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Biopharmaceuticals are defined as proteins and nucleic acids which are used for therapeutic purpose. These are high molecular weight substances prepared by biotechnological means and genetically engineered. Due to their complex structure and intricate molecular composition it is very difficult to characterize and formulate such products. Most of these products are derived from biological species and genetically engineered to produce a potent compound [1-3]. Humulin (biosynthetic recombinant human Insulin) was the first biopharmaceutical product developed by Genentech but licensed and marketed by Eli Lily and Company in 1982. In the modern era biopharmaceutical products have become a major facilitating reason of technological changes in health care sector, causing extraordinary benefits for patients, cost challenges for consumers, and profits for market shareholders.
Over the last decade biopharmaceutical market is the fastest growing segment in the pharmaceutical organizations. After post-recession period vigorous advancement has been seen in this area. It has been reported that approximately 40% of total pharmaceutical R&D investment is occupied by biopharmaceutical products amongst which, monoclonal antibodies and product produced by recombinant DNA method are the most prevalent one.[5,6] Proteins with different amino acid sequences are the primary structure of such products. For determining the biological activity of a protein it is necessary to study its three-dimensional structure. The structure of protein is generally divided into four categories i.e. primary, secondary, tertiary and quaternary (fig. 1). The primary structure is the sequence of amino acid residues which folds and stabilized by the formation of hydrogen bonds with subsequent molecules in the polypeptide chain to produce an Î± helix, which is a spiral, rod-like structure, or a Î² sheet, a planar structure. This structure resembles to the secondary structure of proteins. The tertiary structure is a three-dimensional arrangement which gives an overall conformation of a polypeptide chain. Through hydrophobic interactions between the non-polar side chains and disulfide bonds, this tertiary structure is stabilized. A quaternary or multimeric protein contains two or more polypeptide chains, held together by non-covalent bonds.
fig 1. Structure of protein.
Because of their unique physicochemical characteristic it is very hard and challenging to formulate biopharmaceuticals as products with therapeutic effects and storage characteristics. Meanwhile their formulation is in many ways different from conventional low-molecular drug formulation. Despite of such facts biopharmaceuticals gains lots of attention in the modern era of drug formulation. In the recent reviews it has been discussed that around 400 biotechnology-based medicinal and therapeutic agents are either registered or in the clinical trials are reviewed by the regulatory bodies. These agents are helpful in treating many life threatening diseases some of them are cancer, infectious diseases, autoimmune diseases, and AIDS/HIV. Some of the agents which are already in the market are monoclonal antibodies, recombinant hormones, cytokines, vaccines, recombinant blood factor, and therapeutic enzymes.
In 1970, discovery of recombinant DNA technology and monoclonal antibodies lead to initiate the development of biopharmaceutical industries. A substantial growth from $8 billion in 1992 to $149 billion in 2010 quenched the thirst of investors towards the biopharmaceutical industry. It is expected to reach $239 billion by 2015 with a growth rate of 9.9% annually. There are more than 400 Biotech drugs and vaccines are scrutinized under clinical stage, targeting more than 200 diseases. Meanwhile a large number of the population is now taking benefits from a number of biotechnological innovations like recombinant protein-based products e.g. monoclonal antibodies and some “large molecule” prescription drugs, which include hormones and vaccines. Table 1 illustrates some of the leading biopharmaceutical therapy classes by size worldwide in 2002. In 2008 approximately 39%, among the top 10 drugs sold globally, are biopharmaceuticals and is expected to rise to 79% of the top 10 drug sales by 2014.
Table.1: Leading biopharmaceutical therapy classes by size worldwide 2002. Source: IMS MIDAS December 2002.
