Monoclonal Antibodies

Human monoclonal antibodies The phrase monoclonal antibodies generally refer to murine monoclonal antibodies (mAbs); this is when
the antibodies are rodent-derived. Murine monoclonal antibodies are produced using a mouse and its cells; spleen cells from mice fused with cancer cells. Cancer cells are used as they can infinitely multiply, a hybridoma cell would be produced from this fusion where the hybridomas are cultured, antibody-producing hybridomas are cloned and then the monoclonal antibodies are harvested. The two most common paths of human mAbs production is using transgenic-mouse technology or phage-display technology. Nelson, A.L. et al. (2010, p. 767) state that Human monoclonal antibodies (mAbs) are the fastest-growing category of mAb therapeutics entering clinical study. The other categories of mAbs include; murine, chimeric and humanized. Transgenic mouse technology employs the use of so-called Hu-mice these are mice which carry human immunoglobin loci and produce human antibodies in response to immunisations. According to some research (Lanzavecchia, A. et al., 2007, p. 524) the transgenic-mouse platform is quite suitable for the isolation of antibodies specific for human antigens such as cytokines or cell surface molecule but is less suitable for human pathogens such as HIV, HCV, HBV, or CMV that do not infect mice. Phage-display technology was brought to light in 1985 when it was discovered that DNA sequences could be cloned into bacteriophages where the clones express themselves on the surface of phage particles as proteins. This discovery was then used in conjunction with the Polymerase Chain Reaction as a means to access target specific mAbs without generating a multitude of hybridoma cells. Phage-display derived mAbs were found to be more immunogenic than transgenic-mouse derived mAbs. This links back to the transgenic-mouse platform being less suitable for human pathogens. Human mAbs can also be obtained naturally; this process involves extracting the monoclonal antibodies from the body. The best source cells in the process are plasma cells and human memory B cells. Specific antibodies can be obtained from newly generated plasma cells which are secreted 6-10 days after booster immunisations. The plasma cells move to the bone marrow where they exist as long-lived plasma cells. As per their biology, plasma cells are available in blood only for a narrow time period that can be precisely timed in the case of a booster immunisation however; in the case of a natural infection it would be difficult to ascertain the correct timeframe. Memory B cells have a long cell life and therefore are ideal archive of the antibody specifities which is generated in the event of an infection or vaccination that can be pooled from at any time by just taking a sample of peripheral blood. Memory B cells have a substantial growth potential and can be immortalised by the Epstein Barr Virus (EBV). These newly immortalised cells can then secrete antibodies in larger quantities. Screening is then performed to detect specific antibodies using both binding and functional assays. As of today, 7 human mAbs have been approved by the FDA. The first of these approved human mAbs was adalimumab. Adalimumab is a phage-display derived mAb and neutralises tumour necrosis factor- (TNF). Since its approval in 2002 it has since then been approved for other indications too, these include; rheumatoid arthritis, Crohns disease and plaque psoriasis. Golimumab is a transgenic-mouse derived mAb that was approved in 2009 by the FDA for these indications; rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.
Both these mAbs are TNF-specific however; golimumab requires a once-a-month subcutaneous dosing whereas adalimumab requires it to be administered every other week. From 1985-1986, 16 human monoclonal antibodies fit the required criteria and were put into clinical development as the technology used to produce human mAbs was in early stages, the quantities produced were unreliable. Anything that was produced was also viable to contamination. The source lymphocyte cells were obtained through natural process due to the ethical problem of immunising patients with experimental antigens just to retrieve cells being seen as morally wrong. The numbers (Nelson, A.L. et al., 2010, p. 767) show that these human monoclonal antibodies which were evaluated and were found to be limited to certain targets; 62.5% limited to infectious disease, 37.5% limited to cancer. In 1997 Human mAb therapeutics derived from transgenic-mouse or phage-display technologies entered clinical development for the first time. A grand total of 131 human mAbs entering clinical research; of these, 88 were in active clinical development, with 7 in Phase III studies, 51 in Phase II and 30 in Phase I. 7 were approved for marketing by the FDA, 3 are undergoing review by the FDA and 33 were discontinued. For 125 of the 131, antigenic targets were found and of these 125 mAbs, 55 (44%) targeted antigens relevant to antineoplastic diseases, 36 (29%) targeted antigens that are relevant to immunological diseases and 17 (14%) targeted antigens that are relevant to infectious diseases. More recently, major drug companies have begun to acquire the new technology companies indicating that the interest in human mAb treatment within the pharmaceutical industry is rapidly growing. Not only is the interest growing but to prove that human mAbs are a good source of new therapies is in the numbers, with 7 approved in the United States, 3 under review by the Food and Drug association, 7 in late development and 81 in early development. The current percentages of success rates for human mAbs are superior to those of current humanized mAbs, this proves that not only is there an interest for new therapies like this but also if these drugs are put into practice they would certainly be viable. References
Lanzavecchia, A., Corti, D. & Sallusto, F. (2007). Human monoclonal antibodies by immortalization of memory B cells. Current Opinion in Biotechnology. 18 (6), p523-528. Lonberg, N. (2008). Fully human antibodies from transgenic mouse and phage display platforms. Current Opinion in Immunology. 20 (4), p450-459. Lonberg, N. (2005). Human antibodies from transgenic animals. Nature Biotechnology. 23 (2), p1117-1125. Nelson, A. L., Dhimolea, E & Reichert, J. M. (2010). Development trends for human monoclonal antibody therapeutics. Nature Reviews Drug Discovery. 9 (3), p767-774. Saylora, C., Dadachovaa, E. & Casadevall, A. (2009). Monoclonal antibody-based therapies for microbial diseases. Vaccine. 27 (6), G38-G46.

Monoclonal Antibodies

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Human monoclonal antibodies The phrase monoclonal antibodies generally refer to murine monoclonal antibodies (mAbs); this is when

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