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1. Abstract
1.1 Situation of organ transplant
According to World Health Organization, there are as high as 100,800 solid organ transplants performed around the world annually, in which the highest percentage was found as kidney transplantations. However, it was observed in the past three decades that patients who have had a kidney transplant suffer dramatically from nephrotoxicity created by the immunosuppressive drugs that are essential for their treatment. Traditional immunosuppressive drugs have been studied under the microscope and scientists are continuously exploring new possibilities for immunosuppressants that are non-nephrotoxic with minimum side effects.
1.2 What is Alemtuzumab and its impact on kidney transplant
Alemtuzumab as an FDA approved drug, is current used to treat autoimmune diseases such as multiple sclerosis (MS) and lymphocytic leukemia (U.S. Food and Drug Administration, 2019). Over the past few years, alemtuzumab has drew attention from many scientists for the consideration of its application in organ transplants as a solution for the observed kidney transplant problems and as a possible replacement and optimization for the current CNI drugs used in organ transplant surgeries.
1.3 The goal of this article is to take a closer look into the current status of Alemtuzumab and evaluate how far this drug is to become a treatment for organ transplant patients.
Introduction
Solid organ transplantation has been considered as a lifesaving surgery for many patients with a terminal stage organ failure for more than 30 years now since the discovery of cyclosporine in 1983(Grinyó 2013). According to World Health Organization, around 100, 800 solid organ transplants are performed every year worldwide , in which 69% constitute as kidney transplants (WHO 2008). However, the struggle of balancing the sufficient amount of immunosuppression to protect the graft organ and lowering the dosage enough to avoid related toxicity, especially nephrotoxicity has always been the center topic of organ transplantations and the final solution is still in search (Andrade-Sierra et al. 2018). These situations demonstrate the need of new immunosuppression drugs in the wide application of organ transplantation, which brought the attention to alemtuzumab.
Alemtuzumab is an immunosuppressant drug which is currently in use to treat multiple sclerosis (MS), and lymphocytic leukemia (U.S. Food and Drug Administration, 2019). This medicine is manufactured by Sanofi Pasteur in North America and has common trade names of Campath and Lemtrada. In recent studies, the non-nephrotoxicity feature of this drug draw attentions of scientists to develop and improve this drug for its application in solid organ transplantation and specifically for kidney graft (Almendingen 2019).
What is alemtuzumab
Alemtuzumab is a monoclonal antibody which initially discovered by Herman Waldmann, a British immunologist in 1983. He randomly injected a rat with some human white blood cell residue, and he observed that the rat immune system raised a specific antibody against human lymphocytes. This antibody was named ‘Campath’ by the university of Cambridge at that time (Hale, Geoffrey et al. 1983)
Mechanism
Like a typical antibody, the Y shape molecule structure of alemtuzumab is made up of four polypeptide chains. The two binding sites of this monoclonal antibody are specific to the antigen CD52, which is located on the surface of T and B lymphocytes. The binding of alemtuzumab with CD52 will result in the deactivation and depletion of these cells. (Almendingen 2019)
In vivo bioassay of alemtuzumab
Many bioassays have been done for alemtuzumab. One of the preclinical bioassays that has been done on this drug to study the mechanism of action and estimate minimum efficient dose was In vivo Cynomolgus Monkeys bioassay . According to the studies, Non-human species cannot be selected for preclinical bioassays because the CD52 molecule expressed on their erythrocytes, causes massive hemolysis by administering alemtuzumab and the animal will eventually die. Therefore, an animal with a body type close to humans is needed to perform the bioassay. Based on the data collected from screening different types of monkeys, an Indonesian monkey, Cynomolgus Monkeys, demonstrate no CD52 on the erythrocytes and 85% homology with human CD52. (Van Der Windt et al. 2010).
The In vivo Cynomolgus Monkeys bioassay was performed on six Cynomolgus Monkeys. In two monkeys, mycophenolate mofetil (MMF) was added as maintenance therapy. Based on the result obtained from this bioassay, complete depletion of T and B lymphocytes (>99.5%) was achieved with 20 mg/kg of body weight (Van Der Windt et al. 2010).
Manufacture and purification of alemtuzumab
Alemtuzumab was previously marketed under the name Campath, but have been removed by Sanofi Pasteur for a higher-priced relaunch with the new name Lemtrada, targeting multiple sclerosis specifically (Mckee 2012).
There have been two main production lines being used for the manufacture of alemtuzumab: rat hybridoma cell line and Chinese hamster ovary (CHO) cell line, in which the CHO cell production line is the one currently being used for the manufacture by Sanofi Pasteur (FDA 2019).
A paper from the University of Cambridge described a detailed procedure for the manufacture of alemtuzumab. The cells were cultured in hollow-fiber fermentors and a single bioreactor designed for adherent cells was installed specifically for the CHO cell line production. After 7 days of establishment, the product was harvested using 25% fetal bovine serum, then continuously run through a 0.2 ¼m for 14 days and stored at -40°C until being further processed (Phillips et al. 2001).
