Vaccines approved biopharmaceuticals

After the approval of the first product, recombinant insulin, in 1982, progress in the development of new recombinant protein pharmaceuticals was slow ([10], Fig. 17.1). The number of biotechnology-derived drugs and vaccines approved by the US Food and Dmg Administration (FDA) has increased significantly only since 1995. More recently, sales of biologies have skyrocketed, e.g. from 900 million in 1999 to an estimated 3.5 billion in 2001 for monoclonal antibodies [11]. The annual global market for biopharmaceuticals is estimated to have increased from 12 billion US to 30 billion US in 2003 [12]. 500 candidate biopharmaceuticals are undergoing clinical evaluation and over one hundred protein-based therapeutics are in the... 

Walsh (2003) defined biopharmaceuticals as therapeutic protein or nucleic acid preparations made by techniques involving recombinant deoxyribonucleic acid (DNA) technology. Therapeutic proteins include blood clotting factors and plasminogen activators, hemopoietic factors, hormones, interferons and interleukins, and monoclonal antibodies (LeVine, 2006). Over time, the term biopharmaceutical has broadened, and, in addition to proteins and nucleic acids, now includes bacteriophages, viral and bacterial vaccines, vectors for gene therapy, and cells for cell therapy (Primrose and Twyman, 2004). Attention here focuses on proteins, since the majority of approved biopharmaceuticals are proteins. 

Although most biopharmaceuticals approved to date are intended for human use, a number of products destined for veterinary application have also come on the market. One early such example is that of recombinant bovine GH (Somatotrophin), which was approved in the USA in the early 1990s and used to increase milk yields from dairy cattle. Additional examples of approved veterinary biopharmaceuticals include a range of recombinant vaccines and an interferon-based product (Table 1.7). 

In order to overcome environmental concerns in particular, some companies are investigating the use of engineered plant cell lines as opposed to intact transgenic plants in the context of biopharmaceutical production. One company (DowAgroSciences) gained approval in 2006 for a veterinary subunit vaccine against Newcastle disease in poultry produced by such means. 

To date, most approved protein-based drugs are for therapeutic or replacement therapies. They are recombinant versions of natural proteins such as insulin and erythropoietin. Their characteristics and functions are relatively well defined and known. The next phase of biopharmaceuticals, such as antibodies and vaccines, is more complex and requires more tests and characterizations. Controls for the reliability, contamination, and fidelity of expression systems will be high on the agenda in the coming decade. 

Amongst the limited number of biopharmaceuticals approved for animal use (Chapter 1), recombinant vaccines represent the single largest sub-group. Several such products target pigs,... 

Here, an overview of biopharmaceutical products thus far approved (within the EU and US at least) is presented. The products have been grouped into nine categories recombinant blood factors, recombinant thrombolytics, recombinant insulins, additional recombinant hormones, recombinant hematopoietic growth factors, recombinant IFNs and ILs, recombinant vaccines, monoclonal and engineered antibodies, and additional biopharmaceuticals (e.g., cell therapy, gene therapy, siRNA). 

Yeast is the third expression system used to produce biopharmaceuticals. As mammalian systems, they possess the ability to cany out post-translational modifications of proteins, although the glycosylation pattern usually varies somewhat from the patterns observed on the native protein or on the protein expressed in mammalian cells. Two recombinant proteins expressed in Saccharomyces cerevisiae are now approved for general medical use hepatitis B surface antigen vaccine and the anticoagulant Hirudin . Alternative promising production systems, in particular transgenic animal and plant systems, are still in development but these systems have to prove that they are technically and economically attractive. 

Modern biotechnology has resulted in the production of a great variety of pharmaceutically active proteins (1). Recent statistics show that the Food and Drug Administration (FDA) has approved 130 biotechnology-derived protein medicines and vaccines (2). The unfavorable biopharmaceutical properties of these protein drugs, however, have severely hampered their therapeutic and clinical application. First of... 

Since the first product, the recombinant kallilcrein inhibitor ecallantide (KALBITOR , Dyax, USA), was approved by the FDA in 2009, several more followed, mainly being peptides and small proteins. Antibodies and fragments thereof are currently in clinical trials awaiting approval [154]. Several more biopharmaceutical products such as insulin, interferon-alpha 2b, and hepatitis B vaccine are on the market in India and other Asian countries [155]. Apart from biopharmaceuticals, a range of industrial enzymes, among them phytase, nitrate reductase, or lipase, are commercially available. Direct information on the production process is mostly not available, but it can be concluded from journal and patent literature that mostly the AOXl promoter is used in these cases, and other expression systems like the GAP promoter are applied as well. In total, approximately 70 products are on the market, and a list can be found at http // www.pichia.com/science-center/commercialized-products/ [156]. 

From 1982 (when the first recombinant product was approved) through 2008, there have been 403 approvals of biopharmaceutical products by FDA, including vaccines, blood products, recombinant proteins (including monoclonal antibodies (mAb)), and other biopharmaceuticals. Among these, 103 are recombinant proteins. The market for therapeutic proteins should show double-digit growth over the next few years. 

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