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TGN1412 was an CD28 super-agonist discovered in 1997 by Thomas Hunig, a professor at Wurzburg university. It was thought to be a potential anti-inflammatory drug with unique mechanism of action. It could directly activate T -cells bypassing the need to activate T cell receptors (Beyersdorf, Hanke et al. 2005). After conducting all preliminary non clinical and clinical tests in order to demonstrate its safety in humans the first-in-man clinical trial was conducted on March 13, 2006 by Paraxel one of the largest clinical trial company in UK under the contract of TeGenero. In this study humanized form of TGN1412 was administered in to six healthy volunteers who experienced a life threatening cytokine storm. This raised many ethical issues about the clinical trials and thorough analysis of the preclinical data submitted by the sponsor was done by various regulatory authorities.
DEVELOPMENT OF TGN-1412:
The understanding of the role of CD28 receptor and its agonist in immune system led to the discovery of TGN1412. CD28 receptor is a co-stimulatory receptor expressed on the cell surface of all human CD4 T Lymphocytes (T cells) and on a large fraction of CD8 T cells (Riley and June 2005). Along with the signal form T cell antigen receptor, CD28 receptors are responsible for the stimulation of resting T-cells. A subclass of CD28 specific antibodies known as CD28 Super-agonists or anti-CD28 antibodies were found having the ability to bypass the requirement of the TCR signaling and activated T-cells irrespective of their TCR specificity. This class of super-agonist not only activated T cells in vitro but in vivo as was shown in experiments on rats. Unlike anti-CD3 stimulation, anti-CD28 antibodies did not show occurrence of cytokine storm. Further it was found that these CD28 super-agonist were efficacious in treatment of autoimmune disorders in different animal models (Beyersdorf, Hanke et al. 2005). The therapeutic effect observed in animal models suggested that CD28 super-agonist were promising and could be developed for the treatment of human autoimmune and inflammatory diseases. Hence in order to isolate human CD28 super-agonist TeGenero generated a collection of mouse anti-human CD28 mAb and screened them for the ability to induce T-cell proliferation with or without TCR signaling. A fully humanized Ig4 monoclonal antibody was developed by means of genetic engineering from a super-agonistic mouse anti-human CD28 antibody selected from this collection. Since it was known that Ig4 antibodies have less propensity to show cytotoxic effector mechanism via Fc portion, the company advanced to develop a human super-agonist of this isotype namely TGN-1412 (Hunig 2007).
From in-vitro assays such as flow cytometric analysis and Biacore analysis specificity of TGN1412 for human CD28 was shown. The affinity determined from this assays was in nanomolar range and comparable to those of normal antibodies. Epitope mapping studies showed that human or rat CD28 agonistic antibodies bind to the laterally exposed C''D loop near to the plasma membrane whereas conventional antibodies bind close to the binding site of natural CD80/CD86 ligands. Because of this shared specificity anti-human CD28 agonists TGN1112, TGN1412 and anti-rat antibodies were considered to be true orthologues (Hunig 2007).
Not everything is known about a medicine when it receives its licence for marketing. The merits of a new drug, balancing its beneficial and its untoward effects, become only established after sufficient experience has been gained from its use in real practice. Part of the reason for this is that our extensive phase III clinical trials fail to detect some side-effects. Why is this so? Three groups of reasons may be envisaged, namely (1) our trials lack the power to detect rare side-effects; (2) some side-effects do not occur in the context of clinical trials; (3) some side-effects, though common enough, fully or partly escape detection due to lack of suitable detection techniques
Antigen-presenting cells (APCs) pick up antigens (generally proteins), break them into small pieces and present them on their surface attached to MHC molecules (see the figure below). If the APC has encountered signals of pathogenicity such as bacterial surface proteins or responses to viral attack while it was picking up the antigen, it will have costimulatory molecules CD80 and CD86 on its surface. When a T cell binds to those small pieces (peptides) of antigen on the surface of an APC, using its T cell receptors (TCRs), it is activated, but in the absence of costimulatory signals (in other words, when the antigen being presented is most likely a protein from a harmless self cell, or a commensal bacteria, or some food or dust) it is only partially activated and ends up either tolerised or deleted (so it can't respond to that antigen in the future) or possibly becomes a regulatory T cell which can suppress the responses of other T cells to that same antigen. If CD80 or CD86 are present on the APC, however, these bind to CD28 on the surface of the T cell which is then fully activated, proliferates and produces an effective response to attack and eliminate the pathogen from which the antigen was derived.
Ximelagatran - a direct thrombin inhibitor was a new class of oral anticoagulant developed by AstraZeneca as an alternative therapy to conventional vitamin K antagonist (VKA's). Due to the several limitations of Vitamin K antagonists(Hawkins 2004) constant efforts were made by leading pharmaceutical companies to develop oral anticoagulant alternative to VKA's. Ximelagatran was first drug in 50 years since the introduction of warfarin to reach the late stages of clinical trials. On December 3rd 2008 it was submitted for approval of the FDA. Upon administration it was quickly converted to its active form melagatran which is a direct thrombin inhibitor and displayed stable and reproducible pharmacokinetic properties .It showed no food and drug interactions and no constant monitoring was required.(Vaughan 2005) This drug was indicated for patients undergoing elective surgery for hip and knee replacement and was also found efficacious for secondary prevention of venous thromboembolism , acute coronary syndrome, acute deep vein thrombosis, stroke in patients with atrial fibrillation.(Dorani, Schutzer et al. 2007)Hence the drug displayed high potential to revolutionize OAC therapy.
But AstreZeneca on 14th Feb 2006 decided to withdraw the drug from market and stop its development. This decision was taken as FDA did not approve the drug because of safety related concerns. The downfall of this drug first began with results of SPORTIF II study .The study was designed to asses the safety, tolerability and dose of ximelagatran compared to warfarin. Around 4.3% patients were found to have ALT (Alanine transferase) levels 3 times greater than upper limit of normal(ULN)(Boos and Lip 2006). Upon retrospective analysis of patients (6948 patients in ximelagatran group , 6230 comparators) who had taken the drug for more than 35 day combined elevation of ALT>3XULN and bilirubin>2X ULN was found in 0.5% and 0.1% patients respectively(Boos and Lip 2006). Three patients treated with ximlelagatran died and it was a major concern as the adverse liver effects were unpredictable and not found to be dose related. Altough in the large clinical studies SPORTIF III and THRIVE (thrombin inhibitor in Venous thromboembolism) treatment studies ximelagatran was found non-inferior than warfarin in treatment of Acute venous thromboembolism and Atrial Fibrillation(Albers, Diener et al. 2005; Fiessinger, Huisman et al. 2005). Later these studies highlighted the safety concern related to liver toxicity and also increased coronary events were observed. A slight increase in myocardial infarction was found in patients after cessation of ximelagatran therapy. In addition the validity of the SPORTIF III and V studies were questioned and were considered to liberal. FDA found the study