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Agonist antibodies nowadays have a great potentially use as therapeutics agents for the treatment of many diseases. In 1978, C. Milstein and G. Kohler showed that the idea of using an immortalized B cells myeloma and cloning these cells with the healthy antibody producing B cells. It can result many of identical progeny secreting a single type of antibody called monoclonal antibodies (Mabs). The development of monoclonal antibodies with their obvious avantage over polyclonal antibodies such as drug-targeting devices, triggered a considerable increase in efforts to produce effective chemoimmunoconjugates for the treatment of cancer. Mabs is possible for the therapeutically treatment of cancer which only binds to the cancer cell specific antigens to induce an immunological response against cancer cell. Mabs have been proposed for the therapy of myocardial infarctions and for the reversal of drug resistance gene product. An "agonistic" monoclonal antibody is one that triggersÂ a response in the molecule it binds to and then produces many clones which secrete the same antibody. Agonist antibodies have many advantages and disadvantages as therapeutic agents, for the last decades, the development of Mabs as therapeutic agent has grown a significant trend in the pharmaceutical industry because of their long lived in the body. The major disadvantage is the difficulty on the human test as clinical trials
Antibodies (also known as immunoglobulins, abbreviated Ig) are gamma globulin proteins that are found in blood or other bodily fluids of vertebrates, and are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses.
Eight normal healthy volunteers took part of the phase I drug trial of TGN 1412 on March 13, 2006. TGN 1412 is a new humanized monoclonal superagonist of the CD28 T cell surface receptor (N.Beyersdorf et al. 2006). The antibody was supposed to mitigate autoimmune and immunodeficiency disease but within two hours of the trial six of the volunteers experienced catastrophic symptoms. The TGN 1412 trial raised many questions in the way clinical research is undertaken and many lessons were learnt from the tragedy.
The function of antibodies is to prevent the infectious disease by binding the infected cells and activate the immune system against the foreign agents. Antibodies have been fo-und to be extremely valuable therapeutics in the clinical treatments of various diseases without the serious adverse effects through their intrinsic features such as specific binding to the target antigen with strong affinity, clinical safety as serum proteins, and long half-life. They are expected to increase the value of therapeutic antibodies.
In 1994 it was estimated by the Centre for Exploitation of Science and Technology that the total world market for these particular antibodies would reach $1000 million (Savin J., 1990), however the success of the antibodies was greater than expected. In 2006 it was estimated that the market size for monoclonal antibodies was over $20 billion (US) (Wiles.M & Andreassen., 2006). The market was dominated by five antibody drugs Avastin (bevacizumab), Herceptin (trastuzumab), Humira (adalimumab), Remicade (infliximab) and Rituxin (rituximab), which in total account for about 80 percent of the market (Wiles.M & Andreassen., 2006).
TGN1412 Trial from TeGenero: in 2006, at Nothwick park hospital, London eight volunteers took part in a phase I trial received a Tcell agonist. TGN1412 is known as CD28 super Mab is the working name of an immune modulatory drug which was withdrawn from development, originally intended for the treatment of B cell chronic lymphocytic leukemia and rheumatoid arthritis. However, the trial turned to a disaster when six of eight volunteers were feeling something had gone wrong and they terribly begun to complain they had headache, backache, fever, pain and multisystem failures i.e. kidney, heart, liver.
The TGN1412 trial from TeGenero raised many questions and lessons that can be learnt such as How were the volunteers recruited and motivated? How much accurate information, based on full risk analysis, do volunteers receive? Why was the drug tested on healthy volunteers rather than patients? Another criticism is the near simultaneous administration of the drug. A period of time need to be waited to see what would develop in the first patient to ensure no risk before continue on the next patient, so Why were all eight volunteers given the drug at the same time? It has been proved that the target of the TGN 1412 drug, CD28 T cell surface receptor, only shares about 68% of identity of amino acids between human and mouse (Gross JA et al., 1990).
The advantages and disadvantages of agonist antibodies as therapeutic agents:
There are significant costs involved in the identification, optimization and the production of these antibodies because of the price of manufacturing and intellectual property involved. Due to their complicated structure, Mabs in the IgG format are usually limited to the production in mammalian cells. These drugs need post-transitional modifications and critical disulphide bonds for full activity. They are usually produced in Chinese hamster ovary (CHO) or mouse myeloma (NS0) cell lines which can be very expensive and time consuming. Particular technologies required for production include affinity maturation, humanisation methods, the expression systems (promoter and poly A sequence) and cells lines. The costs for licensing these technologies are very high.
For antibody drugs which target cancer, they should be used with chemotherapy or radiotherapy which can increase the total cost to the patient. For example, the FOLFOX regimen (Fluorouracil, leucovorin, and oxaliplatin) costs approximately $12,000 dollars for an 8-week course whereas it costs approximately $21,000 for FOLFOX combined with the antibody drugs bevacizumab, but the combination with antibody drug results in a significant increased benefit in the median survival time (Schrag, D., 2004).
Agonist antibodies are encouraged over most pharmaceuticals and peptides due to their long life in the body. Neuron growth can be advanced using agonist antibodies which can be applied directly to the site of surgery. They can be applied locally in burns and wounds and also delivered intravenously. The doses of agonist antibodies that are effective but that don't cause secondary implications can be experimentally determined. Agonist antibodies can be used to induce growth and receptors and improve production of monocytes, macrophages, B cells, T cells and platelets in various leukemia and hematopoietic deficiencies.