However after the post recession period, fundings over health care and other sector is reduced which impede the growth rate of pharmaceutical industries up to significant extent. Although biopharmaceutical global sales thrive to attain high numbers in the global health sector. Biotechnological based products have generated $229 billion revenue in 2012 with an annual growth rate of 10.4%. Meanwhile the major focus of pharmaceutical organizations is on biopharmaceutical vs. Small molecule drugs which enables to allocate high funding towards this area. This may be due to very less generic biosimilar products available in the market. In year 2009 there are total 18 biopharmaceutical products are approved by US FDA which is higher than the previous years i.e. 11 in 2008 and 10 in 2007. In a report of Battelle Technology Partnership Practice, it was estimated that the overall impact of biopharmaceutical sector on the US economy is $917 billion. These companies are making alliances with other essential services such as computing and information, clinical trial and regulatory support services, technologies, manufacturing and equipment, and transportation and logistics providers.[9-11]
Types of Biopharmaceuticals
Cytokines are a diverse group of non-antibody intercellular signalling regulatory proteins i.e. glycoprotein and low molecular weight peptides produced in very little amount inside the body. They function as a mediator for communication between various cells and induce certain response by binding to specific cell surface receptors which results in triggering various intracellular signal transduction mechanism. There are over 80 sub class of cytokines have been found. Some of these are categorized in table 2. They play an important role in coordinating embryonic development, cell growth and maturation, wound repair and healing, the immune response including acute phase reactions and septic shock, and new blood vessel formation. Cancer is among the major class of disease which is thoroughly scrutinized by the researchers with an emphasis on cytokines. However cytokines also play a vital role in mediating signalling response to systemic inflammation which tends to regulate specific neuronal network to induce sickness. Some animal studies reveal the role of cytokines in situations characterized by abnormal sleep, with emphasis on the pathogenesis of symptoms and consequences of OSAS (Obstructive sleep apnoea syndrome). Cytokines interact with specific cells via (1) intracrine, in which both cytokine and receptor remain within the cell (rare); (2) autocrine, where a cytokine acts on the receptors of the same cell it is produced; and (3) paracrine, where the cytokine from one cell type interacts with receptors on other cell types.[12-16]
Table 2: categorization of cytokines.
There are various cytokines products available in the market and some of them are reviewed under the clinical phase for example Interleukin-2 (IL-2) aldesleukin (Proleukin), for treating renal cell carcinoma is approved by FDA. IL-1 blocker, anakinra (Kineret) and rilonacept (Arcalyst) are used for the treatment of rheumatoid arthritis and cryopyrin-associated periodic syndromes respectively.
Enzymes are complex molecules produced by living cells. They increase the rate of chemical reaction without even showing their own effect in the process and hence act as a catalyst in living organisms. Because of their reaction specificity, catalytic efficiency and ability to operate under mild condition of temperature and hydrogen ion concentration they are preferred as a novel class of therapeutic agents. Despite of their therapeutic role enzyme endures significant importance as a replacement therapy in many genetic disorders. However there are some disadvantages as well associated with their use such as, their parental administration required extensive purification to remove contaminants. They are also very costly to prepare and due to their large molecular structure they have limited distribution in the body. As they are proteins hence when administered inside the body act as antigen to the host cell.[18,19]
Enzymes are categorized under six major classes i.e transferases, lysases, hydrolases, isomerases, ligases, and oxidoreductases. The potential utility of enzyme as pharmaceutical was noted many decades ago. However most of the enzyme therapies are used to treat functional defects. Activase® (alteplase; recombinant human tissue plasminogen activator), is the first recombinant enzyme drug which was approved by the Food and Drug Administration in 1987. Pulmozyme® (Dornase alpha), a recombinant DNAse I that digests DNA in the mucous secretions in lungs, used to treat cystic fibrosis. Adagen® (pegadamase bovine), is the first marketed product as enzyme therapy for the treatment of SCID (severe combined immunodeficiency disease).
