Theralizumab
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TGN1412 (also known as CD28-SuperMAB®) is the working name of an immunomodulatory drug intended for the treatment of B cell chronic lymphocytic leukemia (B-CLL) and rheumatoid arthritis.[1] TGN1412 is a humanised monoclonal antibody which not only binds, but is superagonistic to the CD28 receptor of the immune system's T cells[2]. It received designation as an orphan medical product from the European Medicines Agency for the treatment of B cell chronic lymphocytic leukemia in March 2005[3]. It was developed by TeGenero Immuno Therapeutics and manufactured by Boehringer-Ingelheim.[4]
Mechanism of action
T-cells normally require signal 1 (the antigen receptor) and signal 2 (co-stimulation) to become fully activated. The superagonistic properties of this agent means it fully activates T-cells without the need for additional antigen-receptor stimulation. Superantagonism of these antibodies was found to be dependent on binding to a specific part of the CD28 molecule called the C"D loop[5]. Once the investigators found antibodies with these properties they wondered if they could be therapeutically useful in stimulating the immune system in immunosuppressed patients as these antibodies would be expected to crudely activate all T-cells simultaneously. However, in vitro and in vivo data from animal studies later suggested that administration would lead to increased activation of regulatory T cells, leading to a net effect of immunosuppression. However, the results of the first trial in human beings (see below) indicate that this may not always be the case.
Clinical trials
Phase I clinical trials conducted by PAREXEL[6] at Northwick Park Hospital, London, hospitalised 6 volunteers in March 2006, with at least 2 of them suffering major organ failure[7].
The trials were carried out by PAREXEL International, a company that carries out drug trials on behalf of pharmaceutical companies. The trial took place at PAREXEL's facilities at Northwick Park Hospital, north west London. Eight young, healthy men participated in the trial with two receiving placebo and the remaining six receiving TGN1412. After the drug was administered to the last participant, the first participant started complaining of a severe headache, fever and pain and collapsed shortly after. Within a few hours, the remaining participants who received the actual drug had become ill as well, vomiting and complaining of severe pain. Within 12 hours all 6 had collapsed. At least one participant begged the doctors to "put him to sleep" because of the suffering.[8]
Some of the men are reported to have experienced severe swelling with comparisons being made to The Elephant Man. According to doctors, this is caused by the large amount of fluids given as part of the treatment. The patients are being treated with anti-inflammatory steroids. Two of the men were reported to be in a critical condition with the remaining four being in a serious, but improving condition.[9] TeGenero has apologized to the families involved and insist that these effects were completely unexpected and that all protocols have been followed. An investigation of the case by authorities has now been commenced to find out if the reaction seen is due to a contamination of the drug given, a wrong dose being administered or if it is an inherent flaw in the drug. Criticism has been raised that 6 participants were given the drug in such a short time, which is against the recommendations of some standard literature.
TGN1412 had not previously been given to humans, however, the trial was preceded by animal testing including testing in primates but the company claims that these did not indicate any safety issues. 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."[10]
Questioned on Channel 4 News, a spokesman from the Medicines and Healthcare products Regulatory Agency (MHRA) explained that the initial doses of TGN1412 had been intended to be the first of a course of injections, with the dosage being ramped up over time. The initial dose, he said, was one five-hundredth of that which the animal studies indicated was the maximum safe amount.[11].
External links
- Patent applications for TGN1412
References
- ^ TeGenero (2006-02-20). "Drug Development". TeGenero. Retrieved 2006-03-16.
{{cite web}}: CS1 maint: year (link) - ^ *Abstract #2519 American Society of Haematology Meeting 2004, appears in abstract form only in Blood, Volume 104, issue 11, November 16, 2004. This is the only academic reference. [1]
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- ^ Luhder F, Huang Y, Dennehy KM, Guntermann C, Muller I, Winkler E, Kerkau T, Ikemizu S, Davis SJ, Hanke T, Hunig T (2003). "Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists". J Exp Med. 197 (8): 955–66. PMID 12707299.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Template:Press release reference
- ^ "Six taken ill after drug trials". BBC News. 2006-03-15. Retrieved 2006-03-16.
{{cite news}}: Check date values in:|date=(help) - ^ "Ryan: Spare me this pain". The Sun. 2006-03-16. Retrieved 2006-03-16.
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- ^ United States patent application US20060009382 filed by Thomas Hanke, Chia-Huey Lin
- ^ "Interview with spokesman from the Medicines and Healthcare products Regulatory Agency". Channel 4 News. 2006-03-16.
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