Monoclonal antibodies 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... 

There are at present about 165 biopharmaceutical drugs approved for marketing in the United States and the European Union. This market is worth more than US 50 billion, projected to reach US 70 billion by 2010. Approvals in the past 3 years are mainly for monoclonal antibodies, enzymes, and growth factors. 

Over half of all biopharmacuticals thus far approved are produced in recombinant E. coli or S. cerevisiae. Industrial-scale bacterial and yeast fermentation systems share many common features, an overview of which is provided below. Most remaining biopharmaceuticals are produced using animal cell culture, mainly by recombinant BFIK or CFiO cells (or hybridoma cells in the case of some monoclonal antibodies Appendix 1). While industrial-scale animal cell culture shares many common principles with microbial fermentation systems, it also differs in several respects, as subsequently described. Microbial fermentation/animal cell culture is a vast speciality area in its own right. As such, only a summary overview can be provided below and the interested reader is referred to the Further Reading section. 

In 1996, about 10 years after the introduction of the first recombinant DNA product for human use, the FDA modified and streamlined the approval process for biotechnology products considered to be well characterized. These modifications, in essence, established the direction of how biologic macromolecules are researched and developed today in biotechnology-based and traditional pharmaceutical companies [2]. Well-characterized biotechnology products include (1) synthetic peptides consisting of fewer than 20 amino acids, (2) monoclonal antibodies and derivatives, and (3) recombinant DNA-derived products. Anticipating future developments, the FDA is also prepared to consider DNA plasmid products as well-characterized when the first medicinal in this class is submitted for approval. CBER now approves well-characterized biopharmaceuticals under the BLA process [3]. 

While no biopharmaceutical is approved with the requirement of genotyping as a part of its therapeutic indication, a recently approved monoclonal antibody therapy against breast cancer, trastuzumab (Herceptin), is indicated only for those tumors measurably expressing the protein expressed by the gene erbB-2. Because the oncogene product of erbB-2 is elevated... 

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. 

Reviews of the results from the reproductive toxicity testing for the approved monoclonal antibody biopharmaceuticals have shown very few incidences of harm to fetuses. The only notable effects that have been observed are hematologic changes in macaque fetuses exposed to natalizumab, skeletal abnormalities in rabbit fetuses exposed to bevacizumab, and immunological deficits in mice exposed to the efalizumab murine surrogate. In each of these examples the effects seen in the fetuses were predicable based on effects seen in the adult animals. 

A number of immunomodulatory biopharmaceuticals (IMBPs), such as peptides, recombinant proteins, soluble receptors, and monoclonal antibodies, have been approved or are currently in development to treat chronic inflammatory diseases. These agents may be administered daily or, if long-acting,... 

It can be deduced from Table 39.1 that most biopharmaceuticals approved to date are monoclonal antibodies and the most common indication is oncology. However, barring oncology, the biopharmaceuticals span an impressive range of indications. In addition to monoclonal antibodies, other prevalent types of biopharmaceuticals are fusion or conjugate proteins, growth factors, replacement enzymes, and peptides. Cellular and tissue therapies are rarer but becoming more prevalent. 

Bioseparations frequently entail separations of proteins and related materials from biological matrices.1 This book is planned to serve as a handbook of bioseparations, where the primary focus is separations of proteins however, separations of other materials of interest such as nucleic acids and oligonucleotides are also covered to assist the reader in tackling their particular bioseparation problems. Included in this text is a chapter on the separation of monoclonal antibodies, as these materials have found numerous uses in the biopharmaceutical industry. As a matter of fact, in the last few decades, monoclonal antibodies and recombinant antibodies have become one of the largest classes of proteins that have received FDA approval as therapeutics and diagnostics. 

The biopharmaceuticals sales are about 45 billion and represent 10 percent of the total pharma market. Today, 25 percent of new drugs are biopharmaceuticals. Since the introduction of insulin over 25 years ago, 160 biopharma products, ranging from proteins, monoclonal antibodies, and nucleic acid-based products, have been approved for use. In 2004 alone, 12 new biopharmaceuticals have been approved, of which only 3 are produced by microbial fermentation, as cell culture is the preferred method for production of biopharma drugs. 

Biotechnology-derived pharmaceuticals or biopharmaceuticals (BPs) are molecules such as monoclonal antibodies, soluble/decoy receptors, hormones, enzymes, cytokines, and growth factors that are produced in various biological expression systems and are used to diagnose, treat, or prevent various diseases. Safety pharmacology (SP) assessment of BPs has evolved since the approval of the first BP (recombinant human insulin) in 1982. This evolution is ongoing and... 

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. 

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). 

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