Hormone is characterized as an important group of regulatory molecule which is synthesized in an organ or in tissue and then secreted into circulatory system where it affects respective organs whose cell bears an appropriate receptors. They are chemical messengers either small or a large macromolecule and are fairly defined as endocrine hormones. Approximately all endocrine hormones possess therapeutic importance and hence subsequently used by the researchers e.g. insulin(Insugen®, Humulin®, Novolin®), human growth hormone (Ascellacrin®, Crescormon®), glucagon, and the gonadotrophins.
Antibodies or immunoglobulin are proteins produced, as an immune response, through white blood cells when a foreign particle or antigen intrudes inside the body. There are five classes of immunoglobulin IgE, IgM, IgG, IgD, and IgA. Amongst them IgG is the most common as a biopharmaceutical agents. A more specified term i.e. monoclonal antibodies (mAb or moAb) are the novel class compounds that are first developed in mid 1970s by kohler and Milstein, who successfully fused immortal cells with antibody- producing B lymphocytes. This fusion results in a hybrid which is stable, cancerous, antibody- producing cells. These are referred as hybridoma cells which unveil great source of monoclonal antibody. mAb identify antigens on a particular foreign body very specifically. mAbs are categorized under four groups according to their source: murine (derived solely from mice), chimeric (mixture of murine and human sequences), humanised (contain over 90% human sequences) and fully human.[8,17] In 1986, Murobmonab (OKT3), a murine antibody, is the first monoclonal antibody tested as a therapeutic in humans. However it fails to produce a substantial response in the transplantation rejection patients because of production of anti-murine antibody.
Monoclonal antibodies are the fastest growing therapeutic class in the field of biopharmaceutical market. The market of monoclonal antibodies crosses the mark of $30 billion in 2011. Infliximab (Remicade) is the top selling monoclonal antibody in 2002 which was developed by Centocor and is marketed by Centocor and Schering-Plough for the treatment of rheumatoid arthritis (RA) and Crohn’s disease. Rituximab (Rituxan), developed by Genentech and IDEC and marketed by Genentech, IDEC and Roche, for the treatment of non-Hodgkin’s lymphoma, is the second largest selling monoclonal antibody.
Vaccines are antigenic proteins which are either partial or modified form of bacteria, viruses and toxins which causes certain diseases against which vaccine protects. The antigenic property of vaccines is altered from its original form by certain processes such as utilizing attenuated viruses, inactivated viruses, part of a virus or bacteria and toxin produced by bacteria; hence they lack ability to cause disease although, endures ability to produce an immune response. Vaccines are the only known prophylactic approach which are commonly available to cure many infective diseases. Vaccines cover the global market share of $ 3 billion annually. Government health agencies run different immunization programs which alleviate the risk of many infective disorders. However, there are approximately 15 million people die every year from certain infectious diseases that can be cured by vaccination process. Pharmaceutical and biopharmaceutical industries seek great potential in this area but the use is limited because of their high production cost, delivery and distribution problems. Vaccines may contain animal derived products such as Bovine serum albumin or fetal calf serum or human derived product for example using cell lines of human tissues. However in recent years transgenic and recombinant plants are also utilized for the production of vaccines.[12,23,24] There are different vaccines available in the market for many infectious diseases such as poliomyelitis, cholera, diphtheria, tetanus, hepatitis B, hepatitis A, measles, meningitis etc. For hepatitis B virus some examples are Baraclude (Entecavir®), Adefovir dipivoxil (Hepsera®), Lamivudine (Epivir®-HBV, 3TC), Alfa Interferon (Intron® A, Infergen®, Roferon®).[1,25]
Antisense compounds are non-coding strand of messenger RNA(mRNA), which hybridize with mRNA and inactivates the ability of genes to produce the protein for which it holds the recipe. They do not alter human gene causing variation in human genetic information. It was first developed in 1978 using a string of DNA nucleotide which binds with messenger RNA and block its function. These drugs are designed to treat a wide range of diseases such inflammatory, infectious, cancer and cardiovascular diseases. Fomiversen was the first antisense drug approved in 1998 for the treatment of cytomegalovirus retinits in AIDS patients. These are categorized under three sub-classes i.e. antisense oligonucleotides(ASONs), ribozymes and RNA interference(RNAi). Affinitak, manufactured by ISIS pharmaceuticals and Eli Lilly, is used for the treatment of non-small-cell lung carcinoma(NSCLC). There are certain antisense compound are under review by health agencies for their therapeutic efficacy towards many anomalies[27,28]
