The term biologies refers to a broad class of medicinal products that share a number of common features. Unlike traditional medicines that are made by chemical synthesis, biologics are made by biosynthesis in living cells. Biologics are generally much larger than traditional synthetic medicinal products and range from highly complex inactivated vaccines and plasma-derived factors to highly purified, well characterised recombinant therapeutic proteins. As new biological therapies come to market, the term biologics may encompass a diverse portfolio and include therapeutic options such as gene and cellular therapies, therapeutic vaccines, and nucleic acid preparations. The scope of this chapter focuses primarily on therapeutic proteins produced in mammalian cell culture processes.
The use of therapeutic proteins as the treatment of choice for certain unmet medical needs was enabled by the convergence of two emerging technologies in the 1970s: genetic engineering and the science of cell culture. These technologies provided researchers with the ability to create specific recombinant DNA molecules encoding specific proteins and the methodology to introduce these recombinant DNA molecules into bacterial or animal cells that synthesised the protein. Further advances in cell culture technology permitted the development of high-viability, high-density cell cultures and the ability to scale cultures to larger volumes. Cell cultures, maintained in large, computer-controlled, stainless steel bioreactors enabled large-scale protein production.
An interesting illustrative case history in the development of a biologic can be seen with the medicinal product alpha-interferon. In the early 1970s, interferons were heralded as promising therapeutics for a vari ety of disease conditions from viral infections to cancer. Initially, alpha-interferon was produced by purification of the active protein from human white blood cells. As cell culture technology advanced, a number of groups were successful in producing alpha-interferon in vitro, from cultures of transformed human lym-phoblastoid cells that spontaneously produced a range of endogenous interferons. The advent of recombinant DNA technology enabled the creation of DNA vectors containing the alpha-interferon gene and the successful expression of the gene in bacterial cells. In 1986, both nonrecombinant and recombinant alpha-interferons gained regulatory approval.
The introduction of recombinant expression systems cleared the way for several major protein products to be launched as therapeutics. Peptide hormones (erythropoietin, growth hormone, beta-interferon, reproductive hormones) (Chu and Robinson 2001; Lubiniecki and Lupker 1994; Simson 2002; Walsh 2003a) and enzymes (tissue plasminogen activator) (Walsh 2003a, 2003b) were produced. These molecules were used as "replacement therapies" to treat patients with diseases caused by the deficiency of specific molecules; supplementation of endogenous protein levels with the recombinant product provided a therapeutic benefit. Frozen cell banks, containing recombinant cells producing these replacement proteins, provided a readily available supply of the required factor that was not dependent on rare and potentially hazardous raw materials such as human blood and tissue.
The next generation of protein therapeutics moved beyond the established strategies of managing disease states by restoring or supplementing endogenous proteins. Recombinant proteins emerged in the 1990s that included antibodies designed to bind to specific antigens or the cells they were attached to, permitting the removal or destruction of the antibody-bound moiety by the immune system or via toxic molecules attached to the antibodies. Antibodies targeting tumor markers [alemtuzumab (CamPath 2005), gemtuzumab ozoga-micin (Mylotarg 2006) and trastuzumab (Herceptin 2005)] and markers of inflammatory disease [anti-tumour necrosis factor (TNF) antibodies for rheumatoid arthritis (Humira 2005, Remicade 2005) and anti-IgE for asthma (Xolair 2005)] were successfully developed and deployed in the clinic, having a profound impact on a range of diseases. Additionally, the ability to screen patients and identify those who would respond to a particular therapy added a further refinement in treatment of various diseases. The trastuzu-mab molecule (Herceptin 2005), targeted toward the human epidermal growth factor receptor 2 (HER2) antigen present on certain tumor cells, has been described as an early example of "patient-directed-medicine". In this model, the patient is first assessed for the presence and level of a specific cancer antigen, allowing for treatment with an antibody that binds to that specific antigen and recruits the immune system to attack the tumor cells. Additional mechanisms are suspected in the case of trastuzumab. Fusion proteins such as etanercept (Enbrel 2005), an anti-TNF-targeted therapy, joined the arsenal of therapeutic proteins in the late 1990s. Etanercept contains a portion of the human endogenous TNF receptor fused to the constant region (Fc) of an immunoglobulin molecule; the therapeutic effect of the molecule is to bind and sequester the proinflammatory cytokine, TNF.
The development of biologics for therapeutic purposes has shown a rapid series of advances over the past 25 years from the extraction of endogenous human proteins to the development and manufacture
Erypo/Procrit (Johnson & Johnson)
Remicade (Johnson & Johnson/
Avonex (Biogen Idec)
Global biotech market of specifically designed molecules targeting specific mediators of disease processes. "Designer" antibodies, containing significant modifications and specialization, add an even further level of complexity: some antibodies that target tumor cells contain a covalently bound toxin or radionuclide to replace or supplement the potency of the immune system. Additionally, advances in formulation science have allowed the development of liquid formulations that have improved patient convenience, compliance, and persistence with treatment.
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