Although agonist antibodies have many advantages, the main disadvantage of agonist antibodies is that they are difficult to test on humans as clinical trials, such as the TGN 1412 trial, have encountered problems such as inadequate dosage and side effects. Agonist antibodies have also been found to be time consuming and expensive to produce.
Also, the use of these therapeutic agents in cancer has had a low success rate because the antibodies have difficulty gaining entry into tumors, especially in brain tumours, if the antibody is injected intravenously, it cannot reach the brain tumour because the brain does not have a lymphatic system. Monoclonal antibodies can have no effect if the tumor changes or if the antibody is engulfed by the tumor.
Examples of other agonist antibody drugs
Another agonist antibody which has had a tragedy includes Rituximab, which is a chimeric monoclonal antibody which is being used in the treatment of B cell non-Hodgkins lymphoma and some autoimmune diseases. It was developed by IDEC Pharmaceuticals and approved by the Food and Drug Administration (FDA) in 1997. It works by depleting B cells and is thus used to treat diseases which are associated with having excessive B cells, overactive B cells or abnormal B cells. Rituximab was used for the treatment of systemic lupus erythematosus (SLE), however, in December 2006, the FDA issued warnings for the use of Rituximab for the treatment of SLE after two deaths resulted from the drug use.
Trastuzumab is a fully-humanized monoclonal antibody that reacts with the HER2 receptor. It is especially used as a anti-cancer therapy for breast cancer. When trastuzumab is applied to the cells, it causes the G1 phase of the cell cycle to stop which significantly decreases cell proliferation. This drug has demonstrated to prevent HER2/neu ectodomain cleavage in breast cancer cells (Albanell et al., 2003). Trastuzumab has had a "major impact in the treatment of HER2-positive metastatic breast cancer" (Tan and Swaim., 2002). Combining Trastuzumab with chemotherapy has demonstrated an increase in both survival and response rate, whereas the use of Trastuzumab alone has had a significantly lower success rate (Nahta et al., 2003).
Trastusumab has demonstrated in clinical trials to decrease relapse in breast cancer patients by up to 50 per cent when given in the adjuvant setting, before the cancer has spread any further, for one year (Romond et al., 2005). However, there are also disadvantages to this type of treatment. The costs involved are enormous, The costs of Trastuzumab is approximately seventy thousand US dollars for a full course of treatment (Fleck., 2006).Also, during the trastuzumab trials women treated with trastusumab encountered cardiac dysfunction which lead to a number of changes in the trials such as the establishment of an independent Cardiac Review and Evaluation Committee (CREC). Approximately 7% of patients treated with trastuzumab, have encountered cardiac dysfunction (Roland., 2007), which is still a very high risk.
However, not all agonist antibodies have resulted in a negative trial or a patient/s death. Infliximab is one of many important agonist antibodies which can be used to demonstrate the success on agonist antibodies in therapy today. Infliximab, also called Remicade, is a chimeric monoclonal antibody used to treat autoimmune disorders. It works by blocking the action of TNF-alpha and prevents the binding of TNF-alpha with its receptors. It is also able to lyse cells that involved in inflammation. The drug was initally used in 1999 for the treatment of Crohn's disease. Phase II clinical trial using 94 patients demonstrated that Infliximab was effective in closing fistulae between the skin and bowel in approximately 56-68% of patients who participated in the trial (Present et al., 1999).
In a trial called the ACCENT 2 trial which was a phase III clinical trial using 296 patients showed that infliximab was additionally beneficial in maintaining closure of fistulae, with upto two-thirds of all patients treated with the 3 initial doses REMICADE having a fistula response after 14 weeks, and 36% of patients maintaining closure of fistulae after a year compared to those patients who received a placebo having only 19% of closure of fistulae. After this final trial, the FDA approved the drug to treat fistulizing disease (Sands et al., 2004). Infliximab has also been approved for treating CrohnHYPERLINK "http://en.wikipedia.org/wiki/Crohn's_disease"'HYPERLINK "http://en.wikipedia.org/wiki/Crohn's_disease"s disease, ankylosing spondylitis, fistulizing Crohn's disease, pediatric Crohn's disease, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. This drug can also be prescribed (out of indication) for the treatment of Behcet's disease (Sfikakis., 2002)
The trials which are conducted to test agonist antibodies on humans can be significantly improved simply by taking extra precautions such as testing single doses on an individual and observing any side effects before administering the drug to others. The trials can be put up for public review and the volunteers should be warned of the potential side effects and that the drug could ultimately result in death. The volunteers should also always be thoroughly educated on the trial. Agonist antibodies have limitless possibilities. They are so diverse and therefore new and remarkable properties of antibodies continue to arise. They can mimic the action of specific ligands such as hormones; others can block of inactivate receptors on cell surfaces. The properties and specificities of antibodies that can be selected are effectively limitless. It is estimated that more than 1/3 of all drugs presently being developed by drug companies are monoclonal antibodies which will therefore enable antibody technology to reach many more medical milestones in the near future.
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