Peptides are polymers having one or two amino acids linked with amides and are chemically synthesized by using liquid phase or solid phase synthesis. Their chemical synthesis is preferred over biosynthetic approach because it facilitates the conjugation or incorporation of small molecules and non-natural amino acids. This approach reveals the potential of such molecules as cytotoxic agents for antitumor therapy. Peptides with non-natural opens up the possibility for greater chemical diversity, analogous to small-molecule medicinal chemistry approaches for developing high-af¬nity, highspeci¬city molecular recognition. Cationic antimicrobial peptides (CAMPs) and peptidoglycan recognition proteins (PGRPs)are developed from the effectors of innate immune response in eukaryotes during their defense mechanism. However there are not many products of peptides found in the market but researchers are trying to develop some therapeutic peptides and proteins with significant effect towards certain diseases. Nesiritide (Natrecor, Noratak) is produced by Johnson & Johnson2001, Teriparatide (Forteo) is developed and marketed by Lily in 2002 Enfuvirtide (Fuzeon) is manufactured by Trimeris 2003.[29-31]
Challenges associated with biopharmaceutical products:
Biopharmaceutical products such as monoclonal antibodies, vaccines, certain hormones, and cell therapies are rewarded as some of the most promising innovation in the field of medicine and health. However there are certain risk and challenges associated with such products which hamper their performance. One of the major challenges is the purification of proteins although it can be achieved by various processes but still purification of such compound is very critical hence requires a lot of attention during manufacturing. Next generation pharmaceutical.
However the whole process is carried out under two phases i.e. upstream and downstream regulation. Immunogenicity associated with some of these proteins is also a major concern for biopharmaceutical agents. A repeated injection of human protein may affect the immune tolerance towards self- antigen, leading to humoral response.
Biopharmaceutical products require greater attention, process level as well as monitory level, in the development phase of the drug discovery process it requires approximately $200 million to develop a biopharmaceutical product hence the risk associated with their failure during development stage is increased. Apart from purification and immunogenicity some other issues also make some impact during their development such as government regulations which influence the cost of such products. As discussed earlier it takes a large amount of money to develop such agents hence companies also compensate their development cost and earn profits from their products, ones marketed, which exponentially increases the cost of the drugs.
Last and one of the most important risk associated with such products is the introduction of biosimilar products. Biopharmaceutical market is growing very fast, the initial compounds of the first generation are now coming to an end. The expiry of the patents opens the market for generic products which not only influence the established market of some very popular brands, it also forms a milieu of competition to sell the products at cheaper rates which is compensated by their quality.
Biopharmaceutical products are one amongst the novel class of therapeutic compounds. These are medical agents obtained from biological sources and some special one are manufactured by biotechnological means. They are cellular products, therapeutic proteins, vaccines, gene therapy products and plasma blood product derivatives. Erythropoietins, insulins, and monoclonal antibodies, are some of the leading biopharmaceutical products available in the market hence biopharmaceutical companies are now focusing on their use in long-term conditions such as cardiovascular disease, diabetes and asthma. The blockbuster sales of some existing biopharmaceutical products accompanied by the tremendous innovation and a plethora of pipeline products demonstrate the vigorous growth in the biopharmaceutical market in upcoming years. This significant growth is supported by some of the key segments of the field like monoclonal antibody and vaccines. In addition approaches like gene therapy and peptide therapeutics holds enormous potential for some life threatening anomalies and the combined approach of proteomics, genomics and biotechnology is predicted to empower the most part of the healthcare sector in the upcoming days.
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