and in animal experiments , the first test on humans took place on March 13, 2006 in a phase I study , in which a total of eight test subjects took part in the Northwick Park Hospital in London. The study was carried out by the contract research institute Parexel . As is customary with drug tests, the test subjects each received a sum of £ 2,000 (about € 2,900) for participating. They received only an assumed subclinical dose of 0.1 mg per kg of body weight (about 1/500 of the amount previously determined to be safe in animal experiments).

Symptoms

All six men who received the drug had severe reactions within five minutes of the administration; the other two subjects were given a placebo and showed no effects. The affected subjects initially complained of headache, severe hot flashes and fever, followed by vomiting, severe pain and symptoms of a severe inflammatory reaction. One of the subjects said he felt burning all over his body.

A few hours later, doctors found multiple organ failure ; some of the subjects had to be artificially ventilated. The six patients were transferred to the hospital's intensive care unit 12 to 16 hours after administration of the antibody , where their lives were in danger for days. One of those affected stated in the press that he was only given effective medication there; he spent three weeks in a coma .

Medicinal effects

Five of the patients were discharged from the hospital within a month, the sixth left after 14 weeks on June 26, 2006.

Investigations with a view to the long-term effects then showed a proportion of regulatory T lymphocytes in the blood of less than one percent in four of those affected , while three to five percent is common in healthy people. Since these cells are of crucial importance for the mediation of the immune system's tolerance to the body's own tissue, doctors rated the risk of further serious secondary diseases such as multiple sclerosis or other autoimmune diseases as high.

causes

According to TeGenero, there were no problems with animal testing. The manufacturer apologized to the families of those affected and assured them that the effects occurred completely unexpectedly and that the procedural regulations were strictly observed. A public prosecutor's committee of inquiry further investigated the question of guilt.

Contamination, dosage errors, or an unforeseen effect of the drug on the human immune system were initially considered as possible causes . The British Medicines and Healthcare Products Regulatory Agency (MHRA) carried out an investigation, including an inspection of the manufacturer from March 22nd to 24th, 2006. According to this report, the reaction was not due to faulty manufacture, to contamination of the preparation or attributed to an incorrect dose. Thus, in this "unforeseeable accident ... no irregularities" were caused by the manufacturer. Rather, the reaction is to be ascribed to the actual target effect ("on target effects") of the substance.

A cytokine storm triggered by the antibodies, which triggered a systemic inflammatory response syndrome , was identified as the cause of the symptoms observed in the test subjects . The antibody was finally only tested in monkeys ( macaques ) in which the antibody was well tolerated in much higher doses. As a possible underlying species difference between humans and macaques, differences in the amino acid sequence of the CD28 molecule, the target of TGN1412, were initially discussed. These could lead to different binding strengths and thus different levels of activation of the T lymphocytes by TGN1412. In fact, even before the phase I study was approved, TeGenero had shown that the antibody TGN1412 binds the CD28 molecules of both species with the same affinity , despite slight sequence differences . It was not until 2010, four years after the disastrous clinical study, that it was finally possible to explain why the animal experiments on macaques could not predict a safe dose for use in humans: the initiators of the cytokine storm in humans are so-called effector memory T cells , which produce CD28 -Molecule and when stimulated by TGN1412 release the proinflammatory cytokines IL-2 and IFN-γ . Effector memory T cells in macaques do not carry the CD28 molecule and therefore cannot be stimulated by TGN1412.

Effects

As a result, a heated debate has flared up in Great Britain and other countries about the safety precautions for drug tests. In particular, it is criticized that the drug was administered to all test subjects at the same time, which, however, was the usual practice at the time.

In Germany, the study was approved by both the former ethics committee of the Berlin Medical Association and the responsible federal authority, the Paul Ehrlich Institute . Shortly after the disaster, the developer of the antibody, Thomas Hünig , stated that, in his opinion, the immune reaction was “mechanistically inexplicable”.

A group of experts set up to evaluate the incidents came to the conclusion that the tests carried out in cell cultures and on laboratory animals prior to the approval of the phase I study did not predict a safe dose for use in humans, although all regulations were observed. The expert group accordingly recommended a revision of the regulations. The TeGenero company subsequently went bankrupt.

Regulatory consequences

As a consequence of this case, the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency adopted new guidelines on July 19, 2007 for the identification and minimization of risks in the first-time use of new medicinal products in humans, which have been binding since September 1, 2007. According to them, a comprehensive risk assessment must be carried out for all first-time applications on humans. If the substance shows a novel mechanism of action, has a target structure in the body with an increased risk potential or if the relevance of the animal models used in preclinical research is questionable, the initial dose must be determined according to the Minimal Anticipated Biological Effect Level (MABEL) . Other mandatory precautionary measures in such cases relate to the study design, such as sequential administration to individual subjects. In October 2007, the Paul Ehrlich Institute published supplements and specifications for these EU-wide guidelines for Germany. Nevertheless, another serious incident occurred in 2016 during a phase 1 study with the active ingredient BIA 10-2474 .

Individual evidence

  1. ^ TeGenero AG: TGN1412 Investigators Brochure . ( circare.org [PDF]).
  2. ^ Søren Hansen, R. Graham Q. Leslie: TGN1412: scrutinizing preclinical trials of antibody-based medicines . In: Nature . tape 441 , no. 7091 , May 18, 2006, p. 282 , doi : 10.1038 / 441282a , PMID 16710395 .
  3. ↑ Thomas Hanke: Lessons from TGN1412 . In: Lancet (London, England) . tape 368 , no. 9547 , November 4, 2006, p. 1569-1570; author reply 1570 , doi : 10.1016 / S0140-6736 (06) 69651-7 , PMID 17084746 .
  4. ^ D. Eastwood, L. Findlay, S. Poole, C. Bird, M. Wadhwa: Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4 + effector memory T-cells . In: British Journal of Pharmacology . tape 161 , no. 3 , October 2010, p. 512-526 , doi : 10.1111 / j.1476-5381.2010.00922.x , PMID 20880392 , PMC 2990151 (free full text).
  5. ↑ Expert Scientific Group on Phase One Clinical Trials: Final Report . ( gov.uk [PDF]).
  6. ↑ Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products (pdf).
  7. ^ CK Schneider, U. Kalinke: After the TGN1412 incident. Principles of the evaluation of first-in-man studies with monoclonal antibodies by the Paul Ehrlich Institute. Bundesgesundheitsblatt 50, issue 10, October 2007, pp. 1213–1220, doi: 10.1007 / s00103-007-0331-6 .

Web links