The purification process of alemtuzumab consists 2 cycle of precipitations with ammonium sulphate first, and then a series of different chromatography purifications was carried on using Biopilot chromatography system (Pharmacia). Additional steps will be further proceeded to ensure the removal of DNA and viruses. At the end, quality control tests like radioactive labeled biological activity testing and antigen-binding activity testing by ELISA using microtitre plates will be performed on the product. Samples were saved and stored at -70°C for long-term stability testing and monitoring(Phillips et al. 2001).
Advantages of alemtuzumab
The most important advantage of Alemtuzumab is that there is no nephrotoxicity for patients with kidney transplantation, therefore, it could be considered as a replacement for drugs that has high nephrotoxicity, such as CNI drugs(calcineurin inhibitors). Moreover, the same effect can be achieved by administration of less amount of the drug. Alemtuzumab has the advantage of intravenous injection which reduces the annual relapse rate by 55% in and has a lower impact on patients daily life. Patients are able to get injections only a few times during a year instead of receiving daily dosage (given as two annual courses on five consecutive days at baseline and on three consecutive days 12 months later) (Ziemssen and Thomas).
Disadvantages of alemtuzumab
One of the most serious and life threatening problems with this drug is cytokine release syndrome caused by infusion reactions. based on clinical studies, 92% of LEMTRADA-treated patients experienced infusion reactions (U.S. Food and Drug Administration). Patients treated with alemtuzumab have also been seen to be vulnerable against norovirus-related (virus family Caliciviridae), a chronic diarrhea infection, due to partially inactive immune system (Ronchetti et al.), and have a high risk of serious autoimmune mediated conditions. Moreover, based on in controlled clinical studies, 0.3% LEMTRADA-treated patients developed thyroid cancer, MalIgnancies (U.S. Food and Drug Administration).
Conclusion
Despite the disadvantages alemtuzumab demonstrated, it is still considered as a very valuable molecule by many, especially for its non-nephrotoxic feature. It has already been considered by scientists for the application in organ transplants with a combination of other drugs to reach the final goal of having a balanced immunosuppression without toxicity and side effects (Andrade-Sierra et al. 2018). We believe that it also can be a great inspiration for future immunosuppressant development, especially for methods like rational drug design and side chain modifications. As our research goes on, other interesting immunosuppressive molecules was encountered, belatacept and efalizumab as two outstanding examples, drew our attention and are considered as very prospective options for the usage as a combination for immunosuppression in the near future (Almendingen 2019).
- Almendingen, Tora Elisabeth. 2019. Immunosuppression and Tolerance in Adult Liver Transplantation. UiT The Artic University of Norway.
- Andrade-Sierra, Jorge et al. 2018. Immunosuppressive Minimization Strategies in Kidney Transplantation. In Organ Donation and Transplantation – Current Status and Future Challenges, InTech. http://www.intechopen.com/books/organ-donation-and-transplantation-current-status-and-future-challenges/immunosuppressive-minimization-strategies-in-kidney-transplantation.
- Grinyó, Josep M. 2013. Why Is Organ Transplantation Clinically Important? Cold Spring Harbor Perspectives in Medicine 3(6): 110.
- Hale, G., Bright, S., Chumbley, G., Hoang, T., Metcalf, D., Munro, A. J., & Waldmann, H. (1983). Removal of T Cells From Bone Marrow for Transplantation:A Monoclonal Antilymphocyte Antibody That Fixes Human Complement. October, 62(4), 873882.
- Mckee, Selina. 2012. Sanofi Withdraws Campath in US and EU. Pharmatimes: 13. http://www.pharmatimes.com/news/sanofi_withdraws_campath_in_us_and_eu_976762.
- Phillips, J. et al. 2001. Manufacture and Quality Control of CAMPATH-1 Antibodies for Clinical Trials. Cytotherapy 3(3): 23342.
- Van Der Windt, D. J., Smetanka, C., MacEdo, C., He, J., Lakomy, R., Bottino, R., & Lakkis, F. G. (2010). Investigation of lymphocyte depletion and repopulation using alemtuzumab (Campath-1H) in cynomolgus monkeys. American Journal of Transplantation, 10(4), 773783. https://doi.org/10.1111/j.1600-6143.2010.03050.x
- Ziemssen, Tjalf, and Katja Thomas. Alemtuzumab in the Long-Term Treatment of Relapsing-Remitting Multiple Sclerosis: An Update on the Clinical Trial Evidence and Data from the Real World. Therapeutic Advances in Vaccines, vol. 10, 2017, doi:10.1177.
- Ronchetti, Anne Marie, et al. Norovirus-Related Chronic Diarrhea in a Patient Treated with Alemtuzumab for Chronic Lymphocytic Leukemia. BMC Infectious Diseases, vol. 14, no. 1, 2014, pp. 25, doi:10.1186/1471-2334-14-239.
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